Polymers with steroids or vitamins

Abstract

Disclosed is a compound useful as a biologically active compound, said compound having the following structure (I): JPEG2025531423000122.jpg43170 or a stereoisomer, tautomer, or salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , M 1 , M 2 , p, q, m, and n are as defined in this disclosure. The compounds of structure (I) are useful in many applications, including use as therapeutic agents in various methods of treatment.

Description

[Technical Field]

[0001] (Field) FIELD OF THE DISCLOSURE Embodiments of the present disclosure generally relate to polymeric biologically active compounds having steroids or vitamins and methods for making the same. [Background technology]

[0002] Description of Related Art Targeted drug conjugates deliver drugs to target cells and exhibit little or no off-target activity, unlike chemotherapy, for example. Typically, targeted drug conjugates contain a targeting molecule attached to a biologically active payload or drug. By combining unique targeting capabilities with the therapeutic effects of the biologically active drug (or moiety), the conjugate can deliver the drug only to the intended target and minimize potential side effects. Antibody-drug conjugates (ADCs) are one type of targeted drug conjugate and are of particular interest for the treatment of various diseases. While ADCs for cancer treatment are becoming common, ADCs for other uses are in their infancy. Thus, there is a need in the art to develop potent targeted drug conjugates, and methods for their preparation, that have high therapeutic indices beyond oncology. The present disclosure fulfills this need and provides further related advantages. Summary of the Invention

[0003] In one embodiment, a compound is provided having the following structure (I): [ka] or a stereoisomer, tautomer, or salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , M1 , M 2 , p, q, m, and n are as defined herein. The compounds of structure (I) are useful in a number of applications, including as therapeutic agents for a variety of treatment methods.

[0004] In another embodiment, a composition is provided that comprises a compound of structure (I) and a pharmaceutically acceptable carrier. In yet another embodiment, there is provided a method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structure (I) or a composition comprising a compound of structure (I), wherein each M 2 is independently a biologically active moiety and is effective for treating the above diseases. These and other aspects of the present disclosure will become evident upon reference to the following detailed description.

[0005] (Detailed explanation) In the following description, some specific details are set forth to provide a thorough understanding of various embodiments of the present disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these details. Unless the context requires otherwise, throughout this specification and the claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in their open and inclusive sense, i.e., "including, but not limited to."

[0006] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0007] "Amino" refers to the -NH2 group. "Carboxy" refers to the group -CO2H. "Cyano" refers to the group --CN. "Formyl" refers to the group -C(=O)H. "Hydroxy" or "hydroxyl" refers to the --OH group. "Imino" refers to the =NH group. "Nitro" refers to the -NO2 group. "Oxo" refers to the =O substituent. "Sulfhydryl" refers to the -SH group. "Thioxo" refers to the ═S group. "Alkyl" refers to a linear or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having 1 to 12 carbon atoms (C1-C 12alkyl), 1 to 8 carbon atoms (C1-C8 alkyl), or 1 to 6 carbon atoms (C1-C6 alkyl) and attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless specifically stated otherwise in this disclosure, alkyl groups are optionally substituted.

[0008] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group, consists solely of carbon and hydrogen, is free of saturation, and has 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule by a single bond and to the radical group by a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise in this disclosure, alkylenes are optionally substituted.

[0009] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group, consists solely of carbon and hydrogen, contains at least one carbon-carbon double bond, and has 2 to 12 carbon atoms, such as ethenylene, propenylene, and n-butenylene. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double or single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise in this disclosure, alkenylenes are optionally substituted.

[0010] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group, consists solely of carbon and hydrogen, contains at least one carbon-carbon triple bond, and has 2 to 12 carbon atoms, such as ethynylene, propynylene, n-butynylene, and the like. The alkynylene chain is connected to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise in the disclosure, alkynylene is optionally substituted.

[0011] "Alkylether" refers to any alkyl group, as defined above, in which at least one carbon-carbon bond is replaced with a carbon-oxygen bond. The carbon-oxygen bond can be terminal (as in an alkoxy group), or the carbon-oxygen bond can be internal (i.e., COC). An alkyl ether contains at least one carbon-oxygen bond, but can contain multiple. For example, polyethylene glycol (PEG) is included within the meaning of alkyl ether. Unless otherwise specifically stated in this disclosure, alkyl ether groups are optionally substituted. For example, in some embodiments, an alkyl ether can be replaced with an alcohol or -OP(=R a )(R b )R c where R a , R b , and R c are defined for compounds of structure (I).

[0012] "Alkoxy" means a group of the formula -OR a refers to a group, wherein R a is an alkyl group, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in this disclosure, alkoxy groups are optionally substituted. "Alkoxyalkylether" means an alkyl group of the formula -OR a Rb refers to a group, wherein R a is an alkylene group as defined above containing 1 to 12 carbon atoms, and R b is an alkyl ether group as defined herein. Unless otherwise specifically stated in this disclosure, an alkoxyalkyl ether group may be optionally substituted, for example, an alcohol or -OP(=R a )(R b )R c wherein R a , R b and R c are defined for compounds of structure (I).

[0013] "Heteroalkyl" refers to an alkyl group, as defined above, that contains at least one heteroatom (e.g., N, O, P, or S) within or at a terminus of the alkyl group. In some embodiments, the heteroatom is within the alkyl group (i.e., the heteroalkyl contains at least one carbon-[heteroatom] x -carbon bond, where x is 1, 2, or 3. In other embodiments, the heteroatom is at the end of the alkyl group, thus connecting the alkyl group to the remainder of the molecule (e.g., M1-HA), where M1 is a portion of the molecule, H is a heteroatom, and A is an alkyl group. Unless otherwise specifically stated in this disclosure, heteroalkyl groups are optionally substituted. Exemplary heteroalkyl groups include ethylene oxide (e.g., polyethylene oxide), optionally containing a phosphorus-oxygen bond, e.g., a phosphodiester bond.

[0014] "Heteroalkoxy" refers to a group of the formula -OR a refers to a group, wherein R a is a heteroalkyl group, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in this disclosure, heteroalkoxy groups are optionally substituted.

[0015] "Heteroalkylene" refers to an alkylene group, as defined above, that includes at least one heteroatom (e.g., Si, N, O, P, or S) within the alkylene chain or at a terminus of the alkylene chain. In some embodiments, the heteroatom is within the alkylene chain (i.e., the heteroalkylene includes at least one carbon-[heteroatom]-carbon bond, where x is 1, 2, or 3). In other embodiments, the heteroatom is at the terminus of the alkylene, thereby connecting the alkylene to the remainder of the molecule (e.g., M 1 -HAM 2 , where M 1 and M 2 is a part of the above molecule, H is a heteroatom, and A is alkylene. Unless stated otherwise specifically in this disclosure, heteroalkylene groups are optionally substituted. Exemplary heteroalkylene groups include ethylene oxide (e.g., polyethylene oxide) and the "C," "HEG," and "PEG 1K" linking groups shown below. [ka]

[0016] Various embodiments of heteroalkylene linkers include multimers of the above C-linkers, HEG linkers, and / or PEG 1K linkers. In some embodiments of the above PEG 1K linkers, n ranges from 19 to 25, e.g., n is 19, 20, 21, 22, 23, 24, or 25. Multimers can include, for example, the following structures: [ka] In the formula, x is 0 or an integer greater than 0, for example, x ranges from 0 to 100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0017] "Linker" refers to a contiguous chain of at least one atom, e.g., carbon, oxygen, nitrogen, sulfur, phosphorus, and combinations thereof, that connects one portion of a molecule to another portion of the same molecule, or to a different molecule, moiety, or solid support (e.g., a microparticle). The linker may connect the molecules by a covalent bond or other means, e.g., ionic or hydrogen bonding interactions. In some embodiments, the linker is a heteroatom linker (e.g., containing 1-10 Si, N, O, P, or S atoms), a heteroalkylene (e.g., containing 1-10 Si, N, O, P, or S atoms and an alkylene chain), or an alkylene linker (e.g., containing 1-12 carbon atoms). In some embodiments, the heteroalkylene linker comprises the following structure: [ka] During the ceremony, x 9 and x 10 are each independently an integer greater than 0. In some embodiments, the heteroatom linker is -O-, -S-, or -OP(=O)O - In some embodiments, the heteroalkylene linker is —OP(═O)O - In some embodiments, the heteroalkylene linker comprises at least one S—S bond.

[0018] A "physiologically cleavable linker" refers to a molecular linkage that can be split or separated in a predetermined manner, such as into two or more molecules, in the in vivo or in vitro environment of a tissue or cell system. Generally, physiological conditions that induce such cleavage or scission can include a temperature of about 20-40°C, an atmospheric pressure of about 1 atm (101 kPa or 14.7 psi), a pH of about 5-8, a glucose concentration of about 1-20 mM, atmospheric oxygen concentration, and Earth's gravity. In some embodiments, physiological conditions include enzymatic conditions (i.e., enzymatic cleavage activated by cathepsins). Bond cleavage or scission can be homolytic or heterolytic.

[0019] "Heteroalkenylene" refers to heteroalkylene, as defined above, containing at least one carbon-carbon double bond. Unless stated otherwise specifically in this disclosure, heteroalkenylene groups are optionally substituted. "Heteroalkynylene" is a heteroalkylene that contains at least one carbon-carbon triple bond. Unless stated otherwise specifically in the present disclosure, heteroalkynylene groups are optionally substituted.

[0020] "Heteroatomic," in reference to a "heteroatomic linker," refers to a linker group consisting of one or more heteroatoms. Exemplary heteroatomic linkers include single atoms selected from the group consisting of O, N, P, and S, and multiple heteroatoms, e.g., linkers having the formula -P(O-)(=O)O- or -OP(O-)(=O)O-, as well as multimers and combinations thereof.

[0021] "Phosphate" is -OP(=O)(R a )R b refers to a group, wherein R ais OH, O-, or OR c and R b OH, O-, OR c , thiophosphate, or further phosphate groups, where R c is the counter ion (e.g., Na + etc.). "Phosphoalkyl" refers to -OP(=O)(R a )R b R a is OH, O-, or OR c and R b is -Oalkyl, where R c is the counter ion (e.g., Na + Unless otherwise specifically stated in this disclosure, phosphate alkyl groups are optionally substituted. For example, in some embodiments, the -Oalkyl portion of the phosphoalkyl group is replaced with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, thiophosphoalkylether, or -OP(=R a )(R b )R c wherein R a , R b , and R c are defined for compounds of structure (I).

[0022] "Phosphoalkylether" is -OP(=O)(R a )R b refers to a group, wherein R a is OH, O-, or OR c and R b is an -O alkyl ether, where R c is the counter ion (e.g., Na +etc.) Unless otherwise specifically stated in this disclosure, phosphoalkyl ether groups are optionally substituted. For example, in some embodiments, the -O alkyl ether portion of the phosphoalkyl ether group is optionally substituted with one or more hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, thiophosphoalkyl ether, or -OP(=R a )(R b )R c where R a , R b , and R c are defined for compounds of structure (I).

[0023] "Thiophosphate" is -OP(=R a )(R b )R c refers to a group, wherein R a is O or S, and R b OH, O-, S-, OR d , or SR d and R c OH, SH, O-, S-, OR d , S.R. d , a phosphate group, or a further thiophosphate group, where R d is the counter ion (e.g., Na + etc.), and only if the following conditions are met:(1)R a is S; (2) R b is S- or SR d (3) R c is SH, S-, or SR d or (4) a combination of (1), (2), and / or (3).

[0024] "Thiophosphoalkyl" is -OP(=R a )(R b )R c refers to a group, wherein R a is O or S, and R b OH, O-, S-, ORd , or SR d and R c is -Oalkyl, where R d is the counter ion (e.g., Na + etc.), and only if the following conditions are met:(1)R a is S; (2) R b is S- or SR d or (3) R a is S and R b is S- or SR d Unless otherwise specifically stated in the present disclosure, thiophosphoalkyl groups are optionally substituted. For example, in some embodiments, the -Oalkyl portion of the thiophosphoalkyl group is optionally substituted with one or more hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, thiophosphoalkylether, or -OP(=R a )(R b )R c where R a , R b , and R c are defined for compounds of structure (I).

[0025] "Thiophosphoalkylether" is -OP(=R a )(R b )R c refers to a group, wherein R a is O or S, and R b OH, O-, S-, OR d , or SR d and R c is an -O alkyl ether, where R d is the counter ion (e.g., Na + etc.), provided that the following conditions are met: (1) R a is S; (2) R b is S- or SR d or (3) R a is S and R b is S- or SR dUnless otherwise specifically stated in this disclosure, thiophosphoalkyl ether groups are optionally substituted. For example, in some embodiments, the -O alkyl ether portion of the thiophosphoalkyl group is optionally substituted with one or more hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, thiophosphoalkyl ether, or -OP(=R a )(R b )R c where R a , R b , and R c are each defined for compounds of structure (I).

[0026] "Carbocyclic" refers to a stable 3- to 18-membered aromatic or non-aromatic ring containing 3 to 18 carbon atoms. Unless otherwise stated in this disclosure, a carbocyclic ring may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems and may be partially or fully saturated. Non-aromatic carbocyclyl radicals include cycloalkyl, and aromatic carbocyclyl radicals include aryl. Unless otherwise stated in this disclosure, carbocyclic groups are optionally substituted.

[0027] "Cycloalkyl" refers to a stable non-aromatic mono- or polycyclic carbocyclic ring, which may include fused or bridged ring systems, having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, saturated or unsaturated, and attached to the remainder of the molecule by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo-[2.2.1]heptanyl, and the like. Unless stated otherwise specifically in this disclosure, cycloalkyl groups are optionally substituted.

[0028] "Aryl" refers to a ring system containing at least one carbocyclic aromatic ring. In some embodiments, an aryl contains 6 to 18 carbon atoms. The aryl ring can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused or bridged ring systems. Aryl includes, but is not limited to, aryl, which is derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise stated in this disclosure, aryl groups are optionally substituted.

[0029] "Heterocyclic" refers to a stable 3- to 18-membered aromatic or non-aromatic ring containing 1 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless otherwise specified in this disclosure, the heterocyclic ring can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocyclic ring can be optionally oxidized, the nitrogen atom can be optionally quaternized, and the heterocyclic ring can be partially or fully saturated. Examples of aromatic heterocyclic rings are listed below in the definition of heteroaryl (i.e., heteroaryl is a subset of heterocyclic). Examples of non-aromatic heterocyclic rings include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, pyrazolopyrimidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in this disclosure, heterocyclic groups are optionally substituted.

