Boronic Ester Prodrugs and Their Uses - Patent application

Abstract

Disclosed herein are compounds represented by formula (I) or (II). The compounds contain an agent (e.g., a pharmaceutical agent, a cosmetic agent, or a nutraceutical agent) via a linker containing a boronic ester moiety in the backbone of the linker. The compounds can be monomers. Polymers prepared by polymerizing the monomers are also provided. The polymers can be useful for delivering agents to subjects, tissues, biological samples, or cells. Methods for preparing the polymers, compositions and kits containing the polymers, and methods of use involving the polymers or compositions (e.g., use in delivering agents, treating diseases, preventing diseases, and diagnosing diseases) are also provided. The structure of the boronic ester moiety can be fine-tuned so that the properties for delivery to subjects, biological samples, tissues, or cells can be fine-tuned.

Description

Technical field

[0001] Related application This application claims priority under 35 U.S.C. § 119(e) to U.S. provisional application, U.S.S.N. incorporated. [Background technology]

[0002] government support This invention was made with Government support under Grant No. R01 CA220468 awarded by the National Institutes of Health. The Government has certain rights in this invention.

[0003] Background of the invention The delivery of agents (eg, drugs) via nanoparticles or other delivery vehicles has previously been investigated. The linker between vehicle and pharmaceutical agent is important for successful delivery that balances between stability and deliverability. Preferably, the linker is stable under physiological conditions until the vehicle reaches the destination where the linker is cleaved, which allows delivery of the agent. Linkers may also be used to modulate potency, efficacy, bioavailability, toxicity, absorption, distribution, metabolism, excretion, tolerability, compliance, and / or combinations thereof, which may affect linker stability. and adjustability are important components for successful delivery.

[0004] Previously, delivery systems containing covalent linkers have been developed for the delivery of chemotherapeutic drugs such as ixazomib and bortezomib via functionalization of the drugs via their boronic acid moieties. A problem with these reported delivery systems is poor linker stability in aqueous solution and / or poor linker tunability. For example, MIDA (N-methyliminodiacetic acid, 1) based boronic acid ligands were found to have poor stability when the secondary amine was functionalized with a longer alkyl change than the methyl group (Ashley et al. , J. C. et al., J. Med. Chem., 2014, 57, 5282). Increased steric hindrance makes boron more difficult to coordinate, which makes it ineffective for increasing the stability of boronic acid functional groups in aqueous solutions (PBS, blood, etc.). Additional boronate esters based on 2 below have also been reported, but were also found to have poor stability in aqueous solutions due to the boronic acid moiety (Ashley, J. C. et al. , J. Med. Chem., 2014, 57, 5282). Boronate esters of 3 have been used to make prodrugs for ixazomib, a drug used for the treatment of multiple myeloma. Linkers 1, 2, and 3 have been used with the multiple myeloma and mantle cell lymphoma chemotherapy bortezomib, liposomes with known stability problems in blood due to dilution above the critical micelle concentration. was made (Ashley, J. C. et al., J. Med. Chem., 2014, 57, 5282). After all, these linkers are not tunable. Linker 3 could not be functionalized with other moieties than the boronic acid drug (Ashley, J. C. et al., J. Med. Chem., 2014, 57, 5282). In addition, boronate esters of 4, oxazaborolidines 5, and diazaborolidines of 6 have previously been reported as linkers for bortezomib, but the boronic acid functionality in each case poses stability problems in aqueous solutions. and has been limited to use with trialkoxysilyl functional groups to bind to silica (Pasqua, L. et al., PCT Publication WO 2016 / 174693 A1, 2016). In addition, each of these examples show poor biological data, showing little improvement compared to free bortezomib and other boronic drugs. Ultimately, there remains a need for improved drug delivery systems. [formation]

[0005] Multiple myeloma (MM) is a lethal plasma cell dysplasia that progresses from the precursors of monoclonal gammaglobulinemia (MGUS) and smoldering multiple myeloma (SMM). 1,2 The incidence of MGUS is approximately 3% of the general population over the age of 50. 3,4 Proteasome inhibitors (PIs) are a standard of care treatment in MM, often used in combination with immunomodulators (lenalidomide, pomalidomide), and corticosteroids (dexamethasone). 5,6 PI targets the ubiquitin proteasome pathway (UPP), which is highly dependent due to the increased need for immunoglobin production in MM. UPP plays a role as a key regulator of cell function, such as cell growth and cell survival, across many cell types. 7,8 PIs were originally investigative probes to study the catalytic function of the proteasome, but due to their tremendous efficacy in suppressing tumor growth and inducing apoptosis, PIs have become a therapeutic for MM. was rapidly investigated as a drug. 9 Bortezomib (Btz) became a first-in-class PI approved by the FDA in 2003 for the treatment of MM and is now widely used as a first-line treatment for MM. 10 Nevertheless, Btz has been a first-line therapy for over a decade, but suffers from several drawbacks, including high degrees of neurotoxicity, thrombocytopenia, and lymphopenia. 11 Btz also suffers from poor drug-like properties, including poor water solubility and stability. 11 Altogether, these factors greatly limit the pharmacokinetic parameters of Btz, such as maximum serum concentration and exposure time, which impose a very narrow therapeutic index (TI) and limit its efficacy in MM.

[0006] To address these issues, drug discovery has been conducted to establish new PI candidates. For example, carfilzomib (CFZ), a second-generation irreversible PI, was developed and subsequently approved by the FDA in 2012. 12 A structurally distinct form from its first-generation counterpart, CFZ exhibits higher stability up to 14 days at room temperature, as well as lower toxicity due to higher target specificity. 13 Despite its improvement in patient outcomes in clinical trials, CFZ requires several procedures that are more cumbersome than its traditional subcutaneous injection route, with long continuous infusion sessions. Another attempt to address Btz's shortcomings from a drug discovery perspective has resulted in the 2015 approval of Btz's structural analog, ixazomib (Ixa). In this PI, the active site is conjugated with the citric acid molecule, allowing oral administration of the molecule. Its performance over Btz has not been demonstrated in terms of efficacy, but its ease of use has led to rapid clinical adoption. However, all these PIs still lack target specificity and have undesirable toxicities. 14,15

[0007] As an alternative to medicinal chemistry efforts, drug delivery—particularly via nanotechnology—offers another approach to alleviate the shortcomings of Btz without the need to rediscover entirely new drug candidates. Towards this end, attempts to introduce free Btz drug or conjugated Btz prodrugs into drug delivery systems (DDS) have ranged from liposomal formulation via encapsulation to formation of micelles via a self-assembly process. A few have been considered. 16-29 Although incorporating Btz into DDS improves its stability and in-vivo pharmacokinetics, the final size of the Btz-loaded vehicle typically falls in the 100-200 nm range for liposomes. 16-22 , or ~50 nm for micelles. 23-27 This size range is not optimal for MM therapy because these sizes cannot effectively penetrate and accumulate in pathological plasma cells or non-vascular, circulating tumor cells residing in the bone marrow niche. do not have. 30 Moreover, current problems with liposome-based DDS, such as poor tissue penetration or rupture, uncontrolled payload release, remain unresolved. 31-33 To address these shortcomings, various studies have been conducted with the aim of utilizing the boronic acid moiety on Btz to give a more controlled release and exposure profile via the prodrug formation process. 21-29 Most of these boronate ester prodrugs have naturally occurring binding motifs containing catechol / dopamine analogues, 24,26-29 natural diols, pinanediol, etc. 23 and sugar-based 21,25 Utilize compounds. These strategies are limited by the availability of these linker structures; this is in turn through rational design of the linker structures to achieve precise and desired in vivo release profiles. , prevent this prodrug approach from being fully exploited. [Outline of the invention]

[0008] SUMMARY OF THE INVENTION Previous work by our group has yielded fully covalent bottle-brush (BBP) and brush-arm star polymer (BASP) delivery platforms. 34-39These polymers are built from macromonomers containing exactly one payload per unit, and ring-opening metathesis polymerization (ROMP) in which the monomer feed ratio is readily reflected in the final composition of the resulting polymer. ). Furthermore, by chemically modifying the linker that conjugates each payload to its macromonomer building block, payload release kinetics can be rationally optimized. 40,41 The size of these polymers can also be controlled through systematic variations in polymer composition and nanoarchitecture, allowing a wide range of choices depending on the target diseased tissue. 37-43 This rich toolbox has so far incorporated a variety of therapeutic agents (or combinations thereof), allowing subsequent in vivo delivery in solid mouse cancer models. 34-43

[0009] Herein, we deploy this platform towards MM, a hematologic malignancy with liquid tumors that is difficult to target and thus requires further specialization of this unique BBP nanoarchitecture. to report an attempt to To achieve this goal, Btz is conjugated to the macromonomer scaffold via an entirely synthetic linker, giving freedom to modify its structure to influence the final release profile. Subsequent ROMP of these monomers yielded polymers designed to ~10 nm in size, which is in the same regime as therapeutic proteins, facilitating efficient accumulation and penetration of MM in tumor targets described above. Conceivable. 30,44 In vitro cellular assays revealed comparable toxicity of Btz-BBP compared to its free Btz counterpart, confirming the ability of Btz-BBP to release its payload in the tumor microenvironment. Furthermore, the in vivo toxicity of Btz-BBP in healthy BALB / c mice showed a significant ≧20-fold increase in maximal tolerated dose (MTD) compared to free Btz, which in turn was associated with tumor-bearing mice. It resulted in improved effectiveness in the model. In the subcutaneous model, Btz-BBP outperforms its parent drug at the same dose (MTD of Btz) and further improves in the MTD of Btz-BBP. Furthermore, in an aggressive orthotopic model in which parental Btz did not result in improvement in treatment outcome, Btz-BBP effectively inhibited tumor growth and subcutaneous and orthotopic multiple marrow in multiple myeloma. In both tumor mouse models, we were able to prolong survival by 2-fold and 3-fold, respectively. Taken together, these results clearly confirm the DDS design principle and demonstrate this promising PI-improved TI.

[0010] Described herein are compounds that include an agent via a linker that includes a boronate ester moiety in the backbone of the linker. In some embodiments, the agent is a pharmaceutical agent (eg, bortezomib), cosmetic agent, or nutraceutical agent. In some embodiments, the compound includes a polymerizing handle and is thus a monomer. Polymers (e.g., homopolymers, copolymers, charged polymers, hydrophilic polymers , linear polymers, branched polymers, brush polymers, bottle brush polymers) are also provided. Polymers can be useful for delivering agents to a subject, tissue, biological sample, or cell. Methods of preparing the polymers, compositions and kits comprising the polymers, and methods of use involving the polymers or compositions (e.g., delivering agents, treating disease, preventing disease, diagnosing disease) use in doing) is also provided.

[0011] The structure of the boronate ester moiety may be fine-tuned to fine-tune properties (eg, stability under physiological conditions) for delivery to a subject, biological sample, tissue, or cell. Polymers with the desired properties for delivery are associated with higher potency, higher efficacy, higher bioavailability, less toxicity, higher absorption, greater distribution, faster or slower metabolism, faster or slower excretion, drug may result in a broader therapeutic window for , higher tolerability, higher subject compliance, and / or combinations thereof. Without being bound by any particular theory, the majority of the boronate ester moieties may be fine-tuned to fine tune delivery properties.

[0012] In one aspect, compounds of the disclosure are represented by Formula (I) or (II): [formation] or its salt, where X, L 1 , Y, c, L, M, m, and d are as described herein.

[0013] In certain embodiments, the compound represented by Formula (I) is represented by Formula (I-1): [formation] or its salt.

[0014] In another aspect, the disclosure provides a method of preparing a polymer comprising polymerizing the monomers described herein. In some embodiments, the polymerizing step includes the presence of a metathesis catalyst.

[0015] In another aspect, the disclosure provides polymers prepared by the methods described herein.

[0016] In another aspect, the disclosure provides compositions comprising the polymers described herein and optionally excipients.

[0017] In another aspect, the disclosure provides a kit comprising a polymer or composition described herein; and instructions for using the polymer or composition.

[0018] In another aspect, the present disclosure provides a method of delivering an agent to a biological sample, tissue, or cell, the method comprising contacting the biological sample, tissue, or cell with a polymer described herein. The method is provided, comprising:

[0019] In another aspect, the disclosure is a method of delivering an agent to a subject in need thereof, the method comprising administering a polymer described herein to the subject in need thereof. , to provide the method.

[0020] In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, comprising administering a therapeutically effective amount of a polymer or composition described herein , to a subject in need thereof, wherein at least one M is a therapeutic agent.

[0021] In another aspect, the present disclosure provides a method of preventing disease in a subject in need thereof, comprising administering a therapeutically effective amount of a polymer or composition described herein , to a subject in need thereof, wherein at least one M is a prophylactic agent.

[0022] In another aspect, the present disclosure provides a method of diagnosing a disease in a subject in need thereof, comprising administering a therapeutically effective amount of a polymer or composition described herein , to a subject in need thereof, wherein at least one M is a diagnostic agent.

[0023] In another aspect, the disclosure provides uses of the polymers, compositions, and kits described herein (eg, use in methods described herein).

[0024] Details of certain embodiments of the invention are presented in the "Detailed Description of Certain Embodiments" section below. Other features, objects, and advantages of the invention will become apparent from the definitions, figures, examples, and claims. It is to be understood that the aspects described herein are not limited to particular embodiments, methods, apparatus, or configurations, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting unless specifically defined herein. should. [Brief description of the drawing]

[0025]

Figure 1

[0026]

Figure 2

[0027] [Fig.3] Figure 3 shows the GPC graph of Btz-BBP.

[0028] [Figure 4]FIG. 4 shows the mass spectrum using MALDI of Ixa-BBP.

[0029] [Fig.5] Figure 5 shows the GPC graph of Ixa-BBP.

[0030] [Fig.6] FIG. 6 shows the mass spectrum of BtzC-BBP using MALDI-TOF.

[0031] [Fig.7] Figure 7 shows a GPC graph of BtzC-BBP.

[0032] [Fig. 8A] FIG. 8A shows in vitro cell viability in MM1S.

[0033] [Fig. 8B] FIG. 8B shows in vitro cell viability in KMS11.

[0034] [Figures 9A-9E] Figures 9A-9E show the in vivo maximum tolerated dose by survival rate, and each group (n = 3-5) was administered 4 times, except for the 20 mg / kg group, which was administered 3 times.

[0035] [Fig. 9A] Figure 9A shows Kaplan-Meier survival curves of injected mice.

[0036] [Figure 9B] FIG. 9B shows body weight measurements (n=5) of mice injected intravenously with various doses of Btz-BBP. The dashed line corresponds to the 20% weight loss toxicity threshold.

[0037] [Figure 9C] FIG. 9C Metabolic profile of healthy BALB / c mice (n=3) treated for 2 weeks (2 injections / week) followed by a 2-week rest period (no injections) prior to blood collection and analysis. indicates

[0038] [Fig.9D] Figure 9D shows whole blood from healthy BALB / c mice (n=3) treated for 2 weeks (2 injections / week) followed by a 2-week rest period (no injections) prior to blood collection and analysis. show calculations.

[0039] [Figure 9E] Figure 9E shows differences in leukocytes in healthy BALB / c mice (n=3) treated for 2 weeks (2 injections / week) followed by a 2-week rest period (no injections) prior to blood collection and analysis. indicate the number.

[0040] [Fig. 10A] Figure 10A shows assessment of tumor accumulation and penetration of Btz-BBP (Cy5.5 labeled) by fluorescence microscopy; tumors were harvested 1 hour after injection (iv). For efficacy evaluation, KMS11 subcutaneous tumor-bearing mice (Btz-resistant) were injected with PBS, Btz, or Btz-BBP (2 injections / week, 4 weeks) until the maximum axis of the tumor was 5 mm long. started when it reached

[0041] [Fig. 10B] FIG. 10B shows fold-change individual spider plots (n=5) showing the progression of tumor size over the period of the study. Statistical analysis was performed between the Btz and Btz-BBP groups using a two-tailed t-test.

[0042] [Fig. 10C] FIG. 10C shows the fold change in tumor volume in a SCID KMS11 subcutaneous mouse model, where the dosing schedule consists of weekly injections. Statistical analysis was performed between the Btz and Btz-BBP groups using a two-tailed t-test.

[0043] [Fig. 10D] FIG. 10D shows Kaplan-Meier survival curves in a mouse model of SCID KMS11 subcutaneous, where the dosing schedule consists of weekly injections. These demonstrate an improvement in therapeutic outcome of Btz-BBP over free Btz at both the same and higher doses. Statistical analysis was performed using the Log-Rank test. (*P<0.05, **P<0.01, ***P<0.001)

[0044] [Fig. 11A] FIG. 11A shows the fold change in tumor volume in a SCID MM.1A subcutaneous mouse model, where the dosing schedule consists of weekly injections.

[0045] [Fig. 11B] FIG. 11B shows survival in a mouse model of SCID MM.1A subcutaneous, where the dosing schedule consists of weekly injections.

[0046] [Fig. 11C] FIG. 11C shows individual spider plots showing tumor size progression over the period of the study (n=5). Statistical analysis was performed between the Btz and Btz-BBP groups using a two-tailed t-test.

[0047] [Fig. 12A] FIG. 12A shows tumors imaged via bioluminescence at day 20 in a control group not receiving Btz.

[0048] [Fig. 12B] FIG. 12B shows tumors imaged via bioluminescence on day 20 in groups receiving 0.75 mg / kg Btz per injection.

[0049] [Fig. 12C] FIG. 12C shows tumors imaged via bioluminescence on day 20 in groups receiving 18.75 mg / kg Btz-BBP per injection.

[0050] [Fig. 12D] FIG. 12D shows tumors imaged via bioluminescence imaging of MM.1S GFP+ / LUC+ disseminated cells at day 0 in a control group not receiving Btz.

[0051] [Fig. 12E] FIG. 12E shows tumors imaged via bioluminescence imaging of MM.1S GFP+ / LUC+ disseminated cells on day 0 in groups receiving 0.75 mg / kg Btz per injection.

[0052] [Fig. 12F] FIG. 12F shows tumors imaged via bioluminescence imaging of MM.1S GFP+ / LUC+ disseminated cells on day 0 in groups receiving 18.75 mg / kg Btz-BBP per injection. show.

[0053] [Fig. 13] Figure 13 shows the hydrodynamic diameter (Dh) of Btz-BBP determined by dynamic light scattering (DLS).

[0054] [Fig. 14] Figure 14 shows the weight monitor (BWM) during efficacy studies in the MM subcutaneous mouse model.

[0055] [Fig. 15] Figure 15 shows BWM during efficacy studies in the MM orthotopic mouse model.

[0056] definition For convenience, certain terms used in the specification, examples and appended claims are collected here.

[0057] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0058] The following definitions are for the more general terms used throughout this application:

[0059] The singular terms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0060] All numbers expressing quantities of ingredients or reaction conditions used herein, except in the examples, or where otherwise indicated, are in all instances modified by the term "about." It should be understood that "About" and "approximately" shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%) of a given value or range of values, typically within 10%, more typically within 5%, 4%, 3%, 2%, or Within 1%.

[0061] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are taken from the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., identified according to the inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivities, can be found in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0062] The compounds described herein can contain one or more asymmetric centers, and can therefore exist in various stereoisomeric forms, including enantiomers and / or diastereomers. . For example, the compounds described herein can be in the form of individual enantiomers, diastereomers or geometric isomers, or stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. It can also be in the form of a mixture of isomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; can be prepared. For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962 ); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses the compounds as individual isomers substantially free of other isomers and, alternatively, as mixtures of various isomers.

[0063] When a range of values ​​is stated, it is intended to include each value and subrange within that range. For example, "C 1 -C 6 "Alkyl" is intended to include: C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 Alkyl.

[0064] The term "alkyl" refers to the radical of a straight or branched saturated hydrocarbon group. In some embodiments, the alkyl group has 1-1000 carbon atoms (“C 1 -C 1000 alkyl”), 1 to 900 carbon atoms (“C 1 -C 900 alkyl”), 1 to 800 carbon atoms (“C 1 -C 800 alkyl”), 1 to 700 carbon atoms (“C 1 -C 700 alkyl”), 1 to 600 carbon atoms (“C 1 -C 600 alkyl”), 1 to 500 carbon atoms (“C 1 -C 500 alkyl”), 1 to 400 carbon atoms (“C 1 -C 400 alkyl”), 1 to 300 carbon atoms (“C 1 -C 300 alkyl”), 1 to 200 carbon atoms (“C 1 -C 200 alkyl”), 1 to 100 carbon atoms (“C 1 -C 100 alkyl”). In some embodiments, the alkyl group has 1-10 carbon atoms (“C 1 -C 10 alkyl”), 1 to 9 carbon atoms (“C 1 -C 9 alkyl”), 1 to 8 carbon atoms (“C 1 -C 8 alkyl”), 1 to 7 carbon atoms (“C 1 -C 7 alkyl”), 1 to 6 carbon atoms (“C 1 -C 6 alkyl”), 1 to 5 carbon atoms (“C 1 -C 5 alkyl”), 1 to 4 carbon atoms (“C 1 -C 4 alkyl”), 1 to 3 carbon atoms (“C 1 -C 3 alkyl”), 1-2 carbon atoms (“C 1 -C 2 alkyl”), or one carbon atom (“C 1 alkyl”). C. 1 -C 6 Examples of alkyl groups include: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ). Examples of additional alkyl groups include: n-heptyl (C 7 ), n-octyl (C 8 )etc. Unless specified otherwise, each alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents (“substituted alkyl”).

[0065] The term "alkenyl" refers to radicals of straight or branched hydrocarbon groups having 2 to 1000 carbon atoms and 1 or more carbon-carbon double bonds (eg, 1, 2, 3, or 4 double bonds). Point. In some embodiments, alkenyl groups have from 2 to 1000 carbon atoms (“C 2 -C 1000 alkenyl”), 2 to 900 carbon atoms (“C 2 -C 900 alkenyl”), 2 to 800 carbon atoms (“C 2 -C 800 alkenyl”), 2 to 700 carbon atoms (“C 2 -C 700 alkenyl”), 2 to 600 carbon atoms (“C 2 -C 600 alkenyl”), 2 to 500 carbon atoms (“C 2 -C 500 alkenyl”), 2 to 400 carbon atoms (“C 2 -C 400 alkenyl”), 2-300 carbon atoms (“C 2 -C 300 alkenyl”), 2-200 carbon atoms (“C 2 -C 200 alkenyl”), 2 to 100 carbon atoms (“C 2 -C 100 alkenyl”). In some embodiments, alkenyl groups have 2-9 carbon atoms (“C 2-9 alkenyl”). In some embodiments, alkenyl groups have 2-8 carbon atoms (“C 2-8 alkenyl”). In some embodiments, alkenyl groups have 2-7 carbon atoms (“C 2-7 alkenyl”). In some embodiments, alkenyl groups have 2-6 carbon atoms (“C 2-6 alkenyl”). In some embodiments, an alkenyl group has 2-5 carbon atoms (“C 2-5 alkenyl”). In some embodiments, alkenyl groups have 2-4 carbon atoms (“C 2-4 alkenyl”). In some embodiments, alkenyl groups have 2-3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”). One or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl). C. 2-4 Examples of alkenyl groups include: ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 )etc. C. 2-6 Examples of alkenyl groups include: C 2-4 alkenyl and pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 )etc. Unless otherwise specified, each alkenyl group is independently unsubstituted (“unsubstituted alkenyl”) or substituted with one or more substituents (“substituted alkenyl”). In alkenyl groups, C=C double bonds with unspecified stereochemistry (e.g., -CH=CHCH 3 , [formation] ) may be in the (E)- or (Z)-configuration.

[0066] The term "alkynyl" refers to radicals of straight or branched hydrocarbon groups having from 2 to 1000 carbon atoms and one or more carbon-carbon triple bonds (eg, 1, 2, 3, or 4 triple bonds). . In some embodiments, the alkynyl group has 2-1000 carbon atoms (“C 2 -C 1000 alkynyl”), 2 to 900 carbon atoms (“C 2 -C 900 alkynyl”), 2 to 800 carbon atoms (“C 2 -C 800 alkynyl”), 2 to 700 carbon atoms (“C 2 -C 700 alkynyl”), 2 to 600 carbon atoms (“C 2 -C 600 alkynyl”), 2 to 500 carbon atoms (“C 2 -C 500 alkynyl”), 2 to 400 carbon atoms (“C 2 -C 400 alkynyl”), 2-300 carbon atoms (“C 2 -C 300 alkynyl”), 2-200 carbon atoms (“C 2 -C 200 alkynyl”), 2 to 100 carbon atoms (“C 2 -C 100 alkynyl”). In some embodiments, alkynyl groups have 2-9 carbon atoms (“C 2-9 alkynyl”), 2 to 8 carbon atoms (“C 2-8 alkynyl”), 2 to 7 carbon atoms (“C 2-7 alkynyl”), 2 to 6 carbon atoms (“C 2-6 alkynyl”), 2-5 carbon atoms (“C 2-5 alkynyl”), 2-4 carbon atoms (“C 2-4 alkynyl”), 2-3 carbon atoms (“C 2-3 alkynyl”), or two carbon atoms (“C 2 alkynyl”). One or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl). C. 2-4 Examples of alkynyl groups include, without limitation: ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 )etc. C. 2-6 Examples of alkenyl groups include: C 2-4 alkynyl groups and pentynyl (C 5 ), hexynyl (C 6 )etc. Unless otherwise specified, each n-alkynyl group is independently unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents (“substituted alkynyl”).

[0067] The term "heteroalkyl" includes at least one heteroatom (eg, 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, phosphorus, or sulfur within the parent chain (i.e., adjacent carbon interposed between atoms) and / or at one or more terminal position(s). In some embodiments, a heteroalkyl group has from 1 to 1000 carbon atoms and one or more heteroatoms in the parent chain (“C 1- C. 1000 heteroalkyl”), from 1 to 900 carbon atoms and 1 or more heteroatoms in the parent chain (“C 1- C. 900 heteroalkyl”), from 1 to 800 carbon atoms and 1 or more heteroatoms in the parent chain (“C 1- C. 800 heteroalkyl”), from 1 to 700 carbon atoms and 1 or more heteroatoms in the parent chain (“C 1- C. 700 heteroalkyl”), from 1 to 600 carbon atoms and 1 or more heteroatoms in the parent chain (“C 1- C. 600 heteroalkyl”), from 1 to 500 carbon atoms and 1 or more heteroatoms in the parent chain (“C 1- C. 500 heteroalkyl”), from 1 to 400 carbon atoms and 1 or more heteroatoms in the parent chain (“C 1- C. 400 heteroalkyl”), from 1 to 300 carbon atoms and 1 or more heteroatoms in the parent chain (“C 1- C. 300 heteroalkyl”), from 1 to 200 carbon atoms and 1 or more heteroatoms in the parent chain (“C 1- C. 200 heteroalkyl”), or 1-100 carbon atoms and 1 or more heteroatoms in the parent chain (“C 1 -C 100 heteroalkyl") refers to saturated groups with In some embodiments, a heteroalkyl group has 1-10 carbon atoms and one or more heteroatoms in the parent chain (“C 1- C. 10 heteroalkyl”), from 1 to 9 carbon atoms and one or more heteroatoms in the parent chain (“C 1- C. 9 heteroalkyl"), 1-8 carbon atoms and one or more heteroatoms in the parent chain ("C 1- C. 8 heteroalkyl"), 1-7 carbon atoms and 1 or more heteroatoms in the parent chain ("C 1- C. 7 heteroalkyl"), 1-6 carbon atoms and one or more heteroatoms in the parent chain ("C 1- C. 6 heteroalkyl"), 1-5 carbon atoms and 1 or more heteroatoms in the parent chain ("C 1- C. 5 heteroalkyl"), 1-4 carbon atoms and 1 or more heteroatoms in the parent chain ("C 1- C. 4 heteroalkyl"), 1-3 carbon atoms and one or more heteroatoms in the parent chain ("C 1- C. 3 heteroalkyl”), 1-2 carbon atoms and 1 heteroatom in the parent chain (“C 1- C. 2 heteroalkyl”), or one carbon atom and one heteroatom (“C 1 heteroalkyl") refers to saturated groups with Unless specified otherwise, each heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”).

[0068] The term "heteroalkenyl" includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (i.e., adjacent carbon interposed between atoms) and / or further comprising at one or more terminal position(s). In some embodiments, a heteroalkenyl group has from 1 to 1000 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1- C. 1000 alkenyl”), from 1 to 900 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 900 alkenyl”), from 1 to 800 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 800 alkenyl”), from 1 to 700 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 700 alkenyl”), from 1 to 600 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 600 alkenyl”), from 1 to 500 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 500 alkenyl”), from 1 to 400 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 400 alkenyl”), from 1 to 300 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 300 alkenyl”), from 1 to 200 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 200 alkenyl”), or 1 to 100 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1 -C 100alkenyl”) refers to a saturated group having In some embodiments, a heteroalkenyl group has 2-10 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-10 alkenyl”). In some embodiments, a heteroalkenyl group has 2-9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2-8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2-7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2-6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2-5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2-4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 alkenyl”). In some embodiments, a heteroalkenyl group has 2-3 carbon atoms, at least one double bond, and 1 heteroatom in the parent chain ("heteroC 2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2-6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 alkenyl”). Unless specified otherwise, each heteroalkenyl group is independently unsubstituted (“unsubstituted heteroalkenyl”) or substituted with one or more substituents (“substituted heteroalkenyl”). In some embodiments, the heteroalkenyl group is an unsubstituted heteroC 2-10 It is alkenyl. In some embodiments, the heteroalkenyl group is a substituted heteroC 2-10 It is alkenyl.

[0069] The term "heteroalkynyl" includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (i.e., adjacent carbon interposed between atoms) and / or further comprising at one or more terminal position(s). In some embodiments, a heteroalkynyl group has from 1 to 1000 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1- C. 1000 alkynyl”), from 1 to 900 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 900 alkynyl”), from 1 to 800 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 800 alkynyl”), from 1 to 700 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 700 alkynyl), from 1 to 600 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 600 alkynyl”), from 1 to 500 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 500 alkynyl”), from 1 to 400 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 400 alkynyl”), from 1 to 300 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 300 alkynyl”), from 1 to 200 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1- C. 200 ), or 1 to 100 carbon atoms and 1 or more heteroatoms in the parent chain (“heteroC 1 -C 100 alkynyl”) refers to a saturated group having In some embodiments, a heteroalkynyl group has 2-10 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-10 alkynyl”). In some embodiments, a heteroalkynyl group has 2-9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2-8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-8 alkynyl”). In some embodiments, a heteroalkynyl group has 2-7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2-6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2-5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2-4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2-3 carbon atoms, at least one triple bond, and 1 heteroatom in the parent chain ("heteroC 2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2-6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6 alkynyl”). Unless otherwise specified, each heteroalkynyl group is independently unsubstituted (“unsubstituted heteroalkynyl”) or substituted with one or more substituents (“substituted heteroalkynyl”). In some embodiments, a heteroalkynyl group is an unsubstituted heteroC 2-10 is alkynyl. In some embodiments, a heteroalkynyl group is a substituted heteroC 2-10 is alkynyl.

[0070] The term "carbocyclyl" or "carbocyclic" or "cycloalkyl" means 3 to 10 ring carbon atoms ("C 3-10 Carbocyclyl") and refers to the radical of a non-aromatic cyclic hydrocarbon group having zero heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclyl group has 3-8 ring carbon atoms (“C 3-8 carbocyclyl”), 3-7 ring carbon atoms (“C 3-7 carbocyclyl”), 3-6 ring carbon atoms (“C 3-6 carbocyclyl”), 4-6 ring carbon atoms (“C 4-6 carbocyclyl”), 5-6 ring carbon atoms (“C 5-6 carbocyclyl”), or 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”). Example C 3-6 Carbocyclyl groups include, but are not limited to: cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 )etc. Example C 3-8 Carbocyclyl groups include, but are not limited to: C 3-6 Carbocyclyl and cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 )etc. Example C 3-10 Carbocyclyl groups include, but are not limited to: C 3-8 Carbocyclyl and cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 )etc. As the above examples demonstrate, in certain embodiments, a carbocyclyl group can be monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., fused, bridged, or spiro ring systems, e.g., bicyclic (“bicyclic carbocyclyl”) or tricyclic (containing “tricyclic carbocyclyl”)), and can be saturated, or one or more carbon-carbon double or triple It can contain bonds. "Carbocyclyl" also includes relationships where the carbocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and where such, the number of carbons continues to specify the number of carbons in the carbocyclic ring system. Unless specified otherwise, each carbocyclyl group is independently unsubstituted (“unsubstituted carbocyclyl”) or substituted with one or more substituents (“substituted carbocyclyl”).

[0071] The terms "heterocyclyl" or "heterocyclic" refer to radicals of 3-14 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently nitrogen , oxygen, phosphorus, and sulfur (“3- to 14-membered heterocyclyl”). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valences permit. Heterocyclyl groups may be monocyclic (“monocyclic heterocyclyl”) or polycyclic (eg, bicyclic (“bicyclic heterocyclyl”) or tricyclic (“tricyclic heterocyclyl”) fused) , bridged or spiro ring systems) and can be saturated or contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" means a ring system in which a heterocyclyl ring as defined above is fused with one or more carbocyclyl groups and the point of attachment is either the carbocyclyl or heterocyclyl ring, or a heterocyclyl ring as defined above Also includes ring systems where the ring is fused with one or more aryl or heteroaryl groups and the point of attachment is on a heterocyclyl ring, and in such cases, the number of ring members continues to specify the number of ring members in the heterocyclyl ring system. Unless specified otherwise, each heterocyclyl is independently unsubstituted (“unsubstituted heterocyclyl”) or substituted with one or more substituents (“substituted heterocyclyl”).

[0072] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently nitrogen, oxygen, phosphorus, , and sulfur (“5- to 10-membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently nitrogen, oxygen, phosphorus, and selected from sulfur (“5- to 8-membered heterocyclyl”); In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently nitrogen, oxygen, phosphorus, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0073] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation: azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation: azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2. ,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation: dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation: piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation: triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation: azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation: azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, Tetrahydroisoquinolinyl, Decahydroquinolinyl, Decahydroisoquinolinyl, Octahydrochromenyl, Octahydroisochromenyl, Decahydronaphthyridinyl, Decahydro-1,8-naphthyridinyl, Octahydropyrrolo[3,2 -b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5, 6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c] pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2, 3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3, 4-tetrahydro-1,6-naphthyridinyl and the like.

[0074] The term "aryl" refers to an aromatic ring system ("C 6-14 A monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., cyclic ) radicals with 6, 10, or 14 pi electrons shared in the array. In some embodiments, the aryl group has 6 ring carbon atoms (“C 6 aryl”; as an example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C 10 aryl"; examples include naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C 14 aryl”; for example, anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups and the radical or point of attachment is on the aryl ring; The number of atoms continues to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each aryl group is independently unsubstituted (“unsubstituted aryl”) or substituted with one or more substituents (“substituted aryl”).

[0075] The term "heteroaryl" refers to a 5- to 14-membered monocyclic or polycyclic (eg, bicyclic or tricyclic) ring carbon atoms and 1-4 ring heteroatoms provided in an aromatic ring system. Formula ) refers to a radical of a 4n+2 aromatic ring system (eg, having 6, 10, or 14 π electrons shared in a cyclic array), where each heteroatom is independently nitrogen, acid independently elemental , and sulfur (“5- to 14-membered heteroaryl”). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be on a carbon or nitrogen atom, valency permitting. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, the point of attachment is on the heteroaryl ring, and where such ring members continues to specify the number of ring members in a heteroaryl ring system "Heteroaryl" means a heteroaryl ring, as defined above, fused with one or more aryl groups and the point of attachment is either an aryl or heteroaryl ring and in such cases the number of ring members specifies the number of ring members in a fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., a ring with a heteroatom (eg 2-indolyl) or rings without heteroatoms (eg 5-indolyl). A heteroaryl group may be monovalent or have more than one point of attachment to another moiety (eg, may be divalent, trivalent, etc.), the valency of the group being It may be specified directly in the name. For example, "triazoldiyl" and "triazolylene" refer to a divalent triazolyl moiety.

[0076] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently is selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently is selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently is selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless specified otherwise, each heteroaryl group is independently unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”).

