Programmable polymeric drugs

Abstract

To provide dimeric and biologically active polymeric compounds having spacing groups, and methods for their preparation and use in various therapeutic methods.SOLUTION: Compounds useful as biologically active compounds are disclosed. The compounds have the following structure (I) (where R1, R2, R3, R4, R5, L, L1, L2, M and n are as defined herein) or a stereoisomer, tautomer or salt thereof. Methods associated with preparation and use of such compounds are also provided.SELECTED DRAWING: None

Description

[Technical field]

[0001] SUMMARY OF THE DISCLOSURE Embodiments of the present disclosure are directed generally to dimeric, biologically active polymeric compounds having spacing groups, and methods for their preparation and use in various therapeutic methods. [Background technology]

[0002] Targeted drug conjugates deliver drugs to target cells, with little or no off-target activity, unlike, for example, chemotherapy.Targeted drug conjugates usually contain a targeting molecule that is linked to a biologically active payload or drug.By combining the inherent targeting ability and therapeutic efficacy of biologically active drugs, conjugates can deliver drugs only to intended targets and minimize potential side effects. Antibody-drug conjugates (ADCs) are a class of targeted drug conjugates that are of particular interest, for example, in cancer treatment. ADCs combine the targeting characteristics of monoclonal antibodies with the cancer-killing potential of cytotoxic agents, resulting in a therapy with several advantages over other chemotherapeutic agents. However, the complexity of ADC construction, specifically the challenges involved in the chemical linker between the antibody and the drug, make the development of new and effective therapeutic agents quite difficult. The first ADC was approved in 2001, but it took almost a decade for the next ADC to be approved. At present, only Adcetris®, Besponsa®, Enhertu®, Mylotarg®, Padcev®, Polivy®, and Kadcyla® are commercially available worldwide (Zevalin® is only approved in China). Thus, there is a need in the art for potent targeted drug conjugates with high therapeutic indices. The present disclosure addresses this need and achieves further related advantages. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2019 / 071208 [Patent Document 2] International Publication No. 2017 / 197144 Summary of the Invention

[0004] Briefly, embodiments of the present disclosure are generally directed to compounds that are useful for the delivery of biologically active moieties in vivo.Specific examples include targeted drug conjugates that may include fluorescent and / or colored dyes that allow selective delivery to targets such as tumor cells.Methods and reagents for preparing such molecules are also described, as well as the use of such molecules to provide therapeutic treatment to patients in need thereof. The presently disclosed compound embodiments include one or more biologically active moieties covalently linked to a common backbone by a linker ("L"). Additionally, certain embodiments described herein provide compounds with multiple biologically active moieties within the same compound, which may further include a targeting moiety. The biological moieties may be the same or different, thus allowing for single agent or combination treatment by administration of a single compound. In one embodiment, a compound having the following structure (I):

[0005] [ka] (I) Alternatively, a stereoisomer, tautomer or salt thereof is provided, wherein R 1 , R 2 , R 3 , R 4 , R 5 , L, L 1 , L 2 , M and n are as defined herein.) The compounds of structure (I) find utility in a number of applications, including use as therapeutic agents in a variety of treatment methods.

[0006] In yet another embodiment, there is provided a composition comprising a compound of structure (I) and a pharma- ceutically acceptable carrier. In another embodiment, a method is provided for treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structure (I) or a composition comprising a compound of structure (I), wherein each M is independently a biologically active moiety effective to treat the disease.

[0007] In another embodiment, a compound having the structure: [ka] (In the formula, R a , R b , R c , L ’a , L ’b , m' and n' are as defined herein. Compounds having this structure find use as intermediates for the preparation of compounds of structure (I).

[0008] In another embodiment, a compound having the structure: [ka] (In the formula, R a , R b , R c , L ’a , L ’b , m', n', and p' are as defined herein. Compounds having this structure find use as intermediates for the preparation of compounds of structure (I).

[0009] In another embodiment, a compound having the structure: [ka] (In the formula, R a , R b , R c , L ’a , L’b , m', n', p', and q' are as defined herein. Compounds having this structure find use as intermediates for the preparation of compounds of structure (I).

[0010] In another embodiment, a compound having the structure: [ka] (In the formula, R a , R b , L ’a , L ’b and n' are as defined herein. Compounds having this structure find use as intermediates for the preparation of compounds of structure (I). In another embodiment, there are provided certain phosphoramidite compounds that find utility as intermediates for the preparation of compounds 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 PREFERRED EMBODIMENTS

[0011] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these details. Unless the context requires otherwise, throughout this specification and the claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in their open and inclusive sense, i.e., "including but not limited to."

[0012] With reference to the entire specification, when "one embodiment" or "embodiments" is mentioned, it means that the particular features, structures, or properties described in connection with these embodiments are included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or properties may be combined in any suitable manner in one or more embodiments. "Amino" means -NH 2 Refers to the base. "Carboxy" means -CO 2 Refers to the H group. "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 group =NH. "Nitro" means -NO 2 Refers to the base. "Oxo" refers to the group ═O. "Sulfhydryl," "thiol," or "thio" refers to the --SH group. "Thioxo" refers to the group ═S. "Alkyl" means an alkyl group containing no unsaturation and having 1 to 12 carbon atoms (C 1 -C 12 alkyl), 1 to 8 carbon atoms (C 1 -C 8 alkyl) or 1 to 6 carbon atoms (C 1 -C 6 "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless specifically stated otherwise in this specification, alkyl groups may be optionally substituted.

[0013] "Alkylene" or "alkylene chain" refers to a divalent straight or branched hydrocarbon chain, containing no unsaturation and having 1 to 12 carbon atoms, consisting only of carbon and hydrogen, linking the remainder of the molecule to a radical group, e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, etc. 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 specifically stated otherwise in this specification, alkylene can be optionally substituted.

[0014] "Alkenylene" or "alkenylene chain" refers to a divalent straight or branched hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond and having 2-12 carbon atoms, linking the rest of the molecule to a radical group, e.g., ethenylene, propenylene, n-butenylene, etc. 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 the specification, alkenylene may be substituted. "Alkynylene" or "alkynylene chain" refers to a divalent straight or branched hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond and having 2 to 12 carbon atoms, linking the rest of the molecule to a radical group, e.g., ethenylene, propenylene, n-butenylene, and the like. 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 the specification, alkynylene may be optionally substituted.

[0015] "Alkyl ether" refers to any alkyl group, as defined above, in which at least one carbon-carbon bond is replaced by a carbon-oxygen-carbon bond. The carbon-oxygen-carbon bond may be terminal (as in an alkoxy group) or the carbon-oxygen bond may be internal (i.e., COC). An alkyl ether contains at least one carbon-oxygen-carbon bond, but may contain more than one. For example, polyethylene glycol (PEG) is included within the meaning of alkyl ether. Unless specifically stated otherwise herein, alkyl ether groups may be substituted. For example, in some embodiments, an alkyl ether may be an alcohol or -OP(=R a )(R b )R c is replaced by R a , R b and R c are each as defined for compounds of structure (I). "Alkoxy" means a group of the formula -OR a R refers to the group a is an alkyl group, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted. "Alkoxyalkyl ether" means a group of the formula -OR a R b R refers to the group a is an alkylene group, as defined above, containing 1 to 12 carbon atoms, and Rb is an alkyl ether group, as defined herein. Unless otherwise specifically stated herein, an alkoxyalkyl ether group may be optionally substituted, for example, by an alcohol or -OP(=Ra)(Rb)Rc, where Ra, Rb, and Rc are each as defined for the compounds of structure (I).

[0016] "Heteroalkyl" refers to an alkyl group, as defined above, that contains at least one heteroatom (e.g., Si, N, O, P, or S) within or at the terminus of the alkyl group. In some embodiments, the heteroatom is present within the alkyl group (i.e., a heteroalkyl has at least one carbon-[heteroatom] x -carbon bond, x is 1, 2 or 3). In other embodiments, the heteroatom is at the end of the alkyl group and thus serves to attach the alkyl group to the remainder of the molecule (e.g., M1-HA), where M1 is part of the molecule, H is the heteroatom, and A is the alkyl group. Unless otherwise specifically stated herein, heteroalkyl groups may be substituted. Exemplary heteroalkyl groups include ethylene oxide (e.g., polyethylene oxide), which may include a phosphorus-oxygen bond, such as a phosphodiester bond. "Heteroalkoxy" means a heteroalkoxy group of the formula -OR a R refers to the group a is a heteroalkyl group, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, a heteroalkoxy group may be optionally substituted.

[0017] "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 the end 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, and x is 1, 2, or 3). In other embodiments, the heteroatom is at the end of the alkylene and serves to bond the alkylene to the remainder of the molecule (e.g., M1-HA-M2, where M1 and M2 are part of the molecule, H is a heteroatom, and A is an alkylene). Unless otherwise specifically stated herein, heteroalkylene groups may be substituted. Exemplary heteroalkylene groups include ethylene oxide (e.g., polyethylene oxide), as well as the "C", "HEG", and "PEG 1K" linking groups shown below:

[0018] [ka] Various embodiments of heteroalkylene linkers include multimers of the C linker, HEG linker, and / or PEG 1K linker described above. 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 have, for example, the following structure: [ka] (wherein 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)). "Heteroalkenylene" is a heteroalkylene, as defined above, containing at least one carbon-carbon double bond. Unless stated otherwise specifically in the specification, a heteroalkenylene group may be optionally substituted. "Heteroalkynylene" is a heteroalkylene containing at least one carbon-carbon triple bond. Unless stated otherwise specifically in the specification, a heteroalkynylene group may be optionally substituted.

[0019] "Heteroatom" in reference to a "heteroatom linker" refers to a linker group consisting of one or more heteroatoms. Exemplary heteroatom linkers include single atoms selected from the group consisting of Si, O, N, P, and S, as well as multiple heteroatoms, such as those of the formula -P(O - )(=O)O- or -OP(O - )(=O)O-- and multimers, and combinations thereof. "Phosphate" means -OP(=O)(R a )R b Group(R a OH, O - OR c and R b OH, O - , ORc ), a thiophosphate group or a further phosphate group (R c is the counter ion (e.g., Na + (etc.)

[0020] "Phosphoalkyl" means -OP(=O)(R a )R b R refers to the group a OH, O - OR c and R b is -Oalkyl, R c is the counter ion (e.g., Na + Unless otherwise specifically stated herein, a phosphoalkyl group may be substituted. For example, in certain embodiments, the -Oalkyl portion in a phosphoalkyl group is hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, thiophosphoalkylether, or -OP(=R a )(R b )R c and R a , R b and R c are each as defined for compounds of structure (I).

[0021] "Phosphoalkyl ether" means -OP(=O)(R a )R b R refers to the group a OH, O - OR c and R b is -O alkyl ether, R c is the counter ion (e.g., Na +Unless otherwise specifically stated herein, a phosphoalkyl ether group may be 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 and R a , R b and R c are each as defined for compounds of structure (I). "Thiophosphate" is -OP(=R a )(R b )R c Group(R a is O or S, and R b OH, O - , S - , OR d or S.R. d and R c OH, SH, O - , S - , OR d , S.R. d , a phosphate group or a further thiophosphate group, and R d is the counter ion (e.g., Na + etc.), where i) R a is S, and ii) R b is S - or S.R. d and iii) R c , SH, S - or S.R. d or iv) any combination of i), ii) and / or iii).

[0022] "Thiophosphoalkyl" means -OP(=R a )(R b )R c R refers to the group a is O or S, and Rb OH, O - , S - , OR d or S.R. d and R c is -Oalkyl, R d is the counter ion (e.g., Na + etc.), where i) R a is S, and ii) R b is S - or S.R. d or iii) R a is S and R b is S - or S.R. d Unless otherwise specifically stated herein, a thiophosphoalkyl group may be optionally substituted. For example, in certain embodiments, the -Oalkyl portion in a thiophosphoalkyl group is hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, thiophosphoalkylether, or -OP(=R a )(R b )R c and R a , R b and R c are each as defined for compounds of structure (I).

[0023] "Thiophosphoalkyl ether" means -OP(=R a )(R b )R c R refers to the group a is O or S, and R b OH, O - , S - , OR d or S.R. d and R c is -O alkyl ether, R d is the counter ion (e.g., Na + etc.), where i) R a is S, and ii) R b is S -or S.R. d or iii) R a is S and R b is S - or S.R. d Unless otherwise specifically stated herein, a thiophosphoalkyl ether group may be optionally substituted. For example, in certain embodiments, the -O alkyl ether portion of a thiophosphoalkyl group may be hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, thiophosphoalkyl ether, or -OP(=R a )(R b )R c and R a , R b and R c are each as defined for compounds of structure (I).

[0024] "Carbocyclic" refers to a stable 3- to 18-membered aromatic or non-aromatic ring containing 3 to 18 carbon atoms. Unless otherwise specifically stated herein, a carbocyclic ring can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems, and may be partially saturated or fully saturated. Non-aromatic carbocyclyl radicals include cycloalkyl, while aromatic carbocyclyl radicals include aryl. Unless otherwise specifically stated herein, a carbocyclic group may be optionally substituted. "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic carbocyclic ring, which may include saturated or unsaturated fused or bridged ring systems having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, attached to the remainder of the molecule by a single bond. Monocyclic cyclocalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo-[2.2.1]heptanyl, and the like. Unless otherwise specifically stated in the specification, cycloalkyl groups may be substituted.

[0025] "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 may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl includes, but is not limited to, aryl 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 herein, an aryl group may be substituted.

[0026] "Heterocyclic" refers to a stable 3-18 membered aromatic or non-aromatic ring containing 1-12 carbon atoms and 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless otherwise specifically stated herein, a heterocyclic ring may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems, the nitrogen, carbon or sulfur atoms in the heterocyclic ring may be oxidized, the nitrogen atoms may be 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 heterocyclic). Examples of non-aromatic heterocyclic rings include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, pyrazolopyrimidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclic group may be optionally substituted.

[0027] "Heteroaryl" refers to a 5-14 membered ring system containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of certain embodiments of the present disclosure, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems, and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzyl, 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, indolizinyl 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, pyrimidinyl Heteroaryl groups include aryl, pyrimidine, pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinonyl, quinazolinyl, quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, heteroaryl groups may be optionally substituted.

[0028] "Fused" refers to a ring system containing at least two rings, which share at least one common ring atom, e.g., two common ring atoms. When the fused ring is a heterocyclyl or heteroaryl ring, the common ring atom can be carbon or nitrogen. Fused rings include bicyclic, tricyclic, tertracyclic, etc.

[0029] As used herein, the term "substituted" refers to any of the above groups (e.g., alkyl, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, alkoxy, alkyl ether, alkoxyalkyl ether, heteroalkyl, heteroalkoxy, phosphoalkyl, phosphoalkyl ether, thiophosphoalkyl, thiophosphoalkyl ether, carbocyclic, cycloalkyl, aryl, heterocyclic, and / or heteroaryl) in which at least one hydrogen atom (e.g., 1, 2, 3, or all hydrogen atoms) has been replaced with, but is not limited to, F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl, alkoxy and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfone, sulfonyl and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl and triarylsilyl groups; and bonds to non-hydrogen atoms such as other heteroatoms in various other groups. "Substituted" also refers to any of the above groups in which one or more hydrogen atoms are replaced by a higher bond (e.g., double or triple bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl and ester groups, and nitrogen in groups such as imine, oxime, hydrazone and nitrile. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced by a higher bond (e.g., double or triple bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl and ester groups, and nitrogen in groups such as imine, oxime, hydrazone and nitrile. g R h , -NR g C(=O)Rh , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO 2 R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO 2 R g , -OSO 2 R g , -SO 2 OR g , =NSO 2 R g and -SO 2 NR g R h "Substituted" also includes any of the above groups replaced by one or more hydrogen atoms with -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH 2 SO 2 R g , -CH 2 SO 2 NR g R h In the above, R g and R hare 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 some embodiments, the optional substituents are -OP(=R a )(R b )R c and R a , R b and R c are each as defined for compounds of structure (I). Additionally, any of the aforementioned substituents may also be substituted with one or more of the aforementioned substituents.

[0030] "Conjugation" or "bioconjugation" refers to a chemical strategy that forms 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). The product or compound that results from such a strategy is a conjugate, is conjugated, or is a grammatical equivalent phrase. "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 of skill in the art. "Colored" refers to molecules that absorb light within the color spectrum (ie, red, yellow, blue, etc.). "Linker" refers to a continuous chain of at least one atom, such as carbon, oxygen, nitrogen, sulfur, phosphorus, and combinations thereof, that connects one portion of a molecule to another portion of the same molecule or to a different molecule, moiety, or solid support (e.g., a microparticle). The linker can be attached to the molecule through covalent bonds or other means, such as ionic or hydrogen bonding interactions.

[0031] 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, without limitation, RNA, DNA, oligonucleotides, modified or derivatized nucleotides, enzymes, receptors, prions, receptor ligands (including hormones), antibodies, antigens, and toxins, as well as bacteria, viruses, blood cells, and tissue cells. In some embodiments of the present disclosure, exemplary conjugates (e.g., compounds of structure (I) having a biomolecule linked to a compound of structure (I)) are prepared by contacting a biomolecule with a compound as described above having a reactive group that allows for the binding of the biomolecule to the compound through any available atom or functional group, such as an amino, hydroxyl, carboxyl, or sulfhydryl group, on the biomolecule, as further described herein.

[0032] A "reactive group" is a moiety that can react with a second reactive group (e.g., a "complementary reactive group") to form one or more covalent bonds, for example, by substitution, oxidation, reduction, addition, or cycloaddition reactions. Exemplary reactive groups are provided in Table 1 and include, for example, nucleophiles, electrophiles, dienes, dienophiles, aldehydes, oximes, hydrazones, alkynes, amines, azides, acyl azides, acyl halides, nitriles, nitrones, sulfhydryls, disulfides, sulfonyl halides, isothiocyanates, imidoesters, activated esters, ketones, α,β-unsaturated carbonyls, alkenes, maleimides, α-haloamides, epoxides, aziridines, tetrazines, tetrazoles, phosphines, biotins, thiiranes, and the like. "Solid support" refers to any solid substrate known in the art for stationary phase support of molecules, for example, "microparticle" refers to any of a number of small particles useful for binding to compounds of the present disclosure, including, but not limited to, glass beads, magnetic beads, polymeric beads, non-polymeric beads, etc. In certain embodiments, the microparticle comprises a polystyrene bead. "Solid support moiety" refers to a functional group that remains attached to a molecule once the molecule is cleaved from the solid support. Solid support moieties are known in the art and can be readily derivatized based on the structure of the solid support and the group linking the molecule to the solid support.

[0033] A "targeting moiety" is a moiety that selectively binds to or associates with a particular target, such as a tumor cell antigen. "Selectively" binds or associates means that the targeting moiety preferentially associates with or binds to the desired target compared to other targets. For example, selective binding means that in some embodiments, the targeting moiety or the conjugate that includes the targeting moiety associates with or binds to the desired target at least 10 times or at least 100 times more than other targets. In some embodiments, the compounds disclosed herein include a linking group to the targeting moiety for the purpose of selectively binding or associating the compound with the desired target, such as a tumor cell antigen, thus enabling targeted delivery of the biologically active moiety. Exemplary targeting moieties include, but are not limited to, antibodies, antigens, nucleic acid sequences, enzymes, proteins, cell surface receptor antagonists, or cell surface receptor agonists, 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 the surface of a cell or in a cell, such as a target feature on the surface of a cell membrane or other cell structure, thereby allowing the delivery of a biologically active moiety to or within a cell of interest.Small molecules that selectively bind to or associate with a desired biological target are also contemplated as targeting moieties in certain embodiments.Those skilled in the art will recognize other biological targets and corresponding targeting moieties that are useful in various embodiments.

