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EP-4735414-A2 - CHEMICALLY DEGRADABLE AND FUNCTIONALLY MODIFIABLE POLYMERS AND HYDROGELS

EP4735414A2EP 4735414 A2EP4735414 A2EP 4735414A2EP-4735414-A2

Abstract

Disclosed are degradable covalent chemical crosslinkers. Also disclosed are methods of making and using the degradable covalent chemical crosslinkers.

Inventors

  • KIM, Justin
  • KIM, Thomas T.

Assignees

  • Dana-Farber Cancer Institute, Inc.

Dates

Publication Date
20260506
Application Date
20240627

Claims (1)

  1. What is claimed is: 1. A compound having a structure represented by formula I: Rty Kty - or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: p is 0 or 1; q is 0 or 1; Ri is (Ci-Cs) alkyl, (C3-C10) carbocyclyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S. wherein said alkyl, carbocyclyl or heterocyclyl is further optionally substituted, or Ri and R2, together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl, or Ri and R3. together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl; R2 is hydrogen, (Ci-Cs) alkyl, chloro, bromo, or iodo; R3 is hydrogen, (Ci-Cs) alkyl, chloro, bromo, or iodo; Li 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, a carbonate, a carbamate, a sulfoxide, a sulfonate, a sulfate, a sulfone, a thioester, or a thionoester. 3. The compound of claim 1 or 2, wherein Li is an alkylene chain, which may be interrupted by. and/or terminate (at either or both termini) in at least one of -O-, -S-, - N(R')-, -C=C-, -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(0) 2 - -0S(0)-, -S(0)0- -S(0)-, - 0S(0)2- -S(0) 2 0-. -N(R')S(O) 2 - -S(O) 2 N(R')-, -N(R')S(O)-, -S(O)N(R')-, - N(R')S(O) 2 N(R')- -N(R')S(O)N(R')- -OP(O)O(R')O-, -N(R’)P(O)N(R'R’)N(R’)-, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl or any combination thereof, wherein each R' is independently H or optionally substituted Ci-Ce alkyl, wherein the interrupting and the one or both terminating groups may be the same or different, or a polyethylene glycol chain, which may be interrupted by, and/or terminate (at either or both termini) in at least one of -O-, -S-, -N(R')-, -C=C- -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) 2 O-, -N(R')S(O) 2 -, -S(O) 2 N(R')-, -N(R')S(O)- -S(O)N(R')-, -N(R')S(O) 2 N(R')-, -N(R')S(O)N(R')-, -OP(O)O(R')O- N(R')P(O)N(R'R’)N(R’)-. Cs-Ci 2 carbocyclyl. 3- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl or any combination thereof, wherein each R' is independently H or optionally substituted Ci-Ce alkyl, wherein the interrupting and the one or both terminating groups may be the same or different. 4. The compound of any one of claims 1-3. wherein L 2 is an alkylene chain, which may be interrupted by, and/or terminate (at either or both termini) in at least one of -O-, -S-, - N(R')-, -C=C- -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) 2 O-, -N(R')S(O) 2 -, -S(O) 2 N(R')-, -N(R')S(O)-, -S(O)N(R')-, - N(R')S(O) 2 N(R')-, -N(R')S(O)N(R')-, -OP(O)O(R')O-, -N(R’)P(O)N(R'R’)N(R’)-, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl. 5- to 12-membered heteroaryl or any combination thereof, wherein each R’ is independently H or optionally substituted Ci-Ce alkyl, wherein the interrupting and the one or both terminating groups may be the same or different, or a polyethylene glycol chain, which may be interrupted by, and/or terminate (at either or both termini) in at least one of -O-. -S-. -N(R')-, -C=C-. -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) 2 O- -N(R')S(O)2- -S(O) 2 N(R')-, -N(R')S(O)- -S(O)N(R')-, -N(R')S(O) 2 N(R')-, -N(R')S(O)N(R')-, -OP(O)O(R')O- N(R')P(O)N(R'R’)N(R’)-. Cs-Ci 2 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl or any combination thereof, wherein each R' is independently H or optionally substituted Ci-Ce alkyl, wherein the interrupting and the one or both terminating groups may be the same or different. 5. The compound of claim 1, wherein R.4 and RT are acrylamide. 