Brush prodrugs and uses thereof

Abstract

In some aspects, the present disclosure provides macromonomers of Formula (I) and salts thereof; methods for preparing the macromonomers and salts thereof; brush prodrugs (polymers); methods for preparing the brush prodrugs; compounds of Formula (II); conjugates of Formula (III) and salts thereof; pharmaceutical compositions comprising the brush prodrugs, conjugates, or salts thereof; kits comprising the macromonomers or salts thereof, brush prodrugs, compounds, conjugates, or salts thereof, or pharmaceutical compositions; methods of using the brush prodrugs, conjugates, or salts thereof; and uses of the brush prodrugs and conjugates, or salts thereof. These chemical entities can be useful in delivering pharmaceutical agents to subjects or cells.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 916,036, filed October 16, 2019, which is incorporated herein by reference. [Background technology]

[0002] Background to the disclosure Bottlebrush polymers have found widespread applications in areas ranging from drug delivery and molecular imaging to the preparation of novel materials. 1-3 Graft-through ring-opening metathesis polymerization (ROMP) offers distinct advantages over other bottlebrush synthesis methods. 4、5 The fast-initiating Grubb third-generation catalyst (Ru) has been shown to sustain polymer chain preparation, has exceptionally high tolerance for a wide range of sterically hindered polyvalent macromonomers (MMs), and achieves high degrees of polymerization and low dispersity even at low millimolar concentrations. 6、7 Furthermore, Ru can be used to prepare distinctive polymer structures such as bottle brushes and stars, controlling the composition, morphology, and size of the final polymer. 7-11 Due to the high packing density of their side chains, the backbone of bottle-brush polymers is very rigid, allowing them to accommodate extended conformations with minimal entanglement of the side chains. 6 Recently, the self-assembly behavior of bottle-brush block copolymers (BBCPs) has become an area of ​​active research because these polymers readily undergo phase separation and can be used to design materials with novel mechanical properties in bulk. 6、12 On the other hand, polymeric star nanostructures offer several valuable features, such as tunable nanoscale size and shape, which mimic spherical biopolymers and allow for extended blood circulation and efficient biodistribution and / or tumor accumulation. 13-15These properties make star polymers particularly well suited for bioapplications. 10 . Summary of the Invention

[0003] Summary of disclosure The present disclosure provides, in some aspects, macromonomers and salts thereof; methods for preparing macromonomers and salts thereof; brush prodrugs (polymers); methods for preparing brush prodrugs; pharmaceutical compositions comprising brush prodrugs; kits comprising macromonomers or salts thereof, brush prodrugs, or pharmaceutical compositions; methods of using brush prodrugs; and uses of brush prodrugs.

[0004] Brush prodrugs have the formula (I): [ka] (I) or a salt thereof in the presence of a metathesis catalyst, wherein each instance of -YZ- is independently [ka] is. In some embodiments, the metathesis catalyst is a Grubbs' catalyst.

[0005] Without being bound by any particular theory, the benefits of brush prodrugs are believed to be due in part to [ka] It may be due to. The properties of the brush prodrug (e.g., release of free pharmaceutical agent) can be determined, for example, by the moiety [ka] The release of a pharmaceutical agent can be adjusted by varying the size, polarity, chemical reactivity, and / or photochemical reactivity of one or more of the moieties. For example, the size, polarity, chemical reactivity, and / or photochemical reactivity of the one or more moieties can affect the release (e.g., the rate of release). A bulkier moiety can delay release. A less polar moiety can delay release. Thus, by modifying one or more moieties, the release can be fine-tuned.

[0006] In another aspect, the present disclosure provides a compound of formula (II): [ka] The present invention provides a compound of the formula:

[0007] In another aspect, the present disclosure provides a compound of formula (III): [ka] provides a conjugate of

[0008] In certain embodiments, each instance of T is substituted or unsubstituted methylene; and each instance of M is independently an ammonium or iminium salt of a pharmaceutical agent, wherein the point of attachment is at the N-terminus of the ammonium or iminium salt. + The compounds and conjugates may be useful for conjugating delivery vehicles to pharmaceutical agents that do not contain conventional reactive handles.

[0009] In another aspect, the disclosure provides a method for preparing a brush prodrug. In another aspect, the present disclosure provides macromonomers of formula (I) and salts thereof: In another aspect, the present disclosure provides methods for preparing macromonomers and salts thereof.

[0010] In another aspect, the disclosure provides a pharmaceutical composition comprising a brush prodrug and, optionally, a pharmaceutically acceptable excipient. In another aspect, the present disclosure provides a pharmaceutical composition comprising the conjugate and, optionally, a pharmaceutically acceptable excipient. In another aspect, the disclosure provides a kit comprising a macromonomer or salt thereof, a brush prodrug, or a pharmaceutical composition; and instructions for using the macromonomer or salt thereof, polymer, or pharmaceutical composition.

[0011] In another aspect, the disclosure provides a kit comprising a compound; and instructions for using the compound. In another aspect, the disclosure provides a kit comprising the conjugate, or a salt thereof, or a pharmaceutical composition; and instructions for using the conjugate, or a salt thereof, or the pharmaceutical composition. In another aspect, the present disclosure provides a method of delivering a pharmaceutical agent to a subject in need thereof, the method comprising administering to a subject in need thereof a polymer or pharmaceutical composition.

[0012] In another aspect, the disclosure provides a method of delivering a pharmaceutical agent to a cell, the method comprising contacting the cell with a polymer or pharmaceutical composition. In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to or implanting into a subject in need thereof a therapeutically effective amount of a polymer or pharmaceutical composition; wherein at least one of the pharmaceutical agents is a therapeutic agent. In another aspect, the disclosure provides a method of preventing disease in a subject in need thereof, the method comprising administering to or implanting into a subject in need thereof a prophylactically effective amount of a polymer or pharmaceutical composition; wherein at least one of the pharmaceutical agents is a prophylactic agent.

[0013] In another aspect, the present disclosure provides a method of diagnosing a disease in a subject, the method comprising administering to or implanting into the subject a diagnostically effective amount of a polymer or pharmaceutical composition; wherein at least one of the pharmaceutical agents is a diagnostic agent. In another aspect, the present disclosure provides a method of delivering a pharmaceutical agent to a subject in need thereof, the method comprising administering to a subject in need thereof the conjugate or pharmaceutical composition. In another aspect, the disclosure provides a method of delivering a pharmaceutical agent to a cell, the method comprising contacting the cell with the conjugate or pharmaceutical composition.

[0014] In another aspect, the disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to or implanting into a subject in need thereof a therapeutically effective amount of a conjugate or pharmaceutical composition; wherein at least one of the pharmaceutical agents is a therapeutic agent. In another aspect, the disclosure provides a method of preventing disease in a subject in need thereof, the method comprising administering to or implanting into a subject in need thereof a prophylactically effective amount of a conjugate or pharmaceutical composition; wherein at least one of the pharmaceutical agents is a prophylactic agent.

[0015] In another aspect, the disclosure provides a method of diagnosing a disease in a subject, the method comprising administering to or implanting into the subject a diagnostically effective amount of a conjugate or pharmaceutical composition; wherein at least one of the pharmaceutical agents is a diagnostic agent. In some embodiments, the disease is cancer. This disclosure references various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference.

[0016] definition For convenience, certain terms used in the specification, examples, and appended claims are collected here. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The following definitions are of more general terms used throughout this application. The singular terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise.

[0017] Other than in working examples, or where otherwise indicated, all numbers expressing quantities of materials or reaction conditions used herein should be understood in all instances to be modified by the term "about." "About" and "approximately" should generally refer to an acceptable degree of error for the amount measured, given the nature or accuracy of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5%, 4%, 3%, 2%, or 1% of a given value or range of values.

[0018] The definitions of specific functional groups and chemical terms are described in more detail below.Chemical elements are identified according to the Periodic Table of Elements, CAS version (Handbook of Chemistry and Physics, 75th edition, inside cover), and specific functional groups are generally defined as described herein.In addition, the general principles of organic chemistry and specific functional moieties and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0019] The compounds described herein may contain one or more asymmetric centers, and therefore can exist in various stereoisomeric forms, such as enantiomers and / or diastereomers.For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched with one or more stereoisomers.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; Alternatively, preferred isomers can be prepared by asymmetric synthesis. 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., University of Notre Dame Press, Notre Dame, IN, 1972). The present invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0020] When a range of values ​​("range") is listed, it is intended to encompass each value and subrange within that range. A range includes the two endpoints of the range unless otherwise provided. For example, "an integer from 1 to 4" refers to 1, 2, 3, and 4. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to include alkyl.

[0021] The term "alkyl" refers to C1-C 1000 In some embodiments, an alkyl group refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 200 carbon atoms ("C1-C 200 alkyl), 1 to 20 carbon atoms ("C1-C 20 alkyl), 1 to 10 carbon atoms ("C1-C 10 alkyl"), 1 to 9 carbon atoms ("C1-C9 alkyl"), 1 to 8 carbon atoms ("C1-C8 alkyl"), 1 to 7 carbon atoms ("C1-C7 alkyl"), 1 to 6 carbon atoms ("C1-C6 alkyl"), 1 to 5 carbon atoms ("C1-C5 alkyl"), 1 to 4 carbon atoms ("C1-C4 alkyl"), 1 to 3 carbon atoms ("C1-C3 alkyl"), 1 to 2 carbon atoms ("C1-C2 alkyl"), or 1 carbon atom ("C1 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8). C 30 -C 1000 The alkyl may result from polymerization. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted with one or more substituents (a "substituted alkyl").

[0022] The term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 1000 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 2 to 200 carbon atoms ("C 2-200 In some embodiments, an alkenyl group has 2 to 20 carbon atoms ("C 2-20 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. 30 -C 1000Alkenyl may be obtained by polymerization. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In an alkenyl group, a C=C double bond of unspecified stereochemistry is [ka] may be in the (E)- or (Z)-configuration.

[0023] The term "alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 1000 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2-10 In some embodiments, an alkynyl group has 2 to 200 carbon atoms ("C 2-200 alkynyl), 2 to 20 carbon atoms ("C 2-20 alkynyl), 2 to 9 carbon atoms ("C 2-9 alkynyl), 2 to 8 carbon atoms ("C 2-8 alkynyl), 2 to 7 carbon atoms ("C 2-7 alkynyl), 2 to 6 carbon atoms ("C 2-6 alkynyl), 2 to 5 carbon atoms ("C 2-5 alkynyl), 2 to 4 carbon atoms ("C 2-4 alkynyl), 2-3 carbon atoms ("C 2-3 C2 alkynyl) or 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Examples include alkynyl groups, as well as pentynyl (C5), hexynyl (C6), and the like. 30 -C1000 An alkynyl may result from polymerization. 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.

[0024] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, 4, or more heteroatoms, as valence allows) selected from oxygen, nitrogen, phosphorus, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms thereof) and / or at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkyl group refers to an alkyl group having 1 to 1000 carbon atoms and one or more heteroatoms ("C1-C1") within the parent chain. 1000 heteroalkyl) containing 1 to 20 carbon atoms and one or more heteroatoms ("C1-C 20 heteroalkyl) containing 1 to 10 carbon atoms and one or more heteroatoms ("C-C 10 C refers to saturated groups having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("C1-C9 heteroalkyl"), 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("C1-C8 heteroalkyl"), 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("C1-C7 heteroalkyl"), 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("C1-C6 heteroalkyl"), 1 to 5 carbon atoms and one or more heteroatoms in the parent chain ("C1-C5 heteroalkyl"), 1 to 4 carbon atoms and one or more heteroatoms in the parent chain ("C1-C4 heteroalkyl"), 1 to 3 carbon atoms and one or more heteroatoms in the parent chain ("C1-C3 heteroalkyl"), 1 to 2 carbon atoms and one heteroatom in the parent chain ("C1-C2 heteroalkyl"), or one carbon atom and one heteroatom ("C1 heteroalkyl"). 30 -C 1000A heteroalkyl may result from polymerization. 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.

[0025] The term "heteroalkenyl" refers to an alkenyl group that further includes at least one heteroatom (e.g., 1, 2, 3, 4, or more heteroatoms, as valence allows) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having 2 to 1000 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain ("heteroalkenyl"). 2-1000 In certain embodiments, a heteroalkenyl group refers to a group having 2 to 20 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-20 In certain embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-10 In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-6In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 2-3 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 alkenyl). C 30 -C 1000 The heteroalkenyl may result from polymerization. Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted ("substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2-10 In some embodiments, the heteroalkenyl group is a substituted heteroC 2-10 It is alkenyl.

[0026] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, 4, or more heteroatoms, as valence allows) selected from oxygen, nitrogen, or sulfur, located within the parent chain (i.e., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having 2 to 1000 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("heteroalkynyl"). 2-1000 In certain embodiments, a heteroalkynyl group refers to a group having 2 to 20 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC2-20 In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-10 In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-8 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 2-3 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 alkynyl). C 30 -C 1000Heteroalkynyl may result from polymerization. Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted ("substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2-10 In some embodiments, the heteroalkynyl group is a substituted heteroC 2-10 It is alkynyl.

[0027] The term "carbocyclyl" or "carbocyclic" or "cycloalkyl" refers to a ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C 3-8 carbocyclyl"), 3 to 7 ring carbon atoms ("C 3-7 carbocyclyl"), 3 to 6 ring carbon atoms ("C 3-6 carbocyclyl"), 4 to 6 ring carbon atoms ("C 4-6 carbocyclyl"), 5-6 ring carbon atoms ("C 5-6 carbocyclyl"), or 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). 3-6 Carbocyclyl groups include, without limitation, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8 The carbocyclyl group includes, but is not limited to, the aforementioned C 3-6 Included are carbocyclyl 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 C 3-10The carbocyclyl group includes, but is not limited to, the aforementioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., including fused, bridged, or spiro ring systems such as a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system ("tricyclic carbocyclyl")) and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring; in such cases, the number of carbons continues to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") with one or more substituents.

[0028] The term "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur (a "3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, as valency allows. Heterocyclyl groups may be either monocyclic (a "monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems such as a bicyclic system (a "bicyclic heterocyclyl") or a tricyclic system (a "tricyclic heterocyclyl")), and may be saturated or contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, where the point of attachment is on either the carbocyclyl or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring; in such cases, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.

[0029] In some embodiments, heterocyclyl groups are 5-10 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-8 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-6 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, 5-6 membered heterocyclyls have 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0030] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, 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]diazepine ... nyl, 1,4,5,7-tetrahydropyrano[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-b]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.

[0031] 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 pi electrons shared among the ring array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl": e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl": e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl": e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring; in such cases, the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").

[0032] The term "heteroaryl" refers to the radical of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π-electrons shared among the ring array) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency allows. Heteroaryl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, with the point of attachment being on either the aryl or heteroaryl ring; in such cases, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring containing the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl). A heteroaryl group can be monovalent or have more than one point of attachment to another moiety (e.g., it can be divalent, trivalent, etc.), although the valency may be directly specified in the name of the group. For example, "triazoldiyl" refers to a divalent triazolyl moiety.

[0033] In some embodiments, heteroaryl groups are 5-10 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 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 ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl").

[0034] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0035] As understood above, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heteroaryl groups are optionally substituted in certain embodiments. Optionally substituted refers to a group that may be substituted or unsubstituted (e.g., "substituted" or "unsubstituted" alkyl). In general, the term "substituted" means that at least one hydrogen atom present on the group is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo a transformation such as rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all acceptable substituents of organic compounds, any of the substituents described herein, that result in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may include hydrogen substituents and / or any suitable substituents, as described herein, that satisfy the valences of the heteroatom and result in the formation of a stable moiety.

[0036] The addition of the suffix "ene" to a group indicates that the group is a polyvalent (e.g., divalent, trivalent, tetravalent, or pentavalent) moiety. In some embodiments, the addition of the suffix "ene" to a group indicates that the group is a divalent moiety.

[0037] Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb ) 3+ X-, -N(OR cc )Rbb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)ORaa , -SC(=O)R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)(N(R bb )2)2, -OP(=O)(N(R bb )2)2, -NR bb P(=O)(R aa )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(N(R bb )2)2, -P(R cc )2, -P(OR cc )2, -P(R cc ) 3+ X - , -P(OR cc ) 3+ X - , -P(R cc )4, -P(OR cc )4, -OP(R cc )2, -OP(R cc ) 3+ X - , -OP(OR cc )2, -OP(OR cc ) 3+ X - , -OP(R cc )4, -OP(OR cc )4, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; - is the counterion; Alternatively, two geminal hydrogens on a carbon atom can be bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc Replaced by;

[0038] R aa In each case, independently, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0039] R bb each instance of is independently hydrogen, -OH, -OR aa , -N(R cc)2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; - is the counterion;

[0040] R cc each instance of is independently hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0041] R dd each case independently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff ) 3+ X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff)2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents are linked to form =O or =S; where X - is the counterion;

[0042] R ee In each case, independently, C 1-6 Alkyl, C 1-6Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group;

[0043] R ff each instance of is independently hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, or two R ff The groups are linked to form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; and

[0044] R gg each case independently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3+ X - , -NH(C 1-6 alkyl) 2+ X - , -NH2(C 1-6 alkyl) + X - , -NH 3+ X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl)2, -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hetero C 1-6 Alkyl, Hetero C 2-6 Alkenyl, Hetero C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents are linked to form =O or =S; where X - is the counter ion.

[0045] In some embodiments, the carbon atom substituents are independently halogen, substituted or unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, -NO2, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -OC(=O)R aa , -OCO2R aa, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , or -NR bb C(=O)N(R bb In some embodiments, the carbon atom substituents are independently halogen, substituted or unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, or -NO2.

[0046] Nitrogen atoms may be substituted or unsubstituted, as valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10 Alkenyl, Hetero C2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R attached to the N atom. cc The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group, and wherein R aa , R bb , R cc and R dd is as defined above.

[0047] 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, but are not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 2-10Alkenyl, Hetero C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 and 5- to 14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group, and wherein R aa , R bb , R cc and R dd is 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, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0048] For example, an amide group (e.g., —C(═O)R aa Nitrogen protecting groups such as, but not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacetamide), o-(amino)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.

[0049] Carbamate groups (e.g., -C(=O)OR aa), including, but not limited to, 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, ester (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 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 Bamates, alkyldithiocarbamates, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl 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-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 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-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacyl Vinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate methylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,6-trimethylbenzylcarbamate.

[0050] Sulfonamide groups (e.g., -S(=O)R aa ), including, but not limited to, 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-trimethyl ...4,6-trimethylbenzenesulfonamide (Mtb), 2,4,6-trimethylbenzenesulfonamide (Mtb), 2,4,6-trimethylbenzenesulfonamide (Mtb), 2,4,6-trimethylbenzenesulfonamide (Mtb), 2,4,6-trimethylbenzenesulfonamide (Mtb), 2,4,6-trimethylbenzenesulfonamide (Mtb), 2,4,6-trimethylbenzenesulfonamide (Mtb), 2,4,6-trimethyl anthracenesulfonamide (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.

[0051] Other nitrogen protecting groups include, but are not limited to, 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-pi N-(4-Methoxyphenyl)diphenylmethylamine, ... N-methylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-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-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0052] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc ) 3+ X-, -P(OR cc )2, -P(OR cc ) 3+ X-, -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb)2)2, where X - , R aa , R bb and R cc is 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, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0053] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (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-methyl- ethoxyethoxymethyl (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)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-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trimethyl- Chloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 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-oxide, diphenylmethyl, p,p'-Dinitrobenzohydryl, 5-dibenzosuberyl, triphenylmethyl, 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 )methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 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-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylsilyl isopropylsilyl (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 ester, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), 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-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate benzoate, 2-(methylthiomethoxy)ethyl, 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). ,

[0054] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(Rbb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc ) 3+ X - , -P(OR cc )2, -P(OR cc ) 3+ X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, where R aa , R bb and R cc is 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, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0055] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I). The term "hydroxyl" or "hydroxy" refers to the group --OH. The term "thiol" or "thio" refers to the group --SH. The term "amine" or "amino" refers to the group -NH- or -NH2.

[0056] As used herein, the term "polyethylene glycol" or "PEG" refers to an ethylene glycol polymer containing about 20 to about 2,000,000 linked monomers, typically about 50 to 1,000 linked monomers, and usually about 100 to 300. Polyethylene glycol includes ethylene glycol polymers containing various numbers of linked monomers, such as PEG20, PEG30, PEG40, PEG60, PEG80, PEG100, PEG115, PEG200, PEG300, PEG400, PEG500, PEG600, PEG1000, PEG1500, PEG2000, PEG3350, PEG4000, PEG4600, PEG5000, PEG6000, PEG8000, PEG11000, PEG12000, PEG2000000, and any mixtures thereof.

[0057] A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain electrical neutrality. An anionic counterion may be monovalent (i.e., containing one formal negative charge). An anionic counterion may also be multivalent (i.e., containing more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO 3- , ClO 4- , O.H. - , H2PO 4- , HCO 3- , HSO 4- , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate (triflate), p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetic acid, propionic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, gluconic acid, etc.), BF 4- , P.F. 4- , P.F.6- , AsF 6- , SbF 6- , B[3,5-(CF3)2C6H3]4] - , B(C6F5) 4- , BPh 4- , Al(OC(CF3)3) 4- , and carborane anions (e.g., CB 11 H 12- or (HCB 11 Me5Br6) - Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, gluconic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, salicylic acid, phthalic acid, aspartic acid, glutamic acid, etc.), and carborane. In some embodiments, the counterion is triflate.

[0058] The term "salt" refers to an ionic compound resulting from the neutralization reaction of an acid and a base. Because a salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions), the salt is electrically neutral (carries no net charge). Salts of the compounds of the present invention include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of amino groups 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 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobic acid, and benzoates. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N-methylpropional salts, such as hydroxypropyltrimonials, ... + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Additional salts include ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0059] The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, and 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 pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lanthanide, and lanthanide. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N-methylpropional salts, such as acetobionate, 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 salts, and the like. + (C 1-4alkyl) 4- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0060] The term "leaving group" is given its ordinary meaning in the field of synthetic organic chemistry and refers to an atom or group that can be displaced by a nucleophile. Examples of suitable leaving groups include halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonate 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 cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, 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. The leaving group may also be a phosphine oxide (e.g., formed during the Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0061] "Click chemistry" reaction includes Huisgen alkyne-azide cycloaddition. Any "click chemistry" reaction known in the art can be used for this purpose. Click chemistry is a chemical approach introduced by Sharpless in 2001, and describes chemistry that is tailored to rapidly and reliably generate substances by linking small units together (see, for example, 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 can be classified as "click chemistry") include, but are not limited to, the formation of esters, thioesters, and amides from activated acids or acyl halides (e.g., peptide coupling); nucleophilic substitution reactions (e.g., nucleophilic substitution of halides 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).