[0034] A "physiologically cleavable linker" refers to a molecular linking group that can be split or separated in a defined manner to yield two or more separate molecules while present in the in vivo or in vitro environment of an organism or cellular system. In general, physiological conditions that include such cleavage or scission events can include temperatures in the range of about 20-40° C., atmospheric pressure of about 1 atm (101 kPa or 14.7 psi), pH of about 6-8, glucose concentration of about 1-20 mM, atmospheric oxygen concentration, and gravity of the Earth. In some embodiments, physiological conditions include enzymatic conditions (i.e., cleavage by an enzyme). Bond cleavage or scission can be homogeneous or heterogeneous cleavage.

[0035] The embodiments disclosed herein are also intended to encompass all compounds of structure (I) in which one or more atoms are isotopically labeled by replacement with an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds 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 Includes 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 of skill in the art, or by methods analogous to those described below and in the Examples below, substituting appropriate isotopically labeled reagents in place of the non-labeled reagents previously used. "Stable compound" and "stable structure" are intended 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.

[0036] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances when said event or circumstance occurs as well as instances when it does not occur. For example, "optionally substituted alkyl" means that the alkyl group may be substituted or unsubstituted, and that the description includes both substituted and unsubstituted alkyl groups. "Salt" includes both acid addition salts and base addition salts.

[0037] "Acid addition salts" refers to salts of inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and salts of 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, schizoic acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucous acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutamine ... It refers to salts formed with organic acids such as oleic 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.

[0038] "Base addition salt" refers to a salt prepared from the addition of an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, 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.

[0039] Crystallization may produce solvates of the compounds described herein. The embodiments of the present disclosure include all solvates of the compounds described. As used herein, the term "solvate" refers to an aggregate that includes one or more molecules of the compounds of the present disclosure and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present disclosure may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as corresponding solvate forms. The compounds of the present disclosure may be true solvates, while 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.

[0040] The disclosed compounds (e.g., compounds of structure I), or salts, tautomers, or solvates thereof, may contain one or more stereocenters and may therefore give rise to enantiomers, diastereomers, and other stereoisomers that may be defined in terms of absolute stereochemistry as (R)- or (S)-, or, in the case of amino acids, (D)- or (L)-. The disclosed embodiments are intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When a compound described herein contains an olefinic double bond, or other feature which results in geometric symmetry, unless otherwise specified, the compound is intended to include both E and Z geometric isomers, as well as all tautomers are also intended to be included.

[0041] "Stereoisomers" refers to compounds composed of the same atoms joined by the same bonds but having different three-dimensional structures and which cannot be interconverted. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. "Tautomer" refers to a proton transfer from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the above compounds. Various tautomers of the compounds can be easily derived by one skilled in the art. The chemical naming protocols and structure diagrams used herein are a modification of the IUPAC nomenclature system using the ACD / Nomenclature 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.

[0042] As mentioned above, in one embodiment of the present disclosure, a compound is provided that includes a covalent linker between a biologically active moiety and an optimal targeting moiety. In another embodiment, a compound is provided that is useful as a synthetic intermediate for the preparation of a compound that includes one or more biologically active moieties and an optimal targeting moiety. In general terms, an embodiment of the present disclosure is directed to a polymer with a biologically active moiety side chain. The biologically active moiety is linked to the polymer by a linking moiety. In another aspect, the linker provides a link between the biologically active moiety and the targeting moiety that acts to increase the accumulation of the biologically active moiety in the desired target. That is, the biological activity is increased due to accumulation in the intended target, while off-target effects are reduced, which minimizes the potential side effects of treatment (e.g., cytotoxicity).

[0043] In another embodiment, a compound having the following structure (I): [ka] or a stereoisomer, pharma- ceutically acceptable salt, or tautomer thereof, wherein M is, independently at each occurrence, 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 moiety, provided that at least one occurrence of M is not a fluorescent dye; L is any linker, provided that at least one occurrence of L contains more than four carbons or at least one occurrence of L contains oxygen; L 1 and L2 is, independently at each occurrence, an optional alkylene linker; R 1 is independently at each occurrence H, alkyl or alkoxy; R 2 and R 3 are each independently absent, or H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, dT, -OP(=R a )(R b )R c , Q or a protected form thereof, or L′; R 4 independently for each occurrence, O - , S - , OZ, SZ, or N(R 6 ) 2 where Z is a cation and each R 6 are independently H or alkyl; R 5 is independently at each occurrence oxo, thioxo, or absent; R a is O or S, R b OH, SH, O - , S - , OR d or S.R. d and R c OH, SH, O - , S - , OR d , O.L.', S.R. d , OdT, alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counterion, Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q' of the targeting moiety; L' is, independently at each occurrence, 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 moiety, 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); n is an integer equal to or greater than 1. to provide.

[0044] Another embodiment is a compound having the following structure (I): [ka] (I) (In the formula, M is, independently at each occurrence, 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 moiety, provided that at least one occurrence of M is not a fluorescent dye; L is an optional linker, L 1 and L 2 is, independently at each occurrence, an optional alkylene linker; R 1 is independently at each occurrence H, alkyl or alkoxy; R 2 and R 3 are each independently absent, or H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, dT, -OP(=R a )(R b )R c , Q or a protected form thereof, or L′; R 4 independently for each occurrence, O - , S - , OZ, SZ, or N(R 6 ) 2 where Z is a cation and each R 6 are independently H or alkyl; R 5is independently at each occurrence oxo, thioxo, or absent; R a is O or S, R b OH, SH, O - , S - , OR d or S.R. d and R c OH, SH, O - , S - , OR d , O.L.', S.R. d , OdT, alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counterion, Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q' of the targeting moiety; L' is, independently at each occurrence, 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 moiety, 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); n is an integer of 1 or more, provided that the compound has the following structure: [ka] (In the formula, N' has the structure: [ka] having I' has the structure: [ka] having F has the following structure: [ka] (having or a stereoisomer, pharma- ceutically acceptable salt, or tautomer thereof, provided that the compound does not have one of to provide.

[0045] The linker L may be used as a point of attachment of the M moiety to the remainder of the compound. For example, in some embodiments, a synthetic precursor to a compound of structure (I) is prepared, and the M moiety is attached to the synthetic precursor using any number of readily available methods known in the art, such as those referred to as "click chemistry." For this purpose, any of a number of rapid and substantially irreversible reactions may be used to attach M to the synthetic precursor for forming a compound of structure (I). Exemplary reactions include the copper-catalyzed reaction of an azide with an alkyne to form a triazole (Huisgen 1,3-dipolar cycloaddition), the reaction of a diene with a dienophile (Diels-Alder), strain-promoted alkyne-nitrone cycloaddition, the reaction of a strained alkene with an azide, tetrazine or tetrazole, the [3+2] cycloaddition of an alkene with an azide, the inverse demand Diels-Alder of an alkene with a tetrazine, the photoreaction of an alkene with a tetrazole, and various substitution reactions such as the replacement of a leaving group by a nucleophilic attack on an electrophilic atom. Exemplary substitution reactions include reactions of amines with activated esters, N-hydroxysuccinimide esters, isocyanates, isothiocyanates, etc. In some embodiments, the reaction to form L may be carried out in an aqueous environment.

[0046] Thus, in some embodiments, L, for each occurrence, is a linker that includes 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. In various embodiments, for at least one occurrence of L, the functional group can be formed by reaction of an aldehyde, oxime, hydrazone, alkyne, amine, azide, acyl azide, acyl halide, nitrile, nitrone, sulfhydryl, disulfide, sulfonyl halide, isothiocyanate, imidoester, activated ester (e.g., N-hydroxysuccinimide ester), ketone, α,β-unsaturated carbonyl, alkene, maleimide, α-haloamide, epoxide, aziridine, tetrazine, tetrazole, phosphine, biotin, or thiirane functional group with a complementary reactive group, e.g., reaction of an amine with an N-hydroxysuccinimide ester or an isothiocyanate. In other embodiments, for at least one occurrence of L, the functional group may be formed by reaction of an alkyne and an azide. In other embodiments, for at least one occurrence of L, the functional group may be formed by reaction of an amine (e.g., a primary amine) and an N-hydroxysuccinimide ester or an isothiocyanate.

[0047] In further embodiments, for at least one occurrence of L, the functional group comprises an alkene, ester, amide, thioester, disulfide, carbocyclic, heterocyclic or heteroaryl group. In further embodiments, for at least one occurrence of L, the functional group comprises an alkene, ester, amide, thioester, thiourea, disulfide, carbocyclic, heterocyclic or heteroaryl group. In other embodiments, the functional group comprises an amide or thiourea. In some further specific embodiments, for at least one occurrence of L, L is a linker comprising a triazolyl functional group. In other embodiments, for at least one occurrence of L, L is a linker comprising an amide or thiourea functional group. Some embodiments provide L that is cleavable under appropriate conditions (e.g., physiological conditions). In certain embodiments, at least one occurrence of L comprises a physiologically cleavable linker. In some more specific embodiments, 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, a ketone, a diol, a cyano, a nitro, or a combination thereof.

[0048] In some embodiments, at least one occurrence of L comprises an amino acid sequence recognized by a sortase enzyme. In certain embodiments, the amino acid sequence is Leu-Pro-X-Thr-Gly, where X is any amino acid residue. In some other embodiments, at least one occurrence of L is a linker comprising three or more carbons. In certain other embodiments, at least one occurrence of L is a linker comprising at least one nitrogen. In some embodiments, at least one occurrence of L has the following structure:

[0049] [ka] Contains one of the following:

[0050] In some embodiments, each 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, a ketone, a diol, cyano, nitro, or a combination thereof.

[0051] In some embodiments, each occurrence of L is a linker comprising three or more carbons. In certain embodiments, each occurrence of L is a linker comprising at least one nitrogen. In some other embodiments, each occurrence of L is a linker comprising the following structure: [ka] Contains one of the following:

[0052] In some embodiments, at least one occurrence of L has the following structure: [ka] Includes.

[0053] In certain embodiments, at least one occurrence of L comprises one or more amino acid residues. In some embodiments, the amino acid residue is valine. In certain more specific embodiments, at least one occurrence of L has the following structure: [ka] Contains one of the following:

[0054] In some embodiments, at least one occurrence of L has the following structure: [ka] Contains one of the following:

[0055] In some more specific embodiments, at least one occurrence of L has the following structure: [ka] Includes.

[0056] In some more specific embodiments, at least one occurrence of L has the following structure: [ka] Contains one of the following:

[0057] In some embodiments, each occurrence of L has the following structure: [ka] Includes.

[0058] In some embodiments, each occurrence of L comprises one or more amino acid residues. In certain embodiments, the amino acid residue is valine. In certain specific embodiments, each occurrence of L comprises the following structure: [ka] Contains one of the following:

[0059] In some embodiments, each occurrence of L has the following structure: [ka] Contains one of the following:

[0060] In some embodiments, at least one occurrence of L has the following structure: [ka] has.

[0061] In some embodiments, at least one occurrence of L has the following structure: [ka] has one of the following:

[0062] In certain embodiments, at least one occurrence of L has the following structure: [ka] has.

[0063] In certain embodiments, at least one occurrence of L comprises a linker that is not cleavable under physiological conditions. In some more specific embodiments, at least one occurrence of L comprises a thioether bond. In certain specific embodiments, at least one occurrence of L has the following structure:

[0064] [ka] Includes.

[0065] In some embodiments, at least one occurrence of L has the following structure: [ka] Contains one of the following:

[0066] In some embodiments, each occurrence of L comprises a linker that is not cleavable under physiological conditions. In certain embodiments, each occurrence of L comprises a thioether bond. In certain embodiments, each occurrence of L has the following structure: [ka] Includes.

[0067] In some embodiments, each occurrence of L has the following structure: [ka] Contains one of the following: Thus, in some embodiments, L comprises an amide bond, an ester bond, a disulfide bond, a hydrazone, a phosphotriester, a diester, a β-glucuronide, a double bond, a triple bond, an ether bond, a ketone, a diol, cyano, nitro, or a combination thereof.

[0068] In some embodiments, L comprises tert-butyloxycarbonyl, paramethoxybenzyl, dialkyl or diaryldialkoxysilane, orthoester, acetal, β-thiopropionate, ketal, phosphoramidate, hydrazone, vinyl ether, imine, aconityl, trityl, polyketal, bisarylhydrazone, diazobenzene, bivinaldiol, pyrophosphate diester, or valine citrulline. In certain embodiments, L, independently at each occurrence, is a linker that is cleavable at a pH in the range of 6 to 8. For example, in some embodiments, L is a linker that is cleavable at pH 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0.

[0069] In certain embodiments, L, independently at each occurrence, is a linker that is cleavable at a temperature in the range of 20° C. to 40° C., 25° C. to 35° C., 30° C. to 35° C., 30° C. to 37° C., 35° C. to 37° C., 35° C. to 40° C., or 32° C. to 38° C. In certain embodiments, L, independently at each occurrence, is a linker that is cleavable at a temperature in the range of about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., or about 40° C. In certain embodiments, L is, independently at each occurrence, a linker that is cleavable by an enzyme. For example, in some embodiments, the enzyme is a hydrolase, oxidoreductase, or lyase. In certain embodiments, the enzyme is an EC4.1 (e.g., EC4.1.1, EC4.1.2, EC4.1.3, or EC4.1.99), EC4.2, EC4.3, EC4.4, EC4.5, EC4.6, or EC4.99 enzyme.

[0070] In certain embodiments, L has the structure: [ka] [ka] (In the formula, R is H, methyl, ethyl, isopropyl, tert-butyl or phenyl; X is O or CH 2 and n is an integer greater than 0) Contains one of the following:

[0071] In yet other embodiments, for at least one occurrence of L, LM has the following structure: [ka] (In the formula, L 1a and L 1b are each independently an optional linker.

[0072] In a different embodiment, for at least one occurrence of L, LM has the following structure: [ka] (In the formula, L 1a and L 1b are each independently an optional linker. In the various embodiments described above, L 1a Or L 1b , or both are absent. 1a Or L 1b , or both are present.

[0073] In some embodiments, L 1a or L 1b Each occurrence, if any, is independently alkylene or heteroalkylene. For example, in some embodiments, L 1a or L 1b may, if present, independently have the structure: [ka] has one of the following:

[0074] In some other related embodiments, L has the structure: [ka] Contains one of the following:

[0075] In some embodiments, at least one occurrence of L has the following structure: [ka] (In the formula, a, b, and c are each independently an integer ranging from 1 to 6. has one of the following:

[0076] In some embodiments, each occurrence of L has the following structure: [ka] (In the formula, a, b, and c are each independently an integer ranging from 1 to 6. has one of the following:

[0077] In some embodiments, at least one occurrence of L has the following structure: [ka] (In the formula, a, b, and c are each independently an integer ranging from 1 to 6. Contains one of the following:

[0078] In some embodiments, each occurrence of L has the following structure: [ka] (In the formula, a, b, and c are each independently an integer ranging from 1 to 6. Contains one of the following:

[0079] In some embodiments, at least one occurrence of L has the following structure: [ka] has one of the following:

[0080] In some embodiments, at least one occurrence of L has the following structure: [ka] Contains one of the following:

[0081] In a further embodiment, L 1 and L 2 is expressed independently for each occurrence as C 1 -C 6 Alkylene, C 2 -C 6 Alkenylene or C 2 -C 6 In certain embodiments, each occurrence of L is alkynylene. 1 At least one of is an alkylene linker. For example, in some embodiments, the compound has the following structure (IA): [ka] (IA) (In the formula, a and b are, independently at each occurrence, an integer from 0 to 10. has.

[0082] In some embodiments of the compound of structure (IA), a and b, at each occurrence, are both integers from 0 to 3. In some other embodiments, at each occurrence, a is 0 and b is 1. In some embodiments, at each occurrence, a is 1 and b is 0. In certain embodiments of compounds of structure (IA), at least one occurrence of a or b is 1. In other embodiments, each occurrence of a and b is 1 or 0. In other embodiments, each occurrence of a is 0. In other embodiments, each occurrence of b is 0. In some embodiments, each occurrence of a is 1. In some embodiments, each occurrence of b is 1.

[0083] In still other embodiments of any of the compounds of structure (I), R 4 are independently expressed as OH, O - OR d "ORd " and "SR d " is O bound to a cation - and S - For example, the disodium salt of a phosphate group is: [ka] (In the formula, R d is sodium (Na + ) is) It can be expressed as:

[0084] In other embodiments of any of the compounds of structure (I), R 5 Each occurrence is oxo. In some different embodiments of any of the foregoing compounds, R 1 is H for each occurrence. In various other embodiments, R 2 and R 3 are each independently OH or -OP(=R a )(R b )R c In some different embodiments, R 2 or R 3 is OH or -OP(=R a )(R b )R c and R 2 or R 3 The other is a linker (eg, alkylene or heteroalkylene) that contains a covalent bond to Q or Q.

[0085] In yet another embodiment of any of the foregoing compounds of structure (I), R 2 and R 3 are each independently -OP(=R a )(R b )R c In some of these embodiments, R cis OL'. In some more specific embodiments, L' is a targeting moiety or a linker to a targeting moiety. In related embodiments, L' is a linker to a targeting moiety, where the linker comprises an alkylene oxide or a phosphodiester moiety, or a combination thereof. In other embodiments, R 2 and R 3 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 moiety, a nucleoside, or an additional compound of structure (I). 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) to the compound of structure (I). Advantageously, certain embodiments include the use of an L' moiety that is selected to increase or optimize the aqueous solubility of the compound. In certain embodiments, L' is a heteroalkylene moiety. In certain other embodiments, L' comprises an alkylene oxide or a phosphodiester moiety, or a combination thereof. In certain other embodiments, L' comprises an ethylene oxide. In some embodiments, L' comprises a disulfide.

[0086] In certain embodiments, L' has the structure: [ka] (In the formula, m" and n" are independently an integer from 1 to 10; R e is H, an electron pair or a counterion, L″ is a targeting moiety or a linking group to a targeting moiety. In some embodiments, m" is an integer from 4 to 10, such as 4, 6, or 10. In other embodiments, n" is an integer from 3 to 6, such as 3, 4, 5, or 6.

[0087] In certain embodiments, the targeting moiety is an antibody or a cell surface receptor antagonist. In related 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, a folate or a MET inhibitor. In certain embodiments, the antibody or cell surface receptor antagonist is a tyrosine kinase inhibitor (e.g., gefitinib, erlotinib), lapatinib, vandetanib, neratinib, osimertinib, tovantinib (ARQ197), crizotinib, cabozantinib, tyrphostins (e.g., AG538, AG1024), pyrrolo(2,3-d)-pyrimidine derivatives (e.g., NVP-AEW541), monoclonal antibodies (e.g., Figitumma These include rituximab, cetuximab, panitumumab, necitumumab, ganitumab, cixutumumab, dalotuzumab, lobatumumab, onartuzumab, K1, labetuzumab, milatuzumab, lorvotuzumab, inotuzumab), BMS-777607, PF-02341066, PF-04217903, AMG-458, MK-2461, JNJ-38877605, GSK1363089 (foretinib), XL880, XL184, ARQ197, E7050, or INCB28060.