[0077] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation: pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation: triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups having 4 heteroatoms include, without limitation: tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation: pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation: triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation: azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, Benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation: phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

[0078] As will be appreciated from the above, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heteroaryl groups are, in certain embodiments, optionally substituted. Optionally substituted refers to groups that may be substituted or unsubstituted (eg, "substituted" or "unsubstituted" alkyl). In general, the term "substituted" means that at least one hydrogen present in a group is replaced by an acceptable substituent, eg, by substitution, by a stable compound, eg, by rearrangement, cyclization, elimination, or other reaction, etc. a compound that does not spontaneously undergo a transformation. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and if more than one position in any given structure is substituted, Substituents are either the same or different at each position. The term "substituted" is contemplated to include all permissible substituents of organic compounds, substitution with any substituent described herein that results in the formation of a stable compound. This disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, a heteroatom such as nitrogen is a hydrogen substituent and / or any suitable substituent as described herein that satisfies the valences of the heteroatom and results in the formation of a stable moiety. may have

[0079] Appending the suffix "ene" to a group indicates that the group is a multivalent (eg, divalent, trivalent, tetravalent, or pentavalent) moiety. In some embodiments, adding the suffix "ene" to a group indicates that the group is a divalent moiety (for example, carbocyclene is a carbocyclic ring that is divalent). (For example, C 6 Alkyl-carbocyclyl-C 6 alkyl)).

[0080] Exemplary carbon atom substituents include, but are not limited to: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa , -ON(R bb ) 2 , -N(R bb ) 2 , -N(R bb ) 3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO 2 H, -CHO, -C(OR cc ) 2 , -CO 2 R. aa , -OC(=O)R aa , -OCO 2 R. aa , -C(=O)N(R bb ) 2 , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R. aa , -NR bb C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb ) OR aa , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -C(=NR bb )N(R bb ) 2 , -OC(=NR bb )N(R bb ) 2 , -NR bb C(=NR bb )N(R bb ) 2 , -C(=O)NR bb SO 2 R. aa , -NR bb SO 2 R. aa , -SO 2 N(R bb ) 2 , -SO 2 R. aa , -SO 2 OR aa , -OSO 2 R. aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa ) 3 , -OSi(R aa ) 3 -C(=S)N(R bb ) 2 , -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -OP(=O)(R aa ) 2 , -OP(=O)(OR cc ) 2 , -P(=O)(N(R bb ) 2 ) 2 , -OP(=O)(N(R bb ) 2 ) 2 , -NR bb P(=O)(R aa ) 2 , -NR bb P(=O)(OR cc ) 2 , -NR bb P(=O)(N(R bb ) 2 ) 2 , -P(R cc ) 2 , -P(OR cc ) 2 , -P(R cc ) 3+ X - , -P(OR cc ) 3 + X - , -P(R cc ) 4 , -P(OR cc ) 4 , -OP(R cc ) 2 , -OP(R cc ) 3 + X - , -OP(OR cc ) 2 , -OP(OR cc ) 3 + X - , -OP(R cc ) 4 , -OP(OR cc ) 4 , -B(R aa ) 2 , -B(OR cc ) 2 , -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero C 1-10 Alkyl, heteroC 2-10 alkenyl, hetero C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3 , 4, or 5 R dd substituted with a group; Alternatively, two geminal hydrogens on a carbon atom are in the groups =O, =S, =NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O) 2 R. aa ,=NR bb , or =NOR cc has been replaced by; each R aa is independently selected from: C 1-10 Alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero C 1-10 Alkyl, heteroC 2-10 alkenyl, hetero C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa The groups are taken together to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently 0, 1, 2, 3, 4, or 5 R dd substituted with a group; each R bb is independently selected from: hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R. aa , -SO 2 R. aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R. cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O)(N(R cc ) 2 ) 2 , C 1-10 Alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero C 1-10 Alkyl, heteroC 2-10 alkenyl, hetero C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb The groups are taken together to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently 0, 1, 2, 3, 4, or 5 R dd substituted with a group; each R cc is independently selected from: hydrogen, C 1-10 Alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero C 1-10 Alkyl, heteroC 2-10 alkenyl, hetero C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc The groups are taken together to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently 0, 1, 2, 3, 4, or 5 R dd substituted with a group; each R dd is independently selected from: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR ee , -ON(R ff ) 2 , -N(R ff ) 2 , -N(R ff ) 3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO 2 H, -CO 2 R. ee , -OC(=O)R ee , -OCO 2 R. ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , -NR ff C(=O)R ee , -NR ff CO 2 R. ee , -NR ff C(=O)N(R ff ) 2 , -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff )N(R ff ) 2 , -NR ff SO 2 R. ee , -SO 2 N(R ff ) 2 , -SO 2 R. ee , -SO 2 OR ee , -OSO 2 R. ee , -S(=O)R ee , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee ) 2 , -P(=O)(R ee ) 2 , -OP(=O)(R ee) 2 , -OP(=O)(OR ee ) 2 , C 1-6 Alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero C 1-6 Alkyl, heteroC 2-6 alkenyl, hetero C 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, or 5 R gg or two geminal R dd the substituents may be taken together to form =O or =S; each R ee is independently selected from: C 1-6 Alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero C 1-6 Alkyl, heteroC 2-6 alkenyl, hetero C 2-6 alkynyl, C 3-10 Carbocyclyl, C 6-10 Aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, or 5 Rs gg substituted with a group; each R ff is independently selected from: hydrogen, C 1-6 Alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero C 1-6 Alkyl, heteroC 2-6 alkenyl, hetero C 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl, or two R ff The groups are taken together to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl , and heteroaryl are independently 0, 1, 2, 3, 4, or 5 R gg substituted with a group; each R gg are independently halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) 3 + X - , -NH(C 1-6 alkyl) 2 + X - , -NH 2 (C 1-6 alkyl) + X - , -NH 3 + X - , -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -C(=O)N(C 1-6 alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2 N(C 1-6 alkyl) 2 , -SO 2 NH(C 1-6 alkyl), -SO 2 NH 2 , -SO 2 C. 1-6 Alkyl, -SO 2 OC 1-6 Alkyl, -OSO 2 C. 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl) 3 , -OSi(C 1-6 alkyl) 3 -C(=S)N(C 1-6 alkyl) 2 , C(=S)NH(C 1-6 alkyl), C(=S)NH 2 , -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl) 2 , -P(=O)(C 1-6 alkyl) 2 , -OP(=O)(C 1-6 alkyl) 2 , -OP(=O)(OC 1-6 alkyl) 2 , C 1-6 Alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, hetero C 1-6 Alkyl, heteroC 2-6 alkenyl, hetero C 2-6 alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg the substituents may be taken together to form =O or =S; and each X - is the counterion.

[0081] In some embodiments, the carbon atom substituents are independently halogen, substituted or unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb ) 2 , -CN, -SCN, -NO 2 , -C(=O)R aa , -CO 2 R. aa , -C(=O)N(R bb ) 2 , -OC(=O)R aa , -OCO 2 R. aa , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R. aa , or -NR bb C(=O)N(R bb ) 2 . In some embodiments, the carbon atom substituents are independently halogen, substituted or unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb ) 2 , -CN, -SCN, or -NO 2 is.

[0082] As valences permit, nitrogen atoms can be substituted or unsubstituted, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to: hydrogen, -OH, -OR aa , -N(Rcc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R. aa , -SO 2 R. aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R. cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc ) 2 , -P(=O)(R aa ) 2 , -P(=O)(N(R cc ) 2 ) 2 , C 1-10 Alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, hetero C 1-10 Alkyl, heteroC 2-10 alkenyl, hetero C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R attached to the N atom cc The groups are taken together to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, and where R aa , R bb , R cc and R dd is as defined above.

[0083] In some embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to: -OH, -OR aa , -N(R cc ) 2 , -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R. aa , -SO 2 R. aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R. cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl (e.g. aralkyl, heteroaralkyl), C 2-10 alkenyl, C 2-10 alkynyl, hetero C 1-10 Alkyl, heteroC 2-10 alkenyl, hetero C 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 5- to 14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently 0, 1, 2, 3, 4, or 5 Rs dd is substituted with a group, and where R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0084] For example, an amide group (e.g., -C(=O)R aa ) include, but are not limited to: formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N -benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propane amides, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

[0085] Carbamate groups (e.g., -C(=O)OR aa) include, but are not limited to: methyl carbamate, ethyl carbamate, methyl 9-fluorenylcarbamate (Fmoc), 9-(2-sulfo)fluorenylcarbamate methyl, methyl 9-(2,7-dibromo)fluoroenylcarbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl) ] methyl carbamate (DBD-Tmoc), 4-methoxyphenacylcarbamate (Phenoc), ethyl 2,2,2-trichlorocarbamate (Troc), ethyl 2-trimethylsilylcarbamate (Teoc), 2-phenylcarbamate Ethyl (hZ), Ethyl 1-(1-adamantyl)-1-methylcarbamate (Adpoc), Ethyl 1,1-dimethyl-2-halocarbamate, Ethyl 1,1-dimethyl-2,2-dibromocarbamate ( DB-t-BOC), ethyl 1,1-dimethyl-2,2,2-trichlorocarbamate (TCBOC), ethyl 1-methyl-1-(4-biphenylyl)carbamate (Bpoc), 1-(3, Ethyl 5-di-t-butylphenyl)-1-methylcarbamate (t-Bumeoc), Ethyl 2-(2'- and 4'-pyridyl)carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamide) Ethyl Carbamate, t-Butyl Carbamate (BOC or Boc), 1-Adamantyl Carbamate (Adoc), Vinyl Carbamate (Voc), Allyl Carbamate (Alloc), 1-Isopropyl Allyl Carbamate (Ipaoc), Cinnamyl Carbamate (Coc), 4-nitrocinnamylcarbamate (Noc), 8-quinolylcarbamate, N-hydroxypiperidinylcarbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxycarbamate Benzyl (Moz), benzyl p-nitrocarbamate, benzyl p-bromocarbamate, benzyl p-chlorocarbamate, benzyl 2,4-dichlorocarbamate, benzyl 4-methylsulfinylcarbamate (Msz), 9-anthryl methyl carbamate, methyl diphenylcarbamate, ethyl 2-methylthiocarbamate, ethyl 2-methylsulfonylcarbamate, ethyl 2-(p-toluenesulfonyl)carbamate, [2-(1,3-dithiocarbamate) anyl)] methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), ethyl 2-phosphoniocarbamate (Peoc), 2-triphenylphosphonio Isopropyl carbamate (Ppoc), ethyl 1,1-dimethyl-2-cyanocarbamate, benzyl m-chloro-p-acyloxycarbamate, benzyl p-(dihydroxyboryl)carbamate, 5-benzisoxazolylcarbamate methyl, methyl 2-(trifluoromethyl)-6-chromonylcarbamate (Tcroc), m-nitrophenylcarbamate, benzyl 3,5-dimethoxycarbamate, benzyl o-nitrocarbamate, 3,4-dimethoxy- Benzyl 6-nitrocarbamate, methyl phenyl(o-nitrophenyl)carbamate, t-amylcarbamate, S-benzylthiocarbamate, benzyl p-cyanocarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate , methyl cyclopropylcarbamate, benzyl p-decyloxycarbamate, 2,2-dimethoxyacyl vinylcarbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N, N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, methyl di(2-pyridyl)carbamate, methyl 2-furanylcarbamate, ethyl 2-iodocarbamate, isobornylcarbamate, isobutylcarbamate mate, isonicotinylcarbamate, benzyl p-(p'-methoxyphenylazo)carbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate, methyl 1-methyl-1-cyclopropylcarbamate, 1 Ethyl -methyl-1-(3,5-dimethoxyphenyl)carbamate, Ethyl 1-methyl-1-(p-phenylazophenyl)carbamate, Ethyl 1-methyl-1-phenylcarbamate, 1-methyl-1 -(4-pyridyl)ethylcarbamate, phenylcarbamate, benzyl p-(phenylazo)carbamate, 2,4,6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2 benzyl,4,6-trimethylcarbamate.

[0086] Sulfonamide groups (e.g., -S(=O) 2 R. aa ) include, but are not limited to: p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2 ,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte) , 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8 -pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzene Sulfonamides (DNMBS), benzylsulfonamides, trifluoromethylsulfonamides, and phenacylsulfonamides.

[0087] Other nitrogen protecting groups include, but are not limited to: phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenyl Alanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2, 5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one , 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2 -(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts , N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine ( MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'- oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N '-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxy Phenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl( pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N- Nitrosamines, amine N-oxides, diphenylphosphine amides (Dpp), dimethylthiophosphine amides (Mpt), diphenylthiophosphine amides (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzene sulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-Nitropyridinesulfenamide (Npys).

[0088] In some embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to: -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R. aa , -C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb ) 2 , -S(=O)R aa , -SO 2 R. aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 + X - , -P(OR cc ) 2 , -P(OR cc ) 3+ X - , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , and -P(=O)(N(R bb ) 2 ) 2 , where X - , R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0089] Exemplary oxygen protecting groups include, but are not limited to: methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyl. Oxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxy methyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[( 2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5 ,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxy ethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t -butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p- Halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-dinitrobenzhydryl , 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'- Bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4 ,4',4''-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl) -1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S -dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t -butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate , dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate) , 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzo Art (Mesitoate), Methyl Carbonate, 9-Fluorenyl Methyl Carbonate (Fmoc), Ethyl Carbonate, 2,2,2-Trichloroethyl Carbonate (Troc), 2-(Trimethylsilyl)ethyl Carbonate (TMSEC), 2-(Phenylsulfonyl) Ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p- Methoxybenzyl carbonate, 3,4- Dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4 -methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2, 6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxy Acetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N' ,N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0090] In some embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to: -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R. aa , -C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb ) 2 , -S(=O)R aa , -SO 2 R. aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 + X - , -P(OR cc ) 2 , -P(OR cc ) 3 + X - , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , and -P(=O)(N(R bb ) 2 ) 2 , where R aa , R bb , and R cc is as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0091] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0092] The term "hydroxyl" or "hydroxy" refers to the group -OH.

[0093] The term "thiol" or "thio" refers to the group -SH.

[0094] The term "amine" or "amino" refers to the groups -NH- or -NH 2 point to

[0095] As used herein, the term "polyethylene glycol" or "PEG" refers to ethylene glycol polymers containing from about 20 to about 2,000,000 linked monomers, typically from about 50 to 1,000 linked monomers, often from about 100 to 300 linked monomers. point to Polyethylene glycols are ethylene glycol polymers containing varying numbers of linking monomers such as PEG20, PEG30, PEG40, PEG60, PEG80, PEG100, PEG115, PEG200, PEG300, PEG400, PEG500, PEG600, PEG1000, PEG1500, PEG2000, PEG3350, PEG4000, PEG4600, PEG5000, PEG6000, PEG8000, PEG11000, PEG12000, PEG2000000, and any mixture thereof.

[0096] The term "salt" refers to ionic compounds resulting from the neutralization reaction of acids and bases. A salt is composed of one or more cations (positively charged ions) and one or more anions (anions) such that it is electrically neutral (has no net charge). Salts of the compounds of this disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or salts of amino groups, formed with malonic acid, or by using other methods known in the art, such as ion exchange. Other salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl. Sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate fart, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate , stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salt and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 alkyl) 4 Contains salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and arylsulfonates. contain.

[0097] The term "pharmaceutically acceptable salt" is used within the scope of sound medical judgment and for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc. and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid Salts of amino groups formed with acids, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane pro Pionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, Lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate , picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salt and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 alkyl) - 4 Contains salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts are formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and arylsulfonates, where appropriate. ammonium, quaternary ammonium, and amine cations.

[0098] "Click chemistry" refers to the scientific approach to conjugation, introduced by Sharpless in 2001, describing a chemistry that is tailored to rapidly and reliably produce substances by bringing units together. See, for example, Kolb, Finn and Sharpless Angewandte Chemie International Edition 2001 40, 2004-2021; Evans, Australian Journal of Chemistry 2007 60, 384-395). Exemplary coupling reactions (some of which can be classified as "click chemistry") include, but are not limited to: formation of esters, thioesters, amides from activated acids or acyl halides (e.g. nucleophilic substitution reactions (e.g. nucleophilic substitution of halides or ring opening of strained ring systems); azide-alkyne Huisgen cycloadditions; thiol-ene additions; imine formation; additions (eg, maleimide addition reactions); and Diels-Alder reactions (eg, tetrazine[4+2] cycloadditions). Examples Examples of click chemistry reactions and click chemistry handles can be found in, for example, Kolb, H. C.; Finn, M. G. and Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004-2021. Fokin, V. V. and Shrapless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596-2599; Tomoe 2002, 67, 3057-3064. Wang, Q. et al., J. Am. Chem. Soc. 2003, 125, 3192-3193; Lee, L. V.; et al., J. Am. Chem. Soc. 2003 125, 9588-9589; Lewis, W. G. et al., Angew. Chem. J. Am. Chem. Soc. 2004, 126, 12809-12818; Mocharla, V. P. et al., Angew. Chem., Int. Ed. 2005, 44, 116-120.

[0099] Any method known in the art of bioconjugation can be used (eg click chemistry reaction). For example, a nanoparticle may include a click chemistry handle on its outer shell, which can react with a click chemistry handle on a targeting agent, thereby covalently bonding the nanoparticle with the targeting agent. can be concatenated. In certain embodiments, one or more nanoparticles are conjugated to a targeting agent via click chemistry, and thus the linker comprises moieties derived from click chemistry reactions (e.g., triazoles, diazoles, diazines, sulfide bonds, maleimide ring, succinimide ring, ester, amide).

[0100] The term "average molecular weight" refers to the number average molecular weight (M n ), weight average molecular weight (M w ), high-order average molecular weight (M z or M. z+1), GPC / SEC (gel permeation chromatography / size-exclusion chromatography)-determined average molecular weight (M p ), and viscosity-average molecular weight (M v ).

[0101] As used herein, the term "mean hydrodynamic diameter" (D H ) refers to the average size of the conjugate or particle. The average hydrodynamic diameter may or may not include the solvation layer of the conjugate or particle and is measured by dynamic light scattering, electron microscopy (eg, scanning electron microscopy, transmission electron microscopy), atomic force microscopy, and X-rays. It may be determined via a number of methods including line diffraction. The hydrodynamic diameter, measured by dynamic light scattering (DLS), is defined as "the size of a virtual hard sphere that diffuses in the same manner as the particle being measured". In practice, however, particles or macromolecules in solution are non-spherical, dynamic (tumbling) and solvated. Therefore, the diameter calculated from the diffusion properties of the particles will indicate the apparent size of the dynamic hydrated / solvated particles. Hence the terminology, hydrodynamic diameter. The hydrodynamic diameter, or Stokes diameter, is therefore the diameter of a sphere that assumes a hydrated layer surrounding the particle or molecule and has the same translational diffusion coefficient as the particle being measured. Data measured in dynamic light scattering (DLS) experiments are correlation curves, which should be smooth mono-exponential decay functions for mono-sized particle dispersions (Chu, B., Annual Review of Physical Chemistry, 1970, 21, 145-174). A correlation curve contains all the information about the diffusion of particles in the sample to be measured. By fitting the correlation curve to an exponential function, the diffusion coefficient (D) can be calculated (D is proportional to the exponential decay lifetime). Knowing the diffusion coefficient (D), the hydrodynamic diameter can be calculated by using a variation of the Stokes-Einstein equation. For polydisperse samples, this curve is a sum of exponential decays.

[0102] As used herein, the term "mean polydispersity" (PDI) is, for example, by chromatographic methods such as gel permeation chromatography or size exclusion chromatography, or via dynamic light scattering, Refers to a measure of the distribution of molecular sizes in a mixture to be judged. Polydispersity (PDI) is a measure of the distribution of molecular sizes in a given polymer. Polydispersity is PDI=M w / M n (Stepto, R. F. T., et al., Pure Appl. Chem., 2009, 81, 351-353). M. n is more sensitive to low molecular weight molecules, while M w are more sensitive to high molecular weight molecules. Dispersion indicates the distribution of individual molecular weights in the polymer bath. D has a value of 1 or greater.

[0103] As used herein, the term "agent" means a molecule, group of molecules, complex or substance that is administered to an organism for diagnostic, therapeutic, prophylactic or veterinary purposes. In some embodiments, the agent is a pharmaceutical agent (eg, therapeutic, diagnostic, or prophylactic). In certain embodiments, a compound, conjugate, or particle disclosed herein is an agent(s), such as a first therapeutic agent (eg, at least one (eg, at least two, at least three including one) In some embodiments, the BASP-composition (e.g., compound, conjugate, or particle) further comprises a second therapeutic agent, targeting moiety, diagnostic moiety, e.g., as described herein can be done. Agent(s) can be conjugated to a conjugate or particle. In other embodiments, the agent(s) can be associated with a conjugate or particle. In some embodiments, a first agent can be conjugated to the conjugate or particle, and a second agent, targeting moiety and / or diagnostic moiety can be non-covalently associated with the conjugate or particle. can. Any agent disclosed herein can be used in the compounds, conjugates, particles and other compositions and methods disclosed herein.

[0104] As used herein, the term "therapeutic agent" refers to an agent capable of providing a local or systemic biological, physiological, or therapeutic effect in the biological system to which it is applied. contain. For example, the therapeutic agent may control tumor growth, act to control infection or inflammation, act as an analgesic, promote anti-cell adhesion, and enhance bone growth, among other functions. can. Other suitable therapeutic agents include antiviral agents, hormones, antibodies, or therapeutic proteins. Other therapeutic agents include prodrugs, which are agents that are not biologically active, but are converted to biologically active agents through metabolism or some other mechanism when administered to a subject. contain.

[0105] Agents, including therapeutic agents, encompass a wide variety of different chemical compounds, including: chemical compounds and mixtures of chemical compounds, including small organic or inorganic molecules; saccharin; oligosaccharides; polysaccharides; Biological macromolecules such as peptides, proteins, and peptide analogs and derivatives; peptidomimetics; antibodies and antigen-binding fragments thereof; nucleic acids; nucleic acid analogs and derivatives; fungal or extracts from animal cells; animal tissues; naturally occurring or synthetic compositions; and any combination thereof.

[0106] In some embodiments, the agent is in the form of a prodrug. The term "prodrug" refers to a compound that becomes active, e.g., upon dissolution, reduction, oxidation, or under physiological conditions, e.g., to provide a pharmaceutically active compound in vivo. Derivatives of the pharmaceutically active compound can be included, such as reaction of an acid, or anhydride, or mixed anhydride moiety of the prodrug moiety with a hydroxyl moiety of the pharmaceutically active compound. to form an ester, or to form an amide prepared by the acid, or anhydride, or mixed anhydride moiety of the prodrug moiety and a substituted or unsubstituted amine of the pharmaceutically active compound. Aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups can include prodrugs.In some embodiments, the conjugates or particles described herein are one therapeutic agent or its Incorporates Prodrugs In some embodiments, the conjugates or particles described herein incorporate one or more therapeutic agents or prodrugs.

[0107] In some embodiments, agents, eg, therapeutic agents, small molecules. As used herein, the term "small molecule" can refer to compounds that are "natural product-like." However, the term "small molecule" is not limited to "natural product-like" compounds. Rather, small molecules typically contain several carbon-carbon bonds and have a molecular weight of less than 5000 Daltons (5 kDa), preferably less than 3 kDa, even more preferably less than 2 kDa, and most preferably less than 1 kDa. characterized by having In some cases it is preferred to have a molecular weight of 700 Daltons or less.

[0108] Exemplary agents, such as therapeutic agents, in BBP-compositions include, but are not limited to, those found in: Harrison's Principles of Internal Medicine, 13th Edition, Eds. T.R. Harrison et al., McGraw- Hill N.Y., NY; Physicians' Desk Reference, 50th Edition, 1997, Oradell New Jersey, Medical Economics Co.; Pharmacological Basis of Therapeutics, 8th Edition, Goodman and Gilman, 1990; United States Pharmacopeia, The National Formulary, USP XII NF XVII , 1990; current edition of Goodman and Oilman's The Pharmacological Basis of Therapeutics; and current edition of The Merck Index, the complete contents of all of which are incorporated herein by reference.

[0109] In some embodiments, therapeutic agents in exemplary BBP-compositions include, but are not limited to: one or more of the agents listed in paragraph

[0148] of US Pat. No. 9,381,253, see incorporated herein by.

[0110] In other embodiments, therapeutic agents in exemplary BBP-compositions include, but are not limited to: one or more of the therapeutic agents listed in WO 2013 / 169739, which includes, for example, paragraphs 40-40. 49, 283, 286-295 and / or collagen modifying agents ("AHCM"); examples include microenvironment modulators disclosed in paragraphs 113-121 of WO 2013 / 169739, see also incorporated herein by. In some embodiments, a BBP-composition comprising AHCM and / or a microenvironmental modulator causes one or more of: reduced somatic stress (eg, growth-induced somatic stress in tumors); tumor fibrosis; reduce interstitial hypertension or interstitial fluid pressure (IFP); increase interstitial tumor transport; increase tumor or vascular perfusion; increase and / or compress or collapse vessel diameter reduce or deplete one or more of: cancer cells, or stromal cells (e.g., tumor-associated fibroblasts or immune cells); extracellular matrix components, such as fibers (e.g., collagen); , procollagen), and / or polysaccharides (e.g., glycosaminoglycans such as hyaluronan or hyaluronic acid) levels or production; Decrease production; increase tumor oxygenation; decrease tumor hypoxia; decrease tumor acidosis; allow immune cell infiltration; (also referred to herein as tumor-initiating cells); enhance the efficacy (eg, penetration or diffusion) of immunotherapy).

[0111] Agents, including therapeutic agents, encompass the categories and specific examples disclosed herein. It is not intended that the categories be limited by specific examples. Those skilled in the art will recognize myriad other compounds that fall within the categories and are useful according to the present disclosure.

[0112] Examples of therapeutic agents include, but are not limited to: antimicrobial agents, analgesics, anti-inflammatory agents, counter-irritants, coagulation regulators, diuretics, sympathomimetic agents, appetite suppressants, antacids. drugs and other gastrointestinal drugs; antiparasitics, antidepressants, antihypertensives, anticholinergics, stimulants, antihormones, central and respiratory stimulants, drug antagonists, lipid regulators, uricosurics, cardiac anxieties Glycosides, electrolytes, ergot and their derivatives, expectorants, hypnotics and sedatives, antidiabetic agents, dopamine agonists, antiemetics, muscle relaxants, parasympathomimetic agents, antidrugs, antihistamines, beta-blockers Drugs, laxatives, antiarrhythmic agents, contrast agents, radiopharmaceutical agents, antiallergic agents, tranquilizers, vasodilators, antiviral agents, and other agents with antineoplastic or cytostatic or anticancer properties , or a combination thereof. Other suitable therapeutic agents include: contraceptives and vitamins and micro- and macronutrients. Still other examples include: anti-infectives such as antibiotics and antivirals; analgesics and combination analgesics; appetite suppressants; anthelmintics; antidepressants; antidiuretics; antidiarrheals; antihistamines; antiinflammatory agents; antimigraine preparations; anticholinergics; sympathomimetic agents; xanthine derivatives; cardiovascular preparations, including: calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics; antihypertensives; central nervous system stimulants; cough and cold preparations, including: decongestants; hormones, such as estradiol and other steroids, including: Immunosuppressants; muscle relaxants; parasympatholytics; psychostimulants; sedatives; , glycoproteins, or lipoproteins.

[0113] In some cases, the diagnostic agent is a contrast agent or imaging agent. The terms "contrast agent" and "contrast agent" refer to substances used in medical imaging to enhance the contrast of internal body structures or fluids. Commonly used in medical imaging to enhance visibility of blood vessels and the gastrointestinal tract

[0114] The term "ring-opening metathesis polymerization (ROMP)" refers to a type of olefin metathesis chain extension polymerization driven by relaxation of ring strain in cyclic olefins (eg norbornene and cyclopentene). Catalysts used in ROMP reactions include: RuCl 3 / alcohol mixture, bis(cyclopentadienyl)dimethylzirconium(IV), dichloro[1,3-bis(2,6-isopropylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II) ), dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II), dichloro[1,3-bis(2,4,6-trimethyl Phenyl)-2-imidazolidinylidene][3-(2-pyridinyl)propylidene]ruthenium(II), dichloro(3-methyl-2-butenylidene)bis(tricyclopentylphosphine)ruthenium(II), dichloro[1,3 -bis(2-methylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II) (Grubbs C571), dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II) (Grubbs I) , dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II) (Grubbs II), and dichloro[1,3-bis (2,4,6-Trimethylphenyl)-2-imidazolidinylidene](benzylidene)bis(3-bromopyridine)ruthenium(II) (Grubbs III).

[0115] The terms "composition" and "formulation" are used interchangeably.

[0116] A "subject" contemplated for administration refers to: a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., minor, child, or adolescent) or adult subject (e.g., as young adults, middle-aged adults, or older adults)) or non-human animals. In some embodiments, the non-human animal is a mammal (e.g., a primate (e.g., cynomolgus or rhesus monkey), a commercially relevant mammal (e.g., cattle, pigs, horses, sheep, goats, cats, or dogs), or birds (eg, commercially relevant birds such as chickens, ducks, geese, or turkeys)). In some embodiments, the non-human animal is a fish, reptile, or amphibian. Non-human animals can be male or female, at any stage of development. Non-human animals may be transgenic or genetically modified animals.

[0117] The terms "administer," "administering," or "administration" include implanting, absorbing, ingesting, injecting, inhaling, or otherwise implanting, absorbing, ingesting, injecting, inhaling, or otherwise into or into a subject a compound described herein, or a composition thereof. means to introduce

[0118] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying onset, or inhibiting progression of the diseases described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of disease develop or are observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (eg, in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have disappeared in order to delay and / or prevent recurrence.

[0119] The terms "prevent," "preventing," or "prevention" refer to subjects who do not have or have never had the disease but are at risk of developing the disease, or who have had the disease but do not have the disease. Rather, it refers to prophylactic treatment in subjects at risk of disease regression. In certain embodiments, the subject is more likely to develop the disease or at greater risk of disease regression than the average healthy member of the subject population.

[0120] The terms "condition", "disease" and "disorder" are used interchangeably.

[0121] An "effective amount" of a compound described herein refers to an amount sufficient to elicit the desired biological response. Effective amounts of the compounds described herein will vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. obtain. In some embodiments, an effective amount is a therapeutically effective amount. In some embodiments, an effective amount is a prophylactically effective amount. In some embodiments, an effective amount is the amount of a compound or pharmaceutical composition described herein in a single dose. In some embodiments, an effective amount is a combined amount of a compound or pharmaceutical composition described herein in multiple doses.

[0122] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide therapeutic benefit in treating the condition or to delay or minimize one or more symptoms associated with the condition. is. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in treating the condition. The term "therapeutically effective amount" includes an amount that improves overall therapy, reduces or avoids the cause of a symptom, sign, or condition, and / or enhances the therapeutic effectiveness of another therapeutic agent. be able to.

[0123] A "prophylactically effective amount" of a compound described herein is an amount sufficient to desire or require recurrence of the condition or one or more symptoms associated with the condition. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing the Condition. The term "prophylactically effective amount" includes an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0124] The term "ratiometric" means that the C 1 i is C 0 i , where C 0 i is the delivery of two or more agents (including a first agent) to a subject, tissue, or cell in an amount of the first agent prior to delivery of the first agent to the subject, tissue, or cell refers to the ratio to the total amount of two or more agents before 1 i refers to the ratio of the amount of a first agent delivered to a subject, tissue, or cell to the total amount of two or more agents (including the first agent) delivered to the subject, tissue, or cell. In some embodiments, delivery of each one of the two or more agents is ratiometric.

[0125] The term "orthogonal" refers to the situation where each of the first and second agents contained in the BBPs described herein are independently released from the BBP. In some embodiments, under condition A, the first agent is released from the BBP, but the second agent is not. For example, orthogonal release or delivery of first and second agents includes: under condition A, the first agent is released from the BBP, but the second agent is not; , the second agent is released from the BBP, but not the first. For example, under condition C, if both the first and second agents are released from the BBP, the release or delivery of the first and second agents is not orthogonal.

[0126] This disclosure is not intended to be limited in any way by the above exemplary list of substituents. Additional terms may be defined in other sections of this disclosure.

[0127] Detailed Description of Certain Embodiments Described herein are compounds (eg, monomers) that include an agent via a linker that includes a boronate ester moiety in the backbone of the linker. Also provided are polymers prepared by polymerizing the monomers. Polymers can be useful for delivering agents to a subject, tissue, biological sample, or cell. In some embodiments, the polymer is a bottle brush polymer (BBP). Bottle-brush polymers have been found in a wide range of applications, from drug delivery and molecular imaging to novel materials and stimuli-responsive networks. Graft-through ring-opening metathesis polymerization (ROMP) offers distinct advantages over other bottle-brush synthetic methods. , Fast-starting Grubbs third-generation catalysts (G3-Cat) sustain polymer chain reactions with exceptionally high tolerance to a wide range of sterically hindered polyvalent monomers (e.g., macromonomers (MM)), yielding millimolar It has been shown that high degrees of polymerization and low dispersity values ​​are reached even at low concentrations. , Furthermore, G3-Cat can be used to control the composition, morphology, and size of the final macromolecules, which is useful for superior polymer architectures such as bottle-brush polymers and star polymers. allows the preparation of Due to the high packing density of their side chains, the backbones of bottle-brush polymers are rigid and can adopt an extended morphology with minimal side chain entanglement.

[0128] Methods of preparing the polymers, compositions and kits comprising the polymers, and methods of use involving the polymers or compositions (eg, use in delivery of agents, treatment of disease, prevention of disease, diagnosis of disease) are also provided.

[0129] compounds, e.g. monomers In one aspect, the disclosure provides compounds. In some embodiments, compounds are represented by the formula: [formation] or a salt thereof, where: X is the polymerization handle; L. 1 is a substituted or unsubstituted linker, where L 1 The main chain of contains 2 or more atoms Each Y is independently -C(R 1 ) 2 -is; each R 1 is independently absent, hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR a , -N(R a ) 2 , -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a ) 2 , -C(=O)R a , -C(=O) OR a , -C(=O)N(R a ) 2 , -NO 2 , -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a ) 2 , -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a ) 2 , or two R 1 together form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; each R a is independently hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group when attached to a nitrogen atom, attached to an oxygen atom When attached to an oxygen protecting group, a sulfur protecting group when attached to a sulfur atom, or two respective R a together with the nitrogen atom form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each L is independently a bond, or a substituted or unsubstituted linker, wherein the atom in the backbone of L attached to ring A or ring C is carbon; each M is independently an agent; each m is independently an integer between 1 and 10, inclusive; each c is independently an integer between 1 and 2, inclusive; and d is an integer between 1 and 10 (inclusive).

[0130] In some embodiments, the compound is represented by Formula (I) or a salt thereof. In some embodiments, the compound is represented by Formula (II) or a salt thereof.

[0131] [formation]

[0132] In certain embodiments, R in formula (I) 1 is a carbon-bonded moiety.