[0062] The terms "composition" and "formulation" are used interchangeably. A "subject" to which administration is contemplated refers to a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or elderly adult)) or a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially relevant mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog)), or a bird (e.g., a commercially relevant bird such as a chicken, duck, goose, or turkey). In some embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be male or female, at any stage of development. The non-human animal may be a transgenic or genetically engineered animal.

[0063] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into or onto a subject. The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or exposure to a pathogen). Treatment may also be continued after symptoms have resolved, e.g., to delay and / or prevent recurrence.

[0064] The terms "prevent," "preventing," or "prevention" refer to the prophylactic treatment of a subject who does not have the disease, who has not had the disease but is at risk of developing the disease, or who has had the disease and does not have the disease but is at risk of disease relapse. In some embodiments, the subject is at higher risk of developing the disease or at higher risk of disease relapse than the average healthy member of a population of subjects.

[0065] The terms "condition," "disease," and "disorder" are used interchangeably. The "effective amount" of a compound described herein refers to an amount sufficient to induce a desired biological response. The effective amount of a compound described herein can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount. In some embodiments, the effective amount is the amount of a compound or pharmaceutical composition described herein in a single dose. In some embodiments, the effective amount is the combined amount of a compound or pharmaceutical composition described herein in multiple doses.

[0066] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the symptoms, signs, or causes of a condition, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0067] A "prophylactically effective amount" of a compound described herein is an amount that prevents a condition, or one or more symptoms associated with the condition, or prevents its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or increases the prophylactic efficacy of another prophylactic agent.

[0068] The term "therapeutic agent" includes an agent capable of providing a local or systemic biological, physiological, or therapeutic effect in a biological system to which it is applied. For example, a therapeutic agent can control tumor growth, control infection or inflammation, act as an analgesic, promote anti-cell adhesion, and enhance bone growth, among other functions. Other suitable therapeutic agents may include antiviral agents, hormones, antibodies, or therapeutic proteins. Other therapeutic agents include prodrugs that are not biologically active when administered, but are converted to a biologically active agent through metabolism or some other mechanism upon administration to a subject.

[0069] The term "prodrug" refers to a compound that becomes active, e.g., by solvolysis, reduction, oxidation, or under physiological conditions, to provide a pharmaceutically active compound, e.g., in vivo. Prodrugs can include derivatives of pharmaceutically active compounds, such as, for example, esters formed by reaction of an acid, acid anhydride, or mixed anhydride portion of the prodrug moiety with a hydroxyl moiety of the pharmaceutically active compound.

[0070] The term "small molecule" refers to a molecule, either naturally occurring or artificially created (e.g., via chemical synthesis), that has a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains carbon). A small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyls, carbonyls, heterocyclic rings, and the like). In some embodiments, the molecular weight of a small molecule is 2,000 g / mol or less. In some embodiments, the molecular weight of a small molecule is 1,500 g / mol or less. In some embodiments, the molecular weight of a small molecule is 1,000 g / mol or less, 900 g / mol or less, 800 g / mol or less, 700 g / mol or less, 600 g / mol or less, 500 g / mol or less, 400 g / mol or less, 300 g / mol or less, 200 g / mol or less, or 100 g / mol or less. In some embodiments, the molecular weight of the small molecule is at least 100 g / mol, at least 200 g / mol, at least 300 g / mol, at least 400 g / mol, at least 500 g / mol, at least 600 g / mol, at least 700 g / mol, at least 800 g / mol, or at least 900 g / mol, or at least 1,000 g / mol. Combinations of the above ranges (e.g., at least 200 g / mol and up to 500 g / mol) are also possible. In some embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this case, the small molecule is also referred to as a "small organometallic molecule." Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, and more preferably humans. Small molecules include radionuclides and imaging agents. In some embodiments, the small molecule is a drug. Preferably, but not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by an appropriate government agency or regulatory body.For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331-361, and 440-460, which are incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500-589, which are incorporated herein by reference. All listed drugs are considered acceptable for use according to the present invention.

[0071] A "protein," "peptide," or "polypeptide" includes 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. Protein may refer to an individual protein or a collection of proteins. Proteins preferably contain only naturally occurring amino acids, although unnatural amino acids (i.e., compounds that do not occur in nature but can be incorporated into polypeptide chains) and / or amino acid analogs, as known in the art, may alternatively be used. In certain embodiments, the amino acid residues of a peptide are alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and / or valine in the D- and / or L-form. In some embodiments, the amino acid residues of the peptide are alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and / or valine in the L-form. One or more of the amino acids in the protein may be protected. One or more of the amino acids in the protein may also be modified, for example, by the addition of a chemical moiety 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 a multimolecular complex. A protein may be a fragment of a naturally occurring protein or peptide. A protein may be naturally occurring, recombinant, synthetic, or any combination thereof. In certain embodiments, the protein comprises between 2 and 10, 10 and 30, 30 and 100, 100 and 300, or 300 and 1,000 amino acids (inclusive).In some embodiments, the protein contains 1,000 to 3,000 or 3,000 to 10,000 amino acids (inclusive). In some embodiments, the amino acids in the protein are natural amino acids. In some embodiments, the amino acids in the protein are unnatural amino acids. In some embodiments, the amino acids in the protein are a combination of natural and unnatural amino acids. The present disclosure is in no way intended to be limited by the above list of exemplary substituents. Additional terms may be defined in other sections of this disclosure. The drawings are illustrative and do not limit the scope of the disclosure. [Brief explanation of the drawings]

[0072] [Figure 1] Figure 1 shows the 1H NMR spectrum of JQ-MM in CDCl3. [Figure 2] FIG. 2 shows the matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOF MS) spectrum of JQ-MM. [Figure 3] FIG. 3 shows the 1H NMR spectrum of AZ-MM in CDCl3. [Figure 4] FIG. 4 shows the MALDI-TOF spectrum of AZ-MM. [Figure 5] FIG. 5 shows the 1H NMR spectrum of Vin-MM in CDCl3.

[0073] [Figure 6] FIG. 6 shows the MALDI-TOF spectrum of Vin-MM. [Figure 7] Figure 7 shows the GPC traces of JQ-BBP, AZ-BBP, and Vin-BBP. The small peak at 15.5 min elution time corresponds to residual MM. In all cases, the conversion of the reaction was ≥ 90%. [Figure 8] FIG. 8 shows the hydrodynamic diameter (Dh) of JQ-BBP determined by dynamic light scattering (DLS). [Figure 9]FIG. 9 shows the Dh of AZ-BBP determined by dynamic light scattering (DLS). [Figure 10] FIG. 10 shows the Dh of Vin-BBP determined by dynamic light scattering (DLS).

[0074] [Figure 11] FIG. 11 shows the 1H NMR spectrum of JQ-MM-2 in CDCl3. [Figure 12] FIG. 12 shows the MALDI-TOF spectrum of JQ-MM-2. [Figure 13] FIG. 13 shows the 1H NMR spectrum of JQ-MM-3 in CDCl3. [Figure 14] FIG. 14 shows the MALDI-TOF spectrum of JQ-MM-3. [Figure 15] Figure 15 shows the GPC traces of JQ-BBP, JQ-BBP-2 and JQ-BBP-3. In all cases, the conversion of the reaction was ≧90%.

[0075] [Figure 16] FIG. 16 shows the Dh of JQ-BBP-2 determined by dynamic light scattering (DLS). [Figure 17] FIG. 17 shows the Dh of JQ-BBP-3 determined by dynamic light scattering (DLS). [Figure 18] FIG. 18 shows an exemplary mechanism of release of a pharmaceutical agent from an exemplary brush prodrug described herein. DETAILED DESCRIPTION OF THE INVENTION

[0076] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE DISCLOSURE In one aspect, the present disclosure provides brush prodrugs (brush prodrugs) of pharmaceutical agents. In some embodiments, the pharmaceutical agents are therapeutic, diagnostic, and prophylactic agents. Brush prodrugs can improve the therapeutic application of pharmaceutical agents, optionally with favorable distribution and release of the pharmaceutical agent in tumors compared to other tissues.

[0077] The release (e.g., rate of release) of a pharmaceutical agent from a brush prodrug can be tailored by modifying one or more moieties of the brush prodrug. In some embodiments, the release is as shown in the following scheme: [ka]

[0078] In one embodiment, [ka] is a pharmaceutical agent, optionally wherein R 1 , R 2 and R 3 are linked to form a moiety attached to a nitrogen atom through a double bond (e.g., an imine).

[0079] In some embodiments, the release is as shown in the following scheme: [ka] Brush prodrugs of other pharmaceutical agents offer similar, and optionally additional, advantages over the free pharmaceutical agents. It is expected to show

[0080] Macromonomer In one aspect, the present disclosure provides a compound of formula (I): [ka] (I) and salts thereof, wherein:

[0081] R A each instance of independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 is alkyl; a is an integer between 1 and 20 (inclusive);

[0082] Each instance of -YZ- is independently [ka] and;

[0083] L J each instance of independently a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, or substituted or unsubstituted C 2-200 heteroalkynylene, wherein:

[0084] Optionally, a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more carbons in the heteroalkynylene are independently replaced by a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; and

[0085] Optionally, a substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more heteroatoms in the heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0086] each instance of m is independently an integer from 1 to 10, inclusive; For each E, E A E B is a moiety formed by reacting with; E A In each case, is the first reaction handle; E B is a second reaction handle, where the second reaction handle can react with the first reaction handle;

[0087] Each instance of L is independently a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, or substituted or unsubstituted C 2-200 heteroalkynylene, wherein:

[0088] Optionally, a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more carbons in each instance of heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and

[0089] Optionally, a substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200one or more heteroatoms in each instance of heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0090] Each instance of W is independently a single bond, —O—, —S—, or —NR E - and; R E each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; each instance of W' is independently -O- or -S-; R 1 each instance of independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 is alkyl;

[0091] each instance of y is independently 0 or 1; If y is 0, [ka] is a single bond; If y is 1, [ka] is a single or double bond; [ka] is a single bond, R 2 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a)2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0092] R a each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or R attached to the same nitrogen atom a when two of the following are joined to form a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl;

[0093] [ka] is a double bond, R 2 is absent;

[0094] R3 each instance of independently represents hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0095] R 4 each instance of independently represents hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )Ra , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0096] Or, y is 1, and [ka] is a single bond, R 3 and R 4 are joined with their intervening atoms to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl;

[0097] Or, y is 1, and [ka] is a double bond, R 3 and R 4 are cis to each other and joined with their intervening atoms to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0098] Alternatively, R 4 and R 6 are joined with their intervening atoms to form a substituted or unsubstituted heterocyclyl;

[0099] [ka] is a single bond, R 5 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0100] [ka] is a double bond, R 5 is absent;

[0101] R 6 each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; each instance of T is independently substituted or unsubstituted methylene; Each instance of M is independently an ammonium or iminium salt of a pharmaceutical agent, wherein the point of attachment is at the N + and;

[0102] R B each instance of independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 is alkyl; each instance of b is independently an integer from 1 to 20, inclusive; e is an integer between 1 and 10 (inclusive); X is OR C or N(R D )2;

[0103] R C is hydrogen, substituted or unsubstituted C 1-1000 Alkyl, substituted or unsubstituted C 2-1000 Alkenyl, substituted or unsubstituted C 2-1000 Alkynyl, substituted or unsubstituted C 1-1000 Heteroalkyl, substituted or unsubstituted C 2-1000 Heteroalkenyl, substituted or unsubstituted C 2-1000 is a heteroalkynyl, an oxygen protecting group, or a leaving group; and

[0104] R D each instance of independently represents hydrogen, substituted or unsubstituted C 1-1000 Alkyl, substituted or unsubstituted C 2-1000 Alkenyl, substituted or unsubstituted C 2-1000 Alkynyl, substituted or unsubstituted C 1-1000 Heteroalkyl, substituted or unsubstituted C 2-1000 Heteroalkenyl, substituted or unsubstituted C 2-1000 heteroalkynyl, or a nitrogen protecting group.

[0105] In one aspect, the present disclosure provides a compound of formula (I): [ka] (I) and salts thereof, During the ceremony:

[0106] R A each instance of independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 is alkyl; a is an integer between 1 and 20 (inclusive); Each instance of -YZ- is independently [ka] and;

[0107] L J each instance of independently a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, or C 2-200 heteroalkynylene, wherein:

[0108] Optionally, a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and C 2-200 one or more carbons in the heteroalkynylene are independently replaced by a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; and

[0109] Optionally, a substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C2-200 one or more heteroatoms in the heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0110] each instance of m is independently an integer from 1 to 10, inclusive; For each E, E A E B is a moiety formed by reacting with; E A In each case, is the first reaction handle; E B is a second reaction handle, where the second reaction handle can react with the first reaction handle; Each instance of L is independently a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, or C 2-200 heteroalkynylene, wherein:

[0111] Optionally, a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and C 2-200 one or more carbons in each instance of heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and

[0112] Optionally, a substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more heteroatoms in each instance of heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0113] Each instance of W is independently a single bond, —O—, —S—, or —NR E - and; R E each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; each instance of W' is independently -O- or -S-; R 1 each instance of independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 is alkyl;

[0114] each instance of y is independently 0 or 1; If y is 0, [ka] is a single bond; If y is 1, [ka] is a single or double bond;

[0115] [ka] is a single bond, R 2 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0116] R a each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or R attached to the same nitrogen atom a when two of the following are joined to form a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl;

[0117] [ka] is a double bond, R 2 is absent;

[0118] R 3 each instance of independently represents hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0119] R 4 each instance of independently represents hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0120] Or, y is 1, and [ka] is a single bond, R 3 and R 4 are joined with their intervening atoms to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl;

[0121] Or, y is 1, and [ka] is a double bond, R 3 and R 4are cis to each other and joined with their intervening atoms to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0122] Alternatively, R 4 and R 6 are joined with their intervening atoms to form a substituted or unsubstituted heterocyclyl;

[0123] [ka] is a single bond, R 5 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0124] [ka] is a double bond, R 5 is absent;

[0125] R 6 each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; each instance of T is independently substituted or unsubstituted methylene; Each instance of M is independently an ammonium or iminium salt of a pharmaceutical agent, wherein the point of attachment is at the N + and; R B each instance of independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 is alkyl;

[0126] each instance of b is independently an integer from 1 to 20, inclusive; e is an integer between 1 and 10 (inclusive); X is OR C or N(R D )2;

[0127] R C is hydrogen, substituted or unsubstituted C 1-1000 Alkyl, substituted or unsubstituted C 2-1000 Alkenyl, substituted or unsubstituted C 2-1000 Alkynyl, substituted or unsubstituted C 1-1000 Heteroalkyl, substituted or unsubstituted C 2-1000 Heteroalkenyl, substituted or unsubstituted C 2-1000 is a heteroalkynyl, an oxygen protecting group, or a leaving group; and

[0128] R D each instance of independently represents hydrogen, substituted or unsubstituted C 1-1000 Alkyl, substituted or unsubstituted C 2-1000 Alkenyl, substituted or unsubstituted C2-1000 Alkynyl, substituted or unsubstituted C 1-1000 Heteroalkyl, substituted or unsubstituted C 2-1000 Heteroalkenyl, substituted or unsubstituted C 2-1000 heteroalkynyl, or a nitrogen protecting group.

[0129] Unless otherwise provided, a moiety or variable described in one section of this disclosure also applies to other sections of this disclosure. In some embodiments, the macromonomer has the formula: [ka] or a salt thereof.

[0130] In some embodiments, the macromonomer has the formula: [ka] or a salt thereof.

[0131] In some embodiments, the macromonomer has the formula: [ka] or a salt thereof.

[0132] In some embodiments, the macromonomer has the formula: [ka] or a salt thereof.

[0133] In some embodiments, the macromonomer has the formula: [ka] or a salt thereof, wherein:

[0134] R 7 each instance of independently represents a halogen, a substituted or unsubstituted C 1-6Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a ) 2; and Each instance of z is independently 0, 1, 2, 3, 4, 5, or 6.

[0135] In some embodiments, the macromonomer has the formula: [ka] or a salt thereof, wherein:

[0136] R 7 each instance of independently represents a halogen, a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a ) 2; and Each instance of z is independently 0, 1, 2, 3, or 4.

[0137] In some embodiments, z is 0. When formula (I) includes more than one instance of a moiety, the two or more instances of the moiety are independent of each other (e.g., any two of them can be the same or different).

[0138] In some embodiments, R A is hydrogen. A is hydrogen. A is halogen (e.g., F). A In at least one case, substituted or unsubstituted C 1-6 Alkyl (e.g., unsubstituted C 1-6alkyl, for example, Me).

[0139] In some embodiments, a is 1. In some embodiments, a is an integer from 2 to 20 (inclusive). In some embodiments, a is 3, 4, 5, 6, or 7. In some embodiments, a is 4, 5, or 6. In some embodiments, a is 5.

[0140] In some embodiments, at least one instance of -YZ- is [ka] is.

[0141] In some embodiments, at least one instance of -YZ- is [ka] is.

[0142] Pharmaceutical agents include chemical compounds and mixtures of chemical compounds, e.g., organic or inorganic small molecules; saccharin; oligosaccharides; polysaccharides; biological macromolecules, e.g., peptides, protein and peptide analogs and derivatives; peptidomimetics; antibodies and antigen-binding fragments thereof; nucleic acids; nucleic acid analogs and derivatives; extracts made from biological materials such as bacteria, plant, fungi or animal cells; animal tissue; naturally occurring or synthetic compositions; and any combination thereof.

[0143] In some embodiments, the pharmaceutical agent is a small molecule. In some embodiments, the pharmaceutical agent is a peptide or protein. Exemplary pharmaceutical agents include, but are not limited to, those found in: Harrison's Principles of Internal Medicine, 13th Edition, edited by TR Harrison et al., McGraw-Hill NY, NY; Physicians' Desk Reference, 50th Edition, 1997, Oradell New Jersey, Medical Economics Co.; Pharmacological Basis of Therapeutics, 8th Edition, Goodman and Gilman, 1990; United States Pharmacopeia, The National Formulary, USP XII NF XVII, 1990; the latest edition of Goodman and Oilman's The Pharmacological Basis of Therapeutics; and the latest edition of The Merck Index, the complete contents of all of which are incorporated herein by reference.

[0144] In some embodiments, at least one instance of the pharmaceutical agent is a therapeutic agent. In some embodiments, each instance of the pharmaceutical agent is a therapeutic agent. In some embodiments, exemplary therapeutic agents include, but are not limited to, one or more of the agents listed in paragraph 0148 of U.S. Pat. No. 9,381,253, incorporated herein by reference. In other embodiments, exemplary therapeutic agents include, but are not limited to, one or more of the following: therapeutic agents listed in WO 2013 / 169739, incorporated herein by reference, including, for example, antihypertensive agents and / or collagen modifying agents ("AHCM") disclosed in paragraphs 40-49, 283, 286-295; microenvironment modifiers, for example, disclosed in paragraphs 113-121 of WO 2013 / 169739, incorporated herein by reference. Examples of therapeutic agents include, but are not limited to, antibacterial agents, analgesics, anti-inflammatory agents, counterirritants, coagulation modifiers, diuretics, sympathomimetics, anorexics, antacids and other gastrointestinal agents; antiparasitic agents, antidepressants, antihypertensive agents, anticholinergic agents, stimulants, antihormonal agents, central and respiratory stimulants, drug antagonists, lipid regulating agents, uricosurics, cardiac glycosides, electrolytes, ergot and its derivatives, expectorants, hypnotics and sedatives, antidiabetic agents, dopaminergic agents, antiemetics, muscle relaxants, parasympathomimetics, anticonvulsants, antihistamines, beta-blockers, laxatives, antiarrhythmic agents, contrast agents, radiopharmaceuticals, antiallergic agents, tranquilizers, vasodilators, antiviral agents, and antineoplastic or cytostatic agents or other agents with anticancer properties, or combinations thereof. Other suitable therapeutic agents include contraceptives and vitamins as well as micro- and macronutrients.Still other examples include: anti-infectives such as antibiotics and antivirals; analgesics and analgesic combinations; appetite suppressants; antiparasitic agents; antiarthritics; antiasthmatics; anticonvulsants; antidepressants; antidiuretics; antidiarrheals; antihistamines; anti-inflammatory agents; antimigraine preparations; antiemetics; antineoplastic agents; antiparkinsonian agents; antipruritics; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; and pi cardiovascular preparations, including calcium channel blockers and beta-blockers such as steroids and antiarrhythmics; antihypertensives; diuretics; vasodilators, including general coronary, peripheral, and cerebral; central nervous system stimulants; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids; hypnotics; immunosuppressants; muscle relaxants; parasympatholytics; stimulants; sedatives; and tranquilizers; and naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins.

