Chemically degradable and functionally modifiable polymer and hydrogel

Abstract

Degradable covalent chemical cross-linking agents are disclosed. Methods of making and using the degradable covalent chemical crosslinkers are also disclosed.

Description

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 523,702, filed June 28, 2023, the entire contents of which are incorporated herein by reference.

[0002] Government Support This invention was made with government support under Grant No. DP2 ES030448 awarded by the National Institutes of Health and Grant No. 2238040 awarded by the National Science Foundation. The government has certain rights in the invention.

[0003] Background of the Disclosure Hydrogels are crosslinked polymer networks that contain a large volume fraction of water but are insoluble in water (Wichterle et al., Nature, 185:117-118 (1960)). The high water content of these materials makes them highly deformable and enables rapid diffusion of water-soluble molecules through their surface, which makes them ideally suited for biological applications (Correa et al., Chem. Rev., 121:11385-11457 (2021)). As a result, hydrogel-based biomaterials have been primarily applied for wound closure (Kamoun et al., J. Adv. Res., 8:217-233 (2017); Liang et al., ACS Nano 15:12687-12722 (2021)), as tissue sealants (Lang et al., Sci. Trans. Med., 6:218ra6 (2014); Ferreira et al., J. Biol. Macromol., 40:144-152 (2007); Mehdizadeh et al., Macromol. Biosci., 13:271-288 (2013)), for drug delivery (Hoffman, Adv. Drug Delivery Rev., 64:18-23 (2012); Blackman et al., J. Am. Chem. Soc., 130:13518-13519 (2008); Mejia Oneto et al., ACS Cent. Sci., 2:476-482 (2016)), and for cell encapsulation in three-dimensional cultures (Wang et al., Adv. Mater. (Weinheim, Ger.) 27:3717 (2015); Chaudhuri et al., Nature, 584:535-546 (2020); Tayalia et al., Biomaterials, 32:2634 (2011)) as well as many other bioengineering applications (Correa et al., Chem. Rev., 121:11385-11457 (2021)).

[0004] Hydrogels have been used as tough tissue adhesives. Tough adhesives are biomaterials that do not break under high tensile loads (Li et al., Science, 357:378-381 (2017)). Equally strong adhesive forces enable these materials to adhere to tissues without detaching under high shear, tensile, or peeling forces. Such materials offer an attractive alternative to surgical sutures for wound closure and tissue sealing because they are faster, cause less tissue damage, show a lower incidence of infection, and do not require anesthesia (Li et al., Science, 357:378-381 (2017); Rahman et al., Science Advances, 7:eabk2451 (2021); Liu et al., Adv. Funct. Mater., 32:2107732 (2022)).

[0005] As tissue adhesives become more robust and adhesive, they also present new challenges, such as their removal. Leaving them in place at the site of injury carries the risk of triggering inflammation and tissue fibrosis, and the hydrogel's lifespan may exceed its intended effects (Kyriakides, Chapter 5 - Molecular Events at Tissue–Biomaterial Interface, in Host Response to Biomaterials, Badylak, SF, Ed. Academic Press: Oxford, 2015;pp 81; Padmanabhan et al., WIREs Nanomed. Nanobiotechnol., 7:355-370 (2015); Onuki et al., J. Diabetes Sci. Technol., 2:1003-1015 (2008)); however, the removal of tissue adhesives is a known cause of secondary tissue damage.

[0006] Overview of this disclosure This disclosure solves the above problems by preparing polymers that are easily subjected to diboron-mediated degradation and tough polyacrylamide hydrogels.

[0007] The first aspect of this disclosure relates to compounds represented by Formula I: (I), or its pharmaceutically acceptable salt or stereoisomer. in: p is 0 or 1; q is 0 or 1 ; R1is (Ci-C8)alkyl, (C3-C 10 )carbocyclyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, carbocyclyl, or heterocyclyl is further optionally substituted, or R1and R2together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl, or R1and R3together with the atoms to which they are attached form a 5- to 7- membered heterocyclyl; R2is hydrogen, (Ci-C8)alkyl, chloro, bromo, or iodo; R3is hydrogen, (Ci-C8)alkyl, chloro, bromo, or iodo; L1is absent or a linker; L2is absent or a linker; X is a leaving group; and R4and R4' are independently a polymerizable moiety or a chemical moiety, provided that at least one of R4and R4' is a polymerizable moiety.

[0008] Another aspect of the present disclosure relates to a modifiable polymer / hydrogel that is the reaction product of: i) a compound of Formula I: (I), ii) a polymerizable moiety, and iii) an initiator.

[0009] Other aspects of the present disclosure relate to a modifiable polymer / hydrogel that is the reaction product of: i) 4-arm-cyclooct-2-yn-1-yl, ; and ii) dihydroxylamine, , wherein: each X1is a leaving group; each L is a linker; and each R5is (Ci-C8)alkyl, (C3-C 10 )carbocyclyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, carbocyclyl, or heterocyclyl is further optionally substituted.

[0010] Further aspects of the present disclosure relate to methods of degrading a hydrogel. The methods entail contacting the hydrogel with a diboron reagent.

[0011] BRIEF DESCRIPTION OF DRAWINGS Figure 1 A series of images of a synthetic and diboron-mediated degrading polyacrylamide hydrogel.

[0012] Figure 2 Schematic of synthesis of polyacrylamide / calcium alginate tough hydrogel and diboron-mediated degradation.

[0013] Figures 3A-3B Series of images of synthesized polyacrylamide gels. Figure 3A Series of images of synthesized polyacrylamide gels with different percentages of crosslinker (0.03 to 0.3 wt / vol %). Figure 3B Series of images of synthesized polyacrylamide gels (0.12 wt / vol %) showing tensile loading and unloading.

[0014] Figure 4 Series of images of tough hydrogels synthesized and diboron-mediated degradation.

[0015] Figures 5A-5C Series of images of tough hydrogels synthesized and diboron-mediated degradation. Figure 5A Series of images before gelation. Figure 5B Series of images after gelation. Figure 5C Series of images showing diboron-mediated degradation of hydrogels.

[0016] Figures 6A-6C Series of images of tough hydrogels synthesized and diboron-mediated degradation. Figure 6A Series of images before gelation. Figure 6B Series of images after gelation. Figure 6C Series of images showing diboron-mediated degradation of hydrogels.

[0017] DETAILED DESCRIPTION Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter belongs. The following terms are intended to have the designated meanings, unless otherwise apparent to those of ordinary skill in the art, in order to facilitate understanding of the present disclosure.

[0018] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a composition” includes mixtures of two or more such compositions, reference to “an inhibitor” includes mixtures of two or more such inhibitors, and the like.

[0019] The term “about,” as used herein, means within 10% (e.g., within 5%, within 2%, or within 1%) of the particular value specified in the term “about.”

[0020] The transitional term “comprising,” synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. When used in the context of the number of heteroatoms in a heterocyclic structure, it means that the heterocyclic group has the minimum number of heteroatoms. In contrast, the transitional phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim. The transitional phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the disclosed subject matter.

[0021] The following definitions apply with respect to the compounds of the present disclosure, and for further describing the compounds herein.

[0022] As used herein, the term “alkyl” refers to saturated straight-chain or branched-chain monovalent hydrocarbon radicals. In some embodiments, the alkyl group is a C1-C6 group. In some embodiments, and unless otherwise disclosed for any one or more groups of the compounds of Formula (I or II) or hydrogels disclosed herein, the alkyl group is a C0-C6, C0-C5, C0-C3, C1-C6, C1-C5, C1-C4, or C1-C3 group (where C0 alkyl refers to a bond). Examples of alkyl groups include methyl, ethyl, 1 -propyl, 2-propyl, isopropyl, 1 -butyl, 2-methyl- 1 -propyl, 2-butyl, 2-methyl-2-propyl, 1 -pentyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl- 1 -butyl, 2-methyl- 1 -butyl, 1 -hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. In some embodiments, the alkyl group is a C1-C3 alkyl group. In some embodiments, the alkyl group is a C1-C2 alkyl group. In some embodiments, the alkyl group is a methyl group.

[0023] As used herein, the term "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain linking the rest of the molecule to a group, consisting solely of carbon and hydrogen, containing no unsaturation, having from one to six carbon atoms, for example methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain can be attached to the rest of the molecule by a single bond and to the group by a single bond. In some embodiments, and unless otherwise disclosed for any one or more groups of the compounds of Formula (I or II) or hydrogels disclosed herein, the alkylene contains one to four carbon atoms (Ci-C4alkylene). In other embodiments, the alkylene contains one to three carbon atoms (Ci-C3alkylene). In other embodiments, the alkylene contains one to two carbon atoms (Ci-C2alkylene). In other embodiments, the alkylene contains one carbon atom (Ci alkylene).

[0024] As used herein, the term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having at least one carbon-carbon double bond. Alkenyl groups include groups having "cis" and "trans" orientations or, alternatively, "E" and "Z" orientations. In some embodiments, the alkenyl group is a C2-C 15 group. In some embodiments, and unless otherwise disclosed for any one or more groups of the compounds of Formula (I or II) or hydrogels disclosed herein, the alkenyl group is a C2-C 12 , C2-C 10 , C2-C8, C2-C6, or C2-C3group. Examples include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl.

[0025] As used herein, the term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group is a C2-C 15 group. In some embodiments, and unless otherwise disclosed for any one or more groups of the compounds of Formula (I or II) or hydrogels disclosed herein, the alkynyl group is a C2-C 12 , C2-C 10 , C2-C8, C2-C6, or C2-C3group. Examples include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, and but-3-ynyl.

[0026] As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group, as defined above, having an oxy radical attached to its terminal carbon atom, and the point of attachment is the carbon atom. In some embodiments, the alkoxyl group is methoxyl, ethoxyl, propoxyl, or tert-butoxyl. An "ether" is two hydrocarbon groups covalently linked by an oxygen. Thus, an alkyl substituent that makes the alkyl group an ether is or is analogous to an alkoxyl group, e.g., can be represented as one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

[0027] As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine, or iodine.

[0028] As used herein, the term "cyclyl" refers to any group, either alone or as part of a larger moiety, that contains a saturated, partially saturated, or aromatic ring system, such as carbocyclyl (cycloalkyl, cycloalkenyl), heterocyclyl (heterocycloalkyl, heterocycloalkenyl), aryl, and heteroaryl. A cyclyl group can have one or more (e.g., fused) ring systems. Thus, for example, a cyclyl group can contain one or more carbocyclyl, heterocyclyl, aryl, or heteroaryl groups.

[0029] As used herein, the term "carbocyclyl" (also "carbocyclyl group") refers to a group, either alone or as part of a larger moiety, that contains a saturated, partially unsaturated, or aromatic ring system having 3 to 12 carbon atoms, either alone or as part of a larger moiety (e.g., alkylcarbocyclyl). The term carbocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. In one embodiment, a carbocyclyl group contains 3 to 10 carbon atoms (C3-C10). In one embodiment, a carbocyclyl group contains 3 to 6 carbon atoms (C3-C6). In one embodiment, a carbocyclyl group contains 5 to 6 carbon atoms (C5-C6). In some embodiments, carbocyclyl groups that are bicyclic include C6-C10 10 ) carbocyclyl groups that are spiro ring systems include C5-C10 10 ) carbocyclyl groups that are spiro ring systems include C5-C10 11Representative examples of monocyclic carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and phenyl; bicyclic carbocyclyl groups having 7 to 11 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spiro carbocyclyl groups include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane. The term carbocyclyl includes aryl ring systems as defined herein. The term carbocyclyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated monocyclic, bicyclic, or spiro carbocyclic rings). The term carbocyclyl also includes carbocyclic rings that are fused to one or more (e.g., 1, 2, or 3) distinct cyclic groups (e.g., aryl or heterocyclyl), where the linking group or attachment point is on the carbocyclic ring.

[0030] Thus, the term carbocycloalkyl, as used herein, refers to a group of the formula -R c a carbocyclyl group, where R c is an alkylene chain. The term carbocycloalkyl also includes carbocycloalkoxy groups, as used herein, which refer to a group of the formula -O-R c a carbocyclyl group, where R c is an alkylene chain.

