Programmable polymeric drugs

Abstract

Compounds useful as biologically active compounds are disclosed. The compounds have the following structure (I): # imgabs0 # or a stereoisomer, tautomer or salt thereof, wherein R1, R2, R3, R4, R5, La, Lb, L1, L2, L3, M, m and n are as defined herein. Methods related to their preparation and uses of such compounds are also provided.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of April 10, 2020, an application number of 202080040295.9, and an invention title of "Programmable Polymeric Drugs". Background Technical Field

[0003] Embodiments of the present disclosure generally relate to dimeric and polymeric bioactive compounds having a spacer group, as well as methods for their preparation and uses in various therapeutic methods. Background Art

[0004] Unlike, for example, chemotherapy, targeted drug conjugates deliver drugs to target cells with little or no off-target activity. Generally, a targeted drug conjugate comprises a targeting molecule linked to a bioactive payload or drug. By combining the unique targeting ability with the therapeutic efficacy of a bioactive drug, the conjugate can deliver the drug only to the intended target and minimize potential side effects.

[0005] Antibody-drug conjugates (ADCs) are a class of targeted drug conjugates of particular interest, for example, for cancer treatment. An ADC for cancer treatment combines the targeting properties of a monoclonal antibody with the cancer-killing ability of a cytotoxic agent to provide a therapeutic agent with several advantages over other chemotherapeutic agents. However, challenges associated with the complexity of the ADC structure, particularly the chemical linker between the antibody and the drug, have presented significant difficulties in the development of new and effective therapeutic agents. Although the first ADC was approved in 2001, it took nearly a decade for the next ADC to be approved. As of now, only and are on the market globally ( approved only in China).

[0006] Accordingly, there is a need in the art for effective targeted drug conjugates with a high therapeutic index. The present disclosure meets this need and provides further related advantages. Summary of the Invention

[0007] Briefly, embodiments of the present disclosure generally relate to compounds that can be used to deliver a bioactive moiety in vivo. Specific examples include targeted drug conjugates that optionally comprise a fluorescent and / or colored dye capable of selective delivery to a target, such as a tumor cell. Methods and reagents for preparing such molecules and their use for providing a therapeutic treatment to a patient in need thereof are also described.

[0008] Embodiments of the compounds disclosed herein include one or more bioactive moieties that are linked by a linker (e.g., "L a”and / or“L b ”) are covalently linked to a common backbone. Additionally, certain embodiments described herein provide compounds having multiple bioactive moieties within the same compound and may further optionally include targeting moieties. The bioactive moieties can be the same or different, thus allowing for single-agent or combination therapy by administering a single compound.

[0009] In one embodiment, a compound having the following structure (I) or a stereoisomer, tautomer, or salt thereof is provided:

[0010]

[0011] Wherein R 1 、R 2 、R 3 、R 4 、R 5 、L a 、L b 、L 1 、L 2 、L 3 、M, m, and n are as defined herein. The compounds of structure (I) can be used in a variety of applications, including as therapeutic agents in various treatment methods.

[0012] In another embodiment, a composition is provided that comprises a compound of structure (I) and a pharmaceutically acceptable carrier.

[0013] In another embodiment, a method of treating a disease is provided that comprises administering to a subject in need thereof a therapeutically effective amount of a compound of structure (I) or a composition comprising a compound of structure (I), wherein each M is independently a bioactive moiety that is effective in treating the disease.

[0014] These and other aspects of the present disclosure will be apparent after reference to the following detailed description. Detailed Description

[0015] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments of the present disclosure. However, one skilled in the art will understand that the present disclosure may be practiced without these details.

[0016] Unless the context otherwise requires, throughout the specification and claims, the word “comprise” and its variations, such as “comprises” and “comprising,” are to be construed in an open, inclusive sense, i.e., “including, but not limited to.”

[0017] References to "one embodiment" or "an embodiment" in this specification mean that the particular features, structures, or characteristics described in connection with the embodiment are included in at least one embodiment of the present disclosure. Thus, the phrases "in one embodiment" or "in an embodiment" that appear in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0018] "Amino" means -NH 2 group.

[0019] "Carboxyl" means -CO 2 H group.

[0020] "Cyano" means -CN group.

[0021] "Formyl" means -C(=O)H group.

[0022] "Hydroxy" or "hydroxyl" means -OH group.

[0023] "Imino" means =NH group.

[0024] "Nitro" means -NO 2 group.

[0025] "Oxo" means =O group.

[0026] "Mercapto", "thiol", or "thio" means -SH group.

[0027] "Thioxo" means =S group.

[0028] "Alkyl" means a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing no unsaturation, 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), and which is attached to the remainder of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless specifically stated otherwise in the specification, alkyl is optionally substituted.

[0029] "Alkylene" or "alkylene chain" means a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to the residue group, which consists only of carbon and hydrogen, contains no unsaturation, and has 1 to 12 carbon atoms. For example, methylene, ethylene, propylene, n-butylene, vinylidene, propenylene, n-butenylene, propynylene, n-butynylene, etc. The alkylene chain is connected to the remainder of the molecule by a single bond and to the residue group by a single bond. The connection points of the alkylene chain to the remainder of the molecule and to the residue group can be through one carbon or any two carbons within the chain. Unless specifically stated otherwise in the specification, the alkylene is optionally substituted.

[0030] "Alkenylene" or "alkenylene chain" means a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to the residue group, which consists only of carbon and hydrogen, contains at least one carbon-carbon double bond and has 2 to 12 carbon atoms. For example, vinylidene, propenylene, n-butenylene, etc. The alkenylene chain is connected to the remainder of the molecule by a single bond and to the residue group by a double bond or a single bond. The connection points of the alkenylene chain to the remainder of the molecule and to the residue group can be through one carbon or any two carbons within the chain. Unless specifically stated otherwise in the specification, the alkenylene is optionally substituted.

[0031] "Alkynylene" or "alkynylene chain" means a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to the residue group, which consists only of carbon and hydrogen, contains at least one carbon-carbon triple bond and has 2 to 12 carbon atoms. For example, vinylidene, propenylene, n-butenylene, etc. The alkynylene chain is connected to the remainder of the molecule by a single bond and to the residue group by a double bond or a single bond. The connection points of the alkynylene chain to the remainder of the molecule and to the residue group can be through one carbon or any two carbons within the chain. Unless specifically stated otherwise in the specification, the alkynylene is optionally substituted.

[0032] "Alkyl ether" means any alkyl as defined above, wherein at least one carbon-carbon bond is replaced by a carbon-oxygen-carbon bond. The carbon-oxygen-carbon bond can be at the terminus (as in an alkoxy group), or the carbon-oxygen-carbon bond can be internal (i.e., C-O-C). The alkyl ether includes at least one carbon-oxygen-carbon bond, but can include more than one. For example, polyethylene glycol (PEG) is included within the meaning of alkyl ether. Unless specifically stated otherwise in the specification, the alkyl ether group is optionally substituted. For example, in certain embodiments, the alkyl ether is substituted by an alcohol or -OP(=R a )(R b )R c , where each of R a , R b and R c is as defined for the compounds of structure (I).

[0033] "Alkoxy" represents the formula -OR a group, where R a is an alkyl group as defined above containing 1-12 carbon atoms. Unless specifically stated otherwise in the specification, the alkoxy group is optionally substituted.

[0034] "Alkoxyalkyl ether" represents the formula -OR a R b group, where R a is an alkylene group as defined above containing 1-12 carbon atoms, and R b is an alkyl ether group as defined herein. Unless specifically stated otherwise in the specification, the alkoxyalkyl ether group is optionally substituted, for example by an alcohol or -OP(=R a )(R b )R c where each of R a , R b and R c is defined as for the compounds of structure (I).

[0035] "Heteroalkyl" represents an alkyl group as defined above that contains at least one heteroatom (e.g., Si, N, O, P, or S) within the alkyl or at the end of the alkyl. In certain embodiments, the heteroatom is within the alkyl (i.e., the heteroalkyl contains at least one carbon-[heteroatom] x -carbon bond, where x is 1, 2, or 3). In other embodiments, the heteroatom is at the end of the alkyl and is thus used to connect the alkyl to the rest of the molecule (e.g., M1-H-A), where M1 is part of the molecule, H is the heteroatom, and A is the alkyl). Unless specifically stated otherwise in the specification, the heteroalkyl is optionally substituted. Exemplary heteroalkyls include ethylene oxide (e.g., polyethylene oxide), optionally including a phosphorus-oxygen bond, such as a phosphodiester bond.

[0036] "Heteroalkoxy" represents the formula -OR a group, where R a is a heteroalkyl group as defined above containing 1-12 carbon atoms. Unless specifically stated otherwise in the specification, the heteroalkoxy group is optionally substituted.

[0037] "Heteroalkyl" means an alkyl as defined above that contains at least one heteroatom (e.g., Si, N, O, P, or S) within the alkyl chain or at the terminus of the alkyl chain. In certain embodiments, the heteroatom is within the alkyl chain (i.e., the heteroalkyl contains at least one carbon-[heteroatom]-carbon bond, where x is 1, 2, or 3). In other embodiments, the heteroatom is at the terminus of the alkyl and is thus used to attach the alkyl to the remainder of the molecule (e.g., M1-H-A-M2, where M1 and M2 are portions of the molecule, H is the heteroatom, and A is the alkyl). Unless specifically stated otherwise in the specification, the heteroalkyl is optionally substituted. Exemplary heteroalkyls include ethylene oxide (e.g., polyethylene oxide) and the "C", "HEG", and "PEG 1K" linking groups explained below:

[0038]

[0039] Polymers of the above C-linking group, HEG linking group, and / or PEG 1K linking group are included in different embodiments of the heteroalkyl linking group. In certain embodiments of the PEG 1K linking group, n ranges from 19 - 25, e.g., n is 19, 20, 21, 22, 23, 24, or 25. The polymer can comprise, for example, the following structures:

[0040]

[0041] where x is 0 or an integer greater than 0, e.g., x ranges from 0 - 100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0042] "Heteroalkenyl" is a heteroalkyl as defined above that contains at least one carbon-carbon double bond. Unless specifically stated otherwise in the specification, the heteroalkenyl is optionally substituted.

[0043] "Heteroalkynyl" is a heteroalkyl that contains at least one carbon-carbon triple bond. Unless specifically stated otherwise in the specification, the heteroalkynyl is optionally substituted.

[0044] "Heteroatom" with respect to a "heteroatom linking group" refers to a linking group composed of one or more heteroatoms. Exemplary heteroatom linking groups include single atoms and multiple heteroatoms selected from Si, O, N, P, and S, e.g., a linking group having the formula -P(O - )(=O)O- or -OP(O - )(=O)O- and polymers thereof and combinations thereof.

[0045] "Phosphate" means an -OP(=O)(R a )R b group, where R ais OH, O - or OR c ; and R b is OH, O - , OR c , a thiophosphate group or other phosphate group, where R c is a counterion (e.g., Na + , etc.).

[0046] "Phosphoalkyl" means -OP(=O)(R a )R b group, where R a is OH, O - or OR c ; and R b is -O alkyl, where R c is a counterion (e.g., Na + , etc.). Unless specifically stated otherwise in the specification, the phosphoalkyl is optionally substituted. For example, in certain embodiments, the -O alkyl portion in the phosphoalkyl is optionally substituted by one or more of a hydroxyl group, an amino group, a mercapto group, a phosphate group, a thiophosphate group, a phosphoalkyl group, a thiophosphoalkyl group, a phosphoalkyl ether group, a thiophosphoalkyl ether group, or -OP(=R a )(R b )R c , where each of R a , R b and R c is defined as for the compounds of structure (I).

[0047] "Phosphoalkyl ether" means -OP(=O)(R a )R b group, where R a is OH, O - or OR c ; and R b is -O alkyl ether, where R c is a counterion (e.g., Na + , etc.). Unless specifically stated otherwise in the specification, the phosphoalkyl ether group is optionally substituted. For example, in certain embodiments, the -O alkyl ether portion in the phosphoalkyl ether group is optionally substituted by one or more of a hydroxyl group, an amino group, a mercapto group, a phosphate group, a thiophosphate group, a phosphoalkyl group, a thiophosphoalkyl group, a phosphoalkyl ether group, a thiophosphoalkyl ether group, or -OP(=R a )(R b )R c , where each of R a , R b and R cEach is defined as a compound with respect to Structure (I).

[0048] "Thiophosphate" means -OP(=R a )(R b )R c group, where R a is O or S, R b is OH, O - S - OR d or SR d ; and R c is OH, SH, O - S - OR d SR d phosphate group or other thiophosphate group, where R d is a counterion (e.g., Na + etc.) and the conditions are: i) R a is S; ii) R b is S - or SR d ; iii) R c is SH, S - or SR d ; or iv) a combination of i), ii) and / or iii).

[0049] "Thiophosphorylalkyl" means -OP(=R a )(R b )R c group, where R a is O or S, R b is OH, O - S - OR d or SR d ; and R c is -Oalkyl, where R d is a counterion (e.g., Na + etc.) and the conditions are: i) R a is S; ii) R b is S - or SR d ; or iii) R a is S and R b is S - or SR d。Unless specifically stated otherwise in the specification, the thiophosphorylalkyl is optionally substituted. For example, in certain embodiments, the -Oalkyl moiety in the thiophosphorylalkyl is optionally substituted with one or more of hydroxy, amino, mercapto, phosphate ester, thiophosphate ester, phosphorylalkyl, thiophosphorylalkyl, phosphorylalkyl ether, thiophosphorylalkyl ether, or -OP(=R a )(R b )R c , where each of R a , R b , and R c is as defined for the compounds of structure (I).

[0050] "Thiophosphorylalkyl ether" means the -OP(=R a )(R b )R c group, where R a is O or S, R b is OH, O - , S - , OR d , or SR d ; and R c is -Oalkyl ether, where R d is a counterion (e.g., Na + , etc.) and the conditions are: i) R a is S; ii) R b is S - or SR d ; or iii) R a is S and R b is S - or SR d . Unless specifically stated otherwise in the specification, the thiophosphorylalkyl ether group is optionally substituted. For example, in certain embodiments, the -Oalkyl ether moiety in the thiophosphorylalkyl is optionally substituted with one or more of hydroxy, amino, mercapto, phosphate ester, thiophosphate ester, phosphorylalkyl, thiophosphorylalkyl, phosphorylalkyl ether, thiophosphorylalkyl ether, or -OP(=R a )(R b )R c , where each of R a , R b , and R c is as defined for the compounds of structure (I).

[0051] "Carbocyclic ring" means a stable 3- to 18-membered aromatic or non-aromatic ring containing 3 to 18 carbon atoms. Unless specifically stated otherwise in the specification, the carbocyclic ring can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems, and can be partially or fully saturated. Non-aromatic carbocyclic residues include cycloalkyl, while aromatic carbocyclic residues include aryl. Unless specifically stated otherwise in the specification, the carbocyclic group is optionally substituted.

[0052] "Cycloalkyl" means a stable non-aromatic monocyclic or polycyclic carbocyclic ring, which can include fused or bridged ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and which is saturated or unsaturated and is linked to the remainder of the molecule by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo-[2.2.1]heptanyl, etc. Unless specifically stated otherwise in the specification, the cycloalkyl is optionally substituted.

[0053] "Aryl" means a ring system containing at least one carbocyclic aromatic ring. In certain embodiments, the aryl contains 6 to 18 carbon atoms. The aryl ring can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl includes, but is not limited to, aryls derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, , fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene and benzo[ghi]perylene. Unless specifically stated otherwise in the specification, the aryl is optionally substituted.

[0054] "Heterocycle" means a stable 3- to 18-membered aromatic or non-aromatic ring containing 1 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless specifically stated otherwise in the specification, the heterocycle can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycle can be optionally oxidized; the nitrogen atoms can be optionally quaternized; and the heterocycle can be partially or fully saturated. Examples of aromatic heterocycles are listed below in the definition of heteroaryl (i.e., heteroaryl is a subset of heterocycles). Examples of non-aromatic heterocycles include, but are not limited to, dioxolanyl, thienyl[1,3]dithiacyclohexyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, pyrazolopyrimidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trioxanyl, trithiacyclohexyl, triazinyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless specifically stated otherwise in the specification, the heterocyclic group is optionally substituted.