[0145] In some embodiments, at least one of the therapeutic agents is an anti-cancer agent. Anti-cancer agents include biotherapy anti-cancer agents and chemotherapeutic agents. Exemplary biotherapy anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serum therapy, immunostimulatory and / or immunomodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g., Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexar (tositumomab)). Exemplary chemotherapeutic agents include, but are not limited to, antiestrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g., goserelin and leuprolide), antiandrogens (e.g., flutamide and bicalutamide), photodynamic therapy (e.g., verteporfin (BPD-MA), phthalocyanines, photosensitizer Pc4, and demethoxy-hypocrelin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, isophosphamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU), alkylsulfonates (e.g., busulfan and treosulfan), triazenes (e.g., dacarbazine, temozolomide), platinum-containing compounds (e.g., cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g., paclitaxel or paclitaxel equivalents), docosahexaenoic acid-conjugated paclitaxel (DHA-paclitaxel, Taxoprexin®), polyglutamic acid-conjugated paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX),Tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 conjugated to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel conjugated to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel (e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllin (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnato l), mitomycin C), antimetabolites, DHFR inhibitors (e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonucleotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, raltitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g., cytarabine (arabinan), C), cytosine arabinoside, and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), vitamin D3 analogs (e.g., EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycins (e.g., actinomycin D, dactinomycin), bleomycins (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracyclines (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca, 2+ATPase inhibitors (e.g., thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), ibuprofen (IFN-γ), rifafloxacin (RIBA ... Matinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), )), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK / ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe), and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbazine, prednisolone, dexamethasone, camptothecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurocidin, leurocin, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethylmelamine. In some embodiments, the anticancer agent is JQ1, AZD5153, vincristine, abiraterone acetate (e.g., ZYTIGA), ABVD, ABVE, ABVE-PC, AC, AC-T, ADE, ado-trastuzumab emtansine (e.g., KADCYLA), afatinib dimaleate (e.g., GILOTRIF), aldesleukin (e.g., PROLEUKIN), alemtuzumab (e.g., CAMPATH), anastrozole (e.g., ARIMIDEX), arsenic trioxide (e.g., TRISENOX), ErwiniaChrysanthemi asparaginase (e.g., ERWINAZE), axitinib (e.g., INLYTA), azacitidine (e.g., MYLOSAR, VIDAZA), BEACOPP, belinstat (e.g., BELEODAQ), bendamustine hydrochloride (e.g., TREANDA), BEP, bevacizumab (e.g., AVASTIN), bicalutamide (e.g., CASODEX), bleomycin (e.g., BLENOXANE), blinatumomab (e.g., BLINCYTO), bortezomib (e.g., VELCADE), bosutinib (e.g., BOSULIF), bleomycin (e.g., bleomycin), thiazolinone (e.g., thiazolinone ... ntuximab vedotin (e.g., ADCETRIS), busulfan (e.g., BUSULFEX, MYLERAN), cabazitaxel (e.g., JEVTANA), cabozantinib-s-malate (e.g., COMETRIQ), CAF, capecitabine (e.g., XELODA), CAPOX, carboplatin (e.g., PARAPLAT, PARAPLATIN), carboplatin-taxol, carfilzomib (e.g., KYPROLIS), carmustine (e.g., BECENUM, BICNU, CARMUBRIS), carmustine imprint (e.g., GLIADEL Wafer, Gliadel), ceritinib (e.g., Zykadia), cetuximab (e.g., Erbitux), chlorambucil (e.g., Ambochlorin, Amboclorin, Leukeran, Linfolizin), chlorambucil-prednisone, CHOP, cisplatin (e.g., Platinol, Platinol-AQ), clofarabine (e.g., Clofarex, Clolar), CMF, COPP, COPP-ABV, crizotinib (e.g., Xalkori), CVP, cyclophosphamide (e.g., Clafen, Cytoxan, Neosar), cytarabine (e.g., Cytoxan-U, Tarabine),PFS), dabrafenib (e.g., TAFINLAR), dacarbazine (e.g., DTIC-DOME), dactinomycin (e.g., COSMEGEN), dasatinib (e.g., SPRYCEL), daunorubicin hydrochloride (e.g., CERUBIDINE), decitabine (e.g., DACOGEN), degarelix, denileukin diftitox (e.g., ONTAK), denosumab (e.g., PROLIA, XGEVA), dinutuximab (e.g., UNITUXIN), docetaxel (e.g., TAXOTERE), doxorubicin hydrochloride (e.g., ADRIAMYCIN), PFS, ADRIAMYCIN RDF), doxorubicin hydrochloride liposomal (e.g., DOXIL, DOX-SL, EVACET, LIPODOX), enzalutamide (e.g., XTANDI), epirubicin hydrochloride (e.g., ELLENCE), EPOCH, erlotinib hydrochloride (e.g., TARCEVA), etoposide (e.g., TOPOSAR, VEPESID), etoposide phosphate (e.g., ETOPOPHOS), everolimus (e.g., AFINITOR Disperz, Afinitor), exemestane (e.g., Aromasin), FEC, fludarabine phosphate (e.g., Fludarabine), fluorouracil (e.g., Adrucil, Efudex, Fluoroplex), Folfiri, Folfiri-bevacizumab, Folfiri-cetuximab, FOLFirinox, FOLFox, FU-LV, fulvestrant (e.g., Fasloxacin), gefitinib (e.g., Iressa), gemcitabine hydrochloride (e.g., Gemza), gemcitabine-cisplatin, gemcitabine-oxaliplatin, Gose Relin acetate (e.g., ZOLADEX), Hyper-CVAD, ibritumomab tiuxetan (e.g., ZEVALIN), ibrutinib (e.g., IMBRUVICA), ICE, idelalisib (e.g., ZYDELIG), isophosphamide (e.g., CYFOS, IFEX, IFOSFAMIDUM), imatinib mesylate (e.g., GLEEVEC), imiquimod (e.g., ALDARA), ipilimumab (e.g., YERVOY), irinotecan hydrochloride (e.g., CAMPTOSAR), ixabepilone (e.g., IXEMPRA), lanreotide acetate (e.g., SOMATULINE)DEPOT), lapatinib ditosylate (e.g., TYKERB), lenalidomide (e.g., REVLIMID), lenvatinib (e.g., LENVIMA), letrozole (e.g., FEMARA), leucovorin calcium (e.g., WELLCOVORIN), leuprolide acetate (e.g., LUPRON DEPOT, LUPRON DEPOT-3 MONTH, LUPRON DEPOT-4 MONTH, LUPRON DEPOT-PED, LUPRON, VIADUR), liposomal cytarabine (e.g., DEPOCYT), lomustine (e.g., CEENU), mechlorethamine hydrochloride (e.g., MUSTARGEN), megestrol acetate (e.g., MEGACE), mercaptopurine (e.g., PURINETHOL, PURIXAN), methotrexate (e.g., ABITREXATE, FOLEX PFS, FOLEX, METHOTREXATE) LPF, MEXATE, MEXATE-AQ), mitomycin C (e.g., MITOZYTREX, MUTAM YCIN), mitoxantrone hydrochloride, MOPP, nelarabine (e.g., ARRANON), nilotinib (e.g., TASIGNA), nivolumab (e.g., OPDIVO), obinutuzumab (e.g., GAZYVA), OEPA, ofatumumab (e.g., ARZERRA), OFF, olaparib (e.g., LYNPARZA), omacetaxine mepesuccinate (e.g., SYNRIBO), OPPA, OTX-015, oxaliplatin (e.g., ELOXATIN), paclitaxel (e.g., TAXOL), paclitaxel albumin-stabilized nanoparticle formulation (e.g., ABRAXANE), PAD, palbociclib (e.g., IBRANCE), pamidronate disodium (e.g., AREDIA), panitumumab (e.g., VECTIBIX), panobinostat (e.g., FARYDAK), pazopanib hydrochloride (e.g., VOTRIENT), pegaspargase (e.g., ONCASPAR) , pegylated interferon alfa-2b (e.g., PEG-INTRON), pegylated interferon alfa-2b (e.g., SYLATRON), pembrolizumab (e.g., KEYTRUDA), pemetrexed disodium (e.g., ALIMTA), pertuzumab (e.g., PERJETA), plerixafor (e.g., MOZOBIL), pomalidomide (e.g., POMALYST), ponatinib hydrochloride (e.g., ICLUSIG), pralatrexate (e.g., FOLOTYN), prednisone, procarbazine hydrochloride (e.g., MATULANE), radium-223 dichloride (e.g., XOFIGO), raloxifene hydrochloride (e.g., EVISTA, KEOXIFENE), ramucirumab (e.g., CYRAMZA), R-CHOP, recombinant HPV bivalent vaccine (e.g., CERVARIX), recombinant human papillomavirus (e.g., HPV) nonavalent vaccine (e.g., GARDASIL 9), recombinant human papillomavirus (e.g., HPV) quadrivalent vaccines (e.g., GARDASIL), recombinant interferon alpha-2b (e.g., INTRONA), regorafenib (e.g., STIVARGA), rituximab (e.g., RITUXAN), romidepsin (e.g., ISTODAX), ruxolitinib phosphate (e.g., JAKAFI), siltuximab (e.g., SYLVANT), sipuleucel-t (e.g., PROVENGE), sorafenib tosylate (e.g., NEXAVAR), STANFORD V, sunitinib malate (e.g., SUTENT), TAC, tamoxifen citrate (e.g., NOLVADEX, NOVALDEX), temozolomide (e.g., METHAZOLASTONE, TEMODAR), temsirolimus (e.g., TORISEL), thalidomide (e.g., SYNOVIR, THALOMID), thiotepa, topotecan hydrochloride (e.g., HYCAMTIN), toremifene (e.g., FARESTON), tositumomab, and iodine I 131 tositumomab (e.g., BEXXAR), TPF, trametinib (e.g., MEKINIST), trastuzumab (e.g., HERCEPTIN), VAMP, vandetanib (e.g., CAPRELSA), VEIP, vemurafenib (e.g., ZELBORAF), vinblastine sulfate (e.g., VELBAN, VELSAR), vincristine sulfate (e.g., VINCASAR PFS), vincristine sulfate liposomal (e.g., MARQIBO), vinorelbine tartrate (e.g., NAVELBINE), vismodegib (e.g., ERIVEDGE), vorinostat (e.g., ZOLINZA), XELIRI, XELOX, ziv-aflibercept (e.g., ZALTRAP), or zoledronate (e.g., ZOMETA), or a pharmaceutically acceptable salt thereof. In some embodiments, at least one of the therapeutic agents is a bromodomain inhibitor. In some embodiments, at least one of the therapeutic agents is a BET protein (bromo and extra terminalIn some embodiments, at least one of the therapeutic agents is a bromodomain-containing protein 2 (BRD2) inhibitor, a bromodomain-containing protein 3 (BRD3) inhibitor, a bromodomain-containing protein 4 (BRD4) inhibitor, a TBP (TATA box-binding protein)-associated factor protein (TAF) (e.g., TAF1 or TAF1L) inhibitor, a CREB-binding protein (CBP) inhibitor, or an E1A-binding protein p300 (EP300) inhibitor. In some embodiments, at least one of the pharmaceutical agents is a PARP inhibitor, an ALK inhibitor, or a STING ligand. In some embodiments, at least one of the therapeutic agents is OTX-015.

[0146] In some embodiments, the therapeutic agent is JQ1, AZD5153, or vincristine. [ka] [ka] [ka] is.

[0147] In some embodiments, at least one instance of the pharmaceutical agent is a prophylactic agent. In some embodiments, each instance of the pharmaceutical agent is a prophylactic agent. Prophylactic agents that can be included in the conjugates of the present invention include, but are not limited to, antibiotics, nutritional supplements, and vaccines. Vaccines may include isolated proteins or peptides, inactivated organisms and viruses, killed organisms and viruses, genetically modified organisms and viruses, and cell extracts. Prophylactic agents may be combined with interleukins, interferons, cytokines, and adjuvants such as cholera toxin, alum, and Freund's adjuvant.

[0148] In some embodiments, at least one instance of the pharmaceutical agent is a diagnostic agent. In some embodiments, each instance of the pharmaceutical agent is a diagnostic agent. Exemplary diagnostic agents include, but are not limited to, fluorescent molecules; gases; metals; imaging agents, such as commercially available imaging agents used in positron emission tomography (PET), computer-assisted tomography (CAT), single-photon emission computed tomography, X-ray, fluoroscopy, and magnetic resonance imaging (MRI); and contrast agents. Examples of suitable materials for use as contrast agents in MRI include gadolinium chelates, as well as iron, magnesium, manganese, copper, and chromium. Examples of useful materials for CAT and X-ray imaging include iodine-based materials. In some embodiments, the diagnostic agent is one used in magnetic resonance imaging (MRI), such as iron oxide particles or gadolinium complexes. Gadolinium complexes approved for clinical use include gadolinium chelates with DTPA, DTPA-BMA, DOTA, and HP-DO3A, which are reviewed in Aime et al. (Chemical Society Reviews (1998), 27:19-29), the entire teachings of which are incorporated herein by reference.

[0149] In some embodiments, the diagnostic agent is a metal, an inorganic compound, an organometallic compound, an organic compound, or a salt thereof. In some embodiments, the imaging agent comprises a metal selected from the group consisting of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, rutherfordium, dubnium, seaborgium, bohrium, hassium, meitnerium, gadolinium, gallium, thallium, and barium. In some embodiments, the diagnostic agent is an organic compound. In some embodiments, the diagnostic agent is metal-free. In some embodiments, the diagnostic agent is a metal-free organic compound.

[0150] In some embodiments, the imaging agent is a magnetic resonance imaging (MRI) agent. In some embodiments, the MRI agent is gadolinium. In some embodiments, the MRI agent is a nitroxide radical-containing compound. In some embodiments, the imaging agent is a nuclear medicine imaging agent. 64 Cu diacetyl-bis(N4-methylthiosemicarbazone)( 64 Cu-ASTM), 18 F-fluorodeoxyglucose (FDG), 18 F-fluorine, 3'-deoxy-3'-[ 18 F]fluorothymidine (FLT); 18 F-fluoromisonidazole (FMISO), gallium, technetium-99m, and thallium

[0151] In some embodiments, the imaging agent is a radiographic imaging agent, hi some embodiments, the radiographic imaging agent is selected from the group consisting of barium, gastrografin, and iodine contrast agents.

[0152] In some embodiments, the imaging agent diagnostic agent is a radical-containing compound. In some embodiments, the imaging agent is a nitroxide radical-containing compound. In some embodiments, the imaging agent diagnostic agent has the formula: [ka] It is of the type.

[0153] In some embodiments, the imaging agent diagnostic agent is an organic compound. In some embodiments, the imaging agent is a salt of an organic compound. In some embodiments, the imaging agent diagnostic agent has the formula: [ka] It is of the type.

[0154] In certain embodiments, the diagnostic agent may comprise a fluorescent molecule, a metal chelate, a contrast agent, a radionuclide or positron emission tomography (PET) imaging agent, an infrared imaging agent, a near-infrared imaging agent, a computer-assisted tomography (CAT) imaging agent, a photon emission computed tomography imaging agent, and an X-ray imaging agent, or a magnetic resonance imaging (MRI) agent.

[0155] In some embodiments, the diagnostic agent is a fluorescent molecule. In some embodiments, the fluorescent molecule comprises an acridine dye, a cyanine dye, a rhodamine dye, a BODIPY dye, a fluorescein dye, a dansyl dye, an Alexa dye, an AT dye, a quantum dot or a fluorescent protein. In some embodiments, the fluorescent molecule is a cyanine dye (e.g., Cy3, Cy3.5, Cy5, Cy5.5, Cy7 or Cy7.5).

[0156] In some embodiments, the diagnostic agent is an MRI agent (e.g., a contrast agent). Examples of materials suitable as MRI agents (e.g., contrast agents) include gadolinium chelates, as well as iron, magnesium, manganese, copper, and chromium.

[0157] In some embodiments, the diagnostic agent is a CAT imaging agent or an X-ray imaging agent. Examples of materials useful for CAT and X-ray imaging include iodine-based materials. In some embodiments, the diagnostic agent is a PET imaging agent. Examples of suitable PET imaging agents include positron-emitting radioisotopes. 18 F, 15 O. 13 N, 11 C. 82 Rb, 64 Cu, and 68 Compounds and compositions containing Ga, such as fludeoxyglucose ( 18 F-FDG), 68 Ga-DOTA-pseudopeptides (e.g., 68 Ga-DOTA-TOC), 11 C-metomidate,11 C-acetate, 11 C-methionine, 11 C-choline, 18 F-fluciclovine, 18 F-fluorocholine, 18 F-fluorodeoxysorbitol, 18 F-3'-fluoro-3'-deoxythymidine, 11 C-raclopride, and 18 F-desmethoxyfalipride. In some embodiments, the diagnostic agent is a near-infrared imaging agent.Examples of near-infrared imaging agents include Pz 247, DyLight 750, DyLight 800, cyanine dyes (e.g., Cy5, Cy5.5, Cy7), AlexaFluor 680, AlexaFluor 750, IRDye 680, IRDye 800CW and Kodak X-SIGHT dyes.

[0158] In some embodiments, the agent may be a radionuclide, e.g., for use as a therapeutic, diagnostic, or prognostic agent. Among the radionuclides used, gamma-emitters, positron-emitters, and X-ray-emitters are suitable for diagnosis and / or treatment, while beta-emitters and alpha-emitters can also be used for treatment. Suitable radionuclides for use in accordance with various embodiments of the present invention include, but are not limited to: 123 I, 125 I, 130 I, 131 I, 133 I, 135 I, 47 Sc, 72 As, 72 Sc, 90 Y, 88 Y, 97 Ru, 100 Pd, 101 mRh, 119 Sb, 128 Ba, 197 Hg, 211 At, 212 Bi, 212 Pb,109 Pd, 111 In, 67 Ga, 68 Ga, 67 Cu, 75 Br, 77 Br, 99 mTc, 14 C. 13 N, 15 O. 32 P, 33 P, or 18 F is one example.

[0159] In certain embodiments, at least one instance of the diagnostic agent is an imaging agent. In certain embodiments, at least one instance of the imaging agent is a magnetic resonance signal enhancing agent, an X-ray attenuating agent, an ultrasound scattering agent, or an ultrasound frequency shifting agent.

[0160] In some embodiments, the pharmaceutical agent is a monovalent radical. In some embodiments, the monovalent radical of the pharmaceutical agent is formed by removing a hydrogen atom from the moiety HV of the pharmaceutical agent. In some embodiments, V is a carbon atom. In some embodiments, V is a heteroatom. In some embodiments, V is an oxygen atom. In some embodiments, V is a sulfur atom. In some embodiments, V is a nitrogen atom. In some embodiments, the monovalent radical of the pharmaceutical agent is further formed by changing atom V of the pharmaceutical agent to a substituted or unsubstituted U, where each of V and U is a heteroatom and V and U are different from each other.

[0161] In certain embodiments, M is an ammonium (e.g., quaternary ammonium) or iminium (e.g., tertiary iminium) salt of the pharmaceutical agent, wherein the point of attachment is the N + In some embodiments, the N of the ammonium salt or iminium salt + The nitrogen atom of is a moiety of a pharmaceutical agent.

[0162] In certain embodiments, at least one instance of the pharmaceutical agent comprises a tertiary amino or secondary imine. In certain embodiments, at least one instance of the pharmaceutical agent does not comprise -OH, -SH, -NH-, -NH2, or =NH. In some embodiments, M is electrically neutral. In some embodiments, the macromolecule, compound, or conjugate is electrically neutral. In some embodiments, all instances of M are the same. In some embodiments, at least two instances of M (e.g., all instances of M) are different from one another.

[0163] In some embodiments, at least one instance of m is 1. In some embodiments, each instance of m is 1. In some embodiments, at least one instance of m is an integer from 2 to 10 (inclusive). In some embodiments, at least one instance of m is 2, 3, 4, or 5. When a first divalent moiety contains a second divalent moiety, the second divalent moiety is part of the backbone of the first divalent moiety, e.g., when LF contains -SS-, -SS- is part of the backbone of LF.

[0164] In some embodiments, at least one instance of L is substituted or unsubstituted C 1-200 In some embodiments, at least one instance of L is an unsubstituted C 2-10 In some embodiments, each instance of L is an unsubstituted C 2-10 In some embodiments, at least one instance of L is unsubstituted C 2-20 In some embodiments, each instance of L is unsubstituted C 2-20 In some embodiments, at least one instance of L is substituted or unsubstituted C 2-20 In some embodiments, at least one instance of L is substituted or unsubstituted, C 3-30 In some embodiments, at least one instance of L is substituted or unsubstituted C 2-200In some embodiments, at least one instance of L is substituted or unsubstituted C 2-200 In some embodiments, at least one instance of L is substituted or unsubstituted C 2-200 In some embodiments, at least one instance of L is substituted or unsubstituted C 2-20 In some embodiments, at least one instance of L is substituted or unsubstituted, C 3-30 In some embodiments, at least one instance of L is -CH2CH2-(O-CH2CH2). 1-6 In some embodiments, each instance of L is -CH2CH2-(O-CH2CH2) 1-6 In some embodiments, at least one instance of L is unsubstituted C 2-20 Alkylene or -CH2CH2-(O-CH2CH2) 1-6 In some embodiments, each instance of L is independently an unsubstituted C 2-20 Alkylene or -CH2CH2-(O-CH2CH2) 1-6 In some embodiments, each instance of L is unsubstituted C 2-20 Alkylene or -CH2CH2-(O-CH2CH2) 1-6 In some embodiments, at least one instance of L is substituted or unsubstituted C 2-200 In some embodiments, at least one instance of L is substituted or unsubstituted C 2-200 In some embodiments, at least one instance of L is substituted or unsubstituted C 2-200 heteroalkylene, wherein substituted or unsubstituted C 2-200 One or more carbons and / or one or more heteroatoms of the heteroalkylene are independently replaced with a substituted or unsubstituted heteroarylene. In some embodiments, at least one instance of L is a substituted or unsubstituted C 2-200 Heteroalkylene (e.g., substituted or unsubstituted C 3-30 heteroalkylene), where substituted or unsubstituted C2-200 Heteroalkylene (e.g., substituted or unsubstituted C 3-30 One or two carbons and / or one or two heteroatoms of the heteroalkylene are independently replaced by a substituted or unsubstituted arylene (e.g., phenylene) or a substituted or unsubstituted heteroarylene (e.g., a substituted or unsubstituted, monocyclic, 5- or 6-membered heteroarylene). In some embodiments, at least one instance of L is a substituted or unsubstituted C 2-200 heteroalkylene, wherein substituted or unsubstituted C 2-200 One or more carbons and / or one or more heteroatoms of the heteroalkylene are independently [ka] is replaced by wherein the nitrogen atom labeled with "*" is closer to the attachment point labeled with "**" than to the attachment point labeled with "***". In some embodiments, at least one instance of L is a substituted or unsubstituted C 2-200 heteroalkylene, wherein substituted or unsubstituted C 2-200 One carbon or one heteroatom of a heteroalkylene is [ka] is replaced by wherein the nitrogen atom labeled with "*" is closer to the attachment point labeled with "**" than to the attachment point labeled with "***". In some embodiments, at least one instance of L is [ka] Including,

[0165] where: each instance of p is independently an integer from 1 to 10, inclusive; L F each instance of independently substituted or unsubstituted C 2-180 is heteroalkylene; and The nitrogen atom labeled with "*" is closer to the attachment point labeled with "**" than to the attachment point labeled with "***". In some embodiments, at least one instance of L is [ka] is.

[0166] In certain embodiments, at least one instance of L is: [ka] Including, where: each instance of p is independently an integer from 1 to 10, inclusive; Each instance of q is independently an integer from 1 to 10, inclusive; each instance of r is independently an integer from 0 to 10, inclusive; each instance of s is independently 0 or 1; each instance of t is independently an integer between 0 and 10, inclusive; and The nitrogen atom labeled with "*" is closer to the attachment point labeled with "**" than to the attachment point labeled with "***".