[0031] The term "aryl," as used herein, employed alone or as part of a larger moiety (e.g., "aralkyl" in which the terminal carbon of the alkyl group is the point of attachment, e.g., benzyl, "aralkoxy" in which the oxygen atom is the point of attachment, or "aryloxyalkyl" in which the point of attachment is on the aryl group), refers to groups including monocyclic, bicyclic, or tricyclic carbocyclic rings, which include fused rings where at least one ring is aromatic. In some embodiments, the aralkoxy group is benzoxy. The term "aryl" is used interchangeably with the term "aryl ring." In one embodiment, aryl includes groups having 6-12 carbon atoms. In another embodiment, aryl includes groups having 6-10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, and the like, which can be substituted or independently substituted with one or more substituents described herein. A particular aryl group is phenyl. In some embodiments, aryl includes aryl rings that are fused to one or more (e.g., 1, 2, or 3) distinct cyclic groups (e.g., carbocyclic or heterocyclic), where the linking group or attachment point is on the aryl ring.

[0032] Thus, the term aryl includes aralkyl groups (e.g., benzyl), as disclosed above, which refers to groups of the formula -R c - a group of the formula -R c is an alkylene chain, e.g., methylene or ethylene. In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl also includes aralkoxy groups, as used herein, which refer to groups of the formula -O-R c - a group of the formula -R c is an alkylene chain, e.g., methylene or ethylene.

[0033] As used herein, the term "heterocyclyl" refers to "carbocyclyl" groups that, when used alone or as part of a larger moiety, contain saturated, partially unsaturated, or aromatic ring systems in which one or more (e.g., 1, 2, 3, 4, or 5) carbon atoms have been replaced with a heteroatom or a heteroatom-containing group (e.g., O, N, N(O), S, S(O), or S(O)2). The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. In some embodiments, heterocyclyl refers to 3- to 12-membered heterocyclyl ring systems. In some embodiments, heterocyclyl refers to saturated ring systems, e.g., 3- to 12-membered saturated heterocyclyl ring systems. In some embodiments, heterocyclyl refers to heteroaryl ring systems, e.g., 5- to 12-membered heteroaryl ring systems. The term heterocyclyl also includes C2-C8heterocycloalkyl groups, which are saturated or partially unsaturated monocyclic, bicyclic, or spiro ring systems containing 2-8 carbons and one or more (e.g., 1, 2, or 3) heteroatoms.

[0034] In some embodiments, the heterocyclyl contains 3-12 ring atoms, including monocyclic, bicyclic, tricyclic, and spiro ring systems, in which the ring atoms are carbon and 1 to 5 of the ring atoms are heteroatoms, e.g., nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl includes 3- to 7-membered monocyclic rings having one or more heteroatoms selected from O, N, and S. In some embodiments, the heterocyclyl includes 4- to 6-membered monocyclic rings having one or more heteroatoms selected from O, N, and S. In some embodiments, the heterocyclyl includes 3-membered monocyclic rings. In some embodiments, the heterocyclyl includes 4-membered monocyclic rings. In some embodiments, the heterocyclyl includes 5- to 6-membered monocyclic rings. In some embodiments, the heterocyclyl contains 0 to 3 double bonds. In any of the above embodiments, the heterocyclyl contains 1, 2, 3, or 4 heteroatoms. Any nitrogen or sulfur heteroatom can be optionally oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom can be optionally substituted (e.g., methyl, isopropyl) and / or quaternized (e.g., [NR4] + Cl - , [NR4] + OH -oxazinyl, thiazinyl, thiophenyl, oxazinyl, thiazinediyl, oxazinediyl, dithiazinyl, dioxazinyl, oxathiazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperazinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]dec-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl.Examples of 5-membered heterocyclyl groups containing sulfur or oxygen atoms and 1 to 3 nitrogen atoms are thiazolyl (e.g., thiazol-2-yl), thiadiazolyl (e.g., 1,3,4- thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl), oxazolyl (e.g., oxazol-2-yl), and oxadiazolyl (e.g., 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl). Examples of 5-membered heterocyclyl groups containing 2 to 4 nitrogen atoms include imidazolyl (e.g., imidazol-2-yl), triazolyl (e.g., 1,3,4-triazol-5-yl, 1,2,3-triazol-5-yl, and 1,2,4-triazol-5-yl), and tetrazolyl (e.g., 1H-tetrazol-5-yl). Representative examples of benzo-fused 5-membered heterocyclyl groups include benzo-oxazol-2-yl, benzo-thiazol-2-yl, and benzo-imidazol-2-yl. Examples of 6-membered heterocyclyl groups containing 1 to 3 nitrogen atoms and optionally containing sulfur or oxygen atoms are pyridyl (e.g., pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl and pyrimidin-4-yl), triazinyl (e.g., 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl), pyridazinyl (e.g., pyridazin-3-yl), and pyrazinyl. In some embodiments, heterocyclyl groups include heterocycles that are fused to one or more (e.g., 1 or 2) different cyclic groups (e.g., carbocyclic or heterocyclic), where the linking group or point of attachment is on the heterocycle, and in some embodiments, where the point of attachment is a heteroatom contained in the heterocycle.

[0035] Thus, the term heterocyclyl includes N-heterocyclyl, as used herein, which refers to a heterocyclyl group containing at least one nitrogen atom and where the point of attachment of the heterocyclyl group to the rest of the molecule is through a nitrogen atom in the heterocyclyl group. Representative examples of N-heterocyclyl groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, 1-pyrazolidinyl, 1-imidazolinyl, and 1-imidazolidinyl. The term heterocyclyl also includes C-heterocyclyl, as used herein, which refers to a heterocyclyl group containing at least one heteroatom and where the point of attachment of the heterocyclyl group to the rest of the molecule is through a carbon atom in the heterocyclyl group. Representative examples of C-heterocyclyl groups include 2- or 3-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl. The term heterocyclyl also includes heterocycloalkyl, as disclosed above, which refers to a group of the formula -R c - heterocyclyl, wherein R c is an alkylene chain. The term heterocyclyl also includes heterocycloalkoxy, as used herein, which refers to a group of the formula -O-R c - heterocyclyl, wherein R c is an alkylene chain.

[0036] As used herein, the term "heteroaryl" used alone or as part of a larger moiety (e.g., "heteroarylalkyl" (also "heteroaralkyl") or "heteroarylalkoxy" (also "heteroaralkoxy")) refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 12 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes 5- to 6-membered monocyclic aromatic groups in which one or more ring atoms are O, N, or S. Representative examples of heteroaryl include thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidinyl, imidazopyridyl, pyrazinyl, pyridazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[l,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, and 1,2,3-triazol-5-yl. The term "heteroaryl" also includes groups in which the heteroaryl is fused to one or more rings (e.g., carbocyclyl or heterocyclyl) wherein the linking group or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. The heteroaryl group can be monocyclic, bicyclic or tricyclic. In some embodiments, the heteroaryl includes a heteroaryl ring fused to one or more (e.g., 1 or 2) different ring groups (e.g., carbocyclic or heterocyclic), wherein the linking group or point of attachment is on the heteroaryl ring, and in some embodiments, wherein the point of attachment is a heteroatom contained in the heterocyclic ring.

[0037] Thus, the term heteroaryl includes N-heteroaryl, as used herein, which refers to a heteroaryl group as defined above containing at least one nitrogen and wherein the point of attachment of the heteroaryl to the rest of the molecule is through a nitrogen atom in the heteroaryl group. The term heteroaryl also includes C-heteroaryl, as used herein, which refers to a heteroaryl group as defined above and wherein the point of attachment of the heteroaryl to the rest of the molecule is through a carbon atom in the heteroaryl group. The term heteroaryl also includes heteroaralkyl, as disclosed above, which refers to a group of the formula -R c- A heteroaryl group, wherein R c This refers to an alkylene chain as defined above. The term heteroaryl also includes heteroarylalkoxy (or heteroarylalkoxy), as used herein, which refers to a -OR chain linked by an oxygen atom. c - A heteroaryl group, wherein R c It is an alkylene group as defined above.

[0038] Unless otherwise stated, and unless any particular group is further defined for a compound or hydrogel of formula (I or II) disclosed herein, any group described herein may be substituted or unsubstituted. Representative examples of substituents may include alkyl groups (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), substituted alkyl groups (e.g., substituted C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), alkoxy groups (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), and substituted alkoxy groups (e.g., substituted C1-C6, C1-C5, C1-C4). C1-C3, C1-C2, C1), haloalkyl (e.g., CF3), alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkenyl (e.g., substituted C2-C6, C2-C5, C2-C4, C2-C3, C2), alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkynyl (e.g., substituted C2-C6, C2-C5, C2-C4, C2-C3, C2), cycloyl (e.g., C3-C1), alkyl (e.g., C3-C1), alkyl (e.g., C1-C3, C1-C2, C1), alkyl (e.g., substituted C2-C6, C2-C5, C2-C4, C2-C3, C2), cycloyl (e.g., C3-C1), alkyl (e.g., C1-C3, C1-C2, C1), alkyl (e.g., C1-C ... 12 (C5-C6), substituted cyclic groups (e.g., substituted C3-C6), and substituted cyclic groups. 12 C5-C6), carbocyclic groups (e.g., C3-C6), and carbonyl groups. 12 (C5-C6), substituted carbocyclic groups (e.g., substituted C3-C6), and substituted carbocyclic groups. 12 (C5-C6), heterocyclic groups (e.g., 3 to 12 members, 5 to 6 members), substituted heterocyclic groups (e.g., substituted 3 to 12 members, 5 to 6 members), aryl groups (e.g., benzyl and phenyl), substituted aryl groups (e.g., substituted benzyl or substituted phenyl), heteroaryl groups (e.g., pyridyl or pyrimidinyl), substituted heteroaryl groups (e.g., substituted pyridyl or substituted pyrimidinyl), aralkyl groups (e.g., benzyl), substituted aralkyl groups (e.g., substituted benzyl), halogens, hydroxyl groups, aryloxy groups (e.g., C6-C6), etc. 12 C6), substituted aryloxy groups (e.g., substituted C6-C), and substituted aryloxy groups. 12 C6), alkyl thio (e.g., C1-C6), substituted alkyl thio (e.g., substituted C1-C6), aryl thio (e.g., C6-C6), alkyl thio (e.g., C1-C6), substituted alkyl thio (e.g., C1-C6), aryl thio (e.g., C6-C6), alkyl thio (e.g., C1- 12 C6), substituted aryl thio groups (e.g., substituted C6-C...).12 cyano, carbonyl, substituted carbonyl, carboxy, substituted carboxy, amino, substituted amino, amido, substituted amido, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acid, and peptide. Terminal substituents (unless otherwise specified) can include C1-C6alkyl, C1-C6alkoxy, halogen, hydroxyl, cyano, or amino.

[0039] In one aspect, the compounds of the present disclosure are represented by Formula I: (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: p is 0 or 1 ; q is 0 or 1 ; R1is (C1-C8)alkyl, (C3-C 10 )carbocyclyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, carbocyclyl, or heterocyclyl is further optionally substituted, or R1and R2together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl, or R1and R3together with the atoms to which they are attached form a 5- to 7- membered heterocyclyl; R2is hydrogen, (C1-C8)alkyl, chloro, bromo, or iodo; R3is hydrogen, (C1-C8)alkyl, chloro, bromo, or iodo; L1is absent or a linker; L2is absent or a linker; X is a leaving group; and R4and R4’ are independently a polymerizable moiety or a chemical moiety, provided that at least one of R4and R4’ is a polymerizable moiety.

[0040] In some embodiments, L1is absent.

[0041] In some embodiments, L2is absent.

[0042] In some embodiments, L1is a linker.

[0043] In some embodiments, L2is a linker.

[0044] A linker provides a covalent linkage between the two atoms to which it is bound, and it does not react with other groups in the compound.

[0045] In some embodiments, the linking group is an alkylene chain, which can be interrupted by at least one of the following and / or terminated (at either or both ends) by at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C 12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C 24 alkyl, wherein the interrupting group and the one or two terminating groups can be the same or different.

[0046] In some embodiments, the alkylene chain is C1-C 24 alkylene chain. In some embodiments, the alkylene chain is C1-C 18 alkylene chain. In some embodiments, the alkylene chain is C1-C 12 alkylene chain. In some embodiments, the alkylene chain is C1-C 10alkylene chain is C1-C8 alkylene chain. In some embodiments, the alkylene chain is C1-C6 alkylene chain. In some embodiments, the alkylene chain is C1-C4 alkylene chain. In some embodiments, the alkylene chain is C1-C2 alkylene chain. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by at least one of the following: -N(R')-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)O-, -OC(O)N(R')-, -S(O)2-, -N(R')S(O)2-, -S(O)2N(R')-, a 4- to 6-membered heterocyclyl, or a combination thereof. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by -N(R')-. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by -C(O)-. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by -C(O)O-. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by -C(O)N(R')-. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by -N(R')S(O)2-. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by a 4- to 6-membered heterocyclyl.