[0088] In some embodiments, the 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, iba Therapeutic options include rituximab, idarucizumab, infliximab, itolizumab, ixekizumab, lanadelumab, lokivetmab, mepolizumab, natalizumab, obiltoxaximab, ocrelizumab, omalizumab, palivizumab, ranibizumab, raxibacumab, reslizumab, ramucirumab (Rmab), rovelizumab, ruplizumab, sarilumab, secukinumab, tildrakizumab, thiomab, tocilizumab, ustekinumab, or vedolizumab. In certain more specific embodiments, the antibody is selected from the group consisting of abrilumab, actoxumab, aducanumab, afasevicumab, afelimomab, anifrolumab, anrukinzumab (IMA-638), acelizumab, atorlimumab, bapineuzumab, BCD-100, bertilimumab, besilesomab, biciromab, bimagrumab, bimekizumab, vilutamimab, bleselumab, brosozumab, bococizumab, brazikumab, briakinumab, brolucizumab, carlumab, carotuximab, cedelizumab, clazakizumab, clenoliximab, concizumab, cosfrobiximab, CR6261, crenezumab, crizanlizumab, cloteduumab, depatuximab, Zumab, mafodotin, dellotuximab biotin, desamizumab, dilidabumab, domagrozumab, dusigitumab, ecromeximab, edovacomab, efalizumab, efungumab, eldelumab, elezanumab, enokizumab, eptinezumab, elizumab, etrolizumab, evinacumab, exbivirumab, fano Lesomab, faralimomab, faricimab, fasinumab, felvizumab, fezakinumab, framvotumab, fretikumab, flotetuzumab, fontolizumab, foravirumab, flobocimab, fullanumab, gantenerumab, gavilimomab, gevokizumab, gimsilumab, gomilikimab, goslanemab, ianalumab,Inclakumab, Inolimomab, Iomab-B, Keliximab, Lampalizumab, Landgrozumab, Ralcaviximab, Lebrikizumab, Lenvervimab, Lerdelimumab, Letolizumab, Ribivirumab, Ligelizumab, Roderucizumab, Lulizumab pegol, Marstacimab, Mavrilimumab, Metelimumab, Mirikizumab, Mota Bisumab, muromonab CD3, nebacumab, nemolizumab, NEOD001, nirsevimab, odulimomab, orendalizumab, olokizumab, OMS721, opicinumab, olticumab, otelixizumab, otilimab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, panobacumab, pascolizumab, pateclizumab, PDR001, pera Kizumab, pexelizumab, placumab, prozalizumab, ponezumab, polgabiximab, prasinezumab, priliximab, PRO140, kirusumab, rafivirumab, ralpancizumab, ranevetomab, ravagalimab, ravulizumab, refanezumab, regavirumab, relatorimab, rinukumab, risankizumab, loredumab, romosozumab, rontalizumab Mab, SA237, satralizumab, sevirumab, SHP647, sifalimumab, simtuzumab, siplizumab, sirukumab, solanezumab, sonepcizumab, spartalizumab, stamulumab, sulesomab, sputabumab, stimulimab, subizumab, sublatoxumab, tadocizumab, talizumab, tamtubetomab, tanezumab, tefibazumab, terimomab Telimomab aritox, Teneliximab, Teplizumab, Teprotumumab, Tezepelumab, Tiburizumab, Toralizumab, Tralokinumab, Trevoglumab, Tubilumab, Ulocuplumab, Urtoxazumab, Valisacumab, Vepalimomab, Vesencumab, Visilizumab, Bovalilizumab, or Zolimomab aritox. In some more specific embodiments, the monoclonal antibody is Trastuzumab, Gemtuzumab, Brentuximab, Borsetuzumab, Lorvotuzumab, Cantuzumab, Bivatuzumab, Inotuzumab, or Vadastuximab.

[0089] In certain embodiments, the antibody or cell surface receptor antagonist targets EGFR (e.g., EGFRvIII), HER2, folate receptor, CD19, CD20, CD22, CD27L, CD30, CD33, CD37, CD56, CD66e, CD70, CD74, CD79b, CA6, CD138, CA6, mesothelin, nectin 4, STEAP1, MUC16, MaPi2b, GCC, Trop-2, AGS-5, ENPP3, carbonic anhydrase IX, GPNMB, PDMA.

[0090] In certain other embodiments, the antibody or cell surface receptor antagonist is selected from the group consisting of 1-40-beta-amyloid, activated F9, F10, ACVR2B, amyloid, Ang-2, angiopoietin 3, anthrax toxin, protective antigen, AOC3 (VAP-1), Bacillus anthracis anthrax, BAFF, beta amyloid, C1, C5, calcitonin, calcitonin gene-related peptide alpha, Canis lupus familiaris familiaris)IL31, CCL11 (eotaxin-1), CCR2, CCR5, CD11, CD18, CD125, CD147 (basigin), CD15, CD154 (CD40L), CD19, CD2, CD20, CD23 (IgE receptor), CD25 (α chain of IL-2 receptor), CD28, CD3, CD4, CD40, CD41 (integrin alpha-IIb), CD45, CD5, CD52, CD6, CEA-related antigen, CFD, CGRP, Clostridium difficile, coagulation factor A, complement C5a, CSF2, CXCR4 (CD184), cytomegalovirus, dabigatran, Ebola virus glycoprotein, EGFR, endoglin, endotoxin, Escherichia coli, Respiratory syncytial virus syncytialvirus), F protein, FGF23, fibrin II, beta chain, GCGR, GD3 ganglioside, GDF-8, GMCSF, growth differentiation factor 8, hemagglutinin, hepatitis B surface antigen, histone complex, HIV-1, HNGF, Hsp90, human beta amyloid, human TNF, IgE, IGF-1 receptor (CD221), IGHE, influenza A hemagglutinin, integrin receptors and subunits, interferon receptors, interleukin receptors (various), ITGB2 (CD18), kallikrein, LAG3, LFA-1 (CD11a), LINGO-1, lipoteichoic acid, LOXL2, L-selectin Targeting IL-1, CD62L, LTA, MASP-2, MCP-1, mucosal addressin cell adhesion molecule, myelin associated glycoprotein, myostatin, NACP, NCA-90 (granulocyte antigen), neuronal apoptosis-regulating proteinase 1, NGF, NOGO-A, NRP1, OX-40, oxLDL, PCSK9, PD-1, PDCD1, CD279, platelet-derived growth factor receptor beta, Pseudomonas aeruginosa, rabies virus glycoprotein, RANKL, respiratory syncytial virus, RGMA, RHD, rhesus factor, RSVFR, sclerostin, selectin P, SOST, sphingosine-1-phosphate, Staphylococcus aureus alpha toxin, tau protein, TFPI, TGF beta 1, TGF beta 2, TNF-α, TRAP, TSLP, TYRP1 (glycoprotein 75), VEGF-A, VWF, Zaire Ebola virus glycoprotein.

[0091] In some specific embodiments, the targeting moiety is an antibody or antibody fragment. In certain more specific embodiments, the antibody or antibody fragment is a monoclonal (mAb), antigen-binding fragment (Fab / Fab'), single domain antibody (sdAb), bispecific antibody (BsAb), bispecific T cell engager (BiTE), single chain variable fragment (ScFv), dual-affinity re-targeting antibodies (DART), heavy chain variable domain (VFv), or mAb. H ), minibodies, diabodies, or Abdurins™ (IgG derived).

[0092] In some other embodiments, the targeting moiety is a protein. For example, in some embodiments, the targeting moiety is albumin, interferon, centrin, or a chemotactic receptor ligand.

[0093] In some other embodiments, L" is an alkylene or heteroalkylene moiety. In certain other embodiments, L" comprises an alkylene oxide, a phosphodiester moiety, a sulfhydryl, a disulfide, or a maleimide moiety, or a combination thereof.

[0094] In other more specific embodiments of any of the foregoing compounds of structure (I), R 2 or R 3 has the following structure: [ka] has one of the following:

[0095] Certain embodiments of the compounds of structure (I) can be prepared following solid phase synthesis methods similar to those known in the art for the preparation of oligonucleotides. Thus, in some embodiments, L' is a linking group to a solid support, a solid support residue, or a nucleoside. Solid supports (e.g., polymeric and non-polymeric) containing activated deoxythymidine (dT) groups are readily available and can, in some embodiments, be used as starting materials for the preparation of compounds of structure (I). Thus, in some embodiments, R 2 or R 3 has the following structure:

[0096] [ka] has.

[0097] Those skilled in the art will appreciate that the dT group above is included solely for ease of synthesis and economic efficiency, and is not required. Other solid supports can be used, different nucleosides or solid support moieties can be present on L', or the nucleosides or solid support moieties can be removed or modified after synthesis.

[0098] In some embodiments, R 2 or R 3 is one of the following structures: [ka] Includes.

[0099] In some embodiments, R 2 or R 3 has the following structure: [ka] Contains one of the following:

[0100] In some embodiments, R 3 has the following structure: [ka] Contains one of the following:

[0101] In some embodiments, R 3 has the following structure: [ka] Contains one of the following:

[0102] In yet other embodiments, Q, independently at each occurrence, 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, independently at each occurrence, is a moiety that includes a reactive group capable of forming a covalent bond with a complementary reactive group, Q'. For example, in some embodiments, Q' is present in an additional compound of structure (I) (e.g., R 2 or R3 Positions (Q, 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 covalent dimerization of the compound of structure (I). Multimeric compounds of structure (I) can also be prepared in an analogous manner and are included within the scope of embodiments of the present disclosure. The type of Q group and its attachability to the remainder of the compound of structure (I) are not limited, provided that Q contains a moiety with appropriate reactivity to form the desired bond. In certain embodiments, Q is a moiety (e.g., an amine, azide, or alkyne) that is not susceptible to hydrolysis under aqueous conditions, yet is sufficiently reactive to form a bond with a corresponding group on the analyte molecule or solid support.

[0103] Certain embodiments of the compounds of structure (I) include Q groups 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, a disulfide, an activated ester, an isothiocyanate, an azide, an alkyne, an alkene, a diene, a dienophile, an acid halide, a sulfonyl halide, a phosphine, an α-haloamide, a biotin, an amino, or a maleimide functional group. In some embodiments, the activated ester is an N-succinimide ester, an imido ester, or a polyflourophenyl ester. In other embodiments, the alkyne is an alkyl azide or an acyl azide.

[0104] Q groups can be conveniently provided in protected forms that enhance storage stability or other desired properties, and the protected groups can then be removed at the appropriate time for coupling, for example, with a targeting moiety or analyte. Thus, Q groups include "protected forms" of reactive groups, including any of the reactive groups listed above and in Table 1 below. A "protected form" of Q refers to a moiety that has a lower reactivity under a given reaction condition relative to Q, but 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 that can be reduced to reveal an -SH moiety using common known techniques and reagents. Exemplary Q moieties are provided in Table I below.

[0105] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0106] It should be noted that in some embodiments, when Q is -SH, the -SH moiety tends to form a disulfide bond with another sulfhydryl group, for example, of another compound of structure (I). Thus, some embodiments include a compound of structure (I) in the form of a disulfide dimer, where the disulfide bond is derived from the Q group that is -SH.

[0107] Similarly, compounds of structure (I) are included within the scope of certain embodiments, where R 2 and R 3One or both of R 2 and R 3 One or both of -OP(=R a )(R b )R c and R c is OL', where L' is a linker comprising a covalent bond to an additional compound of structure (I). Such compounds can be prepared, for example, by preparing a first compound of structure (I) having about 10 "M" moieties (i.e., n=9) and having a "Q" suitable for reaction with a complementary Q' group on a second compound of structure (I). In this manner, compounds of structure (I) having any number of "M" moieties, for example 100 or more, can be prepared without the need to sequentially couple each monomer. An exemplary embodiment of such a compound of structure (I) is shown below in structure (I'): [ka] (I') (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , L, L 1 , L 2 , M and n at each occurrence are independently as defined for compounds of structure (I); L″ is a linker (e.g., Table 1, etc.) that contains a functional group resulting from reaction of a Q moiety with a corresponding Q′ moiety; α is an integer greater than 1, for example, 1 to 100, or 1 to 10. has.

[0108] Other compounds of structure (I') can be derived by one of skill in the art, for example, by dimerizing or polymerizing the compounds of structure (I) provided herein.

[0109] In other embodiments, the Q moiety is conveniently hidden (e.g., protected) as a disulfide moiety, which can be subsequently reduced to provide an activated Q moiety for attachment to a desired targeting moiety. For example, the Q moiety has the following structure: [ka] where R is an optionally substituted alkyl group. For example, in some embodiments, Q can be masked as a disulfide having the following structure: [ka] wherein n' is an integer from 1 to 10, for example 6.

[0110] In some other embodiments, R 2 or R 3 One of the groups is OH or -OP (=R a )(R b )R c and R 2 or R 3 The other is a linker that includes a covalent bond to the targeting moiety or a linker that includes a covalent bond to the solid support. For example, in some embodiments, the targeting moiety is an antibody or a cell surface receptor antagonist. In yet another embodiment, the solid support is a polymeric bead or a non-polymeric bead. The value for n is another variable that may be selected based on the desired solubility, osmotic effect, or therapeutic use. In some embodiments, n, independently at each occurrence, is an integer between 1 and 10. In other embodiments, n, independently at each occurrence, is an integer between 1 and 5, e.g., 1, 2, 3, 4, or 5. Solubility, osmotic effect, or retention may also be adjusted by selecting different values ​​of n. 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.

[0111] Tumor cell antigens include tumor-specific and tumor-associated antigens, such as EGFR, HER2, folate receptor, CD20, CD33, oncofetal antigens (e.g., alpha-fetoprotein, carcinoembryonic antigen, immature laminin receptor, TAG-72), CA-125, MUC-1, epithelial tumor antigens, tyrosinase, melanoma-associated antigens (MAGE), and aberrant products of RAS or p53. Tumor cell antigens can also include antigens characterized as oncofetal, oncoviral (e.g., HPV E6, E7), overexpressed / accumulated (e.g., BING-4, calcium activated chloride channel 2, 9D7, Ep-CAM, EphA3, HER2, telomerase, mesothelin, SAP-1, survivin), cancer testis (e.g., BAGE family, CAGE family, GAGE ​​family, MAGE family, SAGE family, XAGE family), lineage restricted, mutated, post-translationally modified, idiotypic, CT9 or CT10 (e.g., NY-ESO-1 / LAGE-1, PRAME). In some embodiments, M is, independently at each occurrence, an NSAID, a kinase inhibitor, an anthracycline, an EGFR inhibitor, or an alkylating agent.

[0112] In some embodiments, the biologically active moiety is an anti-cancer drug. In certain particular embodiments, M, at each occurrence, is independently an anti-cancer drug and the targeting moiety is an antibody specific for a tumor cell antigen. Anti-cancer drugs, as used herein, include derivatives. These are anti-cancer drugs that have been modified or derivatized, such that the drug may be conjugated or attached to another molecule (e.g., to include a Q moiety). For example, maytansine is a cancer drug and maytansinoids are derivatives of cancer drugs.

[0113] In certain embodiments, the anticancer drug is an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor (such as irinotecan or such as etoposide or such as doxorubicin), a taxane (such as an anti-microtubule agent, including paclitaxel and docetaxel), an antimetabolite agent (such as 5-FU or such as gemcitabine), an alkylating agent (such as cisplatin or such as cyclophosphamide), or a taxane.

[0114] Anti-cancer drugs that may be modified and incorporated into compound embodiments of the present disclosure include, for example, auristatin F, auristatin E, maytansine, calicheamicin, paclitaxel, doxorubicin, cryptophycin, erlotinib, CC-1065, carzelesin, SJG-136, DSB-120, afatinib, Iressa, methotrexate, DNA methylating agents (e.g., procarbazine, temozolomide, dacarbazine, N-methylo-N-nitrourea, N-methyl-N'-nitro-N-nitroguanine, etc.).

[0115] Other non-limiting examples of anti-cancer drugs include Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib) and adriamycin, alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethylenediaminetetraacetate, ... melamine and methylmelamine (including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine); chlorambucil, chlornaphazine, clophosfamide, estramustine, ifosamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicin, phenesterine, prednimustine, trofosfamide, nitrogen mustards such as uracil mustard; carmustine, chlorozotocin, fotemustine, lomustine, Nitrosoureas such as mustine, nimustine, and ranimustine; aclacinomycins, actinomycin, ausramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex®, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenone Antibiotics such as folate, nogalamycin, olivomycins, peplomycin, potfilomycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine;Pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as florinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomitine; elliptinium acetate; etoglucide; nitrate Gallium; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenameth; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK.RTM; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2"-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Taxanes, such as paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, NJ), and docetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoic acid;Also included are tamoxifen (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxyphene, ketoxifene, LY117018, onapristone and toremifene (Fareston) and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum analogs such as cisplatin and carboplatin, vinblastine, platinum Suitable cancer drugs include anti-hormonal agents that act to regulate or inhibit hormone action on tumors, such as etoposide (VP-16), ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, navelbine, novantrone, teniposide, daunomycin, aminopterin, xeloda, ibandronate, camptothecin-11 (CPT-11), the topoisomerase inhibitor RFS2000, difluoromethylornithine (DMFO), duocarmycin A, or pemetrexed (Alimta);

[0116] Where desired, embodiments of the disclosed compounds or compositions may be used in combination with other agents such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, avicin, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharazine, alvocidib, 3-aryl ... minopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic agents, antitumor herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, biricoderm, brostallicin, bryostatin, buthionine sulfoxime, CBV (chemotherapy), calyculin, cell cycle nonspecific antineoplastic agents, dichloroacetic acid, discodermolide, elsamitrucin, eno Citabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferginol, holodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, ranicuidar, larotaxel, lenalidomide, lucantone, lurtotecan, mefosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, progesterone, It may be used in combination with commonly prescribed anticancer drugs such as roteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaprofin, taliquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126 or zosquidar.

[0117] M is selected based on desired therapeutic and / or optical properties, for example, treatment of a particular disease or condition (e.g., cancer), or generation of a particular color and / or fluorescent emission wavelength. In some embodiments, M is the same for each occurrence. However, it is important to note that each occurrence of M does not have to be the same M, and certain embodiments include compounds in which M is not the same for each occurrence. For example, in some embodiments, M is not the same for each occurrence, and different M moieties are selected to have different therapeutic properties (e.g., cytotoxicity and anti-inflammatory). In some embodiments, M is not the same for each occurrence, and different M moieties are selected to have the same or similar therapeutic properties (e.g., cytotoxicity).

[0118] Thus, in some embodiments, at least one occurrence of M is an antitumor agent, an enediyne antitumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and an EGFR inhibitor or an alkylating agent. In certain embodiments, at least one occurrence of M is an antitumor agent, an enediyne antitumor antibiotic, a maytansinoid, a topoisomerase inhibitor, or an alkylating agent. In some specific embodiments, M is independently at each occurrence an antitumor agent, an enediyne antitumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and an EGFR inhibitor or an alkylating agent.

[0119] In some embodiments, at least one occurrence of M is selected from the group consisting of auristatin F, monomethylauristatin F, monomethylauristatin 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, siratecan, cositecan, exatecan, rutotecan, gimatecan, belotecan, and rubitecan. In certain embodiments, at least one occurrence of M has the following structure: [ka] [ka] has one of the following:

[0120] In some embodiments, each occurrence of M has the following structure: [ka] [ka] has one of the following:

[0121] In certain embodiments, each M is selected from the following: [ka] are independently selected from

[0122] For ease of illustration, specific points of attachment to the remainder of the molecule (i.e., [ka] ), the M moiety can be attached through any available point (e.g., nitrogen, oxygen, carboxy, carbonyl, etc.). One of skill in the art can determine the appropriate point of attachment.

