Polymers with Dual Therapeutic Agents

Abstract

Disclosed are compounds useful as biologically active compounds. The compounds have the following structure (I): JPEG2025531424000327.jpg35165(I) or a stereoisomer, tautomer, or salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1a , L 1b , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , M 1 , M 2 , M 3 , p, q, w, m, and n are as defined in the present disclosure. The compounds of structure (I) are useful in numerous applications, including use as therapeutic agents for a variety of treatment methods.

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE Embodiments of the present disclosure generally relate to polymeric biologically active compounds having alkylating agents and methods for their preparation. [Background technology]

[0002] Targeted drug conjugates deliver drugs to target cells with little or no off-target activity, unlike, for example, chemotherapy. Typically, targeted drug conjugates contain a biologically active payload or targeting molecule linked to the drug. By combining the inherent targeting ability with the therapeutic effect 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 a type of targeted drug conjugate that has attracted particular attention, for example, for cancer treatment. ADCs for cancer treatment combine the targeting characteristics of monoclonal antibodies with the cancer-killing capabilities of cytotoxic agents, providing a therapy with several advantages over other chemotherapeutic agents. However, the complexity of ADC constructs, particularly challenges associated with the chemical linker between the antibody and the drug, has posed significant challenges to the development of new, effective therapeutic agents. While the first ADC was approved in 2001, it took nearly a decade for the next ADC to be approved. Currently, only Adcetris®, Besponsa®, Enhertu®, Mylotarg®, Padcev®, Polivy®, and Kadcyla® are commercially available worldwide (Zevalin® is approved only in China). Thus, there exists a need in the art for the development of potent targeted drug conjugates with high therapeutic indices and methods for their preparation. The present disclosure fulfills this need and further provides related advantages. Summary of the Invention

[0003] In one embodiment, the following structure (I): [ka] (I) or a stereoisomer, tautomer, or salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1a , L 1b , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , M 1 , M 2 , M 3 , q, w, p, m, and n are as defined in the present disclosure. Compounds of structure (I) are useful in numerous applications, including use as therapeutic agents for a variety of treatment methods. In another embodiment, there is provided a composition comprising a compound of structure (I) and a pharmaceutically acceptable carrier. In yet another embodiment, a method for treating a disease comprises 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 1 or M 3 is independently a biologically active moiety effective in treating a disease.

[0004] In yet another embodiment, the following structure (II): [ka] (II) or a salt, tautomer, or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6, R 7 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , G., M. 2 , M 3 , q, w, p, m, and n are as defined in the present disclosure. The compound of structure (II) is a synthetic intermediate used to form the compound of structure (I). These and other aspects of the present disclosure will become evident upon reference to the following detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0005] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure, but 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 disclosure and the claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are intended to be interpreted in an open and inclusive sense, i.e., meaning "including, but not limited to." The references throughout this disclosure 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 disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this disclosure do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0006] "Amino" refers to the group -NH2. "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 group --OH. "Imino" refers to the =NH group. "Nitro" refers to the -NO2 group. "Oxo" refers to the =O substituent. "Sulfhydryl" refers to an -SH group. "Thioxo" refers to the =S group.

[0007] "Alkyl" means an alkyl group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having 1 to 12 carbon atoms (C1-C 12 refers to a straight or branched hydrocarbon chain group having 1 to 8 carbon atoms (C1-C8 alkyl), 1 to 8 carbon atoms (C1-C6 alkyl), or 1 to 6 carbon atoms (C1-C6 alkyl) 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, and 2-methylhexyl. Unless otherwise specifically stated in this disclosure, alkyl groups are optionally substituted. An "alkylene" or "alkylene chain" is a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, having 1 to 12 carbon atoms, that connects the rest of the molecule to the radical group, such as methylene, ethylene, propylene, and n-butylene. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through 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 specifically in this disclosure, alkylene is optionally substituted. "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, having 2 to 12 carbon atoms, that connects the rest of the molecule to a radical group, 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 bond or a 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 specifically in this disclosure, alkenylene is optionally substituted.

[0008] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, having 2 to 12 carbon atoms, connecting the rest of the molecule to a radical group, such as ethynylene, propynylene, and n-butynylene. The alkynylene chain is attached 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 specifically in this disclosure, alkynylene is optionally substituted.

[0009] "Alkyl ether" refers to any alkyl group, as defined above, in which at least one carbon-carbon bond has been 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 more than one. 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, alkyl ethers are alkyl ethers that are substituted with an alcohol or -OP(=R a )(R b )R cwherein R a , R b , and R c are as defined for compounds of structure (I).

[0010] "Alkoxy" means a group of the formula -OR a In the formula, R a is an alkyl group as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in this disclosure, an alkoxy group is optionally substituted. An "alkoxyalkyl ether" is an alkoxy group of the formula -OR a R b In the formula, 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 in this disclosure. Unless otherwise specifically stated in this disclosure, an alkoxyalkyl ether group is optionally substituted, for example, an alcohol or -OP(=R a )(R b )R c wherein R a , R b , and R c are as defined for compounds of structure (I).

[0011] "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., a 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 terminus of the alkyl group, thus serving to attach 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 the 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, such as a phosphodiester bond.

[0012] "Heteroalkoxy" refers to a group of the formula -OR a In the formula, R a is a heteroalkyl group as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in this disclosure, a heteroalkoxy group is optionally substituted. "Heteroalkylene" refers to an alkylene group, as defined above, containing 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 contains 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, thus serving to attach the alkylene to the remainder of the molecule (e.g., M 1 -HAM 2 , M in the formula 1 and M 2 is a portion of the molecule, H is a heteroatom, and A is alkylene. Unless otherwise specifically stated 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]

[0013] Various embodiments of heteroalkylene linkers include multimers of the above C-linker, HEG-linker, and / or PEG 1K linker. In some embodiments of the PEG 1K linker, n ranges from 19 to 25, e.g., n is 19, 20, 21, 22, 23, 24, or 25. Multimers can be, for example, those having the following structure: [ka] may include 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).

[0014] "Linker" refers to a continuous chain of at least one atom, such as carbon, oxygen, nitrogen, sulfur, phosphorus, and combinations thereof, that connects a 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 molecules by a covalent bond or by other means, such as ionic or hydrogen bonding interactions. In some embodiments, the linker is a heteroatomic 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, a heteroalkylene linker has the following structure: [ka] Including, 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.

[0015] A "physiologically cleavable linker" refers to a molecular linkage that can be split or separated in a predetermined manner in the presence of an in vivo or in vitro environment in a biological or cellular system, resulting in two or more separate molecules. Generally, physiological conditions that induce such a cleavage or scission event can include a temperature in the range of about 20-40°C, an atmospheric pressure of about 1 atm (101 kPa or 14.7 psi), a pH of about 6-8, 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). Bond cleavage or scission can be homolytic or heterolytic.

[0016] "Heteroalkenylene" refers to heteroalkylene, as defined above, containing at least one carbon-carbon double bond. Unless otherwise specified in this disclosure, heteroalkenylene groups are optionally substituted. A "heteroalkynylene" is a heteroalkylene containing at least one carbon-carbon triple bond. Unless stated otherwise specifically in this disclosure, a heteroalkynylene group is optionally substituted. "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, as well as linkers having multiple heteroatoms, for example, linkers having the formula -P(O-)(=O)O- or -OP(O-)(=O)O-, and multimers and combinations thereof.

[0017] "Phosphate" is -OP(=O)(R a )R b R a is OH, O-, or OR c and R b OH, O-, OR c , a thiophosphate group, or a further phosphate group, where R c is the counter ion (e.g., Na + etc.). "Phosphoalkyl" is -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 + etc.) Unless otherwise specifically stated in this disclosure, phosphoalkyl groups are optionally substituted. For example, in certain embodiments, the -Oalkyl portion of a phosphoalkyl group is 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 as defined for compounds of structure (I).

[0018] "Phosphoalkyl ether" is -OP(=O)(R a )R b 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 certain embodiments, the -O alkyl ether portion of a phosphoalkyl ether group is hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, thiophosphoalkyl ether, or -OP(=R a )(R b )R c wherein R a , R b , and R care as defined for compounds of structure (I).

[0019] "Thiophosphate" is -OP(=R a )(R b )R c 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.), where i) R a is S or ii) R b is S- or SR d or iii) R c is SH, S-, or SR d or iv) a combination of i), ii), and / or iii). "Thiophosphoalkyl" is -OP(=R a )(R b )R c R a is O or S, and R b OH, O-, S-, OR d , or SR d and R c is —Oalkyl, where R d is a counter ion (e.g., Na + etc.), where i) R a is S or ii) R b is S- or SR d or iii) R a is S and R b is S- or SR dUnless otherwise specifically stated in this disclosure, thiophosphoalkyl groups are optionally substituted. For example, in certain embodiments, the -Oalkyl portion of a thiophosphoalkyl group is 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 as defined for compounds of structure (I).

[0020] "Thiophosphoalkyl ether" is -OP(=R a )(R b )R c 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 a counter ion (e.g., Na + etc.), where i) R a is S or ii) R b is S- or SR d or iii) R a is S and R b is S- or SR d Unless otherwise specifically stated in this disclosure, thiophosphoalkyl ether groups are optionally substituted. For example, in certain embodiments, the -O alkyl ether portion of a thiophosphoalkyl group is hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, thiophosphoalkyl ether, or -OP(=R a )(R b )R c wherein R a , R b, and R c are as defined for compounds of structure (I).

[0021] "Carbocyclic" refers to a stable 3- to 18-membered aromatic or non-aromatic ring containing from 3 to 18 carbon atoms. Unless otherwise specifically stated in this disclosure, a carbocyclic ring can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems, or can be partially or fully saturated. Non-aromatic carbocyclic radicals include cycloalkyl, and aromatic carbocyclic radicals include aryl. Unless otherwise specifically stated in this disclosure, carbocyclic groups are optionally substituted. "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic carbocyclic ring, which may include fused or bridged ring systems having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, is saturated or unsaturated, and is 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, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specifically stated in this disclosure, cycloalkyl groups are optionally substituted.

[0022] "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, aryls 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 specifically stated in this disclosure, aryl groups are optionally substituted.

[0023] "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 may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, may include fused or bridged ring systems, the nitrogen, carbon, or sulfur atoms of the heterocyclic ring may be optionally oxidized, the nitrogen atom may be optionally quaternized, and the heterocyclic ring may 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 heterocycle). 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-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in this disclosure, a heterocyclic group is optionally substituted.

[0024] "Heteroaryl" refers to a 5- to 14-membered ring system containing 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For purposes of certain embodiments of the present disclosure, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused or bridged ring systems; the nitrogen, carbon, or sulfur atom(s) of the heteroaryl radical can be optionally oxidized, and the nitrogen atom(s) can be optionally quaternized.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl, benzimidazolethionyl, 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, piri 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 this disclosure, heteroaryl groups are optionally substituted.

[0025] The suffix "-ene" refers to a particular structural feature (e.g., alkyl, aryl, heteroalkyl, heteroaryl) that is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In other words, the suffix "-ene" refers to a linker that has the structural feature 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 within the chain or through any two atoms within the chain. For example, heteroarylene refers to a linker that includes a heteroaryl moiety as defined in this disclosure.

[0026] "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 heterocyclyl ring or a heteroaryl ring, the common ring atom can be carbon or nitrogen. Fused rings include bicyclic, tricyclic, tetracyclic, and the like.

[0027] The term "substituted," as used in this disclosure, refers to any of the above groups (e.g., alkyl, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, alkoxy, alkyl ether, phosphoalkyl, phosphoalkyl ether, thiophosphoalkyl, thiophosphoalkyl ether, carbocyclic, cycloalkyl, aryl, heterocyclic, and / or heteroaryl) in which at least one hydrogen atom (e.g., one, two, three, or all hydrogen atoms) has been replaced by a bond to a non-hydrogen atom, such as, but not limited to, the following: "Substituted" refers to any of the above groups in which one or more hydrogen atoms have been replaced by a higher bond (e.g., a double or triple bond) to a heteroatom, such as oxygen in groups such as oxo, carbonyl, carboxyl, and ester groups; or nitrogen in groups such as -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 , -OSO2Rg , -SO2OR g , =NSO2R g , and -SO2NR g R h Also, "substituted" includes any of the above groups replaced with -C(=O)R. g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the above, R g and R h are the same or different and are 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 any of the above groups in which one or more hydrogen atoms are replaced by a bond to 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 above substituents can also be optionally substituted with one or more of the above substituents.

[0028] "Conjugation" refers to the overlap of one p orbital with another p orbital across an intervening sigma 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 sigma bond. For example, 1,3-butadine has a degree of conjugation of one, while benzene and other aromatic compounds typically have multiple degrees of conjugation. Fluorescent and colored compounds typically contain a degree of conjugation of at least one. "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 within the color spectrum (ie, red, yellow, blue, etc.).

[0029] The term "biomolecule" refers to any of a variety of biological substances, including nucleic acids, carbohydrates, amino acids, polypeptides, glycoproteins, hormones, aptamers, and mixtures thereof. More specifically, the term is intended to include, but is not limited to, 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. Visually detectable biomolecules of the present disclosure (e.g., compounds of structure (I) having a biomolecule linked thereto) are prepared by contacting a biomolecule with a compound having a reactive group that allows the biomolecule to be attached to the compound through any available atom or functional group, such as an amino group, hydroxyl group, carboxyl group, or sulfhydryl group, of the biomolecule, as further described in this disclosure.

[0030] 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 reaction. 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, activated esters, ketones, α,β-unsaturated carbonyls, alkenes, maleimides, α-haloamides, epoxides, aziridines, tetrazines, tetrazoles, phosphines, biotin, and thiirane. "Bioconjugation" or "bioconjugate" and related variations refer to a chemical reaction strategy for forming a stable covalent bond between two molecules. The term "bioconjugation" is generally used when one of the molecules is a biomolecule (e.g., an antibody), but can also be used to describe the formation of covalent bonds with non-biomolecules (e.g., polymeric resins). The product or compound resulting from such a reaction strategy is a "conjugate," "bioconjugate," or grammatical equivalent.

[0031] The terms "visible" and "visually detectable" are used in this disclosure to refer to substances observable 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 an IR 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 IR. -1 cm -1 The compounds of the present disclosure may be detected by visual observation or with the aid of optically based detection devices, including, but not limited to, absorption spectrophotometers, transmitted light microscopes, digital cameras, and scanners. Visually detectable substances are not limited to those that emit and / or absorb light in the visible spectrum. 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 substances that emit and / or absorb in other regions of the electromagnetic spectrum are also included within the scope of "visually detectable" substances.

[0032] 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 does not significantly change or decompose upon exposure to light. Preferably, the photostable visible dye does not exhibit significant fading or decomposition after exposure to light for at least one hour. More preferably, the visible dye is stable after exposure to light for at least 12 hours, 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.

[0033] As used in this disclosure, 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 used synonymously. In some preferred embodiments, the derivative (e.g., perylene, pyrene, anthracene, or naphthalene derivative) is an imide, bisimide, or hydrazamimide derivative of perylene, anthracene, naphthalene, or pyrene.

[0034] The visually detectable molecules of various embodiments of the present disclosure are useful in a wide variety of analytical applications, such as biochemical and biomedical applications, where there is a need to determine the presence, location, or amount of a particular analyte (e.g., a biomolecule). Accordingly, in another aspect, the present disclosure provides a method for visually detecting a biomolecule, the method comprising: (a) providing a biological system with a visually detectable biomolecule comprising a compound of structure (I) linked to the biomolecule; and (b) detecting the biomolecule by its visual characteristics. For purposes of this disclosure, the phrase "detecting a biomolecule by its visual characteristics" refers to observing the biomolecule with the naked eye or with the aid of an optical-based detection device, including, but not limited to, an absorption spectrophotometer, a transmitted light microscope, a digital camera, and a scanner, without illumination or chemical or enzymatic activation. Densitometers can be used to quantify the abundance of visually detectable biomolecules. 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 the extinction coefficient of the dye molecule is known, the absolute concentration of the biomolecule can also be determined from optical density measurements. As used in this disclosure, the term "biological system" refers to any solution or mixture containing one or more biomolecules in addition to visually detectable biomolecules. Non-limiting examples of such biological systems include cells, cell extracts, tissue samples, electrophoresis gels, assay mixtures, and hybridization reaction mixtures.

[0035] "Solid support" or "solid resin" refers to any solid substrate known in the art as a solid phase support for molecules, e.g., "microparticle" refers to any of a number of small particles useful for attachment of the disclosed compounds, including, but not limited to, glass beads, magnetic beads, polymeric beads, and non-polymeric beads. In certain embodiments, microparticles comprise polystyrene beads. In some embodiments, the solid support or solid resin is controlled pore glass or macroporous 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 to it.

[0036] A "targeting moiety" is a moiety that selectively binds to or associates with a particular target, such as an analyte molecule. "Selectively" binding or association means that the targeting moiety preferentially associates with or binds to the desired target over other targets. In some embodiments, compounds of the present disclosure include a linkage to a targeting moiety for the purpose of selectively binding or associating the compound with the 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. In certain embodiments, small molecules that selectively bind to or associate with the desired analyte are also contemplated as targeting moieties. Those of skill in the art will recognize other analytes and corresponding targeting moieties that would be useful in various embodiments. "Base pairing moiety" refers to a heterocyclic moiety capable of hybridizing with a complementary heterocyclic moiety through 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.

[0037] Embodiments of the present disclosure are also intended to encompass all compounds that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include, respectively: 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 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. Isotopically labeled compounds of structure (I) may generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described below and in the Examples below, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent. "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted alkyl" means that the alkyl group may or may not be substituted, and the description includes both substituted alkyl groups and alkyl groups that have no substitution. "Salt" includes both acid addition salts and base addition salts.

[0038] "Acid addition salts" include salts formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as salts formed with 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, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, and glutamic acid. It refers to salts formed with organic acids such as lutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric 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.

[0039] "Base addition salt" refers to a salt prepared by the addition of an inorganic base or an 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, and aluminum salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as 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, piperidine, N-ethylpiperidine, and polyamine resins. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0040] Crystallization may produce solvates of the compounds described herein. The embodiments of the present disclosure include all solvates of the compounds described herein. As used in this disclosure, the term "solvate" refers to an aggregate comprising one or more molecules of a compound of the present disclosure with one or more molecules of a solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present disclosure may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as corresponding solvated forms. The compounds of the present disclosure may be true solvates, but in other cases, the compounds of the present disclosure may simply retain incidental water or another solvent, or may be a mixture of water and some incidental solvent.

[0041] 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 that may be specified in terms of absolute stereochemistry as (R)- or (S)-, or, in the case of amino acids, (D)- or (L)-. Embodiments of the disclosure are intended to encompass 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 synthons or chiral reagents or separated using conventional techniques such as, for example, chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include 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 E and Z geometric isomers, as well as all tautomeric forms.

[0042] "Stereoisomers" refer to compounds composed of the same atoms joined by the same bonds but having different three-dimensional structures that are not interconvertible. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other. "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 aforementioned compounds. Various tautomers of the present compounds can be easily derived by one skilled in the art. "Steroid" refers to a biologically active organic compound having a four-fused ring arrangement. The core structure of the steroid 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 the A ring 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.

[0043] "Vitamins" 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 a 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, including α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol.

[0044] "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. The amino acid side chain can be associated with a natural amino acid or an unnatural amino acid. "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 invention include compounds containing certain amino acid sequences as shown. Amino acid sequences are listed by three-letter or one-letter abbreviations where appropriate.

[0045] "Letter code," "one-letter code," or "three-letter code" refers to the representation or abbreviation of an amino acid or amino acid residue in an amino acid sequence. A basic list of one-letter and three-letter codes and their corresponding amino acids is provided below. [Table 1]

[0046] "Beta sheet," "β-sheet," "beta pleated sheet," or "β-pleated sheet" refers to the secondary structure of an amino acid sequence formed by intramolecular folding. The amino acid chain is laterally connected by hydrogen bonds, generally forming a twisted pleated sheet. The amino acid chain forming this secondary structure is generally 3 to 10 amino acid residues in length. The present invention encompasses 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.

[0047] "Alpha helix" or "α-helix" refers to the secondary structure of an amino acid chain formed by intramolecular folding. A helical conformation is formed in which the backbone NH group donates a hydrogen bond to the backbone C=O group of the amino acid four residues prior. The amino acid side chain sequence influences the formation of the alpha helix structure. The present invention includes amino acid sequences containing amino acid residues with helix-forming propensity, where an alpha helix 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. The chemical naming protocols and structure diagrams used in this disclosure are modifications of the IUPAC nomenclature using 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.