[0055] "Heteroaryl" means a 5- to 14-membered ring system containing 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, and at least 1 aromatic ring. For the purposes of certain embodiments of the present disclosure, a heteroaryl residue may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused or bridged ring system; and the nitrogen, carbon or sulfur atoms in the heteroaryl residue may optionally be oxidized; the nitrogen atoms may optionally be quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benz[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxenyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl (benzothiophenyl), benzotriazolyl, benz[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinone, benzimidazolesulfinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indazinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pteridinone, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridone, pyrazinyl, pyrimidinyl, pryrimidinonyl, pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinone, quinazolinyl, quinazolinone, quinoxalinyl, quinoxalinone, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thieno[3,2-d]pyrimidin-4-one, thieno[2,3-d]pyrimidin-4-one, triazolyl, tetrazolyl, triazinyl and thienyl (i.e., thiophenyl). Unless specifically stated otherwise in the specification, heteroaryl is optionally substituted.

[0056] "Fused" means a ring system containing at least 2 rings, where the 2 rings share at least one common ring atom, such as 2 common ring atoms. When the fused rings are heterocyclic or heteroaryl rings, the common ring atoms can be carbon or nitrogen. Fused rings include bicyclic, tricyclic, tetracyclic, etc.

[0057] 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) wherein at least one hydrogen atom (e.g., 1, 2, 3, or all of the hydrogen atoms) is replaced with a bond to a non-hydrogen atom such as, but not limited to, a halogen. Atoms such as F, Cl, Br and I; oxygen atoms in groups such as hydroxyl, alkoxy and ester groups; sulfur atoms in groups such as thiol groups, alkylthio groups, sulfone groups, sulfonyl groups 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; and other heteroatoms in various other groups. "Substitution" also refers to any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., double or triple bond) with a heteroatom, such as oxygen in oxo groups, carbonyl groups, carboxyl groups and ester groups; and nitrogen in groups such as imines, oximes, hydrazones and nitriles. For example, "substitution" includes any of the above groups in which one or more hydrogen atoms are replaced by -NR g R h 、-NR g C(=O)R h 、-NR g C(=O)NR g R h 、-NR g C(=O)OR h 、-NR g 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 refers to any of the above groups in which one or more hydrogen atoms are replaced by -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 is replaced. In the foregoing, R g and R h are the same or different and are independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic group, N - heterocyclic group, heterocyclic alkyl, heteroaryl, N - heteroaryl, and / or heteroarylalkyl. "Substituted" further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to the following groups: amino, cyano, hydroxy, imino, nitro, oxo, thio, halogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic group, N - heterocyclic group, heterocyclic alkyl, heteroaryl, N - heteroaryl, and / or heteroarylalkyl. In certain embodiments, the optional substituent is -OP(=R a )(R b )R c , where R a , R b and R c are each as defined for the compounds of structure (I). Additionally, each of the foregoing substituents may also optionally be substituted by one or more of the above substituents.

[0058] "Conjugation" or "bioconjugation" refers to a chemical strategy for forming a stable covalent bond between two molecules. When one of the molecules is a biomolecule (e.g., an antibody), the term "bioconjugation" is commonly used. The product or compound resulting from such a strategy is a conjugate, is conjugated, or a grammatically equivalent phrase.

[0059] "Fluorescent" refers to a molecule capable of absorbing light at a specific frequency and emitting light at a different frequency. Fluorescence is well known to those of ordinary skill in the art.

[0060] "Colored" refers to a molecule that absorbs light within the visible spectrum (i.e., red, yellow, blue, etc.).

[0061] "Linker" refers to a continuous chain of at least one atom, such as carbon, oxygen, nitrogen, sulfur, phosphorus, and combinations thereof, that connects one part of a molecule to another part of the same molecule or to a different molecule, part, or solid support (e.g., a microparticle). The linker can connect the molecules via a covalent bond or other means, such as ionic or hydrogen - bond interactions.

[0062] The term "biomolecule" refers to any of a variety of biological materials, including nucleic acids, carbohydrates, amino acids, polypeptides, glycoproteins, hormones, aptamers, and mixtures thereof. More specifically, the term is intended to include, but is not limited to, RNA, DNA, oligonucleotides, modified or derivatized nucleotides, enzymes, receptors, prions, receptor ligands (including hormones), antibodies, antigens, and toxins, as well as bacteria, viruses, blood cells, and tissue cells. In certain embodiments of the present disclosure, as further described herein, exemplary conjugates (e.g., compounds of structure (I) having a biomolecule attached thereto) are prepared by contacting a biomolecule with a compound having a reactive group that is capable of attaching the biomolecule to the compound via any available atom or functional group (such as an amino, hydroxy, carboxy, or mercapto group on the biomolecule).

[0063] A "reactive group" is a moiety that is capable of reacting 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, mercaptans, disulfides, sulfonyl halides, isothiocyanates, imidates, activated esters, ketones, α,β-unsaturated carbonyls, alkenes, maleimides, α-haloamides, epoxides, aziridines, tetrazines, tetrazoles, phosphines, biotin, thiiranes, and the like.

[0064] A "solid support" refers to any solid matrix known in the art for use as a solid-phase support for molecules, e.g., a "particle" refers to any of a number of small particles that can be used for attaching to a compound of the present disclosure, including, but not limited to, glass beads, magnetic beads, polymer beads, non-polymer beads, and the like. In certain embodiments, the particles comprise polystyrene beads.

[0065] A "solid support residue" refers to a functional group that remains attached to a molecule when the molecule is cleaved from the solid support. Solid support residues are known in the art and can be readily deduced based on the structure of the solid support and the group to which the molecule is attached.

[0066] "Targeting moiety" is a moiety that selectively binds or associates with a specific target, such as a tumor cell antigen. "Selectively" binding or associating means that the targeting moiety preferentially associates or binds to the desired target relative to other targets. For example, in certain embodiments, selective binding means that the targeting moiety or a conjugate containing it associates or binds with the desired target at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or at least 100-fold relative to other targets. In certain embodiments, the compounds disclosed herein include a linkage to a targeting moiety for the purpose of selectively binding or associating the compound with a desired target, such as a tumor cell antigen, thereby allowing targeted delivery of a bioactive 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, etc. In certain embodiments, the targeting moiety is a moiety, such as an antibody, that selectively binds or associates with a target feature on or in a cell, such as a target feature on a cell membrane or other cell structure, thereby allowing delivery of a bioactive moiety to or into a cell of interest. In certain embodiments, small molecules that selectively bind or associate with a desired biological target are also contemplated as targeting moieties. Those skilled in the art will appreciate other biological targets and corresponding targeting moieties that will be useful in various embodiments.

[0067] "Physiologically cleavable linker" refers to a molecular linkage that can be cleaved or separated in a defined manner in the presence of an in vivo or in vitro environment of an organism or cell system, thereby producing two or more separated molecules. Generally, the physiological conditions that induce such cleavage or breakage events can include a temperature in the range of about 20 - 40 °C, an atmospheric pressure of about 1 atm (101 kPa or 14.7 psi), a pH of about 6 - 8, a glucose concentration of about 1 - 20 mM, an atmospheric oxygen concentration, and earth gravity. In certain embodiments, the physiological conditions include enzymatic conditions (i.e., enzymatic cleavage). The bond cleavage or breakage can be homolytic or heterolytic.

[0068] The embodiments disclosed herein are also intended to cover all compounds of structure (I) that are isotopically labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O,17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I.

[0069] By conventional techniques known to those skilled in the art, or by methods similar to those described below and the methods in the following examples, using appropriate isotopically labeled reagents in place of the previously used unlabeled reagents, compounds of isotopically labeled structure (I) can generally be prepared.

[0070] "Stable compounds" and "stable structures" are intended to indicate compounds that are sufficiently robust to survive isolation to a useful degree of purity from the reaction mixture and formulation into an effective therapeutic agent.

[0071] "Optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" means that the alkyl may or may not be substituted, and the description includes substituted alkyl and unsubstituted alkyl.

[0072] "Salt" includes acid and base addition salts.

[0073] "Acid addition salts" refer to those salts formed with inorganic acids (such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric 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, undecylenic acid, etc.).

[0074] "Base addition salts" refer to those salts prepared by 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, phenethylbenzylamine, dibenzylethylenediamine, ethylenediamine, glucosamine, methyl glucosamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0075] Crystallization can produce solvates of the compounds described herein. Embodiments of the present disclosure include all solvates of the described compounds. The term "solvate" as used herein refers to an aggregate of one or more molecules of a compound of the present disclosure with one or more solvent molecules. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present disclosure can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates and the like, as well as the corresponding solvated forms. The compounds of the present disclosure can be true solvates, while in other cases, the compounds of the present disclosure can merely retain adventitious water or another solvent or a mixture of water plus some adventitious solvent.

[0076] Embodiments of the compounds of the present disclosure (e.g., compounds of Structure I), or salts, tautomers, or solvates thereof, may contain one or more stereocenters and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. Embodiments of the present disclosure 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 the optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other feature that gives rise to geometric asymmetry, and unless otherwise specified, it is meant that the compounds include E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included.

[0077] "Stereoisomers" means compounds that are composed of the same atoms bonded by the same bonds but have different three-dimensional structures that are not interchangeable. The present disclosure encompasses various stereoisomers and mixtures thereof, and includes "enantiomers", which means two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0078] "Tautomers" means the transfer of a proton from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the said compounds. Those of ordinary skill in the art can readily deduce the various tautomeric forms of the compounds.

[0079] The chemical nomenclature and structural diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, using the ACD / Name version 9.07 software program and / or the ChemDraw Ultra version 11.0 software nomenclature program (CambridgeSoft). Common names familiar to those of ordinary skill in the art are also used.

[0080] As noted above, in one embodiment of the present disclosure, compounds are provided that comprise a covalent linker between one or more bioactive moieties and an optional targeting moiety. In other embodiments, compounds are provided that can be used as synthetic intermediates for preparing compounds that comprise one or more bioactive moieties and an optional targeting moiety. Generally, embodiments of the present disclosure relate to polymers having pendant bioactive moieties. The bioactive moieties are attached to the polymer through a linking moiety. In another aspect, the linker provides a connection between the bioactive moiety and the targeting moiety, which serves to increase the accumulation of the bioactive moiety at the desired target. That is, due to the accumulation at the intended target, the bioactivity may increase while off-target effects are reduced, thereby minimizing the potential side effects (e.g., cytotoxicity) of the therapeutic agent.

[0081] In other embodiments, compounds having the following structure (I) or stereoisomers, pharmaceutically acceptable salts, or tautomers thereof are provided:

[0082]

[0083] Wherein:

[0084] M, each occurrence independently, is a bioactive moiety or a fragment thereof, a prodrug of a bioactive moiety or a fragment thereof, a fluorescent dye, an imaging agent, or a radioactive isotope binding site, provided that at least one occurrence of M is not a fluorescent dye;

[0085] L a is, each occurrence independently, an optional physiologically cleavable linker and L b is, each occurrence independently, an optional physiologically non-cleavable linker, provided that, L a and L b together (i.e., ) at least one occurrence contains more than 4 carbons;

[0086] L 1 and L 2 are, each occurrence independently, an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatom linker;

[0087] L 3 is, each occurrence independently, a heteroalkylene, heteroalkenylene, or heteroalkynylene linker greater than 3 atoms in length, wherein the heteroatoms in the heteroalkylene, heteroalkenylene, and heteroalkynylene linkers are selected from O, N, and S;

[0088] R 1 is, each occurrence independently, H, alkyl, or alkoxy;

[0089] R 2 and R 3 are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c , Q or a protected form thereof or L';

[0090] R 4 is independently O - , S - , OZ, SZ or N(R 6 ) 2 , where Z is a cation and each R 6 is independently H or alkyl;

[0091] R 5 is independently oxo, thio or absent;

[0092] R a is O or S;

[0093] R b is OH, SH, O - , S - , OR d or SR d ;

[0094] R c is OH, SH, O - , S - , OR d , OL', SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphonylalkyl, thiophosphonylalkyl, phosphonylalkyl ether or thiophosphonylalkyl ether;

[0095] R d is a counterion;

[0096] Q is independently a moiety containing a reactive group or a protected form thereof, which is capable of forming a covalent bond with a complementary reactive group Q' on the targeting moiety;

[0097] L' is independently a linker containing a covalent bond with Q, a targeting moiety, a linker containing a covalent bond with the targeting moiety, a linker containing a covalent bond with the solid support, a linker containing a covalent bond with the solid support residue, a linker containing a covalent bond with the nucleoside or a linker containing a covalent bond with another compound of structure (I);

[0098] m is independently 0 or a positive integer; and

[0099] n is an integer of 1 or greater.

[0100] In other embodiments, there is provided a compound having the following structure (I) or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof:

[0101]

[0102] Wherein:

[0103] M is independently, at each occurrence, a bioactive moiety or a fragment thereof, a prodrug of a bioactive moiety or a fragment thereof, a fluorescent dye, an imaging agent or a radioisotope binding site, provided that at least one occurrence of M is not a fluorescent dye;

[0104] L a is independently, at each occurrence, an optionally physiologically cleavable linker and L b is independently, at each occurrence, an optionally physiologically non-cleavable linker;

[0105] L 1 and L 2 are independently, at each occurrence, an optionally alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene or heteroatom linker;

[0106] L 3 is independently, at each occurrence, a heteroalkylene, heteroalkenylene or heteroalkynylene linker having a length greater than 3 atoms, wherein the heteroatoms in the heteroalkylene, heteroalkenylene and heteroalkynylene linkers are selected from O, N and S;

[0107] R 1 is independently, at each occurrence, H, alkyl or alkoxy;

[0108] R 2 and R 3 are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c , Q or a protected form thereof or L';

[0109] R 4 is independently, at each occurrence, O - , S - , OZ, SZ or N(R 6 ) 2 , where Z is a cation and each R 6 is independently H or alkyl;

[0110] R 5 is independently, at each occurrence, oxo, thioxo or absent;

[0111] R a is O or S;

[0112] R b is OH, SH, O - , S - , OR d or SR d ;

[0113] R c is OH, SH, O - , S - , OR d , OL', SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphonylalkyl, thiophosphonylalkyl, phosphonylalkyl ether or thiophosphonylalkyl ether;

[0114] R d is a counterion;

[0115] Q is independently, at each occurrence, a moiety containing a reactive group or a protected form thereof, which is capable of forming a covalent bond with a complementary reactive group Q' on a targeting moiety;

[0116] L' is independently, at each occurrence, a linker containing a covalent bond with Q, a targeting moiety, a linker containing a covalent bond with a targeting moiety, a linker containing a covalent bond with a solid support, a linker containing a covalent bond with a solid support residue, a linker containing a covalent bond with a nucleoside, or a linker containing a covalent bond with another compound of structure (I);

[0117] m is independently, at each occurrence, an integer of 0 or greater; and

[0118] n is an integer of 1 or greater,

[0119] provided that the occurrence of M does not have the following structure:

[0120] and

[0121] the compound of structure (I) does not have one of the following structures:

[0122]

[0123] wherein:

[0124] q is an integer from 21 - 26;

[0125] D' has the following structure:

[0126]

[0127] AF has the following structure:

[0128] and

[0129] dT has the following structure:

[0130]

[0131] In certain embodiments, L a and L b together (i.e., ) at least one occurrence does not form the following structure:

[0132]

[0133] The linking group L a and / or L b can be used as a connection point between the M moiety and the rest of the compound. For example, in certain embodiments, a synthetic precursor of a compound of structure (I) is prepared and the M moiety is attached to the synthetic precursor using any number of convenient methods known in the art, such as methods referred to as "click chemistry". For this purpose, any rapid and substantially irreversible reaction can be used to attach M to the synthetic precursor to form a compound of structure (I). Exemplary reactions include the reaction of copper-catalyzed azides and alkynes to form triazoles (Huisgen 1,3-dipolar cycloaddition), the reaction of dienes and dienophiles (Diels-Alder), strain-promoted alkyne-nitrone cycloaddition, the reaction of strained alkenes with azides, tetrazines or tetrazoles, the [3+2] cycloaddition of alkenes and azides, the inverse-demand Diels-Alder of alkenes and tetrazines, the photoreaction of alkenes and tetrazoles, and various substitution reactions, such as the substitution of a leaving group by nucleophilic attack on an electrophilic atom. Exemplary substitution reactions include the reaction of amines with: activated esters; N-hydroxysuccinimide esters; isocyanates; isothiocyanates, etc. In certain embodiments, the reaction to form L a and / or L b can be carried out in an aqueous environment.