[0167] In one embodiment, L F In at least one case, C is substituted or unsubstituted. 3-30 In some embodiments, L is heteroalkylene. F At least one instance of L includes -SS-. F In at least one case, a substituted or unsubstituted C 3-30 In some embodiments, L is heteroalkylene. F In at least one case, the peptide comprises a peptide containing 1 to 20 (eg, 1 to 4) amino acid residues (including the boundaries).

[0168] In certain embodiments, at least one instance of L is: [ka] is. In certain embodiments, at least one instance of L is: [ka] where r is 1, 2, or 3; and t is 1 or 2. In certain embodiments, at least one instance of L is: [ka] Including, where: each instance of p is independently an integer from 1 to 10, inclusive; L C each instance of independently substituted or unsubstituted C 1-180 alkylene; and The nitrogen atom labeled with "*" is closer to the attachment point labeled with "**" than to the attachment point labeled with "***".

[0169] In certain embodiments, at least one instance of L is: [ka] is. In one embodiment, L C In at least one case, substituted or unsubstituted C 1-12 In some embodiments, L is alkylene. C In at least one case, there is a non-substituted C 1-12 In some embodiments, L is alkylene. C each instance of independently being substituted or unsubstituted phenyl and / or substituted or unsubstituted C 1-6 C optionally substituted with one or more of alkyl 1-180It is alkylene. In some embodiments, at least one instance of L comprises a polymer. In some embodiments, at least one instance of the polymer is substituted or unsubstituted polyethylene (e.g., unsubstituted polystyrene). In some embodiments, at least one instance of the polymer has a weight average molecular weight of 300 to 10,000, 300 to 3,000, 300 to 1,000, 1,000 to 10,000, 1,000 to 3,000, or 3,000 to 10,000 g / mol (inclusive). In some embodiments, at least one instance of L comprises an amino acid or a peptide. In some embodiments, at least one instance of the peptide consists of 3 to 60, 3 to 30, 3 to 10, 10 to 60, 10 to 30, or 30 to 60 amino acids (inclusive). In some embodiments, each instance of the amino acid is a naturally occurring amino acid. In some embodiments, at least one instance of the amino acid is an unnatural amino acid.

[0170] A cleavable linker is "cleaved" or "degraded" when one or more bonds of the cleavable linker are broken, resulting in release of an agent, e.g., from, e.g., a brush prodrug or particle. Linker cleavage or agent release need not be 100%, and cleavage or release of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, e.g., over a period of seconds, minutes, hours (e.g., 6, 12, or 24 hours), days (e.g., 2 or 7 days), weeks, or months, is encompassed by the term. In some embodiments, at least 50% of all instances of cleavable L are cleaved after about 10 minutes, about 1 hour, about 6 hours, about 12 hours, about 1 day, about 2 days, about 3 days, about 5 days, or about 7 days of ultraviolet irradiation, hydrolysis, reduction, oxidation, or contact with an enzyme. In some embodiments, the cleavable linker is cleavable by or sensitive to an enzyme (e.g., esterase or protease), pH (e.g., acidic pH, basic pH), light (e.g., ultraviolet light), a nucleophile, reduction, or oxidation. In some embodiments, the cleavable linker is cleavable by or sensitive to an enzyme (e.g., esterase or protease) or pH (e.g., acidic pH, basic pH). In some embodiments, the cleavable linker is not cleavable by light (e.g., ultraviolet light). In some embodiments, at least one instance of L is cleavable by ultraviolet irradiation. In some embodiments, at least one instance of L is cleavable by hydrolysis, reduction, or oxidation. In some embodiments, at least one instance of L is cleavable by contact with an enzyme.

[0171] The cleavable linker may, in part, comprise an atom of a moiety derived from an agent (eg, a therapeutic agent) or a portion of that moiety. In some embodiments, the cleavable linker is cleaved or degraded, e.g., preferentially cleaved or degraded, upon exposure to a first set of conditions compared to a second set of conditions. For example, a cleavable linker can be "preferentially cleaved" or "preferentially degraded" under a first set of conditions compared to a second set of conditions if at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more of the bonds of the cleavable linker are broken or the agent is released under the first set of conditions compared to the second set of conditions.

[0172] In some embodiments, the cleavable linker is degraded or hydrolyzed under physiological conditions. In some embodiments, the linker is pH-sensitive or cleaved at a specific pH. In some embodiments, the linker is degraded or hydrolyzed through the action of an enzyme (e.g., a protease or esterase). For example, in some embodiments, the cleavable linker is preferentially cleaved in a tissue microenvironment, such as a tumor microenvironment, which is referred to herein as a "tissue microenvironment cleavable linker." In embodiments, the tissue (e.g., tumor) microenvironment cleavable linker is preferentially cleaved or degraded upon exposure to a first desired tissue or tumor microenvironment compared to a second tissue or non-tumor tissue. A tissue (e.g., tumor) microenvironment-cleavable linker can be preferentially cleaved when at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more of the linker's bonds are broken or the agent is released in a desired tissue or tumor microenvironment compared to another tissue or non-tumor tissue. In one embodiment, a tissue (e.g., tumor) microenvironment-cleavable linker is preferentially cleaved or degraded when one or more of the linker's bonds are broken or the agent is released at least 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, or 100 times faster upon exposure to a first desired tissue or tumor microenvironment compared to a second tissue or non-tumor tissue. A tissue (e.g., tumor) microenvironment can have a specific set of conditions, such as pH and enzymes, that cause the linker to be cleaved or degraded.

[0173] In some embodiments, at least two instances of L are different from one another. In some embodiments, all instances of L are the same. In one embodiment, the tissue (e.g., tumor) microenvironment cleavable linker is cleavable by an enzyme. In some embodiments, the enzyme comprises an esterase or a protease. Exemplary proteases include MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-14, plasmin, PSA, PSMA, cathepsin D, cathepsin K, cathepsin S, ADAM10, ADAM12, ADAMTS, caspase-1, caspase-2, caspase-3, caspase-4, caspase-5, caspase-6, caspase-7, caspase-8, caspase-9, caspase-10, caspase-11, caspase-12, caspase-13, caspase-14, or TACE.

[0174] In other embodiments, the tissue microenvironment cleavable linker is cleavable at a specific pH. In some embodiments, the tissue microenvironment cleavable linker is cleavable at a pH of about 5.0 to about 7.4, 5.0 to 7.0, 5.0 to 6.5, 5.0 to 5.5, or 5.9 to 6.2. In one embodiment, the tissue microenvironment cleavable linker is cleavable at a pH of about 6.0 to about 7.0, about 6.2 to about 6.9, about 6.5 to about 6.8, or about 6.5 to about 6.7. In one embodiment, the tissue microenvironment cleavable linker is cleavable at a pH of about 5.5 to about 6.5, e.g., 5.9 to 6.2. In one embodiment, the tissue microenvironment cleavable linker is cleavable at a hypoxic pH, e.g., about 6.7 to 6.9, compared to a physiological pH of, e.g., about 7.4.

[0175] In some embodiments, the tissue microenvironment cleavable linker is cleavable and is cleaved at a pH of 7.4 or lower, 7.0 or lower, 6.9 or lower, 6.8 or lower, 6.7 or lower, 6.6 or lower, 6.5 or lower, 6.4 or lower, 6.3 or lower, 6.2 or lower, 6.1 or lower, 6.0 or lower, 5.5 or lower, or lower.

[0176] In one embodiment, the tissue microenvironment cleavable linker is preferentially cleaved or degraded upon exposure to a first pH compared to a second pH. In one embodiment, the tissue microenvironment cleavable linker is cleaved or degraded at least 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, or 100 times faster upon exposure to the first pH compared to the second pH. In other embodiments, the tissue microenvironment cleavable linker exhibits a higher release or degradation rate at a first acidic pH (e.g., pH=6.7) compared to a second, more basic pH (e.g., pH=7.4). In one embodiment, the ratio of the release or degradation rate of the tissue microenvironment cleavable linker at pH=6.7 compared to pH=7.4 is greater than 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, or greater. In one embodiment, the ratio of the rate of release or degradation of the tissue microenvironment cleavable linker at pH=6.7 compared to pH=7.4 is greater than 2.

[0177] In one embodiment, the tissue microenvironment cleavable linker exhibits increased pH sensitivity in hypoxic microenvironments, such as in tumors or fibrotic tissues. In some embodiments, the tissue microenvironment cleavable linker exhibits an increased release rate or increased amount of the agent at a desired site (e.g., a tumor) compared to, e.g., the release rate or amount at another site. In one embodiment, the tissue microenvironment cleavable linker comprises an electron-withdrawing group (e.g., an electron-withdrawing group that enhances the rate or amount of cleavage, e.g., upon exposure to a first set of conditions compared to a second set of conditions).

[0178] In certain embodiments, at least one substituent in at least one instance of L is ═O, halogen (e.g., F), or substituted or unsubstituted C 1-6 It is alkyl. In some embodiments, at least one (e.g., each) instance of W is a single bond. In some embodiments, at least one (e.g., each) instance of W is -O-. In some embodiments, at least one (e.g., each) instance of W is -S-. In some embodiments, at least one (e.g., each) instance of W is -NR E - (e.g., -NH-). In some embodiments, R E is hydrogen. E In at least one case, substituted or unsubstituted C 1-6 In some embodiments, R E is Me. In some embodiments, R E is Et, Pr, Bu, substituted methyl, substituted ethyl, substituted propyl, or substituted butyl. E is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0179] In some embodiments, at least one (eg, each) instance of W' is -O-. In some embodiments, at least one (eg, each) instance of W' is -S-. In some embodiments, R a is hydrogen. a In at least one case, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom. In some embodiments, R aWhen two of the above are joined together, they form a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl.

[0180] In some embodiments, at least one instance of T is independently substituted or unsubstituted C 1-6 Alkyl and -C(=O)OR a one or two substituents selected from (e.g., —C(═O)O (substituted or unsubstituted C 1-6 In some embodiments, at least one instance of T is a methylene substituted with one or two unsubstituted C(=O)OMe or -C(=O)OEt). 1-3 In some embodiments, at least one (e.g., each) instance of T is -CH-. In some embodiments, at least one (e.g., each) instance of T is -CH(R a )-. In some embodiments, at least one (e.g., each) instance of T is -CH(CH3)-. In some embodiments, at least one (e.g., each) instance of T is -CH(CH3)-. In some embodiments, at least one (e.g., each) instance of T is more stable (e.g., 30% to 100%, 1 to 10 times, 10 to 100 times, 100 to 1,000 times, 1,000 to 10,000 times, or 10,000 to 1,000,000 times (inclusive) more stable) than the moiety -WC(=O)-W'-. In some embodiments, more stable refers to more chemically stable. In some embodiments, more stable refers to more stable under physiological conditions. In some embodiments, more stable refers to more slowly degraded by hydrolysis. In some embodiments, more stable refers to more slowly degraded by light (e.g., ultraviolet light), reduction, or oxidation. In some embodiments, more stable refers to more slowly degraded by contact with an enzyme.

[0181] In some embodiments, R B is hydrogen. In some embodiments, each instance of b is independently an integer from 2 to 20, inclusive. In some embodiments, each instance of b is independently 2, 3, 4, 5, or 6. In some embodiments, e is 1. In some embodiments, e is an integer from 2 to 10 (inclusive). In some embodiments, e is 2 or 3.

[0182] In some embodiments, X is OR C In some embodiments, X is N(R D )2. In some embodiments, R C is hydrogen, substituted or unsubstituted C 1-6 alkyl, an oxygen protecting group, or a leaving group; and R D At least one of the following is hydrogen, substituted or unsubstituted C 1-6 In some embodiments, X is -OR C where R C is an oxygen protecting group or leaving group. In some embodiments, X is -OH. In some embodiments, X is [ka] is. In some embodiments, X is [ka] where n is an integer between 40 and 100, inclusive; and R F is hydrogen or unsubstituted C 1-6 It is alkyl.

[0183] In some embodiments, R C , or R D In at least one case, substituted or unsubstituted C 50-1000 In some embodiments, R C , or R D In at least one case, [ka] where: n is an integer from 1 to 300, inclusive; and R F is hydrogen, substituted or unsubstituted C 1-6 alkyl, or oxygen protecting groups.

[0184] R C , or R D In at least one case, [ka] where: u is 1, 2, 3, 4, 5 or 6; R G each instance of independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 is alkyl; v is an integer between 1 and 300, inclusive; and R F is hydrogen, substituted or unsubstituted C 1-6 alkyl, or oxygen protecting groups.

[0185] In one embodiment, [ka] teeth, [ka] is.

[0186] Exemplary macromonomers can be described by a number of characteristics, including molecular weight (kDa) and hydrodynamic diameter (nm). In some embodiments, the molecular weight of the macromonomer is about 1 kDa to about 10 kDa, e.g., about 2 kDa to about 8 kDa or about 3 kDa to about 6 kDa, as detected, for example, by mass spectrometry. In some embodiments, the molecular weight of the macromonomer is about 3 kDa to about 6 kDa. In some embodiments, the molecular weight of the macromonomer is about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, or about 6 kDa. In some embodiments, the hydrodynamic diameter of the macromonomer is about 0.5 nm to about 3 nm, e.g., about 1 nm to about 2 nm, as detected, for example, by dynamic light scattering.

[0187] In some embodiments, R 1 is H. In some embodiments, R 1 In each case, H. In some embodiments, y is 1; [ka] is a single bond; and R 2 is hydrogen, halogen, or substituted or unsubstituted C 1-6 In some embodiments, y is 1; [ka] is a single bond; and R 2 is hydrogen. In some embodiments, y is 1; [ka] is a single bond; and R 3 is hydrogen, halogen, or substituted or unsubstituted C 1-6 In some embodiments, y is 1; [ka] is a single bond; and R3 is hydrogen.

[0188] In some embodiments, y is 1; [ka] is a single bond; R 2 is hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl; and R 3 is hydrogen, halogen, or substituted or unsubstituted C 1-6 In some embodiments, y is 1; [ka] is a single bond; R 2 is hydrogen; and R 3 is hydrogen. In some embodiments, y is 0.

[0189] In some embodiments, y is 0; and R 4 and R 6 are joined with their intervening atoms to form a substituted or unsubstituted heterocyclyl. In some embodiments, y is 0; and R 4 and R 6 are joined with their intervening atoms to form a substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted morpholinyl. In some embodiments, y is 0; and R 4 and R 6 is joined with its intervening atoms to form a substituted or unsubstituted pyrrolidinyl.

[0190] In some embodiments, y is 1; [ka] is a double bond; and R 3 and R 4and are cis to each other and are joined with their intervening atoms to form a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In some embodiments, y is 1; [ka] is a double bond; and R 3 and R 4 and are cis to each other and are joined with their intervening atoms to form a substituted or unsubstituted phenyl. In some embodiments, y is 1; [ka] is a double bond; and R 3 and R 4 and are cis to each other and are joined with their intervening atoms to form a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl (eg, substituted or unsubstituted pyridyl).

[0191] In one embodiment, [ka] is a single bond; and R 5 is hydrogen, halogen, or substituted or unsubstituted C 1-6 In some embodiments, [ka] is a single bond; and R 5 is hydrogen. In some embodiments, R 6 In at least one of the cases, H or substituted or unsubstituted C 1-6 In some embodiments, R 6 In at least one case, there is a non-substituted C 1-3 In some embodiments, R 6 In at least one case, it is Me.

[0192] Compound of formula (II) In another aspect, the present disclosure provides a compound of formula (II): [ka] (II) and salts thereof, During the ceremony:

[0193] E A is the first reaction handle; L is a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, or substituted or unsubstituted C 2-200 is heteroalkynylene;

[0194] Optionally, a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more carbons in the heteroalkynylene are independently replaced by a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene;

[0195] Optionally, a substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200one or more heteroatoms in the heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0196] W is a single bond, -O-, -S-, or -NR E - and; R E is hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; W' is -O- or -S-; R 1 each instance of independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 is alkyl;

[0197] y is 0 or 1; If y is 0, [ka] is a single bond; If y is 1, [ka] is a single or double bond; [ka] is a single bond, R 2 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a)R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0198] R a each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or R attached to the same nitrogen atom a when two of the following are joined to form a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl;

[0199] [ka] is a double bond, R 2 is absent; R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0200] R 4 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)Ra , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0201] Or, y is 1, and [ka] is a single bond, R 3 and R 4 are joined with their intervening atoms to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; Or, y is 1, and [ka] is a double bond, R 3 and R 4 are cis to each other and joined with their intervening atoms to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Alternatively, R 4 and R 6 are joined with their intervening atoms to form a substituted or unsubstituted heterocyclyl;

[0202] [ka] is a single bond, R 5 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0203] [ka] is a double bond, R 5 is absent; R 6 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; T is substituted or unsubstituted methylene; and M is an ammonium or iminium salt of a pharmaceutical agent, where the point of attachment is the N + is.

[0204] In another aspect, the present disclosure provides a compound of formula (II): [ka] (II) or a salt thereof, During the ceremony: E A is the first reaction handle; L is a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, or C 2-200 heteroalkynylene,

[0205] Optionally, a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and C 2-200 one or more carbons in the heteroalkynylene are independently replaced by a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene;

[0206] Optionally, a substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more heteroatoms in the heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0207] W is a single bond, -O-, -S-, or -NR E - and; R Eis hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; W' is -O- or -S-; R 1 each instance of independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 is alkyl;

[0208] y is 0 or 1; If y is 0, [ka] is a single bond; If y is 1, [ka] is a single or double bond;

[0209] [ka] is a single bond, R 2 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)Ra , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0210] R a each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or R attached to the same nitrogen atom a when two of the following are joined to form a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl;

[0211] [ka] is a double bond, R 2 is absent; R 3 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a, -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0212] R 4 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)Ra , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0213] Or, y is 1, and [ka] is a single bond, R 3 and R 4 are joined with their intervening atoms to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; Or, y is 1, and [ka] is a double bond, R 3 and R 4 are cis to each other and joined with their intervening atoms to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Alternatively, R 4 and R 6 are joined with their intervening atoms to form a substituted or unsubstituted heterocyclyl;

[0214] [ka] is a single bond, R 5 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NRa )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0215] [ka] is a double bond, R 5 is absent; R 6 is hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; T is substituted or unsubstituted methylene; and M is an ammonium or iminium salt of a pharmaceutical agent, where the point of attachment is the N + is.

[0216] Unless otherwise provided, the moieties included in the compound of formula (II) are as described herein (e.g., in the "Macromonomer" and / or "Conjugates of Formula (III)" subsections).

[0217] The compounds and conjugates may be useful for conjugating a delivery vehicle (e.g., moiety D) to a pharmaceutical agent that does not contain a conventional reaction handle. In some embodiments, the conventional reaction handle is -OH, -SH, -NH-, -NH, or =NH. In some embodiments, the conventional reaction handle is a nucleophile, an electrophile, a leaving group, a substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, -OH, -SH, -NHR a , -N3, -C(=O)OH, -C(=NR a )OH, -S(=O)OH, -S(=O)2OH, -C(=O)-(leaving group), -C(=NR a )-(leaving group), -S(=O)-(leaving group), or -S(=O)2-(leaving group). In some embodiments, the conventional reaction handle is a nucleophile, an electrophile, a leaving group, -OH, -SH, -NHR a , -N3, -C(=O)OH, -C(=NR a )OH, -S(=O)OH, -S(=O)2OH, -C(=O)-(leaving group), -C(=NR a )-(leaving group), -S(=O)-(leaving group), or -S(=O)2-(leaving group). In certain embodiments, the pharmaceutical agent before conjugation to form a compound or conjugate comprises a tertiary amino or secondary imine. In certain embodiments, the tertiary amino or secondary imine is the conjugation site when the pharmaceutical agent is conjugated to form a compound or conjugate. In certain embodiments, the pharmaceutical agent after conjugation to form a compound or conjugate comprises a quaternary ammonium salt or a tertiary iminium salt. Related drug delivery technologies are reported in references (16) to (18).

[0218] Conjugates of formula (III) In another aspect, the present disclosure provides a compound of formula (III): [ka] (III) and salts thereof, During the ceremony:

[0219] D is a polymeric moiety, a dendrimeric moiety, an antibody, a particle, a bead, a nanostructure, a liposome, a micelle, or a vesicle; c is an integer between 1 and 1000 (inclusive); L J each instance of independently a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, or substituted or unsubstituted C 2-200 heteroalkynylene, wherein:

[0220] Optionally, a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more carbons in the heteroalkynylene are independently replaced by a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; and

[0221] Optionally, a substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more heteroatoms in the heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0222] For each E, E A EB is a moiety formed by reacting with; E A In each case, is the first reaction handle; E B is a second reaction handle, where the second reaction handle can react with the first reaction handle; Each instance of L is independently a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, or substituted or unsubstituted C 2-200 heteroalkynylene, wherein:

[0223] Optionally, a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more carbons in each instance of heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and

[0224] Optionally, a substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more heteroatoms in each instance of heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0225] Each instance of W is independently a single bond, —O—, —S—, or —NR E - and; R E each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; each instance of W' is independently -O- or -S-; R 1 each instance of independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 is alkyl;

[0226] each instance of y is independently 0 or 1; If y is 0, [ka] is a single bond; If y is 1, [ka] is a single or double bond;

[0227] [ka] is a single bond, R 2 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) ORa , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0228] R a each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or R attached to the same nitrogen atom a when two of the following are joined to form a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl;

[0229] [ka] is a double bond, R 2 is absent; R 3 each instance of independently represents hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0230] R 4 each instance of independently represents hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)ORa , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0231] Or, y is 1, and [ka] is a single bond, R 3 and R 4 are joined with their intervening atoms to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; Or, y is 1, and [ka] is a double bond, R 3 and R 4 are cis to each other and joined with their intervening atoms to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Alternatively, R 4 and R 6 are joined with their intervening atoms to form a substituted or unsubstituted heterocyclyl;

[0232] [ka] is a single bond, R 5 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0233] [ka] is a double bond, R 5 is absent; R 6 each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; each instance of T is independently substituted or unsubstituted methylene; and Each instance of M is independently an ammonium or iminium salt of a pharmaceutical agent, wherein the point of attachment is at the N + is.