6. The compound of claim 1, which is of formula lai or Ia2: 8. A polymer or hydrogel which is the reaction product of: i) a compound of formula ii) a polymerizable moiety which is the same as or different from R4 and/or R4’, and iii) an initiator, wherein: Ri is (Ci-Cs) alkyl, (C3-C10) carbocyclyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein said alkyl, carbocyclyl or heterocyclyl is further optionally substituted, or Ri and R2, together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl, or Ri and R3. together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl; R2is hydrogen, (Ci-Cs) alkyl, chloro, bromo, or iodo; Ra is hydrogen, (Ci-Cs) alkyl, chloro, bromo, or iodo; Li 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 7 . 9. The polymer or hydrogel of claim 8, wherein X is an ester, a carbonate, a carbamate, a sulfoxide, a sulfonate, a sulfate, a sulfone, a thioester, or a thionoester. 10. The polymer or hydrogel of claim 8 or 9, wherein Li is an alkylene chain, which may be interrupted by. and/or terminate (at either or both termini) in at least one of -O-, -S-, - N(R')-, -C=C- -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) 2 O-, -N(R')S(O)2- -S(O) 2 N(R')-, -N(R')S(O)-, -S(O)N(R')-, - N(R')S(O) 2 N(R')-, -N(R')S(O)N(R')-, -OP(O)O(R')O-, -N(R’)P(O)N(R'R’)N(R’)-, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl or any combination thereof, wherein each R’ is independently H or optionally substituted Ci-Ce alkyl, wherein the interrupting and the one or both terminating groups may be the same or different, or a polyethylene glycol chain, which may be interrupted by, and/or terminate (at either or both termini) in at least one of -O-, -S-, -N(R')-, -C=C- -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(0) 2 - - 0S(0)-, -S(0)0-, -S(0)-, -0S(0) 2 - -S(0) 2 0- -N(R')S(O) 2 - -S(O) 2 N(R')-, -N(R')S(O)- -S(O)N(R')-, -N(R')S(O) 2 N(R')- -N(R')S(O)N(R')-, -OP(O)O(R')O- N(R’)P(O)N(R'R’)N(R’)-, Cs-Ci 2 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl or any combination thereof, wherein each R' is independently H or optionally substituted Ci-Ce alkyl, wherein the interrupting and the one or both terminating groups may be the same or different. 11. The polymer or hydrogel of any one of claims 8-10, wherein L 2 is an alkylene chain, which may be interrupted by, and/or terminate (at either or both termini) in at least one of - O-, -S-, -N(R')-, -C=C-, -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) 2 O-, -N(R')S(O) 2 - -S(O) 2 N(R')-, -N(R')S(O)-, -S(O)N(R')-, - N(R')S(O) 2 N(R')-, -N(R')S(O)N(R')-, -OP(O)O(R')O-, -N(R’)P(O)N(R'R’)N(R’)-, C 3 -C1 2 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl or any combination thereof, wherein each R’ is independently H or optionally substituted Ci-Ce alkyl, wherein the interrupting and the one or both terminating groups may be the same or different, or a polyethylene glycol chain, which may be interrupted by, and/or terminate (at either or both termini) in at least one of -O-, -S-, -N(R')-, -C=C- -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) 2 O-, -N(R')S(O) 2 -, -S(O) 2 N(R')-, -N(R')S(O)- -S(O)N(R')-, -N(R')S(O) 2 N(R')-, -N(R')S(O)N(R')-, -OP(O)O(R')O- N(R’)P(O)N(R'R’)N(R’)- Cs-Ci 2 carbocyclyl. 3- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl or any combination thereof, wherein each R' is independently H or optionally substituted Ci-Ce alkyl, wherein the interrupting and the one or both terminating groups may be the same or different. 12. The polymer or hydrogel of any one of claims 8-11, wherein R4 is a polymerizable moiety and R4’ is a chemical moiety. 13. The polymer or hydrogel of any one of claims 8-12, wherein the polymerizable moiety is poly (acrylamide). 14. A process of preparing the polymer or hydrogel of any one of claims 8-13, comprising reacting the compound of formula I, a polymerizable moiety, and an initiator, wherein the reacting is carried out in the presence of a solvent. 15. The process of claim 14, wherein the solvent is a non-aqueous solvent. 16. The process of claim 14, wherein the solvent is an aqueous solvent. 17. The process of claim 16, wherein the aqueous solvent is a buffered solvent. 18. The process of claim 17, wherein the buffered solvent is phosphate-buffered saline. 