[0047] In some embodiments, the linker is a polyethylene glycol chain which can be interrupted by at least one of the following and / or terminated (at either or both termini) with at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C 12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C 24 alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different.

[0048] In some embodiments, the polyethylene glycol chain has 1 to 20 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol chain has 1 to 15 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol chain has 1 to 10 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol chain has 1 to 6 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol chain has 1 to 2 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol is interrupted by at least one of and / or terminated (at either or both termini) with at least one of -N(R')-, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)0-, -OC(0)N(R')-, -S(0)2-, -N(R')S(0)2-, -S(0)2N(R')-, a 4- to 6-membered heterocyclyl, or combinations thereof. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -N(R')-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -C(O)-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -C(0)0-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -C(0)N(R')-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -N(R')S(0)2-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with a 4- to 6-membered heterocyclyl.

[0049] In some embodiments, R1is (C1-C8)alkyl, (C3-C 10 )carbocyclyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, carbocyclyl, or heterocyclyl is further optionally substituted. In some embodiments, R1is (C1-C8)alkyl. In some embodiments, R1is methyl.

[0050] In some embodiments, R1and R2together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl.

[0051] In some embodiments, R1and R3together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl.

[0052] In some embodiments, R2is hydrogen. In some embodiments, R2is methyl. In some embodiments, R2is chloro. In some embodiments, R2is bromo. In some embodiments, R2is iodo.

[0053] In some embodiments, R3is hydrogen. In some embodiments, R3is methyl. In some embodiments, R3is chloro. In some embodiments, R3is bromo. In some embodiments, R3is iodo.

[0054] In some embodiments, X is a leaving group, as known in the art, which refers to an atom or group of atoms that departs from the rest of the molecule, taking with it the electron pair that was once shared between the leaving group and the rest of the molecule. Representative examples of leaving groups include esters, carbonates, carbamates, sulfoxides, sulfonates, sulfates, sulfones, thioesters, and thioformates. In some embodiments, the leaving group is OR9, SR9, -OC(0)R9, -OC(0)OR9, -OC(0)NR9R9, -OC(S)R9, -OC(S)OR9, -OC(S)NR9R9, -OS(0)2R9, -OS(0)2OR9, -OP(0)OR9OR9, -OP(0)R9R9, -SC(0)R9, -SC(0)SR9, or -SC(S)SR9, where each R9is independently hydrogen, (Ci-C6)alkyl, (C3-C6)cycloalkyl, or 4- to 7-membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted. 10 )carbocyclyl, or 4- to 7-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted.

[0055] As known in the art, a polymerizable moiety refers to a molecule that reacts with another molecule (which can be the same or different) to form a polymer and a copolymer, respectively. Representative examples of polymerizable moieties that can be suitable for use in the preparation of the disclosed polymers / hydrogels include: carboxymethylcellulose, hydroxypropylmethylcellulose, and hydroxyethylcellulose.

[0056] In some embodiments, R4and R4' are polymerizable moieties. In some embodiments, R4and R4' are acrylamides.

[0057] In some embodiments, R4is a polymerizable moiety and R4' is a chemical moiety. In some embodiments, R4is a chemical moiety and R4' is a polymerizable moiety. In some embodiments, the chemical moiety is a carboxylic acid, an amine, a sulfonic acid, a phenol, a catechol, a metal chelator, a PEG chain, or a drug molecule.

[0058] In some embodiments, the compound of Formula I is a compound of Formula la: (Ia), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0059] In some embodiments, the optional substituents of the compound of Formula I are independently alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N- arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylsulfanyl, haloalkylsulfanyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N- arylaminosulfonyl, N-alkyl-N-heteroaryaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N- arylaminocarbonyl, N-alkyl-N-heteroarylamino carbonyl, cyano, nitro, and azido.

[0060] In some embodiments, the compound of Formula I is a compound of Formula Ia1 or Ia2: (Ia1) or (Ia2), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0061] In some embodiments, the compound of Formula I is: or or a pharmaceutically acceptable salt or stereoisomer thereof.

[0062] Another aspect of the present disclosure relates to a modifiable polymer / hydrogel that is the reaction product of: i) a compound of Formula I: (I), ii) a polymerizable moiety that is the same or different than R4and / or R4', and iii) an initiator, wherein: R1is (Ci-C8)alkyl, (C3-C 10 )carbocyclyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, carbocyclyl, or heterocyclyl is further optionally substituted, or R1and R2together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl, or R1and R3together with the atoms to which they are attached form a 5- to 7- membered heterocyclyl; R2is hydrogen, (Ci-C8)alkyl, chloro, bromo, or iodo; R3is hydrogen, (Ci-C8)alkyl, chloro, bromo, or iodo; L1is absent or a linker; L2is absent or a linker; X is a leaving group; and R4and R4' are independently a polymerizable moiety or a chemical moiety, with the proviso that at least one of R4and R4' is a polymerizable moiety.

[0063] In some embodiments, L1is absent.

[0064] In some embodiments, L2is absent.

[0065] In some embodiments, L1is a linker.

[0066] In some embodiments, L2is a linker.

[0067] In some embodiments, the linking group is an alkylene chain, which can be interrupted by at least one of the following and / or terminated (at either or both ends) by at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C 12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C 24 alkyl, wherein the interrupting group and the one or two terminating groups can be the same or different.

[0068] In some embodiments, the alkylene chain is C1-C 24 alkylene chain. In some embodiments, the alkylene chain is C1-C 18 alkylene chain. In some embodiments, the alkylene chain is C1-C 12 alkylene chain. In some embodiments, the alkylene chain is C1-C 10alkylene chain is a C1-C8alkylene chain. In some embodiments, the alkylene chain is a C1-C6alkylene chain. In some embodiments, the alkylene chain is a C1-C4alkylene chain. In some embodiments, the alkylene chain is a C1-C2alkylene chain. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by at least one of the following: -N(R')-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)O-, -OC(O)N(R')-, -S(O)2-, -N(R')S(O)2-, -S(O)2N(R')-, a 4- to 6-membered heterocyclyl, or a combination thereof. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by -N(R')-. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by -C(O)-. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by -C(O)O-. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by -C(O)N(R')-. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by -N(R')S(O)2-. In some embodiments, the alkylene chain is interrupted by and / or terminated (at either or both termini) by a 4- to 6-membered heterocyclyl.

[0069] In some embodiments, the linker is a polyethylene glycol chain which can be interrupted by at least one of the following and / or terminated (at either or both termini) with at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C 12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C 24 alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different.

[0070] In some embodiments, the polyethylene glycol chain has 1 to 20 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol chain has 1 to 15 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol chain has 1 to 10 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol chain has 1 to 6 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol chain has 1 to 2 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol is interrupted by at least one of and / or terminated (at either or both termini) with at least one of -N(R')-, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)0-, -OC(0)N(R')-, -S(0)2-, -N(R')S(0)2-, -S(0)2N(R')-, a 4- to 6-membered heterocyclyl, or combinations thereof. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -N(R')-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -C(O)-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -C(0)0-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -C(0)N(R')-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -N(R')S(0)2-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with a 4- to 6-membered heterocyclyl.

[0071] In some embodiments, R1is (C1-C8)alkyl, (C3-C 10 )carbocyclyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, carbocyclyl, or heterocyclyl is further optionally substituted. In some embodiments, R1is (C1-C8)alkyl. In some embodiments, R1is methyl.

[0072] In some embodiments, R1and R2together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl.

[0073] In some embodiments, R1and R3together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl.

[0074] In some embodiments, R2is hydrogen. In some embodiments, R2is methyl. In some embodiments, R2is chloro. In some embodiments, R2is bromo. In some embodiments, R2is iodo.

[0075] In some embodiments, R3is hydrogen. In some embodiments, R3is methyl. In some embodiments, R3is chloro. In some embodiments, R3is bromo. In some embodiments, R3is iodo.

[0076] In some embodiments, X is a leaving group, which as known in the art, refers to an atom or group of atoms that departs from the rest of the molecule, taking with it the electron pair that was once shared between the leaving group and the rest of the molecule. Representative examples of leaving groups include esters, carbonates, carbamates, sulfoxides, sulfonates, sulfates, sulfones, thioesters, and thioformates. In some embodiments, the leaving group is OR9, SR9, -OC(0)R9, -OC(0)OR9, -OC(0)NR9R9, -OC(S)R9, -OC(S)OR9, -OC(S)NR9R9, -OS(0)2R9, -OS(0)2OR9, -OP(0)OR9OR9, -OP(0)R9R9, -SC(0)R9, -SC(0)SR9, or -SC(S)SR9, where each R9is independently hydrogen, (Ci-C6)alkyl, (C3-C6)carbocyclyl, or 4- to 7-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted. 10 )carbocyclyl, or 4- to 7-membered heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted.

[0077] In some embodiments, the polymerizable moiety is the same as R4and / or R4'. In this case, the modifiable polymer is a homopolymer.

[0078] In some embodiments, the polymerizable moiety is different from R4and / or R4', and the modifiable polymer / hydrogel is a copolymer, such as a random or block copolymer. In some embodiments, the polymerizable moiety comprises two or more different polymerizable moieties, such as vinyl chloride and vinyl alcohol; styrene and acrylamide; or vinyl chloride, styrene, and acrylamide.

[0079] In some embodiments, R4and R4' are polymerizable moieties. In some embodiments, R4and R4' are acrylamides.

[0080] In some embodiments, R4is a polymerizable moiety and R4' is a chemical moiety. In some embodiments, R4is a chemical moiety and R4' is a polymerizable moiety. In some embodiments, the chemical moiety is a carboxylic acid, amine, sulfonic acid, phenol, catechol, metal chelator, PEG chain, or drug molecule.

[0081] As known in the art, an initiator is a chemical species that reacts with a polymerizable monomer to form an intermediate compound that is capable of being continuously linked to a large number of other polymerizable monomers. Representative examples of initiators include peroxides (e.g., benzoyl peroxide, di-tert-butyl peroxide, methyl ethyl ketone peroxide, acetone peroxide, and peroxodisulfate) and aliphatic azo compounds (e.g., azobisisobutyronitrile (AIBN), azobis(cyclohexanecarbonitrile) (ACHN), and diethyl diazene).

[0082] Other aspects of the present disclosure relate to a modifiable polymer / hydrogel that is the reaction product of: i) a 4-arm-cyclooct-2-yn-1-yl, ; and ii) a dihydroxylamine, , wherein each X1is a leaving group; each L is a linking group; and each R5is (C1-C8)alkyl, (C3-C 10 )carbocyclyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, carbocyclyl, or heterocyclyl is further optionally substituted.

[0083] In some embodiments, the linking group is an alkylene chain, which can be interrupted by at least one of the following and / or terminated (at either or both termini) by at least one of the following: -O-, -S-, -N(R')-, -CºC-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -R'C(O)N(R')R'-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R')S(O)2-, -S(O)2N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O)2N(R')-, -N(R')S(O)N(R')-, -OP(O)O(R')O-, -N(R')P(O)N(R'R')N(R')-, C3-C 12carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C8alkyl, wherein the interrupting group and the one or two terminating groups can be the same or different. 24 alkyl, wherein the interrupting group and the one or two terminating groups can be the same or different.

[0084] In some embodiments, the alkylene chain is a C1-C 24 alkylene chain. In some embodiments, the alkylene chain is a C1-C 18 alkylene chain. In some embodiments, the alkylene chain is a C1-C 12 alkylene chain. In some embodiments, the alkylene chain is a C1-C 10 alkylene chain. In some embodiments, the alkylene chain is a C1-C8alkylene chain. In some embodiments, the alkylene chain is a C1-C6alkylene chain. In some embodiments, the alkylene chain is a C1-C4alkylene chain. In some embodiments, the alkylene chain is a C1-C2alkylene chain. In some embodiments, the alkylene chain is interrupted by at least one of –N(R')–, –C(O)–, –C(O)O–, –OC(O)–, –C(O)N(R')–, –N(R')C(O)–, –N(R')C(O)O–, –OC(O)N(R')–, –S(O)2–, –N(R')S(O)2–, –S(O)2N(R')–, 4- to 6-membered heterocyclyl, or a combination thereof, and / or terminated (at either or both termini) by at least one of –N(R')–, –C(O)–, –C(O)O–, –OC(O)–, –C(O)N(R')–, –N(R')C(O)–, –N(R')C(O)O–, –OC(O)N(R')–, –S(O)2–, –N(R')S(O)2–, –S(O)2N(R')–, 4- to 6-membered heterocyclyl, or a combination thereof. In some embodiments, the alkylene chain is interrupted and / or terminated (at either or both termini) by –N(R')–. In some embodiments, the alkylene chain is interrupted and / or terminated (at either or both termini) by –C(O)–. In some embodiments, the alkylene chain is interrupted and / or terminated (at either or both termini) by –C(O)O–. In some embodiments, the alkylene chain is interrupted and / or terminated (at either or both termini) by –C(O)N(R')–. In some embodiments, the alkylene chain is interrupted and / or terminated (at either or both termini) by –N(R')S(O)2–. In some embodiments, the alkylene chain is interrupted and / or terminated (at either or both termini) by 4- to 6-membered heterocyclyl.