[0030] "Heteroaryl" refers to a 5- to 14-membered ring system containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For purposes of some embodiments of the present disclosure, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atom within the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl, benzimidazolthionyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indo Rizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinonyl, pyrazinyl, pyri Examples of heteroaryl groups include pyrimidinyl, pyrimidinonyl, pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinonyl, quinazolinyl, quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, heteroaryl groups are optionally substituted.

[0031] The suffix "-ene" refers to a particular structural feature (e.g., alkyl, aryl, heteroalkyl, heteroaryl) that is attached to the rest of the molecule by a single bond and to the radical group through a single bond. In other words, the suffix "-ene" refers to a linker that possesses the structural features of the moiety to which it is attached. The points of attachment of the "-ene" chain to the rest of the molecule and to the radical group can be through one atom or any two atoms within the chain. For example, heteroarylene refers to a linker and includes a heteroaryl moiety as defined herein.

[0032] "Fused" refers to a ring system containing at least two rings, wherein the two rings share at least one common ring atom, for example, two common ring atoms. When the fused ring is a heterocyclic or heteroaryl ring, the common ring atom can be carbon or nitrogen. Fused rings include bicyclic, tricyclic, tetracyclic, etc.

[0033] As used herein, "substituted" means replacing at least one hydrogen atom (e.g., 1, 2, 3, or all hydrogen atoms) with a non-hydrogen atom by a bond in any of the above groups (e.g., alkyl, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, alkoxy, alkyl ether, phosphoalkyl, phosphoalkyl ether, thiophosphoalkyl, thiophosphoalkyl ether, carbocycle, cycloalkyl, aryl, heterocyclic, and / or heteroaryl), including, but not limited to, is replaced by a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl, alkoxy, and ester groups; a sulfur atom in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; a nitrogen atom in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; a silicon atom in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also means that one or more hydrogen atoms of any of the above groups are replaced by a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups, through a higher bond (e.g., a double bond or a triple bond), such as the nitrogen atom in groups such as imine, oxime, hydrazone, and nitrile groups. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms have been replaced with -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g, -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , and -SO2NR g R h "Substituted" also refers to replacing one or more hydrogen atoms in any of the above groups with -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h This means exchanging it for the aforementioned R g and R h are the same or different and independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further refers to the replacement of one or more hydrogen atoms in any of the above groups by a bond with an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl group. In addition, each of the foregoing substituents may be optionally substituted with one or more of the above substituents.

[0034] "Conjugation" refers to the overlap of one p orbital with another p orbital across an intervening σ bond. Conjugation can occur in cyclic or acyclic compounds. "Degree of conjugation" refers to the overlap of at least one p orbital with another p orbital across an intervening σ bond. For example, 1,3-butadiene has one degree of conjugation, while benzene and other aromatic compounds typically have multiple degrees of conjugation. Fluorescent and colored compounds typically contain at least one degree of conjugation.

[0035] "Fluorescent" refers to a molecule that can absorb light of a particular frequency and emit light of a different frequency. Fluorescence is well known to those skilled in the art. "Colored" refers to molecules that absorb light in the color spectrum (ie, red, yellow, blue, etc.).

[0036] The term "biomolecule" refers to any of a variety of biological materials, including nucleic acids, carbohydrates, amino acids, polypeptides, glycoproteins, hormones, aptamers, and mixtures thereof. More specifically, the term is intended to include, without limitation, RNA, DNA, oligonucleotides, modified or derivatized nucleotides, enzymes, receptors, prions, receptor ligands (including hormones), antibodies, antigens, and toxins, as well as bacteria, viruses, blood cells, and tissue cells. A visually detectable biomolecule of the present disclosure (e.g., a compound of structure (I) having a biomolecule attached thereto) is prepared by contacting the biomolecule with a compound having a reactive group, as further described herein, allowing the biomolecule to be attached to the compound via any available atom or functional group, such as an amino group, a hydroxyl group, a carboxyl group, or a sulfhydryl group, of the biomolecule.

[0037] A "reactive group" is a moiety that can react with a second reactive group (e.g., a "complementary reactive group") to form one or more covalent bonds, for example, by substitution, oxidation, reduction, addition, or cycloaddition reactions. Exemplary reactive groups are provided in Table 1 and include, for example, nucleophiles, electrophiles, dienes, dienophiles, aldehydes, oximes, hydrazones, alkynes, amines, azides, acyl azides, acyl halides, nitriles, nitrones, sulfhydryls, disulfides, sulfonyl halides, isothiocyanates, imidoesters, active esters, ketones, α,β-unsaturated carbonyls, alkenes, maleimides, α-haloamides, epoxides, azirisines, tetrazines, tetrazoles, phosphines, biotin, thiirane, and the like.

[0038] "Bio-conjugation" or "bio-conjugate" and related variations refer to a chemical reaction strategy that forms a stable covalent bond between two molecules. The term "bio-conjugation" is generally used when one of the molecules is a biological molecule (e.g., an antibody), but can also be used to describe the formation of covalent bonds with non-biological molecules (e.g., polymeric resins). The resulting product or compound of such a reaction strategy is a "conjugate," "bio-conjugate," or grammatical equivalents thereof.

[0039] The terms "visible" and "visually detectable," as used herein, refer to substances that can be observed by visual inspection without prior illumination or chemical or enzymatic activation. Such visually detectable substances absorb and emit light in the spectral region ranging from about 300 to about 900 nm. Preferably, such substances are strongly colored, and preferably have a molar extinction coefficient of at least about 40,000, more preferably at least about 50,000, even more preferably at least about 60,000, even more preferably at least about 70,000, and most preferably at least about 80,000 M. -1 cm -1 The compounds of the present disclosure may be detected by visual observation or using optical detection devices, including, but not limited to, absorption spectrophotometers, penetrant light microscopes, digital cameras, and scanners. Visually detectable substances are not limited to substances that emit and / or absorb light within the visible spectrum. Also included within the scope of "visually detectable" substances are substances that emit and / or absorb light in the ultraviolet (UV) region (about 10 nm to about 400 nm), the infrared (IR) region (about 700 nm to about 1 mm), and other regions of the electromagnetic spectrum.

[0040] For purposes of embodiments of the present disclosure, the term "photostable visible dye" refers to a chemical moiety that is visually detectable, as defined above, and that does not significantly change or decompose upon exposure to light. Preferably, the photostable visible dye does not exhibit significant bleaching or decomposition after at least one hour of exposure to light. More preferably, the visible dye is stable after at least 12 hours of exposure to light, even more preferably at least 24 hours, even more preferably at least one week, and most preferably at least one month. Non-limiting examples of photostable visible dyes suitable for use in the compounds and methods of the present disclosure include azo dyes, thioindigo dyes, quinacridone pigments, dioxazines, phthalocyanines, perinones, diketopyrrolopyrroles, quinophthalones, and truarycarboniums.

[0041] As used herein, the term "perylene derivative" is intended to include any visually detectable substituted perylene. However, the term is not intended to include perylene itself. The terms "anthracene derivative," "naphthalene derivative," and "pyrene derivative" are also used. In some preferred embodiments, the derivative (e.g., a perylene, pyrene, anthracene, or naphthalene derivative) is an imide, bisimide, or hydrazamimide derivative of perylene, anthracene, naphthalene, or pyrene.

[0042] The visually detectable molecules of various embodiments of the present disclosure are useful in a variety of analytical applications, including biochemical and biomedical applications, in which the presence, location, or quantity of a specific analyte (e.g., a biomolecule) needs to be determined. In another aspect, the present disclosure therefore provides methods for visually detecting biomolecules, including: (a) providing a biological system having a visually detectable biomolecule, the method comprising the compound of structure (I) bound to the biomolecule; and (b) detecting the biomolecule by its visible properties. For purposes of this disclosure, the phrase "detecting the biomolecule by its visible properties" refers to observing the biomolecule with the naked eye or using an optical detection device, including, but not limited to, an absorption spectrophotometer, an osmotic light microscope, a digital camera, and a scanner, without illumination or chemical or enzymatic activation. A densitometer may quantify the abundance of a visually detectable biomolecule. For example, the relative amounts of biomolecules in two samples can be determined by measuring their relative optical densities. If the stoichiometry of dye molecules per biomolecule is known, and if the extinction coefficients of the dye molecules are known, the absolute concentrations of the biomolecules can also be determined from optical density measurements. As used herein, the term "biological system" refers to any solution or mixture containing one or more biomolecules in addition to the visually detectable biomolecules described above. Non-limiting examples of such biological systems include cells, cell extracts, tissue samples, electrophoresis gels, assay mixtures, and hybridization reaction mixtures.

[0043] "Solid support" or "solid resin" refers to any solid substrate known in the art as a solid phase support for molecules; for example, "microparticle" refers to any of several small particles useful for attaching compounds of the present disclosure, including, but not limited to, glass beads, magnetic beads, polymeric beads, non-polymeric beads, etc. In some embodiments, the microparticle comprises a polystyrene bead. In some embodiments, the solid support or solid resin is controlled pore glass or large pore polystyrene. "Solid support residue" refers to a functional group that remains attached to a molecule when the molecule is cleaved from the solid support. Solid support residues are known in the art and can be readily derived based on the structure of the solid support and the group linking the molecule.

[0044] A "targeting moiety" refers to a moiety that selectively binds to or associates with a specific target, e.g., an analyte molecule. "Selectively" binding or associating means that the targeting moiety preferentially binds to or associates with the desired target compared to other targets. In some embodiments, compounds of the present disclosure include a linkage to a targeting moiety for the purpose of selectively binding to or associating with an analyte of interest (i.e., the target of the targeting moiety), thereby enabling detection of the analyte. Exemplary targeting moieties include, but are not limited to, antibodies, antigens, nucleic acid sequences, enzymes, proteins, cell surface receptor antagonists, and the like. In some embodiments, the targeting moiety is a moiety, such as an antibody, that selectively binds to or associates with a target feature on or within a cell, e.g., a target feature on a cell membrane or other cellular structure, thereby enabling detection of the cell of interest. Small molecules that selectively bind to or associate with a desired analyte are also considered targeting moieties in some embodiments. Those of skill in the art will recognize that other analytes and corresponding targeting moieties are useful in various embodiments.

[0045] "Base pairing moiety" refers to a heterocyclic moiety that can hybridize with a complementary heterocyclic moiety via hydrogen bonding (e.g., Watson-Crick base pairing). Base pairing moieties include natural and unnatural bases. Non-limiting examples of base pairing moieties include RNA and DNA bases, such as adenosine, guanosine, thymidine, cytosine, and uridine, and analogs thereof.

[0046] Embodiments of the present disclosure are also intended to encompass all isotope-labeled compounds, which are labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as:2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I.

[0047] Isotopically labeled compounds of structure (I) may generally be prepared by conventional techniques known to those skilled in the art, or may be prepared by processes similar to those described below and in the ensuing examples, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0048] "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust that it can be isolated to a useful degree of purity from a reaction mixture and formulated into an efficacious therapeutic agent. "Optional" or "optionally" means that the event or circumstance described below may or may not occur, and the statement includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" includes cases where the alkyl group is substituted and cases where it is not substituted, and the statement is meant to include both substituted and unsubstituted alkyl groups.

[0049] "Salt" includes both acid addition salts and base addition salts. "Acid addition salt" refers to salts formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, oxalic acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoside, methylparaben ... Heptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippoic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0050] "Base addition salt" refers to a salt prepared by adding an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, salts of substituted amines, including naturally occurring substituted amines, salts of cyclic amines, and salts of basic ion exchange resins, such as salts of ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, pipericine, N-ethylpipericine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0051] Crystallization may produce solvates of the compounds described in this disclosure. Embodiments of the present disclosure include all solvates of the compounds described above. As used herein, the term "solvate" refers to an aggregate containing one or more compounds of the present disclosure with one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, compounds of the present disclosure may exist as hydrates, including monohydrates, dihydrates, hemihydrates, pentadecahydrates, trihydrates, tetrahydrates, etc., as well as the corresponding solvates. While compounds of the present disclosure may be true solvates, in other cases, compounds of the present disclosure may only retain incidental water or other solvents, or may be a mixture of water and some incidental solvents.

[0052] Embodiments of the disclosed compounds (e.g., compounds of structure I), or salts, tautomers, or solvates thereof, may contain one or more stereocenters and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or, in the case of amino acids, (D)- or (L)-. Embodiments of the disclosed invention are meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthesizers or chiral reagents or separated using conventional techniques, such as chromatography and fractional crystallization. Preparation / separation of individual enantiomers by conventional techniques includes chiral synthesis from suitable optically pure precursors, or separation of the racemate (or racemate of a salt or derivative), using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both the E and Z geometric isomers, as well as all tautomeric forms.

[0053] "Stereoisomer" refers to compounds composed of the same atoms and connected by the same bonds, but with different three-dimensional structures, and are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other. A "tautomer" refers to a proton migration from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the compounds. Various tautomeric forms of the compounds described above can be readily derived by one skilled in the art.

[0054] "Steroid" refers to a biologically active organic compound having a four-fused ring arrangement. The steroid core structure contains three six-membered cyclohexane rings (i.e., rings A, B, and C) and one five-membered cyclopentane ring. Steroids vary by the functional groups attached to the core structure and the oxidation state of the rings. For example, the 3-position of ring A of the steroid can be a hydroxyl group (e.g., cholesterol, cholic acid, lanosterol, and β-sitosterol) or a carbonyl (-C=O) group (e.g., testosterone, dexamethasone, progesterone, and medrogestone). Examples of steroids for use in some embodiments include cholesterol, cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or beclomethasone.

[0055] "Vitamin" refers to a group of organic compounds that are essential for normal growth and nutrition and are required in small amounts in the diet because they cannot be synthesized in the body. Such compounds include vitamins A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E, and K. Vitamin E is a fat-soluble compound and includes four tocopherols and four tocotrienols. The core structure of vitamin E contains 3,4-dihydro-2H-1-benzopyran. The difference in chemical structure between tocotrienols and tocopherols is that tocotrienols have an unsaturated isoprenoid side chain with three carbon-carbon double bonds separated from the 3,4-dihydro-2H-1-benzopyran core structure, while tocopherols have a saturated isoprenoid side chain. Both tocotrienols and tocopherols have four structural isomers, which include α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol.

