WO2019178547A1 - Benzoxazine polymers and methods of making and using the same - Google Patents

Benzoxazine polymers and methods of making and using the same Download PDF

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Publication number
WO2019178547A1
WO2019178547A1 PCT/US2019/022590 US2019022590W WO2019178547A1 WO 2019178547 A1 WO2019178547 A1 WO 2019178547A1 US 2019022590 W US2019022590 W US 2019022590W WO 2019178547 A1 WO2019178547 A1 WO 2019178547A1
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substituted
unsubstituted
substituent group
independently
nhc
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PCT/US2019/022590
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French (fr)
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Phillip B. Messersmith
Cody J. HIGGINSON
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The Regents Of The University Of California
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Publication of WO2019178547A1 publication Critical patent/WO2019178547A1/en

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J179/00—Adhesives based on macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing nitrogen, with or without oxygen, or carbon only, not provided for in groups C09J161/00 - C09J177/00
    • C09J179/02—Polyamines

Definitions

  • Polybenzoxazines are a relatively new class of phenolic resins with a range of tunable properties including excellent thermal stability, high char yield, high glass transition temperature, and low moisture absorption. These properties are dependent upon the components and functional groups within the polymer. Synthetic challenges have persisted in limiting the types of functional groups, which may be included in the final polymer.
  • L 1 and L 2 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-,
  • L 4 is a covalent linker.
  • R 1 is independently hydrogen, halogen, -CX 1 1, -CHX 1 1, -CH2X 1 , -OCX 1 1, -OCH2X 1 , -OCHX 1 1 , -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO 1 R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -OC(O)R 1C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 ,
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX 3 , -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined
  • the symbols X, X 1 , and X 2 are independently–F, -Cl, -Br, or–I.
  • the symbols n1 and n2 are independently an integer from 0 to 4.
  • the symbols v1, v2, m1, and m2 are each independently 1 to 2.
  • the symbol z2 is an integer from 0 to 5. [0010] In another aspect is provided a polymer of the formula:
  • L 1 , L 2 , and L 3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
  • L 5 and L 6 are each independently a bond or covalent linker.
  • R 1 is independently hydrogen, halogen, -CX 1 1 , -CHX 1 1 , -CH 2 X 1 , -OCX 1 1 , -OCH 2 X 1 , -OCHX 1 1, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO1R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -OC(O)R 1C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -OCH 2 X 2 ,
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted monovalent benzoxazine monomer.
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX 3 , -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined
  • the symbols X, X 1 , and X 2 are independently– F, -Cl, -Br, or–I.
  • the symbols n1 and n2 are independently an integer from 0 to 4.
  • the symbols v1, v2, m1, and m2 are each independently 1 to 2.
  • the symbol z1 is independently an integer from 1 to 1000.
  • the symbol z2 is independently an integer from 0 to 5. [0016] In an aspect is provided a polymer of the formula:
  • L 3 and L 8 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-,
  • L 4 is a covalent linker.
  • L 5 and L 6 are each independently a bond or covalent linker.
  • R 3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted monovalent benzoxazine monomer.
  • the symbol z1 is independently an integer from 1 to 1000.
  • the symbol p5 is independently an integer from 1 to 1000.
  • a polymer including a repeating subunit, the repeating
  • Y has the formula: , ,
  • L 1 , L 2 , and L 3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
  • L 4 is a covalent linker.
  • R 1 is independently hydrogen, halogen, -CX 1 1 , -CHX 1 1 , -CH 2 X 1 , -OCX 1 1 , -OCH 2 X 1 , -OCHX 1 1 , -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO1R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -OC(O)R 1C , substituted or unsubstituted alkyl, substituted or unsubstitute
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 ,
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a monovalent benzoxazine monomer.
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX 3 , -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 2A and R 2B substituents bonded to the same nitrogen atom
  • the symbols X, X 1 , and X 2 are independently–F, -Cl, -Br, or–I.
  • the symbols n1 and n2 are independently an integer from 0 to 4.
  • the symbols v1, v2, m1, and m2 are each independently 1 to 2.
  • the symbol z5 is an integer from 1 to 1000.
  • the symbol z2 is an integer from 0 to 5.
  • the symbols p1, p2, p3, and p4 are each independently an integer from 1 to 1000.
  • L 8 is independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • L 4 is a covalent linker.
  • L 5 and L 6 are each independently a bond or covalent linker.
  • the symbol p5 is independently an integer from 1 to 1000.
  • the symbol“ ” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein the terminator moiety has the formula: -L 3 -R 3 , which is decribed herein.
  • a method of making a monomer having the formula:
  • L 1 and L 2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-,
  • R 1 is independently hydrogen, halogen, -CX 1 3 , -CHX 1 3 , -CH 2 X 1 , -OCX 1 3 , -OCH 2 X 1 , -OCHX 1 3, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO 1 R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1
  • R 5 , R 6 , and R 8 are each independently hydrogen, a protecting group, or a leaving group.
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX 3 , -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsub
  • n1 and n2 are independently an integer from 0 to 4.
  • the symbols v1, v2, m1, and m2 are each independently 1 to 2.
  • the symbols X, X 1 , and X 2 are independently –F, -Cl, -Br, or–I.
  • the symbol z2 is an integer from 0 to 5.
  • the method including mixing compound A and compound B together in a reaction vessel; wherein compound A has the formula:
  • L 2 and L 4 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-,
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 ,
  • R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX 3 , -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • the symbols X and X 2 are independently–F, -Cl, -Br, or–I.
  • the symbol z2 is an integer from 0 to 5.
  • the symbol n2 is independently an integer from 0 to 4.
  • the symbols v2 and m2 are each independently 1 to 2.
  • the symbols R 5 , R 6 , R 8 , and R 9 are each
  • FIG.1 Approaches to polymer coatings and adhesives using catechol-modified benzoxazines.
  • FIGS.2A-2B Thermally assisted ring-opening polymerization of protected benzoxazine monomers 1 (FIG.2A) and 8 (FIG.2B), and subsequent addition of organic solvent to product.
  • FIGS.3A-3B 1 H NMR spectra of protected monobenzoxazine 1 (FIG.3A) and the product of thermally-assisted ring-opening polymerization 2 (FIG.3B). Key peak
  • FIGS.4A-4C FIG.4A: Solutions of polymer 3 in pH 6, 7100 mM bis-tris, and pH 8100 mM bicine containing 600 mM MgCl 2 after 5 minutes, 3 and 16 hours incubation at room temperature.
  • FIG.4B TiO2 substrates after immersion coating in 1 mg/mL polymer 3 solutions at various pH values.
  • FIG.4C Centrifuged coating solutions after 16 hour coating procedure. The arrows indicate dark precipitates that were present in the coating mixtures after prolonged inclubation.
  • FIG.5. High resolution XPS analysis of C1s, O1s, and N1s peaks for coatings of 3 obtained at pH 6, 7, and 8.
  • FIGS.6A-6B FIG.6A: Schematic representation of deprotection conditions tested.
  • FIG.6B Photographs of methanol solution of 13, reaction mixture after addition of sodium methoxide, precipitate formation in aqueous workup, crude black product from methanolic HCl workup.
  • FIG.7 1 H-NMR analysis of protected 13 (top), and product of trial deprotection (bottom). Boxes with an‘X’ highlight characteristic benzoxazine peaks (top), and where they would be expected to appear in MeOD solvent (bottom).
  • FIG.8 1 H-NMR spectrum of crude thermally polymerized monomer 13. Boxes with an‘X’ highlight where characteristic benzoxazine resonances are expected in MeOD solvent. Boxes without an‘X’ indicate resonances assigned to the acetate protecting groups.
  • FIG.9. Deprotection of monomer 21 with tetrabutylammonium fluoride. TLC is taken after 15 minutes, and stained with ferric chloride solution (black spot indicates catechols); left lane is starting material, middle lane is co-spotted, right lane is crude reaction mixture. [0055] FIG.10.
  • FIG.11 Lap shear adhesion testing of bonded metal substrates with 24 and commercial benzoxazines.
  • FIG.12. Main-chain benzoxazine synthesis from 27 and Jeffamine-DA 400.
  • FIG.13 Thermal polymerization of model monomer S1 to form linear product S3.
  • FIG.15 Failed lap joints after adhesion testing. Left: chemical structures of compounds tested; middle: digital photographs of failed lap joint; right: primary failure mode.
  • FIGS.16A-16B FIG.16A: DSC thermogram (-10 to 290 °C, two cycles) for 35.
  • FIG.18 1 H-NMR spectrum of crude 54 collected in deuterated chloroform. This sample contains residual tetrahydrofuran solvent (3.72 and 1.83 ppm). The benzoxazine rings are intact, indicated by key benzoxazine resonances at 4.86 and 3.95 ppm. Deprotection of the catechol is further supported by a positive result of the iron chloride test.
  • FIG.19 Lap shear adhesive strengths for four mussel-inspired benzoxazines, with two commercial benchmarks, and three additional non-catechol benzoxazines for
  • FIG.20 Failed lap joints after adhesion testing for compounds 47, 48, and 45. Left: chemical structures of compounds tested; middle: digital photographs of failed lap joint; right: primary failure mode observed.
  • FIGS.21A-21B FIG.21A: Preparation of di-methoxy derivative precursor.
  • FIG. 21B Preparation of mono-methoxy derivative precursor.
  • FIGS.22A-22D Preparation of di-methoxy derivative precursor.
  • FIG.22A Preparation of mono-TBS-mono-methoxy- and mono- hydroxy-mono-methoxy-bis-benzoxazine derivatives.
  • FIG.22B Preparation of di- methoxyphenyl-bis-benzoxazine derivative.
  • FIG.22C Preparation of stand-alone diphenolic acid-based catechol-bis-benzoxazine.
  • FIG.22D Application of bisphenol from diphenolic acid and dopamine for main-chain benzoxazine synthesis. These main-chain benzoxazine materials have side-chain catechols.
  • FIG.23 1 H NMR analysis of protected main-chain polybenzoxazine 55 in CDCl3.
  • FIG.24 1 H NMR spectrum of crude 56 collected in deuterated chloroform. This sample contains residual tetrabutylammonium (labeled). Key benzoxazine resonances are observed at ⁇ 4.92 and ⁇ 4.00 ppm (arrows).
  • FIG.25 Synthetic route to deprotected benzoxazine monomer 59.
  • FIG.26 Lap-shear adhesion strength of mixtures of 37 with main-chain derivatives 54 and 56 on roughened aluminum 6061 substrates.
  • FIG.27 DSC thermograms for curing of 37.
  • FIG.28 Flexural testing specimens of cured BPA-Aniline, 37, and 36 prepared by compression molding and sanding.
  • FIG.29 Representative flexural stress-strain curves during 3-point bending at a crosshead speed of 0.01 mm/min.
  • FIG.30 Flexural modulus and flexural strength determined by 3-point bending for benchmark materials BPA-Aniline and polybenzoxazine materials 37 and 36.
  • FIG.31 Thermal gravimetric analysis of 36, 37, and BPA-Aniline under nitrogen up to 600 °C.
  • FIG.32 Thermal gravimetric analysis of 37 and BPA-Aniline under air up to 600 °C.
  • FIG.33 Formation of PSA tapes of 56 on PET films.
  • FIG.34A PSA films of 56 holding together glass slides (FIG.34A) or HDPE strips (FIG.34B) under shear load of 200 gram weight.
  • Sample on Glass (FIG.34A) is pictured at 3 days and has remained unchanged (beyond 208 days).
  • Sample on HDPE (FIG.34B) is pictured after 16 hours.
  • the nearly colorless transparent tapes are framed by dotted boxes as a visual aid.
  • FIG.35 PSA films of 56 applied to glass slides that were submerged in deionized water. The adhesive joint was still intact after 24 hours of incubation at room temperature underwater. The tape starts to appear opaque after an hour of submersion. DETAILED DESCRIPTION
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals.
  • the alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons).
  • Alkyl is an uncyclized chain.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4- pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).
  • An alkyl moiety may be an alkenyl moiety.
  • An alkyl moiety may be an alkynyl moiety.
  • An alkyl moiety may be fully saturated.
  • alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds.
  • An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH 2 CH 2 CH 2 CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein.
  • A“lower alkyl” or“lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • the term“alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • the term“heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • heteroatom(s) e.g., N, S, Si, or P
  • the heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • Heteroalkyl is an uncyclized chain.
  • a heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • the term“heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond.
  • a heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds.
  • the term“heteroalkynyl,” by itself or in combination with another term means, unless otherwise stated, a heteroalkyl including at least one triple bond.
  • heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds.
  • heteroalkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO 2 R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as - NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like.
  • heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,
  • halo(C1-C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • acyl means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • heteroaryl refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2- naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4- imidazolyl
  • Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
  • An“arylene” and a“heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively.
  • a heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
  • Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different.
  • Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings).
  • Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene).
  • heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring.
  • substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
  • alkylarylene as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker).
  • alkylarylene group has the formula: .
  • An alkylarylene moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N 3 , - CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3 - SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl).
  • the alkylarylene is unsubstituted.
  • R, R', R'', R'', and R''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • aryl e.g., aryl substituted with 1-3 halogens
  • substituted or unsubstituted heteroaryl substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R', R'', R''', and R''' group when more than one of these groups is present.
  • R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring.
  • -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., - C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).
  • haloalkyl e.g., -CF 3 and -CH 2 CF 3
  • acyl e.g., - C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like.
  • R', R'', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • each of the R groups is independently selected as are each R', R'', R'', and R''' groups when more than one of these groups is present.
  • Substituents for rings e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene may be depicted as
  • substituents on the ring rather than on a specific atom of a ring may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings).
  • the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different.
  • a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent)
  • the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency.
  • a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms.
  • the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring-forming substituents are attached to non- adjacent members of the base structure.
  • the terms“heteroatom” or“ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • A“substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3
  • heteroalkyl cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (i) oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHC
  • heterocycloalkyl 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • unsubstituted aryl e.g., C 6 -C 10 aryl, C 10 aryl, or phenyl
  • unsubstituted heteroaryl e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • alkyl e.g., C 1 -C 8 alkyl, C 1 -C 6 alkyl, or C 1 -C 4 alkyl
  • heteroalkyl e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • cycloalkyl e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl
  • A“size-limited substituent” or“ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and each substituted or unsubstituted heteroaryl is
  • A“lower substituent” or“ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 - C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or un
  • heterocycloalkyl substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.
  • each substituted or unsubstituted alkyl may be a substituted or unsubstituted C 1 -C 20 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 - C10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 20 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered
  • heteroalkylene each substituted or unsubstituted cycloalkylene is a substituted or
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl
  • each substituted or unsubstituted or unsubstituted alkyl is a substituted or
  • heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene
  • unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 7 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
  • the compound is a chemical species set forth in the Examples section, figures, or tables below.
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
  • cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene, respectively).
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one substituent group wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one size-limited substituent group wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different.
  • each size-limited substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each lower substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each substituent group, size-limited substituent group, and/or lower substituent group is different.
  • Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • the term“isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • the term“tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • bioconjugate linker and“bioconjugate” refers to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect.
  • a conjugate between a first bioconjugate reactive group e.g.,–NH 2 ,–COOH,–N- hydroxysuccinimide, or–maleimide
  • a second bioconjugate reactive group e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate
  • covalent bond or linker e.g. a first linker of second linker
  • indirect e.g., by non-covalent bond (e.g. electrostatic interactions (e.g. ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g.
  • bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition).
  • bioconjugate chemistry i.e., the association of two bioconjugate reactive groups
  • nucleophilic substitutions e.g., reactions of amines and alcohols with acyl halides, active esters
  • electrophilic substitutions e.g., enamine reactions
  • additions to carbon-carbon and carbon-heteroatom multiple bonds e.g., Michael reaction, Diels-Alder addition.
  • the first bioconjugate reactive group e.g., maleimide moiety
  • the second bioconjugate reactive group e.g., a sulfhydryl
  • the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group e.g.,–N- hydroxysuccinimide moiety
  • is covalently attached to the second bioconjugate reactive group (e.g., an amine).
  • the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group (e.g.,–sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).
  • bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N- hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.
  • haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom;
  • dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups;
  • aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition;
  • sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides;
  • thiol groups which can be converted to disulf
  • bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein.
  • a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group.
  • the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.
  • an analog is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound. [0126]
  • the terms "a” or "an,” as used in herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R-substituted where a moiety is substituted with an R substituent, the group may be referred to as“R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R 13 substituents are present, each R 13 substituent may be
  • R 13A , R 13B , R 13C , R 13D , etc. wherein each of R 13A , R 13B , R 13C , R 13D , etc. is defined within the scope of the definition of R 13 and optionally differently.
  • Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions.
  • a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.
  • the term“leaving group” is used in accordance with its ordinary meaning in chemistry and refers to a moiety (e.g., atom, functional group, molecule) that separates from the molecule following a chemical reaction (e.g., bond formation, reductive elimination, condensation, cross-coupling reaction) involving an atom or chemical moiety to which the leaving group is attached, also referred to herein as the“leaving group reactive moiety”, and a complementary reactive moiety (i.e., a chemical moiety that reacts with the leaving group reactive moiety) to form a new bond between the remnants of the leaving groups reactive moiety and the complementary reactive moiety.
  • a chemical reaction e.g., bond formation, reductive elimination, condensation, cross-coupling reaction
  • a complementary reactive moiety
  • leaving group reactive moiety and the complementary reactive moiety form a complementary reactive group pair.
  • leaving groups include hydrogen, hydroxide, organotin moieties (e.g., organotin heteroalkyl), halogen (e.g., Br), perfluoroalkylsulfonates (e.g., triflate), tosylates, mesylates, water, alcohols, nitrate, phosphate, thioether, amines, ammonia, fluoride, carboxylate, phenoxides, boronic acid, boronate esters, and alkoxides.
  • organotin moieties e.g., organotin heteroalkyl
  • halogen e.g., Br
  • perfluoroalkylsulfonates e.g., triflate
  • tosylates mesylates, water, alcohols, nitrate, phosphate, thioether, amines, ammonia
  • two molecules with leaving groups are allowed to contact, and upon a reaction and/or bond formation (e.g., acyloin condensation, aldol condensation, Claisen condensation, Stille reaction) the leaving groups separates from the respective molecule.
  • a leaving group is a bioconjugate reactive moiety.
  • at least two leaving groups are allowed to contact such that the leaving groups are sufficiently proximal to react, interact or physically touch.
  • the leaving groups is designed to facilitate the reaction.
  • protecting group is used in accordance with its ordinary meaning in organic chemistry and refers to a moiety covalently bound to a heteroatom, heterocycloalkyl, or heteroaryl to prevent reactivity of the heteroatom, heterocycloalkyl, or heteroaryl during one or more chemical reactions performed prior to removal of the protecting group.
  • a protecting group is bound to a heteroatom (e.g., O) during a part of a multipart synthesis wherein it is not desired to have the heteroatom react (e.g., a chemical reduction) with the reagent. Following protection the protecting group may be removed (e.g., by modulating the pH).
  • the protecting group is an alcohol protecting group.
  • Alcohol protecting groups include acetyl, benzoyl, benzyl, methoxymethyl ether (MOM), tetrahydropyranyl (THP), and silyl ether (e.g., trimethylsilyl (TMS), TBS (tert-butyl dimethylsilyl).
  • the protecting group is an amine protecting group.
  • Non-limiting examples of amine protecting groups include carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl ether (PMB), and tosyl (Ts).
  • the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts.
  • Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • the present disclosure provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure.
  • Prodrugs of the compounds described herein may be converted in vivo after administration.
  • prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
  • Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
  • Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch.
  • the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture.
  • the term“contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.
  • the term“aberrant” as used herein refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples.
  • Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
  • the term“about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using
  • polymer refers to a molecule including repeating subunits (e.g., polymerized monomers).
  • polymeric molecules may be based upon polyethylene glycol (PEG), poly[amino(1-oxo-1,6-hexanediyl)], poly(oxy-1,2- ethanediyloxycarbonyl-1,4-phenylenecarbonyl), tetraethylene glycol (TEG),
  • polyvinylpyrrolidone PVP
  • poly(xylene) poly(xylene)
  • poly(p-xylylene) See, for example, “Chemistry of Protein Conjugation and Cross-Linking” Shan S. Wong CRC Press, Boca Raton, Fla., USA, 1993;“BioConjugate Techniques” Greg T. Hermanson Academic Press, San Diego, Calif., USA, 1996;“Catalog of Polyethylene Glycol and Derivatives for Advanced PEGylation, 2004” Nektar Therapeutics Inc, Huntsville, Ala., USA, which are incorporated by reference in their entirety for all purposes.
  • polystyrene resin refers to a triblock copolymer composed of a central hydrophobic block (e.g., polyoxypropylene) flanked by two hydrophilic blocks (e.g., polyoxyethylene). Poloxamers may be customized by adjusting the degree of hydrophobicity and/or hydrophilicity by extending or retracting the length of the blocks.
  • Non-limiting examples of poloxamers include poloxomer 407, poloxomer 188, poloxomer 127, or poloxomer 388.
  • branched polymer is used in accordance with its meaning in the art of polymer chemistry and refers to a molecule including repeating subunits, wherein at least one repeating subunit (e.g., polymerizable monomer) is covalently bound to an additional subunit substituent (e.g., resulting from a reaction with a polymerizable monomer).
  • a repeating subunit e.g., polymerizable monomer
  • branched polymer has the formula: wherein‘A’ is the first repeating subunit and‘B’ is the second repeating subunit.
  • the first repeating subunit e.g., polyethylene glycol
  • the second repeating subunit e.g., polymethylene glycol
  • at least one repeating subunit e.g., polymerizable monomer
  • an additional non-consecutive subunit substituent e.g., resulting from a reaction with a polymerizable monomer
  • it may be referred to herein as a mesh.
  • a mesh may have the formula:
  • block copolymer is used in accordance with its ordinary meaning and refers to two or more portions (e.g., blocks) of polymerized monomers linked by a covalent bond.
  • a block copolymer is a repeating pattern of polymers.
  • the block copolymer includes two or more monomers in a periodic (e.g., repeating pattern) sequence.
  • a diblock copolymer has the formula:–B-B-B-B- B-B–A-A-A-A-A–, where‘B’ is a first subunit and‘A’ is a second subunit covalently bound together.
  • a triblock copolymer therefore is a copolymer with three distinct blocks, two of which may be the same (e.g.,–A-A-A-A-A–B-B-B-B-B-B–A-A-A-A–) or all three are different (e.g.,–A-A-A-A-A–B-B-B-B-B–C-C-C-C-C—) where‘A’ is a first subunit,‘B’ is a second subunit, and‘C’ is a third subunit, covalently bound together.
  • the term“monovalent benzoxazine monomer” refers to an unpolymerized
  • benzoxaxine monomer having the formula: , wherein, L 7 is a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and R 7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubsti
  • the monovalent benzoxazine monomer is:
  • L 1 and L 2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-,
  • L 4 is a covalent linker.
  • R 1 is independently hydrogen, halogen, -CX 1 1, -CHX 1 1, -CH2X 1 , -OCX 1 1, -OCH2X 1 , -OCHX 1 1, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO 1 R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -OC(O)R 1C , substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or un
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, a protecting group, or a leaving group;
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size
  • the symbols X, X 1 , and X 2 are independently–F, -Cl, -Br, or–I.
  • the symbols n1 and n2 are independently an integer from 0 to 4.
  • the symbols v1, v2, m1, and m2 are each independently 1 to 2.
  • the symbol z2 is an integer from 0 to 5.
  • L 1 and L 2 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membere
  • L 4 is independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent
  • L 4 is independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to
  • R 1 is independently hydrogen, halogen, -CX 1 1, -CHX 1 1, -CH2X 1 , -OCX 1 1, -OCH2X 1 , -OCHX 1 1, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO1R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -OC(
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH 2 X 2 , -OCHX 2 2 , -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C ,
  • substituted or unsubstituted alkyl e.g., C1-C8, C1- C 6 , or C 1 -C 4
  • substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered
  • substituted or unsubstituted cycloalkyl e.g., C3-C8, C3-C6, or C5-C6
  • substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered
  • substituted or unsubstituted aryl e.g., C 6 -C 10 or phenyl
  • substituted or unsubstituted heteroaryl e.g., 5 to 10 membered, 5 to 9
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted or unsubstitute
  • L 1 , L 2 , and L 3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a
  • L 5 and L 6 are each independently a bond or covalent linker.
  • R 1 is independently hydrogen, halogen, -CX 1 1, -CHX 1 1, -CH2X 1 , -OCX 1 1, -OCH2X 1 , -OCHX 1 1, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO 1 R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -OC(O)R 1C , substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or un
  • R 2 is independently–OH, -OTBS (tert-butyl dimethylsilyl ether), or–OCH3. In embodiments, R 2 is independently–OH. In embodiments, R 2 is independently -OTBS (tert-butyl dimethylsilyl ether). In embodiments, R 2 is independently–OCH 3 .
  • R 3 is independently hydrogen, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • unsubstituted cycloalkyl substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, or a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted monovalent benzoxazine monomer.
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, a protecting group, or a leaving group;
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size
  • the symbols X, X 1 , and X 2 are independently–F, -Cl, -Br, or–I.
  • the symbols n1 and n2 are independently an integer from 0 to 4.
  • the symbols v1, v2, m1, and m2 are each independently 1 to 2.
  • the symbol z1 is independently an integer from 1 to 1000.
  • the symbol z2 is independently an integer from 0 to 5.
  • L 1 , L 2 , and L 3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3
  • L 5 and L 6 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a substituent
  • L 5 and L 6 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ), substituted or unsubstituted
  • heteroalkylene e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered
  • substituted or unsubstituted cycloalkylene e.g., C3-C8, C3-C6, or C5-C6
  • substituted or unsubstituted heterocycloalkylene e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered
  • substituted or unsubstituted arylene e.g., C 6 -C 10 or phenylene
  • R 1 is independently hydrogen, halogen, -CX 1 1, -CHX 1 1, -CH2X 1 , -OCX 1 1, -OCH2X 1 , -OCHX 1 1, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO 1 R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -OC(
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN, -SOn2R 2D , -SOv2NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O)m2, -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO 2 R 2D , -NR 2A C(O)R 2C ,
  • R 3 is independently hydrogen, substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or a
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted alkyl (e.
  • L 3 and L 8 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-,
  • L 4 is a covalent linker.
  • L 5 and L 6 are each independently a bond or covalent linker.
  • R 3 is independently hydrogen, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • unsubstituted cycloalkyl substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, or a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted monovalent benzoxazine monomer.
  • L 4 , L 5 , and L 6 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • unsubstituted heteroalkylene substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene.
  • L 3 , L 4 , L 5 , L 6 , and L 8 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or
  • unsubstituted heteroalkylene e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered
  • substituted or unsubstituted cycloalkylene e.g., C3-C8, C3-C6, or C5-C6
  • substituted or unsubstituted heterocycloalkylene e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered
  • substituted or unsubstituted arylene e.g., C6-C10 or phenylene
  • substituted or unsubstituted heteroarylene e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • R 3 is independently hydrogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C 3 -C 6 , or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or a substituted or unsubstituted alkyl (
  • Y has the formula: , ,
  • L 1 , L 2 , R 1 , R 2 , and z2 are as described herein. It is understood that when multiple instances of Y are present, each Y may be different. In embodiments, Y has the formula: . L 1 , L 2 , R 1 , R 2 , and z2 are
  • Y has the formula:
  • L 2 , R 1 , R 2 , and z2 are as described herein.
  • Y has the formula:
  • L 1 , L 2 , R 1 , R 2 , and z2 are as described herein.
  • L 2 , L 4 , R 2 , and z2 are as described herein.
  • the symbol“ ” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein the terminator moiety has the formula: -L 3 -R 3 , which is decribed herein.
  • the polymer includes one or a plurality of optionally different repeating subunits and/or terminator moieities that are each attached to a“ ”.
  • L 1 , L 2 , and L 3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group,
  • L 4 is a covalent linker.
  • R 1 is independently hydrogen, halogen, -CX 1 1 , -CHX 1 1 , -CH 2 X 1 , -OCX 1 1 , -OCH 2 X 1 , -OCHX 1 1, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO1R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -OC(O)R 1C , substituted (e.g., substituted with a substituent group, a size-limited substituent group,
  • R 3 is independently hydrogen, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • R 3 is independently hydrogen. In embodiments, R 3 is independently unsubstituted phenyl. In embodiments, R 3 is
  • R 3 is independently an unsubstituted monovalent benzoxazine monomer.
  • R 3 is independently a substituted monovalent benzoxazine monomer (e.g., substituted with a substituent group).
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX 3 , -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or
  • the symbols X, X 1 , and X 2 are independently–F, -Cl, -Br, or–I.
  • the symbols n1 and n2 are independently an integer from 0 to 4.
  • the symbols v1, v2, m1, and m2 are each independently 1 to 2.
  • the symbol z5 is an integer from 1 to 1000.
  • the symbol z2 is an integer from 0 to 5.
  • the symbols p1, p2, p3, and p4 are each independently an integer from 1 to 1000.
  • Y has the formula: , ,
  • L 1 , L 2 , R 1 , R 2 , and z2 are as described herein.
  • [0191] has the formula: . L 4 , L 5 , L 6 , L 8 , and p5 are as described herein.
  • the symbol z5 is an integer from 1 to 1000.
  • the symbols p1, p2, p3, and p4 are each independently an integer from 1 to 1000.
  • the symbol“ ” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein the terminator moiety has the formula: -L 3 -R 3 , which is decribed herein.
  • the polymer includes one or a plurality of optionally different repeating subunits and/or terminator moieities that are each attached to a“ ”.
  • L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and L 8 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), substituted or unsubstituted alkylene (
  • R 1 is independently hydrogen, halogen, -CX 1 1, -CHX 1 1, -CH2X 1 , -OCX 1 1, -OCH2X 1 , -OCHX 1 1, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO 1 R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -OC(O)R 1C , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN, -SOn2R 2D , -SOv2NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O)m2, -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO 2 R 2D , -NR 2A C(O)R 2C ,
  • R 3 is independently hydrogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C 3 -C 6 , or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or a substituted or unsubstituted alkyl (
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted or unsubstitute
  • the polymer network can have 100 or more repeating subunits having the formula
  • Y has the formula: , R 2 , and z2 are as described herein. In embodiments, Y has the formula:
  • Y has the formula: . L 1 , L 2 , R 1 , R 2 , and z2 are as described herein.
  • R 2 when multiple instances of a substituent (e.g., R 2 ) are present it is understood that they may be optionally different.
  • Y has the formula: , wherein L 1 is as described herein. In embodiments, Y has the formula:
  • L 1 is as described herein.
  • Y has the formula: .
  • Y has the formula: , wherein L 1 is as described herein.
  • L 2 and L 4 is as described herein.
  • a linker or substituent e.g., L 2
  • R 1 is independently hydrogen, halogen, -CX 1 1 , -CHX 1 1 , -CH 2 X 1 , -OCX 1 1, -OCH2X 1 , -OCHX 1 1, -CN, -SOv1NH2, -NHC(O)NH2, -N(O)m1, -NH2, -C(O)H, -COOH, -C(O)NH2, -OH, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 3 , -CH 2 X 2 , -OCX 2 3 , -OCH 2 X 2 , -OCHX 2 3 , -CN, -SO v2 NH 2 , -NHC(O)NH 2 , -N(O) m2 , -NH 2 , -C(O)H, -COOH, -C(O)NH2, -OH, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl. In embodiments, two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl. In embodiments, two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted aryl.
  • R 2 is independently–OH, -OTBS (tert-butyl dimethylsilyl ether), or–OCH 3 .
  • R 2 is independently–OH.
  • R 2 is independently -OTBS (tert-butyl dimethylsilyl ether).
  • R 2 is independently–OCH3.
  • R 1 , R 2 , R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3 , and R 7 are each independently substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 , or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membere
  • R 1 , R 2 , R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3 , and R 7 are each independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • unsubstituted heteroalkyl substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl.
  • R 1 , R 2 , R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3 , and R 7 are each independently unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 1 , R 2 , R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3 , and R 7 are each independently unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen.
  • R 5 is hydrogen.
  • R 7 is hydrogen.
  • R 6 is hydrogen. In embodiments, R 8 is hydrogen. In embodiments, R 9 is hydrogen. In embodiments, R 5 is a protecting group. In embodiments, R 6 is a protecting group. In embodiments, R 8 is a protecting group. In embodiments, R 9 is a protecting group. In embodiments, R 5 is a leaving group. In embodiments, R 6 is a leaving group. In embodiments, R 8 is hydrogen. In embodiments, R 9 is hydrogen. In embodiments, R 5 is a protecting group. In embodiments, R 6 is a protecting group. In embodiments, R 8 is a protecting group. In embodiments, R 9 is a protecting group. In embodiments, R 5 is a leaving group. In embodiments, R 6 is a leaving group. In
  • R 8 is a leaving group.
  • R 9 is a leaving group.
  • R 5 , R 6 , R 8 , and R 9 are each independently hydrogen, a protecting group, or a leaving group.
  • L 1 , L 2 , L 3 , L 4 , L 4A , L 4B , L 4C , L 5 , L 6A , L 6B , L 6C , L 6 , and L 8 are each independently a bond.
  • L 1 , L 2 , L 3 , L 4 , L 4A , L 4B , L 4C , L 5 , L 6A , L 6B , L 6C , L 6 , and L 8 are each independently substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1- C 4 , or C 1 -C 2 ), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered,
  • L 1 , L 2 , L 3 , L 4 , L 4A , L 4B , L 4C , L 5 , L 6A , L 6B , L 6C , L 6 , and L 8 are each independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g.,
  • L 1 , L 2 , L 3 , L 4 , L 4A , L 4B , L 4C , L 5 , L 6A , L 6B , L 6C , L 6 , and L 8 are each independently unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted
  • L 1 , L 2 , L 3 , L 4 , L 4A , L 4B , L 4C , L 5 , L 6A , L 6B , L 6C , L 6 , and L 8 are each independently unsubstituted alkylene.
  • L 1 , L 2 , L 3 , L 4 , L 4A , L 4B , L 4C , L 5 , L 6A , L 6B , L 6C , L 6 , and L 8 are each independently unsubstituted methylene.
  • L 1 , L 2 , L 3 , L 4 , L 4A , L 4B , L 4C , L 5 , L 6A , L 6B , L 6C , L 6 , and L 8 are each independently unsubstituted ethylene.
  • L 1 , L 2 , L 3 , L 4 , L 4A , L 4B , L 4C , L 5 , L 6A , L 6B , L 6C , L 6 , and L 8 are each independently unsubstituted propylene.
  • p5 is independently an integer from 1 to 100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100).
  • 1 to 100 e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,
  • L 1 , L 2 , L 3 , L 4 , L 4A , L 4B , L 4C , L 5 , L 6A , L 6B , L 6C , L 6 , and L 8 are each independently .
  • L 1 , L 2 , L 3 , L 4 , L 4A , L 4B , L 4C , L 5 , L 6A , L 6B , L 6C , L 6 , and L 8 are each independently .
  • L 8 are each independently .
  • p5 is 6.
  • p5 is 31.
  • p5 is 32.
  • p5 is 33.
  • p5 is 34.
  • p5 is 35.
  • R 1 is independently -NHC(O)NR 1A R 1B , -NR 1A R 1B , -C(O)NR 1A R 1B , -NR 1A SO 1 R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 1 is–NH2.
  • R 2 is -C(O)R 2C , -C(O)-OR 2C , -OR 2D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
  • R 2 is–OH or–OTBS.
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl.
  • R 2.3 and R 2.4 are each hydrogen or R 2 at a fixed position on the attached ring.
  • R 2.3 and R 2.4 may
  • R 2.3 and R 2.4 are each independently -OR 2D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 2.3 and R 2.4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • R 2D is independently hydrogen, -CX 2 3, -CN, -COOH, -CONH2, -CHX 2 2, -CH2X 2 , -CONH-(C1-C6 alkyl), -C(O)-(C1-C6 alkyl), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group.
  • independently represented by the formula: is independently represented by the formula: in embodiments, is independently represented by the formula: in embodiments, is independently represented by the formula: in embodiments, independently represented by the formula: . In embodiments, is independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiments, independently represented by the formula: . In embodiment
  • R 3 is independently hydrogen, substituted or unsubstituted phenyl, or a monovalent benzoxazine monomer, wherein the monovalent benzoxazine monomer has
  • L 7 is a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
  • R 3 is independently hydrogen. In embodiments, R 3 is independently substituted or unsubstituted phenyl.
  • R 3 is independently a substituted (e.g., R 7 -substituted) monovalent benzoxazine monomer. In embodiments, R 3 is independently unsubstituted phenyl.
  • L 1 is independently -C(O)-, -C(O)CH 2 -, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L 1 is independently substituted or unsubstituted C 1 -C 6 alkylene or a substituted or unsubstituted 2 to 6 membered
  • L 1 is independently substituted or unsubstituted C1-C3 alkylene. In embodiments, L 1 is independently substituted or unsubstituted C1-C2 alkylene. In embodiments, L 1 is independently . [0226] In embodiments, L 2 is independently -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • L 2 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L 2 is independently substituted or unsubstituted C1-C2 alkylene.
  • L 4 is independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
  • L 4 is independently substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 4 is independently substituted or unsubstituted C 1 -C 2 alkylene.
  • L 4 has the formula: -L 4A -L 4B -L 4C -, wherein L 4A , L 4B , and L 4C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-,
  • unsubstituted cycloalkylene substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • L 4A , L 4B , and L 4C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted
  • R 10 is independently halogen, -CCl3, -CBr3, -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
  • R 10 is independently–OH.
  • R 10 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a
  • z10 is 0. In embodiments, z10 is 1. In embodiments, z10 is 2. [0232] In embodiments, R 10 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • unsubstituted alkyl substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • R 10 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -
  • L 4 is independently . In embodiments, L 4 is independently . In embodiments, L 4 is independently . In embodiments, L 4 is independently . In embodiments, L 4 is independently
  • L 4 is , ,
  • L 4B is unsubstituted C1-C4 alkyl.
  • L 4B is unsubstituted ethyl.
  • L 2 has the formula: -L 2A -L 2B -L 2C -, wherein L 2A , L 2B , and L 2C are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -,
  • unsubstituted cycloalkylene substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • L 2A , L 2B , and L 2C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted
  • L 4 is independently . In embodiments,
  • L 4 is independently .
  • L 2A , L 4A , R 10 , and z10 are as described herein. [0239] In embodiments, L 4 is
  • substituent may be different (e.g., may exist as embodiments, L 2C is unsubstituted C 1 -C 4 alkyl.
  • L 2C is unsubstituted ethyl.
  • L 4 is independently -C(O)CH2-, ,
  • L 5 is independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ), substituted or unsubstituted
  • heteroalkylene e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered
  • substituted or unsubstituted cycloalkylene e.g., C3-C8, C3-C6, or C5-C6
  • substituted or unsubstituted heterocycloalkylene e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered
  • substituted or unsubstituted arylene e.g., C 6 -C 10 or phenyl
  • substituted or unsubstituted heteroarylene e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • L 5 has the formula: -L 5A -L 5B -L 5C -, wherein L 5A , L 5B , and L 5C are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -,
  • unsubstituted cycloalkylene substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene.
  • L 5A , L 5B , and L 5C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e
  • L 5 is independently .
  • L 5A is
  • L 5B is independently .
  • L 5C is independently .
  • L 6 is independently .
  • L 6A is
  • L 6 is independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstit
  • L 6 has the formula: -L 6A -L 6B -L 6C -, wherein L 6A , L 6B , and L 6C are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -,
  • unsubstituted cycloalkylene substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • L 6A , L 6B , and L 6C are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or
  • unsubstituted heteroalkylene e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered
  • substituted or unsubstituted cycloalkylene e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6
  • substituted or unsubstituted heterocycloalkylene e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered
  • substituted or unsubstituted arylene e.g., C6-C10 or phenylene
  • substituted or unsubstituted heteroarylene e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • L 8 is independently -C(O)-, -C(O)CH 2 -, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • L 8 is independently substituted or unsubstituted C 1 -C 6 alkylene or a substituted or unsubstituted 2 to 6 membered
  • L 8 is independently substituted or unsubstituted C1-C3 alkylene. In embodiments, L 8 is independently substituted or unsubstituted C1-C2 alkylene. In embodiments, L 8 is independently . [0250] In embodiments, z1 is independently 1. In embodiments, z1 is independently 6. In embodiments, z1 is independently an integer from 1 to 10. In embodiments, z1 is
  • z1 is independently an integer from 1 to 20. In embodiments, z1 is independently an integer from 1 to 30. In embodiments, z1 is independently an integer from 1 to 15. In embodiments, z1 is independently an integer from 1 to 25. In embodiments, z1 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In embodiments, z1 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. [0251] In embodiments, z2 is independently 0. In embodiments z2 is independently an integer from 0 to 2. In embodiments, z2 is independently 1. In embodiments, z2 is independently 2. In embodiments, z2 is independently 3. In embodiments, z2 is,
  • z5 is independently 1. In embodiments, z5 is independently an integer from 1 to 10. In embodiments, z5 is independently an integer from 1 to 20. In embodiments, z5 is independently an integer from 1 to 30. In embodiments, z5 is
  • z5 is independently an integer from 1 to 15. In embodiments, z5 is independently an integer from 1 to 25. In embodiments, z5 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In embodiments, z5 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000.
  • p1 is independently 1. In embodiments, p1 is independently an integer from 1 to 10. In embodiments, p1 is independently an integer from 1 to 20. In embodiments, p1 is independently an integer from 1 to 30. In embodiments, p1 is
  • p1 is independently an integer from 1 to 15. In embodiments, p1 is independently an integer from 1 to 25. In embodiments, p1 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In embodiments, p1 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. [0254] In embodiments, p2 is independently 1. In embodiments, p2 is independently an integer from 1 to 10. In embodiments, p2 is independently an integer from 1 to 20. In embodiments, p2 is independently an integer from 1 to 30. In embodiments, p2 is
  • p2 is independently an integer from 1 to 15. In embodiments, p2 is independently an integer from 1 to 25. In embodiments, p2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In embodiments, p2 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. [0255] In embodiments, p3 is independently 1. In embodiments, p3 is independently an integer from 1 to 10. In embodiments, p3 is independently an integer from 1 to 20. In embodiments, p3 is independently an integer from 1 to 30. In embodiments, p3 is independently an integer from 1 to 15. In embodiments, p3 is independently an integer from 1 to 25.