[0234] In another aspect, the present disclosure provides a compound of formula (III): [ka] (III) and salts thereof, During the ceremony:

[0235] D is a polymeric moiety, a dendrimeric moiety, an antibody, a particle, a bead, a nanostructure, a liposome, a micelle, or a vesicle; c is an integer between 1 and 1000 (inclusive); L J each instance of independently a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, or C 2-200 heteroalkynylene, wherein:

[0236] Optionally, a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and C 2-200 one or more carbons in the heteroalkynylene are independently replaced by a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; and

[0237] Optionally, a substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200one or more heteroatoms in the heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0238] For each E, E A E B is a moiety formed by reacting with; E A In each case, is the first reaction handle; E B is a second reaction handle, where the second reaction handle can react with the first reaction handle; Each instance of L is independently a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, or C 2-200 heteroalkynylene, wherein:

[0239] Optionally, a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and C 2-200 one or more carbons in each instance of heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and

[0240] Optionally, a substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more heteroatoms in each instance of heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0241] Each instance of W is independently a single bond, —O—, —S—, or —NR E - and; R E each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; each instance of W' is independently -O- or -S-; R 1 each instance of independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 is alkyl;

[0242] each instance of y is independently 0 or 1; If y is 0, [ka] is a single bond; If y is 1, [ka] is a single or double bond;

[0243] [ka] is a single bond, R 2 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0244] R a each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or R attached to the same nitrogen atom a when two of the following are joined to form a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl;

[0245] [ka] is a double bond, R 2 is absent; R 3 each instance of independently represents hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0246] R 4 each instance of independently represents hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0247] Or, y is 1, and [ka] is a single bond, R 3 and R 4 are joined with their intervening atoms to form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; Or, y is 1, and [ka] is a double bond, R 3 and R 4 are cis to each other and joined with their intervening atoms to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Alternatively, R 4 and R 6 are joined with their intervening atoms to form a substituted or unsubstituted heterocyclyl;

[0248] [ka] is a single bond, R 5 is hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0249] [ka] is a double bond, R 5 is absent; R 6each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; each instance of T is independently substituted or unsubstituted methylene; and Each instance of M is independently an ammonium or iminium salt of a pharmaceutical agent, wherein the point of attachment is at the N + is.

[0250] Unless otherwise provided, the moieties included in the conjugate of formula (III) are as described herein (eg, in the "Macromonomer" subsection). The compound may be conjugated to D, which may be a delivery vehicle, to form a conjugate. The conjugate may be useful, for example, for delivering pharmaceutical agents.

[0251] In some embodiments, D is a brush polymeric moiety or a brush-arm star polymeric moiety. In some embodiments, D is a nanoparticle or microparticle. In some embodiments, D is an antibody. In certain embodiments, at least one instance of E is a moiety formed by reacting two click chemistry handles (e.g., two orthogonal click chemistry handles). In certain embodiments, at least one instance of the click chemistry handle comprises C≡C or C═C. In certain embodiments, at least one instance of the click chemistry handle comprises C≡CH, C═CH, CH═CH, C═CH2, or CH═CH2. In certain embodiments, at least one instance of the click chemistry handle is -C≡CH, substituted or unsubstituted cyclooctynyl optionally and independently fused to one or more instances of substituted or unsubstituted phenyl, substituted or unsubstituted cyclopropenyl, substituted or unsubstituted cyclobutenyl, substituted or unsubstituted trans-cyclooctenyl optionally and independently fused to one or more instances of substituted or unsubstituted phenyl, or substituted or unsubstituted [ka] is. In some embodiments, each instance of the click chemistry handle is -C≡CH. In some embodiments, at least one instance of the click chemistry handle is -N3. In some embodiments, each instance of the click chemistry handle is -N3. In some embodiments, at least one instance of E is a single bond, -O-, -S-, -NR a -, -C(=O)O-, -C(=NR a )O-, -S(=O)O-, -S(=O)2O-, -C(=O)NR a -, -C(=NR a )NR a -, -S(=O)NR a -, -S(=O)2NR a -, -OC(=O)-, -OC(=NR a )-, -OS(=O)-, -OS(=O)2-, -NR a C(=O)-, -NR a C(=NR a )-, -NR a S(=O)-, -NR a S(=O)2-, -OC(=O)O-, -OC(=NR a )O-, -OS(=O)O-, -OS(=O)2O-, -NR a C(=O)O-, -NR a C(=NR a )O-, -NR a S(=O)O-, -NR a S(=O)2O-, -OC(=O)NR a -, -OC(=NR a )NR a -, -OS(=O)NR a -, -OS(=O)2NR a -, -NR a C(=O)NR a -, -NR a C(=NR a )NR a -, -NR a S(=O)NR a -, -NR a S(=O)2NR a -, -C(=O)-, -C(=NR a)-, -S(=O)-, or -S(=O)2-.

[0252] In some embodiments, at least one instance of E is: [ka] is. In some embodiments, at least one instance of E is: [ka] where the nitrogen atom labeled with "*" is closer to the attachment point labeled with "**" than to the attachment point labeled with "***". In some embodiments, each instance of E is [ka] is. In some embodiments, each instance of E is [ka] where the nitrogen atom labeled with "*" is closer to the attachment point labeled with "**" than to the attachment point labeled with "***".

[0253] In one embodiment, E A In at least one instance, E is a polymeric handle. A In at least one instance, E is an addition polymerization handle or a condensation polymerization handle. A In at least one instance, E is a metathesis polymerization handle. A In at least one case, substituted or unsubstituted C 2-6 Alkenyl, or substituted or unsubstituted C 2-6 In some embodiments, E is alkynyl. A is —OH, —NH 2 , —C(═O)OH, or —C(═O)H. AIn at least one of the cases, a nucleophile, an electrophile, a leaving group, a substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, -OH, -SH, -NHR a , -N3, -C(=O)OH, -C(=O)N(R a )2, -C(=NR a )OH, -S(=O)OH, -S(=O)2OH, -C(=O)-(leaving group), -C(=NR a )-(leaving group), -S(=O)-(leaving group), or -S(=O)2-(leaving group). In some embodiments, E A In at least one instance, E is a click chemistry handle. A is a click chemistry handle. A is -N3. In some embodiments, E A In each case, it is -N3.

[0254] In one embodiment, E B In at least one instance, E is a click chemistry handle. B is a click chemistry handle. B is —C≡CH. In some embodiments, E B is -C≡CH. In one embodiment, E A In each case of and E B are orthogonal click chemistry handles. A In each case, -N3 and E B In each case, -C≡CH.

[0255] In one embodiment, E B In at least one of the cases, a nucleophile, an electrophile, a leaving group, a substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, -OH, -SH, -NHRa , -N3, -C(=O)OH, -C(=O)N(R a )2, -C(=NR a )OH, -S(=O)OH, -S(=O)2OH, -C(=O)-(leaving group), -C(=NR a )-(leaving group), -S(=O)-(leaving group), or -S(=O)2-(leaving group).

[0256] In one embodiment, L J In at least one case, substituted or unsubstituted C 1-12 Alkylene, or substituted or unsubstituted C 2-12 In some embodiments, L is heteroalkylene. J In at least one case, substituted (e.g., halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a and / or oxo) or unsubstituted C 1-12 In some embodiments, L is alkylene. J In at least one case, substituted (e.g., halogen, substituted or unsubstituted C 1-6 Alkyl, -OR a and / or oxo) or unsubstituted C 2-12 In some embodiments, L is heteroalkylene. J In at least one case, there is a non-substituted C 1-6 In some embodiments, L is alkylene. J In each case, the unsubstituted C 1-6 In some embodiments, L is alkylene. J At least one instance (eg, each instance) of is —CH 2 —.

[0257] In some embodiments, c is an integer between 1 and 100 (e.g., 1 to 10, 11 to 30, 31 to 100), inclusive. In some embodiments, c is an integer between 100 and 300, inclusive. In some embodiments, c is an integer between 300 and 1000, inclusive. In some embodiments, the conjugate includes a salt thereof.

[0258] Methods for preparing macromonomers, compounds, and conjugates In another aspect, the present disclosure provides methods for preparing macromonomers and salts thereof. In an embodiment, the method for preparing a macromonomer, or a salt thereof, comprises: [ka] or a salt thereof, C or HN(R D )2, or a salt thereof. In certain embodiments, the coupling step is carried out in the presence of a reagent for coupling a carboxylic acid with an alcohol or an amine.

[0259] M can be conjugated to the macromonomer using any suitable conjugation technique, such as EDC-NHS chemistry (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide), or reactions involving maleimides or carboxylic acids that can be conjugated to one end of a thiol-, amine-, or similarly functionalized polyether. Conjugation can be carried out in organic solvents, such as, but not limited to, methylene chloride, acetonitrile, chloroform, dimethylformamide, tetrahydrofuran, acetone, and the like. Specific reaction conditions can be determined by one of ordinary skill in the art using only routine experimentation.

[0260] In another set of embodiments, conjugation reactions may be carried out by reacting an agent containing a hydroxyl, thiol, or amino group with a polymer containing a carboxylic acid functional group. Such reactions may occur as a single-step reaction, i.e., conjugation may be carried out with or without an intermediate such as N-hydroxysuccinimide or maleimide. In one embodiment, conjugation reactions between amine-, thiol-, or hydroxyl-containing moieties and carboxylic acid-terminated polymers can be achieved by adding the amine-, thiol-, or hydroxyl-containing moiety dissolved in an organic solvent, such as, but not limited to, dichloromethane, acetonitrile, chloroform, tetrahydrofuran, acetone, formamide, dimethylformamide, pyridine, dioxane, or dimethyl sulfoxide, to a solution containing the carboxylic acid-terminated polymer. The carboxylic acid-terminated polymer may be contained in an organic solvent, such as, but not limited to, dichloromethane, acetonitrile, chloroform, dimethylformamide, tetrahydrofuran, or acetone. The reaction between the amine-containing moiety and the carboxylic acid-terminated polymer may, in some cases, occur spontaneously. Unconjugated macromonomers may be washed away after such reactions and the polymer may be precipitated in a solvent such as, for example, ethyl ether, hexane, methanol or ethanol.

[0261] In some embodiments, the reagents for coupling carboxylic acids with alcohols or amines are N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC / HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), diethyl cyanophosphonate (DEPC), benzotriazol-1-yloxy-trispirrolizinophosphonium (DIPCI), benzotriazol-1-yloxy-trispirrolizinophosphonium hexafluorophosphate (PyBOP), 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopropyl azide (DMPA ... In some embodiments, the reagent for coupling a carboxylic acid with an alcohol or an amine is DCC. In certain embodiments, the reagent for coupling a carboxylic acid with an alcohol or an amine is EDC, or a salt thereof.

[0262] The reagent for coupling the carboxylic acid with the alcohol or amine is used in an amount of about 1 to 20 equivalents of the compound of Formula (D). In some embodiments, the reagent for coupling the carboxylic acid with the alcohol or amine is used in an amount of about 1 to 10 equivalents. In some embodiments, the activator is used in an amount of about 1 to 5 equivalents.

[0263] Examples of solvents useful in the coupling reaction are DMSO, DMF, and methylene chloride. Further exemplary solvents include acetonitrile, chloroform, tetrahydrofuran, and acetone. The coupling reaction can be carried out at 0 to 50° C. In one embodiment, the coupling reaction is carried out at room temperature for about 10 minutes to about 30 hours. In another embodiment, the coupling reaction is carried out for about 15 minutes to about 24 hours.

[0264] In another aspect, the present disclosure provides methods for preparing compounds and salts thereof. In some embodiments, the present disclosure provides methods for preparing compounds of formula (II), the methods comprising: [ka] or a salt thereof with a pharmaceutical agent in the presence of a halide, wherein R 8 is a halogen.

[0265] In some embodiments, the halide is an alkali metal iodide (eg, NaI). In some embodiments, R 8 is Cl. In some embodiments, the reacting step is carried out at a temperature of 20 to 40°C (inclusive). In some embodiments, the reacting step is carried out at a temperature of 40 to 80°C (inclusive). In some embodiments, the reacting step is carried out at a temperature of 50 to 70°C (inclusive). In some embodiments, the reacting step is carried out at a temperature of about 60°C.

[0266] In another aspect, the present disclosure provides a compound of formula (II'): [ka] (II') or a salt thereof, the method comprising: [ka] or a salt thereof with a pharmaceutical agent in the presence of a strong electrophile and a base at a temperature of 20° C. or less, wherein:

[0267] E A is the first reaction handle; L is a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, or substituted or unsubstituted C 2-200 is heteroalkynylene;

[0268] Optionally, a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more carbons in the heteroalkynylene are independently replaced by a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene;

[0269] Optionally, a substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more heteroatoms in the heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0270] W is a single bond, -O-, -S-, or -NR E - and; R E is hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; W' is -O-, -S- or -NR J - and; R J is hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group;

[0271] R K and R L each instance of independently represents hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0272] R a each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or R attached to the same nitrogen atom a when two of the following are joined to form a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl;

[0273] T is substituted or unsubstituted methylene; and M is an ammonium or iminium salt of a pharmaceutical agent, where the point of attachment is the N + is.

[0274] In some embodiments, the present disclosure provides a compound of formula (II'): [ka] (II') or a salt thereof, the method comprising: [ka] or a salt thereof with a pharmaceutical agent in the presence of a strong electrophile and a base at a temperature of 20° C. or less, wherein:

[0275] E A is the first reaction handle; L is a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, or C 2-200 heteroalkynylene,

[0276] Optionally, a substituted or unsubstituted C 1-200 Alkylene, substituted or unsubstituted C 2-200 Alkenylene, substituted or unsubstituted C 2-200 Alkynylene, substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and C 2-200 one or more carbons in the heteroalkynylene are independently replaced by a substituted or unsubstituted carbocyclylene, a substituted or unsubstituted heterocyclylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene;

[0277] Optionally, a substituted or unsubstituted C 2-200 Heteroalkylene, substituted or unsubstituted C 2-200 Heteroalkenylene, and substituted or unsubstituted C 2-200 one or more heteroatoms in the heteroalkynylene are independently replaced by substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0278] W is a single bond, -O-, -S-, or -NR E - and; R E is hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group; W' is -O-, -S- or -NR J - and; R J is hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group;

[0279] R K and R L each instance of independently represents hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR a , -N(R a )2, -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a )2, -C(=O)R a , -C(=O)OR a , -C(=O)N(R a )2, -NO2, -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a )2, -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a )2;

[0280] R a each instance of independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or R attached to the same nitrogen atom a when two of the following are joined to form a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl;

[0281] T is substituted or unsubstituted methylene; and M is an ammonium or iminium salt of a pharmaceutical agent, where the point of attachment is the N + is.

[0282] In some embodiments, the strong electrophile is a stronger electrophile than iodine. In some embodiments, the strong electrophile is a sulfonic acid anhydride or a sulfonyl halide. In some embodiments, the strong electrophile is a sulfonic acid anhydride (e.g., p-toluenesulfonic acid anhydride, methanesulfonic acid anhydride, p-bromobenzenesulfonic acid anhydride, O[S(=O)2(CF2)3CF3]2, or triflate anhydride. In some embodiments, the strong electrophile is a triflate. In some embodiments, the strong electrophile is triflate anhydride. In some embodiments, the strong electrophile is a sulfonyl halide (e.g., p-toluenesulfonyl halide, methanesulfonyl halide, p-bromobenzenesulfonyl halide, X[S(=O)2(CF2)3CF3], where X is a halogen, or triflic acid halide).

[0283] In some embodiments, the base is a tertiary non-aromatic amine or an aromatic amine that does not contain -NH-. In some embodiments, the base is a tertiary non-aromatic amine. In some embodiments, the base is a tertiary non-aromatic amine that does not contain -NH- or -NH2. In some embodiments, the base is an aromatic amine that does not contain -NH-. In some embodiments, the base is an aromatic amine that does not contain -NH- or -NH2. In some embodiments, the base is a trialkylamine (e.g., N,N-diisopropylethylamine).

[0284] In some embodiments, the temperature is 0 to 20°C (inclusive). In some embodiments, the temperature is -30 to 0°C (inclusive). In some embodiments, the temperature is -60 to -30°C (inclusive). In some embodiments, the temperature is -100 to -60°C (inclusive). In some embodiments, the temperature is -90 to -70°C (inclusive). In some embodiments, the temperature is about -78°C.

[0285] The method for preparing the compound of Formula (II') may be advantageous over reported methods that involve high temperatures (e.g., about 60°C) and / or iodide (e.g., iodide electrophiles such as NaI), which may cause decomposition of pharmaceutical agents. By using a strong electrophile (e.g., triflate) that is more electrophilic than iodide as a leaving group, the method for preparing the compound of Formula (II') may be able to reduce the temperature required to functionalize normally unstable pharmaceutical agents (e.g., with azides, using ammonium-based linker chemistry). For example, at about -78°C, JQ1, AZD5153, and vincristine were conjugated without significant decomposition by the method for preparing the compound of Formula (II'). An example is shown in the scheme below. [ka]

[0286] Brush Prodrugs (Polymers) and Methods for Preparing Brush Prodrugs In another aspect, the present disclosure provides brush prodrugs (polymers). In some embodiments, the brush prodrugs are prepared by polymerizing a macromonomer, or a salt thereof, in the presence of a metathesis catalyst. In some embodiments, at least one instance of M in a first macromonomer is different from at least one instance of M in a second macromonomer. In some embodiments, the metathesis catalyst is a transition metal metathesis catalyst (e.g., a ruthenium metathesis catalyst) or a Grubbs catalyst. In some embodiments, the metathesis catalyst has the formula: [ka] It is of the type.

[0287] Methods for preparing the brush prodrugs described herein may include ring-opening metathesis polymerization (ROMP) (Liu et al. J. Am. Chem. Soc. 2012, 134, 16337; Liu, J.; Gao, AX; Johnson, JA J Vis Exp 2013, e50874). In some embodiments, the brush prodrugs described herein are prepared by polymerization of norbornene-terminated macromonomers followed by in situ crosslinking with a bis-norbornene crosslinker. The preparation methods described herein are versatile and have few limitations regarding, for example, the variety of agents that can be incorporated into the brush prodrugs. In some embodiments, agents that can be incorporated into the brush prodrugs include addressable functional groups that are compatible with ROMP.

[0288] In some embodiments, the metathesis catalyst (e.g., the ROMP catalyst) is a tungsten (W), molybdenum (Mo), or ruthenium (Ru) catalyst. In some embodiments, the ROMP catalyst is a ruthenium catalyst. ROMP catalysts useful in the synthetic methods described herein include those described in, and in: Grubbs et al., Acc. Chem. Res. 1995, 28, 446-452; U.S. Pat. No. 5,811,515; Schrock et al., Organometallics (1982) 1 1645; Gallivan et al., Tetrahedron Letters (2005) 46:2577-2580; Furstner et al., J. Am. Chem. Soc. (1999) 121:9453; and Chem. Eur. J. (2001) 7:5299; the entire contents of each of which are incorporated herein by reference.

[0289] In some embodiments, the ROMP catalyst is a Grubbs catalyst. [ka] Benzylidenebis-(tricyclohexylphosphine)-dichlororuthenium (X=Cl); Benzylidenebis-(tricyclohexylphosphine)-dibromorthenium (X=Br); Benzylidenebis-(tricyclohexylphosphine)-diiodoruthenium (X=I); [ka] 1,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(tricyclohexyl-phosphine)ruthenium (X=Cl; R=cyclohexyl); 1,3-(bis(mesityl)-2-imidazolidinylidene)dibromo-(phenylmethylene)(tricyclohexyl-phosphine)ruthenium (X=Br; R=cyclohexyl); 1,3-(bis(mesityl)-2-imidazolidinylidene)diiodo-(phenylmethylene)(tricyclohexyl-phosphine)ruthenium (X=I; R=cyclohexyl); 1,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(triphenylphosphine)ruthenium (X=Cl; R=phenyl); 1,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(tribenzylphosphine)ruthenium (X=Cl; R=benzyl); [ka] [ka] is selected from the group consisting of:

[0290] In some embodiments, the ROMP catalyst is a Grubbs-Hoveyda catalyst. [ka] is selected from the group consisting of:

[0291] In some embodiments, the ROMP catalyst is [ka] [ka] is selected from the group consisting of:

[0292] In some embodiments, the ROMP catalyst has the formula: [ka] [ka] It is of the type.

[0293] ROMP can be carried out in one or more aprotic solvents. The term "aprotic solvent" refers to a non-nucleophilic solvent having a boiling point range of about 25°C to about 190°C above ambient temperature, preferably at atmospheric pressure. In some embodiments, the aprotic solvent has a boiling point of about 80°C to about 160°C at atmospheric pressure. In some embodiments, the aprotic solvent has a boiling point of about 80°C to about 150°C at atmospheric pressure. Examples of such solvents are methylene chloride, acetonitrile, toluene, DMF, diglyme, THF, and DMSO.

[0294] ROMP is the formula [ka] The compound can be quenched with a vinyl ether of R V1 , R V2 , R V3 and R V4 Each of R is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted carbocyclyl, an optionally substituted phenyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl. V1 is optionally substituted alkyl, and R V2 , R V3 and R V4 is hydrogen. In some embodiments, R V1 is unsubstituted alkyl, and R V2 , R V3 and R V4 is hydrogen. In some embodiments, R V1 is a substituted alkyl, and R V2 , R V3 and R V4 is hydrogen. In some embodiments, R V1 is methyl and R V2 , R V3 and R V4 is hydrogen. In some embodiments, R V1 is ethyl, and R V2 , R V3 and R V4is hydrogen. In some embodiments, R V1 is propyl, and R V2 , R V3 and R V4 is hydrogen. In some embodiments, R V1 is optionally substituted alkenyl, and R V2 , R V3 and R V4 is hydrogen. In some embodiments, R V1 is unsubstituted alkenyl, and R V2 , R V3 and R V4 is hydrogen. In some embodiments, R V1 is vinyl and R V2 , R V3 and R V4 is hydrogen. In some embodiments, R V1 , R V2 , R V3 and R V4 At least one of is conjugated to a diagnostic agent as defined above. In some embodiments, the ROMP is quenched with ethyl vinyl ether. Excess ethyl vinyl ether can be removed from the brush prodrug by vacuum.

[0295] In another aspect, the disclosure provides a method for preparing a brush prodrug.

[0296] Brush prodrugs can be described by a number of properties, including average molecular weight (kDa), mean hydrodynamic diameter (nm), and polydispersity. The term "average molecular weight" can include number average molecular weight (Mn), weight average molecular weight (Mw), higher average molecular weight (Mz or Mz+1), average molecular weight determined by GPC / SEC (Mp), and viscosity average molecular weight (Mv). In some embodiments, the average molecular weight is Mw. In some embodiments, Mn is determined by gel permeation chromatography, viscometry (via the Marc-Houwink equation), a colligative method (such as vapor pressure osmometry), end-group determination, or proton NMR. In some embodiments, Mw is determined by static light scattering, small-angle neutron scattering, X-ray scattering, and sedimentation velocity. In some embodiments, the average molecular weight of the brush prodrug is about 10 kDa to about 100 kDa, e.g., about 15 kDa to about 85 kDa, about 20 kDa to about 60 kDa, or about 30 kDa to about 50 kDa, e.g., as determined by gel permeation chromatography. In one embodiment, the average molecular weight of the brush prodrug is about 20 kDa to about 60 kDa. In one embodiment, the average molecular weight of the brush prodrug is about 30 kDa to about 50 kDa.