[0134] Thus, in certain embodiments, L a and / or L b is, at each occurrence, a linking group comprising a functional group capable of being formed by the reaction of two complementary reactive groups, e.g., a functional group that is a product of one of the aforementioned "click" reactions. In different embodiments, for L a and / or L bFor at least one occurrence of, the functional group can be formed by the reaction of aldehyde, oxime, hydrazone, alkyne, amine, azide, acyl azide, acyl halide, nitrile, nitrone, thiol, disulfide, sulfonyl halide, isothiocyanate, iminoester, activated ester (e.g., N-hydroxysuccinimide ester), ketone, α,β-unsaturated carbonyl, alkene, maleimide, α-haloamide, epoxide, aziridine, tetrazine, tetrazole, phosphine, biotin or thietane functional group with a complementary reactive group (e.g., reaction of amine with N-hydroxysuccinimide ester or isothiocyanate).

[0135] In other embodiments, for L a and / or L b For at least one occurrence of, the functional group can be formed by the reaction of alkyne and azide. In other embodiments, for L a and / or L b For at least one occurrence of, the functional group can be formed by the reaction of amine (e.g., primary amine) with N-hydroxysuccinimide ester or isothiocyanate.

[0136] In more embodiments, for L a and / or L b For at least one occurrence of, the functional group contains alkene, ester, amide, thioester, disulfide, carbocyclic, heterocyclic or heteroaryl group. In more embodiments, for L a and / or L b For at least one occurrence of, the functional group contains alkene, ester, amide, thioester, thiourea, disulfide, carbocyclic, heterocyclic or heteroaryl group. In other embodiments, the functional group contains amide or thiourea. In certain more specific embodiments, for L a and / or L b For at least one occurrence of, L a and / or L b is a linker containing a triazole functional group. While in other embodiments, for L a and / or L b For at least one occurrence of, L a and / or L b is a linker containing an amide or thiourea functional group.

[0137] Some embodiments provide L that can be cleaved under appropriate conditions (e.g., physiological conditions). a In certain embodiments, at least one occurrence of L a exists. In certain more specific embodiments, at least one occurrence of L a contains amide bond, ester bond, phosphodiester bond, disulfide bond, double bond, triple bond, ether bond, hydrazone, amino acid sequence, ketone, diol, cyano, nitro or a combination thereof.

[0138] In certain embodiments, L a comprises an amino acid sequence recognized by sortase. 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 a is a linker containing 3 or more carbons. In certain other embodiments, at least one occurrence of L a is a linker containing at least one nitrogen. In certain embodiments, at least one occurrence of L a comprises one of the following structures:

[0139]

[0140] In certain embodiments, each occurrence of L a 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 group, a nitro group, or a combination thereof.

[0141] In certain embodiments, each occurrence of L a is a linker containing 3 or more carbons. In certain embodiments, each occurrence of L a is a linker containing at least one nitrogen. In some other embodiments, each occurrence of L a comprises one of the following structures:

[0142]

[0143]

[0144] In certain embodiments, at least one occurrence of L a comprises the following structure:

[0145]

[0146] In certain embodiments, at least one occurrence of L a comprises one or more amino acid residues. In certain embodiments, the amino acid residue is valine. In certain more specific embodiments, at least one occurrence of L a comprises one of the following structures:

[0147]

[0148] In certain other embodiments, at least one occurrence of L a comprises one of the following structures:

[0149]

[0150]

[0151] In certain embodiments, each occurrence of L a comprises the following structure:

[0152]

[0153] In certain embodiments, each occurrence of L a comprises one or more amino acid residues. In certain embodiments, the amino acid residue is valine. In certain specific embodiments, each occurrence of L a comprises one of the following structures:

[0154]

[0155] In certain embodiments, each occurrence of L a comprises one of the following structures:

[0156]

[0157]

[0158] In certain embodiments, at least one occurrence of L a has the following structure:

[0159]

[0160] In certain embodiments, at least one occurrence of L a has one of the following structures:

[0161]

[0162] In certain embodiments, at least one occurrence of L a has the following structure:

[0163]

[0164] In certain embodiments, at least one occurrence of L b is present. In certain specific embodiments, at least one occurrence of L b comprises a thioether bond. In certain specific embodiments, at least one occurrence of L b comprises the following structure:

[0165]

[0166] In certain embodiments, at least one occurrence of L b comprises one of the following structures:

[0167]

[0168] In certain embodiments, each occurrence of L b comprises a linker that is not cleavable under physiological conditions. In certain embodiments, each occurrence of L b comprises a thioether bond. In certain embodiments, each occurrence of L b comprises the following structure:

[0169]

[0170] In certain embodiments, each occurrence of L b comprises one of the following structures:

[0171]

[0172] Thus, in certain embodiments, L a or L b comprises an amide bond, an ester bond, a disulfide bond, a hydrazone, a triester phosphate, a diester, a β-glucuronide, a double bond, a triple bond, an ether bond, a ketone, a diol, a cyano group, a nitro group, or a combination thereof.

[0173] In certain embodiments, L a or L b together comprise a tert-butoxycarbonyl group, a p-methoxybenzyl group, a dialkyl or diaryldialkoxysilane, an orthoester, an acetal, a β-thiopropionate, a ketal, an aminophosphate, a hydrazone, a vinyl ether, an imine, an aconityl group, a trityl group, a polyketal, a bisarylhydrazone, a diazobenzene, a vivinal diol, a pyrophosphate diester, or a valine-citrulline.

[0174] In certain embodiments, L a is independently, at each occurrence, a linker cleavable at pH 6-8. For example, in certain embodiments, L is a linker 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.

[0175] In certain embodiments, L aIndependently at each occurrence, it is a cleavable linker at a temperature 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, 32°C to 38°C. In certain embodiments, L is independently at each occurrence a cleavable linker at a temperature 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.

[0176] In certain embodiments, L a Independently at each occurrence, it is an enzyme-cleavable linker. For example, in certain embodiments, the enzyme is a hydrolase, an oxidoreductase or a lyase. In certain embodiments, the enzyme is an EC 4.1 (e.g., EC 4.1.1, EC 4.1.2, EC 4.1.3 or EC 4.1.99), EC 4.2, EC 4.3, EC 4.4, EC 4.5, EC 4.6 or EC 4.99 enzyme.

[0177] In certain embodiments, L a Comprises one of the following structures:

[0178]

[0179]

[0180] Wherein:

[0181] R is H, methyl, ethyl, isopropyl, tert-butyl or phenyl;

[0182] X is O or CH 2 ; and

[0183] n is an integer greater than 0.

[0184] In other embodiments, for at least one occurrence of L b -M has the following structure: b -M has the following structure:

[0185]

[0186] Wherein L 1a and L 1b Are each independently an optional linker.

[0187] In different embodiments, for at least one occurrence of L b -M has the following structure: b -M has the following structure:

[0188]

[0189] wherein L 1a and L 1b are each independently optional linking groups.

[0190] In the foregoing different embodiments, L 1a or L 1b or both are absent for one or more occurrences. In other embodiments, L 1a or L 1b or both are present for one or more occurrences.

[0191] In certain embodiments, L 1a and L 1b when present are each independently an alkylene or heteroalkylene group. For example, in certain embodiments, L 1a and L 1b when present independently comprise one of the following structures:

[0192]

[0193] In certain other related embodiments, L b comprises one of the following structures:

[0194]

[0195] In certain embodiments, at least one occurrence of L a and / or L b comprises one of the following structures:

[0196]

[0197] wherein

[0198] a, b, and c are each independently integers in the range of 1 - 6.

[0199] In certain embodiments, each occurrence of L a and / or L b has one of the following structures:

[0200]

[0201] wherein

[0202] a, b, and c are each independently integers in the range of 1 - 6.

[0203] In certain embodiments, at least one occurrence of L a and / or L b has one of the following structures:

[0204]

[0205] In certain embodiments, at least one occurrence of L 3 is a heteroalkylene linking group. In certain embodiments, at least one occurrence of L 3 is an alkylene oxide linking group (e.g., an ethylene oxide linking group). In certain embodiments, L 3 is independently a heteroalkylene linking group at each occurrence. In certain embodiments, L 3 is independently an alkylene oxide linking group at each occurrence.

[0206] In certain more specific embodiments, the compound has the following structure (IA):

[0207]

[0208] where z is an integer from 2 to 100.

[0209] In certain more specific embodiments, z is an integer from 3 to 30. In certain embodiments, z is an integer from 3 to 6 or from 19 to 28. In certain specific embodiments, z is an integer from 3 to 6. In certain embodiments, at least one occurrence of z is 3, 4, 5, or 6. In certain specific embodiments, each occurrence of z is 3, 4, 5, or 6. In certain embodiments, at least one occurrence of z is 3 or 6. In another embodiment, each occurrence of z is 3 or 6. In certain embodiments, z is an integer from 19 to 28 or from 44 to 54.

[0210] In certain embodiments, L 3 comprises polyethylene oxide and the compound has the following structure (IB):

[0211]

[0212] wherein:

[0213] z is an integer from 2 to 30;

[0214] x 1 and x 2 are each independently an integer from 0 to 6; and

[0215] x 3 and x 4 are independently an integer from 0 to 6 at each occurrence.

[0216] In certain more specific embodiments, x 1 and x 2 are each independently an integer from 0 to 3 and x 3 and x 4Independently at each occurrence, it is an integer from 0 to 3. In certain embodiments, for at least one occurrence of n, z is an integer from 3 to 6 and m is 3. In certain other embodiments, for at least one occurrence of m, z is an integer from 22 to 27. In certain embodiments, for at least one occurrence of m, z is an integer from 44 to 54. In certain embodiments, for at least one occurrence of m, z is 3, and for at least one occurrence of n, m is 3. In certain embodiments, for at least one occurrence of m, z is 6, and for at least one occurrence of n, m is 3.

[0217] In other embodiments of any compound of structure (I), R 4 Independently at each occurrence, is OH, O - or OR d . It should be understood that "OR d " and "SR d " are intended to represent O - and S - associated with a cation. For example, the disodium salt of a phosphate group can be represented as:

[0218]

[0219] where R d is sodium (Na + ).

[0220] In other embodiments of any compound of structure (I), R 5 Is oxo at each occurrence.

[0221] In certain different embodiments of any of the foregoing compounds, R 1 Is H at each occurrence.

[0222] In various other embodiments, R 2 and R 3 Are each independently OH or -OP(=R a )(R b )R c . In certain different embodiments, R 2 or R 3 Is OH or -OP(=R a )(R b )R c , and the other of R 2 or R 3 Is Q or a linking group containing a covalent bond to Q (e.g., an alkylene or heteroalkylene).

[0223] In still more different embodiments of any of the foregoing compounds of structure (I), R 2 and R3 Each independently is -OP(=R a )(R b )R c . In some of these embodiments, R c is OL'. In certain 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, the linker comprising an alkylene oxide or a phosphodiester moiety or a combination thereof.

[0224] In other embodiments, R 2 and R 3 each independently is -OP(=R a )(R b )OL', and L' is an alkylene or heteroalkylene linker to: Q, a targeting moiety, an analyte (e.g., an analyte molecule), a solid support, a solid support residue, a nucleoside, or other compounds of structure (I).

[0225] The linker L' can be any linker suitable for linking Q, a targeting moiety, an analyte (e.g., an analyte molecule), a solid support, a solid support residue, a nucleoside, or other compounds of structure (I) to structure (I). Advantageously, certain embodiments include the use of a selected L' moiety for increasing or optimizing the water solubility of the compound. In certain embodiments, L' is a heteroalkylene moiety. In some other certain embodiments, L' comprises an alkylene oxide or a phosphodiester moiety or a combination thereof. In some other certain embodiments, L' comprises ethylene oxide. In certain embodiments, L' comprises a disulfide.

[0226] In certain embodiments, L' has the following structure:

[0227]

[0228] Wherein:

[0229] m” and n” are independently integers from 1 to 10;

[0230] R e is H, an electron pair, or a counterion;

[0231] L” is a targeting moiety or a linker to a targeting moiety.

[0232] In certain 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.

[0233] In certain embodiments, the targeting moiety is an antibody, a cell surface receptor antagonist, a cell surface receptor agonist, etc. In related embodiments, the antibody, cell surface receptor antagonist, cell surface receptor agonist, etc. is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, folic acid, or a MET inhibitor. In certain embodiments, the antibody, cell surface receptor antagonist, cell surface receptor agonist, etc. is a tyrosine kinase inhibitor (e.g., gefitinib, erlotinib), lapatinib, vandetanib, neratinib, osimertinib, Tovantinib (ARQ197), crizotinib, cabozantinib, a tyrosine phosphorylation inhibitor (e.g., AG538, AG1024), a pyrrolo(2,3-d)-pyrimidine derivative (e.g., NVP-AEW541), a monoclonal antibody (e.g., ficlatuzumab, cetuximab, panitumumab, necitumumab, ganitumab, cetuximab, Dalotuzumab, rocitumumab, onartuzumab, K1, ramucirumab, mirvetuximab, lovotuzumab, Inotuzumab), BMS-777607, PF-02341066, PF-04217903, AMG-458, MK-2461, JNJ-38877605, GSK 1363089 (foretinib), XL880, XL 184, ARQ197, E7050, or INCB28060.

[0234] In certain embodiments, the antibody is abciximab, adalimumab, alemtuzumab, alirocumab, avibactam, basiliximab, benralizumab, bezlotoxumab, blinatumomab, brodalumab, broseptumab, canakinumab, carlumab, certolizumab pegol, daclizumab, denosumab, dupilumab, eculizumab, emicizumab, erenumab, evolocumab, fremanezumab, galcanezumab, golimumab, guselkumab, ibalizumab, idarucizumab, infliximab, itolizumab, ixekizumab, lanadelumab, lokivetmab, mepolizumab, natalizumab, obiltoxaximab, ocrelizumab, omalizumab, palivizumab, ranibizumab, raxibacumab, reslizumab, rmab, rovelizumab, ruplizumab, sarilumab, secukinumab, tildrakizumab, thiomab, tocilizumab, ustekinumab, or vedolizumab. In certain more specific embodiments, the antibody is abrilumab, actoxumab, aducanumab, afasevikumab, afelimomab, anifrolumab, anrukinzumab (IMA-638), aselizumab, atorolimumab, bapineuzumab, BCD-100, bertilimumab, besilesomab, biciromab, bimagrumab, bimekizumab,Birtamimab, Bleselumab, Blosozumab, Bococizumab, Brazikumab, Briakinumab, Brolucizumab, Carlumab, Carotuximab, Cedelizumab, Clazakizumab, Clenoliximab, Concizumab, Cosfroviximab, CR6261, Crenezumab, Crizanlizumab, Crotedumab, Depatuxizumab, mafodotin, Derlotuximab biotin, Dezamizumab, Difotuzumab, Domagrozumab, Dusigitumab, Ecromeximab, Edobacomab, Efalizumab, Efungumab, Eldelumab, Elezanumab, Enokizumab, Eptinezumab, Erlizumab, Etrolizumab, Evinacumab, Exbivirumab, Fanolesomab, Faralimomab, Faricimab, Fasinumab, Felvizumab, Fezakinumab, Flanvotumab, Fletikumab, Flotetuzumab, Fontolizumab, Foravirumab, Frovocimab, Fulranumab, Gantenerumab, Gavilimomab, Gevokizumab, Gimsilumab, Gomiliximab, Gosuranemab,Ianalumab, Inclacumab, Inolimomab, Iomab-B, Keliximab, Lampalizumab, Landogrozumab, Larcaviximab, Lebrikizumab, Lenvervimab, Lerdelimumab, Letolizumab, Libivirumab, Ligelizumab, Lodelcizumab, Lulizumab pegol, Marstacimab, Mavrilimumab, Metelimumab, Mirikizumab, Motavizumab, Muromonab CD3, Nebacumab, Nemolizumab, NEOD001, Nirsevimab, Odulimomab, Olendalizumab, Olokizumab, OMS721, Opicinumab, Orticumab, Otelixizumab, Otilimab, Oxelumab, Ozanezumab, Ozoralizumab, Pagibaximab, Panobacumab, Pascolizumab, Pateclizumab, PDR001, Perakizumab, Pexelizumab, Placulumab, Plozalizumab, Ponezumab, Porgaviximab, Prasinezumab, Priliximab, PRO 140, Quilizumab, Rafivirumab, Ralpancizumab, Ranevetmab, Ravagalimab, Ravulizumab, RefanezumabRegavirumab, Relatlimab, Rinucumab, Risankizumab, Roledumab, Romosozumab, Rontalizumab, SA237, Satralizumab, Sevirumab, SHP647, Sifalimumab, Simtuzumab, Siplizumab, Sirukumab, Solanezumab, Sonepcizumab, Spartalizumab, Stamulumab, Sulesomab, Suptavumab, Sutimlimab, Suvizumab, Suvratoxumab, Tadocizumab, Talizumab, Tamtuvetmab, Tanezumab, Tefibazumab, Telimomab aritox, Teneliximab, Teplizumab, Teprotumumab, Tezepelumab, Tibulizumab, Toralizumab, Tralokinumab, Trevogrumab, Tuvirumab, Ulocuplumab, Urtoxazumab, Varisacumab, Vepalimomab, Vesencumab, Visilizumab, Vobarilizumab, or Zolimomab aritox. In certain more specific embodiments, the monoclonal antibody is trastuzumab, gemtuzumab, brentuximab, vorsetuzumab, lorvotuzumab, cantuzumab, bivatuzumab or inotuzumab, or vadastuximab.,

[0235] In certain embodiments, the antibody, cell surface receptor antagonist, cell surface receptor agonist, etc. target EGFR (e.g., EGFRvIII), HER 2, folate receptor, CD19, CD20, CD22, CD27L, CD30, CD33, CD37, CD56, CD66e, CD70, CD74, CD79b, CA6, CD138, CA 6, mesothelin, nectin 4, STEAP1, MUC16, MaPi2b, GCC, Trop-2, AGS-5, ENPP3, carbonic anhydrase IX, GPNMB, PDMA.