  • p3 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In embodiments, p3 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. [0256] In embodiments, p4 is independently 1. In embodiments, p4 is independently an integer from 1 to 10. In embodiments, p4 is independently an integer from 1 to 20. In embodiments, p4 is independently an integer from 1 to 30. In embodiments, p4 is independently an integer from 1 to 15. In embodiments, p4 is independently an integer from 1 to 25.
  • p4 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In embodiments, p4 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. [0257] In embodiments, p5 is independently 6. In embodiments, p5 is independently 31. In embodiments, p5 is independently 32. In embodiments, p5 is independently 33. In embodiments, p5 is independently 34. In embodiments, p5 is independently 35. In embodiments, p5 is independently an integer from 1 to 100.
  • p5 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100.
  • p5 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000.
  • X is independently–F. In embodiments, X is independently–Cl. In embodiments, X is independently–Br. In embodiments, X is independently–I. In embodiments, X 1 is independently–F. In embodiments, X 1 is independently–Cl. In embodiments, X 1 is independently–Br. In embodiments, X 1 is independently–I. In embodiments, X 2 is independently–F. In embodiments, X 2 is independently–Cl. In embodiments, X 2 is independently–Br. In embodiments, X 2 is independently–I. [0259] In embodiments, n1 is independently 0. In embodiments, n1 is independently 1. In embodiments, n1 is independently 2. In embodiments, n1 is independently 3. In
  • n1 is independently 4. In embodiments, n2 is independently 0. In
  • n2 is independently 1. In embodiments, n2 is independently 2. In
  • n2 is independently 3. In embodiments, n2 is independently 4. [0260] In embodiments, v1 is independently 1. In embodiments, v2 is independently 1. In embodiments, m1 is independently 1. In embodiments, m2 is independently 1. In embodiments, v1 is independently 2. In embodiments, v2 is independently 2. In embodiments, v1 is independently 3. In embodiments, n2 is independently 4. [0260] In embodiments, v1 is independently 1. In embodiments, v2 is independently 1. In embodiments, m1 is independently 1. In embodiments, m2 is independently 1. In embodiments, v1 is independently 2. In embodiments, v2 is independently 2. In
  • n1 is independently 2.
  • m2 is independently 2.
  • the polymer or monomer has the formula:
  • the polymer has the formula:
  • the polymer has the formula: , wherein R 3 , L 3 , L 2 , R 2 , z2, and z1 are as described herein, including embodiments.
  • the polymer or monomer has the formula:
  • L 4 is as described herein.
  • the monomer has the formula:
  • the monomer or polymer has the formula:
  • the monomer has the formula:
  • the monomer has the formula:
  • the polymer has the formula:
  • L 2C , L 3 , L 5 , L 6 , L 8 , R 3 , R 10 , p5, z1, and z10 are as described herein, including in embodiments.
  • the polymer has the formula:
  • the polymer has the formula:
  • the polymer has the formula:
  • the polymer has the formula:
  • the polymer has the formula:
  • the polymer has the formula:
  • the polymer has the formula:
  • the polymer has the formula:
  • the polymer or monomer is:
  • the polymer or monomer is:
  • a polymer including a repeating subunit, the repeating
  • formula VI may be referred to herein as a mesh.
  • A“mesh” as used herein refers to a network (e.g., interlaced) structure.
  • a mesh may refer to a three dimensional cross-linked polymer (e.g., a polymer comprising multiple crosslink attachments to polymerizable monomers).
  • Y has the formula: , ,
  • L 2 , L 4 , R 2 , and z2 are as described herein.
  • the polymer includes one or a plurality of optionally different repeating subunits or terminator moieties, wherein said terminator moieties independently have the formula: -L 3 -R 3 .
  • the symbol“ ” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein the terminator moiety has the formula: -L 3 -R 3 .
  • L 3 and R 3 are as described herein.
  • L 1 , L 2 , and L 3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group,
  • L 4 is a covalent linker.
  • R 1 is independently hydrogen, halogen, -CX 1 1, -CHX 1 1, -CH2X 1 , -OCX 1 1, -OCH2X 1 , -OCHX 1 1, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO 1 R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , -OC(O)R 1C , substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or un
  • R 3 is independently hydrogen, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • R 3 is independently hydrogen. In embodiments, R 3 is independently unsubstituted phenyl. In embodiments, R 3 is
  • R 3 is independently an unsubstituted monovalent benzoxazine monomer.
  • R 3 is independently a substituted monovalent benzoxazine monomer (e.g., substituted with a substituent group).
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, a protecting group, or a leaving group;
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size
  • the symbols X, X 1 , and X 2 are independently–F, -Cl, -Br, or–I.
  • the symbols n1 and n2 are independently an integer from 0 to 4.
  • the symbols v1, v2, m1, and m2 are each independently 1 to 2.
  • the symbol z5 is an integer from 1 to 1000.
  • the symbol z2 is an integer from 0 to 5.
  • the symbols p1, p2, p3, and p4 are each independently an integer from 1 to 1000.
  • L 1 , L 2 , and L 3 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), substituted or unsubstituted heterocycloalkylene (e.
  • R 1 is independently hydrogen, halogen, -CX 1 1, -CHX 1 1, -CH2X 1 ,
  • -NR 1A C(O)OR 1C -NR 1A OR 1C , -OC(O)R 1C , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 - C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -OCH2X 2 , -OCHX 2 2, -CN, -SOn2R 2D , -SOv2NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O)m2, -NR 2A R 2B ,
  • substituted or unsubstituted alkyl e.g., C 1 -C 8 , C 1 - C 6 , or C 1 -C 4
  • substituted or unsubstituted heteroalkyl e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered
  • substituted or unsubstituted cycloalkyl e.g., C3-C8, C3-C6, or C5-C6
  • substituted or unsubstituted heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered
  • substituted or unsubstituted aryl e.g., C 6 -C 10 or phenyl
  • substituted or unsubstituted heteroaryl e.g., 5 to 10 membered
  • R 3 is independently hydrogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered)., or a monovalent be
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 ), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsub
  • the monomer is a monomer described herein, including embodiments, schemes, claims, or figures.
  • L 1 and L 2 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-,
  • unsubstituted heterocycloalkylene substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene.
  • R 1 is independently hydrogen, halogen, -CX 1 3, -CHX 1 3, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 3, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)-OR 1C , -C(O)NR 1A R 1B , -OR 1D , -NR 1A SO 1 R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -NR 1A OR 1C , substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 ,
  • unsubstituted heteroalkyl substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl; two adjacent R 2 substituents may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (
  • R 5 , R 6 , and R 8 are each independently hydrogen, a protecting group, or a leaving group.
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl.
  • n1 and n2 are independently an integer from 0 to 4.
  • the symbols v1, v2, m1, and m2 are each independently 1 to 2.
  • the symbols X, X 1 , and X 2 are independently –F, -Cl, -Br, or–I.
  • the symbol z2 is an integer from 0 to 5.
  • the method including mixing compound A and compound B together in a reaction vessel; wherein compound A has the formula:
  • L 2 and L 4 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-,
  • unsubstituted alkylene substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -OCH 2 X 2 ,
  • unsubstituted heteroalkyl substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl; two adjacent R 2 substituents may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (
  • R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX 3 , -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (
  • the symbols X and X 2 are independently–F, -Cl, -Br, or–I.
  • the symbol z2 is an integer from 0 to 5.
  • the symbol n2 is independently an integer from 0 to 4.
  • the symbols v2 and m2 are each independently 1 to 2.
  • the symbols R 5 , R 6 , R 8 , and R 9 are each
  • the method further includes a deprotection step (e.g., a synthetic step involving changing the chemical reaction conditions such that a protecting group is removed).
  • the method further includes a deprotection step wherein the deprotection step includes the addition of stoichiometric tetrabutylammonium fluoride in chilled tetrahydrofuran.
  • the method includes reaction steps described herein (e.g., reaction conditions according to any scheme described herein, Table 1, or Table 3).
  • the method includes a synthetic step substantially similar to a step described herein.
  • compound B has the formula: , wherein L 2 , R 8 , and R 9 are as described herein. [0311] In embodiments, compound B has the formula:
  • compound B has the formula:
  • compound A has the formula: wherein R 5 , R 6 , and R 8 are as described herein. [0314] In embodiments, compound A has the formula: , wherein R 8 is as described herein.
  • compound A has the formula: , wherein R 8 is as described herein.
  • compound A has the formula: , wherein R 5 , R 6 , and R 8 are as described herein.
  • R 8 is independently hydrogen.
  • compound A has the formula: , wherein R 5 and R 6 are as described herein.
  • compound A has the formula: .
  • compound A has the formula: .
  • compound A has the formula: , , erein R 8 and R 9 are as described herein.
  • compound A has the formula: , wherein L 4 is independently ,
  • L 4A , L 4B , L 4C , R 8 , R 9 , R 10 , and z10 are as described herein.
  • compound A has the formula: , wherein L 4 is independently , , , ,
  • Embodiment P A monomer having the formula:
  • L 1 and L 2 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
  • R 1 is independently hydrogen, halogen, - -OCH2X 1 , -OCHX 1 3 , -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B ,
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN, -SOn2R 2D , -SOv2NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O)m2, -NR 2A R 2B , -C(O)R 2C ,
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX 3 , -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted ary
  • L 1 , L 2 , and L 3 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
  • L 5 and L 6 are each independently a covalent linker;
  • R 1 is independently hydrogen, halogen, -CX 1 3, -CHX 1 3, -CH2X 1 , -OCX 1 3, -OCH2X 1 ,
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN,
  • R 2 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX 3 , -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted
  • the symbol“ is a point of attachment to a different repeating subunit or to a terminator moiety, wherein said terminating moiety has the formula: -L 3 -R 3 ;
  • L 1 , L 2 , and L 3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
  • R 1 is independently hydrogen, halogen, -CX 1 3, -CHX 1 3, -CH2X 1 , -OCX 1 3, -OCH2X 1 ,
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -OCH 2 X 2 , -OCHX 2 2 , -CN, -SOn2R 2D , -SOv2NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O)m2, -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -OC(O)R
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to
  • Embodiment P5 The monomer of embodiment P1 or a polymer of one of embodiments P2 or P3, wherein R 1 is–NH2. [0329] Embodiment P6.
  • Embodiment P8 The monomer of one of embodiments P1, P4, or P5 or a polymer of any one of embodiments P2 to P5, wherein L 1 is substituted or unsubstituted C1- C 6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene.
  • Embodiment P8 The monomer of one of embodiments P1, P4, or P5 or a polymer of any one of embodiments P2 to P5, wherein L 1 is substituted or unsubstituted C1- C2 alkylene.
  • Embodiment P10 The polymer of any one of embodiments P2 to P8, wherein L 4 is substituted or unsubstituted C 1 -C 2 alkylene.
  • Embodiment P11 The polymer of any one of embodiments P2 to P8, wherein L 4
  • Embodiment P12 The monomer of one of embodiments P1, P4 to P8, or a polymer of any one of embodiments P2 to P11, wherein L 2 is -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • Embodiment P13 Embodiment P13.
  • Embodiment P14 The monomer of one of embodiments P1, P4 to P8, or a polymer of any one of embodiments P2 to P11, wherein L 2 is substituted or unsubstituted C1- C 2 alkylene.
  • Embodiment P15 The monomer of one of embodiments P1, P4 to P8, or a polymer of any one of embodiments P2 to P11, wherein L 2 is substituted or unsubstituted C1- C 2 alkylene.
  • R 2 is -C(O)R 2C , -C(O)-OR 2C , -OR 2D , -OC(O)R 2C , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
  • Embodiment P16 The monomer of one of embodiments P1, P4 to P8, P12 to P14, or a polymer of any one of embodiments P2 to P14, wherein two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered
  • Embodiment P17 The monomer of one of embodiments P1, P4 to P8, P12 to P14, or a polymer of any one of embodiments P2 to P14, wherein R 2 is–OH, -OCH3, or -OTBS.
  • Embodiment P18 The monomer of one of embodiments P1, P4 to P8, P12 to P14,
  • R 2.3 and R 2.4 are each independently -OR 2D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 2.3 and R 2.4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 2D is independently hydrogen, -CX 2 3 , -CN, -COOH, -CONH 2 , -CHX 2 2 , -CH 2 X 2 ,
  • L 6 has the formula: -L 6A -L 6B -L 6C -, wherein L 6A , L 6B , and L 6C are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
  • Embodiment P20 The polymer of any one of embodiments P2 to P18, wherein R 3 is independently hydrogen, substituted or unsubstituted phenyl, or a monovalent benzoxazine monomer, wherein said monovalent benzoxazine monomer has the formula:
  • L 7 is a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-,
  • R 7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroarylene; and R 7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • Embodiment P21 The polymer of any one of embodiments P2 to P20, wherein z1 is 1.
  • Embodiment P22 The polymer of embodiment P21, wherein the polymer has the formula: .
  • Embodiment P23 The polymer of any one of embodiments P2, or P12 to P20, wherein the polymer has the formula:
  • Embodiment P24 The polymer of any one of embodiments P2, or P12 to P20, wherein the polymer has the formula:
  • Embodiment P25 A method of making a monomer, having the formula:
  • L 1 and L 2 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • R 1 is independently hydrogen, halogen, -CX 1 3, -CHX 1 3, -CH2X 1 , -OCX 1 3, -OCH2X 1 ,
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -OCH 2 X 2 , -OCHX 2 2 , -CN, -SOn2R 2D , -SOv2NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O)m2, -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO 2 R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -OC(O)R
  • said method comprising mixing compound A and compound B together in a reaction vessel;
  • compound A has the formula: ; and compound B has the formula:
  • L 2 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • L 4 is a covalent linker;
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -OCH 2 X 2 , -OCHX 2 2 , -CN, -SO n2 R
  • R 5 , R 6 , R 8 , and R 9 are each independently hydrogen, a protecting group, or a leaving group.
  • Embodiment P27 The method of embodiment P25 or P26, wherein compound B has the formula:
  • Embodiment P28 The method of embodiment P25 or P26, wherein compound B has the formula:
  • Embodiment P29 The method of one of embodiments P25, P27, or P28, wherein compound A has the formula: .
  • Embodiment P30 The method of one of embodiments P25, P27, or P28, wherein compound A has the formula:
  • Embodiment P31 The method of one of embodiments P26 or P28, wherein compound A has the formula: .
  • Embodiment 1 A compound having the formula:
  • L 1 and L 2 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
  • R 1 is independently hydrogen, halogen, -CX 1 3 , -CHX 1 3 , -CH 2 X 1 , -OCX 1 3 , -OCH 2 X 1 ,
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -OC(O)R 2C ,
  • Embodiment 2 The compound of embodiment 1, wherein R 1 is independently -NHC(O)NR 1A R 1B , -NR 1A R 1B , -C(O)NR 1A R 1B , -NR 1A SO 1 R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)O R 1C , -NR 1A OR 1C , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • Embodiment 3 The compound of embodiment 1, wherein R 1 is–NH 2 .
  • Embodiment 5 The compound of one of embodiments 1 to 3, wherein L 1 is substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene. [0360] Embodiment 6.
  • Embodiment 7 The compound of one of embodiments 1 to 6, wherein L 2 is -C(O)-, -C(O)CH 2 -, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • Embodiment 8 The compound of one of embodiments 1 to 6, wherein L 2 is substituted or unsubstituted C 1 -C 6 alkylene.
  • Embodiment 9 The compound of one of embodiments 1 to 6, wherein L 2 is substituted or unsubstituted C1-C2 alkylene.
  • Embodiment 10 The compound of one of embodiments 1 to 9, wherein R 2 is -C(O)R 2C , -C(O)-OR 2C , -OR 2D , -OC(O)R 2C , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
  • Embodiment 11 The compound of one of embodiments 1 to 9, wherein two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl.
  • Embodiment 12 The compound of one of embodiments 1 to 9, wherein R 2 is –OH, -OCH3, or -OTBS.
  • Embodiment 13 The compound of one of embodiments 1 to 9, wherein
  • R 2.3 and R 2.4 are each independently -OR 2D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 2.3 and R 2.4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 2D is independently hydrogen, -CX 2 3, -CN, -COOH, -CONH2, -CHX 2 2, -CH2X 2 ,
  • Embodiment 14 A polymer of the formula:
  • L 1 , L 2 , and L 3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
  • L 5 and L 6 are each independently a covalent linker;
  • R 1 is independently hydrogen, halogen, -CX 1 3, -CHX 1 3, -CH2X 1 , -OCX 1 3, -OCH2X 1 ,
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2,
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubsti
  • Embodiment 15 The polymer of embodiment 14, wherein R 1 is independently -NHC(O)NR 1A R 1B , -NR 1A R 1B , -C(O)NR 1A R 1B , -NR 1A SO 1 R 1D , -NR 1A C(O)R 1C ,
  • Embodiment 16 The polymer of embodiment 14, wherein R 1 is–NH 2 .
  • Embodiment 18 The polymer of any one of embodiments 14 to 16, wherein L 1 is a bond, -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • Embodiment 18 The polymer of any one of embodiments 14 to 16, wherein L 1 is substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene.
  • Embodiment 19 Embodiment 19.
  • Embodiment 20 The polymer of any one of embodiments 14 to 16, wherein L 1 is substituted or unsubstituted C1-C2 alkylene.
  • Embodiment 20 The polymer of any one of embodiments 14 to 19, wherein L 2 is -C(O)-, -C(O)CH 2 -, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • Embodiment 21 Embodiment 21.
  • Embodiment 22 The polymer of any one of embodiments 14 to 19, wherein L 2 is substituted or unsubstituted C1-C2 alkylene.
  • Embodiment 23 The polymer of any one of embodiments 14 to 19, wherein L 2 is substituted or unsubstituted C1-C2 alkylene.
  • R 2.3 and R 2.4 are each independently -OR 2D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 2.3 and R 2.4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 2D is independently hydrogen, -CX 2 3, -CN, -COOH, -CONH2, -CHX 2 2, -CH2X 2 ,
  • L 6 has the formula: -L 6A -L 6B -L 6C -, wherein L 6A , L 6B , and L 6C are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
  • Embodiment 28 The polymer of any one of embodiments 14 to 26, wherein R 3 is independently hydrogen, substituted or unsubstituted phenyl, or a monovalent benzoxazine monomer, wherein said monovalent benzoxazine monomer has the formula:
  • L 7 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-,
  • Embodiment 29 The polymer of any one of embodiments 14 to 28, wherein z1 is 1.
  • Embodiment 30 The polymer of embodiment 29, wherein the polymer
  • Embodiment 31 The polymer of any one of embodiments 14, or 20 to 28, wherein the polymer has the formula:
  • Embodiment 32 The polymer of any one of embodiments 14, or 20 to 28, wherein the polymer has the formula: .
  • Embodiment 33 A polymer of the formula:
  • L 3 , L 4 , L 5 , L 6 , and L 8 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubsti
  • Embodiment 34 The polymer of embodiment 33, wherein the polymer has the formula:
  • L 2C is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-,
  • R 10 is independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -SO4H, -SO2
  • Embodiment 35 The polymer of one of embodiments 33 to 34, wherein L 5 is , , and L 8 is unsubstituted C1-C3 alkylene.
  • Embodiment 36 The polymer of one of embodiments 33 to 35, wherein the polymer has the formula:
  • Embodiment 37 A polymer comprising (1) a repeating subunit, said repeating subunit having the formula:
  • Y has the formula the symbol“ ” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein said terminator moiety has the formula: -L 3 -R 3 ; (2) at each symbol“ ” is attached a different repeating subunit or a terminator moiety, wherein said terminator moiety has the formula: -L 3 -R 3 ; L 1 , L 2 , and L 3 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
  • R 1 is independently hydrogen, halogen, - -OCH2X 1 ,
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO 2 R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -OC(O)R 2C ,
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted
  • Embodiment 38 The polymer of embodiment 37, wherein R 1 is independently -NHC(O)NR 1A R 1B , -NR 1A R 1B , -C(O)NR 1A R 1B , -NR 1A SO 1 R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)O R 1C , -NR 1A OR 1C , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • Embodiment 39 The polymer of embodiment 37, wherein R 1 is–NH 2 .
  • Embodiment 40 Embodiment 40.
  • Embodiment 43 The polymer of any one of embodiments 37 to 42, wherein L 4 is substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene.
  • Embodiment 44 The polymer of any one of embodiments 37 to 42, wherein L 4 is substituted or unsubstituted C1-C2 alkylene.
  • Embodiment 45 The polymer of any one of embodiments 37 to 42, wherein L 4
  • Embodiment 46 The polymer of any one of embodiments 37 to 45, wherein L 2 is -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • Embodiment 47 The polymer of any one of embodiments 37 to 45, wherein L 2 is substituted or unsubstituted C1-C6 alkylene.
  • Embodiment 48 Embodiment 48.
  • Embodiment 49 The polymer of any one of embodiments 37 to 48, wherein R 2 is -C(O)R 2C , -C(O)-OR 2C , -OR 2D , -OC(O)R 2C , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
  • Embodiment 50 The polymer of any one of embodiments 37 to 48, wherein two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl.
  • Embodiment 51 The polymer of any one of embodiments 37 to 48, wherein R 2 is–OH, -OCH 3 , or -OTBS.
  • Embodiment 52 The polymer of any one of embodiments 37 to 48, wherein
  • R 2.3 and R 2.4 are each independently -OR 2D , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 2.3 and R 2.4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 2D is independently hydrogen, -CX 2 3, -CN, -COOH, -CONH2, -CHX 2 2, -CH2X 2 ,
  • L 7 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-,
  • R 7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroarylene; and R 7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • Embodiment 54 A polymer comprising (1) a subunit, said subunit having the formula: wherein the symbol“ is a point of attachment to a different repeating subunit or to a terminator moiety, wherein said terminator moiety has the formula: -L 3 -R 3 ; (2) at each symbol“ ” is attached a different subunit or a terminator moiety, wherein said terminator moiety has the formula: -L 3 -R 3 ; L 3 , L 5 , L 6 , and L 8 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-,
  • L 4 is a covalent linker;
  • R 3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted or unsubstituted cycloalkyl, substituted or unsubstituted or unsubstituted
  • Embodiment 55 A polymer comprising (1) a repeating subunit, said repeating subunit having the formula:
  • the symbol is a point of attachment to a different repeating subunit or to a terminator moiety, wherein said terminator moiety has the formula: -L 3 -R 3 ; (2) at each symbol“ ” is attached a different repeating subunit or a terminator moiety, wherein said terminator moiety has the formula: -L 3 -R 3 ; L 1 , L 2 , L 3 , L 5 , L 6 , and L 8 are each independently a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH 2 -, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substitute
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -OCH 2 X 2 , -OCHX 2 2 , -CN, -SOn2R 2D , -SOv2NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O)m2, -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -OC(O)R
  • R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , and R 2D are each independently hydrogen, -CX 3 , -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a
  • L 1 and L 2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • R 1 is independently hydrogen, halogen, -CX 1 3 , -CHX 1 3 , -CH 2 X 1 , -OCX 1 3 , -OCH 2 X 1 ,
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O) m2 , -NR 2A R 2B , -C(O)R 2C , -C(O)-OR 2C , -C(O)NR 2A R 2B , -OR 2D , -NR 2A SO 2 R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -OC(O)R 2C ,
  • L 2 is a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
  • L 4 is a covalent linker;
  • R 2 is independently halogen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2, -CN, -SOn2R 2D , -SOv2
  • Embodiment 59 The method of embodiment 56 or 57, wherein compound B has the formula:
  • Embodiment 60 The method of one of embodiments 56, 58, or 59, wherein compound A has the formula:
  • Embodiment 61 The method of one of embodiments 56, 58, or 59, wherein compound A has the formula: .
  • Embodiment 62 The method of one of embodiments 57 or 59, wherein compound A has the formula:
  • Example 1 Methods of preparation of mussel-inspired benzoxazine monomers, polymers, and thermoset resins
  • Benzoxazine monomers are typically prepared by Mannich-type reaction of phenols, amines, and formaldehyde. Thermally accelerated cationic ring-opening polymerization of these compounds requires no harsh catalysts, no volatile byproducts are formed, and near-zero volume change is observed on curing. Polymerization typically yields phenolic Mannich- bridged polymers and networks. The modularity of monomer design and synthesis increases the appeal and potential utility of this class of materials. [0419] We take inspiration in our work from marine mussels, which have the ability to adhere strongly to a wide range of substrates through application of an attachment organ called the byssus. This organ is composed of a collection of threads terminated by adhesive plaques.
  • the proteins that comprise this tissue are rich in the unconventional catechol amino acid 3,4-dihydroxyphenylalanine (DOPA), which is a versatile and strong molecular adhesive that is effective even in wet environments. 2
  • DOPA residues are immediately adjacent to basic nitrogen-containing residues such as lysine and histidine.
  • a growing body of literature suggests that there is a synergistic relationship between catechols and amine-containing residues that leads to enhanced adhesion.
  • These adhesive proteins have inspired the design of a number of synthetic adhesives for application in aqueous milieu.
  • the catechol is capable of a profusion of noncovalent and covalent interactions, such as hydrogen bonding, pi-electron interactions (i.e. quadrupole- quadrupole and pi-stacking interactions), hydrophobic forces, and electrophilic aromatic substitution reactions. 4a,5 Additional nucleophilic substitution reactions can take place upon oxidation of the catechol to the quinone, which occurs readily in the presence of chemical oxidants, as well as under alkaline conditions in the presence of dissolved molecular oxygen. This promiscuous reactivity makes catechols powerful players in the preparation of robust adhesives at the nano- through macro-scale. [0421] The inventors have identified a viable synthetic chemical strategy for the incorporation of deprotected catechols in benzoxazine monomers and main-chain
  • silyl ethers were competent protecting groups for the catechol, preventing side-reactions on the electron rich aromatic ring of the catechol in the presence of deprotected phenols during benzoxazine synthesis; silyl ethers were removed after benzoxazine preparation and purification using stoichiometric tetrabutylammonium fluoride reagent.
  • silyl ethers as protecting groups in benzoxazine synthesis has not been previously described.
  • benzoxazines i.e., R1 1 H, Scheme 1
  • R1 1 H, Scheme 1 provides soluble linear polybenzoxazine products with molecular weights typically ⁇ 10 kDa.
  • Protecting groups were efficiently removed under acidic conditions to provide water-soluble polymer salts that formed conformal coatings on a variety of inorganic and organic substrates under a buffered pH range of 6-9 supplemented with 600 mM MgCl2. These coating conditions are analogous to those previously applied for conformal polydopamine dip-coatings. These steps represent a successful demonstration of the strategy proposed in Route A, FIG.2. [0424]
  • the initial target benzoxazines pursued were mono- and bis-1,3-benzoxazine cores modified with protected catechol and amine functional groups, as exemplified in compound 1 (Scheme 2). This monomer is derived from protected tyramine and dopamine precursors, and formaldehyde.
  • reaction mixtures became a deep yellow color upon heating, and a highly UV-active spot appeared at the baseline in TLC analyses. Notably, this color change was less dramatic under the biphasic reaction condition C, and this yellow-colored byproduct was not observed in test reactions with model phenols and amines that did not include 7. It is likely that this color change is the result of side reactions involving 7. Reactions were carried out until both the amine and phenol starting materials were mostly consumed, as determined by thin layer chromatography (TLC) analysis.
  • TLC thin layer chromatography
  • Desired benzoxazine products are easily identified by TLC analysis– staining with ninhydrin produces a rich brown to bronze color, in contrast to the typical purples and yellows observed with this stain.
  • the highest yields of the desired benzoxazine were obtained from reactions conducted in toluene with application of a Dean-Stark apparatus to remove water formed during the course of the reaction, or in chloroform where water separates from the reaction solvent. [0427] Based on the superior yield obtained under condition C in the synthesis of 1, similar conditions were applied to the synthesis of protected bis-benzoxazine 8 (Scheme 6) from dopamine-acetonide 7 and bisphenol A.
  • Coatings were characterized by ellipsometry, water contact angle, and XPS, and results are summarized in Table 2. Water contact angles indicated moderately hydrophilic coatings, but resulted in an overall increase in contact angle relative to fully wetting, freshly cleaned TiO2 substrates. Elemental composition (C/N/O) determined by XPS were similar for coatings formed at all pH values, and were comparable to the calculated composition of the free base of polymer 3 (C/N/O of 78.3/13/8.7). However, distinct differences in coating thickness were observed for different pH values.
  • This material was a solid that was stable to long-term storage outside of a glove box at reduced temperature. This is in contrast to the previously prepared acetonide-protected derivative, which was a viscous oil that slowly darkened after several months of storage at -80 °C in the presence of air.
  • the benzylamine derivatives are less prone to oxidation after deprotection, and reduction of the linker length between catechol and amine relative to dopamine prevents unwanted cyclization reactions in the deprotected benzoxazine products.
  • 3,4-dihydroxybenzylamine is commercially available as a hydrobromide salt, or can be readily prepared from less costly 3,4- dihydroxybenzaldehyde in two steps.
  • a silyl ether-protected benzoxazine was prepared in two steps from 3,4- dihydroxybenzylamine 18 (Scheme 11).
  • benzoxazines which may be beneficial in applications as thermoset adhesives or the preparation of composites.
  • amine functional groups may also be incorporated into monomers by utilizing appropriate fluoride-sensitive protecting groups. 9
  • silyl ethers as protecting groups in benzoxazine synthesis has not been previously reported, and should be considered non-obvious.
  • Scheme 13A-13B (13A) Schematic representation of catechol-modified main-chain benzoxazines derived from bis-phenols and diamines, and (13B) Example bis-phenol mono- catechol precursor 26.
  • N-substituted iminodiacetic acid derivatives are capable of forming a cyclic anhydride in the presence of peptide coupling agents, this intermediate is easily intercepted by amine nucleophiles to provide monoamide monocarboxylic acid derivatives that are competent intermediates in route to diverse diamide and triamide products by subsequent peptide coupling and protecting group manipulation (Scheme 14). 10 We utilized this reactivity to prepare precursor 26 as described below.
  • NMR spectra were obtained on a Brüker AVB-400 instrument in deuterated solvents (Cambridge Isotope Laboratories, Inc. and Sigma-Aldrich), and spectra were referenced to the signals of residual protium in the NMR solvent. Spectra were processed in MestReNova 10.0 (Mestrelab Research). Digital images of benzoxazine samples were collected with the built-in camera of an iPhone 6s. Dip-coatings on TiO 2 were evaluated by optical ellipsometry on a J.A. Woollam Co. ellipsometer. Water contact angle measurements were collected on a Ramé-Hart Goniometer. XPS analyses were performed on a Phi
  • Cleaned substrates were submerged in freshly prepared coating mixtures consisting of 1 mg/mL 3 in 0.1M buffer solutions containing 10 vol% DMSO for coating.
  • Buffers at pH 6 and 7 contained 0.1M bis-tris and 600 mM MgCl2; buffers at pH 8 and 9 contained 0.1M bicine and 600 mM MgCl 2 .
  • Coatings were performed with horizontal substrate orientation in a 24-well plate with agitation at 250 rpm in ambient atmosphere for 16 hours. After the incubation, substrates were washed thoroughly with deionized water, and dried under a stream of nitrogen before characterization by ellipsometry, water contact angle, and XPS.
  • tert-butyl (4-hydroxyphenethyl)carbamate, 4 Tyramine (1 g, 7.29 mmols, 1 eq) was dissolved in methanol (15 mL) and a solution of di-tert-butyl dicarbonate (1.67 g, 7.65 mmols, 1.05 eq) in methanol (2 mL) was added dropwise while stirring at room temperature. Carbon dioxide evolution was observed at this point. Potassium carbonate (3.02 g, 21.9 mmols, 3 eq) was added portion-wise over 3 minutes, followed by dropwise addition of deionized water (5 mL) to dissolve the potassium carbonate.
  • N-(2-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,2,2-trifluoroacetamide, 6 Trifluoro-acetamide-protected dopamine 5 (1.66 g, 6.66 mmols, 1 eq) was dissolved in dry benzene (67 mL) and the solution was degassed by bubbling with argon for 20 minutes. At this time, p-toluenesulfonic acid monohydrate (63 mg, 0.33 mmols, 5 mol%) was added, followed by 2,2-dimethoxypropane (3.26 mL, 26.6 mmols, 4 eq).
  • the resulting solution was degassed for an additional 5 minutes with argon, and then topped with a Dean-Stark apparatus and reflux condenser and heated at 90 °C for 2 hours, at which time the starting material was completely consumed, as indicated by TLC.
  • the reaction was brought to room temperature and filtered through a column of silica gel packed in hexanes. The column was eluted with 350 mL of 30% ethyl acetate/hexanes to produce a yellow eluate, which was condensed in vacuum. The residue was taken up in a minimal volume of dichloromethane, and a rougly 10-fold volume of hexanes was added.
  • the ether layer was washed another 4 times with 3M NaOH until the aqueous washes were colorless, and then washed once with brine.
  • the organic layer was dried over sodium sulfate, filtered, and condensed to a yellow crude, which was further purified by column chromatography in silica gel, eluting with a gradient from hexanes through 20% EtOAc/hexanes to produce a very viscous colorless oil (220 mg, 47% yield). Rf 0.54 (30% EtOAc/hexanes).
  • the crude was diluted with diethyl ether (20 mL), and washed with 3M NaOH (3x10 mL), deionized water (2x10 mL), brine (1x10mL), dried over sodium sulfate, and filtered through a 2 cm plug of silica gel, eluting with diethyl ether.
  • the eluate was condensed to yield a very faintly yellow viscous oil which was further purified by column chromatography on silica gel, eluting with a gradient from hexanes containing 1% triethylamine through 20% EtOAc/hexanes with 1% triethylamine to yield a colorless very viscous oil (463 mg, 63% yield).
  • Condition D Dopamine acetonide (530 mg, 2.743 mmols, 1.01 eq), Boc-tyramine (644 mg, 2.715 mmols, 1 eq), and paraformaldehyde (179 mg, 5.975 mmols, 2.2 eq) were placed in a 20 mL scintillation vial with tight-fitting PTFE-lined cap and 5.2 mL of chloroform were added. The mixture was sealed under argon and heated in a pre-warmed oil bath at 80 °C for 6 hours.
  • the crude was diluted with diethyl ether (20 mL), and washed with 3M NaOH (3x10 mL), deionized water (2x10 mL), brine (1x10mL), dried over sodium sulfate, and filtered through a 2 cm plug of silica gel, eluting with diethyl ether.
  • the eluate was condensed to yield a very faintly yellow viscous oil which was further purified by column chromatography on silica gel, eluting with a gradient from hexanes containing 1% triethylamine through 20% EtOAc/hexanes with 1% triethylamine to yield a colorless very viscous oil (730 mg, 60% yield).
  • Dopamine acetonide (320 mg, 1.655 mmols, 2 eq), bisphenol A (189 mg, 0.828 mmols, 1eq), and paraformaldehyde (109 mg, 3.64 mmols, 4.4 eq) were suspended in toluene (1.2 mL) in a flask topped with a Dean-Stark apparatus and reflux condenser. The suspension was heated at 105 °C under argon with stirring for 2 hours to produce a bright yellow solution. The reaction mixture was diluted with diethyl ether (20 mL) to produce a yellow precipitate and faint yellow supernatant.
  • the precipitate (124 mg) was removed by centrifugation, and the supernatant was washed with 3M NaOH solution (3x10 mL), deionized water (2x10 mL), and brine (1x10 mL), and then dried over sodium sulfate.
  • the organic layer was then filtered through a 2 cm plug of silica gel, eluting with diethyl ether.
  • the eluate was condensed to provide a pale yellow viscous oil that formed an off-white foam after drying in high vacuum (260 mg, 47% yield).
  • Rf 0.51 (30% EtOAc/hexanes).
  • the flask was topped with a Soxhlet extractor filled with activated 4 ⁇ molecular sieves and 50% acetone in benzene.
  • the reaction solution was deoxygenated by bubbling argon for 20 minutes, followed by addition of p-toluenesulfonic acid monohydrate catalyst (66 mg, 0.5 mol%).
  • the reaction mixture was stirred at reflux for 48 hours, and then brought to room temperature and condensed under vacuum.
  • the resulting residue was triturated with hexanes to produce crystals of unreacted pyrocatechol, which were collected by vacuum filtration.
  • the pressure was vented to 100 psi, and the purge cycle was repeated.
  • the pressure vessel was then filled to 740 psi with hydrogen and allowed to stir at room temperature for 4 hours. During this time, the pressure decreased to approximately 650 psi.
  • the vessel was vented and the reaction mixture was filtered through a plug of celite filter aid (5 grams), washing with copious 1,4-dioxane.
  • the pale yellow filtrate was condensed in vacuum, and azeotroped once with toluene to remove water byproduct.
  • the resulting pale yellow oil is sensitive to oxidation, and turns dark upon standing in air.
  • the vessel was vented to atmosphere, and the reaction mixture was passed through a pad of celite filter aid to remove Pd/C catalyst, washing with copious 1,4-dioxane ( ⁇ 70 mL).
  • the filtrate was condensed, and azeotropically dried from toluene to provide an off-white solid (2.833 g, 99% yield).
  • the mixture was sealed in a vial and heated at 80 °C in a preheated oil bath for 6 hours.
  • the reaction mixture was then diluted with 200 ⁇ L triethylamine, and loaded directly onto a pre-packed SiO 2 column.
  • the column was eluted with a gradient from hexanes through 50% EtOAc/hexanes to provide a colorless residue that foamed under vacuum to provide a solid (59 mg, 53% yield).
  • the crude was partitioned between diethyl ether (40 mL) and aqueous saturated ammonium chloride solution (40 mL).
  • the aqueous phase was extracted twice more with diethyl ether (2x20 mL), and the combined organic phases were washed with water (20 mL), saturated aqueous sodium bicarbonate solution (20 mL), and brine (20 mL).
  • the organic layer was dried over anhydrous sodium sulfate, filtered, and condensed in vacuum to provide a pale yellow oil after drying overnight under high vacuum (1.35 g, 99% yield).
  • Rf 0.49 (10% MeOH/CH2Cl2).
  • the crude reaction mixture was diluted with diethyl ether (25 mL) and washed with 3N aqueous NaOH solution (3x15 mL), deionized water (2x15 mL), saturated aqueous ammonium chloride (1x15 mL), brine (1x15 mL), and then dried over anhydrous sodium sulfate.
  • the solids were removed by vacuum filtration, and filtrate was condensed.
  • the crude was further purified by column chromatography on silica gel, eluting with a gradient from hexanes through 3%
  • the mixture was heated to 80 °C while stirring in a sealed vial under argon, and heating was continued for 12 hours, followed by cooling to room temperature.
  • the reaction mixture was then diluted with diethylether (15 mL), and washed with 3N NaOH aqueous solution
  • tert-butyl bis(2-((4-hydroxyphenethyl)amino)-2-oxoethyl)carbamate, 30 Boc- iminodiacetic acid (942 mg, 4.04 mmols, 1 eq) and EDC-HCl (798 mg, 4.16 mmols, 1.03 eq) were combined in dry DMF (40 mL) and stirred at room temperature under argon atmosphere for 1 hour, followed by addition of tyramine (554 mg, 4.04 mmols, 1 eq) in one portion.
  • Tetrabutylammonium fluoride solution (1M, 6.208 mL, 6.208 mmols, 2.05 eq) was added dropwise over 5 minutes to produce a yellow solution. After 40 minutes, ethyl acetate (50 mL) and pH 70.1M sodium phosphate solution (50 mL) were injected, and the mixture was transferred to a separatory funnel. The phases were separated, and the aqueous phase was extracted once more with ethyl acetate (35 mL). The combined organic extracts were washed with sodium phosphate buffer (pH 7, 40 mL), and saturated sodium chloride solution (40 mL), then dried over anhydrous sodium sulfate, filtered and condensed under reduced pressure.
  • sodium phosphate buffer pH 7, 40 mL
  • saturated sodium chloride solution 40 mL
  • the mixture was heated at 85 °C for 16 hours, then cooled to room temperature and condensed under reduced pressure.
  • the crude residue was purified by column chromatography on silica gel, eluting with a gradient from hexanes through 30% acetone in hexanes to provide a white foaming solid after drying under high vacuum. (684 mg, 57% yield). Rf 0.29 (20% acetone/hexanes).
  • Tetrabutylammonium fluoride solution (1M, 0.5389 mL, 0.5389 mmols, 4 eq) was added dropwise over 5 minutes while stirring to produce a yellow solution. After 40 minutes, ethyl acetate (20 mL) and pH 70.1M sodium phosphate buffer (20 mL) were injected, and the organic phase was separated. The aqueous phase was extracted once more with ethyl actetate (20 mL), and the combined organic extracts were washed with sodium phosphate buffer (2 x 20 mL), and saturated aqueous sodium chloride solution (2 x 20 mL).
  • Lap shear adhesion strengths for various cured benzoxazines were measured on aluminum 6061.
  • Single lap joint samples were prepared as follows: 1) Aluminum 6061 substrates with dimensions (1 cm x 10 cm x 0.16 cm). are freshly degreased and cleaned with ethyl acetate and acetone and dried under nitrogen. 2) Drop cast 100 mM benzoxazine solutions/suspensions from acetone (containing ⁇ 0.5-1 w/v% suspended 0.001” glass beads for bond line control) onto a 1 x 1 cm region at end of an aluminum 6061 strip (1 x 10 x 0.16 cm).
  • Shear adhesive strength in Pascals is calculated as the maxium load (N) divided by the lap joint are (m 2 ).
  • Lap shear adhesive strength values for six benzoxazine monomers are shown in FIG.14. Error bars represent the standard deviation in the measured adhesive strength for a group of 3 samples.
  • mussel-inspired benzoxazine monomers 24, 40, 37, and protected monomer 36 exhibited superior adhesion compared to the commercial BPA-aniline monomer.
  • Monomers 37 and 36 provided significantly stronger adhesion compared to both commercial benzoxazines and bis-catechol-bis-benzoxazines 24 and 40. Structures of benzoxazine monomers tested and photographs of failed lap joints are shown in FIG.15.