[0048] compound As noted above, one embodiment of the present disclosure provides compounds useful as covalent linkers between biologically active moieties, such as alkylating agents, and targeting moieties. In other embodiments, compounds useful as synthetic intermediates for preparing compounds comprising one or more biologically active moieties are provided. Thus, in some embodiments, M 1 is, in each occurrence, independently either i) H or ii) a moiety containing a biologically active moiety, provided that L 1b If H, then M 1 does not exist, and M 2 is, independently at each occurrence, a moiety containing a fluorescent dye, and M 3 is, at each occurrence, independently a moiety that comprises a biologically active moiety. 1 or M 3 is an alkylating agent (e.g., monomethylauristatin F, monomethylauristatin E, SN38, and pyrrolobenzodiazepines), and M 2 is a fluorescent dye (e.g., fluorescein, etc.). According to embodiments disclosed in the present disclosure, a biologically active moiety M is attached to a polymer backbone and any subsequent targeting moiety. 1 and M 3 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 1 and M 3 This offers numerous advantages, including the ability to control the spacing between the polymer backbone and the biologically active moieties (e.g., how far apart or close each of the alkylating agents are), as well as the spacing between the polymer backbone and the biologically active moieties (e.g., the length of the linker from the polymer backbone). This allows compounds having biologically active moieties that promote the alkylation of guanine (G) in DNA to be constructed such that the biologically active moieties attached to the polymer backbone are positioned at low-energy positions within the minor groove of DNA. The compounds disclosed in the present disclosure have multiple alkylating agents as biologically active moieties, which can form interstrand and / or intrastrand DNA crosslinks, resulting in greater DNA stability.

[0049] The biologically active moiety may be attached to the polymer backbone via a physiologically cleavable linker or a non-cleavable linker. The procedures described in the present disclosure provide the ability to selectively introduce a physiologically cleavable linker and / or a non-cleavable linker. This allows for the synthesis of compounds with 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, M 1 and the biologically active moiety of M 2 The ratio of biologically active moieties can be fine-tuned based on the type of disease, disease progression, and therapy. Additionally, compounds can be synthesized with multiple biologically active and fluorescent moieties attached by physiologically cleavable and / or non-cleavable linkers.

[0050] Some embodiments of the present disclosure provide combinations of therapeutic agents, targeting moieties, and dye moieties (e.g., chromophores or fluorophores) that can be used for simultaneous targeting, treatment, and detection. The ease of coupling of polymer-drug constructs to targeting agents such as antibodies, antibody fragments, proteins, or other clinically interesting agents provides utility for a wide variety of interesting applications (e.g., surface chemistry, assay development, etc.). Thus, in some embodiments, M 2 is a chromophore or fluorophore (e.g., FITC, 5-FAM, 6-FAM, etc.). Certain embodiment compounds also provide other desirable properties, including enhanced permeability and retention. In addition to providing the necessary solubility characteristics, the chemical characteristics of embodiment compounds of the present invention can be tailored to modulate the ability of the compound to penetrate and be retained in diseased cells / tissues. These characteristics allow for effective delivery of biologically active agents by increasing permeability and increased efficacy by enhancing retention.

[0051] Thus, it is understood that any embodiment of a compound of structure (I), (II), or (III) shown above can be independently combined with other embodiments to form embodiments of the present disclosure not specifically set forth above. It is understood that in the present disclosure, combinations of substituents and / or variables of the depicted formulae are permissible only if such combinations result in stable compounds.

[0052] Thus, one embodiment is a compound having the following structure (I): [ka] (I) or a stereoisomer, pharmaceutical salt, 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 OH, SH, O - , S - , OR d , or SR d and R c 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, in each occurrence, independently H, alkyl, or alkoxy; R 4 are, in each occurrence independently, OH, SH, O - , S - , OR d , or SR d and R 5 is independently, in each occurrence, oxo or thioxo; R 6 and R 7 is H, OH, or halo, at each occurrence; L 1a is, in each occurrence, independently a heteroalkylene or heteroarylene linker; L 1b is, in each occurrence, independently either i) H or ii) a linker; L 2 , L 3 , L 5 , and L 6is, in each occurrence, independently a direct bond or independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 4 is, in each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 7 is, independently in each occurrence, a linker; M 1 is, at each occurrence, independently either i) absent or ii) a moiety that includes a biologically active moiety, with the proviso that L 1b If is H, then M 1 does not exist, M 2 is, independently at each occurrence, a moiety comprising a fluorescent dye; M 3 is, independently at each occurrence, a moiety that comprises a biologically active moiety; Q, in each occurrence, is independently a moiety that contains a reactive group or a protected form thereof that is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L', in each occurrence, is independently a linker that includes a covalent bond to Q, 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 0 or a greater integer; q, in each occurrence, is 0 or a greater integer; p, in each occurrence, is 0 or a greater integer; w, in each occurrence, is an integer equal to or greater than 0; and n is an integer equal to or greater than 1; The sum of p and w is an integer of 2 or greater, and the compound comprises at least two different biologically active moieties.

[0053] Various linkers and substituents (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1a , L 1b , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , M 1 , M 2 , M 3 , and Q) are optionally substituted with one more substituent. For example, in some embodiments, the optional substituents are selected to optimize the water solubility or other properties of the compound of structure (I). In certain 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) is optionally substituted with one more 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 certain embodiments, the optional substituent is -OP(=R a )(R b )R c wherein R a , R b , and R c is as defined for compounds of structure (I).

[0054] In some embodiments, L 1a At least one occurrence of is an optionally substituted 5- to 9-membered heteroarylene linker. 1a is a substituted 5-membered heteroarylene linker. In certain embodiments, L 1a is a substituted 6-membered heteroarylene linker. In certain embodiments, L 1a is a substituted 7-membered heteroarylene linker. In certain embodiments, L 1a is a substituted 8-membered heteroarylene linker. In certain embodiments, L 1a is a substituted 9-membered heteroarylene linker. In some related embodiments, L 1a is substituted with oxo, alkyl (e.g., methyl, ethyl, etc.), or combinations thereof. In certain embodiments, L 1a is unsubstituted in each occurrence. In some more particular embodiments, L 1a is, independently at each occurrence, pyrimidine. In some more particular embodiments, L 1a is, at each occurrence, independently, cytosine or thymine. 1a is, at each occurrence, independently selected from cytosine and thymine, such that the compound comprises a sequence of cytosine and thymine bases capable of forming a triplex with the target DNA sequence. 1a has the following structure: [ka] It has one of the following.

[0055] In other embodiments, L 1a L 1b and M 1 does not exist, the following structure: [ka] and R in the formula 8 is, in each occurrence, independently O, NH, or NRe and R 9 is independently, in each occurrence, H, alkyl, or optionally substituted alkyl; R 10 is, in each occurrence, independently H or F; R e is, at each occurrence, independently alkyl or optionally substituted alkyl.

[0056] In some embodiments, R 8 At least one occurrence of is O. In some embodiments, R 8 At least one occurrence of is NH. In some embodiments, R 8 At least one occurrence of NR e In some more particular embodiments, R 8 is, at each occurrence, independently O. In some more particular embodiments, R 8 is, at each occurrence, independently NH. In some more particular embodiments, R 8 is, in each occurrence independently, NR e is. In some embodiments, R 9 At least one occurrence of is H. In some embodiments, R 9 At least one occurrence of is alkyl. In some more particular embodiments, R 9 At least one occurrence of is a substituted alkyl. For example, in some embodiments, R 9 At least one occurrence of is an acyl group (such as -C(=O)CH3 or -C(=O)CH2CH3).

[0057] In some embodiments, R 10 At least one occurrence of is H. In some embodiments, R 10 At least one occurrence of is F. In some more particular embodiments, R 10 is, at each occurrence, independently H. In some more particular embodiments, R 10 is, at each occurrence independently, F. In certain embodiments, R 8 is O and R 9is H and R 10 is H. Some embodiments have the following structure (IA): [ka] (IA) or a compound having a stereoisomer, salt, or tautomer thereof.

[0058] Some embodiments have the following structure (IB): [ka] (IB) or a stereoisomer, salt, or tautomer thereof. Compounds of structure (IB) have a gemcitabine moiety incorporated into the polymer backbone and can act as a therapeutic agent. In some embodiments, R 6 or R 7 At least one occurrence of is F or H. In certain embodiments, R 6 or R 7 Each occurrence of is F or H. In some more particular embodiments, R 6 and R 7 At least each occurrence of is F and R 8 is O and R 9 is H and R 10 is H.

[0059] Some embodiments have the following structure (IC): [ka] (I C) or a stereoisomer, salt, or tautomer thereof, wherein k in each occurrence is an integer of 0 or greater.

[0060] In some embodiments, L 4 At least one occurrence of L is heteroalkylene. 4 Each occurrence of L is heteroalkylene.4 At least one occurrence of L is an alkylene oxide. 4 In some more particular embodiments, the alkylene oxide is ethylene oxide. In certain embodiments, L 4 In each occurrence, the following structure: [ka] and During the ceremony, z is an integer from 1 to 100, * indicates a bond to an adjacent phosphorus atom.

[0061] 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. In some other embodiments, z ranges from 19 to 28. In certain embodiments, the average z is 23. In some embodiments, the average z is 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28. In other embodiments, L 4 At least one occurrence of is an alkylene linker (e.g., methylene). In some more particular embodiments, L 4 is an alkylene linker (e.g., methylene) in each occurrence.

[0062] In some embodiments, in the compound of structure (I), [ka] At least one occurrence of has the following structure: [ka] including one of the following: In the formula, 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.

[0063] In some embodiments, at each occurrence, in a compound of structure (I), [ka] has the following structure: [ka] including one of the following: In the formula, 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.

[0064] Some embodiments include the following structure (ID), (IE), or (IF): [ka] (ID) JPEG2025531424000020.jpg29165(IE) or JPEG2025531424000021.jpg21165(IF) or a stereoisomer, salt, or tautomer thereof.

[0065] In some embodiments, L 3 , L 5 , and L 6is, at each occurrence, independently a direct bond or independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker. In some embodiments, L 3 , L 5 , or L 6 is, independently at each occurrence, alkylene. In more embodiments, L 3 , L 5 , or L 6 is, in each occurrence, independently C-C alkylene, C-C alkenylene, or C-C alkynylene. 3 and L 5 The alkylene linker in is a C alkyl linker. In some more particular embodiments, L 3 and L 5 The alkylene linker in L is a C alkyl linker. 3 and L 5 The alkylene linker in is a C alkyl linker. In some more particular embodiments, L 3 and L 5 The alkylene linker in is a C4 alkyl linker. In some more particular embodiments, L 3 and L 5 The alkylene linker in is a C5 alkyl linker. In some more particular embodiments, L 3 and L 5 The alkylene linker is a C6 alkyl linker.

[0066] In certain embodiments, L 6 The alkylene linker in L is a C alkyl linker. 6 The alkylene linker in L is a C alkyl linker. 6 The alkylene linker in L is a C alkyl linker. 6 At least one occurrence of L is a direct bond. 6 Each occurrence of is a direct bond.

[0067] Some embodiments include the following structures (IG), (IH), or (IJ): [ka] (IG) JPEG2025531424000023.jpg28165(IH) or JPEG2025531424000024.jpg21165(IJ) or a stereoisomer, salt, or tautomer thereof, During the ceremony, y 1 is, in each occurrence, independently an integer from 0 to 6, y 2 and y 3 is, at each occurrence, independently an integer from 1 to 6.

[0068] In some embodiments, y 1 is the integer 0 in each occurrence (i.e., L 6 is a direct bond). In some embodiments, y 1 is the integer 1 in each occurrence. In some embodiments, y 1 is the integer 2 in each occurrence. In some embodiments, y 1 is the integer 3 in each occurrence. 1 In some embodiments, y is the integer 4 in each occurrence. 1 In some embodiments, y is the integer 5 in each occurrence. 1 is the integer 6 in each occurrence. In some embodiments, y 2 and y 3 is the integer 1 in each occurrence. In some embodiments, y 2 and y 3 is the integer 2 in each occurrence. In some embodiments, y 2 and y 3 is the integer 3 in each occurrence. 2and y 3 In some embodiments, y is the integer 4 in each occurrence. 2 and y 3 In some embodiments, y is the integer 5 in each occurrence. 2 and y 3 is the integer 6 in each occurrence. In certain embodiments, y 1 is an integer 0 or 1 in each occurrence, and y 2 and y 3 is 1 for each occurrence.

[0069] Linker L 1b is the M 1 For example, in some embodiments, a synthetic precursor to a compound of structure (I), depicted below as structure (II), can be prepared and used as a point of attachment for a moiety, M 1 Moieties are attached to synthetic precursors using any number of coupling methods known in the art, such as the method known as "click chemistry." To this end, any reaction that is rapid and substantially irreversible can be used to attach M 1 may be attached to a synthetic precursor to form a compound of structure (I). Exemplary reactions include copper-catalyzed reaction of azides and alkynes to form triazoles (Husgen 1,3-dipolar cycloaddition), reactions of dienes and dienophiles (Diels-Alder), strain-promoted alkyne-nitrone cycloaddition, reactions of strained alkenes with azides, tetrazines, or tetrazoles, alkene and azide [3 + 2] cycloaddition, alkene and tetrazine inverse demand Diels-Alder reactions, alkene and tetrazole photoreactions, and various substitution reactions such as displacement of a leaving group by nucleophilic attack on an electrophilic atom. Exemplary substitution reactions include reactions of amines with activated esters, N-hydroxysuccinimide esters, isocyanates, isothioscyanates, and the like. In some embodiments, L 1b The reaction to form L may be carried out in an aqueous environment. 1bis a linker that, at each occurrence, contains a functional group formable by reaction of two complementary reactive groups, e.g., a functional group that is the product of one of the "click" reactions described above.

[0070] In more embodiments, L 1b At least one occurrence of comprises a functional group formed by reaction of an aldehyde, oxime, hydrazone, alkyne, amine, azide, acyl azide, acyl halide, nitrile, nitrone, sulfhydryl, disulfide, sulfonyl halide, isothiocyanate, imido ester, activated ester, ketone, α,β-unsaturated carbonyl, alkene, maleimide, α-haloamide, epoxide, aziridine, tetrazine, tetrazole, phosphine, biotin, or thiirane with a complementary reactive group.

[0071] In more particular embodiments, L 1b At least one occurrence of L contains a functional group formed by reaction of an alkyne and an azide. 1b At least one occurrence of L is a linker comprising a triazolyl functional group. 1b -M 1 At least one occurrence of has the following structure: [ka] including one of the following: In the formula, L c and L d are each independently an optional linker.

[0072] In some embodiments, L c or L d In some other embodiments, L is absent. c or L d In certain embodiments, L c and L d When present, each independently is alkylene or heteroalkylene. c and L dmay independently have the following structure: [ka] It has one of the following.

[0073] In some embodiments, M 1 -L 1b has the following structure: [ka] including one of the following: wherein a, b, c, and d are each independently an integer ranging from 1 to 6. In some embodiments, a, b, c, and d are each independently the integer 1. In some embodiments, a, b, c, and d are each independently the integer 2. In some embodiments, a, b, c, and d are each independently the integer 3. In some embodiments, a, b, c, and d are each independently the integer 4. In some embodiments, a, b, c, and d are each independently the integer 5. In some embodiments, a, b, c, and d are each independently the integer 6.

[0074] In some embodiments, M 1 -L 1b At least one occurrence of has the following structure: [ka] It has one of the following.

[0075] In some embodiments, M 1 -L 1b Each occurrence of has the following structure: [ka] It has one of the following.

[0076] In other embodiments, L 1b is H in at least one occurrence. In this respect, the compound has the structure (IB), (IC), (IE), (IF), (IH), or (IJ). In other embodiments, L 1bis H in each occurrence. At this point, the compound has the structure (IB), (IE), or (IH).

[0077] Some embodiments have structure (III): [ka] (III) or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein: M 2 is, independently at each occurrence, a moiety comprising a fluorescent dye; M 3 is, independently at each occurrence, a moiety that comprises a biologically active moiety; L 7 is, in each occurrence, independently a linker; L 2 , L 3 , L 5 , and L 6 is, in each occurrence, independently a direct bond or independently an optional 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 OH, SH, O-, S-, OR d , or SR d and R c 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, in each occurrence, is independently a moiety that contains a reactive group or a protected form thereof that is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L', in 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 (III); m in each occurrence is independently 0 or a greater integer; q, in each occurrence, is independently 0 or a greater integer; v, in each occurrence, is independently an integer of 1 or greater; and n is an integer of 2 or greater; The compounds are provided as compounds comprising at least two different biologically active moieties.

[0078] The compounds of structure (III) have a peptide-based backbone. Various linkers and substituents (e.g., M 2 , M 3 , Q, R 1 , R 2 , R 21 , L 1a , L 1b , L 2 , L 3 , L 5 , L 6 , L 7, and L') are optionally substituted with one more 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 (III). In certain embodiments, each alkyl, alkoxy, alkyl ether, heteroalkyl, alkylaminyl, alkylcarbonyl, or alkoxycarbonyl in the compound of structure (III) is optionally substituted with one more substituent selected from the group consisting of hydroxyl, alkoxy, alkyl ether, alkoxyalkyl ether, sulfhydryl, amino, alkylamino, carboxyl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, and thiophosphoalkylether. In certain 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 certain embodiments, the substituents are selected to increase cell or tissue penetration. In related embodiments, the substituents are selected to increase cell or tissue retention.

[0079] 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 21is, in each occurrence, independently H, alkyl, -CH2CO2 - , -CH2CH2CO2 - , -CH2CH2CH2CH2NH3 + , -CH2CH2CH2NHC(=NH2 + )NH2, or imidazolyl. In more particular embodiments, R 21 , L 5 , and m is [ka] But, (G) 10 , (GDGDGDGDGD), or (GKGKGKGKGK).

[0080] In another embodiment, R 21 , L 5 , and m is [ka] is selected to have an amino acid sequence capable of forming an α-helical or β-sheet secondary structure. In some such embodiments, the amino acid sequence is (GGEEFMLVYKFARKHGG) or (GGMSMVVSGG).

[0081] In some embodiments, L 5 or L 3 or both are present in at least one occurrence. In more particular embodiments, when present, L 5 or L 3 or both are heteroalkylene linkers. 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, L 5 or L 3 At least one occurrence of either or both has the following structure: [ka] It has.

[0082] In some embodiments, L 5 or L 3 At least one occurrence of either or both has the following structure: [ka] It has.

[0083] In some embodiments, L 6 and L 2 is independently absent or a heteroalkylene linker. In more particular embodiments, the heteroalkylene linker is a peptidyl linker.

[0084] Some embodiments have structure (IV): [ka] (IV) or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein: M 2 is, independently at each occurrence, a moiety comprising a fluorescent dye; M 3 is, independently at each occurrence, a moiety that comprises a biologically active moiety; L 7 is, independently in each occurrence, a linker; L 2 , L 5 , and L 6 is, in each occurrence, independently a direct bond or independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatomic linker; L 8 is, in each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker that includes one or more charged moieties, provided that at least one charged moiety is not a phosphate ester; R 3is, 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 OH, SH, O - , S - , OR d , or SR d and R c 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, in each occurrence, is independently a moiety that contains a reactive group or a protected form thereof that is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L', in 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 (IV); q, in each occurrence, is independently 0 or a greater integer; v, in each occurrence, is independently an integer of 1 or greater; and n is an integer of 2 or greater; The compounds are provided as compounds comprising at least two different biologically active moieties.

[0085] Various linkers and substituents in compounds of structure (IV) (e.g., M 2 , M 3 , Q, R 1 , R 2 , R 3 , L 1a , L 1b , L 2 , L 5 , L 6 , L 7 , L 8 , and L') are optionally substituted with another substituent. For example, in some embodiments, optional substituents are selected to optimize the water solubility, permeability, retention, or other properties of the compound of structure (IV). In certain embodiments, each alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatomic linker, or alkyl, alkoxy, alkylether, heteroalkyl, alkylaminyl, alkylcarbonyl, or alkoxycarbonyl in the compound of structure (IV) 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 certain 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 counter ion. In certain embodiments, the substituents are selected to increase cell or tissue penetration. 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.

[0086] In some embodiments, the charged moieties are positively charged. In more particular embodiments, the charged moieties comprise a protonated amine or quaternary amine functional group. In more particular embodiments, the charged moieties independently have the following structure: [ka] and During the ceremony, R, in each occurrence, is independently H or C1-C6 alkyl.

[0087] In other embodiments, the charged moiety is negatively charged. In certain embodiments, the charged moiety comprises a carboxylic acid, phosphate, or sulfate functional group. In some embodiments, the charged moiety has the following structure: [ka] It has.

[0088] In some embodiments, the charged moieties include a combination of positively and negatively charged moieties. In certain embodiments, the charged moiety is pendant to the backbone of the compound (e.g., attached to a 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 continuous chain of the linker). In some embodiments, L 8 has the following structure: [ka] including one of the following: During the ceremony, R, in each occurrence, is independently H or C1-C6 alkyl; x is an integer from 0 to 6, m is an integer of 1 or greater, where m is selected such that the compound contains at least two charged moieties.

[0089] Linker L 7 is the M 2 and M 3 For example, in some embodiments, synthetic precursors to compounds of structure (I) can be prepared, and M 2 and M 3 The moiety is attached to the synthetic precursor using any number of coupling methods known in the art. 7 At least one occurrence of L 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, L 7 or L 1b At least one occurrence of has the following structure: [ka] Includes one of the following.

[0090] In more embodiments, L 7Each occurrence of L 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. In more particular embodiments, L 7 or L 1b Each occurrence of has the following structure: [ka] Includes one of the following.

