WO2025006732A2 - Polymères et hydrogels dégradables chimiquement et modifiables fonctionnellement - Google Patents

Polymères et hydrogels dégradables chimiquement et modifiables fonctionnellement Download PDF

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WO2025006732A2
WO2025006732A2 PCT/US2024/035794 US2024035794W WO2025006732A2 WO 2025006732 A2 WO2025006732 A2 WO 2025006732A2 US 2024035794 W US2024035794 W US 2024035794W WO 2025006732 A2 WO2025006732 A2 WO 2025006732A2
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alkyl
carbocyclyl
hydrogel
polymer
membered heterocyclyl
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WO2025006732A3 (fr
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Justin KIM
Thomas T. KIM
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Dana Farber Cancer Institute Inc
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Dana Farber Cancer Institute Inc
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Priority to KR1020267002311A priority Critical patent/KR20260030833A/ko
Priority to EP24832923.7A priority patent/EP4735414A2/fr
Priority to AU2024309725A priority patent/AU2024309725A1/en
Priority to CN202480042179.9A priority patent/CN121368580A/zh
Publication of WO2025006732A2 publication Critical patent/WO2025006732A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
    • C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
    • C07C291/04—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds containing amino-oxide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/52—Amides or imides
    • C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
    • C08F220/56—Acrylamide; Methacrylamide

Definitions

  • 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.
  • 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)).
  • 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.
  • a first aspect of the present disclosure is directed to a compound represented by formula I:
  • 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 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; 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
  • 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.
  • 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.
  • 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 heteroatoms selected from O, N, and S. wherein said alkyl, carbocyclyl or heterocyclyl is further optionally substituted.
  • Further aspects of the present disclosure are directed to methods of degrading hydrogels.
  • the methods entail contacting the hydrogel with a diboron reagent.
  • FIG. 1 is a series of images of synthesized and diboron-mediated degraded polyacrylamide hydrogels.
  • FIG. 2 is a schematic showing the synthesis and diboron-mediated degradation of poly aery lamide/cal ci um alginate tough hydrogels.
  • FIG. 3A-FIG. 3B are a series of images of synthesized polyacrylamide gels.
  • FIG. 3A is a series of images of synthesized polyacrylamide gels with a varying percentage of cross-linker (0.03 to 0.3 w/v%).
  • FIG. 3B is a series of images of synthesized polyacrylamide gels (0.12 w/v%) showing stretch loading and unloading.
  • FIG. 4 is a series of images of synthesized and diboron-mediated degraded tough hydrogels.
  • FIG. 5A-FIG. 5C are a series of images of synthesized and diboron-mediated degraded tough hydrogels.
  • FIG. 5A is a series of pre-gelation images.
  • FIG. 5B is a series of post-gelation images.
  • FIG. 5C is a series of images showing diboron-mediated degradation of hydrogels.
  • FIG. 6A-FIG. 6C are a series of images of synthesized and diboron-mediated degraded tough hydrogels.
  • FIG. 6A is a series of pre-gelation images.
  • FIG. 6B is a series of post-gelation images.
  • FIG. 6C is a series of images showing diboron-mediated degradation of hydrogels.
  • the term “about” means within 10% (e.g., within 5%, 2%, or 1%) of the particular value modified by the term “about.”
  • the transitional term ‘‘comprising,” which is 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 that that minimum number of heteroatoms.
  • 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 disclosure.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical.
  • the alkyl radical is a Ci-Ce group.
  • the alky l radical is a Co- Ce, C0-C5, C0-C3, Ci-Ce, C1-C5. C1-C4 or C1-C3 group (wherein Co alkyl refers to a bond).
  • alkyl groups include methyl, ethyl, 1 -propyl, 2-propyl, i-propyl, 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-I -butyl, 2-methyl-l -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.
  • an alkyl group is a C1-C3 alkyl group.
  • an alkyl group is a C1-C1 alkyl group.
  • alkylene refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to six carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain may be attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkylene group contains one to four carbon atoms (C1-C4 alkylene).
  • an alkylene contains one to three carbon atoms (C1-C3 alkylene). In other embodiments, an alkylene group contains one to two carbon atoms (C1-C2 alkylene). In other embodiments, an alkylene group contains one carbon atom (Ci alkylene).
  • alkenyl refers to a linear or branched-chain monovalent hydrocarbon radical with at least one carbon-carbon double bond. An alkenyl includes radicals having "cis" and “trans” orientations, or alternatively, "E” and “Z” orientations. In some embodiments, the alkenyl radical is a C2-C15 group.
  • the alkenyl radical is a C2-C12. C2-C10, C2-C8, C2-C6 or C2-C3 group. Examples include ethenyl or vinyl, prop-l-enyl. prop-2-enyl.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon triple bond.
  • the alkynyl radical is a C2-C15 group.
  • the alkynyl radical is C2-C12, C2-C10, C2-C8, C2-C6 or C2-C3. Examples include ethynyl prop-l-ynyl. prop-2-ynyl, but-l-ynyl, but-2-ynyl and but-3-ynyl.
  • alkoxy!” or ‘'alkoxy” as used herein refer to an alkyl group, as defined above, having an oxygen radical attached thereto, and which is the point of attachment.
  • the alkoxyl group is methoxy, ethoxy, propyloxy, or tert-butoxy.
  • An “ether” is two hydrocarbyl groups covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • cyclic group refers to any group that used alone or as part of a larger moiety, contains a saturated, partially saturated or aromatic ring system e.g, carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocycloalkyd, heterocycloalkenyl), aryl and heteroaryl groups. Cyclic groups may have one or more (e.g, fused) ring systems. Therefore, for example, a cyclic group can contain one or more carbocyclic, heterocyclic, aryl or heteroaryl groups.