[0085] In some embodiments, the linker is a polyethylene glycol chain which can be interrupted by at least one of the following and / or terminated (at either or both termini) with at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C 12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C 24 alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different.

[0086] In some embodiments, the polyethylene glycol chain has 1 to 20 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol chain has 1 to 15 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol chain has 1 to 10 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol chain has 1 to 6 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol chain has 1 to 2 -(CH2CH2-0)- units. In some embodiments, the polyethylene glycol is interrupted by at least one of and / or terminated (at either or both termini) with at least one of -N(R')-, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)0-, -OC(0)N(R')-, -S(0)2-, -N(R')S(0)2-, -S(0)2N(R')-, a 4- to 6-membered heterocyclyl, or combinations thereof. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -N(R')-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -C(O)-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -C(0)0-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -C(0)N(R')-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with -N(R')S(0)2-. In some embodiments, the polyethylene glycol chain is interrupted by and / or terminated (at either or both termini) with a 4- to 6-membered heterocyclyl.

[0087] In some embodiments, R5 is (Ci-C8)alkyl. In some embodiments, R5 is methyl.

[0088] In some embodiments, X1 is a leaving group, which as known in the art, refers to an atom or group of atoms that departs from the rest of the molecule, taking with it the electron pair that was formerly between the leaving group and the rest of the molecule. Representative examples of leaving groups include esters, carbonates, carbamates, sulfoxides, sulfonates, sulfates, sulfones, thioesters, and thioformates. In some embodiments, the leaving group is OR9, SR9, -OC(0)R9, -OC(0)OR9, -OC(0)NR9R9, -OC(S)R9, -OC(S)OR9, -OC(S)NR9R9, -OS(0)2R9, -OS(0)2OR9, -OP(0)OR9OR9, -OP(0)R9R9, -SC(0)R9, -SC(0)SR9, or -SC(S)SR9, wherein each R9 is independently hydrogen, (Ci-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, heterocyclyl, or combinations thereof.10 ) carbon or 4- to 7-membered heterocyclyl, wherein said alkyl, carbon or heterocyclyl is optionally substituted.

[0089] In some embodiments, the dihydroxylamine is or , or a stereoisomer thereof, wherein n is an integer from 1 to 10,000. In some embodiments, the dihydroxylamine is about 2 kDa. In some embodiments, the dihydroxylamine is about 1 kDa. In some embodiments, the dihydroxylamine is about 400 Da.

[0090] In some embodiments, the 4-arm-cyclooct-2-yn-1-yl is of Formula II: (II) or a stereoisomer thereof, wherein n is an integer from 1 to 10,000. In some embodiments, the 4-arm-cyclooct-2-yn-1-yl is about 10 kDa.

[0091] In some embodiments, the optional substituents of the hydrogel are independently alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylsulfonyl, N-alkyl-N-heteroarylsulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylcabonyl, N-alkyl-N-heteroarylcabonyl, cyano, nitro, and azido.

[0092] The compounds of the present disclosure can be in the form of a free acid or a free base, or a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of the compounds of the present disclosure can be formed, for example, by reaction of a suitable free base of a compound of the present disclosure with a suitable pharmaceutically acceptable acid in a suitable solvent under standard conditions well known in the art. See, e.g., Gould, P. L., "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, R. J., et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000); and Berge, S. M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19 (1977).

[0093] The compounds of the present disclosure can have at least one chiral center and therefore can be in the form of stereoisomers, as used herein, stereoisomers encompass all isomers of a single compound that differ only in the orientation of their atoms in space. The term stereoisomers includes mirror image isomers (enantiomers, including (R-) or (S-) configurations of a compound), mixtures of mirror image isomers (physical mixtures of enantiomers as well as racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of a compound, and isomers of a compound having more than one chiral center that are not mirror images of each other (diastereomers). Chiral centers of a compound can undergo epimerization in vivo; therefore, for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Thus, the compounds of the present disclosure can be prepared and used in the form of a single isomer and substantially free of other isomers, or in the form of a mixture of various isomers (e.g., a racemic mixture of stereoisomers).

[0094] In some embodiments, the compound of Formula I or hydrogel is an isotopically- substituted derivative, i.e., it has at least one atom replaced by a desired isotope and the amount of the isotope is higher than the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound contains deuterium or multiple deuterium atoms. As used herein, the term “compound” encompasses isotopically-substituted derivatives.

[0095] Synthetic methods In another aspect, the present disclosure relates to a method of preparing a compound of Formula I, a modifiable polymer / hydrogel which is the reaction product of a compound of Formula I, a polymerizable moiety, and an initiator, or a modifiable polymer / hydrogel which is the reaction product of a 4-arm-cyclooct-2-yn-1-yl and dihydroxylamine. Broadly, the compounds and pharmaceutically acceptable salts and stereoisomers thereof can be prepared by any method known to be applicable to the preparation of chemically-related compounds. The compounds of the present disclosure, e.g., a compound of Formula I, a modifiable polymer / hydrogel which is the reaction product of a compound of Formula I, a polymerizable moiety, and an initiator, and a modifiable polymer / hydrogel which is the reaction product of a 4-arm-cyclooct-2-yn-1-yl and dihydroxylamine, will be better understood in connection with the synthetic schemes described in the various working examples, which illustrate non-limiting methods by which the compounds can be prepared.

[0096] The compounds of Formula I can be prepared by methods known to those skilled in the art. In one non-limiting example, the disclosed compounds can be prepared by the following scheme.

[0097] Scheme 1. Representative synthetic procedure for a compound of Formula la In another aspect, the present disclosure relates to a method of preparing a modifiable polymer / hydrogel which is the reaction product of: i) a compound of Formula I: (I), ii) a polymerizable moiety which is the same or different than R4and / or R4’, and iii) an initiator.

[0098] As is known in the art, random or block copolymers can be prepared by varying the amount of “polymerizable moiety” (reactant (ii)) or the order in which it / they are added.

[0099] In some embodiments, the reaction is carried out in the presence of a solvent.

[0100] In some embodiments, the solvent is an aprotic solvent. In some embodiments, the aprotic solvent is DCM, CHCl3, CCl4, DCE, toluene, MeCN, or THF.

[0101] In some embodiments, the solvent is a protic solvent. In some embodiments, the protic solvent is water, MeOH, EtOH, iPrOH, nBuOH, TFE, or HFIP.

[0102] In some embodiments, the solvent is a solvent mixture. In some embodiments, the solvent mixture is a mixture of an aprotic solvent and a protic solvent. In some embodiments, the ratio of protic solvent to aprotic solvent in the solvent mixture is 0-100%. The use of aqueous solvents results in a modifiable hydrogel, while the use of non-aqueous solvents results in a modifiable polymer.

[0103] In some embodiments, the solvent is a buffered solvent. In some embodiments, the buffered solvent is phosphate buffered saline. In some embodiments, the phosphate buffered saline has a pH of about 7.4.

[0104] In some embodiments, the reaction is carried out in a solvent at a concentration of 1-25% by weight. In some embodiments, the concentration is 1, 5, 10, or 15% by weight.

[0105] In some embodiments, the reaction ratio of Formula I to polymer is 1-20% by weight. In some embodiments, the ratio of Formula I to polymer is 3, 6, or 12% by weight.

[0106] In some embodiments, the reaction is carried out for a week. In some embodiments, the reaction is carried out for five days. In some embodiments, the reaction is carried out for three days. In some embodiments, the reaction is carried out for a 24 hour period. In some embodiments, the reaction is carried out for an 18 hour period. In some embodiments, the reaction is carried out for a 12 hour period. In some embodiments, the reaction is carried out for a 6 hour period. In some embodiments, the reaction is carried out for a 3 hour period. In some embodiments, the reaction is carried out for a 2 hour period. In some embodiments, the reaction is carried out for a 1 hour period. In some embodiments, the reaction is carried out for a 45 minute period. In some embodiments, the reaction is carried out for a 30 minute period. In some embodiments, the reaction is carried out for a 15 minute period. In some embodiments, the reaction is carried out for a 5 minute period. In some embodiments, the reaction is carried out for a 1 minute period.

[0107] In some embodiments, the solvent is added after the reaction product is formed. In the initial as-built state, the reaction product is a modifiable polymer. When solvent (e.g., water) is introduced, it swells, resulting in a hydrogel.

[0108] In some embodiments, the method of preparing a hydrogel comprises the following operations or steps: 1) dissolving a polymerizable moiety (e.g., acrylamide) in water at a desired weight to volume ratio and stirring for a period of time; 2) adding the solution obtained in step 1) to a mixture containing a compound of Formula I, a catalyst (e.g., tetramethyl ethylene diamine (TMEDA)), an initiator (e.g., ammonium persulfate (APS)), and calcium sulfate (CaS04) and stirring for a period of time; 3) storing the mixture obtained in step 3 at room temperature for a period of time to form a hydrogel.

[0109] In another aspect, the present disclosure relates to a method of preparing a modifiable polymer / hydrogel, which is the reaction product of 1 equivalent of 4-arm-cyclooct-2-yn-1-yl and 2 equivalents of dihydroxylamine .

[0110] In some embodiments, the reaction is carried out in the presence of a solvent.

[0111] In some embodiments, the solvent is an aprotic solvent. In some embodiments, the aprotic solvent is DCM, CHCl3, CCl4, DCE, toluene, MeCN, or THF.

[0112] In some embodiments, the solvent is a protic solvent. In some embodiments, the protic solvent is water, MeOH, EtOH, iPrOH, nBuOH, TFE, or HFIP.

[0113] In some embodiments, the solvent is a mixture of solvents. In some embodiments, the mixture of solvents is a mixture of an aprotic solvent and a protic solvent. In some embodiments, the ratio of protic solvent to aprotic solvent in the mixture of solvents is 0-100%. The use of an aqueous solvent results in a modifiable hydrogel, while the use of a non-aqueous solvent results in a modifiable polymer.

[0114] In some embodiments, the solvent is a buffered solvent. In some embodiments, the buffered solvent is phosphate buffered saline. In some embodiments, the phosphate buffered saline has a pH of about 7.4.

[0115] In some embodiments, the reaction is carried out in a solvent at a concentration of 1-25% by weight. In some embodiments, the concentration is 1, 5, 10, or 15% by weight.

[0116] In some embodiments, the reaction ratio of Formula I to polymer is 1-20% by weight. In some embodiments, the ratio of Formula I to polymer is 3, 6, or 12% by weight.

[0117] In some embodiments, the reaction proceeds for one week. In some embodiments, the reaction proceeds for five days. In some embodiments, the reaction proceeds for three days. In some embodiments, the reaction proceeds for a 24 hour period. In some embodiments, the reaction proceeds for an 18 hour period. In some embodiments, the reaction proceeds for a 12 hour period. In some embodiments, the reaction proceeds for a 6 hour period. In some embodiments, the reaction proceeds for a 3 hour period. In some embodiments, the reaction proceeds for a 2 hour period. In some embodiments, the reaction proceeds for a 1 hour period. In some embodiments, the reaction proceeds for a 45 minute period. In some embodiments, the reaction proceeds for a 30 minute period. In some embodiments, the reaction proceeds for a 15 minute period. In some embodiments, the reaction proceeds for a 5 minute period. In some embodiments, the reaction proceeds for a 1 minute period.

[0118] In some embodiments, a solvent is added after the reaction product is formed. In the initial build state, the reaction product is a modifiable polymer. When a solvent (e.g., water) is introduced, it swells, making a hydrogel.