[0056] "Amino acid side chain" or "side chain" refers to a substituent attached to the α-carbon, β-carbon, or γ-carbon of an amino acid. Amino acid side chains can be those associated with natural or unnatural amino acids. "Amino acid sequence" or "peptide sequence" refers to the primary structure of amino acid residues, linked along a backbone formed by peptide bonds. The sequence is generally listed from N-terminus to C-terminus. Embodiments of the present disclosure include compounds containing partial amino acid sequences listed. Amino acid sequences are listed by three-letter or one-letter abbreviations where appropriate.

[0057] "Letter code," "1-letter code," or "3-letter code" refers to the representation or abbreviation of an amino acid or amino acid residue in an amino acid sequence. A general list of 1-letter and 3-letter codes and the corresponding amino acids is provided below. [Table 1]

[0058] "Beta sheet," "β-sheet," "beta-pleated sheet," or "β-pleated sheet" refers to the secondary structure of an amino acid sequence, a structure formed by intramolecular folding. The amino acid chain is laterally connected by hydrogen bonds, typically forming a twisted pleated sheet. The amino acid chain forming this secondary structure is typically 3 to 10 amino acid residues in length. The present disclosure includes amino acid sequences containing amino acid residues that have a tendency to form beta sheets, where a beta sheet portion is designated. Such residues include, but are not limited to, glycine, methionine, serine, valine, tyrosine, phenylalanine, tryptophan, threonine, and isoleucine.

[0059] "Alpha helix" or "α-helix" refers to the secondary structure of an amino acid chain, which is formed by intramolecular folding to form a helical structure in which the backbone NH group donates a hydrogen bond to the backbone C=O group of the amino acid four residues prior. The arrangement of amino acid side chains influences the formation of the alpha-helical structure. The present disclosure includes amino acid sequences containing residues with helix-forming propensity, whereby an alpha-helical portion is designated. Such residues include, but are not limited to, glycine, methionine, alanine, arginine, histidine, leucine, glutamate, glutamic acid, phenylalanine, valine, tyrosine, and lysine.

[0060] The chemical naming protocol and structure diagrams used in this disclosure are a modification of the IUPAC nomenclature system and use the ACD / Name Version 9.07 software program and / or the ChemDraw Ultra Version 11.0 software naming program (CambridgeSoft). Common names familiar to those skilled in the art are also used.

[0061] (compound) As noted above, in one embodiment of the present disclosure, compounds are provided that are useful as covalent linkers between biologically active moieties, such as steroids and / or vitamins, and targeting moieties. Thus, in some embodiments, M 1 is, at each occurrence, independently a moiety containing a fluorescent or colored dye, and M 2 is, independently at each occurrence, a moiety that contains a biologically active moiety, provided that M 2 is a steroid or a vitamin. In some embodiments, M 2 is a steroid or vitamin (e.g., cholesterol, tocopherol, etc.), M 1 is a fluorescent dye (e.g., fluorescein, etc.).

[0062] The embodiments of the present disclosure offer many advantages, including the ability to bind biologically active moieties M attached to a polymer backbone and any subsequent targeting moieties. 2 the number and type of biologically active moieties, the spacing between adjacent biologically active moieties on the polymer backbone (e.g., biologically active moieties M 2 These include the ability to control the distance between the polymer backbone and the biologically active moiety (e.g., how far apart or close together the polymer backbone is) and the spacing between the polymer backbone and the biologically active moiety (e.g., the length of the linker separating the polymer backbone).

[0063] The biologically active moieties can be attached to the polymer backbone by physiologically cleavable or non-cleavable linkers. The procedures described in this disclosure provide the ability to selectively introduce physiologically cleavable and / or non-cleavable linkers. This allows for the synthesis of both physiologically cleavable and non-cleavable linkers bearing one or more biologically active moieties. In this regard, the biologically active moieties can be sequentially cleaved in response to physiological conditions. Furthermore, compounds can be synthesized in which both multiple biologically active moieties and fluorescent moieties are attached by physiologically cleavable and / or non-cleavable linkers.

[0064] Some embodiments of the present disclosure provide combinations of therapeutic agents, targeting moieties, and dye moieties (e.g., chromophores or fluorophores), which can be used for simultaneous targeting, treatment, and detection. The ease of coupling polymer-drug constructs to targeting agents, such as antibodies, antibody fragments, proteins, or other clinically interesting drugs, provides utility for a wide range of interesting applications (e.g., surface chemistry, assay development, etc.). Thus, in some embodiments, M 1 is a fluorophore (e.g., FITC, 5-FAM, 6-FAM, etc.) or colored moiety.

[0065] The compounds of some embodiments also provide other desirable properties, including enhanced permeability and retention effects. In addition to providing the necessary solubility properties, the chemical characteristics of embodiments of compounds of the present disclosure can be tailored to modulate the ability of the compound to penetrate and retain in diseased cells / tissues. These characteristics allow for effective delivery of biologically active agents through increased permeation and increased efficacy through improved retention.

[0066] Thus, it is understood that any embodiment of the compounds of structure (I), as described above, may be independently combined with other embodiments to form embodiments of the present disclosure not specifically set forth above. It is understood that in this disclosure, combinations of substituents and / or variables of the depicted formulae are permissible only if such combinations result in stable compounds.

[0067] Accordingly, one embodiment provides a compound having the following structure (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R 1 and R 2 are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c , Q, or a protected form thereof, L′; R a is O or S; R b But OH, SH, O - , S - , OR d , or SR d and; R c But OH, SH, O - , S - , OR d , OL′, SR d, alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counterion; R 3 is, in each occurrence, independently H, alkyl, or alkoxy; R 4 However, each occurrence is independently OH, SH, O - , S - , OR d , or SR d and; R 5 is independently, in each occurrence, oxo or thioxo; L 1 , L 2 , L 5 , and L 6 is, in each occurrence, independently a direct bond or independently any alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 3 is, at each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 4 is, independently at each occurrence, a linker; M 1 is, at each occurrence, independently a moiety comprising a fluorescent or colored dye; M 2 is, at each occurrence, independently a moiety comprising a biologically active moiety, provided that at least one M 2 The appearance of steroids or vitamins; Q, in each occurrence, is independently a moiety containing a reactive group, or a protected form thereof, that is capable of forming a covalent bond with a complementary reactive group Q′ of the targeting moiety; L′, at each occurrence, is independently a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a linker that includes a covalent bond to a solid support, a linker that includes a covalent bond to a solid support residue, a solid support residue, a linker that includes a covalent bond to a nucleoside, or a linker that includes a covalent bond to an additional compound of structure (I); and m, in each occurrence, is independently an integer greater than or equal to 1; p, in each occurrence, is an integer greater than or equal to 0; q, in each occurrence, is an integer greater than or equal to 1; and The compound is provided wherein n is an integer of 1 or greater.

[0068] Various linkers and substituents (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , M 1 , M 2, and Q) may be optionally substituted with another substituent. For example, in some embodiments, optional substituents are selected to optimize water solubility or other properties of the compound of structure (I). In some embodiments, each chromophore, alkyl, alkoxy, alkyl ether, heteroarylene, heteroalkyl, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, alkoxyalkyl ether, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, and thiophosphoalkyl ether in the compound of structure (I) above is optionally substituted with another substituent selected from the group consisting of hydroxyl, alkoxy, alkyl ether, alkoxyalkyl ether, sulfhydryl, amino, alkylamino, carboxyl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, and thiophosphoalkyl ether. In some embodiments, the optional substituent is -OP(=R a )(R b )R c where R a , R b , and R c is defined for compounds of structure (I).

[0069] In some embodiments, at least one occurrence of L 3 is heteroalkylene. 3 is heteroalkylene. In some embodiments, at least one occurrence of L 3 In some more particular embodiments, L 3 In some more particular embodiments, the ethylene oxide is polyethylene oxide. 3 has the following structure, in each occurrence: [ka] During the ceremony, z is an integer of 1 to 100, and * indicates a bond to the adjacent phosphorus atom.

[0070] In some embodiments, z is an integer from 3 to 8. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 8. In some other embodiments, z is an integer from 22 to 26. In some embodiments, z is 22. In some embodiments, z is 23. In some embodiments, z is 24. In some embodiments, z is 25. In some embodiments, z is 26.

[0071] In some other embodiments, z ranges from 19 to 28. In some embodiments, the average of z is 23. In some embodiments, the average of z is 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28. In other embodiments, at least one occurrence of L 3 is an alkylene linker (e.g., methylene). In some more particular embodiments, at each occurrence, L 3 is an alkylene linker (e.g., methylene).

[0072] In some embodiments, at least one occurrence of in the compound of structure (I) [ka] comprises one of the following structures: [ka] wherein z is an integer from 1 to 100. In some embodiments, z is an integer from 3 to 8. In some other embodiments, z is an integer from 22 to 26. In some other embodiments, z is in the range of 19 to 28.

[0073] In some embodiments, at each occurrence, in a compound of structure (I), [ka] comprises one of the following structures: [ka] wherein z is an integer from 1 to 100. In some embodiments, z is an integer from 3 to 8. In some other embodiments, z is an integer from 22 to 26. In some other embodiments, z is in the range of 19 to 28.

[0074] Some embodiments provide a compound having the following structure (IA): [ka] or a stereoisomer, salt, or tautomer thereof.

[0075] In some embodiments, L 1 , L 2 , L 5 , and L 6 is, at each occurrence, independently a direct bond or independently any alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker. In some embodiments, L 1 , L 2 , and L 6 is independently at each occurrence alkylene. 1 , L 2 , and L 6is, at each occurrence, independently C1-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene. In some more particular embodiments, L 1 , L 2 , and L 6 In some more particular embodiments, the alkylene linker is a C alkyl linker. 1 , L 2 , and L 6 In some more particular embodiments, the alkylene linker is a C2 alkyl linker. 1 , L 2 , and L 6 In some more particular embodiments, the alkylene linker is a C alkyl linker. 1 , L 2 , and L 6 In some more particular embodiments, the alkylene linker is a C4 alkyl linker. 1 , L 2 , and L 6 In some more particular embodiments, the alkylene linker is a C5 alkyl linker. 1 , L 2 , and L 6 The alkylene linker is a C6 alkyl linker.

[0076] In some particular embodiments, L 5 In some particular embodiments, the alkylene linker is a C alkyl linker. 5 In some particular embodiments, the alkylene linker is a C2 alkyl linker. 5 In some particular embodiments, the alkylene linker is a C alkyl linker. 5 In some particular embodiments, the alkylene linker is a C4 alkyl linker. 5 In some particular embodiments, the alkylene linker is a C5 alkyl linker. 5In another embodiment, at least one occurrence of L 5 is a direct bond. In some other embodiments, each occurrence of L 5 is a direct bond.

[0077] Some embodiments provide a compound having the following structure (IB): [ka] or a stereoisomer, salt, or tautomer thereof, During the ceremony, y 1 , y 2 , and y 6 is, in each occurrence, independently an integer from 1 to 6, and y 5 is, in each occurrence, independently an integer from 0 to 6.

[0078] In some embodiments, y 5 is the integer 0 at each occurrence (i.e., L 5 is a direct bond). In some embodiments, y 5 In some embodiments, y 5 In some embodiments, y 5 In some embodiments, y 5 In some embodiments, y 5 In some embodiments, y 5 is the integer 6 in each occurrence.

[0079] In some embodiments, y 1 , y 2 , and y 6 In some embodiments, y 1 , y 2 , and y 6In some embodiments, y 1 , y 2 , and y 6 In some embodiments, y 1 , y 2 , and y 6 In some embodiments, y 1 , y 2 , and y 6 In some embodiments, y 1 , y 2 , and y 6 is the integer 6 in each occurrence. In some particular embodiments, y 1 is the integer 0 at each occurrence, and y 2 and y 3 In some other particular embodiments, y 1 is the integer 1 at each occurrence, and y 2 and y 3 is 1 for each occurrence.

[0080] Some embodiments provide a compound having the following structure (II): [ka] or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein: M 1 is, at each occurrence independently, a moiety comprising a fluorescent dye; M 2 is, at each occurrence, independently a moiety that comprises a biologically active moiety, provided that at least one occurrence of M 2 is a steroid or vitamin; L 4 is, independently at each occurrence, a linker; L 1 , L 2 , L 3 and L 5is, in each occurrence, independently a direct bond or independently any alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; R 21 is, at each occurrence, independently a natural or unnatural amino acid side chain; R 1 and R 2 are each independently H, OH, SH, -NH2, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c , Q, or a protected form thereof, L′; R a is O or S; R b But OH, SH, O - , S - , OR d , or SR d and; R c But OH, SH, O - , S - , OR d , OL′, SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counterion; Q, in each occurrence, is independently a moiety containing a reactive group, or a protected form thereof, that is capable of forming a covalent bond with a complementary reactive group Q′ of the targeting moiety; L′, at each occurrence, is independently a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a linker comprising a covalent bond to a solid support, a linker comprising a covalent bond to a solid support residue, a solid support residue, a linker comprising a covalent bond to a nucleoside, or a linker comprising a covalent bond to an additional compound of structure (II); m, in each occurrence, is independently an integer greater than or equal to 0; p, in each occurrence, is independently an integer greater than or equal to 0; v, in each occurrence, is independently an integer greater than or equal to 1; and n is an integer of 1 or greater.

[0081] Compounds of structure (II) have a peptide-based backbone. Various linkers and substituents (e.g., M 1 , M 2 , Q, R 1 , R 2 , R 21 , L 1 , L 2 , L 3 , L 4 , and L′) may be optionally substituted with another substituent. For example, in some embodiments, the optional substituents are selected to optimize the water solubility, permeability, retention, or other properties of the compound of structure (II). In some embodiments, each alkyl, alkoxy, alkyl ether, heteroalkyl, alkylaminyl, alkylcarbonyl, or alkoxycarbonyl in the compound of structure (II) is optionally substituted with another substituent selected from the group consisting of hydroxyl, alkoxy, alkyl ether, alkoxyalkyl ether, sulfhydryl, amino, alkylamino, carboxyl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, and thiophosphoalkyl ether. In some embodiments, the optional substituent is —OP(═R a )(R b )R c where R a is O or S, and R b OH, SH, O - , S - , OR d , or SR d and R c OH, SH, O - , S - , OR d , S.R. d, alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is a counterion. In some embodiments, the substituents are selected to increase cell or tissue permeability. In related embodiments, the substituents are selected to increase cell or tissue retention.