[0236] In certain other embodiments, the antibody, cell surface receptor antagonist, cell surface receptor agonist, etc. target 1-40-β-amyloid; activated F9, F10; ACVR2B; amyloid; Ang-2; angiopoietin 3; anthrax toxin, protective antigen; AOC3 (VAP-1); Bacillus anthracis anthrax; BAFF; β-amyloid; C1s; C5; calcitonin; calcitonin gene-related peptide α; Canis lupus 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 α-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; F protein of respiratory syncytial virus; FGF 23; fibrin II, β-chain; GCGR; GD3 ganglioside; GDF-8; GMCSF; growth differentiation factor 8; hemagglutinin; hepatitis B surface antigen; histone complex; HIV-1; HNGF; Hsp90; human β-amyloid; human TNF; IgE; IGF-1 receptor (CD221); IGHE; influenza A hemagglutinin; integrin receptors and subunits; interferon receptor; interleukin receptors (various); ITGB2 (CD18); kallikrein; LAG3; LFA-1 (CD11a); LINGO-1; lipoteichoic acid; LOXL2; L-selectin (CD62L); LTA; MASP-2; MCP-1; mucosal addressin cell adhesion molecule; myelin-associated glycoprotein; myostatin; NACP; NCA-90 (granulocyte antigen); protease-1 regulating neuronal apoptosis; NGF; NOGO-A; NRP1; OX-40; oxLDL; PCSK9; PD-1; PDCD1, CD279; platelet-derived growth factor receptor β; Pseudomonas aeruginosa; rabies virus glycoprotein; RANKL; respiratory syncytial virus; RGMA; RHD; rhesus factor; RSVFR; sclerostin; selectin P; SOST; sphingosine-1-phosphate; Staphylococcus aureus α-toxin; tau protein; TFPI; TGFβ1; TGFβ2; TNF-α; TRAP; TSLP; TYRP1 (glycoprotein 75);VEGF-A; VWF; or Zaire Ebola virus glycoprotein;

[0237] In certain specific embodiments, the targeting moiety is an antibody or an antibody fragment. In certain more specific embodiments, the antibody or antibody fragment is a monoclonal antibody (mAb), an antigen-binding fragment (Fab / Fab'), a single-domain antibody (sdAb), a bispecific antibody (BsAb), a bispecific T-cell engager (BiTE), a single-chain variable fragment (ScFv), a dual-affinity retargeting antibody (DART), a heavy-chain variable domain (V H ), a minibody, a diabody, or an Abdurin TM (derived from IgG).

[0238] In some other embodiments, the targeting moiety is a protein. For example, in certain embodiments, the targeting moiety is albumin, interferon, centyrin, or a chemotactic receptor ligand.

[0239] In some other embodiments, L” is an alkylene or heteroalkylene moiety. In some other certain embodiments, L” comprises an alkylene oxide, a phosphodiester moiety, a thiol, a disulfide, or a maleimide moiety, or a combination thereof.

[0240] In other more specific embodiments of any of the foregoing compounds of structure (I), R 2 or R 3 has one of the following structures:

[0241]

[0242]

[0243] Certain embodiments of the compounds of structure (I) can be prepared according to solid-phase synthesis methods similar to those known in the art for preparing oligonucleotides. Thus, in certain embodiments, L' is a linkage to a solid support, a solid support residue, or a nucleoside. Solid supports (e.g., polymers and non-polymers) containing an activated deoxythymidine (dT) group are readily available and, in certain embodiments, can be used as starting materials for preparing the compounds of structure (I). Thus, in certain embodiments, R 2 or R 3 has the following structure:

[0244]

[0245] Those skilled in the art will understand that including the above dT group is merely for ease of synthesis and economic efficiency and is not essential. Other solid carriers can be used and will result in different nucleoside or solid carrier residues being present on L', or the nucleoside or solid carrier residues can be removed or modified after synthesis.

[0246] In certain embodiments, R 2 or R 3 comprises one of the following structures:

[0247]

[0248] In certain embodiments, R 2 or R 3 comprises one of the following structures:

[0249]

[0250]

[0251] In certain embodiments, R 3 comprises one of the following structures:

[0252]

[0253]

[0254] In certain embodiments, R 3 comprises one of the following structures:

[0255]

[0256]

[0257] The values of m and n are variables that can be selected based on the desired solubility, permeability, or therapeutic application. In other embodiments, n is independently an integer from 1 to 5 each time it appears, such as 1, 2, 3, 4, or 5. By selecting different values of n, solubility, permeability, or retention can also be adjusted. In certain embodiments, n is an integer from 1 to 100. In other embodiments, n is an integer from 1 to 10. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8. In certain embodiments, n is 9. In certain embodiments, n is 10. In certain embodiments, n is an integer from 1 to 10.

[0258] In certain embodiments, m is an integer from 1 to 10. In more specific embodiments, at least one occurrence of m is an integer from 1 to 5. In certain embodiments, each occurrence of m is an integer from 1 to 15. In certain embodiments, each occurrence of m is an integer from 1 to 10. In more embodiments, each occurrence of m is an integer from 1 to 5.

[0259] In other embodiments, Q is independently, at each occurrence, a moiety comprising a reactive group that is capable of forming a covalent bond with an analyte molecule or a solid support. In other embodiments, Q is independently, at each occurrence, a moiety comprising a reactive group that is capable of forming a covalent bond with a complementary reactive group Q'. For example, in certain embodiments, Q' is present on another compound of structure (I) (e.g., at the R 2 or R 3 position), and Q and Q' comprise complementary reactive groups such that reaction of the compound of structure (I) and another compound of structure (I) yields a dimer of the covalently bound compounds of structure (I). Multimeric compounds of structure (I) can also be prepared in a similar manner and are included within the scope of the embodiments of the present disclosure.

[0260] The type of Q group and the connectivity of the Q group to the remainder of the compound of structure (I) are not limited, provided that Q comprises a moiety having suitable reactivity for forming the desired bond.

[0261] In certain embodiments, Q is a moiety that is not readily hydrolyzable under aqueous conditions but has sufficient reactivity to form a bond with a corresponding group (e.g., amine, azide, or alkyne) on an analyte molecule or a solid support.

[0262] Certain embodiments of the compounds of structure (I) comprise Q groups that are commonly used in the field of bioconjugation. For example, in certain embodiments, Q comprises a nucleophilic reactive group, an electrophilic reactive group, or a cycloaddition reactive group. In certain more specific embodiments, Q comprises a thiol, disulfide, activated ester, isothiocyanate, azide, alkyne, alkene, diene, dienophile, acyl halide, sulfonyl halide, phosphine, α-haloamide, biotin, amino, or maleimide functional group. In certain embodiments, the activated ester is an N-succinimidyl ester, imidate ester, or polyfluorophenyl ester. In other embodiments, the alkyne is an alkyl azide or acyl azide.

[0263] The Q group can be conveniently provided in a protected form to increase storage stability or other desired properties, and then the protecting group can be removed at an appropriate time for conjugation with, for example, a targeting moiety or an analyte. Thus, the Q group includes a "protected form" of a reactive group, including any of the reactive groups described above and in Table 1 below. The "protected form" of Q refers to a moiety that is less reactive relative to Q under a predetermined reaction condition, but can be converted to Q under conditions that preferably do not degrade other parts of the compound of structure (I) or do not react with them. Depending on the particular Q and the desired end use and storage conditions, one of ordinary skill in the art can deduce an appropriate protected form of Q. For example, when Q is SH, the protected form of Q includes disulfides, which can be reduced using well-known techniques and reagents to reveal the SH moiety.

[0264] Exemplary Q moieties are provided in Table I below.

[0265] Table 1 . Exemplary Q moieties

[0266]

[0267]

[0268]

[0269]

[0270] It should be noted that in certain embodiments, where Q is SH, the SH moiety will tend to form a disulfide bond with another thiol group (e.g., on another compound of structure (I)). Thus, some embodiments include compounds of structure (I) in the form of disulfide dimers, the disulfide bond being derived from the SH Q group.

[0271] Also included within the scope of certain embodiments are compounds of structure (I) wherein R 2 and R 3 include a linkage to another compound of structure (I) in one or both. For example, wherein R 2 and R 3 in one or both are -OP(=R a )(R b )R c , and R cis OL', and L' is a linking group that includes a covalent bond with another compound of structure (I). Such compounds can be prepared as follows: Prepare a first compound of structure (I) that has, for example, about 10 "M" moieties (i.e., n = 9) and has a suitable "Q" for reacting with a complementary Q' group on a second compound of structure (I). In this way, compounds of structure (I) having any number of "M" moieties (e.g., 100 or more) can be prepared without sequentially coupling each monomer. Exemplary embodiments of such compounds of structure (I) have the following structure (I')

[0272]

[0273] wherein:

[0274] R 1 、R 2 、R 3 、R 4 、R 5 、L a 、L b 、L 1 、L 2 、L 3 each occurrence of R, R, R, R, R, R, L, L, L, L, L, L, M, m, and n is independently defined as for the compounds of structure (I);

[0275] L” is a linking group that includes a functional group generated by the reaction of a Q moiety (e.g., as in Table 1) with a corresponding Q' moiety; and

[0276] α is an integer greater than 1, e.g., 1 - 100, or 1 - 10.

[0277] Other compounds of structure (I') can be derived by one of ordinary skill in the art, e.g., by dimerization or polymerization of the compounds of structure (I) provided herein.

[0278] In other embodiments, the Q moiety is conveniently masked (e.g., protected) as a disulfide moiety, which can subsequently be reduced to provide an activated Q moiety for binding to a desired targeting moiety. For example, the Q moiety can be masked as a disulfide having the following structure:

[0279]

[0280] wherein R is an optionally substituted alkyl. For example, in certain embodiments, Q is provided as a disulfide moiety having the following structure:

[0281]

[0282] where n' is an integer from 1 - 10, e.g., 6.

[0283] In some other embodiments, R 2 or R 3 is one of OH or -OP(=R a )(R b )R c , and the other of R 2 or R 3 is a linker containing a covalent bond to a targeting moiety or a linker containing a covalent bond to a solid support. For example, in certain embodiments, the targeting moiety is an antibody, a cell surface receptor antagonist, a cell surface receptor agonist, etc. In more diverse embodiments, the solid support is a polymeric bead or a non-polymeric bead. The targeting moiety can be directed against any number of strategic targets. For example, a biological target can be a cell surface receptor such as a tumor cell antigen. Tumor cell antigens include tumor-specific antigens and tumor-associated antigens, such as EGFR, HER 2, folate receptor, CD20, CD33, oncofetal antigen (e.g., alpha-fetoprotein, carcinoembryonic antigen, immature laminin receptor, TAG-72), CA-125, MUC-1, epithelial tumor antigen, tyrosinase, melanoma-associated antigen (MAGE), and aberrant products of RAS or p53. Tumor cell antigens can also include antigens characterized as oncofetal, tumor virus (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, individual genotype, CT9 or CT10 (e.g., NY-ESO-1 / LAGE-1, PRAME).

[0284] In certain embodiments, M is independently, each time it appears, an NSAID, a kinase inhibitor, an anthracycline, and an EGFR inhibitor or an alkylating agent. In certain embodiments, the bioactive moiety is an anticancer drug. In certain specific embodiments, M is independently, each time it appears, an anticancer drug, and the targeting moiety is an antibody specific for a tumor cell antigen.

[0285] The anticancer drugs used herein include derivatives. That is, the anticancer drugs have been modified or derivatized such that the drug can be conjugated or linked to another molecule (e.g., to include the Q moiety). For example, maytansine is an anticancer drug, and maytansinoid is an anticancer drug derivative.

[0286] In certain embodiments, the anti-cancer 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 anti-metabolite (such as 5-FU or such as gemcitabine), an alkylating agent (such as cisplatin or such as cyclophosphamide), or a taxane.

[0287] Anti-cancer drugs that can be modified and incorporated into the compounds of the embodiments of the present disclosure include, for example, auristatin F; auristatin E; maytansine; calicheamicin; paclitaxel; doxorubicin; nostocarboline; erlotinib; CC-1065; carzelesin; SJG-136; DSB-120; afatinib; Iressa; methotrexate; DNA methylating agents (e.g., procarbazine, temozolomide, dacarbazine, N-methyl-N-nitrosourea, N-methyl-N'-nitro-N-nitrosoguanidine, etc.).

[0288] Other non-limiting examples of anti-cancer drugs include (imatinib mesylate), (bortezomib), Casodex (bicalutamide), (gefitinib) and doxorubicin, alkylating agents such as thiotepa and cyclophosphamide Alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodepa, carboquone, meturedepa and uredepa; ethyleneimines and methylmelamines, including altretamine, tretamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, nitrogen mustard hydrochloride, melphalan, novembichin, phenester mustard, prednimustine, trophosphamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclarubicin, actinomycin, authramycin, azaserine, bleomycin, actinomycin C, calicheamicin, carabicin, carminomycin, carcinomycin, Chromomycin, actinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, isorubicin, idarubicin, mazethramycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, triferric doxorubicin, rhodomycin, streptozocin, streptozotocin, tubercidin, bestrabucil, bisantrene, edatraxate, defofamine, colchicine amide, diaziquone, elfomithine, elisidepsin, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenylalanine mustard, pirarubicin, podophyllic acid, 2-ethylhydrazine, procarbazine, PSK.RTM., razoxane, sizofiran, spirogermanium, tenuzoic acid, triaziquone, 2,2',2”-trichloroethylamine, urethan, vindesine, dacarbazine, mannomustine, dibromomannitol, dibromodulcitol, pipobroman, gacytosine, cytarabine (“Ara-C”), cyclophosphamide, thiotepa, taxanes, such as paclitaxel (Taxol TM , Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (Taxotere TM , Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicin or capecitabine. Also included as suitable anti-cancer drugs are anti-hormonal agents for modulating or inhibiting the hormonal action on tumors, such as anti-estrogens, including for example tamoxifen, (Nolvadex TM)、raloxifene, 4(5)-imidazoles that inhibit aromatase, 4-hydroxytamoxifen, trioxifene, raloxifene, LY 117018, 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; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; Navelbine; Novasine; teniposide; daunomycin; aminopterin; Xeloda; ibandronate; irinotecan-11 (CPT-11); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO), esperamicin A or pemetrexed (Alimta).