  • the residue was dissolved in diethyl ether (50 mL), and washed with 0.5 M citric acid solution (25 mL), saturated aqueous ammonium chloride solution (2x25 mL), and saturated aqueous sodium chloride solution (25 mL) before drying over anhydrous sodium sulfate, filtering, and condensing under reduced pressure.
  • the residue bis-TBS intermediate
  • the solution was stirred and chilled on a sodium chloride/ice bath (-15 °C) under argon, and a solution of 41 (457 mg, 0.213 mmols, 1.1 eq) in chloroform (1 mL) was added dropwise over 5 minutes; white vapors were observed during this addition (HCl formation).
  • the mixture was allowed to reach room temperature and then stirred for 14 hours, at which time the mixture was poured into 0.1 M aqueous HCl (50 mL), and saturated aqueous sodium chloride solution (25 mL) was added.
  • the aqueous mixture was extracted with ethyl acetate (5x20 mL) and the combined organic phases were washed with brine (3x25 mL), dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluting with a gradient from dichloromethane through 10% methanol/dichloromethane to provide an off-white foam solid (837 mg, 79% yield).
  • paraformaldehyde (136 mg, 4.4 mmols, 4.4 eq) were combined in toluene (3 mL) and placed under a reflux condenser and argon atmosphere before heating at 100 °C for 18 hours.
  • Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 1.04 mL, 1.04 mmols, 2.2 eq) was added drop-wise over 2 minutes, the mixture was stirred for 30 minutes, and then the reaction was quenched by addition of pH 70.1 M sodium phosphate buffer (30 mL) and ethyl acetate (25 mL). The organic layer was washed with addition sodium phosphate buffer (2x25 mL), saturated aqueous sodium chloride solution (2x25mL), dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure. The crude was taken up in minimal dichloromethane and precipitated by addition of hexanes.
  • Tetrabutylammonium fluoride solution (1M, 1.124 mL, 1.124 mmols, 2.2 eq per repeating unit) was added dropwise over 2 minutes. The mixture was stirred for 1.5 hours, and then quenched by addition of 0.1 M pH 7 sodium phosphate buffer and dichloromethane (10 mL each). The layers were separated, and the organic phase was washed once more with phosphate buffer (10 mL). Brine was added to the organic phase (10 mL) to produce a yellow sticky precipitate and yellow solution. The solution was separated and dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure.
  • Scheme 32 Schematic representation of end group identities observed in phenol-initiated polymerization of benzoxazines.
  • end groups are likely to be a proton on one end, and either a phenol fragment, Mannich base (secondary amine) or intact benzoxazine.
  • Mannich base secondary amine
  • an intact benzoxazine end group is not likely to be observed following deprotection of side-chains under acidic conditions. This is due to the acid-mediated ring opening of the benzoxazine, with loss of formaldehyde, providing the Mannich base with secondary amine as a possible end group (Scheme 33).
  • tetrabutylammonium fluoride (TBAF, 2.3 mL, 2.3 mmols, 2.05 eq) was added dropwise by syringe over 3 minutes while stirring to produce an immediate development of a yellow color. Stirring was continued for 30 minutes, at which time pH 70.1 M aqueous sodium phosphate buffer (20 mL) was injected to quench the reaction. The mixture was transferred to a separatory funnel extracted with ethyl acetate (2 x 25 mL).
  • TBAF tetrabutylammonium fluoride
  • thermoset monomer 37 could be further improved by increasing substrate roughness and by blending with main-chain derivatives 54 and 56 as performance modifiers.
  • Lap-shear adhesion strength was assessed on aluminum 6061 substrates that were etched with sodium hydroxide to enhance roughness.
  • Compounds 37 and either 54 or 56 were combined in 15 vol% methanol in tetrahydrofuran at various feed ratios, followed by solvent casting onto aluminum substrates. The samples were dried, overlapped and clamped in antiparallel fashion, and then cured in an air oven (130 °C to 195 °C over 2 hours, and held at 195 °C for 6 hours), cooling slowly to room temperature.
  • Bonded substrates were tested in shear at a strain rate of 0.5% strain/minute.
  • the bond line uniformity and adhesive strength were maximal when 4 parts by weight of 37 were combined with 3 parts by weight of either 54 or 56.
  • Adhesion strengths up to 16.1 ⁇ 1.6 MPa were obtained for formulations of 37 and 56 on roughened Al 6061 substrates.
  • Example 10 Mechanical properties of 36 and 37 compared to BPA-Aniline by 3-point bending
  • Curing behavior of purified 37 was assessed by differential scanning calorimetry, revealing an overlap of melting (181 °C) and curing onset, with a maximum curing exotherm occurring at 196 °C.
  • compression molding was applied for all three resins.
  • Cured BPA-Aniline provided red-orange specimens, while those obtained from 36 and 37 were significantly darker brown in color, indicating potential oxidation of catechol functional groups during curing.
  • Polybenzoxazines as a class of materials exhibit excellent thermal stability.
  • the thermal stability of compression molded and cured 36 and 37 were compared to BPA- Aniline up to 600 °C in nitrogen by thermal gravimetric analysis on specimens extracted from flexural testing samples prepared by compression molding.
  • Decomposition of polymerized 36 begins at a lowest temperature for the series, with 10% weight loss occurring by 295 °C (T10%) with a heating rate of 10 °C/min.
  • BPA-Aniline are comparable at 322 and 328 °C, respectively.
  • the char yields at 600 °C were higher for both bioinspired derivatives (60% and 54% for 36 and 37, respectively) compared to BPA-Aniline (37%), indicating a lower quantity of volatiles formed during decomposition at elevated temperatures.
  • 36 produces the greatest char yield in the series, it exhibits the earliest onset of degradation.
  • the thermal degradation of 37 and BPA-Aniline in air were assessed up to 600 °C. Comparable degradation behaviors were observed for both resins, with all material degrading by 600 °C.
  • Example 12 Main-chain polybenzoxazine 56 as a pressure sensitive adhesive
  • the film tapes stick readily to a variety of surfaces, including stainless steel, polycarbonate, aluminum 6061, Kapton, high density polyethylene, and glass. Taped pairs of HDPE or glass substrates resisted moderate shear, determined by their ability to support 200 grams of weight for extended periods of time. Control experiments performed with silyl ether protected 55 revealed that cohesion was severely diminished in this material, as these materials were unable to resist shear of a 200 gram weight for any period of time.

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Abstract

Disclosed herein, inter alia, are novel benzoxazine containing compounds and compositions, including polymers, and methods for making and using the same.

Description

Benzoxazine Polymers and Methods of Making and Using the Same CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No.62/644,307, filed March 16, 2018, which is incorporated herein by reference in their entirety and for all purposes. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[0002] This invention was made with government support under HR0011-15-9-0014 awarded by the Defense Advanced Research Projects Agency. The government has certain rights in the invention. BACKGROUND
[0003] Polybenzoxazines are a relatively new class of phenolic resins with a range of tunable properties including excellent thermal stability, high char yield, high glass transition temperature, and low moisture absorption. These properties are dependent upon the components and functional groups within the polymer. Synthetic challenges have persisted in limiting the types of functional groups, which may be included in the final polymer.
Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY
[0004] In an aspect is provided a monomer having the formula:
Figure imgf000002_0001
[0005] L1 and L2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-,
-C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. [0006] L4 is a covalent linker. [0007] R1 is independently hydrogen, halogen, -CX11, -CHX11, -CH2X1, -OCX11, -OCH2X1, -OCHX1 1, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0008] R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2,
-OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0009] R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. The symbols X, X1, and X2 are independently–F, -Cl, -Br, or–I. The symbols n1 and n2 are independently an integer from 0 to 4. The symbols v1, v2, m1, and m2 are each independently 1 to 2. The symbol z2 is an integer from 0 to 5. [0010] In another aspect is provided a polymer of the formula:
Figure imgf000004_0001
[0011] L1, L2, and L3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. L5 and L6 are each independently a bond or covalent linker. [0012] R1 is independently hydrogen, halogen, -CX1 1, -CHX1 1, -CH2X1, -OCX1 1, -OCH2X1, -OCHX11, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0013] R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2,
-OCHX2 2, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0014] R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted monovalent benzoxazine monomer. [0015] R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. The symbols X, X1, and X2 are independently– F, -Cl, -Br, or–I. The symbols n1 and n2 are independently an integer from 0 to 4. The symbols v1, v2, m1, and m2 are each independently 1 to 2. The symbol z1 is independently an integer from 1 to 1000. The symbol z2 is independently an integer from 0 to 5. [0016] In an aspect is provided a polymer of the formula:
Figure imgf000005_0001
[0017] L3 and L8 are each independently a bond, -S(O)2-, -NH-, -O-, -S-,
-C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. L4 is a covalent linker. L5 and L6 are each independently a bond or covalent linker. [0018] R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted monovalent benzoxazine monomer.
[0019] The symbol z1 is independently an integer from 1 to 1000. The symbol p5 is independently an integer from 1 to 1000.
[0020] In an aspect is provided a polymer including a repeating subunit, the repeating
subunit having the formula:
[0021] Y has the formula:
Figure imgf000006_0001
, ,
Figure imgf000006_0002
[0023] The symbol“ ” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein the terminator moiety has the formula: -L3-R3, which is decribed herein. [0024] L1, L2, and L3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. L4 is a covalent linker. [0025] R1 is independently hydrogen, halogen, -CX1 1, -CHX1 1, -CH2X1, -OCX1 1, -OCH2X1, -OCHX1 1, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0026] R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2,
-OCHX2 2, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0027] R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a monovalent benzoxazine monomer. [0028] R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. [0029] The symbols X, X1, and X2 are independently–F, -Cl, -Br, or–I. The symbols n1 and n2 are independently an integer from 0 to 4. The symbols v1, v2, m1, and m2 are each independently 1 to 2. The symbol z5 is an integer from 1 to 1000. The symbol z2 is an integer from 0 to 5. The symbols p1, p2, p3, and p4 are each independently an integer from 1 to 1000. [0030] In an aspect is provided a polymer including a subunit, the subunit having the
formula:
Figure imgf000008_0001
[0031] L8 is independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. L4 is a covalent linker. L5 and L6 are each independently a bond or covalent linker. [0032] The symbol p5 is independently an integer from 1 to 1000. [0033] The symbol“ ” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein the terminator moiety has the formula: -L3-R3, which is decribed herein. [0034] In an aspect is provided a method of making a monomer, having the formula:
Figure imgf000009_0001
the method including mixing compound A and compound B
together in a reaction vessel; wherein compound A has the formula:
Figure imgf000009_0002
compound
B has the formula:
Figure imgf000009_0003
. [0035] L1 and L2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-,
-C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. [0036] R1 is independently hydrogen, halogen, -CX1 3, -CHX1 3, -CH2X1, -OCX1 3, -OCH2X1, -OCHX13, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0037] R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2,
-OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0038] R5, R6, and R8 are each independently hydrogen, a protecting group, or a leaving group. [0039] R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. [0040] The symbols n1 and n2 are independently an integer from 0 to 4. The symbols v1, v2, m1, and m2 are each independently 1 to 2. The symbols X, X1, and X2 are independently –F, -Cl, -Br, or–I. The symbol z2 is an integer from 0 to 5. [0041] In another aspect is provided a method of making a benzoxazine monomer, having the formula:
Figure imgf000011_0001
, the method including mixing compound A and compound B together in a reaction vessel; wherein compound A has the formula:
Figure imgf000011_0003
; and compound B has the formula:
Figure imgf000011_0002
. [0042] L2 and L4 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-,
-C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. [0043] R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2,
-OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0044] R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. [0045] The symbols X and X2 are independently–F, -Cl, -Br, or–I. The symbol z2 is an integer from 0 to 5. The symbol n2 is independently an integer from 0 to 4. The symbols v2 and m2 are each independently 1 to 2. The symbols R5, R6, R8, and R9, are each
independently hydrogen, a protecting group, or a leaving group. BRIEF DESCRIPTION OF THE DRAWINGS
[0046] FIG.1. Approaches to polymer coatings and adhesives using catechol-modified benzoxazines. [0047] FIGS.2A-2B. Thermally assisted ring-opening polymerization of protected benzoxazine monomers 1 (FIG.2A) and 8 (FIG.2B), and subsequent addition of organic solvent to product. [0048] FIGS.3A-3B. 1H NMR spectra of protected monobenzoxazine 1 (FIG.3A) and the product of thermally-assisted ring-opening polymerization 2 (FIG.3B). Key peak
assignments indicated by arrows. [0049] FIGS.4A-4C. FIG.4A: Solutions of polymer 3 in pH 6, 7100 mM bis-tris, and pH 8100 mM bicine containing 600 mM MgCl2 after 5 minutes, 3 and 16 hours incubation at room temperature. FIG.4B: TiO2 substrates after immersion coating in 1 mg/mL polymer 3 solutions at various pH values. FIG.4C: Centrifuged coating solutions after 16 hour coating procedure. The arrows indicate dark precipitates that were present in the coating mixtures after prolonged inclubation. [0050] FIG.5. High resolution XPS analysis of C1s, O1s, and N1s peaks for coatings of 3 obtained at pH 6, 7, and 8. Dotted lines are a guide for the eyes to compare relevant areas of interest in the spectra. Peaks corresponding to key chemical species are labeled in each spectrum. [0051] FIGS.6A-6B. FIG.6A: Schematic representation of deprotection conditions tested. FIG.6B: Photographs of methanol solution of 13, reaction mixture after addition of sodium methoxide, precipitate formation in aqueous workup, crude black product from methanolic HCl workup. [0052] FIG.7. 1H-NMR analysis of protected 13 (top), and product of trial deprotection (bottom). Boxes with an‘X’ highlight characteristic benzoxazine peaks (top), and where they would be expected to appear in MeOD solvent (bottom). Boxes without an‘X’ indicate the acetate peak (top), and the absence of this peak in the deprotected products (bottom). [0053] FIG.8. 1H-NMR spectrum of crude thermally polymerized monomer 13. Boxes with an‘X’ highlight where characteristic benzoxazine resonances are expected in MeOD solvent. Boxes without an‘X’ indicate resonances assigned to the acetate protecting groups. [0054] FIG.9. Deprotection of monomer 21 with tetrabutylammonium fluoride. TLC is taken after 15 minutes, and stained with ferric chloride solution (black spot indicates catechols); left lane is starting material, middle lane is co-spotted, right lane is crude reaction mixture. [0055] FIG.10. Representative curing behavior of 24 and other bis-benzoxazine monomers without the catechol group. [0056] FIG.11. Lap shear adhesion testing of bonded metal substrates with 24 and commercial benzoxazines. [0057] FIG.12. Main-chain benzoxazine synthesis from 27 and Jeffamine-DA 400. [0058] FIG.13. Thermal polymerization of model monomer S1 to form linear product S3. [0059] FIG.14. Lap shear adhesive strengths for four mussel-inspired benzoxazines, with two commercial benchmarks. (*) = statistically significant difference, i.e. p values of <0.05 for pairwise comparisons by the two-tailed t-test. (n.s.) = no statistically significant difference between groups in pairwise comparisons by two-tailed t-test, i.e., p ³ 0.05. [0060] FIG.15. Failed lap joints after adhesion testing. Left: chemical structures of compounds tested; middle: digital photographs of failed lap joint; right: primary failure mode. [0061] FIGS.16A-16B. FIG.16A: DSC thermogram (-10 to 290 °C, two cycles) for 35. FIG.16B: DSC thermogram (-10 to 290 °C, two cycles) for TBS protected 36. Sharp melting of monomer observed. [0062] FIG.17. 1H NMR spectrum of crude 53 collected in deuterated chloroform. This sample contains residual toluene. Key benzoxazine resonances are observed at 4.96 and 4.04 ppm, and TBS protecting groups are intact. [0063] FIG.18. 1H-NMR spectrum of crude 54 collected in deuterated chloroform. This sample contains residual tetrahydrofuran solvent (3.72 and 1.83 ppm). The benzoxazine rings are intact, indicated by key benzoxazine resonances at 4.86 and 3.95 ppm. Deprotection of the catechol is further supported by a positive result of the iron chloride test. [0064] FIG.19. Lap shear adhesive strengths for four mussel-inspired benzoxazines, with two commercial benchmarks, and three additional non-catechol benzoxazines for
comparison. (*) = statistically significant difference, i.e., p values of <0.05 for pairwise comparisons by the two-tailed t-test. (n.s.) = no statistically significant difference between groups in pairwise comparisons by two-tailed t-test, i.e., p ³ 0.05. [0065] FIG.20. Failed lap joints after adhesion testing for compounds 47, 48, and 45. Left: chemical structures of compounds tested; middle: digital photographs of failed lap joint; right: primary failure mode observed. [0066] FIGS.21A-21B. FIG.21A: Preparation of di-methoxy derivative precursor. FIG. 21B: Preparation of mono-methoxy derivative precursor. [0067] FIGS.22A-22D. FIG.22A: Preparation of mono-TBS-mono-methoxy- and mono- hydroxy-mono-methoxy-bis-benzoxazine derivatives. FIG.22B: Preparation of di- methoxyphenyl-bis-benzoxazine derivative. FIG.22C: Preparation of stand-alone diphenolic acid-based catechol-bis-benzoxazine. FIG.22D: Application of bisphenol from diphenolic acid and dopamine for main-chain benzoxazine synthesis. These main-chain benzoxazine materials have side-chain catechols. [0068] FIG.23. 1H NMR analysis of protected main-chain polybenzoxazine 55 in CDCl3. Arrows at 4.91 and 3.99 ppm indicate characteristic benzoxazine resonances. [0069] FIG.24. 1H NMR spectrum of crude 56 collected in deuterated chloroform. This sample contains residual tetrabutylammonium (labeled). Key benzoxazine resonances are observed at ~4.92 and ~4.00 ppm (arrows). [0070] FIG.25. Synthetic route to deprotected benzoxazine monomer 59. [0071] FIG.26. Lap-shear adhesion strength of mixtures of 37 with main-chain derivatives 54 and 56 on roughened aluminum 6061 substrates. [0072] FIG.27. DSC thermograms for curing of 37. Monomer Tmelting = 181 °C, Tmax = 196 °C, broad weak glass transition (Tg) centered at 208 °C (inset) in the cured thermoset (second cycle). Compare to FIG.16A for curing of monomer without recrystallization. [0073] FIG.28. Flexural testing specimens of cured BPA-Aniline, 37, and 36 prepared by compression molding and sanding. [0074] FIG.29. Representative flexural stress-strain curves during 3-point bending at a crosshead speed of 0.01 mm/min. [0075] FIG.30. Flexural modulus and flexural strength determined by 3-point bending for benchmark materials BPA-Aniline and polybenzoxazine materials 37 and 36. (BPA-Aniline N = 8, 37 N = 9, 36 N = 6. * indicates statistically significant difference, ** indicates very significant difference, and **** indicates extremely significant difference compared to BPA- Aniline by a two-tailed student’s T-test. [0076] FIG.31. Thermal gravimetric analysis of 36, 37, and BPA-Aniline under nitrogen up to 600 °C. [0077] FIG.32. Thermal gravimetric analysis of 37 and BPA-Aniline under air up to 600 °C. [0078] FIG.33. Formation of PSA tapes of 56 on PET films. [0079] FIGS.34A-34B. PSA films of 56 holding together glass slides (FIG.34A) or HDPE strips (FIG.34B) under shear load of 200 gram weight. Sample on Glass (FIG.34A) is pictured at 3 days and has remained unchanged (beyond 208 days). Sample on HDPE (FIG.34B) is pictured after 16 hours. The nearly colorless transparent tapes are framed by dotted boxes as a visual aid. [0080] FIG.35. PSA films of 56 applied to glass slides that were submerged in deionized water. The adhesive joint was still intact after 24 hours of incubation at room temperature underwater. The tape starts to appear opaque after an hour of submersion. DETAILED DESCRIPTION
[0081] Disclosed herein are several organic synthetic approaches toward mussel-inspired benzoxazine monomers and polymers bearing protected and deprotected catechol and amine sidechains. Compounds disclosed herein represent the first example of 1,3-benzoxazines in which the catechol functional group is covalently bound to the monomer and available for subsequent adhesive interactions and chemical bonding. These materials are expected to be useful, for example, in the preparation of thermoset resins, coatings, and adhesives. I. Definitions
[0082] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. [0083] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to - OCH2-. [0084] The term“alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4- pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds. [0085] The term“alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, - CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A“lower alkyl” or“lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term“alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. [0086] The term“heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)- CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, - Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and - CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term“heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. The term“heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds. [0087] Similarly, the term“heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For
heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO2R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as - NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term“heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. [0088] The terms“cycloalkyl” and“heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of“alkyl” and“heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for
heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,
tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A“cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. [0089] The terms“halo” or“halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as“haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. [0090] The term“acyl” means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0091] The term“aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term“heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term“heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2- naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4- imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3- quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An“arylene” and a“heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen. [0092] Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different. [0093] The symbol“ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula. [0094] The term“oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. [0095] The term“alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:
Figure imgf000020_0001
. [0096] An alkylarylene moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, - CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3 - SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In embodiments, the alkylarylene is unsubstituted. [0097] Each of the above terms (e.g.,“alkyl,”“heteroalkyl,”“cycloalkyl,”
“heterocycloalkyl,”“aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. [0098] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R',
-NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., - C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like). [0099] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'SO2R'',
-NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R'', R''', and R'''' groups when more than one of these groups is present. [0100] Substituents for rings (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as
substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency. [0101] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non- adjacent members of the base structure. [0102] As used herein, the terms“heteroatom” or“ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). [0103] A“substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered
heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered
heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3,-OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0104] A“size-limited substituent” or“ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. [0105] A“lower substituent” or“ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3- C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. [0106] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted
heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group. [0107] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered
heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6- C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered
heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or
unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered
heteroarylene. [0108] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted
heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or
unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below. [0109] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and/or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene, respectively). [0110] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different. [0111] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different. [0112] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different. [0113] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group is different. [0114] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. [0115] As used herein, the term“isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. [0116] The term“tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. [0117] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. [0118] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. [0119] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this disclosure. [0120] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. [0121] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit. [0122] As used herein, the term“bioconjugate linker” and“bioconjugate” refers to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect. For example, a conjugate between a first bioconjugate reactive group (e.g.,–NH2,–COOH,–N- hydroxysuccinimide, or–maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g. a first linker of second linker), or indirect, e.g., by non-covalent bond (e.g. electrostatic interactions (e.g. ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g. dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol.198, American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g.,–N- hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g.,–sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). [0123] Useful bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N- hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc. (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido or maleimide groups; (e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal silicon oxide bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds; (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and (o) biotin conjugate can react with avidin or strepavidin to form a avidin-biotin complex or streptavidin-biotin complex. [0124] The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group. [0125] “Analog,” or“analogue” is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound. [0126] The terms "a" or "an," as used in herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. [0127] Moreover, where a moiety is substituted with an R substituent, the group may be referred to as“R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R13 substituents are present, each R13 substituent may be
distinguished as R13A, R13B, R13C, R13D, etc., wherein each of R13A, R13B, R13C, R13D, etc. is defined within the scope of the definition of R13 and optionally differently. [0128] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds. [0129] The term“leaving group” is used in accordance with its ordinary meaning in chemistry and refers to a moiety (e.g., atom, functional group, molecule) that separates from the molecule following a chemical reaction (e.g., bond formation, reductive elimination, condensation, cross-coupling reaction) involving an atom or chemical moiety to which the leaving group is attached, also referred to herein as the“leaving group reactive moiety”, and a complementary reactive moiety (i.e., a chemical moiety that reacts with the leaving group reactive moiety) to form a new bond between the remnants of the leaving groups reactive moiety and the complementary reactive moiety. Thus, the leaving group reactive moiety and the complementary reactive moiety form a complementary reactive group pair. Non limiting examples of leaving groups include hydrogen, hydroxide, organotin moieties (e.g., organotin heteroalkyl), halogen (e.g., Br), perfluoroalkylsulfonates (e.g., triflate), tosylates, mesylates, water, alcohols, nitrate, phosphate, thioether, amines, ammonia, fluoride, carboxylate, phenoxides, boronic acid, boronate esters, and alkoxides. In embodiments, two molecules with leaving groups are allowed to contact, and upon a reaction and/or bond formation (e.g., acyloin condensation, aldol condensation, Claisen condensation, Stille reaction) the leaving groups separates from the respective molecule. In embodiments, a leaving group is a bioconjugate reactive moiety. In embodiments, at least two leaving groups are allowed to contact such that the leaving groups are sufficiently proximal to react, interact or physically touch. In embodiments, the leaving groups is designed to facilitate the reaction. [0130] The term“protecting group” is used in accordance with its ordinary meaning in organic chemistry and refers to a moiety covalently bound to a heteroatom, heterocycloalkyl, or heteroaryl to prevent reactivity of the heteroatom, heterocycloalkyl, or heteroaryl during one or more chemical reactions performed prior to removal of the protecting group.
Typically a protecting group is bound to a heteroatom (e.g., O) during a part of a multipart synthesis wherein it is not desired to have the heteroatom react (e.g., a chemical reduction) with the reagent. Following protection the protecting group may be removed (e.g., by modulating the pH). In embodiments the protecting group is an alcohol protecting group. Non-limiting examples of alcohol protecting groups include acetyl, benzoyl, benzyl, methoxymethyl ether (MOM), tetrahydropyranyl (THP), and silyl ether (e.g., trimethylsilyl (TMS), TBS (tert-butyl dimethylsilyl). In embodiments the protecting group is an amine protecting group. Non-limiting examples of amine protecting groups include carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl ether (PMB), and tosyl (Ts). [0131] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art. [0132] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. [0133] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent. [0134] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. [0135] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated, however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture. The term“contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway. [0136] The term“aberrant” as used herein refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms. [0137] As used herein, the term“about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using
measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about includes the specified value. [0138] The term“polymer” refers to a molecule including repeating subunits (e.g., polymerized monomers). For example, polymeric molecules may be based upon polyethylene glycol (PEG), poly[amino(1-oxo-1,6-hexanediyl)], poly(oxy-1,2- ethanediyloxycarbonyl-1,4-phenylenecarbonyl), tetraethylene glycol (TEG),
polyvinylpyrrolidone (PVP), poly(xylene), or poly(p-xylylene). See, for example, “Chemistry of Protein Conjugation and Cross-Linking” Shan S. Wong CRC Press, Boca Raton, Fla., USA, 1993;“BioConjugate Techniques” Greg T. Hermanson Academic Press, San Diego, Calif., USA, 1996;“Catalog of Polyethylene Glycol and Derivatives for Advanced PEGylation, 2004” Nektar Therapeutics Inc, Huntsville, Ala., USA, which are incorporated by reference in their entirety for all purposes. [0139] The term“poloxamer” is used in accordance with its meaning in the art of polymer chemistry and refers to a triblock copolymer composed of a central hydrophobic block (e.g., polyoxypropylene) flanked by two hydrophilic blocks (e.g., polyoxyethylene). Poloxamers may be customized by adjusting the degree of hydrophobicity and/or hydrophilicity by extending or retracting the length of the blocks. Non-limiting examples of poloxamers include poloxomer 407, poloxomer 188, poloxomer 127, or poloxomer 388. Certain poloxomers are understood to be safe for use in humans, see for example Singh-Joy and McLain (Int J Toxicol.2008;27 Suppl 2:93-128) which is incorporated by reference in its entirety for all purposes. [0140] The terms“polymerizable monomer” and“monomer” are used in accordance with its meaning in the art of polymer chemistry and refers to a compound that may covalently bind chemically to other monomer molecules (such as other polymerizable monomers that are the same or different) to form a polymer. [0141] The term“branched polymer” is used in accordance with its meaning in the art of polymer chemistry and refers to a molecule including repeating subunits, wherein at least one repeating subunit (e.g., polymerizable monomer) is covalently bound to an additional subunit substituent (e.g., resulting from a reaction with a polymerizable monomer). For example, a
branched polymer has the formula:
Figure imgf000037_0001
wherein‘A’ is the first repeating subunit and‘B’ is the second repeating subunit. In embodiments, the first repeating subunit (e.g., polyethylene glycol) is optionally different than the second repeating subunit (e.g., polymethylene glycol). When at least one repeating subunit (e.g., polymerizable monomer) is covalently bound to an additional non-consecutive (e.g., non-adjacent) subunit substituent (e.g., resulting from a reaction with a polymerizable monomer) it may be referred to herein as a mesh. For example, a mesh may have the formula:
Figure imgf000037_0002
, wherein‘A’ is the first repeating subunit and‘B’ is the second repeating subunit. [0142] The term“block copolymer” is used in accordance with its ordinary meaning and refers to two or more portions (e.g., blocks) of polymerized monomers linked by a covalent bond. In embodiments, a block copolymer is a repeating pattern of polymers. In
embodiments, the block copolymer includes two or more monomers in a periodic (e.g., repeating pattern) sequence. For example, a diblock copolymer has the formula:–B-B-B-B- B-B–A-A-A-A-A–, where‘B’ is a first subunit and‘A’ is a second subunit covalently bound together. A triblock copolymer therefore is a copolymer with three distinct blocks, two of which may be the same (e.g.,–A-A-A-A-A–B-B-B-B-B-B–A-A-A-A-A–) or all three are different (e.g.,–A-A-A-A-A–B-B-B-B-B-B–C-C-C-C-C–) where‘A’ is a first subunit,‘B’ is a second subunit, and‘C’ is a third subunit, covalently bound together. [0143] The term“monovalent benzoxazine monomer” refers to an unpolymerized
benzoxaxine monomer having the formula:
Figure imgf000038_0001
, wherein, L7 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and R7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments,
the monovalent benzoxazine monomer is:
Figure imgf000038_0002
.
Figure imgf000038_0003
Compounds
[0144] In an aspect is provided a monomer having the formula:
Figure imgf000038_0004
[0145] L1 and L2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-,
-C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene. [0146] L4 is a covalent linker. [0147] R1 is independently hydrogen, halogen, -CX11, -CHX11, -CH2X1, -OCX11, -OCH2X1, -OCHX11, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. [0148] R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2,
-OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted heteroaryl. [0149] R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heteroaryl. The symbols X, X1, and X2 are independently–F, -Cl, -Br, or–I. The symbols n1 and n2 are independently an integer from 0 to 4. The symbols v1, v2, m1, and m2 are each independently 1 to 2. The symbol z2 is an integer from 0 to 5. [0150] In embodiments, L1 and L2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or
unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0151] In embodiments, L4 is independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene. [0152] In embodiments, L4 is independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or
unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0153] In embodiments, R1 is independently hydrogen, halogen, -CX11, -CHX11, -CH2X1, -OCX11, -OCH2X1, -OCHX11, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0154] In embodiments, R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX2 2, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C,
-NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0155] In embodiments, R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0156] In another aspect is provided a polymer of the formula:
Figure imgf000043_0001
[0157] L1, L2, and L3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene. L5 and L6 are each independently a bond or covalent linker. [0158] R1 is independently hydrogen, halogen, -CX11, -CHX11, -CH2X1, -OCX11, -OCH2X1, -OCHX11, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. [0159] R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2,
-OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted(e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted heteroaryl. In embodiments, R2 is independently–OH, -OTBS (tert-butyl dimethylsilyl ether), or–OCH3. In embodiments, R2 is independently–OH. In embodiments, R2 is independently -OTBS (tert-butyl dimethylsilyl ether). In embodiments, R2 is independently–OCH3. [0160] R3 is independently hydrogen, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, or a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted monovalent benzoxazine monomer. [0161] R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heteroaryl. The symbols X, X1, and X2 are independently–F, -Cl, -Br, or–I. The symbols n1 and n2 are independently an integer from 0 to 4. The symbols v1, v2, m1, and m2 are each independently 1 to 2. The symbol z1 is independently an integer from 1 to 1000. The symbol z2 is independently an integer from 0 to 5. [0162] In embodiments, L1, L2, and L3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0163] In embodiments, L5 and L6 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene. [0164] In embodiments, L5 and L6 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted
heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or
unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0165] In embodiments, R1 is independently hydrogen, halogen, -CX11, -CHX11, -CH2X1, -OCX11, -OCH2X1, -OCHX11, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0166] In embodiments, R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C,
-NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0167] In embodiments, R3 is independently hydrogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or a substituted or unsubstituted monovalent benzoxazine monomer. [0168] In embodiments, R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0169] In an aspect is provided a polymer of the formula:
Figure imgf000048_0001
[0170] L3 and L8 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-,
-C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene. L4 is a covalent linker. L5 and L6 are each independently a bond or covalent linker. [0171] R3 is independently hydrogen, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, or a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted monovalent benzoxazine monomer. [0172] The symbol z1 is independently an integer from 1 to 1000. The symbol p5 is independently an integer from 1 to 1000. [0173] In embodiments, L4, L5, and L6 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene. [0174] In embodiments, L3, L4, L5, L6, and L8 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or
unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0175] In embodiments, R3 is independently hydrogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or a substituted or unsubstituted monovalent benzoxazine monomer. [0176] In an aspect is provided a polymer including a repeating subunit, the repeating
subunit having the formula:
Figure imgf000050_0003
[0177] Y has the formula:
Figure imgf000050_0001
, ,
Figure imgf000050_0002
L1, L2, R1, R2, and z2 are as described herein. It is understood that when multiple instances of Y are present, each Y may be different. In embodiments, Y has the formula:
Figure imgf000051_0001
. L1, L2, R1, R2, and z2 are
as described herein. In embodiments, Y has the formula:
Figure imgf000051_0002
L2, R1, R2, and z2 are as described herein. In embodiments, Y has the formula:
L1, L2, R1, R2, and z2 are as described herein.
Figure imgf000051_0003
[0178]
Figure imgf000051_0005
has the formula:
Figure imgf000051_0004
L2, L4, R2, and z2 are as described herein. [0179] The symbol“ ” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein the terminator moiety has the formula: -L3-R3, which is decribed herein. [0180] In embodiments, the polymer includes one or a plurality of optionally different repeating subunits and/or terminator moieities that are each attached to a“ ”. [0181] L1, L2, and L3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene. L4 is a covalent linker. [0182] R1 is independently hydrogen, halogen, -CX1 1, -CHX1 1, -CH2X1, -OCX1 1, -OCH2X1, -OCHX11, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. [0183] R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2,
-OCHX2 2, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted heteroaryl. [0184] R3 is independently hydrogen, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, or a monovalent benzoxazine monomer. In embodiments, R3 is independently hydrogen. In embodiments, R3 is independently unsubstituted phenyl. In embodiments, R3 is
independently an unsubstituted monovalent benzoxazine monomer. In embodiments, R3 is independently a substituted monovalent benzoxazine monomer (e.g., substituted with a substituent group). [0185] R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heteroaryl. [0186] The symbols X, X1, and X2 are independently–F, -Cl, -Br, or–I. The symbols n1 and n2 are independently an integer from 0 to 4. The symbols v1, v2, m1, and m2 are each independently 1 to 2. The symbol z5 is an integer from 1 to 1000. The symbol z2 is an integer from 0 to 5. The symbols p1, p2, p3, and p4 are each independently an integer from 1 to 1000. [0187] In an aspect is provided a polymer including a subunit, the subunit having the
formula:
Figure imgf000054_0001
are as described herein. [0188] The symbol“ ” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein the terminator moiety has the formula: -L3-R3, which is decribed herein. [0189] In an aspect is provided a polymer including a repeating subunit, the repeating
subunit having the formula:
Figure imgf000055_0001
[0190] Y has the formula:
Figure imgf000055_0002
, ,
. L1, L2, R1, R2, and z2 are as described herein.
Figure imgf000055_0005
[0191]
Figure imgf000055_0004
has the formula:
Figure imgf000055_0003
. L4, L5, L6, L8, and p5 are as described herein. [0192] The symbol z5 is an integer from 1 to 1000. The symbols p1, p2, p3, and p4 are each independently an integer from 1 to 1000. [0193] The symbol“ ” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein the terminator moiety has the formula: -L3-R3, which is decribed herein. [0194] In embodiments, the polymer includes one or a plurality of optionally different repeating subunits and/or terminator moieities that are each attached to a“ ”. [0195] In embodiments, L1, L2, L3, L4, L5, L6, and L8 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0196] In embodiments, R1 is independently hydrogen, halogen, -CX11, -CHX11, -CH2X1, -OCX11, -OCH2X1, -OCHX11, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0197] In embodiments, R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C,
-NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0198] In embodiments, R3 is independently hydrogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), or a substituted or unsubstituted monovalent benzoxazine monomer. [0199] In embodiments, R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0200] In embodiments, the polymer has the formula:
Figure imgf000058_0001
, wherein the symbol“ ” is a point of attachment to a different repeating subunit having
the formula
Figure imgf000058_0002
throughout thereby forming a network (e.g., a mesh), or to a terminator moiety, wherein said terminator moiety has the formula: -L3-R3. In embodiments, each instance of–L3-R3 is optionally different. In embodiments, the polymer network can have 100 or more repeating subunits having the formula
[
Figure imgf000058_0003
,
Figure imgf000059_0001
, wherein p1, p2, p3, p4, L4, and z5 are described herein. When multiple instances of a linker or substituent (e.g., R1, L1, L2, R2, or z2) are present it is understood that they may be optionally different.
[0202] In embodiments, Y has the formula:
Figure imgf000059_0002
, R2, and z2 are as described herein. In embodiments, Y has the formula:
Figure imgf000059_0003
. L1, L2, R1, R2, and z2 are as described herein. In embodiments, Y has the formula:
Figure imgf000060_0001
. L1, L2, R1, R2, and z2 are as described herein. In embodiments, when multiple instances of a substituent (e.g., R2) are present it is understood that they may be optionally different.
[0203] In embodiments, Y has the formula:
Figure imgf000060_0005
, wherein L1 is as described herein. In embodiments, Y has the formula:
Figure imgf000060_0002
, wherein L1 is as described herein.
[0204] In embodiments, Y has the formula:
Figure imgf000060_0003
Figure imgf000060_0004
. [0205] In embodiments, Y has the formula:
Figure imgf000061_0001
, wherein L1 is as described herein.
[0206] In embodiments,
Figure imgf000061_0002
has the formula:
Figure imgf000061_0003
, wherein R2, z2, and L4 is as described herein.
[0207] In embodiments,
Figure imgf000061_0004
has the formula: , wherein L4 is as described herein.
Figure imgf000061_0005
[0208] In embodiments,
Figure imgf000062_0002
has the formula:
Figure imgf000062_0003
wherein L2 and L4 is as described herein. In embodiments, when two instances of a linker or substituent (e.g., L2) are present it is understood that they may be optionally different, for example in an embodiment of
Figure imgf000062_0001
g . [0209] In embodiments, R1 is independently hydrogen, halogen, -CX1 1, -CHX1 1, -CH2X1, -OCX11, -OCH2X1, -OCHX11, -CN, -SOv1NH2, -NHC(O)NH2, -N(O)m1, -NH2, -C(O)H, -COOH, -C(O)NH2, -OH, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0210] In embodiments, R2 is independently halogen, -CX2 3, -CHX2 3, -CH2X2, -OCX2 3, -OCH2X2, -OCHX2 3, -CN, -SOv2NH2, -NHC(O)NH2, -N(O)m2, -NH2, -C(O)H, -COOH, -C(O)NH2, -OH, -NHC(O)H, -NHC(O)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl. In embodiments, two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl. In embodiments, two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted aryl. In embodiments, two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted heteroaryl. In embodiments, R2 is independently–OH, -OTBS (tert-butyl dimethylsilyl ether), or–OCH3. In embodiments, R2 is independently–OH. In embodiments, R2 is independently -OTBS (tert-butyl dimethylsilyl ether). In embodiments, R2 is independently–OCH3. [0211] In embodiments, R1, R2, R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3, and R7 are each independently substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0212] In embodiments, R1, R2, R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3, and R7 are each independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. [0213] In embodiments, R1, R2, R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3, and R7 are each independently unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In
embodiments, R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen. [0214] In embodiments, R5 is hydrogen. In embodiments, R7 is hydrogen. In
embodiments, R6 is hydrogen. In embodiments, R8 is hydrogen. In embodiments, R9 is hydrogen. In embodiments, R5 is a protecting group. In embodiments, R6 is a protecting group. In embodiments, R8 is a protecting group. In embodiments, R9 is a protecting group. In embodiments, R5 is a leaving group. In embodiments, R6 is a leaving group. In
embodiments, R8 is a leaving group. In embodiments, R9 is a leaving group. In
embodiments, R5, R6, R8, and R9 are each independently hydrogen, a protecting group, or a leaving group. [0215] In embodiments, L1, L2, L3, L4, L4A, L4B, L4C, L5, L6A, L6B, L6C, L6, and L8 are each independently a bond. In embodiments, L1, L2, L3, L4, L4A, L4B, L4C, L5, L6A, L6B, L6C, L6, and L8 are each independently substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1- C4, or C1-C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0216] In embodiments, L1, L2, L3, L4, L4A, L4B, L4C, L5, L6A, L6B, L6C, L6, and L8 are each independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene. [0217] In embodiments, L1, L2, L3, L4, L4A, L4B, L4C, L5, L6A, L6B, L6C, L6, and L8 are each independently unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted
cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, or unsubstituted heteroarylene. In embodiments, L1, L2, L3, L4, L4A, L4B, L4C, L5, L6A, L6B, L6C, L6, and L8 are each independently unsubstituted alkylene. [0218] In embodiments, L1, L2, L3, L4, L4A, L4B, L4C, L5, L6A, L6B, L6C, L6, and L8 are each independently unsubstituted methylene. In embodiments, L1, L2, L3, L4, L4A, L4B, L4C, L5, L6A, L6B, L6C, L6, and L8 are each independently unsubstituted ethylene. In embodiments, L1, L2, L3, L4, L4A, L4B, L4C, L5, L6A, L6B, L6C, L6, and L8 are each independently unsubstituted propylene. In embodiments, p5 is independently an integer from 1 to 100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100). In embodiments, L1, L2, L3, L4, L4A, L4B, L4C, L5, L6A, L6B, L6C, L6, and L8 are each independently
Figure imgf000065_0001
. In embodiments, L1, L2, L3, L4, L4A, L4B, L4C, L5, L6A, L6B, L6C, L6, and
L8 are each independently . In embodiments, p5 is 6. In embodiments, p5 is 31. In embodiments, p5 is 32. In embodiments, p5 is 33. In embodiments, p5 is 34. In embodiments, p5 is 35. [0219] In embodiments, R1 is independently -NHC(O)NR1AR1B, -NR1AR1B, -C(O)NR1AR1B, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R1 is–NH2. [0220] In embodiments, R2 is -C(O)R2C, -C(O)-OR2C, -OR2D, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. In embodiments, R2 is–OH or–OTBS. [0221] In embodiments, two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl.