[0133] In some embodiments, the compound includes a polymeric handle as moiety X. If the compound includes a polymerizing handle as part X, the compound is a monomer. In some embodiments, X comprises one or more functional groups selected from the group consisting of: alkenes, vinyl halides, alkynes, amines, -N 3 , carboxylic acids, non-aromatic alcohols, and aldehydes. In some embodiments, X comprises one or more functional groups selected from the group consisting of: -N 3 , -NH 2 , -C(=O)OH, -OH, and -C(=O)H. In some embodiments, X comprises one or more functional groups selected from the group consisting of: -NH 2, -C(=O)OH, and -C(=O)H. In some embodiments, X comprises only one functional group (eg, alkenes, vinyl halides, alkynes, amines, -N 3 , carboxylic acid, non-aromatic alcohol, aldehyde, -NH 2 , -C(=O)OH, -OH, or -C(=O)H). In some embodiments, X comprises two or more functional groups (eg, two or more alkenes, vinyl halides, alkynes, amines, -N 3 , carboxylic acid, non-aromatic alcohol, aldehyde, -NH 2 , -C(=O)OH, -OH, or -C(=O)H, or combinations thereof). In some embodiments, X is -N 3 including. In some embodiments, X is -N 3 is. In some embodiments, X is an addition polymerization handle. In some embodiments, X comprises a functional group selected from the group consisting of: alkenes, alkynes, or vinyl halides. In some embodiments, X comprises an alkene. In some embodiments, X comprises alkyne. In some embodiments, X is a condensation polymerization handle. In some embodiments, X comprises functional groups selected from the group consisting of: amines (eg, primary amines, secondary amines), carboxylic acids, and non-aromatic alcohols (eg, alkyl alcohols). . In some embodiments, X comprises two non-aromatic alcohols, two carboxylic acids, or two amines. In some embodiments, X is a metathesis polymerization handle. In some embodiments, X is a ring-opening metathesis polymerization handle. In some embodiments, X includes a substituted or unsubstituted, partially unsaturated carbocyclyl. In some embodiments, X includes a substituted or unsubstituted, partially unsaturated heterocyclyl. In some embodiments, X is a radical polymerization handle. In some embodiments, X is a cationic polymeric handle. In some embodiments, X is an anionic polymeric handle. In some embodiments, X includes: substituted or unsubstituted styrene, substituted or unsubstituted acrylate, substituted or unsubstituted methacrylate, substituted or unsubstituted cyclooctene, or substituted or unsubstituted maleimide. In some embodiments, X includes: an alkyl acrylate, a hydroxyalkyl acrylate, a haloalkyl acrylate, a polymethacrylate, an alkyl methacrylate, a hydroxyalkyl methacrylate, or a haloalkyl methacrylate. In some embodiments, X includes: ethylene, tetrafluoroethylene, propylene, isobutylene, styrene, acrylonitrile, vinyl chloride, methyl acrylate, methyl methacrylate, butadiene, chloroprene, cis-1,4-isoprene, or trans-1,4-isoprene. In some embodiments, X includes ethylene. In some embodiments, X includes styrene. In some embodiments, X comprises methyl methacrylate. In some embodiments, X includes: amides, aramids, esters, carbonates, or silicones.

[0134] In some embodiments, X does not include a hydroxy-(substituted or unsubstituted phenyl) group. In some embodiments, X does not include a hydroxy-(substituted phenyl) group.

[0135] In some embodiments, X is represented by the formula: [formation] In the formula: Z is C(R P ) 2 or is O; each R P is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 is an alkyl; [formation] is a single or double bond; and [formation] is Ring D, wherein Ring D is a substituted or unsubstituted monocyclic carbocyclic ring, a substituted or unsubstituted monocyclic heterocyclic ring, a substituted or unsubstituted monocyclic A cyclic aryl ring or a substituted or unsubstituted monocyclic heteroaryl ring.

[0136] In some embodiments, Z is O. In some embodiments Z is C(R P ) 2 is. In some embodiments Z is CH 2 is. In some embodiments Z is C(CH 3 ) 2 is.

[0137] In some embodiments, each R P is hydrogen. In some embodiments, at least one R P is hydrogen. In some embodiments, each R P is a halogen. In some embodiments, at least one R P is a halogen. In some embodiments, at least one R P is the unsubstituted C 1-6 is alkyl. In some embodiments, at least one R P is the permutation C 1-6 is alkyl. In some embodiments, each R P is unsubstituted methyl. In some embodiments, at least one R P is unsubstituted methyl.

[0138] In some embodiments, [formation] is a single bond. In one aspect, [formation] is a double bond.

[0139] In some embodiments, Ring D is a substituted or unsubstituted monocyclic carbocyclic ring. In some embodiments, Ring D is an unsubstituted monocyclic heterocyclic ring. In some embodiments, Ring D is a substituted monocyclic heterocyclic ring. In some embodiments, Ring D is a 5-membered nitrogen-containing ring. In some embodiments, Ring D is a 5-membered nitrogen-containing ring substituted with oxo (=O). In some embodiments, Ring D is a 5-membered nitrogen-containing ring substituted with two oxo.

[0140] In some embodiments, X is the formula [formation] is represented by In some embodiments, X is the formula [formation] is represented by In some embodiments, X is the formula [formation] is represented by In some embodiments, X is the formula [formation] is represented by In some embodiments, X is the formula [formation] is represented by In some embodiments, X is the formula [formation] is represented by In some embodiments, X is the formula [formation] is represented by In some embodiments, X is the formula [formation] is represented by In some embodiments, X is the formula [formation] is represented by

[0141] The compounds described herein are linker L 1 encompasses In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) is alkylene. In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) alkenylene. In some embodiments, L 1 is unsubstituted or substituted, C 2-300 (For example, C 10-40 ) alkynylene. In some embodiments, L 1 is unsubstituted or substituted, C 2-300 (For example, C 10-40 ) heteroalkylene. In some embodiments, L 1 is unsubstituted or substituted, C 2-300 It is a heteroalkenylene. In some embodiments, L 1 is unsubstituted or substituted, C 2-300 (For example, C 10-40 ) heteroalkynylene.

[0142] In some embodiments, L 1None of the backbone carbon atoms of is replaced with: substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, L 1 is independently replaced with a substituted or unsubstituted heteroarylene. In some embodiments, L 1 is independently replaced with a substituted or unsubstituted arylene. In some embodiments, L 1 One or more backbone carbon atoms of are independently replaced by substituted or unsubstituted heteroarylene and substituted or unsubstituted arylene.

[0143] In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) alkylene, wherein 0, 1, 2, 3, or more of its backbone carbon atoms are independently replaced with: substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) alkenylene, wherein 0, 1, 2, 3, or more of its backbone carbon atoms are independently replaced with: substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) alkynylene, wherein 0, 1, 2, 3, or more of its backbone carbon atoms are independently replaced with: substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene , substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) heteroalkylene, wherein 0, 1, 2, 3, or more of its backbone carbon atoms are independently replaced with: substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) heteroalkenylene, wherein 0, 1, 2, 3, or more of its backbone carbon atoms are independently replaced with: substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) heteroalkynylene, wherein 0, 1, 2, 3, or more of its backbone carbon atoms are independently replaced with: substituted or unsubstituted carbocyclene, substituted or unsubstituted substituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) alkylene, wherein at least one of its backbone carbon atoms is a substituted or unsubstituted heteroarylene [formation] has been replaced by In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) alkenylene, wherein at least one of its backbone carbon atoms is a substituted or unsubstituted heteroarylene [formation] has been replaced by In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) alkynylene, wherein at least one of its backbone carbon atoms is a substituted or unsubstituted heteroarylene [formation] has been replaced by In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) heteroalkylene, wherein at least one of its backbone carbon atoms is a substituted or unsubstituted heteroarylene [formation] has been replaced by In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) heteroalkenylene, wherein at least one of its backbone carbon atoms is a substituted or unsubstituted heteroarylene [formation] has been replaced by In some embodiments, L 1 is unsubstituted or substituted, C 2 - 300 (For example, C 10-40 ) heteroalkynylene, wherein at least one of its backbone carbon atoms is a substituted or unsubstituted heteroarylene [formation] has been replaced by In some embodiments, L 1 is a substituted or unsubstituted C 10 - 40 alkylene, or substituted or unsubstituted, C 10-40 heteroalkylene, wherein at least one of its backbone carbon atoms is [formation] has been replaced by

[0144] In some embodiments, L 1 is a substituted or unsubstituted C 2-200 alkylene, or substituted or unsubstituted, C 2-200 substituted with heteroalkylene. In some embodiments, L 1 is permutation, C 2-200 substituted with heteroalkylene. In some embodiments, L 1 is a C containing at least one nitrogen atom and at least one oxygen atom 2-200 substituted with heteroalkylene. In some embodiments, L 1 is C 2-200 C containing at least one nitrogen atom and one or more oxygen atoms, including heteroalkylene 2-200 substituted with heteroalkylene. In some embodiments, L 1 is an oxo-substituted containing at least one nitrogen atom and at least one oxygen atom, C 2-200 substituted with heteroalkylene. In some embodiments, L 1 contains at least one nitrogen atom and one or more oxygen atoms, oxo-substituted, C 2-200 substituted with heteroalkylene.

[0145] In some embodiments, L 1 includes polymers. In some embodiments, L 1 includes substituted or unsubstituted polyethylene. In some embodiments, L 1 includes unsubstituted polyethylene. In some embodiments, L 1 includes substituted or unsubstituted polystyrene. In some embodiments, L 1 contains PEG. In some embodiments, L 1 is between 200 and 500; Including a polymer with a molecular weight (eg, PEG). In some embodiments, L 1 includes polymers (eg, PEG) with weight-average molecular weights between 1,000 and 5,000 (inclusive) g / mol. In some embodiments, L 1 includes polymers (eg, PEG) with weight-average molecular weights between 2,000 and 5,000 (inclusive) g / mol.

[0146] A compound of any one of the preceding claims, or a salt thereof, wherein L 1 is represented by the following formula: [formation] In the formula: n is an integer between 0 and 12 (inclusive); k is an integer between 1 and 12 (inclusive); L. 1a independently, substituted or unsubstituted, C 1-200 alkylene, substituted or unsubstituted, C 2-200 alkenylene, substituted or unsubstituted, C 2-200 alkynylene, substituted or unsubstituted, C 2-200 heteroalkylene, substituted or unsubstituted, C 2-200 heteroalkenylene, or C 2-200 is a heteroalkynylene, where: optionally substituted or unsubstituted C 1-200 alkylene, substituted or unsubstituted, C 2-200 alkenylene, substituted or unsubstituted, C 2-200 alkynylene, substituted or unsubstituted, C 2-200 heteroalkylene, substituted or unsubstituted, C 2-200 heteroalkenylene, and C 2-200 each main chain carbon atom in heteroalkynylene is independently substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene may be replaced; optionally substituted or unsubstituted C 2-200 heteroalkylene, substituted or unsubstituted, C 2-200 heteroalkenylene, and substituted or unsubstituted C 2-200 each main chain carbon atom in heteroalkynylene is independently substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene may be replaced; L. 1b is a substituted or unsubstituted C 1-200 alkyl, substituted or unsubstituted, C 2-200 alkenyl, substituted or unsubstituted, C 2-200 alkynyl, substituted or unsubstituted, C 2-200 heteroalkyl, substituted or unsubstituted, C 2-200 heteroalkenyl, C 2-200 heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted acyl, nitrogen protecting groups, polymers, peptides, or proteins Yes; and " * is attached to X and the other attachment points are attached to ring A of formula I or ring B of formula II.

[0147] In some embodiments, L 1 is represented by the following formula: [formation] In the formula: n is an integer between 0 and 12 (inclusive); k is an integer between 1 and 12 (inclusive); j is an integer between 0 and 300 (inclusive); and L. 1a are independently substituted or unsubstituted C 1-200 alkylene, substituted or unsubstituted, C 2-200 alkenylene, substituted or unsubstituted, C 2-200 alkynylene, substituted or unsubstituted, C 2-200 heteroalkylene, substituted or unsubstituted, C 2-200 heteroalkenylene, or C 2-200 is a heteroalkynylene, where: optionally substituted or unsubstituted C 1-200 alkylene, substituted or unsubstituted, C 2-200 alkenylene, substituted or unsubstituted, C 2-200 alkynylene, substituted or unsubstituted, C 2-200 heteroalkylene, substituted or unsubstituted, C 2-200 heteroalkenylene, and C 2-200 each main chain carbon atom in heteroalkynylene is independently substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene may be replaced; optionally substituted or unsubstituted C 2-200 heteroalkylene, substituted or unsubstituted, C 2-200 heteroalkenylene, and substituted or unsubstituted C 2-200 each main chain carbon atom in heteroalkynylene is independently substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene may be replaced; and " * is attached to X and the other attachment points are attached to ring A of formula I or ring B of formula II.

[0148] In some embodiments, L 1 is the expression [formation] is represented by In some embodiments, L 1 is the expression [formation] is represented by In some embodiments, L 1 is the expression [formation] is represented by

[0149] In some embodiments, L 1 is represented by the following formula: [formation] In the formula: f is an integer between 1 and 10 (inclusive); and " * is attached to X and the other attachment points are attached to ring A of formula I or ring B of formula II.

[0150] In some embodiments, n is three. In some embodiments, n is four. In some embodiments, n is 5. In some embodiments, n is 6.

[0151] In some embodiments, at least one k is 1. In some embodiments, at least one k is two. In some embodiments, at least one k is 3 or 4.

[0152] In some embodiments, j is between 10 and 200, inclusive. In some embodiments, j is between 20 and 150, inclusive. In some embodiments, j is between 40 and 100, inclusive. In some embodiments, j is between 60 and 80, inclusive.

[0153] In some embodiments, f is 1. In some embodiments, f is two. In some embodiments, f is 3.

[0154] In some embodiments, n is 4, each k is 1, j is between 60 and 80 (inclusive), and f is 1. In some embodiments, n is 5, each k is 1, j is between 60 and 80 (inclusive), and f is 1. In some embodiments, n is 4, each k is 2, j is between 60 and 80 (inclusive), and f is 1. In some embodiments, n is 5, each k is 2, j is between 60 and 80 (inclusive), and f is 1.

[0155] In some embodiments, L 1 is the expression [formation] is represented by In some embodiments, L 1 is the expression [formation] is represented by In some embodiments, L 1 is the expression [formation] is represented by

[0156] In some embodiments, at least one L 1a is permutation, C 2-200 is alkylene. In some embodiments, at least one L 1a is a substituted or unsubstituted C 2-100 is alkylene. In some embodiments, at least one L 1a is a substituted or unsubstituted C 2-100 alkylene, wherein one or more backbone carbon atoms are independently replaced with: an oxygen atom, a substituted or unsubstituted nitrogen atom (e.g., -N(H)-, -N( CH 3 )-), substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene. In some embodiments, at least one L 1a is a substituted or unsubstituted C2-100 alkylene, wherein one or more backbone carbon atoms are replaced by oxygen atoms and one or more backbone carbon atoms are substituted or unsubstituted nitrogen atoms (e.g., -N(H)-, -N (CH 3 )-), one or more backbone carbon atoms are replaced with substituted or unsubstituted heteroarylene, or one or more backbone carbon atoms are replaced with substituted or unsubstituted arylene. In some embodiments, at least one L 1a is a substituted or unsubstituted C 2-100 Alkylene, wherein one or more backbone carbon atoms are replaced with a substituted or unsubstituted heteroarylene. In some embodiments, at least one L 1a is a substituted or unsubstituted C 2-100 Alkylene, wherein one or more backbone carbon atoms are replaced with oxygen atoms and one or more backbone carbon atoms are replaced with a substituted or unsubstituted heteroarylene. In some embodiments, at least one L 1a is an oxo-substitution, C 2-100 alkylene, wherein one or more backbone carbon atoms are replaced by oxygen atoms and one or more backbone carbon atoms are substituted or unsubstituted nitrogen (e.g., -N(H)-, -N( CH 3 )-), one or more backbone carbon atoms are replaced with substituted or unsubstituted heteroarylene, or one or more backbone carbon atoms are replaced with substituted or unsubstituted arylene. In some embodiments, at least one L 1a is a substituted or unsubstituted C 2-100 alkylene, wherein one or more backbone carbon atoms are replaced with oxygen atoms, one or more backbone carbon atoms are replaced with substituted or unsubstituted heteroarylene, or one or more backbone carbon atoms are , substituted or unsubstituted arylene.

[0157] In some embodiments, at least one L 1a is permutation, C 2-200 It is heteroalkylene. In some embodiments, at least one L 1a is a substituted or unsubstituted C 2-100 It is heteroalkylene. In some embodiments, at least one L 1a is a substituted or unsubstituted C 2-100 Heteroalkylene, wherein one or more backbone carbon atoms are replaced with substituted or unsubstituted arylene. In some embodiments, at least one L 1a is a substituted or unsubstituted C 2-200 (For example, C 2-100 ) heteroalkylene, wherein one or more backbone carbon atoms are replaced with a substituted or unsubstituted heteroarylene. In some embodiments, at least one L 1a is a substituted or unsubstituted C 2-200 (For example, C 2-100 ) heteroalkylene, wherein one or more backbone carbon atoms are [formation] is replaced with, and in the expression " ** "teeth" # " is attached near the nitrogen atom marked with " *** is attached near either ring A of formula I or ring B of formula II. In some embodiments, at least one L 1a is a substituted or unsubstituted C 2-100 heteroalkylene, wherein one or more backbone carbon atoms are independently [formation] is replaced with, and in the expression " ** "teeth" # " is attached near the nitrogen atom marked with " *** is attached near either ring A of formula I or ring B of formula II. In some embodiments, at least one L 1a is a substituted or unsubstituted C 2-100 heteroalkylene, wherein one main chain carbon atom is [formation] is replaced with, and in the expression " ** "teeth" # " is attached near the nitrogen atom marked with " *** is attached near either ring A of formula I or ring B of formula II.

[0158] In some embodiments, at least one L 1a teeth 、 It is represented by the following formula: [formation] In the formula: each p is independently an integer between 0 and 12 (inclusive); each q is independently an integer between 0 and 12 (inclusive); each ring E is independently substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; each g is independently an integer between 0 and 12 (inclusive); and " ** "teeth" # " is attached near the nitrogen atom marked with " *** is attached near either ring A of formula I or ring B of formula II.

[0159] In some embodiments, at least one p is 0. In some embodiments, at least one p is 1. In some embodiments, at least one p is two. In some embodiments, at least one p is 3, 4, 5, or 6. In some embodiments, at least one p is an integer from 7 to 12 (inclusive).

[0160] In some embodiments, at least one q is 0. In some embodiments, at least one q is 1. In some embodiments, at least one q is two. In some embodiments, at least one q is three. In some embodiments, at least one q is 4, 5, or 6. In some embodiments, at least one q is an integer from 7 to 12 (inclusive).

[0161] In some embodiments, at least one ring E is a substituted or unsubstituted carbocyclene (eg, a substituted or unsubstituted 3- to 7-membered monocyclic carbocyclene). In some embodiments, at least one ring E is a substituted or unsubstituted heterocyclene (eg, a substituted or unsubstituted 3- to 7-membered monocyclic heterocyclene). In some embodiments, at least one ring E is substituted or unsubstituted arylene. In some embodiments, at least one ring E is substituted or unsubstituted phenylene (eg, 1,4-phenylene). In some embodiments, at least one ring E is a substituted or unsubstituted heteroarylene (eg, a substituted or unsubstituted 5-6 membered monocyclic heteroarylene). In some embodiments, at least one ring E is a substituted or unsubstituted 1,2,3-triazolylene (e.g., [formation] , in the expression " ** "teeth" # " is attached near the nitrogen atom marked with " *** is attached near either ring A of formula I or ring B of formula II. )

[0162] In some embodiments, at least one g is 0. In some embodiments, at least one g is 1. In some embodiments, at least one g is two. In some embodiments, at least one g is 3. In some embodiments, at least one g is 3, 4, or 5. In some embodiments, at least one g is an integer from 6 to 12 (inclusive).

[0163] In some embodiments, at least one L 1a is the expression [formation] where at least one ring E is [formation] is. In some embodiments, at least one L 1a is the expression [formation] where at least one ring E is [formation] where at least one p is between 1 and 2 (inclusive) and at least one q is between 4 and 12 (inclusive).

[0164] In some embodiments, at least one L 1a is the expression [formation] where at least one ring E is [formation] is. In some embodiments, at least one L 1a is the expression [formation] where at least one ring E is [formation] and at least one p is or between 2, inclusive. In some embodiments, at least one L 1a is the expression [formation] where at least one ring E is [formation] and at least one p is between 1 or 2, inclusive, and at least one g is 3, 4, or 5.

[0165] In some embodiments, at least one L 1a is represented by the following formula: [formation] In the formula: " ** "teeth" # " is attached near the nitrogen atom marked with " *** is attached near either ring A of formula I or ring B of formula II.

[0166] In some embodiments, at least one L 1a is the expression [formation] where p is 1 or 2. In some embodiments, at least one L 1a is the expression [formation] where p is 1 or 2 and q is between 8 and 12, inclusive. In some embodiments, at least one L 1a is the expression [formation] where p is 1 or 2 and q is between 1 and 3, inclusive. In some embodiments, at least one L 1a is the expression [formation] where p is 1 or 2. In some embodiments, at least one L 1a is the expression [formation] where p is 1 or 2 and g is 3, 4, or 5. In some embodiments, at least one L 1a is the expression [formation] where p is 1 or 2 and g is 3, 4, or 5.

[0167] In some embodiments, at least one L 1a is represented by the following formula: [formation] In the formula: each p is independently an integer from 1 to 12 (inclusive); each L F are independently substituted or unsubstituted C 2-180 is heteroalkylene; each -L B -L A - is independently -C(=O)O-, -OC(=O)-, -C(=O)NR E -, -NR E C(=O)-, or a single bond, where each R E is independently hydrogen, substituted or unsubstituted, C 1-6 is an alkyl, or nitrogen protecting group; and " ** "teeth" # " is attached near the nitrogen atom marked with " *** is attached near either ring A of formula I or ring B of formula II.

[0168] In some embodiments, at least one L 1a is the expression [formation] where L F is a substituted or unsubstituted C 5-20 It is heteroalkylene. In some embodiments, at least one L 1a is the expression [formation] where L F is a substituted or unsubstituted C 5-20 It is heteroalkylene. In some embodiments, at least one L 1a is the expression [formation] where p is 1 or 2 and L F is a substituted or unsubstituted C 5-20 is heteroalkylene and -L B -L A - is -CH 2 -is.

[0169] In some embodiments, at least one L 1a is represented by the following formula: [formation] In the formula: each p is independently an integer from 1 to 12 (inclusive); each q is independently an integer from 1 to 12 (inclusive); each g is independently an integer from 0t to 12 (inclusive); each s is independently 0 or 1; each t is independently an integer from 0 to 10 (inclusive); each -L B -L A - is independently -C(=O)O-, -OC(=O)-, -C(=O)NR E -, -NR E C(=O)-, or a single bond, where each R E is independently hydrogen, substituted or unsubstituted, C 1-6 is an alkyl, or nitrogen protecting group; and " ** "teeth" # " is attached near the nitrogen atom marked with " *** is attached near either ring A of formula I or ring B of formula II.

[0170] In some embodiments, at least one L 1a is the expression [formation] where p is between 1 and 2 (inclusive), q is 1 and g is between 2 and 10 (inclusive). In some embodiments, at least one L 1a is the expression [formation] where p is 1, q is 1, g is 3, 4, or 5, and s is 0. In some embodiments, at least one L 1a is the expression [formation] where p is 1 or 2 (inclusive), q is 1, g is 3, 4, or 5, s is 0, and -L B -L A - is a join.

[0171] In some embodiments, at least one L 1a is represented by the following formula: [formation] In the formula: each p is independently an integer from 1 to 12 (inclusive); each L C independently, substituted or unsubstituted, C 1-180 is alkylene; each -L B -L A - is independently -C(=O)O-, -OC(=O)-, -C(=O)NR E -, -NRE C(=O)-, or a single bond, where each R E is independently hydrogen, substituted or unsubstituted, C 1-6 is an alkyl, or nitrogen protecting group; and " ** "teeth" # " is attached near the nitrogen atom marked with " *** is attached near either ring A of formula I or ring B of formula II.

[0172] In some embodiments, at least one L 1a is the expression [formation] where L C is a substituted or unsubstituted C 5-20 is alkylene. In some embodiments, at least one L 1a is the expression [formation] where L C is at least one substituted or unsubstituted phenyl or substituted or unsubstituted C 1-6 C substituted with alkyl 5-20 is alkylene. In some embodiments, at least one L 1a is the expression [formation] where L C is C substituted with at least one substituted or unsubstituted phenyl 5-20 is alkylene. In some embodiments, at least one L 1a is the expression [formation] where L C is at least one substituted or unsubstituted C 1-6 C substituted with alkyl 5-20 is alkylene. In some embodiments, at least one L 1a is the expression [formation] where p is 1 or 2 and L C is a substituted or unsubstituted C 5-20 is alkylene and -L B -L A - is -C(=O)O-.

[0173] In some embodiments, L 1b is permutation, C 1-200 is alkyl. In some embodiments, L 1b is at least the oxo-substituted C 1-200 is alkyl. In some embodiments, L 1b は、 permutation, C 2-200 is heteroalkyl. In some embodiments, L 1b contains one or more oxygen atoms in its backbone, substituted, C 2-200 is heteroalkyl. In some embodiments, L 1b contains one or more oxygen atoms in its backbone, substituted, C 2-200 is heteroalkyl. In some embodiments, L 1b includes polymers. In some embodiments, L 1b is between 200 and 500; Includes polymers with average molecular weights (eg, PEG). In some embodiments, L 1b includes polymers (eg, PEG) with weight-average molecular weights between 1,000 and 5,000, inclusive, in g / mol. In some embodiments, L 1b includes polymers (eg, PEG) with weight-average molecular weights between 2,000 and 5,000, inclusive, in g / mol. In some embodiments, L 1b は、 PEG (eg, PEG with a weight average molecular weight between 1,000 and 5,000).

[0174] In some embodiments, L 1b contains a zwitterionic unit. In some embodiments, L 1b is the zwitterionic unit. In some embodiments, L 1b contains hydrophilic moieties (eg, small-molecular hydrophilic moieties). In some embodiments, L 1b is a hydrophilic moiety (eg, a small-molecular hydrophilic moiety).

[0175] In some embodiments, each R 1 are the same. In some embodiments, each R 1 is different. In some embodiments, some R 1 are the same and some R 1 is different. In some embodiments, each R 1 is independently substituted or unsubstituted 3- to 12-membered carbocyclyl (e.g., cyclopentyl, cyclohexyl, cyclopropyl) or substituted or unsubstituted 3- to 12-membered heterocyclyl (e.g., morpholinyl, piperdinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl). In some embodiments, each R 1 is independently substituted or unsubstituted 5- to 10-membered aryl (eg, phenyl, naphthalyl) and substituted or unsubstituted 5- to 10-membered heteroaryl (eg, pyridinyl, pyrimidinyl).

[0176] In some embodiments, each R 1 is independently absent, hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R 1 together form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl.

[0177] In some embodiments, any R 1 is not hydrogen. In some embodiments, some R 1 is hydrogen.

[0178] In some embodiments, each R 1 independently, substituted or unsubstituted, C 1-12 is alkyl. In some embodiments, each R 1 independently, substituted or unsubstituted, C 1-6 is alkyl. In some embodiments, each R 1 is independently substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted butyl, substituted or unsubstituted pentyl, and substituted or unsubstituted hexyl . In some embodiments, each R 1 independently, unsubstituted, C 1-6 Alkyl (eg, methyl, ethyl, propyl, isopropyl). In some embodiments, each R 1 is independently unsubstituted methyl. In some embodiments, each R 1 is unsubstituted methyl. In some embodiments, R 1 is the unsubstituted C 1-6 Alkyl (eg, trifluoromethyl, fluoromethyl).

[0179] In some embodiments, two R 1 together form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl. two R's 1 taken together to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, then L 1 is ring A, ring B, or two R 1 may be attached to the carbocyclyl or heterocyclyl that together form. In some embodiments, two R 1 together form substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In some embodiments, two R 1 together form a substituted or unsubstituted cyclohexyl. In some embodiments, two R 1 taken together is a substituted or unsubstituted, monocyclic, 3- to 7-membered heterocyclyl (for example, substituted or unsubstituted morpholinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrrolinyl, substituted or unsubstituted substituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, or substituted or unsubstituted piperidinyl).

[0180] In some embodiments, [formation] is. In one aspect, [formation] where R 1 is neither absent nor H. In one aspect, [formation] , where each R 1 is neither absent nor H. In one aspect, [formation] , where each R 1 is neither absent nor H.

[0181] In one aspect, [formation] is. In one aspect, [formation] , where each R 1 is neither absent nor H. In some embodiments, [formation] , where each R 1 is neither absent nor H. In one aspect, [formation] , where each R 1 is neither absent nor H.

[0182] In one aspect, [formation] wherein Ring A and Ring F are independently substituted (eg, independently substituted with one or more substituted or unsubstituted alkyl) or unsubstituted. In one aspect, [formation] is.

[0183] In some embodiments, [formation] , provided that any R 1 neither absent nor H.

[0184] In one aspect, [formation] is. In some embodiments, [formation] is. In some embodiments, [formation] is. In one aspect, [formation] is.

[0185] In some embodiments, each R a is hydrogen. In some embodiments, at least one R a is hydrogen. In some embodiments, each R a is a halogen. In some embodiments, at least one R a is a halogen. In some embodiments, each R a is the unsubstituted C 1-6 is alkyl. In some embodiments, at least one R a is the unsubstituted C 1-6 is alkyl. In some embodiments, each R a is the permutation C 1-6 is alkyl. In some embodiments, at least one R a is the permutation C 1-6 is alkyl. In some embodiments, each R a is substituted methyl. In some embodiments, at least one R a is a substituted methyl (for example, CF 3 , CHF 2 , CH 2 F). In some embodiments, R a is a substituted or unsubstituted C 2-6 alkenyl or substituted or unsubstituted, C 2-6 is alkynyl. In some embodiments, at least one R a is a substituted or unsubstituted carbocyclyl (e.g., a substituted or unsubstituted, monocyclic, 3- to 7-membered, carbocyclyl containing 0, 1, or 2 double bonds in a carbocyclic ring system where valences permit carbocyclyl). In some embodiments, at least one R a is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In some embodiments, at least one R a is substituted or unsubstituted heterocyclyl (eg, substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In some embodiments, at least one R a is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted substituted morpholinyl, or substituted or unsubstituted piperazinyl. In some embodiments, at least one R a is a substituted or unsubstituted aryl. In some embodiments, at least one R a is substituted or unsubstituted phenyl. In some embodiments, at least one R a is substituted or unsubstituted naphthyl. In some embodiments, at least one R a is a substituted or unsubstituted heteroaryl. In some embodiments, at least one R a is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. In some embodiments, at least one R a is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl , or substituted or unsubstituted isothiazolyl. In some embodiments, at least one R a is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In some embodiments, at least one R a is a substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl. In some embodiments, at least one R a is a nitrogen protecting group (eg, Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts) when attached to a nitrogen atom. In some embodiments, at least one R a is an oxygen protecting group (for example, silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom be. In some embodiments, two R a together form a substituted or unsubstituted heterocyclyl (eg, a substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In some embodiments, two R a together form a substituted or unsubstituted heteroaryl (eg, a substituted or unsubstituted 5- to 6-membered monocyclic heteroaryl).

[0186] In some embodiments, each L is the same. In some embodiments, each L is different. In some embodiments, some L are the same and some L are different. In some embodiments, each L is a bond. In some embodiments, some L are bonds.

[0187] In some embodiments, at least one L is a substituted or unsubstituted C 2-300 alkenylene, substituted or unsubstituted, C 2-300 alkynylene, substituted or unsubstituted, C 2-300 heteroalkenylene, or C 2-300 heteroalkynylene, wherein each substituted or unsubstituted C 2 - 300 alkylene, substituted or unsubstituted, C 2-300 alkenylene, substituted or unsubstituted, C 2-300 alkynylene, substituted or unsubstituted, C 2-300 heteroalkylene, substituted or unsubstituted, C 2-300 heteroalkenylene, or C 2-300 Optionally, one or more backbone carbon atoms in the heteroalkynylene are independently replaced with: substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0188] In some embodiments, at least one L is a substituted or unsubstituted C 2 - 300alkylene, wherein optionally one or more backbone carbon atoms are independently replaced with: substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; In some embodiments, at least one L is a substituted or unsubstituted C 2 - 300 Alkylene, wherein optionally one or more backbone carbon atoms are independently replaced with: substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. In some embodiments, at least one L is a substituted or unsubstituted C 2 - 300 Alkylene, wherein optionally one or more backbone carbon atoms are independently replaced with: substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene.

[0189] In some embodiments, at least one L is a substituted or unsubstituted C 2-300 heteroalkylene, wherein optionally one or more backbone carbon atoms and / or heteroatoms are independently replaced with: substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, at least one L is a substituted or unsubstituted C 2-300 Heteroalkylene, wherein optionally one or more backbone carbon atoms and / or heteroatoms are independently replaced with: substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene. In some embodiments, at least one L is a substituted or unsubstituted C 2-300 Heteroalkylene, wherein optionally one or more backbone carbon atoms and / or heteroatoms are independently replaced with: substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene.

[0190] In some embodiments, at least one L comprises a polymer in its backbone. In some embodiments, the at least one polymer is polyethylene glycol (PEG), polyethylene oxide (PEO), polypropylene glycol (PPG), polyglycerol (PG), poloxamine (POX), polybutylene oxide (PBO), polylactic acid. (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), polydioxanone (PDO), polyanhydride, polyacrylide, polyvinyl, or polyorthoester be. In some embodiments, at least one polymer is polyethylene glycol (PEG). In some embodiments, the weight-average molecular weight of at least one polymer is between 200 and 500, between 500 and 1,000, between 1,000 and 2,000, between 2,000 and 5,000, between 5,000 and 10,000, or between 10,000 and 50,000. between (inclusive), g / mol. In some embodiments, the weight-average molecular weight of at least one polymer is between 1,000 and 5,000, inclusive, g / mol. In some embodiments, the weight-average molecular weight of at least one polymer is between 2,000 and 5,000, inclusive, g / mol.

[0191] In some embodiments, the agent is covalently attached to the polymer chain via a cleavable linker (which can also be referred to as a "susceptible linker"). In some embodiments, at least one (eg each) L comprises a cleavable linker. In some embodiments, at least one (eg, each) L is a cleavable linker. A cleavable linker is "cleaved" or "cleaved" when one or more bonds of the cleavable linker are broken, resulting in, eg, release of the agent, eg, from the conjugate or particle. Linker cleavage or agent release need not be 100%, for example at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or Further cuts or releases, e.g., over a period of seconds, minutes, hours (e.g., 6 hours, 12 hours, or 24 hours), days (e.g., 2 days or 7 days), weeks, or months are encompassed by this term.

[0192] In some embodiments, cleavable linkers are enzymes (eg, esterases or proteases), pH (eg, acidic pH, basic pH), light (eg, ultraviolet light), nucleophiles, reducing , or are cleavable by or susceptible to oxidation. In some embodiments, the cleavable linker is cleavable or sensitive to an enzyme (eg, esterase or protease) or pH (eg, acidic pH, basic pH). be. In some embodiments, the cleavable linker is not cleavable by light (eg, ultraviolet light).

[0193] In some embodiments, cleavable linkers include: esters, acetals, ketals, phosphoramidites, hydrazones, imines, oximes, disulfides, or silyl moieties, combinations of acetals or ketals with ester groups, oligo-acetals or An oligo-ketal group, a combination of an oligo-ketal and a silyl ether group, or a combination of an oligo-ketal and a vinyl ether group. In some embodiments, the cleavable linker comprises an ester. In some embodiments, the cleavable linker comprises an acetal. In some embodiments, the cleavable linker comprises a phosphoramidite. In some embodiments, the cleavable linker comprises hydrazine. In some embodiments, the cleavable linker comprises an imine. In some embodiments, the cleavable linker comprises an oxime. In some embodiments, the cleavable linker comprises a silyl moiety. In some embodiments, the cleavable linker comprises a disulfide.

[0194] In other embodiments, the cleavable linker is selected from: an acetal or ketal in combination with a cis-aconityl, hydrazine, oxime, imidazole, or trityl group. Any of the foregoing groups or combinations of groups can be modified to increase the pH sensitivity of the cleavable linker, eg, as described herein.

[0195] In some embodiments, the cleavable linker is an amide, urea, carbamate, carbonate, or disulfide.

[0196] .

[0197] A cleavable linker may include a portion of an atom or moiety that is partially derived from an agent (eg, a therapeutic agent).

[0198] In some embodiments, a cleavable linker is preferentially cleaved or degraded upon exposure to a first set of conditions, as compared to a second set of conditions, for example. For example, a cleavable linker has at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more bonds ( (singular) or bond(s) is broken, or the agent is released under the first set of conditions relative to the second set of conditions, then under the first set of conditions, the second set of It can be "preferentially cleaved" or "preferentially degraded" relative to the conditions.