[0091] In some embodiments, R 3 At least one occurrence of is H. In some embodiments, R 3 At least one occurrence of R is alkyl. 3 At least one occurrence of R is alkoxy. 3 Each occurrence of is H. In some embodiments, R 5 At least one occurrence of is oxo (=O). In some embodiments, R 5 At least one occurrence of is thioxo (=S). In certain embodiments, R 5 Each occurrence of is an oxo (=O). In some embodiments, R 4 At least one occurrence of is OH. In some embodiments, R 4 At least one occurrence of R is SH. 4 At least one occurrence of O - In some embodiments, R 4 At least one occurrence of S - In certain embodiments, R 4 Each occurrence of O - is.

[0092] In various other embodiments, R 1 and R 2 are each independently OH or -OP(=R a )(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 is Q or a linker comprising a covalent bond to Q. In yet another embodiment of the above compounds of structures (I), (III), and (IV), R 1 and R 2 are each independently -OP(=R a )(R b )R c In some of these embodiments, R c is OL'.

[0093] 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 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), (III), or (IV). 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), (III), or (IV) to a compound of structure (I), (III), or (IV). Advantageously, certain embodiments include the use of an L' moiety selected to increase or optimize the water solubility of the compound. In certain embodiments, L' is a heteroalkylene moiety. In some other certain embodiments, L' comprises an alkylene oxide or a phosphodiester moiety, or a combination thereof.

[0094] In some embodiments, R 2is 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 other embodiments, R 2 or R 1 is L', where L' is a linker comprising a covalent bond to a solid support. In certain embodiments, the solid support is a polymeric bead or a non-polymeric bead.

[0095] In certain embodiments, L' is a linker to a targeting moiety, said linker comprising an alkylene oxide or a phosphodiester moiety, or a combination thereof. In other embodiments, L' has the following structure: [ka] and During the ceremony, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 are independently integers from 1 to 10, R b is H, an electron pair, or a counterion, L'' is a targeting moiety or a link to a targeting moiety.

[0096] 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 8is 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 , x 2 , 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.

[0097] 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.

[0098] In some embodiments, L" is a 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 particular 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, guselkumab ab), Ibalizumab, Idarucizumab, Infliximab, Itolizumab, Ixekizumab, Lanadelumab, Lokivetmab, Mepolizumab, Natalizumab, Obiltoxaximab,Ocrelizumab, Omalizumab, Palivizumab, Ranibizumab, Raxibacumab, Reslizumab, Rmab, Rovelizumab, Ruplizumab, Sarilumab, Secukinumab, Tildrakizumab, 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 ikumab), Briakinumab, Brolucizumab, Carlumab, Carotuximab, Cedelizumab, Clazakizumab, Clenoliximab, Concizumab, Cosfroviximab, CR6261, Crenezumab, Crizanlizumab, Clotedumab,Depatuxizumab, mafodotin, derlotuximab biotin, dezamizumab, diridavumab, domagrozumab, dusigitumab, ecromeximab, edobacomab, efalizumab, efungumab, eldelumab, elezanumab, enokizumab, Eptinezumab, Erlizumab, Etrolizumab, Evinacumab, Exbivirumab, Fanolesomab, Faralimomab, Faricimab, Fasinumab, Felvizumab, Fezakinumab, Flavotumab Nvotumab, Fletikumab, Flotetuzumab, Fontolizumab, Foravirumab, Frovocimab, Fulranumab, Gantenerumab, Gavilimomab, Gevokizumab, Gimsilumab, Gomiliximab imab), 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, Otelixizumab Otelixizumab, Otilimab, Oxelumab, Ozanezumab, Ozoralizumab, Pagibaximab, Panobacumab, Pascolizumab, Pateclizumab, PDR001, Pela Perakizumab, Pexelizumab, Placulumab, Plozalizumab, Ponezumab, Porgaviximab, Prasinezumab, Priliximab, PRO140, Quilizumab ab), Rafivirumab, Ralpancizumab, Ranevetmab, Ravagalimab, Ravulizumab, Refanezumab, Regavirumab, Relatlimab, Linucumab,Risankizumab, Rolezumab, Romosozumab, Rontalizumab, SA237, Satralizumab, Sevirumab, SHP647, Sifalimumab, Simtuzumab, Siplizumab, Sirukumab, Solanezumab, Sonepcizumab, Spa 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, is.

[0099] In other more particular embodiments of any of the above-described compounds of structure (I), R 1 or R 2 has the following structure: [ka] and R in the formula a is H or a solid support.

[0100] In certain embodiments, R 2 has the following structure: [ka] It has one of the following.

[0101] Certain embodiments of compounds of structure (I) 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 may, in some embodiments, be used as starting materials for preparing compounds of structure (I). Thus, in certain embodiments, R 1 has the following structure: [ka] It has.

[0102] Those skilled in the art will appreciate that the dT group depicted above is included merely 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 in L', or the nucleoside or solid support moiety may be removed or modified after synthesis. 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 some further embodiments, the solid support is a polymeric bead or a non-polymeric bead.

[0103] In still other embodiments, Q, at each occurrence, independently, is a moiety that includes a reactive group capable of forming a covalent bond with an analyte molecule or a solid support. In other embodiments, Q, at each occurrence, independently, is a moiety that includes a reactive group that can form a covalent bond with a complementary reactive group, Q'. For example, in some embodiments, Q' is present in a further compound of structure (I) (e.g., R 1 Rank or R 2 Positions (Q), Q, and Q' contain complementary reactive groups, such that reaction of a compound of structure (I) with an additional compound of structure (I) results in a covalently linked dimer of the compound of structure (I). Multimeric compounds of structure (I) may also be prepared in an analogous manner and are included within the scope of embodiments of the present disclosure.

[0104] The type of Q group and its connectability to the remainder of the compound of structure (I) is not limited, so long as Q contains a moiety with appropriate reactivity to form the desired bond. In certain embodiments, Q is a moiety that is resistant to hydrolysis under aqueous conditions but is sufficiently reactive to form a bond with a corresponding group (e.g., an amine, azide, or alkyne) on an analyte molecule or solid support. Certain embodiments of the compound of structure (I) include a Q group commonly used in the field of bioconjugation. For example, in some embodiments, Q includes a nucleophilic reactive group, an electrophilic reactive group, or a cycloaddition reactive group. In some more specific embodiments, Q includes a sulfhydryl, disulfide, activated ester, isothiocyanate, azide, alkyne, alkene, diene, dienophile, acid halide, sulfonyl halide, phosphine, α-haloamide, biotin, amino, or maleimide functional group. In some embodiments, the activated 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.

[0105] The Q group can be conveniently provided in a protected form to increase storage stability or other desired properties, and the protecting group is then removed at a time appropriate for conjugation, for example, with a targeting moiety or analyte. Thus, the Q group includes a "protected form" of a reactive group, including any of the reactive groups described above and in Table 1 below. A "protected form" of Q refers to a moiety that is less reactive than Q under given reaction conditions, but that can be converted to Q under conditions that preferably do not decompose or react with other moieties of the compound of structure (I). Those 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 includes a disulfide, which can be reduced to expose the SH moiety using commonly known techniques and reagents.

[0106] Exemplary Q moieties are provided in Table I below. [Table 2-1] [Table 2-2] [Table 2-3]

[0107] It should be noted that in some embodiments, when Q is SH, the SH moiety will have a tendency to form a disulfide bond with another sulfhydryl group of another compound, for example, of structure (I). Thus, some embodiments include compounds of structure (I) that are in the form of a disulfide dimer, where the disulfide bond is derived from the SH Q group.

[0108] 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 conjugation to a desired analyte molecule or targeting moiety. For example, the Q moiety may have the following structure: [ka] and wherein R is an optionally substituted alkyl group. For example, in some embodiments, Q has the following structure: [ka] and a disulfide moiety having the formula: In the formula, n is an integer from 1 to 10.

[0109] In some embodiments, M 2 is, in one or more occurrences, independently a moiety that contains four or more aryl or heteroaryl rings or a combination thereof. In some embodiments, M 2 is, in one or more occurrences, independently fluorescent or colored. In certain embodiments, M 2 is fluorescent in one or more occurrences. In other embodiments, M 2 In one or more occurrences, independently, M comprises a fused polycyclic aryl or heteroaryl moiety comprising at least four fused rings. 2is, 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. 2 is, at each occurrence, independently selected from the group consisting of p-terphenyl, perylene, azobenzene, phenazine, phenanthroline, acridine, thioxanthrene, chrysene, rubrene, coronene, cyanine, perylene imide, perylene amide, and derivatives thereof. 2 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. 2 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. In certain embodiments, M 2 may, in each occurrence, independently have the structure: [ka] It has one of the following.

[0110] In some embodiments, M 2 At least one occurrence of has the following structure: [ka] It has.

[0111] In some more particular embodiments, M 2 Each occurrence of has the following structure: [ka] It has.

[0112] In some embodiments, -L 7 -M 2 At least one occurrence of has the following structure: [ka] It has one of the following. In some more particular embodiments, -L 7 -M 2 Each occurrence of has the following structure: [ka] It has one of the following.

[0113] M 1 and M 3 is selected based on the desired alkylation properties. 1 and M 3 is the same in each occurrence, but M 1 and M 3 Each occurrence of 1 and M 3 It is not necessary that the 1 and M 3 It is important to note that each occurrence of M includes compounds that are not the same. For example, in some embodiments, each M 1 and M 3 are not the same, but different M 1 and M 3 The moieties are selected to have different alkylating agents. 1 and M 3 The moieties may be appropriately selected by one skilled in the art based on the desired end use. Furthermore, in some embodiments, the alkylating agent is protected with protecting groups such as allyloxycarbonyl (-Alloc) and tert-butyldimethylsilyl ether (-TBS) to survive the DNA synthesis cycle. The Alloc protecting group can be easily cleaved with a palladium catalyst, e.g., Pd(PPh) with PhSiH, to give the corresponding amine. The TBS protecting group can be cleaved with a fluoride source, such as tetra-n-butylammonium fluoride (TBAF), to give the corresponding alcohol. Once deprotection is complete, the PBD moiety is activated and capable of alkylation. At this point, the PBD moiety remains protected with a protecting group until the DNA synthesis cycle is complete. Deprotection can then convert the alkylation-inactive protected PBD moiety into an alkylation-active deprotected PBD moiety.

[0114] In some embodiments, M 1 or M 3 At least one occurrence of the moiety is an alkylating agent, an antimetabolite, a microtubule inhibitor, a topoisomerase inhibitor, or a cytotoxic antibiotic. 1 or M 3 Each occurrence of M is an alkylating agent, an antimetabolite, a microtubule inhibitor, a topoisomerase inhibitor, or a cytotoxic antibiotic. 1 or M 3 At least one occurrence of M is a nitrogen mustard, a nitrosourea, a tetrazine, an aziridine, cisplatin or a cisplatin derivative, or a non-classical alkylating agent. 1 or M 3At least one occurrence of is mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide, busulfan, N-nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU), semustine (MeCCNU), fotemustine, streptozotocin, dacarbazine, mitozolomide, temozolomide, thiotepa, mytomycin, diaziquone (AZQ), cisplatin, carboplatin, oxaliplatin, procarbazine, or hexamethylmelamine. 1 or M 3 At least one occurrence of M is an antifolate, a fluoropyrimidine, a deoxynucleoside analog, or a thiopurine. 1 or M 3 At least one occurrence of is methotrexate, pemetrexed, fluorouracil, capecitabine, cytarabine, gemcitabine, decitabine, azacitidine, fludarabine, nelarabine, cladribine, clofarabine, pentostatin, thioguanine, and mercaptopurine. 1 or M 3 At least one occurrence of M is an auristatin, a vinca alkaloid, or a taxane. 1 or M 3 At least one occurrence of M is auristatin F, auristatin E, vincristine, vinblastine, vinorelbine, vindesine, vinflunine, paclitaxel, docetaxel, etoposide, or teniposide. 1 or M 3 At least one occurrence of M is irinotecan, SN38, topotecan, camptothecin, doxorubicin, mitoxantrone, teniposide, novobiocin, mervalone, or aclarubicin. 1 or M 3 At least one occurrence of M is an anthracycline or a bleomycin. 1 or M 3At least one occurrence of M is doxorubicin, daunorubicin, epirubicin, idarubicin, pirarubicin, aclarubicin, or mitoxantrone. 1 or M 3 is auristatin F, monomethyl auristatin F, monomethyl auristatin E, paciltaxol, SN-38, calicheamicin, anthramycin, aveimicin, ticamycin, DC-81, mazethramycin, neothramycin A, neothramycin B, polothramycin, prothracarcin, sivanomycin, sibiromycin, tomamycin, mertansine, emtansine, irinotecan, camptothecin, topotecan, silatecan, cositecan, exatecan, lurtotecan, gimatecan, belotecan, and rubitecan. 1 or M 3 are auristatin F, monomethyl auristatin F, monomethyl auristatin E, paciltaxol, SN-38, calicheamicin, anthramycin, abeimicin, ticamycin, DC-81, mazethramycin, neothramycin A, neothramycin B, polothramycin, prothracarcin, sivanomycin, sibiromycin, tomamycin, mertansine, emtansine, irinotecan, camptothecin, topotecan, ciratecan, cositecan, exatecan, lurtotecan, gimatecan, belotecan, and rubitecan.

[0115] M 1 or M 3 are M 1 or M 3 The remainder of the molecule may be attached at any position (i.e., atom) of M. 1 or M 3 For example, M 1 or M 3 can be attached to the rest of the molecule through the nitrogen of the diazepine, the oxygen of the diazepine or phenyl ring, or the carbon of the pyrrolidine ring.

[0116] In some embodiments, M 1 or M 3 At least one occurrence of has the following structure: [ka] It has one of the following.

[0117] In some embodiments, M 1 or M 3 Each occurrence of has the following structure: [ka] It has one of the following.

[0118] In some certain embodiments, the compound is a compound selected from Table 2A. The compounds of Table 2A are prepared according to the procedures provided 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

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

Table 3-22

Table 3-23

Table 3-24

Table 3-25

Table 3-26

Table 3-27

[0119] Additionally, in some embodiments, M 3 At least one occurrence of M is an anti-inflammatory compound. 3 is a steroid, a biologically active organic compound having four rings arranged in a specific molecular configuration as shown below. For example, in some embodiments, M 3 At least one occurrence of is cholesterol, cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or beclomethasone. 3 At least one occurrence of has the following structure: [ka] and During the ceremony, R 11 is H or a halogen, R 12 and R 13 are 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 R18 is H, alkyl, or substituted alkyl, and [ka] represents a single or double carbon-carbon bond.

[0120] In some embodiments, M 3 At least one occurrence of has the following structure: [ka] It has one of the following.

[0121] In certain embodiments, the compound is a compound selected from Table 2B. The compounds of Table 2B are prepared according to the procedures provided in the Examples. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] M in the formula 3has the following structure: [ka] and During the ceremony, [ka] has the following structure: [ka] is selected from M in the formula 1 has the following structure: [ka] It has one of the following.

[0122] In some embodiments, M 3 At least one occurrence of is a vitamin. For example, in some embodiments, 3 At least one occurrence of M is vitamin E. In some more particular embodiments, M 3 At least one occurrence of M is tocopherol. 3 is α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, or δ-tocotrienol.

[0123] In some embodiments, M 3 At least one occurrence of has the following structure: [ka] and During the ceremony, R 19 and R 20 is independently H or CH3, and [ka] represents a single or double carbon-carbon bond.

[0124] In certain embodiments, M 3 At least one occurrence of has the following structure: [ka] It has one of the following.

[0125] In certain embodiments, the compound is a compound selected from Table 2C. The compounds of Table 2C are prepared according to the procedures provided in the Examples. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] M in the formula 3 has the following structure: [ka] and During the ceremony, [ka] has the following structure: [ka] is selected from M in the formula 1 has the following structure: [ka] It has one of the following.

[0126] In certain embodiments, the compound of structure (III) is selected from Table 2D. The compounds of Table 2D are prepared according to the procedures set forth in the Examples. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0127] In certain embodiments, the compound of structure (IV) is selected from Table 2E. The compounds of Table 2E are prepared according to the procedures set forth in the Examples. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8]

[0128] As used in Tables 2D-2E and throughout this application, M 3 has the following structure: [ka] [ka] [ka] It has one of the following.

[0129] The fluorescence intensity or efficacy for DNA alkylation may also be adjusted by selecting different values ​​of n. In some embodiments, for Structure (I), n is an integer of 1 or greater. In certain embodiments, for Structure (I), n is an integer from 1 to 100. In other embodiments, for Structure (I), n is an integer from 1 to 10. In some embodiments, for Structure (I), n is 1. In some embodiments, for Structure (I), n is 2. In some embodiments, for Structure (I), n is 3. In some embodiments, for Structure (I), n is 4. In some embodiments, for Structure (I), n is 5. In some embodiments, for Structure (I), n is 6. In some embodiments, for Structure (I), n is 7. In some embodiments, for Structure (I), n is 8. In some embodiments, for Structure (I), n is 9. In some embodiments, for Structure (I), n is 10.

[0130] In some embodiments of Structures (III) and (IV), n is an integer of 2 or greater. In certain embodiments, for Structures (III) and (IV), n is an integer from 2 to 100. In other embodiments, for Structures (III) and (IV), n is an integer from 2 to 10. In some embodiments, for Structures (III) and (IV), n is 2. In some embodiments, for Structures (III) and (IV), n is 3. In some embodiments, for Structures (III) and (IV), n is 4. In some embodiments, for Structures (III) and (IV), n is 5. In some embodiments, for Structures (III) and (IV), n is 6. In some embodiments, for Structures (III) and (IV), n is 7. In some embodiments, for Structures (III) and (IV), n is 8. In some embodiments, for Structures (III) and (IV), n is 9. In some embodiments, for Structures (III) and (IV), n is 10.

[0131] The fluorescence or effectiveness for DNA alkylation can also be adjusted by selecting the value of m. The value of m is determined by the adjacent M 1 , M 2 , or M 3 In some embodiments, m is an integer between 0 and 100. In certain embodiments, m is an integer between 0 and 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 certain embodiments, m is 1 or 2. Fluorescence intensity can be tuned by the number of fluorescent dye moieties attached to the polymer backbone. The value of q has the ability to control the brightness of the compound. In some embodiments, q, in each occurrence, is an integer of 0 or greater. In some more specific embodiments, q is from 0 to 10. In some embodiments, q is from 0 to 5. For example, in some embodiments, q is 0. 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 other embodiments, q is 0, 1, 2, 3, or 4. In some other embodiments, q is 1 or 2.

[0132] The effectiveness of DNA alkylation can also be adjusted by selecting the value of p. In some embodiments, p, in each occurrence, is an integer of 0 or greater. 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 1, 2, 3, or 4. In some other embodiments, p is 2 or 3. The effectiveness of DNA alkylation can also be adjusted by selecting the value of w. In some embodiments, w is an integer of 0 or greater in each occurrence. In some more particular embodiments, w is 0 to 10. In some embodiments, w is 0 to 5. In some embodiments, w is 1 to 5. For example, in some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, w is 5. In some other embodiments, w is 0, 1, 2, 3, or 4. In some other embodiments, w is 1 or 2.

[0133] In some embodiments of structure (III) or (IV), v is an integer of 1 or greater. 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. The values ​​of n, q, w, p, and m are closely related, providing the ability to control fluorescence and efficacy for DNA alkylation. In certain embodiments, n is 1, q is 2, w is 2, p is 2, and m is 1. In certain other embodiments, n is 1, q is 2, w is 1, p is 3, and m is 1.

[0134] M 1 The biologically active moiety of the fluorescent dye M 2 , and M 3 The ratio of biologically active moieties of M may be fine-tuned based on the type of disease, the progression of the disease, the treatment method, and / or the diagnostic method used for treatment. For example, in some embodiments, 1 :M 2 :M 3 In some other embodiments, the ratio of M 1 :M 2 :M 3 In some still further embodiments, M 1 :M 2 :M 3 is 2:1:1. In another embodiment, when q is 0, M 1 :M 2 :M 3 In other particular embodiments, when q is 0, M 1 :M 2 :M 3 is 1:0:2. In yet another embodiment, when q is 0, M 1 :M 2 :M3 is 2:0:1.

[0135] Pharmaceutical Composition In one embodiment, a composition is provided comprising a compound according to any one of the embodiments of the present disclosure (e.g., a compound of structure (I), (III), or (IV)) and a pharmaceutically acceptable carrier. Other embodiments are directed to pharmaceutical compositions. The pharmaceutical composition comprises any one (or more) of the compounds of structure (I), (III), or (IV) and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In even more embodiments, the pharmaceutical composition comprises a compound of structure (I), (III), or (IV) and an additional therapeutic agent (e.g., an anti-cancer agent). Non-limiting examples of such therapeutic agents are described below.

[0136] 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 delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection. In certain embodiments, the compound of structure (I), (III), or (IV) is administered locally rather than systemically, for example, by injecting the compound directly into an organ, often in a depot or sustained-release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered by a targeted drug delivery system, for example, a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets and is selectively taken up by the organ. In still other embodiments, the compound of structure (I), (III), or (IV) is provided in the form of an immediate-release formulation, a sustained-release formulation, or an intermediate-release formulation. In still other embodiments, the compound of structure (I), (III), or (IV) is administered locally.