[0222] In embodiments,
Figure imgf000066_0002
has the formula:
Figure imgf000066_0001
wherein, R2.3 and R2.4 are each hydrogen or R2 at a fixed position on the attached ring. R2.3 and R2.4 may
independently be hydrogen or any value (e.g., substituent) of R2 described herein, including in any aspect, embodiment, example, figure, or claim. In embodiments, R2.3 and R2.4 are each independently -OR2D, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R2.3 and R2.4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. In embodiments, R2D is independently hydrogen, -CX23, -CN, -COOH, -CONH2, -CHX22, -CH2X2, -CONH-(C1-C6 alkyl), -C(O)-(C1-C6 alkyl), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group.
[0223] In embodiments,
Figure imgf000066_0003
independently represented by the formula:
In embodiments,
Figure imgf000066_0004
independently represented by the formula:
Figure imgf000066_0005
. In embodiments,
Figure imgf000066_0006
independently represented by the formula:
Figure imgf000067_0005
. In embodiments, is independently represented by the formula:
Figure imgf000067_0006
In embodiments,
Figure imgf000067_0008
is independently represented by the formula:
Figure imgf000067_0007
In embodiments,
Figure imgf000067_0001
independently represented by the formula:
Figure imgf000067_0002
. In embodiments, is independently represented by the formula:
Figure imgf000067_0003
. In embodiments,
Figure imgf000067_0004
independently represented by the formula:
Figure imgf000068_0001
. In embodiments,
Figure imgf000068_0002
independently represented by the formula:
Figure imgf000068_0003
. In embodiments,
Figure imgf000068_0004
independently represented by the formula:
Figure imgf000068_0005
. In embodiments,
Figure imgf000068_0006
independently represented by the formula:
Figure imgf000068_0007
. In embodiments,
Figure imgf000068_0008
independently represented by the formula:
Figure imgf000068_0009
. In embodiments,
Figure imgf000068_0010
independently represented by the formula:
Figure imgf000068_0011
. In embodiments,
Figure imgf000068_0012
independently represented by the formula:
Figure imgf000069_0001
. In embodiments,
Figure imgf000069_0002
independently represented by the
formula:
Figure imgf000069_0003
. [0224] In embodiments, R3 is independently hydrogen, substituted or unsubstituted phenyl, or a monovalent benzoxazine monomer, wherein the monovalent benzoxazine monomer has
the formula
Figure imgf000069_0004
, wherein, L7 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and R7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R3 is independently hydrogen. In embodiments, R3 is independently substituted or unsubstituted phenyl. In embodiments, R3 is independently a substituted (e.g., R7-substituted) monovalent benzoxazine monomer. In embodiments, R3 is independently unsubstituted phenyl. [0225] In embodiments, L1 is independently -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L1 is independently substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted 2 to 6 membered
heteroalkylene. In embodiments, L1 is independently substituted or unsubstituted C1-C3 alkylene. In embodiments, L1 is independently substituted or unsubstituted C1-C2 alkylene. In embodiments, L1 is independently
Figure imgf000070_0001
. [0226] In embodiments, L2 is independently -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L2 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L2 is independently substituted or unsubstituted C1-C2 alkylene. [0227] In embodiments, L4 is independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. [0228] In embodiments, L4 is independently substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L4 is independently substituted or unsubstituted C1-C2 alkylene. [0229] In embodiments, L4 has the formula: -L4A-L4B-L4C-, wherein L4A, L4B, and L4C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-,
-NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heteroarylene. [0230] In embodiments, L4A, L4B, and L4C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0231] In embodiments, L4 is independently
Figure imgf000071_0001
, wherein R10 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2,
-NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH,
-OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. In embodiments, R10 is independently–OH. In embodiments, R10 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. The symbol z10 is an integer from 0 to 5. In
embodiments, z10 is 0. In embodiments, z10 is 1. In embodiments, z10 is 2. [0232] In embodiments, R10 is independently substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heteroaryl. [0233] In embodiments, R10 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0234] In embodiments, L4 is independently
Figure imgf000073_0001
. In embodiments, L4 is independently
Figure imgf000073_0002
. In embodiments, L4 is independently
Figure imgf000073_0003
. In embodiments, L4 is independently
Figure imgf000073_0005
. In embodiments, L4 is independently
Figure imgf000073_0004
[0235] In embodiments, L4 is
Figure imgf000074_0004
, ,
Figure imgf000074_0003
, wherein z10, L4B, and R10 are as described herein. It is understood that when multiple instances of a substituent (e.g., R10) are present, each
substituent may be different (
Figure imgf000074_0002
may exist as
Figure imgf000074_0001
embodiments, L4B is unsubstituted C1-C4 alkyl. In
embodiments, L4B is unsubstituted ethyl. [0236] In embodiments, L2 has the formula: -L2A-L2B-L2C-, wherein L2A, L2B, and L2C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-,
-NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heteroarylene. [0237] In embodiments, L2A, L2B, and L2C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0238] In embodiments, L4 is independently
Figure imgf000075_0001
. In embodiments,
L4 is independently
Figure imgf000075_0002
. L2A, L4A, R10, and z10 are as described herein. [0239] In embodiments, L4 is
Figure imgf000075_0006
wherein L2C, R10, and z10 are as described herein. It is
Figure imgf000075_0005
understood that when multiple instances of a substituent (e.g., R10) are present, each
substituent may be different (e.g.,
Figure imgf000075_0003
may exist as
Figure imgf000075_0004
embodiments, L2C is unsubstituted C1-C4 alkyl. In
embodiments, L2C is unsubstituted ethyl. [0240] In embodiments, L4 is independently -C(O)CH2-,
Figure imgf000076_0001
,
Figure imgf000076_0002
. [0241] In embodiments, L5 is independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted
heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0242] In embodiments, L5 has the formula: -L5A-L5B-L5C-, wherein L5A, L5B, and L5C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-,
-NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene. [0243] In embodiments, L5A, L5B, and L5C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).
[0244] In embodiments, L5 is independently
Figure imgf000077_0001
. In embodiments, L5A is
independently
Figure imgf000077_0002
. In embodiments, L5B is independently
Figure imgf000077_0003
. In embodiments, L5C is independently
Figure imgf000077_0004
.
[0245] In embodiments, L6 is independently
Figure imgf000077_0005
. In embodiments, L6A is
independently
Figure imgf000077_0006
. In embodiments, L6B is independently
Figure imgf000077_0007
. In embodiments, L6C is independently
Figure imgf000077_0008
. [0246] In embodiments, L6 is independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or
unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0247] In embodiments, L6 has the formula: -L6A-L6B-L6C-, wherein L6A, L6B, and L6C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-,
-NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heteroarylene. [0248] In embodiments, L6A, L6B, and L6C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or
unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0249] In embodiments, L8 is independently -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L8 is independently substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted 2 to 6 membered
heteroalkylene. In embodiments, L8 is independently substituted or unsubstituted C1-C3 alkylene. In embodiments, L8 is independently substituted or unsubstituted C1-C2 alkylene. In embodiments, L8 is independently
Figure imgf000079_0001
. [0250] In embodiments, z1 is independently 1. In embodiments, z1 is independently 6. In embodiments, z1 is independently an integer from 1 to 10. In embodiments, z1 is
independently an integer from 1 to 20. In embodiments, z1 is independently an integer from 1 to 30. In embodiments, z1 is independently an integer from 1 to 15. In embodiments, z1 is independently an integer from 1 to 25. In embodiments, z1 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In embodiments, z1 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. [0251] In embodiments, z2 is independently 0. In embodiments z2 is independently an integer from 0 to 2. In embodiments, z2 is independently 1. In embodiments, z2 is independently 2. In embodiments, z2 is independently 3. In embodiments, z2 is
independently 4. In embodiments, z2 is independently 5. [0252] In embodiments, z5 is independently 1. In embodiments, z5 is independently an integer from 1 to 10. In embodiments, z5 is independently an integer from 1 to 20. In embodiments, z5 is independently an integer from 1 to 30. In embodiments, z5 is
independently an integer from 1 to 15. In embodiments, z5 is independently an integer from 1 to 25. In embodiments, z5 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In embodiments, z5 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. [0253] In embodiments, p1 is independently 1. In embodiments, p1 is independently an integer from 1 to 10. In embodiments, p1 is independently an integer from 1 to 20. In embodiments, p1 is independently an integer from 1 to 30. In embodiments, p1 is
independently an integer from 1 to 15. In embodiments, p1 is independently an integer from 1 to 25. In embodiments, p1 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In embodiments, p1 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. [0254] In embodiments, p2 is independently 1. In embodiments, p2 is independently an integer from 1 to 10. In embodiments, p2 is independently an integer from 1 to 20. In embodiments, p2 is independently an integer from 1 to 30. In embodiments, p2 is
independently an integer from 1 to 15. In embodiments, p2 is independently an integer from 1 to 25. In embodiments, p2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In embodiments, p2 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. [0255] In embodiments, p3 is independently 1. In embodiments, p3 is independently an integer from 1 to 10. In embodiments, p3 is independently an integer from 1 to 20. In embodiments, p3 is independently an integer from 1 to 30. In embodiments, p3 is independently an integer from 1 to 15. In embodiments, p3 is independently an integer from 1 to 25. In embodiments, p3 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In embodiments, p3 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. [0256] In embodiments, p4 is independently 1. In embodiments, p4 is independently an integer from 1 to 10. In embodiments, p4 is independently an integer from 1 to 20. In embodiments, p4 is independently an integer from 1 to 30. In embodiments, p4 is independently an integer from 1 to 15. In embodiments, p4 is independently an integer from 1 to 25. In embodiments, p4 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. In embodiments, p4 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. [0257] In embodiments, p5 is independently 6. In embodiments, p5 is independently 31. In embodiments, p5 is independently 32. In embodiments, p5 is independently 33. In embodiments, p5 is independently 34. In embodiments, p5 is independently 35. In embodiments, p5 is independently an integer from 1 to 100. In embodiments, p5 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100. In embodiments, p5 is independently about 35, 40, 45, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000. [0258] In embodiments, X is independently–F. In embodiments, X is independently–Cl. In embodiments, X is independently–Br. In embodiments, X is independently–I. In embodiments, X1 is independently–F. In embodiments, X1 is independently–Cl. In embodiments, X1 is independently–Br. In embodiments, X1 is independently–I. In embodiments, X2 is independently–F. In embodiments, X2 is independently–Cl. In embodiments, X2 is independently–Br. In embodiments, X2 is independently–I. [0259] In embodiments, n1 is independently 0. In embodiments, n1 is independently 1. In embodiments, n1 is independently 2. In embodiments, n1 is independently 3. In
embodiments, n1 is independently 4. In embodiments, n2 is independently 0. In
embodiments, n2 is independently 1. In embodiments, n2 is independently 2. In
embodiments, n2 is independently 3. In embodiments, n2 is independently 4. [0260] In embodiments, v1 is independently 1. In embodiments, v2 is independently 1. In embodiments, m1 is independently 1. In embodiments, m2 is independently 1. In embodiments, v1 is independently 2. In embodiments, v2 is independently 2. In
embodiments, m1 is independently 2. In embodiments, m2 is independently 2. [0261] In embodiments, the polymer or monomer has the formula:
Figure imgf000081_0001
, wherein L2, R2, and z2 are as described herein. [0262] In embodiments, the polymer has the formula:
Figure imgf000081_0002
, wherein R3, L3, L6C, L2, R2, z2, and z1 are as described herein, including embodiments. [0263] In embodiments, the polymer has the formula:
Figure imgf000082_0001
, wherein R3, L3, L2, R2, z2, and z1 are as described herein, including embodiments.
[0264] In embodiments, the polymer or monomer has the formula:
Figure imgf000082_0002
, wherein L4 is as described herein.
[0265] In embodiments, the monomer has the formula:
Figure imgf000082_0003
.
[0266] In embodiments, the monomer or polymer has the formula:
Figure imgf000083_0001
. [0267] In embodiments, the polymer or monomer has the formula:
Figure imgf000083_0002
. [0268] In embodiments, the monomer has the formula:
Figure imgf000084_0001
.
[0269] In embodiments, the monomer has the formula:
Figure imgf000084_0002
.
[0270] In embodiments, the polymer has the formula:
Figure imgf000084_0003
. L2C, L3, L5, L6, L8, R3, R10, p5, z1, and z10 are as described herein, including in embodiments.
[0271] In embodiments, the polymer has the formula:
Figure imgf000084_0004
, or
Figure imgf000085_0001
, wherein z1, L3, and R3 are described herein. In embodiments, when two instances of a substituent (e.g., R3 or L3) are present it is understood that they may be optionally different. [0272] In embodiments, the polymer has the formula:
Figure imgf000085_0002
, wherein z1, L3, and R3 are described herein. In embodiments, when two instances of a substituent (e.g., R3 or L3) are present it is understood that they may be optionally different. [0273] In embodiments, the polymer has the formula:
Figure imgf000085_0003
Figure imgf000086_0003
, wherein z1, L3, and R3 are described herein. In embodiments, when two instances of a substituent (e.g., R3 or L3) are present it is understood that they may be optionally different. [0274] In embodiments, the polymer has the formula:
Figure imgf000086_0001
, wherein z1, L3, and R3 are described herein. In embodiments, when two instances of a substituent (e.g., R3 or L3) are present it is understood that they may be optionally different. [0275] In embodiments, the polymer has the formula:
Figure imgf000086_0002
, wherein z1, L3 and R3 are described herein. In embodiments, when two instances of a substituent (e.g., R3 or L3) are present it is understood that they may be optionally different. [0276] In embodiments, the polymer has the formula:
Figure imgf000087_0001
, wherein z1, L3 and R3 are described herein. In embodiments, when two instances of a substituent (e.g., R3 or L3) are present it is understood that they may be optionally different. [0277] In embodiments, the polymer has the formula:
Figure imgf000087_0002
, wherein L3 and R3 are described herein. In embodiments, when two instances of a substituent (e.g., R3 or L3) are present it is understood that they may be optionally different. [0278] In embodiments, the polymer has the formula:
Figure imgf000088_0001
, wherein L3 and R3 are described herein. In embodiments, when two instances of a substituent (e.g., R3 or L3) are present it is understood that they may be optionally different. [0279] In embodiments, the polymer or monomer is:
Figure imgf000088_0002
. [0280] In embodiments, the polymer or monomer is:
Figure imgf000089_0001
. [0281] In an aspect is provided a polymer including a repeating subunit, the repeating
subunit having the formula:
Figure imgf000089_0002
p1, p2, p3, p4, and z5 are as described herein. In embodiments, formula VI may be referred to herein as a mesh. A“mesh” as used herein refers to a network (e.g., interlaced) structure. A mesh may refer to a three dimensional cross-linked polymer (e.g., a polymer comprising multiple crosslink attachments to polymerizable monomers). [0282] Y has the formula:
Figure imgf000090_0001
, ,
Figure imgf000090_0002
are as described herein.
[0283]
Figure imgf000090_0004
. L2, L4, R2, and z2 are as described herein. In embodiments, the polymer includes one or a plurality of optionally different repeating subunits or terminator moieties, wherein said terminator moieties independently have the formula: -L3-R3. [0284] The symbol“
Figure imgf000090_0003
” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein the terminator moiety has the formula: -L3-R3. L3 and R3 are as described herein. [0285] L1, L2, and L3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene. L4 is a covalent linker. [0286] R1 is independently hydrogen, halogen, -CX11, -CHX11, -CH2X1, -OCX11, -OCH2X1, -OCHX11, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. [0287] R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2,
-OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted heteroaryl. [0288] R3 is independently hydrogen, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, or a monovalent benzoxazine monomer. In embodiments, R3 is independently hydrogen. In embodiments, R3 is independently unsubstituted phenyl. In embodiments, R3 is
independently an unsubstituted monovalent benzoxazine monomer. In embodiments, R3 is independently a substituted monovalent benzoxazine monomer (e.g., substituted with a substituent group). [0289] R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heteroaryl. [0290] The symbols X, X1, and X2 are independently–F, -Cl, -Br, or–I. The symbols n1 and n2 are independently an integer from 0 to 4. The symbols v1, v2, m1, and m2 are each independently 1 to 2. The symbol z5 is an integer from 1 to 1000. The symbol z2 is an integer from 0 to 5. The symbols p1, p2, p3, and p4 are each independently an integer from 1 to 1000. [0291] In embodiments, L1, L2, and L3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or
unsubstituted heteroarylene (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0292] In embodiments, R1 is independently hydrogen, halogen, -CX11, -CHX11, -CH2X1,
Figure imgf000093_0001
-NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0293] In embodiments, R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, |-C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C,
-NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl (e.g., C1-C8, C1- C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0294] In embodiments, R3 is independently hydrogen, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered)., or a monovalent benzoxazine monomer. [0295] In embodiments, R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, or C1-C4), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, or 2 to 4 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., C6-C10 or phenyl), substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered), a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, or 5 to 6 membered), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0296] In embodiments, the polymer is a polymer described herein, including
embodiments, schemes, claims, or figures. In embodiments, the monomer is a monomer described herein, including embodiments, schemes, claims, or figures. III. Methods
[0297] In an aspect is provided a method of making a monomer, having the formula:
Figure imgf000095_0001
the method including mixing compound A and compound B
together in a reaction vessel; wherein compound A has the formula:
Figure imgf000095_0002
compound
B has the formula:
Figure imgf000095_0003
. In embodiments, the method further includes substantially similar synthetic steps recited in the synthetic schemes and tables described herein. [0298] L1 and L2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-,
-C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene. [0299] R1 is independently hydrogen, halogen, -CX13, -CHX13, -CH2X1, -OCX13, -OCH2X1, -OCHX13, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1A OR1C, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. [0300] R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2,
-OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. [0301] R5, R6, and R8 are each independently hydrogen, a protecting group, or a leaving group. [0302] R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently
hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. [0303] The symbols n1 and n2 are independently an integer from 0 to 4. The symbols v1, v2, m1, and m2 are each independently 1 to 2. The symbols X, X1, and X2 are independently –F, -Cl, -Br, or–I. The symbol z2 is an integer from 0 to 5. [0304] In another aspect is provided a method of making a benzoxazine monomer, having the formula:
Figure imgf000098_0001
, the method including mixing compound A and compound B together in a reaction vessel; wherein compound A has the formula:
Figure imgf000098_0003
; and compound B has the formula:
Figure imgf000098_0002
. [0305] L2 and L4 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-,
-C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted alkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heterocycloalkylene, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted arylene, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroarylene. [0306] R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2,
-OCHX2 2, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or
unsubstituted aryl, or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. [0307] R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted aryl, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl, a protecting group, or a leaving group; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted (e.g., substituted with a substituent group, a size- limited substituent group, or lower substituent group) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroaryl. [0308] The symbols X and X2 are independently–F, -Cl, -Br, or–I. The symbol z2 is an integer from 0 to 5. The symbol n2 is independently an integer from 0 to 4. The symbols v2 and m2 are each independently 1 to 2. The symbols R5, R6, R8, and R9, are each
independently hydrogen, a protecting group, or a leaving group. [0309] In embodiments, the method further includes a deprotection step (e.g., a synthetic step involving changing the chemical reaction conditions such that a protecting group is removed). In embodiments, the method further includes a deprotection step wherein the deprotection step includes the addition of stoichiometric tetrabutylammonium fluoride in chilled tetrahydrofuran. In embodiments, the method includes reaction steps described herein (e.g., reaction conditions according to any scheme described herein, Table 1, or Table 3). In embodiments the method includes a synthetic step substantially similar to a step described herein.
[0310] In embodiments, compound B has the formula:
Figure imgf000100_0001
, wherein L2, R8, and R9 are as described herein. [0311] In embodiments, compound B has the formula:
Figure imgf000101_0001
[0312] In embodiments, compound B has the formula:
Figure imgf000102_0001
[0313] In embodiments, compound A has the formula:
Figure imgf000102_0002
wherein R5, R6, and R8 are as described herein. [0314] In embodiments, compound A has the formula:
Figure imgf000103_0001
, wherein R8 is as described herein.
[0315] In embodiments, compound A has the formula:
Figure imgf000103_0002
, wherein R8 is as described herein. [0316] In embodiments, compound A has the formula:
Figure imgf000103_0003
, wherein R5, R6, and R8 are as described herein. In embodiments, R8 is independently hydrogen. [0317] In embodiments, compound A has the formula:
Figure imgf000103_0004
, wherein R5 and R6 are as described herein. [0318] In embodiments, compound A has the formula:
Figure imgf000104_0001
. [0319] In embodiments, compound A has the formula:
Figure imgf000104_0002
.
[0320] In embodiments, compound A has the formula:
Figure imgf000104_0003
,
Figure imgf000104_0004
, erein R8 and R9 are as described herein.
[0321] In embodiments, compound A has the formula:
Figure imgf000104_0005
, wherein L4 is independently
Figure imgf000104_0006
,
Figure imgf000105_0001
, L4A, L4B, L4C, R8, R9, R10, and z10 are as described herein.
[0322] In embodiments, compound A has the formula:
Figure imgf000105_0002
, wherein L4 is independently ,
Figure imgf000105_0003
, ,
Figure imgf000106_0001
, L4, L4A, L4C, R8, R9, R10, and z10 are as described herein. [0323] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. IV. Embodiments
[0324] Embodiment P1. A monomer having the formula:
Figure imgf000106_0002
wherein, L1 and L2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L4 is a covalent linker; R1 is independently hydrogen, halogen, -
Figure imgf000107_0001
-OCH2X1, -OCHX1 3, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B,
-C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C,
-NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C,
-C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X, X1, and X2 are independently–F, -Cl, -Br, or–I; n1 and n2 are independently an integer from 0 to 4; v1, v2, m1, and m2 are each independently 1 to 2; and z2 is an integer from 0 to 5. [0325] Embodiment P2. A polymer of the formula:
Figure imgf000108_0001
wherein, L1, L2, and L3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L5 and L6 are each independently a covalent linker; R1 is independently hydrogen, halogen, -CX13, -CHX13, -CH2X1, -OCX13, -OCH2X1,
-OCHX1 3, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN,
Figure imgf000108_0002
-OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a monovalent benzoxazine monomer; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X, X1, and X2 are independently–F, -Cl, -Br, or–I; n1 and n2 are independently an integer from 0 to 4; v1, v2, m1, and m2 are each independently 1 to 2; z1 is independently an integer from 1 to 1000; and z2 is an integer from 0 to 5. [0326] Embodiment P3. A polymer comprising a repeating subunit, said repeating subunit having the formula:
Figure imgf000109_0001
wherein
Y has the formula
Figure imgf000110_0001
Figure imgf000110_0002
the symbol“ is a point of attachment to a different repeating subunit or to a terminator moiety, wherein said terminating moiety has the formula: -L3-R3; L1, L2, and L3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L4 is a covalent linker; R1 is independently hydrogen, halogen, -CX13, -CHX13, -CH2X1, -OCX13, -OCH2X1,
-OCHX13, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX2 2, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted monovalent benzoxazine monomer; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X, X1, and X2 are independently–F, -Cl, -Br, or–I; n1 and n2 are independently an integer from 0 to 4; v1, v2, m1, and m2 are each independently 1 to 2; z5 is an integer from 1 to 1000; z2 is independently an integer from 0 to 5; and p1, p2, p3, and p4 are each independently an integer from 1 to 1000. [0327] Embodiment P4. The monomer of embodiment P1 or a polymer of one of embodiments P2 or P3, wherein R1 is independently -NHC(O)NR1AR1B, -NR1AR1B,
-C(O)NR1AR1B, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. [0328] Embodiment P5. The monomer of embodiment P1 or a polymer of one of embodiments P2 or P3, wherein R1 is–NH2. [0329] Embodiment P6. The monomer of one of embodiments P1, P4, or P5, or a polymer of any one of embodiments P2 to P5, wherein L1 is a bond, -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. [0330] Embodiment P7. The monomer of one of embodiments P1, P4, or P5 or a polymer of any one of embodiments P2 to P5, wherein L1 is substituted or unsubstituted C1- C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene. [0331] Embodiment P8. The monomer of one of embodiments P1, P4, or P5 or a polymer of any one of embodiments P2 to P5, wherein L1 is substituted or unsubstituted C1- C2 alkylene. [0332] Embodiment P9. The polymer of any one of embodiments P2 to P8, wherein L4 is substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene. [0333] Embodiment P10. The polymer of any one of embodiments P2 to P8, wherein L4 is substituted or unsubstituted C1-C2 alkylene. [0334] Embodiment P11. The polymer of any one of embodiments P2 to P8, wherein L4
Figure imgf000112_0001
[0335] Embodiment P12. The monomer of one of embodiments P1, P4 to P8, or a polymer of any one of embodiments P2 to P11, wherein L2 is -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. [0336] Embodiment P13. The monomer of one of embodiments P1, P4 to P8, or a polymer of any one of embodiments P2 to P11, wherein L2 is substituted or unsubstituted C1- C6 alkylene. [0337] Embodiment P14. The monomer of one of embodiments P1, P4 to P8, or a polymer of any one of embodiments P2 to P11, wherein L2 is substituted or unsubstituted C1- C2 alkylene. [0338] Embodiment P15. The monomer of one of embodiments P1, P4 to P8, P12 to P14, or a polymer of any one of embodiments P2 to P14, wherein R2 is -C(O)R2C, -C(O)-OR2C, -OR2D, -OC(O)R2C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. [0339] Embodiment P16. The monomer of one of embodiments P1, P4 to P8, P12 to P14, or a polymer of any one of embodiments P2 to P14, wherein two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered
heterocycloalkyl. [0340] Embodiment P17. The monomer of one of embodiments P1, P4 to P8, P12 to P14, or a polymer of any one of embodiments P2 to P14, wherein R2 is–OH, -OCH3, or -OTBS. [0341] Embodiment P18. The monomer of one of embodiments P1, P4 to P8, P12 to P14,
or a polymer of any one of embodiments P2 to P14, wherein
Figure imgf000113_0001
has the formula:
Figure imgf000113_0002
wherein, R2.3 and R2.4 are each independently -OR2D, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R2.3 and R2.4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2D is independently hydrogen, -CX2 3, -CN, -COOH, -CONH2, -CHX2 2, -CH2X2,
-CONH-(C1-C6 alkyl), -C(O)-(C1-C6 alkyl), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group. [0342] Embodiment P19. The polymer of embodiment P2, wherein L6 has the formula: -L6A-L6B-L6C-, wherein L6A, L6B, and L6C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. [0343] Embodiment P20. The polymer of any one of embodiments P2 to P18, wherein R3 is independently hydrogen, substituted or unsubstituted phenyl, or a monovalent benzoxazine monomer, wherein said monovalent benzoxazine monomer has the formula:
Figure imgf000114_0001
, wherein, L7 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-,
-NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and R7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0344] Embodiment P21. The polymer of any one of embodiments P2 to P20, wherein z1 is 1. [0345] Embodiment P22. The polymer of embodiment P21, wherein the polymer has the formula:
Figure imgf000115_0001
. [0346] Embodiment P23. The polymer of any one of embodiments P2, or P12 to P20, wherein the polymer has the formula:
Figure imgf000115_0002
.
[0347] Embodiment P24. The polymer of any one of embodiments P2, or P12 to P20, wherein the polymer has the formula:
Figure imgf000115_0003
. [0348] Embodiment P25. A method of making a monomer, having the formula:
Figure imgf000115_0004
said method comprising mixing compound A and compound B together in a reaction vessel; wherein compound A has the formula:
Figure imgf000116_0001
compound B has the formula:
Figure imgf000116_0002
wherein, L1 and L2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R1 is independently hydrogen, halogen, -CX13, -CHX13, -CH2X1, -OCX13, -OCH2X1,
-OCHX13, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX2 2, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5, R6, and R8 are each independently hydrogen, a protecting group, or a leaving group; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; n1 and n2 are independently an integer from 0 to 4; v1, v2, m1, and m2 are each independently 1 to 2; X, X1, and X2 are independently–F, -Cl, -Br, or–I; and z2 is an integer from 0 to 5. [0349] Embodiment P26. A method of making a monomer, having the formula:
Figure imgf000117_0001
, said method comprising mixing compound A and compound B together in a reaction vessel; wherein
compound A has the formula:
Figure imgf000117_0002
; and compound B has the formula:
Figure imgf000118_0001
wherein, L2 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L4 is a covalent linker; R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX2 2, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X and X2 are independently–F, -Cl, -Br, or–I; z2 is an integer from 0 to 5; n2 is independently an integer from 0 to 4; v2 and m2 are each independently 1 to 2; and
R5, R6, R8, and R9, are each independently hydrogen, a protecting group, or a leaving group.
[0350] Embodiment P27. The method of embodiment P25 or P26, wherein compound B has the formula:
Figure imgf000119_0001
.
[0351] Embodiment P28. The method of embodiment P25 or P26, wherein compound B has the formula:
Figure imgf000119_0002
. [0352] Embodiment P29. The method of one of embodiments P25, P27, or P28, wherein compound A has the formula:
Figure imgf000120_0001
. [0353] Embodiment P30. The method of one of embodiments P25, P27, or P28, wherein compound A has the formula:
Figure imgf000120_0002
. [0354] Embodiment P31. The method of one of embodiments P26 or P28, wherein compound A has the formula:
Figure imgf000120_0003
. [0355] Embodiment 1. A compound having the formula:
Figure imgf000121_0001
wherein, L1 and L2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L4 is a covalent linker; R1 is independently hydrogen, halogen, -CX1 3, -CHX1 3, -CH2X1, -OCX1 3, -OCH2X1,
-OCHX1 3, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X, X1, and X2 are independently–F, -Cl, -Br, or–I; n1 and n2 are independently an integer from 0 to 4; v1, v2, m1, and m2 are each independently 1 to 2; and z2 is an integer from 0 to 5. [0356] Embodiment 2. The compound of embodiment 1, wherein R1 is independently -NHC(O)NR1AR1B, -NR1AR1B, -C(O)NR1AR1B, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)O R1C, -NR1AOR1C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. [0357] Embodiment 3. The compound of embodiment 1, wherein R1 is–NH2. [0358] Embodiment 4. The compound of one of embodiments 1 to 3, wherein L1 is a bond, -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. [0359] Embodiment 5. The compound of one of embodiments 1 to 3, wherein L1 is substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene. [0360] Embodiment 6. The compound of one of embodiments 1 to 3, wherein L1 is substituted or unsubstituted C1-C2 alkylene. [0361] Embodiment 7. The compound of one of embodiments 1 to 6, wherein L2 is -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. [0362] Embodiment 8. The compound of one of embodiments 1 to 6, wherein L2 is substituted or unsubstituted C1-C6 alkylene. [0363] Embodiment 9. The compound of one of embodiments 1 to 6, wherein L2 is substituted or unsubstituted C1-C2 alkylene. [0364] Embodiment 10. The compound of one of embodiments 1 to 9, wherein R2 is -C(O)R2C, -C(O)-OR2C, -OR2D, -OC(O)R2C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. [0365] Embodiment 11. The compound of one of embodiments 1 to 9, wherein two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl. [0366] Embodiment 12. The compound of one of embodiments 1 to 9, wherein R2 is –OH, -OCH3, or -OTBS. [0367] Embodiment 13. The compound of one of embodiments 1 to 9, wherein
has the formula:
Figure imgf000123_0001
wherein, R2.3 and R2.4 are each independently -OR2D, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R2.3 and R2.4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2D is independently hydrogen, -CX23, -CN, -COOH, -CONH2, -CHX22, -CH2X2,
-CONH-(C1-C6 alkyl), -C(O)-(C1-C6 alkyl), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group. [0368] Embodiment 14. A polymer of the formula:
Figure imgf000124_0001
wherein, L1, L2, and L3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L5 and L6 are each independently a covalent linker; R1 is independently hydrogen, halogen, -CX13, -CHX13, -CH2X1, -OCX13, -OCH2X1,
-OCHX13, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, | -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22,
-CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C,
-C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a monovalent benzoxazine monomer; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X, X1, and X2 are independently–F, -Cl, -Br, or–I; n1 and n2 are independently an integer from 0 to 4; v1, v2, m1, and m2 are each independently 1 to 2; z1 is independently an integer from 1 to 1000; and z2 is an integer from 0 to 5. [0369] Embodiment 15. The polymer of embodiment 14, wherein R1 is independently -NHC(O)NR1AR1B, -NR1AR1B, -C(O)NR1AR1B, -NR1ASO1R1D, -NR1AC(O)R1C,
-NR1AC(O)OR1C, -NR1AOR1C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. [0370] Embodiment 16. The polymer of embodiment 14, wherein R1 is–NH2. [0371] Embodiment 17. The polymer of any one of embodiments 14 to 16, wherein L1 is a bond, -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. [0372] Embodiment 18. The polymer of any one of embodiments 14 to 16, wherein L1 is substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene. [0373] Embodiment 19. The polymer of any one of embodiments 14 to 16, wherein L1 is substituted or unsubstituted C1-C2 alkylene. [0374] Embodiment 20. The polymer of any one of embodiments 14 to 19, wherein L2 is -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. [0375] Embodiment 21. The polymer of any one of embodiments 14 to 19, wherein L2 is substituted or unsubstituted C1-C6 alkylene. [0376] Embodiment 22. The polymer of any one of embodiments 14 to 19, wherein L2 is substituted or unsubstituted C1-C2 alkylene. [0377] Embodiment 23. The polymer of any one of embodiments 14 to 22, wherein R2 is -C(O)R2C, -C(O)-OR2C, -OR2D, -OC(O)R2C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. [0378] Embodiment 24. The polymer of any one of embodiments 14 to 22, wherein two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl. [0379] Embodiment 25. The polymer of any one of embodiments 14 to 22, wherein R2 is–OH, -OCH3, or -OTBS. [0380] Embodiment 26. The polymer of any one of embodiments 14 to 22, wherein
Figure imgf000126_0001
has the formula:
Figure imgf000127_0001
wherein, R2.3 and R2.4 are each independently -OR2D, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R2.3 and R2.4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2D is independently hydrogen, -CX23, -CN, -COOH, -CONH2, -CHX22, -CH2X2,
-CONH-(C1-C6 alkyl), -C(O)-(C1-C6 alkyl), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group. [0381] Embodiment 27. The polymer of embodiment 14, wherein L6 has the formula: -L6A-L6B-L6C-, wherein L6A, L6B, and L6C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. [0382] Embodiment 28. The polymer of any one of embodiments 14 to 26, wherein R3 is independently hydrogen, substituted or unsubstituted phenyl, or a monovalent benzoxazine monomer, wherein said monovalent benzoxazine monomer has the formula:
Figure imgf000127_0002
, wherein, L7 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-,
-NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and R7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0383] Embodiment 29. The polymer of any one of embodiments 14 to 28, wherein z1 is 1. [0384] Embodiment 30. The polymer of embodiment 29, wherein the polymer has the formula:
Figure imgf000128_0001
. [0385] Embodiment 31. The polymer of any one of embodiments 14, or 20 to 28, wherein the polymer has the formula:
Figure imgf000128_0002
. [0386] Embodiment 32. The polymer of any one of embodiments 14, or 20 to 28, wherein the polymer has the formula:
Figure imgf000129_0001
. [0387] Embodiment 33. A polymer of the formula:
Figure imgf000129_0002
wherein, L3, L4, L5, L6, and L8 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted monovalent benzoxazine monomer; z1 is independently an integer from 1 to 1000; and p5 is independently an integer from 1 to 100. [0388] Embodiment 34. The polymer of embodiment 33, wherein the polymer has the formula:
Figure imgf000129_0003
L2C is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-,
-NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R10 is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; and z10 is an integer from 0 to 5. [0389] Embodiment 35. The polymer of one of embodiments 33 to 34, wherein L5 is
Figure imgf000130_0001
, , and L8 is unsubstituted C1-C3 alkylene. [0390] Embodiment 36. The polymer of one of embodiments 33 to 35, wherein the polymer has the formula:
Figure imgf000130_0002
. [0391] Embodiment 37. A polymer comprising (1) a repeating subunit, said repeating subunit having the formula:
Figure imgf000131_0001
wherein
Y has the formula
Figure imgf000131_0002
Figure imgf000131_0003
the symbol“ ” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein said terminator moiety has the formula: -L3-R3; (2) at each symbol“
Figure imgf000131_0004
” is attached a different repeating subunit or a terminator moiety, wherein said terminator moiety has the formula: -L3-R3; L1, L2, and L3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L4 is a covalent linker; R1 is independently hydrogen, halogen, -
Figure imgf000132_0001
-OCH2X1,
-OCHX1 3, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted monovalent benzoxazine monomer; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X, X1, and X2 are independently–F, -Cl, -Br, or–I; n1 and n2 are independently an integer from 0 to 4; v1, v2, m1, and m2 are each independently 1 to 2; z5 is an integer from 1 to 1000; z2 is independently an integer from 0 to 5; and p1, p2, p3, and p4 are each independently an integer from 1 to 1000. [0392] Embodiment 38. The polymer of embodiment 37, wherein R1 is independently -NHC(O)NR1AR1B, -NR1AR1B, -C(O)NR1AR1B, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)O R1C, -NR1AOR1C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. [0393] Embodiment 39. The polymer of embodiment 37, wherein R1 is–NH2. [0394] Embodiment 40. The polymer of any one of embodiments 37 to 39, wherein L1 is a bond, -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. [0395] Embodiment 41. The polymer of any one of embodiments 37 to 39, wherein L1 is substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene. [0396] Embodiment 42. The polymer of any one of embodiments 37 to 39, wherein L1 is substituted or unsubstituted C1-C2 alkylene. [0397] Embodiment 43. The polymer of any one of embodiments 37 to 42, wherein L4 is substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene. [0398] Embodiment 44. The polymer of any one of embodiments 37 to 42, wherein L4 is substituted or unsubstituted C1-C2 alkylene. [0399] Embodiment 45. The polymer of any one of embodiments 37 to 42, wherein L4
Figure imgf000133_0001
[0400] Embodiment 46. The polymer of any one of embodiments 37 to 45, wherein L2 is -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. [0401] Embodiment 47. The polymer of any one of embodiments 37 to 45, wherein L2 is substituted or unsubstituted C1-C6 alkylene. [0402] Embodiment 48. The polymer of any one of embodiments 37 to 45, wherein L2 is substituted or unsubstituted C1-C2 alkylene. [0403] Embodiment 49. The polymer of any one of embodiments 37 to 48, wherein R2 is -C(O)R2C, -C(O)-OR2C, -OR2D, -OC(O)R2C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. [0404] Embodiment 50. The polymer of any one of embodiments 37 to 48, wherein two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl. [0405] Embodiment 51. The polymer of any one of embodiments 37 to 48, wherein R2 is–OH, -OCH3, or -OTBS. [0406] Embodiment 52. The polymer of any one of embodiments 37 to 48, wherein
has the formula:
Figure imgf000134_0001
wherein, R2.3 and R2.4 are each independently -OR2D, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R2.3 and R2.4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2D is independently hydrogen, -CX23, -CN, -COOH, -CONH2, -CHX22, -CH2X2,
-CONH-(C1-C6 alkyl), -C(O)-(C1-C6 alkyl), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group. [0407] Embodiment 53. The polymer of any one of embodiments 37 to 52, wherein R3 is independently hydrogen, substituted or unsubstituted phenyl, or a monovalent benzoxazine monomer, wherein said monovalent benzoxazine monomer has the formula:
Figure imgf000135_0001
, wherein, L7 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-,
-NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and R7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0408] Embodiment 54. A polymer comprising (1) a subunit, said subunit having the formula:
Figure imgf000136_0001
wherein the symbol“ is a point of attachment to a different repeating subunit or to a terminator moiety, wherein said terminator moiety has the formula: -L3-R3; (2) at each symbol“ ” is attached a different subunit or a terminator moiety, wherein said terminator moiety has the formula: -L3-R3; L3, L5, L6, and L8 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-,
-C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L4 is a covalent linker; R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted monovalent benzoxazine monomer; and p5 are each independently an integer from 1 to 100. [0409] Embodiment 55. A polymer comprising (1) a repeating subunit, said repeating subunit having the formula:
Figure imgf000136_0002
wherein
Y has the formula
Figure imgf000137_0001
Figure imgf000137_0002
the symbol
Figure imgf000137_0004
is a point of attachment to a different repeating subunit or to a terminator moiety, wherein said terminator moiety has the formula: -L3-R3; (2) at each symbol“
Figure imgf000137_0003
” is attached a different repeating subunit or a terminator moiety, wherein said terminator moiety has the formula: -L3-R3; L1, L2, L3, L5, L6, and L8 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L4 is a covalent linker; R1 is independently hydrogen, halogen, -CX13, -CHX13, -CH2X1, -OCX13, -OCH2X1, -OCHX13, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B,
-C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)O R1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX2 2, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted monovalent benzoxazine monomer; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X, X1, and X2 are independently–F, -Cl, -Br, or–I; n1 and n2 are independently an integer from 0 to 4; v1, v2, m1, and m2 are each independently 1 to 2; z5 is an integer from 1 to 1000; z2 is independently an integer from 0 to 5; and p1, p2, p3, p4, and p5 are each independently an integer from 1 to 1000. [0410] Embodiment 56. A method of making a compound, having the formula:
Figure imgf000139_0001
said method comprising mixing compound A and compound B together in a reaction vessel; wherein
compound A has the formula:
Figure imgf000139_0002
compound B has the formula:
Figure imgf000139_0003
wherein, L1 and L2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R1 is independently hydrogen, halogen, -CX1 3, -CHX1 3, -CH2X1, -OCX1 3, -OCH2X1,
-OCHX13, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5, R6, and R8 are each independently hydrogen, a protecting group, or a leaving group; R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; n1 and n2 are independently an integer from 0 to 4; v1, v2, m1, and m2 are each independently 1 to 2; X, X1, and X2 are independently–F, -Cl, -Br, or–I; and z2 is an integer from 0 to 5. [0411] Embodiment 57. A method of making a compound, having the formula:
Figure imgf000141_0001
, said method comprising mixing compound A and compound B together in a reaction vessel; wherein
compound A has the formula:
Figure imgf000141_0002
compound B has the formula:
Figure imgf000141_0003
wherein, L2 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L4 is a covalent linker; R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X and X2 are independently–F, -Cl, -Br, or–I; z2 is an integer from 0 to 5; n2 is independently an integer from 0 to 4; v2 and m2 are each independently 1 to 2; and R5, R6, R8, and R9, are each independently hydrogen, a protecting group, or a leaving group. [0412] Embodiment 58. The method of embodiment 56 or 57, wherein compound B has the formula:
Figure imgf000142_0001
. [0413] Embodiment 59. The method of embodiment 56 or 57, wherein compound B has the formula:
Figure imgf000143_0001
. [0414] Embodiment 60. The method of one of embodiments 56, 58, or 59, wherein compound A has the formula:
Figure imgf000143_0002
. [0415] Embodiment 61. The method of one of embodiments 56, 58, or 59, wherein compound A has the formula:
Figure imgf000144_0001
. [0416] Embodiment 62. The method of one of embodiments 57 or 59, wherein compound A has the formula:
Figure imgf000144_0002
. EXAMPLES
Example 1: Methods of preparation of mussel-inspired benzoxazine monomers, polymers, and thermoset resins
[0417] Several organic synthetic approaches toward mussel-inspired benzoxazine monomers and polymers bearing protected and deprotected catechol and amine sidechains are disclosed. These compounds represent the first example of 1,3-benzoxazines in which the catechol functional group is covalently bound to the monomer and available for subsequent adhesive interactions and chemical bonding. These materials are expected to be useful for the preparation of thermoset resins, coatings, and adhesives. [0418] Polybenzoxazines are a relatively new class of phenolic resins with a range of attractive properties including excellent thermal stability, high char yield, high glass transition temperature, and low moisture absorption.1 A number of applications for this class of materials exist, including their use in resins and composites in aerospace industry.