[0119] Methods of synthesizing hydrogels are known in the art. It is within the ability of one skilled in the art to modify the properties of the hydrogel (e.g., molecular weight and viscosity) to suit current clinical needs. See, Freedman et al., Adv. Mater., 2021, 33(17):e2008553 and Ahmed, J. Adv. Res., 2015, 6(2): 105-121. For example, a hydrogel of a desired viscosity is formed by adding an appropriate amount of water. To obtain a gel that changes viscosity in vivo, calcium citrate tetrahydrate can be added to the water component, or after gel formation, to obtain a gel of higher viscosity. See, PCT Pub. No. WO 2013 / 112381. Other parameters that can be varied to produce a hydrogel with a desired specific property include: % w / v crosslinker, % w / v monomer, solvent, mol% initiator, reaction time, temperature, and pH.

[0120] Methods of use As known in the art, hydrogels are useful as suitable drug delivery systems for drugs due to their tunable properties, controllable degradation, and ability to protect unstable drugs. See, Vigata et al., Pharmaceutics, 2020, 12(12): 1188. Thus, in some embodiments, an effective amount of a therapeutically active agent can be added at some point in the hydrogel preparation. As known in the art, modifiable non-hydrogel polymers are useful as films and plastics.

[0121] In some aspects, the present disclosure relates to methods of degrading modifiable polymers / hydrogels.

[0122] In some embodiments, the method comprises contacting the modifiable polymer / hydrogel with a diboron reagent.

[0123] In some embodiments, the diboron reagent is a symmetric diboron reagent. In some embodiments, the diboron reagent is an asymmetric diboron reagent. In some embodiments, the diboron reagent is B2(OH)4, B2pin2, , or . Other representative examples of diboron reagents include bis(o-phenolato)diboron, bis(hexanediol)diboron, bis[(-)pinanediol]diboron, bis(diisopropyl-l-tartrate diol)diboron, bis(N,N,N',N'-tetramethyl-d-tartramide diol)diboron, and 2,2'-bi-1,3,2-dioxaborinane. Still other diboron reagents that can be suitable for use in the present disclosure are disclosed in Ali et al., Studies in Inorganic Chemistry, “Chapter 1 - Chemistry of the diboron compounds” 22:1-57 (2005); Neeve et al., Chem. Rev. 116(16):9091-9161 (2016); Ding et al., Molecules 24(7):1325 (2019).

[0124] In some embodiments, the diboron reagent is used at a concentration of about 1 pM to about 1 M. In some embodiments, the diboron reagent is used at a concentration of about 1 pM to about 100 mM. In some embodiments, the diboron reagent is used at a concentration of about 1 pM to about 10 mM. In some embodiments, the diboron reagent is used at a concentration of about 1 pM to about 1 mM. In some embodiments, the diboron reagent is used at a concentration of about 1 pM to about 100 µM. In some embodiments, the diboron reagent is used at a concentration of about 1 pM to about 10 µM. In some embodiments, the diboron reagent is used at a concentration of about 1 pM to about 1 µM. In some embodiments, the diboron reagent is used at a concentration of about 1 pM to about 100 nM. In some embodiments, the diboron reagent is used at a concentration of about 1 pM to about 10 nM. In some embodiments, the diboron reagent is used at a concentration of about 1 pM to about 1 nM. In some embodiments, the diboron reagent is used at a concentration of about 1 pM to about 100 pM. In some embodiments, the diboron reagent is formulated in DMSO.

[0125] In some embodiments, the diboron solution contains a calcium chelator. In some embodiments, the calcium chelator is ethylenediaminetetraacetic acid (EDTA) or citric acid.

[0126] In some embodiments, the diboron reagent is formulated, e.g., into a solution, in water or saline. In some embodiments, the solution further comprises a solubilizing additive, e.g., DMSO. In some embodiments, the diboron reagent is formulated as a solid.

[0127] These and other aspects of the present disclosure will be further understood upon consideration of the following Examples, which are intended to illustrate certain particular embodiments of the present disclosure, but are not intended to limit the scope thereof, as defined by the claims. Examples

[0128] Example 1: Synthesis of (E)-N-(2-(2-propenoylaminoethoxy)ethyl)-3-(((2- propenoylaminoethyl)carbamoyl)oxy)-N-methylprop-1-en-1-amine oxide (1) N-(2-(2-iodoethoxy)ethyl)-3-(phenylsulfanyl)propanamide To a round bottom flask containing tert-butyl (2-(2-iodoethoxy)ethyl)carbamate (14.9 g, 47.3 mmol, 1.15 equiv) (Kang et al., Chem., 2022, 8(8):2260-2277) was added trifluoroacetic acid (TFA) in dichloromethane (DCM, 20% v / v, 200 mL). The resulting solution was stirred at room temperature (rt) for 1 hour. The solution was concentrated under reduced pressure and then azeotropically distilled with toluene (3 x 15 mL). The crude oil was left under reduced pressure for 3 hours.

[0129] To another round bottom flask was added 3-phenylsulfanylpropanoic acid (7.51 g, 41.2 mmol, 1.00 equiv) and purged with nitrogen. DCM (200 mL) was added via syringe. The solution was then cooled to 0 °C in an ice water bath. Oxalyl chloride (3.70 mL, 43.2 mmol, 1.05 equiv) and N,N-dimethylformamide (DMF, 60.4 μL, 0.780 mmol, 0.020 equiv) were then added dropwise via syringe. The reaction was monitored by1H NMR. The reaction was complete in 2 hours and the acyl chloride solution was stored at 0 °C until further use. 1 The reaction was monitored by1H NMR. The reaction was complete in 2 hours and the acyl chloride solution was stored at 0 °C until further use.

[0130] DCM (200 mL) was added to the crude oily mass containing the alkyl iodide and cooled to 0 °C in an ice water bath. Triethylamine (TEA, 12.9 mL, 94.7 mmol, 2.30 equiv) was added dropwise via syringe. The acyl chloride solution was then added dropwise via cannula. After 1 h, the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (250 mL). The aqueous layer was extracted with DCM (3 x 200 mL), the combined organic layers were washed with water (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude oily mass was purified by flash column chromatography on silica gel (eluent: 20→30% ethyl acetate / hexanes) to give the title compound as a white oil (8.05 g, 52%). 1 H NMR (500 MHz, CDCl3, 25 °C): δ 7.34 (dd, J = 8.3, 1.3 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H), 7.20–7.16 (m, 1H), 6.01 (s, 1H), 3.68 (t, J = 6.2 Hz, 2H), 3.53 (dd, J = 5.6, 4.5 Hz, 2H), 3.47–3.42 (m, 2H), 3.25–3.19 (m, 4H), 2.48 (t, J = 7.3 Hz, 2H).

[0131] N-(2-(2-(hydroxy(methyl)amino)ethoxy)ethyl)-3-(phenylsulfanyl)acrylamide To a round bottom flask was added N-(2-(2-iodoethoxy)ethyl)-3-(phenylsulfanyl)acrylamide (1.78 g, 4.69 mmol, 1 equiv) and N-methylhydroxylamine hydrochloride (785 mg, 9.40 mmol, 2.00 equiv) and then purged with nitrogen gas. Dimethyl sulfoxide (DMSO, 5 mL) and TEA (2.63 mL, 18.8 mmol, 4.00 equiv) were added via syringe. The reaction mixture was heated to 70 °C and stirred for 2 h. The mixture was then cooled to 0 °C in an ice water bath and diluted with saturated aqueous sodium bicarbonate solution (10 mL). The aqueous layer was extracted with ethyl acetate (3 x 30 mL), the combined organic layers were washed with water (4 x 100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude oily mass was purified by flash column chromatography on silica gel (eluent: 10→30% CMA / chloroform) to give the title compound as a yellowish oil (672 mg, 47%). 1H NMR (500 MHz, CDC13, 25 °C): δ 7.33 (dd, J = 8.2, 1.3 Hz, 2H), 7.26 (t, J = 7.7 Hz, 2H), 7.20 - 7.13 (m, 1H), 6.55 (s, NH), 3.68 - 3.55 (m, 2H), 3.51 (t, J = 5.1 Hz, 2H), 3.46 - 3.37 (m, 2H), 3.21 (t, J = 7.4 Hz, 2H), 2.79 (s, 2H), 2.64 (s, 3H), 2.50 (t, J = 7.4 Hz, 2H).

[0132] tert-Butyl (2-(3-(phenylthio)propanamido)ethyl)carbamate To a round bottom flask was added 3-phenylthiopropanoic acid (1.09 g, 6.00 mmol, 1 equiv) and l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 2.51 g, 6.60 mmol, 1.10 equiv) and purged with nitrogen. DMF (10 mL) was added via syringe, followed by diisopropylethylamine (DIPEA, 3.14 mL, 18.0 mmol, 3.00 equiv) and stirred at room temperature. After 15 minutes, N-Boc-ethylenediamine (1.14 mL, 7.12 mmol, 1.20 equiv) was added via syringe. After 16 hours, the reaction was quenched with water (50 mL) and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (4 x 300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography on silica gel (eluent: 30% ethyl acetate / hexanes) to afford the title compound as a white solid (2.01 g, 98%). 1H NMR (500 MHz, CDCl3, 25 °C): δ 7.34 (dd, J = 8.3, 1.3 Hz, 2H), 7.27 (dd, J = 8.5, 6.9 Hz, 2H), 7.20 - 7.16 (m, 1H), 6.17 (s, NH), 4.86 (s, NH), 3.32 (td, J = 6.5, 5.5, 4.3 Hz, 2H), 3.24 (d, J = 5.4 Hz, 2H), 3.19 (t, J = 7.3 Hz, 2H), 2.45 (t, J = 7.2 Hz, 2H), 1.41 (s, 9H).

[0133] Prop-2-yn-1-yl (2-(3-(phenylthio)propanamido)ethyl)carbamate To a round bottom flask containing tert-butyl (2-(3-(phenylthio)propanamido)ethyl)carbamate (2.01 g, 6.20 mmol, 1.00 equiv) was added TFA in DCM (50% v / v, 3 mL). After 2 h, the reaction mixture was concentrated under reduced pressure and then placed under reduced pressure for 2 h. To the crude oil was then added DCM (50 mL) and TEA (2.60 mL, 18.6 mmol, 3.00 equiv) sequentially via syringe. The solution was then cooled to 0 °C in an ice water bath. Propargyl chloroformate (637 μL, 6.53 mmol, 1.10 equiv) was added dropwise via syringe. After complete addition, the reaction mixture was allowed to warm to room temperature. After 3 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with DCM (3 x 50 mL), the combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting white solid was purified by flash column chromatography on silica gel (eluent: 20% ethyl acetate / hexanes) to give the title compound as a white solid (1.89 g, 99%). 1H NMR (500 MHz, CDCl3, 25°C): δ 7.37–7.32 (m, 2H), 7.31–7.26 (m, 2H), 7.21–7.16 (m, 1H), 5.96 (s, NH), 5.18 (s, NH), 4.64 (d, J = 2.4 Hz, 2H), 3.34 (dt, J = 18.6, 6.1 Hz, 4H), 3.20 (t, J = 7.2 Hz, 2H), 2.46 (t, J = 7.1 Hz, 2H), 2.43 (t, J = 2.4 Hz, 1H).

[0134] (E)-N-methyl-N-(2-(2-(3-(phenylsulfanyl)propanamido)ethoxy)ethyl)-3-(((2-(3- (phenylsulfanyl)propanamido)ethyl)carbamoyl)oxy)prop-1-en-1-amine oxide To a glass vial containing N-(2-(2-(hydroxy(methyl)amino)ethoxy)ethyl)-3- (phenylsulfanyl)acrylamide (141 mg, 0.473 mmol, 1.00 equiv) and prop-2-yn-1-yl (2-(3- (phenylsulfanyl)propanamido)ethyl)carbamate (137 mg, 0.447 mmol, 1.00 equiv) was added a solution of 2,2,2-trifluoroethanol in chloroform (20% v / v, 1 mL). The reaction was heated to 60 °C. After 16 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel flash column chromatography (eluent: 10→60% CMA / chloroform) to give the title compound as a yellow oil (116 mg, 42%). 1H NMR (500 MHz, CD3OD, 25 °C): δ 7.38–7.35 (m, 4H), 7.30 (t, J = 7.8 Hz, 4H), 7.21–7.17 (m, 2H), 6.52 (d, J = 13.4 Hz, 1H), 6.46 (dt, J = 13.2, 5.1 Hz, 1H), 4.64 (dd, J = 5.0, 1.4 Hz, 2H), 3.90 (ddd, J = 11.8, 6.1, 3.2 Hz, 1H), 3.76 (ddd, J = 11.9, 6.4, 3.1 Hz, 1H), 3.56–3.52 (m, 1H), 3.48 (t, J = 5.5 Hz, 2H), 3.38–3.32 (m, 3H), 3.26 (d, J = 5.8 Hz, 2H), 3.24 (s, 3H), 3.21–3.15 (m, 7H), 2.53–2.48 (m, 4H).