  • carbocyclic refers to a group that used alone or as part of a larger moiety, contains a saturated, partially unsaturated, or aromatic ring system having 3 to 12 carbon atoms, that is alone or part of a larger moiety (e.g, an alkcarbocyclic group).
  • carbocyclyl includes mono-, bi-, tri-, fused, bridged, and spiro-ring systems, and combinations thereof.
  • carbocyclyl includes 3 to 10 carbon atoms (Cs-Cio).
  • carbocyclyl includes 3 to 6 carbon atoms (Cs-Ce).
  • carbocyclyl includes 5 to 6 carbon atoms (Cs-Ce).
  • carbocyclyl, as a bicycle includes Ce-Cio.
  • carbocyclyl, as a spiro system includes C5-C11.
  • monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cy clopent- 1-enyl, 1-cyclopent- 2-enyL I-cyclopent-3-enyl, cyclohexyl.
  • bicyclic carbocyclyls having 7 to 11 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, such as for example bicyclo[2.2.1]heptane.
  • spiro carbocyclyls include spiro[2.2] pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane.
  • carbocyclyl includes aryl ring systems as defined herein.
  • carbocycyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated mono-, bi-, or spiro-carbocycles).
  • carbocyclic group also includes a carbocyclic ring fused to one or more (e.g.. 1, 2 or 3) different cyclic groups (e.g.. aryl or heterocyclic nngs), where the radical or point of attachment is on the carbocyclic ring.
  • different cyclic groups e.g.. aryl or heterocyclic nngs
  • carbocyclic also embraces carbocyclylalkyl groups which as used herein refer to a group of the formula — R c -carbocyclyl where R c is an alkylene chain.
  • carbocyclic also embraces carbocyclylalkoxy groups which as used herein refer to a group bonded through an oxygen atom of the formula — O— R c -carbocyclyl where R c is an alkydene chain.
  • ary l used alone or as part of a larger moiety' (e.g., "aralkyl", wherein the terminal carbon atom on the alkyl group is the point of attachment, e.g., a benzyd group),"aralkoxy” wherein the oxygen atom is the point of attachment, or "aroxyalkyd” wherein the point of attachment is on the ary l group) refers to a group that includes monocyclic, bicyclic or tricyclic, carbon ring system, that includes fused rings, wherein at least one ring in the system is aromatic.
  • the aralkoxy group is a benzoxy group.
  • aryl may be used interchangeably with the term "aryl ring".
  • aryl includes groups having 6-12 carbon atoms.
  • ary l includes groups having 6-10 carbon atoms.
  • Examples of aryl groups include phenyl, naphthyl, biphenyl, 1,2,3,4-tetrahydronaphthalenyl, and the like, which may be substituted or independently substituted by one or more substituents described herein.
  • a particular aryl is phenyl.
  • an aryl group includes an aryl ring fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e.g., carbocyclic rings or heterocyclic rings), where the radical or point of attachment is on the aryl ring.
  • aryl embraces aralkyl groups (e.g., benzyl) which as disclosed above refer to a group of the formula — R c -aryl where R c is an alkylene chain such as methylene or ethylene.
  • the aralkyl group is an optionally substituted benzyl group.
  • aryl also embraces aralkoxy groups which as used herein refer to a group bonded through an oxygen atom of the formula — O — R c — aryl where R c is an alkylene chain such as methylene or ethylene.
  • heterocyclyl refers to a "carbocyclyl” that used alone or as part of a larger moiety, contains a saturated, partially unsaturated or aromatic ring system, wherein one or more (e.g., 1, 2, 3, 4, or 5) carbon atoms have been replaced with a heteroatom or heteroatom-containing group (e.g., O, N, N(O), S, S(O), or S(O)2).
  • a heterocyclyl refers to a 3- to 12-membered heterocyclyl ring system.
  • a heterocyclyl refers to a saturated ring system, such as a 3- to 12-membered saturated heterocyclyl ring system.
  • a heterocyclyl refers to a heteroaryl ring system, such as a 5- to 12-membered heteroaryl ring system.
  • the term heterocyclyl also includes C2-C8 heterocycloalkyl, which is a saturated or partially unsaturated mono-, bi-, or spiro-ring system containing 2-8 carbons and one or more (e.g, 1, 2, or 3) heteroatoms.
  • a heterocyclyl group includes 3-12 ring atoms and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, and one to 5 ring atoms is a heteroatom such as nitrogen, sulfur or oxygen.
  • heterocyclyl includes 3- to 7-membered monocycles having one or more heteroatoms selected from O, N, and S.
  • heterocyclyl includes 4- to 6- membered monocycles having one or more heteroatoms selected from O, N, and S.
  • heterocyclyl includes 3-membered monocycles.
  • heterocyclyl includes 4-membered monocycles.
  • heterocyclyl includes 5- to 6-membered monocycles. In some embodiments, the heterocyclyl group includes 0 to 3 double bonds. In any of the foregoing embodiments, heterocyclyl includes 1, 2, 3 or 4 heteroatoms. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO2). and any nitrogen heteroatom may optionally be substituted (e.g., methyl, isopropyl) and/or quatemized (e.g., [NR4] + C1‘.
  • Representative examples of heterocyclyls include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl.
  • thietanyl 1,2-dithietanyl. 1,3- dithietanyl, pyrrolidinyl, dihydro- IH-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl.
  • azepanyl oxepanyl. thiepanyl, oxazepinyl. oxazepanyl. diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4, 5,6,7- tetrahydrobenzo[d]imidazolyl.