Benzoxazine monomers are typically prepared by Mannich-type reaction of phenols, amines, and formaldehyde. Thermally accelerated cationic ring-opening polymerization of these compounds requires no harsh catalysts, no volatile byproducts are formed, and near-zero volume change is observed on curing. Polymerization typically yields phenolic Mannich- bridged polymers and networks. The modularity of monomer design and synthesis increases the appeal and potential utility of this class of materials. [0419] We take inspiration in our work from marine mussels, which have the ability to adhere strongly to a wide range of substrates through application of an attachment organ called the byssus. This organ is composed of a collection of threads terminated by adhesive plaques. The proteins that comprise this tissue are rich in the unconventional catechol amino acid 3,4-dihydroxyphenylalanine (DOPA), which is a versatile and strong molecular adhesive that is effective even in wet environments.2 In addition, a significant number of these DOPA residues are immediately adjacent to basic nitrogen-containing residues such as lysine and histidine. A growing body of literature suggests that there is a synergistic relationship between catechols and amine-containing residues that leads to enhanced adhesion. These adhesive proteins have inspired the design of a number of synthetic adhesives for application in aqueous milieu. [0420] Functional groups bearing labile protons, such as carboxylic acids and phenols, have been incorporated into benzoxazine monomers previously, and the ability of these functional groups to accelerate benzoxazine polymerization and reduce polymerization temperature is known in the art.3 However, no examples of deprotected catechol (i.e., 1,2- dihydroxybenzene) derivatives of 1,3-benzoxazines have been reported to date. In addition to offering analogous benefits as phenols in accelerating benzoxazine curing and performing as initiation sites for benzoxazine polymerization, catechols are known to be extremely versatile adhesives,4 and are expected to improve the adhesive performance of catechol-modified benzoxazine thermoset adhesives. The catechol is capable of a profusion of noncovalent and covalent interactions, such as hydrogen bonding, pi-electron interactions (i.e. quadrupole- quadrupole and pi-stacking interactions), hydrophobic forces, and electrophilic aromatic substitution reactions.4a,5 Additional nucleophilic substitution reactions can take place upon oxidation of the catechol to the quinone, which occurs readily in the presence of chemical oxidants, as well as under alkaline conditions in the presence of dissolved molecular oxygen. This promiscuous reactivity makes catechols powerful players in the preparation of robust adhesives at the nano- through macro-scale. [0421] The inventors have identified a viable synthetic chemical strategy for the incorporation of deprotected catechols in benzoxazine monomers and main-chain
polybenzoxazine polymers, that is not practical utilizing strategies described in the prior art for the incorporation of other functional groups bearing labile protons into 1,3-benzoxazines. Specifically, it was found that silyl ethers were competent protecting groups for the catechol, preventing side-reactions on the electron rich aromatic ring of the catechol in the presence of deprotected phenols during benzoxazine synthesis; silyl ethers were removed after benzoxazine preparation and purification using stoichiometric tetrabutylammonium fluoride reagent. The use of silyl ethers as protecting groups in benzoxazine synthesis has not been previously described. A number of unsuccessful synthetic strategies toward deprotected catechol-modified benzoxazines were identified, which further emphasizes the non- obviousness of the disclosed approach. In addition, strategies for the preparation of soluble linear polybenzoxazines with alternating catechol and primary amine side chains is disclosed. These synthetic chemical approaches may be generalized to a range of molecular designs, configurations, and catechol:benzoxazine stoichiometric ratio for tuning the adhesive behavior, properties, and performance of the resulting thermoset resins, adhesives, and soluble polymeric products. [0422] Benzoxazine resin monomers and precursors are prepared by the Mannich-type reaction of phenols, amines, and formaldehyde (Scheme 1). Thermally accelerated ring- opening polymerization of these compounds typically yields phenolic Mannich-bridged polymers and networks (Scheme 1). Polymerization of 4-substituted monomeric
benzoxazines (i.e., R1 ¹ H, Scheme 1) provides soluble linear polybenzoxazine products with molecular weights typically <10 kDa. Multivalent benzoxazines and 4-unsubsubstituted monomers (i.e., R1 = H, Scheme 1) produce highly crosslinked insoluble thermoset resins.
Figure imgf000146_0001
Scheme 1. Synthesis and polymerization of 1,3-benzoxazines. [0423] We initially envisioned that protected catechol- and amine-modified benzoxazine monomers would be suitable for polymerization in bulk to provide protected polymers that could be later deprotected (Route A, FIG.1), or the monomers could be deprotected for coating purposes, enabled by the synergistic adhesive properties of catechols and amines, followed by subsequent thermally accelerated polymerization (Route B, FIG.2). During our pursuit of materials capable of being applied in both routes shown in FIG.2, we identified significant synthetic challenges stemming from the decomposition of 1,3-benzoxazines under deprotection conditions for commonly used catechol and amine protecting groups, such as acidic reaction conditions, catalytic hydrogenation in the presence of palladium on charcoal, and hydride-based reducing agents, such as sodium borohydride. These difficulties prompted our exploration of a number of monomer designs utilizing a range of protecting group strategies and benzoxazine precursors. Through these exploratory efforts, we arrived at a strategy for incorporating deprotected catechols in 1,3-benzoxazine monomers by using silyl ethers as protecting groups, and achieved protecting group removal by treatment with stoichiometric tetrabutylammonium fluoride reagent without degrading the 1,3-benzoxazine functionality. In addition, we identified protected mussel-inspired benzoxazine monomers that can be polymerized to form linear soluble polybenzoxazines with alternating catechol and amine side-chains. Protecting groups were efficiently removed under acidic conditions to provide water-soluble polymer salts that formed conformal coatings on a variety of inorganic and organic substrates under a buffered pH range of 6-9 supplemented with 600 mM MgCl2. These coating conditions are analogous to those previously applied for conformal polydopamine dip-coatings. These steps represent a successful demonstration of the strategy proposed in Route A, FIG.2. [0424] The initial target benzoxazines pursued were mono- and bis-1,3-benzoxazine cores modified with protected catechol and amine functional groups, as exemplified in compound 1 (Scheme 2). This monomer is derived from protected tyramine and dopamine precursors, and formaldehyde.
Figure imgf000147_0001
Scheme 2. Design of mussel-inspired mono-benzoxazine monomer and planned
polymerization. [0425] Monomer synthesis began by protection of the primary amine functionality of tyramine with the tert-butyl carbamate (Boc). This reaction was carried out with di-tert-butyl dicarbonate in aqueous methanol containing potassium carbonate to produce protected precursor 4 in 95% yield (Scheme 3A). Next, dopamine acetonide 7 was prepared by previously published methods (Scheme 3B). Briefly, the primary amine of dopamine hydrochloride was masked as the trifluoroacetamide by treatement with ethyl trifluoroacetate in methanol in the presence of triethylamine, producing intermediate 5 in nearly quantitative yield. The catechol on compound 5 was converted to the acetonide by treatment with 2,2- dimethoxypropane in dry benzene in the presence of a catalytic amount of p-toluenesulfonic acid. Fully protected intermediate 6 was obtained in 81% yield after recrystallization. Finally, saponification of the trifluoroacetamide by lithium hydroxide in a 70% (v/v) mixture of tetrahydrofuran and water produced dopamine acetonide 7 in nearly quantitative yield as a pale-yellow oil after aqueous workup.
Figure imgf000148_0001
Schemes 3A and 3B. Preparation of protected benzoxazine precursors. (3A) Protection of tyramine with tert-butyl carbamate (Boc) group; (3B) preparation of dopamine acetonide, as previously described. [0426] Following the preparation of the protected precursors, a number of reaction conditions were adapted from previously described benzoxazine syntheses and screened for yield and ease of product purification. Briefly, precursors 4 and 7 were treated at
approximately a 1:1 molar ratio with 2–2.2 molar equivalents of either aqueous formaldehyde solution (37% w/w) or paraformaldehyde (Scheme 4, Table 1). In all cases, reaction mixtures became a deep yellow color upon heating, and a highly UV-active spot appeared at the baseline in TLC analyses. Notably, this color change was less dramatic under the biphasic reaction condition C, and this yellow-colored byproduct was not observed in test reactions with model phenols and amines that did not include 7. It is likely that this color change is the result of side reactions involving 7. Reactions were carried out until both the amine and phenol starting materials were mostly consumed, as determined by thin layer chromatography (TLC) analysis. Desired benzoxazine products are easily identified by TLC analysis– staining with ninhydrin produces a rich brown to bronze color, in contrast to the typical purples and yellows observed with this stain. The highest yields of the desired benzoxazine were obtained from reactions conducted in toluene with application of a Dean-Stark apparatus to remove water formed during the course of the reaction, or in chloroform where water separates from the reaction solvent. [0427] Based on the superior yield obtained under condition C in the synthesis of 1, similar conditions were applied to the synthesis of protected bis-benzoxazine 8 (Scheme 6) from dopamine-acetonide 7 and bisphenol A. The lower yield obtained here relative to that obtained for 1 is attributed to a competing degradation of the protected dopamine in the presence of formaldehyde under heating. The lower effective equivalents of dopamine present due to this competition leads to formation of monophenolic monobenzoxazine products that are removed in the aqueous workup. Still, 8 was obtained in reasonable purity as a foaming off-white solid after organic-aqueous extraction and filtration through a pad of silica gel.
Figure imgf000149_0001
Scheme 4. Synthesis of protected aminocatechol monobenzoxazine 1. [0428] Table 1. Conditions screened for synthesis of monomer 1.
Figure imgf000150_0003
Figure imgf000150_0002
Figure imgf000150_0001
Scheme 5. Acetonide protected dopamine-derived bis-benzoxazine 8. [0429] With mono- and bis-benzoxazine monomers in hand, a preliminary investigation of thermally accelerated ring-opening polymerization behavior was conducted. Briefly, 1 and 8 were sealed under argon and heated at 160 °C for 4 hours. Upon heating in both cases the monomers became non-viscous liquids, and turned from colorless to yellow within 30 minutes of incubation. In the case of 8 the reaction solution no longer flowed when the vial was tilted after 1.5 hours of heating; heating was continued for a total of 4 hours. The reaction with 1, on the other hand, yielded a viscous liquid after 4 hours of heating. The reaction products were treated with deuterated chloroform. As expected, polymerization of 1 produces soluble linear product 2 (Scheme 2, FIG.2A), whereas the ring-opening
polymerization of 8 produces crosslinked polymer 9, which is not readily dissolved in organic or aqueous solvents (FIG.2B). [0430] 1H-NMR analysis of the soluble product 2 revealed almost complete disappearance of peaks associated with the benzoxazine ring methylene protons (arrows, FIG.3A), with concomitant peak broadening and appearance of a new resonance assigned to the benzylic protons present in the Mannich-bridged 2 (FIG.3B). Similar spectral changes were observed for the polymerization of model monobenzoxazine S1 derived from p-cresol and 2- methoxyethylamine (see Experimental Examples section below). Insolubility of polymer 9 prevented NMR analysis, but is consistent with the expected crosslinking of bis-benzoxazine precursors. Analogously, a model bis-benzoxazine S2 derived from bisphenol A and 2- methoxyethylamine produced insoluble yellow resin upon thermally assisted ring-opening polymerization, again consistent with the formation of a crosslinked polymeric product). It is important to note that the protecting groups remained intact after polymerization of 1 at 160 °C (green arrows, FIGS.3A-3B). Example 2: Dip coating of mussel-inspired polybenzoxazines
[0431] We found that the trifluoroacetate salt of polymer 3, obtained after trifluoroacetic acid-mediated deprotection of oligomer 2 (Scheme 6) easily dissolved in deionized water or DMSO at greater than 25 mg/mL concentration. However, almost immediate precipitation was observed when a 10 mg/mL stock solution was diluted ten-fold in pH 7.0100 mM sodium phosphate buffer. In contrast, dilution into 100 mM sodium acetate, bicine, or bis-tris buffers containing 0-600 mM MgCl2 salt in a pH range of 5.0-9.0 yielded initially homogeneous solutions. It was found that the initially pale-yellow solutions darkened more rapidly in alkaline buffers, consistent with the more rapid oxidation of catechols at elevated pH values (FIG.4A). Inspired by similar behavior in alkaline aqueous solutions of polydopamine, we next investigated the ability of 3 to form nanocoatings on various substrates.
Figure imgf000151_0001
Scheme 6. Acid-mediated deprotection of oligobenzoxazine 2 to yield 3. [0432] Initial dip coating experiments were performed on TiO2-coated silicon wafer substrates. This material was chosen to facilitate characterization of coatings formed by ellipsometry and XPS. Coatings were formed by submersion of TiO2 substrates in 1 mL of 1 mg/mL solutions of 3 in pH 6, 7, 8, and 9 buffers (100 mM bis tris or bicine) containing 600 mM MgCl2. The samples were rotated on an orbital shaker at 200 rpm for 16 hours at room temperature without special precautions to exclude oxygen; the substrates were then washed extensively with water and dried under a stream of nitrogen gas. There were notable differences in appearance of coatings formed at different pH values (FIG.4B). Additionally, the amount of precipitates formed in coating mixtures after incubation increased with increased buffer pH (FIG.4C). [0433] Coatings were characterized by ellipsometry, water contact angle, and XPS, and results are summarized in Table 2. Water contact angles indicated moderately hydrophilic coatings, but resulted in an overall increase in contact angle relative to fully wetting, freshly cleaned TiO2 substrates. Elemental composition (C/N/O) determined by XPS were similar for coatings formed at all pH values, and were comparable to the calculated composition of the free base of polymer 3 (C/N/O of 78.3/13/8.7). However, distinct differences in coating thickness were observed for different pH values. Among the conditions tested, the thickest coatings were obtained at pH 7 (~55 nm), while the thinnest coatings were formed at pH 9 (~9 nm). Comparable thickness was obtained at pH 6 and 8. [0434] Table 2. Summary of characterization data for coatings of 3 on TiO2 substrates.
Figure imgf000152_0001
[0435] The observation of similar coating thickness obtained under conditions where slow (pH 6) and more rapid (pH 8) catechol oxidation (pH 8) are expected to occur implies that there is an interplay between the rate of oxidation and oligomerization of 3 and the thickness of coatings obtained, with the thickest coatings obtained at neutral pH. As pH increases, the relative fraction of nucleophilic deprotonated primary amines increases, leading to an increased likelihood of cross-linking of oxidized catechols (orthoquinone) and primary amines through Schiff base formation and conjugate addition. This process, when occurring in solution, can compete with growth of the coatings, and leads to more rapid formation of precipitates at elevated pH. It is possible that the initial adsorption of 3 to the TiO2 under acidic conditions is mediated by the adaptive synergy between primary ammonium cations and intact catechols.4a,5b-d While survey spectra for these coatings were quite similar, high resolution XPS analysis revealed a progressive increase in the amount of carbonyl-containing species, and decrease in the amount of primary ammonium species in the coatings as pH of the coating buffer was increased (FIG.5). Coatings formed at pH 9 were not included in this comparison, as TiO2 substrate signal was not completely attenuated by this thinner coating. [0436] After preliminary exploration of the polymerization behavior of protected monomers 1 and 8, we sought to investigate the behavior of deprotected catechol-modified monomers. In an attempt to produce a fully deprotected version of monomer 1 (Route B, FIG.1), we encountered a competing Pictet-Spengler side reaction by the activated electron- rich catechol ring adjacent to the benzoxazine 3-methylene unit, leading to the production of isoquinoline 10 (Scheme 7A).6 The transformation occurred within 30 minutes upon treatment of 1 with 50% trifluoroacetic acid in dichloromethane at room temperature. A plausible proposed mechanism for this transformation is depicted in Scheme 7B.1H-NMR analysis revealed a complete disappearance of benzoxazine methylene units and one of the phenyl protons. The appearance of the isoquinoline methylene protons as relatively broad multiplets indicates that the isoquinoline ring flip may be hindered by the formation of a hydrogen bond between the amine and the proximal phenol. Similar hydrogen bonding is present in polybenzoxazine materials and contributes to their increased thermal stability.1a
Figure imgf000153_0001
Figure imgf000154_0001
Schemes 7A-7B. Attempted acid-mediated deprotection of 1 and unexpected byproduct 10 (7A). A proposed acid-catalyzed mechanism for the formation of 10 following protonation. This mechanism can occur before or after removal of the acetonide and Boc protecting groups. [0437] This competing Pictet-Spengler reaction is cause for concern in terms of obtaining a deprotected version of 1 for dip-coating and subsequent polymerization. As suggested in Scheme 7B, deprotection of the acetonide may not be a prerequisite for the formation of the isoquinoline byproduct. Additionally, the use of acid in deprotection reactions catalyzes the ring-opening step of this side reaction (second step, Scheme 7B). For this reason, we explored other monomer designs that are incapable of participating in the Pictet-Spengler reaction, namely through reducing the linker length between the benzoxazine amine and the pendant (protected) catechol. [0438] Initial approaches toward alternative monomer designs utilized a similar acid sensitive protection group strategy, incorporating Boc and acetonide protecting groups for masking amine and catechol groups, respectively (Scheme 8). However, the electron-rich character of the acetonide-protected dihydroxyaniline derivative led to exceedingly low yields in the benzoxazine syntheses, in addition to the formation of side-products resulting from electrophilic aromatic substitution of the aniline ring. The synthetic difficulties encountered using precursor 12 likely stem from the electron-rich character of the phenyl ring. Therefore, we investigated the use of the more electron-withdrawing acetate esters as protecting groups for the catechol. We utilized the trifluoroacetamide protecting group for amines, envisioning a one pot base-mediated deprotection of amino-catechol benzoxazine monomer 13 (Scheme 9).
Figure imgf000155_0001
Scheme 8. Retro-synthesis of alternative monomer utilizing acid sensitive protecting groups.
Figure imgf000155_0002
Scheme 9. Retro-synthesis of acetate and trifluroacetamide protected monomer. [0439] This monomer was prepared by first protecting tyramine with the trifluoroacetamide in nearly quantitative yield by treatment with methyl trifluoroacetate in the presence of trimethylamine to produce 14 (Scheme 10A). The diacetate protected 4-aminocatechol was prepared in two steps from 4-nitrocatechol, in 83% overall yield (Scheme 10B).4- nitrocatechol was first acetylated in the presence of pyridine and acetic anhydride at room temperature to provide 16. The nitro substituent was then reduced by high-pressure catalytic hydrogenation in nearly quantitative yield to provide 15. This material was a solid that was stable to long-term storage outside of a glove box at reduced temperature. This is in contrast to the previously prepared acetonide-protected derivative, which was a viscous oil that slowly darkened after several months of storage at -80 °C in the presence of air.
Figure imgf000156_0001
Schemes 10A-10B. Preparation of precursors for protected monomer 13. [0440] Attempts to prepare the desired benzoxazine 13 by treatment of phenol 14, and amine 15 with paraformaldehyde in toluene were very low yielding. As a result, a range of conditions suitable for benzoxazine synthesis were explored to optimizing the yield of the reaction for scale-up (Table 3). After screening a number of different reaction times, temperatures, and solvents, it was found that acceptable yields approaching 50% were achieved in a few conditions, including at moderate temperature in chloroform. In general, reduced temperatures are desirable to avoid degradation of benzoxazine products by ring- opening reactions, so these conditions (Table 3, G) were selected for larger scale synthesis of 13. [0441] Table 3. Conditions screened in the synthesis of benzoxazine 13.
Figure imgf000157_0001
Figure imgf000157_0003
Figure imgf000157_0002
Figure imgf000157_0004
[0442] Two trial deprotection reaction were carried out with ~250 mg of 13 (FIG.6A). The first condition utilized potassium tert-butoxide to generate potassium methoxide deprotecting agent in situ, while the second utilized a standard 1M solution of sodium methoxide as deprotecting agent. In both cases, the reaction mixtures became very dark colored almost immediately after addition of base (FIG.6B). After 15 minutes, reactions were condensed under vacuum, and two different work-up conditions were tested. In the first case, a mildly acidic aqueous workup was attempted in saturated ammonium chloride solution after addition of chloroform, yielding a pale yellow organic phase, and a large amount of black precipitate that aggregated in the aqueous phase. In an alternative approach, the basic reaction mixture was quenched by addition of three stoichiometric equivalents of methanolic HCl solution (prepared by addition of trimethylsilyl chloride to anhydrous methanol), followed by evaporation to dryness. [0443] The resulting dark-colored material easily dissolved in methanol for 1H-NMR analysis, which revealed that the desired benzoxazine had decomposed and almost complete removal of acetate protecting groups was achieved (FIG.7). The NMR spectrum was somewhat reminiscent of polymerized benzoxazine spectra. In order to directly compare the spectrum of the product obtained in trial deprotections with a similar polybenzoxazine material, monomer 13 was subjected to thermal polymerization by heating at 180 °C for 2 hours under argon.1H-NMR analysis of the resulting material revealed a similar spectrum to the material obtained in trial deprotection reactions with the exception the presence of acetate peaks at 1.5-2.5 ppm, and a shift in the broad resonance at 4-5.5ppm to 3.5-4.5ppm. The presence of several peaks in the acetate region suggest that transfer of acetate groups to pendant phenols present on poly- and oligobenzoxazine products may have occurred. The decomposition of benzoxazine monomer 13 upon deprotection likely stems from the exceptionally facile oxidation of 4-aminocatechol derivatives.7 It is likely that operations performed with this monomer would require the use of a glove-box to prevent oxidation. Example 3: Successful incorporation of deprotected catechols in benzoxazine
monomers: a viable protecting group strategy
[0444] While the base-triggered oligomerization of 13 during deprotection is fundamentally interesting, it prevents our access to well-defined benzoxazine monomers modified with catechol side chains. While it is likely a base-mediated deprotection strategy would be viable with less electron-rich catechols, the rapid oxidation of catechols under basic condition necessitates strictly oxygen free conditions to avoid decomposition of deprotected products. Guided by model reactions, we proceeded to explore an alternative monomer design based on 3,4-dihydroxybenzylamine derivatives and an alternative protecting group strategy utilizing silyl ethers. In comparison to the previously explored aniline derivatives, the benzylamine derivatives are less prone to oxidation after deprotection, and reduction of the linker length between catechol and amine relative to dopamine prevents unwanted cyclization reactions in the deprotected benzoxazine products.3,4-dihydroxybenzylamine is commercially available as a hydrobromide salt, or can be readily prepared from less costly 3,4- dihydroxybenzaldehyde in two steps.8 [0445] A silyl ether-protected benzoxazine was prepared in two steps from 3,4- dihydroxybenzylamine 18 (Scheme 11). We first protected the catechol by treatment with tert-butyldimethylsilyl chloride and excess imidazole in dichloromethane. The reaction proceeded overnight at room temperature to yield the desired bis-TBS-protected precursor 19 in 99% yield after aqueous workup. This amine was reacted with paraformaldehyde in the presence of p-cresol to yield protected benzoxazine 20 in 53% yield without optimization.
Figure imgf000159_0001
Scheme 11. Synthesis of bis-TBS-protected benzoxazine 20. [0446] We next cleaved the silyl ethers by addition of stoichiometric tetrabutylammonium fluoride in tetrahydrofuran (FIG.9). Previous test reactions with a model benzoxazine monomer S1 revealed that benzoxazines are tolerant of these reaction conditions. We observed an almost immediate color change of the reaction from colorless to pale green. TLC analysis of the reaction after 15 minutes revealed complete consumption of the starting material, and the development of a new catechol-containing compound of higher polarity (FIG.9). After aqueous workup, a pale yellow residue was collected and dried thoroughly in vacuum to remove residual volatile silyl fluoride byproducts. [0447] Analysis of the product revealed that the desired benzoxazine monomer 21 was still intact, with key resonances observed in both 1H- and 13C-NMR spectra. We did not observe any isoindoline, indicating that reduction of the linker length between amine and catechol relative to dopamine was effective at preventing unwanted cyclization reactions. It is worth noting that attempts to use a similar approach with benzoxazine monomers derived from bis- TBS-protected dopamine provided intact benzoxazines in the crude reaction prior to workup. However, these compounds degraded upon aqueous workup as indicated by NMR analysis, and the desired catecol-modified benzoxazines were not isolable. [0448] The methodology outlined above extends to the preparation of bis-benzoxazine monomers as well. Combination of 19 with paraformaldehyde and bisphenol A at 70 °C in chloroform for 12 hours yielded a mixture of the desired bis-benzoxazine 22, and mono- benzoxazine mono-phenol 23 in 46% and 45% yield, respectively (Scheme 12).
Figure imgf000160_0002
Scheme 12. Synthesis of protected bis-catechol bis-benzoxazine 22, and byproduct 23 [0449] Silyl ethers were efficiently removed from 22 by treatment with stoichiometric tetrabutylammonium fluoride in THF to provide the deprotected bis-catechol bis-benzoxazine 24 in 90% yield after aqueous workup (Scheme 13).
Figure imgf000160_0001
Scheme 13. Removal of silyl ethers to obtain deprotected bis-catechol bis-benzoxazine 24. [0450] A preliminary investigation of the curing behavior of monomer 24 and other model bis-benzoxazines that do not contain catechols was conducted on model substrates, including stainless steel, glass, and PEEK. Briefly, 100 mM solutions in acetone were drop-cast onto substrates, dried in a fume hood at room temperature for 20 minutes, and cured in a pre- heated oven at 160 °C for 3 hours. Notable differences between catechol-modified monomer 25 and the other monomers tested in this series. While commercial monomers XU 35910 and XU 35610, and model monomer 25 dewetted the surfaces upon heating and curing, 24 formed thin films that did not dewet during curing (FIG.10). Additionally, it was found that 24 produces films that are insoluble in organic or aqueous solvents, implying curing has proceeded at least to the gelation point of this thermoset. On the other hand, cured products from XU 35910 and XU 35610 were soluble in chloroform, indicating incomplete curing and failure to reach the gelation point at 160 °C for 3 hours. [0451] Additionally, a preliminary lap shear adhesion study was performed on copper and aluminum shim stock to compare the performance of 24 with commercial XU 35910 and XU 35610. Curing was performed under conditions known to give fully cured XU 35910 and XU 35610, as well as at reduced temperature for 24. Comparable adhesive strengths were observed for 24 and the commercial benzoxazines (Entries 1-3, FIG.11). However, it is worth noting that the mode of failure observed for 24 is cohesive failure, as compared to adhesive failure observed for XU 35910 and XU 35610. The results obtained in preliminary curing and adhesion studies suggest an adhesive advantage for catechol-modified
benzoxazines, which may be beneficial in applications as thermoset adhesives or the preparation of composites. [0452] We consider our results utilizing 3,4-dihydroxybenzylamine with a silyl ether protecting group strategy to be highly enabling for further work with catechol-modified benzoxazine materials. We expect that amine functional groups may also be incorporated into monomers by utilizing appropriate fluoride-sensitive protecting groups.9 Utilizing silyl ethers as protecting groups in benzoxazine synthesis has not been previously reported, and should be considered non-obvious. In light of the sensitivity of benzoxazines toward nucleophiles, it is worth noting that we found model benzoxazine S1 (see further Examples section for structure), which does not contain a protected catechol, to remain largely intact after room temperature incubation for 24 hours in the presence of a stoichiometric excess of
tetrabutylammonium fluoride (i.e. nucleophilic fluoride source). Therefore, our approach of unmasking silyl ether protected catechols should be generally applicable to a wide variety of monomer configurations, and is not limited to benzoxazines derived from 3,4- dihydroxybenzylamine. Example 4: Main-chain polybenzoxazines with catechol side chains
[0453] With the ability to prepare catechol-modified benzoxazines using a silyl ether protecting group strategy, we turned our attention to the preparation of multifunctional precursors suitable for the preparation of novel small-molecule and polymeric main-chain benzoxazine derivatives with catechol side-chains. For example, a schematic catechol- modified main-chain benzoxazine, and potential bis-phenol mono-catechol precursor are shown in Scheme 13.
Figure imgf000162_0001
Scheme 13A-13B. (13A) Schematic representation of catechol-modified main-chain benzoxazines derived from bis-phenols and diamines, and (13B) Example bis-phenol mono- catechol precursor 26. [0454] While N-substituted iminodiacetic acid derivatives are capable of forming a cyclic anhydride in the presence of peptide coupling agents, this intermediate is easily intercepted by amine nucleophiles to provide monoamide monocarboxylic acid derivatives that are competent intermediates in route to diverse diamide and triamide products by subsequent peptide coupling and protecting group manipulation (Scheme 14).10 We utilized this reactivity to prepare precursor 26 as described below.
Figure imgf000162_0002
Scheme 14. Representative functionalization of N-Boc-diaminoacetic acid to form triamides. [0455] We began by preparing silyl ether protected 3,4-dihydroxyphenylacetic acid, which has not been previously described in literature. We treated 3,4-dihyroxyphenylacetic acid with tert-butyldimethylsilyl chloride and imidazole in dichloromethane. This approach provided 51% yield of the desired bis-TBS ether 27, but also produced the tris-TBS product 28 (Scheme 15). Similar side-reactions have been reported for gallic acid derivatives.11 Selective acid-mediated hydrolysis of the unwanted TBS-ester was achieved by treatment with aqueous acetic acid solution to provide the desired bis-TBS ether in quantitative yield. While 27 and 28 were separated in this example, direct treatment of a crude containing both 27 and 28 also produces 27 in ~90% yield.
Figure imgf000163_0001
Figure imgf000163_0003
Figure imgf000163_0002
Scheme 15. Preparation of protected intermediate 27. [0456] With intermediate 27 in hand, we prepared the bis-phenol fragment taking an approach similar to those described previously.10 We installed the Boc protecting group on the secondary amine of iminodiacetic acid to prepare dicarboxylate 29, which is also commercially available. Consecutive peptide coupling reactions with tyramine were performed in one pot to provide 30 in 76% yield, followed by removal of the Boc protecting group under acidic conditions to yield hydrochloride 31 in 98% yield. The final peptide coupling step directly with 27, mediated by PyBOP and DIPEA in DMF at room temperature, produced protected bisphenol monocatechol 26 in 42% yield. Further optimization of this final coupling reaction employing the acid chloride 33 provided the desired bis-phenol 26 in 74% yield. Reagent 33 was prepared immediately before use in quantitative yield by treatment of 27 with oxalyl chloride in toluene.
Figure imgf000164_0001
Scheme 16. Synthetic route to protected bisphenol monocatechol 26. [0457] Intermediate 26 serves as a useful precursor for the preparation of a range of small molecule catechol-modfied bis-benzoxazine materials, and for the synthesis of main-chain type polybenzoxazines. An example main-chain benzoxazine was prepared by treating 26 with paraformaldehyde in toluene with telechelic polypropylene diamine, Jeffamine-DA-400 (FIG.12).1H-NMR analysis revealed that the desired benzoxazine was formed, and silyl- ether protecting groups remained intact. [0458] In addition to the telechelic polypropylene diamines, direct Mannich condensation of 26 with aliphatic diamines 1,4-diaminobutane, and 1,5-diaminopentane produced main- chain benzoxazine products 34 and 35, respectively (Schemes 17 and 18).
Figure imgf000165_0001
Scheme 17. Main-chain benzoxazine from 26 and 1,4-diaminobutane.
Figure imgf000165_0002
Scheme 18. Main-chain benzoxazine from 26 and 1,5-diaminopentane. [0459] As mentioned above, 26 serves as a versatile precursor suitable for the preparation of both main-chain type and standalone benzoxazine monomers. To demonstrate this, we prepared a soluble protected mono-catechol-bis-benzoxazine 36 by reaction of 26 with aniline and paraformaldehyde in toluene (Scheme 19). The desired protected mono-catechol- bis-benzoxazine was isolated in 60-76% yield (over multiple scales from 600 mg to nearly 5 g of input 26).
Figure imgf000166_0001
Scheme 19. Synthesis of standalone protected mono-catechol-bis-benzoxazine 26. [0460] The silyl ether protecting groups were smoothly removed by treatment with stoichiometric tetrabutylammonium fluoride in chilled tetrahydrofuran. The product was isolated in 96% yield after precipitation in hexanes.
Figure imgf000166_0002
Scheme 20. Cleavage of silyl ethers to provide mono-catechol-bis-benzoxazine 27. [0461] In addition to 37 we have also prepared an additional bis-catechol-bis-benzoxazine monomer that utilizes a custom bisphenol core other than bisphenol A (Schemes 21–21). Briefly, the amido-bisphenol 38 was prepared by reaction of tyramine with the acid chloride derived from treatment of phloretic acid with oxalyle chloride. The coupling product was isolated in 54% yield by precipitation; this reaction is unoptimized, and yields can likely be improved by use of a non-nucleophilic solvent in the coupling step.
Figure imgf000167_0001
Figure imgf000167_0003
Figure imgf000167_0004
Scheme 21. Preparation of amido-bisphenol 38 from tyramine and phloretic acid. [0462] The novel bisphenol was converted to the protected bis-catechol-bis-benzoxazine in 57% yield by reaction with TBS-protected 3,4-dihydroxybenzylamine and paraformaldehyde in chloroform.
Figure imgf000167_0002
Scheme 22. Preparation of protected bis-catechol-bis-benzoxazine 39. [0463] Cleavage of the silyl ethers by treatment with stoichiometric tetrabutylammonium fluoride provided the desired product as a yellow solid in 66% yield after aqueous workup and precipitation in hexanes.
Figure imgf000168_0001
Scheme 23. Deprotection of bis-catechol-bis-benzoxazine 39 to provide 40. [0464] Additional lap shear adhesion studies were performed with various benzoxazines on aluminum 6061 alloy substrates, comparing adhesion strengths to those of two commercial benzoxazines (BPA-aniline, and thiodiphenol-aniline derivatives). These experiments are summarized in the experimental examples section herein. The curing behavior of protected monomer 36 and deprotected monomer 37 were investigated by differential scanning calorimetry. This data is summarized in the experimental examples section herein. Example 5: Synthesis and characterization data
[0465] Supplies and equipment. All chemicals were purchased from commercial sources and used as received, unless otherwise stated. Thin layer chromatography was performed on aluminum-backed silica gel 60 plates containing F254 fluorescent contrast agent, and compounds were visualized under UV lamp, and by iodine, potassium permanganate, or ninhydrin staining, and FeCl3 staining for catechol-containing compounds. Dry solvents were obtained by prolonged storage over activated 4 Å molecular sieves under dry nitrogen or argon gas. Water was purified on a Millipore Synergy-R apparatus. Chromatography was performed on hand-packed silica gel 60 columns, eluting under positive pressure of air or nitrogen. NMR spectra were obtained on a Brüker AVB-400 instrument in deuterated solvents (Cambridge Isotope Laboratories, Inc. and Sigma-Aldrich), and spectra were referenced to the signals of residual protium in the NMR solvent. Spectra were processed in MestReNova 10.0 (Mestrelab Research). Digital images of benzoxazine samples were collected with the built-in camera of an iPhone 6s. Dip-coatings on TiO2 were evaluated by optical ellipsometry on a J.A. Woollam Co. ellipsometer. Water contact angle measurements were collected on a Ramé-Hart Goniometer. XPS analyses were performed on a Phi
Electronics 5600/5800 instrument equipped with a monochromatic Al Ka X-ray source operating at 350 W. The spectra were calibrated to a C1s peak at 284.5 eV and evaluated with a MultiPak software. [0466] General procedure for bulk ring-opening polymerization of benzoxazines. (1
Figure imgf000169_0001
, 8 ^9, 13 ^polymerized 13): Monomer and magnetic stir bar was added to a vial and sealed under argon with a septum; magnetic stir bar was excluded in the case of polymerization of 8. The vial was heated at 160 °C for 4 hours, or 180 °C for 2 hours with stirring before cooling to room temperature. The reaction crude was dissolved in deuterated chloroform or methanol for analysis by 1H-NMR.2 was further purified by dissolution in minimal CH2Cl2, and dropping into ice-chilled stirring hexanes to produce a pale-yellow precipitate that was collected by vacuum filtration (72% yield).1H-NMR spectrum is presented in FIGS.3A-3B. [0467] Immersion coating of polymer 3 on TiO2 Substrate. Coatings were performed on TiO2 (~90nm on silicon wafer). Substrates were prepared for coating by sequential sonic bath treatment in isopropanol, acetone, and MilliQ water, and then treating for 5 minutes in dry air plasma at 100W. Cleaned substrates were submerged in freshly prepared coating mixtures consisting of 1 mg/mL 3 in 0.1M buffer solutions containing 10 vol% DMSO for coating. Buffers at pH 6 and 7 contained 0.1M bis-tris and 600 mM MgCl2; buffers at pH 8 and 9 contained 0.1M bicine and 600 mM MgCl2. Coatings were performed with horizontal substrate orientation in a 24-well plate with agitation at 250 rpm in ambient atmosphere for 16 hours. After the incubation, substrates were washed thoroughly with deionized water, and dried under a stream of nitrogen before characterization by ellipsometry, water contact angle, and XPS. [0468] Bonding of copper and aluminum shim stock substrates for adhesive testing: 100 mM benzoxazine stock solutions in acetone were drop cast onto 1.27 cm x 1 cm areas at the end of copper strips of 1.27 x 6 cm dimensions and allowed to dry in a fume hood for 10 minutes prior to vacuum drying. Coated area was confined/defined using PDMS film tape or electrical tape as a mask. The coated areas were then overlapped and clamped prior to curing in a preheated oven at the indicated temperature and time to produce lap joints. The joints were slowly cooled to room temperature prior to tensile testing at 0.2% strain per minute. The maximum load at failure was divided by the overlap area to calculate adhesion strength, and the failure mode was noted. [0469] tert-butyl (4-hydroxyphenethyl)carbamate, 4: Tyramine (1 g, 7.29 mmols, 1 eq) was dissolved in methanol (15 mL) and a solution of di-tert-butyl dicarbonate (1.67 g, 7.65 mmols, 1.05 eq) in methanol (2 mL) was added dropwise while stirring at room temperature. Carbon dioxide evolution was observed at this point. Potassium carbonate (3.02 g, 21.9 mmols, 3 eq) was added portion-wise over 3 minutes, followed by dropwise addition of deionized water (5 mL) to dissolve the potassium carbonate. The mixture was stirred vigorously at room temperature under argon for 3.5 hours, at which time a large amount of white precipitate is present. The reaction was condensed under vacuum, and the resulting residue was taken up in ethyl acetate (25 mL) and 50% saturated ammonium chloride (25 mL). The organic layer was washed as second time with deionized water, and the combined aqueous layers were back-extracted once with ethyl acetate (25 mL). The combined organic layers were washed with brine (25 mL), and dried over anhydrous sodium sulfate, filtered, and condensed in vacuum to produce an off-white solid (1.64 g, 95% yield). Rf 0.79 (10% MeOH/CH2Cl2).1H NMR (400 MHz, CDCl3) d ppm 7.00 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 6.51 (bs, 1H), 4.64 (bs, 1H), 3.33 (q, J = 6.9 Hz, 2H), 2.70 (t, J = 7.2 Hz, 2H), 1.44 (s, 9H).13C NMR (101 MHz, CDCl3) d 156.38, 154.87, 130.47, 129.93, 115.63, 79.76, 77.16, 42.20, 35.39, 28.55. [0470] N-(3,4-dihydroxyphenethyl)-2,2,2-trifluoroacetamide, 5: Dopamine
hydrochloride (1 g, 5.27 mmols, 1 eq) was suspended in methanol (11.6 mL) at triethylamine was added (3.012 mL, 21.6 mmols, 4.1 eq) to produce a clear solution. The solution was degassed by bubbling argon for 10 minutes, and then methyl trifluoroacetate (1.087 mL, 10.8 mmols, 2.05 eq) was added and the reaction was stirred in the dark under argon for 4 hours. The pale yellow reaction mixture was condensed under vacuum and the residue was taken up in ethyl acetate (25 mL). The organic layer was washed once with 0.1 N HCl (25 mL) and twice with saturated ammonium chloride (25 mL). The combined aqueous layers were back- extracted once with ethyl acetate (25 mL), and the combined organic layers were washed once with brine (20 mL), dried over sodium sulfate, filtered, and condensed in vacuum to produce a pale tan solid (1.28 g, 98% yield). Rf 0.87 (10% MeOH/CH2Cl2).1H NMR (400 MHz, DMSO-d6) d ppm 9.44 (t, J = 5.7 Hz, 1H), 8.71 (bs, 2H), 6.64 (d, J = 7.9 Hz, 1H), 6.58 (d, J = 2.1 Hz, 1H), 6.43 (dd, J = 8.0, 2.1 Hz, 1H), 3.37– 3.23 (m, 2H), 2.60 (t, J = 7.5 Hz, 2H).13C NMR (101 MHz, DMSO) d 156.13 (q, J = 36 Hz, C-CF3), 145.16, 143.75, 129.35, 119.29, 119.29, 116.00 (q, J = 289 Hz, CF3), 116.02, 115.55, 41.07, 39.52, 33.66. [0471] N-(2-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-2,2,2-trifluoroacetamide, 6: Trifluoro-acetamide-protected dopamine 5 (1.66 g, 6.66 mmols, 1 eq) was dissolved in dry benzene (67 mL) and the solution was degassed by bubbling with argon for 20 minutes. At this time, p-toluenesulfonic acid monohydrate (63 mg, 0.33 mmols, 5 mol%) was added, followed by 2,2-dimethoxypropane (3.26 mL, 26.6 mmols, 4 eq). The resulting solution was degassed for an additional 5 minutes with argon, and then topped with a Dean-Stark apparatus and reflux condenser and heated at 90 °C for 2 hours, at which time the starting material was completely consumed, as indicated by TLC. The reaction was brought to room temperature and filtered through a column of silica gel packed in hexanes. The column was eluted with 350 mL of 30% ethyl acetate/hexanes to produce a yellow eluate, which was condensed in vacuum. The residue was taken up in a minimal volume of dichloromethane, and a rougly 10-fold volume of hexanes was added. Almost immediate crystallization was observed, and the mixture was cooled at -20 °C overnight to complete the crystallization. A colorless crystalline solid was collected by filtration, washing with chilled hexanes and drying under high vacuum (1.57 g, 81% yield). Rf 0.68 (30% EtOAc/hexane).1H NMR (400 MHz, Chloroform-d) d ppm 6.67 (d, J = 8.2 Hz, 1H), 6.57 (dq, J = 3.4, 1.8 Hz, 2H), 6.40 (bs, 1H), 3.56 (q, J = 6.7 Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H), 1.67 (s, 6H).13C NMR (101 MHz, CDCl3) d 157.27 (q, J = 37 Hz, C-CF3), 148.06, 146.60, 130.61, 121.14, 118.20, 115.93 (q, J = 288 Hz, CF3), 108.79, 108.47, 77.16, 41.32, 34.83, 25.97. [0472] 2-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethan-1-amine, 7: Trifluoroacetamide- protected dopamine acetonide 6 (298 mg, 1.03 mmols, 1 eq) was dissolved in tetrahydrofuran (5 mL) at room temperature and a 1M solution of LiOH (2.06 mmols, 2 eq) in water (2 mL) was added dropwise with stirring. The resulting biphasic solution was stirred vigorously at room temperature for 2 hours, at which time the starting material was completely consumed, as determined by TLC analysis. The THF was removed under vacuum and the reaction mixture was diluted with saturated sodium bicarbonate (15 mL), and extracted with ethyl acetate (6 mL) 3 times. The combined organic layers were dried over sodium sulfate, filtered, and condensed in vacuum to yield a yellow slightly viscous oil (199 mg, quantitative yield). Rf 0.0 (30% EtOAc/hexanes) and 0.25 (10% MeOH/CH2Cl2).1H NMR (400 MHz,
Chloroform-d) d ppm 6.66-6.59 (m, 3H), 2.92 (t, J = 6.9 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H), 1.91 (br, 2H), 1.67 (s, 6H).13C NMR (CDCl3): 147.6, 145.9, 132.1, 121.1, 117.6, 108.9, 108.0, 42.8, 38.0, 25.8. [0473] tert-butyl-(2-(3-(2-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-3,4-dihydro-2H- benzo[e][1,3] oxazin-6-yl)ethyl)carbamate, protected mussel-inspired monobenzoxazine, 1: Condition A: Dopamine acetonide (199 mg, 1.03 mmols, 1 eq) was dissolved in THF (200 µL) and saturated sodium bicarbonate solution (1 mL). A 37% (w/w) formaldehyde solution (210 µL, 2.58 mmols, 2.5 eq) was added dropwise with stirring at room temperature. Stirring was continued for 10 minutes, at which time Boc-tyramine (244 mg, 1.03 mmols, 1 eq) in THF (800 µL) was added. The mixture was stirred at room temperature for 1 hour, followed by heating in a pre-warmed oil bath at 80 °C for 7 hours with vigorous stirring. During this time, the organic layer became a pale yellow color. The reaction mixture was diluted with 10 mL 3M NaOH solution and 20 mL diethyl ether. The ether layer was washed another 4 times with 3M NaOH until the aqueous washes were colorless, and then washed once with brine. The organic layer was dried over sodium sulfate, filtered, and condensed to a yellow crude, which was further purified by column chromatography in silica gel, eluting with a gradient from hexanes through 20% EtOAc/hexanes to produce a very viscous colorless oil (220 mg, 47% yield). Rf 0.54 (30% EtOAc/hexanes).1H NMR (400 MHz, Chloroform-d) d 6.91 (dd, J = 8.4, 2.2 Hz, 1H), 6.77 (s, 1H), 6.69 (d, J = 8.3 Hz, 1H), 6.63– 6.56 (m, 3H), 4.84 (s, 2H), 4.65 (s, 1H), 3.98 (s, 2H), 3.31 (q, J = 6.8 Hz, 2H), 3.01– 2.87 (m, 2H), 2.83– 2.71 (m, 2H), 2.67 (t, J = 7.1 Hz, 2H), 1.63 (s, 6H), 1.43 (s, 9H).13C NMR (101 MHz, CDCl3) d 155.96, 152.79, 147.46, 145.79, 132.87, 130.98, 128.04, 127.73, 120.86, 120.22, 117.63, 116.49, 108.97, 108.01, 82.39, 79.20, 77.16, 53.42, 50.50, 42.02, 35.49, 34.60, 28.49, 25.88.