19. The process of claim 18, wherein the pH of the phosphate-buffered saline is about 7.4. 20. The process of any one of claims 17-19, wherein the reacting is carried in the solvent with a concentration of is 1-25 wt%. 21. The process of claim 20, wherein the concentration is 1, 5, 10, or 15 wt%. 22. The process of any one of claims 14-21, wherein the reacting of the compound of formula I with the polymerizable moiety is in a ratio of 1-20 wt%. 23. The process of claim 22, wherein the ratio of the compound of formula I to polymerizable moiety is 3, 6, or 12 wt%. 24. The process of claim of any one of claims 14-23, wherein the polymerizable moiety' is the same as R.4 and/or RT. 25. The process of claim of any one of claims 14-23. wherein the polymerizable moiety is different than R4 and/or RT. 26. The process of claim 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 the compound of formula II with a diboron reagent. 28. The method of claim 27, wherein the diboron reagent is a symmetrical diboron reagent. 29. The method of claim 27, wherein the diboron reagent is an unsymmetrical diboron reagent. 30. A polymer or hydrogel which is the reaction product of i) a 4-arm-cyclooct-2-yn-l-yl, ii) a dihydroxylamine, wherein each Xi is a leaving group: each L is a linker; and each Rs is (Ci-Cs) alkyl, (Cs-Cio) carbocyclyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein said alkyl, carbocyclyl or heterocyclyl is further optionally substituted. 31. The polymer or hydrogel of claim 30, wherein each Xi is an ester, a carbonate, a carbamate, a sulfoxide, a sulfonate, a sulfate, a sulfone, a thioester, or a thionoester. 32. The polymer or hydrogel of claim 30 or 31, wherein each L is an alkylene chain, which may be interrupted by, and/or terminate (at either or both termini) in at least one of-O-, -S-, -N(R')-, -C=C- -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) 2 O-, -N(R')S(O) 2 -, -S(O) 2 N(R')-, -N(R')S(O)-, -S(O)N(R')-, - N(R')S(O) 2 N(R')- -N(R')S(O)N(R')-, -OP(O)O(R')O-, -N(R’)P(O)N(R'R )N(R )-, C3-C12 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl or any combination thereof, wherein each R' is independently H or optionally substituted Ci-Ce alkyl, wherein the interrupting and the one or both terminating groups may be the same or different, or a polyethylene glycol chain, which may be interrupted by, and/or terminate (at either or both termini) in at least one of -O-, -S-, -N(R')-, -C=C-, -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) 2 O- -N(R')S(O) 2 - -S(O) 2 N(R')-, -N(R')S(O)- -S(O)N(R')-, -N(R')S(O) 2 N(R')-, -N(R')S(O)N(R')-, -OP(O)O(R')O- N(R’)P(O)N(R'R’)N(R’)-, C3-Ci 2 carbocyclyl, 3- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl or any combination thereof, wherein each R' is independently H or optionally substituted Ci-Ce alkyl, wherein the interrupting and the one or both terminating groups may be the same or different. OH i i 33. The polymer or hydrogel of claim 30, wherein the dihydroxylamine is OH or OH OH , or stereoisomer thereof, wherein n is an integer from 1-10000. 34. The polymer or hydrogel of claim 33, wherein the dihydroxyl amine is about 2 kDa, about 1 kDa, or about 400Da. 35. The polymer or hydrogel of claim 30, wherein the 4-arm-cyclooct-2-yn-l-yl is of formula II: (II) or stereoisomer thereof, wherein n is an integer from 1-10000. 36. The modifible polymer or hydrogel of claim 35, wherein the 4-arm-cyclooct-2-yn-l-yl is about 10 kDa. 37. A process of preparing the polymer or hydrogel of claim 30, comprising reacting about one equivalent of the 4-arm-cyclooct-2-yn-l-yl with about two equivalents of the dihydroxylamine. 38. The process of claim 37, wherein the reacting is carried out in the presence of a solvent. 39. The process of claim 38, wherein the solvent is a buffered solvent. 40. The process of claim 39, wherein the buffered solvent is phosphate-buffered saline. 41. The process of claim 40, wherein the pH of the phosphate-buffered saline is 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 symmetrical diboron reagent. 44. The method of claim 42, wherein the diboron reagent is an unsymmetrical diboron reagent.