  • pyrazolinyl pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl.
  • pyrimidindionyl pyrimidin-2.4-dionyl, piperazinonyl.
  • 1,1-dioxohexahydrothiopyranyl examples include thiazolyl (e.g, thiazol-2-yl), thiadiazolyl (e.g, l,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol- 5-yl), oxazolyl (e.g, oxazol-2-yl), and oxadiazolyl (e.g, l,3,4-oxadiazol-5-yl and 1,2,4- oxadiazol-5-yl).
  • thiazolyl e.g, thiazol-2-yl
  • thiadiazolyl e.g, l,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol- 5-yl
  • oxazolyl e.g, oxazol-2-yl
  • oxadiazolyl e.g, l,3,4-oxadiazol-5-yl and 1,2,4- o
  • Example of 5-membered heterocyclyls containing 2 to 4 nitrogen atoms include imidazolyl (e.g., imidazol-2-yl), triazolyl (e.g., l,3,4-triazol-5-yl, l,2,3-triazol-5-yl, and l,2,4-triazol-5-yl), and tetrazolyl (e.g., lH-tetrazol-5-yl).
  • Representative examples of benzo-fused 5-membered heterocyclyls include benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.
  • Example of 6-membered heterocyclyls containing one to three nitrogen atoms and optionally a sulfur or oxygen atom are pyridyl (e.g., pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl), pyrimidyl (e.g., pyrimid-2-yl and pyrimid-4-yl), triazinyl (e.g., 1.3.4-triazin-2-yl and l,3,5-triazin-4-yl), pyridazinyl (e.g., pyridazin-3-yl). and pyrazinyl.
  • pyridyl e.g., pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl
  • pyrimidyl e.g., pyrimid-2-yl and pyrimid-4-yl
  • triazinyl e.g.
  • a heterocyclic group includes a heterocyclic ring fused to one or more (e.g, 1 or 2) different cyclic groups (e.g., carbocyclic rings or heterocyclic rings), where the radical or point of attachment is on the heterocyclic ring, and in some embodiments wherein the point of attachment is a heteroatom contained in the heterocyclic ring.
  • heterocyclic embraces N-heterocyclyl groups which as used herein refer 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.
  • heterocyclic also embraces C-heterocyclyl groups which as used herein refer 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 radicals include 2- or 3- morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl.
  • heterocyclic also embraces heterocyclylalkyl groups which as disclosed above refer to a group of the formula — R c -heterocyclyl where R c is an alkylene chain.
  • heterocyclic also embraces heterocyclylalkoxy groups which as used herein refer to a radical bonded through an oxygen atom of the formula -O— R c -heterocyclyl where R c is an alkylene chain.
  • 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.
  • heteroar l includes 5- to 6- membered monocyclic aromatic groups where one or more ring atoms is O, N, or S.
  • heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, imidazopyridyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[l,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuryl.
  • heteroaryl also includes groups in which a heteroaryl is fused to one or more cyclic (e.g., carbocyclyl, or heterocyclyl) rings, where the radical or point of attachment is on the heteroaryl ring.
  • cyclic e.g., carbocyclyl, or heterocyclyl
  • Nonlimiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzthiazolyl, 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.
  • a heteroaryl group may be mono-, bi- or tri-cyclic.
  • a heteroaryl group includes a heteroaryl ring fused to one or more (e.g., 1 or 2) different cyclic groups (e.g., carbocyclic rings or heterocyclic rings), where the radical or point of attachment is on the heteroar l ring, and in some embodiments wherein the point of attachment is a heteroatom contained in the heterocyclic ring.
  • heteroaryl embraces N-heteroaryl groups which as used herein refer to a heteroaryl group as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl group to the rest of the molecule is through a nitrogen atom in the heteroaryl group.
  • heteroaryl also embraces C-heteroaryl groups which as used herein refer to a heteroaryl group as defined above and where the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group.
  • heteroaryl also embraces heteroaiylalkyl groups which as disclosed above refer to a group of the formula — R c -heteroaryl, wherein R c is an alkylene chain as defined above.
  • heteroaryl also embraces heteroaralkoxy (or heteroarylalkoxy) groups which as used herein refer to a group bonded through an oxygen atom of the formula — O-R c - heteroaryl. where R c is an alky lene group as defined above.
  • any of the groups described herein may be substituted or unsubstituted.
  • substituents may include alky l (e.g., Ci-Ce, C1-C5, C1-C4, C1-C3, C1-C2, Ci), substituted alkyl (e.g., substituted Ci-Ce, C1-C5, C1-C4, C1-C3, C1-C2, Ci), alkoxy (e.g., Ci-C 6 , C1-C5, C1-C4. C1-C3.
  • Ci substituted alkoxy (e.g.. substituted Ci-Ce. C1-C5, C1-C4, C1-C3. C1-C2.
  • Ci haloalkyl (e.g.. CF3), alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkenyl (e.g., substituted C2- C 6 , 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), cyclic (e.g., C3-C12, C 5 -C 6 ), substituted cyclic (e.g., substituted C3-C12, Cs-Cs), carbocyclic (e.g., C3-C12.
  • Cs-Ce substituted carbocyclic (e.g., substituted C3-C12, Cs-Ce), heterocyclic (e.g., 3- to 12- membered. 5-to 6-membered), substituted heterocyclic (e.g.