Condition B: Dopamine acetonide (192 mg, 0.994 mmols, 1 eq), Boc-tyramine (236 mg, 0.994 mmols, 1 eq), and paraformaldehyde (75 mg, 2.49 mmols, 2.5 eq) were heated in a sealed vial at 110 °C in an oil bath with gentle stirring for 4 hours, at which time the reaction mixture had become a homogeneous bright yellow oil. The reaction crude was taken up in 20 mL diethyl ether and washed with 3M NaOH solution (5x10 mL) and brine (1x10 mL), dried over sodium sulfate, filtered and condensed. The yellow crude residue was further purified by column chromatography on silica gel, eluting with a gradient from hexanes through 20% EtOAc/hexanes to produce a very viscous colorless oil (80 mg, 17% yield). See characterization in Condition A. Condition C: Dopamine acetonide (310 mg, 1.607 mmols, 1 eq), Boc-tyramine (381 mg, 1.607 mmols, 1 eq), and paraformaldehyde (106 mg, 3.54 mmols, 2.2 eq) were suspended in toluene (1.6 mL), sealed under argon with a Dean-Stark apparatus and reflux condenser, and heated at 105 °C with stirring in a pre-warmed oil bath for 5 hours to produce a bright yellow reaction mixture. The crude was diluted with diethyl ether (20 mL), and washed with 3M NaOH (3x10 mL), deionized water (2x10 mL), brine (1x10mL), dried over sodium sulfate, and filtered through a 2 cm plug of silica gel, eluting with diethyl ether. The eluate was condensed to yield a very faintly yellow viscous oil which was further purified by column chromatography on silica gel, eluting with a gradient from hexanes containing 1% triethylamine through 20% EtOAc/hexanes with 1% triethylamine to yield a colorless very viscous oil (463 mg, 63% yield). See characterization in Condition A. Condition D: Dopamine acetonide (530 mg, 2.743 mmols, 1.01 eq), Boc-tyramine (644 mg, 2.715 mmols, 1 eq), and paraformaldehyde (179 mg, 5.975 mmols, 2.2 eq) were placed in a 20 mL scintillation vial with tight-fitting PTFE-lined cap and 5.2 mL of chloroform were added. The mixture was sealed under argon and heated in a pre-warmed oil bath at 80 °C for 6 hours. The crude was diluted with diethyl ether (20 mL), and washed with 3M NaOH (3x10 mL), deionized water (2x10 mL), brine (1x10mL), dried over sodium sulfate, and filtered through a 2 cm plug of silica gel, eluting with diethyl ether. The eluate was condensed to yield a very faintly yellow viscous oil which was further purified by column chromatography on silica gel, eluting with a gradient from hexanes containing 1% triethylamine through 20% EtOAc/hexanes with 1% triethylamine to yield a colorless very viscous oil (730 mg, 60% yield). See characterization in Condition A. [0474] Deprotected mussel-inspired polybenzoxazine, 3: Protected polybenzoxazine 2 (133 mg, 0.29 mmols of repeating unit) was dissolved in dichloromethane (3 mL) and stirred at room temperature. Trifluoroacetic acid (3 mL) was added dropwise over 1 minute, and the resulting clear yellow solution was stirred at room temperature for 3 hours, prior to removal of volatiles under vacuum. The oily residue was further dried under high vacuum overnight to yield a dark yellow solid (TFA salt, 165 mg, quantitative).1H NMR (400 MHz, CD3OD) d 7.35– 6.35 (broad m, 5H), 4.5– 4.1 (broad m, 4H), 3.17– 2.5 (broad m, 8H). [0475] 6,6'-(propane-2,2-diyl)bis(3-(2-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)ethyl)-3,4- dihydro-2H-benzo[e][1,3]oxazine), protected catechol-modified bis-benzoxazine, 8:
Dopamine acetonide (320 mg, 1.655 mmols, 2 eq), bisphenol A (189 mg, 0.828 mmols, 1eq), and paraformaldehyde (109 mg, 3.64 mmols, 4.4 eq) were suspended in toluene (1.2 mL) in a flask topped with a Dean-Stark apparatus and reflux condenser. The suspension was heated at 105 °C under argon with stirring for 2 hours to produce a bright yellow solution. The reaction mixture was diluted with diethyl ether (20 mL) to produce a yellow precipitate and faint yellow supernatant. The precipitate (124 mg) was removed by centrifugation, and the supernatant was washed with 3M NaOH solution (3x10 mL), deionized water (2x10 mL), and brine (1x10 mL), and then dried over sodium sulfate. The organic layer was then filtered through a 2 cm plug of silica gel, eluting with diethyl ether. The eluate was condensed to provide a pale yellow viscous oil that formed an off-white foam after drying in high vacuum (260 mg, 47% yield). Rf 0.51 (30% EtOAc/hexanes).1H NMR (400 MHz, Chloroform-d) d 6.99 (dd, J = 8.5, 2.1 Hz, 2H), 6.86 (d, J = 2.0 Hz, 2H), 6.72 (d, J = 8.5 Hz, 2H), 6.69– 6.60 (m, 6H), 4.89 (s, 4H), 4.02 (s, 4H), 3.06– 2.95 (m, 4H), 2.87– 2.77 (m, 4H), 1.68 (s, 12H), 1.63 (s, 6H).13C NMR (101 MHz, CDCl3) d 152.01, 147.52, 145.85, 143.08, 132.97, 126.38, 125.50, 120.92, 119.38, 117.71, 115.92, 109.03, 108.09, 82.27, 77.15, 53.52, 50.94, 41.83, 34.65, 31.22, 25.96. [0476] 2-(5-(2-aminoethyl)-2-hydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol, deprotection of monomer 1, isoquinoline 10: Fully protected monomer 1 (80 mg, 0.176 mmols) was dissolved in 760 µL dichloromethane. While stirring at room temperature, 760 µL of trifluoroacetic acid was added dropwise. An immediate color change was observed from colorless to yellow to purple. After 10 minutes, thin layer chromatography analysis revealed complete consumption of starting material. The reaction mixture was condensed under vacuum, and the residue was repeatedly dissolved in dichloromethane and condensed to remove residual trifluoroacetic acid. Attempts to precipitate the product in cold diethyl ether produced a sticky solid that was dried under vacuum (56 mg, quantitiative). Rf 0.0 (50% EtOAc/hexanes).1H NMR (400 MHz, Chloroform-d) d 1H NMR (400 MHz, Methanol-d4) d 7.32– 7.20 (m, 2H), 6.95 (d, J = 8.2 Hz, 1H), 6.62 (s, 1H), 6.53 (s, 1H), 4.40 (s, 2H), 4.25 (q, J = 14.2 Hz, 2H), 3.78– 3.63 (m, 1H), 3.42– 3.31 (m, 1H), 3.15 (t, J = 7.7 Hz, 2H), 3.09– 2.95 (m, 2H), 2.90 (t, J = 7.7 Hz, 2H).13C NMR (101 MHz, MeOD) d 157.22, 146.93, 145.99, 134.05, 133.26, 129.34, 122.91, 119.33, 117.40, 117.13, 115.92, 114.03, 55.46, 53.77, 50.74, 49.00, 41.91, 33.50, 25.41. [0477] 2,2-dimethylbenzo[d][1,3]dioxol-5-amine, 12: Pyrocatechol (7.72 grams, 70.1 mmols) was added to a two-necked flask with magnetic stir bar and dissolved in benzene (21 mL) and acetone (21 mL, excess). The flask was topped with a Soxhlet extractor filled with activated 4 Å molecular sieves and 50% acetone in benzene. The reaction solution was deoxygenated by bubbling argon for 20 minutes, followed by addition of p-toluenesulfonic acid monohydrate catalyst (66 mg, 0.5 mol%). The reaction mixture was stirred at reflux for 48 hours, and then brought to room temperature and condensed under vacuum. The resulting residue was triturated with hexanes to produce crystals of unreacted pyrocatechol, which were collected by vacuum filtration. The clear yellow filtrate was condensed again and loaded onto a column of silica gel packing in hexanes (neuralized with 3 vol% triethylamine), and eluted with 300 mL of hexanes. The fractions containing product, as determined by TLC, were collected and condensed in vacuum to produce a very pale yellow oil with a pungent almost piney odor: 2,2-dimethylbenzo[d][1,3]dioxole, pyrocatechol acetonide (3.827 grams, 33% yield). Rf 0.43 (hexanes).1H NMR (400 MHz, Chloroform-d) d 6.86– 6.69 (m, 4H), 1.70 (s, 6H).13C NMR (101 MHz, CDCl3) d 147.43, 121.15, 117.48, 108.60, 77.16, 25.95. [0478] 2,2-dimethylbenzo[d][1,3]dioxole (3.715 grams, 24.74 mmols) was dissolved in 1,2-dichloroethane (5.4 mL) and stirred at 15 °C under air. A solution of 50 vol% aqueous nitric acid (9.15 mL, ~3 eq) was added dropwise while stirring over a period of 10 minutes. The resulting yellow solution was stirred for an additional 20 minutes, then poured into chilled water (50 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (50 mL) and brine (70 mL), dried over anhydrous sodium sulfate, filtered, and condensed in vacuum. The resulting slurry of yellow crystals and orange-colored oil was transferred to a vial and dissolved in minimal tetrahydrofuran (approximately 3 mL). Hexane was added and crystallization began almost instantaneously upon mixing. Yellow crystalline product was collected after storage at -20 °C for 12 hours: 2,2-dimethyl-5-nitrobenzo[d][1,3]dioxole (3.28 grams, 68% yield). Rf 0.54 (10% EtOAc/hexanes).1H NMR (400 MHz, Chloroform-d) d 7.84 (dd, J = 8.6, 2.3 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 1.72 (s, 6H).13C NMR (101 MHz, CDCl3) d 153.09, 147.97, 142.54, 121.35, 119.55, 107.45, 104.41, 77.16, 26.02. [0479] 2,2-dimethyl-5-nitrobenzo[d][1,3]dioxole (1.00 grams, 5.12 mmols) was dissolved in 1,4-dioxane (5.14 mL) and 10 wt% palladium on activated carbon (196 mg, 0.18 mmols, 3.6 mol%) was added. The mixture was placed in a high pressure reactor (SPAN brand), and filled to 600 psi with hydrogen gas. The pressure was vented to 100 psi, and the purge cycle was repeated. The pressure vessel was then filled to 740 psi with hydrogen and allowed to stir at room temperature for 4 hours. During this time, the pressure decreased to approximately 650 psi. The vessel was vented and the reaction mixture was filtered through a plug of celite filter aid (5 grams), washing with copious 1,4-dioxane. The pale yellow filtrate was condensed in vacuum, and azeotroped once with toluene to remove water byproduct. The resulting pale yellow oil is sensitive to oxidation, and turns dark upon standing in air.
Therefore, the product was stored under argon at -80°C: 2,2-dimethylbenzo[d][1,3]dioxol-5- amine (824 mg, 99% yield). Rf 0.49 (CH2Cl2).1H NMR (400 MHz, Chloroform-d) d 6.53 (d, J = 8.2 Hz, 1H), 6.20 (d, J = 2.4 Hz, 1H), 6.08 (dd, J = 8.1, 2.3 Hz, 1H), 3.41 (s, 2H), 1.64 (s, 6H).13C NMR (101 MHz, CDCl3) d 148.04, 140.98, 140.37, 117.39, 108.32, 106.26, 98.02, 77.16, 25.73. [0480] tert-butyl (2-(3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-3,4-dihydro-2H- benzo[e][1,3]oxazin-6-yl)ethyl)carbamate, alternative protected catechol-amine mussel- inspired benzoxazine, 11: Protected aniline 12 (109 mg, 0.659 mmols, 1 eq), N-Boc-tyramine 4 (156 mg, 0.659 mmols, 1 eq), and paraformaldehyde (43.2 mg, 1.45 mmols, 2.2 eq) were suspended in toluene (620 µL) and placed under argon. The resulting mixture was heated and stirred at 105 °C for 2.5 hours to produce a yellow crude. The reaction mixture was diluted with diethyl ether (15 mL) and this solution was washed with 1N sodium hydroxide solution (3 x 10 mL), deionized water (2 x 10 mL), and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and condensed under vacuum before further purification by silica gel column chromatography. The desired compound eluted as in intractable mixture with byproduct, and produced an off-white foaming solid upon drying under high vacuum. Characteristic benzoxazine peaks assigned to the monomer were discernable in 1H-NMR analysis (152 mg crude, ~65% purity). Rf 0.64 (30%
EtOAc/hexanes).1H NMR (400 MHz, Chloroform-d) d 6.93 (dd, J = 8.2, 2.2 Hz, 1H), 6.81 (s, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.61– 6.56 (m, 2H), 6.52 (dd, J = 8.4, 2.3 Hz, 1H), 5.22 (s, 2H), 4.49 (s, 2H), 3.37– 3.27 (m, 2H), 2.68 (t, J = 7.1 Hz, 2H), 1.63 (s, 6H), 1.43 (s, 9H). [0481] 2,2,2-trifluoro-N-(4-hydroxyphenethyl)acetamide, 14: Tyramine (1.00 g, 7.29 mmols, 1 eq) was dissolved in methanol (16 mL), and methyl trifluoroacetate (1.5 mL, 14.9 mmols, 2.05 eq) was added. The mixture was placed under argon atmosphere, and triethylamine (4.1 mL, 29.9 mmols, 4.1 eq) was added by syringe. The resulting solution was stirred at room temperature for 16 hours, and volatiles were removed under reduced pressure. The resulting residue was taken up in ethyl acetate (EtOAc, 30 mL), and the solution was washed with 1N aqueous HCl (2x20 mL), and saturated aqueous ammonium chloride solution (2x20mL). The combined aqueous layers were back-extracted with EtOAc (50 mL), and the combined organic layers were then washed once with saturated aqueous sodium chloride (brine, 1x40 mL), dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure to provide an off-white solid (1.69 g, 99% yield). Rf 0.73 (10% MeOH/CH2Cl2).1H NMR (400 MHz, DMSO-d6) d 9.45 (t, J = 5.8 Hz, 1H), 9.20 (s, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.5 Hz, 2H), 3.35– 3.30 (m, 2H), 2.67 (t, J = 7.4 Hz, 2H). 13C NMR (101 MHz, DMSO) d 156.0 (q, J = 36 Hz), 155.82, 155.57, 129.53, 128.60, 116.0 (q, J = 286 Hz), 115.17, 40.98, 33.34. [0482] 4-nitro-1,2-phenylene diacetate, 16: 4-nitrocatechol (2.510 g, 16.18 mmols, 1 eq) was dissolved in pyridine (6.5 mL, 5 eq) at room temperature, and acetic anhydride (4.6 mL, 48.54 mmols, 3 eq) was added dropwise while stirring. The brown homogeneous mixture was stirred overnight under argon, then diluted into ice cold 0.3N aqueous HCl (75 mL). The aqueous suspension was extracted with diethyl ether (Et2O, 3x30 mL). The combined organic layers were washed with 1N HCl (25 mL), brine (2x25 mL), and dried over anhydrous sodium sulfate. The supernatant was collected by filtration and condensed to yield a pale off- white solid that was further purified by recrystallization in 1:2 EtOAc:hexanes. White solid was collected by vacuum filtration and dried under reduced pressure (3.244 g, 83.8% yield). Rf 0.55 (30% EtOAc/hexanes).1H NMR (400 MHz, Chloroform-d) d 8.15 (dd, J = 8.9, 2.7 Hz, 1H), 8.11 (d, J = 2.6 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 2.33 (2 s, 6H).13C NMR (101 MHz, CDCl3) d 167.64, 167.35, 147.49, 145.52, 142.41, 124.14, 121.97, 119.73, 20.72, 20.60. [0483] 4-amino-1,2-phenylene diacetate, 15: 16 (3.24 g, 13.54 mmols, 1 eq), and 10 wt% palladium on activated carbon (512 mg, 0.481 mmols, 3.55m mol%) were added to a Pall- type high-pressure reactor insert with a magnetic stir bar and suspended in 1,4-dioxane (13.5 mL). The vessel was sealed and placed under H2 atmosphere by three consecutive cycles of pressurization to 700 psi and venting to 100 psi. The vessel was then pressurized to 700 psi, sealed, and stirred at room temperature for 4 hours, at which point the pressure had reduced to ~500 psi. The vessel was vented to atmosphere, and the reaction mixture was passed through a pad of celite filter aid to remove Pd/C catalyst, washing with copious 1,4-dioxane (~70 mL). The filtrate was condensed, and azeotropically dried from toluene to provide an off-white solid (2.833 g, 99% yield). Rf 0.11 (30% EtOAc/hexanes) 1H NMR (400 MHz, Chloroform-d) d 6.92 (d, J = 8.6 Hz, 1H), 6.50 (dd, J = 8.6, 2.7 Hz, 1H), 6.47 (d, J = 2.7 Hz, 1H), 3.69 (s, 2H), 2.25 (d, J = 5.4 Hz, 6H).13C NMR (101 MHz, CDCl3) d 169.12, 168.46, 145.35, 142.60, 133.90, 123.79, 112.93, 109.73, 20.79, 20.71. [0484] 4-(6-(2-(2,2,2-trifluoroacetamido)ethyl)-2H-benzo[e][1,3]oxazin-3(4H)-yl)-1,2- phenylene diacetate, 13, alternative mussel-inspired monobenzoxazine (Table 3, Condition G): 15 (50.04 mg, 0.239 mmols, 1 eq) and paraformaldehyde (14.7 mg, 0.478 mmols, 2.1 eq) were combined in a vial in chloroform (500 µL) at room temperature for 10 mins, followed by addition of 14 (55.7 mg, 0.239 mmol, 1 eq). The mixture was sealed in a vial and heated at 80 °C in a preheated oil bath for 6 hours. The reaction mixture was then diluted with 200 µL triethylamine, and loaded directly onto a pre-packed SiO2 column. The column was eluted with a gradient from hexanes through 50% EtOAc/hexanes to provide a colorless residue that foamed under vacuum to provide a solid (59 mg, 53% yield). Rf 0.62 (50% EtOAc/hexanes) 1H NMR (400 MHz, Chloroform-d) d 7.05 (d, J = 8.8 Hz, 1H), 6.96 (dd, J = 8.9, 2.8 Hz, 1H), 6.89 (dd, J = 11.8, 2.5 Hz, 2H), 6.79– 6.72 (m, 2H), 6.62 (s, 1H), 5.27 (s, 2H), 4.55 (s, 2H), 3.47 (q, J = 6.7 Hz, 2H), 2.72 (t, J = 7.0 Hz, 2H), 2.25 (d, J = 6.6 Hz, 6H).13C NMR (101 MHz, CDCl3) d 168.90, 168.43, 157.28 (q, J = 36 Hz, O=C-CF3), 153.10, 147.17, 142.52, 136.22, 130.24, 128.42, 126.96, 123.82, 120.83, 117.40, 116.48 (q, J = 36 Hz, O=C-CF3), 116.34, 113.30, 79.10, 51.01, 41.27, 34.15, 20.72, 20.68. [0485] Trial base-mediated deprotection of 13: 13 (48 mg, 0.103 mmols, 1 eq) was dissolved in methanol (1.2 mL) in a septum-sealed vial charged with a stir bar. The solution was purged by gentle bubbling with argon for 5 mintues, placed under argon atmosphere, and stirred in an ice water bath. A solution of sodium methoxide (650 µL of 0.48M stock, 0.314 mmols, 3.05 eq) in methanol was added dropwise over 2 minutes, at which time the reation mixture became a deep greenish-black color. Stirring was continued for 10 minutes, followed by addition of 1 mL of a methanolic solution of HCl to quench (prepared by addition of 3.2 eq TMSCl to 1 mL of methanol at room temperature and incubating for 15 minutes). The resulting dark-colored solution was condensed under reduced pressure without exposure to air. The resulting black solid was taken up in deuterated methanol for 1H-NMR analysis. The spectrum is shown in FIGS.6A-6B. [0486] Thermal polymerization of 13: 13 (41 mg, 0.088 mmols, 1 eq) was added to a 2 mL scintillation vial and placed under argon atmosphere. The vial was heated at 180 °C for 2 hours, followed by cooling to room temperature. The resulting dark amber residue was analyzed by 1H-NMR in deuterated methanol; the spectrum is presented in FIG.8. [0487] (3,4-bis((tert-butyldimethylsilyl)oxy)phenyl)methanamine, 19: The
hydrobromide salt of 3,4-dihydroxybenzylamine 18 (815 mg, 3.70 mmols, 1 eq), tert- butyldimethylsilyl chloride (1.228 g, 8.147 mmols, 2.2 eq), and imidazole (756 mg, 11.1 mmols, 3 eq) were combined in a round-bottom flask with stir bar, and dry dichloromethane (14.7 mL) was added. The reaction mixture (suspension) was stirred overnight under argon at room temperature, and a large amount of white precipitate was present, which was removed by vacuum filtration, and the filtrate was condensed under reduced pressure. The crude was partitioned between diethyl ether (40 mL) and aqueous saturated ammonium chloride solution (40 mL). The aqueous phase was extracted twice more with diethyl ether (2x20 mL), and the combined organic phases were washed with water (20 mL), saturated aqueous sodium bicarbonate solution (20 mL), and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and condensed in vacuum to provide a pale yellow oil after drying overnight under high vacuum (1.35 g, 99% yield). Rf 0.49 (10% MeOH/CH2Cl2).1H NMR (400 MHz, Chloroform-d) d 6.86– 6.62 (m, 3H), 3.70 (s, 2H), 1.88 (br s, 2H), 0.97 (app d, J = 3.8 Hz, 18H), 0.18 (app d, J = 3.2 Hz, 12H).13C NMR (101 MHz, CDCl3) d 146.75, 145.69, 136.48, 121.03, 120.11, 119.97, 45.95, 26.00, 18.45, -4.03, -4.05. [0488] 3-(3,4-bis((tert-butyldimethylsilyl)oxy)benzyl)-6-methyl-3,4-dihydro-2H- benzo[e][1,3]-oxazine, 20: Amine 19 (166.12 mg, 0.452 mmols, 1.03 eq) and
paraformaldehyde (29 mg, 0.965 mmols, 2.2 eq) were combined in chloroform (2 mL) in a vial containing a stir bar. After 10 minutes, p-cresol (47.4 mg, 0.439 mmols, 1 eq) was added, and the mixture was purged under argon and sealed. The mixture was heated at 80 °C in a pre-warmed oil bath for 5 hours, then cooled to room temperature. The crude reaction mixture was diluted with diethyl ether (25 mL) and washed with 3N aqueous NaOH solution (3x15 mL), deionized water (2x15 mL), saturated aqueous ammonium chloride (1x15 mL), brine (1x15 mL), and then dried over anhydrous sodium sulfate. The solids were removed by vacuum filtration, and filtrate was condensed. The crude was further purified by column chromatography on silica gel, eluting with a gradient from hexanes through 3%
EtOAc/hexanes, to provide a white solid after drying under vacuum (101.4 mg, 53% yield). Rf 0.74 (10% EtOAc/hexanes).1H NMR (400 MHz, Chloroform-d) d 7.04– 6.61 (m, 6H), 4.85 (s, 2H), 3.93 (s, 2H), 3.81 (s, 2H), 2.27 (s, 3H), 1.02 (app d, J = 1.3 Hz, 18H), 0.23 (app d, J = 2.3 Hz, 12H).13C NMR (101 MHz, CDCl3) d 152.04, 146.77, 146.23, 131.40, 129.83, 128.33, 128.12, 122.13, 122.05, 120.99, 119.84, 116.22, 82.13, 55.10, 49.55, 26.10, 20.73, 18.59, -3.94. Characteristic benzoxazine resonances are 4.85 ppm and 3.93 ppm in the 1H NMR, and 82.13 ppm and 55.10 ppm in the 13C NMR. [0489] 4-((6-methyl-2H-benzo[e][1,3]oxazin-3(4H)-yl)methyl)benzene-1,2-diol, 21: Protected benzoxazine monomer 20 (44 mg, 0.10 mmols, 1 eq) was dissolved in
tetrahydrofuran (1 mL) in a vial containing a magnetic stir bar. The vessel was purged with argon, and the solution stirred at 4 °C while tetrabutylammonium fluoride, TBAF (1M in THF, 200 µL, 0.2 mmols, 2 eq) was added dropwise. The reaction mixture turned from a clear colorless solution to a pale green color over the next 15 minutes. After stirring for 30 minutes, EtOAc was injected (5 mL), followed by 0.1 M pH 7 sodium phosphate buffer (5 mL). The green color disappeared, yielding a pale yellow organic phase, and a colorless aqueous phase. The organic layer was separated and washed again with phosphate buffer (5 mL), and brine (5 mL), and dried over anhydrous sodium sulfate. Solids were removed by filtration, and the filtrate was condensed under reduced pressure to provide a yellow residue that was dried thoroughly in high vacuum to remove residual tert-butyldimethylsilyl fluoride byproduct (21 mg, quantitative). Rf 0.11 (10% MeOH/CH2Cl2).1H NMR (400 MHz,
Chloroform-d) d 6.94 (dd, J = 8.3, 2.1 Hz, 1H), 6.85 (d, J = 1.9 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.74– 6.68 (m, 3H), 6.03 (s, 2H), 4.77 (s, 2H), 3.90 (s, 2H), 3.74 (s, 2H), 2.24 (s, 3H). 13C NMR (101 MHz, CDCl3) d 151.55, 144.10, 143.86, 130.31, 130.00, 128.55, 128.11, 122.08, 119.32, 116.70, 116.27, 115.44, 81.38, 55.06, 49.69, 20.72. Characteristic benzoxazine resonances are 4.77 ppm and 3.90 ppm in the 1H NMR, and 81.38 ppm and 55.06 ppm in the 13C NMR. [0490] 6,6'-(propane-2,2-diyl)bis(3-(3,4-bis((tert-butyldimethylsilyl)oxy)benzyl)-3,4- dihydro-2H-benzo[e][1,3]oxazine), 22: Amine 19 (156 mg, 0.424 mmols, 2.1 eq) and paraformaldehyde (26.7 mg, 0.889 mmols, 4.4 eq) were stirred in chloroform (2 mL) at room temperature for 10 minutes, followed by addition of bisphenol A (46 mg, 0.202 mmols, 1 eq). The mixture was heated to 80 °C while stirring in a sealed vial under argon, and heating was continued for 12 hours, followed by cooling to room temperature. The reaction mixture was then diluted with diethylether (15 mL), and washed with 3N NaOH aqueous solution
(3x10mL), deionized water (2x10 mL), and saturated sodium chloride solution (10 mL) before drying over anhydrous sodium sulfate, filtering, and condensing under vacuum. The crude residue was further purified by column chromatography on silica gel, eluting with a gradient from hexanes through 20% ethyl acetate in hexanes to provide the desired product 22 as a white foam solid (94 mg, 46% yield) Rf 0.37 (10% EtOAc/hexanes), and
monophenol-monobenzoxazine 23 as a white foam solid (56 mg, 45% yield) Rf 0.13 (10% EtOAc/hexanes).1H NMR (400 MHz, Chloroform-d) d 6.98 (dd, J = 8.6, 2.4 Hz, 2H), 6.87– 6.79 (m, 8H), 6.72 (d, J = 8.6 Hz, 2H), 4.84 (s, 4H), 3.94 (s, 4H), 3.81 (s, 4H), 1.61 (s, 6H), 1.00 (dd, J = 3.0, 1.7 Hz, 36H), 0.22 (d, J = 2.6 Hz, 24H).13C NMR (101 MHz, CDCl3) d 152.07, 146.75, 146.23, 143.10, 131.39, 126.40, 125.59, 122.13, 122.09, 121.02, 119.34, 115.93, 82.07, 55.21, 49.92, 41.84, 31.23, 26.11, 26.10, 18.59, -3.90, -3.94. [0491] 4-(2-(3-(3,4-bis((tert-butyldimethylsilyl)oxy)benzyl)-3,4-dihydro-2H- benzo[e][1,3]oxazin-6-yl)propan-2-yl)phenol, 23: (56 mg, 45% yield) Rf 0.13 (10%
EtOAc/hexanes). 1H NMR (400 MHz, Chloroform-d) d 7.13– 7.07 (m, 2H), 6.98 (dd, J = 8.5, 2.5 Hz, 1H), 6.85 (t, J = 1.2 Hz, 1H), 6.80 (d, J = 1.1 Hz, 3H), 6.72 (app dd, J = 8.6, 2.1 Hz, 3H), 4.83 (s, 2H), 3.93 (s, 2H), 3.80 (s, 2H), 1.62 (s, 6H), 1.00 (d, J = 3.3 Hz, 18H), 0.21 (d, J = 4.7 Hz, 12H).13C NMR (101 MHz, CDCl3) d 153.61, 151.95, 146.75, 146.28, 143.31, 143.08, 131.15, 128.02, 126.38, 125.67, 122.26, 122.18, 121.05, 119.22, 115.91, 114.87, 81.88, 55.16, 49.86, 41.81, 31.21, 26.09, 18.58, -3.92, -3.94. [0492] 4,4'-((propane-2,2-diylbis(2H-benzo[e][1,3]oxazine-6,3(4H)- diyl))bis(methylene))bis-(benzene-1,2-diol), 24: Protected bis-benzoxazine 23 (231 mg, 0.228 mmols, 1 eq) was dissolved in tetrahydrofuran (4.5 mL) at 4 °C and sealed under argon while stirring. A 1M solution of tetrabutylammonium in THF (0.912 mL, 4 eq) was added dropwise by syringe to produce an immediate color change to pale yellow-green in the reaction mixture. Stirring at 4 °C was continued for 30 minutes, at which time TLC analysis indicated complete consumption of the starting material. Ethyl acetate (10 mL) was added, followed by 0.1 M sodium phosphate buffer (pH 7, 10 mL). The layers were separated and the organic phase was washed again with sodium phosphate buffer, saturated ammonium chloride solution (2x10 mL), brind (10 mL), and then dried over anhydrous sodium sulfate. The suspension was filtered, and the filtrate was condensed under vacuum, and azeotroped twice from toluene to yield a pale yellow solid mass after drying under high vacuum. The solid was washed once with minimal diethyl ether and dried again under high vacuum to produce a pale yellow solid (113 mg, 90% yield). Rf 0.37 (10% MeOH/CH2Cl2+1% AcOH, streak with positive FeCl3 stain).1H NMR (400 MHz, Methanol-d4) d 6.93 (dd, J = 8.5, 2.4 Hz, 2H), 6.80 (dd, J = 11.4, 2.2 Hz, 4H), 6.70 (d, J = 8.0 Hz, 2H), 6.67– 6.57 (m, 4H), 4.71 (s, 4H), 3.84 (s, 4H), 3.68 (s, 4H), 1.55 (s, 6H).13C NMR (101 MHz, MeOD) d 153.01, 146.26, 145.77, 144.52, 130.42, 127.27, 126.69, 121.88, 120.30, 117.41, 116.60, 116.09, 82.30, 56.02, 50.92, 42.68, 31.50. [0493] 2-(3,4-bis((tert-butyldimethylsilyl)oxy)phenyl)acetic acid, 27: 3,4- dihydroxyphenylacetic acid (1.00 g, 5.95 mmols, 1 eq), tert-butydimethylsilyl choride (2.7 g, 17.92 mmols, 3.01 eq), and imidazole (1.620 g, 23.8 mmols, 4 eq) were combined in dichloromethane (24 mL) at room temperature and stirred for 16 hours. The white solid formed was removed by vacuum filtration, and the filtrate was condensed under reduced pressure. The resulting residue was taken up in diethyl ether (50 mL), and washed with ammonium chloride solution (30 mL), water (30 mL), and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure. The crude was purified by flash chromatography on silica gel, eluting with 4% EtOAc/hexanes, then 50% EtOAc/hexanes. The tris-TBS 28 product eluted in 4% EtOAc/hexanes was retained (1.117 g, 37% yield), while the desired bis-TBS product was collected in the 50% EtOAc/hexanes fraction as pale yellow oil (1.21 g, 51% yield).28 was dissolved in THF (20 mL), and 1:3 acetic acid:water (40 mL) was added, and the resulting mixture was stirred overnight, then condensed in vacuo, taken up in hexanes, and purified by flash chromatography on silica gel, eluting in 50% EtOAc:Hexanes (866 mg, quant., 88% overall combined yield). 1H NMR (400 MHz, Chloroform-d) d 7.98 (br s, 1H), 6.78 (d, J = 2.2 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.71 (dd, J = 8.1, 2.2 Hz, 1H), 3.51 (s, 2H), 0.99 (s, 18H), 0.19 (app d, J = 1.2 Hz, 12H). 13C NMR (101 MHz, CDCl3) d 177.92, 146.88, 146.28, 126.42, 122.41, 122.36, 121.04, 40.58, 26.07, 18.56, -3.98, -3.99. [0494] tert-butyldimethylsilyl 2-(3,4-bis((tert-butyldimethylsilyl)oxy)phenyl)acetate, 28: Rf 0.93 (10% MeOH/CH2Cl2).1H NMR (400 MHz, Chloroform-d) d 6.76 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 2.1 Hz, 1H), 6.70 (dd, J = 8.0, 2.2 Hz, 1H), 3.47 (s, 2H), 0.98 (app d, J = 3.0 Hz, 18H), 0.84 (s, 9H), 0.22 (s, 6H), 0.18 (app d, J = 1.4 Hz, 12H).13C NMR (101 MHz, CDCl3) d 172.25, 146.74, 145.93, 127.89, 122.47, 122.32, 121.13, 42.86, 26.11, 26.08, 25.59, 18.61, 18.55, 17.72, -3.98, -4.78. [0495] tert-butyl bis(2-((4-hydroxyphenethyl)amino)-2-oxoethyl)carbamate, 30: Boc- iminodiacetic acid (942 mg, 4.04 mmols, 1 eq) and EDC-HCl (798 mg, 4.16 mmols, 1.03 eq) were combined in dry DMF (40 mL) and stirred at room temperature under argon atmosphere for 1 hour, followed by addition of tyramine (554 mg, 4.04 mmols, 1 eq) in one portion. Stirring was continued overnight, and then the reaction mixture was poured into 150 mL 1N HCl and extracted with 50 mL ethyl acetate, followed by 5x20 mL of ethyl acetate. The combined organic phases were washed with 1N HCl (2x20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and condensed in vacuum to provide crude intermediate (1.22 g with ~30 mol% DMF, 3.46 mmols). The crude was carried on to the next coupling without further purification. [0496] In the second step, crude product from above was dissolved in dry DMF (50 mL), and tyramine (474 mg, 3.46 mmols, 1 eq) was added, followed by diisopropylethylamine (1.2 mL, 6.92 mmols, 2 eq) while stirring. PyBOP (1.80 g, 3.46 mmols, 1 eq) was then added, and stirring under argon was continued at room temperature for 12 hours, at which time the reaction mixture was poured into 200 mL of 10% HCl. The resulting solution was extracted with ethyl acetate (2x75 mL), and the organic layers were washed with 10% HCl solution (2x50 mL), 50% saturated sodium bicarbonate (50 mL), saturated ammonium chloride solution (50 mL), brine (2x50 mL), and the dried over anhydrous sodium sulfate. The dried extract was filtered, and condensed under reduced pressure to provide 820 mg of an off-white solid (820 mg, 50% yield). Rf 0.35 (10% MeOH/CH2Cl2+0.5% AcOH).1H NMR (400 MHz, DMSO-d6) d 9.17 (s, 2H), 8.71 (t, J = 5.5 Hz, 1H), 8.62 (t, J = 5.6 Hz, 1H), 7.00 (dd, J = 8.5, 3.1 Hz, 4H), 6.72– 6.61 (m, 4H), 3.78 (d, J = 11.2 Hz, 4H), 3.30– 3.19 (m, 4H), 2.60 (td, J = 9.0, 6.7 Hz, 4H), 1.33 (s, 9H).13C NMR (101 MHz, MeOD) d 172.50, 172.17, 156.91, 156.83, 156.67, 131.17, 131.01, 130.76, 130.66, 116.24, 116.18, 82.41, 53.99, 53.63, 42.37, 35.67, 35.52, 28.45. [0497] 2,2'-azanediylbis(N-(4-hydroxyphenethyl)acetamide) hydrochloride, 31: 30 (820 mg, 1.74 mmols, 1 eq) was suspended in 1,4-dioxane (4.5 mL) and 4N hydrochloric acid solution in 1,4-dioxane (4.35 mL, 17.4 mL, ~10 eq) was added at room temperature. The mixture was stirred vigorously at room temperature for 2 hours, and then condensed under reduced pressure to produce a pale tan oil. Addition of toluene (3 mL) and repeated drying in vacuum provided an off-white solid product (695 mg, 98% yield). Rf 0.01 (10%
MeOH/CH2Cl2+0.5% AcOH).1H NMR (400 MHz, DMSO-d6) d 9.28 (s, 2H), 9.09 (s, 2H), 8.55 (t, J = 5.6 Hz, 2H), 7.12– 6.94 (m, 4H), 6.78– 6.62 (m, 4H), 3.70 (s, 4H), 3.28 (q, J = 6.9 Hz 4H), 2.61 (t, J = 7.3 Hz, 4H). [0498] 2-(3,4-bis((tert-butyldimethylsilyl)oxy)phenyl)-N,N-bis(2-((4- hydroxyphenethyl)amino)-2-oxoethyl)acetamide, 26: 31 (450 mg, 1.103 mmols, 1 eq), 27 (438 mg, 1.103 mmols, 1 eq), and PyBOP (574 mg, 1.103 mmols, 1 eq) were dissolved in dry DMF (16 mL) with stirring, followed by addition of diisopropylethylamine (577 µL, 3.309 mmols, 3 eq) by syringe under argon atmosphere at room temperature. Stirring was continued overnight, at which time the reaction was poured into 60 mL of 4% HCl (aq) and extracted with ethyl acetate (3x35mL). The organic layers were washed with 10% HCl (2x20 mL), saturated sodium bicarbonate solution (2x35 mL), saturated ammonium chloride solution (35 mL), and brine (35 mL). The organic extract was then dried over sodium sulfate, filtered, and condensed in vacuum. The crude product was further purified by column chromatography on silica gel, eluting with a gradient from dichloromethane through 10% methanol in
dichloromethane to produce a white solid foam after drying under high vacuum (352 mg, 42% yield). Rf 0.41 (10% MeOH/CH2Cl2+0.5% AcOH).1H NMR (400 MHz, Chloroform-d) d 6.96 (app ddd, J = 8.3, 5.9, 3.4 Hz, 4H), 6.74– 6.62 (m, 6H), 6.54 (dd, J = 8.2, 2.2 Hz, 1H), 3.76 (d, J = 56.1 Hz, 4H), 3.47– 3.29 (m, 6H), 2.68 (dt, J = 20.9, 7.2 Hz, 4H), 0.93 (d, J = 1.9 Hz, 18H), 0.13 (d, J = 1.6 Hz, 12H).13C NMR (101 MHz, CDCl3) d 173.29, 169.55, 169.01, 155.25, 155.17, 146.99, 146.13, 129.83, 126.40, 121.82, 121.55, 121.16, 115.46, 115.37, 54.39, 53.41, 41.30, 41.10, 40.98, 39.64, 34.44, 34.20, 25.93, 18.44, -4.11. [0499] Main-chain benzoxazines with protected catechol side-chain, 32: 26 (104 mg, 0.1386 mmols, 1 eq), Jeffamine-DA-400 (57.17 µL, 0.1386 mmols, 1 eq), and
paraformaldehyde (17 mg, 0.5504 mmols, 4 eq) were combined in a round bottom flask with 550 µL of toluene and topped with a reflux condenser and argon balloon. The mixture was heated at 90 °C for 8 hours, followed by cooling to room temperature, and condensing under reduced pressure. The crude was further dried under high vacuum overnight to provide crude 32 in quantitative yield. Analysis of the material was performed by 1H-NMR, and the spectrum is presented in FIG.12. 1H NMR (400 MHz, Chloroform-d) d 9.16 (broad s, 1H), 7.10– 6.61 (broad m, 9H), 6.56 (broad s, 1H), 4.93 (broad s, ~3H), 4.05 (broad s, ~3H), 3.97 (broad s, 2H), 3.82 (broad s, 2H), 3.69– 3.34 (broad m, 23H), 3.25– 3.07 (broad m, 2H), 2.88– 2.66 (broad m, 4H), 1.25– 1.10 (broad m, 18H), 0.99 (s, 18H), 0.21 (s, 6H), 0.20 (s, 6H). [0500] 26–1,4-diaminobutane main-chain benzoxazine, 34: 26 (202 mg, 0.2693 mmols, 1 eq), 99% 1,4-diaminobutane (23.97 mg, 0.2693 mmols, 1 eq), and 95% paraformaldehyde (33.3 mg, 1.077 mmols, 4 eq) were combined in 2:1 toluene:ethanol (1 mL) and heated at 80 °C under argon atmosphere and reflux condenser for 8 hours, then cooled to room
temperature and condensed under vacuum to produce a pale yellow solid foam (248 mg crude, quantitative).1H NMR (400 MHz, Chloroform-d) d 9.14 (broad s, 1H), 7.11– 6.55 (broad m, 9H), 6.54– 6.37 (broad m, 1H), 4.89– 4.67 (m, ~3H), 3.98– 3.85 (m, 5H), 3.84– 3.74 (m, 2H), 3.53– 3.38 (broad m, 6H), 2.82– 2.56 (broad m, 8H), 1.66– 1.44 (m, 4H), 0.95 (s, 18H), 0.17 (s, 6H), 0.16 (s, 6H). [0501] 26–1,5-diaminopentane main-chain benzoxazine, 35: 26 (203 mg, 0.2711 mmols, 1 eq), 98% 1,5-diaminopentane (27.70 mg, 0.2711 mmols, 1 eq), and 95% paraformaldehyde (33.6 mg, 1.08 mmols, 4 eq) were combined in 2:1 toluene:ethanol (1 mL) and heated at 80 °C under argon atmosphere and reflux condenser for 8 hours, then cooled to room
temperature and condensed under vacuum to produce a pale yellow solid foam (260 mg crude, quantitative).1H NMR (400 MHz, Chloroform-d) d 9.12 (broad s, 1H), 7.05– 6.55 (broad m, 9H), 6.51– 6.31 (m, 1H), 4.89– 4.68 (m, 3H), 4.06– 3.85 (m, 5H), 3.83– 3.72 (m, 2H), 3.52– 3.35 (m, 6H), 2.89– 2.52 (m, 8H), 1.74– 1.40 (m, 4H), 1.33 (s, 2H), 0.95 (s, 18H), 0.16 (s, 6H), 0.16 (s, 6H).