[0199] In some embodiments, cleavable linkers degrade or hydrolyze under physiological conditions. In some embodiments, the linker is pH sensitive or cleaved at a pH. In some embodiments, the linker degrades or hydrolyzes through the action of enzymes (eg, proteases or esterases). For example, in some embodiments, a cleavable linker is preferentially cleaved in a tissue microenvironment, such as a tumor microenvironment, referred to herein as a "tissue microenvironment cleavable linker." . In embodiments, the tissue (eg, tumor) microenvironment cleavable linker is preferentially upon exposure to a first desired tissue or tumor microenvironment over a second tissue or non-tumor tissue. cut or disassembled into Tissue (e.g., tumor) microenvironment cleavable linkers bind at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more of the linkers The singular or bond(s) may be broken or preferentially cleaved if the agent is released in the desired tissue or tumor microenvironment relative to another tissue or non-tumor tissue. can. In one embodiment, a tissue (eg, tumor) microenvironment cleavable linker is such that upon breakage of one or more bonds of the linker or exposure to a first desired tissue or tumor microenvironment, a second Preferentially if the agent is released at least 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, or 100 times faster than the tissue or non-tumor tissue cut or disassembled into A tissue (eg, tumor) microenvironment can have a specific set of conditions, eg, pH, enzymes, that cause linker cleavage or degradation.

[0200] In some embodiments, the cleavable linker is a peptide. In some embodiments, the linker is a peptide and the peptide sequence is made up of naturally occurring amino acids. In some embodiments, the linker is a peptide, and the peptide sequence contains at least one synthetically derived amino acid, such as at least 2, at least 3, at least 4, at least 5, at least 8, at least 10, at least 15, Contains at least 20 or more amino acids of synthetic origin (non-natural amino acids). In some embodiments, the peptide has a linear structure. In some embodiments, the peptide has a branched structure. In some embodiments, the peptide has a branched structure with, for example, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 branch points. In some embodiments, the peptide has a cyclic structure.

[0201] In some embodiments, the cleavable linker is a peptide and the peptide sequence comprises at least 2 amino acid residues. In some embodiments, the peptide sequence comprises at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 amino acid residues. In some embodiments, peptide sequences are from about 1 to about 10 amino acid residues. In some embodiments, the peptide sequence is about 1 to about 15, about 20, about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 amino acid residues. be. In some embodiments, peptide sequences are from about 10 to about 100 amino acid residues. In some embodiments, peptide sequences are from about 25 to about 100 amino acid residues. In some embodiments, peptide sequences are from about 50 to about 100 amino acid residues.

[0202] In some embodiments, the cleavable linker is cleavable by a matrix metalloprotease (MMP) selected from the sequences disclosed in U.S. Patent Application No. 2015 / 0087810 having a publication date of March 26, 2015, e.g. contains the substrate peptide to be activated. In some embodiments, the substrate peptide comprises a protease substrate comprising an amino acid sequence selected from the group consisting of: SEQ ID NOs: 353-363, 372-, 353-363, 372-, for example, as described in US Patent Application No. 2015 / 0087810. 375, 376-378, 395-401, 411-419, 426-433, 437-449, 454-456, 459-469, 475-482, 487-495, 318-323, 325-327, 330-335, 341-347, 14-33, and 159. In some embodiments, the linker comprises a substrate peptide derived from the sequences disclosed in U.S. Pat. No. 8,541,203, eg, the substrate peptide is selected from enzymes selected from the group consisting of: MMP- 1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-14, plasmin, PSA, PSMA, cathepsin D, cathepsin K, cathepsin S, ADAM10, ADAM12, ADAMTS, caspase-1, caspase-2 , caspase-3, caspase-4, caspase-5, caspase-6, caspase-7, caspase-8, caspase-9, caspase-10, caspase-11, caspase-12, caspase-13, caspase-14, and TACE. In some embodiments, the linker comprises a sequence disclosed in US Pat. No. 8,513,390. In some embodiments, the linker comprises a sequence disclosed in International Patent Publication WO 2003 / 079972. In some embodiments, the linker comprises a sequence disclosed in US Pat. No. 7,495,099. In some embodiments, the linker comprises a sequence disclosed in US Pat. No. 8,580,244. In some embodiments, the linker comprises a sequence disclosed in one of the following: van Kempen, et al., Eur Cancer (2006) 42:728-734; Desnoyers, L.R. et al., Sci Transl. Med (2013) 5:207ra144; Rice, J.J. et al., Protein Sci (2006) 15:825-836; Boulware, K.T. and Daugherty, P.S. Proc Natl Acad Sci USA (2006) 103:7583-7588; Biol Chem (2002) 383:1107-1112; Harris, J.L. Proc Natl Acad Sci USA (2000) 97:7754-7759; Salmaso S. and Caliceti, P. J Drug Deliv (2013) 2013:1-19; Eckhard, U et al., Matrix Biol (2015) doi: 10.1016 / j.matbio.2015.09.003 (epub before printing). The contents of any publications referred to herein are hereby expressly incorporated by reference.

[0203] In some embodiments, the cleavable linker is a protease, e.g., a protease present in a tumor or fibrotic microenvironment (e.g., matrix metalloprotease (MMP), e.g., Desnoyers, L.R. et al., Sci Transl.). Med (2013) 5:207ra144; Eckhard, U et al Matrix Biol (2015) doi: 10.1016 / j.matbio.2015.09.003 (epub before printing); and van Kempen, et al., Eur Cancer (2006) 42:728-734.) include substrate peptides that are cleaved, eg, activated by. In one embodiment, the linker comprises an amino acid sequence of a substrate for uPA, which includes the amino acid sequence LSGRSDNH (SEQ ID NO: 1), eg, described in US Pat. No. 8,513,390. In some embodiments, the linker sequence further includes Gly-Ser-containing peptide linkers at either or both ends of the substrate peptide. Additional exemplary proteases that may be upregulated in the tumor microenvironment include, but are not limited to: Urokinase-type plasminogen activator (uPA) upregulated in human cancers (S. Ulisse, et al.). al., Curr. Cancer Drug Targets 9, 32-71 (2009)), membrane serine protease 1 (MT-SP1 / matriptase) (K. Uhland Cell. Mol. Life Sci. 63, 2968-2978 (2006) A. M. LeBeau, et al., Proc. Natl. Acad. Sci. U.S.A. 110, 93-98 (2013)), and is a lysosomal protease found to be released and activated in the acidic extracellular tumor microenvironment. Legumain (C. Liu, et al., Cancer Res. 63, 2957-2964 (2003)). In some embodiments, proteases are produced by inflammatory cells, eg, tumor-infiltrating leukocytes (eg, leukocyte-derived MMPs), eg, van Kempen, et al., Eur Cancer (2006) 42:728-734. described by In other embodiments, the MMP is selected from: MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13 or MMP14, eg, as described by Eckhard, U et al., supra.

[0204] In some embodiments, the substrate peptide is derived from a CLiPS library (described in K. T. Boulware, P. S. Daugherty, Proc. Natl. Acad. Sci. U.S.A. 103, 7583-7588 (2006). In other embodiments, the substrate is Peptide specificity is assessed using a combinatorial fluorogenic substrate library, for example described by Harris, J.L. Proc Natl Acad Sci USA (2000) 97:7754-7759.In other embodiments, the substrate peptide is , derived from a phage display library (which is a phase display substrate), for example described by Deperthes, D. Biol Chem (2002) 383:1107-1112.For example, a phage display substrate is exposed to multiple proteases;peptides released by specific cleavage can be amplified in an expression system.In other embodiments, substrate peptides are derived from bacterial display libraries, eg, Rice, J.J. et al. al., Protein Sci (2006) 15:825-836.

[0205] In one aspect, the tissue (eg, tumor) microenvironment cleavable linker is enzymatically cleavable. In some embodiments, the enzyme comprises an esterase or protease. Exemplary proteases include: MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-14, plasmin, PSA, PSMA, cathepsin D, cathepsin K, cathepsin S, ADAM10. , ADAM12, ADAMTS, caspase-1, caspase-2, caspase-3, caspase-4, caspase-5, caspase-6, caspase-7, caspase-8, caspase-9, caspase-10, caspase-11, caspase -12, caspase-13, caspase-14, or TACE.

[0206] In other embodiments, the tissue microenvironment cleavable linker is cleavable at a specific pH. In some embodiments, the tissue microenvironment cleavable linker is Can be cut. In one embodiment, the tissue microenvironment cleavable linker is cleavable at a pH between about 6.0 and about 7.0, between about 6.2 and about 6.9, between about 6.5 and about 6.8, or between about 6.5 and about 6.7. is. In one embodiment, the tissue microenvironment cleavable linker is cleavable at a pH between about 5.5 and about 6.5, such as between 5.9 and 6.2. In one embodiment, the tissue microenvironment cleavable linker is cleavable at a hypoxic pH, eg, about pH 6.7-6.9, compared to a physiological pH of about 7.4, eg, about 7.4.

[0207] In some embodiments, the tissue microenvironment cleavable linker is no greater than 7.4, no greater than 7.0, no greater than 6.9, no greater than 6.8, no greater than 6.7, no greater than 6.6, no greater than 6.5, no greater than 6.4, no greater than 6.3, no greater than 6.2, no greater than 6.1, no greater than 6.0 , is cleavable or is cleaved at a pH of only 5.5 or less.

[0208] In one aspect, the tissue microenvironment cleavable linker is preferentially cleaved or degraded upon exposure to a first pH relative to a second pH. In one aspect, the tissue microenvironment cleavable linker is at least 2, 5, 10, 20, 30, 40, 50, 60, 70% lower than the second pH upon exposure to the first pH. , 80, or 100 times faster to cut or decompose. In other embodiments, the tissue microenvironment cleavable linker has a Shows a higher release or decomposition rate. In one embodiment, the ratio of the tissue microenvironment cleavable linker release or degradation rate at pH=6.7 to pH=7.4 is 1, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3 or higher than that. In one embodiment, the ratio of tissue microenvironment cleavable linker release or degradation rates at pH=6.7 to pH=7.4 is greater than two.

[0209] In one aspect, the tissue microenvironment cleavable linker exhibits increased pH-sensitivity in a hypoxic microenvironment, eg, in tumors, or fibrotic tissue.

[0210] In some embodiments, the tissue microenvironment cleavable linker provides an increased rate of release of an agent at a desired site (e.g., a tumor) relative to an increased rate of release or increased yield of release at another site. or exhibit increased release yield. In one aspect, the tissue microenvironment cleavable linker comprises an electron withdrawing group (eg, an electron withdrawing group that enhances cleavage rate or yield).

[0211] In some embodiments, M is an agent. In some embodiments, at least one M is a pharmaceutical agent. In some embodiments, all M are pharmaceutical agents. An agent can be a molecule, group of molecules, complex or substance administered to an organism for diagnostic, therapeutic, preventative medical or veterinary purposes. In some embodiments, the agent is a pharmaceutical agent. In some embodiments, the pharmaceutical agent is a therapeutic, diagnostic, or prophylactic agent.

[0212] In some embodiments, the therapeutic agent is an immunomodulatory agent. In some embodiments, the therapeutic agent is an immunosuppressive drug. In some embodiments, the therapeutic agent is an immune activator. In some embodiments, the therapeutic agent is an interleukin (eg, IL-2, IL-7, IL-12). In some embodiments, the therapeutic agent is a cytokine (eg, interferon, G-CSF). In some embodiments, the therapeutic agent is a chemokine (eg, CCL3, CCL26, CXCL7). In some embodiments, the therapeutic agent is an immunomodulatory imide drug. In some embodiments, the therapeutic agent is thalidomide, lenalidomide, or pomalidomide. In some embodiments, the therapeutic agent is cytosine phosphate-guanosine, oligodeoxynucleotide, or glucan.

[0213] In some embodiments, the therapeutic agent is an immune checkpoint inhibitor.

[0214] An immune checkpoint inhibitor, as used herein, is an agent that inhibits or prevents the activity of an immune checkpoint molecule, eg, by binding to the molecule. An immune checkpoint inhibitor reduces immune checkpoint molecule activity in a cell or organism, e.g., by at least 5%, at least 10%, at least 20%, as compared to a cell or organism not exposed to the immune checkpoint inhibitor. It can be reduced by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or about 100%. Immune checkpoint molecule activity can be interfered with by antibodies that selectively bind to the immune checkpoint molecule and block its activity. The activity of immune checkpoint molecules can also be inhibited or blocked by molecules other than antibodies that bind to immune checkpoint molecules, such as proteins, small molecules, and peptides. Agents that bind to and degrade or inhibit DNA or mRNA encoding immune checkpoint molecules can also function as immune checkpoint inhibitors. Examples include siRNAs and antisense oligonucleotides. Non-limiting examples of immune checkpoint molecules include: programmed cell death 1 protein (PD-1), programmed cell death 1 protein ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 ( CTLA-4), T-cell immunoglobulin domain and mucin domain 3 (TIM3), lymphocyte activation gene-3 (LAG3), T-cell activation inhibitor 1 containing V-set domains (VTCN1 or B7-H4 ), surface antigen class 276 (CD276 or B7-H3), B and T lymphocyte attenuator (BTLA), galectin-9 (GAL9), checkpoint kinase 1 (Chk1), adenosine A2A receptor (A2AR), indole Amine 2,3-dioxygenase (IDO), killer cell immunoglobulin-like receptor (KIR), and V-domain Ig suppressor of T cell activation (VISTA).

[0215] In some embodiments, immune checkpoint inhibitors are antibodies, such as humanized or human antibodies. As used herein, the term "antibody" refers to an immunoglobulin molecule that specifically binds to a particular antigen, such as an immune checkpoint molecule (eg, PD-L1, PD-1, or CTLA- 4), and includes polyclonal, monoclonal, genetically modified and other modified forms of antibodies, including but not limited to: chimeric antibodies, humanized antibodies, fully human antibodies, heterozygous antibodies. Conjugate antibodies (eg, bispecific, bispecific, trispecific, and tetraspecific antibodies), and antigen-binding fragments of antibodies, which include, for example, Fab', F( ab')2, Fab, Fv, rlgG, and scFv fragments. Moreover, unless otherwise indicated, the term "monoclonal antibody" includes intact molecules as well as antibody fragments (such as Fab and F(ab')2 fragments) capable of specifically binding to an antigen. meant to include both. Antibodies may include: immunoglobulin constant regions from any immunoglobulin, such as IgG1, IgG2, IgG3, or IgG4 subtypes, IgA (including IgA1 and IgA2), IgE, IgD or IgM.

[0216] In some embodiments, the immune checkpoint inhibitor is an immune checkpoint molecule such as programmed cell death 1 protein (PD-1), programmed cell death 1 protein ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated T-cell activation inhibitor 1 (VTCN1 or B7-H4), surface antigen class 276 (CD276 or B7-H3), B and T lymphocyte attenuator (BTLA), galectin-9 (GAL9), checkpoint kinase 1 (Chk1), adenosine A2A receptor (A2AR) ), indoleamine 2,3-dioxygenase (IDO), killer cell immunoglobulin-like receptor (KIR), or V-domain Ig suppressor activation of T cell activation (VISTA), antibodies (e.g., monoclonal antibodies, such as human or humanized monoclonal antibodies).

[0217] In some embodiments, the immune checkpoint inhibitor is a small molecule, wherein the small molecule has a molecular weight of 1,500 g / mol or less.

[0218] In some embodiments, the immune checkpoint inhibitor is programmed cell death ligand 1 (PD-L1) or programmed cell death 1 (PD-1) inhibitor.

[0219] APD-1 inhibitors, as used herein, are agents that inhibit or prevent PD-1 activity, eg, by binding to PD-1. PD-1 reduces PD-1 activity in a cell or organism by, for example, at least 5%, at least 10%, at least 20%, at least 30% compared to a cell or organism not exposed to a PD-1 inhibitor. , at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or about 100%. Human PD-1 is encoded by the gene PDCD1 (Genbank Entrez ID 5133). Functions as a PD-1 immune checkpoint and negatively regulates immune responses, e.g. CD8 + Inhibits the activation, expansion and / or function of T cells and other immune cells. PD-L1 is the ligand for PD-1. PD-L1 is a type 1 transmembrane protein with immunoglobulin V-like and C-like domains. Human PD-L1 is encoded by the CD274 gene (Genbank Entrez ID 29126). PD-L1 is also a ligand for B7.1.

[0220] The activity of PD-1 can be blocked by antibodies that selectively bind PD-1 and inhibit its activity. The activity of PD-1 can also be inhibited or blocked by molecules other than antibodies that bind PD-1, such as proteins, small molecules, and peptides. Agents that bind to and degrade or inhibit DNA or mRNA encoding PD-1 can also act as PD-1 inhibitors. Examples include anti-PD-1 siRNA and anti-PD-1 antisense oligonucleotides.

[0221] A PD-L1 inhibitor, as used herein, is an agent that inhibits or prevents PD-L1 activity, eg, by binding PD-L1. A PD-L1 inhibitor reduces PD-L1 activity in a cell or organism, e.g. %, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or about 100%.

[0222] PD-L1 activity can be blocked by molecules that selectively bind and block active PD-L1, such as by blocking interaction and activation with PD-1 and / or B7-1. . The activity of PD-L1 can also be inhibited or blocked by molecules other than antibodies that bind PD-L1, such as proteins, small molecules, and peptides. Agents that bind to and degrade or inhibit DNA or mRNA encoding PD-L1 can also act as PD-L1 inhibitors. Examples include anti-PD-L1 siRNA and anti-PD-L1 antisense oligonucleotides.

[0223] Exemplary PD-1 inhibitors are described in U.S. Publications 20130280265, 20130237580, 20130230514, 20130109843, 20130108651, 20130017199, 20120251537, and 20110271358, and European Patent EP2170959B1, the disclosure of which is incorporated herein by reference in its entirety. incorporated into the specification.

[0224] Examples PD-1 inhibitors include: nivolumab (eg OPDIVO® from Bristol-Myers Squibb), a fully human IgG4 monoclonal antibody that binds to PD-1; pidilizumab (eg CT-011, CureTech from ), a humanized IgG1 monoclonal antibody that binds to PD-1; pembrolizumab (eg, KEYTRUDA®, from Merck), a humanized IgG4-kappa monoclonal antibody that binds to PD-1; MEDI- 0680 (AstraZeneca / MedImmune) monoclonal antibody that binds to PD-1; and REGN2810 (Regeneron / Sanofi) monoclonal antibody that binds to PD-1. Another exemplary PD-1 inhibitor is a recombinant fusion protein, AMP-224 (Glaxo Smith Kline and Amplimmune).

[0225] Examples PD-L1 inhibitors include those described in US Publications 20090055944, 20100203056, 20120039906, 20130045202, 20130309250, and 20160108123, the entire disclosures of which are incorporated herein by reference.

[0226] Examples PD-L1 inhibitors include: For example: atezolizumab (TECENTRIQ TM also called, Genentech / Roche), human monoclonal antibody that binds to PD-L1; durvalumab (also called MEDI4736, AstraZeneca / MedImmune), human immunoglobulin IgG1 kappa monoclonal antibody that binds to PD-L1; BMS-936559 (Bristol-Meyers) Squibb), a fully human IgG4 monoclonal antibody that binds to PD-L1; avelumab (also called MSB 0010718C, Merck KGaA / Pfizer), a fully human IgG1 monoclonal antibody that binds to PD-L1; and CA-170 (Aurigene / Curis) PD -Small molecule antagonist of L1.

[0227] In some embodiments, the immune checkpoint inhibitor is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor.

[0228] CTLA-4 inhibitors, as used herein, are agents that inhibit or prevent CTLA-4 activity, eg, by binding to CTLA-4. A CTLA-4 inhibitor reduces CTLA-4 activity in a cell or organism, e.g. %, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or about 100%. Human CTLA-4 is encoded by the gene CTLA4 (Genbank Entrez ID 1493). CTLA-4 negatively regulates immune responses, eg, by transmitting inhibitory signals to T cells.

[0229] CTLA-4 activity can be interfered with by antibodies that selectively bind to CTLA-4 and block its activity. The activity of CTLA-4 can also be inhibited or blocked by molecules other than antibodies that bind CTLA-4, such as proteins, small molecules, and peptides. Agents that bind to and degrade or inhibit DNA or mRNA encoding CTLA-4 can also act as CTLA-4 antagonists. Examples include anti-CTLA-4 siRNA and anti-CTLA-4 antisense oligonucleotides.

[0230] Examples CTLA-4 antagonists are disclosed in PCT Publication Nos. WO2001 / 014424, WO2012 / 118750, European Patent No. EP1212422B1, U.S. Pat. , 8,318,916, 8,685,394, U.S. Publication Nos. 2002 / 0039581, 2005 / 0201994, and 2009 / 0117037, the entire disclosures of which are incorporated herein by reference.

[0231] Example CTLA-4 antagonists include: ipilimumab (YERVOY®, Bristol-Myers Squibb), which is a recombinant human IgG1 monoclonal antibody against CTLA-4, and tremelimumab (AstraZeneca; MedImmune / Pfizer). , which is a human IgG2 monoclonal antibody against CTLA-4.

[0232] In some embodiments, the immune checkpoint inhibitor is a T-cell immunoglobulin domain and mucin domain 3 (TIM3) inhibitor, a lymphocyte activation gene-3 (LAG3) inhibitor, a T-cell activity containing V-set domains Metabolism inhibitor 1 (VTCN1 or B7-H4) inhibitor, surface antigen class 276 (CD276 or B7-H3) inhibitor, B and T lymphocyte attenuator (BTLA) inhibitor, galectin-9 (GAL9) inhibitor, checkpoint kinase 1 (Chk1) inhibitors, adenosine A2A receptor (A2AR) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, killer cell immunoglobulin-like receptor (KIR) inhibitors, or V-domain Ig of T cell activation Suppressor (VISTA) inhibitor.

[0233] In some embodiments, the therapeutic agent is an anticancer agent. Anticancer agents include biotherapeutic anticancer agents as well as chemotherapeutic agents. Exemplary biotherapeutic anti-cancer agents include, but are not limited to: interferons, cytokines (eg, tumor necrosis factor, interferon alpha, interferon gamma), vaccines, hematopoietic growth factors, monoclonal serum therapy, immune Stimulatory and / or immunomodulatory agents (eg IL-1, 2, 4, 6, or 12), immune cell growth factors (eg GM-CSF), and antibodies (eg Herceptin (trastuzumab), T -DM1, AVASTIN (bevacizumab), Erbitux (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexar (tositumomab)). Exemplary chemotherapeutic agents include, but are not limited to: antiestrogens (eg, tamoxifen, raloxifene, and megestrol), LHRH agonists (eg, goscurculin and leuprolide), antiandrogens (eg, flutamide and bicalutamide), photodynamic therapy (e.g. vertoporphine (BPD-MA), phthalocyanines, photosensitizers Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide) , ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine (CCNU)), alkyl sulfonates (e.g. busulfan and threosulfan), triazenes (e.g. dacarbazine , temozolomide), platinum-containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or paclitaxel equivalent) docosaxaenoic acid conjugate-paclitaxel (DHA -paclitaxel, taxoplexin), polyglutamate-conjugated-paclitaxel (PG-paclitaxel, paclitaxel-polygumex, CT-2103, XYOTAX), tumor-activating prodrug (TAP) ANG1005 (Angiopep-2 conjugated to three molecules of paclitaxel) ), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognition peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol). , epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mitomycin C), antimetabolites, DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimester) trexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonucleotide reductase inhibitors (e.g. oxyurea and deferoxamine), uracil analogues (e.g. 5-fluorouracil (5-FU), floxuridine, doxifluridine, latitrexed, tegafur-uracil, capecitabine), cytosine analogues (e.g. cytarabine (araC), cytosine arabinoside, and fludarabine), purine analogues (eg, mercaptopurine and thioguanine), vitamin D3 analogues (eg, EB1089, CB1093, and KH1060), isoprenylation inhibitors (eg, lovastatin), dopaminergic neurotoxins (e.g. 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycins (e.g. actinomycin D, dactinomycin), bleomycins (e.g. bleomycin A2 , bleomycin B2, peplomycin), anthracyclines (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca 2+ ATPase inhibitors (e.g. thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g. axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN TM , AZD2171), dasatinib (SPRYCEL (登録商標) , BMS-354825), erlotinib (TARCEVA (登録商標) ), gefitinib (IRESSA (登録商標) ), imaginative (Gleevec (登録商標) , CGP57148B, STI-571), lapatinib (TYKERB (登録商標) , TYVERB (登録商標) ), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA (登録商標) ), semaxanib (semaxinib, SU5416), sunitinib (SUTENT (登録商標) , SU11248), toceranib (PALLADIA (登録商標) ), vandetanib (ZACTIMA (登録商標) , ZD6474), vatalanib (PTK787, PTK / ZK), trastuzumab (Herceptin (登録商標) ), bevacizumab (AVASTIN (登録商標) ), rituximab (Rituxan (登録商標) ), cetuximab (Erbitux (登録商標) ), panitumumab (Vectibix (登録商標) ), ranibizumab (Lucentis (登録商標) ), nilotinib (TASIGNA (登録商標) ), sorafenib (NEXAVAR (登録商標) ), everolimus (AFINITOR (登録商標) ), alemtuzumab (CAMPATH (登録商標) ), gemtuzumab ozogamicin (MYLOTARG (登録商標) ), temsirolimus (TORISEL (登録商標) ), ENMD-2076, PCI-32765, AC220, Dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK TM ), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF (登録商標)), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228) , proteasome inhibitors (e.g. bortezomib (VELCADE)), mTOR inhibitors (e.g. rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe), and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbidine, prednisolone, dexamethasone, campatecin, plicamycin, asparaginase, aminopterin, metopterin, porphyromycin, melphalan, leurocidin, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethylmelamine. In some embodiments, the anticancer agent is selected from the group consisting of: abiraterone acetate, ABVD, ABVE, ABVE-PC, AC, AC-T, ADE, adtrastuzumab emtansine, afatinib dimaleate. , aldesleukin, alemtuzumab, anastrozole, arsenic trioxide, asparaginase erwinia chrysanthymy, axitinib, azacitidine, BEACOPP, belinostat, bendamustine hydrochloride, BEP, bevacizumab, bicalutamide, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib-s-malate, CAF, capecitabine, CAPOX, carboplatin, carboplatin-taxol, carfilzomib carmustine, carmustine implant, ceritinib, cetuximab, chlorambucil, chlorambucil-prednisone, CHOP, cisplatin, Clofarabine, CMF, COPP, COPP-ABV, crizotinib, CVP, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin hydrochloride, decitabine, degarelix, denileukin diftitox, denosumab, dinutuximab, docetaxel , doxorubicin hydrochloride, doxorubicin hydrochloride liposomes, enzalutamide, epirubicin hydrochloride, EPOCH, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, exemestane, FEC, fludarabine phosphate, fluorouracil, FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, fulvestrant, gefitinib, gemcitabine hydrochloride, gemcitabine-cisplatin, gemcitabine-oxaliplatin, goserelin acetate, Hyper-CVAD, ibritumomab tiuxetan, ibrutinib, ICE, idelalisib, ifosfamide, imani Tibumesylate, imiquimod, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotide acetate, lapatinib ditosylate, lenalidomide, lenvatinib, letrozole, leucovorin calcium, leuprolide acetate, liposomal cytarabine, lomustine, mechlorethamine hydrochloride , megestrolua Cetate, mercaptopurine, methotrexate, mitomycin C, mitoxantrone hydrochloride, MOPP, nerarabine, nilotinib, nivolumab, obinutuzumab, OEPA, ofatumumab, OFF, olaparib, omacetaxine mepesuccinate, OPPA, oxaliplatin, paclitaxel, paclitaxel albumin - stabilized nanoparticle formulations, PAD, palbociclib, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, pegaspargase, peginterferon alfa-2b, peginterferon alfa-2b, pembrolizumab, pemetrexed disodium, pertuzumab, plelixafor, pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone, procarbazine hydrochloride, radium-223 dichloride, raloxifene hydrochloride, ramucirumab, R-CHOP, recombinant HPV bivalent vaccine, recombinant human papillomavirus, 9 valent vaccine, recombinant human papillomavirus, tetravalent vaccine, recombinant interferon alpha-2b, regorafenib, rituximab, romidepsin, ruxolitinib phosphate, siltuximab, sipuleucel-t, sorafenib tosylate, STANFORD V, sunitinib malate, TAC , tamoxifen citrate, temozolomide, temsirolimus, thalidomide, thiotepa, topotecan hydrochloride, toremifene, tositumomab and iodine I 131, tositumomab, TPF, trametinib, trastuzumab, VAMP, vandetanib, VEIP, vemurafenib, vinblastine sulfate, vincristine sulfate, vincristine Sulfate liposomes, vinorelbine tartrate, vismodegib, vorinostat, XELIRI, XELOX, ziv-aflibercept, and zoledronic acid. In some embodiments, the anticancer agent is bortezomib.

[0234] In some embodiments, the agent is an antihypertensive agent. Exemplary antihypertensive agents include, but are not limited to: amiloride, amlodipine, atenolol, azilsartan, benazepril, bendroflumethiazide, betaxolol, bisoprolol, bucindolol, bumetanide, candesartan, captopril, carteolol, carvedilol, chlorothiazide, chlorthalidone, cilnidipine, clevidipine, diltiazem, doxazosin, enalapril, epitidide, eplerenone, eprosartan, ethacrynic acid, felodipine, fimasartan, fosinopril, furosemide, hydrochlorothiazide, indapamide, indolamine, irbesartan, isradipine, labetalol, lercanidipine, levamlodipine, lisinopril, losartan, methyclothiazide, metolazone, metoprolol, moexipril, nadolol, nebivolol, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, olmesartan, oxprenolol, penbutolol, perindopril, pindolol, phenoxybenzamine, fenthol Amines, polythiazides, prazosin, propranolol, quinapril, ramipril, spironolactone, telmisartan, terazosin, timolol, tolazoline, torsemide, trandolapril, triamterene, valsartan, and verapamil. In some embodiments, the antihypertensive agent is telmisartan.

[0235] Exemplary diagnostic agents include, but are not limited to: fluorescent molecules; gases; metals; contrast agents such as positron emission tomography (PET), computer aided tomography (CAT), single photon emission computers Commercial contrast agents used in tomography, X-ray, fluoroscopy, and magnetic resonance imaging (MRI); and contrast agents such as magnetic resonance signal enhancers, X-ray attenuation agents, ultrasound scattering agents. and ultrasonic frequency shifting agents. Examples of materials suitable for use as contrast agents in MRI include gadolinium chelates, as well as iron, magnesium, manganese, copper, and chromium. Examples of materials useful for CAT and X-ray imaging include iodine-based materials. In some embodiments, the diagnostic agent is used in magnetic resonance imaging (MRI), such as iron oxide particles or gadolinium complexes. Gadolinium conjugates approved for clinical use include DTPA, DTPA-BMA, DOTA and HP-DO3A, reviewed in Aime, et al., (Chemical Society Reviews (1998), 27:19-29). The entire teachings of which are incorporated herein by reference.

[0236] In some embodiments, the diagnostic agent is a metal, inorganic compound, organometallic compound, organic compound, or salt thereof. In some embodiments, the contrast agent contains a metal selected from the group consisting of: scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technesium. , ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, zaforium, dabnium, seabhodium, bohlium, hassium, meitnerium, gadolinium, gallium, thallium, and barium. In some embodiments, the diagnostic agent is an organic compound. In some embodiments, the diagnostic agent is metal-free. In some embodiments, the diagnostic agent is a metal-free organic compound.

[0237] In some embodiments, the contrast agent is a magnetic resonance imaging (MRI) agent. In some embodiments, the MRI agent is gadolinium. In some embodiments, the MRI agent is a nitroxide radical-containing compound.

[0238] In some embodiments, the contrast agent is a nuclear medicine contrast agent. In some embodiments, the nuclear medicine contrast agent is selected from the group consisting of: 64 Cu diacetyl-bis(N 4 -methylthiosemicarbazone)( 64 Cu-ASTM), 18 F-fluorodeoxyglucose (FDG), 18 F-fluoride, 3'-deoxy-3'-[ 18 F]fluorothymidine (FLT), 18F-fluoromisonoidazole (FM iso), gallium, technetium-99m, and thallium.

[0239] In some embodiments, the contrast agent is a radiographic contrast agent. In some embodiments, the radiographic contrast agent is selected from the group consisting of: barium, gastrografin, and iodine contrast agents.

[0240] In some embodiments, the contrast agent is a radical-containing compound. In some embodiments, the contrast agent is a nitroxide radical containing compound. In some embodiments, the contrast agent or diagnostic agent has the formula: [formation]

[0241] In some embodiments, the contrast agent or diagnostic agent is an organic compound. In some embodiments, the contrast agent is a salt of an organic compound. In some embodiments, the contrast agent or diagnostic agent has the formula: [formation]

[0242] In some embodiments, the diagnostic agent is a fluorescent molecule, a metal chelate, a contrast agent, a radionuclide, or a positron emission tomography (PET) contrast agent, an infrared contrast agent, a near-infrared contrast agent, a computer-assisted tomography (CAT) contrast agent. , photon emission computed tomography contrast agents, X-ray contrast agents, or magnetic resonance imaging (MRI) agents.

[0243] In some embodiments, the diagnostic agent is a fluorescent molecule. In some embodiments, fluorescent molecules include: acridine dyes, cyanine dyes, rhodamine dyes, BODIPY dyes, fluorescein dyes, dansyl dyes, Alexa dyes, atto dyes, quantum dots, or fluorescent proteins. In some embodiments, the fluorescent molecule is a cyanine dye (eg, Cy3, Cy3.5, Cy5, Cy5.5, Cy7, or Cy7.5).

[0244] In some embodiments, the diagnostic agent is an MRI agent (eg, contrast agent). Examples of materials suitable for use as MRI agents (eg, contrast agents) include: gadolinium chelates, as well as iron, magnesium, manganese, copper, and chromium.

[0245] In some embodiments, the diagnostic agent is a CAT contrast agent or an X-ray contrast agent. Examples of materials useful for CAT and X-ray imaging include iodine-based materials.

[0246] In some embodiments, the diagnostic agent is a PET contrast agent. Examples suitable for PET contrast agents include: Positron emitting radioisotopes 18 F. 15 O 13 N, 11 C. 82 Rb, 64 Cu, and 68 Ga, for example, fludeoxyglucose ( 18 F-FDG), 68 Ga-DOTA-pseudopeptide (for example, 68 Ga-DOTA-TOC), 11 C-methomidate, 11 C-acetate, 11 C-methionine, 11 C-choline, 18 F-fluciclovine, 18 F-fluorocholine, 18 F-fluorodeoxysorbitol, 18 F-3'-fluoro-3'-deoxythymidine, 11 C-raclopride, and 18 Compounds and compositions comprising F-desmethoxyfaripride.

[0247] In some embodiments, the diagnostic agent is a near-infrared contrast agent. Examples of near-infrared contrast agents include: Pz 247, DyLight 750, DyLight 800, cyanine dyes (eg Cy5, Cy5.5, Cy7), AlexaFluor 680, AlexaFluor 7500, IRDye 680, IRDye 800CW, and Kodak X-SIGHT dye.

[0248] In some embodiments, the agent can be a radionuclide, eg, for use as a therapeutic, diagnostic, or prognostic agent. Of the radionuclides used, gamma-emitters, positron-emitters and X-ray-emitters are suitable for diagnosis and / or therapy, while beta-emitters and alpha-emitters are also suitable for therapy. may be used for Suitable radionuclides for forming uses in the various aspects of this disclosure include, but are not limited to: 123 I 125 I 130 I 131 I 133 I 135 I 47 Sc 72 As 72 Sc 90 Y, 88 Y, 97 Ru, 100 Pd, 101m Rh, 119 Sb, 128 Ba 197 Hg, 211 At 212 Bi 212 Pb, 109 Pd, 111 In, 67 Ga 68 Ga 67 Cu, 75 Br, 77 Br, 99m Tc, 14 C. 13 N, 15 O 32 P. 33 P, or 18 F.

[0249] Prophylactic agents that can be included in the conjugates of the present disclosure include, but are not limited to: antibiotics, nutritional supplements, and vaccines. Vaccines may include isolated proteins or peptides, inactivated organisms and viruses, dead organisms and viruses, genetically modified organisms or viruses, and cell extracts. Prophylactic agents may be combined with interleukins, interferons, cytokines, and adjuvants such as cholera toxin, alum, Freund's adjuvant.