  • aryl e.g, benzyl and phenyl
  • substituted aryl e.g, substituted benzyl or substituted phenyl
  • heteroaryl e.g., pyridyl or py rimidyl
  • substituted heteroaryl e.g, substituted pyridyl or substituted pyrimidyl
  • aralkyl e.g, benzy l
  • substituted aralky l e.g, substituted aralky l (e.g, substituted benzyl), halo, hydroxyl, aryloxy (e.g., C6-C12, Ce), substituted aryloxy (e.g, substituted C6-C12.
  • alkylthio e.g, Ci-Ce
  • substituted alkydthio e.g, substituted Ci-Ce
  • arylthio e.g, C6-C12, Ce
  • substituted arylthio e.g, substituted C6-C12, Ce
  • cyano carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinamide, substituted sulfinamide.
  • Terminal substituents may include Ci-Ce alky l, Ci-Ce alkoxy, halo, hydroxy l, cyano or amino.
  • 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
  • Rz is hydrogen. (Ci-Cs) alkyl, chloro, bromo, or iodo; R? 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;
  • R4 and R4’ are independently a polymerizable moiety or a chemical moiety, provided that at least one of R.4 and R4’ is a polymerizable moiety.
  • Li is absent.
  • L2 is absent.
  • Li is a linker
  • L2 is a linker
  • the linker provides a covalent attachment between the two atoms to which the linker is bound, and which is nonreactive with the other groups in the compound.
  • the alkylene chain is a C1-C24 alkylene chain. In some embodiments, the alky ene chain is a Ci-Cis alkylene chain. In some embodiments, the alky lene chain is a Ci-Ci 2 alky lene chain. In some embodiments, the alkylene chain is a Ci- C10 alkylene chain. In some embodiments, the alkylene chain is a Ci-Cs alkylene chain. In some embodiments, the alkylene chain is a Ci-Cs alkylene chain. In some embodiments, the alkylene chain is a C1-C4 alkylene chain. In some embodiments, the alkylene chain is a Ci-C 2 alky dene chain.
  • the alkylene chain is interrupted by, and/or terminates (at either or both termini) in 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) 2 N(R')-, 4- to 6-membered heterocyclyl, or a combination thereof.
  • the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -N(R')-. In some embodiments, the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -C(O)-. In some embodiments, the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -C(O)O- In some embodiments, the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -C(O)N(R')-.
  • the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -N(R')S(O)2- In some embodiments, the alky lene chain is interrupted by, and/or terminates (at either or both termini) with a 4- to 6- membered heterocyclyl.
  • the polyethylene glycol chain has 1 to 20 -(CH2CH2-O)- units. In some embodiments, the polyethylene glycol chain has 1 to 15 -(CH2CH2-O)- units. In some embodiments, the polyethylene glycol chain has 1 to 10 -(CH2CH2-O)- units. In some embodiments, the polyethylene glycol chain has 1 to 6 -(CH2CH2-O)- units. In some embodiments, the polyethylene glycol chain has 1 to 2 -(CH2CH2-O)- units.
  • the polyethylene glycol is interrupted by, and/or terminates (at either or both termini) in 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) 2 N(R')-, 4- to 6-membered heterocyclyl, or a combination thereof.
  • the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -N(R')-. In some embodiments, the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -C(O)-. In some embodiments, the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -C(O)O- In some embodiments, the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -C(O)N(R')-. In some embodiments, the polyethylene glycol chain is interrupted by.
  • the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with 4- to 6-membered heterocyclyl.
  • 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.
  • Ri is (Ci-Cs) alkyl.
  • Ri is methyl.
  • Ri and R2 together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl.
  • Ri and Rs together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl.
  • R2 is hydorgen. In some embodiments, R2 is methyl. In some embodiments, R2 is chloro. In some embodiments, R2 is bromo. In some embodiments, R2 is iodo.
  • R3 is hydorgen. In some embodiments, R3 is methyl. In some embodiments, Rs is chloro. In some embodiments, R3 is bromo. In some embodiments, R3 is iodo.
  • X is a leaving group, which as known in the art refers to an atom or group of atoms which breaks away from the rest of the molecule, taking with it the electron pair which used to be the bond 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 thionoesters.
  • the leaving group is OR9, SR9, -OC(O)R 9 .
  • polymerizable moieties refer to a molecule that reacts with another molecule, which may the same or different, to form a polymer and a co-polymer. respectively.
  • Representative examples of polymerizable moieties that may be suitable for use in preparing the disclosed polymers/hydrogels include:
  • R.4 and R4’ are a polymerizable moiety. In some embodiments, R4 and R4’ are acrylamide.
  • R4 is a polymerizable moiety and R4’ is a chemical moiety.
  • R4 is a chemical moiety and R4' is a polymerizable moiety.
  • the chemical moiety 7 is a carboxylic acid, amine, sulfonic acid, phenol, catechol, a metal chelator, a PEG chain, or a drug molecule.
  • the compound of formula I is of formula la: (la), or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the optional substituent for a compound of formula I is independently alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkyenyloxy, 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-arylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl, formyl, alkyl carbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, hetero
  • the compound of formula la is of formula lai or Ia2: [0061] In some embodiments, the compound of formula I is: , or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Another aspect of the present disclosure is directed to a modifiable polymer/hydrogel which is the reaction product of i) a compound of formula ii) a polymerizable moiety which is the same as or different from Rj and/or Rf, and iii) an initiator.
  • Ri is (Ci-Cs) alkyd, (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
  • 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.
  • Li is absent.
  • L2 is absent.
  • Li is a linker
  • L2 is a linker.