[0082] In some embodiments, at least one R 21 is a neutral amino acid side chain. In some embodiments, at least one R 21 is a charged amino acid side chain. In some embodiments, R 21 is, in each occurrence, independently H, alkyl, -CH2CO2 - , -CH2CH2CO2 - , -CH2CH2CH2CH2NH3 + , -CH2CH2CH2NHC(=NH2 + )NH2, or imidazolyl.

[0083] In more particular embodiments, R 21 , L 5 , and m are selected, [ka] However, the amino acid sequence (G) 10 , (GDGDGDGDGD) or (GKGKGKGKGK).

[0084] In another embodiment, R 21 , L 5 , and m are selected, [ka] In some of these embodiments, the amino acid sequence is (GGEEFMLVYKFARKHGG) or (GGMSMVVSGG), which allows the amino acid sequence to form an α-helical or β-sheet secondary structure.

[0085] In some embodiments, L 5 Or L 2 , or both are present in at least one occurrence. 5 Or L 2 When either or both are present, it is a heteroalkylene linker. In some of these embodiments, the heteroalkylene linker comprises a functional group capable of maintaining a positive or negative charge in aqueous solution at pH values ​​ranging from 3 to 11. In more particular embodiments, at least one occurrence of L 5 Or L 2 , or both have the following structure: [ka]

[0086] In some embodiments, at least one occurrence of L 5 Or L 2 , or both have the following structure: [ka]

[0087] In some embodiments, L 1 and L 3 is independently absent or is a heteroalkylene linker. In more particular embodiments, the heteroalkylene linker is a peptidyl linker.

[0088] Some embodiments provide a compound having the following structure (III): [ka] or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein: M 1 is, at each occurrence independently, a moiety comprising a fluorescent dye; M 2 is, at each occurrence, independently a moiety that comprises a biologically active moiety, provided that at least one occurrence of M 2 is a steroid or vitamin; L 4 is, independently at each occurrence, a linker; L 1 , L 2 and L 3 is, in each occurrence, independently a direct bond or independently any alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatom linker; L 5 is, in each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker and includes one or more charged moieties, with the proviso that at least one charged moiety is not a phosphate ester; R 3 is, in each occurrence, independently H, alkyl, or alkoxy; R 1 and R 2 are each independently -H, -OH, -SH, alkyl, alkoxy, alkyl ether, heteroalkyl, alkylaminyl, alkylcarbonyl, alkoxycarbonyl, -OP(=R a )(R b )R c , Q, or a protected form thereof, or L′; R a is O or S; R b But OH, SH, O - , S - , OR d , or SR d and; R c But OH, SH, O - , S -, OR d , OL′, SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counterion; Q, in each occurrence, is independently a moiety containing a reactive group, or a protected form thereof, that is capable of forming a covalent bond with a complementary reactive group Q′ of the targeting moiety; L′, at each occurrence, is independently a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a solid support or a solid support residue, a linker that includes a covalent bond to a solid support or a solid support residue, or a linker that includes a covalent bond to an additional compound of structure (III); p, in each occurrence, is independently an integer greater than or equal to 0; v, in each occurrence, is independently an integer greater than or equal to 1; and The compound is provided wherein n is an integer of 1 or greater.

[0089] Various linkers and substituents in compounds of structure (III) (e.g., M 1 , M 2 , Q, R 1 , R 2 , R 3 , L 1 , L 2 , L 5, and L′) are optionally substituted with another substituent. For example, in some embodiments, optional substituents are selected to optimize water solubility, permeability, retention, or other properties of the compounds of structure (III). In some embodiments, each alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatom linker, or alkyl, alkoxy, alkylether, heteroalkyl, alkylaminyl, alkylcarbonyl, or alkoxycarbonyl in the compounds of structure (III) is optionally substituted with another substituent selected from the group consisting of hydroxyl, alkoxy, alkylether, alkoxyalkylether, sulfhydryl, amino, alkylamino, carboxyl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, and thiophosphoalkylether. In some embodiments, the optional substituent is —OP(═R a )(R b )R c where R a is O or S, and R b OH, SH, O - , S - , OR d , or SR d and R c OH, SH, O - , S - , OR d , S.R. d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R dis a counter ion. In some embodiments, the substituents are selected to increase cell or tissue permeability. In related embodiments, the substituents are selected to increase cell or tissue retention. In some embodiments, the alkyl, alkoxy, alkyl ether, heteroalkyl, alkylaminyl, alkylcarbonyl, and alkyloxycarbonyl are optionally substituted with hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, or thiophosphoalkylether, or combinations thereof.

[0090] In some embodiments, the charged moieties are positively charged. In more particular embodiments, the charged moieties comprise a protonated amine or a quaternary amine functional group. In more particular embodiments, the charged moieties independently have one of the following structures: [ka] During the ceremony: R in each occurrence is independently H or C1-C6 alkyl.

[0091] In other embodiments, the charged moiety is negatively charged. In some embodiments, the charged moiety comprises a carboxylic acid, phosphate, or sulfate functional group. In some embodiments, the charged moiety has the following structure: [ka] In some embodiments, the charged moieties include a combination of positively charged and negatively charged moieties.

[0092] In some embodiments, the charged moiety is attached to the backbone of the compound (e.g., attached to the linker via an alkylene or heteroalkylene linker), while in some embodiments, the charged moiety is part of the backbone of the compound (e.g., part of the contiguous chain of the linker).

[0093] In some embodiments, L 5 has one of the following structures: [ka] During the ceremony: R, in each occurrence, is independently hydrogen or C1-C6 alkyl; x is an integer from 0 to 6, and m is an integer greater than or equal to 1, provided that m is selected such that the compound contains at least two charged moieties.

[0094] The above linker L 4 The above M 1 and M 2 For example, in some embodiments, a synthetic precursor of structure (I), (II), or (III) can be prepared and attached to the M moiety using any of several methods known in the art. 1 and M 2 In a further embodiment, at least one occurrence of L 4 comprises an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence comprising one or more amino acid residues, a ketone, a diol, a cyano, a nitro, or a combination thereof. In other embodiments, the functional group comprises an amide or an ester. In more particular embodiments, at least one occurrence of L 4 includes one of the following structures: [ka]

[0095] In a further embodiment, each occurrence of L 4comprises an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence comprising one or more amino acid residues, a ketone, a diol, a cyano, a nitro, or a combination thereof. In other embodiments, the functional group comprises an amide. In more particular embodiments, each occurrence of L 4 includes one of the following structures: [ka]

[0096] In some embodiments, at least one occurrence of R 3 is H. In some embodiments, at least one occurrence of R 3 is alkyl. In some embodiments, at least one occurrence of R 3 is alkoxy. In some embodiments, each occurrence of R 3 is H. In some embodiments, at least one occurrence of R 5 is oxo (=O). In some embodiments, at least one occurrence of R 5 is thioxo (=S). In some embodiments, each occurrence of R 5 is oxo (=O).

[0097] In some embodiments, at least one occurrence of R 4 is OH. In some embodiments, at least one occurrence of R 4 is SH. In some embodiments, at least one occurrence of R 4 O - In some embodiments, at least one occurrence of R 4 is S - In some embodiments, each occurrence of R 4 O - is. In various other embodiments, R 1 and R 2 are each independently OH or -OP(=Ra )(R b )R c In some different embodiments, R 1 or R 2 is OH or -OP(=R a )(R b )R c and R 1 or R 2 The other of these groups comprises Q or a linker that covalently bonds to Q.

[0098] In yet another embodiment of any of the compounds of structure (I), (II), or (III) above, R 1 and R 2 are each independently -OP(=R a )(R b )R c In some of these embodiments, R c is OL′.

[0099] In other embodiments, R 1 and R 2 are each independently -OP(=R a )(R b ) OL′, where L′ is an alkylene or heteroalkylene linker and is a linker to Q, a targeting moiety, an analyte (e.g., an analyte molecule), a solid support, a solid support residue, a nucleoside, or an additional compound of structure (I), (II), or (III).

[0100] The linker L' can be any linker suitable for attaching Q, a targeting moiety, an analyte (e.g., an analyte molecule), a solid support, a solid support residue, a nucleoside, or an additional compound of structure (I), (II), or (III) to a compound of structure (I), (II), or (III). Advantageously, some embodiments include the use of an L' moiety selected to improve or optimize the water solubility of the compound. In some embodiments, L' is a heteroalkylene moiety. In some other embodiments, L' comprises an alkylene oxide or a phosphodiester moiety, or a combination thereof.

[0101] In some other embodiments, R 2 is L'. For example, in some embodiments, L' is a linker to a targeting moiety. In another example, in some embodiments, R 2 is -NH2. In another embodiment, R 2 or R 1 wherein one of is L', and L' is a linker comprising a covalent bond to the solid support. In some embodiments, the solid support is a polymeric bead or a non-polymeric bead.

[0102] In some particular embodiments, L' is a linker to the targeting moiety, wherein the linker comprises an alkylene oxide or a phosphodiester moiety, or a combination thereof. In other embodiments, L' comprises one of the following structures: [ka] During the ceremony: x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 are independently an integer from 1 to 10, R b is H, an electron pair, or a counterion, L" is the targeting moiety or a linkage to the targeting moiety.

[0103] In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 is independently the integer 1. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 is independently the integer 2. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 is independently the integer 3. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 is independently the integer 4. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 is independently the integer 5. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 is independently the integer 6. In some embodiments, x 1 , x2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 is independently the integer 7. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 is independently the integer 8. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 is independently the integer 9. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 are independently the integer 10.

[0104] In some embodiments, R b is H. In some embodiments, R b is a counter ion. For example, in some embodiments, R b Na + In some embodiments, R b is K + is.

[0105] In some embodiments, L" is the targeting moiety. In some other embodiments, L" is a linkage to a targeting moiety. For example, the targeting moiety is an antibody. In another example, the targeting moiety is a cell surface receptor antagonist. In some more specific embodiments, the antibody or cell surface receptor antagonist is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, folic acid, or a MET inhibitor. In other embodiments, the targeting moiety is a monoclonal antibody. For example, in some embodiments, the monoclonal antibody is selected from the group consisting of Abciximab, Adalimumab, Alemtuzumab, Alirocumab, Avibactam, Basiliximab, Benralizumab, Bezlotoxumab, Blinatumomab, Brodalumab, Burosumab, Canakinumab, Caplacizumab, Certolizumab pegol, pegol, daclizumab, denosumab, dupilumab, eculizumab, emicizumab, erenumab, evolocumab, fremanezumab, galcanezumab, golimumab, guse Guselkumab, Ibalizumab, Idarucizumab, Infliximab, Itolizumab, Ixekizumab, Lanadelumab, Lokivetmab, Mepolizumab, Natalizumab,Obiltoxaximab, Ocrelizumab, Omalizumab, Palivizumab, Ranibizumab, Raxibacumab, Reslizumab, Rmab, Rovelizumab, Ruplizumab, Sarilumab, Secukinumab, Tildrakizumab ldrakizumab, thiomab, tocilizumab, ustekinumab, vedolizumab, abrilumab, actoxumab, aducanumab, afasevikumab, afelimomab, anifrolumab, anrukinumab (IMA-638) (IMA-638), Aselizumab, Atorolimumab, Bapineuzumab, BCD-100, Bertilimumab, Besilesomab, Biciromab, Bimagrumab, Bimekizumab, Virtamimab, Bleselumab, Blosozumab, Bococizumab, Brazikumab, Briakinumab, Brolucizumab, Carlumab, Carotuximab, Cedelizumab, Clazakizumab, Clenoliximab, Concizumab, Cosfroviximab, CR6261, Crenezumab, Crizanlizumab,Crotedumab, Depatuxizumab, Mafodotin, Derlotuximab biotin, Dezamizumab, Diridavumab, Domagrozumab, Dusigitumab, Ecromeximab, Edobacomab, Efalizumab, Efungumab, Eldelumab, Elezanumab, Enokizumab ab), Eptinezumab, Erlizumab, Etrolizumab, Evinacumab, Exbivirumab, Fanolesomab, Faralimomab, Faricimab, Fasinumab, Felvizumab, Fezakinumab, Flanvotumab, Fletikumab, Flotetuzumab, Fontolizumab, Foravirumab, Frovocimab, Fulranumab, Gantenerumab, Gavilimomab, Gevokizumab, Gimsilumab , Gomiliximab, Gosuranemab, Ianalumab, Inclacumab, Inolimomab, Iomab-B, Keliximab, Lampalizumab, Landogrozumab, Larcaviximab, Lebrikizumab,Lenvervimab, Lerdelimumab, Letolizumab, Ribivirumab, Ligelizumab, Lodelcizumab, Lulizumab pegol, Marstacimab, Mavrilimumab, Metelimumab, Mirikizumab, Motavizumab, Muromonab CD3 CD3), Nebacumab, Nemolizumab, NEOD001, Nirsevimab, Odulimomab, Olendalizumab, Olokizumab, OMS721, Opicinumab, Orticumab, Oteri Otelixizumab, Otilimab, Oxelumab, Ozanezumab, Ozoralizumab, Pagibaximab, Panobacumab, Pascolizumab, Pateclizumab, PDR001, Perakizumab, Pexelizumab, Placulumab, Plozalizumab, Ponezumab, Porgaviximab, Prasinezumab, Priliximab, PRO140, Qui Quilizumab, Rafivirumab, Ralpancizumab, Ranevetmab, Ravagalimab, Ravulizumab, Refanezumab, Regavirumab, Relatlimab,Rinucumab, Risankizumab, Rolezumab, Romosozumab, Rontalizumab, SA237, Satralizumab, Sevirumab, SHP647, Sifalimumab, Simtuzumab, Siplizumab, Sirukumab, Solanezumab, Sonepcizumab umab, Spartalizumab, Stamulumab, Sulesomab, Suptavumab, Sutimlimab, Suvizumab, Suvratoxumab, Tadocizumab, Talizumab, Tamtuvetmab, Tanezumab, Tefibazumab, Telimomab Aritox, Teneliximab, Teplizumab, Teprotumumab, Tezepelumab, Tibulizumab, Toralizumab, Tralokinumab, Trevogrumab, Tuvirumab, Ulocuplumab, Urtoxazumab, Varisacumab, Bepalimomab, Vesencumab, Visilizumab, Vobarilizumab, Zolimomab aritox), trastuzumab, gemtuzumab, brentuximab, vorsetuzumab, lorvotuzumab,Cantuzumab, bivatuzumab, inotuzumab, or vadastuximab.