[0123] In some embodiments, at least one of the Ms occurring is an antitumor agent (e.g., auristatin F, monomethylauristatin F, monomethylauristatin E, paciltaxol, SN-38), an enediyne antitumor antibiotic (e.g., calicheamicin, or more specifically calicheamicin gamma 1), an alkylating agent (e.g., a PBD or a pyrrolobenzodiazepine), a maytansinoid (e.g., mertansine, emtansine) a topoisomerase inhibitor (e.g., SN38, irinotecan, camptothecin, topotecan, ciratecan, cositecan, exatecan, lutotecan, gimatecan, belotecan, rubitecan).

[0124] In some embodiments, M, at each occurrence, is an antitumor agent (e.g., auristatin F, monomethylauristatin F, monomethylauristatin E, paciltaxol, SN-38), an enediyne antitumor antibiotic (e.g., calicheamicin, or more specifically calicheamicin gamma 1), an alkylating agent (e.g., a PBD or a pyrrolobenzodiazepine), a maytansinoid (e.g., mertansine, emtansine), a topoisomerase inhibitor (e.g., SN38, irinotecan, camptothecin, topotecan, ciratecan, cositecan, exatecan, lutotecan, gimatecan, belotecan, rubitecan).

[0125] In certain embodiments, LM has the following structure: [ka] [ka] has one of the following: In further embodiments of any of the above, M are the same. In other embodiments, each M is different. In further embodiments, one or more M are the same and one or more M are different.

[0126] In some embodiments, the selected occurrences of M are not the same, and different M moieties are selected to have absorbance and / or emission for use in fluorescence resonance energy transfer (FRET) methods. For example, in such embodiments, different M moieties are selected so that the absorbance of radiation at one wavelength causes the emission of radiation at a different wavelength by FRET mechanism. Exemplary M moieties can be appropriately selected by those skilled in the art based on the desired end use. Exemplary M moieties for FRET methods include fluorescein and 5-TAMRA (5-carboxytetramethylrhodamine, succinimidyl ester) dyes. M may be attached to the remainder of the molecule from any position (i.e., atom) on M. Those of skill in the art will recognize means by which M can be attached to the remainder of the molecule. Exemplary methods include the "click" reaction described herein.

[0127] In some embodiments, M is a fluorescent or chromogenic moiety. Any fluorescent and / or chromogenic moiety may be used, such as those known in the art and commonly used in colorimetric, UV and / or fluorescent assays. Examples of M moieties useful in various embodiments of the present disclosure include, but are not limited to, xanthene derivatives (e.g., fluorescein, rhodamine, Oregon Green, eosin, or Texas Red); cyanine derivatives (e.g., cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, or merocyanine); squaraine derivatives and ring-substituted squaraines (including Seta, SeTau, and Squara dyes); naphthalene derivatives (e.g., dansyl and polodan derivatives); coumarin derivatives; oxadiazole derivatives (e.g., pyridyloxazole, nitro benzoxadiazoles or benzoxadiazoles); anthracene derivatives (e.g., anthraquinones, including DRAQ5, DRAQ7, and CyTRAK orange); pyrene derivatives such as cascade blue; oxazine derivatives (e.g., Nile red, Nile blue, cresyl violet, oxazine 170); acridine derivatives (e.g., proflavine, acridine orange, acridine yellow); arylmethine derivatives: auramine, crystal violet, malachite green; and telapyrrole derivatives (e.g., porphine, phthalocyanine, or bilirubin). Other exemplary M moieties include cyanine dyes, xanthate dyes (e.g., Hex, Vic, Nedd, Joe, or Tet); Yakima yellow, Redmond red; Tamura; Texas red, and alexa fluor® dyes.

[0128] In still other embodiments of any of the above, M comprises three or more aryl or heteroaryl rings, or a combination thereof, for example, four or more aryl or heteroaryl rings, or a combination thereof, or even five or more aryl or heteroaryl rings, or a combination thereof. In some embodiments, M comprises six aryl or heteroaryl rings, or a combination thereof. In further embodiments, the rings are fused. For example, in some embodiments, M comprises three or more fused rings, four or more fused rings, five or more fused rings, or even six or more fused rings.

[0129] In some embodiments, M is cyclic. For example, in some embodiments, M is carbocyclic. In other embodiments, M is heterocyclic. In still other embodiments described above, M, independently at each occurrence, comprises an aryl moiety. In some of these embodiments, the aryl moiety is polycyclic. In other further specific examples, the aryl moiety is a fused polycyclic aryl moiety, for example, the fused polycyclic aryl moiety can include at least three, at least four, or even more than four aryl rings. In other embodiments of any of the above compounds, M comprises at least one heteroatom. For example, in some embodiments, the heteroatom is nitrogen, oxygen, or sulfur. In further embodiments of any of the above, M comprises at least one substituent, for example, in some embodiments, the substituent is a fluoro, chloro, bromo, iodo, amino, alkylamino, arylamino, hydroxy, sulfhydryl, alkoxy, aryloxy, phenyl, aryl, methyl, ethyl, propyl, butyl, isopropyl, t-butyl, carboxy, sulfonate, amido, or formyl group.

[0130] In some more specific embodiments of the above, M is a dimethylaminostilbene, quinacridone, fluorophenyl-dimethyl-BODIPY, his-fluorophenyl-BODIPY, acridine, terylene, sexiphenyl, porphyrin, benzopyrene, (fluorophenyl-dimethyl-difluorobora-diaza-indacene)phenyl, (bis-fluorophenyl-difluorobora-diaza-indacene)phenyl, quaterphenyl, bi-benzothiazole, ter-benzothiazole, bi-naphthyl, bi-anthracyl, squaraine, squarylium, 9,10-ethynylanthracene, or ter-naphthyl moiety. In other embodiments, M is p-terphenyl, perylene, azobenzene, phenazine, phenanthroline, acridine, thioxanthrene, chrysene, rubrene, coronene, cyanine, perylene imide, or perylene amide, or a derivative thereof. In further embodiments, M is a coumarin dye, a resorufin dye, a dipyrrometheneboron difluoride dye, a ruthenium bipyridyl dye, an energy transfer dye, a thiazole orange dye, a polymethine, or an N-aryl-1,8-naphthalimide dye.

[0131] In some embodiments, M is pyrene, perylene, perylene monoimide or 6-FAM, or a derivative thereof. In some other embodiments, M has the following structure: [ka] has one of the following: The M moiety containing the carboxylic acid group can be used in the anionic form (CO 2 - ), but one of skill in the art will appreciate that this will vary with pH and that the protonated form (CO 2 It will be appreciated that H) is included in various embodiments.

[0132] In some specific embodiments, the compound is a compound selected from Table 2. The compounds in Table 2 were prepared according to the procedures described in the Examples, and their identities were confirmed by mass spectrometry.

[0133] [Table 2-1] [Table 2-2]

[0134] As used in Table 2 and throughout this application, R 2 , R 3 , M, n, and L' have the definitions provided for the compounds of structure (I) unless otherwise indicated. In some embodiments, M is F, F', F", N', I', D', D", or AF. F, F', and F'' each have the following structures: [ka] It refers to a fluorescein moiety having the formula:

[0135] "N'" refers to the following structure: [ka] Refers to...

[0136] "I'" refers to the following structure: [ka] Refers to...

[0137] "D'" refers to the following structure: [ka] Refers to...

[0138] "D" means the following structure: [ka] Refers to...

[0139] "dT" has the following structure: [ka] (In the formula, R is H or a direct bond. Refers to...

[0140] "AF" means the following structure: [ka] Refers to...

[0141] In some embodiments, the compound of structure (I) has the following structure: [ka] (In the formula, N' has the structure: [ka] having; I' has the structure: [ka] having; F has the following structure: [ka] ) has one of the following:

[0142] Thus, in some embodiments, at least one occurrence of M has the following structure: [ka] has one of the following:

[0143] In some more specific embodiments, each occurrence of M has the structure: [ka] has.

[0144] In certain embodiments, treating comprises reducing or alleviating pain or inflammation. In certain embodiments, treating comprises pain control or pain management. In some specific embodiments, at least one occurrence of M has the following structure: [ka] has one of the following:

[0145] In some more specific embodiments, each occurrence of M has the structure: [ka] has one of the following:

[0146] Some embodiments include any of the compounds presented in Table 2 and described above, including specific compounds conjugated to a targeting moiety such as an antibody. In some embodiments, one of the compounds of structure (I) is conjugated to an antibody. In some embodiments, one to two compounds of structure (I) are conjugated to an antibody. In some embodiments, two compounds of structure (I) are conjugated to an antibody. In some embodiments, three compounds of structure (I) are conjugated to an antibody. In some embodiments, four compounds of structure (I) are conjugated to an antibody. In some embodiments, five compounds of structure (I) are conjugated to an antibody. In some embodiments, five or fewer compounds of structure (I) are conjugated to an antibody.

[0147] In various embodiments, reactive polymers can be used to prepare compounds of structure (I). In certain embodiments, these reactive polymers are synthetic intermediates that contain moieties that are useful for reacting with complementary moieties to form covalent bonds between M and the reactive polymer by any number of synthetic methodologies (e.g., the "click" reaction described above), thus forming compounds of structure (I). Thus, in various embodiments, compounds of structure (I) can be prepared according to the following structure (II): [ka] (II) or a stereoisomer, salt or tautomer thereof, wherein G is, independently at each occurrence, a moiety that contains a reactive group or a protected analogue thereof that is capable of forming a covalent bond with a complementary reactive group; L a is an optional linker, L 1 and L 2 is, independently at each occurrence, an optional alkylene or heteroalkylene linker; R 1 is independently at each occurrence H, alkyl or alkoxy; R 2 and R 3 are each independently absent, or H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, dT, -OP(=R a )(R b )R c , Q or a protected form thereof, or L′; R 4 independently for each occurrence, O - , S - , OZ, SZ, or N(R 6 ) 2 where Z is a cation and each R 6 are independently H or alkyl; R 5 is independently at each occurrence oxo, thioxo, or absent; R a is O or S, R b OH, SH, O - , S - , OR d or S.R. d and R c OH, SH, O - , S - , OR d , O.L.', S.R. d, OdT, alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counterion, Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q' of the targeting moiety; L' is, independently at each occurrence, 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 moiety, 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); n is an integer equal to or greater than 1. The polymer is formed using a reactive polymer having the formula: In some embodiments, the reactive polymer is selected from Table 3 below.

[0148] [Table 3-1] [Table 3-2]

[0149] Certain embodiments are directed to therapeutically effective fluorescent compounds, with the proviso that at least one of the occurrences of M is not a fluorescent dye, and at least one of the occurrences of M is a fluorescent dye. Therapeutically effective fluorescent compounds include compounds that contain at least one biologically active moiety or fragment thereof, or a prodrug of a biologically active moiety or fragment thereof, which emit a fluorescent signal when excited by light, such as ultraviolet light. In a further embodiment, the compound of structure (I) contains at least one ethylene oxide moiety.

[0150] Also provided is a composition comprising a compound of any one of the preceding embodiments and a targeting moiety. The presently disclosed compound embodiments are "tunable," meaning that by appropriate selection of variables in any of the compounds described above, one of skill in the art can arrive at a compound with a desired molar fluorescence and / or a given molar fluorescence (molar brightness). The "tunability" of certain embodiments of the compounds allows the user to easily arrive at a compound with a desired fluorescence and / or color for use in a particular assay. While all variables can affect the molar fluorescence of certain embodiments of the compounds disclosed herein, the following variables are not limited to M, L, and / or β-aminobutyric acid. 1 , L 2 It is believed that the appropriate selection of m, n and n plays an important role in the molar fluorescence of the disclosed compound embodiments. Thus, in one embodiment, a method for obtaining a compound with a desired molar fluorescence comprises the steps of selecting an M moiety with known fluorescence, preparing a compound of structure (I) containing the M moiety, and adjusting L to reach the desired molar fluorescence. 1 , L 2 and selecting appropriate variables for n.

[0151] For ease of illustration, various compounds that contain phosphorus moieties (e.g., phosphate, etc.) can be present in an anionic state (e.g., -OPO(OH)O - , -OPO 3 2- ) as a charge. One of ordinary skill in the art will readily appreciate that the charge is pH dependent, and that uncharged (e.g., protonated or salts such as sodium or other cations) forms are also included within the scope of embodiments of the present disclosure. Compositions comprising any of the above-mentioned compounds and one or more targeting moieties (e.g., antibodies or cell surface receptor antagonists) are provided in various other embodiments. In some embodiments, the use of such compositions in a method for treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structure (I) or a composition comprising a compound of structure (I), wherein each M is independently a biologically active moiety effective to treat the disease, is also provided.

[0152] Additionally, the present disclosure is directed to compounds useful for preparing compounds of structure (I). Accordingly, one embodiment is a compound having the following structure: [ka] (In the formula, R a and R b are each independently H, an OH protecting group, or -P(R d )R e and R c is H or an amine protecting group, R d and R e are each independently cyanoalkyl or -N(R f )R g where R f and R g are each independently C 1 -C 6 is alkyl, L' a and L' b are each independently a direct bond or CH 2 and n' and m' are each independently an integer of 1 to 6. to provide.

[0153] In some embodiments, n' is 2, 3, or 4. In some embodiments, n' is 3. In some embodiments, m' is 1, 2, or 3. In some embodiments, m' is 1. In some embodiments, n' is 3 and m' is 1. Another embodiment has the following structure: [ka] (In the formula, R a and R b are each independently H, an OH protecting group, or -P(R d )R e and R d and R e are each independently cyanoalkyl or -N(R f )R g where R f and R g are each independently C 1 -C 6 is alkyl, L' a and L' b are each independently a direct bond or CH 2 and n', m', and P' are each independently an integer of 1 to 6. The present invention provides a compound having the formula:

[0154] In some embodiments, n' is 2, 3, or 4. In some embodiments, n' is 3. In some embodiments, m' is 1, 2, or 3. In some embodiments, m' is 1. In some embodiments, p' is 1, 2, 3, 4, 5, or 6. In some embodiments, p' is 2. In some embodiments, n' is 1, m' is 3, and p' is 2.

[0155] Yet another embodiment has the following structure: [ka] (In the formula, R a and R b are each independently H, an OH protecting group, or -P(R d )R e and R c is H or an amine protecting group, R d and R e are each independently cyanoalkyl or -N(R f )R g where R f and R g are each independently C 1 -C 6 is alkyl, L' a and L' b are each independently a direct bond or CH 2 and n', m', P', and q' are each independently an integer of 1 to 6. The present invention provides a compound having the formula:

[0156] In some embodiments, n' is 2, 3, or 4. In some embodiments, n' is 3. In some embodiments, m' is 1, 2, or 3. In some embodiments, m' is 1. In some embodiments, n' is 3 and m' is 1. In some embodiments, p' is 1, 2, or 3. In some embodiments, p' is 2. In some embodiments, q' is 1, 2, or 3. In some embodiments, q' is 2. In some embodiments, n' is 3, m' is 1, p' is 2, and q' is 1.

[0157] Yet another embodiment has the following structure: [ka] (In the formula, R a and R b are each independently H, an OH protecting group, or -P(R d )R e and R d and R e are each independently cyanoalkyl or -N(R f )R g where R f and R g are each independently C 1 -C 6 is alkyl, L' a and L' b are each independently a direct bond or CH 2 and n' is an integer from 1 to 6. The present invention provides a compound having the formula:

[0158] In some embodiments, n' is 1, 2, or 3. In some embodiments, n' is 2. Hydroxyl protecting groups include methoxymethyl, tetrahydropyran, tert-butyl, allyl, benzyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetate, pivalate, benzoate, dimethoxytrityl, β-methoxyethoxymethyl, para-methoxybenzyl, methylthiomethyl, tetrahydrofuran, trityl, ethoxyethyl, methyl, and the like. Thus, in some of the above embodiments, R a is a trityl protecting group (e.g., dimethoxytrityl, trityl).

[0159] In some embodiments, R a is an OH protecting group, and R b -P(R d )R e In some embodiments, R f and R g is methyl, ethyl, n-propyl, or isopropyl. f and R g are both isopropyl. In some embodiments, R d is cyanoalkyl (e.g., cyanoethyl).

[0160] In some embodiments, R b has the following structure: [ka] has.

[0161] In some embodiments of the foregoing compounds, L ’a is a direct bond. In some embodiments, L ’a is CH 2 In some embodiments, L ’b is a direct bond. In some embodiments, L ’b is CH 2 It is.

[0162] Amine protecting groups include BOC (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), benzyl, para-methoxyphenyl, para-methoxybenzyl, para-methoxybenzylcarbonyl, acetyl, benzyl carbamate (carbobenzyloxy), acetamide, trifluoroacetamide, phthalimide, triphenylmethyl, benzylidene, para-toluenesulfone, sulfonamide, Troc (trichloroethyl chloroformate), tosyl, 3,4-dimethoxybenzyl, benzoyl, and the like. Thus, in some embodiments, R c is BOC. In some embodiments, R c is Fmoc. In some embodiments, R c is H.

[0163] Certain embodiments have the following structure: [ka] (In the formula, Fmoc has the following structure: [ka] having DMTr has the following structure: [ka] (having The present invention provides a compound having one of the following:

[0164] Pharmaceutical Compositions One embodiment provides a composition comprising a compound according to any one of the embodiments disclosed herein and a pharma- ceutically acceptable carrier.

[0165] Another embodiment provides a composition comprising a plurality of conjugates comprising an antibody (e.g., a compound of structure (I)) covalently bound to two or more biologically active moieties via a single linking group, wherein the plurality of conjugates has at least 90% structural homogeneity. In more specific embodiments, the plurality of conjugates has at least 95% structural homogeneity. In related embodiments, the plurality of conjugates has greater than 99% structural homogeneity. In certain embodiments, the single linking group is a linking group to a polymer backbone, the polymer backbone comprising two or more biologically active moieties covalently bound thereto. In some of the foregoing embodiments, the conjugate or plurality of conjugates comprises a compound of structure (I).

[0166] In certain embodiments, each conjugate is independently a compound of structure (I), where R 2 and R 3 One of them is -OP(=R a )(R b ) OL' or L', where L' is an antibody or a linker comprising a covalent bond to an antibody.

[0167] Other embodiments are directed to pharmaceutical compositions. The pharmaceutical compositions include any one (or more) of the compounds of structure (I) and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions are formulated for oral administration. In other embodiments, the pharmaceutical compositions are formulated for injection. In further embodiments, the pharmaceutical compositions include the compounds of structure (I) and an additional therapeutic agent (e.g., an anti-cancer agent). Non-limiting examples of such therapeutic agents are described herein below. 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. Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic and intranasal injection.

[0168] In certain embodiments, the compound of structure (I) is administered locally rather than systemically, for example, by injecting the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, a long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to the organ and selectively taken up by the organ. In still other embodiments, the compound of structure (I) is provided in the form of a fast-release formulation, a sustained-release formulation, or an intermediate-release formulation. In still other embodiments, the compound of structure (I) is administered locally.

[0169] The compounds of structure (I) 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 examples of dosages that may be used in certain embodiments. An exemplary dosage is 10-30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the weight of the subject being treated, and the preference and experience of the attending physician. In some embodiments, the compound of structure (I) is administered in a single dose. Usually, such administration will be by injection, for example intravenous injection, to rapidly introduce the drug. However, other routes may be used when appropriate. A single dose of the compound of structure (I) may also be used to treat acute conditions.