[0250] In some embodiments, at least one agent comprises one or more boron-containing moieties before the agent is included in the compound, and the at least one boron-containing moiety, when included in the compound or after, has the formula It forms ring A represented by (I) or ring B represented by formula (II). In some embodiments, the at least one boron-containing moiety is a boronic acid moiety (eg, -B(OH) 2 ). In some embodiments, the at least one boron-containing moiety is a boronate ester moiety (eg, -B(OH)-OR 2 , -B(OR 2 ) 2 , where each R 2 independently, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group, or two R 2 together form a substituted or unsubstituted heterocyclyl). In some embodiments, the agent comprising one or more boron-containing moieties is bortezomib. In some embodiments, the agent comprising one or more boron-containing moieties is Tavabolol [formation] , a boron-containing derivative of bocepevir [formation] , benzo[b]thiophene-2-boronic acid [formation] , TRI50c [formation] , or dutogliptin [formation] is. In certain embodiments, when the agent comprises one or more boron-containing moieties, the agent corresponds to the formula: [formation] . In certain embodiments, the boron atom contained in ring A of formula (I) or ring C of formula (II) is such that at least one agent comprises one or more boron atoms before the agent is included in the compound. is part of at least one agent when it contains a portion containing

[0251] In certain embodiments, the boron atom contained in ring A of formula (I) or ring C of formula (II) is not part of at least one agent. In some embodiments, at least one agent does not contain a boronic acid or boronic ester moiety. In some embodiments, at least one agent does not contain a boron atom.

[0252] In some embodiments, m is 1. In some embodiments, m is two. In some embodiments, m is three.

[0253] In some embodiments, d is 1. In some embodiments, d is two. In some embodiments d is 3.

[0254] In some embodiments, at least two (eg, two) of M are different from each other. In some embodiments, at least three (eg, three) M are different from each other. In some embodiments, at least four (eg, four) of M are different from each other. In some embodiments, at least one M is an immunomodulatory agent (eg, an immunomodulatory imide drug), and at least one M is an anticancer agent. In some embodiments, at least one M is thalidomide, lenalidomide, or pomalidomide and at least one M is bortezomib. In certain embodiments, at least one M is thalidomide, at least one M is pomalidomide, and at least one M is bortezomib.

[0255] In certain embodiments, compounds of Formula I are represented by the formula: [formation]

[0256] In some embodiments, the compound represented by Formula I is represented by the formula: [formation]

[0257] In certain embodiments, compounds of Formula I are represented by Formula I-1: [formation]

[0258] polymer This disclosure describes polymers (eg, bottle brush polymers (BBPs)) and materials made from polymerizing monomers represented by Formula (I) and Formula (II). In some embodiments, the polymer comprises one or more types of repeat units, wherein at least one repeat unit has the formula: [formation] In the formula: L. 1 is a substituted or unsubstituted linker, where L 1 the backbone of contains 2 or more atoms; Each Y is independently -C(R 1 ) 2 -is; each R 1 is independently absent, hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR a , -N(R a ) 2 , -SR a , -CN, -SCN, -C(=NR a )R a , -C(=NR a ) OR a , -C(=NR a )N(R a ) 2 , -C(=O)R a , -C(=O) OR a , -C(=O)N(R a ) 2 , -NO 2 , -NR a C(=O)R a , -NR a C(=O)OR a , -NR a C(=O)N(R a ) 2 , -OC(=O)R a , -OC(=O)OR a , or -OC(=O)N(R a ) 2 or two R 1 together form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; each R a is independently hydrogen, halogen, substituted or unsubstituted, C 1-6 alkyl, substituted or unsubstituted, C 2-6 alkenyl, substituted or unsubstituted, C 2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitrogen protecting group when attached to a nitrogen atom, attached to an oxygen atom an oxygen protecting group when attached to a sulfur atom, or a sulfur protecting group when attached to a sulfur atom, or two R a is taken together with the nitrogen atom to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; each L is independently a bond or a substituted or unsubstituted linker, wherein the atom in the backbone of L attached to ring A or ring C is carbon; each M is independently an agent; each m is independently an integer between 1 and 10, inclusive; each c is independently an integer between 1 and 2, inclusive; and d is an integer between 1 and 10, inclusive; Including the part represented by.

[0259] The moieties and variables in formulas (I-A) and (II-A) are as described herein.

[0260] The present disclosure also relates to monomers prepared from polymers as described herein. In some embodiments, the polymer contains monomers as described herein. In some embodiments, the polymer comprises a first monomer and a second monomer as described herein, wherein all M are the same. In some embodiments, the polymer comprises a first monomer and a second monomer as described herein, wherein at least one M of the first monomer is at least one of the second monomer different from the one M.

[0261] In some embodiments, the polymer is a homopolymer. In some embodiments, the polymer is a copolymer (eg, a copolymer prepared by polymerizing two different types of monomers). In some embodiments, the polymer is a linear polymer. In some embodiments, the polymer is a linear copolymer (eg, block copolymer, alternating copolymer, periodic copolymer, statistical copolymer, stereoblock copolymer, gradient copolymer). In some embodiments, the polymer is a branched polymer (eg, a branched copolymer). In some embodiments, the polymer is a graft copolymer (eg, a star copolymer). In some embodiments, the polymer is a regular copolymer. In some embodiments, the polymer is a random copolymer. In some embodiments, the polymer is a brush polymer. In some embodiments, the polymer is a bottle brush polymer. In some embodiments, the polymer is a charged polymer. In some embodiments, the polymer is a hydrophilic polymer. In some embodiments, the polymer is a hydrophobic polymer.

[0262] In some embodiments, the terms "polymer," "conjugate," and "particle" are used interchangeably. Exemplary conjugates or particles are M n = average molecular weight (kDa), D H = mean hydrodynamic diameter (nm), and PDI = polydispersity.

[0263] In some embodiments, M n is determined by gel permeation chromatography, viscosity measurements via (Mark-Huwink equation), colligative methods (such as vapor pressure osmosis), end group quantification, or proton NMR. In some embodiments, M w is determined by static light scattering, small angle neutron scattering, X-ray scattering, and sedimentation velocity. In some embodiments, the average molecular weight of the conjugate is between about 10 kDa and about 100 kDa, such as between about 15 kDa and about 85 kDa, between about 20 kDa and about Between 60 kDa, or between about 30 kDa and about 50 kDa. In one aspect, the average molecular weight of the conjugate is between about 20 kDa and about 60 kDa. In one aspect, the average molecular weight of the conjugate is between about 30 kDa and about 50 kDa.

[0264] In some embodiments, the average molecular weight of the conjugate is less than about 100 kDa (eg, about 95 kDa, about 90 kDa, about 85 kDa, about 80 kDa, about 75 kDa, about 70 kDa, about 65 kDa, about 60 kDa, about 55 kDa, or less than about 50 kDa). In some embodiments, the conjugate has an average molecular weight of less than about 75 kDa (eg, less than about 70 kDa, about 65 kDa, about 60 kDa, about 55 kDa, or about 50 kDa).

[0265] In some embodiments, the average molecular weight of the particles is, for example, between about 100 kDa and about 1,000 kDa, such as between about 200 kDa and about 700 kDa, or between about 300 kDa, eg, as determined by gel permeation chromatography. between about 500 kDa. In one aspect, the average molecular weight of the particles is between about 2000 kDa and about 70 kDa. In one aspect, the average molecular weight of the particles is between about 300 kDa and about 500 kDa.

[0266] In some embodiments, the average molecular weight of the particles is less than about 1,000 kDa (e.g., about 950 kDa, about 900 kDa, about 850 kDa, about 800 kDa, about 750 kDa, about 700 kDa, about 650 kDa, about 600 kDa, about 550 kDa, or less than about 500 kDa). In some embodiments, the particles have an average molecular weight of less than about 750 kDa (eg, less than about 700 kDa, about 650 kDa, about 600 kDa, about 550 kDa, or about 500 kDa). In some embodiments, the particles have an average molecular weight of about 500 kDa (eg, about 450 kDa, about 400 kDa, about 350 kDa, or less than 300 kDa).

[0267] In some embodiments, the weight average molecular weight of the polymer is between 3,000 and 1,000,000 g / mol, inclusive. In some embodiments, the weight average molecular weight of the polymer is between 3,000 and 300,000 g / mol, inclusive. In some embodiments, the weight average molecular weight of the polymer is between 3,000 and 100,000 g / mol, inclusive. In some embodiments, the weight average molecular weight of the polymer is between 3,000 and 10,000 g / mol, inclusive. In some embodiments, the weight average molecular weight of the polymer is between 10,000 and 1,000,000 g / mol, inclusive. In some embodiments, the weight average molecular weight of the polymer is between 10,000 and 100,000 g / mol, inclusive. In some embodiments, the weight average molecular weight of the polymer is between 100,000 and 1,000,000 g / mol, inclusive. In some embodiments, the weight average molecular weight of the polymer is between 10,000 and 50,000 g / mol, inclusive. In some embodiments, the weight average molecular weight of the polymer is between 20,000 and 50,000 g / mol, inclusive.

[0268] In some embodiments, the average hydrodynamic diameter of the conjugate is less than 50 nm (eg, about 45 nm, about 40 nm, about 35 nm, about 25 nm, about 20 nm, about 15 nm, about 10 nm, about 7.5 nm, or less). In some embodiments, the average hydrodynamic diameter of the conjugate is between about 1 nm and 20 nm (eg, between about 2.5 nm and about 17.5 nm, or between about 5 nm and about 15 nm). In some embodiments, the average hydrodynamic diameter of the conjugate is between about 5 nm and about 15 nm.

[0269] In some embodiments, the average hydrodynamic diameter of the particles is less than 100 nm (eg, about 90 nm, about 80 nm, about 75 nm, about 70 nm, about 65 nm, about 60 nm, about 55 nm, about 50 nm, about 45 nm, about 40 nm, about 35 nm, about 25 nm, or less). In some embodiments, the average hydrodynamic diameter of the particles is between about 5 nm and about 100 nm (eg, between about 7.5 nm and about 75 nm, between about 10 nm and about 50 nm, between about 12.5 nm and about 40 nm). , or between about 15 nm and about 30 nm). In some embodiments, the average hydrodynamic diameter of the particles is between about 10 nm and about 50 nm. In some embodiments, the particles have an average hydrodynamic diameter of about 15 nm to about 30 nm.

[0270] In some embodiments, the average polydispersity of the conjugates or particles is less than about 0.5 (eg, less than about 0.4, about 0.35, about 0.3, about 0.25, about 0.2, about 0.15, or less). In some embodiments, the average polydispersity of the conjugates or particles is less than about 0.3. In some embodiments, the average polydispersity of the conjugates or particles is less than about 0.2. In some embodiments, the conjugates or particles are monodisperse. In some embodiments, the conjugates or particles are about 50% monodisperse (eg, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85% monodisperse). %, about 90%, about 95%, about 99%, or about 99.9% monodispersity).

[0271] In some embodiments, the conjugate or particle is substantially water soluble (eg, hydrophilic). In some embodiments, the conjugate or particle is substantially water insoluble (eg, hydrophobic). In some embodiments, the conjugate or particle is substantially insoluble in water, requiring more than about 10,000 parts water to dissolve 1 part polymer. In one aspect, the conjugate or particle is amphipathic. In one aspect, the conjugate or particle comprises a segment that is hydrophobic and a segment that is hydrophilic.

[0272] The BBPs described herein can deliver multiple agents ratiometrically and / or orthogonally. Different chemical and / or physical conditions may be employed to individually release multiple agents upon delivery. Convergent synthesis of BBPs can be performed using different linkers (e.g. reduction, hydrolysis (e.g. esters), oxidation, UV irradiation cleavable linkers (e.g. reduction, hydrolysis (e.g. esters), oxidation, UV irradiation cleavable linkers)). allows different agents to be attached to the BBP via Hydrolysis, oxidation, UV irradiation, and reduction may be performed in any order and at the same time or at different times.

[0273] In some embodiments, BBP has the formula: [formation] [formation] A polymer comprising at least 100 repeating units selected from

[0274] Methods of preparing compounds and polymers The present disclosure describes methods of preparing polymers from monomers, as described herein. In some embodiments, a method of preparing a polymer includes polymerizing monomers as described herein.

[0275] The present disclosure also provides a method of preparing a polymer comprising reacting an existing polymer with a compound described herein, wherein the existing polymer contains a reaction handle capable of reacting with X, and The method is described wherein, in step, a react handle capable of reacting with X reacts with X. In some embodiments, the polymer present is a polymer described herein. In some embodiments, the polymer present is an addition polymer (eg, polyethylene, poly(tetrafluoroethylene), polypropylene, polyisobutylene, polystyrene, polyacrylonitrile, poly(vinyl chloride), poly(methyl acrylate), poly(methyl methacrylate), polybutadiene, polychloroprene, poly(cis-1,4-isoprene), or poly(trans-1,4-isoprene)). In some embodiments, the polymer present is a condensation polymer (eg, polyamide, polyaramid, polyester, polycarbonate, or silicone). In some embodiments, the polymers present are poly(alkyl acrylates), poly(hydroxyalkyl acrylates), poly(haloalkyl acrylates), polymethacrylates, poly(alkyl methacrylates), poly(hydroxyalkyl methacrylates), or poly(haloalkyl methacrylate). In some embodiments, the polymer present is poly(methyl methacrylate). In some embodiments, the polymer present is polystyrene. In some embodiments, the polymer present is polyethylene. In some embodiments, the polymer present is a copolymer (eg, a copolymer prepared by polymerizing two different types of monomers). In some embodiments, the polymer present is an alternating copolymer prepared by polymerizing two different types of substituted or unsubstituted ethene.

[0276] In certain embodiments, the reaction handle capable of reacting with X is a reaction handle described herein. In some embodiments, the reactive handle that can react with X is an alkyne (eg, -C≡CH). In some embodiments, the reaction handle capable of reacting with X is part of at least one type of repeating unit (eg, as a substituent on the backbone). In some embodiments, at least 30%, at least 50%, at least 70%, at least 90%, at least 95%, or at least 99% of all reactive handles capable of reacting with X react with a compound described herein. do.

[0277] In some embodiments, a method of preparing a polymer comprises polymerizing a first monomer and a second monomer described herein, wherein all M are the same. In some embodiments, a method of preparing a polymer comprises polymerizing a first monomer and a second monomer described herein, wherein M of at least one of the first monomer is is different from M in at least one of the monomers of In some embodiments, additional monomers are present in the polymerizing step. In some embodiments, the additional monomer is different than the monomers described herein (eg, first monomer, second monomer). In some embodiments, substantially no additional monomers are present in the polymerizing step.

[0278] In some embodiments, X comprises carboxylic acids, alcohols, and / or amines. In some embodiments, reagents for coupling carboxylic acids with alcohols or amines are N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-Dimethylaminopropyl)carbodiimide hydrochloride (WSC / HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), diethyl cyanophosphonate (DEPC), benzotriazol-1-yloxy-trispyrrolidinophosphonium ( DIPCI), benzotriazol-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy-7- Azabenzotriazole (HOAt), Hydroxyphthalimide (HOPht), Pentafluorophenol (Pfp-OH), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate fart (HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphonate (HATU), O-benzotriazol-1-yl-1, 1,3,3-tetramethyluronium tetrafluoroborate (TBTU), or 3,4-dihydro-3-hydrodi-4-oxa-1,2,3-benzotriazine (Dhbt), or salts thereof; or A combination of them (for example, a combination of two).

[0279] A reagent for coupling a carboxylic acid with an alcohol or amine is used in an amount of about 1 to 20 equivalents of the compound represented by formula (I) or formula (II). In some embodiments, reagents for coupling carboxylic acids with alcohols or amines are used in amounts of about 1-10 equivalents. In some embodiments, the activator is used in an amount of about 1-5 equivalents.

[0280] Any solvent suitable for coupling reactions can be used to carry out the coupling reactions described herein. Examples of solvents useful for coupling reactions are DMSO, DMF, and methylene chloride. Additional exemplary solvents include acetonitrile, chloroform, tetrahydrofuran, and acetone.

[0281] The coupling reaction can be performed at 0-50°C. In some embodiments, the coupling reaction is performed at room temperature for about 10 minutes to about 30 hours. In some embodiments, the coupling reaction is performed for about 15 minutes to about 24 hours.

[0282] In some embodiments, preparing a polymer as described herein comprises a conjugation reaction. Illustrative examples are EDC-NHS chemistry (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide), or maleimides that can be conjugated to one end of thiol, amine, or similar functionalized polyethers. Or reactions involving carboxylic acids. Conjugation can be carried out in organic solvents such as, but not limited to, methylene chloride, acetonitrile, chloroform, dimethylformamide, tetrahydrofuran, acetone, or the like. Specific reaction conditions can be determined by those skilled in the art using no more than routine experimentation.

[0283] In another series of embodiments, the conjugation reaction may be performed by reacting an agent containing hydroxyl, thiol, or amino groups with a polymer containing carboxylic acid functional groups. Such reactions may occur as a single step reaction, ie conjugation is performed with or without the use of intermediates such as N-hydroxysuccinimide or maleimide. Conjugation reactions between amine-, thiol-, or hydroxyl-containing moieties and carboxylic acid-terminated polymers are, in one aspect, performed using organic solvents, including, but not limited to, dichloromethane, acetonitrile, chloroform, tetrahydrofuran, acetone, formamide, dimethyl This can be accomplished by adding amine-, thiol-, or hydroxyl-containing moieties solubilized in formamide, pyridine, dioxane, or dimethylsulfoxide, or the like, to a solution containing the carboxylic acid-terminated polymer. Carboxylic acid terminated polymers may be contained in organic solvents such as, but not limited to, dichloromethane, acetonitrile, chloroform, dimethylformamide, tetrahydrofuran, acetone. Reaction between amine-containing moieties and carboxylic acid-terminated polymers can occur spontaneously in some cases. After such reaction, unconjugated monomers may be washed away and the polymer may be precipitated in solvents such as ethyl ether, hexane, methanol, or ethanol, by way of example.

[0284] In some embodiments, the monomer contains a metathesis polymerization handle. In some embodiments, the polymer is prepared using a metathesis catalyst. In some embodiments, the metathesis catalyst is a transition metal metathesis catalyst. In some embodiments, methods of preparing the polymers described herein (ie, BBPs) may involve metathesis reactions. In some embodiments, the metathesis reaction is ring-opening metathesis polymerization (ROMP) (Liu et al., J. Am. Chem. Soc. 2012, 134, 16337; Liu, J.; Gao, A. X.; Johnson, J. A. J Vis Exp 2013, e50874). In some embodiments, the polymers described herein are prepared by polymerization of one or more monomers represented by Formula (I) and / or Formula (II) in the presence of a metathesis catalyst. The preparation methods described herein are versatile and, by way of example, almost limitless in terms of the variety of agents that can be incorporated into the BBP. In some embodiments, agents that can be incorporated into BBPs contain functional groups that are compatible with ROMP.

[0285] In some embodiments, the metathesis catalyst (eg, ROMP catalyst) is a tungsten (W), molybdenum (Mo), or ruthenium (Ru) catalyst. In some embodiments, the ROMP catalyst is a ruthenium catalyst. ROMP catalysts useful in the synthetic methods described herein include those as depicted and described in Grubbs et al., Acc. Chem. Res. 1995, 28, 446. No. 5,811,515; Schrock et al., Organometallics (1982) 1 1645; Gallivan et al., Tetrahedron Letters (2005) 46:2577-2580; (1999) 121:9453; and Chem. Eur. J. (2001) 7:5299; the entire contents of each of which are incorporated herein by reference.

[0286] In some embodiments, the ROMP catalyst is a Grubbs catalyst. In some embodiments, the Grubbs catalyst is: [formation] benzylidenebis-(tricyclohexylphosphine)-dichlororuthenium (X=Cl); benzylidenebis-(tricyclohexylphosphine)-dibromo-ruthenium (X=Br); ); [formation] 1,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(tricyclohexyl-phosphine)ruthenium (X=Cl; R=cyclohexyl); 1,3-(bis(mesityl)-2 -imidazolidinylidene)dibromo-(phenylmethylene)(tricyclohexyl-phosphine)ruthenium (X=Br; R=cyclohexyl); 1,3-(bis(mesityl)-2-imidazolidinylidene)diiodo-(phenylmethylene) (Tricyclohexyl-phosphine)ruthenium (X=I; R=cyclohexyl);1,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(triphenylphosphine)ruthenium (X=Cl; R=phenyl); 1,3-(bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)(tribenzylphosphine)ruthenium (X=Cl; R=benzyl); [formation] selected from the group consisting of

[0287] In some embodiments, the ROMP catalyst is a Grubbs-Hoveyda catalyst. In some embodiments, the Grubbs-Hoveyda catalyst comprises: [formation] selected from the group consisting of

[0288] In some embodiments, the ROMP catalyst is: [formation] [formation] selected from the group consisting of

[0289] In some embodiments, the ROMP catalyst has the formula: [formation] is represented by

[0290] ROMP is performed in one or more aprotic solvents. The term "aprotic solvent" means a non-nucleophilic solvent having a boiling range of from about 25°C to about 190°C above ambient temperature, preferably at atmospheric pressure. In some embodiments, the aprotic solvent has a boiling point of about 80°C to about 160°C at atmospheric pressure. In some embodiments, the aprotic solvent has a boiling point of about 80°C to about 150°C. Examples of such solvents are methylene chloride, acetonitrile, toluene, DMF, diglyme, THF, and DMSO.

[0291] ROMP is the formula [formation] can be quenched with a vinyl ether represented by R. V1 , R V2 , R V3 , and R V4 is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally It is optionally substituted phenyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In some embodiments, R V1 is optionally substituted alkyl, and R V2 , R V3 , and R V4 is hydrogen. In some embodiments, R V1 is unsubstituted alkyl, and R V2 , R V3 , and R V4 is hydrogen. In some embodiments, R V1 is substituted alkyl, and R V2 , R V3 , and R V4 is hydrogen. In some embodiments, R V1 is methyl, and R V2 , R V3 , and R V4 is hydrogen. In some embodiments, R V1 is ethyl, and R V2 , R V3 , and R V4 is hydrogen. In some embodiments, R V1 is propyl, and R V2 , R V3 , and R V4 is hydrogen. In some embodiments, R V1 is optionally substituted alkenyl, and R V2 , R V3 , and R V4 is hydrogen. In some embodiments, R V1 is unsubstituted alkenyl, and R V2 , R V3 , and R V4 is hydrogen. In some embodiments, R V1 is vinyl, and R V2 , R V3 , and R V4 is hydrogen. In some embodiments, R V1 , R V2 , R V3 , and R V4 is conjugated to a diagnostic agent as defined above. In some embodiments, ROMP is quenched with ethyl vinyl ether. Excess ethyl vinyl ether can be removed from the BBP by vacuum.

[0292] Compositions and kits The disclosure provides compositions (eg, pharmaceutical compositions) comprising polymers as described herein and optionally excipients (eg, pharmaceutically acceptable excipients). In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the excipient is a pharmaceutically acceptable excipient.

[0293] In certain embodiments, pharmaceutical compositions are useful for delivering agents (eg, to a subject or cell). In certain embodiments, pharmaceutical compositions are useful for treating disease in a subject in need thereof. In some embodiments, pharmaceutical compositions are useful for preventing disease in a subject. In some embodiments, the pharmaceutical compositions are useful for diagnosing disease in a subject.

[0294] In some embodiments, the polymers described herein are provided in pharmaceutical compositions in effective amounts. In some embodiments, an effective amount is a therapeutically effective amount. In some embodiments, an effective amount is a prophylactically effective amount. In some embodiments, an effective amount is an amount effective to treat a proliferative disorder in a subject in need thereof. In some embodiments, an effective amount is an amount effective to prevent proliferative disease in a subject in need thereof. In some embodiments, an effective amount is an amount effective to treat cancer in a subject in need thereof. In some embodiments, an effective amount is an amount effective to prevent cancer in a subject in need thereof. In some embodiments, an effective amount is an amount effective to treat a hematological disorder in a subject in need thereof. In some embodiments, an effective amount is an amount effective to prevent blood disease in a subject in need thereof. In some embodiments, an effective amount is an amount effective to treat a neurological disease in a subject in need thereof. In some embodiments, an effective amount is an amount effective to prevent neurological disease in a subject in need thereof. In some embodiments, an effective amount is an amount effective to prevent neurological disease in a subject in need thereof. In some embodiments, an effective amount is an amount effective to treat a pain condition in a subject in need thereof. In some embodiments, an effective amount is an amount effective to prevent a painful condition in a subject in need thereof. In certain embodiments, an effective amount is an amount effective to treat a psychiatric disorder in a subject in need thereof. In certain embodiments, an effective amount is an amount effective to prevent mental disorders in a subject in need thereof. In some embodiments, an effective amount is an amount effective to treat a metabolic disorder in a subject in need thereof. In some embodiments, an effective amount is an amount effective to prevent metabolic disorders in a subject in need thereof. In some embodiments, the effective amount is to reduce the risk of developing a disease (e.g., a proliferative disease, a hematologic disease, a neurological disease, a pain condition, a psychiatric disorder, or a metabolic disorder) in a subject in need thereof. is an effective amount for In some embodiments, an effective amount is an amount effective to inhibit protein kinase activity (eg, abnormal activity, such as increased activity) in a subject or cell. In some embodiments, an effective amount is an amount effective to prevent disease in a subject in need thereof. In some embodiments, an effective amount is an amount effective to diagnose disease in a subject in need thereof.

[0295] In some embodiments, an effective amount is an amount effective to deliver a pharmaceutical agent to a biological sample or cell. In some embodiments, the cells are in vitro. In some embodiments, the cells are in vivo. In some embodiments, the cells are malignant cells. In some embodiments, the cells are precancerous cells.

[0296] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally, such preparative methods involve associating the polymers described herein (which may contain a therapeutic agent (“active ingredient”)) with a carrier or excipient, and / or one or more other accessory ingredients. , and then, if required and / or desired, forming and / or packaging the product into desired single- or multi-dose units.

[0297] A pharmaceutical composition can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as multiple single unit doses. A "unit dose" is discrete amount of the pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of active ingredient is generally equal to the dosage of active ingredient that would be administered to a subject and / or a convenient fraction such as one-half or one-third of such dosage.

[0298] The relative amounts of active ingredient, pharmaceutically acceptable excipients, and / or any additional ingredients in the compositions described herein may vary depending on the identity, size, and / or It will vary depending on the condition and also on the route by which the composition is administered. The composition may contain 0.1% to 100% (w / w) of active ingredient.

[0299] Pharmaceutically acceptable excipients used in the preparation of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrants, binders , preservatives, buffers, lubricating agents and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents can also be present in the compositions.

[0300] Exemplary diluents are calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol , sorbitol, inositol, sodium chloride, dried starch, corn starch, powdered sugar, and mixtures thereof.

[0301] Exemplary granulating and / or dispersing agents are potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponges, cationic -exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), Including methylcellulose, pregelatinized starch (Starch 1500), microcrystalline starch, water-insoluble starch, carboxymethylcellulose calcium, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0302] Exemplary surfactants and / or emulsifiers include natural emulsifiers such as acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, waxes, and lecithin), colloidal clays (e.g. bentonite (aluminum silicate) and Veegum (aluminum magnesium silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin). monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol, carbomers (eg, carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, Cellulose derivatives (e.g. sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate (Tween® 20) , polyoxyethylene sorbitan monostearate (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (for example , Cremophor®), polyoxyethylene ethers (e.g. toshite, polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, trieta Nolamine Oleate, Sodium Oleate, Potassium Oleate, Ethyl Oleate, Oleic Acid, Ethyl Laurate, Sodium Lauryl Sulfate, Pluronic® F-68, Poloxamer P-188, Cetrimonium Bromide, Cetylpyridinium Chloride , benzalkonium chloride, sodium doxelate, and / or mixtures thereof.

[0303] Exemplary binders are starches (eg corn starch and starch paste), gelatin, sugars (eg sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (eg , Acacia, Sodium Alginate, Irish Moss Extract, Panwar Gum, Ghatti Gum, Issapol Husk Mucilage, Carboxymethylcellulose, Methylcellulose, Ethylcellulose, Hydroxyethylcellulose, Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Microcrystals. cellulose, cellulose acetate, poly(vinyl-pyrrolidone), (magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, Including silicic acid, polymethacrylates, waxes, water, alcohols, and / or mixtures thereof.

[0304] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal preservatives, alcohol preservatives, acid preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0305] Exemplary antioxidants are alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate. , sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0306] Exemplary chelating agents are ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (eg, sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.); Citric acid and its salts and hydrates (e.g. citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates , and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives are benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorcresol, chlorxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidourea. , phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0307] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0308] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0309] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid and phytic acid.

[0310] Other preservatives include tocopherols, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate ( SLES), Sodium Bisulfite, Sodium Metabisulfite, Potassium Sulfite, Potassium Metabisulfite, Glydant® Plus, Phenonip®, Methylparaben, Germall® 115, Germaben® II, Neolone ®, Kathon ® , and Euxyl ® .

[0311] Exemplary buffers include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconate, Calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxyphosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dibasic phosphate potassium, potassium phosphate monobasic, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, sodium phosphate dibasic, sodium phosphate monobasic, sodium phosphate mixture, Tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0312] Exemplary lubricating agents are magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, lauryl Including sodium sulfate and mixtures thereof.

[0313] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, and cod. Liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, Litsea cubeba, macadamia nut. , mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, coconut kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood , sascanna, savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof. .

[0314] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate. , ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g. cottonseed, peanut, corn, germ, olive, castor, sesame), glycerol, tetrahydro Furfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and the like, and mixtures thereof may also be included. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are solubilized, such as Cremophor®, alcohols, oils, denatured oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof. mixed with the agent.

[0315] Injectables, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0316] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. .

[0317] It is often desirable to slow the absorption of drugs from subcutaneous or intramuscular injections in order to prolong the drug's effect. This can be accomplished by the use of a crystalline or amorphous liquid suspension with poor water solubility. The absorption rate of a drug depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug can be accomplished by dissolving or suspending the drug in a vehicle.

[0318] Compositions for rectal or vaginal administration are typically prepared by mixing the conjugates described herein with a suitable nonirritating excipient or carrier, such as cocoa butter, polyethylene glycol, and the like. or a suppository wax that is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity releasing the active ingredient.

[0319] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active ingredient is combined with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or (a) starch, lactose, sucrose, (b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, acacia, (c) humectants such as glycerol, (d) agar. , calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) solution retarding agents such as paraffin; (f) absorption enhancers such as quaternary ammonium compounds. (g) humectants such as cetyl alcohol, glycerol monostearate, (h) adsorbents such as kaolin and bentonite clays, and (i) talc, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl. Mixed with lubricants such as sodium sulfate, mixtures thereof, and the like. In the case of capsules, tablets and pills, the dosage form may contain buffering agents.

[0320] Similar types of solid compositions can be employed as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmacological art. They may optionally contain opacifying agents and are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally with a delay. be able to. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

[0321] The active ingredient can be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may contain additional substances other than the customary inert diluents, for example tabletting lubricants such as magnesium stearate and microcrystalline cellulose, and other tabletting aids. In the case of capsules, tablets and pills, the dosage form may contain buffering agents. They may optionally contain opacifying agents, and can be of a composition that they release the active ingredient only in a certain part of the intestinal tract, or preferentially, optionally with a delay. Examples of encapsulating agents that can be used include polymeric substances and waxes.

[0322] Dosage forms for and / or transdermal administration of the polymers described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient may be admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the correct medium. Alternatively or additionally, the rate can be controlled by providing a rate controlling membrane and / or dispersing the active ingredient in a polymer matrix and / or gel.

[0323] Suitable devices for use in delivering the intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions may be administered by a device that limits the effective penetration length of the needle into the skin. Alternatively or additionally, a conventional syringe can be used for intradermal administration of the classic Mantoux technique. Liquid jet injection devices and / or jet injection devices that deliver liquid formulations to the dermis via needles that pierce the stratum corneum and produce jets that reach the dermis are preferred. Ballistic powder / particle delivery devices that use compressed gas to accelerate the polymer in powder form from the outer layers of the skin to the dermis are preferred.

[0324] Suitable formulations for topical administration are liquid and / or semi-liquid formulations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments and / or pastes, and / or solutions, suspensions. Including turbidity and the like. Topically administrable formulations may contain, for example, from about 1% to about 10% (w / w) active ingredient, but the concentration of the active ingredient should be as high as the solubility limit of the active ingredient in the solvent. be able to. Formulations for topical administration may further comprise one or more additional ingredients described herein.

[0325] A pharmaceutical composition described herein may be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such formulations comprise the active ingredient and may comprise dry particles having diameters ranging from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are dissolved and / or suspended in a low boiling point propellant in a closed container and / or using a device containing a dry powder reservoir into which a stream of propellant can be directed to disperse the powder. It is conveniently in the form of a dry powder for administration with a self-propelled solvent / powder dispenser such as a device containing the active ingredient. Such powders comprise particles wherein at least 98% by weight of the particles have a diameter greater than 0.5 nanometers and at least 95% by weight of the particles have a diameter less than 7 nanometers. Alternatively, at least 95% by weight of the particles have a diameter greater than 1 nanometer and at least 90% by number of the particles have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and may conveniently be provided in unit dose form.

[0326] Low boiling point propellants generally include liquid propellants having boiling points below 65° F. at atmospheric pressure. Generally, the propellant may constitute 50-99.9% (w / w) of the composition, and the active ingredient may constitute 0.1-20% (w / w) of the composition. Propellants may further include liquid nonionic and / or solid anionic surfactants and / or solid diluents (which may have particle sizes of the same order as the particles making up the active ingredient). May contain additional ingredients.

[0327] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations may be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions containing the active ingredient, optionally sterile, and any nebulization and / or atomization device. can be conveniently administered using Such formulations may further comprise one or more additional ingredients including flavorings such as sodium saccharin, volatile oils, buffers, surfactants and / or preservatives such as methylhydroxybenzoate.

[0328] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of the pharmaceutical compositions described herein. Another formulation suitable for intranasal administration is a coarse powder containing the active ingredient and having an average particle size of about 0.2-500 micrometers. Such formulations are administered by rapid inhalation through the nasal passages from a container of powder held near the nostril.

[0329] Formulations for nasal administration may contain, for example, as little as about 0.1% (w / w) to about 100% (w / w) active ingredient, and may include one or more additional ingredients described herein. good. A pharmaceutical composition described herein may be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods and contain, for example, 0.1-20% (w / w) active ingredient, orally dissolving and / or disintegrating and optionally one or more of the additional ingredients described herein. Alternatively, formulations for buccal administration may comprise a powder and / or an aerosolized and / or nebulized solution and / or suspension containing the active ingredient. Such powdered, aerosolized and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size ranging from about 0.1 to about 200 nanometers, and may contain one or more of the present It may further contain additional ingredients as described herein.

[0330] A pharmaceutical composition described herein may be prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops containing a 0.1-1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffers, salts, and / or other components of one or more of the additional components described herein. Other ophthalmic formulations that are useful include those containing the active ingredient in microcrystalline form and / or in liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure.

[0331] Although the description of pharmaceutical compositions provided herein is directed primarily to pharmaceutical compositions suitable for administration to humans, such compositions are generally suitable for administration to animals of all kinds. This will be understood by those skilled in the art. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to various animals are well understood and the ordinarily skilled veterinary pharmacist may make such modifications through routine experimentation. Modifications can be designed and / or implemented.

[0332] Polymers provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. A particular therapeutically effective dose level for any particular subject or organism will depend on the severity of the disease and disorder being treated; the activity of the particular active ingredient employed; the particular composition employed; age, weight, general health, sex and diet; time of administration, route of administration and excretion rate of the particular active ingredient employed; duration of treatment; used in combination or contemporaneously with the particular active ingredient employed. It will be determined by a variety of factors, including drugs; and similar factors well known in the medical arts.

[0333] The polymers and compositions provided herein can be used for enteral (eg, oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intracerebroventricular, transdermal, transdermal inter, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal, bronchial, and / or inhalation and / or as oral sprays, nasal sprays, and / or aerosols by any route. Specifically contemplated routes are oral administration, intravenous administration (eg, systemic intravenous injection), local administration via blood and / or lymph supply, and / or direct administration to the affected area. In general, the most suitable route of administration will vary depending on the nature of the agent (eg, its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (eg, whether the subject can tolerate oral administration). will depend on factors. In some embodiments, the polymers or pharmaceutical compositions described herein are suitable for topical administration to the eye of a subject.