[0135] (E)-N-methyl-N-(2-(2-(3-(phenylsulfonyl)propanamido)ethoxy)ethyl)-3-(((2-(3- (phenylsulfonyl)propanamido)ethyl)carbamoyl)oxy)prop-1-en-1-amine oxide To a round bottom flask containing (E)-N-methyl-N-(2-(2-(3-(phenylsulfanyl)propanamido)ethoxy)ethyl)-3-(((2-(3-(phenylsulfanyl)propanamido)ethyl)carbamoyl)oxy)prop-1-en-1-amine oxide (2.52 g, 4.17 mmol, 1.00 equiv) was added methanol (75 mL). The solution was cooled to 0 °C in an ice water bath, then meta-chloroperoxybenzoic acid (4.57 g, 17.5 mmol, 4.20 equiv) was added. After 3 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: 10→60% CMA / chloroform) to give the title compound as a white solid (1.4 g, 52%). 1H NMR (500 MHz, CD3OD, 25 °C): δ 7.94 (t, J = 1.2 Hz, 2H), 7.93 (t, J = 1.3 Hz, 2H), 7.74 (td, J = 7.3, 1.3 Hz, 2H), 7.65 (td, J = 7.8, 1.8 Hz, 4H), 6.54 (d, J = 13.4 Hz, 1H), 6.51 - 6.43 (m, 1H), 4.67 - 4.63 (m, 2H), 4.58 (s, 1H), 3.88 (dd, J = 10.0, 6.4 Hz, 1H), 3.79 - 3.73 (m, 1H), 3.61 (t, J = 7.1 Hz, 1H), 3.55 (d, J = 3.6 Hz, 1H), 3.51 (td, J = 7.4, 2.3 Hz, 5H), 3.47 - 3.44 (m, 2H), 3.27 (t, J = 5.5 Hz, 2H), 3.25 (s, 3H), 3.21 (d, J = 4.5 Hz, 2H), 3.19 - 3.16 (m, 2H).

[0136] (E)-N-(2-(2-Propenoylaminoethoxy)ethyl)-3-(((2-propenoylaminoethyl)carbamoyl)oxy)-N-methylprop-1-en-1-amine oxide To a round bottom flask was added (E)-N-methyl-N-(2-(2-(3-(phenylsulfonyl)propanamido)ethoxy)ethyl)-3-(((2-(3-(phenylsulfonyl)propanamido)ethyl)carbamoyl)oxy)prop-1-en-1-amine oxide (241 mg, 0.360 mmol, 1.00 equiv) and purged with nitrogen. DMF (2 mL) was added via syringe and the reaction mixture was cooled to 0 °C in an ice water bath. Potassium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran (THF), 720 μL, 0.720 mmol, 2.00 equiv) was then added via syringe. After 30 min, the solvent was concentrated under reduced pressure and the crude mixture was purified by silica gel column chromatography (eluent: 10→30% methanol / dichloromethane, 0.2% triethylamine) to give the title compound as a off-white solid (74 mg, 53%). 1H NMR (500 MHz, CD3OD, 25 °C): δ 6.55 (d, J = 13.4 Hz, 1H), 6.50-6.46 (m, 1H), 6.30-6.17 (m, 4H), 5.68-5.63 (m, 2H), 4.73-4.63 (m, 2H), 3.93 (dq, J = 9.0, 2.9 Hz, 1H), 3.82-3.77 (m, 1H), 3.61-3.51 (m, 5H), 3.44 (dt, J = 9.4, 5.5 Hz, 2H), 3.39-3.35 (m, 2H), 3.27-3.25 (m, 4H).

[0137] Example 2: Synthesis of (E)-1-(3-(((2-vinylaminoethyl)carbamoyl)oxy)cyclooct-1-en-1- yl)-4-vinylpiperazine 1-oxide 4-((tert-butyldimethylsilyl)oxy)piperazine-1-carboxylic acid tert-butyl ester To a round bottom flask containing N-Boc-piperazine hydroxylamine (2.99 g, 14.8 mmol, 1.00 equiv) was added DCM (20 mL). The flask was purged with nitrogen and cooled to -78 °C in a dry ice-acetone bath. To this solution was added TEA (6.22 mL, 44.5 mmol, 3.00 equiv) followed by tert-butyldimethylsilyl triflate (4.09 mL, 17.8 mmol, 1.20 equiv) dropwise via syringe. The resulting mixture was allowed to warm to room temperature by removing the dry ice-acetone bath. After 1 h, the solution was diluted with saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with DCM (3 x 50 mL), the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude oil was purified by silica gel flash column chromatography (eluent: 5→ 15% ethyl acetate / hexanes) to give the title compound as a white solid (2.92 g, 62%). 1 H NMR (500 MHz, CDCl3, 25 °C): δ 3.89 (s, 2H), 2.97 (d, J = 12.4 Hz, 4H), 2.51 (td, J = 10.9, 3.4 Hz, 2H), 1.43 (s, 9H), 0.88 (s, 9H), 0.08 (s, 6H). 13CNMR (125.8 MHz, CDCl3, 25ºC): δ 154.9, 80.0, 57.9, 42.5, 52.1, 28.6, 26.4,18.1, –5.2.

[0138] 1-((tert-butyldimethylsilyl)oxy)piperazine To a round-bottom flask containing tert-butyl 4-((tert-butyldimethylsilyl)oxy)piperazine-1-carboxylate (350 mg, 1.11 mmol, 1.00 equiv) was added DCM (4 mL). Trimethylsilyl iodide (630 μL, 4.43 mmol, 4.00 equiv) was then added dropwise via syringe. After 5 min, the crude mixture was quenched with a mixture of saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate (50% v / v, 20 mL). The aqueous layer was extracted with DCM (3 x 10 mL), the combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil was used without further purification.

[0139] 1-(4-((tert-butyldimethylsilyl)oxy)piperazin-1-yl)prop-2-en-1-one To a round-bottom flask containing 1-((tert-butyldimethylsilyl)oxy)piperazine (1.10 g, 5.08 mmol, 1.00 equiv) was added DCM (20 mL), triethylamine (1.42 mL, 10.2 mmol, 2.00 equiv), and Amberlyst-26 (3.00 g, 60.0 mg per 0.10 mmol of 1-((tert-butyldimethylsilyl)oxy)piperazine) sequentially. The flask was then purged with nitrogen and cooled to 0 °C in an ice-water bath. Acryloyl chloride (452 μL, 5.59 mmol, 1.10 equiv) was added dropwise via syringe. The reaction mixture was allowed to warm to room temperature by removing the ice-water bath. After 45 min, the reaction mixture was quenched with methanol (500 μL) and then concentrated under reduced pressure. The crude oil was purified by flash column chromatography on silica gel (eluent: 15→30% ethyl acetate / hexanes) to give the title compound as a white foam (976 mg, 71% yield over two steps). 1H NMR (500 MHz, CDC13, 25 °C): δ 6.53 (dd, J = 16.8, 10.6 Hz, 1H), 6.26 (dd, J = 16.8, 1.9 Hz, 1H), 5.68 (dd, J = 10.6, 1.9 Hz, 1H), 4.34 (d, J = 13.4 Hz, 1H), 3.86 (d, J = 13.4 Hz, 1H), 3.30 (t, J = 12.1 Hz, 1H), 3.08 (d, J = 30.0 Hz, 3H), 2.58 (td, J = 10.7, 3.3 Hz, 2H), 0.89 (s, 9H), 0.09 (s, 6H).

[0140] (2-Propenylaminoethyl)carbamic acid cyclooct-2-yn-1-yl ester To a round bottom flask containing (2-aminoethyl)carbamic acid cyclooct-2-yn-1-yl ester (560 mg, 2.67 mmol, 1.00 equiv) was added DCM (10 mL), TEA (744 μL, 5.32 mmol, 2.00 equiv), and Amberlyst-26 (800 mg, 60.0 mg per 0.20 mmol of (2-aminoethyl)carbamic acid cyclooct-2-yn-1-yl ester) sequentially. The flask was then purged with nitrogen and cooled to 0 °C in an ice water bath. Acryloyl chloride (226 μL, 2.79 mmol, 1.05 equiv) was added dropwise via syringe. The reaction mixture was allowed to warm to room temperature by removing the ice water bath. After 45 min, the reaction mixture was quenched with methanol (500 μL) and then concentrated under reduced pressure. The crude oil was purified by silica gel flash column chromatography (eluent: 60→ 100% ethyl acetate / hexanes) to give the title compound as a white foam (471 mg, 67%). 1HNMR (500 MHz, CDCl3, 25℃): δ 6.55 (t, J = 5.6 Hz, 1H), 6.23 (dd, J = 17.1,1.5 Hz, 1H), 6.09 (dd, J = 17.0, 10.3 Hz, 1H), 5.60 (dd, J = 10.2, 1.5 Hz,1H), 5.35 (s, 1H), 5.22 (d, J = 3.5 Hz, 1H), 3.45–3.39 (m, 2H), 3.32 (d, J =5.8 Hz, 2H), 2.27–2.19 (m, 1H), 2.13 (dddd, J = 24.1, 14.2, 7.6, 3.9 Hz, 2H),1.95 (ddd, J = 14.4, 9.0, 6.6 Hz, 1H), 1.86 (dtt, J = 15.4, 7.2, 6.1, 2.3 Hz,2H), 1.78–1.70 (m, 1H), 1.67–1.57 (m, 2H), 1.54–1.44 (m, 1H). 13 C NMR (125.8MHz, CDCl3, 25ºC): δ 166.5, 156.8, 131.0, 126.7, 101.9, 91.1, 67.5, 42.0,40.9, 40.6, 34.4, 29.8, 26.3, 20.9.

[0141] (E)-1-(3-(((2-acrylamidoethyl)carbamoyl)oxy)cyclooct-1-en-1-yl)-4-acryloylpiperazine 1-oxide THF (1 mL) and (2-acrylamidoethyl)carbamate cyclooctyl-2-yn-1-yl ester (48.9 mg, 185 μmol, 1.00 equivalence) were added sequentially to a 4 mL glass vial containing 1-(4-((tert-butyldimethylsilyl)oxy)piperazin-1-yl)prop-2-en-1-one (50.0 mg, 185 μmol, 1.00 equivalence). The vial was purged with nitrogen. Tetrabutylammonium fluoride solution (1.0 M, in THF, 203 μL, 203 μmol, 1.10 equivalence) was added dropwise via syringe at room temperature. After 2 hours, the crude mixture was concentrated under reduced pressure and purified by silica gel rapid column chromatography (eluent: 5→20% methanol / DCM, 0.2% TEA) to give the title compound as a white foamy substance (73 mg, 94%).1 H NMR (500MHz, CD3OD, 25ºC): δ 6.82 (dd, J = 16.8, 10.7 Hz, 1H), 6.52–6.44 (m, 1H), 6.30–6.18 (m, 3H), 5.82 (dd, J = 10.6, 1.9 Hz, 1H), 5.67 (dd, J = 8.4, 3.7 Hz, 1H), 5.41 (ddd, J = 11.8, 7.5, 4.5 Hz, 1H), 4.61 (d, J = 12.4 Hz, 1H), 4.17 (d, J = 14.0 Hz, 1H), 4.05 (t, J = 13.1 Hz, 1H), 3.85 (dt, J = 24.5, 11.3 Hz, 1H), 3.69 (dq, J = 24.0, 13.0, 12.4 Hz, 2H), 3.36 (q, J = 6.4 Hz, 2H), 3.24 (dd, J = 7.1, 5.1 Hz, 3H), 3.11–2.99 (m, 1H), 2.84 (d, J = 15.9 Hz, 1H), 2.59 (ddd, J = 16.0, 12.7, 4.2 Hz, 1H), 2.01 (ddd, J = 13.8, 8.8, 4.2 Hz, 1H), 1.91 (ddd, J = 14.7, 7.6, 3.3 Hz, 1H), 1.79–1.51 (m, 6H), 1.34 (t, J = 7.3 Hz, 1H). 13 C NMR (125.8 MHz, CD3OD, 25ºC): δ 167.0, 166.1, 156.9, 130.7, 128.0, 127.0, 125.4, 124.4, 72.0, 39.9, 38.9, 34.6, 25.4, 24.8, 23.4.