[0137] The compounds of structure (I), (III), or (IV) are effective over a wide dosage range. 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 vary depending on the route of administration, the form in which the compound is administered, the subject being treated, the body weight of the subject being treated, and the preference and experience of the attending physician. In some embodiments, the compound of structure (I), (III), or (IV) is administered in a single dose. Typically, such administration will be by injection, e.g., intravenous injection, to rapidly introduce the agent. However, other routes may be used if desired. A single dose of the compound of structure (I), (III), or (IV) may also be used to treat acute conditions. In some embodiments, the compound of structure (I), (III), or (IV) is administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, dosing is about once per month, once every two weeks, once per week, or once every other day. In another embodiment, the compound of structure (I), (III), or (IV) and another agent are administered together about once per day to about six times per day. In another embodiment, administration of the compound of structure (I), (III), or (IV) and the agent continues for less than about 7 days. In yet another embodiment, administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous dosing is achieved and maintained for as long as necessary.

[0138] Administration of a compound of structure (I), (III), or (IV) can continue for as long as necessary. In some embodiments, a compound of structure (I) is administered for a period longer than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of structure (I), (III), or (IV) is administered for a period shorter than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of structure (I), (III), or (IV) is administered chronically, for example, to treat a chronic effect, on an ongoing basis. In some embodiments, the compound of structure (I), (III), or (IV) is administered in multiple dosages.It is known in the art that compound pharmacokinetics varies between subjects, so optimal treatment requires individualized dosing regimens.Dosages for the compounds of the present disclosure can be found by routine experimentation in light of the present disclosure.

[0139] In some embodiments, the compound of structure (I), (III), or (IV) is formulated into a pharmaceutical composition. In certain embodiments, the pharmaceutical composition is conventionally formulated using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. The pharmaceutical compositions described in this disclosure may be formulated using any pharmaceutically acceptable techniques, carriers, and excipients suitable as described in Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, PA: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York City, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999).

[0140] The present disclosure provides pharmaceutical compositions comprising a compound of structure (I), (III), or (IV) and a pharmaceutically acceptable diluent, excipient, or carrier. In certain embodiments, the described compounds are administered as pharmaceutical compositions in which a compound of structure (I), (III), or (IV) is mixed with other active ingredients, such as in combination therapy. The present disclosure encompasses all combinations of active agents set forth in the Combination Therapy section below and throughout the disclosure. In certain embodiments, the pharmaceutical composition comprises one or more compounds of structure (I), (III), or (IV). As used in this disclosure, a pharmaceutical composition refers to a mixture of a compound of structure (I), (III), or (IV) with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, the methods of treatment or use provided herein are practiced by administering a therapeutically effective amount of a compound of structure (I), (III), or (IV) provided herein as a pharmaceutical composition to a mammal having the disease, disorder, or medical condition to be treated. In certain embodiments, the mammal is a human. In certain 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 compound of structure (I), (III), or (IV) is used alone or in combination with one or more therapeutic agents as a component of a mixture.

[0141] In one embodiment, one or more compounds of structure (I), (III), or (IV) are formulated in an aqueous solution. In certain embodiments, the aqueous solution is selected from a physiologically compatible buffer, such as, by way of example only, Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more compounds of structure (I), (III), or (IV) are formulated for transmucosal administration. In certain embodiments, the transmucosal formulation includes a penetrant appropriate for the barrier to be permeated. In still other embodiments, where the compounds described herein are formulated for parenteral injection, suitable formulations include aqueous or non-aqueous solutions. In certain embodiments, such solutions include physiologically compatible buffers and / or excipients. In another embodiment, the compounds described herein are formulated for oral administration.The compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient.In various embodiments, the compounds described herein are formulated into oral dosage forms, including, but not limited to, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, and suspensions.

[0142] In certain embodiments, pharmaceutical preparations for oral use are prepared by mixing one or more solid excipients with one or more compounds described in the present disclosure, optionally grinding the resulting mixture, adding suitable adjuvants as needed, and then processing the granular mixture to obtain 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.

[0143] In one embodiment, dosage forms such as dragee cores and tablets are coated with one or more suitable coatings. In certain embodiments, concentrated sugar solutions are used to coat dosage forms. The sugar solutions optionally contain additional ingredients such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Also, color substances and / or pigments are optionally added to the coating for identification purposes. In addition, color substances and / or pigments are optionally used to distinguish different combinations of active compound doses.

[0144] In certain embodiments, at least one therapeutically effective amount of a compound described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. In certain embodiments, the push-fit capsules contain the active ingredient mixed 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 compounds 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.

[0145] In other embodiments, a therapeutically effective amount of at least one compound 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 yet other embodiments, a compound described herein is formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In certain embodiments, the injectable formulation is provided in unit dosage form (e.g., ampoules) or in multi-dose containers. Preservatives are optionally added to the injectable formulation. In still other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. Parenteral injection formulations optionally contain formulatory agents such as suspending agents, stabilizers, and / or dispersing agents. In certain embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In additional embodiments, suspensions of the active compound (e.g., a compound of structure (I), (III), or (IV)) are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain detailed 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 agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

[0146] In yet other embodiments, the compounds of structure (I), (III), or (IV) are administered topically. The compounds described herein 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. In yet other embodiments, the compounds of structure (I), (III), or (IV) are formulated for transdermal administration. In certain embodiments, transdermal formulations may be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in polymers or adhesives using transdermal delivery devices and transdermal delivery patches. In various embodiments, such patches are constructed to deliver pharmaceutical agents continuously, pulsatilely, or on demand. In additional embodiments, transdermal delivery of compounds of structure (I), (III), or (IV) is achieved by iontophoretic patches, etc. In certain embodiments, transdermal patches provide controlled delivery of compounds of structure (I), (III), or (IV). In certain embodiments, the rate of absorption is slowed by using rate-controlling membranes or by entrapment of the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist penetration through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage that includes a backing member, a reservoir containing the compound, optionally with a carrier, optionally a rate-controlling barrier for delivering the compound to the host's skin at a controlled, predetermined rate over an extended period of time, and a means for securing the device to the skin.

[0147] In other embodiments, the compounds of structure (I), (III), or (IV) are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders. Pharmaceutical compositions of any of the compounds of structure (I), (III), or (IV) are conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer by 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 certain embodiments, by way of example only, capsules and cartridges of gelatin or the like for use in an inhaler or insufflator are formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0148] In yet other embodiments, the compounds of structure (I), (III), or (IV) 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 and synthetic polymers such as polyvinylpyrrolidone and PEG. In suppository forms of the composition, a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with melted cocoa butter, is used. In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used suitably. Pharmaceutical compositions containing compounds of structure (I), (III), or (IV) are manufactured by conventional methods, such as, by way of example only, conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing methods.

[0149] Pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one compound of structure (I), (III), or (IV) as described herein as an active ingredient. The active ingredient may be in the form of a free acid, free base, or 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 such compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated forms and solvated forms with pharmaceutically acceptable solvents, such as water and ethanol. Solvated forms of the compounds presented herein are also considered to be disclosed herein. Additionally, pharmaceutical compositions optionally contain other medicinal or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, wetting agents, or emulsifiers, solubility enhancers, salts for regulating osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0150] Methods for preparing compositions containing the 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, 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 disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. 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 may also optionally contain minor amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents and pH buffering agents.

[0151] In some embodiments, pharmaceutical compositions comprising at least one compound of structure (I), (III), or (IV) are illustratively in the form of a liquid in which the agent is in solution, in suspension, or both. Typically, when the composition is administered as a solution or suspension, a first portion of the agent is in solution, and a second portion of the agent is 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. In certain 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 such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein contain a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0152] Useful pharmaceutical compositions also optionally include a solubilizing agent to aid in the solubility of the compounds of structure (I), (III), or (IV). The term "solubilizing agent" generally includes agents that result in the formation of a micellar or true solution of the agent. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers. Additionally, 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 citrate / dextrose, sodium bicarbonate, and ammonium chloride, etc. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0153] In addition, useful compositions optionally also contain one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include salts having sodium, potassium, or ammonium cations and 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. 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.

[0154] Still other useful compositions contain one or more surfactants to enhance 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. Still other useful compositions optionally include one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite. In certain embodiments, the aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case a preservative is typically included in the composition. In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery vehicles or carriers useful in the present disclosure. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In additional embodiments, the compounds described in the present disclosure are delivered using sustained-release systems, such as semipermeable matrices 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 up to 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization are used.

[0155] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizers. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% weight / volume glycerol, (b) about 0.1% to about 1% weight / volume methionine, (c) about 0.1% to about 2% weight / volume monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% weight / volume ascorbic acid, (f) 0.003% to about 0.02% weight / volume polysorbate 80, (g) 0.001% to about 0.05% weight / volume 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.

[0156] 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%, 0.06%, 0.1%. less 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% mass / mass, mass / volume, or volume / volume.

[0157] In some embodiments, the concentration of one or more compounds is 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%, 15%, 15%, 16 ...7.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15%, 15 4.75%, 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%, 0.05%, 0 Higher than 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% mass / mass, mass / volume, or volume / volume.

[0158] In some embodiments, the concentration of the 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 23%, The range is from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, from about 1% to about 10% mass / mass, mass / volume, or volume / volume. In some embodiments, the concentration of the 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%, about 0.1% to about 0.9% mass / mass, mass / volume, or volume / volume.

[0159] 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, 0.2 g, 0.15 g , 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g.

[0160] 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, 0.003g , 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.007 5g, 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, 0.5g , 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or more than 10g. In some embodiments, the amount of one or more compounds ranges from 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0161] Treatment method Certain compounds of the present disclosure are useful in the treatment of diseases (i.e., compounds of structure (I), (III), or (IV)). Such compounds disclosed in the present disclosure provide a targeted approach to drug delivery strategies. Accordingly, one embodiment provides a method for treating a disease (or a symptom thereof), comprising administering a therapeutically effective amount of a compound of structure (I), (III), or (IV) to a mammal (e.g., a human) in need thereof. For example, in certain embodiments, the present disclosure provides methods for treating solid tumors, multiple myeloma, glioma, clear cell renal cell carcinoma, prostate cancer, ovarian cancer, non-small cell lung cancer, GI malignancies, acute lymphoblastic leukemia, acute myeloid leukemia, renal cell carcinoma, colorectal cancer, epithelial cancer, pancreatic and gastric cancer, renal cell carcinoma, non-Hodgkin's lymphoma, metastatic renal cell carcinoma, malignant mesothelioma, pancreatic, ovarian, and / or lung adenocarcinoma, B-cell malignancies, breast cancer, melanoma, recurrent multiple myeloma, small cell lung cancer, CD22-positive B-cell malignancies, Hodgkin's lymphoma / anaplastic large cell lymphoma, or HER2-positive breast cancer.

[0162] In some of the above-described embodiments, the disease is cancer. For example, in certain embodiments, the cancer is breast cancer, non-Hodgkin's lymphoma, acute myeloid leukemia, multiple myeloma, gastric cancer, renal cell carcinoma, a solid tumor, ovarian cancer, prostate cancer, colorectal cancer, pancreatic cancer, small cell lung cancer, diffuse large B-cell lymphoma, a neoplasm, urothelial carcinoma, ALL, CLL, glioblastoma, Hodgkin's lymphoma, lymphoma, mesothelioma, non-small cell lung cancer, recurrent head and neck cancer, or a combination thereof.

[0163] Certain embodiments also relate to a method for treating a hyperproliferative disorder in a mammal (e.g., a human), comprising administering to the mammal a therapeutically effective amount of a compound of structure (I), (III), or (IV), or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.In some embodiments, the methods include the treatment of acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, notochordal tumor, tumors, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, central nervous system cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, osteofibrous histiocytoma, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumors, gastrointestinal Stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell neck cancer of unknown primary, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, bacteria Mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer for the treatment of cancers such as pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric (stomach) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, renal pelvis and ureter transitional cell carcinoma, trophoblastic tumor, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancers.In some embodiments, the methods relate to the treatment of non-cancerous hyperproliferative disorders, such as benign hyperplasia of the skin (eg, psoriasis), restenosis, or prostate (eg, benign prostatic hyperplasia (BPH)).

[0164] Certain detailed embodiments provide a method for treating lung cancer, comprising administering an effective amount of any of the compounds described above (or pharmaceutical compositions containing them) of structure (I), (III), or (IV) to a subject in need thereof. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In other embodiments, the lung cancer is small cell lung cancer. Other lung cancers that can be treated with the compounds of the present disclosure include, but are not limited to, adenocarcinoma, carcinoid tumor, and undifferentiated carcinoma.

[0165] Thus, in some embodiments of structure (I), (III), or (IV), A is an antibody or a cell surface receptor antagonist, such as 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 even more embodiments, the methods further comprise inducing apoptosis. In some embodiments, the method of treatment includes treating a tumor having tumor cells with tumor cell receptors. In some embodiments, the tumor cells have receptors in the range of 1,000-100,000, 1,000-50,000, 1,000-25,000, or 1,000-10,000 per cell. For example, in some embodiments, the tumor cells have less than about 1,000, about 10,000, or 100,000 receptors per cell.

[0166] Additional therapeutic agents that can be combined with the compounds of the present disclosure are found in Goodman and Gilman's "The Pharmacological Basis of Therapeutics," 10th Edition, edited by Hardman, Limbird, and Gilman, or the Physician's Desk Reference, both of which are incorporated by reference in their entireties into this disclosure. The compounds of structure (I), (III), or (IV) described herein may be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure will be co-administered with other agents, such as those described above. When used in combination therapy, the compounds described herein are administered simultaneously or separately with the second agent. This co-administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the agents described above may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds described herein and any of the agents described above may be administered simultaneously if both agents are in separate formulations. In another alternative, the compounds described herein may be administered followed by the agents described above, or vice versa. In some embodiments of the separate administration protocol, the compounds described herein and any of the agents described above are administered within minutes, hours, or days of each other.

[0167] In some embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of an anti-neoplastic agent, an enediyne antitumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and an EGFR inhibitor, an alkylating agent, and combinations thereof. In some more particular embodiments, the methods further comprise administering an additional therapeutic agent selected from the group consisting of an anti-neoplastic agent, an enediyne antitumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and an EGFR inhibitor, an alkylating agent, and combinations thereof.

[0168] In certain embodiments, the additional therapeutic agent comprises auristatin F, monomethyl auristatin F, monomethyl auristatin E, paciltaxol, SN-38, calicheamicin, anthramycin, aveimicin, ticamycin, DC-81, mazethramycin, neothramycin A, neothramycin B, polothramycin, prothracarcin, sivanomycin, sibiromycin, tomamycin, mertansine, emtansine, irinotecan, camptothecin, topotecan, ciratecan, cositecan, exatecan, lurtotecan, gimatecan, belotecan, and rubitecan. In some embodiments, a pharmaceutical composition comprises a compound of any of the above structures and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, a method for treating a disease or disorder comprises administering a therapeutically effective amount of a compound of any of the above structures, or a pharmaceutical composition thereof, to a subject in need thereof. In certain embodiments, the disease or disorder is cancer. In some more particular embodiments, the cancer is breast cancer, gastric cancer, lung cancer, ovarian cancer, lymphoma, and bladder cancer.

[0169] The examples and preparations provided below further describe and illustrate the compounds of the present disclosure and methods for preparing such compounds. It should be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. In the examples below, and throughout this disclosure and claims, molecules and moieties with a single stereocenter exist as racemic mixtures unless otherwise specified. Such molecules and moieties with two or more stereocenters exist as racemic mixtures of diastereomers unless otherwise specified. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0170] As detailed above, compounds of structure (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), and (IJ) can be prepared by oligomerization using well-known phosphoramidite chemistry. Applicant has discovered intermediate compounds useful in the synthesis of compounds of structure (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), and (IJ). Accordingly, embodiments of the present disclosure provide compounds of structure (II): [ka] (II) 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 OH, SH, O - , S - , OR d , or SR d and R c 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, in each occurrence, independently H, alkyl, or alkoxy; R 4are, in each occurrence independently, OH, SH, O - , S - , OR d , or SR d and R 5 is independently, in each occurrence, oxo or thioxo; R 6 and R 7 is independently, in each occurrence, H, OH, or halo; L 2 , L 3 , L 5 , and L 6 is, in each occurrence, independently a direct bond or independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 4 is, in each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 7 is, independently in each occurrence, a linker; M 2 is, independently at each occurrence, a moiety comprising a fluorescent dye; M 3 is, independently at each occurrence, a moiety that comprises a biologically active moiety; G, in each occurrence, is independently a moiety reactive under cycloaddition; Q, in each occurrence, is independently a moiety that contains a reactive group or a protected form thereof that is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L', in 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 0 or a greater integer; q, in each occurrence, is 0 or a greater integer; p, in each occurrence, is 0 or a greater integer; w, in each occurrence, is 0 or a greater integer; k, in each occurrence, is 0 or a greater integer; x 9 is, in each occurrence, an integer from 1 to 6, and n is an integer equal to or greater than 1; The sum of p and w is an integer of 2 or greater, and the compound comprises at least two different biologically active moieties.

[0171] In some embodiments, L 4 At least one occurrence of L is heteroalkylene. 4 Each occurrence of L is heteroalkylene. 4 At least one occurrence of L comprises an alkylene oxide. 4 In some more particular embodiments, the ethylene oxide is polyethylene oxide. In certain embodiments, L 4 In each occurrence, the following structure: [ka] and During the ceremony, z is an integer from 1 to 100, * indicates a bond to an adjacent phosphorus atom.

[0172] 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.

[0173] 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. In some other embodiments, z ranges from 19 to 28. In certain embodiments, the average z is 23. In some embodiments, the average z is 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28.

[0174] In other embodiments, L 4 At least one occurrence of is an alkylene linker (e.g., methylene). In some more particular embodiments, L 4 In each occurrence, is an alkylene linker (e.g., methylene).

[0175] In some embodiments, in the compound of structure (II), [ka] At least one occurrence of has the following structure: [ka] including one of the following: In the formula, 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.

[0176] In some embodiments, in the compound of structure (II), [ka] Each occurrence of has the following structure: [ka] including one of the following: In the formula, 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.

[0177] Some embodiments have the following structure (IIA): [ka] (IIA) or a compound having a stereoisomer, salt, or tautomer thereof.

[0178] In some embodiments, L 3 , L 5 , and L 6 is, at each occurrence, independently a direct bond or independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker. In some embodiments, L 3 , L 5 , or L 6 is, independently at each occurrence, alkylene. In more embodiments, L 3 , L 5 , or L 6 is, in each occurrence, independently C-C alkylene, C-C alkenylene, or C-C alkynylene. 3 and L 5 The alkylene linker in is a C alkyl linker. In some more particular embodiments, L 3 and L 5 The alkylene linker in L is a C alkyl linker. 3 and L 5 The alkylene linker in is a C alkyl linker. In some more particular embodiments, L 3 and L 5 The alkylene linker in is a C4 alkyl linker. In some more particular embodiments, L 3 and L 5The alkylene linker in is a C5 alkyl linker. In some more particular embodiments, L 3 and L 5 The alkylene linker is a C6 alkyl linker.

[0179] In certain embodiments, L 6 The alkylene linker in L is a C alkyl linker. 6 The alkylene linker in L is a C alkyl linker. 6 The alkylene linker in L is a C alkyl linker. 6 At least one occurrence of L is a direct bond. 6 Each occurrence of is a direct bond.

[0180] Some embodiments have the following structure (IIB): [ka] (IIB) or a stereoisomer, salt, or tautomer thereof, During the ceremony, y 1 is, in each occurrence, independently an integer from 0 to 6, and y 2 and y 3 is, at each occurrence, independently an integer from 1 to 6.

[0181] In some embodiments, y 1 is the integer 0 in each occurrence (i.e., L 6 is a direct bond). In some embodiments, y 1 In some embodiments, y 1 In some embodiments, y is an integer 2 in each occurrence. 1 In some embodiments, y is an integer 3 in each occurrence. 1 In some embodiments, y is an integer 4 in each occurrence. 1In some embodiments, y is an integer 5 in each occurrence. 1 is the integer 6 in each occurrence.

[0182] In some embodiments, y 2 and y 3 In some embodiments, y 2 and y 3 In some embodiments, y is an integer 2 in each occurrence. 2 and y 3 In some embodiments, y is an integer 3 in each occurrence. 2 and y 3 In some embodiments, y is an integer 4 in each occurrence. 2 and y 3 In some embodiments, y 2 and y 3 In some particular embodiments, y 1 is, in each occurrence, an integer 0 or 1, and y 2 and y 3 is 1 for each occurrence.

[0183] As detailed above, compounds of structure (III) can be prepared by oligomerization using well-known phosphoramidite chemistry. Applicant has discovered intermediate compounds (V) useful in the synthesis of compounds of structure (III). Accordingly, some embodiments comprise compounds of structure (V): [ka] (V) or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein G 2 is, independently in each occurrence, a moiety reactive under cycloaddition; G 3 is, independently in each occurrence, a moiety reactive under cycloaddition; L 1a is, in each occurrence, independently a heteroalkylene or heteroarylene linker; L 1b is, at each occurrence, independently either i) absent or ii) a linker; L 7 is, independently in each occurrence, a linker; L 2 , L 3 , L 5 , and L 6 is, in each occurrence, independently a direct bond or independently an optional 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 OH, SH, O-, S-, OR d , or SR d and R c 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, in each occurrence, is independently a moiety that contains a reactive group or a protected form thereof that is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L', in 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 (V); m in each occurrence is independently 0 or a greater integer; q, in each occurrence, is independently 0 or a greater integer; v, in each occurrence, is independently an integer of 1 or greater; and n is an integer of 2 or greater; The compounds provide intermediate compounds that contain at least two different biologically active moieties.