Figure imgf000185_0001
[0502] 2-(3,4-bis((tert-butyldimethylsilyl)oxy)phenyl)-N,N-bis(2-oxo-2-((2-(3-phenyl-3,4- dihydro-2H-benzo[e][1,3]oxazin-6-yl)ethyl)amino)ethyl)acetamide, protected mono- catechol-bis-benzoxazine 36: 26 (4.804 g, 6.404 mmols, 1 eq), aniline (1.223 g, 13.129 mmols, 2.05 eq), and 97% paraformaldehyde (872 mg, 28.178 mmols, 4.4 eq) were combined in a 50 mL round bottom flask equipped with a stir bar. Toluene (16 mL) was added, and the flask was placed under a reflux condenser and balloon filled with argon. The reaction was heated at 100 °C for 24 hours, and then cooled to room temperature and condensed under reduced pressure. The crude was purified by column chromatography on silica gel, eluting with a gradient of dichloromethane through 20 vol% acetone in dichloromethane to provide the desired product as a white solid foam after drying under reduced pressure (3.921 g, 62% yield). Rf 0.37 (20% acetone/CH2Cl2).1H NMR (400 MHz, Chloroform-d) d 8.98 (t, J = 5.5 Hz, 1H), 7.29– 7.18 (m, 3H), 7.13– 7.04 (m, 3H), 6.98– 6.83 (m, 6H), 6.77– 6.65 (m, 4H), 6.59 (dd, J = 8.2, 2.3 Hz, 1H), 5.82 (t, J = 5.8 Hz, 1H), 5.34 (s, 2H), 5.30 (s, 2H), 4.62 (s, 2H), 4.58 (s, 2H), 3.87 (s, 2H), 3.63 (s, 2H), 3.52– 3.40 (m, 4H), 3.40 (s, 2H), 2.73 (dt, J = 22.2, 7.2 Hz, 4H), 0.97 (s, 17H), 0.17 (d, J = 3.8 Hz, 12H).13C NMR (101 MHz, CDCl3) d 172.53, 169.45, 168.57, 153.13, 152.90, 148.46, 148.44, 147.01, 146.13, 131.30, 130.88, 129.38, 129.35, 128.31, 127.18, 127.05, 126.59, 121.86, 121.60, 121.47, 121.43, 121.16, 121.13, 120.78, 118.24, 118.19, 117.14, 116.92, 79.40, 79.36, 54.92, 53.96, 50.60, 50.58, 41.18, 40.94, 39.76, 34.63, 34.50, 26.05, 26.02, 18.51, -3.95, -3.99.
Figure imgf000186_0001
[0503] 2-(3,4-dihydroxyphenyl)-N,N-bis(2-oxo-2-((2-(3-phenyl-3,4-dihydro-2H- benzo[e][1,3]oxazin-6-yl)ethyl)amino)ethyl)acetamide, mono-catechol-bis-benzoxazine, 37: 36 (2.981 g, 3.028 mmols, 1 eq) was dissolved in tetrahydrofuran (15.2 mL) while cooling in an ice bath and stirred under argon atmosphere. Tetrabutylammonium fluoride solution (1M, 6.208 mL, 6.208 mmols, 2.05 eq) was added dropwise over 5 minutes to produce a yellow solution. After 40 minutes, ethyl acetate (50 mL) and pH 70.1M sodium phosphate solution (50 mL) were injected, and the mixture was transferred to a separatory funnel. The phases were separated, and the aqueous phase was extracted once more with ethyl acetate (35 mL). The combined organic extracts were washed with sodium phosphate buffer (pH 7, 40 mL), and saturated sodium chloride solution (40 mL), then dried over anhydrous sodium sulfate, filtered and condensed under reduced pressure. The residue was taken up in dichloromethane (5 mL) and dropped into stirring hexanes (150 mL), and the resulting pale-yellow precipitate was collected by vacuum filtration. The precipitation was repeated twice more before drying the precipitate under high vacuum at room temperature. (2.2 g, 96% yield). Rf 0.44 (10% methanol/CH2Cl2).1H NMR (400 MHz, DMSO-d6) d 8.87 (t, J = 5.6 Hz, 1H), 8.82 (s, 1H), 8.75 (s, 1H), 8.33 (t, J = 5.6 Hz, 1H), 7.27– 7.16 (m, 4H), 7.10 (t, J = 7.4 Hz, 4H), 6.94 (d, J = 6.4 Hz, 4H), 6.84 (t, J = 7.3 Hz, 2H), 6.73– 6.54 (m, 4H), 6.45– 6.34 (m, 1H), 5.38 (d, J = 11.9 Hz, 4H), 4.59 (d, J = 14.7 Hz, 4H), 4.01 (s, 2H), 3.86 (s, 2H), 3.35 (s, 2H), 3.29– 3.18 (m, 4H), 2.71– 2.54 (m, 4H).13C NMR (101 MHz, CDCl3) d 173.65, 170.06, 169.62, 152.84, 148.20, 144.61, 143.83, 127.00, 125.48, 121.33, 120.92, 118.00, 116.85, 116.25, 115.74, 79.30, 54.07, 50.15, 41.28, 39.45, 34.47.
Figure imgf000187_0001
Figure imgf000187_0002
Figure imgf000187_0003
[0504] N-(4-hydroxyphenethyl)-3-(4-hydroxyphenyl)propanamide, 38: Phloretic acid (1 g, 6.02 mmols, 1 eq) was suspended in dry dichloromethane (13 mL) containing 1 drop of dry N,N-dimethylformamide as catalyst at room temperature under an argon atmosphere. Oxalyl chloride (1.290 mL, 15.0 mmols, 2.5 eq) was added slowly by syringe while stirring. Stirring was continued for 2 hours at room temperature, and then condensed under reduced pressure. The residue was taken up in dichloromethane (5 mL) and added dropwise by syringe to a chilled (-10 °C) suspension of tyramine (748 mg, 5.455 mmols, 0.9 eq) and potassium carbonate (754 mg, 13.63 mmols, 2.5 eq) in methanol. The resulting suspension was stirred vigorously and allowed to reach room temperature overnight. The mixture was then poured into 75 mL of 0.3N HCl (aq) to produce an off-white precipitate, which was isolated by vacuum filtration and dried under reduced pressure. (835 mg, 54% yield). Rf 0.43 (10% methanol/CH2Cl2).1H NMR (400 MHz, DMSO-d6) d 9.17 (d, J = 9.7 Hz, 2H), 7.84 (t, J = 5.7 Hz, 1H), 6.95 (dd, J = 11.4, 8.1 Hz, 4H), 6.66 (dd, J = 8.3, 3.5 Hz, 4H), 3.17 (q, J = 6.9 Hz, 2H), 2.68 (t, J = 7.8 Hz, 2H), 2.54 (t, J = 7.5 Hz, 2H), 2.28 (t, J = 7.8 Hz, 2H).13C NMR (101 MHz, DMSO) d 171.38, 155.63, 155.46, 131.45, 129.59, 129.51, 129.09, 115.11, 115.05, 40.60, 37.59, 34.48, 30.42.
Figure imgf000188_0001
[0505] 3-(3-(3,4-bis((tert-butyldimethylsilyl)oxy)benzyl)-3,4-dihydro-2H- benzo[e][1,3]oxazin-6-yl)-N-(2-(3-(3,4-bis((tert-butyldimethylsilyl)oxy)benzyl)-3,4- dihydro-2H-benzo[e][1,3]oxazin-6-yl)ethyl)propanamide, 39: 38 (320 mg, 1.1215 mmols, 1 eq), 19 (845 mg, 2.2990 mmols, 2.05 eq), and 97% paraformaldehyde (145.8 mg, 4.71 mmols, 4.2 eq), and dichloromethane (5 mL) were combined in a 15 mL pressure vessel fitted with a teflon threaded stopper and a magnetic stir bar. The mixture was heated at 85 °C for 16 hours, then cooled to room temperature and condensed under reduced pressure. The crude residue was purified by column chromatography on silica gel, eluting with a gradient from hexanes through 30% acetone in hexanes to provide a white foaming solid after drying under high vacuum. (684 mg, 57% yield). Rf 0.29 (20% acetone/hexanes).1H NMR (400 MHz, Chloroform-d) d 6.94 (dd, J = 8.4, 2.2 Hz, 1H), 6.88– 6.70 (m, 10H), 6.68 (d, J = 2.1 Hz, 1H), 5.38 (t, J = 5.8 Hz, 1H), 4.81 (d, J = 4.8 Hz, 4H), 3.91 (d, J = 2.1 Hz, 4H), 3.76 (d, J = 5.0 Hz, 4H), 3.43 (q, J = 6.7 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 2.64 (t, J = 6.8 Hz, 2H), 2.38 (t, J = 7.6 Hz, 2H), 0.99– 0.95 (m, 36H), 0.24– 0.13 (m, 24H).13C NMR (101 MHz, CDCl3) d 172.10, 152.88, 152.64, 146.71, 132.86, 131.12, 130.76, 129.63, 127.92, 127.88, 127.82, 127.77, 127.53, 122.59, 122.00, 121.90, 120.87, 120.29, 120.07, 116.45, 81.94, 55.04, 49.59, 40.80, 38.84, 35.05, 31.01, 25.99, 25.96, 18.49, -4.04.
Figure imgf000189_0001
[0506] 3-(3-(3,4-dihydroxybenzyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-N-(2-(3- (3,4-dihydroxybenzyl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)ethyl)propanamide, 40: 39 (144 mg, 0.1347 mmols, 1 eq) was dissolved in tetrahydrofuran (2.7 mL) and chilled on ice while stirring under argon atmosphere. Tetrabutylammonium fluoride solution (1M, 0.5389 mL, 0.5389 mmols, 4 eq) was added dropwise over 5 minutes while stirring to produce a yellow solution. After 40 minutes, ethyl acetate (20 mL) and pH 70.1M sodium phosphate buffer (20 mL) were injected, and the organic phase was separated. The aqueous phase was extracted once more with ethyl actetate (20 mL), and the combined organic extracts were washed with sodium phosphate buffer (2 x 20 mL), and saturated aqueous sodium chloride solution (2 x 20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure to provide a yellow residue. This was triturated with toluene (20 mL) to produce a yellow solid, which was collected by vacuum filtration, washed with additional toluene, and dried under vacuum. (55 mg, 66% yield). Rf 0.00 (20% acetone/hexanes).1H NMR (400 MHz, Methanol-d4) d 6.97–6.81 (m, 2H), 6.81– 6.51 (m, 10H), 4.73 (d, J = 3.8 Hz, 4H), 3.84 (s, 4H), 3.66 (d, J = 5.5 Hz, 4H), 3.29 (t, J = 5.9 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.57 (t, J = 7.1 Hz, 2H), 2.38 (t, J = 7.6 Hz, 2H). Example 6: Lap shear adhesion of various benzoxazines on aluminum 6061
[0507] Lap shear adhesion strengths for various cured benzoxazines were measured on aluminum 6061. Single lap joint samples were prepared as follows: 1) Aluminum 6061 substrates with dimensions (1 cm x 10 cm x 0.16 cm). are freshly degreased and cleaned with ethyl acetate and acetone and dried under nitrogen. 2) Drop cast 100 mM benzoxazine solutions/suspensions from acetone (containing ~0.5-1 w/v% suspended 0.001” glass beads for bond line control) onto a 1 x 1 cm region at end of an aluminum 6061 strip (1 x 10 x 0.16 cm). 3) Air dry samples at room temperature in a fume hood for 5-10 mins, then dry in a high vacuum desiccator at room temperature for 20-30 minutes.4) Overlap benzoxazine- coated ends in antiparallel fashion and clamp with small binder clips (2 per lap joint) and transfer to an air oven for a curing program consisting of 1 hour at 100 °C, a 1 hour ramp to 205 °C, and a 3 hour hold at 205 °C. The samples are then allowed to cool slowly overnight in the oven.5) Remove binder clips, and remove excess benzoxazine from edges of sample with a razor prior to lap shear adhesive strength measurement in an Instron mechanical tester at 0.5% strain/min. Shear adhesive strength in Pascals is calculated as the maxium load (N) divided by the lap joint are (m2). [0508] Lap shear adhesive strength values for six benzoxazine monomers are shown in FIG.14. Error bars represent the standard deviation in the measured adhesive strength for a group of 3 samples. Overall, mussel-inspired benzoxazine monomers 24, 40, 37, and protected monomer 36 exhibited superior adhesion compared to the commercial BPA-aniline monomer. Monomers 37 and 36 provided significantly stronger adhesion compared to both commercial benzoxazines and bis-catechol-bis-benzoxazines 24 and 40. Structures of benzoxazine monomers tested and photographs of failed lap joints are shown in FIG.15. [0509] The ability of phenolic additives to lower benzoxazine curing temperature and accelerate curing is known. It can be expected that monomers bearing a pendant catechol functional group would also exhibit accelerated curing occurring at a lower temperature than monomers without the catechol. The role of the catechol in lowering the curing temperature of mussel-inspired benzoxazine monomers was assessed by differential scanning calorimetry for monomers 37 and 36. Two dynamic heating and cooling cycles ranging from -10 °C to 290 °C under nitrogen gas at a rate of 10 °C/min were performed to investigate the curing (1st heating), and the glass transition temperature for the cured thermoset (2nd cycle). The reduction in curing temperature in the presence of deprotected catechol is clearly visible comparing Figures 35 and 36. The shift of the curing exotherm onset and maximum to <200 °C for the free catechol 37 compared to ~230 °C (onset) and 267 °C (maximum) for the protected monomer 36. Monomer 37 does not exhibit a sharp melting behavior in the first heating cycle. A clear glass transition for cured 37 is observed at ~205 °C in the first cooling and second heating cycles, and shifts to a slightly higher temperature in the second cooling cycle (possibly indicating formation of additional crosslinks during the second heating cycle. In the thermogram of the protected monomer 36, a sharp melting is observed with minimum at 58 °C. A weak apparent glass transition is observed at ~104 °C in the second heating cycle in the temperature range examined. [0510] Derivatives related to compound 37 were prepared, in addition to an alternative example of a mono-catechol-bis-phenol core scaffold derived from dopamine and commercially available diphenolic acid. These examples and details on their preparation are outlined below.
Figure imgf000191_0001
Schemes 24A-24B. Preparation of alternative phenylacetic acid derivatives bearing methoxy ethers.
Figure imgf000192_0001
Scheme 25. Synthesis of 45, a 3,4-dimethoxyphenylacetic acid derivative of 37.
Figure imgf000192_0003
Figure imgf000192_0002
Scheme 26. Synthesis of 48, a 3-methoxy-4-hydroxy-phenylacetic acid derivative of 37.
Figure imgf000193_0001
Scheme 27. Synthesis of diphenolic acid derivatives 50–52. Similar to 26, compound 50 can served as a versatile precursor for the synthesis of standalone or main-chain benzoxazine derivatives. Compound 52 represents an alternative approach to standalone benzoxazines with varying side-chain functionalities, such as a catechol.
Figure imgf000193_0002
Scheme 28. Compound 50 was applied in the synthesis of main-chain benzoxazine derivatives (53), notably with deprotected catechol side-chains (54) and intact benzoxazine moieties. [0511] 2-(3,4-dimethoxyphenyl)acetyl chloride, 41: 3,4-dimethoxyphenylacetic acid (417 mg, 2.128 mmols, 1 eq) was suspended in dry toluene (5 mL) containing dry N,N- dimethylformamide (10 µL). The mixture was placed under argon atmosphere and oxalyl chloride (459 µL, 5.32 mmols, 2.5 eq) was added drop-wise by syringe over 1.5 minutes. The mixture was stirred for 1.5 hours, followed by removal of volatile materials under reduced pressure to yield a yellow liquid which was used without further purification or processing (457 mg, quantitative yield).1H NMR (400 MHz, Chloroform-d) d 6.86 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.2, 1.9 Hz, 1H), 6.76 (d, J = 1.9 Hz, 1H), 4.08 (s, 2H), 3.88 (overlapping s, 6H).13C NMR (101 MHz, CDCl3) d 172.33, 149.31, 149.08, 123.67, 122.10, 112.51, 111.44, 56.07, 56.03, 52.83. [0512] 2-(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)acetic acid, 42:
Homovanillic acid (700 mg, 4.167 mmols, 1 eq), tert-butyldimethylsilyl chloride (1.570 g, 10.419 mmols, 2.5 eq), and imidazole (993 mg, 14.585 mmols, 3.5 eq) were combined in dry dichloromethane (16 mL) at 4 °C under argon for 10 minutes, followed by continued stirring at room temperature for 16 hours. A white precipitate was removed by filtration, and the filtrate was condensed. The residue was dissolved in diethyl ether (50 mL), and washed with 0.5 M citric acid solution (25 mL), saturated aqueous ammonium chloride solution (2x25 mL), and saturated aqueous sodium chloride solution (25 mL) before drying over anhydrous sodium sulfate, filtering, and condensing under reduced pressure. The residue (bis-TBS intermediate) was dissolved in tetrahydrofuran (10 mL), water (10 mL), and glacial acetic acid (3.5 mL) and stirred vigorously for 4 hours before diluting into ice-chilled water (50 mL), and extracting with ethyl acetate (3x25 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (3x25 mL), dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure to yield a pale yellow oil, which was dried under high vacuum further to provide a white solid (1.122 g, 91% yield). Rf 0.39 (30% EtOAc/hexanes).1H NMR (400 MHz, Chloroform-d) d 10.29 (s, 1H), 6.81– 6.76 (m, 2H), 6.73 (dd, J = 8.0, 2.1 Hz, 1H), 3.79 (s, 3H), 3.57 (s, 2H), 0.99 (s, 9H), 0.15 (s, 6H).13C NMR (101 MHz, CDCl3) d 178.26, 151.01, 144.49, 126.61, 121.82, 120.97, 113.40, 55.62, 40.91, 25.85, 18.58, -4.47. [0513] 2-(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)acetyl chloride, 43: 42 (632 mg, 2.13 mmols, 1 eq) was dissolved in dry toluene (5 mL) containing dry N,N- dimethylformamide (5 µL) at room temperature and stirred under argon atmosphere. Oxalyl chloride (457 µL, 5.32 mmols, 2.5 eq) was added by syringe over 1.5 minutes while stirring, and the resulting yellow solution was stirred at room temperature for 1.5 hours before removing volatile contents under reduced pressure. The residue was used without further purification (670 mg, quantitative yield).1H NMR (400 MHz, Chloroform-d) d 6.82 (d, J = 7.7 Hz, 1H), 6.75– 6.69 (m, 2H), 4.06 (s, 2H), 3.81 (s, 3H), 0.99 (s, 9H), 0.16 (s, 6H).13C NMR (101 MHz, CDCl3) d 172.27, 151.30, 145.22, 124.52, 122.23, 121.24, 113.40, 55.67, 52.92, 25.83, 18.58, -4.48. [0514] 2-(3,4-dimethoxyphenyl)-N,N-bis(2-((4-hydroxyphenethyl)amino)-2- oxoethyl)acetamide, 44: 31 (778 mg, 1.91 mmols, 1 eq) was dissolved in N,N- dimethylformamide (9.5 mL) and diisopropylethylamine (832 µL, 4.775 mmols, 2.5 eq) was added at room temperature. The solution was stirred and chilled on a sodium chloride/ice bath (-15 °C) under argon, and a solution of 41 (457 mg, 0.213 mmols, 1.1 eq) in chloroform (1 mL) was added dropwise over 5 minutes; white vapors were observed during this addition (HCl formation). The mixture was allowed to reach room temperature and then stirred for 14 hours, at which time the mixture was poured into 0.1 M aqueous HCl (50 mL), and saturated aqueous sodium chloride solution (25 mL) was added. The aqueous mixture was extracted with ethyl acetate (5x20 mL) and the combined organic phases were washed with brine (3x25 mL), dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient from dichloromethane through 10% methanol/dichloromethane to provide an off-white foam solid (837 mg, 79% yield). Rf 0.39 (10% MeOH/CH2Cl2).1H NMR (400 MHz, Methanol-d4) d 7.01 (t, J = 8.2 Hz, 4H), 6.83 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.74– 6.63 (m, 5H), 4.05 (s, 2H), 3.91 (s, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.49 (s, 2H), 3.37– 3.28 (m, 4H), 2.66 (app dt, J = 14.1, 7.3 Hz, 4H). [0515] 2-(3,4-dimethoxyphenyl)-N,N-bis(2-oxo-2-((2-(3-phenyl-3,4-dihydro-2H- benzo[e][1,3]-oxazin-6-yl)ethyl)amino)ethyl)acetamide, 45: 44 (550 mg, 1.00 mmols, 1 eq), aniline (191 mg, 2.05 mmols, 2.05 eq), 97% paraformaldehyde (136 mg, 4.4 mmols, 4.4 eq) were combined in toluene (3 mL) and ethanol (0.5 mL), placed under an argon atmosphere, and heated at 100 °C under a reflux condenser for 20 hours before cooling to room temperature, condensing under reduced pressure and purifying by silica gel column chromatography, eluting with a gradient from dichloromethane containing 0.4% triethylamine through 1% MeOH/CH2Cl2 with 0.4% triethylamine. A white foam solid was collected (366.5 mg, 47% yield). Rf 0.31 (4% MeOH/CH2Cl2 + 0.2% triethylamine).1H NMR (400 MHz, Chloroform-d) d 9.09 (t, J = 5.5 Hz, 1H), 7.22 (dt, J = 8.7, 7.1 Hz, 5H), 7.13 – 7.00 (m, 4H), 6.95 (dd, J = 8.5, 2.1 Hz, 1H), 6.93– 6.83 (m, 5H), 6.77– 6.70 (m, 4H), 6.69 (dd, J = 8.4, 1.8 Hz, 1H), 6.64 (t, J = 5.7 Hz, 1H), 5.30 (s, 2H), 5.27 (s, 2H), 4.57 (s, 2H), 4.55 (s, 2H), 3.90 (s, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.66 (s, 2H), 3.46 (s, 2H), 3.40 (dq, J = 14.0, 6.5 Hz, 4H), 2.71 (dt, J = 19.8, 7.4 Hz, 4H).13C NMR (101 MHz, CDCl3) d 172.37, 169.36, 168.46, 152.85, 152.71, 148.90, 148.16, 148.01, 131.07, 130.78, 129.18, 129.16, 128.05, 128.00, 126.99, 126.84, 126.11, 121.20, 121.06, 120.89, 120.65, 117.91, 116.83, 116.69, 112.15, 111.19, 79.17, 55.78, 55.74, 54.68, 53.54, 50.19, 41.05, 40.79, 39.70, 34.40, 34.26. [0516] 2-(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)-N,N-bis(2-((4- hydroxyphenethyl)- amino)-2-oxoethyl)acetamide, 46: 31 (778 mg, 1.91 mmols, 1 eq) and diisopropylethylamine (832 µL, 4.775 mmols, 2.5 eq) were combined in N,N- dimethylformamide (9.5 mL) and stirred at -15 °C on an ice-sodium chloride bath. A solution of 43 (670 mg, 2.1 mmols, 1.1 eq) in chloroform (1 mL) was added dropwise over 5 minutes while stirring under an argon atmosphere; white vapors were observed during this step. The mixture was allowed to reach room temperature and then stirred for 14 hours, at which time the mixture was poured into 0.1 M aqueous HCl (50 mL), and saturated aqueous sodium chloride solution (25 mL) was added. The aqueous mixture was extracted with ethyl acetate (5x20 mL) and the combined organic phases were washed with brine (3x25 mL), dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient from dichloromethane through 7% methanol/dichloromethane to provide an off-white foam solid (996 mg, 80% yield). Rf 0.52 (10% MeOH/CH2Cl2).1H NMR (400 MHz, Methanol-d4) d 7.09– 6.94 (m, 4H), 6.78 (d, J = 2.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.73– 6.66 (m, 4H), 6.61 (dd, J = 8.1, 2.1 Hz, 1H), 4.06 (s, 2H), 3.92 (s, 2H), 3.77 (s, 3H), 3.49 (s, 2H), 3.41– 3.19 (m, 4H), 2.68 (q, J = 7.8 Hz, 4H), 0.97 (s, 9H), 0.11 (s, 6H).13C NMR (101 MHz, MeOD) d 175.01, 171.38, 170.87, 156.91, 156.87, 152.28, 145.18, 131.17, 130.95, 130.78, 128.84, 122.37, 121.79, 116.22, 114.14, 55.92, 54.60, 53.62, 42.44, 42.13, 40.73, 35.60, 35.24, 26.21, 19.27, - 4.43. [0517] 2-(4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenyl)-N,N-bis(2-oxo-2-((2-(3- phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)ethyl)amino)ethyl)acetamide, 47: 46 (650 mg, 1.00 mmols, 1 eq), aniline (191 mg, 2.05 mmols, 2.05 eq), and 97%
paraformaldehyde (136 mg, 4.4 mmols, 4.4 eq) were combined in toluene (3 mL) and placed under a reflux condenser and argon atmosphere before heating at 100 °C for 18 hours.
Volatiles were removed under reduced pressure before purifying by silica gel column chromatography, eluting with a gradient from dichloromethane through 35%
acetone/dichloromethane to provide a pale-yellow foam solid (570 mg, 64% yield). Rf 0.33 (5% MeOH/CH2Cl2).1H NMR (400 MHz, Chloroform-d) d 8.94 (t, J = 5.5 Hz, 1H), 7.26– 7.18 (m, 4H), 7.14– 7.03 (m, 4H), 6.98– 6.83 (m, 7H), 6.74 (s, 1H), 6.73– 6.66 (m, 2H), 6.60 (dd, J = 8.1, 2.1 Hz, 1H), 5.82 (t, J = 5.8 Hz, 1H), 5.34 (s, 2H), 5.29 (s, 2H), 4.62 (s, 2H), 4.57 (s, 2H), 3.90 (s, 2H), 3.75 (s, 3H), 3.63 (s, 2H), 3.44 (q, J = 5.6, 4.8 Hz, 6H), 2.72 (dt, J = 14.8, 7.2 Hz, 4H), 0.97 (s, 9H), 0.12 (s, 6H).13C NMR (101 MHz, CDCl3) d 172.46, 169.45, 168.55, 152.84, 152.73, 150.90, 148.20, 148.17, 144.06, 131.10, 130.85, 129.19, 129.17, 128.09, 128.02, 127.03, 126.96, 126.86, 121.21, 121.10, 120.89, 120.77, 120.65, 117.96, 117.91, 116.82, 116.71, 112.90, 79.18, 55.39, 54.67, 53.51, 50.19, 41.09, 40.82, 39.77, 34.40, 34.31, 25.66, 18.34, -4.65. [0518] 2-(4-hydroxy-3-methoxyphenyl)-N,N-bis(2-oxo-2-((2-(3-phenyl-3,4-dihydro-2H- benzo[e][1,3]oxazin-6-yl)ethyl)amino)ethyl)acetamide, 48: 47 (335 mg, 0.379 mmols, 1 eq) was dissolved in tetrahydrofuran (1.5 mL) and placed under argon atmosphere. While stirrint at 4 °C, a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.398 mL, 0.398 mmols, 1.05 eq) was added, and the resulting solution was stirred for 1 hour before quenching by addition of pH 70.1M sodium phosphate buffer (10 mL) by syringe. The mixture was extracted with ethyl acetate (2x10 mL), and the organic phases were washed with 1:10.1M sodium phosphate buffer and saturated aqueous ammonium chloride solution (20 mL), and saturated aqueous sodium chloride solution (15 mL). The organic phase was dried over sodium sulfate, filtered, and condensed under reduced pressure. The crude was further purified by silica gel column chromatography, eluting with a gradient from
dichloromethane through 10% methanol/dichloromethane to provide a pale-yellow solid foam (78.7 mg, 28% yield pure). Additional material was collected containing minor unidentified impurities, potentially due to ring-opening of the benzoxazine on silica gel. Rf 0.50 (10% MeOH/CH2Cl2).1H NMR (400 MHz, Chloroform-d) d 8.99 (t, J = 5.5 Hz, 1H), 7.25– 7.16 (m, 4H), 7.12– 7.04 (m, 4H), 6.97– 6.87 (m, 4H), 6.85 (t, J = 2.9 Hz, 2H), 6.80 (d, J = 8.1 Hz, 1H), 6.76– 6.67 (m, 3H), 6.61 (dd, J = 8.1, 2.0 Hz, 1H), 6.29 (t, J = 5.8 Hz, 1H), 6.14 (s, 1H), 5.31 (s, 2H), 5.28 (s, 2H), 4.58 (s, 2H), 4.55 (s, 2H), 3.88 (s, 2H), 3.79 (s, 3H), 3.62 (s, 2H), 3.51– 3.34 (m, 6H), 2.79– 2.53 (m, 4H).13C NMR (101 MHz, CDCl3) d 172.69, 169.47, 168.65, 153.06, 152.87, 148.35, 146.91, 144.94, 131.21, 130.84, 129.35, 129.32, 128.23, 128.19, 127.13, 127.01, 125.35, 121.71, 121.43, 121.39, 121.08, 120.81, 118.15, 118.11, 117.06, 116.87, 114.71, 111.76, 79.37, 79.33, 55.96, 54.81, 53.76, 50.44, 41.17, 40.94, 40.00, 34.56, 34.38. [0519] 2-(3,4-bis((tert-butyldimethylsilyl)oxy)phenyl)ethan-1-amine, 49: Dopamine (2.50 g, 13.183 mmols, 1 eq), tert-butyldimethylsilyl chloride (4.967 g, 32.957 mmols, 2.5 eq), and imidazole (3.590 g, 52.732 mmols, 4 eq) were combined in dry dichloromethane (30 mL) and stirred under argon atmosphere for 16 hours. A white precipitate was removed by vacuum filtration, and the filtrate was condensed under reduced pressure. The residue was taken up in diethyl ether (100 mL) and washed with saturated aqueous ammonium chloride (3x50 mL), saturated aqueous sodium bicarbonate (2x50 mL), and saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure to provide a pale-yellow oil which was used without further purification (4.9 grams, 97% yield).1H NMR (400 MHz, Chloroform-d) d 6.74 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 2.1 Hz, 1H), 6.63 (dd, J = 8.0, 2.2 Hz, 1H), 2.92 (t, J = 6.9 Hz, 2H), 2.64 (t, J = 6.9 Hz, 2H), 2.12 (s, 2H), 0.98 (d, J = 1.4 Hz, 18H), 0.18 (d, J = 0.8 Hz, 12H). [0520] N-(3,4-bis((tert-butyldimethylsilyl)oxy)phenethyl)-4,4-bis(4- hydroxyphenyl)pentanamide, 50: Diphenolic acid (3.41 g, 11.91 mmols, 1 eq), 49 (5.00 g, 13.10 mmols, 1.1 eq), and diisopropylethylamine (6.224 mL, 35.73 mmols, 3 eq) were combined in dry N,N-dimethylformamide (90 mL) to produce a thick gel-like mixture.
PyBOP (6.819 g, 13.099 mmols, 1.1 eq) dissolved in N,N-dimethylformamide (30 mL) was added dropwise over 30 minutes while stirring (with some assistance from a spatula) to produce a yellow solution. Stirring was continued at room temperature for 16 hours, at which time the mixture was diluted into 250 mL saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3x50 mL). The combined organic phases were washed once with ammonium chloride solution (50 mL), and this aqueous wash was back-extracted once with ethyl acetate (20 mL). The combined organic phases were then washed with saturated aqueous sodium chloride solution (3x50 mL), dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure. The resulting sticky mass was diluted with hexanes and chilled to produce a white solid (2.5 g, pure product). The supernatant was condensed and the residue was purified by column chromatography, eluting with a gradient from dichloromethane through 10% methanol/dichloromethane to produce a white solid (pure product) and off-white solid (mixed fractions, impure product). The combined yield of the desired bisphenol product was 84%.1H NMR (400 MHz, Methanol-d4) d 7.01– 6.90 (m, 4H), 6.73 (d, J = 8.1 Hz, 1H), 6.68– 6.59 (m, 6H), 3.27– 3.23 (m, 2H), 2.59 (t, J = 7.3 Hz, 2H), 2.34– 2.20 (m, 2H), 1.95– 1.86 (m, 2H), 1.49 (s, 3H), 0.95 (d, J = 1.4 Hz, 18H), 0.14 (d, J = 1.3 Hz, 12H).13C NMR (101 MHz, MeOD) d 176.38, 156.16, 147.78, 146.45, 141.47, 133.94, 129.31, 122.93, 122.88, 122.14, 115.66, 45.55, 42.07, 38.97, 35.65, 33.27, 28.47, 26.54, 26.52, 19.32, -3.73, -3.79. [0521] N-(3,4-bis((tert-butyldimethylsilyl)oxy)phenethyl)-4,4-bis(3-phenyl-3,4- dihydro-2H-benzo[e][1,3]oxazin-6-yl)pentanamide, 51: 50 (500 mg, 0.769 mmols, 1 eq), aniline (147 mg, 1.577 mmols, 2.05 eq), and 97% paraformaldehyde (101 mg, 3.384 mmols, 4.4 eq) were combined in toluene (5 mL) under argon atmosphere and heated at 110 °C for 16 hours, followed by cooling to room temperature and diluting with toluene (20 mL). The solution was washed with saturated aqueous sodium bicarbonate solution (3x15 mL), and saturated aqueous sodium chloride solution (2x20 mL), dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient from dichloromethane through 2%
acetone/dichloromethane to provide an off-white solid (211 mg, 31% yield). A similar approach utilizing chloroform as the reaction solvent, with heating at 80 °C produced similar yields of the desired compound (32% yield). Rf 0.34 (2% acetone/CH2Cl2).1H NMR (400 MHz, Chloroform-d) d 7.34– 7.24 (m, 4H), 7.14– 7.10 (m, 4H), 6.98– 6.91 (m, 4H), 6.89 (d, J = 2.3 Hz, 2H), 6.81 (d, J = 8.1 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 2.2 Hz, 1H), 6.64 (dd, J = 8.1, 2.2 Hz, 1H), 5.41 (t, J = 5.8 Hz, 1H), 5.35 (s, 4H), 4.60 (s, 4H), 3.41 (q, J = 6.8 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H), 2.49– 2.36 (m, 2H), 1.98– 1.87 (m, 2H), 1.55 (s, 3H), 1.05 (d, J = 2.4 Hz, 18H), 0.25 (d, J = 5.2 Hz, 12H).13C NMR (101 MHz, CDCl3) d 172.92, 152.34, 148.37, 146.72, 145.44, 141.38, 131.90, 129.27, 126.89, 125.23, 121.56, 121.53, 121.14, 121.03, 120.26, 117.88, 116.51, 79.01, 50.61, 44.64, 40.77, 37.15, 34.94, 32.33, 27.84, 25.99, 18.45, -3.99, -4.03. [0522] N-(3,4-dihydroxyphenethyl)-4,4-bis(3-phenyl-3,4-dihydro-2H- benzo[e][1,3]oxazin-6-yl)pentanamide, 52: 51 (418 mg, 0.473 mmols, 1 eq) was dissolved in tetrahydrofuran (4 mL) and stirred at 4 °C under argon. Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 1.04 mL, 1.04 mmols, 2.2 eq) was added drop-wise over 2 minutes, the mixture was stirred for 30 minutes, and then the reaction was quenched by addition of pH 70.1 M sodium phosphate buffer (30 mL) and ethyl acetate (25 mL). The organic layer was washed with addition sodium phosphate buffer (2x25 mL), saturated aqueous sodium chloride solution (2x25mL), dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure. The crude was taken up in minimal dichloromethane and precipitated by addition of hexanes. The pale-yellow solid was collected by vacuum filtration. Rf 0.00 (2% acetone/CH2Cl2).1H NMR (400 MHz, Chloroform-d) d 7.27– 7.19 (m, 6H), 7.08 (d, J = 8.1 Hz, 4H), 6.91 (t, J = 7.3 Hz, 2H), 6.83 (dd, J = 8.6, 2.3 Hz, 2H), 6.81 – 6.75 (m, 3H), 6.67 (d, J = 8.4 Hz, 3H), 6.52 (dd, J = 8.1, 2.0 Hz, 1H), 5.31 (s, 4H), 5.31 (t, J = 8.7 Hz) 4.54 (s, 4H), 3.32 (q, J = 6.7 Hz, 2H), 2.58 (t, J = 7.0 Hz, 2H), 2.28 (dd, J = 10.3, 6.0 Hz, 2H), 1.83 (dd, J = 10.5, 5.9 Hz, 2H), 1.45 (s, 3H). [0523] Protected 50–Jeffamine-400 main-chain benzoxazine, 53: 50 (351 mg, 0.5409 mmols, 1 eq), Jeffamine-400 diamine (216.4 mg, 0.5409 mmols, 1 eq), and 97%
paraformaldehyde (67 mg, 2.191 mmols, 4.05 eq) were combined in a 9:1 toluene:ethanol mixture (3 mL), and heated at 82 °C under argon atmosphere for 13 hours. The reaction was then cooled to room temperature and condensed under reduced pressure to provide a tacky yellow residue (611 mg, quantitative yield). 1H NMR (400 MHz, Chloroform-d) d 7.07– 6.69 (m, 5H), 6.66– 6.55 (m, 4H), 5.35 (broad s, 1H), 4.92 (broad s, ~4H), 4.00 (broad s, ~4H), 3.64– 3.29 (broad m, 22H), 3.11 (broad q, J = 5.6, 5.1 Hz, 2H), 2.64 (broad t, J = 7.0 Hz, 2H), 1.87 (broad s, 2H), 1.49 (broad s, 3H), 1.17– 1.07 (broad m, 21H), 0.97 (apparent d, J = 1.7 Hz, 18H), 0.18 (s, 6H), 0.17 (s, 6H). [0524] Deprotected 50–Jeffamine-400 main-chain benzoxazine, 54: 53 (561 mg, 0.511 mmols of repeating unit = 0.511 mmols of protected catechol) was dissolved in
tetrahydrofuran (5 mL) and placed under argon atmosphere at 4 °C. Tetrabutylammonium fluoride solution (1M, 1.124 mL, 1.124 mmols, 2.2 eq per repeating unit) was added dropwise over 2 minutes. The mixture was stirred for 1.5 hours, and then quenched by addition of 0.1 M pH 7 sodium phosphate buffer and dichloromethane (10 mL each). The layers were separated, and the organic phase was washed once more with phosphate buffer (10 mL). Brine was added to the organic phase (10 mL) to produce a yellow sticky precipitate and yellow solution. The solution was separated and dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure. The crude was precipitated in hexanes to yield a pale yellow solid (60% yield). 1H NMR (400 MHz, Chloroform-d) d 6.98– 6.52 (broad m, 8H), 6.45 (d, J = 7.9 Hz, 1H), 4.86 (broad s, 2H), 3.95 (broad s, 3H), 3.58– 3.26 (broad m, 19H), 3.07 (broad s, 2H), 2.91 (broad s, 1H), 2.75– 2.49 (broad m, 8H), 2.35– 2.13 (broad m, 2H), 1.81– 1.75 (m, 2H), 1.44 (broad s, 3H), 1.17– 1.00 (broad m, 20H). [0525] Additional lap shear adhesion testing was performed with derivatives 47, 48, and 45. The updated graph, updated relative to FIG.14, is shown in FIG.19. [0526] Supplementary Reactions with Model Benzoxazine Substrate. Reaction conditions were adapted from previously described benzoxazine syntheses and were screened in model reactions prior to syntheses with precursors 4 and 7. Briefly, p-cresol, 2-methoxy-ethylamine, and either aqueous formaldehyde solution (formalin, 37% w/w) or paraformaldehyde were reacted in a 1:1:2.2 respective molar ratio (Scheme 29) to produce 1,3-benzoxazine S1. The reaction conditions and yields obtained are summarized in Table 4. In these model reactions, the highest yield (69%) was obtained in refluxing toluene at a combined concentration of 50 wt% of starting materials (condition C). It is worth noting that benzoxazine monomer of sufficient purity for polymerization is obtained under condition C after conventional extractive workup, whereas conditions 1 and 2 require chromatography after workup to obtain monomer of comparable purity.