[0142] Example 3: Synthesis of Polyamine-1 (E)-4-acryloyl-1-(3-(((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)oxy)cyclooct-1-en-1-yl)piperazine 1-oxide To a round bottom flask containing 1-(4-((tert-butyldimethylsilyl)oxy)piperazin-1-yl)prop-2-en-1-one (215 mg, 795 μmol, 1.00 equiv) was added THF (4 mL) and tert-butyl ethane-1,2-diylbis(carbamate) cyclooct-2-yn-1-yl ester (246 mg, 795 μmol, 1.00 equiv) sequentially. The flask was then purged with nitrogen and cooled to 0 °C in an ice water bath. A solution of tetra- butylammonium fluoride (1.0 M in THF, 880 μL, 880 μmol, 1.10 equiv) was then added dropwise via syringe and the solution was allowed to warm to room temperature by removing the ice water bath. After 2 h, the crude mixture was concentrated under reduced pressure and purified by silica gel flash column chromatography (eluent: 5→ 15% methanol / dichloromethane, 0.2% triethylamine) to give the title compound as a white foam (291 mg, 79%). 1 H NMR (500 MHz, CD3OD, 25 °C): δ 6.82 (dd, J = 16.8, 10.7 Hz, 1H), 6.41 (d, J = 7.2 Hz, 1H), 6.30 (dd, J = 16.8, 1.9 Hz, 1H), 5.85 (dd, J = 10.7, 1.8 Hz, 1H), 5.44–5.32 (m, 1H), 4.76 (s, 1H), 4.36 (s, 1H), 3.95 (d, J = 49.5 Hz, 5H), 3.58 (s, 1H), 3.28–3.24 (m, 7H), 3.22–3.09 (m, 4H), 2.89 (dt, J = 15.9, 4.2 Hz, 1H), 2.68 (ddd, J = 16.4, 12.5, 4.1 Hz, 1H), 2.17 (s, 2H), 2.00 (dddd, J = 41.1, 10.0, 7.8, 3.9 Hz, 2H), 1.45 (s, 9H). 13 C NMR (125.8 MHz, CD3OD, 25 °C): δ 166.1, 128.5, 126.6, 78.7, 71.8, 62.4, 62.0, 58.1, 40.6, 34.1, 29.9, 25.2, 24.5, 23.4, 23.0, 22.8, 19.3, 12.5.

[0143] Polyamine-1 To a glass vial containing (E)-4-acryloyl-1-(3-(((2-((tert- butoxycarbonyl)amino)ethyl)carbamoyl)oxy)cyclooct-1-en-1-yl)piperazine 1-oxide (104 mg, 220 μmol, 1.00 equiv) was added a solution of TFA in DCM (20% v / v, 2 mL). The resulting solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and then left under reduced pressure for 2 h. To the crude oil was added an aqueous phosphate buffer solution (100 mM, 110 μL) and tetramethylethylenediamine (10.6 μL, 71.0 μmol, 0.323 equiv) sequentially. The reaction mixture was degassed by bubbling nitrogen gas through for 5 min. Oxone (10.0 mg, 44.0 μmol, 0.20 equiv) was added in one portion under nitrogen and stirred at room temperature for 16 h. The reaction mixture was diluted with water to a final volume of 500 μL and purified by spin filter (3K MWCO, 4 x 3800 g) to give the polyamine-1 with a mass recovery of 52%.

[0144] Example 4: Synthesis procedure for chemically degradable polyacrylamide hydrogels Chemically degradable hydrogels were prepared following previous reports (Freedman et al., Adv. Mater., 2021, 33(17): e2008553) using (E)-N-(2-(2-acrylamidoethoxy)ethyl)-3-(((2-acrylamidoethyl)carbamoyl)oxy)-N-methylprop-1-en-1-amine oxide and (E)-1-(3-(((2-acrylamidoethyl)carbamoyl)oxy)cyclooct-1-en-1-yl)-4-acryloylpiperazine 1-oxide as chemical crosslinkers. Polyacrylamide gels were synthesized by mixing acrylamide in water at the desired weight volume percentage (e.g. 0.03 to 20 w / v%). To the fully dissolved solution was added the desired weight volume percentage of (E)-N-(2-(2-acrylamidoethoxy)ethyl)-3-(((2-acrylamidoethyl)carbamoyl)oxy)-N-methylprop-1-en-1-amine oxide or (E)-1-(3-(((2-acrylamidoethyl)carbamoyl)oxy)cyclooct-1-en-1-yl)-4-acryloylpiperazine 1-oxide. Tetramethylethylenediamine (2% w / v) and oxone (6.6% w / v) were added and briefly stirred. The resulting solution was left to gel. Gelling was verified by inversion test Figure 1 ) and remained at the bottom of the vial. A schematic of the procedure is shown in Figure 2 A range of polyacrylamide gels were synthesized and cast with different percentages of crosslinker (0.03 to 0.3 w / v%)Figure 3A ). Figure 3B Example 1 : Characterization of polyacrylamide hydrogels

[0145] Example 5: Degradation procedure for polyacrylamide hydrogels Chemically degradable gels were immersed in tetrahydroxydiboron (100 mM) in water. Degradation was verified by inverting the test tube Figures 4-6C ) and the degraded gel no longer remained at the bottom of the vial.

[0146] Example 6: Synthesis of 4-arm-PEG-COT and dihydroxylamine 4-arm PEG-COT 10 kDa 4-arm PEG-OTs To a round bottom flask containing 10 kDa 4-arm PEG-OH (Jenkem, 6.00 g, 0.600 mmol, 1.00 equiv), 4-dimethylaminopyridine (36.7 mg, 0.300 mmol, 0.500 equiv), and p-toluenesulfonyl chloride (686 mg, 3.60 mmol, 6.00 equiv) was added DCM (20 mL). TEA (1.01 mL, 7.20 mmol, 12.0 equiv) was then added via syringe and the resulting solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the resulting solid was re-dissolved in DCM (10 mL) and diethyl ether (200 mL). The mixture was stirred at room temperature for 30 minutes and then placed in a refrigerator (4 °C) for 6 hours. The precipitate was filtered, washed with diethyl ether (3 x 100 mL), and dried under reduced pressure to yield the title compound as a white solid (5.88 g, 98%).

[0147] 10 kDa 4-arm PEG-N3 To a round bottom flask was added 10 kDa 4-arm PEG-OTs (1.00 g, 0.100 mmol, 1.00 equiv) and sodium azide (32.5 mg, 0.500 mmol, 5.00 equiv) and purged with nitrogen. DMF (5 mL) was added via syringe and the resulting solution was heated to 60 °C and stirred for 16 h. The crude mixture was concentrated under reduced pressure and diluted with water (30 mL). The aqueous layer was extracted with DCM (3 x 20 mL), the combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid was re-dissolved in DCM (5 mL) and precipitated with diethyl ether (200 mL) at 4 °C for 6 h. The solid was filtered, washed with diethyl ether (3 x 100 mL), and dried under reduced pressure to give the title compound as a white solid (721 mg, 72%).

[0148] 10 kDa 4-arm PEG-NH2 To a round bottom flask was added 10 kDa 4-arm PEG-OTs (1.00 g, 0.100 mmol, 1.00 equiv) and sodium azide (32.5 mg, 0.500 mmol, 5.00 equiv) and purged with nitrogen. DMF (5 mL) was added via syringe and the resulting solution was heated to 60 °C and stirred for 16 h. The crude mixture was concentrated under reduced pressure and diluted with water (30 mL). The aqueous layer was extracted with DCM (3 x 20 mL), the combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid was re-dissolved in DCM (5 mL) and precipitated with diethyl ether (200 mL) at 4 °C for 6 h. The solid was filtered, washed with diethyl ether (3 x 100 mL), and dried under reduced pressure to give the title compound as a white solid (721 mg, 72%).

[0149] 10 kDa 4-arm PEG-COT To a round bottom flask was added 10 kDa 4-arm PEG-OTs (1.00 g, 0.100 mmol, 1.00 equiv) and sodium azide (32.5 mg, 0.500 mmol, 5.00 equiv) and purged with nitrogen. DMF (5 mL) was added via syringe and the resulting solution was heated to 60 °C and stirred for 16 h. The crude mixture was concentrated under reduced pressure and diluted with water (30 mL). The aqueous layer was extracted with DCM (3 x 20 mL), the combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid was re-dissolved in DCM (5 mL) and precipitated with diethyl ether (200 mL) at 4 °C for 6 h. The solid was filtered, washed with diethyl ether (3 x 100 mL), and dried under reduced pressure to give the title compound as a white solid (721 mg, 72%).

[0150] 2-arm PEG-NOH 400 Da 2-arm PEG-I To a round bottom flask containing triphenylphosphine (1.52 g, 3.00 mmol, 3.00 equiv) and imidazole (544 mg, 4.00 mmol, 4.00 equiv) was added DCM (15 mL). The flask was then purged with nitrogen and cooled to 0 °C in an ice water bath. To the stirring solution was added iodine (1.57 g, 3.00 mmol, 3.00 equiv) dissolved in DCM (5 mL) via syringe and the reaction mixture was allowed to warm to room temperature by removing the ice water bath. To this slurry was added 400 Da 2-arm PEG-OH (Jenkem, 800 mg, 2.00 mmol, 1.00 equiv) dissolved in DCM (2 mL) dropwise via syringe and the flask was covered with foil and stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure, diluted with ethyl acetate (20 mL), filtered through a bed of Celite®, and washed with cold ethyl acetate (3 x 20 mL). The solution was concentrated under reduced pressure, then diluted with saturated aqueous sodium bicarbonate solution and the aqueous layer was extracted with DCM (3 x 100 mL). The combined organic layers were washed with saturated aqueous sodium thiosulfate solution (100 mL), then with aqueous hydrochloric acid (1 N, 100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil was purified by flash column chromatography on silica gel (eluent: 5→ 10% methanol / DCM) to give an inseparable mixture of the title compound and triphenylphosphine oxide. The resulting off-white oil was used directly in the next step.

[0151] 400 Da 2-arm PEG-NOH·TFA A round bottom flask was charged with 400 Da 2-arm PEG-I (800 mg, 2.00 mmol, 1.00 equiv) and N-methyl-hydroxylamine hydrochloride (669 mg, 8.00 mmol, 4.00 equiv). The reaction flask was purged with nitrogen. DMSO (4 mL) and TEA (2.24 mL, 16.0 mmol, 8.00 equiv) were added sequentially via syringe. The flask was covered with foil, heated to 80 °C and stirred for 6 hours. The reaction flask was cooled to 0 °C in an ice water bath and diluted with saturated aqueous sodium bicarbonate (25 mL). The aqueous layer was extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine (4 x 200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The yellow oil was purified by silica gel flash column chromatography (eluent: 10→ 60% CMA in chloroform) to give the title compound as a light yellow oil (482 mg, 60% yield over two steps). The 400 Da 2-arm PEG-NOH was then introduced into an Isolera Biotage (eluent: 0→ 100% acetonitrile / water, 0.1% TFA) to give 400 Da 2-arm PEG-NOH·TFA as a di-trifluoroacetate salt. The product was stored as the salt to inhibit air oxidation of the hydroxylamine.

[0152] 1 kDa 2-arm PEG-I To a round bottom flask was added 1 kDa 2-arm PEG-I (1.00 g, 1.00 mmol, 1.00 equiv) and N-methyl-hydroxylamine hydrochloride (334 mg, 4.00 mmol, 4.00 equiv). The reaction flask was purged with nitrogen. DMSO (4 mL) and TEA (1.12 mL, 8.00 mmol, 8.00 equiv) were added sequentially via syringe. The flask was covered with foil, heated to 80 °C and stirred for 6 h. The reaction flask was cooled to 0 °C in an ice water bath and diluted with saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine (4 x 200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The yellow oil was purified by silica gel flash column chromatography (eluent: 10→60% CMA / chloroform) to afford the title compound as a light yellow oil (688 mg, 69%).

[0153] 1 kDa 2-arm PEG-NOH To a round bottom flask was added 1 kDa 2-arm PEG-I (1.00 g, 1.00 mmol, 1.00 equiv) and N-methyl-hydroxylamine hydrochloride (334 mg, 4.00 mmol, 4.00 equiv). The reaction flask was purged with nitrogen. DMSO (4 mL) and TEA (1.12 mL, 8.00 mmol, 8.00 equiv) were added sequentially via syringe. The flask was covered with foil, heated to 80 °C and stirred for 6 h. The reaction flask was cooled to 0 °C in an ice water bath and diluted with saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine (4 x 200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The yellow oil was purified by silica gel flash column chromatography (eluent: 10→60% CMA / chloroform) to afford the title compound as a light yellow oil (688 mg, 69%).