[0106] In other more particular embodiments, in the above compounds of any of structures (I), (II), or (III), R 1 or R 2 has one of the following structures: [ka] [ka] In the formula, R a is H or a solid support.

[0107] In some particular embodiments, R 2 has one of the following structures: [ka]

[0108] Compounds of structure (I), (II), or (III) in some embodiments may be prepared according to solid phase synthesis methods similar to those known in the art for preparing oligonucleotides. Thus, in some embodiments, L' is a linkage to a solid support, a solid support residue, or a nucleoside. Solid supports containing activated deoxythymidine (dT) groups are readily available and, in some embodiments, may be used as starting materials for preparing compounds of structure (I), (II), or (III). Thus, in some particular embodiments, R 1 has the following structure: [ka]

[0109] Those skilled in the art will appreciate that the dT group shown above is included solely for ease of synthesis and economic efficiency and is not required. Other solid supports may be used, resulting in different nucleosides or solid support moieties being present on L', or the nucleosides or solid support moieties may be removed or modified after synthesis.

[0110] In some embodiments, the analyte molecule is a nucleic acid, an amino acid, or a polymer thereof. In some embodiments, the analyte molecule is an enzyme, a receptor, a receptor ligand, an antibody, a glycoprotein, an aptamer, or a prion. In some embodiments, the targeting moiety is an antibody or a cell surface receptor antagonist. In further embodiments, the solid support is a polymeric bead or a non-polymeric bead.

[0111] In still other embodiments, Q, at each occurrence, is independently a moiety that includes a reactive group and is capable of forming a covalent bond with an analyte molecule or a solid support. In other embodiments, Q, at each occurrence, is independently a moiety that includes a reactive group and is capable of forming a covalent bond with a complementary reactive group, Q'. For example, in some embodiments, Q' is present in an additional compound of structure (I), (II), or (III) (e.g., R 1 or R 2 (positions (I), (II), or (III)), Q and Q' contain complementary reactive groups, so that reaction of a compound of structure (I), (II), or (III) with an additional compound of structure (I), (II), or (III) results in the formation of a covalently linked dimer of a compound of structure (I), (II), or (III). Multimeric compounds of structure (I), (II), or (III) can also be prepared in an analogous manner and are included within the scope of embodiments of the present disclosure.

[0112] The type of Q group and its connectability to the remainder of the compound of structure (I), (II), or (III) are not limited, provided that Q contains a moiety with appropriate reactivity to form the desired bond. In some embodiments, Q is a moiety that is not susceptible to hydrolysis under aqueous conditions, yet is sufficiently reactive to form a bond with a corresponding group on the analyte molecule or solid support (e.g., an amine, azide, or alkyne).

[0113] In some embodiments, the compounds of structure (I), (II), or (III) comprise a Q group commonly used in the field of bioconjugation. For example, in some embodiments, Q comprises a nucleophilic reactive group, an electrophilic reactive group, or a cycloaddition reactive group. In some more specific embodiments, Q comprises a sulfhydryl, disulfide, active ester, isothiocyanate, azide, alkyne, alkene, diene, dienophile, acid halide, sulfonyl halide, phosphine, α-haloamide, biotin, amino, or maleimide functional group. In some embodiments, the active ester is an N-succinimide ester, an imidoester, or a polyfluorophenyl ester. In other embodiments, the alkyne is an alkyl azide or an acyl azide.

[0114] The Q group can be conveniently provided in a protected form to enhance storage stability or other desired properties, with the protecting group subsequently removed at the appropriate time for conjugation, e.g., with a targeting moiety or analyte. Thus, the Q group includes "protected forms" of reactive groups, including any of the reactive groups listed above and in Table 1 below. A "protected form" of Q refers to a moiety that has reduced reactivity compared to Q under given reaction conditions, but can be converted to Q, preferably under conditions that do not degrade or react with other moieties of the compound of structure (I), (II), or (III). One skilled in the art can derive an appropriate protected form of Q based on the particular Q and the desired end use and storage conditions. For example, if Q is SH, the protected form of Q contains a disulfide, which can be reduced using commonly known techniques and reagents to expose the SH moiety.

[0115] Exemplary Q moieties are provided in Table I below. [Table 2-1] [Table 2-2] [Table 2-3]

[0116] It should be noted that in some embodiments, when Q is SH, the SH moiety tends to form a disulfide bond with another sulfhydryl group, such as a sulfhydryl group on another compound of structure (I), (II), or (III). Thus, some embodiments include compounds of structure (I), (II), or (III) that are in the form of a disulfide dimer, and the disulfide bond is derived from the SH group of Q.

[0117] In other embodiments, the Q moiety is conveniently masked (e.g., protected) as a disulfide moiety, which can be subsequently reduced to provide an activated Q moiety for attachment to a desired analyte molecule or targeting moiety. For example, the Q moiety can be masked as a disulfide having the structure: [ka] wherein R is an optionally substituted alkyl group. For example, in some embodiments, Q is provided as a disulfide moiety having the structure: [ka] In the formula, n is an integer from 1 to 10.

[0118] In some embodiments, M 1 In one or more occurrences, M is independently a moiety containing four or more aryl or heteroaryl rings, or a combination thereof. 1is, in one or more occurrences, independently fluorescent or colored. 1 is fluorescent in one or more occurrences. 1 In one or more occurrences, independently, M comprises a fused polycyclic aryl or heteroaryl moiety and comprises at least four fused rings. 1 is, at each occurrence, independently selected from the group consisting of phenyl, (bis-fluorophenyl-difluorobora-diaza-indacene)phenyl, quaterphenyl, bi-benzothiazole, ter-benzothiazole, bi-naphthyl, bi-anthracyl, squaraine, squarylium, 9,10-ethynylanthracene, and ter-naphthyl moieties. 1 is, at each occurrence, independently selected from the group consisting of p-terphenyl, perylene, azobenzene, phenazine, phenanthroline, acridine, thioxanthene, chrysene, rubrene, coronene, cyanine, perylene imide, perylene amide, and derivatives thereof. 1 is, at each occurrence, independently selected from the group consisting of coumarin dyes, resorufin dyes, dipyrrometheneboron difluoride dyes, ruthenium bipyridyl dyes, thiazole orange dyes, polymethines, and N-aryl-1,8-naphthalimide dyes. 1 is, at each occurrence, independently selected from the group consisting of coumarin dyes, boron-dipyrromethene, rhodamine, cyanine, pyrene, perylene, perylene monoimide, 6-carboxyfluorescein (6-FAM), 5-carboxyfluorescein (5-FAM), 6-fluorescein isothiocyanate (6-FITC), 5-fluorescein isothiocyanate (5-FITC), and derivatives thereof.

[0119] In some other embodiments, M 1 has, at each occurrence, independently one of the following structures: [ka] [ka]

[0120] In some embodiments, M 1 has, at each occurrence, independently one of the following structures: [ka]

[0121] In some particular embodiments, at least one occurrence of M 1 has the following structure: [ka]

[0122] In some more particular embodiments, each occurrence of M 1 has the following structure: [ka]

[0123] In some embodiments, at least one occurrence of -L 4 -M 1 has one of the following structures: [ka]

[0124] In some more particular embodiments, each occurrence of -L 4 -M 1 has one of the following structures: [ka]

[0125] In some embodiments, M 2is the same for each occurrence, but M 2 is not necessarily the same M 2 In some embodiments, M 2 It is important to note that compounds in which M are not the same include compounds in which M is not the same. For example, in some embodiments, each M 2 are not the same, but different M 2 The moieties are selected to have different steroids or vitamins. In some other embodiments, each M 2 is a different M 2 part, and at least one M 2 is a steroid or vitamin.

[0126] In some embodiments, at least one occurrence of M 2 is an anti-inflammatory compound. 2 is a steroid, which is a biologically active organic compound having four rings arranged in the particular molecular configuration shown below. For example, in some embodiments, at least one occurrence of M 2 is cholesterol, cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or beclomethasone. 2 has one of the following structures: [ka] During the ceremony: R 11 is H or halogen; R 12 and R 13 is independently OH, H, alkyl, substituted alkyl, or heteroalkyl; R 14 is H, halogen, OH, or alkyl; R 15 is H or OH; R 16 , R 17 , and R 18 is H, alkyl, or substituted alkyl; and TIFF2025531423000044.tif10170 represents a single or double carbon-carbon bond.

[0127] In some embodiments, at least one occurrence of M 2 has one of the following structures: [ka]

[0128] Furthermore, in some embodiments, at least one occurrence of M 2 is a vitamin. For example, in some embodiments, at least one occurrence of M 2 is vitamin E. In some more particular embodiments, at least one occurrence of M 2 is tocopherol. In some embodiments, at least one occurrence of M 2 is α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, or δ-tocotrienol.

[0129] In some embodiments, at least one occurrence of M 2 has the following structure: [ka] During the ceremony, R 19 and R 20 is independently H or CH; and JPEG2025531423000047.jpg10170 represents a single or double carbon-carbon bond.

[0130] In some particular embodiments, at least one occurrence of M 2has one of the following structures: [ka]

[0131] In some particular embodiments, the compound is a compound selected from Table 2. The compounds in Table 2 are prepared according to the procedures described in the Examples. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11]

[0132] M 2has one of the following structures: [ka] [ka]

[0133] In some particular embodiments, the above compounds of structures (II) and (III) are selected from Table 3. The compounds in Table 3 are prepared according to the procedures set forth in the Examples. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7]

[0134] As used in Table 3 and throughout this disclosure, M 2 has one of the following structures: [ka] [ka]

[0135] The fluorescence intensity or efficacy against arthritis can be varied by selecting different values ​​of n. In some embodiments, n is an integer greater than or equal to 1. In some embodiments, n is an integer from 1 to 100. In other embodiments, n is an integer from 1 to 10. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[0136] The efficacy against fluorescence or arthritis can also be varied by selecting the value of m. The value of m is determined by the adjacent M 1 and M 2 In some embodiments, m is an integer greater than or equal to 0. In some embodiments, m is an integer from 0 to 100. In some embodiments, m is an integer from 0 to 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 1 or 2. In some embodiments, m is 1, 2, 3, 4, or 5. The value of m is M 1 or M 2 It depends on the hydrophobicity of the 1 or M 2 may require more spacing units, increasing the value of m. In this respect, the less hydrophobic M 1 or M 2may require fewer spacing units, decreasing the value of m.

[0137] The fluorescence intensity can vary depending on the number of fluorescent dye moieties attached to the polymer backbone. The value of p has the ability to control the brightness of the compound. In some embodiments, p, in each occurrence, is an integer greater than or equal to 0. In some more particular embodiments, p is 0 to 10. In some embodiments, p is 0 to 5. For example, in some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some other embodiments, p is 0, 1, 2, 3, or 4. In some other embodiments, p is 1.

[0138] The efficacy against arthritis can also be varied by selecting the value of q. In some embodiments, q, at each occurrence, is an integer greater than or equal to 1. In some more specific embodiments, q is 1 to 10. In some embodiments, q is 1 to 6. For example, in some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6. In some other embodiments, q is 1, 2, 3, 4, 5, or 6.

[0139] In some embodiments of structure (II) or (III), v is an integer greater than or equal to 1. For example, in some embodiments, v is an integer from 1 to 100. Further, in some embodiments, v is an integer from 1 to 10. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 3. In some embodiments, v is 4. In some embodiments, v is 5. In some embodiments, v is 6. In some embodiments, v is 7. In some embodiments, v is 8. In some embodiments, v is 9. In some embodiments, v is 10.

[0140] The values ​​of n, p, q, and m are closely related and provide the ability to control fluorescence and anti-arthritis efficacy. In some specific embodiments, n is 1, p is 1, q is 5, and m is 1 or 2. In some other specific embodiments, n is 1, p is 1, q is 4, and m is 1 or 2.

[0141] (Pharmaceutical composition) One embodiment provides a composition comprising a compound according to any embodiment of the present disclosure (e.g., a compound of structure (I), (II), or (III)) and a pharmaceutically acceptable carrier.

[0142] Other embodiments are directed to pharmaceutical compositions. The pharmaceutical compositions include one or more of the compounds of structure (I), (II), or (III) and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions are formulated for oral administration. In other embodiments, the pharmaceutical compositions are formulated for injection. In even more embodiments, the pharmaceutical compositions include a compound of structure (I), (II), or (III) and an additional therapeutic agent (e.g., an anti-cancer agent). Non-limiting examples of such therapeutic agents are described below.

[0143] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intraosseous injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0144] In some embodiments, the compounds of structure (I), (II), or (III) are administered locally rather than systemically, for example, by injection of the compound directly into an organ, often in the form of a depot preparation or sustained-release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to and selectively taken up by the organ. In still other embodiments, the compounds of structure (I), (II), or (III) are provided in the form of a rapid-release formulation, an extended-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds of structure (I), (II), or (III) are administered locally.

[0145] The compounds of structure (I), (II), or (III) are effective over a wide range of dosages. For example, in the treatment of adult humans, dosages of 0.01-1000 mg per day, 0.5-100 mg per day, 1-50 mg per day, and 5-40 mg per day are exemplary dosages for use in some embodiments. An exemplary dosage is 10-30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the subject's weight, and the preference and experience of the attending physician.

[0146] In some embodiments, a single dose of a compound of structure (I), (II), or (III) is administered. Typically, such administration is by injection, e.g., intravenous injection, to rapidly introduce the drug. However, other routes may be used if desired. A single dose of a compound of structure (I), (II), or (III) may also be used to treat acute conditions.

[0147] In some embodiments, the compound of structure (I), (II), or (III) is administered multiple times. In some embodiments, administration is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, administration is about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compound of structure (I), (II), or (III) and another agent are administered together from one to six times per day. In another embodiment, administration of the compound of structure (I), (II), or (III) and the agent continues for less than about seven days. In yet another embodiment, the administration continues for about six, ten, fourteen, twenty-eight days, two months, six months, or one year or more. In some cases, continuous administration is achieved and maintained for as long as necessary.

[0148] Administration of the compound of structure (I), (II), or (III) can continue for as long as necessary. In some embodiments, the compound of structure (I) is administered for 1 or more days, 2 or more days, 3 or more days, 4 or more days, 5 or more days, 6 or more days, 7 or more days, 14 or more days, or 28 or more days. In some embodiments, the compound of structure (I), (II), or (III) is administered for less than 28 days, less than 14 days, less than 7 days, less than 6 days, less than 5 days, less than 4 days, less than 3 days, less than 2 days, or less than 1 day. In some embodiments, the compound of structure (I), (II), or (III) is administered chronically on an ongoing basis, e.g., to treat a chronic effect.