  • the alkylene chain is a Ci-C 2 4 alkylene chain. In some embodiments, the alkylene chain is a Ci-Cis alkylene chain. In some embodiments, the alky lene chain is a Ci-Ci 2 alkylene chain. In some embodiments, the alkylene chain is a Ci- Cio alkylene chain. In some embodiments, the alkylene chain is a Ci-Cs alkylene chain. In some embodiments, the alkylene chain is a Ci-Ce alkylene chain. In some embodiments, the alkylene chain is a Ci-C alkylene chain. In some embodiments, the alkylene chain is a Ci-C 2 alkylene chain.
  • the alkylene chain is interrupted by, and/or terminates (at either or both termini) in 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) 2 N(R')-, 4- to 6-membered heterocyclyl, or a combination thereof.
  • the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -N(R')-. In some embodiments, the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -C(O)-. In some embodiments, the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -C(O)O- In some embodiments, the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -C(O)N(R')-.
  • the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -N(R')S(O) 2 - In some embodiments, the alkylene chain is interrupted by, and/or terminates (at either or both termini) with a 4- to 6- membered heterocyclyl.
  • the polyethylene glycol chain has 1 to 20 -(CH 2 CH 2 -O)- units. In some embodiments, the polyethylene glycol chain has 1 to 15 -(CH2CH 2 -O)- units. In some embodiments, the polyethylene glycol chain has 1 to 10 -(CH2CH 2 -O)- units. In some embodiments, the polyethylene glycol chain has 1 to 6 -(CH2CH2-O)- units. In some embodiments, the polyethylene glycol chain has 1 to 2 -(CH2CH2-O)- units.
  • the polyethylene glycol is interrupted by, and/or terminates (at either or both termini) in 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) 2 N(R')-, 4- to 6-membered heterocyclyl, or a combination thereof.
  • the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -N(R')-. In some embodiments, the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -C(O)-. In some embodiments, the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -C(O)O- In some embodiments, the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -C(O)N(R')-.
  • the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -N(R')S(O) 2 -. In some embodiments, the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with 4- to 6-membered heterocyclyl.
  • 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.
  • Ri is (Ci-Cs) alkyl. In some embodiments, Ri is methyl.
  • Ri and R 2 together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl.
  • Ri and R3, together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl.
  • R2 is hydorgen. In some embodiments, R2 is methyl. In some embodiments, R2 is chloro. In some embodiments, R2 is bromo. In some embodiments, R2 is iodo.
  • Rs is hydorgen. In some embodiments, Rs is methyl. In some embodiments, Rs is chloro. In some embodiments, Rs is bromo. In some embodiments. Rs is iodo.
  • X is a leaving group, which as known in the art refers to an atom or group of atoms which breaks away from the rest of the molecule, taking with it the electron pair which used to be the bond between the leaving group and the rest of the molecule.
  • leaving groups include esters, carbonates, carbamates, sulfoxides, sulfonates, sulfates, sulfones, thioesters, and thionoesters.
  • the leaving group is OR9, SR9, -OC(O)R 9 , -OC(O)OR 9 , -OC(O)NR 9 R9, -OC(S)R 9 , - -OC(S)OR 9 , -OC(S)NR 9 R9, -OS(O) 2 R9, -OS(O) 2 OR 9 .
  • each R9 is independently hydrogen, (Ci-Cs) alkyl, (C3-C10) carbocyclyl, or 4- to 7-membered heterocyclyl, wherein said alkyd, carbocyclyl, or heterocyclyl is optionally substituted.
  • the polymerizable moiety is the same as R4 and/or R4'.
  • the modifiable polymer is a homopolymer.
  • the polymerizable moiety is different than R4 and/or R4’, and the modifiable polymer/hydrogel is a co-polymer, e.g., a random or block co-polymer.
  • the polymerizable moiety comprises tw o or more different polymerizable moieties, e.g., vinyl chloride and vinyl alcohol, styrene and acrylamide, or vinyl chloride, styrene, and acrylamide.
  • R4 and R4’ are a polymerizable moiety. In some embodiments, R4 and R4’ are acrylamide.
  • R4 is a polymerizable moiety and R4' is a chemical moiety.
  • R4 is a chemical moiety and R4’ is a polymerizable moiety.
  • the chemical moiety is a carboxylic acid, amine, sulfonic acid, phenol, catechol, a metal chelator, a PEG chain, or a drug molecule.
  • initiators are chemical species that react with a polymerizable monomer to form an intermediate compound that is capable of linking successively with a large number of other polymerizable monomers.
  • Representative examples of initiators include peroxides (e.g., benzoyl peroxide, di-/e/7-butyl peroxide, methyl ethyl ketone peroxide, acetone peroxide, and peroxydisulfate) and aliphatic azo compounds (e.g., azobisisobutyronitrile (AIBN), azobis(cyclohexanecarbonitrile (ACHN), and diethyldiazene).
  • peroxides e.g., benzoyl peroxide, di-/e/7-butyl peroxide, methyl ethyl ketone peroxide, acetone peroxide, and peroxydisulfate
  • aliphatic azo compounds e.g., azobisisobutyronitrile
  • modifiable polymers/hydrogels which are the reaction product of: i) a 4-arm-cyclooct-2-yn-l ii) a dihydroxylamine, , wherein each Xi is a leaving group; each L is a linker; and each Rs 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.
  • the alkylene chain is a C1-C24 alkylene chain. In some embodiments, the alkylene chain is a Ci-Cis alkylene chain. In some embodiments, the alkylene chain is a C1-C12 alkylene chain. In some embodiments, the alkylene chain is a Ci- C10 alkylene chain. In some embodiments, the alkylene chain is a Ci-Cs alkylene chain. In some embodiments, the alkylene chain is a Ci-Ce alkylene chain. In some embodiments, the alkylene chain is a C1-C4 alkylene chain. In some embodiments, the alkylene chain is a C1-C2 alkylene chain.