[0289] When needed, embodiments of the compounds or compositions of the present disclosure can be used in combination with commonly prescribed anti-cancer drugs, which are such as ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, Alpharadin, avicine, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, aminopterin, anthraquinone, anti-CD22 immunotoxin, anti-neoplastic agent, anti-tumor herbal medicine, apaziquone, atimolol, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, bromotacrolimus, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle non-specific anti-neoplastic agent, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, fomitipin, fostriecin, ICE chemotherapy regimen, IT-101, imetelstat, imiquimod, indolocarbazole, irofulven, lanifibranor, larotaxel, lenalidone, lomotil, leptotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, oteracil, PAC-1, passion fruit, picoplatin, proteasome inhibitor, pteropodine, resiquimod, rubitecan, SN-38, Salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfene, taliridine, tegafur-uracil, Temodar, tesetaxel, trinuclear platinum(IV) nitrate, tris(2-chloroethyl)amine, troxacitabine, uracil mustard, Vadimezan, vinflunine, ZD6126 or zosuquidar.

[0290] M is selected based on desired therapeutic and / or optical properties, such as for treating a particular disease or disorder (e.g., cancer) or producing a particular color and / or fluorescence emission wavelength. In certain embodiments, M is the same each occurrence; however, importantly, note that M need not be the same M each occurrence, and some embodiments include compounds where M is not the same each occurrence. For example, in certain embodiments, each M is not the same and different M moieties are selected to have different therapeutic properties (e.g., cytotoxic and anti-inflammatory). In certain embodiments, each M is not the same and different M moieties are selected to have the same or similar therapeutic properties (e.g., cytotoxic).

[0291] Accordingly, in certain embodiments, at least one occurrence of M is an antineoplastic agent, enediyne antitumor antibiotic, maytansine compound, topoisomerase inhibitor, kinase inhibitor, anthracycline antibiotic, and EGFR inhibitor, or an alkylating agent. In certain embodiments, at least one occurrence of M is an antineoplastic agent, enediyne antitumor antibiotic, maytansine compound, topoisomerase inhibitor, or an alkylating agent. In certain specific embodiments, M is independently, at each occurrence, an antineoplastic agent, enediyne antitumor antibiotic, maytansine compound, topoisomerase inhibitor, kinase inhibitor, anthracycline antibiotic, and EGFR inhibitor, or an alkylating agent. In certain specific embodiments, M is independently, at each occurrence, an antineoplastic agent, enediyne antitumor antibiotic, maytansine compound, topoisomerase inhibitor, or an alkylating agent.

[0292] In certain embodiments, at least one occurrence of M is selected from: auristatin F, monomethyl auristatin F, monomethyl auristatin E, paciltaxol, SN-38, calicheamicin, anthramycin, abbeymycin, chicamycin, DC-81, mazethramycin, neothramycin A, neothramycin B, porothramycin, prothracarcin, sibanomicin, sibiromycin, tomatomycin, DM1 (mertansine), emtansine, irinotecan, camptothecin, topotecan, silatecan, cositecan, elsamitrucin, leotecan, gemtuzumab, belotecan, and rubitecan. In certain embodiments, at least one occurrence of M has one of the following structures:

[0293]

[0294]

[0295] In certain embodiments, each occurrence of M has one of the following structures:

[0296]

[0297]

[0298] In certain embodiments, each M is independently selected from the following:

[0299]

[0300] Although described for purposes of illustration with a specific point of attachment to the remainder of the molecule (i.e., ), the M moiety can be attached via any available point (e.g., at nitrogen, oxygen, carboxyl, carbonyl, etc.). One of ordinary skill in the art can determine the appropriate point of attachment.

[0301] In certain embodiments, at least one occurrence of M is an anti-neoplastic agent (e.g., auristatin F, monomethyl auristatin F, monomethyl auristatin E, paclitaxel, SN-38), enediyne anti-tumor antibiotic (e.g., calicheamicin or more specifically calicheamicin γ1), alkylating agent (e.g., PBD or pyrrolobenzodiazepines), maytansine compounds (e.g., DM1 cytotoxic, emtansine) topoisomerase inhibitor (e.g., SN38, irinotecan, camptothecin, topotecan, silatecan, cositecan, exatecan, letolecan, gemitecan, belotecan, rubitecan).

[0302] In certain embodiments, each occurrence of M is an anti-neoplastic agent (e.g., auristatin F, monomethyl auristatin F, monomethyl auristatin E, paclitaxel, SN-38), enediyne anti-tumor antibiotic (e.g., calicheamicin or more specifically calicheamicin γ1), alkylating agent (e.g., PBD or pyrrolobenzodiazepines), maytansine compounds (e.g., DM1 cytotoxic, emtansine) topoisomerase inhibitor (e.g., SN38, irinotecan, camptothecin, topotecan, silatecan, cositecan, exatecan, letolecan, gemitecan, belotecan, rubitecan).

[0303] In certain embodiments, L a -M has the following structure:

[0304]

[0305] In certain embodiments, L b -M has one of the following structures:

[0306]

[0307]

[0308] or

[0309]

[0310] In further embodiments of any of the foregoing, the Ms are the same. In other embodiments, each M is different. In further embodiments, one or more Ms are the same and one or more Ms are different.

[0311] In certain embodiments, the selected occurrences of M are not the same and different M moieties are selected to have absorption and / or emission for use in a fluorescence resonance energy transfer (FRET) method. For example, in such embodiments, different M moieties are selected such that absorption of radiation at one wavelength causes emission of radiation at a different wavelength via an FRET mechanism. One of ordinary skill in the art can appropriately select exemplary M moieties based on the desired end use. Exemplary M moieties for use in FRET methods include fluorescein and 5-TAMRA (5-carboxytetramethylrhodamine, succinimidyl ester) dyes.

[0312] M can be attached to the remainder of the molecule from any position (i.e., atom) on M. One of ordinary skill in the art will recognize methods for attaching M to the remainder of the molecule. Exemplary methods include the "click" reactions described herein.

[0313] In certain embodiments, M is a fluorescent or colored moiety. Any fluorescent and / or colored moiety can be used, such as those known in the art and commonly used in colorimetric, UV, and / or fluorescence assays. Examples of M moieties useful in different 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, indocyanine, oxacarbocyanine, thiacarbocyanine, or merocyanine); squaraine derivatives and ring-substituted squaraines, including Seta, SeTau, and Square dyes; naphthalene derivatives (e.g., dansyl and prodan derivatives); coumarin derivatives; oxadiazole derivatives (e.g., pyridyl oxazole, nitrobenzoxadiazole, or benzoxadiazole); anthracene derivatives (e.g., anthraquinone, 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., diaminoacridine, acridine orange, acridine yellow); arylmethine derivatives: auramine, crystal violet, malachite green; and tetrapyrrole 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; tamra; Texas Red, and alexa dyes.

[0314] In other embodiments of any of the foregoing, M comprises 3 or more aryl or heteroaryl rings or combinations thereof, such as 4 or more aryl or heteroaryl rings or combinations thereof, or even 5 or more aryl or heteroaryl rings or combinations thereof. In certain embodiments, M comprises 6 aryl or heteroaryl rings or combinations thereof. In other embodiments, the rings are fused. For example, in certain embodiments, M comprises 3 or more fused rings, 4 or more fused rings, 5 or more fused rings, or even 6 or more fused rings.

[0315] In certain embodiments, M is cyclic. For example, in certain embodiments, M is carbocyclic. In other embodiments, M is heterocyclic. In other embodiments of the foregoing, M independently comprises an aryl moiety each time it appears. In some of these embodiments, the aryl moiety is polycyclic. In other more specific instances, the aryl moiety is a fused polycyclic aryl moiety, which can, for example, comprise at least 3, at least 4, or even more than 4 aryl rings.

[0316] In other embodiments of any of the foregoing compounds, M contains at least one heteroatom. For example, in certain embodiments, the heteroatom is nitrogen, oxygen, or sulfur.

[0317] In further embodiments of any of the foregoing, M contains at least one substituent. For example, in certain embodiments, the substituent is fluorine, chlorine, bromine, iodine, amino, alkylamino, arylamino, hydroxy, mercapto, alkoxy, aryloxy, phenyl, aryl, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, carboxyl, sulfonate, amide, or formyl.

[0318] In certain even more specific embodiments of the foregoing, M is dimethylaminostilbene, quinacridone, fluorophenyl-dimethyl-BODIPY, his-fluorophenyl-BODIPY, acridine, terrylene, hexaphenyl, porphyrin, benzopyrene, (fluorophenyl-dimethyl-difluorobora-diazaindacene)phenyl, (bis-fluorophenyl-difluorobora-diazaindacene)phenyl, tetraphenyl, bis-benzothiazole, tris-benzothiazole, bis-naphthyl, bis-anthryl, squarylium, squarylium, 9,10-ethynylanthracene, or terryl group. In other embodiments, M is p-terphenyl, perylene, azobenzene, phenazine, phenanthroline, acridine, thioxanthrene, , rubrene, coronene, cyanine, perylene diimide, or perylene amide or derivatives thereof. In further embodiments, M is a coumarin dye, eosin dye, boron dipyrromethene difluoride dye, ruthenium bipyridine dye, energy transfer dye, thiazole orange dye, polymethine, or N-aryl-1,8-naphthalimide dye.

[0319] In certain embodiments, M is pyrene, perylene, perylene monoimide, or 6-FAM or derivatives thereof. In some other embodiments, M has one of the following structures:

[0320]

[0321] Although the M moiety containing a carboxylic acid group has been described above in its anionic form (CO 2 - ), those skilled in the art will understand that this will vary depending on the pH and include the protonated form (CO 2 H) in different embodiments.

[0322] In certain specific embodiments, the compound is a compound selected from Table 2. The compounds in Table 2 are prepared according to the procedures described in the Examples and their identity can be confirmed by mass spectrometry.

[0323]

[0324]

[0325]

[0326]

[0327]

[0328] Unless otherwise indicated, as used in Table 2 and throughout the application, M has the definition provided for compounds of structure (I). In certain embodiments, M is F, F', F", N', I', D', D", or AF. F, F′, and F″ each represent a fluorescein moiety having the following structures:

[0329]

[0330] “N'” represents the following structure:

[0331]

[0332] “I'” represents the following structure:

[0333]

[0334] “D'” represents the following structure:

[0335]

[0336] “D”” represents the following structure:

[0337]

[0338] “dT” represents the following structure:

[0339]

[0340] Wherein:

[0341] R is H or a direct bond.

[0342] “AF” represents the following structure:

[0343]

[0344] Thus, in certain embodiments, at least one occurrence of M has one of the following structures:

[0345]

[0346]

[0347] In certain more specific embodiments, each occurrence of M has the following structure:

[0348]

[0349] In certain embodiments, treatment includes alleviating or relieving pain or inflammation. In certain embodiments, treatment includes pain control or pain management. In certain specific embodiments, at least one occurrence of M has one of the following structures:

[0350]

[0351] In certain more specific embodiments, each occurrence of M has one of the following structures:

[0352]

[0353] Some embodiments include any of the foregoing compounds conjugated to a targeting moiety (such as an antibody), including the specific compounds provided in Table 2. In certain embodiments, a compound of structure (I) is conjugated to an antibody. In certain embodiments, 1 - 2 compounds of structure (I) are conjugated to an antibody. In certain embodiments, 2 compounds of structure (I) are conjugated to an antibody. In certain embodiments, 3 compounds of structure (I) are conjugated to an antibody. In certain embodiments, 4 compounds of structure (I) are conjugated to an antibody. In certain embodiments, 5 compounds of structure (I) are conjugated to an antibody. In certain embodiments, no more than 5 compounds of structure (I) are conjugated to an antibody.

[0354] In different 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 can be used to react with complementary moieties to form a covalent bond between M and the reactive polymer, said reaction via any number of synthetic methods (such as the "click" reaction above), thereby forming a compound of structure (I). Thus, in different embodiments, a reactive polymer having the following structure (II) or a stereoisomer, salt, or tautomer thereof is used to form a compound of structure (I):

[0355]

[0356] Wherein:

[0357] G, each occurrence independently, is a moiety containing a reactive group or a protected analogue thereof, which is capable of forming a covalent bond with a complementary reactive group;

[0358] L a is, each occurrence independently, an optional physiologically cleavable linker and L b is, each occurrence independently, an optional physiologically non - cleavable linker, provided that La and L b at least one occurrence together with L contains more than 4 carbons;

[0359] L 1 and L 2 are each independently, upon each occurrence, an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene or heteroatom linking group;

[0360] L 3 are each independently, upon each occurrence, an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene or heteroalkynylene linking group;

[0361] R 1 are each independently, upon each occurrence, H, alkyl or alkoxy;

[0362] R 2 and R 3 are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c , Q or a protected form thereof or L';

[0363] R 4 are each independently, upon each occurrence, O - , S - , OZ, SZ or N(R 6 ) 2 , where Z is a cation and each R 6 is independently H or alkyl;

[0364] R 5 are each independently, upon each occurrence, oxo, thioxo or absent;

[0365] R a is O or S;

[0366] R b is OH, SH, O - , S - , OR d or SR d ;

[0367] R c is OH, SH, O - , S - , OR d , OL', SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether or thiophosphoalkyl ether;

[0368] Rd is the counter ion;

[0369] Q, at each occurrence, is independently a moiety comprising a reactive group, or a protected form thereof, which is capable of forming a covalent bond with a complementary reactive group Q′ on the targeting moiety;

[0370] L' is independently at each occurrence a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a linker comprising a covalent bond to a solid support, a linker comprising a covalent bond to a solid support residue, a linker comprising a covalent bond to a nucleoside, or a linker comprising a covalent bond to another compound of structure (I);

[0371] m, at each occurrence, is independently an integer of 0 or greater; and

[0372] n is an integer of 1 or greater.

[0373] In certain embodiments, one occurrence of G comprises a fluorescent dye moiety.

[0374] In certain embodiments, the reactive polymer is selected from Table 3 below.

[0375]

[0376]

[0377] Certain embodiments are directed to therapeutically effective fluorescent compounds, provided that at least one occurrence of M is not a fluorescent dye and at least one occurrence of M is a fluorescent dye. Therapeutically effective fluorescent compounds include compounds comprising 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 upon excitation with light, such as ultraviolet light.

[0378] The "tunability" of the embodiments of the compounds disclosed herein means that by appropriate selection of variables in any of the aforementioned compounds, one skilled in the art can obtain compounds having a desired and / or predetermined molar fluorescence (molar brightness). The "tunability" of certain embodiments of the compounds allows the user to easily obtain compounds having a desired fluorescence and / or color for a particular assay. Although all variables may have an effect on the molar fluorescence of certain embodiments of the compounds disclosed herein, it is believed that M, L 3 The appropriate selection of m and n plays an important role in the molar fluorescence of the disclosed compound embodiments. Therefore, in one embodiment, a method for obtaining a compound with a desired molar fluorescence is provided, the method comprising selecting an M moiety with a known fluorescence, preparing a compound of structure (I) comprising the M moiety, and 3 , m, and n are selected appropriately to achieve the desired molar fluorescence.

[0379] For ease of illustration, various compounds containing phosphorus moieties (e.g., phosphates, etc.) are present in anionic form (e.g., -OPO(OH)O - 、-OPO 3 2- Those skilled in the art will readily appreciate that charge is dependent on pH, and that uncharged (e.g., protonated or salt, such as sodium or other cation) forms are also included within the scope of embodiments of the present disclosure.

[0380] In various other embodiments, compositions comprising any of the foregoing compounds and one or more targeting moieties (e.g., antibodies, cell surface receptor antagonists, cell surface receptor agonists, etc.) are provided. In certain embodiments, use of such compositions in methods for treating a disease is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structure (I) or a composition comprising a compound of structure (I), wherein each M is independently a biologically active moiety effective for treating a disease.

[0381] Drug composition

[0382] One embodiment provides a composition comprising a compound according to any one of the embodiments disclosed herein and a pharmaceutically acceptable carrier.