[0149] In some embodiments, the compounds of structure (I), (II), or (III) are administered at a dosage. It is known in the art that due to subject-to-subject variability in the pharmacokinetics of compounds, individualized administration regimens are necessary for optimal treatment. Dosages for compounds of the present disclosure can be found by routine experimentation in light of the instant disclosure.

[0150] In some embodiments, the compounds of structure (I), (II), or (III) are formulated into pharmaceutical compositions. In certain embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers, which include excipients and adjuvants that aid in processing the active compound into a pharmaceutically usable preparation. The exact formulation will depend on the selected route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients may be used to formulate the pharmaceutical compositions described herein, including, but not limited to, Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0151] Provided in this disclosure are pharmaceutical compositions comprising a compound of structure (I), (II), or (III) and a pharmaceutically acceptable diluent, excipient, or carrier. In some embodiments, the compounds described above are administered as pharmaceutical compositions in which a compound of structure (I), (II), or (III) is combined with other active ingredients to form a combination therapy. Included in this disclosure are all combinations of active ingredients described in the combination therapy section below and throughout this disclosure. In certain embodiments, the pharmaceutical composition comprises one or more compounds of structure (I), (II), or (III).

[0152] As used herein, a pharmaceutical composition refers to a mixture of a compound of structure (I), (II), or (III) with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In some embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, the therapeutic methods or uses provided herein are practiced by administering a therapeutically effective amount of a compound of structure (I), (II), or (III) provided herein as a pharmaceutical composition to a mammal having a disease, disorder, or medical condition to be treated. In certain embodiments, the mammal is a human. In some embodiments, the therapeutically effective amount will vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds of structure (I), (II), or (III) are used alone or as components of a mixture in combination with one or more therapeutic agents.

[0153] In one embodiment, one or more compounds of structure (I), (II), or (III) are formulated in an aqueous solution. In certain embodiments, the aqueous solution is selected from, by way of example only, physiologically compatible buffers, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more compounds of structure (I), (II), or (III) are formulated for transmucosal administration. In certain embodiments, transmucosal formulations include penetrants suitable for permeating barriers. In yet other embodiments, when the compounds described in this disclosure are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In certain embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0154] In another embodiment, the compounds described in this disclosure are formulated for oral administration. The compounds described in this disclosure are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compounds described in this disclosure are formulated into oral dosage forms, which include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0155] In some embodiments, pharmaceutical formulations for oral administration are prepared by mixing one or more solid excipients with one or more compounds described herein, optionally milling the resulting mixture, processing the granulated mixture, and, if desired, adding suitable additives to obtain granulated tablets or dragee cores. Suitable excipients include, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In certain embodiments, disintegrants are optionally added. Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

[0156] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coatings. In a specific embodiment, a concentrated sugar solution is used to coat the dosage form. The sugar solution optionally contains additional ingredients, such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes and / or pigments are also optionally added to the coating for identification purposes. In addition, the dyes and / or pigments are optionally used to distinguish different combinations of active compound doses.

[0157] In some embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and sealed soft capsules, which are made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain embodiments, the push-fit capsules contain the active ingredient in admixture with one or more fillers. Fillers include, by way of example only, binders such as lactose or starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In other embodiments, the soft capsules contain one or more active ingredients, which are dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0158] In other embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, the compounds described herein are formulated for non-alimentary administration, including formulations suitable for bolus injection or continuous infusion. In certain embodiments, the injectable formulation is presented in a unit dosage form (e.g., an ampule) or in a multi-dose container. A preservative is optionally added to the injectable formulation. In still other embodiments, the pharmaceutical composition is formulated in a form suitable for non-alimentary administration, such as a sterile suspension, solution, or emulsion in an oily or aqueous medium. Formulations for non-alimentary administration optionally include formulating agents, such as suspending, stabilizing, and / or dispersing agents. In certain embodiments, the pharmaceutical formulation for non-alimentary administration comprises an aqueous solution of the active compound in water-soluble form. In additional embodiments, suspensions of the active compounds (e.g., compounds of structure (I), (II), or (III)) are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, e.g., ethyl oleate or triglycerides, or liposomes. In some embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or substances that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form and is combined with a suitable vehicle, e.g., pyrogen-free water, before use.

[0159] In yet other embodiments, the compounds of structure (I), (II), or (III) are administered topically. The compounds described in this disclosure are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compositions optionally include solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0160] In yet other embodiments, the compounds of structure (I), (II), or (III) are formulated for transdermal administration. In certain embodiments, transdermal formulations use transdermal delivery devices and transdermal delivery patches, which may be lipophilic emulsions or buffers, aqueous solutions, dissolved and / or dispersed in polymers or adhesives. In various embodiments, such patches are constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of the compounds of structure (I), (II), or (III) is achieved by iontophoretic patches, etc. In some embodiments, transdermal patches provide controlled delivery of the compounds of structure (I), (II), or (III). In certain embodiments, the absorption rate is slowed by the use of rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. The absorption enhancer or carrier comprises an absorbable pharmaceutically acceptable solvent to aid passage through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage and includes a support member, a reservoir containing the compound and optionally a carrier, optionally a rate-controlling barrier for delivering the compound to the skin of a host at a controlled, predetermined rate over an extended period of time, and means for securing the device to the skin.

[0161] In other embodiments, the compounds of structure (I), (II), or (III) are formulated for inhalation administration. Various forms suitable for inhalation administration include, but are not limited to, aerosols, mists, or powders. Pharmaceutical compositions of any of the compounds of structure (I), (II), or (III) are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers, using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In certain embodiments, the dosage unit of the pressurized aerosol is determined by providing a valve to deliver a metered amount. In some embodiments, capsules and cartridges, for example, by way of example only, made of gelatin for use in an inhaler or insufflator, are formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0162] In other embodiments, the compounds of structure (I), (II), or (III) are formulated into rectal compositions, such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases, such as cocoa butter or other glycerides, as well as synthetic polymers, such as polyvinylpyrrolidone, PEG, etc. The compositions in suppository form may contain a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with melted cocoa butter.

[0163] In some embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants, which facilitate processing of the active compound into a pharmaceutically acceptable preparation. The exact formulation will depend on the chosen route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used, as appropriate. Pharmaceutical compositions containing compounds of structure (I), (II), or (III) are prepared in a conventional manner, for example, by means of conventional mixing, dissolving, granulating, making dragees, mashing, emulsifying, encapsulating, entrapping, or compressing processes, by way of example only.

[0164] Pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one compound of structure (I), (II), or (III), as set forth in the present disclosure, as an active ingredient. The active ingredient may be in the form of a free acid or free base, or a pharmaceutically acceptable salt. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds that possess the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented in this disclosure. Additionally, the compounds described herein include unsolvated and solvated forms, including those with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Solvated forms of the compounds presented in this disclosure are also considered to be disclosed herein. In addition, the pharmaceutical composition optionally contains other medicinal or pharmaceutical agents, carriers, adjuvants such as preservatives, stabilizers, wetting agents, or emulsifiers, solution promoters, salts for regulating osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0165] Methods for preparing compositions containing compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form solid, semi-solid, or liquid forms. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, wafer cachets, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds described herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The pharmaceutical compositions described herein may take the form of liquid solutions or suspensions, solid forms suitable for dissolution or suspension in liquid prior to use, or emulsions. These compositions optionally contain minor amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, and pH buffering agents.

[0166] In some embodiments, a pharmaceutical composition comprising at least one compound of structure (I), (II), or (III) is illustratively in the form of a liquid, with the pharmaceutical agent being present in solution, suspension, or both. Typically, when the composition is administered as a solution or suspension, a first portion of the pharmaceutical agent is present in solution and a second portion of the pharmaceutical agent is present in particulate form in suspension in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0167] In some embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulose polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers, e.g., cross-linked carboxyl-containing polymers. Some pharmaceutical compositions described herein contain a mucoadhesive polymer, e.g., selected from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0168] Useful pharmaceutical compositions also optionally include a solubilizing agent to aid in the solubility of the compounds of structure (I), (II), or (III). The term "solubilizing agent" generally includes agents that result in the formation of a micellar solution or a true solution of the drug. Some acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0169] In addition, useful pharmaceutical compositions optionally contain one or more pH adjusting or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citric acid / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in the amounts necessary to maintain the pH of the composition within an acceptable range.

[0170] In addition, useful compositions also optionally contain one or more salts in an amount necessary to bring the osmolality of the composition within an acceptable range. Such salts include those having sodium, potassium, or ammonium cations and those having chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0171] Other useful pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances, such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0172] Still other useful compositions include one or more surfactants to improve physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as Octoxynol 10 and Octoxynol 40.

[0173] Yet other useful compositions include one or more antioxidants to enhance chemical stability as needed. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0174] In some embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0175] In alternative embodiments, other delivery systems are used for hydrophobic pharmaceutical compounds. Liposomes and emulsions are examples of delivery vehicles or carriers useful in the present disclosure. In some embodiments, organic solvents such as N-methylpyrrolidone are also used. In additional embodiments, the compounds described in the present disclosure are delivered using a sustained-release system, for example, using a semipermeable matrix of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful in the present disclosure. In some embodiments, sustained-release capsules release the compound for several weeks to over 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization are used.

[0176] In some embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizing agents. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0177] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical composition is 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0. 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v or v / v.

[0178] In some embodiments, the concentrations of one or more compounds are 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 16%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25 ... 5%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7. .25%,7%,6.75%,6.50%,6.25%,6%,5.75%,5.50%,5.25%,5%,4.75%,4.50%,4.25%,4%,3.75%,3.50%,3.25%,3%,2.75%,2.50%,2.25%,2%,1.75%,1.50%,125%,1%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07%,0.06%,0 Greater than 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0179] In some embodiments, the concentration of one or more compounds is between about 0.0001% and about 50%, between about 0.001% and about 40%, between about 0.01% and about 30%, between about 0.02% and about 29%, between about 0.03% and about 28%, between about 0.04% and about 27%, between about 0.05% and about 26%, between about 0.06% and about 25%, between about 0.07% and about 24%, between about 0.08% and about The range is from about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v or v / v.

[0180] In some embodiments, the concentration of one or more compounds is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9% w / w, w / v, or v / v.

[0181] In some embodiments, the amount of one or more compounds is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 ... g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

[0182] In some embodiments, the amount of one or more compounds is 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.0 03g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0. 0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g , 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5 g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5g , 3g, 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g.

[0183] In some embodiments, the amount of one or more compounds ranges from 0.0001 g to 10 g, 0.0005 g to 9 g, 0.001 g to 8 g, 0.005 g to 7 g, 0.01 g to 6 g, 0.05 g to 5 g, 0.1 g to 4 g, 0.5 g to 4 g, or 1 g to 3 g.

[0184] (Treatment method) Some compounds of the present disclosure are useful in the treatment of diseases (i.e., compounds of structure (I), (II), or (III)). These compounds of the present disclosure provide a targeted approach to drug delivery strategies. Thus, one embodiment provides a method of treating a disease (or a symptom thereof), comprising administering a therapeutically effective amount of a compound of structure (I), (II), or (III) to a mammal (e.g., a human) in need thereof.

[0185] For example, in some embodiments, the present disclosure provides a method of treating an autoimmune disease, such as rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcet's disease, spondyloarthritis, psoriasis, or osteoarthritis.

[0186] Additional therapeutic agents that may be combined with the compounds of the present disclosure can be found in "The Pharmacological Basis of Therapeutics," 10th Edition, by Goodman and Gilman, edited by Hardman, Limbird, and Gilman, or in the "Physician's Desk Reference," both of which are incorporated by reference in their entireties into this disclosure.

[0187] The compounds of structure (I), (II), or (III) described herein may be used in combination with the drugs of the present disclosure or other suitable drugs, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure may be co-administered with other drugs, as described above. When used in combination therapy, the compounds described herein may be administered simultaneously with the second drug or separately. This co-administration may include simultaneous administration of the two drugs in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the drugs described above may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present disclosure and any of the drugs described above may be administered simultaneously, in which case both drugs are present in separate formulations. In another alternative, the compounds of the present disclosure may be administered immediately after any of the drugs described above, or vice versa. In some embodiments of separate administration protocols, the compounds of the present disclosure and any of the drugs described above are administered minutes, hours, or days apart.

[0188] The examples and formulations provided below further describe and illustrate the compounds of the present disclosure and methods for making such compounds. It will be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and formulations. In the following examples and throughout this disclosure and claims, molecules and moieties with one stereocenter exist as racemic mixtures unless otherwise noted. Molecules and moieties with two or more stereocenters exist as racemic mixtures of diastereomers unless otherwise noted. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0189] [Figure 1] JPEG2025531423000071.jpg116170

[0190] Oligomerization typically begins by removing a protecting group (e.g., dimethoxytrityl group, DMTr) to expose a free -OH (hydroxyl) group (Step 1, detritylation). In the next coupling step, a phosphoramidite monomer is introduced, which reacts with the free -OH group to create a new covalent bond to phosphorus, simultaneously losing the diisopropylamine group (Step 2, coupling). The synthesized phosphite triester is oxidized (e.g., with I2 and pyridine) to a more stable phosphate ester (Step 3, oxidation), and a capping step inactivates any remaining free -OH groups (Step 4, capping). The new product, a phosphate oligomer, contains the DMTr-protected -OH group, which can be deprotected to restart the synthesis cycle and add another phosphoramidite monomer to the oligomer.

[0191] Customization occurs through the selection of phosphoramidite monomers in step 2. The nature of L (i.e., linker group) and M (i.e., chemotherapeutic agent) in the above scheme is selected to synthesize a compound of the desired structure (I), (III), or (IV). M can optionally be absent to incorporate desired spacing between M moieties. One skilled in the art can select multiple monomer types to arrive at compounds of the present disclosure containing multiple therapeutic agents and / or other moieties (e.g., fluorophores or chromophores) with simultaneous variability in linker groups.