  • the alkylene chain is interrupted by, and/or terminates (at either or both termini) in 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.
  • the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -N(R')-. In some embodiments, the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -C(O)-. In some embodiments, the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -C(O)O- In some embodiments, the alkylene chain is interrupted by, and/or terminates (at either or both termini) with -C(O)N(R')-. In some embodiments, the alkylene chain is interrupted by.
  • the alkydene chain is interrupted by, and/or terminates (at either or both termini) with a 4- to 6- membered heterocyclyl.
  • the polyethylene glycol chain has 1 to 20 -(CH2CH2-O)- units. In some embodiments, the polyethylene glycol chain has 1 to 15 -(CH2CH2-O)- units. In some embodiments, the polyethylene glycol chain has 1 to 10 -(CH2CH2-O)- units. In some embodiments, the polyethylene glycol chain has 1 to 6 -(CH2CH2-O)- units. In some embodiments, the polyethylene glycol chain has 1 to 2 -(CH2CH2-O)- units.
  • the polyethylene glycol is interrupted by, and/or terminates (at either or both termini) in 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')-.
  • the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -N(R')-. In some embodiments, the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -C(O)-. In some embodiments, the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -C(O)O- In some embodiments, the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -C(O)N(R')-.
  • the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with -N(R')S(O)2- In some embodiments, the polyethylene glycol chain is interrupted by, and/or terminates (at either or both termini) with 4- to 6-membered heterocyclyl.
  • Rs is (Ci-Cs) alkyd. In some embodiments, Rs is methyl.
  • Xi is a leaving group, which as know n in the art refers to an atom or group of atoms which breaks away from the rest of the molecule, taking w ith it the electron pair which used to be the bond 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 thionoesters.
  • the leaving group is OR9, SR9, -OC(O)R 9 .
  • the dihydroxylamine is OH or OH OH or stereoisomer thereof, wherein n is an integer from 1-10000. 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.
  • the 4-arm-cyclooct-2-yn-l-yl is of formula II: stereoisomer thereof, wherein n is an integer from 1-10000. In some embodiments, the 4-arm-cyclooct-2-yn-l-yl is about 10 kDa.
  • the optional substituent for the hydrogel is independently alkyl, alkenyl, alkynyl. halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy. heteroaryloxy, aralkyloxy.
  • haloalkylsulfonylamino cycloalkylsulfonylamino, heterocycloalk lsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alk lcarbonylamino, haloalkylcarbonylamino. cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl.
  • alkylaminocarbonyl cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N- heteroarylaminocarbonyl, cyano, nitro, and azido.
  • Compounds of the present disclosure may be in the form of a free acid or free base, or a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt of the compounds of this disclosure can be formed, for example, by reaction of an appropriate free base of a compound of the disclosure and an appropriate pharmaceutically acceptable acid in a suitable solvent under standard conditions well known in the art. See, for example, 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).
  • stereoisomer may have at least one chiral center and thus may be in the form of a stereoisomer, which as used herein, embraces all isomers of individual compounds that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers which include the (R-) or (S-) configurations of the compounds), mixtures of mirror image isomers (physical mixtures of the enantiomers, and racemates or racemic mixtures) of compounds, geometric (cis/trans or E/Z, R/S) isomers of compounds and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • the chiral centers of the compounds may undergo epimerization in vivo,' thus, for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Accordingly, the compounds of the present disclosure may be made and used in the form of individual isomers and substantially free of other isomers, or in the form of a mixture of various isomers, e.g., racemic mixtures of stereoisomers.
  • the compound of formula I or the hydrogel is an isotopic derivative in that it has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e.. enriched.
  • the compound includes deuterium or multiple deuterium atoms.
  • the term “compound” embraces isotopic derivatives.
  • the present disclosure is directed to a method for making 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-l-yl and a dihydroxylamine.
  • the compounds and their pharmaceutically acceptable salts and stereoisomers may be prepared by any process known to be applicable to the preparation of chemically related compounds.
  • the compounds of formula I can be prepared by methods known by those skilled in the art. In one non-limiting example the disclosed compounds can be made by the following schemes.
  • the present disclosure is directed to methods for preparing modifiable polymers/hydrogels which are the reaction product of: i) a compound of formula ii) a polymerizable moiety which is the same as or different from R4 and/or RT, and iii) an initiator.
  • random or block co-polymers can be made by varying the amounts of the "‘polymerizable moiety’” (reactant (ii)) or the sequence in which it/they are added.
  • the reacting is carried out in the presence of a solvent.
  • the solvent is an aprotic solvent.
  • the aprotic solvent is DCM, CHCh, CC14, DCE. toluene, MeCN, or THF.
  • the solvent is a protic solvent.
  • the protic solvent is water, MeOH, EtOH, iPrOH, nBuOH, TFE, or HFIP.
  • the solvent is a solvent mixture.
  • the solvent mixture is a mixture of an aprotic solvent and a protic solvent.
  • the solvent mixture is 0-100% protic to aprotic.
  • the solvent is a buffered solvent.
  • the buffered solvent is phosphate-buffered saline.
  • the pH of the phosphate-buffered saline is about 7.4.
  • the reacting is carried in the solvent with a concentration of is 1-25 wt%. In some embodiments, the concentration is 1, 5, 10, or 15 wt%.
  • the reacting of formula I with the polymer is in a ratio of 1- 20 wt%. In some embodiments, the ratio of formula I to polymer is 3, 6, or 12 wt%.