[0383] 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 connection, wherein the plurality of conjugates have at least 90% structural homogeneity. In a more specific embodiment, the plurality of conjugates have at least 95% structural homogeneity. In a related embodiment, the plurality of conjugates have greater than 99% structural homogeneity. In certain embodiments, the single connection is a connection to a polymer backbone comprising two or more biologically active moieties covalently bound thereto. In some of the foregoing embodiments, the one or more conjugates comprise a compound of structure (I).

[0384] In certain embodiments, each conjugate is independently a compound of structure (I), wherein R 2 and R 3 One of them is -OP(=R a )(R b )OL' or L', and L' is an antibody or a linker comprising a covalent bond to an antibody.

[0385] Other embodiments relate to pharmaceutical compositions. The pharmaceutical compositions comprise a compound of any one (or more) of structures (I) and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In further embodiments, the pharmaceutical composition comprises a compound of structure (I) and an additional therapeutic agent (e.g., an anti-cancer agent). Non-limiting examples of such therapeutic agents are described below.

[0386] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0387] In certain embodiments, the compound of structure (I) is administered in a local rather than a systemic manner, e.g., by directly injecting the compound into an organ, typically in a depot or sustained release formulation. In a specific embodiment, a long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Additionally, in other embodiments, in a targeted drug delivery system, e.g., in liposomes coated with an organ-specific antibody, the drug is delivered. In such an embodiment, the liposomes target the organ and are selectively taken up by the organ. In other embodiments, the compound of structure (I) is provided in the form of an immediate release formulation, an extended release formulation, or an intermediate release formulation. In other embodiments, the compound of structure (I) is administered topically.

[0388] Compounds of structure (I) are effective over a wide dosage range. For example, in the treatment of adults, doses of 0.01 - 1000 mg, 0.5 - 100 mg, 1 - 50 mg / day, and 5 - 40 mg / day are examples of doses used in certain embodiments. An exemplary dose is 10 - 30 mg / day. The exact dose will depend on the route of administration, the form of the compound being administered, the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

[0389] In certain embodiments, the compound of structure (I) is administered in a single dose. Generally, such administration will be by injection, e.g., intravenous injection, in order to rapidly introduce the agent. However, other routes may also be used as appropriate. A single dose of the compound of structure (I) may also be used to treat acute conditions.

[0390] In certain embodiments, the compounds of structure (I) are administered in multiple doses. In certain embodiments, the administration is about once, twice, three times, four times, five times, six times or more than six times per day. In other embodiments, the administration is about once per month, once every two weeks, once per week or once every other day. In another embodiment, the compounds of structure (I) and another agent are co-administered about once to about six times per day. In another embodiment, the administration of the compounds of structure (I) and the agent lasts less than about 7 days. In another embodiment, the administration lasts more than about 6, 10, 14, 28 days, two months, six months or one year. In certain cases, continuous administration can be achieved and maintained as long as needed.

[0391] The administration of the compounds of structure (I) can continue as long as needed. In certain embodiments, the compounds of structure (I) are administered for more than 1, 2, 3, 4, 5, 6, 7, 14 or 28 days. In certain embodiments, the compounds of structure (I) are administered for less than 28, 14, 7, 6, 5, 4, 3, 2 or 1 day. In certain embodiments, the compounds of structure (I) are administered chronically on an ongoing basis, for example for treating chronic effects.

[0392] In certain embodiments, the compounds of structure (I) are administered in a dosage. It is known in the art that, due to the inter-subject variability of compound pharmacokinetics, the individualization of the dosing regimen is necessary for optimal treatment. Taking into account the disclosure of the present invention, the dosing of the compounds for the present disclosure can be found by routine experimentation.

[0393] In certain embodiments, the compounds of structure (I) are formulated into pharmaceutical compositions. In specific embodiments, one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate processing of the active compounds into pharmaceutically acceptable formulations, are used to formulate the pharmaceutical compositions in a conventional manner. Suitable formulations depend on the chosen route of administration. Any pharmaceutically acceptable technique, carrier, and excipient are suitable for formulating the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999).

[0394] The present disclosure provides pharmaceutical compositions that comprise a compound of structure (I) and a pharmaceutically acceptable diluent, excipient, or carrier. In certain embodiments, the described compounds are administered as pharmaceutical compositions, wherein the compounds of structure (I) are mixed with other active ingredients, such as in combination therapies. All combinations of active substances set forth in the following combination therapies section and throughout this disclosure are encompassed herein. In specific embodiments, the pharmaceutical composition comprises one or more compounds of structure (I).

[0395] The pharmaceutical compositions used herein represent a mixture of a compound of structure (I) with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates the administration of the compound to an organism. In certain embodiments of practicing the therapeutic methods or uses provided herein, a therapeutically effective amount of the compound of structure (I) provided herein is administered in a pharmaceutical composition to a mammal suffering from a 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 alone or in combination with one or more therapeutic agents (as components of a mixture).

[0396] 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, by way of example only, physiologically compatible buffers such as Hank's solution, Ringer's solution, or saline buffer. In other embodiments, one or more compounds of structure (I) are formulated for transmucosal administration. In a specific embodiment, the transmucosal formulation includes a penetrant suitable for the barrier to be penetrated. In other embodiments in which the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In a specific embodiment, such solutions include physiologically compatible buffers and / or excipients.

[0397] In another embodiment, the compounds described herein are formulated for oral administration. The compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In different embodiments, the compounds described herein are formulated into oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, pastes, suspensions, etc.

[0398] In certain embodiments, a pharmaceutical composition for oral use is obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the granule mixture with suitable auxiliaries (if required) to obtain tablets or dragee cores. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose products such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, a disintegrant is optionally added. Disintegrants include, by way of example only, croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.

[0399] In one embodiment, one or more suitable coatings are provided for the dosage forms such as dragee cores and tablets. In specific embodiments, a concentrated sugar solution is used to coat the dosage forms. The sugar solution optionally contains 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 are also optionally added to the coating for identification purposes. Additionally, dyes and / or pigments are optionally used to characterize different combinations of the active compound dosage.

[0400] 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 a plasticizer such as glycerol or sorbitol. In specific embodiments, the push-fit capsules contain the active ingredient admixed with one or more fillers. Fillers include, by way of example only, lactose, binders such as starch and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin or liquid polyethylene glycol. Additionally, stabilizers are optionally added.

[0401] In other embodiments, a therapeutically effective amount of at least one compound described herein is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In other embodiments, the compounds described herein are formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In a specific embodiment, injectable formulations are presented in unit dosage forms (e.g., in an ampoule) or in multi-dose containers. A preservative is optionally added to the injection formulation. In other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection, such as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. Parenteral injection formulations optionally contain formulating agents such as suspending, stabilizing, and / or dispersing agents. In a specific embodiment, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In a further embodiment, a suspension of the active compound (e.g., a compound of structure (I)) is prepared as a suitable oily injection suspension. Suitable lipophilic solvents or vehicles for the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the compound to permit the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0402] In other embodiments, the compounds of structure (I) are administered topically. The compounds described herein are formulated into a variety of topical administration compositions, such as solutions, suspensions, lotions, gels, pastes, sticks, balms, creams, or ointments. Such pharmaceutical compositions optionally contain solubilizing agents, stabilizing agents, tonicity enhancing agents, buffers, and preservatives.

[0403] In other embodiments, the compounds of structure (I) are formulated for transdermal administration. In specific embodiments, the transdermal formulations employ a transdermal delivery device and a transdermal delivery patch, and can be a lipophilic emulsion or a buffered aqueous solution, dissolved and / or dispersed in a polymer or adhesive. In various embodiments, such patches are configured for continuous, pulsatile or on-demand delivery of a pharmaceutical agent. In additional embodiments, transdermal delivery of the compounds of structure (I) is accomplished by means of an iontophoresis patch or the like. In certain embodiments, the transdermal patch provides controlled delivery of the compounds of structure (I). In specific embodiments, the rate of absorption is slowed by using a rate controlling membrane 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 pharmaceutically acceptable solvents that are absorbable and assist in passing through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage that includes a backing member, a reservoir containing the compound optionally with a carrier, an optional rate controlling barrier (to deliver the compound to the skin of the host at a controlled and predetermined rate over an extended period of time), and means for securing the device to the skin.

[0404] In other embodiments, the compounds of structure (I) are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders. Using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas), a pharmaceutical composition of any compound of structure (I) is conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer. In specific embodiments, the dosage unit of the pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, for example, by way of illustration only, capsules and cartridges of gelatin for use in an inhaler or insufflator are formulated as a powder mixture containing the compound and a suitable powder base such as lactose or starch.

[0405] In other embodiments, 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, which contain conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, etc. In the suppository form of the composition, low melting point waxes such as, but not limited to, mixtures of fatty acid glycerides are optionally combined with melted cocoa butter.

[0406] In certain embodiments, the pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers, which carriers include excipients and auxiliaries that facilitate processing of the active compounds into pharmaceutically acceptable preparations. Suitable formulations depend on the chosen route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as appropriate. The pharmaceutical compositions containing the compounds of structure (I) are prepared in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0407] The pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one compound of structure (I) (described herein as the active ingredient). The active ingredient is in the form of the free acid or free base, or in the form of a pharmaceutically acceptable salt. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystal forms (also referred to as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomeric forms of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass the unsolvated form as well as the solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein. Further, the pharmaceutical compositions optionally include other drugs or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solubilizing agents, salts for regulating osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0408] Methods for preparing compositions containing the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form solids, semi-solids, or liquids. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The forms of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid prior to use, or as emulsions. These compositions also optionally contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, etc.

[0409] In certain embodiments, a pharmaceutical composition comprising a compound of formula (I) exemplary takes a liquid form, wherein the agent is present in a solution, a suspension, or both. Generally, when the composition is administered as a solution or a suspension, a first portion of the agent is present in the solution and a second portion of the agent is present as particles in a suspension in a liquid matrix. In certain embodiments, the liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

[0410] 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 crosslinked carboxyl-containing polymers. Certain pharmaceutical compositions described herein contain 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.

[0411] Useful pharmaceutical compositions also optionally include solubilizing agents that facilitate the dissolution of the compound of formula (I). The term "solubilizing agent" generally includes agents that result in the formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, e.g., polysorbate 80, can be used as solubilizing agents, and ophthalmically acceptable diols, polyglycols (e.g., polyethylene glycol 400), and glycol ethers can also be used as solubilizing agents.

[0412] In addition, useful pharmaceutical compositions optionally include one or more pH regulators or buffers, 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(hydroxymethyl)aminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in an amount required to maintain the pH of the composition within an acceptable range.

[0413] In addition, useful compositions also optionally include one or more salts in an amount required to bring the osmolality of the composition to an acceptable range. Such salts include salts having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0414] Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as phenylmercuric borate (merfen) and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0415] Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, for example, polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkyl phenyl ethers, for example, octoxynol 10, octoxynol 40.

[0416] Still other useful compositions include one or more antioxidants to enhance chemical stability when needed. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0417] In certain embodiments, the aqueous suspension composition is packaged in a single-dose non-reclosable container. Alternatively, a multi-dose reclosable container is used, in which case a preservative is typically included in the composition.

[0418] 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, sustained release systems are used to deliver the compounds described herein, such as a semipermeable matrix of a solid hydrophobic polymer containing a therapeutic agent. A variety of sustained release materials are useful herein. In certain embodiments, the sustained release capsules release the compound for weeks up to over 100 days. Additional strategies for protein stabilization are employed depending on the chemical nature and biological stability of the therapeutic agent.

[0419] In certain embodiments, the formulations described herein contain one or more antioxidants, metal chelators, thiol-containing compounds, and / or other common stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0420] In certain embodiments, the concentration of one or more compounds provided in the pharmaceutical composition is less than 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%, 0.05%, 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.

[0421] In certain embodiments, the concentration of one or more compounds is greater than 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%, 0.01%, 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.

[0422] In certain embodiments, the concentration of one or more compounds is in the range of 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 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, from about 1% to about 10% w / w, w / v or v / v.

[0423] In certain embodiments, the concentration of one or more compounds is in the range of from about 0.001% to about 10%, from about 0.01% to about 5%, from about 0.02% to about 4.5%, from about 0.03% to about 4%, from about 0.04% to about 3.5%, from about 0.05% to about 3%, from about 0.06% to about 2.5%, from about 0.07% to about 2%, from about 0.08% to about 1.5%, from about 0.09% to about 1%, from about 0.1% to about 0.9% w / w, w / v or v / v.

[0424] In certain embodiments, the amount of one or more compounds is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g or 0.0001 g.

[0425] In certain embodiments, the amount of one or more compounds exceeds 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g or 10 g.

[0426] In certain embodiments, the amount of one or more compounds ranges from 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.

[0427] Therapeutic method

[0428] The compounds of the present disclosure can be used to treat diseases. The compounds disclosed herein provide a targeting scheme for drug delivery strategies. In addition, due to their ability to incorporate almost any therapeutic moiety, the compounds of structure (I) offer distinct advantages over previously known compounds. The bioactive moiety (e.g., therapeutic agent) can be reversibly or irreversibly linked and delivered to the target.

[0429] Thus, in certain embodiments, the compounds can be used in different methods of treating a disease or disorder. One embodiment provides a method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structure (I) or a composition comprising a compound of structure (I), wherein at least one M is a bioactive moiety effective for treating the disease. In a more specific embodiment, each M is a bioactive moiety effective for treating the disease.

[0430] In certain embodiments, the disease bioactive moiety degrades a protein. In certain more specific embodiments, the protein is an amyloid protein or a tau protein. In certain embodiments, the disease is amyloidosis or Alzheimer's disease. In certain embodiments, the disease is prostate cancer, pancreatic cancer or breast cancer. In certain embodiments, the disease is a tumor disease, a cardiovascular disease, a renal disease, a metabolic disease or a respiratory disease.

[0431] In certain embodiments, the disease is a lung disease or a central nervous system disease. In a more specific embodiment, the disease is metastatic castration-resistant prostate cancer or metastatic breast cancer. In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of the embodiments disclosed herein or a composition according to any one of the embodiments disclosed herein, wherein each M is independently a bioactive moiety effective for treating the disease.

[0432] In certain embodiments, the disease is cancer and each M is independently an anti-cancer drug. In certain embodiments, at least one occurrence of M has one of the following structures:

[0433]

[0434]

[0435] In certain embodiments, each occurrence of M has one of the following structures:

[0436]

[0437]

[0438] For example, in certain embodiments, the present 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 lymphocytic leukemia, acute myeloid leukemia, renal cell carcinoma, colorectal carcinoma, epithelial carcinoma, pancreatic and gastric cancer, renal cell cancer, non-Hodgkin lymphoma, metastatic renal cell carcinoma, malignant mesothelioma, pancreatic, ovarian, and / or lung adenocarcinoma, B-cell malignancies, breast cancer, melanoma, relapsed multiple myeloma, small cell lung cancer, CD22-positive B-cell malignancies, Hodgkin lymphoma / anaplastic large cell lymphoma, or HER2-positive breast cancer.

[0439] In certain of the foregoing embodiments, the disease is cancer. For example, in certain embodiments, the cancer is breast cancer, non-Hodgkin 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 lymphoma, lymphoma, mesothelioma, non-small cell lung cancer, recurrent head and neck cancer, or a combination thereof.

[0440] Certain embodiments also relate to methods of treating a hyperproliferative disorder in a mammal (e.g., a human), the methods comprising administering to the mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. In certain embodiments, the methods relate to treating cancers such as acute myeloid leukemia, cancers in adolescents, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt 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, ductal carcinoma in situ (DCIS) of the extrahepatic, embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of unknown primary, midline tract carcinoma, oral cancer, 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 of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric (stomach) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, rare cancers in childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.In certain embodiments, the method involves treating non-cancerous hyperproliferative disorders such as benign skin hyperplasia (e.g., psoriasis), restenosis benign hyperplasia, or benign prostatic hyperplasia (e.g., benign prostatic hypertrophy (BPH)).

[0441] Certain specific embodiments provide methods for treating lung cancer, the methods comprising administering to a subject in need thereof an effective amount of any one of the above-described compounds (or a pharmaceutical composition comprising them). In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In other embodiments, the lung cancer is small cell lung cancer. Other lung cancers treatable with the disclosed compounds include, but are not limited to, adenomatous tumors, carcinoid tumors, and undifferentiated carcinomas.