[0184] The compounds of structure (V) have a peptide-based backbone. Various linkers and substituents (e.g., G 2 , G 3 , Q, R 1 , R 2 , R 21 , L 2 , L 3 , L 5 , L 6 , L 7 , and L') are 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 (V). In certain embodiments, each alkyl, alkoxy, alkyl ether, heteroalkyl, alkylaminyl, alkylcarbonyl, or alkoxycarbonyl in the compound of structure (V) 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, phosphoalkylether, and thiophosphoalkylether. In certain embodiments, the optional substituent is -OP(=Ra )(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 certain embodiments, the substituents are selected to increase cell or tissue penetration. In related embodiments, the substituents are selected to increase cell or tissue retention.

[0185] 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.

[0186] In more particular embodiments, R 21 , L 5 , and m is [ka] But, (G) 10 , (GDGDGDGDGD), or (GKGKGKGKGK). In another embodiment, R 21 , L 5 , and m is [ka] is selected to have an amino acid sequence capable of forming an α-helical or β-sheet secondary structure. In some such embodiments, the amino acid sequence is (GGEEFMLVYKFARKHGG) or (GGMSMVVSGG).

[0187] In some embodiments, L 5 or L 3 or both are present in at least one occurrence. In more particular embodiments, when present, L 5 or L 3 or both are heteroalkylene linkers. 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, L 5 or L 3 At least one occurrence of either or both has the following structure: [ka] It has.

[0188] In some embodiments, L 5 or L 3 At least one occurrence of either or both has the following structure: [ka] It has. In some embodiments, L 6 and L 2 is independently absent or a heteroalkylene linker. In more particular embodiments, the heteroalkylene linker is a peptidyl linker.

[0189] As detailed above, compounds of structure (IV) can be prepared by oligomerization using well-known phosphoramidite chemistry. Applicant has discovered intermediate compounds (VI) useful in the synthesis of compounds of structure (IV). Accordingly, some embodiments comprise compounds of structure (VI): [ka] (VI) or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein: G 2 is, independently in each occurrence, a moiety reactive under cycloaddition; G 3 is, independently in each occurrence, a moiety reactive under cycloaddition; L 7 is, independently in each occurrence, a linker; L 2 , L 5 , and L 6 is, in each occurrence, independently a direct bond or independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatomic linker; L 8 is, in each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker that includes one or more charged moieties, provided 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 OH, SH, O - , S - , OR d , or SR d and R c 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, in each occurrence, is independently a moiety that contains a reactive group or a protected form thereof that is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L', in 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 (VI); q, in each occurrence, is independently 0 or a greater integer; v, in each occurrence, is independently an integer of 1 or greater; and n is an integer of 2 or greater; The compounds are provided as compounds comprising at least two different biologically active moieties.

[0190] Various linkers and substituents in compounds of structure (VI) (e.g., G 2 , G 3 , Q, R 1 , R 2 , R 3 , L 2 , L 5 , L 6 , L 7 , L 8, and L') are optionally substituted with one more substituent. For example, in some embodiments, optional substituents are selected to optimize the water solubility, permeability, retention, or other properties of the compound of structure (VI). In certain embodiments, each alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatomic linker, or alkyl, alkoxy, alkylether, heteroalkyl, alkylaminyl, alkylcarbonyl, or alkoxycarbonyl in the compound of structure (VI) is optionally substituted with one more substituent selected from the group consisting of hydroxyl, alkoxy, alkylether, alkoxyalkylether, sulfhydryl, amino, alkylamino, carboxyl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, and thiophosphoalkylether. In certain 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 certain embodiments, the substituents are selected to increase cell or tissue penetration. 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.

[0191] 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 the following structure: [ka] and During the ceremony, R, in each occurrence, is independently H or C1-C6 alkyl.

[0192] In other embodiments, the charged moiety is negatively charged. In certain embodiments, the charged moiety comprises a carboxylic acid, phosphate, or sulfate functional group. In some embodiments, the charged moiety has the following structure: [ka] It has.

[0193] In some embodiments, the charged moieties include a combination of positively and negatively charged moieties.

[0194] In certain embodiments, the charged moiety is pendant to the backbone of the compound (e.g., attached to a 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 continuous chain of the linker).

[0195] In some embodiments, L 8 has the following structure: [ka] including one of the following: During the ceremony, R, in each occurrence, is independently H or C1-C6 alkyl; x is an integer from 0 to 6, and m is an integer of 1 or greater, where m is selected such that the compound contains at least two charged moieties.

[0196] Linker L 7 is the ratio of M 2 and M 3 G in the case of moieties or structures (V) and (VI) 2 and G 3 For example, in some embodiments, a synthetic precursor (II) leading to a compound of structure (I) can be prepared, and M 2 and M 3 Moieties are attached to the synthetic precursors using any number of coupling methods known in the art. 7 At least one occurrence of L 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, L 7 At least one occurrence of has the following structure: [ka] Includes one of the following.

[0197] In more embodiments, L 7Each occurrence of L 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. In more particular embodiments, L 7 Each occurrence of has the following structure: [ka] Includes one of the following.

[0198] In some embodiments, R 3 At least one occurrence of is H. In some embodiments, R 3 At least one occurrence of R is alkyl. 3 At least one occurrence of R is alkoxy. 3 Each occurrence of is H. In some embodiments, R 5 At least one occurrence of is oxo (=O). In some embodiments, R 5 At least one occurrence of is thioxo (=S). In certain embodiments, R 5 Each occurrence of is an oxo (=O).

[0199] In some embodiments, R 4 At least one occurrence of is OH. In some embodiments, R 4 At least one occurrence of R is SH. 4 At least one occurrence of O - In some embodiments, R 4 At least one occurrence of S - In certain embodiments, R 4 Each occurrence of O - is. In various other embodiments, R 1 and R 2 are each independently OH or -OP(=R a )(R b )R cIn 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 is Q or a linker comprising a covalent bond to Q.

[0200] In still further embodiments of any of the above-described compounds of structures (II), (V), and (VI), R 1 and R 2 are each independently -OP(=R a )(R b )R c In some of these embodiments, R c is OL'. 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 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 (II), (V), or (VI). 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 (II), (V), or (VI) to a compound of structure (II), (V), or (VI). Advantageously, certain embodiments include the use of an L' moiety selected to increase or optimize the water solubility of the compound. In certain embodiments, L' is a heteroalkylene moiety. In some other certain embodiments, L' comprises an alkylene oxide or a phosphodiester moiety, or a combination thereof.

[0201] In some embodiments, R 2is L'. For example, in some embodiments, L' is a linker to a targeting moiety. In certain embodiments, L' is a linker to a targeting moiety, wherein the linker comprises an alkylene oxide or a phosphodiester moiety, or a combination thereof. In other embodiments, L' has the following structure: [ka] and During the ceremony, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 are independently integers from 1 to 10. R b is H, an electron pair, or a counterion, L'' is a targeting moiety or a link to a targeting moiety.

[0202] 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 , x3 , 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 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 are independently integers 7. 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 are independently the integer 8. In some embodiments, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8 are 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.

[0203] 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.

[0204] In some embodiments, L" is a 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 particular 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, guselkumab ab), Ibalizumab, Idarucizumab, Infliximab, Itolizumab, Ixekizumab, Lanadelumab, Lokivetmab, Mepolizumab, Natalizumab, Obiltoxaximab,Ocrelizumab, Omalizumab, Palivizumab, Ranibizumab, Raxibacumab, Reslizumab, Rmab, Rovelizumab, Ruplizumab, Sarilumab, Secukinumab, Tildrakizumab, 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 ikumab), Briakinumab, Brolucizumab, Carlumab, Carotuximab, Cedelizumab, Clazakizumab, Clenoliximab, Concizumab, Cosfroviximab, CR6261, Crenezumab, Crizanlizumab, Clotedumab,Depatuxizumab, mafodotin, derlotuximab biotin, dezamizumab, diridavumab, domagrozumab, dusigitumab, ecromeximab, edobacomab, efalizumab, efungumab, eldelumab, elezanumab, enokizumab, Eptinezumab, Erlizumab, Etrolizumab, Evinacumab, Exbivirumab, Fanolesomab, Faralimomab, Faricimab, Fasinumab, Felvizumab, Fezakinumab, Flavotumab Nvotumab, Fletikumab, Flotetuzumab, Fontolizumab, Foravirumab, Frovocimab, Fulranumab, Gantenerumab, Gavilimomab, Gevokizumab, Gimsilumab, Gomiliximab imab), 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, Otelixizumab Otelixizumab, Otilimab, Oxelumab, Ozanezumab, Ozoralizumab, Pagibaximab, Panobacumab, Pascolizumab, Pateclizumab, PDR001, Pela Perakizumab, Pexelizumab, Placulumab, Plozalizumab, Ponezumab, Porgaviximab, Prasinezumab, Priliximab, PRO140, Quilizumab ab), Rafivirumab, Ralpancizumab, Ranevetmab, Ravagalimab, Ravulizumab, Refanezumab, Regavirumab, Relatlimab, Linucumab,Risankizumab, Rolezumab, Romosozumab, Rontalizumab, SA237, Satralizumab, Sevirumab, SHP647, Sifalimumab, Simtuzumab, Siplizumab, Sirukumab, Solanezumab, Sonepcizumab, Spa 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 (bivatuzumaborinotuzumab), or vadastuximab.

[0205] In other more particular embodiments of any of the above-described compounds of structure (II), (V), or (VI), R 1 or R 2 has the following structure: [ka] [ka] and R in the formula a is H or a solid support.

[0206] In certain embodiments, R 2 has the following structure: [ka] It has one of the following.

[0207] Certain embodiments of compounds of structure (II), (V), or (VI) 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 may, in some embodiments, be used as starting materials for preparing compounds of structure (II), (V), or (VI). Thus, in certain embodiments, R 1 has the following structure: [ka] It has.

[0208] Those skilled in the art will appreciate that the dT group depicted above is included merely 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 in L', or the nucleosides or solid support moieties may be removed or modified after synthesis.

[0209] 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 some further embodiments, the solid support is a polymeric bead or a non-polymeric bead.

[0210] In some embodiments, M 2 In one or more occurrences, is independently a moiety that contains four or more aryl or heteroaryl rings or a combination thereof. In some embodiments, M 2 is, in one or more occurrences, independently fluorescent or colored. In certain embodiments, M 2 is fluorescent in one or more occurrences. In other embodiments, M 2 In one or more occurrences, independently, M comprises a fused polycyclic aryl or heteroaryl moiety comprising at least four fused rings. 2 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. 2is, at each occurrence, independently selected from the group consisting of p-terphenyl, perylene, azobenzene, phenazine, phenanthroline, acridine, thioxanthrene, chrysene, rubrene, coronene, cyanine, perylene imide, perylene amide, and derivatives thereof. 2 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. 2 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. In certain embodiments, M 2 may, in each occurrence, independently have the structure: [ka] It has one of the following.

[0211] In certain embodiments, M 2 At least one occurrence of has the following structure: [ka] It has.

[0212] In some more particular embodiments, M 2 Each occurrence of has the following structure: [ka] It has.

[0213] In some embodiments, -L 7 -M 2At least one occurrence of has the following structure: [ka] It has one of the following. In some more particular embodiments, -L 7 -M 2 Each occurrence of has the following structure: [ka] It has one of the following.

[0214] M 3 is selected based on the desired alkylation properties. 3 The moieties may be appropriately selected by one skilled in the art based on the desired end use.

[0215] In some embodiments, M 3 At least one occurrence of the moiety is an alkylating agent, an antimetabolite, a microtubule inhibitor, a topoisomerase inhibitor, or a cytotoxic antibiotic. 3 Each occurrence of M is an alkylating agent, an antimetabolite, a microtubule inhibitor, a topoisomerase inhibitor, or a cytotoxic antibiotic. 1 or M 3 At least one occurrence of M is a nitrogen mustard, a nitrosourea, a tetrazine, an aziridine, cisplatin or a cisplatin derivative, or a non-classical alkylating agent. 3 At least one occurrence of is mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide, busulfan, N-nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU), semustine (MeCCNU), fotemustine, streptozotocin, dacarbazine, mitozolomide, temozolomide, thiotepa, mitomycin, diaziquone (AZQ), cisplatin, carboplatin, oxaliplatin, procarbazine, or hexamethylmelamine. 3At least one occurrence of M is an antifolate, a fluoropyrimidine, a deoxynucleoside analog, or a thiopurine. 3 At least one occurrence of is methotrexate, pemetrexed, fluorouracil, capecitabine, cytarabine, gemcitabine, decitabine, azacitidine, fludarabine, nelarabine, cladribine, clofarabine, pentostatin, thioguanine, and mercaptopurine. 3 At least one occurrence of M is an auristatin, a vinca alkaloid, or a taxane. 3 At least one occurrence of M is auristatin F, auristatin E, vincristine, vinblastine, vinorelbine, vindesine, vinflunine, paclitaxel, docetaxel, etoposide, or teniposide. 3 At least one occurrence of M is irinotecan, SN38, topotecan, camptothecin, doxorubicin, mitoxantrone, teniposide, novobiocin, mervalone, or aclarubicin. 3 At least one occurrence of M is an anthracycline or a bleomycin. 3 At least one occurrence of M is doxorubicin, daunorubicin, epirubicin, idarubicin, pirarubicin, aclarubicin, or mitoxantrone. 3 is auristatin F, monomethyl auristatin F, monomethyl auristatin E, paciltaxol, SN-38, calicheamicin, anthramycin, aveimicin, ticamycin, DC-81, mazethramycin, neothramycin A, neothramycin B, polothramycin, prothracarcin, sivanomycin, sibiromycin, tomamycin, mertansine, emtansine, irinotecan, camptothecin, topotecan, ciratecan, cositecan, exatecan, lurtotecan, gimatecan, belotecan, and rubitecan. 3are auristatin F, monomethyl auristatin F, monomethyl auristatin E, paciltaxol, SN-38, calicheamicin, anthramycin, abeimicin, ticamycin, DC-81, mazethramycin, neothramycin A, neothramycin B, polothramycin, prothracarcin, sivanomycin, sibiromycin, tomamycin, mertansine, emtansine, irinotecan, camptothecin, topotecan, ciratecan, cositecan, exatecan, lurtotecan, gimatecan, belotecan, and rubitecan.

[0216] M 3 is M 3 The group M can be attached to the rest of the molecule at any position (i.e., atom) of the group M. 3 to the remainder of the molecule. For example, M 3 can be attached to the rest of the molecule through the nitrogen of the diazepine, the oxygen of the diazepine or phenyl ring, or the carbon of the pyrrolidine ring.

[0217] In some embodiments, M 3 At least one occurrence of M is an anti-inflammatory compound. 3 is a steroid, a biologically active organic compound having four rings arranged in a specific molecular configuration as shown below. For example, in some embodiments, M 3 At least one occurrence of is cholesterol, cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or beclomethasone. 3 At least one occurrence of has the following structure: [ka] and During the ceremony, R 11 is H or a halogen, R 12 and R 13 are 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 [ka] represents a single or double carbon-carbon bond.

[0218] In some embodiments, M 3 At least one occurrence of has the following structure: [ka] [ka] It has one of the following.

[0219] In some embodiments, M 3 Each occurrence of has the following structure: [ka] [ka] It has one of the following.

[0220] In some embodiments, G, G 2 , or G 3 is a reactive moiety that undergoes cycloaddition. In certain embodiments, the cycloaddition is a click reaction between an azide and an alkyne. In some embodiments, G, G 2 , or G 3 has the following structure: [ka] or [ka] In certain embodiments, G, G 2 , or G 3 is, at each occurrence, [ka] In certain other embodiments, G, G 2 , or G 3 is, at each occurrence, [ka] It has the following structure.

[0221] The fluorescence intensity or efficacy for DNA alkylation can also be adjusted by selecting different values ​​of n. In some embodiments, n is an integer of 1 or greater. In certain embodiments, n is an integer between 1 and 100. In other embodiments, n is an integer between 1 and 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.

[0222] The fluorescence or effectiveness for DNA alkylation can also be adjusted by selecting the value of m. The value of m is determined by the adjacent M 1 , M 2 , or M 3 (or G, G 2 , or G 3) with the ability to control the spacing between them. In some embodiments, m is 0 or a greater integer. In certain embodiments, m is an integer from 0 to 100. In certain 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.

[0223] Fluorescence intensity can be tuned by the number of fluorescent dye moieties attached to the polymer backbone. The value of q has the ability to control the brightness of the compound. In some embodiments, q, in each occurrence, is an integer of 0 or greater. In some more specific embodiments, q is from 0 to 10. In some embodiments, q is from 0 to 5. For example, in some embodiments, q is 0. 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 other embodiments, q is 0, 1, 2, 3, or 4. In some other embodiments, q is 1 or 2.

[0224] The effectiveness of DNA alkylation can also be adjusted by selecting the value of p. In some embodiments, p, in each occurrence, is an integer of 0 or greater. 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 other embodiments, p is 1, 2, 3, or 4. In some other embodiments, p is 2 or 3. The effectiveness of DNA alkylation can also be adjusted by selecting the value of w. In some embodiments, w is an integer of 0 or greater in each occurrence. In some more particular embodiments, w is 0 to 10. In some embodiments, w is 0 to 5. In some embodiments, w is 1 to 5. For example, in some embodiments, w is 1. In some embodiments, w is 2. In some embodiments, w is 3. In some embodiments, w is 4. In some embodiments, w is 5. In some other embodiments, w is 1, 2, 3, or 4. In some other embodiments, w is 1 or 2.

[0225] The effectiveness of DNA alkylation can also be adjusted by selecting the value of k. In some embodiments, k, in each occurrence, is an integer of 0 or greater. In some more specific embodiments, k is from 0 to 10. In some embodiments, k is from 0 to 5. For example, in some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4. In some embodiments, k is 5. In other embodiments, k is 0, 1, 2, 3, or 4. In some other embodiments, k is 0 or 1. In some embodiments of structure (V) or (VI), v is an integer of 1 or greater. 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.

[0226] The values ​​of n, q, w, p, k, and m are closely related, providing the ability to control fluorescence and efficacy for DNA alkylation. In certain embodiments, n is 1, q is 2, w is 2, k is 0, p is 2, and m is 1. In certain other embodiments, n is 1, q is 2, w is 1, k is 0, p is 3, and m is 1. In some other particular embodiments, n is 3, q ​​is 1 in the first occurrence, q is 0 in the second occurrence, q is 0 in the third occurrence, w is 0 in the first occurrence, w is 0 in the second occurrence, w is 1 in the third occurrence, k is 0 in the first occurrence, k is 1 in the second occurrence, k is 0 in the third occurrence, p is 1 in the first occurrence, p is 0 in the second occurrence, p is 0 in the third occurrence, and m is 1 in all occurrences.

[0227] In some embodiments, the sum of p and w is an integer of 2 or greater, and the compound comprises at least two different biologically active moieties. In some embodiments, R 6 or R 7 At least one occurrence of is F or H. In other embodiments, R 6 and R 7 At least each occurrence of is F or H. In certain embodiments, R 6 and R 7 At least each occurrence of is F and R 8 is O and R 9 is H and R 10 is H. In some other embodiments, R 6 and R 7 At least each occurrence of is H and R 8 is O and R 9 is H and R 10 is H. In some embodiments, x 9 In each occurrence, x is an integer from 1 to 6. For example, in some embodiments, 9 Each occurrence of x is 1. 9 Each occurrence of x is 2.9 Each occurrence of x is 3. 9 Each occurrence of x is 4. 9 Each occurrence of x is 5. 9 Each occurrence of x is 6. 9 Each occurrence of x is 2, 4, or 6. 9 Each occurrence of is either 2 or 4.

[0228] In certain embodiments, the compound is a compound selected from Table 3 A. The compounds of Table 3 A are prepared according to the procedures provided in the Examples. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10] In the formula, M 3 has the following structure: [ka] It has.

[0229] Additionally, in some embodiments, M 3 At least one occurrence of M is an anti-inflammatory compound. 3 is a steroid, a biologically active organic compound having four rings arranged in a specific molecular configuration as shown below. For example, in some embodiments, M 3 At least one occurrence of is cholesterol, cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or beclomethasone. 3 At least one occurrence of has the following structure: [ka] and During the ceremony, R 11 is H or a halogen, R 12 and R 13 are 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 [ka] represents a single or double carbon-carbon bond.

[0230] In some embodiments, M 3 At least one occurrence of has the following structure: [ka] It has one of the following.

[0231] In some embodiments, the compound is a compound selected from Table 3B. The compounds of Table 3B are prepared according to the procedures provided in the Examples. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] [Table 9-9] M in the formula 3 has the following structure: [ka] and During the ceremony, [ka] has the following structure: [ka] is selected from.

[0232] In some embodiments, M 3At least one occurrence of is a vitamin. For example, in some embodiments, 3 At least one occurrence of M is vitamin E. In some more particular embodiments, M 3 At least one occurrence of M is tocopherol. 3 is α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, or δ-tocotrienol.