Description

CHEMICALLY DEGRADABLE AND FUNCTIONALLY MODIFIABLE POLYMERS AND HYDROGELS RELATED APPLICATIONS [0001] 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, which is incorporated herein by reference in its entirety. GOVERNMENT SUPPORT [0002] This invention was made with government support under grant number DP2 ES030448 awarded by The National Institutes of Health and grant number 2238040 awarded by The National Science Foundation. The government has certain rights in the invention. BACKGROUND OF THE DISCLOSURE [0003] Hydrogels are cross-linked polymer networks that comprise a significant volume fraction of water but do not dissolve in water (Wichterle et al.. Nature, J 85: 117-1 18 (I960)). The large water content of these materials makes them highly deformable and enables the rapid diffusion of water-soluble molecules across their surface, making them ideally suited for applications in biology (Correa el al., Chem. Rev., 727: 11385-11457 (2021)). Hydrogelbased biomaterials have therefore found major use in wound closure (Kamoun et al., J. Adv. Res., N:217-233 (2017); Liang et al., ACS Nano 75: 12687-12722 (2021)), as tissue sealants (Lang et al., Sci. Trans. Med., 6:218ra6 (2014); Ferreira et al., J. Biol. Macromol., -70: 144- 152 (2007); Mehdizadeh et al., Macromol. Biosci., 73:271-288 (2013)), in drug delivery (Hoffman, Adv. Drug Delivery Rev., 6-7: 18-23 (2012); Blackman et al.. J. Am. Chem. Soc., 130: 13518-13519 (2008); Mejia Oneto et ai., 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, 554:535-546 (2020); Tayalia et al., Biomaterials, 32:2634 (2011)) among many other bioengineering applications (Correa et al., Chem. Rev., 727: 11385-11457 (2021)). [0004] Hydrogels have been used as tough tissue adhesives. Tough adhesives are biomaterials that do not fracture under large tensile loads (Li et al., Science, 357:378-381 (2017)). Equally strong adhesive forces enable these materials to adhere to tissues without becoming detached in the face of high shearing, tensile, or peeling forces. Materials like these offer appealing alternatives to surgical sutures in closing wounds and sealing tissues because they are faster, are less damaging to tissues, show fewer incidence of infections, and do not require anesthesia (Li et al., Science, 357:378-381 (2017); Rahman et al., Science Advances, 7:eabk2451 (2021); Liu etal., Adv. Funct. Mater., 32:2107732 (2022)). [0005] As tissue adhesives have become tougher and more strongly adherent, they introduce new challenges, such as their removal. Leaving them in place at the site of injury risks inflammation and tissue fibrosis, and the hydrogels may outlive their intended impact (Kyriakides, Chapter 5 - Molecular Events at Tissue-Biomaterial Interface, in Host Response to Biomaterials, Badylak, S. F., 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 act of removing tissue adhesives is a well- known cause of secondary tissue injuries. SUMMARY OF DISCLOSURE [0006] The current disclosure solves the problems mentioned above by producing polymers and tough polyacrylamide hydrogels that are susceptible to diboron-mediated degradation. [0007] A first aspect of the present disclosure is directed to a compound represented by formula I: R2 _0 Rl R3 (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: p is 0 or 1; q is 0 or 1; Ri is (Ci-Cs) alkyl, (C3-C10) carbocyclyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein said alkyd, carbocyclyl or heterocyclyl is further optionally substituted, or Ri and R2. together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl. or Ri and R3, together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl; R2is hydrogen. (Ci-Cs) alkyl, chloro, bromo, or iodo; Ra is hydrogen. (Ci-Cs) alkyl, chloro, bromo, or iodo; Li is absent or a linker; L2 is absent or a linker; X is a leaving group; and R4 and RT are independently a polymerizable moiety or a chemical moiety, provided that at least one of R4 and R4’ is a polymerizable moiety. [0008] Another aspect of the present disclosure is directed to modifiable polymers/hydrogels which are the reaction product of: i) a compound of formula I ii) a polymerizable moiety, and iii) an initiator. [0009] Other aspects of the present disclosure are directed to modifiable polymers/hydrogels which are the reaction product of: i) a 4-arm-cyclooct-2-yn-l-yl, ii) a dihydroxylamine, wherein: each Xi is a leaving group; each L is a linker; and each R5 is (Ci-Cs) alkyl, (C3-C10) carbocyclyl, or 4- to 10-membered heterocyclyl comprising 1 to 3 h