[0297] In some embodiments, the average molecular weight of the brush prodrug is less than about 100 kDa (e.g., less than about 95 kDa, about 90 kDa, about 85 kDa, about 80 kDa, about 75 kDa, about 70 kDa, about 65 kDa, about 60 kDa, about 55 kDa, or about 50 kDa), e.g., as determined by gel permeation chromatography. In some embodiments, the average molecular weight of the brush prodrug is less than about 75 kDa (e.g., less than about 70 kDa, about 65 kDa, about 60 kDa, about 55 kDa, or about 50 kDa). In some embodiments, the weight average molecular weight of the polymer is 3,000-1,000,000, 3,000-100,000, 3,000-10,000, 10,000-1,000,000, 10,000-100,000, or 100,000-1,000,000 (inclusive) g / mol. In some embodiments, the weight average molecular weight of the polymer is 10,000-30,000, 30,000-100,000, 100,000-300,000, or 300,000-1,000,000 (inclusive) g / mol. In some embodiments, the weight average molecular weight of the polymer is 30,000-300,000 (inclusive) g / mol.

[0298] In some cases, the brush prodrug is in the form of a particle (e.g., a nanoparticle, i.e., the particle has a characteristic dimension of less than about 1 micrometer). In some embodiments, the characteristic dimension of a particle is the diameter of a perfect sphere having the same volume as the particle. In some embodiments, the brush prodrug particle has a characteristic dimension of less than about 300 nm. In some embodiments, the brush prodrug particle has a characteristic dimension of less than about 200 nm. In some embodiments, the brush prodrug particle has a characteristic dimension of less than about 150 nm. In some embodiments, the brush prodrug particle has a characteristic dimension of less than about 100 nm. In some embodiments, the brush prodrug particle has a characteristic dimension of less than about 50 nm. In some embodiments, the brush prodrug particle has a characteristic dimension of less than about 30 nm. In some embodiments, the brush prodrug particle has a characteristic dimension of less than about 20 nm. In some embodiments, the brush prodrug particle has a characteristic dimension of less than about 10 nm. In some embodiments, the brush prodrug particle has a characteristic dimension of between 6 and 250 nm (inclusive). In some embodiments, the brush prodrug particles have a characteristic dimension of 8 to 200 nm (inclusive). In some embodiments, the brush prodrug particles have a characteristic dimension of 12 to 200 nm (inclusive). In some embodiments, the brush prodrug particles have a characteristic dimension of 50 to 200 nm (inclusive). The term "mean hydrodynamic diameter," as used herein, refers to the average size of the brush prodrug or particle. The mean hydrodynamic diameter may or may not include the solvation layer of the brush prodrug or particle and can be determined through a number of methods, including dynamic light scattering, electron microscopy (e.g., scanning electron microscopy, transmission electron microscopy), atomic force microscopy, and X-ray diffraction. In some embodiments, the average hydrodynamic diameter of the brush prodrug is less than 50 nm (e.g., less than about 45 nm, less than about 40 nm, less than about 35 nm, less than about 25 nm, less than about 20 nm, less than about 15 nm, less than about 10 nm, less than about 7.5 nm, or less), e.g., as determined by dynamic light scattering.In some embodiments, the average hydrodynamic diameter of the brush prodrug is about 1 nm to about 20 nm (e.g., about 2.5 nm to about 17.5 nm, or about 5 nm to about 15 nm). In some embodiments, the average hydrodynamic diameter of the brush prodrug is about 5 nm to about 15 nm.

[0299] In some embodiments, the average hydrodynamic diameter of the particles is less than 100 nm (e.g., about 90 nm, about 80 nm, about 75 nm, about 70 nm, about 65 nm, about 60 nm, about 55 nm, about 50 nm, about 45 nm, about 40 nm, about 35 nm, less than about 25 nm, or less), e.g., as determined by dynamic light scattering. In some embodiments, the average hydrodynamic diameter of the particles is about 5 nm to about 100 nm (e.g., about 7.5 nm to about 75 nm, about 10 nm to about 50 nm, about 12.5 nm to about 40 nm, or about 15 nm to about 30 nm). In some embodiments, the average hydrodynamic diameter of the particles is about 10 nm to about 50 nm. In some embodiments, the average hydrodynamic diameter of the particles is about 15 nm to about 30 nm.

[0300] The term "average polydispersity," as used herein, refers to a measure of the distribution of molecular sizes in a mixture, as determined, for example, by chromatographic methods such as gel permeation chromatography or molecular sieve chromatography, or through dynamic light scattering. In some embodiments, the average polydispersity of the brush prodrug or particle is less than about 0.5 (e.g., less than about 0.4, about 0.35, about 0.3, about 0.25, about 0.2, about 0.15, or less). In some embodiments, the average polydispersity of the brush prodrug or particle is less than about 0.3. In some embodiments, the average polydispersity of the brush prodrug or particle is less than about 0.2. In some embodiments, the average polydispersity of the brush prodrug or particle is less than about 0.15. In some embodiments, the brush prodrug or particle is monodisperse. In some embodiments, the brush prodrug or particle is about 50% monodisperse (e.g., about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 99.9% monodisperse).

[0301] In some embodiments, the brush prodrug or particle is substantially soluble in water (e.g., hydrophilic). In some embodiments, the brush prodrug or particle is substantially insoluble in water (e.g., hydrophobic). In some embodiments, the brush prodrug or particle is substantially insoluble in water, requiring more than about 10,000 parts water to dissolve one part polymer. In one embodiment, the brush prodrug or particle is amphiphilic. In one embodiment, the brush prodrug or particle comprises a segment that is hydrophobic and a segment that is hydrophilic.

[0302] Pharmaceutical Compositions and Kits The present disclosure provides compositions (e.g., pharmaceutical compositions) comprising a polymer described herein and, optionally, an excipient (e.g., a pharmaceutically acceptable excipient). The present disclosure also provides compositions (e.g., pharmaceutical compositions) comprising a conjugate described herein and, optionally, an excipient (e.g., a pharmaceutically acceptable excipient). In some embodiments, the pharmaceutical compositions described herein comprise a polymer described herein and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions described herein comprise a conjugate described herein and a pharmaceutically acceptable excipient.

[0303] In some embodiments, the pharmaceutical composition is useful for delivering an agent (e.g., to a subject or a cell). In some embodiments, the pharmaceutical composition is useful for treating a disease in a subject in need thereof. In some embodiments, the pharmaceutical composition is useful for preventing a disease in a subject.

[0304] In some embodiments, the polymer or conjugate described herein is provided in an effective amount in a pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount. In some embodiments, the effective amount is an amount effective to treat a proliferative disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective to prevent a proliferative disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective to treat a hematological disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective to prevent a hematological disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective to treat a neurological disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective to prevent a neurological disease in a subject in need thereof. In some embodiments, the effective amount is an amount effective to treat a painful condition in a subject in need thereof. In some embodiments, the effective amount is an amount effective to prevent a painful condition in a subject in need thereof. In some embodiments, the effective amount is an amount effective to treat a psychiatric disorder in a subject in need thereof. In some embodiments, an effective amount is an amount effective to prevent a psychiatric disorder in a subject in need thereof. In some embodiments, an effective amount is an amount effective to treat a metabolic disorder in a subject in need thereof. In some embodiments, an effective amount is an amount effective to prevent a metabolic disorder in a subject in need thereof. In some embodiments, an effective amount is an amount effective to reduce the risk of developing a disease (e.g., a proliferative disease, a blood disease, a neurological disease, a painful condition, a psychiatric disorder, or a metabolic disorder) in a subject in need thereof. In some embodiments, an effective amount is an amount effective to inhibit the activity (e.g., abnormal activity, such as increased activity) of a protein kinase in a subject or cell.

[0305] In some embodiments, the cell is in vitro. In some embodiments, the cell is in vivo. The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacy. Generally, such preparative methods include bringing into association a polymer or conjugate described herein, which may include a therapeutic agent ("active ingredient"), with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into the desired single or multiple dosage unit.

[0306] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses. A "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject, and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0307] The amount of active ingredient, pharmaceutically acceptable excipient, and / or any additional material in the pharmaceutical compositions described herein will vary depending on the identity, size, and / or condition of the subject being treated, and further depending on the route of administration by which the composition is to be administered. The compositions may contain from 0.1% to 100% (w / w) of the active ingredient.

[0308] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants and / or fats. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents and fragrances may also be present in the compositions.

[0309] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0310] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation exchange resins, calcium carbonate, silicic acid, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0311] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan monostearate (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate, (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone),Diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, doxate sodium, and / or mixtures thereof.

[0312] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, isapol crust mucilage, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabinogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0313] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal preservatives, alcoholic preservatives, acidic preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0314] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0315] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0316] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcoholic preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol. Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0317] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0318] Exemplary buffering agents include citrate buffer solution, acetate buffer solution, phosphate buffer solution, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0319] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0320] Exemplary natural oils and fats include almond oil, apricot kernel oil, avocado oil, bassau oil, bergamot oil, blackcurrant seed oil, borage oil, cade oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon bark oil, cocoa butter oil, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol oil, gourd oil, grape seed oil, hazelnut oil, hyssop oil, and myristin. isopropyl betaine oil, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, lily of the valley oil, macadamia nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange roughy oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasquana oil, savory oil, sea buckthorn oil, sesame oil, shea butter oil, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil, and wheat germ oil. Exemplary synthetic oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0321] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active ingredients, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and fragrances. In some embodiments, for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0322] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated using suitable dispersing or wetting agents and suspending agents according to known techniques.Sterile injectable preparations can be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol.Among acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution.In addition, sterile fixed oils are commonly used as solvents or suspending media.For this purpose, any bland fixed oil can be used, including synthetic mono- or di-triglycerides.In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0323] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0324] In order to prolong the effect of drugs, it is often desirable to slow down the absorption of drugs from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of drugs is therefore dependent on the dissolution rate, which can also depend on the size of plasma and crystalline form.Alternatively, the delayed absorption of parenterally administered drugs can be achieved by dissolving or suspending the drug in an oily vehicle.

[0325] Compositions for rectal or vaginal administration are typically suppositories, which can be prepared by mixing the conjugates described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active ingredient.

[0326] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) solution retarding agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) humectants such as, for example, cetyl alcohol and glycerol monostearate; (h) absorbents such as kaolin and bentonite clay; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0327] Solid compositions of similar type can be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical arts.They can optionally contain opacifying agents and can be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner.Examples of encapsulating compositions that can be used include polymeric substances and waxes.Solid compositions of similar type can be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0328] The active ingredient can be microencapsulated with one or more excipients as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active ingredient can be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is commonly practiced. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and be of a composition that releases the active ingredient only, or preferentially, in a specific part of the intestinal tract, optionally in a delayed manner. Examples of encapsulating agents that can be used include polymeric substances and waxes.

[0329] Dosage forms for topical and / or transdermal administration of the polymers or conjugates described herein can include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient, and / or any needed preservatives and / or buffers, if required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of the active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispersing the active ingredient in a suitable medium. Alternatively, or additionally, the rate can be controlled by providing a rate-controlling membrane and / or dispersing the active ingredient in a polymer matrix and / or gel.

[0330] Suitable devices for use in delivering the intradermal pharmaceutical compositions described herein include short needle devices.Intradermal compositions can be administered by devices that limit the effective penetration length of needles into the skin.Alternatively, or in addition, conventional syringes can be used in the classic Mantoux method of intradermal administration.Jet injection devices are suitable, which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle that creates a jet that penetrates the stratum corneum and reaches the dermis.Ballistic powder / particle delivery devices are suitable, which use compressed gas to accelerate polymers or conjugates in powder form through the outer layer of skin to the dermis.

[0331] Suitable formulations for topical administration include liquid and / or semi-liquid preparations, such as liniments, lotions, oil-in-water and / or water-in-oil emulsions, such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may contain, for example, about 1% to about 10% (w / w) of the active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further include one or more of the additional ingredients described herein.

[0332] The pharmaceutical compositions described herein can be prepared, packaged, and / or sold in formulations suitable for pulmonary administration via the buccal cavity. Such formulations may comprise dry particles containing the active ingredient having a diameter ranging from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of a dry powder for administration using a device containing a dry powder reservoir capable of directing a propellant stream to disperse the powder, and / or using a self-propelled solvent / powder dispersing vessel (such as a device containing the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed vessel). Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid particulate diluent such as sugar and are conveniently provided in a unit dose form.

[0333] Low boiling point propellants generally include liquid propellants having a boiling point below 65°F at atmospheric pressure. Generally, the propellant may comprise 50-99.9% (w / w) of the composition, and the active ingredient may comprise 0.1-20% (w / w) of the composition. The propellant may further comprise additional materials such as liquid nonionic and / or solid anionic surfactants and / or solid diluents (which may have particle sizes on the same order as the particles containing the active ingredient).

[0334] Pharmaceutical compositions formulated for pulmonary delivery described herein can provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, containing the active ingredient, and can be conveniently administered using any inhalation and / or atomization device. Such formulations may further contain one or more additional ingredients, including flavoring agents such as sodium saccharin, volatile oils, buffers, surfactants, and / or preservatives such as methyl hydroxybenzoate. The droplets provided by this route of administration can have an average diameter in the range of about 0.1 to about 200 nanometers.

[0335] The formulations described herein as useful for pulmonary delivery are also useful for intranasal delivery of the pharmaceutical compositions described herein. Another formulation suitable for intranasal administration is a coarse powder containing the active ingredient, having an average particle size of about 0.2 to 500 micrometers. Such formulations are administered by rapid inhalation through the nasal passages from a container of the powder held near the nostrils.

[0336] Formulations for nasal administration may contain, for example, as little as about 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may include one or more of the additional ingredients described herein. The pharmaceutical compositions described herein can also be prepared, packaged, and / or sold in formulations for buccal administration. Such formulations may be, for example, in the form of tablets and / or lozenges prepared using conventional methods and may contain, for example, 0.1 to 20% (w / w) of the active ingredient, the balance being an orally dissolvable and / or disintegrable composition, and optionally one or more of the additional ingredients described herein. Alternatively, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension containing the active ingredient. Such powdered, aerosolized and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range of about 0.1 to about 200 nanometers and may further comprise one or more of the additional materials described herein.

[0337] The pharmaceutical compositions described herein can be prepared, packaged, and / or sold in formulations for ocular administration. Such formulations can be, for example, in the form of eye drops, comprising, for example, a 0.1-1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional materials described herein. Other useful ophthalmically administrable formulations include those comprising the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of the present disclosure.

[0338] Although the description of pharmaceutical compositions provided herein is directed primarily to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to animals of all kinds. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and a veterinary pharmacologist of ordinary skill can design and / or make such modifications with routine experimentation.

[0339] The polymer provided herein is typically formulated in dosage units for ease of administration and uniformity of dosage.However, it will be understood that the total daily use of the compositions described herein will be determined by a physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism will depend on a variety of factors, including the severity of the disease and disorder being treated; the activity of the specific active ingredient used; the specific composition used; the age, weight, general health, sex and diet of the subject; the time of administration, route of administration and the excretion rate of the specific active ingredient used; the duration of treatment; the drugs used in combination with or simultaneously with the specific active ingredient used; and similar factors well known in the field of medicine.

[0340] The polymers, conjugates, and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, vaginal, intraperitoneal, topical (such as by powder, ointment, cream, and / or drops), mucosal, nasal, buccal, sublingual; intratracheal instillation, bronchial instillation, and / or inhalation; and / or oral spray, nasal spray, and / or aerosol. Particularly contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymphatic replenishment, and / or direct administration to the affected site. Generally, the most appropriate route of administration will depend on various factors, including the nature of the agent (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In certain embodiments, the polymers, conjugates, or pharmaceutical compositions described herein are suitable for topical administration to the eye of a subject.

[0341] The exact amount of polymer or conjugate required to achieve an effective dose will vary from subject to subject, depending, for example, on the subject's species, age, and general condition, the severity of side effects or disorders, the identity of the particular polymer or conjugate, the mode of administration, etc. An effective amount may be contained in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In some embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses contain different or substantially the same amounts of a polymer or conjugate described herein. In some embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency with which the multiple doses are administered to a subject or applied to a tissue or cell is three doses per day, two doses per day, one dose per day, one dose per two days, one dose per three days, one dose per week, one dose per two weeks, one dose per three weeks, or one dose per four weeks. In some embodiments, the frequency with which the multiple doses are administered to a subject or applied to a tissue or cell is one dose per day. In some embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to tissue or cells is two doses per day. In some embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to tissue or cells is three doses per day. In some embodiments, when multiple doses are administered to a subject or applied to tissue or cells, the period between the first dose and the last dose of the multiple doses is 1 day, 2 days, 4 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years, 10 years, 15 years, 20 years, or the lifespan of the subject, tissue or cell. In some embodiments, the period between the first dose and the last dose of the multiple doses is 3 months, 6 months, or 1 year. In some embodiments, the period between the first dose and the last dose of the multiple doses is the lifespan of the subject, tissue or cell.In some embodiments, the doses described herein (e.g., a single dose, or any of the multiple doses) independently comprise 0.1 μg to 1 μg, 0.001 mg to 0.01 mg, 0.01 mg to 0.1 mg, 0.1 mg to 1 mg, 1 mg to 3 mg, 3 mg to 10 mg, 10 mg to 30 mg, 30 mg to 100 mg, 100 mg to 300 mg, 300 mg to 1,000 mg, or 1 g to 10 g, inclusive, of a polymer or conjugate described herein. In some embodiments, the doses described herein independently comprise 1 mg to 3 mg, inclusive, of a polymer or conjugate described herein. In some embodiments, the doses described herein independently comprise 3 mg to 10 mg, inclusive, of a polymer or conjugate described herein. In some embodiments, the doses described herein independently comprise between 10 mg and 30 mg (inclusive) of a polymer or conjugate described herein. In some embodiments, the doses described herein independently comprise between 30 mg and 100 mg (inclusive) of a polymer or conjugate described herein.

[0342] The dosage ranges provided herein provide guidance for the administration of provided pharmaceutical compositions to adults.For example, the amount to be administered to children or adolescents can be determined by a doctor or person skilled in the art, and can be lower than or the same as that administered to adults.In some embodiments, the dosages described herein are the dosages for adult humans with a body weight of 70 kg.

[0343] The polymers, conjugates, or compositions described herein can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The polymers, conjugates, or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., efficacy and / or potency) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk of developing a disease in a subject in need thereof, and / or in inhibiting the activity of a protein kinase in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be understood that the treatments used may achieve the desired effect for the same disorder and / or may achieve different effects. In certain embodiments, pharmaceutical compositions described herein comprising a polymer or conjugate described herein and an additional pharmaceutical agent exhibit a synergistic effect that is absent in pharmaceutical compositions comprising one of the polymer / conjugate and the additional pharmaceutical agent, but not both.

[0344] The polymer, conjugate, or composition can be administered simultaneously with, prior to, or subsequent to one or more additional pharmaceutical agents different from the polymer, conjugate, or composition, which may be useful, for example, as a combination therapy. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration, as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In some embodiments, the additional pharmaceutical agents are pharmaceutical agents useful for treating and / or preventing diseases (e.g., proliferative diseases, blood disorders, neurological disorders, painful conditions, psychiatric disorders, or metabolic disorders). Each additional pharmaceutical agent may be administered at a dose and / or time schedule determined for the pharmaceutical agent. The additional pharmaceutical agents may also be administered in a single dose, together with each other and / or with the polymers, conjugates, or compositions described herein, or may be administered separately in different doses. The particular combination to be used in a regimen will take into consideration the compatibility of the polymer or conjugate described herein with the additional pharmaceutical agent and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agents in the combination should be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in the combination will be lower than those used individually.

[0345] The additional pharmaceutical agent may include an antiproliferative agent, an anticancer agent, a cytotoxic agent, an antiangiogenic agent, an anti-inflammatory agent, an immunosuppressant, an antibacterial agent, an antiviral agent, a cardiovascular agent, a cholesterol-lowering agent, an antidiabetic agent, an antiallergic agent, a contraceptive agent, and a pain-relieving agent. In some embodiments, the additional pharmaceutical agent is an antiproliferative agent. In some embodiments, the additional pharmaceutical agent is an anticancer agent. In some embodiments, the additional pharmaceutical agent is an antiviral agent. In some embodiments, the additional pharmaceutical agent is a protein kinase binder or inhibitor. In some embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modifiers (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), mitotic inhibitors (e.g., taxanes and vinca alkaloids), hormone receptor modifiers (e.g., estrogen receptor modifiers and androgen receptor modifiers), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), protein stability modifiers (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other agents that promote differentiation. In some embodiments, the polymers or conjugates or pharmaceutical compositions described herein can be administered in combination with anti-cancer treatments, including surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.

[0346] Also encompassed by the present disclosure are kits (e.g., pharmaceutical packs). In some embodiments, the kit includes a macromonomer, or a salt thereof, a brush prodrug, or a pharmaceutical composition; and instructions for using the macromonomer, or a salt thereof, a polymer, a conjugate, or a pharmaceutical composition.

[0347] In some embodiments, the kit comprises a compound, or a salt thereof; and instructions for using the compound or salt. In some embodiments, the kit comprises a compound; and instructions for using the compound. In some embodiments, the kit comprises the conjugate, or a salt thereof, or a pharmaceutical composition; and instructions for using the conjugate, or a salt thereof, or a pharmaceutical composition.

[0348] The provided kits may include a pharmaceutical composition, conjugate, or polymer described herein and a container (e.g., a vial, ampoule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the provided kits may optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition, conjugate, or polymer described herein. In some embodiments, the pharmaceutical composition, conjugate, or polymer described herein provided in a first container and the second container are combined to form a single unit dosage form.