[0170] In some embodiments, the compound of structure (I) is administered in multiple doses. In some embodiments, administration is about once, twice, three times, four times, five times, six times, or more per day. In other embodiments, administration is about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compound of structure (I) and another agent are administered together about once a day to about six times a day. In another embodiment, administration of the compound of structure (I) 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. Administration of the compound of structure (I) may continue for as long as necessary. In some embodiments, the compound of structure (I) is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compound of structure (I) is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compound of structure (I) is administered continuously for an extended period of time, e.g., for treatment of long duration of action. In some embodiments, the compound of structure (I) is administered at a dosage.It is known in the art that due to the subject-to-subject variability of the pharmacokinetics of the compound, individualization of the administration regimen is necessary for optimal treatment.The administration for the compound of the present disclosure can be found by routine experimentation in light of the present disclosure.

[0171] In some embodiments, the compound of structure (I) is formulated into pharmaceutical composition.In a specific embodiment, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents, which facilitate the processing of active compound into medicament-usable preparations.The suitable formulation depends on the route of administration selected. Any pharma- ceutical acceptable techniques, carriers, and excipients may be used to formulate the pharmaceutical compositions described herein, as appropriate: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0172] Provided herein is a pharmaceutical composition comprising a compound of structure (I) and a pharma- ceutical acceptable diluent, excipient or carrier.In certain embodiments, the described compound is administered as a pharmaceutical composition in which the compound of structure (I) is mixed with other active ingredients, as in combination therapy.All combinations of active agents described in the combination therapy section below and throughout this disclosure are encompassed herein.In specific embodiments, the pharmaceutical composition comprises one or more compounds of structure (I). Pharmaceutical composition, as used herein, refers to a mixture of a compound of structure (I) and 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 of carrying out the methods of treatment or methods of use provided herein, a therapeutically effective amount of a compound of structure (I) provided herein is administered in a pharmaceutical composition to a mammal having the disease, disorder, or medical condition to be treated. In a specific embodiment, the mammal is a human. In certain embodiments, the therapeutically effective amount varies 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) is used as a component of a mixture, alone or in combination with one or more therapeutic agents.

[0173] In one embodiment, one or more compounds of structure (I) are formulated in an aqueous solution. In a specific embodiment, the aqueous solution is selected from physiologically compatible buffers, such as Hanks' solution, Ringer's solution, or saline buffer, by way of example only. In other embodiments, one or more compounds of structure (I) are formulated for transmucosal administration. In a specific embodiment, the transmucosal formulation comprises a penetrant appropriate for the barrier to be permeated. In yet other embodiments, when the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In a specific embodiment, such solutions comprise 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 active compounds with, for example, pharma-ceutically acceptable carriers or excipients.In various embodiments, the compounds described herein are formulated in oral dosage forms, including, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc.

[0174] In certain embodiments, pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, grinding the resulting mixture, and then processing the mixture of granules to obtain tablet or dragee cores, after adding suitable auxiliary agents if desired.Suitable excipients are 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 fillers such as polyvinylpyrrolidone (PVP or povidone) or others such as calcium phosphate.In specific embodiments, disintegrants can be added.Disintegrants include, by way of example only, cross-linked sodium croscarmellose, polyvinylpyrrolidone, agar or alginic acid or its salts, such as sodium alginate.

[0175] In one embodiment, dosage forms such as dragee cores and tablets are coated with one or more suitable coatings. In a specific embodiment, a concentrated sugar solution is used to coat the dosage form. The sugar solution may contain additional components 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. Dyes and / or pigments may be added to the coating for identification purposes. Furthermore, dyes and / or pigments may be utilized to characterize different combinations of active compound doses.

[0176] In certain embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. In specific embodiments, the push-fit capsules contain the active ingredient in a mixture with one or more fillers. The fillers include, by way of example only, binders such as lactose, starch, and / or lubricants such as talc or magnesium stearate, and may also include 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. Additionally, stabilizers may be added.

[0177] In other embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated for oral or sublingual administration. Formulations suitable for oral or sublingual administration include, by way of example only, tablets, lozenges, or gels. In yet other embodiments, the compounds described herein are formulated for parental administration, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, the injectable formulations are provided in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives may be added to the injectable formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles. Parenteral injection formulations may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. In specific 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., compounds of structure (I)) 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 embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran.Suspensions may contain suitable stabilizers or agents that increase the solubility of compounds, allowing the preparation of highly concentrated solutions.Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0178] In yet another embodiment, the compound of structure (I) is administered topically.The compounds described herein are formulated into various compositions that can be administered topically, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.Such pharmaceutical compositions may contain solubilizers, stabilizers, tonicity enhancers, buffering agents and preservatives.

[0179] In yet other embodiments, the compounds of structure (I) are formulated for transdermal administration. In specific embodiments, transdermal formulations can 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 for continuous, pulsatile, or on-demand delivery of pharmaceutical agents. In additional embodiments, transdermal delivery of the compounds of structure (I) is achieved by iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of the compounds of structure (I). In specific embodiments, the absorption rate is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharma- ceutically acceptable solvents that aid in passage 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 (which may include a carrier), optionally a rate-controlling barrier for delivering the compound to the host's skin at a controlled and predetermined rate over an extended period of time, and a means for securing the device to the skin.

[0180] In other embodiments, the compound of structure (I) is formulated to be administered by inhalation.Various forms suitable for administration by inhalation include, but are not limited to, aerosol, mist or powder.Any pharmaceutical composition of the compound of structure (I) is conveniently delivered in the form of an aerosol spray supply from a pressurized pack or nebulizer with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).In a specific embodiment, the dosage unit of the pressurized aerosol is determined by providing a valve to deliver a metered amount.In certain embodiments, capsules or cartridges, such as gelatin, by way of example only, are formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch, for use in an inhaler or insufflator.

[0181] In yet another embodiment, the compounds of structure (I) 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, PEG, etc. Suppository forms of the composition contain a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, which may be combined with melted cocoa butter.

[0182] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries, which facilitate the processing of active compounds into medicament-usable preparations.The appropriate formulation depends on the route of administration selected.Any pharma-ceutically acceptable technique, carrier and excipient may be used where appropriate.The pharmaceutical compositions containing the compound of structure (I) are prepared in a conventional manner, such as by conventional mixing, dissolving, granulating, dragee making, wet milling, emulsifying, encapsulating, entrapping or compressing processes, for example only.

[0183] The pharmaceutical composition comprises at least one pharma- ceutically acceptable carrier, diluent or excipient, and at least one compound of structure (I) as described herein as an active ingredient. The active ingredient is in free acid or free base form, or in pharma- ceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds provided herein. In addition, the compounds described herein include unsolvated forms and solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds provided herein are also considered to be disclosed herein. In addition, the pharmaceutical composition may include other medicinal or pharmaceutical agents, carriers, preservatives, stabilizing agents, wetting or emulsifying agents, solution promoters, adjuvants such as salts for regulating osmotic pressure, buffering agents, and / or therapeutically valuable substances.

[0184] The method of preparing a composition comprising the compound described herein includes formulating the compound with one or more inert pharma- ceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compound disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The forms of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquid before use, or emulsions. These compositions may also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like. In some embodiments, the pharmaceutical composition comprising at least one compound of structure (I) is illustratively in the form of a liquid, in which the drug is in solution, in suspension, or both.Usually, when the composition is administered as a solution or suspension, a first portion of the drug is in solution, and a second portion of the drug 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.

[0185] 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.Some pharmaceutical compositions described herein include mucoadhesive polymers, e.g., selected from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran. Useful pharmaceutical compositions may also include solubilizing agents that aid in the dissolution of the compound of structure (I). The term "solubilizing agent" generally includes agents that result in the formation of a micellar or true solution of the drug. Certain acceptable non-ionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers.

[0186] In addition, useful pharmaceutical compositions may 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. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition in an acceptable range.

[0187] Further useful compositions may also contain one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions, with suitable salts including sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. Other useful pharmaceutical compositions may 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.

[0188] 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 alkyl phenyl ethers, such as octoxynol 10, octoxynol 40. Still other useful compositions optionally contain one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite. In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case it is customary to include a preservative 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 herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In additional embodiments, the compounds described herein are delivered using sustained release systems, such as semi-transparent matrices of solid hydrophobic polymers containing therapeutic agents. A variety of sustained release materials are useful herein. In some embodiments, sustained release capsules release compounds for several weeks up to 100 days. Depending on the chemical nature and biological stability of therapeutic reagents, additional strategies for protein stabilization are used.

[0189] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizing agents. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc, or (n) combinations thereof.

[0190] 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%. %, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v or v / v.

[0191] 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%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%,4.75%,4.50%,4.25%,4%,3.75%,3.50%,3.25%,3%,2.75%,2.50%,2.25%,2%,1.75%,1.50%,125%,1%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07%,0.06%,0.05%,0.04%,0.03%,0.02%,0 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 greater than 0.0001% w / w, w / v or v / v.

[0192] In some embodiments, the concentration of the one or more compounds is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 100%, from about 0.09% to about 120%, from about 0.10% to about 130%, from about 0.11% to about 140%, from about 0.12% to about 150%, from about 0.13% to about 160%, from about 0.14% to about 170%, from about 0.15% to about 180%, from about 0.16% to about 190%, from about 0.18% to about 200%, from about 0.19% to about 210%, from about 0.19% to about 220%, from about 0.19% to about 230%, from about 0.19% to about 240%, from about 0.19% to about 250%, from about 0.19% to about 260%, from about 0.19% to about 250%, from about 0.19% to about 220%, from about 0.19% to about 230%, from about 0.19% to about 240%, from about 0.19% to about 25 ... about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v or v / v. 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% w / w, w / v or v / v.

[0193] 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, 0.15g, 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.

[0194] 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, 0.004 ... g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.00 75g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0 .085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5 g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 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 is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0195] Treatment The compounds of the present disclosure are useful for the treatment of diseases. The compounds disclosed herein provide a targeted approach to drug delivery strategies. Furthermore, the compounds of structure (I) offer distinct advantages over previously known compounds due to their ability to include virtually any therapeutic moiety. Biologically active moieties (e.g., therapeutic agents) can be reversibly or irreversibly bound and delivered to targets.

[0196] Thus, in some embodiments, the compounds are useful in various methods of treating diseases or conditions.One embodiment provides a method of treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structure (I) or a composition comprising a compound of structure (I), wherein at least one M is a biologically active moiety effective for treating the disease.In more specific embodiments, each M is a biologically active moiety effective for treating the disease. In some embodiments, the biologically active portion of the disease degrades proteins. In some more specific embodiments, the protein is amyloid or tau protein. In certain embodiments, the disease is amyloidosis or Alzheimer's disease. In some embodiments, the disease is prostate cancer, pancreatic cancer, or breast cancer. In some embodiments, the disease is an oncological, cardiovascular, renal, metabolic, or respiratory disease.

[0197] In certain embodiments, the disease is pulmonary disease or central nervous system disease.In more specific embodiments, the disease is metastatic castration-resistant prostate cancer or metastatic breast cancer.In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of the embodiments disclosed herein or the composition according to any one of the embodiments disclosed herein, wherein each M is independently an effective biologically active moiety for treating disease.

[0198] In some embodiments, the disease is cancer and each M is independently an anti-cancer drug. In some embodiments, at least one occurrence of M has the following structure: [ka] [ka] has one of the following:

[0199] In some embodiments, each occurrence of M has the following structure: [ka] [ka] has one of the following:

[0200] For example, in certain embodiments, the disclosure provides methods of 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, adenocarcinoma of the pancreas, ovary and / or lung, 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.

[0201] In some of the above 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, solid tumor, ovarian cancer, prostate cancer, colorectal cancer, pancreatic cancer, small cell lung cancer, diffuse large B-cell lymphoma, neoplasm, urothelial carcinoma, ALL, CLL, glioblastoma, Hodgkin's lymphoma, lymphoma, mesothelioma, non-small cell lung cancer, recurrent head and neck cancer, or combinations thereof.

[0202] Certain embodiments also relate to a method of treating a hyperproliferative disorder in a mammal (e.g., a human), comprising administering to the mammal a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.In some embodiments, the method relates to a method for treating acute myeloid leukemia, adolescent cancer, adrenocortical carcinoma of childhood, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, 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 teratoid, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer. , colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic bile duct carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer , liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of unknown primary site, midline canal carcinoma, cancer of the mouth, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma for the treatment of cancers such as bronchial carcinoma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, chorioepithelial tumor, rare cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer or virus-induced cancer.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 the prostate (eg, benign prostatic hyperplasia (BPH)).

[0203] Certain specific embodiments provide a method of treating lung cancer, comprising administering to a subject in need thereof an effective amount of any of the above compounds (or pharmaceutical compositions comprising same). In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung carcinoma, or large cell lung carcinoma. In other embodiments, the lung cancer is small cell lung carcinoma. Other lung cancers treatable by the disclosed compounds include, but are not limited to, adenoma, carcinoid tumor, and undifferentiated carcinoma.

[0204] Thus, in some embodiments of the above-described method, R 2 is a linker that includes a covalent linking group to a targeting moiety, such as an antibody or cell surface receptor antagonist, for example, an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, a folate or a MET inhibitor. In a further embodiment, the method further comprises inducing apoptosis. In some embodiments, the method for treating a disease includes: (a) For example, R 2 or R 3 is a linker that contains a covalent bond to the analyte molecule, and R 2 or R 3 The other is H, OH, alkyl, alkoxy, alkyl ether or -OP(=R a )(R b )R c providing a compound of structure (I), (b) detecting the compound by its visible property.

[0205] In some embodiments, the analyte molecule is a nucleic acid, an amino acid, or a polymer thereof (e.g., a polynucleotide or a polypeptide). In further embodiments, the analyte molecule is an enzyme, a receptor, a receptor ligand, an antibody, a glycoprotein, an aptamer, or a prion. In certain embodiments, the providing step further comprises mixing the compound of structure (I) with the analyte molecule. Thus, embodiments of the present compounds find use in any number of methods, including, but not limited to, drug delivery, quantification of apoptosis, qualifying the delivery of therapeutic agents, and diagnosis and treatment of diseases such as hematological cancers.

[0206] In addition to the methods described above, embodiments of the compounds of structure (I) find utility in a variety of fields and methods including, but not limited to, cancer treatment and imaging, and / or drug delivery, by including targeting moieties in the compounds of structure (I), such as antibodies or sugars, or other moieties that preferentially bind to cancer cells. In some embodiments, the method of treatment includes treating a tumor having tumor cells with a tumor cell receptor. In some embodiments, the tumor cells have receptors in the range of 1,000-100,000, 1,000-50,000, 1,000-25,000, 1,000-10,000 receptors per cell. For example, in some embodiments, the tumor cells have about 1,000, about 10,000 receptors, or less than 100,000 receptors per cell. The embodiments of the present disclosure are not limited to the treatment of cancer.In fact, the present disclosure is not particularly limited with respect to the disease, symptoms, conditions, indications, and types of treatment that the compounds and methods of the present disclosure can be applied to.That is, the present disclosure provides compounds, compositions, and methods for treating or preventing a wide variety of diseases.For example, the compounds and compositions disclosed herein can be modified by selecting the appropriate biological moiety or combination of biological moieties to treat a particular disease as desired.Based on the present disclosure, it will be readily apparent to those skilled in the art how to modify the presently disclosed compounds and compositions to treat, prevent, or target a disease, symptom, or clinical indication.

[0207] Thus, methods of the disclosure include methods of administering a compound of the disclosure to treat a disease, condition, or a symptom of a disease or condition, methods of preventing a disease or a symptom of a disease or condition, methods of prophylactically treating a disease, condition, or a symptom of a disease or condition, methods of identifying at-risk subjects and treating a disease, condition, or a symptom of a disease or condition, methods of slowing or halting the progression of a disease, condition, or a symptom of a disease or condition, methods of increasing the survival of a subject having a disease, condition, or a symptom of a disease or condition, methods of ameliorating a disease, condition, or a symptom of a disease or condition, and the like.

[0208] Additionally, diseases, conditions, symptoms, afflictions, side effects, illnesses, syndromes, biological manifestations, biological abnormalities, medical conditions, disorders, pathologies, and the like are meant to be included within the present disclosure, and include, but are not limited to, cancer, inflammation, pain, pain control, inflammatory diseases, infectious diseases, viral infections, genetic disorders, bacterial infections, fungal infections, skin conditions, endocrine conditions, eye disorders, bowel disorders, neurological disorders, liver disorders, lung infections, cardiac diseases and disorders, mental disorders (e.g., eating disorders, mood disorders, personality disorders, disorders), norovirus infections, blood borne pathogens, protozoan infections, viral hepatitis, HIV / AIDS, diabetes, sclerosis, Crohn's and colitis, lupus, arthritis, allergies and asthma, celiac disease, polychondritis, scleroderma, liver disease, heart disease, acquired diseases, acute diseases, chronic conditions or diseases, congenital diseases or disorders, genetic diseases or disorders, iatrogenic diseases, idiopathic diseases, primary diseases, secondary diseases, terminal diseases, or the like. The foregoing may be acute, chronic, clinical, relapsing, progressive, refractory, asymptomatic, localized, disseminated, systemic, and the like. Any of the foregoing examples may include those caused as a result of airborne infections, foodborne infections, or lifestyle events.

[0209] In some embodiments, the biologically active moiety is an antibiotic. In certain specific embodiments, M is, independently at each occurrence, an antibiotic, and the targeting moiety is an antibody specific for an infectious disease antigen. Antibiotics, as used herein, include derivatives. These are modified or derivatized antibiotics, such that the drug can be conjugated or attached to another molecule (e.g., to include a Q moiety).

[0210] Exemplary antibiotic moieties include, for example, Actinomyces israelii, Bacillus anthracis, Bacteroides fragilis, Bordetella pertussis, Borrelia sp., Brucella sp., Campylobacter jejuni, Chlamydia sp., Chlamydophila psittaci, Clostridium sp., Corynebacterium diphtheria, Ehrlichia sp., Enterococcus sp., sp., Escherichia sp., Francisella tularensis, Haemophilus influenza, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, Leptospira sp., Listeria monocytogenes, Mycobacterium sp., Mycoplasma pneumoniae, Neisseria sp., Pseudomonas aeruginosa, Nocardia asteroids, Rickettsia rickettsia, Salmonella sp., Shigella sp., Staphylococcus sp., Streptococcus sp.The compounds may include compounds for treating bacterial species including Staphylococcus aureus, Treponema pallidum, Vibrio cholera, and Yersinia pestis. Additionally, bacterial species that may be treated include drug-resistant strains such as Methicillin-Resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci (VRE), and various multi-drug resistant (MDR) strains commonly associated with hospital-acquired (nosocomial) infections, such as Acinetobacter baumannii, Klebsiella pneumoniae, and Enterobacter cloacae. In another embodiment, the bacterial disease or condition that can be treated with the compounds of structure (I) can be, for example, anthrax, whooping cough, Lyme disease, brucellosis, gastrointestinal abscess, relapsing fever, enteritis, bloody diarrhea, atypical pneumonia, botulism, tetanus, bacterial meningitis, gangrene, bacterial endocarditis, epilepsy, legionnaires' disease, leptospirosis, tuberculosis, plague, cholera, necrotizing fasciitis, typhoid fever, and nocardiosis.