[0334] The precise amount of polymer required to achieve an effective amount will depend, for example, on the species, age, and general condition of the subject, severity of side effects or disorders, identity of the particular polymer, mode of administration, and the like. and will vary from subject to subject. An effective amount can be contained in a single dose (eg, single oral dose) or multiple doses (eg, multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two of the multiple doses contain different amounts or substantially the same amounts of including polymers described in In certain embodiments, when multiple doses are administered to a subject or applied to tissues or cells, the frequency of multiple doses to the subject or application of multiple doses to tissues or cells is 3 per day. 1 dose, 2 doses per day, 1 dose per day, 1 dose every other day, 1 dose every 3 days, 1 dose every 2 weeks, 1 dose every 2 weeks 1 dose every 3 weeks, 1 dose every 3 weeks, or 1 dose every 4 weeks. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is one dose per day. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is two doses per day. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is 3 doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to tissues or cells, the duration between the first and last dose of the multiple doses is 1 day, 2 days, 4 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years, 10 years , 15 years, 20 years or the life span of a subject, tissue or cell. In some embodiments, the duration between the first and last dose of multiple doses is 3 months, 6 months, or 1 year. In some embodiments, the duration between the first and last dose of the multiple doses is the life span of the subject, tissue, or cell. In some embodiments, the doses described herein (eg, a single dose, or any dose in multiple doses) are independently between 0.1 μg and 1 μg of the polymer described herein, between 0.001mg and 0.01mg, between 0.01mg and 0.1mg, between 0.1mg and 1mg, between 1mg and 3mg, between 3mg and 10mg, between 10mg and 30mg, between 30mg and 100mg, between 300mg and 1,000mg mg, or between 1 g and 10 g, inclusive. In some embodiments, the doses described herein independently encompass between 1 mg and 3 mg, inclusive, of the polymers described herein. In some embodiments, the doses described herein independently encompass between 3 mg and 10 mg of the polymers described herein. In some embodiments, doses described herein independently encompass between 10 mg and 30 mg of a polymer described herein, inclusive. In some embodiments, doses described herein independently encompass between 30 mg and 100 mg of a polymer described herein, inclusive.

[0335] The dose ranges described herein provide guidance for the administration of provided pharmaceutical compositions to adults. For example, the dose administered to a child or adolescent can be determined by a physician or one skilled in the art, and may be lower than or the same as the dose administered to an adult. In some embodiments, the doses described herein are for adult humans weighing 70 kg.

[0336] A polymer or composition described herein can be administered in combination with one or more additional pharmaceutical agents (eg, therapeutically and / or prophylactically active agents). The polymer or composition is characterized by its activity (e.g., in treating disease in a subject in need thereof, in preventing disease in a subject in need thereof, in reducing the risk of developing disease in a subject in need thereof). , and / or improve activity (e.g. potency and / or efficacy), improve bioavailability, improve safety, reduce drug resistance, and / or in diagnosing diseases in subjects in need thereof; It can be administered in combination with additional pharmaceutical agents that reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in a subject or cell. It will also be appreciated that the treatments employed may achieve the desired effect and / or achieve different effects for the same disorder. In some embodiments, a pharmaceutical composition described herein comprising a polymer described herein and an additional pharmaceutical agent is present in a pharmaceutical composition comprising one of the polymer and the additional pharmaceutical agent, but not both. do not exhibit synergistic effects.

[0337] The polymer or composition can be administered concurrently, before, or after one or more additional pharmaceutical agents that are different from the polymer or composition and which can be useful, for example, as a combination therapy. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. A pharmaceutical agent is a small organic molecule such as a drug compound (e.g., approved by the Food and Drug Administration for human or veterinary use as specified in the Code of Federal Regulations (CFR)). synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, Including DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, cells, and the like. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease (eg, proliferative disease, hematological disease, neurological disease, pain condition, psychiatric disorder, or metabolic disorder). be. Each additional pharmaceutical agent may be administered at the dose and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered in a single dose or separately in different doses with each other, together and / or with the polymers or compositions described herein. The particular combination employed in a regimen will take into account compatibility of the polymers described herein with additional pharmaceutical agents, and / or the desired therapeutic and / or prophylactic effect to be achieved. deaf. Generally, it is expected that the additional pharmaceutical agent(s) in the combination will be utilized at levels no greater than those at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than the levels utilized individually.

[0338] Additional pharmaceutical agents include anti-proliferative agents, anti-cancer agents, cytotoxic agents, anti-angiogenic agents, anti-inflammatory agents, immunosuppressive agents, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-inflammatory agents. Includes diabetic agents, antiallergic agents, contraceptive agents and analgesics. In some embodiments, the additional pharmaceutical agent is an antiproliferative agent. In some embodiments, the additional pharmaceutical agent is an anticancer agent. In some embodiments, the additional pharmaceutical agent is an antiviral agent. In some embodiments, the additional pharmaceutical agent is a protein kinase binder or inhibitor. In some embodiments, the additional pharmaceutical agent is an epigenetic or transcriptional modulator (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), an anti-mitotic drug (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g. estrogen and androgen receptor modulators), cell signaling pathway inhibitors (e.g. tyrosine protein kinase inhibitors), modulators of protein stability (e.g. proteasome inhibitors) ), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other agents that promote differentiation.

[0339] In some embodiments, the polymers or pharmaceutical compositions described herein are combined with anti-cancer therapies, including surgery, radiation therapy, transplantation (eg, stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. can be administered as In some embodiments, the polymers or pharmaceutical compositions described herein can be administered in combination with additional therapies. In some embodiments, the polymers or pharmaceutical compositions described herein can be administered in combination with radiation therapy.

[0340] Also included in this disclosure are kits (eg, pharmaceutical packs). A provided kit can include a pharmaceutical composition or polymer described herein and instructions for use. Kits may further include containers (eg, vials, ampoules, bottles, syringes, and / or dispenser packages, or other suitable containers). In some embodiments, provided kits further optionally comprise a second container comprising a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or polymer described herein. good too. In some embodiments, the pharmaceutical compositions or polymers described herein provided in the first container and the second container are combined to form one unit dosage form.

[0341] In some embodiments, the percentage of polymer that includes the agent is between about 1 and about 100% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%). In some embodiments, the percentage of conjugates comprising the agent is less than about 50%, such as less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15% %, or less than about 10%. In some embodiments, the percentage of polymer that makes up the agent is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 25%, or about 5% to about 5%. % to about 20%. In some embodiments, the percentage of polymer containing agents is between about 5% and 90%. In some embodiments, the percentage of polymer containing the agent is between about 5% and about 75%. In some embodiments, the percentage of polymer containing the agent is between about 5% and about 50%. In some embodiments, the percentage of polymer containing the agent is between about 10% and about 25%.

[0342] In some embodiments, the total amount of agent present in the polymer is about 5% (e.g., about 6%, about 7%, about 8%, about 9%, about 10%) of the total size or weight of the polymer. , about 12%, about 15%, about 20%, about 25%, about 30%, or more). In some embodiments, the total amount of agent present in the polymer is about 10% (e.g., about 12%, about 15%, about 20%, about 25%, about 30%) of the total size or weight of the polymer. , or greater).

[0343] Without being bound by theory, the polymers disclosed herein can localize and / or release agents to target cells (eg, cancer or fibrotic cells; cells associated with a hypoxic environment). (e.g., preferential release), or increase the half-life of the agent, thus resulting in greater amounts of released agent at the target site (e.g., tumor or liver (e.g., cirrhotic cells)). The efficiency of the agent can be improved by one or more of the following: Thus, the polymers disclosed herein are more therapeutically effective than the free agent (eg, due to enhanced drug uptake in the target tissue) and / or, by way of example, Allows lower therapeutic doses of the agent without substantially compromising the drug concentration provided. In some embodiments, the polymers disclosed herein reduce adverse effects associated with systemic administration of agents in free form (eg, not associated with polymers, conjugates or particles described herein). can be done.

[0344] Without being bound by theory, due to the local delivery of the polymers (eg, BBP) or compositions described herein, lower doses of agents in particles or Amounts can be administered (eg, by local sustained delivery). In other embodiments, agent-containing particles are administered at a dose or amount that is lower than the dose or amount of the agent in free form in order to have the desired effect (eg, the desired therapeutic effect).

[0345] In some embodiments, the agent is administered at a dose or amount of the agent in free form to have a desired effect (e.g., a desired therapeutic effect), e.g., a standard care dose for the intended use of the free agent. is incorporated into the polymer at a lower dose than In one embodiment, the agent is incorporated into the particles at a dose or amount of the agent that is less than the standard care dose of the agent for the desired treatment (e.g., about 0.01, about 0.02, about 0.03, about 0.04 of the standard care dose of the agent). , about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9 or about 0.95).

[0346] In some embodiments, the agent is intended to have a desired effect (e.g., a desired therapeutic effect), e.g. It is incorporated into the polymer at standard care doses for use. In these embodiments, the polymer provides greater therapeutic benefit and / or less harm than the free agent. In some embodiments, the polymer increases the amount of agent delivered to tissues or cells in need thereof and reduces the amount of agent exposed to non-target tissues or cells compared to free agent.

[0347] In some embodiments, the agent has a desired effect (e.g., a desired therapeutic effect), such as a dose or amount of the agent in free form, e.g. Incorporated into the polymer at doses higher than the care dose. In some embodiments, the agent is incorporated into the polymer at a dose or amount higher than that of the free form of the agent that would cause adverse effects (eg, lowering blood pressure) upon systemic administration. In some embodiments, the polymers described herein release the agent at the target site based on the pH microenvironment such that other non-target sites (eg, blood vessels) with different pH are exposed to the agent. will be less likely to be

[0348] In another aspect, provided is a kit comprising a first container comprising a polymer or pharmaceutical composition described herein. In some embodiments, the kits are useful for delivering agents (eg, to a subject or cell). In certain embodiments, the kits are useful for treating diseases (eg, proliferative diseases, hematologic diseases, neurological diseases, pain conditions, psychiatric disorders, or metabolic disorders) in subjects in need thereof. In certain embodiments, the kits are useful for preventing diseases (eg, proliferative diseases, hematologic diseases, neurological diseases, pain conditions, psychiatric disorders, or metabolic disorders) in subjects in need thereof. In some embodiments, the kit is used to reduce the risk of developing a disease (e.g., a proliferative disease, a hematologic disease, a neurological disease, a pain condition, a psychiatric disorder, or a metabolic disorder) in a subject in need thereof. Useful. In some embodiments, the kit is used to reduce the risk of developing a disease (e.g., a proliferative disease, a hematologic disease, a neurological disease, a pain condition, a psychiatric disorder, or a metabolic disorder) in a subject in need thereof. Useful. In some embodiments, the kits are useful for inhibiting protein kinase activity (eg, abnormal activity, such as increased activity) in a subject or cell. In some embodiments, the kits are useful for diagnosing disease in a subject or cell.

[0349] In some embodiments, the kits described herein further include instructions for using the kit. The kits described herein may contain information required by regulatory agencies such as the US Food and Drug Administration (FDA). In some embodiments, the kit includes a polymer or composition described herein and instructions for using the polymer or composition. In some embodiments, the information included in the kit is prescribing information. In some embodiments, the kit and instructions provide for delivering the agent. In some embodiments, the kit and instructions are for treating a disease in a subject in need thereof (e.g., a proliferative disease, a hematologic disease, a neurological disease, a pain condition, a psychiatric disorder, or a metabolic disorder). offer. In some embodiments, the kit and instructions are used to prevent a disease in a subject in need thereof (e.g., a proliferative disease, a hematologic disease, a neurological disease, a pain condition, a psychiatric disorder, or a metabolic disorder). offer. In certain embodiments, the kit and instructions reduce the risk of developing a disease (e.g., a proliferative disease, a hematologic disease, a neurological disease, a pain condition, a psychiatric disorder, or a metabolic disorder) in a subject in need thereof. Offer to reduce. In some embodiments, kits are provided for inhibiting protein kinase activity (eg, abnormal activity, such as increased activity) in a subject or cell. In some embodiments, the kits and instructions are useful for diagnosing diseases in a subject or cell. Kits described herein may include one or more additional pharmaceutical agents described herein as separate compositions.

[0350] Methods of treatment and uses The disclosure also provides methods of using the polymers described herein, or pharmaceutical compositions thereof, to deliver agents. The disclosure also provides methods of using the polymers described herein, or pharmaceutical compositions thereof, for the treatment, prevention, or diagnosis of diseases or conditions.

[0351] The present disclosure provides methods of treating disease in a subject in need thereof. In some embodiments, the methods described herein comprise administering to a subject in need thereof a therapeutically effective amount of the polymer or composition. In some embodiments, the methods described herein comprise administering to a subject in need thereof a therapeutically effective amount of the polymer or composition, wherein at least one M is It is a therapeutic agent. In some embodiments, the disease is a proliferative disease. In some embodiments, the disease is cancer. In some embodiments, the disease is lung cancer, head and neck cancer, esophageal cancer, gastric cancer, breast cancer, pancreatic cancer, liver cancer, kidney cancer, prostate cancer, glioblastoma, metastatic melanoma, peritoneal cancer Or pleural mesothelioma.

[0352] In some embodiments, the methods described herein comprise administering to a subject an effective amount of a polymer described herein or a pharmaceutical composition thereof. In some embodiments, the methods described herein comprise administering to a subject an effective amount of a polymer described herein, or a pharmaceutical composition thereof. In some embodiments, the methods described herein are directed to a therapeutically effective amount of: a polymer described herein; or a pharmaceutical composition thereof; wherein at least one M is a therapeutic agent; treating a disease or condition in a subject in need thereof by administering to the body. In some embodiments, the methods described herein comprise a prophylactically effective amount of: a polymer described herein; or a pharmaceutical composition thereof; wherein at least one of M is a prophylactic agent; Including preventing a disease or condition in a subject in need thereof by administering to the subject. In some embodiments, the methods described herein are directed to a diagnostically effective amount of: a polymer described herein; or a pharmaceutical composition thereof; wherein at least one M is a diagnostic agent; diagnosing a disease or condition in a subject in need thereof by administering to

[0353] In some embodiments, the disease or condition is a proliferative disease, blood disease, neurological disease, pain condition, psychiatric disorder, metabolic disorder, or long-term medical condition. In some embodiments, the disease is cancer (e.g., lung cancer, colon cancer, pancreatic cancer, biliary tract cancer, or endometrial cancer), benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, or an autoimmune disease. In some embodiments, the long-term medical condition is hypertension.

[0354] In some embodiments, the polymers, or pharmaceutical compositions thereof, described herein are useful for treating cancer. In some embodiments, the polymers described herein, or pharmaceutical compositions thereof, are useful for delaying the onset of cancer, slowing progression, or ameliorating cancer symptoms. In some embodiments, the polymers described herein, or pharmaceutical compositions thereof, are administered in combination with other compounds, drugs, or therapeutics to treat cancer. In some embodiments, the polymers described herein, or pharmaceutical compositions thereof, are administered in combination with additional therapies. In some variations, the polymers described herein, or pharmaceutical compositions thereof, are administered in combination with radiation therapy.

[0355] In some embodiments, the polymers, or pharmaceutical compositions thereof, described herein are useful for treating cancers, including but not limited to :acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, hemangiosarcoma), appendiceal cancer, benign monoclonal tumors, Biliary tract cancer (e.g. bile duct cancer), bladder cancer, breast cancer (e.g. mammary adenocarcinoma, papillary carcinoma, breast adenocarcinoma, medullary carcinoma of the breast), brain cancer (e.g. meningioma; glioma, e.g. astrocytoma, oligodendroglioma; medulloblastoma), bronchial carcinoma, carcinoid tumor, cancer of the cervix (e.g. cervical adenocarcinoma ), choriocarcinoma, chordoma, craniopharyngeal cancer, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma) , multiple idiopathic hemorrhagic sarcoma), endometrial cancer (eg, uterine cancer, uterine sarcoma), esophageal cancer (eg, adenocarcinoma of the esophagus, Barrett's adenocarcinoma), Ewing's sarcoma, eye Cancer (e.g., intraocular melanoma, retinoblastoma), familial hypereosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g. head and neck squamous cell carcinoma, oral cavity cancer (e.g. oral squamous cell carcinoma (OSCC)), pharyngeal cancer (e.g. laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer) , oropharyngeal cancer)), hematopoietic cancer (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) ( e.g. B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g. B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g. B-cell CLL, T-cell CML) lymphomas such as Hodgkin's lymphoma (HL) (e.g. B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g. diffuse large cell lymphoma (DLCL) (e.g. diffuse large cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g. intramucosal lymphoma) tissue (MALT) lymphoma, muscular marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., "Waldenstroem's macroglobulinemia"), hairy cell leukemia (HCL), immune blastic large cell lymphoma, precursor B-lymphocytic lymphoma, primary central nervous system (CNS) lymphoma; CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, undifferentiated large cell lymphoma); a mixture of one or more of the leukemia / lymphomas as described above; and multiple myeloma), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblasts tumor, inflammatory myofibroblastoma, immunocellular amyloidosis, kidney cancer (e.g. nephroblastoma called Wilms tumor, renal cell carcinoma), liver cancer (e.g. hepatocellular carcinoma ( HCC), malignant liver cancer), lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g. systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g. polycythemia vera (PV), essential thrombocytosis (ET) , malignant myeloma (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CML), hypereosinophilic syndrome (HES) ), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis), neuroendocrine cancer (e.g., gastrointestinal pancreatic neuroendocrine tumor (GEP-NET) ), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonic carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic cancer, intraductal papillary mucinous neoplasm (IPMN), pancreatic islet cell tumor), penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g. prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g. squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, Basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminiferous carcinoma, testicular embryonic carcinoma) , thyroid cancer (eg papillary thyroid cancer (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (eg Paget's disease of the vulva).

[0356] In some embodiments, the polymers described herein, or pharmaceutical compositions thereof, are useful in lung cancer, head and neck cancer, esophageal cancer, gastric cancer, breast cancer, pancreatic cancer, liver cancer, kidney cancer, It is useful in the treatment of prostate cancer, glioblastoma, metastatic melanoma, peritoneal or pleural mesothelioma. In some embodiments, the polymers described herein, or pharmaceutical compositions thereof, are useful in lung cancer, head and neck cancer, esophageal cancer, gastric cancer, breast cancer, pancreatic cancer, liver cancer, kidney cancer, Used in combination with radiation therapy to treat prostate cancer, glioblastoma, metastatic melanoma, peritoneal or pleural mesothelioma.

[0357] In some embodiments, the proliferative disease is a benign neoplasm. All types of benign neoplasms disclosed herein or known in the art are contemplated to be within the scope of the present disclosure. In some embodiments, the proliferative disease is associated with an inflammatory disease. All types of inflammatory diseases disclosed herein or known in the art are contemplated to be within the scope of the present disclosure. In some embodiments, the inflammatory disease is rheumatoid arthritis. In some embodiments, the proliferative disease is an autoinflammatory disease. All types of autoinflammatory diseases disclosed herein or known in the art are contemplated within the scope of the present disclosure. In some embodiments, the proliferative disease is an autoimmune disease. All types of autoimmune diseases disclosed herein or known in the art are contemplated within the scope of this disclosure.

[0358] In some embodiments, the polymers, or pharmaceutical compositions thereof, herein contain at least one M useful for treating cancer. In some embodiments, M is a therapeutic agent. In some embodiments, the therapeutic agent is an anticancer agent. In some embodiments, the anticancer agent is bortezomid. In some embodiments, the anticancer agent is selected from the group consisting of abiraterone acetate, ABVD, ABVE, ABVE-PC, AC, AC-T, ADE, adtrastuzumab emtansine, afatinibdi maleate, aldesleukin, alemtuzumab, anastrozole, arsenic trioxide, asparaginase erwinia chrysanthymy, axitinib, azacitidine, BEACOPP, belinostat, bendamustine hydrochloride, BEP, bevacizumab, bicalutamide, bleomycin, blinatumomab, bortezomib, bosutinib, bren tuximab vedotin, busulfan, cabazitaxel, cabozantinib-s-malate, CAF, capecitabine, CAPOX, carboplatin, carboplatin-taxol, carfilzomib carmustine, carmustine implant, ceritinib, cetuximab, chlorambucil, chlorambucil-prednisone, CHOP, Cisplatin, clofarabine, CMF, COPP, COPP-ABV, crizotinib, CVP, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin hydrochloride, decitabine, degarelix, denileukin diftitox, denosumab, dinutuximab , docetaxel, doxorubicin hydrochloride, doxorubicin hydrochloride liposomes, enzalutamide, epirubicin hydrochloride, EPOCH, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, exemestane, FEC, fludarabine phosphate, fluorouracil, FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI- CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, fulvestrant, gefitinib, gemcitabine hydrochloride, gemcitabine-cisplatin, gemcitabine-oxaliplatin, goserelin acetate, Hyper-CVAD, ibritumomab tiuxetan, ibrutinib, ICE, idelalisib, ifosfamide , imatinib mesylate, imiquimod, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotide acetate, lapatinib ditosylate, lenalidomide, lenvatinib, letrozole, leucovorin calcium, leuprolide acetate, liposomal cytarabine, lomustine, mechlorethamine hydrochloride, megestro molacetate, mercaptopurine, methotrexate, mitomycin C, mitoxantrone hydrochloride, MOPP, nerarabine, nilotinib, nivolumab, obinutuzumab, OEPA, ofatumumab, OFF, olaparib, omacetaxine mepesuccinate, OPPA, oxaliplatin, paclitaxel, paclitaxel albumin - stabilized nanoparticle formulations, PAD, palbociclib, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, pegaspargase, peginterferon alfa-2b, peginterferon alfa-2b, pembrolizumab, pemetrexed disodium, pertuzumab, plelixafor, pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone, procarbazine hydrochloride, radium-223 dichloride, raloxifene hydrochloride, ramucirumab, R-CHOP, recombinant HPV bivalent vaccine, recombinant human papillomavirus, 9 valent vaccine, recombinant human papillomavirus, tetravalent vaccine, recombinant interferon alpha-2b, regorafenib, rituximab, romidepsin, ruxolitinib phosphate, siltuximab, sipuleucel-t, sorafenib tosylate, STANFORD V, sunitinib malate, TAC , tamoxifen citrate, temozolomide, temsirolimus, thalidomide, thiotepa, topotecan hydrochloride, toremifene, tositumomab and iodine I 131, tositumomab, TPF, trametinib, trastuzumab, VAMP, vandetanib, VEIP, vemurafenib, vinblastine sulfate, vincristine sulfate, vincristine Sulfate liposomes, vinorelbine tartrate, vismodegib, vorinostat, XELIRI, XELOX, ziv-aflibercept, and zoledronic acid. Anticancer agents include biological anticancer agents as well as chemotherapeutic agents. Exemplary biological anti-cancer agents are interferons, cytokines (eg, tumor necrosis factor, interferon-alpha, interferon-gamma), vaccines, hematopoietic growth factors, monoclonal serum therapy, immunostimulants and / or immunomodulators (eg IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g. GM-CSF) and antibodies (e.g. Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (e.g. panitumumab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)). Exemplary chemotherapeutic agents include, but are not limited to: antiestrogens (eg tamoxifen, raloxifene, and megestrol), LHRH agonists (eg goscrclin and leuprolide), antiandrogens (eg flutamide and bicalutamide), photodynamic treatments (eg verteporfin (BPD-MA), phthalocyanines, photosensitizers Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (eg cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkyl sulfonates (e.g., busulfan and treosul fan), triazenes (e.g. dacarbazine, temozolomide), platinum-containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel) or paclitaxel equivalents such as albumin-bound paclitaxel (ABRAXANE) nanoparticles, docosahexaenoic acid-bound-paclitaxel (DHA-paclitaxel, taxoplexin), polyglutamate-bound-paclitaxel (PG-paclitaxel, paclitaxel polygumex, CT-2103, XYOTAX), Tumor-activating prodrug (TAP) ANG1005 (Angiopep-2 conjugated with 3 molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel conjugated to erbB2 recognition peptide EC-1), and glucose-conjugated paclitaxel, e.g. 2'-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisna Toll, mitomycin C), antimetabolites, DHFR inhibitors (e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (eg, mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonucleotide reductase inhibitors (eg, hydroxyurea and deferoxamine), uracil analogues (eg, 5-fluorouracil (5-FU), floxuridine) , doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g. cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g. mercaptopurine and thioguanine), vitamin D3 analogs (eg EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (eg lovastatin), dopaminergic neurotoxins (eg 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (eg 1-methyl-4-phenylpyridinium ion) staurosporine), actinomycins (e.g. actinomycin D, dactinomycin), bleomycins (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracyclines (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin) , idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca 2+ ATPase inhibitors (e.g. thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g. axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN TM, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), Lapatinib (TYKERB®, TYVERB®), Lestaurtinib (CEP-701), Neratinib (HKI-272), Nilotinib (TASIGNA®), Semaxanib (Semaxinib, SU5416), Sunitinib (SUTENT®) trademark), SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK / ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN® )), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib ( NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD -2076, PCI-32765, AC220, Dovitinibractate (TKI258, CHIR-258), BIBW2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL- 647, and / or XL228), proteasome inhibitors (eg bortezomib (VELCADE)), mTOR inhibitors (eg rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (eg Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (SanofiAventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porphyromycin, melphalan, leurocidin, leulocine, chlorambucil, trabectedin, procarbazine , discodermolide, carminomycin, aminopterin, and hexamethylmelamine.

[0359] In some embodiments, the methods provided herein comprise administering a pharmaceutical agent to a subject in need thereof. In some embodiments, pharmaceutical agents are administered to deliver the pharmaceutical agent to a subject in need thereof. In some embodiments, the pharmaceutical agent is administered via the polymer or pharmaceutical composition thereof. In some embodiments, the pharmaceutical agent is delivered to the biological sample. In some embodiments, pharmaceutical agents are delivered to cells. In some embodiments, the biological sample or cells are in vitro. In some embodiments, the biological sample or cells are in vivo. In some embodiments, the cells are malignant cells. In some embodiments, the cells are precancerous cells. In some embodiments, pharmaceutical agents are delivered to biological samples or cells to treat disease. In some embodiments, pharmaceutical agents are delivered to biological samples or cells to prevent disease. In some embodiments, pharmaceutical agents are delivered to biological samples or cells to diagnose disease. example

[0360] For a more complete understanding of this disclosure, the following examples are provided. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are to be construed in any way as limiting the scope thereof. shouldn't.

[0361] Detailed description of the example Rational design of boronic ester-based Btz prodrugs. To construct a Btz-bearing BBP, we first investigated linkers that sufficiently stabilize and inactivate Btz during circulation in vivo and also allow Btz to be released 'on-demand' within the tumor microenvironment. The linker structure should be amenable to chemical modifications that would allow tuning of the release rate depending on the end use, a design strategy similar to some reported drug conjugates. 40,41 Therefore, the 1,2-diol azid linker A5 was prepared (Figure 1, full synthetic details described in SI). A5 contains a tetraethylene glycol spacer for hydrophilicity and a fully substituted diol for steric hindrance that improves the stability of the Btz prodrug. Both agents were designed into the final linker via commercially available precursors (tetraethylene glycol and 2,3-dimethyl-2-butene, respectively), allowing convenient modification of the linker structure to alter release profiles. is now possible. Btz then complexes to A5 via boronic ester formation, prodrug azide A6 (Btz-N 3 ) was obtained (Fig. 1). Btz-supported macromonomers were synthesized by the copper-catalyzed alkyne-azide cycloaddition (CuAAC) 'click' reaction of azides to previously reported alkyne-functionalized macromonomer precursors. 45 The identity of all components is 1 H and 13 C nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HR-MS) were confirmed by matrix-assisted laser desorption ionization time-of-flight (MALDI-ToF, Figure 2) mass spectrometry when appropriate. ROMP of the Btz-macromonomer yielded the final Btz-BBP (Fig. 1). These polymers were characterized by gel permeation chromatography (GPC, Figure 3) and dynamic light scattering (DLS, Figure 13), demonstrating efficient conversion of macromonomers to polymers as well as targeted hydrodynamic diameters. of 10±2 nm was revealed. Cyanine 5.5-based macromonomers for in vivo studies 37-39、42 was also incorporated at a molar ratio of 1% to the Btz-macromonomer, providing a convenient way to track these BBPs in vivo by near-infrared fluorescence (NIRF) imaging.

[0362] In vitro validation of Btz-BBP in MM cell lines. The potency of Btz-BBP was compared directly with free Btz in two MM cell lines (MM.1S, KMS11). We compared the effect of each agent on cell proliferation after culturing for 48 hours. Although Btz-BBP requires an additional step to release Btz from BBP, both Btz and Btz-BBP displayed comparable efficacy against MM.1S (each, IC 50 =3.5±1.4 nM and 4.9±1.1 nM, Fig. 8A). This result suggests that Btz-BBP has both high permeability to tumor cells and controlled release of Btz. In another cell line, KMS11, Btz-BBP exceeded free Btz (IC 50 =7.3±08 nM vs. 29.9±1.6 nM for free Btz) (FIG. 8B). This increased efficacy may be due to the different mechanisms by which these two species are internalized into cells: free Btz utilizes membrane perfusion for penetration, whereas polymer uptake is determined by endocytosis. be done. With the latter, efflux pump mechanisms can be circumvented, leading to higher intracellular levels of Btz.

[0363] In vivo toxicity of Btz-BBP using healthy BALB / c mice. After confirming the retention of Btz activity of Btz-BBP in vitro, we next decided to validate the ability of the BBP platform to minimize Btz toxicity in vitro by its design as described above. To this end, we performed in vivo studies of Btz (0.75, 1, 1.25 mg / kg, twice weekly) and Btz-BBP (5, 10, and 18.75 mg / kg, twice weekly) in healthy BALB / c mice. A toxicity profile was performed (Figure 9A). Btz-free polymers were previously established to be well tolerated up to 2 g / kg and were not tested in this study. 37 Consistent with the results, for free Btz it was previously established that a dose of 0.75 mg / kg was safe for animals (Fig. 9A). 16 . However, higher doses confirm the toxicity of the drug as reflected by a rapid decline in survival. In contrast, Btz-BBP remained well tolerated up to 18.75 mg / kg, a 25-fold improvement over its parent drug. No mortality, significant weight loss (Figure 9B), or signs of toxicity were observed. These results strongly suggest that Btz remains conjugated to BBP even in the absence of the tumor microenvironment, allowing much larger doses to be administered.

[0364] In parallel, toxicology studies were performed in BALB / c mice based on the same dosing schedule (twice weekly injections for 4 weeks) to determine metabolic profiles (Figure 9C), complete blood counts (Figure 9D) and leukocyte counts. Btz-BBP-induced changes were evaluated in differential counts (Fig. 9E). Mice were treated with either Btz (0.75 mg / kg) or Btz-BBP (18.75 mg / kg) at the respective MTD and testing was performed 2 weeks after treatment. Mice exposed to Btz-BBP showed no signs of toxicity compared to PBS controls (two-tailed Student's t-test, P>0.05). Overall, it was concluded that the Btz-BBP compound was well tolerated and provided a 25-fold improvement in MTD compared to its parent Btz.

[0365] Btz-BBP improves therapeutic outcome in MM mouse model. It was hypothesized that Btz-BBP, when released at the tumor site, would provide a significant improvement in efficacy and constitute an advance in Btz TI worthy of further translation. A comparison of the efficacy of Btz and Btz-BBP was performed in two different animal models of MM. First, in a subcutaneous model of KMS11 (FIGS. 10A-10D), Btz-BBP is administered and accumulates in tumor tissue via passive uptake. One hour after injection, tumors were harvested and examined by fluorescence microscopy, revealing accumulation of Btz-BBP as well as deep penetration into tumor tissue (FIG. 10A).

[0366] This result prompted us to set up an efficacy study using this subcutaneous model, which included PBS, Btz, MTD (0.75 mg / kg, twice weekly, i.p.), Btz-BBP dose-matched (0.75 mg / kg, i.v.), and mice (n=5) treated with either the MTD of Btz-BBP (18.75 mg / kg, i.v.). Treatment was given for 50 days, after which tumors progressed freely. Compared to controls, Btz, dose-matched Btz-BBP, and high-dose Btz-BBP demonstrated improved treatment outcomes. However, free Btz, even at its MTD, provided little effect in slightly delaying tumor progression and subsequent improved median survival time (42±6 days compared to the control group of 22±5 days). days) (Figures 10B-10D). Interestingly, even at the same dose, Btz-BBP outperformed its parent drug, reflected in both tumor progression and improved survival (mean survival time of 61 ± 9 days) (Figure 10B). 10D). This has been attributed to the improved pharmacokinetics and tumor accumulation provided by DDS, allowing higher Btz concentrations at the tumor site over longer exposure times. Furthermore, at 18.75 mg / kg, Btz-BBP produced a nearly complete response in all mice as well as a survival benefit (mean survival time 84±13 days, P<0.01).

[0367] Motivated by these promising results, our next aim was to validate DDS in an orthotopic model of MM, which occurs primarily in the bone marrow of animals. tumor, MM.1S Luc+ / GFP+ Cells were induced by intravenous injection and tumor progression was quantified by bioluminescence via the luciferase signal expressed by MM (FIGS. 12A-12F). Study endpoints were reached when animals exhibited hind limb paralysis or >20% loss of initial body weight. Mice (n=5) were treated for 30 days with the same treatment groups and dosing schedule as described for the previous tumor model. Furthermore, decreased improvement was observed for both free Btz MTD and Btz-BBP when doses were matched (FIGS. 11A-11C). While the group administered free drug still achieved only a small therapeutic effect (Figures 11A-11C), the TI was extremely narrowed, and side effects were a problem before reaching the effective dose for achieving treatment results—sorry. However, some cases were observed which were not uncommon problems with many free drugs in this field. In stark contrast, at a 25-fold higher MTD than Btz-BBP, tumor suppression and survival benefit (mean survival 108 ± 11 days vs. 24 ± 4 days in the control group) was reduced in 2 of 5 (40%) animals. Complete remission was demonstrated (Figures 11A-11C). In both models, utilization of the BBP platform resulted in therapeutic outcomes superior to standard Btz, the current ...