[0349] In some embodiments, the percentage of conjugate (e.g., in a particle) that comprises an agent is about 1 to about 100% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%). In some embodiments, the percentage of conjugate that comprises an agent is less than about 50%, e.g., less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, about 15%, or less than about 10%. In some embodiments, the percentage of conjugate (e.g., in a particle) that comprises an agent is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 25%, or about 5% to about 20%. In some embodiments, the percentage of the conjugate (e.g., in a particle) that comprises the agent is about 5% to about 90%. In some embodiments, the percentage of the conjugate (e.g., in a particle) that comprises the agent is about 5% to about 75%. In some embodiments, the percentage of the conjugate (e.g., in a particle) that comprises the agent is about 5% to about 50%. In some embodiments, the percentage of the conjugate (e.g., in a particle) that comprises the agent is about 10% to about 25%.

[0350] In some embodiments, the total amount of agent present in the brush prodrug or particle is greater than about 5% (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 12%, about 15%, about 20%, about 25%, about 30%, or more) of the total size or weight of the brush prodrug or particle. In some embodiments, the total amount of agent present in the brush prodrug or particle is greater than about 10% (e.g., about 12%, about 15%, about 20%, about 25%, about 30%, or more) of the total size or weight of the brush prodrug or particle.

[0351] Without being bound by theory, the conjugates or particles disclosed herein can improve the efficacy of an agent by one or more of increasing the localization and / or release (e.g., preferential release) of the agent to target cells (e.g., cancer cells or fibrotic cells; cells associated with a hypoxic environment) or prolonging the half-life of the agent, thereby resulting in the release of a significantly higher amount of agent at the target site (e.g., tumor (e.g., cirrhotic cells) in the liver). Thus, the conjugates and particles disclosed herein can be more therapeutically effective than the free agent (e.g., due to enhanced drug uptake in the target tissue) and / or allow for lower therapeutic doses of the agent, e.g., without substantially compromising the resulting drug concentration in the target tissue. In some embodiments, the conjugates and particles disclosed herein can reduce adverse effects associated with systemic administration of the agent in its free form (e.g., not coupled to a polymer, conjugate, brush prodrug, or particle described herein).

[0352] Without being bound by theory, due to the localized delivery of the compositions (e.g., particles containing an agent) described herein, a lower dose or amount of agent can be administered in the particle compared to the agent in free form (e.g., through localized sustained delivery). In other embodiments, the particles containing an agent are administered at a dose or amount of agent that is lower than the dose or amount of the agent in free form to have a desired effect (e.g., a desired therapeutic effect).

[0353] In some embodiments, the agent is incorporated into the particle at a dose or amount lower than the standard care dose of the agent in free form, for example, a dose lower than the standard care dose of the free agent for the intended use, to achieve a desired effect (e.g., a desired therapeutic effect).In one embodiment, the agent is incorporated into the particle at a dose or amount lower than the standard care dose of the agent for the desired treatment (e.g., about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 0.95 lower than the standard care dose of the agent).

[0354] In some embodiments, the agent is incorporated into the particle at a dose or amount of the agent in free form, for example, a dose equivalent to the standard care dose for the intended use of the free agent, to have a desired effect (e.g., a desired therapeutic effect).In these embodiments, the particle provides a higher therapeutic effect and / or a lower adverse effect than the free agent.In some embodiments, the particle increases the amount of agent delivered to tissues or cells that require it and reduces the amount of agent exposed to non-target tissues or cells compared to the free agent.

[0355] In some embodiments, the agent is incorporated into the particle at a dose or amount higher than the standard dose of the agent in free form, for example, the standard care dose for the intended use of the free agent, to have a desired effect (e.g., a desired therapeutic effect). In some embodiments, the agent is incorporated into the particle at a dose or amount higher than the dose or amount of the agent in free form that would cause adverse effects (e.g., a decrease in blood pressure) upon systemic administration. In some embodiments, the particles described herein release the agent at the target site based on the pH microenvironment, so that other non-target sites (e.g., blood vessels) with a different pH are less likely to be exposed to the agent.

[0356] In another aspect, provided is a kit comprising a first container containing a polymer or pharmaceutical composition described herein. In some embodiments, the kit further comprises instructions for using the polymer or pharmaceutical composition. In another aspect, provided is a kit comprising a first container containing a compound described herein. In some embodiments, the kit further comprises instructions for using the compound. In another aspect, provided is a kit comprising a first container containing a conjugate, or a salt thereof, or a pharmaceutical composition described herein. In some embodiments, the kit further comprises instructions for using the conjugate or pharmaceutical composition.

[0357] In some embodiments, the kit is useful for delivering an agent (e.g., to a subject or cell). In some embodiments, the kit is useful for treating a disease (e.g., a proliferative disease, a hematological disease, a neurological disease, a painful condition, a psychiatric disorder, or a metabolic disorder) in a subject in need thereof. In some embodiments, the kit is useful for preventing a disease (e.g., a proliferative disease, a hematological disease, a neurological disease, a painful condition, a psychiatric disorder, or a metabolic disorder) in a subject in need thereof. In some embodiments, the kit is useful for reducing the risk of developing a disease (e.g., a proliferative disease, a hematological disease, a neurological disease, a painful condition, a psychiatric disorder, or a metabolic disorder) in a subject in need thereof. In some embodiments, the kit is useful for inhibiting the activity (e.g., abnormal activity, such as increased activity) of a protein kinase in a subject or cell.

[0358] In some embodiments, the kits described herein further include instructions for using the kit. The kits described herein may also include information as required by regulatory authorities, such as the U.S. Food and Drug Administration (FDA). In some embodiments, the information included in the kit is prescribing information. In some embodiments, the kit and instructions provide for delivery of an agent. In some embodiments, the kit and instructions provide for treating a disease (e.g., a proliferative disease, a hematological disease, a neurological disease, a painful condition, a psychiatric disorder, or a metabolic disorder) in a subject in need thereof. In some embodiments, the kit and instructions provide for preventing a disease (e.g., a proliferative disease, a hematological disease, a neurological disease, a painful condition, a psychiatric disorder, or a metabolic disorder). In some embodiments, the kit and instructions provide for reducing the risk of developing a disease (e.g., a proliferative disease, a hematological disease, a neurological disease, a painful condition, a psychiatric disorder, or a metabolic disorder) in a subject in need thereof. In some embodiments, the kit and instructions provide for inhibiting the activity (e.g., abnormal activity, such as increased activity) of a protein kinase in a subject or cell. The kits described herein may also include one or more additional pharmaceutical agents described herein as separate compositions.

[0359] Method and use The present disclosure also provides methods of using the polymers described herein, or pharmaceutical compositions thereof, for the delivery of agents. The present disclosure also provides methods of using the polymers described herein, or pharmaceutical compositions thereof, for the treatment or prevention of diseases. In some embodiments, the disease is a proliferative disease, a blood disease, a neurological disease, a painful condition, a psychiatric disorder, or a metabolic disorder. In some embodiments, the disease is cancer (e.g., lung cancer, colon cancer, pancreatic cancer, bile duct cancer, or endometrial cancer), a benign neoplasm, angiogenesis, an inflammatory disease, an autoinflammatory disease, or an autoimmune disease. In some embodiments, the polymer is useful for the treatment or prevention of a disease, in part because at least one of the pharmaceutical agents contained in the polymer is useful for the treatment or prevention of the disease. In some embodiments, the polymer is more advantageous for the treatment or prevention of a disease than at least one of the pharmaceutical agents, in part because the polymer improves (e.g., increases) the delivery of at least one of the pharmaceutical agents to a subject (e.g., to a target organ, tissue, or cell of the subject).

[0360] In another aspect, the present disclosure provides a method of delivering a pharmaceutical agent to a subject in need thereof, the method comprising administering to a subject in need thereof a polymer or pharmaceutical composition. In another aspect, the disclosure provides a method of delivering a pharmaceutical agent to a cell, the method comprising contacting the cell with a polymer or pharmaceutical composition.

[0361] In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to or implanting into a subject in need thereof a therapeutically effective amount of a polymer or pharmaceutical composition; wherein at least one of the pharmaceutical agents is a therapeutic agent. In another aspect, the disclosure provides a method of preventing disease in a subject in need thereof, the method comprising administering to or implanting into a subject in need thereof a prophylactically effective amount of a polymer or pharmaceutical composition; wherein at least one of the pharmaceutical agents is a prophylactic agent.

[0362] In another aspect, the present disclosure provides a method for diagnosing a disease in a subject, the method comprising administering to or implanting into the subject a diagnostically effective amount of a polymer or pharmaceutical composition; wherein at least one of the pharmaceutical agents is a diagnostic agent. In some embodiments, the polymer is useful for diagnosing a disease. This is in part because at least one of the pharmaceutical agents contained in the polymer is useful for diagnosing a disease. In some embodiments, the polymer is more advantageous for diagnosing a disease than at least one of the pharmaceutical agents. This is in part because the polymer improves (e.g., increases) delivery of at least one of the pharmaceutical agents to the subject (e.g., to a target organ, tissue, or cell of the subject).

[0363] The present disclosure also provides methods of using the conjugates described herein, or pharmaceutical compositions thereof, to deliver an agent. The present disclosure also provides methods of using the conjugates described herein, or pharmaceutical compositions thereof, for the treatment or prevention of a disease.

[0364] In some embodiments, the disease is a proliferative disease, a blood disease, a neurological disease, a painful condition, a psychiatric disorder, or a metabolic disorder. In some embodiments, the disease is a proliferative disease. In some embodiments, the disease is a proliferative disease, and at least one of the pharmaceutical agents is an anti-proliferative agent. In some embodiments, the disease is cancer (e.g., lung cancer, colon cancer, pancreatic cancer, bile duct cancer, or endometrial cancer), a benign neoplasm, angiogenesis, an inflammatory disease, an autoinflammatory disease, or an autoimmune disease. In some embodiments, the disease is cancer. In some embodiments, the disease is cancer, and at least one of the pharmaceutical agents is an anti-cancer agent.

[0365] In another aspect, the present disclosure provides a method of delivering a pharmaceutical agent to a subject in need thereof, the method comprising administering to a subject in need thereof the conjugate or pharmaceutical composition. In another aspect, the disclosure provides a method of delivering a pharmaceutical agent to a cell, the method comprising contacting the cell with the conjugate or pharmaceutical composition.

[0366] In another aspect, the disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to or implanting into a subject in need thereof a therapeutically effective amount of a conjugate or pharmaceutical composition; wherein at least one of the pharmaceutical agents is a therapeutic agent. In another aspect, the disclosure provides a method of preventing disease in a subject in need thereof, the method comprising administering to or implanting into a subject in need thereof a prophylactically effective amount of a conjugate or pharmaceutical composition; wherein at least one of the pharmaceutical agents is a prophylactic agent. In another aspect, the disclosure provides a method of diagnosing a disease in a subject, the method comprising administering to or implanting into the subject a diagnostically effective amount of a conjugate or pharmaceutical composition; wherein at least one of the pharmaceutical agents is a diagnostic agent.

[0367] In certain embodiments, the conjugate is useful for treating, preventing, or diagnosing a disease, in part because at least one of the pharmaceutical agents contained in the conjugate is useful for treating, preventing, or diagnosing a disease. In certain embodiments, the conjugate is more advantageous for treating, preventing, or diagnosing a disease than at least one of the pharmaceutical agents, in part because the conjugate improves (e.g., increases) delivery of at least one of the pharmaceutical agents to a subject (e.g., to a target organ, tissue, or cell of the subject).

[0368] In some embodiments, the polymers or conjugates described herein, or pharmaceutical compositions thereof, are useful in treating cancer. In some embodiments, the polymers or conjugates described herein, or pharmaceutical compositions thereof, are useful for delaying the onset, slowing the progression, or ameliorating symptoms of cancer. In some embodiments, the polymers or conjugates described herein, or pharmaceutical compositions thereof, are administered in combination with other compounds, drugs, or therapeutic agents to treat cancer.

[0369] In some embodiments, the polymers or conjugates described herein, or pharmaceutical compositions thereof, are useful for treating cancers, including, but not limited to, acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, angiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary tract cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast carcinoma, medullary carcinoma), brain cancer (e.g., meningioma; Glioma (e.g., normocytoma, oligodendroglioma; medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine carcinoma, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familial hypereosinophilia, gallbladder cancer, gastric cancer (e.g., , gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC)), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal carcinoma, oropharyngeal cancer)), hematopoietic cancer (e.g., leukemia, e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL);Lymphomas, such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL, e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., , "Waldenstrom's hypergammaglobulinemia"), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more leukemias / lymphomas as above;and multiple myeloma), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., systemic hypertension, Myelodysplastic syndromes (MDS), mesothelioma, myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibromas (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis), neuroendocrine carcinomas (e.g., , gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., adenocarcinoma of the pancreas, intraductal papillary mucinous neoplasm (IPMN), pancreatic islet tumor), penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., adenocarcinoma of the prostate), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), Keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC), small intestine cancer (e.g., appendix cancer), soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovium, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva);

[0370] In some embodiments, the polymers or conjugates described herein, or pharmaceutical compositions thereof, are useful in treating lung cancer, head and neck cancer, esophageal cancer, gastric cancer, breast cancer, pancreatic cancer, liver cancer, kidney cancer, prostate cancer, glioblastoma, metastatic melanoma, peritoneal or pleural mesothelioma.

[0371] In some embodiments, the proliferative disease is a benign neoplasm. All types of benign neoplasms disclosed herein or known in the art are contemplated as being within the scope of the present invention. In some embodiments, the proliferative disease is associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are contemplated as being within the scope of the present invention. In some embodiments, the proliferative disease is an inflammatory disease. All types of inflammatory diseases disclosed herein or known in the art are contemplated as being within the scope of the present invention. In some embodiments, the inflammatory disease is rheumatoid arthritis. In some embodiments, the proliferative disease is an autoinflammatory disease. All types of autoinflammatory diseases disclosed herein or known in the art are contemplated as being within the scope of the present invention. In some embodiments, the proliferative disease is an autoimmune disease. All types of autoimmune diseases disclosed herein or known in the art are contemplated as being within the scope of the present invention.

[0372] In some embodiments, the methods described herein comprise administering to a subject an effective amount of a polymer or conjugate described herein or a pharmaceutical composition thereof. In some embodiments, the methods described herein comprise implanting into a subject an effective amount of a polymer or conjugate described herein or a pharmaceutical composition thereof.

[0373] In some embodiments, the polymer or conjugate described herein or its pharmaceutical composition is administered in combination with one or more additional pharmaceutical agents described herein. In some embodiments, the additional pharmaceutical agent is an anti-cancer agent. Anti-cancer agents include biotherapy anti-cancer agents and chemotherapeutic agents. Exemplary biotherapy anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serum therapy, immunostimulatory and / or immunomodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g., Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexar (tositumomab)). Exemplary chemotherapeutic agents include, but are not limited to, antiestrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g., goserelin and leuprolide), antiandrogens (e.g., flutamide and bicalutamide), photodynamic therapy (e.g., verteporfin (BPD-MA), phthalocyanines, photosensitizer Pc4, and demethoxy-hypocrelin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, isophosphamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosamines (e.g., nitrosamines), and nitrosamines. Rosourea (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulfonates (e.g., busulfan and treosulfan), triazenes (e.g., dacarbazine, temozolomide), platinum-containing compounds (e.g., cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g., paclitaxel or paclitaxel equivalents, such as nanoparticle albumin-bound paclitaxel (Abraxane), docosahexaenoic acid-bound paclitaxel (DHA-paclitaxel,Taxoprexin®), polyglutamic acid-conjugated paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 conjugated to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel conjugated to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllin (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, anti-inflammatory drugs (e.g., cyclosporine, camptoirinotecan, irinotecan, crisnatol, mitomycin C), antimetabolites, DHFR inhibitors (e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonucleotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, raltitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g., cytarabine (arabinan), C), cytosine arabinoside, and fludarabine), purine analogs (e.g., mercaptopurine and thioguanine), vitamin D3 analogs (e.g., EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycins (e.g., actinomycin D, dactinomycin), bleomycins (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracyclines (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca, 2+ATPase inhibitors (e.g., thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), ibuprofen (IFN-γ), rifafloxacin (RIBA ... Matinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), )), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK / ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe), and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbazine, prednisolone, dexamethasone, camptothecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurocidin, leurocin, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethylmelamine.

[0374] example In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described herein are offered to illustrate the disclosure and are not to be construed as limiting the scope thereof in any way.

[0375] Preparation and Characterization of Exemplary Macromonomers, Compounds, and Polymers Described Herein Certain synthetic intermediates are or can be prepared by reported methods, such as those described in U.S. Pat. Nos. 6,812,238 and 10,716,85; U.S. Patent Application Publications 2014 / 0308234 and 2017 / 0348431; International PCT applications PCT / US2017 / 064784, filed 12 / 5 / 2017 and published as WO 2018 / 106738, and PCT / US2019 / 027414, filed 4 / 13 / 2019 and published as WO 2019 / 200367; U.S. Provisional Patent Application 62 / 528,010, filed 6 / 30 / 2017, and U.S. Provisional Patent Application 62 / 520,473, filed 6 / 15 / 2017; Ohwada et al., Bioorganic & Medicinal Chemistry Letters, Vol. 13, No. 2, 2003, pp. 191-196; the entire contents of each of which are incorporated herein by reference.

[0376] Example 1.1. Synthesis of JQ-N3 (loaded with JQ1) [ka] To an oven-dried, N2-filled vial was added trifluoromethanesulfonic anhydride (108 mg, 0.380 mmol). Anhydrous THF (1.20 mL) was then added to the vial. The solution was kept under N2 and cooled to -78 °C. A solution of compound 1 (100 mg, 0.38 mmol) and DIPEA (52 mg, 0.38 mmol) in anhydrous THF (0.40 mL) was then added dropwise to the reaction mixture over 10 minutes. After the addition was complete, the reaction was allowed to react at -78 °C for 30 minutes. At this point, a solution of JQ1 (176 mg, 0.38 mmol) in anhydrous THF (0.40 mL) was added dropwise to the reaction mixture over 10 minutes. After the addition was complete, the reaction was kept at -78 °C for another hour, at which point MeOH (80 μL) was added to quench the reaction. The reaction mixture was concentrated and purified using a neutral alumina column (MeOH in DCM) to give the product as a solid (130 mg, 0.16 mmol, 43% yield). 1H NMR (600 MHz, CDCl3, ppm) δH 7.44 (d, 2H), 7.42 (d, 2H), 7.35 (d, 2H), 7.09 (d, 2H), 5.63 (dd, 2H), 4.71 (dd, 1H), 3.49 (dd, 1H), 3.40 (dd, 1H), 3.29 (t, 2H), 3.06 (s, 3H), 2.56 (t, 2H), 2.46 (s, 3H), 1.75 (p, 2H), 1.72 (s, 3H), 1.66 (m, 2H), 1.50-1.47 (overlap, 11H). 13C NMR (150 MHz, CDCl3, ppm): δC 171.9, 169.2, 164.9, 154.6, 151.6, 150.8, 137.7, 136.0, 135.6, 133.7, 131.5, 130.4, 130.4, 130.1, 129.9, 129.1, 129.0, 122.8, 122.6, 81.8, 55.4, 53.0, 51.3, 37.1, 34.2, 28.6, 28.2, 28.1, 26.3, 24.4, 14.4, 13.5, 11.9.

[0377] Example 1.2. Synthesis of JQ-N3-2 (loaded with JQ1) [ka] To an oven-dried, N2-filled vial was added trifluoromethanesulfonic anhydride (54 mg, 0.19 mmol). Anhydrous THF (0.60 mL) was then added to the vial. The solution was kept under N2 and cooled to -78 °C. A solution of compound 2 (55 mg, 0.19 mmol) and DIPEA (26 mg, 0.19 mmol) in anhydrous THF (0.20 mL) was then added dropwise to the reaction mixture over 10 minutes. After the addition was complete, the reaction was allowed to react at -78 °C for 30 minutes. At this point, a solution of JQ1 (88 mg, 0.19 mmol) in anhydrous THF (0.20 mL) was added dropwise to the reaction mixture over 10 minutes. After the addition was complete, the reaction was kept at -78 °C for another hour, at which point MeOH (40 μL) was added to quench the reaction. The reaction mixture was concentrated and purified (MeOH in DCM) using a neutral alumina column to give the product as a solid (65 mg, 0.077 mmol, 40% yield). 1H NMR (600 MHz, CDCl3, ppm) δH 7.43 (d, 2H), 7.34 (d, 2H), 7.13 (s, 1H), 6.98 (d, 1H), 6.95 (d, 1H), 5.56 (s, 2H), 4.70 (dd, 1H), 3.82 (s, 3H), 3.47 (dd, 1H), 3.38 (dd, 1H), 3.28 (t, 2H), 3.06 (s, 3H), 2.56 (t, 2H), 2.45 (s, 3H), 1.74 (m, 2H), 1.70 (s, 3H), 1.64 (m, 2H), 1.50-1.46 (overlap, 11H). 13C NMR (150 MHz, CDCl3, ppm): δC 171.5, 169.2, 164.9, 154.5, 151.8, 150.9, 140.7, 137.6, 135.9, 135.6, 133.7, 131.5, 130.2, 130.1, 129.0, 127.9, 123.6, 121.4, 113.6, 81.7, 56.3, 55.7, 53.0, 51.3, 37.1, 33.8, 28.6, 28.2, 28.2, 28.2, 26.2, 24.5, 14.4, 13.5, 11.8.

[0378] Example 1.3. Synthesis of JQ-N3-3 (loaded with JQ1) [ka] To an oven-dried, N-filled vial was added trifluoromethanesulfonic anhydride (118 mg, 0.42 mmol). Anhydrous THF (1.50 mL) was then added to the vial. The solution was kept under N and cooled to -78 °C. A solution of compound 3 (150 mg, 0.42 mmol) and DIPEA (55 mg, 0.42 mmol) in anhydrous THF (0.60 mL) was then added dropwise to the reaction mixture over 10 minutes. After the addition was complete, the reaction was allowed to react at -78 °C for 30 minutes. At this point, a solution of JQ1 (192 mg, 0.42 mmol) in anhydrous THF (0.60 mL) was added dropwise to the reaction mixture over 10 minutes. After the addition was complete, the reaction was kept at -78 °C for another hour, at which point MeOH (150 μL) was added to quench the reaction. The reaction mixture was concentrated and purified using a neutral alumina column (MeOH in DCM) to give the product as a solid (206 mg, 0.22 mmol, 52% yield). 1 H NMR (600 MHz, CDCl, ppm) δH 7.44-7.43 (overlapped, 4H), 7.35 (d, 2H), 7.11 (d, 2H), 5.63 (q, 2H), 4.72 (dd, 1H), 3.84 (t, 2H), 3.67-3.62 (overlapped, 14H), 3.50 (dd, 1H), 3.40 (dd, 1H), 3.37 (t, 2H), 3.10 (s, 3H), 2.82 (t, 2H), 2.46 (s, 3H), 1.72 (s, 1H), 1.50 (s, 9H).