[0233] In some embodiments, M 3 At least one occurrence of has the following structure: [ka] and During the ceremony, R 19 and R 20 is independently H or CH3, and [ka] represents a single or double carbon-carbon bond.

[0234] In certain embodiments, M 3 At least one occurrence of has the following structure: [ka] It has one of the following.

[0235] In certain embodiments, the compound is a compound selected from Table 3C. The compounds of Table 3C are prepared according to the procedures provided in the Examples. [Table 10-1] [Table 10-2] [Table 10-3] M in the formula 3 has the following structure: [ka] and During the ceremony, [ka] has the following structure: [ka] is selected from.

[0236] In certain embodiments, the compound of structure (V) is selected from Table 3D. The compounds of Table 3D are prepared according to the procedures set forth in the Examples. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4]

[0237] In certain embodiments, the compound of structure (VI) is selected from Table 3E. The compounds of Table 3E are prepared according to the procedures set forth in the Examples. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6] [Table 12-7] [Table 12-8]

[0238] A typical DNA synthesis cycle [ka]

[0239] Oligomerization is typically initiated by removing a protecting group (e.g., dimethoxytrityl group, DMTr) to expose a free -OH (hydroxyl) group (Step 1, detritylation). A subsequent coupling step introduces a phosphoramidite monomer that reacts with the free OH group to form a new covalent bond with phosphorus, with concomitant loss of the diisopropylamine group (Step 2, coupling). The resulting phosphite triester is oxidized (e.g., with I2 and pyridine) to the more stable phosphate ester (Step 3, oxidation), and a capping step renders any remaining free OH groups unreactive (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.

[0240] Customization is achieved by 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 are selected to synthesize the desired compound of structure (I), (III), or (IV). M may optionally be absent to incorporate desired spacing between M moieties. One of skill 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 the linker group.

[0241] 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]

[0242] Basic Reaction Scheme 1 (Phosphoramidite) [ka] Reaction Scheme I illustrates a method for preparing a phosphoramidite intermediate useful in preparing compounds of structure (I). Referring to Reaction Scheme I, G 1represents a desired moiety containing a carboxylic acid functional group (e.g., a drug moiety such as auristatin F or SN38), L represents a bivalent linker moiety (e.g., an alkylene or alkylene ether), X represents a leaving group (e.g., a halo such as Cl), and PG represents a protecting group (e.g., 4,4'-dimethoxytriphenylmethyl). Step 1 of Reaction Scheme I begins with activation of the carboxylic acid functional group of the first compound shown using known reagents (e.g., HATU and DIPEA in DMF) under basic conditions. The activated acid is then reacted with an amine to yield the reaction product of Step 1. The resulting diol is then protected under standard conditions (e.g., 4,4'-dimethoxytriphenylmethyl chloride and pyridine). The protected product is then reacted with 3-((chloro(diisopropylamino)phosphanyl)oxy)propanenitrile (or other appropriate reagent) to yield the desired compound of structure (VII) shown above.

[0243] The resulting compound of structure (VII) can then be used to synthesize the desired compound of structure (I) by reaction under well-known (automated) DNA synthesis conditions. In addition to the compound of structure (VII), additional repeat units can be incorporated to arrive at the final compound of structure (I). Generally, the following structure is obtained: [ka] A compound having the formula: During the ceremony, L is a desired linker moiety (including, for example, PEG or a dye-containing moiety).

[0244] In certain embodiments, the following compounds may be used in the synthesis of compounds of structure (I): [ka] [Example]

[0245] Basic method Mass spectral analysis was performed on a Waters / Micromass Quattro micro MS / MS system (MS-only mode) using MassLynx 4.1 aquadistribution 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), pH 8. The phosphoramidites and precursor molecules were analyzed on a 2.1 mm x 50 mm Acquity BEH-C column maintained at 45 °C using an acetonitrile / water mobile phase gradient. 18 Analysis is performed using a Waters Acquity UHPLC system with a column. Molecular weights of monomer intermediates are obtained using tropylium cation infusion 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.

[0246] Unless otherwise noted, all reactions are carried out in oven-dried glassware under a nitrogen atmosphere. Commercial DNA synthesis reagents are purchased from Glen Research (Sterling, VA). Anhydrous pyridine, 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.

[0247] Example 1 Synthesis of DMT-protected gemcitabine compounds [ka]

[0248] Gemcitabine (0.5057 mmol) was added to a dry round-bottom flask with a magnetic stir bar under an inert gas blanket, followed by anhydrous pyridine (5.06 mL). The reaction flask was then transferred to an ice-water bath (0 °C) and cooled with mixing until thermal equilibrium was reached (approximately 10 min). 4,4'-Dimethoxytrityl chloride (0.257 g, 0.759 mmol) was then added to the cooled mixture with continuous mixing under inert gas. The reaction mixture was allowed to warm to room temperature and then sampled for TLC analysis. Once the reaction was confirmed to be complete, any remaining unreacted 4,4'-dimethoxytrityl chloride was quenched by adding methanol to the reaction mixture (0.160 g, 5.06 mmol). The solvent was removed by rotary evaporation under vacuum (10 mbar) and heating (55 °C). The concentrated residue is then suspended in toluene (5.06 mL) and the toluene is removed by rotary evaporation under vacuum (1000 Pa (10 mbar)) and heating (55°C), and this operation is repeated twice. The crude product is dissolved in dichloromethane (5.06 mL), washed with sodium bicarbonate (5.06 mL, saturated aqueous solution), and separated. This process is repeated once. The separated organic phase is washed with sodium chloride (5.06 mL, saturated aqueous solution) and separated. The separated organic phase is dried over anhydrous sodium sulfate, and the sodium sulfate is removed by filtration. The product containing organic phase is sampled for TLC and LC-UV / MS analysis. The solvent is removed by rotary evaporation to obtain crude DMT-protected gemcitabine.

[0249] This crude material is then combined with crude material from a small-scale pilot reaction. The combined crude material is purified by silica gel flash chromatography using a dichloromethane / methanol mobile phase, and product-containing fractions are pooled and the solvent is removed by rotary evaporation, followed by placing on a vacuum line for at least 24 hours to yield DMT-protected gemcitabine.

[0250] Example 2 Synthesis of DMT-protected gemcitabine phosphoramidite [ka] Purified DMT-protected gemcitabine (0.226 mmol) was dried under vacuum for at least 24 hours and dissolved in dichloromethane (2.26 mL) using a magnetic stir bar under an inert gas blanket. Subsequently, DIPEA (0.117 g) was added, followed by Cl-Phos. (0.107 g). The reaction was mixed for approximately 15 minutes and then sampled for TLC analysis (TLC indicated the reaction was complete). Once the reaction was complete, the reaction mixture was washed by direct addition with sodium bicarbonate (2.26 mL, saturated aqueous solution), and the organic phase was separated. This process was repeated once. The organic phases were combined and dried over anhydrous sodium sulfate, and the sodium sulfate was then removed by filtration. The product-containing organic phase was sampled for TLC and LC-UV / MS analysis. The dichloromethane was then removed by rotary evaporation, and the crude material was then used for purification without crude weight. This crude material was then combined with the crude material from the small-scale pilot reaction. The combined crude material is purified by silica gel solid-phase extraction, dichloromethane / methanol / triethylamine mobile phase, and the product-containing fractions are pooled. The mobile phase is removed by rotary evaporation and placed on a vacuum line for at least 24 hours to obtain the DMT-protected gemcitabine phosphoramidite. Alternatively, the DMT-protected gemcitabine phosphoramidite can be purchased from Glen Research and used directly without further purification.

[0251] Example 3 Synthesis of auristatin F phosphoramidites [ka] Auristatin F (0.501 g, 0.671 mmol) was added to a dry round-bottom flask with a magnetic stir bar under an inert gas blanket, followed by DMF (6.10 mL). Auristatin F was allowed to completely dissolve at room temperature under inert gas. DIPEA (0.351 g, 2.013 mmol) was then added to the mixture, followed by HATU (0.278 g, 0.732 mmol). 6,7-Dihydroxy-4-oxaheptylamine (0.091 g, 0.610 mmol) was added to a dry round-bottom flask with a magnetic stir bar under an inert gas blanket, followed by DMF (6.10 mL) and allowed to completely dissolve at room temperature. The auristatin F reaction mixture was then added to the solution containing 6,7-dihydroxy-4-oxaheptylamine, and the reaction was stirred until complete by TLC and LC-UV / MS analysis (analytical LC-UV). 248nm The chromatogram showed 12% of the total peak area of ​​the desired product or approximately 60% of the related peak area, identified by MS), and the resulting mixture was mixed under inert gas at room temperature.

[0252] Upon completion of the reaction, the solvent was removed by rotary evaporation under vacuum (10 mbar) and heating (55° C.). The concentrated residue was placed under full vacuum at room temperature for several hours to give 1.09 g of crude compound by mass (theoretical, 0.535 g, 0.610 mmol). [ka]

[0253] The crude compound (a portion of the crude material from the previous step, 0.444 g, 0.5057 mmol, theoretical) was added to a dry round-bottom flask with a magnetic stir bar under an inert gas blanket, followed by the addition of anhydrous pyridine (5.06 mL). The reaction flask was then transferred to an ice-water bath (0 °C) and cooled with mixing until thermal equilibrium was reached (approximately 10 min). 4,4'-Dimethoxytrityl chloride (0.257 g, 0.759 mmol) was then added to the cooled mixture with continuous mixing under inert gas. The reaction mixture was allowed to warm to room temperature and then sampled for TLC analysis. Once the reaction was confirmed to be complete, residual unreacted 4,4'-dimethoxytrityl chloride was quenched by the addition of methanol to the reaction mixture (0.160 g, 5.06 mmol). The solvent was removed by rotary evaporation under vacuum (10 mbar) and heating (55 °C). The concentrated residue was then suspended in toluene (5.06 mL) and the toluene was removed by rotary evaporation under vacuum (1000 Pa (10 mbar)) and heating (55°C), which was repeated twice. The crude product was dissolved in dichloromethane (5.06 mL), washed with sodium bicarbonate (5.06 mL, saturated aqueous solution) and separated. This process was repeated once. The separated organic phase was washed with sodium chloride (5.06 mL, saturated aqueous solution) and separated. The separated organic phase was dried over anhydrous sodium sulfate, and the sodium sulfate was removed by filtration. The organic phase containing the product was sampled for TLC and LC-UV / MS analysis (analytical LC-UV 248nm The chromatogram showed approximately 24% of the target product by total peak area, which was identified by MS.) The solvent was removed by rotary evaporation to give 0.769 g of crude DMT-protected compound.

[0254] This crude material was then combined with crude material from a small-scale test reaction (0.135 g) for a combined crude yield of 0.931 g. The combined crude material was purified by silica gel flash chromatography using a dichloromethane / methanol mobile phase; fractions containing the product were pooled and the solvent removed by rotary evaporation, then placed on a vacuum line for at least 24 hours to give 0.399 g (analytical LC-UV). 248nmThe chromatogram showed 82% of the total peak area as the desired product, which was identified by MS). [ka]

[0255] The purified DMT-protected compound (0.267% of material, 0.226 mmol) was dried under vacuum for at least 24 hours and dissolved in dichloromethane (2.26 mL) using a magnetic stir bar under an inert gas blanket, followed by the addition of DIPEA (0.117 g) and then Cl-Phos. (0.107 g). The reaction was mixed for approximately 15 minutes and then sampled for TLC analysis (TLC indicated the reaction was complete). Once the reaction was complete, the reaction mixture was washed by adding directly to sodium bicarbonate (2.26 mL, saturated aqueous solution), and the organic phase was separated; this was repeated once. The organic phases were combined and dried over anhydrous sodium sulfate, which was then filtered off. The product-containing organic phase was sampled for TLC and LC-UV / MS analysis (analytical LC-UV). 248nm The chromatogram showed two product peaks (diastereomers) with a total peak area of ​​approximately 64% and were identified by MS. The dichloromethane was then removed by rotary evaporation, and the crude mass was removed and proceeded to purification. This crude material was then combined with crude material from a small-scale test reaction. The combined crude material was purified by silica gel solid-phase extraction, dichloromethane / methanol / triethylamine mobile phase, and fractions containing the product were pooled (as determined by TLC) and sampled for TLC and LC-UV / MS analysis. The mobile phase was removed by rotary evaporation, then placed on a vacuum line for at least 24 hours, yielding 0.363 g of auristatin F phosphoramidite. (Analytical LC-UV 248nm The chromatogram showed 68% of the target product by total peak area, which was identified by MS).

[0256] Similarly, SN38 phosphoramidite, ibuprofen phosphoramidite, and naproxen phosphoramidite are synthesized according to the above procedures. SN38 phosphoramidite, ibuprofen phosphoramidite, and naproxen phosphoramidite include the following: [ka]

[0257] Example 4 Synthesis of alanine-linked SN38 [ka] Step 1 A 500 mL round-bottom flask was charged with Boc-Ala-Ala-OH (4.0 g, 15.4 mmol, Chem-Impex catalog number 04505), DMF (150 mL), and a magnetic stir bar. HATU coupling agent (7.0 g, 18.4 mmol) was added, and the mixture was stirred for 5 min. After that, Fmoc-1,2-diaminoethane-HCl (4.9 g, 15.4 mmol) and diisopropylethylamine (8.0 mL, 46.1 mmol) were added. After stirring overnight, TLC (silica plates with F254, dichloromethane:methanol elution 9:1) indicated the reaction was complete. The reaction mixture was concentrated on a rotary evaporator and then partitioned between dichloromethane and water. The solvent layers were separated in an extraction funnel, and the aqueous layer was extracted three more times with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The product was used in the next step without further purification.

[0258] Step 2 A 250 mL round-bottom flask equipped with a magnetic stir bar was charged with the Boc-Ala-Ala derivative (2.5 g, 4.8 mmol) prepared in the previous step. Dichloromethane (30 mL) and DMF (10 mL) were added, and the mixture was stirred. To this was added 4 M hydrochloric acid in dioxane (30 mL, Sigma catalog no. 345547), and the mixture was stirred. After 1 h, TLC (silica plate with F254, eluted with 9:1 dichloromethane:methanol) indicated the reaction was complete. The solvent was removed by rotary evaporation. Acetonitrile (50 mL) was added, and the mixture was shaken for several minutes. The heterogeneous mixture was cooled to 4 °C for 1 h, and then the solid was collected by filtration (2.0 g). LC-MS confirmed that the solid was the product.

[0259] Step 3 A 250 mL round-bottom flask was charged with the amine from the previous step (1.5 g, 3.5 mmol), DMF (35 mL), and a magnetic stir bar. Succinic anhydride (1.8 g, 17.7 mmol) was added in one portion, followed by triethylamine (6.6 mL, 47.2 mmol). The mixture was stirred for 2 h, at which point TLC indicated the reaction was complete (TLC elution 4:1 DCM:MeOH). The mixture was concentrated on a rotary evaporator and then treated with potassium carbonate solution (1 M, 50 mL). The mixture was stirred for 60 min. The mixture was acidified with hydrochloric acid (20%, 50 mL) to precipitate the product. The mixture was cooled on ice for 30 min, and the solid was collected on a medium fritted glass filter. The solid yield was 1.32 g. The product was confirmed by LC-MS.

[0260] Step 4 A small 20 mL glass vial was charged with 6,7-dihydroxy-4-oxaheptylamine (443 mg, 3.0 mmol, Berry & Associates catalog number LK4010) and DMF (5 mL). The sample was warmed for 10 minutes on a heat plate set at 60 °C before assembling the other components of the reaction. A 200 mL round-bottom flask was charged with the succinylated Ala-Ala derivative (1.3 g, 2.5 mmol) prepared in the previous step, a magnetic stir bar, and DMF (18 mL). HATU (1.1 g, 3.0 mmol, Anaspec) was added, and the mixture was stirred for 5 minutes. The DMF-aminodiol solution in the 20 mL glass vial was added to the reaction flask. The vial was rinsed with 2 mL of DMF, which was added to the reaction vessel. Diisopropylethylamine (1.3 mL, 7.44 mmol) was added, and the flask was capped and stirred overnight at room temperature. The magnetic stir bar was removed, and the mixture was concentrated on a rotary evaporator and placed under high vacuum overnight. The reaction was purified on a silica column (Teledyne-Isco) eluted with a dichloromethane:methanol gradient (yield 1.3 g). The product was confirmed by LC-MS.

[0261] Step 5 The Fmoc protecting group is cleaved with a base such as piperidine, 4-methylpiperidine, piperazine, 1,8-diazabicyclo[5.4.0]undec-7-ene, or morpholine. The choice of base depends on the acid resistance of the substrate. The Fmoc-protected diol is added to a dry round-bottom flask with a magnetic stir bar under an inert gas blanket, followed by DMF. In a separate dry round-bottom flask with a magnetic stir bar, 20% piperidine in 80% DMF is prepared. To the DMF solution containing the Fmoc-protected diol, 20% piperidine in 80% DMF is added, and the resulting mixture is stirred at room temperature under inert gas until the reaction is complete as determined by TLC and LC-UV / MS analysis. Upon completion of the reaction, the solvent is removed by rotary evaporation under vacuum (10 mbar) with heating (55°C). The concentrated residue is placed under full vacuum at room temperature for several hours to obtain the crude compound. The products are separated by flash chromatography on a 24 g silica column (Teledyne-ISCO) eluting with a dichloromethane:methanol gradient.

[0262] Step 6 The carbonylated camptothecin derivative prepared according to the carbonylation method described above was added to a dry round-bottom flask with a magnetic stir bar under an inert gas blanket, followed by the addition of DMF (6.10 mL). The carbonylated camptothecin derivative was completely dissolved at room temperature under inert gas. DIPEA (0.351 g, 2.013 mmol) was then added to the mixture, followed by HATU (0.278 g, 0.732 mmol). Aminediol (0.610 mmol) was added to a dry round-bottom flask with a magnetic stir bar under an inert gas blanket, followed by the addition of DMF (6.10 mL) and completely dissolved at room temperature. The carbonylated camptothecin derivative reaction mixture was then added to the solution containing the aminediol, and the resulting mixture was mixed at room temperature under inert gas until the reaction was complete as determined by TLC and LC-UV / MS analysis.

[0263] Upon reaction completion, the solvent was removed by rotary evaporation under vacuum (1000 Pa (10 mbar)) and heating (55°C). The concentrated residue was placed under full vacuum at room temperature for several hours to give crude alanine-linked SN38. Alanine-linked camptothecin can also be prepared similarly using camptothecin derivatives bearing a hydroxyl group at the 11-position rather than the 10-position.

[0264] Step 7 A 200 mL round-bottom flask equipped with a magnetic stir bar is charged with the diol (1.9 mmol) prepared in the previous step and pyridine (38 mL). 4,4-Dimethoxytrityl chloride is added to the solution in one portion. The flask is capped and stirred overnight. The mixture is concentrated under reduced pressure, and the product is isolated by flash chromatography on a 24 g silica column (Teledyne-ISCO) eluting with a dichloromethane:methanol gradient to give the crude product.

[0265] Step 8 Place the tritylated product (0.28 mmol) in a 50 mL RB flask with a magnetic stir bar. Add dichloromethane (5.5 mL) and 0.4-0.54 nm (4-5.4 Å) molecular sieves. Add 2-cyanoethyl N,N-diisopropylchlorophosphoramidite (192 μL, 0.6 mmol) and diisopropylethylamine (192 μL, 1.1 mmol) via syringe. Stir the reaction for 2 h. Monitor the reaction by TLC (TLC plate pre-washed with 100% DCM with 5% TEA). Concentrate the reaction and load onto silica gel (12 g column - Teledyne-ISCO) and elute with a hexane:ethyl acetate gradient with 2.5% trimethylamine to give alanine-linked SN38.

[0266] Example 5 Synthesis of doxorubicin-PEG-azide [ka] 128 Doxorubicin-PEG-azide was synthesized on a 50 mg scale following the reaction sequence shown above. Azide 7-1 was reacted with dihydrofuran-2,5-dione to give intermediate 7-2, which was then reacted with perfluorophenol to give intermediate 7-3. Intermediate 7-3 was coupled with doxorubicin to give the desired product, doxorubicin-PEG-azide, in good yield (74%). The presence of the desired product was confirmed by LC-MS.

[0267] Similarly, SN38 azide, alanine-linked SN38, and monomethyl auristatin E (MMAE) azide were prepared, the structures of which are shown below. [ka]

[0268] Example 6 Synthesis of doxorubicin polymers [ka] An exemplary alkynyl-containing polymer is coupled to doxorubicin-PEG-azide. Reaction conditions include CuSO, tris(3-hydroxypropyltriazolylmethyl)amine (THPTA), and sodium ascorbate. The reaction is carried out in a phosphate-buffered aqueous solvent with 60% DMS at pH 7.6. The reaction is carried out at room temperature, and the presence of the desired product is confirmed by LC-MS. D' denotes another biologically active moiety attached to the backbone structures (I)-(VI) that is different from doxorubicin. Other moieties in the compounds, such as fluorescent dyes / other alkyne moieties that may be present and attached to the backbone structures (I)-(VI), have been omitted from the reaction scheme shown above for clarity.