[0211] In some more specific embodiments, the antibiotic is a β-lactam antibiotic. β-lactam antibiotics include compounds that include penicillin, monobactam, carbapenem, and cephalosporin. In some embodiments, M is selected from the group consisting of oxacillin, dicloxacillin, nafcillin, amoxicillin, ampicillin, piperacillin, cloxacillin, flucloxacillin, methicillin, oxacillin, temocillin, benzylpenicillin (penicillin G), almesillin (penicillin O), phenoxymethylpenicillin (penicillin V), mecillinam, carbenicillin, ticarcillin, azlocillin, mezlocillin, cephalospor ... Zolin, Cephalexin, Cephalosporin C, Cefotaxime, Cefdinir, Cefpirome, Biapenem, Doripenem, Ertapenem, Faropenem, Imipenem, Meropenem, Panipenem, Raspenem, Tebipenem, Thienamycin, Aztreonam, Tigemonam, Nocardicin A, Tabtoxinine β-lactam, Lenapenem, Tomopenem, Cefazolin, Cephalexin, Cefadroxil, Cephapirin, Cefazedone, Cefazaflur, Cephradine , Cefroxadine, Ceftezole, Cephaloglycin, Cephacetrile, Cephalonium, Cephaloridine, Cephalothin, Cefatrizine, Cefaclor, Cefotetan, Cephamycin, Cefoxitin, Cefprozil, Cefuroxime, Cefuroxime axetil, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefbuperazone, Cefuzonam, Cefmetazole, Carbacephem (Loracarbef), Cefixime, Ceftriaxone, Ceftazidime , cefoperazone cefdinir, cefcapene, cefdaloxime, ceftizoxime, cefmenoxime, cefotaxime, cefpiramide, cefpodoxime, ceftibuten, cefditoren, cefetamet, cefodizime, cefpimizole, cefsulodin, cefteram, ceftiolene, oxacephem, flomoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftaroline fosamil, ceftolozane, ceftobiprole, ceftiofur, cefquinome, or cefovecin.

[0212] In other embodiments, the antibiotic is a tetracycline antibiotic. More specifically, in some embodiments, M, at least one occurrence of M or each occurrence of M, is doxycycline, tetracycline, minocycline, demeclocycline, chlortetracycline, oxytetracycline, lymecycline, methacycline, rolitetracycline, tigecycline, eravacycline, seracycline, omadacycline, clomocycline, demeclocycline, meclocycline, methacycline, or penimepicycline.

[0213] In a further embodiment, the antibiotic is a quinolone antibiotic. Quinolone antibiotics comprise a large subgroup of fluoroquinolones. In particular, in some embodiments, M is selected from the group consisting of oxolinic acid (Uroxin), losoxacin (Eradacil), ciprofloxacin (Zoxan, Ciprobay, Cipro, Ciproxin), fleroxacin (Megalone, Roquinol), lomefloxacin (Maxaquin), nadifloxacin (Acuatim, Nadoxin, Nadixa), norfloxacin (Lexinor, Noroxin, Quinabic, Janacin), ofloxacin (Floxin, Oxaldin, Tarivid), pefloxacin (Peflacine), rufloxacin (Uroflox), balofloxacin (Baloxin), grepafloxacin (Raxar), levofloxacin (Valoxin ... These include oxafloxacin (Cravit, Levaquin), pazufloxacin (Pasil, Pazucross), sparfloxacin (Zagam), temafloxacin (Omniflox), clinafloxacin, gatifloxacin (Zigat, Tequin) (Zymar-opth), moxifloxacin (Avelox, Vigamox), sitafloxacin (Gracevit), prulifloxacin, besifloxacin (Besivance), delafloxacin (Baxdela), gemifloxacin (Factive), ozenoxacin, tosufloxacin, cinoxacin (Cinobac), nalidixic acid (NegGam, Wintomylon), piromidic acid (Panacid), pipemidic acid (Dolcol), nemonoxacin, or enoxacin.

[0214] In yet another embodiment, the antibiotic is a lincosamide antibiotic. In some embodiments, M at least one occurrence of M or every occurrence of M is clindamycin, lincomycin, or pirlimycin. In some embodiments, the antibiotic is a macrocyclic antibiotic. Macrocyclic antibiotics include the group including macrolides, ketolides, fluoroketolides, and polyenes. In some embodiments, M, at least one occurrence of M or each occurrence of M, is amphotericin B, azithromycin, boromycin, carbomycin A, cethromycin, clarithromycin, dirithromycin, erythromycin, fidaxomicin, flurithromycin, josamycin, kitasamycin, midecamycin, miokamycin, oleandomycin, rifampicin (or rifampin), rifabutin, rifapentine, rifalazil, rifaximin, rifamycin SV, rokitamycin, roxithromycin, solithromycin, spiramycin, telithromycin, troleandomycin, or tylosin.

[0215] In some embodiments, the antibiotic is a sulfonamide antibiotic (sulfa or sulfa drug). Sulfonamide antibiotics exert bacteriostatic effects through the inhibition of dihydropteroate synthase (DHPS), thereby interfering with the organism's ability to synthesize folic acid and nucleic acid. In some embodiments, M is sulfafurazole, sulfacetamide, sulfadiazine, sulfadimidine, sulfafurazole (sulfisoxazole), sulfisomidine (sulfaisodimidine), sulfanitran, sulfadimethoxine, sulfamethoxypyridazine, sulfamethoxydiazine, sulfadoxine, sulfamethopyrazine, terephthyl, sulfamethoxazole, or sulfamoxole in at least one occurrence of M.

[0216] In some embodiments, the antibiotic is a glycopeptide antibiotic. In certain embodiments, M in at least one occurrence of M or every occurrence of M is vancomycin, teicoplanin, telavancin, ramoplanin, oritavancin, or decaplanin.

[0217] In some embodiments, the antibiotic is an aminoglycoside antibiotic. Aminoglycoside antibiotics exert their biological effect through protein synthesis inhibition. In more specific embodiments, M in at least one occurrence of M or each occurrence of M is streptomycin, dihydrostreptomycin, neomycin, framycetin, paromomycin, ribostamycin, kanamycin, amikacin, arbekacin, bekanamycin, dibekacin, tobramycin, spectinomycin, hygromycin B, apramycin, puromycin, nourseothricin, gentamicin, netilmicin, sisomicin, plazomicin, isepamicin, verdamycin, or astromycin.

[0218] In some embodiments, the antibiotic is an oxazolidinone antibiotic.The oxazolidinone antibiotic exerts its biological effect through protein synthesis inhibition.In some specific embodiments, at least one of the M occurrences or each occurrence of M is eperezolid, linezolid, pocizolid, radezolid, rambezolid, stezolid, or tedizolid. In some embodiments, M in at least one occurrence of M or in each occurrence of M is platensimycin, chloramphenicol, metronidazole, trimethoprim, azitoprim, brodimoprim, clofazimine, iclaprim, tetroxoprim, or nitrofurantoin.

[0219] In some embodiments, the biologically active moiety is an antifungal drug. In certain specific embodiments, M is, independently at each occurrence, an antifungal drug, and the targeting moiety is an antibody specific for an infectious disease antigen. Antifungal drug, as used herein, includes derivatives. This is a modified or derivatized antifungal drug, such that the drug can be conjugated or attached to another molecule (e.g., to include a Q moiety). Fungal species that can be treated with the compounds of the present disclosure include, for example, Candida sp., Aspergillus sp., Cryptococcus sp., Histoplasma sp., Pneumocystis sp., and Stachybotrys sp. Additionally, fungal species requiring treatment include emerging drug-resistant strains, such as Candida auris, Candida glabrata, and Candida krusei, which have shown significant resistance to existing treatment options and are often hospital-acquired infections, thus presenting a public health concern.

[0220] In some embodiments, the fungal disease or condition that can be treated with a compound of structure (I) in at least one occurrence of M, or in each occurrence of M, can be, for example, aspirugirosis, invasive candidiasis, onychomycosis, or histoplasmosis. In certain embodiments, the antifungal agent is a polyene. In more specific embodiments, M is selected from the group consisting of amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, and rimocidin; allylamines such as amorolfine, butenafine, naftifine, and terbinafine; echinocandins such as anidulafungin, caspofungin, and micafungin; or bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, The azoles, which can be classified as imidazoles, such as ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole; the triazoles, such as albaconazole, efinaconazole, epoxiconazole, fluconazole, isabconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, and voriconazole; and the thiazole, abafungin.

[0221] In some more specific embodiments, M in at least one occurrence of M or each occurrence of M is ciclopirox, flucytosine or 5-fluorocytosine, griseofulvin, tolnaftate, orotomide, miltefosine, piroctone olamine, iodoquinol, clioquinol, acrisorcin, or fumagillin.

[0222] In some embodiments, the biologically active moiety is an anthelmintic drug. In certain specific embodiments, M is, independently at each occurrence, an anthelmintic drug, and the targeting moiety is an antibody specific for an infectious disease antigen. An anthelmintic drug, as used herein, includes derivatives. This is an anthelmintic drug that is modified or derivatized, such that the drug can be conjugated or attached to another molecule (e.g., to include a Q moiety). Parasites with their associated diseases that can be treated with the compounds of the present disclosure include protozoans such as Plasmodium sp. (malaria), Leishmania sp. (leishmaniasis), Trypanosoma sp. (African trypanosomiasis / sleeping sickness, Chagas disease), Giardia sp. (giardiasis / beaver fever), oxoplasma gondii (toxoplasmosis), and amoebas such as Cryptosporidium sp. (cryptosporidiosis); Entamoeba histolytica (amebiasis).

[0223] In certain embodiments, M, in at least one occurrence of M or each occurrence of M, is chloroquine, amodiaquine, pyrimethamine (Daraprim), proguanil, sulfadoxine, sulfamethoxypyridazine, mefloquine, paromomycin, atovaquone, primaquine, artemisinin, amphotericin B, artemether, artesunate, dihydroartemisinin, arteether, doxycycline, clindamycin, halofantrine, diloxanide, eflornithine, furazolidone, melarsoprol, metronidazole, nifursemiso, nitazoxanide, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, quinapyramine, or tinidazole. In some embodiments, the biologically active moiety is an antiviral drug. In certain specific embodiments, M is, independently at each occurrence, an antiviral drug, and the targeting moiety is an antibody specific for an infectious disease antigen. Antiviral drugs, as used herein, include derivatives. These are modified or derivatized antiviral drugs, and thus the drug can be conjugated or bound to another molecule (e.g., to include a Q moiety).

[0224] Viral diseases that can be treated with the compounds of the present disclosure include, for example, HIV, Zika, Ebola, Hepatitis B and C, and influenza. In some embodiments, M in at least one occurrence of M or each occurrence of M is pegylated interferon-alpha-2a / 2b, entecavir, tenofovir disoproxil fumarate, asunaprevir, tribavirin, beclabuvir, daclatasvir, dasabuvir, grazoprevir, paritaprevir, simeprevir, sofosbuvir, or velpatasvir. In other embodiments, the antiviral agent treats HIV. In some embodiments, M, at least one occurrence of M or each occurrence of M, is a nucleoside / nucleotide reverse transcriptase inhibitor, such as abacavir, lamivudine, tenofovir disoproxil fumarate, and zidovudine; a non-nucleoside reverse transcriptase inhibitor, such as efavirenz or nevirapine; a protease inhibitor, such as atazanavir, darunavir, lopinavir, and ritonavir; or an integrase inhibitor, such as dolutegravir or raltegravir.

[0225] In yet another embodiment, the antiviral agent treats influenza. For example, in some embodiments, M at at least one occurrence of M or at each occurrence of M is laninamivir, oseltamivir, peramivir, zanamivir, or baloxavir marboxil.

[0226] In some embodiments, the antiviral agent treats Ebola. For example, in some embodiments, M is Favipiravir, Brincidofovir, Galidesivir (BCX4430, Immu- cillin-A), JK-05, or AVI-7537 in at least one of the M occurrences or in each occurrence of M. In some embodiments, the biologically active moiety is a drug for the treatment of immunological or anti-inflammatory conditions.In certain specific embodiments, M, independently at each occurrence, is an immunological drug, and the targeting moiety is an antibody specific to an antigen associated with a disease / condition.As used herein, immunological drug includes derivatives.This is a modified or derivatized immunological drug, so that the drug can be conjugated or attached to another molecule (e.g., to include a Q moiety).

[0227] In some embodiments, the disease or condition is asthma, rheumatoid arthritis, lupus, multiple sclerosis, psoriasis, Crohn's disease, colitis, or organ rejection therapy. Thus, in some embodiments, M at at least one occurrence of M, or at each occurrence of M, is a corticosteroid (e.g., prednisone), methotrexate, mycophenolate mofetil, or azathioprine. In some embodiments, the compound of structure (I) comprises a covalent bond to a therapeutic antibody, such as Humira (i.e., adalimumab). In some embodiments, the disease or condition is psoriasis. Thus, in some embodiments, M at least one occurrence of M or each occurrence of M is acitretin, prednisone, a retinoid, methotrexate, cyclosporine, thioguanine, etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), ustekinumab (Stelara), golimumab (Simponi), apremilast (Otezla), secukinumab (Cosentyx), or ixekizumab (Taltz).

[0228] In some embodiments, the disease or condition is Crohn's disease or colitis. In some more specific embodiments, M at least one occurrence of M or each occurrence of M is sulfasalazine, mesalamine, balsalazide, olsalazine, prednisone, hydrocortisone, mercaptopurine, azathioprine, cyclosporine, methotrexate, budesonide, ciprofloxacin, metronidazole, or azathioprine. In some embodiments, the compound of structure (I) comprises a covalent bond to a therapeutic antibody, such as infliximab (Remicade), adalimumab (Humira), vedolizumab (Entyvio), certolizumab, natalizumab (Tysabri), ustenkinumab (Stelara), or golimumab (Simponi). In some embodiments, the disease or condition is asthma. In some embodiments, M in at least one occurrence of M or in each occurrence of M is a corticosteroid, a long-acting beta agonist (e.g., salmeterol, leukotrienes), omalizumab, zafirlukast, or fluticasone. In some embodiments, the disease or condition is multiple sclerosis. In some embodiments, M at least one occurrence of M or each occurrence of M is hydroxychloroquine, methotrexate, azathioprine, mycophenolic acid, prednisone, methylprednisolone, belimumab, or rituximab (Rituxan).

[0229] In some embodiments, the disease or condition is organ rejection. In more specific embodiments, M in at least one occurrence of M or each occurrence of M is prednisolone, hydrocortisone, sirolimus, everolimus, cyclosporine, tacrolimus, mycophenolic acid, or azathioprine, basiliximab, daclizumab, or rituximab.

[0230] In some embodiments, the disease or condition is lupus. In more specific embodiments, M in at least one occurrence of M or each occurrence of M is hydroxychloroquine, methotrexate, azathioprine, mycophenolic acid, prednisone, methylprednisolone, belimumab, or rituximab (Rituxan).

[0231] In some embodiments, the disease or condition is rheumatoid arthritis. In more specific embodiments, M in at least one occurrence of M or each occurrence of M is prednisone, methotrexate, mycophenolate mofetil, leflunomide, hydroxychloroquine, sulfasalazine, azathioprine, abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), baricitinib (Olumiant), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan), sarilumab (Kevzara), tocilizumab (Actemra), or tofacitinib (Xeljanz).

[0232] In some embodiments, the disease or condition treated by administering a compound of structure (I) is selected from the group consisting of bone marrow ablation; acute sciatica; allergic asthma; ALS and multiple sclerosis; Alzheimer's disease; amyloidosis; angioedema; angiogenesis; hemangiosarcoma; ankylosing spondylitis; anthrax (prevention and treatment); arthritis; asthma; atopic diseases; atypical hemolytic uremic syndrome; autoimmune hepatitis; anthrax spores; B cell malignancies; cardiovascular disease; choroidal and retinal neovascularization; chronic asthma; chronic hepatitis B; clinical signs of canine atopic dermatitis; Clostridium difficile colitis; cold agglutinin disease; Crohn's disease; cryopyrin-associated periodontal syndrome; cytoplasmic leukemia; pulmonary edema; and pulmonary edema. Megalovirus infection;Diabetes mellitus;Diabetic nephropathy and arteriovenous graft patency;Duchenne muscular dystrophy;Dyslipidemia;Ebola virus;Eczema;Fibrosis;Geographic atrophy secondary to age-related macular degeneration;Glioblastoma;Graft-versus-host disease;Hemophilia A;Hemorrhagic shock;Heart attack, stroke, traumatic shock;Hematologic malignancies;Hemolytic disease of the newborn;Hepatitis B;HIV infection;Hypercholesterolemia;Immunologically mediated inflammatory diseases;Infections / influenza A;Inflammation;Inflammation of the airways, skin and gastrointestinal tract;Inflammatory bowel disease;Invasive Candida infection;Juvenile idiopathic arthritis;Lupus nephritis;Macular degeneration (wet);Medically required attended)lower respiratory tract disease;melanoma;migraine;multiple sclerosis;orthopedic disuse muscle atrophy and sarcopenia;muscle wasting disorders;muscular dystrophies;myostatin inhibitors;neovascular age-related macular degeneration;neuromyelitis optica;hospital-acquired pneumonia;ocular vascular disease;oncology / immune indications;organ transplant rejection;osteoarthritis;osteomyelitis (imaging);osteoporosis;osteoporosis, bone metastases, etc;Parkinson's disease;paroxysmal nocturnal hemoglobinuria;percutaneous coronary intervention;psoriasis vulgaris;platelet aggregation inhibitors;rabies Post-exposure prophylaxis of disease; prevention of organ transplant rejection; primary systemic amyloidosis; progressive supranuclear palsy; Pseudomonas aeruginosa infection; psoriasis; psoriatic arthritis; rabies (prophylaxis); restoration of motor function after stroke; recurrent glioblastoma multiforme; reduction of scarring after glaucoma surgery; reduction of side effects of cardiac surgery; respiratory syncytial virus; reversal of the anticoagulant effect of dabigatran; Rh disease; rheumatic diseases; rheumatoid arthritis; sepsis; severe allergic diseases; severe asthma and chronic spontaneous urticaria; sickle cell disease; SLE, dermatomyositis, polymyositis;Solid malignancies; Staphylococcus aureus infection; Systemic lupus erythematosus; Systemic sclerosis; Thromboembolism (diagnosis); Thrombotic thrombocytopenic purpura, thrombosis; Thyroid eye disease; TNF; Ulcerative colitis; Uveitis, Rheumatoid arthritis, Psoriasis; Viral infection; Wet age-related macular degeneration; White blood cell disorders; X-linked hypophosphatemia or a combination thereof.

[0233] Additional therapeutic agents that can be combined with the compounds of the present disclosure can be found in "The Pharmacological Basis of Therapeutics," 10th Edition, by Goodman and Gilman, edited by Hardman, Limbird and Gilman, or the Physician's Desk Reference, both of which are incorporated herein by reference in their entireties.

[0234] The compounds described herein can 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 as described above. When used in combination therapy, the compounds described herein are administered simultaneously or separately with the second agent. This combined administration can include co-administration of the two agents in the same dosage form, co-administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the agents described above can be formulated together in the same dosage form and administered at the same time. Alternatively, the compounds of the present disclosure and any of the agents described above can be administered at the same time, with both agents being in separate formulations. In another alternative, any of the agents described above can be administered immediately after administration of the compounds of the present disclosure, or vice versa. In some embodiments of the separate administration protocol, the compounds of the present disclosure and any of the agents described above are administered minutes apart, or hours apart, or days apart.