[0442] Thus, in certain embodiments of the foregoing methods, R 2 is a linker comprising a covalent linkage to a targeting moiety such as an antibody, a cell surface receptor antagonist, a cell surface receptor agonist, etc. For example, an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, folic acid, or a MET inhibitor.

[0443] In even more embodiments, the method further comprises inducing apoptosis.

[0444] In certain embodiments, the method of treating a disease further comprises:

[0445] (a) providing a compound of structure (I), for example, wherein R 2 or R 3 is one a linker comprising a covalent bond to an analyte molecule, and R 2 or R 3 is the other is H, OH, alkyl, alkoxy, alkyl ether, or -OP(=R a )(R b )R c ; and

[0446] (b) detecting the compound by its visual properties.

[0447] In certain embodiments, the analyte molecule is a nucleic acid, an amino acid, or a polymer thereof (e.g., a polynucleotide or a polypeptide). In more embodiments, the analyte molecule is an enzyme, a receptor, a receptor ligand, an antibody, a glycoprotein, an aptamer, or a prion.

[0448] In certain embodiments, the providing further comprises co-administering the compound of structure (I) with the analyte molecule.

[0449] Accordingly, embodiments of the compounds of the present invention can be used in any number of methods, including, but not limited to: drug delivery; quantifying apoptosis; effecting therapeutic drug delivery; quantifying apoptosis; and diagnosing and treating diseases such as blood cancers.

[0450] In addition to the above methods, embodiments of the compounds of structure (I) can be used in different disciplines and methods, including, but not limited to: cancer treatment and imaging, such as by including in the compounds of structure (I) targeting moieties such as antibodies or sugars or other moieties that preferentially bind to cancer cells; and / or drug delivery.

[0451] In certain embodiments, the treatment method includes treating a tumor having tumor cells that have tumor cell receptors. In certain embodiments, the tumor cells have receptors in the range of 1,000 to 100,000, 1,000 to 50,000, 1,000 to 25,000 receptors, 1,000 to 10,000 receptors per cell. For example, in certain embodiments, the tumor cells have about 1,000, about 10,000 or less than 100,000 receptors per cell.

[0452] Embodiments of the present disclosure are not limited to the treatment of cancer. In fact, there is no particular limitation on the types of diseases, syndromes, disorders, indications, and treatments to which the compounds and methods of the present disclosure can be applied. That is, the present disclosure provides compounds, compositions, and methods for treating or preventing a variety of diseases. For example, by selecting a suitable biological moiety or combination of biological moieties, the compounds and compositions disclosed herein can be modified to treat a particular disease as needed. Based on the present disclosure, it will be apparent to those of ordinary skill in the art how to modify the currently disclosed compounds and compositions in order to treat, prevent, or target a disease, syndrome, or clinical indication.

[0453] Accordingly, the methods of the present disclosure include methods of administering the compounds of the present disclosure for treating a disease, disorder, or symptom of a disease or disorder, preventing a disease or symptom of a disease or disorder, prophylactically treating a disease, disorder, or symptom of a disease or disorder, identifying a subject at risk and treating a disease, disorder, or symptom of a disease or disorder, slowing or halting the progression of a disease, disorder, or symptom of a disease or disorder, increasing the survival rate of a subject having a disease, disorder, or symptom of a disease or disorder, improving the symptoms of a disease, disorder, or symptom of a disease or disorder, etc.

[0454] In addition, diseases, disorders, symptoms, ailments, side effects, illnesses, syndromes, biological events, biological abnormalities, medical conditions, being sick, morbidity, pathologies, etc. are intended to be included in the present disclosure and are not particularly limited; examples 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 diseases, neurological disorders, liver disorders, lung infections, heart conditions and disorders, mental diseases (e.g., eating disorders, mood disorders, personality disorders), norovirus infections, blood-borne pathogens, protozoal infections, viral hepatitis, HIV / AIDS, diabetes, sclerosis, Crohn's and colitis, lupus, arthritis, allergy and asthma, celiac disease, polychondritis, scleroderma, liver diseases, heart diseases, acquired diseases, acute diseases, chronic conditions or diseases, congenital diseases or disorders, genetic diseases or disorders, iatrogenic diseases, idiopathic diseases, primary diseases, secondary diseases, advanced diseases or the like. The foregoing may be acute, chronic, clinical, flare-up, progressive, refractory, subclinical, local, disseminated, systemic, etc. Any of the foregoing examples may be caused by airborne, food-borne, infectious or lifestyle events.

[0455] In certain embodiments, the bioactive moiety is an antibiotic drug. In certain specific embodiments, M is independently an antibiotic drug each time it appears, and the targeting moiety is an antibody specific for an infectious disease antigen. Antibiotic drugs as used herein include derivatives. That is, the antibiotic drug has been modified or derivatized such that the drug can be conjugated or linked to another molecule (e.g., to include the Q moiety).

[0456] Exemplary antibiotic moieties can include compounds that treat bacterial species including, 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., 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., Treponema pallidum, Vibrio cholera, and Yersinia pestis.In addition, bacterial species that can 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, including Acinetobacter baumannii, Klebsiella pneumoniae, and Enterobacter cloacae. In another embodiment, the bacterial diseases or disorders that can be treated with a compound of structure (I) can be, for example, anthrax, pertussis, Lyme disease, brucellosis, gastrointestinal abscess, relapsing fever, enteritis, bloody diarrhea, atypical pneumonia, botulism, tetanus, bacterial meningitis, gangrene, bacterial endocarditis, leprosy, Legionnaire’s disease, leptospirosis, tuberculosis, plague, cholera, necrotizing fasciitis, typhoid, and nocardiosis.

[0457] In certain more specific embodiments, the antibiotic drug is a β-lactam antibiotic. β-lactam antibiotics include compounds comprising penicillins, monobactams, carbapenems, and cephalosporins. In certain embodiments, for at least one occurrence of M or at each occurrence of M, M is oxacillin, dicloxacillin, nafcillin, amoxicillin, ampicillin, piperacillin, cloxacillin, flucloxacillin, methicillin, oxacillin, temocillin, benzylpenicillin (penicillin G), amoxicillin (penicillin O), phenoxymethylpenicillin (penicillin V), mecillinam, carbenicillin, ticarcillin, azlocillin, mezlocillin, cefazolin, cephalexin, cephalosporin C, cefotaxime, cefdinir, cefepime, biapenem, doripenem, ertapenem, faropenem, imipenem, meropenem, panipenem, razupenem, temocillin, thienamycin, aztreonam, tigemonam, nocardicin A, α,ε-diamino-β-hydroxyheptanedioic acid β-lactam (Tabtoxinine β-lactam), lenapenem, tomopenem, cefazolin, cephalexin, cefadroxil, cefapirin, cefoxitin, cefazedone, cefradine, cefroxadine, ceftezole, cefaloridine, cefacetrile, cefalonium, cefalothin, cefatrizine, cefaclor, cefotetan, cefoxitin, cefprozil, cefuroxime, cefuroxime axetil, cefamandole, cefminox, cefonicid, cefretan, cefotiam, cefbuperazone, cefozopran, cefmetazole, carbacephem (loracarbef), cefixime, ceftriaxone, ceftazidime, cefoperazone, cefdinir, cefcapene, cefdaloxime, cefozopran, cefotaxime, cefpimizole, cefsulodin, cefatrizine, cefotiam, cefathiamidine, oxacephem, flomoxef, cefepime, cefozopran, cefquinome, ceftobiprole, cefovecin, cefquinome, or cefovecin.

[0458] In other embodiments, the antibiotic drug is a tetracycline antibiotic. More specifically, in certain embodiments, for at least one occurrence of M or at each occurrence of M, M is doxycycline, tetracycline, minocycline, demeclocycline, chlortetracycline, oxytetracycline, lymecycline, metacycline, rolitetracycline, tigecycline, eravacycline, sarecycline, omadacycline, clomocycline, demeclocycline, methacycline, metacycline, or pipacycline.

[0459] In other embodiments, the antibiotic drug is a quinolone antibiotic. Quinolone antibiotics include the large subgroup fluoroquinolones. Specifically, in certain embodiments, for at least one occurrence of M or at each occurrence of M, M is oxolinic acid (Uroxin), rosoxacin (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 (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), ozagoxacin, tosufloxacin, cinoxacin (Cinobac), nalidixic acid (NegGam, Wintomylon), pipemidic acid (Panacid), pipemidic acid (Dolcol), nemonoxacin or enoxacin.

[0460] In another embodiment, the antibiotic drug is a lincosamide antibiotic. In certain embodiments, for at least one occurrence of M or at each occurrence of M, M is clindamycin, lincomycin or piromidic acid.

[0461] In certain embodiments, the antibiotic drug is a macrocyclic antibiotic. Macrocyclic antibiotics include the group consisting of macrolides, ketolides, fluoroketolides and polyenes. In certain embodiments, for at least one occurrence of M or at each occurrence of M, M is amphotericin B, azithromycin, boromycin, carbomycin A, cethromycin, clarithromycin, dirithromycin, erythromycin, fidaxomicin, flurithromycin, josamycin, kitasamycin, midecamycin, oleandomycin, rifampicin (or rifampin), rifabutin, rifapentine, rifalazil, rifaximin, rifamycin SV, rokitamycin, roxithromycin, solithromycin, spiramycin, telithromycin, triacetyloleandomycin or tylosin.

[0462] In certain embodiments, the antibiotic drug is a sulfonamide antibiotic (sulfanilamide or sulfa drug). Sulfonamide antibiotics exert their bacteriostatic effect by inhibiting dihydropteroate synthase (DHPS), thereby interrupting folic acid synthesis and the organism's ability to synthesize nucleic acids. In certain embodiments, for at least one occurrence of M or at each occurrence of M, M is sulfisoxazole, sulfacetamide, sulfadiazine, sulfamethazine, sulfisoxazole, sulfisomidine, sulfanitran, sulfadimethoxine, sulfamethoxypyridazine, sulfamethoxazole, sulfadoxine, sulfalin, Terephtyl, sulfamethoxazole, or sulfathiazole.

[0463] In certain embodiments, the antibiotic drug is a glycopeptide antibiotic. In certain embodiments, for at least one occurrence of M or at each occurrence of M, M is vancomycin, teicoplanin, telavancin, ramoplanin, oritavancin, or decaplanin.

[0464] In certain embodiments, the antibiotic drug is an aminoglycoside antibiotic. Aminoglycoside antibiotics exert their biological effects through protein synthesis inhibition. In more specific embodiments, for at least one occurrence of M or at each occurrence of M, M is streptomycin, dihydrostreptomycin, neomycin, neomycin B, paromomycin, ribostamycin, kanamycin, amikacin, arbekacin, kanamycin B, dibekacin, tobramycin, spectinomycin, hygromycin B, apramycin, puromycin, nosiheptide, gentamicin, netilmicin, sisomicin, plazomicin, isepamicin, verdamycin, or asmicin.

[0465] In certain embodiments, the antibiotic drug is an oxazolidone antibiotic. Oxazolidone antibiotics exert their biological effects through protein synthesis inhibition. In certain specific embodiments, for at least one occurrence of M or at each occurrence of M, M is eperzolid, linezolid, Posizolid, Radezolid, Ranbezolid, Sutezolid, or tedizolid.

[0466] In certain embodiments, for at least one occurrence of M or at each occurrence of M, M is platensimycin, chloramphenicol, metronidazole, trimethoprim, adefovir dipivoxil, brodimoprim, clofazimine, ilaprazole, tetroxoprim, or nitrofurantoin.

[0467] In certain embodiments, the bioactive moiety is an antifungal agent. In certain specific embodiments, M is independently an antifungal agent each time it appears, and the targeting moiety is an antibody specific for an infectious disease antigen. Antifungal agents used herein include derivatives. That is, the antifungal agent has been modified or derivatized such that the agent can be conjugated or linked to another molecule (e.g., to include moiety Q).

[0468] 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 in need of treatment include emerging drug-resistant strains such as Candida auris, Candida glabrata, and Candida krusei, which exhibit significant resistance to existing treatment options and pose public health concerns due to their frequent healthcare facility-acquired infections.

[0469] In certain embodiments, for at least one occurrence of M or each time M appears, the fungal disease or disorder that can be treated with the compound of structure (I) can be, for example, aspergillosis, invasive candidiasis, onychomycosis, or histoplasmosis.

[0470] In certain embodiments, the antifungal agent is a polyene. In more specific embodiments, for at least one occurrence of M or each time M appears, M is 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 azoles, which can be divided into imidazoles such as bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole; triazoles such as abaconazole, isavuconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, and voriconazole; and thiazole, abafungin.

[0471] In certain more specific embodiments, for at least one occurrence of M or each time M appears, M is ciclopirox, flucytosine or 5-fluorocytosine, griseofulvin, tolnaftate, orotomide, miltefosine, piroctone olamine, iodochlorhydroxyquin, clioquinol, acridine sulfanilamide, or farnesol.

[0472] In certain embodiments, the bioactive moiety is an anti-parasitic drug. In certain specific embodiments, M is independently an anti-parasitic drug each time it appears, and the targeting moiety is an antibody specific for an infectious disease antigen. Anti-parasitic drugs as used herein include derivatives. That is, the anti-parasitic drug has been modified or derivatized such that the drug can be conjugated or linked to another molecule (e.g., to include the Q moiety).

[0473] Parasites for which the compounds of the present disclosure can treat associated diseases include protozoa such as Plasmodium sp. (malaria), Leishmania sp. (leishmaniasis), Trypanosoma sp. (African trypanosomiasis / sleeping sickness, Chagas disease), Giardia sp. (giardiasis / beaver fever), Toxoplasma gondii (toxoplasmosis), and Cryptosporidium sp. (cryptosporidiosis); and amobae such as Entamoeba histolytica (amoebiasis).

[0474] In certain embodiments, for at least one occurrence of M or each time M appears, M is chloroquine, amodiaquine, pyrimethamine (Daraprim), proguanil, sulfadoxine, sulfamethoxypyridazine, mefloquine, paromomycin, atovaquone, primaquine, artemisinin, amphotericin B, artemether, artesunate, dihydroartemisinin, artemotil, doxycycline, clindamycin, halofantrine, diloxanide, eflornithine, furazolidone, melarsoprol, metronidazole, nitrofurazone, nitazoxanide, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, quipyramine, or tinidazole.

[0475] In certain embodiments, the bioactive moiety is an antiviral agent. In certain specific embodiments, M is independently an antiviral agent each time it appears, and the targeting moiety is an antibody specific for an infectious disease antigen. Antiviral agents as used herein include derivatives. That is, the antiviral agent has been modified or derivatized such that the agent can be conjugated or linked to another molecule (e.g., to include the Q moiety).

[0476] 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.

[0477] In certain embodiments, for at least one occurrence of M or at each occurrence of M, M is pegylated interferon-α-2a / 2b, entecavir, tenofovir disoproxil fumarate, asunaprevir, tribavirin, beclabuvir, daclatasvir, dasabuvir, grazoprevir, paritaprevir, simeprevir, sofosbuvir, or velpatasvir.

[0478] In other embodiments, the antiviral agent treats HIV. In certain embodiments, for at least one occurrence of M or at each occurrence of M, 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.

[0479] In another embodiment, the antiviral agent treats influenza. For example, in certain embodiments, for at least one occurrence of M or at each occurrence of M, M is laninamivir, oseltamivir, peramivir, zanamivir, or baloxavir marboxil.

[0480] In certain embodiments, the antiviral agent treats Ebola. For example, in certain embodiments, for at least one occurrence of M or at each occurrence of M, M is favipiravir, brincidofovir, galidesivir (BCX4430, immucillin-A), JK-05, or AVI-7537.

[0481] In certain embodiments, the bioactive moiety is a drug for treating immunological or anti-inflammatory disorders. In certain specific embodiments, M is independently an immunological drug at each occurrence, and the targeting moiety is an antibody specific for a disease / condition-related antigen. Immunological drugs as used herein include derivatives. That is, the immunological drug has been modified or derivatized such that the drug can be conjugated or linked to another molecule (e.g., to include the Q moiety).