[0269] In some embodiments, SN38 azide, alanine-linked SN38, and monomethyl auristatin E (MMAE) azide were also coupled to compounds of structure (II), (V), or (VI) via the click reaction shown above.

[0270] Example 7 Synthesis of Compound I-1 Stock solution preparation Prepare 250 mM, pH 10 borate buffer. Prepare a 350 mM fluorescein-NHS solution (300 mg in 1.35 mL of DMSO:acetonitrile 25:75). solid phase synthesis Compound I-1 is prepared on a solid support using standard DNA synthesis techniques (i.e., DMT-protected 2-cyanoethyl phosphoramidite) on a DNA synthesizer. The polymer is removed from the solid support with ammonium hydroxide and lyophilized to a paste. A 250 mg aliquot is dissolved in water. A small aliquot is removed and serial dilutions are prepared in 100 mM NaCO3, pH 9 to determine the concentration (A263ε=10,000). The final stock concentration is found to be 14.5 mM.

[0271] 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 stir bar. Wrap the tube in aluminum foil and stir the mixture overnight at room temperature.

[0272] Size exclusion filtration Add 1 mL of water to an Amicon Ultra-15 centrifugal filter (Millipore UFC900324, MW cutoff = 3000). Add the crude reaction mixture (4.5 mL) from the dye coupling reaction to the filter. Rinse the reaction vessel twice with 4 mL of 100 mM NaOH and transfer the rinse to the filter. Centrifuge the filter 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 as above. Remove the filtrate again and add a third 10 mL aliquot of 100 mM NaOH to the retentate. Centrifuge the filter as above and remove the filtrate. Add a fourth 10 mL aliquot of 100 mM NaOH to the retentate and centrifuge as above. Remove the filtrate and add 10 mL of water to the filter. Centrifuge the mixture as above. The retentate is removed and the filter vessel is washed with water, bringing the rinse to a final volume of 3.5 mL. The desired product is confirmed by LC-MS, and the concentration is determined using absorbance.

[0273] Example 8 Activation of Compound I-1 and Antibody Conjugation [ka] 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. This reaction results in a final product with a polymer to antibody ratio of 1:1, as detected by size exclusion chromatography. In some embodiments, anti-CD33, anti-CD70, or anti-CD123 may be used with bis-maleimidoethane ("BMOE") to reduce disulfide bonds.

[0274] Example 9 Post-synthetic drug conversion of compound II-10 to compound I-29 [ka]

[0275] A mixture of CuSO4 (2 mM), sodium ascorbate (10 mM), and tris-hydroxypropyltriazolylmethylamine (THPTA) (4 mM) in water was vigorously stirred at room temperature for 15 minutes. To the mixture, compound II-10 (5 mM), which contains an alkyne moiety, and doborubicin azide (25 mM) were sequentially added, and the resulting mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted by adding EtOAc and aqueous NH4Cl solution. The mixture was stirred for an additional 30 minutes, and the two layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated on a rotary evaporator. The resulting crude product was optionally further purified by recrystallization, but was sufficiently pure to be used without further purification. The presence of compound I-29 was confirmed by mass spectrometry. The mass spectrum of the crude product, compound I-29, after 4 hours is included below. After 4 hours, the reaction was a 1:1 mixture of conjugated and unconjugated polymer. The theoretical molecular weight (MW) of I-29 is 5307 and the measured molecular weight (MW) is 5307.3.

[0276] Example 10 Basic synthesis of peptide backbone by solid phase synthesis [ka] The above reaction scheme shows an exemplary method for preparing intermediates useful in preparing compounds of structure (III), 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.

[0277] Small porous beads are first treated with functional units, which are attached to the surface of the porous beads. Peptide chains are assembled at the functional unit sites, and remain covalently attached to the beads until cleaved. Once attached, the peptide chains are immobilized on the solid phase and retained during the filtration process, during which liquid reagents and synthesis by-products are washed away.

[0278] The basic cycle of solid-phase synthesis is one of repeated deprotection-wash-coupling-wash cycles. The free N-terminal amine of a peptide attached to a solid support is coupled to an N-protected amino acid group (e.g., with Fmoc or Boc). The newly introduced amino acid unit is deprotected to expose a new N-terminal amine, which can then be further reacted with additional amino acids. This process is repeated to elongate the peptide chain.

[0279] Once all desired amino acids and monomer units have been incorporated into the peptide chain, the peptide chain is cleaved from the bead. Cleavage reagents such as anhydrous hydrogen fluoride or trifluoroacetic acid may be used to cleave the peptide chain from the bead. The peptide chain is then collected, purified, and characterized.

[0280] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referenced in this disclosure and / or listed in Application Data Sheets, including U.S. Provisional Patent Application No. 63 / 409,065, filed September 22, 2022, are incorporated by reference in their entirety into this disclosure to the extent not inconsistent herewith. Where appropriate, concepts from the various patents, applications, and publications may be employed to modify aspects of the embodiments to provide still further embodiments.

[0281] From the foregoing, it will be appreciated that, although specific embodiments of the present disclosure have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the present disclosure. Accordingly, the present disclosure is limited only by the appended claims.

Claims

1. The following structure (I): 【Chemical 1】 (I) 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, in each occurrence, independently H, alkyl, or alkoxy; R 4 may, in each occurrence independently, be OH, SH, O - , S - , OR d , or SR d and R 5 is, in each occurrence, independently oxo or thioxo; R 6 and R 7 is, independently at each occurrence, H, OH, or halo; L 1a is, in each occurrence, independently a heteroalkylene or heteroarylene linker; L 1b is, in each occurrence, independently either i) H or ii) a linker; L 2 , L 3 , L 5 , and L 6 is, in each occurrence, independently a direct bond or independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 4 is, in each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 7 is, independently in each occurrence, a linker; M 1 is, at each occurrence, independently either i) absent, or ii) a moiety that comprises a biologically active moiety, with the proviso that L 1b If is H, then M 1 does not exist; M 2 is, independently at each occurrence, a moiety comprising a fluorescent dye; M 3 is, at each occurrence, independently a moiety that comprises a biologically active moiety; Q, in each occurrence, independently, is a moiety that includes a reactive group or a protected form thereof that is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L′, in 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 0 or a greater integer; q, in each occurrence, is 0 or a greater integer; p, in each occurrence, is 0 or a greater integer; w, in each occurrence, is 0 or a greater integer; and n is an integer of 1 or greater; A compound wherein the sum of p and w is an integer of 2 or greater, and said compound comprises at least two different biologically active moieties.

2. L 1a 10. The compound of claim 1, wherein, in each occurrence, is independently an optionally substituted 5- to 7-membered heteroarylene linker.

3. L 1a but has the following structure: 【Chemistry 2】 3. The compound according to claim 1 or 2, having one of:

4. L 1a But, L 1b and M 1 does not exist, the following structure: 【Chemistry 3】 and During the ceremony: R 8 is, in each occurrence, independently O, NH, or NR e and R 9 is, in each occurrence, independently H, alkyl, or optionally substituted alkyl; R 10 is, in each occurrence, independently H or F; and R e is, at each occurrence, independently alkyl or optionally substituted alkyl; 3. The compound according to claim 1 or 2.

5. The following structure (IA): 【Chemistry 4】 (IA) or a stereoisomer, salt, or tautomer thereof.

6. The following structure (IB): 【Chemistry 5】 (IB) 5. The compound according to any one of claims 1 to 2 and 4, which has a stereoisomer, salt, or tautomer thereof.

7. The following structure (IC): 【Chemistry 6】 (IC) or a stereoisomer, salt, or tautomer thereof, 5. The compound of any one of claims 1 to 4, wherein k in each occurrence is an integer of 0 or greater.

8. L 4 at least one occurrence of is heteroalkylene, or L 4 The compound of any one of claims 1 to 7, wherein each occurrence of is heteroalkylene.

9. The compound of claim 8 , wherein the heteroalkylene comprises an alkylene oxide.

10. The compound of claim 9 , wherein the heteroalkylene comprises ethylene oxide.

11. 11. The compound of claim 10, wherein the ethylene oxide is polyethylene oxide.

12. L 4 wherein, in each occurrence, the following structure: 【Chemistry 7】 and During the ceremony: z is an integer from 1 to 100; and * indicates a bond to the adjacent phosphorus atom, The compound according to any one of claims 1 to 11.

13. The compound according to claim 12, wherein z is an integer from 3 to 8 or an integer from 22 to 26.

14. The following structures (ID), (IE), or (IF): 【Chemistry 8】 (ID) 【change】 (IE) or 【change】 (IF) or a stereoisomer, salt, or tautomer thereof.

15. L 5 15. The compound of any one of claims 1 to 14, wherein at least one occurrence of is alkylene.

16. L 5 16. The compound of any one of claims 1 to 15, wherein each occurrence of is alkylene.

17. L 3 17. The compound of any one of claims 1 to 16, wherein at least one occurrence of is alkylene.

18. L 3 18. The compound of any one of claims 1 to 17, wherein each occurrence of is alkylene.

19. L 6 19. The compound of any of claims 1 to 18, wherein at least one occurrence of is a direct bond.

20. The following structures (IG), (IH), or (IJ): 【Chemistry 9】 (IG) 【change】 (IH) or 【change】 (IJ) or a stereoisomer, salt, or tautomer thereof, During the ceremony: y 1 is, in each occurrence, independently an integer from 0 to 6; and y 2 and y 3 is, in each occurrence, independently an integer from 1 to 6; The compound according to any one of claims 17 to 19.

21. L 1b 21. The compound of any of claims 1 to 20, wherein at least one occurrence of comprises a functional group formed by reaction of an aldehyde, oxime, hydrazone, alkyne, amine, azide, acyl azide, acyl halide, nitrile, nitrone, sulfhydryl, disulfide, sulfonyl halide, isothiocyanate, imido ester, activated ester, ketone, α,β-unsaturated carbonyl, alkene, maleimide, α-haloimide, epoxide, aziridine, tetrazine, tetrazole, phosphine, biotin, or thiirane with a complementary reactive group.

22. L 1b 22. The compound of claim 21, wherein at least one occurrence of comprises a functional group formed by reaction of an alkyne and an azide.

23. L 1b 23. The compound of claim 22, wherein at least one occurrence of is a linker comprising a triazolyl functionality.

24. L 1b -M 1 at least one occurrence of the following structure: 【Chemistry 10】 including one of In the ceremony, L c and L d 24. The compound of any one of claims 1 to 23, wherein each independently is an optional linker.

25. L c or L d 25. The compound of claim 24, wherein either or both are absent.

26. L c or L d or both are present.

27. L c and L d 27. The compound of claim 26, wherein, if present, each is independently alkylene or heteroalkylene.

28. L c and L d may independently have the following structure: 【Chemistry 11】 27. The compound of claim 26, having one of:

29. M 1 -L 1b has the following structure: 【Chemistry 12】 and During the ceremony, 29. The compound of any one of claims 1 to 28, wherein a, b, c, and d are each independently an integer ranging from 1 to 6.

30. M 1 -L 1b at least one occurrence of the following structure: 【Chemistry 13】 The compound according to any one of claims 1 to 29, having one of:

31. M 1 -L 1b each occurrence of 【Chemistry 14】 The compound according to any one of claims 1 to 30, having one of:

32. The following structure (III): 【Chemistry 15】 (III) or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein: M 2 is, independently at each occurrence, a moiety comprising a fluorescent dye; M 3 is, at each occurrence, independently a moiety that comprises a biologically active moiety; L 2 , L 3 , L 5 , and L 6 is, in each occurrence, independently a direct bond or independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 7 is, independently in each occurrence, a linker; R 21 is, in 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 OH, SH, O-, S-, OR d , or SR d and R c 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, in each occurrence, is independently a moiety that includes a reactive group or a protected form thereof that is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L′, in 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 (III); m, in each occurrence, is independently 0 or a greater integer; q, in each occurrence, is independently 0 or a greater integer; v, in each occurrence, is independently an integer of 1 or greater; n is an integer of 2 or greater; A compound, wherein said compound comprises at least two different biologically active moieties.

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

34. At least one R 21 34. The compound of claim 32 or 33, wherein is a charged amino acid side chain.

35. 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.

36. R 21 , L 5 , and m is 【Chemistry 16】 But, (G) 10 36. The compound of any of claims 32-35, selected to have the amino acid sequence of (GDGDGDGDGD), (GKGKGKGKGK), or (GKGKGKGK).

37. R 21 , L 5 , and m is 【Chemistry 17】 is selected to have an amino acid sequence capable of forming an α-helical or β-sheet secondary structure.

38. 38. The compound of claim 37, wherein the amino acid sequence is (GGEEFMLVYKFARKHGG) or (GGMSMVVSGG).

39. L 5 or L 3 or both are present in at least one occurrence.

40. If present, L 5 or L 3 or both are heteroalkylene linkers.

41. 41. The compound of claim 40, wherein 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.

42. L 5 or L 3 or at least one occurrence of both has the following structure: 【Chemistry 18】 42. The compound of claim 41, having the formula:

43. L 5 or L 3 or at least one occurrence of both has the following structure: 【Chemistry 19】 42. The compound of claim 41 having the formula:

44. L 6 and L 2 The compound of any one of claims 32 to 43, wherein is independently absent or a heteroalkylene linker.

45. 45. The compound of claim 44, wherein the heteroalkylene linker is a peptidyl linker.

46. The following structure (IV): 【Chemistry 20】 (IV) or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein: M 2 is, independently at each occurrence, a moiety comprising a fluorescent dye; M 3 is, at each occurrence, independently a moiety that comprises a biologically active moiety; L 7 is, independently in each occurrence, a linker; L 2 , L 5 , and L 6 is, in each occurrence, independently a direct bond or independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatomic linker; L 8 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 counter ion; Q, in each occurrence, independently, is a moiety that includes a reactive group or a protected form thereof that is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L', in 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 (IV); q, in each occurrence, is independently 0 or a greater integer; v, in each occurrence, is independently an integer of 1 or greater; n is an integer of 2 or greater; A compound, wherein said compound comprises at least two different biologically active moieties.

47. 47. The compound of claim 46, wherein the charged moiety is positively charged.

48. The charged moieties independently have the following structure: 【Chemical 21】 and During the ceremony: R, in each occurrence, is independently H or C 1 ~C 6 48. The compound of claim 47, which is alkyl.

49. 47. The compound of claim 46, wherein the charged moiety is negatively charged.

50. The charged moiety has the following structure: 【Chemical 22】 50. The compound of claim 49, having the formula:

51. L 8 but has the following structure: 【Chemistry 23-1】 【Chemistry 23-2】 and 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 m is an integer of 1 or greater; The compound according to any one of claims 46 to 50.

52. L 7 52. The compound of any of claims 1-51, wherein at least one occurrence of 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.

53. L 7 53. The compound of claim 52, wherein comprises an amide or ester functionality.

54. L 7 or L 1b at least one occurrence of the following structure: 【Chemistry 24】 54. The compound of any one of claims 1 to 53, comprising one of:

55. L 7 55. The compound of any of claims 1-54, wherein each occurrence of 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.

56. L 7 or L 1b each occurrence of 【Chemistry 25】 56. The compound of any one of claims 1 to 55, comprising one of:

57. R 3 57. The compound of any preceding claim, wherein at least one occurrence of is H.

58. R 5 58. The compound of any one of claims 1 to 57, wherein, at each occurrence, is oxo.

59. R 4 But in each occurrence, O - The compound according to any one of claims 1 to 58,

60. R 1 and R 2 are each independently OH or —OP(═R a ) (R b ) R c 60. The compound according to any one of claims 1 to 59,

61. 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 60, wherein the other of is Q or a linker comprising a covalent bond to Q.

62. 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 61,

63. R 2 The compound of any one of claims 1 to 62, wherein is L'.

64. R 2 Ga-NH 2 The compound according to any one of claims 1 to 63,

65. R 2 or R 1 65. The compound of any one of claims 1 to 64, wherein one of is L', and L' is a linker comprising a covalent bond to a solid support.

66. 66. The compound of claim 65, wherein the solid support is a polymeric bead or a non-polymeric bead.

67. 67. The compound of any one of claims 1 to 66, wherein L' is a linker to a targeting moiety.

68. 68. The compound of any one of claims 1 to 67, wherein L' is a linker to a targeting moiety, said linker comprising an alkylene oxide or a phosphodiester moiety, or a combination thereof.

69. L' is a group having the following structure: 【Chemical 26】 and 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; and L″ is the targeting moiety or a linkage to the targeting moiety; A compound according to any one of claims 1 to 68.

70. 70. The compound of any one of claims 1 to 69, wherein the targeting moiety is an antibody or a cell surface receptor antagonist.

71. 71. The compound of claim 70, 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.

72. 72. The compound of any one of claims 1 to 71, wherein the targeting moiety is a monoclonal antibody.

73. 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 73. The compound of claim 72, 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.

74. 74. The compound of claims 1-73, wherein the targeting moiety is an antibody specific for a tumor cell antigen.

75. 75. The compound of claim 74, wherein the tumor cell antigen is EGFR, HER2, folate receptor, CD20, or CD33.

76. R 1 or R 2 but has the following structure: 【Chemistry 27-1】 【Chemistry 27-2】 and During the ceremony, R a is H or a solid support; A compound according to any one of claims 1 to 75.

77. R 2 but has the following structure: 【Chemical 28】 77. The compound of any one of claims 1 to 76, having one of:

78. R 1 but has the following structure: 【Chemical 29】 78. The compound of any one of claims 1 to 77, having the formula:

79. M 2 79. The compound of any of claims 1-78, wherein, in one or more occurrences, independently, is a moiety that includes four or more aryl or heteroaryl rings, or a combination thereof.

80. M 2 80. The compound of any one of claims 1 to 79, wherein, in one or more occurrences, is independently fluorescent or colored.

81. M 2 is fluorescent.

82. M 2 In one or more occurrences, independently comprises a fused polycyclic aryl or heteroaryl moiety comprising at least four fused rings.

83. M 2 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.

84. M 2 is, at each occurrence, independently selected from the group consisting of p-terphenyl, perylene, azobenzene, phenazine, phenanthroline, acridine, thioxanthrene, chrysene, rubrene, coronene, cyanine, perylene imide, perylene amide, and derivatives thereof.

85. M 2 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.

86. M 2 is, at each occurrence, independently selected from the group consisting of coumarin dyes, boron-dipyrromethenes, rhodamines, cyanines, pyrenes, perylenes, perylene monoimides, 6-FAM, 5-FAM, 6-FITC, 5-FITC, and derivatives thereof.

87. M 2 may, in each occurrence, independently have the structure: 【Chemistry 30】 87. The compound of any one of claims 1 to 86, having one of:

88. M 2 at least one occurrence of the following structure: 【Chemical 31】 88. The compound of any one of claims 1 to 87, having the formula:

89. M 2 each occurrence of 【Chemical 32】 89. The compound of any one of claims 1 to 88, having the formula:

90. -L 7 -M 2 at least one occurrence of the following structure: 【Chemical 33】 90. The compound of any one of claims 1 to 89, having one of:

91. -L 7 -M 2 each occurrence of 【Chemical Formula 34】 The compound according to any one of claims 1 to 90, having one of

92. M 1 or M 3 92. The compound of any of claims 1-91, wherein at least one occurrence of is an alkylating agent, antimetabolite, microtubule inhibitor, topoisomerase inhibitor, or cytotoxic antibiotic.

93. M 1 or M 3 93. The compound of any of claims 1-92, wherein each occurrence of is an alkylating agent, an antimetabolite, a microtubule inhibitor, a topoisomerase inhibitor, or a cytotoxic antibiotic.

94. M 1 or M 3 94. The compound of any of claims 1-93, wherein at least one occurrence of is a nitrogen mustard, a nitrosourea, a tetrazine, an aziridine, cisplatin or a cisplatin derivative, or a non-classical alkylating agent.

95. M 1 or M 3 is mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide, busulfan, N-nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU), semustine (MeCCNU), fotemustine, streptozotocin, dacarbazine, mitozolomide, temozolomide, thiotepa, mitomycin, diaziquone (AZQ), cisplatin, carboplatin, oxaliplatin, procarbazine, or hexamethylmelamine.

96. M 1 or M 3 96. The compound of any of claims 1-95, wherein at least one occurrence of is an antifolate, a fluoropyrimidine, a deoxynucleoside analog, or a thiopurine.

97. M 1 or M 3 is methotrexate, pemetrexed, fluorouracil, capecitabine, cytarabine, gemcitabine, decitabine, azacitidine, fludarabine, nelarabine, cladribine, clofarabine, pentostatin, thioguanine, and mercaptopurine.

98. M 1 or M 3 98. The compound of any of claims 1-97, wherein at least one occurrence of is an auristatin, a vinca alkaloid, or a taxane.

99. M 1 or M 3 is auristatin F, auristatin E, vincristine, vinblastine, vinorelbine, vindesine, vinflunine, paclitaxel, docetaxel, etoposide, or teniposide.

100. M 1 or M 3 100. The compound of any of claims 1-99, wherein at least one occurrence of is irinotecan, SN38, topotecan, camptothecin, doxorubicin, mitoxantrone, teniposide, novobiocin, mervalone, or aclarubicin.

101. M 1 or M 3 101. The compound of any preceding claim, wherein at least one occurrence of is an anthracycline or a bleomycin.