[0235] In some embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of an anti-tumor agent, an enediyne anti-tumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and an EGFR inhibitor or alkylating agent, and combinations thereof. In some more specific embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of an anti-tumor agent, an enediyne anti-tumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and an EGFR inhibitor or alkylating agent, and combinations thereof.

[0236] In certain embodiments, the additional therapeutic agent comprises auristatin F, monomethylauristatin F, monomethylauristatin 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, lutotecan, gimatecan, belotecan, and rubitecan. The examples and preparations provided below further describe and illustrate the compounds of the present disclosure and the methods of preparing such compounds.It should be understood that the scope of the present disclosure is in no way limited by the scope of the following examples and preparations.In the following examples and throughout the specification and claims, molecules and moieties that have a single stereocenter are present as racemic mixtures unless otherwise specified.Unless otherwise specified, molecules and moieties that contain two or more stereocenters are present as racemic mixtures of diastereomers.Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0237] Preparation method Numerous advantages are provided by the embodiments disclosed herein, including the ability to control the number of bioactive or fluorescent dye moieties that are linked to the polymer and then to any targeting moiety.The composition of the polymer backbone can also be selected to achieve desired solubility properties, for example, by controlling the incorporation of charge moieties (e.g., number, frequency, spacing, etc.).In addition to the properties provided by the composition of the backbone, the side chains can be selected to provide a basis for adjusting the solubility of the compounds disclosed herein. The embodiments disclosed herein also provide compounds that can advantageously include multiple therapeutic agents, for example, for complimentary or synergistic therapeutic strategies.Furthermore, the embodiments of the present disclosure provide combinations of therapeutic agents, targeting moieties and dye moieties (e.g., fluorophores) that can be used for targeting, treatment and detection simultaneously.The ease of coupling the polymer-drug constructs to targeting agents such as antibodies, antibody fragments, proteins or other agents of clinical interest makes them useful for a wide range of applications of interest (e.g., surface chemistry, assay development, etc.).

[0238] The compounds of certain embodiments also achieve other desirable properties, including enhanced permeability and retention. In addition to achieving the necessary solubility, the chemical characteristics of the compound embodiments can be adjusted to modulate the ability of the compound to penetrate diseased cells / tissues and to be retained within them. These characteristics allow for effective delivery of bioactive agents through enhanced permeability, and increased efficacy through enhanced retention.

[0239] Thus, embodiments of the compounds of structure (I) above, as well as the variable factor R in the compounds of structure (I) above, 1 , R 2 , R 3 , R 4 , R 5 , L, L 1 , L 2It is understood that any specific choice described herein for R, M and / or n may be independently combined with other embodiments and / or variables of the compounds of structure (I) to form embodiments of the disclosure not specifically described above. Additionally, the list of choices may be combined with any particular R in a particular embodiment and / or claim. 1 , R 2 , R 3 , R 4 , R 5 , L, L 1 , L 2 , M and / or n variables, it is understood that each individual selection may be excluded from the scope of a particular embodiment and / or claim, and that the remaining listing of selections is considered to be within the scope of the present disclosure. It is understood that in this description, combinations of substituents and / or variables of the depicted formulae are permissible if such contributions result in stable compounds.

[0240] It will also be appreciated by those skilled in the art that in the processes described herein, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R" (wherein R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups can be added or removed according to standard techniques known to those skilled in the art and described herein. The use of protecting groups is described in detail in Green, TW and PGM Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As will be appreciated by those skilled in the art, these protecting groups can also be polymeric resins such as Wang resin, Rink resin or 2-chlorotrityl chloride resin. Additionally, all compounds of the present disclosure that exist in free base or free acid form can be converted to their salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of compounds of the present disclosure can be converted to their free base or acid form by standard techniques.

[0241] The following reaction scheme illustrates an exemplary method for making the compounds of the present disclosure. It is understood that those skilled in the art may be able to make these compounds by similar methods or by combining other methods known to those skilled in the art. It is also understood that those skilled in the art may be able to make other compounds of structure (I) that are not specifically exemplified below by similar methods as described below by using appropriate starting components and modifying synthesis parameters as necessary. In general, starting components can be obtained from suppliers such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI and Fluorochem USA, or can be synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)), or can be prepared as described in the present disclosure.

[0242] Reaction Scheme I [ka]

[0243] Reaction Scheme I shows the reaction 1 , R 4 , R 5 , L 1 , L 2 and M is as defined above, and R 2 and R 3The following illustrates an exemplary method for preparing intermediates useful for the preparation of compounds of structure (I), where x is as defined above or a protected variant thereof, and L is an optional linker. Referring to reaction scheme 1, compounds of structure a can be purchased or prepared by methods well known to those skilled in the art. Reaction with MX (x is a halogen, such as bromo) under Suzuki coupling conditions known in the art provides compounds of structure b. Compounds of structure b can be used to prepare compounds of structure (I), as described below.

[0244] Reaction Scheme II [ka] Reaction Scheme II illustrates an alternative method for the preparation of intermediates useful in the preparation of compounds of structure (I). 1 , L, L 1 , L 2 and M is as defined above, and R 2 and R 3 Referring to Reaction Scheme II, where L is as defined above or a protected variant thereof, a compound of structure c, which can be purchased or prepared by well-known techniques, is reacted with M-G' to produce a compound of structure d, where G and G' represent functional groups with complementary reactivity (i.e., functional groups that react to form a covalent bond). G' can be a side chain to M or part of the structural backbone of M. a The reaction shown above is L a is an intermediate selected to convert L to L. G and G' can be any number of functional groups as described herein, such as an alkyne and azide, respectively, an amine and activated ester, respectively, or an amine and isothiocyanate, respectively.

[0245] Compounds of structure (I) can be synthesized to give the following structure (e): [ka] (e) wherein each L is independently an optional linker. It can be prepared from one of structures b or d by reaction with a phosphoramidite compound having the formula: DNA synthesis methods are well known in the art. Briefly, two alcohol groups, such as R in intermediates b or d above, are 2 and R 3 are functionalized with a dimethoxytrityl (DMT) group and a 2-cyanoethyl-N,N-diisopropylamino phosphoramidite group, respectively. The phosphoramidite group is usually attached to an alcohol group in the presence of an activating agent such as tetrazole, followed by oxidation of the phosphorus atom with iodine. The dimethoxytrityl group can be removed with an acid (e.g., chloroacetic acid) to expose a free alcohol, which can be reacted with the phosphoramidite group. The 2-cyanoethyl group can be removed after oligomerization by treatment with aqueous ammonia.

[0246] The preparation of phosphoramidites used in oligomerization methods is also well known in the art. For example, primary alcohols (e.g., R 3 ) can be protected as a DMT group by reaction with DMT-Cl. A secondary alcohol (e.g., R 2 ) is functionalized as a phosphoramidite by reaction with a suitable reagent such as 2-cyanoethyl N,N-diisopropylchlorophosphoramidite. Methods for preparing phosphoramidites and their oligomerization are well known in the art. Compounds of structure (I) are prepared by oligomerization of intermediates b or d and e according to the well-known phosphoramidite chemistry described above. The desired number of repeating n units is incorporated into the molecule by repeating the phosphoramidite coupling a desired number of times. In certain embodiments, compounds of structure (I) are prepared from one or more of the following phosphoramidites (e): [ka]

[0247] In exemplary embodiments, the G moiety can be selected from any of the Q moieties described herein, including specific examples thereof provided in Table 1. In some embodiments, G, at each occurrence independently, comprises a moiety suitable for reactions including the following: copper catalyzed reaction of azides with alkynes to form triazoles (Huisgen 1,3-dipolar cycloaddition), reactions of dienes with dienophiles (Diels-Alder), strain-promoted alkyne-nitrone cycloaddition, reactions of strained alkenes with azides, tetrazines, or tetrazoles, [3+2] cycloaddition of alkenes with azides, inverse demand Diels-Alder of alkenes with tetrazines, photoreactions of alkenes with tetrazoles, and various substitution reactions such as replacement of leaving groups by nucleophilic attack on an electrophilic atom.

[0248] In some embodiments, G, at each occurrence, is independently a moiety that contains 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 functional group.

[0249] In other embodiments, G, independently at each occurrence, comprises an alkyne or azide group. In other embodiments, G, independently at each occurrence, comprises an amino, isothiocyanate, or activated ester group. In different embodiments, G, independently at each occurrence, comprises a reactive group that can form a functional group that includes an alkene, ester, amide, thioester, disulfide, carbocyclic group, heterocyclic group, or heteroaryl group upon reaction with a complementary reactive group. For example, in some embodiments, heteroaryl is triazolyl.

[0250] In some embodiments, compounds of structure (I) are prepared by oligomerization of intermediates b or d and e according to phosphoramidite chemistry, so that multiple different linking groups (e.g., "L groups") can be introduced that have multiple different release mechanisms (e.g., by esterase, cathepsin B, in vivo hydrolysis, etc.) as described herein and are not cleavable under physiological conditions. Furthermore, these compounds can be modified to include one or more M moieties, which are the same or different. Thus, compounds of structure (I) can be customized or "programmed" so that, for example, the M moiety is "released" or separated from the remainder of the molecule to induce a pharmacological effect under specific physiological conditions. Thus, compounds of structure (I) are particularly useful as targeted therapeutic agents that can be administered systemically with minimal toxic side effects.

[0251] Introduction of the desired number of repeat units and desired linkers ("L groups") into the molecule is achieved by repeating the phosphoramidite coupling the desired number of times and by selecting an appropriate phosphoramidite monomer compound, such as the compound of structure (e) provided above.

[0252] A representative, non-limiting example of a compound of structure (I) having a variety of different L and M groups is structure (f): [ka] (f) is represented below by the compound Here, M a ~M d Each represents a different M molecule, where the linker contains functional groups (from left to right, respectively: tetrazole, oxime, disulfide, and ester) that have different cleavage methods (oxime - acid hydrolysis; disulfide - reduction by TCEP (in vitro) or glutathione (in vivo); ester - esterase or base hydrolysis) or are not cleavable (triazole).

[0253] The compounds of structure (I) can include multiple biologically active moieties (M groups), e.g., M groups can be selected based on complimentary or synergistic therapeutic strategies. Additionally, embodiments of the present disclosure provide combinations of therapeutic agents, targeting moieties and dye moieties (e.g., fluorophores) that can be used for simultaneous targeting, treatment and detection. The ease of coupling the polymer-drug constructs to targeting agents such as antibodies, antibody fragments, proteins, sugar moieties, receptors, receptor ligands, prions, aptamers, enzymes, or other agents of clinical interest makes them useful for a wide range of applications of interest (e.g., surface chemistry, assay development, etc.). Methods for preparing compounds of structure (II), as well as methods for using automated DNA synthesis techniques to prepare the compounds, are described in PCT Publication Nos. 2015 / 027176, WO2016 / 138461, and WO2016 / 183185, all of which are incorporated by reference in their entireties. The following examples are offered by way of illustration and not by way of limitation. EXAMPLES

[0254] General method Mass spectral analysis was performed on a Waters / Micromass Quattro micro MS / system MS (MS mode only) using MassLynx 4.1 acquisition software. The mobile phase used for LC / MS was 100 mM 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), 8.6 mM triethylamine (TEA), pH 8. Phosphoramidite and precursor molecules were also analyzed using a Waters Acquity UHPLC system equipped with a 2.1 mm x 50 mm Acquity BEH-C18 column, held at 45 °C, using an acetonitrile / water mobile phase gradient. Molecular weights of monomer intermediates were obtained on a Waters / Micromass Quattro micro MS / system MS (MS mode only) using tropylium cation injection enhanced ionization. Excitation and emission profile experiments were recorded on a Cary Eclipse spectrophotometer. All reactions were carried out in oven-dried glassware under a nitrogen atmosphere unless otherwise noted. Commercial DNA synthesis reagents were purchased from Glen Research (Sterling, VA). Anhydrous pyridine, toluene, dichloromethane, diisopropylethylamine, triethylamine, acetic acid, pyridine and THF were purchased from Aldrich. All other chemicals were purchased from Aldrich or TCI and used as received without further purification.

[0255] Example 1 NHS activation [ka]

[0256] NHS-activated M moieties are synthesized using standard coupling conditions: the carboxy-containing M moiety is dissolved in dichloromethane, and N,N'-dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide (NHS) are added to the mixture. The final product is then purified as necessary and used in the next synthetic step. Alternatively, the M moiety can be modified to contain a carboxy group, for example, using the synthetic strategy shown in Example 3 below.

[0257] Example 2 Monomer synthesis [ka]

[0258] NHS-activated M is reacted with 2-aminopropane-1,3-diol followed by the addition of a trityl protecting group to give a trityl-protected intermediate. The trityl-protected intermediate is then reacted with 3-((chloro(diisopropylamino)phosphanyl)oxy)propanenitrile to give the final phosphoramidite product. The final phosphoramidite product is then used in automated DNA synthesis to incorporate a moiety containing M (e.g., as a representative biologically active or dye moiety) into an embodiment of the compound of structure (I).

[0259] Example 3 Synthesis of M-PEG-Azide [ka]

[0260] M-PEG-azide is synthesized according to the reaction sequence shown above. 2-(2-(2-azidoethoxy)ethoxy)ethan-1-amine is reacted with dihydrofuran-2,5-dione to give the intermediate 4-((2-(2-(2-azidoethoxy)ethoxy)ethyl)amino)-4-oxobutanoic acid. This intermediate is reacted with perfluorophenol to give 4-((2-(2-(2-azidoethoxy)ethoxy)ethyl)amino)-4-oxobutanoate, which is coupled to M amine to give the desired product, M-PEG-azide. The presence of the desired product is confirmed by LC-MS.

[0261] Example 4 Post-polymerization modification 1 [ka]

[0262] As shown in the reaction sequence above, an exemplary compound of structure (II) bearing three amine functional side chains is coupled with an NHS-activated M moiety (Note - for clarity, not all structural features of the compound of structure (II) are depicted). This reaction is carried out in borate buffered H2SO4 containing magnesium chloride. 2 O / DMSO mixture (1:3) is used. This reaction successfully appends the M moiety to each of the three amine functional groups, giving a representative compound of structure (I) as identified by LC-MS.

[0263] Example 5 Post-polymerization modification 2 [ka]

[0264] An exemplary compound of structure (II) having three alkynyl functional side chains is linked to M-PEG-azide. The reaction conditions are: CuSO 4, tris(3-hydroxypropyltriazolylmethyl)amine (THPTA) and sodium ascorbate. The reaction is carried out in an aqueous phosphate buffer containing 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. a represents a heteroalkylene linker.

[0265] Example 6 Activation and antibody conjugation [ka]

[0266] The thiol protecting group of a representative compound of structure (I) is removed using standard reduction conditions (i.e., TCEP) and the deprotected thiol is functionalized with 1,1'-(ethane-1,2-diyl)bis(1H-pyrrole-2,5-dione (bismaleimidoethane or "BMOE") to give 6-2. In parallel, UCHT-1 antibody is treated with TCEP to reduce the disulfide bond. The reduced antibody is reacted with 6-2 (1.5 g) at a polymer to antibody molar ratio of 5:1.

[0267] Example 7 VAL-CIT-PABC(VCP) phosphoramidite monomer synthesis [ka]

[0268] 4-Nitrophenol activated Val-Cit-PABC carbonate is reacted with 3-(3-aminopropoxy)propane-1,2-diol (step 1), followed by addition of a trityl protecting group to give a trityl protected intermediate (step 2). The trityl protected intermediate is then reacted with 3-((chloro(diisopropylamino)phosphanyl)oxy)propanenitrile to give the final phosphoramidite product. The final phosphoramidite product can then be used in synthesis to give a compound of structure (I).

[0269] Example 8 Pyridyl disulfide phosphoramidite monomer synthesis [ka]

[0270] The N-hydroxysuccinimide activated pyridyl disulfide is reacted with 3-(3-aminopropoxy)propane-1,2-diol followed by addition of a trityl protecting group to give a trityl protected intermediate. The trityl protected intermediate is then reacted with 3-((chloro(diisopropylamino)phosphaneyl)oxy)propanenitrile to give the final phosphoramidite product. The final phosphoramidite product can then be used in synthesis to give a compound of structure (I).

[0271] Example 9 Ethylamino disulfide phosphoramidite monomer synthesis [ka]

[0272] The trityl-protected pyridyl disulfide from Example 8 is reacted with cysteamine, followed by the addition of an Fmoc protecting group to give a protected ethylamino disulfide intermediate. This intermediate is then reacted with 3-((chloro(diisopropylamino)phosphaneyl)oxy)propanenitrile to give the final phosphoramidite product. The final phosphoramidite product can then be used in synthesis to give a compound of structure (I).

[0273] Example 10 N-Hydroxyphthalimide phosphoramidite monomer synthesis [ka]

[0274] N-hydroxyphthalimide is reacted with (2,2-dimethyl-1,3-dioxolan-4-yl)methanol under Mitsunobu conditions followed by deprotection under acidic conditions to give a diol intermediate. The diol intermediate is then reacted with DMTr-Cl and pyridine to protect the primary alcohol as the trityl derivative. Subsequent reaction with 3-((chloro(diisopropylamino)phosphaneyl)oxy)propanenitrile gives the final phosphoramidite product. The final phosphoramidite product can then be used in synthesis to give compounds of structure (I).

[0275] Example 11 Synthesis of Representative Compounds of Structure (II) (Synthesis 1) [ka]

[0276] The Val-Cit-PABC phosphoramidite monomer described in Example 7 is reacted under appropriate conditions to give an Fmoc-protected polymer which, after a subsequent base-promoted deprotection step, for example with piperidine in DMF, provides a compound of structure (II). The amine functionality can be linked to an M moiety, for example, as described in Example 4 above (for clarity, not all structural features of the compound of structure (II) are depicted).

[0277] Example 12 Synthesis of Representative Compounds of Structure (II) (Synthesis 2) [ka]

[0278] The pyridyl disulfide phosphoramidite monomer described in Example 8 is reacted under appropriate conditions to give a pyridyl disulfide monomer. Reduction of this polymer with, for example, TCEP, cleaves the disulfide, leaving a sulfhydryl group that can be used for post-synthetic introduction of an M moiety, for example, through reaction with another sulfhydryl group (-SH) or a maleimide group (for clarity, not all structural features of the compound of structure (II) are depicted).

[0279] Example 13 Synthesis of Representative Compounds of Structure (II) (Synthesis 3) [ka]

[0280] The ethylamino disulfide phosphoramidite monomer described in Example 9 is reacted under appropriate conditions to give an N-Fmoc protected polymer which, after a subsequent base-promoted deprotection step, for example with piperidine in DMF, provides a compound of the invention containing an ethylamine functionalized disulfide. The amine functionality can be linked to an M moiety, for example, as described in Example 4 above (for clarity, not all structural features of the compound of structure (II) are depicted).

[0281] Example 14 Synthesis of Representative Compounds of Structure (II) (Synthesis 4) [ka]

[0282] The N-hydroxyphthalimide phosphoramidite monomers described in Example 10 are reacted under appropriate conditions to provide a phthalimide polymer derivative which reacts with hydrazine to form an alkoxyamine functional group. The alkoxyamine is reacted with a complementary group, such as an aldehyde or ketone, to form an oxime linker to the M moiety (for clarity, not all structural features of the compound of structure (II) are depicted).