Claims

1. A compound of formula (I) or a salt thereof, Formula (I) is 【Chemistry 1】 and During the ceremony: 【Chemistry 2】 X is a substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ alkynyl, substituted or unsubstituted partially unsaturated carbocyclyl, substituted or unsubstituted partially unsaturated heterocyclyl, or -N 3 ; L １ is a substituted or unsubstituted C ２～３００ Alkylene, or substituted or unsubstituted, C ２～３００ heteroalkylene, optionally wherein substituted or unsubstituted, C ２～３００ Alkylene, and substituted or unsubstituted, C ２～３００ one or more main chain carbon atoms of each of the heteroalkylenes are independently replaced with a substituted or unsubstituted carbocyclene, a substituted or unsubstituted heterocyclene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; Each R １ are independently halogen, unsubstituted C １～６ Alkyl, or -OR ａ or two R １ taken together form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; Each R ａ is independently substituted or unsubstituted, C １～６ alkyl, or oxygen protecting groups; L is a bond; or a substituted or unsubstituted C 2-10 alkylene, or a substituted or unsubstituted C 2-10 heteroalkylene, where the atom in the backbone of L that is attached to Ring A is carbon; each M is independently a radical of a therapeutic agent, a radical of a diagnostic agent, or a radical of a prophylactic agent; Each therapeutic agent may be independently selected from the group consisting of ixazomib, tavaborole, benzo[b]thiophene-2-boronic acid, TRI50c, dutogliptin, IL-2, IL-7, IL-12, interferon, G-CSF, CCL3, CCL26, CXCL7, cytosine phosphate-guanosine, oligodeoxynucleotides, glucan, pidilizumab, MEDI-0680, and REGN28. 10, AMP-224, atezolizumab, durvalumab, BMS-936559, avelumab, CA-170, tremelimumab, tumor necrosis factor, interferon α, interferon γ, IL-1, IL-4, IL-6, GM-CSF, T-DN1, tamoxifen, raloxifene, megestrol, goscurucrine, leuprolide, flutamide, vertoporfin, phthalocinamide Anine, photosensitizer Pc4, demethoxy-hypocrelin A, trofosfamide, estramustine, melphalan, treosulfan, vincristine, vinblastine, vindesine, vinorelbine, docosaxaenoic acid-conjugated paclitaxel, polyglutamate-conjugated paclitaxel, ANG1005, paclitaxel-EC-1, glucose-conjugated paclitaxel, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, trimetrexate, edatrexate, mycophenolic acid, tiazofurin, ribavirin, EICAR, hydroxyurea, deferoxamine, floxuridine, doxifluridine, latitrexed, tegafur-uracil, cytosine arabinoside, fludarabine, thioguanine, EB 1089, CB 1093, KH 1060, lovastatin, 1-methyl-4-phenylpyridinium ion, staurosporine, daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone, verapamil, thapsigargin, imatinib, cediranib, lapatinib, lestaurtinib, neratinib, semaxanib, sunitinib, toceranib, vatalanib, ranibizumab, sorafenib, ENMD-2076, PCI-32765, AC220, dovitinib lactate, BIBW 2992, SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869,MP470, BIBF 1120, AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib, OSI-930, MM-121, XL-184, XL-647, XL228, rapamycin, ridaforolimus, AP23573, AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126, OSI-027, oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, procarbidine, prednisolone , dexamethasone, campatecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, leurocidin, leurosine, trabectedin, procarbazine, discodermolide, hexamethylmelamine, abiraterone acetate, ado-trastuzumab emtansine, afatinib dimaleate, aldesleukin, alemtuzumab, anastrozole, arsenic trioxide, asparaginase, erwinia chrysanthemum, axitinib, azacitidine, belinostat, bendamustine hydrochloride, bevacizumab, bica lutamide, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib-s-malate, CAF, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, cetuximab, chlorambucil, cisplatin, clofarabine, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin hydrochloride, decitabine, degarelix, denileukin diftitox, denosumab, dinu Tuximab, docetaxel, doxorubicin hydrochloride, enzalutamide, epirubicin hydrochloride, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, exemestane, fludarabine phosphate, fluorouracil, fulvestrant, gefitinib, gemcitabine hydrochloride, goserelin acetate, ibritumomab tiuxetan, ibrutinib, idelalisib, ifosfamide, imatinib mesylate, imiquimod, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotide acetate, lapatinib ditosylate,Lenalidomide, lenvatinib, letrozole, leucovorin calcium, leuprolide acetate, lomustine, mechlorethamine hydrochloride, megestrol acetate, mercaptopurine, methotrexate, dichloromethotrexate, mitomycin C, mitoxantrone hydrochloride, nelarabine, nilotinib, nivolumab, obinutuzumab, ofatumumab, olaparib, omacetaxine mepesuxinate, oxaliplatin, paclitaxel, palbociclib, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, Pegaspargase, peginterferon alfa-2b, pembrolizumab, pemetrexed disodium, pertuzumab, plerixafor, pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone, procarbazine hydrochloride, raloxifene hydrochloride, ramucirumab, recombinant interferon alfa-2b, regorafenib, rituximab, romidepsin, ruxolitinib phosphate, siltuximab, sorafenib tosylate, sunitinib malate, tamoxifen citrate, temozolomide, temsirolimus, thalidomide, Thiotepa, topotecan hydrochloride, toremifene, tositumomab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine sulfate, vincristine sulfate, vinorelbine tartrate, vismodegib, vorinostat, ziv-aflibercept, zoledronic acid, amiloride, amlodipine, atenolol, azilsartan, benazepril, bendroflumethiazide, betaxolol, bisoprolol, bucindolol, bumetanide, candesartan, captopril, carteolol, carvedilol, chlorothiazide , chlorthalidone, cilnidipine, clevidipine, diltiazem, doxazosin, enalapril, epitizide, eplerenone, eprosartan, ethacrynic acid, felodipine, fimasartan, fosinopril, furosemide, hydrochlorothiazide, indapamide, indoramin, irbesartan, isradipine, labetalol, lercanidipine, levamlodipine, lisinopril, losartan, methyclothiazide, metolazone, metoprolol, moexipril, nadolol, nebivolol, nicardipine, nifedipine, nimodipine, nisoldipine,nitrendipine, olmesartan, oxprenolol, penbutolol, perindopril, pindolol, phenoxybenzamine, phentolamine, polythiazide, prazosin, propranolol, quinapril, ramipril, spironolactone, telmisartan, terazocine, timolol, tolazoline, torsemide, trandolapril, triamterene, or valsartan, or a compound of the formula: 【Chemistry 3】 It is represented by: The radicals of each diagnostic agent are independently selected from gadolinium chelate with DTPA, gadolinium chelate with DTPA-BMA, gadolinium chelate with DOTA, gadolinium chelate with HP-DO3A, 64 Cu diacetyl-bis(N 4 -methylthiosemicarbazone), 18 F-fluorodeoxyglucose, 3'-deoxy-3'-[ 18 F]fluorothymidine, 18 F-fluoromisonoidazole, gastrografin, acridine dyes, cyanine dyes, rhodamine dyes, BODIPY dyes, fluorescein dyes, dansyl dyes, Alexa dyes, ato dyes, fludeoxyglucose, 68 Ga-DOTA-TOC, 11 C-methomidate, 11 C-acetate, 11 C-methionine, 11 C-choline, 18 F-fluciclovine, 18 F-fluorocholine, 18 F-fluorodeoxysorbitol, 18 F-3'-fluoro-3'-deoxythymidine, 11 C-raclopride, 18 F-desmethoxyfalipride, Pz 247, DyLight 750, DyLight 800, IRDye 680, IRDye 800CW, or Kodak X-SIGHT, or a compound of the formula: 【Chemistry 4】 It is represented by: each prophylactic agent is independently an antibiotic, a nutritional supplement, or a vaccine; m is 1, 2, or 3; When a substituted alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, heteroalkylene, carbocyclene, heterocyclene, arylene, or heteroarylene substituent is located on a carbon atom, each substituent is independently selected from halogen, -CN, -NO, -CH, -CH2, -CH3, -CH4, -CH5, -CH6, -CH7, -CH8, -CH1, -CH1, -CH1, -CH2, -CH3, -CH4, -CH5, -CH6, -CH1, -CH2, -CH3, -CH4 ...2, -CH ２ , -N ３ , -SO ２ H, -SO ３ H, -OH, -OR ａａ , -ON(R ｂｂ ) ２ , -N(R ｂｂ ) ２ , -N(R ｂｂ ) ３ ＋ X - , -N(OR ｃｃ )R ｂｂ , -SH, -SR ａａ , -SSR ｃｃ , -C(=O)R ａａ , -CO ２ H, -CHO, -CO ２ R ａａ , -OC(=O)R ａａ , -OCO ２ R ａａ , -C(=O)N(R ｂｂ ) ２ , -OC(=O)N(R ｂｂ ) ２ , -NR ｂｂ C(=O)R ａａ , -NR ｂｂ CO ２ R ａａ , -NR ｂｂ C(=O)N(R ｂｂ ) ２ , -C(=NR ｂｂ )R ａａ , -C(=NR ｂｂ ) OR ａａ , -OC(=NR ｂｂ )R ａａ , -OC(=NR ｂｂ ) OR ａａ , -C(=NR ｂｂ )N(R ｂｂ ) ２ , -OC(=NR ｂｂ )N(R ｂｂ ) ２ 、-NR ｂｂ C(=NR ｂｂ )N(R ｂｂ ) ２ 、-C(=O)NR ｂｂ SO ２ R ａａ 、-NR ｂｂ SO ２ R ａａ 、-SO ２ N(R ｂｂ ) ２ 、-SO ２ R ａａ 、-SO ２ OR ａａ 、-OSO ２ R ａａ 、-S(=O)R ａａ 、-OS(=O)R ａａ 、-Si(R ａａ ) ３ 、-OSi(R ａａ ) ３ -C(=S)N(R ｂｂ ) ２ 、-C(=O)SR ａａ 、-C(=S)SR ａａ 、-SC(=S)SR ａａ 、-SC(=O)SR ａａ 、-OC(=O)SR ａａ 、-SC(=O)OR ａａ 、-SC(=O)R ａａ 、-P(=O)(R ａａ ) ２ 、-P(=O)(OR ｃｃ ) ２ 、-OP(=O)(R ａａ ) ２ 、-OP(=O)(OR ｃｃ ) ２ 、-P(=O)(N(R ｂｂ ) ２ ) ２ 、-OP(=O)(N(R ｂｂ ) ２ ) ２ 、-NR ｂｂ P(=O)(R ａａ ) ２ 、-NR ｂｂ P(=O)(OR ｃｃ ) ２ 、-NR ｂｂ P(=O)(N(R ｂｂ ) ２ ) ２ , -P(R ｃｃ ) ２ , -P(OR ｃｃ ) ２ , -P(R ｃｃ ) ３ ＋ X - , -P(OR ｃｃ ) ３ ＋ X - , -P(R ｃｃ ) ４ , -P(OR ｃｃ ) ４ , -OP(R ｃｃ ) ２ , -OP(R ｃｃ ) ３ ＋ X - , -OP(OR ｃｃ ) ２ , -OP(OR ｃｃ ) ３ ＋ X - , -OP(R ｃｃ ) ４ , -OP(OR ｃｃ ) ４ , -B(R ａａ ) ２ , -B(OR ｃｃ ) ２ , -BR ａａ (OR ｃｃ ), C １～１０ Alkyl, C １～１０ Perhaloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, Hetero C １～１０ Alkyl, Hetero C ２～１０ Alkenyl, Hetero C ２～１０ Alkynyl, C ３～１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６～１４ Aryl, 5-14 membered heteroaryl, =O, =S, =NN(R ｂｂ ) ２ , =NNR ｂｂ C(=O)R ａａ , =NNR ｂｂ C(=O)OR ａａ , =NNR ｂｂ S (=O) ２ R ａａ , =NR ｂｂ , or =NOR ｃｃ wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R ｄｄ substituted with a group; When a substituent of a substituted heterocyclyl, substituted heteroaryl, substituted heteroalkylene, substituted heterocyclene or substituted heteroarylene is on a nitrogen atom, each substituent can be selected from a nitrogen protecting group, hydrogen, -OH, -OR ａａ , -N(R ｃｃ ) ２ , -CN, -C(=O)R ａａ , -C(=O)N(R ｃｃ ) ２ , -CO ２ R ａａ , -SO ２ R ａａ , -C(=NR ｂｂ )R ａａ , -C(=NR ｃｃ ) OR ａａ , -C(=NR ｃｃ )N(R ｃｃ ) ２ , -SO ２ N(R ｃｃ ) ２ , -SO ２ R ｃｃ , -SO ２ OR ｃｃ , -SOR ａａ , -C(=S)N(R ｃｃ ) ２ , -C(=O)SR ｃｃ , -C(=S)SR ｃｃ , -P(=O)(OR ｃｃ ) ２ , -P(=O)(R ａａ ) ２ , -P(=O)(N(R ｃｃ ) ２ ) ２ , C １～１０ Alkyl, C １～１０ Perhaloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, Hetero C １～１０ Alkyl, Hetero C ２～１０ Alkenyl, Hetero C ２～１０ Alkynyl, C ３～１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６～１４ aryl, or 5-14 membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ｄｄ substituted with a group; Each nitrogen protecting group is independently -OH, -OR ａａ , -N(R ｃｃ ) ２ , -C(=O)R ａａ , -C(=O)N(R ｃｃ ) ２ , -CO ２ R ａａ , -SO ２ R ａａ , -C(=NR ｃｃ )R ａａ , -C(=NR ｃｃ ) OR ａａ , -C(=NR ｃｃ )N(R ｃｃ ) ２ , -SO ２ N(R ｃｃ ) ２ , -SO ２ R ｃｃ , -SO ２ OR ｃｃ , -SOR ａａ , -C(=S)N(R ｃｃ ) ２ , -C(=O)SR ｃｃ , -C(=S)SR ｃｃ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, Hetero C １～１０ Alkyl, Hetero C ２～１０ Alkenyl, Hetero C ２～１０ Alkynyl, C ３～１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６～１４ aryl, and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ｄｄ and when combined with the nitrogen atom to which it is directly attached, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydro 2-(2-(amino)phenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, methyl carbamate, ethyl carbamate, methyl 9-fluorenylcarbamate (Fmoc), methyl 9-(2-sulfo)fluorenylcarbamate methyl 9-(2,7-dibromo)fluoroenylcarbamate, methyl 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthy-l)]carbamate (DBD-Tmoc), 4-methoxyphenacylcarbamate (Phenoc), ethyl 2,2,2-trichlorocarbamate (Troc), ethyl 2-trimethylsilylcarbamate (Teoc), ethyl 2-phenylcarbamate (hZ), 1-(1-adamantyl)-1-methylcarbamate Ethyl 1,1-dimethyl-2-halocarbamate, ethyl 1,1-dimethyl-2,2-dibromocarbamate (DB-t-BOC), ethyl 1,1-dimethyl-2,2,2-trichlorocarbamate (TCBOC), ethyl 1-methyl-1-(4-biphenylyl)carbamate (Bpoc), ethyl 1-(3,5-di-t-butylphenyl)-1-methylcarbamate (t-Bumeoc), ethyl 2-(2'- and 4'-pyridyl)carbamate (Pyoc), ethyl 2-(N,N-Dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), benzyl p-methoxycarbamate (Mo z), benzyl p-nitrocarbamate, benzyl p-bromocarbamate, benzyl p-chlorocarbamate, benzyl 2,4-dichlorocarbamate, benzyl 4-methylsulfinylcarbamate (Msz), methyl 9-anthrylcarbamate, methyl diphenylcarbamate, ethyl 2-methylthiocarbamate, ethyl 2-methylsulfonylcarbamate, ethyl 2-(p-toluenesulfonyl)carbamate, methyl [2-(1,3-dithianyl)]carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-di Methylthiophenylcarbamate (Bmpc), ethyl 2-phosphoniocarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), ethyl 1,1-dimethyl-2-cyanocarbamate, benzyl m-chloro-p-acyloxycarbamate, benzyl p-(dihydroxyboryl)carbamate, methyl 5-benzisoxazolylcarbamate, methyl 2-(trifluoromethyl)-6-chromonylcarbamate (Tcroc), m-nitrophenylcarbamate, benzyl 3,5-dimethoxycarbamate, o-nitrophenylcarbamate, Benzyl trocarbamate, benzyl 3,4-dimethoxy-6-nitrocarbamate, methyl phenyl (o-nitrophenyl)carbamate, t-amyl carbamate, S-benzylthiocarbamate, benzyl p-cyanocarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, methyl cyclopropylcarbamate, benzyl p-decyloxycarbamate, 2,2-dimethoxyacyl vinyl carbamate, benzyl o-(N,N-dimethylcarboxamido)carbamate, 1,1-dimethyl-3-(N,N-Dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, methyl di(2-pyridyl)carbamate, methyl 2-furanylcarbamate, ethyl 2-iodocarbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, benzyl p-(p'-methoxyphenylazo)carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, methyl 1-methyl-1-cyclopropylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)carbamate ethyl 1-methyl-1-(p-phenylazophenyl)carbamate, ethyl 1-methyl-1-phenylcarbamate, ethyl 1-methyl-1-(4-pyridyl)carbamate, phenylcarbamate, benzyl p-(phenylazo)carbamate, 2,4,6-tri-t-butylphenylcarbamate, benzyl 4-(trimethylammonium)carbamate, benzyl 2,4,6-trimethylcarbamate, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilyl Ethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, phenacylsulfonamide, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-Triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)methylamine] N-phenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidene Diamines, N-p-nitrobenzylideneamines, N-salicylideneamines, N-5-chlorosalicylideneamines, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamines, N-cyclohexylideneamines, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amines, N-[phenyl(pentaacylchromium- or tungsten)acyl]amines, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamides (Dpp), dimethylthio is selected from groups forming phosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, or 3-nitropyridinesulfenamide (Npys), Each oxygen protecting group is independently -R ａａ , -N(R ｂｂ ) ２ , -C(=O)SR ａａ , -C(=O)R ａａ , -CO ２ R ａａ , -C(=O)N(R ｂｂ ) ２ , -C(=NR ｂｂ )R ａａ , -C(=NR ｂｂ ) OR ａａ , -C(=NR ｂｂ )N(R ｂｂ ) ２ , -S(=O)R ａａ , -SO ２ R ａａ , -Si(R ａａ ) ３ , -P(R ｃｃ ) ２ , -P(R ｃｃ ) ３ ＋ X - , -P(OR ｃｃ ) ２ , -P(OR ｃｃ ) ３ ＋ X - , -P(=O)(R ａａ ) ２ , -P(=O)(OR ｃｃ ) ２ , -P(=O)(N(R ｂｂ ) ２ ) ２ , methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethyl Silyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a- Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o -Nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-Tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), and when combined with the oxygen atom to which it is directly attached, formate, benzo ylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethyl Benzoate (mesitoate), methyl carbonate, 9-fluorenyl methyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-Dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethyl) 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, or tosylate (Ts) forming groups; Each sulfur protecting group is independently R ａａ , -N(R ｂｂ ) ２ , -C(=O)SR ａａ , -C(=O)R ａａ , -CO ２ R ａａ , -C(=O)N(R ｂｂ ) ２ , -C(=NR ｂｂ )R ａａ , -C(=NR ｂｂ ) OR ａａ , -C(=NR ｂｂ )N(R ｂｂ ) ２ , -S(=O)R ａａ , -SO ２ R ａａ , -Si(R ａａ ) ３ , -P(R ｃｃ ) ２ , -P(R ｃｃ ) ３ ＋ X - , -P(OR ｃｃ ) ２ , -P(OR ｃｃ ) ３ ＋ X - , -P(=O)(R ａａ ) ２ , -P(=O)(OR ｃｃ ) ２ , and -P(=O)(N(R ｂｂ ) ２ ) ２ Selected from; Each R ａａ is independently selected from: １～１０ Alkyl, C １～１０ Perhaloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, Hetero C １～１０ Alkyl, Hetero C ２～１０ Alkenyl, Hetero C ２～１０ Alkynyl, C ３～１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６～１４ aryl, and 5- to 14-membered heteroaryl, or two R ａａ The groups taken together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R ｄｄ substituted with a group; Each R ｂｂ is independently selected from hydrogen, -OH, -OR ａａ , -N(R ｃｃ ) ２ , -CN, -C(=O)R ａａ , -C(=O)N(R ｃｃ ) ２ , -CO ２ R ａａ , -SO ２ R ａａ , -C(=NR ｃｃ ) OR ａａ , -C(=NR ｃｃ )N(R ｃｃ ) ２ , -SO ２ N(R ｃｃ ) ２ , -SO ２ R ｃｃ , -SO ２ OR ｃｃ , -SOR ａａ , -C(=S)N(R ｃｃ ) ２ , -C(=O)SR ｃｃ , -C(=S)SR ｃｃ , -P(=O)(R ａａ ) ２ , -P(=O)(OR ｃｃ ) ２ , -P(=O)(N(R ｃｃ ) ２ ) ２ , C １～１０ Alkyl, C １～１０ Perhaloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, Hetero C １～１０ Alkyl, Hetero C ２～１０ Alkenyl, Hetero C ２～１０ Alkynyl, C ３～１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６～１４ aryl, and 5- to 14-membered heteroaryl, or two R ｂｂ The groups taken together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R ｄｄ substituted with a group; Each R ｃｃ is independently selected from: hydrogen, C １～１０ Alkyl, C １～１０ Perhaloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, Hetero C １～１０ Alkyl, Hetero C ２～１０ Alkenyl, Hetero C ２～１０ Alkynyl, C ３～１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６～１４ aryl, and 5- to 14-membered heteroaryl, or two R ｃｃ The groups taken together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R ｄｄ substituted with a group; Each R ｄｄ is independently selected from: halogen, -CN, -NO ２ , -N ３ , -SO ２ H, -SO ３ H, -OH, -OR ｅｅ , -ON(R ｆｆ ) ２ , -N(R ｆｆ ) ２ , -N(R ｆｆ ) ３ ＋ X - , -N(OR ｅｅ )R ｆｆ , -SH, -SR ｅｅ , -SSR ｅｅ , -C(=O)R ｅｅ , -CO ２ H, -CO ２ R ｅｅ , -OC(=O)R ｅｅ , -OCO ２ R ｅｅ , -C(=O)N(R ｆｆ ) ２ , -OC(=O)N(R ｆｆ ) ２ , -NR ｆｆ C(=O)R ｅｅ , -NR ｆｆ CO ２ R ｅｅ , -NR ｆｆ C(=O)N(R ｆｆ ) ２ , -C(=NR ｆｆ ) OR ｅｅ , -OC(=NR ｆｆ )R ｅｅ , -OC(=NR ｆｆ ) OR ｅｅ , -C(=NR ｆｆ )N(R ｆｆ ) ２ , -OC(=NR ｆｆ )N(R ｆｆ ) ２ , -NR ｆｆ C(=NR ｆｆ )N(R ｆｆ ) ２ , -NR ｆｆ SO ２ R ｅｅ , -SO ２ N(R ｆｆ ) ２ , -SO ２ R ｅｅ , -SO ２ OR ｅｅ , -OSO ２ R ｅｅ , -S(=O)R ｅｅ , -Si(R ｅｅ ) ３ , -OSi(R ｅｅ ) ３ , -C(=S)N(R ｆｆ ) ２ , -C(=O)SR ｅｅ , -C(=S)SR ｅｅ , -SC(=S)SR ｅｅ , -P(=O)(OR ｅｅ ) ２ , -P(=O)(R ｅｅ ) ２ , -OP(=O)(R ｅｅ ) ２ , -OP(=O)(OR ｅｅ ) ２ , C １～６ Alkyl, C １～６ Perhaloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, Hetero C １～６ Alkyl, Hetero C ２～６ Alkenyl, Hetero C ２～６ Alkynyl, C ３～１０ Carbocyclyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl, 5-10 membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ｇｇ or two geminal R ｄｄ The substituents may be taken together to form =O or =S; Each R ｅｅ is independently selected from: １～６ Alkyl, C １～６ Perhaloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, Hetero C １～６ Alkyl, Hetero C ２～６ Alkenyl, Hetero C ２～６ Alkynyl, C ３～１０ Carbocyclyl, C ６～１０ aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ｇｇ substituted with a group; Each R ｆｆ is independently selected from: hydrogen, C １～６ Alkyl, C １～６ Perhaloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, Hetero C １～６ Alkyl, Hetero C ２～６ Alkenyl, Hetero C ２～６ Alkynyl, C ３～１０ Carbocyclyl, 3- to 10-membered heterocyclyl, C ６～１０ Aryl and 5-10 membered heteroaryl, or two R ｆｆ The groups, taken together, form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R ｇｇ substituted with a group; Each R ｇｇ are independently halogen, -CN, -NO ２ , -N ３ , -SO ２ H, -SO ３ H, -OH, -OC １～６ Alkyl, -ON(C １～６ Alkyl) ２ , -N(C １～６ Alkyl) ２ , -N(C １～６ Alkyl) ３ ＋ X - , -NH(C １～６ Alkyl) ２ ＋ X - , -NH ２ (C １～６ Alkyl) ＋ X - , -NH ３ ＋ X - , -N(OC １～６ Alkyl)(C １～６ alkyl), -N(OH)(C １～６ alkyl), -NH(OH), -SH, -SC １～６ Alkyl, -SS(C １～６ alkyl), -C(=O)(C １～６ alkyl), -CO ２ H, -CO ２ (C １～６ alkyl), -OC(=O)(C １～６ alkyl), -OCO ２ (C １～６ alkyl), -C(=O)NH ２ , -C(=O)N(C １～６ Alkyl) ２ , -OC(=O)NH(C １～６ alkyl), -NHC(=O)(C １～６ alkyl), -N(C １～６ Alkyl)C(=O)(C １～６ alkyl), -NHCO ２ (C １～６ alkyl), -NHC(=O)N(C １～６ Alkyl) ２ , -NHC(=O)NH(C １～６ alkyl), -NHC(=O)NH ２ , -C(=NH)O(C １～６ alkyl), -OC(=NH)(C １～６ alkyl), -OC(=NH)OC １～６ Alkyl, -C(=NH)N(C １～６ Alkyl) ２ , -C(=NH)NH(C １～６ alkyl), -C(=NH)NH ２ , -OC(=NH)N(C １～６ Alkyl) ２ , -OC(NH)NH(C １～６ alkyl), -OC(NH)NH ２ , -NHC(NH)N(C １～６ Alkyl) ２ , -NHC(=NH)NH ２ , -NHSO ２ (C １～６ alkyl), -SO ２ N(C １～６ Alkyl) ２ , -SO ２ NH(C １～６ alkyl), -SO ２ N.H. ２ , -SO ２ C １～６ Alkyl, -SO ２ O.C. １～６ Alkyl, -OSO ２ C １～６ Alkyl, -SOC １～６ Alkyl, -Si(C １～６ Alkyl) ３ , -OSi(C １～６ Alkyl) ３ , -C(=S)N(C １～６ Alkyl) ２ , C(=S)NH(C １～６ alkyl), C(=S)NH ２ , -C(=O)S(C １～６ Alkyl), -C(=S)SC １～６ Alkyl, -SC(=S)SC １～６ Alkyl, -P(=O)(OC １～６ Alkyl) ２ , -P(=O)(C １～６ Alkyl) ２ , -OP(=O)(C １～６ Alkyl) ２ , -OP(=O)(OC １～６ Alkyl) ２ , C １～６ Alkyl, C １～６ Perhaloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, Hetero C １～６ Alkyl, Hetero C ２～６ Alkenyl, Hetero C ２～６ Alkynyl, C ３～１０ Carbocyclyl, C ６～１０ aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; or two geminal R ｇｇ the substituents may be taken together to form =O or =S; and Each X - is a counter ion,