[0192] Several steroid and vitamin phosphoramidites are commercially available and can be used in the DNA synthesis cycle described above, including cholesterol phosphoramidite and tocopherol / tocotrienol phosphoramidite, as shown below. [ka] DETAILED DESCRIPTION OF THE INVENTION

[0193] (Example) (General method) Mass spectrometry was performed on a Waters / Micromass Quattro micro MS / MS system (MS-only mode) using MassLynx 4.1 acquisition software. The mobile phase used for LC / MS of the dyes was 100 mM 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), 8.6 mM triethylamine (TEA) at pH 8. The phosphoramidites and precursor molecules were also analyzed using a Waters Acquity UHPLC system, which consisted of a 2.1 mm x 50 mm Acquity BEH-C column maintained at 45°C. 18 The column is equipped with an acetonitrile / water mobile phase gradient. Molecular weights of the monomer intermediates are obtained using tropylium cation injection-enhanced ionization on a Waters / Micromass Quattro micro MS / MS system (MS-only mode). Excitation and emission profile experiments are recorded on a Cary Eclipse spectrophotometer.

[0194] All reactions are performed in oven-dried glassware under a nitrogen atmosphere unless otherwise stated. Commercial DNA synthesis reagents are purchased from Glen Research (Sterling, VA). Pyridine anhydride, toluene, dichloromethane, diisopropylethylamine, triethylamine, acetic acid, pyridine, and THF are purchased from Aldrich. All other chemicals are purchased from Aldrich or TCI and used as is without further purification.

[0195] Example 1 (Synthesis of Compound I-1) (Preparation of stock solutions) 250mM borate buffer adjusted to pH 10 Fluorescein-NHS solution adjusted to 350 mM (300 mg in 1.35 mL of 25:75 DMSO:acetonitrile)

[0196] (solid phase synthesis) Compound I-1 was prepared on a DNA synthesizer using standard DNA synthesis techniques (i.e., DMT-protected 2-cyanoethyl phosphoramidite) on a solid support. The polymer was removed from the solid support using ammonium hydroxide and lyophilized to a paste. A 250 mg aliquot was reconstituted in water. Small aliquots were serially diluted with 100 mM NaCO3, pH 9, to determine the concentration (A263ε = 10,000). The final stock concentration was 14.5 mM.

[0197] (dye coupling reaction) Place 1.110 μL of water, 1.800 μL of borate buffer, 466 μL of compound I-1 polymer solution, 137.5 μL of acetonitrile, 313 μL of triethylamine, and 675 μL of fluorescein-NHS solution in a 50 mL centrifuge tube equipped with a magnetic stirrer. Wrap the tube in aluminum foil and stir overnight at room temperature.

[0198] (size exclusion filtration) Add 1 mL of water to an Amicon Ultra-15 centrifugal filter (Millipore UFC900324, MW cutoff = 3000). Add 4.5 mL of crude reaction mixture from the dye coupling reaction to the filter device. Wash the reaction vessel twice with 4 mL of 100 mM NaOH and transfer the washes to the filter device. Centrifuge the filter device at maximum speed (3220 g, swinging bucket, 30 min). Remove the filtrate and treat the retentate with an additional 10 mL of 100 mM NaOH. Centrifuge the filter device as before. Remove the filtrate again and add a third 10 mL aliquot of 100 mM NaOH to the retentate. Centrifuge the filter device as before and remove the filtrate. Add a fourth 10 mL aliquot of 100 mM NaOH to the retentate and centrifuge as before. Remove the filtrate and add 10 mL of water to the filter device. Centrifuge the mixture as before. The retentate is removed, the filter vessel is washed with water, and the wash is added to the final volume (3.5 mL). The desired product is confirmed by LC-MS, and the concentration is determined using absorbance.

[0199] Example 2 (Activation of Compound I-1 and Antibody Conjugation) [Figure 2] JPEG2025531423000073.jpg134170

[0200] Maleimide-functionalized compound I-1 is prepared according to the method described in Example 1. In parallel, UCHT-1 antibody is treated with bis-maleimidoethane ("BMOE") to reduce disulfide bonds. The reduced antibody is reacted with compound I-1 at a polymer to antibody molar ratio of 5:1. The reaction results in a final product, and a polymer to antibody ratio of 1:1 is detected by size exclusion chromatography. In some embodiments, anti-CD33, anti-CD70, or anti-CD123 can be used with bis-maleimidoethane ("BMOE") to reduce disulfide bonds.

[0201] Example 3 (General synthesis of peptide backbones by solid phase synthesis) [Figure 3] JPEG2025531423000074.jpg92170

[0202] The above reaction scheme shows an exemplary method for preparing intermediates useful in preparing compounds of structure (II), where PG is a suitable protecting group, X is a functional unit to which a peptide chain may be constructed, the shaded circle is a suitable solid support, and "BAM" is a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding site, with the proviso that at least one occurrence of M is not a fluorescent dye.

[0203] Small porous beads are first treated with functional units that are attached to the surface of the porous beads. Peptide chains are assembled onto the functional units and remain covalently attached to the beads until cleaved. Once attached, the peptide chains are immobilized on the solid phase and are retained during the filtration process, where liquid reagents and synthesis by-products are washed away.

[0204] The general cycle of solid-phase synthesis is one of repeated deprotection-wash-coupling-wash cycles. The free N-terminal amine of a peptide is attached to a solid support and coupled with an N-protected amino acid group (e.g., Fmoc or Boc). The newly introduced amino acid unit is deprotected, exposing a new N-terminal amine, which can then react with an additional amino acid. The process is repeated, and the peptide chain is extended.

[0205] When the peptide chain incorporates all the desired amino acids and monomer units, it is cleaved from the beads. A cleavage reagent, such as anhydrous hydrogen fluoride or trifluoroacetic acid, can be used to cleave the peptide chain from the beads. The peptide chain is then collected, purified, and characterized.

[0206] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent literature mentioned in this disclosure and / or application data sheet, including U.S. Provisional Patent Application No. 63 / 409,000, filed September 22, 2022, are incorporated herein by reference in their entirety to the extent they do not contradict statements in this disclosure. Aspects of the embodiments can be modified, if necessary, to employ concepts from various patents, applications, and publications and still provide embodiments.

[0207] While specific embodiments of the present disclosure have been described for purposes of illustration, it will be appreciated from the foregoing that various modifications can be made without departing from the spirit and scope of the disclosure. Accordingly, the disclosure is not limited except as by the appended claims.

Claims

1. A compound having the following structure (I): 【Chemical 1】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 1 and R 2 are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a ) (R b ) R c , Q, or a protected form thereof, L′; R a is O or S; R b But, OH, SH, O - , S - , OR d , or SR d and R c But, OH, SH, O - , S - , OR d , OL', SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counter ion; R 3 is, at each occurrence, independently H, alkyl, or alkoxy; R 4 may each occur independently as OH, SH, or O - , S - , OR d , or SR d and R 5 is independently in each occurrence oxo or thioxo; L 1 , L 2 , L 5 , and L 6 is, in each occurrence, independently a direct bond or independently any alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 3 is, at each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 4 is, independently at each occurrence, a linker; M 1 is, at each occurrence, independently a moiety comprising a fluorescent or colored dye; M 2 is, at each occurrence, independently a moiety comprising a biologically active moiety, provided that at least one M 2 The occurrence of is a steroid or vitamin; Q, at each occurrence, is independently a moiety containing a reactive group, or a protected form thereof, that is capable of forming a covalent bond with a complementary reactive group Q′ of the targeting moiety; L′, at each occurrence, is independently a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a linker that includes a covalent bond to a solid support, a linker that includes a covalent bond to a solid support residue, a solid support residue, a linker that includes a covalent bond to a nucleoside, or a linker that includes a covalent bond to an additional compound of structure (I); and m in each occurrence is independently an integer greater than or equal to 1; p in each occurrence is independently an integer greater than or equal to 0; q in each occurrence is independently an integer greater than or equal to 1; and A compound wherein n is an integer of 1 or more.

2. At least one occurrence of L 3 The compound of claim 1 , wherein is heteroalkylene.

3. L of each occurrence 3 The compound according to claims 1-2, wherein is heteroalkylene.

4. The compound of claim 3 , wherein the heteroalkylene comprises an alkylene oxide.

5. The compound of claim 4 , wherein the heteroalkylene comprises ethylene oxide.

6. The compound of claim 5 , wherein the ethylene oxide is polyethylene oxide.

7. L 3 has the following structure in each occurrence: 【Chemistry 2】 During the ceremony: z is an integer from 1 to 100; and * The compound according to any one of claims 1 to 6, wherein represents a bond to an adjacent phosphorus atom.

8. The compound of claim 7, wherein z is an integer from 3 to 8.

9. The compound of claim 7, wherein z is an integer from 22 to 26.

10. It has the following structure (IA): 【Chemistry 3】 or a stereoisomer, salt, or tautomer thereof.

11. At least one occurrence of L 1 The compound according to any one of claims 1 to 10, wherein is alkylene.

12. L of each occurrence 1 The compound according to any one of claims 1 to 11, wherein is alkylene.

13. At least one occurrence of L 2 The compound of any one of claims 1 to 12, wherein is alkylene.

14. L of each occurrence 2 The compound according to any one of claims 1 to 13, wherein is alkylene.

15. At least one occurrence of L 5 The compound according to any one of claims 1 to 14, wherein is a direct bond.

16. L of each occurrence 5 The compound according to any one of claims 1 to 15, wherein is a direct bond.

17. At least one occurrence of L 6 The compound of any one of claims 1 to 16, wherein is alkylene.

18. L of each occurrence 6 The compound of any one of claims 1 to 17, wherein is alkylene.

19. It has the following structure (IB): 【Chemistry 4】 or a stereoisomer, salt, or tautomer thereof, In the formula, y 1 , y 2 , and y 6 is, in each occurrence, independently an integer from 1 to 6; and y 5 19. The compound of any one of claims 1 to 18, wherein, at each occurrence, is independently an integer from 0 to 6.

20. A compound having the following structure (II): 【Chemistry 5】 or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein: M 1 is, at each occurrence, independently a moiety comprising a fluorescent dye; M 2 is, at each occurrence, independently a moiety that comprises a biologically active moiety, provided that at least one occurrence of M 2 is a steroid or vitamin; L 1 , L 2 , L 3 and L 5 is, in each occurrence, independently a direct bond or independently any alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 4 is, independently at each occurrence, a linker; R 21 is, at each occurrence, independently a natural or unnatural amino acid side chain; R 1 and R 2 are each independently H, OH, SH, or —NH 2 , alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a ) (R b ) R c , Q, or a protected form thereof, L′; R a is O or S; R b But, OH, SH, O - , S - , OR d , or SR d and R c But, OH, SH, O - , S - , OR d , OL', SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counter ion; Q, at each occurrence, is independently a moiety containing a reactive group, or a protected form thereof, that is capable of forming a covalent bond with a complementary reactive group Q′ of the targeting moiety; L′, at each occurrence, is independently a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a linker that includes a covalent bond to a solid support, a linker that includes a covalent bond to a solid support residue, a solid support residue, a linker that includes a covalent bond to a nucleoside, or a linker that includes a covalent bond to an additional compound of structure (II); m in each occurrence is independently an integer greater than or equal to 0; p in each occurrence is independently an integer greater than or equal to 0; v in each occurrence is independently an integer greater than or equal to 1; and A compound wherein n is an integer of 1 or more.

21. At least one R 21 is a neutral amino acid side chain.

22. At least one R 21 is a charged amino acid side chain.

23. R 21 is, in each occurrence, independently H, alkyl, —CH 2 CO 2 - , -CH 2 CH 2 CO 2 - , -CH 2 CH 2 CH 2 CH 2 NH 3 + , -CH 2 CH 2 CH 2 NHC (=NH 2 + ) NH 2 or imidazolyl.

24. R 21 , L 5 , and m are selected such that 【Chemistry 6】 The amino acid sequence (G) 10 24. The compound of any one of claims 20 to 23, having the following structure: (GDGDGDGDGD), or (GKGKGKGKGK).

25. R 21 , L 5 , and m are selected such that 【Chemistry 7】 has an amino acid sequence capable of forming an α-helix or a β-sheet secondary structure.

26. 26. The compound of claim 25, wherein the amino acid sequence is (GGEEFMLVYKFARKHGG) or (GGMSMVVSGG).

27. At least one occurrence of L 5 Or L 2 27. The compound of any one of claims 20 to 26, wherein

28. L 5 Or L 2 28. The compound of claim 27, wherein, when present, or both, are heteroalkylene linkers.

29. 29. The compound of claim 28, wherein the heteroalkylene linker comprises a functional group, and the functional group is capable of maintaining a positive or negative charge in an aqueous solution at a pH value ranging from 3 to 11.

30. At least one occurrence of L 5 Or L 2 30. The compound of claim 29, wherein, or both, have the following structure: 【Chemistry 8】

31. At least one occurrence of L 5 Or L 2 30. The compound of claim 29, wherein, or both, have the structure: 【Chemistry 9】

32. L 1 and L 3 The compound of any of claims 20-31, wherein is independently absent or is a heteroalkylene linker.

33. 33. The compound of claim 32, wherein the heteroalkylene linker is a peptidyl linker.

34. A compound having the following structure (III): 【Chemistry 10】 or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein: M 1 is, at each occurrence, independently a moiety comprising a fluorescent dye; M 2 is, at each occurrence, independently a moiety that comprises a biologically active moiety, provided that at least one occurrence of M 2 is a steroid or vitamin; L 4 is, independently at each occurrence, a linker; L 1 , L 2 and L 3 is, in each occurrence, independently a direct bond or independently any alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatom linker; L 5 is, at each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker and includes one or more charged moieties, with the proviso that at least one charged moiety is not a phosphate ester; R 3 is, at each occurrence, independently H, alkyl, or alkoxy; R 1 and R 2 each occurrence independently represents -H, -OH, -SH, alkyl, alkoxy, alkylether, heteroalkyl, alkylaminyl, alkylcarbonyl, alkoxycarbonyl, -OP(=R a ) (R b ) R c , Q, or a protected form thereof, or L′; R a is O or S; R b But, OH, SH, O - , S - , OR d , or SR d and R c But, OH, SH, O - , S - , OR d , OL', SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counter ion; Q, at each occurrence, is independently a moiety containing a reactive group, or a protected form thereof, that is capable of forming a covalent bond with a complementary reactive group Q′ of the targeting moiety; L′, at each occurrence, is independently a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a solid support or a solid support residue, a linker that includes a covalent bond to a solid support or a solid support residue, or a linker that includes a covalent bond to an additional compound of structure (III); p in each occurrence is independently an integer greater than or equal to 0; v in each occurrence is independently an integer greater than or equal to 1; and A compound wherein n is an integer of 1 or more.

35. 35. The compound of claim 34, wherein the charged moiety is positively charged.