  • the reaction is carried out over a week. In some embodiments, the reaction is carried out over five days. In some embodiments, the reaction is carried out over three days. In some embodiments, the reaction is carried out over a period of 24 hours. In some embodiments, the reaction is carried out over a period of 18 hours. In some embodiments, the reaction is carried out over a period of 12 hours. In some embodiments, the reaction is carried out over a period of 6 hours. In some embodiments, the reaction is carried out over a period of 3 hours. In some embodiments, the reaction is carried out over a period of 2 hours. In some embodiments, the reaction is carried out over a period of 1 hour. In some embodiments, the reaction is carried out over a period of 45 minutes.
  • the reaction is carried out over a period of 30 minutes. In some embodiments, the reaction is carried out over a period of 15 minutes. In some embodiments, the reaction is carried out over a period of 5 minutes. In some embodiments, the reaction is carried out over a period of 1 minute.
  • the solvent is added after the reaction product is formed. In the initial constructed state, the reaction product would be a modifiable polymer. It would be made into a hydrogel as it swells upon introduction of the solvent, e.g., water.
  • the methods of preparing the hydrogels comprises the following operations or steps: 1) dissolving a polymerizable moiety (e g., acrylamide) in water at a desired weight per volume and stirring for a period of time; 2) the solution obtained in step 1) is added to a mixture containing a compound of formula I, a catalyst (e.g.. tetramethylethylenediamine (TMEDA)), an initiator (e.g., ammonium persulfate (APS)), and calcium sulfate (CaSO-i) and stirred for a period of time; 3) the mixture obtained in step 3 is stored at room temperature for a period of time, forming the hydrogel.
  • a polymerizable moiety e g., acrylamide
  • the present disclosure is directed to methods for preparing modifiable polymers/hydrogels which are the reaction product of one equivalent of a 4-arm- cyclooct-2-yn-l -yl, and two equivalents of a dihydroxylamine,
  • the reacting is carried out in the presence of a solvent.
  • the solvent is an aprotic solvent.
  • the aprotic solvent is DCM, CHCh, CC14. DCE. toluene, MeCN, or THF.
  • the solvent is a protic solvent.
  • the protic solvent is water, MeOH, EtOH, iPrOH, nBuOH, TFE, or HFIP.
  • the solvent is a solvent mixture.
  • the solvent mixture is a mixture of an aprotic solvent and a protic solvent.
  • the solvent mixture is 0-100% protic to aprotic.
  • the use of an aqueous solvent results in the production of a modifiable hydrogel and the use of a non-aqueous solvent results in the production of a modifiable polymer.
  • the solvent is a buffered solvent.
  • the buffered solvent is phosphate-buffered saline.
  • the pH of the phosphate-buffered saline is about 7.4.
  • the reacting is carried in the solvent with a concentration of is 1-25 wt%. In some embodiments, the concentration is 1, 5, 10, or 15 wt%.
  • the reacting of formula I with the polymer is in a ratio of 1- 20 wt%. In some embodiments, the ratio of formula I to polymer is 3, 6, or 12 wt%.
  • the reaction is carried out over a week. In some embodiments, the reaction is carried out over five days. In some embodiments, the reaction is carried out over three days. In some embodiments, the reaction is carried out over a period of 24 hours. In some embodiments, the reaction is earned out over a period of 18 hours. In some embodiments, the reaction is carried out over a period of 12 hours. In some embodiments, the reaction is carried out over a period of 6 hours. In some embodiments, the reaction is carried out over a period of 3 hours. In some embodiments, the reaction is carried out over a period of 2 hours. In some embodiments, the reaction is carried out over a period of 1 hour. In some embodiments, the reaction is carried out over a period of 45 minutes.
  • the reaction is carried out over a period of 30 minutes. In some embodiments, the reaction is carried out over a period of 15 minutes. In some embodiments, the reaction is carried out over a period of 5 minutes. In some embodiments, the reaction is carried out over a period of 1 minute.
  • the solvent is added after the reaction product is formed.
  • the reaction product In the initial constructed state, the reaction product would be a modifiable polymer. It would be made into a hydrogel as it swells upon introduction of the solvent, e.g., water.
  • hydrogels Methods of synthesizing hydrogels are known in the art. Varying the properties of the hydrogels, e.g., molecular weight and viscosity, to suit the clinical need at hand, is also within the level of skill in the art. See, Freedman et al.. Adv. Mater., 2021, 33/77):e2008553 and Ahmed, J. Adv. Res., 2015, 6(2) : 105-121.
  • a hydrogel of desired viscosity is formed by adding appropriate amounts of water. To obtain a gel that changes viscosity in vivo, calcium citrate tetrahydrate can be added to the water component or added after gel formation to obtain gels with higher viscosity.
  • hydrogels may be used as a suitable drug delivery system for drugs due to their tunable properties, controllable degradation, and ability to protect labile drugs. See, Vigata et al., Pharmaceutics, 2020, 72(72/ 1188. Accordingly, in some embodiments, effective amounts of a therapeutically active agent may be added at some point in the preparation of the hydrogels. As known in the art, modifiable non-hydrogel polymers may be used as films and plastics.
  • the present disclosure is directed to methods of degrading modifiable polymers/hydrogels.
  • the present method comprises contacting a modifiable polymer/hydrogel with a diboron reagent.
  • the diboron reagent is a symmetrical diboron reagent. In some embodiments, the diboron reagent is an unsymmetrical diboron reagent. In some embodiments, the diboron reagent is B2(OH)4, fhpim, .
  • diboron reagents include bis(catecholato)diboron, bis(hexylene glycolato)diboron, bis [(-)pinanediolato] diboron, bis(diisopropyl-l-tartrate glycolato)diboron, bis(N,N,N',N'-tetramethyl-d-tartaramide glycolato)diboron, and 2,2'-bi-l,3,2-dioxaborinane.