[0283] Example 15 Exemplary Synthesis of Polymers of Structure (I) [ka]

[0284] DNA synthesis methodology can be applied to construct compounds of structure (I). Monomers (e.g., phosphoramidite monomers) can be purchased commercially (e.g., from ChemGenes Corporation, Wilmington Mass.) or can be synthesized using methods described herein (see, e.g., Examples 2 and 7-10). Introduction of the M moiety is accomplished either during the DNA synthesis step by including the M moiety as part of the monomer, or during a post-polymerization modification step (e.g., as described in Examples 4-6 and 11-14). An exemplary DNA synthesis scheme is shown below.

[0285] A typical DNA synthesis cycle [ka]

[0286] Oligomerization is usually initiated by removing a protecting group (e.g., dimethoxytrityl group, DMTr) to reveal a free -OH (hydroxyl) group (step 1, detritylation). In a subsequent coupling step, a phosphoramidite monomer is introduced which reacts with the free OH group to form a new covalent bond with phosphorus with concomitant loss of a diisopropylamine group (step 2, coupling). The resulting phosphite triester (e.g., I 2and pyridine) to the more stable phosphate ester (step 3, oxidation), and a capping step renders the remaining free OH group unreactive (step 4, capping). The new product, the phosphate oligomer, contains a DMTr-protected OH group that can be deprotected to restart the synthesis cycle, thus allowing another phosphoramidite monomer to be added to the oligomer.

[0287] Customization is accomplished in step 2 by the selection of phosphoramidite monomers. The nature of L, M, and G are selected such that the desired compound of structure (I) is synthesized. M and G may be absent to incorporate desired spacing between the M and / or G moieties. One of skill in the art can select multiple monomer types and simultaneously vary the linker groups to arrive at compounds of the invention containing multiple therapeutic agents and / or other moieties (e.g., dyes). All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referred to in this specification, including U.S. Provisional Patent Application Nos. 62 / 832,723, filed April 11, 2019, and 62 / 877,144, filed July 22, 2019, are hereby incorporated by reference in their entirety to the extent not inconsistent herewith.

[0288] 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 not limited except as by the appended claims.

Claims

1. A compound having the following structure (I): 【Chemistry 1】 (I) or a stereoisomer, pharma- ceutically acceptable salt, or tautomer thereof, wherein M is, independently at each occurrence, 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 moiety, provided that at least one occurrence of M is not a fluorescent dye; L is any linker, provided that at least one occurrence of L contains more than four carbons or at least one occurrence of L contains oxygen; L 1 and L 2 is, independently at each occurrence, an optional alkylene linker; R 1 is independently at each occurrence H, alkyl or alkoxy; R 2 and R 3 are each independently absent, or H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, dT, -OP(=R a ) (R b ) R c , Q or a protected form thereof, or L′; R 4 is expressed independently for each occurrence as O - , S - , OZ, SZ, or N(R 6 ) 2 where Z is a cation and each R 6 is independently H or alkyl; R 5 is independently at each occurrence oxo, thioxo, or absent; R a is O or S, R b OH, SH, O - , S - , OR d or S.R. d and R c OH, SH, O - , S - , OR d , O.L.', S.R. d , OdT, alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counterion, Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety; L' is, independently at each occurrence, 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 moiety, 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 n is an integer of 1 or more.

2. A compound having the following structure (I): 【Chemistry 2】 (I) (In the formula, M is, independently at each occurrence, 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 moiety, provided that at least one occurrence of M is not a fluorescent dye; L is an optional linker; L 1 and L 2 is, independently at each occurrence, an optional alkylene linker; R 1 is independently at each occurrence H, alkyl or alkoxy; R 2 and R 3 are each independently absent, or H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, dT, -OP(=R a ) (R b ) R c , Q or a protected form thereof, or L′; R 4 is expressed independently for each occurrence as O - , S - , OZ, SZ, or N(R 6 ) 2 where Z is a cation and each R 6 is independently H or alkyl; R 5 is independently at each occurrence oxo, thioxo, or absent; R a is O or S, R b OH, SH, O - , S - , OR d or S.R. d and R c OH, SH, O - , S - , OR d , O.L.', S.R. d , OdT, alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counterion, Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety; L' is, independently at each occurrence, 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 moiety, 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); n is an integer of 1 or more, However, the following structure 【Chemistry 3】 (In the formula, N′ has the following structure: 【Chemistry 4】 having I′ has the following structure: 【Chemistry 5】 having F has the following structure: 【Chemistry 6】 (having or a stereoisomer, pharma- ceutically acceptable salt, or tautomer thereof, provided that the compound does not have one of:

3. Appearing L 1 3. The compound of claim 1, wherein at least one of is an alkylene linker.

4. The following structure (IA): 【Chemistry 7】 (IA) (In the formula, a and b are, independently at each occurrence, an integer from 0 to 10. The compound according to any one of claims 1 to 3, having the formula:

5. 5. The compound of claim 4, wherein a and b are both integers from 0 to 3, for each occurrence.

6. 6. The compound according to claim 4, wherein at each occurrence, a is 0 and b is 1.

7. 6. A compound according to claim 4 or 5, wherein for each occurrence, a is 1 and b is 0.

8. The compound of any one of claims 1 to 7, wherein at least one occurrence of L comprises a physiologically cleavable linker.

9. 9. The compound of any one of claims 1 to 8, wherein 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, a ketone, a diol, a cyano, a nitro, or a combination thereof.

10. 10. The compound of claim 9, wherein at least one occurrence of L comprises an amino acid sequence recognized by a sortase enzyme.

11. 11. The compound according to claim 10, wherein the amino acid sequence is Leu-Pro-X-Thr-Gly, where X is any amino acid residue.

12. The compound of any one of claims 1 to 11, wherein at least one occurrence of L is a linker containing three or more carbons.

13. A compound according to any one of claims 1 to 12, wherein at least one occurrence of L is a linker containing at least one nitrogen.

14. At least one occurrence of L has the structure: 【Chemistry 8】 The compound according to any one of claims 1 to 13, comprising one of:

15. 15. The compound of any one of claims 1 to 14, wherein L, at each occurrence, 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.

16. The compound of any one of claims 1 to 15, wherein L, at each occurrence, is a linker containing 3 or more carbons.

17. The compound of any one of claims 1 to 16, wherein L, at each occurrence, is a linker containing at least one nitrogen.

18. Each occurrence of L has the structure: 【Chemistry 9】 The compound according to any one of claims 1 to 17, comprising one of:

19. At least one occurrence of L has the structure: 【Chemistry 10】 The compound according to any one of claims 1 to 18, comprising:

20. 20. The compound of any one of claims 1 to 19, wherein at least one occurrence of L comprises one or more amino acid residues.

21. 21. The compound of claim 20, wherein the amino acid residue is valine.

22. At least one occurrence of L has the structure: 【Chemistry 11】 The compound according to any one of claims 1 to 21, comprising one of:

23. Each occurrence of L has the structure: 【Chemistry 12】 The compound according to any one of claims 1 to 22, comprising:

24. 24. The compound of any one of claims 1 to 23, wherein L, at each occurrence, comprises one or more amino acid residues.

25. 25. The compound of claim 24, wherein the amino acid residue is valine.

26. Each occurrence of L has the structure: 【Chemistry 13】 The compound according to any one of claims 1 to 25, comprising one of:

27. At least one occurrence of L has the structure: 【Chemistry 14】 The compound according to any one of claims 1 to 26, having one of the following:

28. 27. The compound of any one of claims 1 to 26, wherein at least one occurrence of L comprises a linker that is not cleavable under physiological conditions.

29. 29. The compound of any one of claims 1 to 26 or 28, wherein at least one occurrence of L contains a thioether bond.

30. At least one occurrence of L has the structure: 【Chemistry 15】 30. The compound according to any one of claims 1 to 26, 28 or 29, comprising:

31. At least one occurrence of L has the structure: 【Chemistry 16】 30. The compound according to any one of claims 1 to 26, 28 or 29, comprising one of:

32. 32. The compound of any one of claims 1 to 26 or 28 to 31, wherein L, at each occurrence, comprises a linker that is not cleavable under physiological conditions.

33. 33. The compound of any one of claims 1 to 26 or 28 to 32, wherein L, at each occurrence, comprises a thioether bond.

34. Each occurrence of L has the structure: 【Chemistry 17】 The compound according to any one of claims 1 to 26 or 28 to 33, comprising:

35. Each occurrence of L has the structure: 【Chemistry 18】 The compound according to any one of claims 1 to 26 or 28 to 33, comprising one of:

36. R 4 However, each occurrence is independent, OH, O - OR d The compound according to any one of claims 1 to 35,

37. R 5 The compound according to any one of claims 1 to 36, wherein each occurrence of is oxo.

38. R 1 A compound according to any one of claims 1 to 37, wherein each occurrence of is H.

39. R 2 and R 3 are each independently H, OH, or -OP(=R a ) (R b ) R c The compound according to any one of claims 1 to 38,

40. R 2 is H, and R 3 -OP (=R a ) (R b ) R c , Q, or a linker comprising a covalent bond to Q.

41. R 3 But -OP(=R a ) (R b ) R c or L'.

42. R c The compound of claim 41, wherein is OL'.

43. 43. The compound of claim 41 or 42, wherein L' is a targeting moiety or a linker to a targeting moiety.

44. 44. The compound of claim 43, wherein L' is a linker to the targeting moiety, the linker comprising an alkylene oxide or a phosphodiester moiety, or a combination thereof.

45. L' has the following structure: 【Chemistry 19】 (In the formula, m″ and n″ are independently integers from 1 to 10; R e is H, an electron pair or a counterion, L" is a targeting moiety or a linking group to a targeting moiety.

45. The compound of claim 44, having the formula:

46. 46. ​​The compound of claim 45, wherein n" is 6.

47. The compound of any one of claims 1 to 46, wherein the targeting moiety is an antibody or a cell surface receptor antagonist.

48. 48. The compound of claim 47, 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, a folate or a MET inhibitor.

49. 48. The compound of claim 47, wherein the targeting moiety is a monoclonal antibody.

50. Monoclonal antibodies include 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 loxivetomab. , mepolizumab, natalizumab, obiltoxaximab, ocrelizumab, omalizumab, palivizumab, ranibizumab, raxibacumab, reslizumab, ramucirumab (Rmab), rovelizumab, ruplizumab, sarilumab, secukinumab, tildrakizumab, thiomab, tocilizumab, ustekinumab, vedolizumab, abrilumab, actoxumab, aducanumab, afacevicumab, afelimomab, anifrolumab, anrukinzumab (IMA-638), acelizumab, atorlimumab, bapineuzumab, BCD-100, vertilimumab besilesomab, biciromab, bimagrumab, bimekizumab, virutamimab, bleselumab, brosozumab, bococizumab, brazikumab, briakinumab, brolucizumab, carlumab, carotuximab, cedelizumab, clazakizumab, crenoliximab, concizumab, cosfrobiximab, CR6261, crenezumab, crizanlizumab, clotidumab, depatuximab, mafodotin, dellotuximab biotin, desamizumab, dilidabumab, domagurozumab, dusigitumab, ecloneximab, edovacomab, efalizumab , efungumab, eldelumab, elezanumab, enokizumab, eptinezumab, elizumab, etrolizumab, evinacumab, exbivirumab, fanolesomab, faralimomab, faricimab, fasinumab, felvizumab, fezakinumab, framvotumab, fretikumab, flotetuzumab, fontolizumab, foravirumab, frobocimab, fullanumab, gantenerumab, gavilimomab, gevokizumab, gimsilumab, gomilikimab, goslanemab, ianalumab, inlacumab, inolimomab, Iomab-B, keliximab,Lampalizumab, Landgrozumab, Ralcaviximab, Lebrikizumab, Lenvervimab, Lerdelimumab, Letolizumab, Ribivirumab, Ligelizumab, Roderucizumab, Lulizumab pegol, Marstacimab, Mavrilimumab, Metelimumab, Mirikizumab, Motavizumab, Muromonab CD3, Nebacumab, Nemori izumab, NEOD001, nirsevimab, odulimomab, orendalizumab, olokizumab, OMS721, opicinumab, olticumab, otelixizumab, otilimab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, panobacumab, pascolizumab, pateclizumab, PDR001, perakizumab, pexelizumab, praxam Curumab, prosalizumab, ponezumab, polgabiximab, prasinezumab, priliximab, PRO140, kirusumab, rafivirumab, ralpancizumab, ranevetomab, ravagalimab, ravulizumab, refanezumab, regavirumab, relatorimab, linukumab, risankizumab, loredumab, romosozumab, rontalizumab, SA23 7. Satralizumab, sevirumab, SHP647, sifalimumab, simtuzumab, siplizumab, sirukumab, solanezumab, sonepcizumab, spartalizumab, stamulumab, sulesomab, sputabumab, stimulimab, subizumab, sublatoxumab, tadocizumab, talizumab, tamtubetomab, tanezumab, tefibazumab, terimomab Telimomab aritox, Teneliximab, Teplizumab, Teprotumumab, Tezepelumab, Tiburizumab, Toralizumab, Tralokinumab, Trevoglumab, Tubilumab, Ulocuplumab, Urtoxazumab, Valisacumab, Vepalimomab, Vesencumab, Visilizumab, Bovalilizumab, Zolimomab 50. The compound of claim 49, which is selected from the group consisting of trastuzumab, gemtuzumab, brentuximab, borsetuzumab, lorvotuzumab, cantuzumab, bivatuzumab, or inotuzumab, or vadastuximab.

51. R 2 Or R 3 has the following structure: 【Chemistry 20】 The compound according to any one of claims 1 to 50, having one of the following formulas:

52. R 3 has the following structure: 【Chemistry 21】 The compound according to any one of claims 1 to 42, having the formula:

53. R 2 Or R 3 has the following structure: 【Chemical 22】 The compound according to any one of claims 1 to 42, comprising one of:

54. R 3 has the following structure: 【Chemistry 23】 The compound according to any one of claims 1 to 42, comprising one of:

55. The compound according to any one of claims 1 to 54, wherein n is an integer from 1 to 100.

56. 56. The compound according to any one of claims 1 to 55, wherein n is an integer from 1 to 10.

57. 57. The compound of any one of claims 1 to 56, wherein at least one occurrence of M is an antitumor agent, an enediyne antitumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and an EGFR inhibitor or an alkylating agent.

58. 58. The compound of any one of claims 1 to 57, wherein at least one occurrence of M is an antitumor agent, an enediyne antitumor antibiotic, a maytansinoid, a topoisomerase inhibitor, or an alkylating agent.

59. 59. The compound of any one of claims 1 to 58, wherein M is, independently at each occurrence, an antitumor agent, an enediyne antitumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and an EGFR inhibitor or an alkylating agent.

60. 59. The compound of any one of claims 1 to 58, wherein M is, independently at each occurrence, an antitumor agent, an enediyne antitumor antibiotic, a maytansinoid, a topoisomerase inhibitor, or an alkylating agent.

61. 61. The compound of any one of claims 1 to 60, wherein at least one occurrence of M is selected from the group consisting of auristatin F, monomethylauristatin F, monomethylauristatin 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, siratecan, cositecan, exatecan, rutotecan, gimatecan, belotecan, and rubitecan.

62. At least one occurrence of M has the structure: 【Chemistry 24-1】 【Chemistry 24-2】 The compound according to any one of claims 1 to 61, having one of the following:

63. Each occurrence of M has the following structure: 【Chemistry 25-1】 【Chemistry 25-2】 The compound according to any one of claims 1 to 62, having one of the following:

64. A compound selected from Table 2.

65. 65. A composition comprising a compound according to any one of claims 1 to 64, and a pharma- ceutically acceptable carrier.

66. 66. A method of treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 64, or a composition of claim 65, wherein at least one M is a biologically active moiety effective to treat the disease.

67. 67. The method of claim 66, wherein each M is a biologically active moiety effective to treat a disease.

68. 68. The method of any one of claims 66 or 67, wherein the disease is cancer.

69. 69. The method of claim 68, wherein 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, neoplasms, urothelial carcinoma, ALL, CLL, glioblastoma, Hodgkin's lymphoma, lymphoma, mesothelioma, non-small cell lung cancer, recurrent head and neck cancer, or a combination thereof.

70. 70. The method of any one of claims 66-69, further comprising the step of administering an additional therapeutic agent selected from the group consisting of an anti-tumor agent, an enediyne anti-tumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and an EGFR inhibitor or an alkylating agent, and combinations thereof.

71. 71. The method of any one of claims 66-70, further comprising the step of administering an additional therapeutic agent selected from the group consisting of an anti-tumor agent, an enediyne anti-tumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and an EGFR inhibitor or an alkylating agent, and combinations thereof.

72. 72. The method of claim 71, wherein the additional therapeutic agent comprises auristatin F, monomethylauristatin F, monomethylauristatin 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, siratecan, cositecan, exatecan, lutotecan, gimatecan, belotecan, and rubitecan.

73. 68. The method of any one of claims 66 or 67, wherein a biologically active portion of the disease causes protein degradation.

74. 74. The method of claim 73, wherein the protein is an amyloid or tau protein.

75. 75. The method of any one of claims 66, 67, 73, or 74, wherein the disease is amyloidosis or Alzheimer's disease.

76. 75. The method of any one of claims 66, 67, 73, or 74, wherein the disease is prostate cancer, pancreatic cancer, or breast cancer.

77. 74. The method of any one of claims 65, 66, 72, or 73, wherein the disease is an oncological, cardiovascular, renal, metabolic, or respiratory disease.

78. 75. The method of any one of claims 66, 67, 73, or 74, wherein the disease is a pulmonary disease or a central nervous system disease.

79. 75. The method of any one of claims 66, 67, 73, or 74, wherein the disease is metastatic castration-resistant prostate cancer or metastatic breast cancer.

80. The structure: 【Chemistry 26】 (In the formula, R a and R b are each independently H, an OH protecting group, or -P(R d ) R e and R c is H or an amine protecting group, R d and R e are each independently cyanoalkyl or -N(R f ) R g where R f and R g are each independently C 1 -C 6 is alkyl, L' a and L' b each independently represents a direct bond or CH 2 and n' and m' are each independently an integer from 1 to 6. A compound having the formula:

81. The structure: 【Chemical 27】 (In the formula, R a and R b are each independently H, an OH protecting group, or -P(R d ) R e and R d and R e are each independently cyanoalkyl or -N(R f ) R g where R f and R g are each independently C 1 -C 6 is alkyl, L' a and L' b each independently represents a direct bond or CH 2 and n', m', and P' are each independently an integer from 1 to 6. A compound having the formula:

82. The structure: 【Chemistry 28】 (In the formula, R a and R b are each independently H, an OH protecting group, or -P(R d ) R e and R c is H or an amine protecting group, R d and R e are each independently cyanoalkyl or -N(R f ) R g where R f and R g are each independently C 1 -C 6 is alkyl, L' a and L' b each independently represents a direct bond or CH 2 and n', m', p', and q' are each independently an integer of 1 to 6. A compound having the formula:

83. The structure: 【Chemical Formula 29】 (In the formula, R a and R b are each independently H, an OH protecting group, or -P(R d ) R e and R d and R e are each independently cyanoalkyl or -N(R f ) R g where R f and R g are each independently C 1 -C 6 is alkyl, L' a and L' b each independently represents a direct bond or CH 2 and n' is an integer from 1 to 6. A compound having the formula:

84. The structure: 【Chemistry 30】 (In the formula, Fmoc has the following structure: 【Chemistry 31】 having DMTr has the following structure: 【Chemistry 32】 (having A compound having one of the following:

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