36. The charged moieties independently have one of the following structures: 【Chemistry 11】 During the ceremony: R, in each occurrence, is independently H or C 1 -C 6 36. The compound of claim 35, which is alkyl.

37. 35. The compound of claim 34, wherein the charged moiety is negatively charged.

38. 38. The compound of claim 37, wherein the charged moiety has the structure: 【Chemistry 12】

39. L 5 has any of the following structures: 【Chemistry 13-1】 【Chemistry 13-2】 During the ceremony: R, in each occurrence, is independently H or C 1 -C 6 is alkyl; x is an integer from 0 to 6; and The compound according to any one of claims 34 to 38, wherein m is an integer of 1 or more.

40. At least one occurrence of L 4 comprises an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence comprising one or more amino acid residues, a ketone, a diol, a cyano, a nitro, or a combination thereof.

41. L 4 41. The compound of claim 40, wherein comprises an amide or ester functionality.

42. At least one occurrence of L 4 The compound of any one of claims 1 to 41, wherein: 【Chemistry 14-1】 【Chemistry 14-2】

43. L of each occurrence 4 comprises an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence, a ketone, a diol, a cyano, a nitro, or a combination thereof.

44. L of each occurrence 4 The compound of any one of claims 1 to 43, wherein: 【Chemistry 15】

45. At least one occurrence of R 3 The compound of any one of claims 1 to 44, wherein is H.

46. R of each occurrence 3 The compound of any one of claims 1 to 45, wherein is H.

47. R 5 47. The compound of any one of claims 1 to 46, wherein each occurrence is oxo.

48. R 4 But at each occurrence, O - The compound according to any one of claims 1 to 47,

49. R 1 and R 2 are each independently OH or —OP(═R a ) (R b ) R c The compound according to any one of claims 1 to 48,

50. R 1 or R 2 One of the groups is OH or -OP(=R a ) (R b ) R c and R 1 or R 2 The compound according to any one of claims 1 to 49, wherein the other of is Q or a linker comprising a covalent bond to Q.

51. R 1 and R 2 are each independently -OP(=R a ) (R b ) R c The compound according to any one of claims 1 to 50,

52. R 2 or R 1 52. The compound of any one of claims 1 to 51, wherein one of is L', and L' is a linker comprising a covalent bond to a solid support.

53. 53. The compound of any one of claims 1 to 52, wherein L' is a linker to a targeting moiety.

54. 54. The compound of any one of claims 1 to 53, wherein L' is a linker to a targeting moiety, said linker comprising an alkylene oxide or a phosphodiester moiety, or a combination thereof.

55. L' has one of the following structures: 【Chemistry 16】 During the ceremony: x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 is independently an integer from 1 to 10; R b is H, an electron pair, or a counterion; and 55. The compound of any one of claims 1 to 54, wherein L" is the targeting moiety or a linkage to a targeting moiety.

56. 56. The compound of any one of claims 1 to 55, wherein the targeting moiety is an antibody or a cell surface receptor antagonist.

57. 57. The compound of claim 56, wherein the antibody or cell surface receptor antagonist is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, folic acid, or a MET inhibitor.

58. The compound of claims 1 to 57, wherein the targeting moiety is a monoclonal antibody.

59. The monoclonal antibody is selected from the group consisting of abciximab, adalimumab, alemtuzumab, alirocumab, avibactam, basiliximab, benralizumab, bezlotoxumab, blinatumomab, brodalumab, burosumab, canakinumab, caplacizumab, certolizumab pegol, daclizumab, denosumab, dupilumab, eculizumab, emicizumab, erenumab, evolocumab, fremanezumab, galcanezumab, golimumab, guselkumab, ibalizumab, idarucizumab, infliximab, itolizumab, ixekizumab, lanadelumab, and loxavetoma. , mepolizumab, natalizumab, obiltoxaximab, ocrelizumab, omalizumab, palivizumab, ranibizumab, raxibacumab, reslizumab, Rmab, rovelizumab, ruplizumab, sarilumab, secukinumab, tildrakizumab, thiomab, tocilizumab, ustekinumab, vedolizumab, abrilumab, actoximab, aducanumab, afacevicumab, afelimomab, anifrolumab, anurukinumab (IMA-638), acelizumab, atorlimumab, bapineuzumab, BCD-100, valtiliumab, besilesomab, Biciromab, bimagrumab, bimekizumab, viltamimab, bleselumab, brosozumab, bococizumab, brazikumab, briakinumab, brolucizumab, carlumab, carotuximab, cedelizumab, clazakizumab, clenoliximab, concizumab, cosfrobiximab, CR6261, crenezumab, crizanlizumab, clotidumab, depatuximab, mafodotin, dellotuximab-biotin, dezamizumab, dilidabumab, domagrozumab, dusigitumab, eclomeximab, edovacomab, efalizumab, efangamab, Rudelumab, elezanumab, enokizumab, eptinezumab, erlizumab, etrolizumab, evinacumab, exbivirumab, fanolesomab, faralimomab, faricimab, fasinumab, felvizumab, fezakinumab, framvotumab, fluticumab, flotetuzumab, fontolizumab, foravirumab, flovokimab, furanumab, gantenerumab, gavilimomab, gevokizumab, gimsilumab, gomiliximab, goslanemab, ianalumab, inlacumab, inolimomab, Iomab-B, keliximab,Lampalizumab, landgrozumab, ralcabiximab, lebrikizumab, lembervimab, lerdelimumab, letolizumab, ribivirumab, ligelizumab, roderucizumab, lurizumab pegol, marstacimab, mavrilimumab, metelimumab, mirikizumab, motavizumab, muromonab CD3, nebacumab, nemolizumab, NEOD001, nirsevimab, odulimomab, orendalizumab, olokizumab, OMS721, opicinumab, olticumab, oteli Xyzumab, otilimab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, panobacumab, pascolizumab, pateclizumab, PDR001, perakizumab, pexelizumab, placulumab, prosalizumab, ponezumab, polgabiximab, prasinezumab, priliximab, PRO140, quilizumab, rafivirumab, ralpancizumab, ranevetomab, ravagalimab, ravutomib, refanezumab, regavirumab, relatolimab, linucille Mab, risankizumab, lorezumab, romosozumab, lontalizumab, SA237, satralizumab, cevilimab, SHP647, sifalimumab, simtuzumab, siplizumab, sirukumab, solanezumab, sonepcizumab, spartalizumab, stamulumab, sulesomab, sputumumab, stimulimab, subizumab, subratoximab, tadocizumab, talizumab, tamtubetomab, tanezumab, tefibazumab, terimomab-allitoxin, teneliximab, tep 59. The compound of claim 58, which is tafamidis, teprotumumab, tezepelumab, tiburizumab, toralizumab, tralokinumab, trevoglumab, tubilimab, urocupulumab, urtoxazumab, valisacumab, beparimomab, besencumab, visilizumab, bovalilizumab, zolimoab alitox, trastuzumab, gemtuzumab, brentuximab, borsetuzumab, lorvotuzumab, cantuzumab, bivatuzumab, inotuzumab, or vadastuximab.

60. R 1 or R 2 has one of the following structures: 【Chemistry 17-1】 【Chemistry 17-2】 In the formula, R a is H or a solid support.

61. R 2 61. The compound of any of claims 1 to 60, wherein: 【Chemistry 18】

62. R 1 62. The compound of any one of claims 1 to 61, wherein: 【Chemistry 19】

63. M 1 63. The compound of any of claims 1-62, wherein, in one or more occurrences, independently, is a moiety that includes four or more aryl or heteroaryl rings, or a combination thereof.

64. M 1 64. The compound of any one of claims 1 to 63, wherein, in one or more occurrences, is independently a fused polycyclic aryl or heteroaryl moiety comprising at least four fused rings.

65. M 1 is independently selected at each occurrence from the group consisting of phenyl, (bis-fluorophenyl-difluorobora-diaza-indacene)phenyl, quaterphenyl, bi-benzothiazole, ter-benzothiazole, bi-naphthyl, bi-anthracyl, squarine, squarylium, 9,10-ethynylanthracene, and ter-naphthyl moieties.

66. M 1 is independently selected at each occurrence from the group consisting of p-terphenyl, perylene, azobenzene, phenazine, phenanthroline, acrisine, thioxanthene, chrysene, rubrene, coronene, cyanine, perylene imide, perylene amide, and derivatives thereof.

67. M 1 is, at each occurrence, independently selected from the group consisting of coumarin dyes, resorufin dyes, dipyrrometheneboron difluoride dyes, ruthenium bipyridyl dyes, thiazole orange dyes, polymethines, and N-aryl-1,8-naphthalimide dyes.

68. M 1 is independently selected at each occurrence from the group consisting of coumarin dyes, boron-dipyrromethene, rhodamine, cyanine, pyrene, perylene, perylene monoimide, 6-carboxyfluorescein (6-FAM), 5-carboxyfluorescein (5-FAM), 6-fluorescein isothiocyanate (6-FITC), 5-fluorescein isothiocyanate (5-FITC), and derivatives thereof.

69. M 1 69. The compound of any of claims 1-68, wherein each occurrence independently has one of the following structures: 【Chemistry 20】

70. At least one occurrence of M 1 70. The compound of any one of claims 1 to 69, wherein: 【Chemical 21】

71. M of each occurrence 1 71. The compound of any one of claims 1 to 70, wherein: 【Chemical 22】

72. At least one occurrence of -L 4 -M 1 72. The compound of any one of claims 1 to 71, wherein: 【Chemical 23】

73. -L of each occurrence 4 -M 1 73. The compound of any of claims 1 to 72, wherein: 【Chemistry 24】

74. At least one occurrence of M 2 74. The compound of any one of claims 1 to 73, wherein is a steroid.

75. At least one occurrence of M 2 75. The compound of claim 74, wherein is cholesterol, cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or beclomethasone.

76. At least one occurrence of M 2 has one of the following structures: 【Chemistry 25】 During the ceremony: R 11 is H or halogen; R 12 and R 13 is independently OH, H, alkyl, substituted alkyl, or heteroalkyl; R 14 is H, halogen, OH, or alkyl; R 15 is H or OH; R 16 , R 17 and R 18 is H, alkyl, or substituted alkyl; and 【change】 The compound according to any one of claims 74 to 75, wherein represents a single or double carbon-carbon bond.

77. At least one occurrence of M 2 77. The compound of any one of claims 1 to 76, wherein: 【Chemistry 26-1】 【Chemistry 26-2】

78. At least one occurrence of M 2 78. The compound of claim 77, wherein: 【Chemical 27】

79. M of each occurrence 2 79. The compound of claim 78, wherein: 【Chemical Formula 28】

80. At least one occurrence of -L 4 -M 2 80. The compound of claim 79, wherein: 【Chemical formula 29】

81. -L of each occurrence 4 -M 2 81. The compound of claim 80, wherein: 【Chemistry 30】

82. At least one occurrence of M 2 The compound according to any one of claims 1 to 73, wherein is a vitamin.

83. At least one occurrence of M 2 is vitamin E.

84. At least one occurrence of M 2 84. The compound of claim 83, wherein is α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, or δ-tocotrienol.

85. At least one occurrence of M 2 has the following structure: 【Chemical 31】 During the ceremony: R 19 and R 20 are independently H or CH 3 and 【change】 The compound according to any one of claims 82 to 84, wherein represents a single bond or a double bond in a carbon-carbon bond.

86. At least one occurrence of M 2 The compound of any of claims 82 to 85, wherein: 【Chemical Formula 32】

87. At least one occurrence of M 2 87. The compound of claim 86, wherein: 【Chemical 33】

88. M of each occurrence 2 88. The compound of claim 87, wherein: 【Chemical 34】

89. At least one occurrence of -L 4 -M 2 87. The compound of claim 86, wherein: 【Chemistry 35】

90. -L of each occurrence 4 -M 2 90. The compound of claim 89, wherein: 【Chemical 36】

91. M 2 91. The compound of any of claims 1 to 90, wherein: 【Hua 37-1】 【Hua 37-2】 【Hua 37-3】

92. 92. The compound of any one of claims 1 to 91, wherein Q has the following structure: 【Hua 38-1】 【Chemistry 38-2】

93. 93. The compound of any one of claims 1 to 92, wherein m is 0 to 10.

94. 94. The compound of any one of claims 1 to 93, wherein m is 1, 2, 3, 4, or 5.

95. 95. The compound of any one of claims 1 to 94, wherein m is 1 or 2.

96. 96. The compound of any one of claims 1 to 95, wherein n is 1, 2, 3, or 4.

97. 97. The compound of any one of claims 1 to 96, wherein n is 1 or 2.

98. 98. The compound of any one of claims 1 to 97, wherein p is 0, 1, 2, 3, or 4.

99. 99. The compound of any one of claims 1 to 98, wherein p is 0.

100. 100. The compound of any one of claims 1 to 99, wherein p is 1.

101. 81. The compound of any one of claims 1 to 80, wherein q is 1, 2, 3, 4, 5, or 6.

102. The compound of any one of claims 1 to 101, wherein q is 1.

103. The compound of any one of claims 1 to 102, wherein q is 4.

104. The compound of any one of claims 1 to 103, wherein q is 5.

105. The compound according to any one of claims 20 to 104, wherein v is an integer from 1 to 100.

106. The compound of any one of claims 20 to 105, wherein v is an integer from 1 to 10.

107. y 1 , y 2 , and y 6 is the integer 1 in each occurrence, and y 5 The compound of any one of claims 1 to 104, wherein, in each occurrence, is the integer 0.

108. y 1 , y 2 , y 5 , and y 6 The compound of any one of claims 1 to 104, wherein, at each occurrence, is the integer 1.

109. 105. The compound of any one of claims 1 to 104, wherein n is 1, p is 1, q is 5, and m is 1 or 2.

110. 105. The compound of any one of claims 1 to 104, wherein n is 1, p is 1, q is 4, and m is 1 or 2.

111. 111. The compound of any of claims 1-110, wherein the compound has any of the structures of Tables 2-3, or a salt or tautomer thereof.

112. A pharmaceutical composition comprising a compound according to any one of claims 1 to 111 and a pharmaceutically acceptable carrier, diluent, or excipient.

113. 114. A method for treating a disease or disorder, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 111, or a pharmaceutical composition according to claim 112, to a subject in need thereof.

114. 114. The method of claim 113, wherein the disease or disorder is an autoimmune disease.

115. 115. The method of claim 113 or 114, wherein the autoimmune disease comprises rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcet's disease, spondyloarthropathy, psoriasis, and osteoarthritis.

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