Figure imgf000201_0001
Scheme 29. Synthesis of model benzoxazine. [0527] Table 4. Conditions screened for synthesis of model benzoxazine monomer.
Figure imgf000201_0002
[0528] Trial thermally accelerated ring opening polymerization of model benzoxazine S1 was carried out as described for compound 1. Briefly, neat monomer was heated in a sealed vial under argon at 160 °C for 4 hours to yield a yellow viscous liquid. This was taken up in CDCl3 and analyzed by 1H-NMR. After heating, the characteristic benzoxazine peaks (arrows, FIG.13) had almost completely disappeared, peak broadening was observed, and a new group of peaks assigned to the benzylic protons was observed (blue arrows, FIG.13). This is consistent with the observations made for the polymerization of monomer 1. Example 7: End group identity on benzoxazine polymers
Figure imgf000202_0001
Scheme 30. Linear mussel-inspired polybenzoxazine structure. [0529] The identity of chain ends in soluble linear benzoxazines has not been widely studied or described in the primary literature. In an idealized case, where no initiator or catalyst is added to the polymerization, the benzoxazine monomers undergo a ring opening polymerization that results in one chain end (R1) as a hydrogen, and the second chain end (R2) as an intact benzoxazine (See Scheme 30 and Scheme 31). However, this is a very simplified view, and many other reaction pathways are possible during benzoxazine polymerization so varying extents. For example, fragmentation of the Mannich bridge structure resulting in loss of the amine fragment ultimately leads to methylene linkages directly between two phenols. Just as these linkages can be present in the main chain of benzoxazines, these types of linkages can be present as chain ends.
Figure imgf000202_0002
Scheme 31. Example linear polybenzoxazine homopolymer structure prepared from methylamine and p-cresol. [0530] It is also possible to initiate the polymerization of benzoxazines by addition of a phenol with an unsubstituted ortho position. This may result in the formation of phenol end groups (R1 and/or R2) that are substituted by the phenol initiator, as shown schematically in Scheme 32. For this reason, it is possible for different phenol identities to exist as possible end group structures when the phenol is employed as an initiator in the polymerization.
Figure imgf000203_0001
Scheme 32. Schematic representation of end group identities observed in phenol-initiated polymerization of benzoxazines. [0531] For“self-initiated” polymerizations of benzoxazines, end groups are likely to be a proton on one end, and either a phenol fragment, Mannich base (secondary amine) or intact benzoxazine. In the particular case of our mussel-inspired polybenzoxazines, an intact benzoxazine end group is not likely to be observed following deprotection of side-chains under acidic conditions. This is due to the acid-mediated ring opening of the benzoxazine, with loss of formaldehyde, providing the Mannich base with secondary amine as a possible end group (Scheme 33).
Figure imgf000203_0002
Scheme 33. Potential end groups for mussel-inspired polybenzoxazines after deprotection. [0532] Some references from the primary literature that mention end groups in linear soluble oligo/polybenzoxazines (or analogous structures), or attempt to determine end group identities with the use of model compounds are listed herein, for example, Chutayothin, P.; Ishida, H., 31P NMR spectroscopy in benzoxazine model compounds and benzoxazine chemistry– main chain and end group studies. European Polymer Journal 2009, 45 (5), 1493-1505; 2. Chutayothin, P.; Ishida, H., Polymerization of p-cresol, formaldehyde, and piperazine and structure of monofunctional benzoxazine-derived oligomers. Polymer 2011, 52 (18), 3897-3904; or 3. Kirschbaum, S.; Landfester, K.; Taden, A., Synthesis and Thermal Curing of Benzoxazine Functionalized Polyurethanes. Macromolecules 2015, 48 (12), 3811- 3816, which are incorporated herein by reference in their entirety. [0533] Additional references to be considered include: Ishida, H., Agag, T., Handbook of Benzoxazine Resins, 1st ed.; Elsevier: Netherlands, 2011; Ishida, H., Froimowicz, P., Advanced and Emerging Polybenzoxazine Science and Techology, 1st ed.; Elsevier:
Netherlands, 2017; Lee, H., Dellatore, S.M., Miller, W.M., Messersmith, P.B., Mussel- inspired surface chemistry for multifunctional coatings, Science, 2007, 318, 426-430; Lin, L., Zeng, H., Marine mussel adhesion and bio-inspired wet adhesives, Biotribology, 2016, 5, 44- 51; and Maier, G.P., Rapp, M.V., Waite, J.H., Israelachvili, J.N., Butler, A., Adaptive synergy between catechol and lysine promotes wet adhesion by surface salt displacement, Science, 2015, 349, 628, which are incorporated herein by reference in their entirety. Example 8: Additional compounds
Figure imgf000204_0001
[0534] TBS-protected Jeffamine-2000 main-chain benzoxazine, 55: Bisphenol 50 (803 mg, 1.235 mmols, 1 eq), Jeffamine-2000 diamine (2.47 g, 1.235 mmols, 1 eq), and 97% paraformaldehyde (153 mg, 4.94mmols, 4 eq of formaldehyde) were combined in a 9:1 toluene:ethanol mixture (2.5 mL), and heated at 82 °C under argon atmosphere for 13 hours. The reaction was then cooled to room temperature and condensed under reduced pressure to provide a very sticky pale-yellow to orange residue (3.34, quantitative yield by mass). Crude 1H-NMR analysis reveals a degree of ring-closure of ~89 mol%. This was calculated by comparing the integration of the peak at ~4.91 ppm to that of the diphenolic acid-derived methyl peak at ~1.49 ppm. Molecular weight was determined by gel permeation
chromatography in tetrahydrofuran at a flow rate of 1 mL/minute, calibrating with linear low- dispersity polystyrene standards. Mw = 22,424 g/mol, Mn = 3,944 g/mol (Đ = 5.6). The large dispersity value indicates that this material likely exhibits some degree of branching due to side reactions occurring in the Mannich condensation employed to prepare these materials. 1H NMR (400 MHz, Chloroform-d) d 6.87– 6.68 (broad m, 5H), 6.66– 6.55 (broad m, 4H), 5.32 (broad s, 1H), 4.97– 4.80 (m, ~4H), 3.99 broad (s, ~4H), 3.77– 3.63 (broad m, 3H), 3.61– 3.28 (broad m, 126H), 3.21– 3.06 (broad m, 3H), 2.63 (broad t, J = 7.0 Hz, 2H), 2.40 – 2.24 (broad m, 2H), 1.96– 1.73 (broad m, ~8H), 1.49 (broad s, 3H), 1.20– 1.05 (broad m, 126H), 0.97 (apparent d, J = 1.6 Hz, 18H), 0.17 (s, 6H), 0.16 (s, 6H).
Figure imgf000205_0001
[0535] Jeffamine2000 main-chain benzoxazine, 56: 55 (3.5 grams, ~1.32 mmols of repeating unit = ~1.32 mmols of protected catechol) was dissolved in tetrahydrofuran (14 mL) and placed under argon atmosphere at 4 °C. Tetrabutylammonium fluoride solution (Sigma, 1M, 2.76 mL, 2.76 mmols mmols, 2.1 eq per repeating unit) was added dropwise over 2 minutes. The mixture was stirred for 1.5 hours, and then quenched by addition of 0.1 M pH 7 sodium phosphate buffer (15 mL) and dichloromethane (15 mL). The layers were separated, and the organic phase was washed once more with 0.1 M pH 7 sodium phosphate buffer (10 mL), and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure. The crude was taken up in minimal tetrahydrofuran (6 mL), and the viscous solution was added to stirring ice-chilled diethyl ether (120 mL) to produce a dense oil layer. Stirring was stopped, and the oil layer was allowed to settle for 1 hour. The supernatant was decanted, and the residue was dried under high vacuum to provide an amber-colored, tough, tacky transparent rubber (2.03 g, 62% yield by mass). Crude 1H- NMR analysis reveals a degree of ring-closure of ~61 mol%.12 This was calculated by comparing the integration of the peak at ~4.91 ppm to that of the diphenolic acid-derived methyl peak at ~1.48 ppm. Gel permeation chromatography was not performed due to the adhesive nature of the abundant catechol side-chains. Glass transition temperature (Tg) was measured by differential scanning calorimetry as -54 °C prior to curing and -62 °C after curing. 1H NMR (400 MHz, Chloroform-d) d 7.02– 6.39 (broad m, 9H), 5.36 (broad s, 1H), 5.05– 4.76 (broad m, ~3H), 3.99 (broad s, ~3H), 3.80– 3.61 (broad m, 3H), 3.60– 3.29 (broad m, 96H), 3.19– 3.05 (broad m, 2H), 2.61 (broad t, J = 7.3 Hz, 2H), 2.35– 2.24 (broad m, 2H), 1.95– 1.75 (broad m, 2H), 1.48 (broad s, 3H), 1.16– 1.09 (m, 97H).
Figure imgf000206_0002
[0536] 2-(3,4-bis((tert-butyldimethylsilyl)oxy)phenyl)-N-(4-hydroxyphenethyl)acetamide, 57: Acid 27 (500 mg, 1.26 mmols, 1 eq) was dissolved in dichloromethane (6.4 mL) in a round bottom flask containing a magnetic stir bar and placed under argon. Carbonyl diimidazole (CDI, 225 mg, 1.39 mmols, 1.1 eq) was added portion-wise over 5 minutes, and stirring was continued at room temperature for 20 minutes, at which time tyramine (199 mg, 1.45 mmols, 1.15 eq) was added. The mixture was stirred at room temperature for 1 hour more, and then the solvent was removed under reduced pressure. The residue was taken up in diethyl ether (40 mL), and the solution was washed with saturated aqueous ammonium chloride solution ( 3 x 20 mL), saturated aqueous sodium bicarbonate solution (2 x 20 mL), and brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and condensed under reduced pressure. The resulting crude was further purified by column chromatography on silica gel, eluting with a gradient from hexanes through 40% ethyl acetate/hexanes. Fractions containing product, as determined by TLC, were condensed under reduced pressure to provide a white solid (533 mg, 82% yield). Rf 0.53 (50% EtOAc/hexane).1H NMR (400 MHz, Chloroform-d) d 7.92 (bs, 1H), 6.93– 6.85 (m, 2H), 6.82– 6.74 (m, 3H), 6.69 (d, J = 2.2 Hz, 1H), 6.60 (dd, J = 8.1, 2.2 Hz, 1H), 5.66 (t, J = 5.8 Hz, 1H), 3.46– 3.39 (m, 4H), 2.62 (t, J = 7.1 Hz, 2H), 1.00 (s, 9H), 0.98 (s, 9H), 0.21 (s, 6H), 0.18 (s, 6H).13C NMR (101 MHz, CDCl3) d 172.34, 155.47, 147.24, 146.48, 129.66, 129.43, 127.35, 122.63, 122.43, 121.50, 115.73, 43.06, 41.32, 34.75, 25.99, 25.97, 18.51, -4.00.
Figure imgf000206_0001
[0537] 2-(3,4-bis((tert-butyldimethylsilyl)oxy)phenyl)-N-(2-(3-phenyl-3,4-dihydro-2H- benzo[e][1,3]-oxazin-6-yl)ethyl)acetamide, 58: Phenol precursor 57 (663 mg, 1.285 mmols, 1 eq), paraformaldehyde (87 mg, 2.827 mmols, 2.2 eq of formaldehyde), and aniline (126 mg, 1.349 mmols, 1.05. eq) were combined in toluene (4 mL) in a round bottom flask topped with a reflux condenser under argon and heated at 105 °C for 16 hours. The reaction was cooled to room temperature, loaded directly onto a column of silica gel equilibrated with 1%
triethylamine/hexanes, and eluted with a gradient from hexanes through 20% ethyl acetate/hexanes. Fractions containing product were condensed under reduced pressure to provide an off-white solid after further drying under high vacuum (565 mg, 69% yield). Rf 0.31 (30% EtOAc/hexane).1H NMR (400 MHz, Chloroform-d) d 7.29– 7.21 (m, 2H), 7.14– 7.06 (m, 2H), 6.96– 6.88 (m, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.78 (dd, J = 8.3, 2.0 Hz, 1H), 6.74– 6.67 (m, 3H), 6.62 (dd, J = 8.1, 2.2 Hz, 1H), 5.50 (t, J = 5.9 Hz, 1H), 5.33 (s, 2H), 4.57 (s, 2H), 3.42 (s, 2H), 3.39 (q, J = 7.1 Hz, 2H), 2.60 (t, J = 7.0 Hz, 2H), 1.01 (s, 9H), 0.99 (s, 9H), 0.21 (s, 6H), 0.19 (s, 6H).13C NMR (101 MHz, CDCl3) d 171.32, 153.02, 148.43, 147.21, 146.32, 131.00, 129.32, 128.14, 127.87, 126.81, 122.51, 122.37, 121.45, 121.41, 120.98, 118.25, 117.05, 79.40, 50.49, 43.26, 40.99, 34.96, 25.99, 25.99, 18.51, 18.51, -3.98, - 4.00.
Figure imgf000207_0001
[0538] 2-(3,4-dihydroxyphenyl)-N-(2-(3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-6- yl)ethyl)-acetamide, 59: Protected benzoxazine 58 (711 mg, 1.123 mmols, 1 eq) was dissolved in tetrahydrofuran (5.6 mL) in a round bottom flask containing a magnetic stir bar and chilled on an ice bath under argon. A solution of tetrabutylammonium fluoride (TBAF, 2.3 mL, 2.3 mmols, 2.05 eq) was added dropwise by syringe over 3 minutes while stirring to produce an immediate development of a yellow color. Stirring was continued for 30 minutes, at which time pH 70.1 M aqueous sodium phosphate buffer (20 mL) was injected to quench the reaction. The mixture was transferred to a separatory funnel extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with pH 70.1 M sodium phosphate buffer (30 mL), 1:1 sodium phosphate buffer:brine (30 mL), and brine (30 mL) before drying over anhydrous sodium sulfate, filtering, and condensing under reduced pressure. The residue was further purified by column chromatography on silica gel packed in dichloromethane, eluting with a gradient from dichloromethane through 50% acetone/dichloromethane.
Fractions containing product were condensed under reduced pressure to provide a pale- yellow foaming solid (434 mg, 96% yield). Rf 0.48 (30% acetone/hexane).1H NMR (400 MHz, Chloroform-d) d 7.29– 7.20 (m, 2H), 7.12– 7.03 (m, 2H), 6.95– 6.86 (m, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.72 (dd, J = 8.4, 2.0 Hz, 1H), 6.70– 6.61 (m, 3H), 6.47 (dd, J = 8.0, 2.1 Hz, 1H), 5.81 (t, J = 5.9 Hz, 1H), 5.29 (s, 2H), 4.51 (s, 2H), 3.42– 3.29 (m, 4H), 2.56 (t, J = 6.8 Hz, 2H).13C NMR (101 MHz, CDCl3) d 173.31, 153.07, 148.34, 144.94, 144.15, 130.63, 129.41, 128.21, 126.91, 126.14, 121.58, 121.41, 121.12, 118.29, 117.17, 116.23, 115.80, 79.50, 50.43, 43.04, 41.23, 34.60. Example 9: Improving adhesion of cured 37 by formulation with main-chain
benzoxazines 54 and 56 as performance-modifying additives
[0539] The adhesive performance of thermoset monomer 37 could be further improved by increasing substrate roughness and by blending with main-chain derivatives 54 and 56 as performance modifiers. Lap-shear adhesion strength was assessed on aluminum 6061 substrates that were etched with sodium hydroxide to enhance roughness. Compounds 37 and either 54 or 56 were combined in 15 vol% methanol in tetrahydrofuran at various feed ratios, followed by solvent casting onto aluminum substrates. The samples were dried, overlapped and clamped in antiparallel fashion, and then cured in an air oven (130 °C to 195 °C over 2 hours, and held at 195 °C for 6 hours), cooling slowly to room temperature. Bonded substrates were tested in shear at a strain rate of 0.5% strain/minute. The bond line uniformity and adhesive strength were maximal when 4 parts by weight of 37 were combined with 3 parts by weight of either 54 or 56. Adhesion strengths up to 16.1 ± 1.6 MPa were obtained for formulations of 37 and 56 on roughened Al 6061 substrates. Example 10: Mechanical properties of 36 and 37 compared to BPA-Aniline by 3-point bending
[0540] Based on the high adhesion strength of 37 and the protected derivative 36 on unmodified aluminum 6061, the mechanical properties were assessed by 3-point bending, and benchmarked against commercially available BPA-Aniline (XU 35610). Rectangular samples were prepared for 3-point flexural testing by compression molding in hand-cut PDMS molds between steel plates at 205 °C and 550 psi for 2 hours. Samples were sanded to provide rectangular specimens. Compression molding was employed due to the rapid curing of 37, catalyzed by the deprotected catechols. Curing behavior of purified 37 was assessed by differential scanning calorimetry, revealing an overlap of melting (181 °C) and curing onset, with a maximum curing exotherm occurring at 196 °C. To allow consistent comparisons of polybenzoxazine mechanical properties compression molding was applied for all three resins. Cured BPA-Aniline provided red-orange specimens, while those obtained from 36 and 37 were significantly darker brown in color, indicating potential oxidation of catechol functional groups during curing. Fourier transform infrared (FTIR) spectroscopic analysis of cured samples revealed a disappearance of characteristic peaks affiliated with the oxazine ring at 940, 947 and 946 cm-1 for BPA-Aniline, 37 and 36, respectively, demonstrating effective ring-opening polymerization. [0541] Flexural testing by 3-point bending revealed an elastic response with minimal plastic deformation, terminated by brittle failure. The flexural modulus and strength measured for our benchmark material, BPA-Aniline, are consistent with values previously reported in literature and provided by the manufacturer at 4.71 ± 0.69 GPa and 136.4 ± 6.5 MPa, respectively (Figures 4D and 4E).13 Thermoset 37 possesses a slightly higher flexural modulus (5.52 ± 0.80 GPa) and comparable flexural strength (141.2 ± 11.8 MPa) than
BPA-Aniline, indicating that the strong adhesive properties of this monomer do not come at the cost of favorable mechanical performance. Cured 36, in contrast, exhibited a substantially lower flexural modulus and strength (3.47 ± 0.38 GPa and 85.3 ± 11.0 MPa, respectively). The bulky silyl ethers in this material likely disrupt hydrogen bonding interactions that contribute to polybenzoxazine mechanical properties, leading to a decline in modulus and strength relative to 37 and BPA-Aniline.14 Example 11: Thermal stability of cured 36 and 37 relative to BPA-Aniline
[0542] Polybenzoxazines as a class of materials exhibit excellent thermal stability. The thermal stability of compression molded and cured 36 and 37 were compared to BPA- Aniline up to 600 °C in nitrogen by thermal gravimetric analysis on specimens extracted from flexural testing samples prepared by compression molding. Decomposition of polymerized 36 begins at a lowest temperature for the series, with 10% weight loss occurring by 295 °C (T10%) with a heating rate of 10 °C/min. The T10% values for cured 37 and
BPA-Aniline are comparable at 322 and 328 °C, respectively. However, the char yields at 600 °C were higher for both bioinspired derivatives (60% and 54% for 36 and 37, respectively) compared to BPA-Aniline (37%), indicating a lower quantity of volatiles formed during decomposition at elevated temperatures. While 36 produces the greatest char yield in the series, it exhibits the earliest onset of degradation. The thermal degradation of 37 and BPA-Aniline in air were assessed up to 600 °C. Comparable degradation behaviors were observed for both resins, with all material degrading by 600 °C. Example 12: Main-chain polybenzoxazine 56 as a pressure sensitive adhesive
[0543] During the course of our preparation and characterization of catechol-modified main-chain benzoxazine 56 as a potential performance modifying additive for 37, we observed that this material has several characteristics of a rubber pressure sensitive adhesive: low glass transition temperature, tackiness, and resistance to shear. To probe this behavior further, 10 wt% solutions of 56 in 15 vol% methanol in tetrahydrofuran solvent cast onto strips of polyethylene terephthalate (PET) film. The density of material cast in the dried film was approximately 4.1 mg/cm2. After drying under vacuum, these strips were nearly colorless in appearance, much like common packing tape. [0544] Qualitatively, the film tapes stick readily to a variety of surfaces, including stainless steel, polycarbonate, aluminum 6061, Kapton, high density polyethylene, and glass. Taped pairs of HDPE or glass substrates resisted moderate shear, determined by their ability to support 200 grams of weight for extended periods of time. Control experiments performed with silyl ether protected 55 revealed that cohesion was severely diminished in this material, as these materials were unable to resist shear of a 200 gram weight for any period of time. In stark contrast, two glass substrates adhered with a PSA film tape of 56 (4.8 cm2 with 4.1 mg/cm256) have resisted shearing under a 200 gram load for greater than 208 days, while HDPE samples secured with a 2.5 cm256 PSA held a 200 gram weight for 16 hours with minimal changes; increasing the load to 1 kg cause the tape to slip from the HDPE after 20 minutes (primarily adhesive failure, assessed visually). [0545] Inspired by the ability of mussels to bind to surfaces underwater, we attempted to apply 56 tape films to glass slides that were submerged underwater. This experiment consisted of taking a 56 PSA into deionized water and pressing it to the surfaces of two adjacent glass slides. We observed that the PSA adhered to the glass slides, and the adhesive joint remained intact after submersion in water for 24 hours more at room temperature.
However, the tape became opaque, and if peeled from the surface had noticeably lower tackiness than pristine tapes. REFERENCES
[0546] (1) (a) Ishida, H.; Agag, T. Handbook of Benzoxazine Resins; Elsevier: Amsterdam, Netherlands, 2011. (b) Ishida, H.; Froimowicz, P. Advanced and Emerging Polybenzoxazine Science and Technology; Elsevier Science, 2017. (2) (a) Waite, J. H., Timothy J. Housley, and Marvin L. Tanzerg BioChem.1985, 24, 5010. (b) Danner, E. W.; Kan, Y.; Hammer, M. U.; Israelachvili, J. N.; Waite, J. H. Biochemistry 2012, 51, 6511. (3) (a) Andreu, R.; Reina, J. A.; Ronda, J. C. Journal of Polymer Science Part A: Polymer Chemistry 2008, 46, 3353. (b) Andreu, R.; Espinosa, M. A.; Galià, M.; Cádiz, V.; Ronda, J. C.; Reina, J. A. Journal of Polymer Science Part A: Polymer Chemistry 2006, 44, 1529. (c) Andreu, R.; Reina, J. A.; Ronda, J. C. Journal of Polymer Science Part A: Polymer Chemistry 2008, 46, 6091. (4) (a) Ahn, B. K.; Das, S.; Linstadt, R.; Kaufman, Y.; Martinez-Rodriguez, N. R.; Mirshafian, R.; Kesselman, E.; Talmon, Y.; Lipshutz, B. H.; Israelachvili, J. N.; Waite, J. H. Nature
Communications 2015, 6, 8663. (b) Lee, H.; Scherer, N. F.; Messersmith, P. B. Proceedings of the National Academy of Sciences 2006, 103, 12999. (5) (a) Harrington, M. J.; Masic, A.; Holten-Andersen, N.; Waite, J. H.; Fratzl, P. Science 2010, 328, 216. (b) Gebbie, M. A.; Wei, W.; Schrader, A. M.; Cristiani, T. R.; Dobbs, H. A.; Idso, M.; Chmelka, B. F.; Waite, J. H.; Israelachvili, J. N. Nat Chem 2017, advance online publication. (c) Maier, G. P.; Rapp, M. V.; Waite, J. H.; Israelachvili, J. N.; Butler, A. Science 2015, 349, 628. (d) Rapp, M. V.; Maier, G. P.; Dobbs, H. A.; Higdon, N. J.; Waite, J. H.; Butler, A.; Israelachvili, J. N. Journal of the American Chemical Society 2016, 138, 9013. (e) Ahn, B. K.; Lee, D. W.; Israelachvili, J. N.; Waite, J. H. Nat Mater 2014, 13, 867. (6) Liu, Z.; Hu, B.-H.; Messersmith, P. B.
Tetrahedron Letters 2010, 51, 2403. (7) Jacobs, W. A.; Heidelberger, M.; Rolf, I. P. Journal of the American Chemical Society 1919, 41, 458. (8) Shi, J.; Zhang, J.; Yue, Z.; Li, M.; Zhu, C.; Zhang, Y.; Zi, J.; Wang, Y.; Fan, X.; Xu, R.; Google Patents: 2013. (9) Golkowski, M.; Ziegler, T. Molecules (Basel, Switzerland) 2011, 16, 4695. (10) Cheng, S.; Comer, D. D.; Williams, J. P.; Myers, P. L.; Boger, D. L. Journal of the American Chemical Society 1996, 118, 2567. (11) Malik, G.; Natangelo, A.; Charris, J.; Pouységu, L.; Manfredini, S.;
Cavagnat, D.; Buffeteau, T.; Deffieux, D.; Quideau, S. Chemistry– A European Journal 2012, 18, 9063. (12) Sawaryn, C.; Landfester, K.; Taden, A., Advanced chemically induced phase separation in thermosets: Polybenzoxazines toughened with multifunctional thermoplastic main-chain benzoxazine prepolymers. Polymer 2011, 52 (15), 3277-3287. (13) Allen, D. J.; Ishida, H., Physical and mechanical properties of flexible polybenzoxazine resins: Effect of aliphatic diamine chain length. Journal of Applied Polymer Science 2006, 101 (5), 2798-2809. (14) Kim, H.-D.; Ishida, H., A study on hydrogen-bonded network structure of polybenzoxazines. The Journal of Physical Chemistry A 2002, 106 (14), 3271- 3280.

Claims

WHAT IS CLAIMED IS: 1. A compound having the formula:
Figure imgf000212_0001
wherein,
L1 and L2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
L4 is a covalent linker;
R1 is independently hydrogen, halogen, -CX13, -CHX13, -CH2X1, -OCX13, -OCH2X1, -OCHX13, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)O R1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B,
-C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)O R2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
X, X1, and X2 are independently–F, -Cl, -Br, or–I;
n1 and n2 are independently an integer from 0 to 4;
v1, v2, m1, and m2 are each independently 1 to 2; and
z2 is an integer from 0 to 5.
2. The compound of claim 1, wherein R1 is independently -NHC(O)NR1AR1B, -NR1AR1B, -C(O)NR1AR1B, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)O R1C, -NR1AOR1C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
3. The compound of claim 1, wherein R1 is–NH2.
4. The compound of claim 1, wherein L1 is a bond, -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
5. The compound of claim 1, wherein L1 is substituted or unsubstituted C1-C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene.
6. The compound of claim 1, wherein L1 is substituted or unsubstituted C1-C2 alkylene.
7. The compound of claim 1, wherein L2
is -C(O)-, -C(O)CH2-, -C(O)NH-,
-NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
8. The compound of claim 1, wherein L2 is substituted or unsubstituted C1-C6 alkylene.
9. The compound of claim 1, wherein L2 is substituted or unsubstituted C1-C2 alkylene.
10. The compound of claim 1, wherein R2
is -C(O)R2C, -C(O)-OR2C, -OR2D,
-OC(O)R2C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
11. The compound of claim 1, wherein two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl.
12. The compound of claim 1, wherein R2 is–OH, -OCH3, or -OTBS.
13. The compound of claim 1, wherein
Figure imgf000214_0001
has the formula:
Figure imgf000214_0002
wherein,
R2.3 and R2.4 are each independently -OR2D, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R2.3 and R2.4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R2D is independently
hydrogen, -CX2 3, -CN, -COOH, -CONH2, -CHX2 2, -CH2X2, -CONH-(C1-C6 alkyl), -C(O)- (C1-C6 alkyl), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group.
14. A polymer of the formula:
Figure imgf000215_0001
wherein,
L1, L2, and L3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
L5 and L6 are each independently a covalent linker;
R1 is independently hydrogen, halogen, -CX13, -CHX13, -CH2X1, -OCX13, -OCH2X1, -OCHX13, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)O R1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a monovalent benzoxazine monomer;
R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
X, X1, and X2 are independently–F, -Cl, -Br, or–I;
n1 and n2 are independently an integer from 0 to 4;
v1, v2, m1, and m2 are each independently 1 to 2;
z1 is independently an integer from 1 to 1000; and
z2 is an integer from 0 to 5.
15. The polymer of claim 14, wherein R1 is
independently -NHC(O)NR1AR1B,
-NR1AR1B, -C(O)NR1AR1B, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
16. The polymer of claim 14, wherein R1 is–NH2.
17. The polymer of claim 14, wherein L1 is a bond, -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
18. The polymer of claim 14, wherein L1 is substituted or unsubstituted C1- C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene.
19. The polymer of claim 14, wherein L1 is substituted or unsubstituted C1- C2 alkylene.
20. The polymer of claim 14, wherein L2 is -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
21. The polymer of claim 14, wherein L2 is substituted or unsubstituted C1- C6 alkylene.
22. The polymer of claim 14, wherein L2 is substituted or unsubstituted C1- C2 alkylene.
23. The polymer of claim 14, wherein R2 is -C(O)R2C, -C(O)-OR2C, -OR2D, -OC(O)R2C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
24. The polymer of claim 14, wherein two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl.
25. The polymer of claim 14, wherein R2 is–OH, -OCH3, or -OTBS.
26. The polymer of claim 14, wherein
Figure imgf000217_0001
has the formula:
Figure imgf000217_0002
wherein,
R2.3 and R2.4 are each independently -OR2D, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R2.3 and R2.4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R2D is independently
hydrogen, -CX23, -CN, -COOH, -CONH2, -CHX22, -CH2X2, -CONH-(C1-C6 alkyl), -C(O)- (C1-C6 alkyl), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group.
27. The polymer of claim 14, wherein L6 has the formula: -L6A-L6B-L6C-, wherein
L6A, L6B, and L6C are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
28. The polymer of claim 14, wherein R3 is independently hydrogen, substituted or unsubstituted phenyl, or a monovalent benzoxazine monomer, wherein said monovalent benzoxazine monomer has the formula:
Figure imgf000218_0001
,
wherein,
L7 is a
bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-,
-NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and
R7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
29. The polymer of claim 14, wherein z1 is 1.
30. The polymer of claim 29, wherein the polymer has the formula:
Figure imgf000219_0001
.
31. The polymer of claim 14, wherein the polymer has the formula:
Figure imgf000219_0002
.
32. The polymer of claim 14, wherein the polymer has the formula:
Figure imgf000219_0003
.
33. A polymer of the formula:
Figure imgf000219_0004
wherein, L3, L4, L5, L6, and L8 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted monovalent benzoxazine monomer;
z1 is independently an integer from 1 to 1000; and
p5 is independently an integer from 1 to 100.
34. The polymer of claim 33, wherein the polymer has the formula:
Figure imgf000220_0001
L2C is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R10 is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -O CH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
z10 is an integer from 0 to 5.
35. The polymer of claim 33, wherein L5 is
Figure imgf000221_0001
, L6 is
Figure imgf000221_0002
, and L8 is unsubstituted C1-C3 alkylene.
36. The polymer of claim 33, wherein the polymer has the formula:
Figure imgf000221_0003
.
37. A polymer comprising
(1) a repeating subunit, said repeating subunit having the formula:
Figure imgf000221_0004
wherein
Y has the formula:
Figure imgf000221_0005
Figure imgf000222_0001
the symbol“ ” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein said terminator moiety has the formula: -L3-R3;
(2) at each symbol“ ” is attached a different repeating subunit or a terminator moiety, wherein said terminator moiety has the formula: -L3-R3;
L1, L2, and L3 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
L4 is a covalent linker;
R1 is independently hydrogen, halogen, -CX13, -CHX13, -CH2X1, -OCX13, -OCH2X1, -OCHX13, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)O R1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted monovalent benzoxazine monomer;
R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
X, X1, and X2 are independently–F, -Cl, -Br, or–I;
n1 and n2 are independently an integer from 0 to 4;
v1, v2, m1, and m2 are each independently 1 to 2;
z5 is an integer from 1 to 1000;
z2 is independently an integer from 0 to 5; and
p1, p2, p3, and p4 are each independently an integer from 1 to 1000.
38. The polymer of claim 37, wherein R1 is
independently -NHC(O)NR1AR1B,
-NR1AR1B, -C(O)NR1AR1B, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
39. The polymer of claim 37, wherein R1 is–NH2.
40. The polymer of claim 37, wherein L1 is a bond, -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
41. The polymer of claim 37, wherein L1 is substituted or unsubstituted C1- C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene.
42. The polymer of claim 37, wherein L1 is substituted or unsubstituted C1- C2 alkylene.
43. The polymer of claim 37, wherein L4 is substituted or unsubstituted C1- C6 alkylene or a substituted or unsubstituted 2 to 6 membered heteroalkylene.
44. The polymer of claim 37, wherein L4 is substituted or unsubstituted C1- C2 alkylene.
45. The polymer of claim 37, wherein L4 is -C(O)CH2-,
Figure imgf000224_0001
46. The polymer of claim 37, wherein L2 is -C(O)-, -C(O)CH2-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
47. The polymer of claim 37, wherein L2 is substituted or unsubstituted C1- C6 alkylene.
48. The polymer of claim 37, wherein L2 is substituted or unsubstituted C1- C2 alkylene.
49. The polymer of claim 37, wherein R2 is -C(O)R2C, -C(O)-OR2C, -OR2D, -OC(O)R2C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.
50. The polymer of claim 37, wherein two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted 5 to 6 membered heterocycloalkyl.
51. The polymer of claim 37, wherein R2 is–OH, -OCH3, or -OTBS.
52. The polymer of claim 37, wherein
Figure imgf000225_0001
has the formula:
Figure imgf000225_0002
wherein,
R2.3 and R2.4 are each independently -OR2D, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R2.3 and R2.4 substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R2D is independently
hydrogen, -CX2 3, -CN, -COOH, -CONH2, -CHX2 2, -CH2X2, -CONH-(C1-C6 alkyl), -C(O)- (C1-C6 alkyl), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group.
53. The polymer of claim 37, wherein R3 is independently hydrogen, substituted or unsubstituted phenyl, or a monovalent benzoxazine monomer, wherein said monovalent benzoxazine monomer has the formula:
Figure imgf000225_0003
,
wherein,
L7 is a
bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-,
-NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and
R7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
54. A polymer comprising
(1) a subunit, said subunit having the formula:
Figure imgf000226_0001
wherein
the symbol“
Figure imgf000226_0002
” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein said terminator moiety has the formula: -L3-R3;
(2) at each symbol“ ” is attached a different subunit or a terminator moiety, wherein said terminator moiety has the formula: -L3-R3;
L3, L5, L6, and L8 are each independently a
bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-,
-C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
L4 is a covalent linker;
R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted monovalent benzoxazine monomer; and
p5 are each independently an integer from 1 to 100.
55. A polymer comprising (1) a repeating subunit, said repeating subunit having the formula:
Figure imgf000227_0005
wherein
Y has the formula:
Figure imgf000227_0004
,
Figure imgf000227_0003
Figure imgf000227_0001
has the formula:
Figure imgf000227_0002
the symbol“ ” is a point of attachment to a different repeating subunit or to a terminator moiety, wherein said terminator moiety has the formula: -L3-R3;
(2) at each symbol“ ” is attached a different repeating subunit or a terminator moiety, wherein said terminator moiety has the formula: -L3-R3;
L1, L2, L3, L5, L6, and L8 are each independently a
bond, -S(O)2-, -NH-, -O-, -S-,
-C(O)-, -C(O)NH-, -C(O)CH2-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
L4 is a covalent linker;
R1 is independently hydrogen, halogen, -CX13, -CHX13, -CH2X1, -OCX13, -OCH2X1, -OCHX1 3, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)O R1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted monovalent benzoxazine monomer;
R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
X, X1, and X2 are independently–F, -Cl, -Br, or–I;
n1 and n2 are independently an integer from 0 to 4; v1, v2, m1, and m2 are each independently 1 to 2;
z5 is an integer from 1 to 1000;
z2 is independently an integer from 0 to 5; and
p1, p2, p3, p4, and p5 are each independently an integer from 1 to 1000.
56. A method of making a compound, having the formula:
Figure imgf000229_0001
said method comprising mixing compound A and compound B together in a reaction vessel; wherein
compound A has the formula:
Figure imgf000229_0002
compound B has the formula:
Figure imgf000229_0003
wherein,
L1 and L2 are each independently a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted
cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R1 is independently hydrogen, halogen, -CX13, -CHX13, -CH2X1, -OCX13, -OCH2X1, -OCHX13, -CN, -SOn1R1D, -SOv1NR1AR1B, -NHC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)-OR1C, -C(O)NR1AR1B, -OR1D, -NR1ASO1R1D, -NR1AC(O)R1C, -NR1AC(O)O R1C, -NR1AOR1C, -OC(O)R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R5, R6, and R8 are each independently hydrogen, a protecting group, or a leaving group;
R1A, R1B, R1C, R1D, R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
n1 and n2 are independently an integer from 0 to 4;
v1, v2, m1, and m2 are each independently 1 to 2;
X, X1, and X2 are independently–F, -Cl, -Br, or–I; and
z2 is an integer from 0 to 5.
57. A method of making a compound, having the formula:
Figure imgf000231_0001
said method comprising mixing compound A and compound B together in a reaction vessel; wherein
compound A has the formula:
Figure imgf000231_0002
compound B has the formula:
Figure imgf000231_0003
wherein,
L2 is a bond, -S(O)2-, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-,
-NHC(O)NH-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
L4 is a covalent linker;
R2 is independently halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX2 2, -CN, -SOn2R2D, -SOv2NR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)-OR2C, -C(O)NR2AR2B, -OR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -OC(O)R2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2A, R2B, R2C, and R2D are each independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a protecting group, or a leaving group; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
X and X2 are independently–F, -Cl, -Br, or–I;
z2 is an integer from 0 to 5;
n2 is independently an integer from 0 to 4;
v2 and m2 are each independently 1 to 2; and
R5, R6, R8, and R9, are each independently hydrogen, a protecting group, or a leaving group.
58. The method of claim 56 or 57, wherein compound B has the formula:
Figure imgf000232_0001
.
59. The method of claim 56 or 57, wherein compound B has the formula:
Figure imgf000233_0001
60. The method of claim 56, wherein compound A has the formula:
Figure imgf000233_0002
.
61. The method of claim 56, wherein compound A has the formula:
Figure imgf000234_0001
.
62. The method of claim 57, wherein compound A has the formula:
Figure imgf000234_0002
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