102. M 1 or M 3 102. The compound of any of claims 1-101, wherein at least one occurrence of is doxorubicin, daunorubicin, epirubicin, idarubicin, pirarubicin, aclarubicin, or mitoxantrone.

103. M 1 or M 3 at least one occurrence of the following structure: 【Hua 35-1】 【Chemistry 35-2】 The compound according to any one of claims 1 to 102, having one of:

104. M 1 or M 3 each occurrence of 【Chemical 36】 The compound according to any one of claims 1 to 103, having one of:

105. M 3 105. The compound of any of claims 1 to 104, wherein at least one occurrence of is an anti-inflammatory compound.

106. M 3 106. The compound of claim 105, wherein at least one occurrence of is a steroid.

107. M 3 107. The compound of claim 105 or 106, wherein at least one occurrence of is cholesterol, cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or beclomethasone.

108. M 3 at least one occurrence of the following structure: 【Chemical 37】 and 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 【Chemical 38】 represents a single or double carbon-carbon bond; The compound according to any one of claims 105 to 107.

109. M 3 at least one occurrence of the following structure: 【Chemical 39】 The compound according to any one of claims 1 to 108, having one of:

110. M 3 110. The compound of any of claims 1 to 109, wherein at least one occurrence of is a vitamin.

111. M 3 111. The compound of claim 110, wherein at least one occurrence of is vitamin E.

112. M 3 is α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, or δ-tocotrienol.

113. M 3 at least one occurrence of the following structure: 【Chemistry 40】 and During the ceremony: R 19 and R 20 are independently H or CH 3 and 【Chemistry 41】 represents a single or double carbon-carbon bond; A compound according to any one of claims 110 to 112.

114. M 3 at least one occurrence of the following structure: 【Chemistry 42】 The compound according to any one of claims 1 to 113, having one of:

115. Q has the following structure: 【Chemistry 43】 The compound of any one of claims 1 to 114, having the formula:

116. The compound of any one of claims 1 to 115, wherein m is 0 to 10.

117. The compound of any one of claims 1 to 116, wherein m is 0, 1, 2, 3, 4, or 5.

118. The compound of any one of claims 1 to 116, wherein m is 1 or 2.

119. The compound of any one of claims 1 to 118, wherein n is 1, 2, 3, or 4.

120. The compound of any one of claims 1 to 119, wherein n is 1 or 2.

121. The compound of any one of claims 1 to 120, wherein q is 0, 1, 2, 3, or 4.

122. The compound of any one of claims 1 to 120, wherein q is 1 or 2.

123. The compound of any one of claims 1 to 122, wherein p is 1, 2, 3, or 4.

124. The compound of any one of claims 1 to 122, wherein p is 2 or 3.

125. The compound of any one of claims 1 to 124, wherein w is 1, 2, 3, or 4.

126. The compound of any one of claims 1 to 124, wherein w is 1 or 2.

127. 127. The compound of any one of claims 1 to 126, wherein v is an integer from 1 to 100.

128. 127. The compound of any one of claims 1 to 126, wherein v is an integer from 1 to 10.

129. y 1 is, in each occurrence, an integer 0 or 1; and y 2 and y 3 The compound of any one of claims 1 to 128, wherein, in each occurrence, is 1.

130. 130. The compound of any one of claims 1 to 129, wherein n is 1, q is 2, w is 2, p is 2, and m is 1.

131. 130. The compound of any one of claims 1 to 129, wherein n is 1, q is 2, w is 1, p is 3, and m is 1.

132. M 1 : M 2 : M 3 The compound according to any one of claims 1 to 131, wherein the ratio of

133. M 1 : M 2 : M 3 The compound according to any one of claims 1 to 131, wherein the ratio of

134. M 1 : M 2 : M 3 The compound according to any one of claims 1 to 131, wherein the ratio of

135. R 6 or R 7 135. The compound of any of claims 1 to 134, wherein at least one occurrence of is F or H.

136. R 6 and R 7 is F or H.

137. R 6 and R 7 is F, and R 8 is O and R 9 is H and R 10 The compound of any one of claims 1 to 136, wherein is H.

138. 138. The compound of any of claims 1-137, wherein the compound has one of the structures in Table 2A, 2B, 2C, 2D, or 2E, or a salt or tautomer thereof.

139. 139. A pharmaceutical composition comprising a compound according to any one of claims 1 to 138 and a pharmaceutically acceptable carrier, diluent, or excipient.

140. 140. A method for treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of claims 1 to 138, or a pharmaceutical composition of claim 139.

141. 141. The method of claim 140, wherein the disease or disorder is cancer.

142. 142. The method of claim 140 or 141, wherein the cancer is breast cancer, gastric cancer, lung cancer, ovarian cancer, lymphoma, or bladder cancer.

143. The following structure (II): 【Chemical 44】 (II) 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, in each occurrence, independently H, alkyl, or alkoxy; R 4 may, in each occurrence independently, be OH, SH, O - , S - , OR d , or SR d and R 5 is, in each occurrence, independently oxo or thioxo; R 6 and R 7 is, independently at each occurrence, H, OH, or halo; R 8 is, in each occurrence, independently O, NH, or NR e and R 9 is, in each occurrence, independently H, alkyl, or optionally substituted alkyl; R 10 is, at each occurrence, independently H or F; R e is, in each occurrence, independently alkyl or optionally substituted alkyl; L 2 , L 3 , L 5 , and L 6 is, in each occurrence, independently a direct bond or independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 4 is, in each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; L 7 is, independently in each occurrence, a linker; M 2 is, independently at each occurrence, a moiety comprising a fluorescent dye; M 3 is, at each occurrence, independently a moiety that comprises a biologically active moiety; G, in each occurrence, is independently a moiety reactive under cycloaddition; Q, in each occurrence, independently, is a moiety that includes a reactive group or a protected form thereof that is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L', in 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); m, in each occurrence, is independently 0 or a greater integer; q, in each occurrence, is 0 or a greater integer; p, in each occurrence, is 0 or a greater integer; w, in each occurrence, is 0 or a greater integer; k, in each occurrence, is an integer of 0 or greater; x 9 is, in each occurrence, an integer from 1 to 6; and n is an integer of 1 or greater; A compound wherein the sum of p and w is an integer of 2 or greater, and said compound comprises at least two different biologically active moieties.

144. L 4 at least one occurrence of is heteroalkylene, or L 4 144. The compound of claim 143, wherein each occurrence of is heteroalkylene.

145. 145. The compound of claim 144, wherein the heteroalkylene comprises an alkylene oxide.

146. 146. The compound of claim 145, wherein the heteroalkylene comprises ethylene oxide.

147. 147. The compound of claim 146, wherein the ethylene oxide is polyethylene oxide.

148. L 4 wherein, in each occurrence, the following structure: 【Chemistry 45】 and During the ceremony: z is an integer from 1 to 100; and * indicates a bond to the adjacent phosphorus atom, A compound according to any one of claims 143 to 147.

149. 149. The compound of claim 148, wherein z is an integer from 3 to 8 or an integer from 22 to 26.

150. The following structure (IIA): 【Chemistry 46】 (IIA) or a stereoisomer, salt, or tautomer thereof.

151. L 5 151. The compound of any of claims 143-150, wherein at least one occurrence of is alkylene.

152. L 5 152. The compound of any of claims 143-151, wherein each occurrence of is alkylene.

153. L 3 153. The compound of any of claims 143-152, wherein at least one occurrence of is alkylene.

154. L 3 154. The compound of any of claims 143-153, wherein each occurrence of is alkylene.

155. L 6 155. The compound of any of claims 143-154, wherein at least one occurrence of is a direct bond.

156. The following structure (IIB): 【Chemistry 47】 (IIB) or a stereoisomer, salt, or tautomer thereof, During the ceremony: y 1 is, in each occurrence, independently an integer from 0 to 6; and y 2 and y 3 is, in each occurrence, independently an integer from 1 to 6; A compound according to any one of claims 143 to 155.

157. The following structure (V): 【Chemistry 48】 (V) or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein: G 2 is, in each occurrence, independently a moiety reactive under cycloaddition; G 3 is, in each occurrence, independently a moiety reactive under cycloaddition; L 7 is, independently in each occurrence, a linker; L 2 , L 3 , L 5 , and L 6 is, in each occurrence, independently a direct bond or independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, or heteroalkynylene linker; R 21 is, in 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 OH, SH, O-, S-, OR d , or SR d and R c 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, in each occurrence, independently, is a moiety that includes a reactive group or a protected form thereof that is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L′, in 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 (V); m, in each occurrence, is independently 0 or a greater integer; q, in each occurrence, is independently 0 or a greater integer; v, in each occurrence, is independently an integer of 1 or greater; and n is an integer of 2 or greater; A compound, wherein said compound comprises at least two different biologically active moieties.

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

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

160. 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.

161. R 21 , L 5 , and m is 【Chemistry 49】 But, (G) 10 161. The compound of any of claims 157-160, selected to have the amino acid sequence of (GDGDGDGDGD), (GKGKGKGKGK), or (GKGKGKGK).

162. R 21 , L 5 , and m is 【Chemistry 50】 is selected to have an amino acid sequence capable of forming an α-helical or β-sheet secondary structure.

163. 163. The compound of claim 162, wherein the amino acid sequence is (GGEEFMLVYKFARKHGG) or (GGMSMVVSGG).

164. L 5 or L 3 or both are present in at least one occurrence.

165. If present, L 5 or L 3 or both are heteroalkylene linkers.

166. 166. The compound of claim 165, wherein 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.

167. L 5 or L 3 or at least one occurrence of both has the following structure: 【Chemistry 51】 167. The compound of claim 166, having the formula:

168. L 5 or L 3 or at least one occurrence of both has the following structure: 【Chemistry 52】 167. The compound of claim 166, having the formula:

169. L 6 and L 2 is independently absent or a heteroalkylene linker.

170. 170. The compound of claim 169, wherein the heteroalkylene linker is a peptidyl linker.

171. The following structure (VI): 【Chemistry 53】 (VI) or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein: G 2 is, in each occurrence, independently a moiety reactive under cycloaddition; G 3 is, in each occurrence, independently a moiety reactive under cycloaddition; L 7 is, independently in each occurrence, a linker; L 2 , L 5 , and L 6 is, in each occurrence, independently a direct bond or independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatomic linker; L 8 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 counter ion; Q, in each occurrence, independently, is a moiety that includes a reactive group or a protected form thereof that is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety; L', in 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 (VI); q, in each occurrence, is independently 0 or a greater integer; v, in each occurrence, is independently an integer of 1 or greater; and n is an integer of 2 or greater; A compound, wherein said compound comprises at least two different biologically active moieties.

172. 172. The compound of claim 171, wherein the charged moiety is positively charged.

173. The charged moieties independently have the following structure: 【Chemical 54】 and During the ceremony: R, in each occurrence, is independently H or C 1 -C 6 is alkyl, The compound of claim 172.

174. The compound of claim 171, wherein the charged moiety is negatively charged.

175. The charged moiety has the following structure: 【Chemistry 55】 175. The compound of claim 174, having the formula:

176. L 8 but has the following structure: 【Chemistry 56-1】 【Chemistry 56-2】 including one of 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 m is an integer of 1 or greater; A compound according to any one of claims 171 to 175.

177. L 7 177. The compound of any of claims 171-176, wherein at least one occurrence of 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.

178. L 7 178. The compound of claim 177, wherein comprises an amide or ester functional group.

179. L 7 at least one occurrence of the following structure: 【Chemical 57】 The compound according to any one of claims 171 to 178, comprising one of:

180. L 7 180. The compound of any of claims 171-179, wherein each occurrence of 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.

181. L 7 each occurrence of 【Chemistry 58】 The compound according to any one of claims 171 to 180, comprising one of:

182. R 3 182. The compound of any of claims 171-181, wherein at least one occurrence of is H.

183. R 5 But in each occurrence, O - The compound according to any one of claims 171 to 182,

184. R 4 184. The compound of any of claims 171-183, wherein, at each occurrence, is oxo.

185. 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 171 to 184,

186. 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 171 to 185, wherein the other is Q or a linker comprising a covalent bond to Q.

187. R 1 and R 2 are each independently -OP(=R a ) (R b ) R c The compound according to any one of claims 171 to 186,

188. R 2 The compound of any one of claims 171 to 187, wherein is L'.

189. The compound of any one of claims 171 to 188, wherein L' is a linker to a targeting moiety.

190. 190. The compound of any one of claims 171-189, wherein L' is a linker to a targeting moiety, said linker comprising an alkylene oxide or a phosphodiester moiety, or a combination thereof.

191. L' is a group having the following structure: 【Chemical Formula 59】 and 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; and L″ is the targeting moiety or a linkage to the targeting moiety; A compound according to any one of claims 171 to 190.

192. 192. The compound of any one of claims 171 to 191, wherein the targeting moiety is an antibody or a cell surface receptor antagonist.

193. The compound of claim 192, 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.

194. 194. The compound of any one of claims 171 to 193, wherein the targeting moiety is a monoclonal antibody.

195. 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 195. The compound of claim 194, 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.

196. R 1 or R 2 but has the following structure: 【Chemistry 60-1】 【Chemistry 60-2】 and In the formula R a is H or a solid support; A compound according to any one of claims 171 to 195.

197. R 2 but has the following structure: 【Hua 61】 The compound according to any one of claims 171 to 196, having one of:

198. R 1 but has the following structure: 【Hua 62】 The compound according to any one of claims 171 to 197, having the formula:

199. M 2 is, in one or more occurrences, independently a moiety that includes four or more aryl or heteroaryl rings, or a combination thereof.

200. M 2 200. The compound of any of claims 171-199, wherein, in one or more occurrences, is independently fluorescent or colored.

201. M 2 The compound of claim 200, wherein is fluorescent.

202. M 2 in one or more occurrences independently comprises a fused polycyclic aryl or heteroaryl moiety comprising at least four fused rings.

203. M 2 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.

204. M 2 is, at each occurrence, independently selected from the group consisting of p-terphenyl, perylene, azobenzene, phenazine, phenanthroline, acridine, thioxanthrene, chrysene, rubrene, coronene, cyanine, perylene imide, perylene amide, and derivatives thereof.

205. M 2 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.

206. M 2 is, at each occurrence, independently selected from the group consisting of coumarin dyes, boron-dipyrromethenes, rhodamines, cyanines, pyrenes, perylenes, perylene monoimides, 6-FAM, 5-FAM, 6-FITC, 5-FITC, and derivatives thereof.

207. M 2 may, in each occurrence, independently have the structure: 【Chemistry 63】 The compound according to any one of claims 171 to 206, having one of:

208. M 2 at least one occurrence of the following structure: 【Hua 64】 The compound according to any one of claims 171 to 207, having the formula:

209. M 2 each occurrence of 【Chemistry 65】 The compound according to any one of claims 171 to 208, having the formula:

210. -L 7 -M 2 at least one occurrence of the following structure: 【Hua 66】 The compound according to any one of claims 171 to 209, having one of:

211. -L 7 -M 2 each occurrence of 【Chemical 67】 The compound according to any one of claims 171 to 210, having one of:

212. M 3 212. The compound of any of claims 171-211, wherein at least one occurrence of is an alkylating agent, antimetabolite, microtubule inhibitor, topoisomerase inhibitor, or cytotoxic antibiotic.

213. M 3 213. The compound of any of claims 171-212, wherein each occurrence of is an alkylating agent, an antimetabolite, a microtubule inhibitor, a topoisomerase inhibitor, or a cytotoxic antibiotic.

214. M 3 is a nitrogen mustard, a nitrosourea, a tetrazine, an aziridine, cisplatin or a cisplatin derivative, or a non-classical alkylating agent.

215. M 3 is mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide, busulfan, N-nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU), semustine (MeCCNU), fotemustine, streptozotocin, dacarbazine, mitozolomide, temozolomide, thiotepa, mitomycin, diaziquone (AZQ), cisplatin, carboplatin, oxaliplatin, procarbazine, or hexamethylmelamine.

216. M 3 216. The compound of any of claims 171-215, wherein at least one occurrence of is an antifolate, a fluoropyrimidine, a deoxynucleoside analog, or a thiopurine.

217. M 3 is methotrexate, pemetrexed, fluorouracil, capecitabine, cytarabine, gemcitabine, decitabine, azacitidine, fludarabine, nelarabine, cladribine, clofarabine, pentostatin, thioguanine, and mercaptopurine.

218. M 3 218. The compound of any of claims 171-217, wherein at least one occurrence of is an auristatin, a vinca alkaloid, or a taxane.

219. M 3 is auristatin F, auristatin E, vincristine, vinblastine, vinorelbine, vindesine, vinflunine, paclitaxel, docetaxel, etoposide, or teniposide.

220. M 3 is irinotecan, SN38, topotecan, camptothecin, doxorubicin, mitoxantrone, teniposide, novobiocin, mervalone, or aclarubicin.

221. M 3 221. The compound of any of claims 171-220, wherein at least one occurrence of is an anthracycline or a bleomycin.

222. M 3 222. The compound of any of claims 171-221, wherein at least one occurrence of is doxorubicin, daunorubicin, epirubicin, idarubicin, pirarubicin, aclarubicin, or mitoxantrone.

223. M 3 223. The compound of any of claims 171-222, wherein at least one occurrence of is an anti-inflammatory compound.

224. M 3 224. The compound of claim 223, wherein at least one occurrence of is a steroid.

225. M 3 225. The compound of claim 223 or 224, wherein at least one occurrence of is cholesterol, cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, deflazacort, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, or beclomethasone.

226. M 3 at least one occurrence of the following structure: 【Chemistry 68】 and 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 【Chemical Formula 69】 represents a single or double carbon-carbon bond; A compound according to any one of claims 223 to 225.

227. M 3 at least one occurrence of the following structure: 【Chemistry 70-1】 【Chemistry 70-2】 The compound according to any one of claims 171 to 226, which is one of:

228. M 3 each occurrence of 【Hua 71-1】 【Chemistry 71-2】 The compound according to any one of claims 171 to 227, having one of:

229. M 3 229. The compound of any of claims 171-228, wherein at least one occurrence of is a vitamin.

230. M 3 230. The compound of claim 229, wherein at least one occurrence of is vitamin E.

231. M 3 is α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, or δ-tocotrienol.

232. M 3 at least one occurrence of the following structure: 【Chemical Formula 72】 and During the ceremony: R 19 and R 20 are independently H or CH 3 and 【Chemical 73】 represents a single or double carbon-carbon bond; A compound according to any one of claims 229 to 231.

233. M 3 at least one occurrence of the following structure: 【Chemical Formula 74】 The compound according to any one of claims 171 to 232, having one of:

234. Q has the following structure: 【Chemistry 75】 The compound according to any one of claims 171 to 233, having the formula:

235. The compound of any one of claims 171 to 234, wherein the cycloaddition is a click reaction.

236. G, G 2 , or G 3 but has the following structure: 【Chemical Formula 76】 The compound according to any one of claims 171 to 235, having one of:

237. G, G 2 , or G 3 wherein, in each occurrence, the following structure: 【Chemical 77】 The compound according to any one of claims 171 to 236, having the formula:

238. x 9 is an integer of 4, 5, or 6.

239. x 9 is an integer equal to 4.

240. 240. The compound of any one of claims 171 to 239, wherein m is 0, 1, 2, 3, 4, or 5.

241. The compound according to any one of claims 171 to 240, wherein m is 1 or 2.

242. 242. The compound of any one of claims 171 to 241, wherein n is 1, 2, 3, or 4.

243. The compound according to any one of claims 171 to 242, wherein n is 1 or 2.

244. The compound of any one of claims 171 to 243, wherein q is 0, 1, 2, 3, or 4.

245. The compound of any one of claims 171 to 244, wherein q is 1 or 2.

246. The compound of any one of claims 171 to 245, wherein p is 1, 2, 3, or 4.

247. The compound of any one of claims 171 to 246, wherein p is 2 or 3.

248. The compound of any one of claims 171 to 247, wherein w is 1, 2, 3, or 4.

249. The compound of any one of claims 171 to 248, wherein w is 1 or 2.

250. 250. The compound of any one of claims 171 to 249, wherein k is 0, 1, 2, 3, or 4.

251. The compound of any one of claims 171 to 250, wherein k is 0 or 1.

252. y 1 is, in each occurrence, an integer 0 or 1; and y 2 and y 3 The compound of any one of claims 171 to 251, wherein, in each occurrence, is 1.

253. The compound of any one of claims 171 to 252, wherein n is 1, q is 2, w is 2, p is 2, and m is 1.

254. The compound of any one of claims 171 to 252, wherein n is 1, q is 2, w is 1, p is 3, and m is 1.

255. R 6 or R 7 is F or H.

256. R 6 and R 7 is F or H.

257. R 6 and R 7 is F, and R 8 is O and R 9 is H and R 10 The compound of any one of claims 171 to 256, wherein is H.

258. R 6 and R 7 is H, and R 8 is O and R 9 is H and R 10 The compound of any one of claims 171 to 256, wherein is H.

259. x 9 is 2, 4, or 6.

260. x 9 260. The compound of any of claims 171-259, wherein each occurrence of is 2 or 4.

261. 261. The compound of any of claims 171-260, wherein the compound has one of the structures in Table 3, or a salt or tautomer thereof.

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