[0379] Example 1.4. Synthesis of AZ-N3 (loaded with AZD5153) [ka] To an oven-dried, N-filled vial was added trifluoromethanesulfonic anhydride (540 mg, 1.90 mmol). Anhydrous THF (3.0 mL) was then added to the vial. The solution was kept under N and cooled to -78 °C. A solution of compound 1 (500 mg, 1.90 mmol) and DIPEA (250 mg, 1.90 mmol) in anhydrous THF (0.50 mL) was then added dropwise to the reaction mixture over 10 minutes. After the addition was complete, the reaction was allowed to react at -78 °C for 30 minutes. At this point, a solution of AZD5153 (830 mg, 1.70 mmol) in anhydrous THF (0.10 mL) was added dropwise to the reaction mixture over 10 minutes. After the addition was complete, the reaction was held at -78°C for another hour, at which point MeOH (0.40 mL) was added to quench the reaction. The reaction mixture was concentrated and purified (MeOH in DCM) using a neutral alumina column to give the product as a solid (530 mg, 0.61 mmol, 36% yield). LRMS: C 39 H 49 N 10 Calculated for O5: m / z = 725.4; Found: 725.3 [M-OTf] + . 1H NMR (600 MHz, CDCl3, ppm) δH 9.15 (d, 1H), 7.77 (d, 1H), 7.65 (d, 2H), 7.09 (dd, 4H), 6.83 (d, 2H), 5.84 (s, 2H), 4.43 (br, 1H), 4.41 (br, 1H), 4.35 (s, 3H), 4.06 (br, 2H), 3.34 (br, 2H), 3.32-3.25 (overlap, 4H), 3.14 (overlap, 3H), 3.03 (overlap, 2H), 2.94 (s, 3H), 2.87 (br, 1H), 2.81-2.75 (overlap, 2H), 2.58 (t, 13C NMR (150 MHz, CDCl3, ppm): δC 171.9, 170.59, 157.4, 155.8, 151.9, 151.5, 137.1, 136.8, 130.5, 130.3, 127.8, 122.8, 122.6, 119.9, 114.8, 66.6, 60.6, 60.08, 54.2, 52.9, 51.3, 48.3, 46.8, 46.8, 41.5, 34.6, 34.2, 32.9, 28.6, 26.3, 24.4, 15.5.

[0380] Example 1.5. Synthesis of Vin-N3 (Vincristine-loaded) [ka] To an oven-dried, N2-filled vial was added trifluoromethanesulfonic anhydride (6.0 mg, 0.021 mmol). Anhydrous THF (0.15 mL) was then added to the vial. The solution was kept under N2 and cooled to -78 °C. A solution of compound 1 (5.2 mg, 0.021 mmol) and DIPEA (5.5 mg, 0.043 mmol) in anhydrous THF (0.05 mL) was then added dropwise to the reaction mixture over 10 minutes. After the addition was complete, the reaction was allowed to react at -78 °C for 30 minutes. At this point, a solution of vincristine (20 mg, 0.021 mmol) in anhydrous THF (0.05 mL) was added dropwise to the reaction mixture over 10 minutes. After the addition was complete, the reaction was kept at -78 °C for another hour, at which point MeOH (10 μL) was added to quench the reaction. The reaction mixture was concentrated and purified using a neutral alumina column (MeOH in DCM) to give the product as a solid (13 mg, 0.012 mmol, 57% yield). LRMS: C 59 H 72 N7O 12 Calculated for: m / z = 1071.3; Found: 1071.4 [M-OTf] + . 1H NMR (600 MHz, CDCl3, ppm) δH 9.42 (br, 1H), 8.76 (s, 1H), 8.16 (s, 1H), 8.04 (br, 2H), 7.74 (s, 1H), 7.55 (s, 1H), 7.54 (s, 1H), 7.21-7.12 (overlap, 6H), 6.91 (s, 1H), 6.79 (s, 1H), 5.91 (m, 2H), 5.41 (s, 1H), 5.39 (s, 1H), 5.25 (s, 1H), 5.21 (s, 1H), 4.74 (s, 1H), 4.51 (s, 1H), 4.00 (overlap, 2H). 3.90 (s, 3H), 3.88 (s, 3H), 3.78 (s, 3H), 3.72 (s, 3H), 3.67 (s, 6H), 3.40-3.25 (overlap, 8H), 3.19 (s, 3H), 3.16 (br, 2H), 2.93-2.88 (overlap, 4H), 2.81 (br, 3H), 2.62 (overlap, 2H), 2.36 (overlap, 4H), 2.15 (m, 1H), 2.10 (s, 2H), 2.06 (s, 3H), 1.75-1.60 (overlap), 1.50-1.28 (overlap), 0.91-0.84 (overlap, 12H).

[0381] Example 1.6. Synthesis of JQ-MM (loaded with JQ1) [ka] To a vial was added Yn-MM (67.7 mg, 0.020 mmol, 1.0 eq), JQ-N3 (20.5 mg, 0.023...

Claims

1. Formula (I): 【Chemistry 1】 (I) During the ceremony: R Ａ Each instance of is independently hydrogen, halogen, or substituted or unsubstituted C １－６ is alkyl; a is an integer from 1 to 20; Each instance of -Y-Z- is independently 【Chemistry 2】 and L Ｊ each instance of independently being a substituted or unsubstituted C １－１２ Alkylene, or substituted or unsubstituted C ２－１２ is heteroalkylene; each instance of m is independently an integer from 1 to 10; In each case of E, E can be converted to E via an azide-alkyne Huisgen cycloaddition, a thiol-yne addition, or a Diels-Alder reaction. Ａ E Ｂ a moiety formed by reacting E Ａ is a first click chemistry handle; wherein each first click chemistry handle is independently capable of undergoing an azide-alkyne Huisgen cycloaddition, a thiol-yne addition, or a Diels-Alder reaction; E Ｂ is a second reaction handle, wherein the second reaction handle is capable of reacting with the first reaction handle via an azide-alkyne Huisgen cycloaddition, a thiol-yne addition, or a Diels-Alder reaction; Each instance of L is independently substituted or unsubstituted C ２－２０ Alkylene, or substituted or unsubstituted C ２－２０ is heteroalkylene, each instance of W is independently a single bond or —O—; each instance of W' is -O-; R １ Each instance of is independently hydrogen, halogen, or substituted or unsubstituted C １－６ is alkyl; each instance of y is independently 0 or 1; If y is 0, 【Transformation 3】 is a single bond, and R ４ and R ６ is attached to an intervening atom to form a substituted or unsubstituted heterocyclyl; y is 1, and 【Chemistry 4】 is a single bond, R ２ is hydrogen, halogen, substituted or unsubstituted C １－６ Alkyl, substituted or unsubstituted C ２－６ Alkenyl, substituted or unsubstituted C ２－６ Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR ａ , -N(R ａ ) ２ , -SR ａ , -CN, -SCN, -C (=NR ａ ) R ａ , -C(=NR ａ ) OR ａ , -C(=NR ａ ) N (R ａ ) ２ , -C(=O)R ａ , -C(=O)OR ａ , -C(=O)N(R ａ ) ２ , -NO ２ , -NR ａ C(=O)R ａ , -NR ａ C(=O)OR ａ , -NR ａ C(=O)N(R ａ ) ２ , -OC(=O)R ａ , -OC(=O)OR ａ , or —OC(═O)N(R ａ ) ２ where R ３ and R ４ joins with an intervening atom to form a substituted or unsubstituted carbocyclyl, R ６ is hydrogen, substituted or unsubstituted C １－６ alkyl, or nitrogen protecting group, R ａ each instance of independently represents hydrogen, substituted or unsubstituted C １－６ Alkyl, substituted or unsubstituted C ２－６ Alkenyl, substituted or unsubstituted C ２－６ alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or R ａ when two of the following are joined to form a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, or a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl; y is 1, and 【Transformation 5】 is a double bond, R ２ is absent; where R ３ and R ４ are cis to each other and are joined to intervening atoms to form a substituted or unsubstituted aryl; R ６ is hydrogen, substituted or unsubstituted C １－６ alkyl, or nitrogen protecting group, 【Transformation 6】 is a single bond, R ５ is hydrogen, halogen, substituted or unsubstituted C １－６ Alkyl, substituted or unsubstituted C ２－６ Alkenyl, substituted or unsubstituted C ２－６ Alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR ａ , -N(R ａ ) ２ , -SR ａ , -CN, -SCN, -C (=NR ａ ) R ａ , -C(=NR ａ ) OR ａ , -C(=NR ａ ) N (R ａ ) ２ , -C(=O)R ａ , -C(=O)OR ａ , -C(=O)N(R ａ ) ２ , -NO ２ , -NR ａ C(=O)R ａ , -NR ａ C(=O)OR ａ , -NR ａ C(=O)N(R ａ ) ２ , -OC(=O)R ａ , -OC(=O)OR ａ , or —OC(═O)N(R ａ ) ２ and 【Transformation 7】 is a double bond, R ５ is absent; each instance of T is independently substituted or unsubstituted methylene; Each instance of M is independently an ammonium or iminium salt of a pharmaceutical agent, wherein the point of attachment is at the N-terminus of the ammonium or iminium salt. ＋ and R Ｂ Each instance of is independently hydrogen, halogen, or substituted or unsubstituted C １－６ is alkyl; each instance of b is independently an integer from 1 to 20; e is 1, 2, or 3; X is N(R Ｄ ) ２ and R Ｄ each instance of independently represents hydrogen, substituted or unsubstituted C １－６ Alkyl, or substituted or unsubstituted C ５０－１０００ heteroalkyl, where R Ｄ At least one of is substituted or unsubstituted C ５０－１０００ is heteroalkyl, or a salt thereof.

2. The macromonomer has the formula 【Transformation 8】 The macromonomer according to claim 1 , or a salt thereof, represented by the following formula:

3. The macromonomer has the formula 【Chemistry 9】 The macromonomer according to claim 1 , or a salt thereof, represented by the following formula:

4. The macromonomer has the formula 【Chemistry 10】 The macromonomer according to claim 1 , or a salt thereof, represented by the following formula:

5. The macromonomer has the formula 【Chemistry 11】 The macromonomer according to claim 1 , or a salt thereof, represented by the following formula:

6. The macromonomer has the formula 【Chemistry 12】 In the formula, R ７ each instance of independently represents a halogen, substituted or unsubstituted C １－６ Alkyl, substituted or unsubstituted C ２－６ Alkenyl, substituted or unsubstituted C ２－６ alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR ａ , -N(R ａ ) ２ , -SR ａ , -CN, -SCN, -C(=NR ａ ) R ａ , -C(=NR ａ ) OR ａ , -C(=NR ａ ) N (R ａ ) ２ , -C(=O)R ａ , -C(=O)OR ａ , -C(=O)N(R ａ ) ２ , -NO ２ , -NR ａ C(=O)R ａ , -NR ａ C(=O)OR ａ , -NR ａ C(=O)N(R ａ ) ２ , -OC(=O)R ａ , -OC(=O)OR ａ , or —OC(═O)N(R ａ ) ２ and each instance of z is 0, 1, 2, 3, 4, or 5; The macromonomer according to claim 1 , or a salt thereof, represented by the following formula:

7. The macromonomer has the formula 【Chemistry 13】 In the formula, R ７ each occurrence of independently represents a halogen, a substituted or unsubstituted C １－６ Alkyl, substituted or unsubstituted C ２－６ Alkenyl, substituted or unsubstituted C ２－６ alkynyl, substituted or unsubstituted 3- to 7-membered monocyclic carbocyclyl, substituted or unsubstituted 3- to 7-membered monocyclic heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, -OR ａ , -N(R ａ ) ２ , -SR ａ , -CN, -SCN, -C(=NR ａ ) R ａ , -C(=NR ａ ) OR ａ , -C(=NR ａ ) N (R ａ ) ２ , -C(=O)R ａ , -C(=O)OR ａ , -C(=O)N(R ａ ) ２ , -NO ２ , -NR ａ C(=O)R ａ , -NR ａ C(=O)OR ａ , -NR ａ C(=O)N(R ａ ) ２ , -OC(=O)R ａ , -OC(=O)OR ａ , or —OC(═O)N(R ａ ) ２ and each instance of z is 0, 1, 2, 3, or 4; The macromonomer according to claim 1 , or a salt thereof, represented by the following formula:

8. At least one case of -Y-Z- 【Chemistry 14】 2. The macromonomer according to claim 1, or a salt thereof,

9. At least one case of -Y-Z- 【Chemistry 15】 9. The macromonomer according to claim 8, or a salt thereof,

10. R Ａ is hydrogen, and / or R Ｂ 10. The macromonomer of any one of claims 1, 8, and 9, or a salt thereof, wherein each occurrence of is hydrogen.

11. each occurrence of a is independently 4, 5, or 6; and / or 11. The macromonomer according to any one of claims 1 to 10, or a salt thereof, wherein each occurrence of b is independently 2, 3, 4, 5, or 6.

12. X is 【Chemistry 16】 where n is an integer from 40 to 100, and R Ｆ is hydrogen or unsubstituted C １～６ The macromonomer according to any one of claims 1 to 11, or a salt thereof, which is alkyl.

13. 13. The macromonomer according to any one of claims 1 and 8 to 12, or a salt thereof, wherein e is 1.

14. 14. The macromonomer according to any one of claims 1 and 10 to 13, or a salt thereof, wherein at least one instance of m is 1.

15. The macromonomer is 【Chemistry 17-1】 or 【Chemistry 17-2】 2. The macromonomer according to claim 1, or a salt thereof,

16. L Ｊ At least one instance of １－６ The macromonomer or salt according to any one of claims 1 to 14, which is an alkylene.

17. At least one instance of E is [Chemistry 18] 17. The macromonomer according to any one of claims 1, 2, 4, 6 to 14, and 16, or a salt thereof.

18. E Ａ At least one case of -N ３ and E Ｂ is a substituted or unsubstituted cyclooctynyl group optionally fused with one or more substituted or unsubstituted phenyl groups, a substituted or unsubstituted cyclopropenyl group, a substituted or unsubstituted cyclobutenyl group, a substituted or unsubstituted trans-cyclooctenyl group optionally fused with one or more substituted or unsubstituted phenyl groups, or a substituted or unsubstituted 【Chemistry 19】 17. The macromonomer according to any one of claims 1, 2, 4, 6 to 14, and 16, or a salt thereof,

19. E Ａ At least one of is -N ３ and E Ｂ The macromonomer according to claim 18, or a salt thereof, wherein at least one of the following is —C≡CH:

20. At least one instance of L is unsubstituted C ２～２０ Alkylene, unsubstituted C ２～２０ Heteroalkylene or C substituted with at least one oxo ２～２０ The macromonomer according to any one of claims 1 to 14 and 16 to 19, or a salt thereof, which is a heteroalkylene.

21. 21. The macromonomer or salt thereof according to any one of claims 1 to 3, 6 to 8, 10 to 14, and 16 to 20, wherein at least one instance of W is a single bond.

22. R １ The macromonomer or salt thereof according to any one of claims 1 to 14 and 16 to 21, wherein at least one of is hydrogen. 【Request Item 23】 【Chemistry 20】 In at least one instance, y is 0; 【Chemistry 21】 is a single bond, and R ４ and R ６ is joined with intervening atoms to form a substituted or unsubstituted pyrrolidinyl, and R ５ The macromonomer or salt thereof according to any one of claims 1, 8 to 14, and 16 to 22, wherein is hydrogen. 【Request Item 24】 【Chemistry 22】 in at least one instance: y is 1; 【Chemistry 23】 is a double bond, and R ２ and R ５ does not exist, and R ３ and R ４ are cis to each other and are joined with their intervening atoms to form a substituted or unsubstituted phenyl; R ６ is hydrogen or substituted or unsubstituted C １～６ The macromonomer or salt thereof according to any one of claims 1, 8 to 14, and 16 to 22, which is alkyl.

25. At least one of T is -CH(CH ３ )- or -CH ２ The macromonomer according to any one of claims 1 to 14 and 16 to 24, or a salt thereof, wherein

26. The macromonomer or salt thereof according to any one of claims 1 to 14 and 16 to 25, wherein at least one of the pharmaceutical agents is an anticancer agent.

27. In some cases, the pharmaceutical agent is selected from the group consisting of JQ1, AZD5153, vincristine, abiraterone acetate, ado-trastuzumab emtansine, afatinib dimaleate, aldesleukin, alemtuzumab, anastrozole, Erwinia chrysanthemi asparaginase, axitinib, azacitidine, bendamustine hydrochloride, bevacizumab, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, cabozantinib-s-malate, carfilzomib, ceritinib, cetuximab, chlorambucil, cisplatin, clofarabine, crizotinib, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin hydrochloride, decitabine, and degarelli. oxalate, denileukin diftitox, denosumab, dinutuximab, doxorubicin hydrochloride, epirubicin hydrochloride, erlotinib hydrochloride, fludarabine phosphate, gefitinib, gemcitabine hydrochloride, goserelin acetate, ibritumomab tiuxetan, ibrutinib, idelalisib, imatinib mesylate, imiquimod, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotide acetate, lapatinib ditosylate, lenalidomide, lenvatinib, letrozole, leucovorin calcium , leuprolide acetate, mechlorethamine hydrochloride, mercaptopurine, methotrexate, mitomycin C, mitoxantrone hydrochloride, nelarabine, nilotinib, nivolumab, obinutuzumab, ofatumumab, olaparib, omacetaxine mepesuccinate, OTX-015, oxaliplatin, palbociclib, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, pegaspargase, peginterferon alfa-2b, pembrolizumab, pemet Rexed disodium, pertuzumab, plerixafor, pomalidomide, ponatinib hydrochloride, pralatrexate, procarbazine hydrochloride, raloxifene hydrochloride, ramucirumab, recombinant interferon alpha-2b, regorafenib, rituximab, ruxolitinib phosphate, siltuximab, sorafenib tosylate, sunitinib malate, tamoxifen citrate, temozolomide, topotecan hydrochloride, toremifene, tositumomab, trametinib, trastuzumab, vandetanib,The macromonomer or salt thereof according to any one of claims 1 to 14 and 16 to 25, which is vemurafenib, vinblastine sulfate, vinorelbine tartrate, vismodegib, ziv-aflibercept, or zoledronate, or a pharmaceutically acceptable salt thereof.

28. At least one instance of M is 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 The macromonomer or salt according to any one of claims 1 to 14 and 16 to 25,

29. A method for preparing the macromonomer, or a salt thereof, according to any one of claims 1 to 14 and 16 to 28, comprising the steps of: formula: 【Chemistry 27】 or a salt thereof, Ｄ ) ２ or a salt thereof.

30. The method of claim 29, wherein the coupling step is carried out in the presence of a reagent for coupling a carboxylic acid with an amine.

31. A polymer prepared by polymerizing the macromonomer or salt thereof according to any one of claims 1 to 14 and 16 to 28 in the presence of a metathesis catalyst.

32. 29. A polymer prepared by polymerizing a first macromonomer, or a salt thereof, according to any one of claims 1 to 14 and 16 to 28, and a second macromonomer, or a salt thereof, according to any one of claims 1 to 14 and 16 to 28, in the presence of a metathesis catalyst, wherein at least one instance of M of the first macromonomer is different from at least one instance of M of the second macromonomer.

33. 33. The polymer of claim 31 or 32, wherein the weight average molecular weight of the polymer is from 3,000 to 1,000,000, 3,000 to 100,000, 3,000 to 10,000, 10,000 to 1,000,000, 10,000 to 100,000, or 100,000 to 1,000,000 (inclusive) g / mol.

34. The polymer has the formula 【Chemistry 28】 or 【Chemistry 29】 34. The polymer of claim 31 or 33, wherein:

35. A method for preparing a polymer, comprising polymerizing the macromonomer according to any one of claims 1 to 14 and 16 to 28, or a salt thereof, in the presence of a metathesis catalyst.

36. The method of claim 35, wherein at least one instance of M of the first macromonomer is different from at least one instance of M of the second macromonomer.

37. The method of claim 35 or 36, wherein the metathesis catalyst is a transition metal metathesis catalyst or a Grubbs catalyst.

38. The metathesis catalyst of claim 38, wherein the metathesis catalyst has the formula: 【Transformation 30】 37. The method of claim 35 or 36, wherein

39. A pharmaceutical composition comprising a polymer according to any one of claims 31 to 34, and optionally a pharmaceutically acceptable excipient.

40. A polymer according to any one of claims 31 to 34, or a pharmaceutical composition according to claim 39, for use in delivering a pharmaceutical agent to a subject in need thereof.

41. A polymer according to any one of claims 31 to 34, or a pharmaceutical composition according to claim 39, for use in delivering a pharmaceutical agent to a cell.

42. A polymer for use as described in claim 41, or a pharmaceutical composition for use as described in claim 41, wherein the cells are in vitro.

43. 40. The polymer of any one of claims 31 to 34, or the pharmaceutical composition of claim 39, wherein at least one example of said pharmaceutical agent is a therapeutic agent, for use in treating a disease in a subject in need thereof.

44. 40. The polymer of any one of claims 31 to 34, or the pharmaceutical composition of claim 39, wherein at least one example of the pharmaceutical agent is a prophylactic agent, for use in preventing a disease in a subject in need thereof.

45. A polymer according to any one of claims 31 to 34, or a pharmaceutical composition according to claim 39, for use in diagnosing a disease in a subject, wherein at least one pharmaceutical agent is a diagnostic agent.

46. (i) A polymer for use according to any one of claims 43 to 45, or a pharmaceutical composition for use according to any one of claims 43 to 45, wherein the disease is a proliferative disease.

47. A polymer for use as described in claim 46, or a pharmaceutical composition for use as described in claim 46, wherein at least one pharmaceutical agent is an antiproliferative agent.

48. A polymer for use according to claim 46, or a pharmaceutical composition for use according to claim 46, wherein the disease is cancer.

49. A polymer for use according to claim 48, or a pharmaceutical composition for use according to claim 48, wherein at least one pharmaceutical agent is an anticancer agent.

50. An in vitro method of delivering a pharmaceutical agent to a cell, comprising contacting the cell with a polymer according to any one of claims 31 to 34, or a pharmaceutical composition according to claim 39.

51. A kit comprising a macromonomer or a salt thereof according to any one of claims 1 to 14 and 16 to 28, and instructions for using said macromonomer or a salt thereof.

52. A kit comprising a polymer described in any one of claims 31 to 34, or a pharmaceutical composition described in claim 39, and instructions for using the polymer or pharmaceutical composition.

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