  • 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 pM. In some embodiments, the diboron reagent is used at a concentration of about 1 pM to about 10 pM.
  • the diboron reagent is used at a concentration of about 1 pM to about 1 pM. 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.
  • the biboron solution contains a calcium chelator.
  • the calcium chelator is ethylenediaminetetraacetic acid (EDTA) or citric acid.
  • the diboron reagent is formulated, e.g., as a solution, in water or saline.
  • the solution further comprises a solubilizing additive, e.g., DMSO.
  • the diboron agent is formulated as a solid.
  • Example 1 Synthesis of (E)-A-(2-(2-acrylamidoethoxy)ethyl)-3-(((2- acrylamidoethyl)carbamoyl)oxy)-A-methylprop- 1 -en- 1 -amine oxide (1 )
  • a round bottom flask was charged with A-(2-(2-iodoethoxy)ethyl)-3- (phenylthio)propenamide (1.78 g, 4.69 mmol, 1 equiv) and A-methylhydroxylamine hydrochloride (785 mg, 9.40 mmol, 2.00 equiv) then purged with nitrogen.
  • Dimethylsulfoxide (DMSO. 5 mL) and TEA (2.63 mL, 18.8 mmol. 4.00 equiv) was added via syringe. The reaction mixture was heated to 70°C and stirred for 2 hours.
  • a round botom flask was charged with 3-phenylthiopropanoic acid (1.09 g, 6.00 mmol, 1 equiv) and l-[bis(dimethylamino)methylene]-17f-l,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU, 2.51 g, 6.60 mmol, 1.10 equiv) then 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 rt.
  • DIPEA diisopropylethylamine
  • Propargyl chloroformate (637 pL, 6.53 mmol, 1.10 equiv) was added dropwise via syringe. After complete addition, the reaction mixture was warmed to rt. After 3 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with DCM (3 x 50 mL), and the combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the aqueous layer was extracted with DCM (3 x 10 mL), and 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.
  • Example 3 Synthesis of Poly amine- 1 [00157] (E)-4-Acryloyl-l-(3-(((2-((tert- butoxycarbonyl)amino)ethyl)carbamoyl)oxy)cyclooct-l-en-l-yl)piper azine 1 -oxide
  • THF (4 mL) and /erf-but l cyclooct-2-yn-l-yl ethane- 1 ,2-diyldicarbamate (246 mg, 795 pmol, 1.00 equiv) were sequentially added to a round bottom flask charged with 1- (4-((tert-butyldimethylsilyl)oxy)piperazin-l-yl)prop-2-en-l-one (215 mg, 795 pmol, 1.00 equiv). The flask was then purged with nitrogen and cooled to 0°C in an ice-water bath. A solution of tetrabutylammonium fluoride (1.0 M in THF.
  • Example 4 Procedure for the synthesis of chemically degradable polyacrylamide hydrogels
  • Polyacrylamide gels were synthesized by mixing acrylamide in water at the desired weight per volume percentage (e.g., 0.03 to 20 w/v%). To the fully dissolved solution was added a desired weight per volume of (E)-A-(2- (2-acrylamidoethoxy)ethyl)-3-(((2-acrylamidoethyl)carbamoyl)oxy)-N-methylprop-l-en-l- amine oxide or (E)-l-(3-(((2-acrylamidoethyl)carbamoyl)oxy)cyclooct-l-en-l-yl)-4- acryloylpiperazine 1-oxide.
  • FIG. 1 A schematic of the process is shown in FIG. 2.
  • a series of polyacrylamide gels with a varying percentage of cross-linker (0.03 to 0.3 w/v%) were synthesized and cast (FIG. 3A).
  • FIG. 3B confirms that an exemplary' polyacrylamide gel (0.12 w/v%) is resistant to stretch loading and unloading.
  • the reaction mixture was concentrated under reduced pressure, and the resulting solids were re-dissolved in DCM (10 mL) and diethyl ether (200 mL). The mixture was stirred at rt for 30 min before placing it in a refrigerator (4°C) for 6 hours. The precipitates were filtered and washed with diethyl ether (3 x 100 mL), and dried under reduced pressure to give the title compound as a white solid (5.88 g, 98%).
  • a round bottom flask was charged with 400 Da 2-Arm PEG-I (800 mg, 2.00 mmol, 1.00 equiv) and A-methyl-hydroxylamine hydrochloride salt (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 sequentially added via syringe.
  • the flask was covered with foil and 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 flash column chromatography on silica gel (eluent: 10 ⁇ 60% CMA in chloroform) to give the title compound a pale-yellow oil (688 mg, 69%).
  • a round bottom flask was charged with 2 kDa 2-Arm PEG-1 (10.0 g, 5.00 mmol, 1.00 equiv) and A-methyl-hydroxylamine hydrochloride salt (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 sequentially added via syringe.
  • the flask was covered with foil and 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 (200 mL).
  • Example 7 General procedure for gelation of hydrogels containing 4-Arm PEGCOT and 2- Arm PEG-NOH

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  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Dispersion Chemistry (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Processes Of Treating Macromolecular Substances (AREA)
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Abstract

La divulgation concerne des agents de réticulation chimiques covalents dégradables. La divulgation concerne également des procédés de fabrication et d'utilisation des agents de réticulation chimiques covalents dégradables.
PCT/US2024/035794 2023-06-28 2024-06-27 Polymères et hydrogels dégradables chimiquement et modifiables fonctionnellement Ceased WO2025006732A2 (fr)

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