2. A bottle brush polymer comprising one or more types of repeating units, at least one of the types of repeating units comprising a moiety represented by formula (IA), wherein: Formula (IA) is 【Chemistry 5】 and During the ceremony: 【Chemistry 6】 L １ teeth, formula: 【Chemistry 7】 During the ceremony, n is an integer between 0 and 12, inclusive; k is an integer between 1 and 12, inclusive; L 1a is independently substituted or unsubstituted C 1-200 alkylene, or substituted or unsubstituted C 2-200 heteroalkylene; Optionally, wherein one or more main chain carbon atoms of each of the substituted or unsubstituted C 1-200 alkylene, substituted or unsubstituted C 2-200 heteroalkylene are independently replaced with a substituted or unsubstituted carbocyclene, substituted or unsubstituted heterocyclene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 1b is a substituted or unsubstituted C 2-200 heteroalkyl, a nitrogen protecting group, or a polymer; and The attachment point to which L 1a is attached is represented by, which is attached to ring A; Each R １ are independently halogen, unsubstituted C １～６ Alkyl, or -OR ａ or two R １ taken together form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; Each R ａ is independently substituted or unsubstituted, C １～６ alkyl, or oxygen protecting groups; each L is independently a bond; or a substituted or unsubstituted C 2-10 alkylene, or a substituted or unsubstituted C 2-10 heteroalkylene, where the atom in the backbone of L that is attached to ring A is carbon; each M is independently a radical of a therapeutic agent, a radical of a diagnostic agent, or a radical of a prophylactic agent; Each therapeutic agent may be independently selected from the group consisting of ixazomib, tavaborole, benzo[b]thiophene-2-boronic acid, TRI50c, dutogliptin, IL-2, IL-7, IL-12, interferon, G-CSF, CCL3, CCL26, CXCL7, cytosine phosphate-guanosine, oligodeoxynucleotides, glucan, pidilizumab, MEDI-0680, and REGN28. 10, AMP-224, atezolizumab, durvalumab, BMS-936559, avelumab, CA-170, tremelimumab, tumor necrosis factor, interferon α, interferon γ, IL-1, IL-4, IL-6, GM-CSF, T-DN1, tamoxifen, raloxifene, megestrol, goscurucrine, leuprolide, flutamide, vertoporfin, phthalocinamide Anine, photosensitizer Pc4, demethoxy-hypocrelin A, trofosfamide, estramustine, melphalan, treosulfan, vincristine, vinblastine, vindesine, vinorelbine, docosaxaenoic acid-conjugated paclitaxel, polyglutamate-conjugated paclitaxel, ANG1005, paclitaxel-EC-1, glucose-conjugated paclitaxel, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, trimetrexate, edatrexate, mycophenolic acid, tiazofurin, ribavirin, EICAR, hydroxyurea, deferoxamine, floxuridine, doxifluridine, latitrexed, tegafur-uracil, cytosine arabinoside, fludarabine, thioguanine, EB 1089, CB 1093, KH 1060, lovastatin, 1-methyl-4-phenylpyridinium ion, staurosporine, daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone, verapamil, thapsigargin, imatinib, cediranib, lapatinib, lestaurtinib, neratinib, semaxanib, sunitinib, toceranib, vatalanib, ranibizumab, sorafenib, ENMD-2076, PCI-32765, AC220, dovitinib lactate, BIBW 2992, SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869,MP470, BIBF 1120, AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib, OSI-930, MM-121, XL-184, XL-647, XL228, rapamycin, ridaforolimus, AP23573, AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126, OSI-027, oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, procarbidine, prednisolone , dexamethasone, campatecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, leurocidin, leurosine, trabectedin, procarbazine, discodermolide, hexamethylmelamine, abiraterone acetate, ado-trastuzumab emtansine, afatinib dimaleate, aldesleukin, alemtuzumab, anastrozole, arsenic trioxide, asparaginase, erwinia chrysanthemum, axitinib, azacitidine, belinostat, bendamustine hydrochloride, bevacizumab, bica lutamide, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib-s-malate, CAF, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, cetuximab, chlorambucil, cisplatin, clofarabine, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin hydrochloride, decitabine, degarelix, denileukin diftitox, denosumab, dinu Tuximab, docetaxel, doxorubicin hydrochloride, enzalutamide, epirubicin hydrochloride, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, exemestane, fludarabine phosphate, fluorouracil, fulvestrant, gefitinib, gemcitabine hydrochloride, goserelin acetate, ibritumomab tiuxetan, ibrutinib, idelalisib, ifosfamide, imatinib mesylate, imiquimod, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotide acetate, lapatinib ditosylate,Lenalidomide, lenvatinib, letrozole, leucovorin calcium, leuprolide acetate, lomustine, mechlorethamine hydrochloride, megestrol acetate, mercaptopurine, methotrexate, dichloromethotrexate, mitomycin C, mitoxantrone hydrochloride, nelarabine, nilotinib, nivolumab, obinutuzumab, ofatumumab, olaparib, omacetaxine mepesuxinate, oxaliplatin, paclitaxel, palbociclib, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, Pegaspargase, peginterferon alfa-2b, pembrolizumab, pemetrexed disodium, pertuzumab, plerixafor, pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone, procarbazine hydrochloride, raloxifene hydrochloride, ramucirumab, recombinant interferon alfa-2b, regorafenib, rituximab, romidepsin, ruxolitinib phosphate, siltuximab, sorafenib tosylate, sunitinib malate, tamoxifen citrate, temozolomide, temsirolimus, thalidomide, Thiotepa, topotecan hydrochloride, toremifene, tositumomab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine sulfate, vincristine sulfate, vinorelbine tartrate, vismodegib, vorinostat, ziv-aflibercept, zoledronic acid, amiloride, amlodipine, atenolol, azilsartan, benazepril, bendroflumethiazide, betaxolol, bisoprolol, bucindolol, bumetanide, candesartan, captopril, carteolol, carvedilol, chlorothiazide , chlorthalidone, cilnidipine, clevidipine, diltiazem, doxazosin, enalapril, epitizide, eplerenone, eprosartan, ethacrynic acid, felodipine, fimasartan, fosinopril, furosemide, hydrochlorothiazide, indapamide, indoramin, irbesartan, isradipine, labetalol, lercanidipine, levamlodipine, lisinopril, losartan, methyclothiazide, metolazone, metoprolol, moexipril, nadolol, nebivolol, nicardipine, nifedipine, nimodipine, nisoldipine,nitrendipine, olmesartan, oxprenolol, penbutolol, perindopril, pindolol, phenoxybenzamine, phentolamine, polythiazide, prazosin, propranolol, quinapril, ramipril, spironolactone, telmisartan, terazocine, timolol, tolazoline, torsemide, trandolapril, triamterene, or valsartan, or a compound of the formula: 【Chemistry 8】 It is represented by: The radicals of each diagnostic agent are independently selected from gadolinium chelate with DTPA, gadolinium chelate with DTPA-BMA, gadolinium chelate with DOTA, gadolinium chelate with HP-DO3A, 64 Cu diacetyl-bis(N 4 -methylthiosemicarbazone), 18 F-fluorodeoxyglucose, 3'-deoxy-3'-[ 18 F]fluorothymidine, 18 F-fluoromisonoidazole, gastrografin, acridine dyes, cyanine dyes, rhodamine dyes, BODIPY dyes, fluorescein dyes, dansyl dyes, Alexa dyes, ato dyes, fludeoxyglucose, 68 Ga-DOTA-TOC, 11 C-methomidate, 11 C-acetate, 11 C-methionine, 11 C-choline, 18 F-fluciclovine, 18 F-fluorocholine, 18 F-fluorodeoxysorbitol, 18 F-3'-fluoro-3'-deoxythymidine, 11 C-raclopride, 18 F-desmethoxyfalipride, Pz 247, DyLight 750, DyLight 800, IRDye 680, IRDye 800CW, or Kodak X-SIGHT, or a compound of the formula: 【Chemistry 9】 It is represented by: each prophylactic agent is independently an antibiotic, a nutritional supplement, or a vaccine; m is 1, 2, or 3; When a substituted alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, alkylene, heteroalkylene, carbocyclene, heterocyclene, arylene, or heteroarylene substituent is located on a carbon atom, each substituent is independently selected from halogen, -CN, -NO, -CH, -CH2, -CH3, -CH4, -CH5, -CH6, -CH7, -CH8, -CH1, -CH1, -CH1, -CH2, -CH3, -CH4, -CH5, -CH6, -CH1, -CH2, -CH3, -CH4 ...2, -CH ２ , -N ３ , -SO ２ H, -SO ３ H, -OH, -OR ａａ , -ON(R ｂｂ ) ２ , -N(R ｂｂ ) ２ , -N(R ｂｂ ) ３ ＋ X - , -N(OR ｃｃ )R ｂｂ , -SH, -SR ａａ , -SSR ｃｃ , -C(=O)R ａａ , -CO ２ H, -CHO, -CO ２ R ａａ , -OC(=O)R ａａ , -OCO ２ R ａａ , -C(=O)N(R ｂｂ ) ２ , -OC(=O)N(R ｂｂ ) ２ , -NR ｂｂ C(=O)R ａａ , -NR ｂｂ CO ２ R ａａ , -NR ｂｂ C(=O)N(R ｂｂ ) ２ , -C(=NR ｂｂ )R ａａ , -C(=NR ｂｂ ) OR ａａ , -OC(=NR ｂｂ )R ａａ , -OC(=NR ｂｂ ) OR ａａ , -C(=NR ｂｂ )N(R ｂｂ ) ２ , -OC(=NR ｂｂ )N(R ｂｂ ) ２ 、-NR ｂｂ C(=NR ｂｂ )N(R ｂｂ ) ２ 、-C(=O)NR ｂｂ SO ２ R ａａ 、-NR ｂｂ SO ２ R ａａ 、-SO ２ N(R ｂｂ ) ２ 、-SO ２ R ａａ 、-SO ２ OR ａａ 、-OSO ２ R ａａ 、-S(=O)R ａａ 、-OS(=O)R ａａ 、-Si(R ａａ ) ３ 、-OSi(R ａａ ) ３ -C(=S)N(R ｂｂ ) ２ 、-C(=O)SR ａａ 、-C(=S)SR ａａ 、-SC(=S)SR ａａ 、-SC(=O)SR ａａ 、-OC(=O)SR ａａ 、-SC(=O)OR ａａ 、-SC(=O)R ａａ 、-P(=O)(R ａａ ) ２ 、-P(=O)(OR ｃｃ ) ２ 、-OP(=O)(R ａａ ) ２ 、-OP(=O)(OR ｃｃ ) ２ 、-P(=O)(N(R ｂｂ ) ２ ) ２ 、-OP(=O)(N(R ｂｂ ) ２ ) ２ 、-NR ｂｂ P(=O)(R ａａ ) ２ 、-NR ｂｂ P(=O)(OR ｃｃ ) ２ 、-NR ｂｂ P(=O)(N(R ｂｂ ) ２ ) ２ , -P(R ｃｃ ) ２ , -P(OR ｃｃ ) ２ , -P(R ｃｃ ) ３ ＋ X - , -P(OR ｃｃ ) ３ ＋ X - , -P(R ｃｃ ) ４ , -P(OR ｃｃ ) ４ , -OP(R ｃｃ ) ２ , -OP(R ｃｃ ) ３ ＋ X - , -OP(OR ｃｃ ) ２ , -OP(OR ｃｃ ) ３ ＋ X - , -OP(R ｃｃ ) ４ , -OP(OR ｃｃ ) ４ , -B(R ａａ ) ２ , -B(OR ｃｃ ) ２ , -BR ａａ (OR ｃｃ ), C １～１０ Alkyl, C １～１０ Perhaloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, Hetero C １～１０ Alkyl, Hetero C ２～１０ Alkenyl, Hetero C ２～１０ Alkynyl, C ３～１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６～１４ Aryl, 5-14 membered heteroaryl, =O, =S, =NN(R ｂｂ ) ２ , =NNR ｂｂ C(=O)R ａａ , =NNR ｂｂ C(=O)OR ａａ , =NNR ｂｂ S (=O) ２ R ａａ , =NR ｂｂ , or =NOR ｃｃ wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R ｄｄ substituted with a group; When a substituent of a substituted heterocyclyl, substituted heteroaryl, substituted heteroalkylene, substituted heterocyclene or substituted heteroarylene is on a nitrogen atom, each substituent can be selected from a nitrogen protecting group, hydrogen, -OH, -OR ａａ , -N(R ｃｃ ) ２ , -CN, -C(=O)R ａａ , -C(=O)N(R ｃｃ ) ２ , -CO ２ R ａａ , -SO ２ R ａａ , -C(=NR ｂｂ )R ａａ , -C(=NR ｃｃ ) OR ａａ , -C(=NR ｃｃ )N(R ｃｃ ) ２ , -SO ２ N(R ｃｃ ) ２ , -SO ２ R ｃｃ , -SO ２ OR ｃｃ , -SOR ａａ , -C(=S)N(R ｃｃ ) ２ , -C(=O)SR ｃｃ , -C(=S)SR ｃｃ , -P(=O)(OR ｃｃ ) ２ , -P(=O)(R ａａ ) ２ , -P(=O)(N(R ｃｃ ) ２ ) ２ , C １～１０ Alkyl, C １～１０ Perhaloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, Hetero C １～１０ Alkyl, Hetero C ２～１０ Alkenyl, Hetero C ２～１０ Alkynyl, C ３～１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６～１４ aryl, or 5-14 membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ｄｄ substituted with a group; Each nitrogen protecting group is independently -OH, -OR ａａ , -N(R ｃｃ ) ２ , -C(=O)R ａａ , -C(=O)N(R ｃｃ ) ２ , -CO ２ R ａａ , -SO ２ R ａａ , -C(=NR ｃｃ )R ａａ , -C(=NR ｃｃ ) OR ａａ , -C(=NR ｃｃ )N(R ｃｃ ) ２ , -SO ２ N(R ｃｃ ) ２ , -SO ２ R ｃｃ , -SO ２ OR ｃｃ , -SOR ａａ , -C(=S)N(R ｃｃ ) ２ , -C(=O)SR ｃｃ , -C(=S)SR ｃｃ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, Hetero C １～１０ Alkyl, Hetero C ２～１０ Alkenyl, Hetero C ２～１０ Alkynyl, C ３～１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６～１４ aryl, and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ｄｄ and when combined with the nitrogen atom to which it is directly attached, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)acetamide, 4-(4-phenylphenyl)acetamide, 5-(4-phenylphenyl)acetamide, 6-(4-phenylphenyl)acetamide, 7-(4-phenylphenyl)acetamide, 8-(4-phenylphenyl)acetamide, 9-(4-phenylphenyl)acetamide, 10-(4-phenylphenyl)acetamide, 11-(4-phenylphenyl)acetamide, 12-(4-phenylphenyl)acetamide, 13-(4-phenylphenyl)acetamide, 14-(4-phenylphenyl)acetamide, 15-(4-phenylphenyl)acetamide, 16-(4-phenylphenyl)acetamide, 17-(4-phenylphenyl)acetamide, 18-(4-phenylphenyl)acetamide, 19-(4-phenylphenyl)acetamide, 20-(4-phenylphenyl)acetamide, 21-(4-phenylphenyl)acetamide, 22-(4-phenylphenyl)acetamide, 23-(4-phenylphenyl)acetamide, 24-(4-phenylphenyl)acetamide, 25-(4-phenylphenyl)acetamide, 26-(4-phenylphenyl)acetamide, 27-(4-phenylphenyl)acetamide, 28-(4-phenylphenyl)acetamide, 29-(4-phenylphenyl)acetamide, 30-(4-phenylphenyl)acetamide, 31-(4-phenylphenyl)acetamide, 32-(4-phenylphenyl)acetamide, 33-(4-phenylphenyl)acetamide, 2-(o-phenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, methyl carbamate, ethyl carbamate, 9-fluorenyl methylcarbamate (Fmoc), 9-(2-sulfo)fluorenylcarbamate methyl 9-(2,7-dibromo)fluoroenylcarbamate, methyl 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]carbamate (DBD-Tmoc), 4-methoxyphenacylcarbamate (Phenoc), ethyl 2,2,2-trichlorocarbamate (Troc), ethyl 2-trimethylsilylcarbamate (Teoc), ethyl 2-phenylcarbamate (hZ), 1-(1-adamantyl)-1-methylcarbamate Ethyl 1,1-dimethyl-2-halocarbamate, ethyl 1,1-dimethyl-2,2-dibromocarbamate (DB-t-BOC), ethyl 1,1-dimethyl-2,2,2-trichlorocarbamate (TCBOC), ethyl 1-methyl-1-(4-biphenylyl)carbamate (Bpoc), ethyl 1-(3,5-di-t-butylphenyl)-1-methylcarbamate (t-Bumeoc), ethyl 2-(2'- and 4'-pyridyl)carbamate (Pyoc), ethyl 2-(N,N-Dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), benzyl p-methoxycarbamate (Mo z), benzyl p-nitrocarbamate, benzyl p-bromocarbamate, benzyl p-chlorocarbamate, benzyl 2,4-dichlorocarbamate, benzyl 4-methylsulfinylcarbamate (Msz), methyl 9-anthrylcarbamate, methyl diphenylcarbamate, ethyl 2-methylthiocarbamate, ethyl 2-methylsulfonylcarbamate, ethyl 2-(p-toluenesulfonyl)carbamate, methyl [2-(1,3-dithianyl)]carbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-di Methylthiophenylcarbamate (Bmpc), ethyl 2-phosphoniocarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), ethyl 1,1-dimethyl-2-cyanocarbamate, benzyl m-chloro-p-acyloxycarbamate, benzyl p-(dihydroxyboryl)carbamate, methyl 5-benzisoxazolylcarbamate, methyl 2-(trifluoromethyl)-6-chromonylcarbamate (Tcroc), m-nitrophenylcarbamate, benzyl 3,5-dimethoxycarbamate, o-nitrophenylcarbamate, Benzyl trocarbamate, benzyl 3,4-dimethoxy-6-nitrocarbamate, methyl phenyl (o-nitrophenyl)carbamate, t-amyl carbamate, S-benzylthiocarbamate, benzyl p-cyanocarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, methyl cyclopropylcarbamate, benzyl p-decyloxycarbamate, 2,2-dimethoxyacyl vinyl carbamate, benzyl o-(N,N-dimethylcarboxamido)carbamate, 1,1-dimethyl-3-(N,N-Dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, methyl di(2-pyridyl)carbamate, methyl 2-furanylcarbamate, ethyl 2-iodocarbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, benzyl p-(p'-methoxyphenylazo)carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, methyl 1-methyl-1-cyclopropylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)carbamate ethyl 1-methyl-1-(p-phenylazophenyl)carbamate, ethyl 1-methyl-1-phenylcarbamate, ethyl 1-methyl-1-(4-pyridyl)carbamate, phenylcarbamate, benzyl p-(phenylazo)carbamate, 2,4,6-tri-t-butylphenylcarbamate, benzyl 4-(trimethylammonium)carbamate, benzyl 2,4,6-trimethylcarbamate, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilyl Ethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, phenacylsulfonamide, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-Triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)methylamine] N-phenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidene Diamines, N-p-nitrobenzylideneamines, N-salicylideneamines, N-5-chlorosalicylideneamines, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamines, N-cyclohexylideneamines, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amines, N-[phenyl(pentaacylchromium- or tungsten)acyl]amines, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamides (Dpp), dimethylthio is selected from groups forming phosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, or 3-nitropyridinesulfenamide (Npys), Each oxygen protecting group is independently -R ａａ , -N(R ｂｂ ) ２ , -C(=O)SR ａａ , -C(=O)R ａａ , -CO ２ R ａａ , -C(=O)N(R ｂｂ ) ２ , -C(=NR ｂｂ )R ａａ , -C(=NR ｂｂ ) OR ａａ , -C(=NR ｂｂ )N(R ｂｂ ) ２ , -S(=O)R ａａ , -SO ２ R ａａ , -Si(R ａａ ) ３ , -P(R ｃｃ ) ２ , -P(R ｃｃ ) ３ ＋ X - , -P(OR ｃｃ ) ２ , -P(OR ｃｃ ) ３ ＋ X - , -P(=O)(R ａａ ) ２ , -P(=O)(OR ｃｃ ) ２ , -P(=O)(N(R ｂｂ ) ２ ) ２ , methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethyl Silyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a- Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o -Nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-Tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), and when combined with the oxygen atom to which it is directly attached, formate, benzo ylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethyl Benzoate (mesitoate), methyl carbonate, 9-fluorenyl methyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-Dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylphenyl)acetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, or tosylate (Ts), Each sulfur protecting group is independently R ａａ , -N(R ｂｂ ) ２ , -C(=O)SR ａａ , -C(=O)R ａａ , -CO ２ R ａａ , -C(=O)N(R ｂｂ ) ２ , -C(=NR ｂｂ )R ａａ , -C(=NR ｂｂ ) OR ａａ , -C(=NR ｂｂ )N(R ｂｂ ) ２ , -S(=O)R ａａ , -SO ２ R ａａ , -Si(R ａａ ) ３ , -P(R ｃｃ ) ２ , -P(R ｃｃ ) ３ ＋ X - , -P(OR ｃｃ ) ２ , -P(OR ｃｃ ) ３ ＋ X - , -P(=O)(R ａａ ) ２ , -P(=O)(OR ｃｃ ) ２ , and -P(=O)(N(R ｂｂ ) ２ ) ２ Selected from; Each R ａａ is independently selected from: １～１０ Alkyl, C １～１０ Perhaloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, Hetero C １～１０ Alkyl, Hetero C ２～１０ Alkenyl, Hetero C ２～１０ Alkynyl, C ３～１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６～１４ aryl, and 5- to 14-membered heteroaryl, or two R ａａ The groups taken together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R ｄｄ substituted with a group; Each R ｂｂ is independently selected from hydrogen, -OH, -OR ａａ , -N(R ｃｃ ) ２ , -CN, -C(=O)R ａａ , -C(=O)N(R ｃｃ ) ２ , -CO ２ R ａａ , -SO ２ R ａａ , -C(=NR ｃｃ ) OR ａａ , -C(=NR ｃｃ )N(R ｃｃ ) ２ , -SO ２ N(R ｃｃ ) ２ , -SO ２ R ｃｃ , -SO ２ OR ｃｃ , -SOR ａａ , -C(=S)N(R ｃｃ ) ２ , -C(=O)SR ｃｃ , -C(=S)SR ｃｃ , -P(=O)(R ａａ ) ２ , -P(=O)(OR ｃｃ ) ２ , -P(=O)(N(R ｃｃ ) ２ ) ２ , C １～１０ Alkyl, C １～１０ Perhaloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, Hetero C １～１０ Alkyl, Hetero C ２～１０ Alkenyl, Hetero C ２～１０ Alkynyl, C ３～１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６～１４ aryl, and 5- to 14-membered heteroaryl, or two R ｂｂ The groups taken together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R ｄｄ substituted with a group; Each R ｃｃ is independently selected from: hydrogen, C １～１０ Alkyl, C １～１０ Perhaloalkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, Hetero C １～１０ Alkyl, Hetero C ２～１０ Alkenyl, Hetero C ２～１０ Alkynyl, C ３～１０ Carbocyclyl, 3- to 14-membered heterocyclyl, C ６～１４ aryl, and 5- to 14-membered heteroaryl, or two R ｃｃ The groups taken together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R ｄｄ substituted with a group; Each R ｄｄ is independently selected from: halogen, -CN, -NO ２ , -N ３ , -SO ２ H, -SO ３ H, -OH, -OR ｅｅ , -ON(R ｆｆ ) ２ , -N(R ｆｆ ) ２ , -N(R ｆｆ ) ３ ＋ X - , -N(OR ｅｅ )R ｆｆ , -SH, -SR ｅｅ , -SSR ｅｅ , -C(=O)R ｅｅ , -CO ２ H, -CO ２ R ｅｅ , -OC(=O)R ｅｅ , -OCO ２ R ｅｅ , -C(=O)N(R ｆｆ ) ２ , -OC(=O)N(R ｆｆ ) ２ , -NR ｆｆ C(=O)R ｅｅ , -NR ｆｆ CO ２ R ｅｅ , -NR ｆｆ C(=O)N(R ｆｆ ) ２ , -C(=NR ｆｆ ) OR ｅｅ , -OC(=NR ｆｆ )R ｅｅ , -OC(=NR ｆｆ ) OR ｅｅ , -C(=NR ｆｆ )N(R ｆｆ ) ２ , -OC(=NR ｆｆ )N(R ｆｆ ) ２ , -NR ｆｆ C(=NR ｆｆ )N(R ｆｆ ) ２ , -NR ｆｆ SO ２ R ｅｅ , -SO ２ N(R ｆｆ ) ２ , -SO ２ R ｅｅ , -SO ２ OR ｅｅ , -OSO ２ R ｅｅ , -S(=O)R ｅｅ , -Si(R ｅｅ ) ３ , -OSi(R ｅｅ ) ３ , -C(=S)N(R ｆｆ ) ２ , -C(=O)SR ｅｅ , -C(=S)SR ｅｅ , -SC(=S)SR ｅｅ , -P(=O)(OR ｅｅ ) ２ , -P(=O)(R ｅｅ ) ２ , -OP(=O)(R ｅｅ ) ２ , -OP(=O)(OR ｅｅ ) ２ , C １～６ Alkyl, C １～６ Perhaloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, Hetero C １～６ Alkyl, Hetero C ２～６ Alkenyl, Hetero C ２～６ Alkynyl, C ３～１０ Carbocyclyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl, 5-10 membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ｇｇ or two geminal R ｄｄ The substituents may be taken together to form =O or =S; Each R ｅｅ is independently selected from: １～６ Alkyl, C １～６ Perhaloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, Hetero C １～６ Alkyl, Hetero C ２～６ Alkenyl, Hetero C ２～６ Alkynyl, C ３～１０ Carbocyclyl, C ６～１０ aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ｇｇ substituted with a group; Each R ｆｆ is independently selected from: hydrogen, C １～６ Alkyl, C １～６ Perhaloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, Hetero C １～６ Alkyl, Hetero C ２～６ Alkenyl, Hetero C ２～６ Alkynyl, C ３～１０ Carbocyclyl, 3- to 10-membered heterocyclyl, C ６～１０ Aryl and 5- to 10-membered heteroaryl, or two R ｆｆ The groups, taken together, form a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R ｇｇ substituted with a group; Each R ｇｇ are independently halogen, -CN, -NO ２ , -N ３ , -SO ２ H, -SO ３ H, -OH, -OC １～６ Alkyl, -ON(C １～６ Alkyl) ２ , -N(C １～６ Alkyl) ２ , -N(C １～６ Alkyl) ３ ＋ X - , -NH(C １～６ Alkyl) ２ ＋ X - , -NH ２ (C １～６ Alkyl) ＋ X - , -NH ３ ＋ X - , -N(OC １～６ Alkyl)(C １～６ alkyl), -N(OH)(C １～６ alkyl), -NH(OH), -SH, -SC １～６ Alkyl, -SS(C １～６ alkyl), -C(=O)(C １～６ alkyl), -CO ２ H, -CO ２ (C １～６ alkyl), -OC(=O)(C １～６ alkyl), -OCO ２ (C １～６ alkyl), -C(=O)NH ２ , -C(=O)N(C １～６ Alkyl) ２ , -OC(=O)NH(C １～６ alkyl), -NHC(=O)(C １～６ alkyl), -N(C １～６ Alkyl)C(=O)(C １～６ alkyl), -NHCO ２ (C １～６ alkyl), -NHC(=O)N(C １～６ Alkyl) ２ , -NHC(=O)NH(C １～６ alkyl), -NHC(=O)NH ２ , -C(=NH)O(C １～６ alkyl), -OC(=NH)(C １～６ alkyl), -OC(=NH)OC １～６ Alkyl, -C(=NH)N(C １～６ Alkyl) ２ , -C(=NH)NH(C １～６ alkyl), -C(=NH)NH ２ , -OC(=NH)N(C １～６ Alkyl) ２ , -OC(NH)NH(C １～６ alkyl), -OC(NH)NH ２ , -NHC(NH)N(C １～６ Alkyl) ２ , -NHC(=NH)NH ２ , -NHSO ２ (C １～６ alkyl), -SO ２ N(C １～６ Alkyl) ２ , -SO ２ NH(C １～６ alkyl), -SO ２ N.H. ２ , -SO ２ C １～６ Alkyl, -SO ２ O.C. １～６ Alkyl, -OSO ２ C １～６ Alkyl, -SOC １～６ Alkyl, -Si(C １～６ Alkyl) ３ , -OSi(C １～６ Alkyl) ３ , -C(=S)N(C １～６ Alkyl) ２ , C(=S)NH(C １～６ alkyl), C(=S)NH ２ , -C(=O)S(C １～６ Alkyl), -C(=S)SC １～６ Alkyl, -SC(=S)SC １～６ Alkyl, -P(=O)(OC １～６ Alkyl) ２ , -P(=O)(C １～６ Alkyl) ２ , -OP(=O)(C １～６ Alkyl) ２ , -OP(=O)(OC １～６ Alkyl) ２ , C １～６ Alkyl, C １～６ Perhaloalkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, Hetero C １～６ Alkyl, Hetero C ２～６ Alkenyl, Hetero C ２～６ Alkynyl, C ３～１０ Carbocyclyl, C ６～１０ aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R ｇｇ the substituents may be taken together to form =O or =S; and Each X - is a counter ion of the bottle brush polymer.

3. X is -N ３ 2. The compound according to claim 1, wherein:

4. X is a substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted, C ２～６ 2. The compound of claim 1, which is alkynyl, substituted or unsubstituted partially unsaturated carbocyclyl, or substituted or unsubstituted partially unsaturated heterocyclyl, or a salt thereof.

5. X is of the formula: 【Chemistry 10】 During the ceremony: Z is C(R Ｐ ) ２ or O; Each R Ｐ are independently hydrogen, halogen, or substituted or unsubstituted C １～６ is alkyl; 【Chemistry 11】 is a single or double bond; and 【Chemistry 12】 is Ring D, where Ring D is a substituted or unsubstituted monocyclic carbocyclic ring, a substituted or unsubstituted monocyclic heterocyclic ring, a substituted or unsubstituted monocyclic aryl ring, or a substituted or unsubstituted monocyclic heteroaryl ring; The compound according to claim 1 , or a salt thereof,

6. X is of the formula: 【Chemistry 13】 The compound according to claim 1 , or a salt thereof,

7. L １ is substituted or unsubstituted, C ２～３００ Alkylene, or substituted or unsubstituted, C ２～３００ heteroalkylene, where 0, 1, 2, or 3 main chain carbon atoms are independently replaced with a substituted or unsubstituted carbocyclene, a substituted or unsubstituted heterocyclene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; or L １ is substituted or unsubstituted, C １０～４０ Alkylene, or substituted or unsubstituted, C １０～４０ heteroalkylene, wherein at least one main chain carbon atom thereof is 【Chemistry 14】 has been replaced by The compound according to any one of claims 1 and 3 to 6, or a salt thereof.

8. L １ but, formula: 【Chemistry 15】 During the ceremony, n is an integer between 0 and 12, inclusive; k is an integer between 1 and 12, inclusive; L １ａ is independently substituted or unsubstituted, C １～２００ Alkylene, or substituted or unsubstituted, C ２～２００ heteroalkylene, where: Optionally, substituted or unsubstituted, C １～２００ Alkylene, and substituted or unsubstituted, C ２～２００ one or more main chain carbon atoms of the heteroalkylene are independently replaced with a substituted or unsubstituted carbocyclene, a substituted or unsubstituted heterocyclene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; L １ｂ is a substituted or unsubstituted C ２～２００ is a heteroalkyl, a nitrogen protecting group, or a polymer; and " ＊ " is attached to X, and the other attachment point is attached to ring A; The compound according to any one of claims 1 and 3 to 6, or a salt thereof, represented by the formula:

9. The compound according to claim 1, wherein L 1 is a group represented by the formula: 【Chemistry 16】 wherein L 1a is a substituted or unsubstituted C ２～２００ heteroalkylene, wherein substituted or unsubstituted, C ２～２００ One or more main chain carbon atoms of the heteroalkylene are independently 【Chemistry 17】 In the formula, " ＊＊ "teeth," ♯ " is attached near the nitrogen atom marked with " ＊＊＊ " is attached near ring A, The compound according to any one of claims 1 and 3 to 6, or a salt thereof.

10. L １ But the formula: 【Chemistry 18】 During the ceremony, n is an integer between 0 and 12, inclusive; k is an integer between 1 and 12, inclusive; j is an integer between 0 and 300, inclusive; and L １ａ is a substituted or unsubstituted C １～２００ Alkylene, or substituted or unsubstituted, C ２～２００ heteroalkylene, where: Optionally, substituted or unsubstituted, C １～２００ Alkylene, and substituted or unsubstituted, C ２～２００ One or more main chain carbon atoms of the heteroalkylene may be independently replaced with a substituted or unsubstituted carbocyclene, a substituted or unsubstituted heterocyclene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; and " ＊ " is attached to X, and the other attachment point is attached to ring A; Represented by The compound according to any one of claims 1 and 3 to 6, or a salt thereof.

11. L 1a is 【Chemistry 19】 During the ceremony: p is an integer from 1 to 12, inclusive; L C is a substituted or unsubstituted C １～１８０ is alkylene; -L Ｂ -L Ａ - is -C(=O)O-, -OC(=O)-, -C(=O)NR Ｅ -, -NR Ｅ C(=O)-, or a single bond, where R E is hydrogen, substituted or unsubstituted C １～６ alkyl, or nitrogen protecting group; and " ＊＊ "teeth" ＃ " is attached near the nitrogen atom marked with " ＊＊＊ " is attached near ring A, The compound according to any one of claims 8 to 10, or a salt thereof. Claim 12: L 1a is a compound of the formula: 【Chemistry 20】 During the ceremony: p is an integer between 1 and 12, inclusive; q is an integer between 1 and 12, inclusive; g is an integer between 0 and 12, inclusive; and " ＊＊ "teeth," ＃ " is attached near the nitrogen atom marked with " ＊＊＊ " is attached near ring A of formula (I), The compound according to any one of claims 8 to 11, or a salt thereof, represented by the formula:

13. 【Chemical 21】 but, 【Chemical 22】 13. The compound according to any one of claims 1 and 3 to 12, wherein

14. 【Catalogue 23】 but, 【Chemistry 24】 【Chemistry 25】 14. The compound according to claim 13, wherein:

15.

26. but, 【Chemistry 27】 【Chemistry 28】 or 【Chemical Formula 29】 but, 【Chemistry 30】 or 【Chemistry 31】 but, 【Chemistry 32】 wherein ring A and ring F are independently substituted or unsubstituted.

13. The compound according to any one of claims 1 and 3 to 12, or a salt thereof.

16. At least one R １ is unsubstituted, C １～６ is alkyl, The compound according to any one of claims 1, 3 to 13, and 15, or a salt thereof.

17. The compound or salt thereof according to claim 16, wherein R 1 is unsubstituted methyl.

18. At least one M is a radical of a therapeutic agent; 18. The compound according to any one of claims 1 and 3 to 17, or a salt thereof.

19. At least one M is a radical of a therapeutic agent that is an anticancer drug, and the anticancer drug is selected from the group consisting of abiraterone acetate, ado-trastuzumab emtansine, afatinib dimaleate, aldesleukin, alemtuzumab, anastrozole, arsenic trioxide, asparaginase erwinia chrysanthemumii, axitinib, azacytidine, belinostat, bendamustine hydrochloride, bevacizumab, bicalutamide, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib-s-malate, CAF, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, cetuximab, chlorambucil, cisplatin, clofarabine, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin hydrochloride, decitabine, degarelix, denileukin diftitox, denosumab, dinutuximab, docetaxel, doxorubicin hydrochloride, enzalutamide, epirubicin hydrochloride, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, exem Stan, fludarabine phosphate, fluorouracil, fulvestrant, gefitinib, gemcitabine hydrochloride, goserelin acetate, ibritumomab tiuxetan, ibrutinib, idelalisib, ifosfamide, imatinib mesylate, imiquimod, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotide acetate, lapatinib ditosylate, lenalidomide, lenvatinib, letrozole, leucovorin calcium, leuprolide acetate, lomustine, mechlorethamine hydrochloride, megestrol acetate, mercaptopurine , methotrexate, mitomycin C, mitoxantrone hydrochloride, nelarabine, nilotinib, nivolumab, obinutuzumab, ofatumumab, olaparib, omacetaxine mepescusate, oxaliplatin, paclitaxel, palbociclib, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, pegaspargase, peginterferon alfa-2b, pembrolizumab, pemetrexed disodium, pertuzumab, plerixafor, pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone,The compound or salt thereof according to any one of claims 1 and 3 to 17, selected from procarbazine hydrochloride, raloxifene hydrochloride, ramucirumab, recombinant interferon alpha-2b, regorafenib, rituximab, romidepsin, ruxolitinib phosphate, siltuximab, sorafenib tosylate, sunitinib malate, tamoxifen citrate, temozolomide, temsirolimus, thalidomide, thiotepa, topotecan hydrochloride, toremifene, tositumomab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine sulfate, vincristine sulfate, vinorelbine tartrate, vismodegib, vorinostat, ziv-aflibercept, and zoledronic acid.

20. The therapeutic, diagnostic, or prophylactic agent comprises a moiety containing boron, the therapeutic, diagnostic, or prophylactic agent having the formula: 【Chemical 33】 Corresponding to, 18. The compound according to any one of claims 1 and 3 to 17, or a salt thereof.

21. The compound of claim 20, wherein bortezomib has the formula: 【Chemical Formula 34】 21. The compound of claim 20, corresponding to:

22. 20. The compound or salt thereof according to any one of claims 1 and 3 to 19, wherein m is 1.

23. 20. The compound or salt thereof according to any one of claims 1 and 3 to 19, wherein m is 2 or 3.

24. Formula I is of the formula: 【Chemistry 35】 11. The compound according to claim 10, or a salt thereof, represented by:

25. Formula I is of the formula: 【Chemical 36】 During the ceremony: p is an integer from 1 to 12, inclusive; q is an integer from 1 to 12, inclusive; g is an integer from 0 to 12, inclusive; s is 0 or 1; t is an integer from 0 to 10, inclusive; and -L Ｂ -L Ａ - is -C(=O)O-, -OC(=O)-, -C(=O)NR Ｅ -, -NR Ｅ C(═O)—, or a single bond, where R E is hydrogen, substituted or unsubstituted C １～６ 11. The compound of claim 10, or a salt thereof, which is represented by an alkyl, or nitrogen protecting group, or a stereoisomer thereof.

26. The compound of formula (I) is as follows: 【Chemical 37】 2. The compound according to claim 1, or a salt thereof, which is represented by one of the following:

27. Formula (I) 【Chemical Formula 38】 2. The compound according to claim 1, wherein:

28. L １ But the formula: 【Chemical Formula 39】 The bottle brush polymer of claim 2 ,

29. L １ But the formula: 【Chemistry 40】 It is expressed as During the ceremony, L 1a is a substituted or unsubstituted C 2-200 heteroalkylene, wherein one or more main chain carbon atoms of the substituted or unsubstituted C 2-2000 heteroalkylene are independently 【Chemistry 41】 has been replaced by In the formula, "**" is attached near the nitrogen atom marked with "#", and "***" is attached near the ring A. The bottle brush polymer of claim 2.

30. The compound of claim 1, wherein L 1 is a group represented by the formula: 【Chemistry 42】 It is expressed as 3. The bottle brush polymer of claim 2, wherein j is an integer between 0 and 300, inclusive.

31. L １ａ but, 【Chemistry 43】 During the ceremony: p is an integer from 1 to 12, inclusive; L C is a substituted or unsubstituted C 1-180 alkylene; -L B -L A - is -C(=O)O-, -OC(=O)-, -C(=O)NR E -, -NR E C(=O)-, or a single bond, where R E is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group; and "**" is attached near the nitrogen atom marked with "#", and "***" is attached near the ring A. The bottle brush polymer of any one of claims 28 to 30, comprising:

32. The compound of claim 1, wherein L 1a is a group represented by the formula: 【Chemistry 44】 During the ceremony: p is an integer between 1 and 12, inclusive; q is an integer between 1 and 12, inclusive; g is an integer between 0 and 12, inclusive; and "**" is attached near the nitrogen atom marked with "#", and "***" is attached near ring A of formula (I); The bottle brush polymer of any one of claims 28 to 30, wherein the polymer is represented by the formula: 【Request 33】 【Chemical 45】 but, 【Chemistry 46】 That is, The bottle brush polymer of any one of claims 2 and 28-32. 【Request 34】 【Chemical 47】 but, 【Chemistry 48】 【Chemistry 49】 34. The bottle brush polymer of claim 33,

35. 【Catalysis 50】 but, 【Chemistry 51】 【Chemistry 52】 or 【Chemistry 53】 but, 【Chemical 54】 or 【Chemistry 55】 but, 【Chemistry 56】 and 33. The bottle brush polymer of claim 2 or any one of claims 28-32, wherein ring A and ring F are independently substituted or unsubstituted.

36. At least one R 1 is unsubstituted C 1-6 alkyl. The bottle brush polymer of any one of claims 2, 28-33, and 35.

37. The bottle brush polymer of claim 36, wherein R 1 is unsubstituted methyl.

38. A bottle brush polymer described in any one of claims 2 and 28 to 37, wherein at least one M is a radical of a therapeutic agent.

39. At least one M is a radical of a therapeutic agent that is an anticancer drug, and the anticancer drug is selected from the group consisting of abiraterone acetate, ado-trastuzumab emtansine, afatinib dimaleate, aldesleukin, alemtuzumab, anastrozole, arsenic trioxide, asparaginase erwinia chrysanthemumii, axitinib, azacytidine, belinostat, bendamustine hydrochloride, bevacizumab, bicalutamide, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib-s-malar t, CAF, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, cetuximab, chlorambucil, cisplatin, clofarabine, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin hydrochloride, decitabine, degarelix, denileukin diftitox, denosumab, dinutuximab, docetaxel, doxorubicin hydrochloride, enzalutamide, epirubicin hydrochloride, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, Exemestane, fludarabine phosphate, fluorouracil, fulvestrant, gefitinib, gemcitabine hydrochloride, goserelin acetate, ibritumomab tiuxetan, ibrutinib, idelalisib, ifosfamide, imatinib mesylate, imiquimod, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotide acetate, lapatinib ditosylate, lenalidomide, lenvatinib, letrozole, leucovorin calcium, leuprolide acetate, lomustine, mechlorethamine hydrochloride, megestrol acetate, mel Captopurine, methotrexate, mitomycin C, mitoxantrone hydrochloride, nelarabine, nilotinib, nivolumab, obinutuzumab, ofatumumab, olaparib, omacetaxine mepescusate, oxaliplatin, paclitaxel, palbociclib, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, pegaspargase, peginterferon alfa-2b, pembrolizumab, pemetrexed disodium, pertuzumab, plerixafor, pomalidomide, ponatinib hydrochloride, pralatrexate,38. The bottlebrush polymer of any one of claims 2 and 28 to 37, selected from prednisone, procarbazine hydrochloride, raloxifene hydrochloride, ramucirumab, recombinant interferon alpha-2b, regorafenib, rituximab, romidepsin, ruxolitinib phosphate, siltuximab, sorafenib tosylate, sunitinib malate, tamoxifen citrate, temozolomide, temsirolimus, thalidomide, thiotepa, topotecan hydrochloride, toremifene, tositumomab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine sulfate, vincristine sulfate, vinorelbine tartrate, vismodegib, vorinostat, ziv-aflibercept, and zoledronic acid.

40. The therapeutic, diagnostic, or prophylactic agent comprises a moiety that contains boron, wherein the therapeutic, diagnostic, or prophylactic agent has the formula: 【Chemistry 57】 Corresponding to, 38. The bottle brush polymer of any one of claims 2 and 28-37.

41. The compound of claim 1, wherein bortezomib has the formula: 【Chemistry 58】 41. The bottle brush polymer of claim 40, which corresponds to:

42. A bottle brush polymer described in any one of claims 2 and 28 to 39, wherein m is 1.

43. A bottle brush polymer described in any one of claims 2 and 28 to 39, wherein m is 2 or 3.

44. (i) X is a substituted or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted, C ２～６ 28. A method for preparing a bottlebrush polymer, comprising polymerizing a compound according to any one of claims 1 and 5 to 27, or a salt thereof, which is alkynyl, substituted or unsubstituted partially unsaturated carbocyclyl, or substituted or unsubstituted partially unsaturated heterocyclyl, in the presence of a metathesis catalyst.

45. Each repeat unit has the formula: 【Chemistry 59】 The bottle brush polymer of claim 2 ,

46. The bottle brush polymer of any one of claims 2, 28-43, and 45; and Pharmaceutically acceptable excipients A composition comprising:

47. 16. An in vitro method of delivering a therapeutic, diagnostic, or prophylactic agent to a biological sample, tissue, or cell, the method comprising contacting the biological sample, tissue, or cell with a bottle brush polymer described in any one of claims 2, 28-43, and 45, or a composition described in claim 46.

48. 47. The composition of claim 46 for use in delivering a therapeutic, diagnostic, or prophylactic agent to a subject, biological sample, tissue, or cell in need thereof.

49. 47. The composition of claim 46, wherein at least one M is a radical of a therapeutic agent, for use in treating a disease in a subject in need thereof.

50. 47. The composition of claim 46, wherein at least one M is a radical of a prophylactic agent, for use in preventing a disease in a subject in need thereof.

51. The disease is cancer and at least one M is selected from the group consisting of abiraterone acetate, ado-trastuzumab emtansine, afatinib dimaleate, aldesleukin, alemtuzumab, anastrozole, arsenic trioxide, asparaginase erwinia chrysanthemumii, axitinib, azacytidine, belinostat, bendamustine hydrochloride, bevacizumab, bicalutamide, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib-s-malate, CAF, capecitabine, Carboplatin, carfilzomib, carmustine, ceritinib, cetuximab, chlorambucil, cisplatin, clofarabine, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin hydrochloride, decitabine, degarelix, denileukin diftitox, denosumab, dinutuximab, docetaxel, doxorubicin hydrochloride, enzalutamide, epirubicin hydrochloride, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, exemestane, fludarabine phosphatase Sulfate, fluorouracil, fulvestrant, gefitinib, gemcitabine hydrochloride, goserelin acetate, ibritumomab tiuxetan, ibrutinib, idelalisib, ifosfamide, imatinib mesylate, imiquimod, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotide acetate, lapatinib ditosylate, lenalidomide, lenvatinib, letrozole, leucovorin calcium, leuprolide acetate, lomustine, mechlorethamine hydrochloride, megestrol acetate, mercaptopurine, methotrexate, ma Itomycin C, mitoxantrone hydrochloride, nelarabine, nilotinib, nivolumab, obinutuzumab, ofatumumab, olaparib, omacetaxine mepescusate, oxaliplatin, paclitaxel, palbociclib, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, pegaspargase, peginterferon alpha-2b, pembrolizumab, pemetrexed disodium, pertuzumab, plerixafor, pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone, procarbazine hydrochloride,The composition for use according to claim 49 or 50, wherein the radical of the anticancer drug is selected from raloxifene hydrochloride, ramucirumab, recombinant interferon alpha-2b, regorafenib, rituximab, romidepsin, ruxolitinib phosphate, siltuximab, sorafenib tosylate, sunitinib malate, tamoxifen citrate, temozolomide, temsirolimus, thalidomide, thiotepa, topotecan hydrochloride, toremifene, tositumomab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine sulfate, vincristine sulfate, vinorelbine tartrate, vismodegib, vorinostat, ziv-aflibercept, and zoledronic acid.

52. 47. The composition of claim 46, wherein at least one M is a radical of a diagnostic agent, for use in diagnosing a disease in a subject in need thereof.

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