[0154] 2 kDa 2-Arm PEG-I To a round bottom flask was added 2 kDa 2-Arm PEG-I (10.0 g, 5.00 mmol, 1.00 equiv) and N-methyl-hydroxylamine hydrochloride (1.67 g, 20.0 mmol, 4.00 equiv). The reaction flask was purged with nitrogen. DMSO (20 mL) and TEA (5.60 mL, 40.0 mmol, 8.00 equiv) were added via syringe. The flask was covered with foil, heated to 80 °C and stirred for 6 h. The reaction flask was cooled to 0 °C in an ice water bath and diluted with saturated aqueous sodium bicarbonate (200 mL). The aqueous layer was extracted with DCM (3 x 250 mL). The combined organic layers were washed with brine (4 x 300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The yellow oil was purified by flash column chromatography on silica gel (eluent: 10→60% CMA / chloroform) to give the title compound as a light yellow oil (7.29 g, 73% yield over two steps).

[0155] 2 kDa 2-Arm PEG-I To a round bottom flask was added 2 kDa 2-Arm PEG-I (10.0 g, 5.00 mmol, 1.00 equiv) and N-methyl-hydroxylamine hydrochloride (1.67 g, 20.0 mmol, 4.00 equiv). The reaction flask was purged with nitrogen. DMSO (20 mL) and TEA (5.60 mL, 40.0 mmol, 8.00 equiv) were added via syringe. The flask was covered with foil, heated to 80 °C and stirred for 6 h. The reaction flask was cooled to 0 °C in an ice water bath and diluted with saturated aqueous sodium bicarbonate (200 mL). The aqueous layer was extracted with DCM (3 x 250 mL). The combined organic layers were washed with brine (4 x 300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The yellow oil was purified by flash column chromatography on silica gel (eluent: 10→60% CMA / chloroform) to give the title compound as a light yellow oil (7.29 g, 73% yield over two steps).

[0156] Example 7: General procedure for gelation of hydrogels containing 4-arm PEG-COT and 2-arm PEG-NOH In a glass vial, 4-arm PEG-COT (1 equivalent) was mixed with 2-arm PEG-NOH (2 equivalents) at the desired weight percent (1%, 5%, 10%, 20%) in water. The mixture was sonicated until complete dissolution and left to stand until gelation. For 2-arm PEG-NOH stored in trifluoroacetate form, 1 N aqueous sodium hydroxide (2 equivalents) was used to in situ desalt the hydroxylamine for gelation.

[0157] All patent publications and non-patent publications are indicative of the level of those skilled in the art to which this disclosure pertains. All such publications are herein incorporated by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference.

[0158] While the disclosure herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present disclosure. It is therefore to be understood that numerous modifications can be made to the illustrative embodiments and that other arrangements can be devised without departing from the spirit and scope of the present disclosure as defined by the appended claims.

Claims

1. A compound having the structure of Formula I: Formula I or a pharmaceutically acceptable salt or stereoisomer thereof, (I)， wherein: p is 0 or 1 ; q is 0 or 1 ; R1 and R2 together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl group, or R1is (Ci-C8)alkyl, (C3-C6)cycloalkyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, cycloalkyl, or heterocyclyl is further optionally substituted, or 10 R1is (Ci-C8)alkyl, (C3-C6)cycloalkyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, cycloalkyl, or heter R1 and R3 together with the atoms to which they are attached form a 5- to 7- membered heterocyclyl group; R2 is hydrogen, (Ci-C8)alkyl, chloro, bromo, or iodo; R3 is hydrogen, (Ci-C8)alkyl, chloro, bromo, or iodo; L1 is absent or a linker; L2 is absent or a linker; X is a leaving group; and R4 and R4 are independently a polymerizable moiety or a chemical moiety, provided that at least one of R4 and R4 is a polymerizable moiety.

2. The compound of claim 1, wherein X is an ester, carbonate, carbamate, sulfoxide, sulfonate, sulfate, sulfone, thioester, or thioformate.

5. The compound of claim 1, wherein R4 and R4 are acrylamides.

3. The compound according to claim 1 or 2, wherein L1is an alkylene chain, which can be interrupted by at least one of the following and / or terminated (at either or both ends) by at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C12carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C6alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different, or 12 C3-C12carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C6alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different, or polyethylene glycol chain which can be interrupted by at least one of the following and / or terminated (at either or both ends) by at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C 12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C6 alkyl, wherein the interrupting group and the one or two terminating groups can be the same or different.

4. The compound according to any one of claims 1-3, wherein L2is an alkylene chain, which can be interrupted by at least one of the following and / or terminated (at either or both termini) by at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -R'C(O)N(R')R'-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R')S(O)2-, -S(O)2N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O)2N(R')-, -N(R')S(O)N(R')-, -OP(O)O(R')O-, -N(R')P(O)N(R'R')N(R')-, C3-C 12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C6alkyl, wherein the interrupting group and the one or two terminating groups can be the same or different; or polyethylene glycol chain which can be interrupted by at least one of the following and / or terminated (at either or both ends) by at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C 12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C6 alkyl, wherein the interrupting group and the one or two terminating groups can be the same or different.

6. The compound of claim 1, which is a compound of Formula Ia1 or Ia2:

8. A polymer or hydrogel that is the reaction product of: (Ia1) or (Ia2).

7. The compound of claim 6, which is or . ii) a polymerizable moiety that is the same or different than R4 and / or R4, and i) a compound of formula I: (I), iii) an initiator, wherein: R1 and R2 together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl group, or R1is (Ci-C8)alkyl, (C3-C6)cycloalkyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, cycloalkyl, or heterocyclyl is further optionally substituted, or 10 R1is (Ci-C8)alkyl, (C3-C6)cycloalkyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, cycloalkyl, or heter R1 and R3 together with the atoms to which they are attached form a 5- to 7- membered heterocyclyl group; R2 is hydrogen, (Ci-C8)alkyl, chloro, bromo, or iodo; R3 is hydrogen, (Ci-C8)alkyl, chloro, bromo, or iodo; L1 is absent or a linker; L2 is absent or a linker; X is a leaving group; and R4 and R4 are independently a polymerizable moiety or a chemical moiety, provided that at least one of R4 and R4 is a polymerizable moiety.

9. The polymer or hydrogel of claim 8, wherein X is an ester, carbonate, carbamate, sulfoxide, sulfonate, sulfate, sulfone, thioester, or thioformate.

12. The polymer or hydrogel of any one of claims 8-11, wherein R4 is a polymerizable moiety and R4 is a chemical moiety.

10. The polymer or hydrogel of claim 8 or 9, wherein L1is an alkylene chain, which can be interrupted by at least one of the following and / or terminated (at either or both termini) by at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C 12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C6 alkyl, wherein the interrupting group and the one or two terminating groups can be the same or different, or polyethylene glycol chain which can be interrupted by at least one of the following and / or terminated (at either or both ends) by at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C 12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C6 alkyl, wherein the interrupting group and the one or two terminating groups can be the same or different.

11. The polymer or hydrogel of any one of claims 8-10, wherein L2is an alkylene chain which can be interrupted by at least one of the following and / or terminated (at either or both termini) by at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C12carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C6alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different; or 12 C3-C12carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C6alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different; or polyethylene glycol chain which can be interrupted by at least one of the following and / or terminated (at either or both ends) by at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C 12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C6 alkyl, wherein the interrupting group and the one or two terminating groups can be the same or different.

13. The polymer or hydrogel of any one of claims 8-12, wherein the polymerizable moiety is poly(acrylamide).

14. A method of making the polymer or hydrogel of any one of claims 8-13, comprising reacting a compound of Formula I, a polymerizable moiety, and an initiator, wherein the reaction is performed in the presence of a solvent.

15. The method of claim 14, wherein the solvent is a non-aqueous solvent.

16. The method of claim 14, wherein the solvent is an aqueous solvent.

17. The method of claim 16, wherein the aqueous solvent is a buffered solvent.

18. The method of claim 17, wherein the buffered solvent is phosphate buffered saline.

19. The method of claim 18, wherein the phosphate buffered saline has a pH of about 7.

4.

20. The method of any one of claims 17-19, wherein the reaction is performed in the solvent at a concentration of 1-25% by weight. ​ 21. The method of claim 20, wherein the concentration is 1, 5, 10, or 15% by weight.

22. The method of any one of claims 14-21, wherein the ratio of the compound of Formula I to polymerizable moiety is 1-20% by weight.

23. The method of claim 22, wherein the ratio of the compound of Formula I to polymerizable moiety is 3, 6, or 12% by weight.

24. The method of any one of claims 14-23, wherein the polymerizable moiety is the same as R4and / or R4’.

25. The method of any one of claims 14-23, wherein the polymerizable moiety is different from R4and / or R4’.

26. The method of any one of claims 14-23, wherein the polymerizable moiety comprises two or more polymerizable moieties.

27. A method of degrading the polymer or hydrogel of any one of claims 8-13, comprising contacting a compound of Formula II with a diboron reagent.

28. The method of claim 27, wherein the diboron reagent is a symmetric diboron reagent.

29. The method of claim 27, wherein the diboron reagent is an asymmetric diboron reagent.

30. A polymer or hydrogel that is the reaction product of: i) 4- arm - cyclooct-2-yn-1-yl, ; and ii) dihydroxylamine, , wherein: each X1is a leaving group; each L is a linker; and each R5is (Ci-C8)alkyl, (C3-C6)cycloalkyl, or 4- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, cycloalkyl, or heterocyclyl is further optionally substituted. 10 ) carbon ring group or 4- to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, carbon ring group, or heterocyclyl is further optionally substituted.

31. The polymer or hydrogel of claim 30, wherein each X1is an ester, carbonate, carbamate, sulfoxide, sulfonate, sulfate, sulfone, thioester, or thioformate.

32. The polymer or hydrogel of claim 30 or 31, wherein each L is an alkylene chain, which can be interrupted by at least one of the following and / or terminated (at either or both termini) by at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C12carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C6alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different; or 12 C3-C12carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C6alkyl, wherein the interrupting groups and the one or two terminating groups can be the same or different; or polyethylene glycol chain which can be interrupted by at least one of the following and / or terminated (at either or both ends) by at least one of the following: -0-, -S-, -N(R')-, -CºC-, -C(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(NOR')-, -C(0)N(R')-, -C(0)N(R')C(0)-, -R'C(0)N(R')R'-, -C(0)N(R')C(0)N(R')-, -N(R')C(0)-, -N(R')C(0)N(R')-, -N(R')C(0)0-, -OC(0)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)0-, -S(0)2-, -OS(O)-, -S(0)0-, -S(O)-, -OS(0)2-, -S(0)20-, -N(R')S(0)2-, -S(0)2N(R')-, -N(R')S(0)-, -S(0)N(R')-, -N(R')S(0)2N(R')-, -N(R')S(0)N(R')-, -OP(0)0(R')0-, -N(R')P(0)N(R'R')N(R')-, C3-C 12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or any combination thereof, wherein each R' is independently H or optionally substituted C1-C6 alkyl, wherein the interrupting group and the one or two terminating groups can be the same or different.

33. The polymer or hydrogel of claim 30, wherein the dihydroxylamine is or or a stereoisomer thereof. wherein n is an integer from 1-10,000.

34. The polymer or hydrogel of claim 33, wherein the dihydroxylamine is about 2 kDa, about 1 kDa, or about 400 Da.

35. The polymer or hydrogel of claim 30, wherein the 4-arm-cyclooct-2-yn-1-yl is of Formula II: (II) or a stereoisomer thereof. wherein n is an integer from 1-10,000.

36. The modifiable polymer or hydrogel of claim 35, wherein the 4-arm-cycloocta-2- ynyl-1-yl is about 10 kDa.

37. A method of making the polymer or hydrogel of claim 30, comprising reacting about 1 equivalent of the 4-arm-cycloocta-2-yn-1-yl with about 2 equivalents of the dihydroxylamine.

38. The method of claim 37, wherein the reaction is performed in the presence of a solvent.

39. The method of claim 38, wherein the solvent is a buffered solvent.

40. The method of claim 39, wherein the buffered solvent is phosphate buffered saline.

41. The method of claim 40, wherein the phosphate buffered saline has a pH of about 7.

4.

42. A method of degrading the polymer or hydrogel of claim 30, comprising contacting the hydrogel with a diboron reagent.

43. The method of claim 42, wherein the diboron reagent is a symmetric diboron reagent.

44. The method of claim 42, wherein the diboron reagent is an asymmetric diboron reagent.

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