[0482] In certain embodiments, the disease or disorder is asthma, rheumatoid arthritis, lupus, multiple sclerosis, psoriasis, Crohn's disease, colitis, or an organ rejection therapy. Thus, in certain embodiments, for at least one occurrence of M or at each occurrence of M, M is a corticosteroid (e.g., prednisone), methotrexate, mycophenolate mofetil, or azathioprine. In certain embodiments, the compound of structure (I) comprises a covalent bond with a therapeutic antibody such as Humira (i.e., adalimumab).

[0483] In certain embodiments, the disease or disorder is psoriasis. Thus, in certain embodiments, for at least one occurrence of M or at each occurrence of M, M is acitretin, prednisone, retinoids, methotrexate, cyclosporine, thioguanine, etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), ustekinumab (Stelara), golimumab (Simponi), apremilast (Otezla), secukinumab (Cosentyx), or ixekizumab (Taltz).

[0484] In certain embodiments, the disease or disorder is Crohn's disease or colitis. In certain more specific embodiments, for at least one occurrence of M or at each occurrence of M, M is sulfasalazine, mesalamine, balsalazide, olsalazine, prednisone, hydrocortisone, mercaptopurine, azathioprine, cyclosporine, methotrexate, budesonide, ciprofloxacin, metronidazole, or azathioprine. In certain embodiments, the compound of structure (I) comprises a covalent bond with a therapeutic antibody such as infliximab (Remicade), adalimumab (Humira), vedolizumab (Entyvio), certolizumab, natalizumab (Tysabri), ustenkinumab (Stelara), or golimumab (Simponi).

[0485] In certain embodiments, the disease or disorder is asthma. In certain embodiments, for at least one occurrence of M or at each occurrence of M, M is a corticosteroid, a long-acting β-agonist (e.g., salmeterol, leukotrienes), omalizumab, zileuton, or fluticasone.

[0486] In certain embodiments, the disease or disorder is multiple sclerosis. In certain embodiments, for at least one occurrence of M or at each occurrence of M, M is hydroxychloroquine, methotrexate, azathioprine, mycophenolate, prednisone, methylprednisolone, belimumab, or rituximab (Rituxan).

[0487] In certain embodiments, the disease or disorder is organ rejection. In more specific embodiments, for at least one occurrence of M or at each occurrence of M, M is prednisone, hydrocortisone, sirolimus, everolimus, cyclosporine, tacrolimus, mycophenolate, or azathioprine, basiliximab, daclizumab, or rituximab.

[0488] In certain embodiments, the disease or disorder is lupus. In more specific embodiments, for at least one occurrence of M or at each occurrence of M, M is hydroxychloroquine, methotrexate, azathioprine, mycophenolate, prednisone, methylprednisolone, belimumab, or rituximab (Rituxan).

[0489] In certain embodiments, the disease or disorder is rheumatoid arthritis. In more specific embodiments, for at least one occurrence of M or at each occurrence of M, 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).

[0490] In certain embodiments, the diseases or disorders to be treated by administering a compound of structure (I) are: ablation of the bone marrow; acute sciatica pain; allergic asthma; ALS and multiple sclerosis; Alzheimer's disease; amyloidosis; angioedema; angiogenesis; angiosarcoma; ankylosing spondylitis; anthrax (prophylaxis and treatment); arthritis; asthma; atopic diseases; atypical hemolytic uremic syndrome; autoimmune hepatitis; Bacillus anthracis spores; B-cell malignancies; cardiovascular diseases; choroidal and retinal neovascularization; chronic asthma; chronic hepatitis B; clinical signs of atopic dermatitis in dogs; Clostridium difficile colitis; cold agglutinin disease; Crohn's disease; cryopyrin-associated periodic syndromes; cytomegalovirus infection; diabetes; 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; neonatal hemolytic disease; hepatitis B; HIV infection; hypercholesterolemia; immunologically mediated inflammatory disorders; infectious diseases / Influenza A; inflammation; inflammation of the airways, skin and gastrointestinal tract; inflammatory bowel disease; invasive Candida infections; juvenile idiopathic arthritis; lupus nephritis; macular degeneration (wet form); medically attended lower respiratory disease; melanoma; migraine; multiple sclerosis; muscle atrophy caused by orthopedic disuse and sarcopenia; muscular dystrophy disorders; myostatin inhibitors; neovascular age-related macular degeneration; neuromyelitis optica; hospital-acquired pneumonia; ocular vascular diseases; oncology / immunological indications; organ transplant rejection; osteoarthritis; osteomyelitis (imaging); osteoporosis; osteoporosis, bone metastases, etc.; Parkinson's disease; paroxysmal nocturnal hemoglobinuria; percutaneous coronary intervention; plaque psoriasis; platelet aggregation inhibitors; post-exposure prophylaxis for rabies; prevention of organ transplant rejection; primary systemic amyloidosis; progressive supranuclear palsy; Pseudomonas aeruginosa infection; psoriasis; psoriatic arthritis; rabies (prophylaxis); recovery of motor function after stroke; reduction of scar formation 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 disorders; 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 infections; wet age-related macular degeneration; white blood cell diseases; X-linked hypophosphatemia or combinations thereof.;

[0491] Other therapeutic agents that can be combined with the compounds of the present disclosure can be found in Goodman and Gilman's “The Pharmacological Basis of Therapeutics” (Tenth Edition, edited by Hardman, Limbird, and Gilman) or Physician’s Desk Reference, both of which are incorporated herein by reference in their entirety.

[0492] Depending on the condition being treated, the compounds described herein can be used in combination with the agents disclosed herein or other suitable agents. Thus, in certain 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 from the second agent. Such co-administration can include co-administering the two agents in the same dosage form, co-administering and separately administering in separate dosage forms. That is, the compounds described herein and any of the above agents can be formulated together in the same dosage form and co-administered. Alternatively, the compounds of the present disclosure and any of the above agents can be co-administered, where the two agents are present in separate formulations. In another alternative, the compounds of the present disclosure can be administered immediately following any of the above agents, or vice versa. In certain embodiments of the separate administration scenario, the compounds of the present disclosure and any of the above agents are administered minutes, or hours, or days apart.

[0493] In certain embodiments, the method further comprises administering an additional therapeutic agent selected from: anti-neoplastic agents, enediyne antitumor antibiotics, maytansinoids, topoisomerase inhibitors, kinase inhibitors, anthracycline antibiotics, and EGFR inhibitors, alkylating agents, and combinations thereof.

[0494] In certain more specific embodiments, the method further comprises administering an additional therapeutic agent selected from: anti-neoplastic agents, enediyne antitumor antibiotics, maytansinoids, topoisomerase inhibitors, kinase inhibitors, anthracycline antibiotics, and EGFR inhibitors, alkylating agents, and combinations thereof.

[0495] In certain embodiments, the additional therapeutic agent comprises auristatin F, monomethyl auristatin F, monomethyl auristatin E, paclitaxel, SN-38, calicheamicin, anthramycin, abbeymycin, chelocarcin, DC-81, methylanisomycin, neanisomycin A, neanisomycin B, porothramycin, prothracarcin, sibiromycin, siberomycin, tomatomycin, DM1 cytotoxic, emtansine, irinotecan, camptothecin, topotecan, silatecan, cositecan, exatecan, leotecan, gemitecan, belotecan, and rubitecan.

[0496] The examples and preparations provided below further illustrate and exemplify the compounds of the present disclosure and methods of preparing such compounds. It should be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. In the following examples and throughout the specification and claims, unless otherwise indicated, molecules and moieties having a single stereocenter are present as a racemic mixture. Unless otherwise indicated, those molecules and moieties having two or more stereocenters are present as a racemic mixture of diastereomers. The single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0497] Preparation method

[0498] The embodiments disclosed herein provide numerous advantages, including the ability to control the number of bioactive moieties or fluorophore moieties conjugated to the polymer and any subsequent targeting moieties. The composition of the polymer backbone can also be selected to provide desired solubility characteristics, e.g., by controlling the introduction of charged moieties (e.g., number, frequency, spacing, etc.). In addition to the characteristics provided by the composition of the backbone, the side chains can be selected to provide a source for modulating the solubility of the compounds disclosed herein.

[0499] The embodiments disclosed herein also provide compounds that can advantageously include multiple therapeutic agents, e.g., for complementary or synergistic therapeutic strategies. In addition, the 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 conjugating polymer-drug constructs to targeting reagents such as antibodies, antibody fragments, proteins, or other clinically relevant reagents provides utility for a variety of applications of interest, e.g., surface chemistry, assay development, etc.

[0500] Compounds of certain embodiments also provide other desirable properties, including enhanced permeability and retention effects. In addition to providing the necessary solubility properties, the chemical features of embodiments of the compounds of the present invention can be adjusted to modulate the ability of the compounds to penetrate diseased cells / tissues and remain inside them. These features allow for the effective delivery of bioactive agents by increasing potency through increased penetration and enhanced retention.

[0501] Accordingly, it should be understood that any embodiment of the compounds of structure (I) as described above, and R as described hereinabove with respect to the compounds of structure (I) 1 、R 2 、R 3 、R 4 、R 5 、L a 、L b 、L 1 、L 2 、L 3 、M, m and / or any specific selection of the n variables can be independently combined with other embodiments and / or variables of the compounds of structure (I) to form embodiments of the present disclosure not specifically set forth above. Additionally, if in a particular embodiment and / or claim any particular R 1 、R 2 、R 3 、R 4 、R 5 、L a 、L b 、L 1 、L 2 、L 3 、M, m and / or the n variables lists a list of selections, it should be understood that each individual selection can be deleted from the particular embodiment and / or claim, and the remaining list of selections will be considered to be within the scope of the present disclosure.

[0502] It should be understood that in this specification, combinations of substituents and / or variables of the described formulae are permitted only if such combinations result in stable compounds.

[0503] Those skilled in the art will also understand that in the methods described herein, the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxyl include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for mercapto include -C(O)-R” (where R” is alkyl, aryl or arylalkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. The protecting groups can be added or removed according to standard techniques known to those skilled in the art and as described herein. The application of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Edition, Wiley. Those skilled in the art will understand that the protecting group can also be a polymer resin such as Wang resin, Rink resin or 2-chlorotrityl-chloride resin.

[0504] In addition, all compounds of the present disclosure in free base or acid form can be converted to their salts by treatment with a suitable inorganic or organic base or acid by methods known to those skilled in the art. The salts of the compounds of the present disclosure can be converted to their free base or acid form by standard techniques.

[0505] The following reaction schemes illustrate exemplary methods for preparing the compounds of the present disclosure. It should be understood that those skilled in the art can prepare 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 will be able to prepare other compounds of structure (I) not specifically described below in a similar manner as described below, by using appropriate starting components and modifying the synthetic parameters as needed. Generally, the starting components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI and Fluorochem USA, etc., or 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 prepared as described in the present disclosure.

[0506] Reaction scheme I

[0507]

[0508] Reaction Scheme I illustrates an exemplary method for preparing intermediates useful for preparing compounds of structure (I), where R 1 , L 1 , L 2 and M are as defined above, R 2 and R 3 are as defined above or a protected variant thereof and L a is an optional linking group. Referring to Reaction Scheme 1, compounds of structure a can be purchased or prepared by methods well known to those of ordinary skill in the art. Reaction of a with M-X (where X is a halogen such as bromine) under Suzuki coupling conditions known in the art yields a compound of structure b. The compounds of structure b can be used to prepare compounds of structure (I) as described below.

[0509] Reaction scheme II

[0510]

[0511] Reaction Scheme II illustrates an alternative method for preparing intermediates useful for preparing compounds of structure (I). Referring to Reaction Scheme II, where R 1 , L a , L b , L 1 , L 2 and M are as defined above, and R 2 and R 3 are as defined above, or a protected variant thereof, reacting a compound of structure c (which can be purchased or prepared by well-known techniques) with M-G' to yield a compound of structure d. Here, 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 group of M or part of the main structure of M. L a’ is a selected intermediate such that the above reaction will convert L a ' into L a . G and G' can be any number of functional groups described herein, such as an alkyne and an azide, an amine and an activated ester, or an amine and an isothiocyanate, etc., respectively.

[0512] Compounds of structure (I) can be prepared from one of structures b or d by reaction with a phosphoramidite compound having the following structure (e) under well-known automated DNA synthesis conditions:

[0513]

[0514] where each L is independently an optional linking group.

[0515] DNA synthesis methods are well known in the art. Briefly, two alcohol groups, such as R in intermediate b or d above 2 and R 3 , are functionalized with a dimethoxytrityl (DMT) group and a 2-cyanoethyl-N,N-diisopropylaminophosphoramidite group, respectively. The phosphoramidite group is coupled to the alcohol group, usually in the presence of an activator such as tetrazole, and then the phosphorus atom is oxidized with iodine. The dimethoxytrityl group can be removed with an acid (e.g., chloroacetic acid) to expose the free alcohol, which can react with the phosphoramidite group. By treatment with ammonia, the 2-cyanoethyl group can be removed after oligomerization.

[0516] The preparation of phosphoramidites used in oligomerization methods is also well known in the art. For example, a primary alcohol (e.g., R 3 ) can be protected as a DMT group by reaction with DMT-Cl. Then, a secondary alcohol (e.g., R 2 ) can be 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.

[0517] According to the well-known phosphoramidite chemistry described above, compounds of structure (I) are prepared by oligomerization of intermediate b or d and e. By repeating the phosphoramidite coupling the desired number of times, the desired number of n repeating units are incorporated into the molecule.

[0518] In certain embodiments, compounds of structure (I) are prepared from one or more of the following phosphoramidites (e):

[0519]

[0520] In an exemplary embodiment, the G moiety can be selected from any of the Q moieties described herein, including the specific examples provided in Table 1. In certain embodiments, G independently comprises a moiety suitable for use in a reaction each time it appears, said reaction including: the reaction of a copper-catalyzed azide and alkyne to form a triazole (Huisgen 1,3-dipolar cycloaddition), the reaction of a diene and a dienophile (Diels-Alder), a strain-promoted alkyne-nitrone cycloaddition, the reaction of a strained alkene with an azide, tetrazine or tetrazole, an alkene and azide [3+2] cycloaddition, an alkene and tetrazine inverse-demand Diels-Alder, an alkene and tetrazole photoreaction and various substitution reactions, such as substitution of a leaving group by nucleophilic attack on an electrophilic atom.

[0521] In certain embodiments, G is independently, at each occurrence, a moiety comprising an aldehyde, oxime, hydrazone, alkyne, amine, azide, acyl azide, acyl halide, nitrile, nitrone, thiol, disulfide, sulfonyl halide, isothiocyanate, imidate, activated ester, ketone, α,β-unsaturated carbonyl, alkene, maleimide, α-haloamide, epoxide, aziridine, tetrazine, tetrazole, phosphine, biotin, or thietane functional group.

[0522] In other embodiments, G independently, at each occurrence, comprises an alkyne or an azide group. In other embodiments, G independently, at each occurrence, comprises an amino, isothiocyanate, or activated ester group. In various embodiments, G independently, at each occurrence, comprises a reactive group that is capable of forming, upon reaction with a complementary reactive group, a functional group comprising an alkene, ester, amide, thioester, disulfide, carbocyclic, heterocyclic, or heteroaryl group. For example, in some embodiments, the heteroaryl is a triazolyl group.

[0523] In certain embodiments, the compounds of structure (I) are prepared as follows: The oligomerization of intermediates b or d and e is carried out according to the phosphoramidite chemistry described above such that multiple different linking groups (e.g., “L a groups”) can be introduced, which have a variety of different release mechanisms as described herein (e.g., by esterases, cathepsin B, in vivo hydrolysis, etc.) or are non-cleavable under physiological conditions. In addition, these compounds can be modified to include one or more identical or different M moieties. Thus, the compounds of structure (I) can be customized or “programmed” such that the M moiety “releases” or dissociates from the rest of the molecule, e.g., to induce a pharmacological effect under specific physiological conditions. Consequently, the compounds of structure (I) are particularly useful as targeted therapeutic agents that can be administered systemically and have minimal toxic side effects.

[0524] By repeating the phosphoramidite coupling the desired number of times and by selecting appropriate phosphoramidite monomer compounds, e.g., the compounds of structure (e) provided above, the introduction of the desired number of repeating units and the desired linking group (“L a groups”) into the molecule is accomplished.

[0525] The following compound of structure (f) represents a representative non-limiting example of a compound of structure (I) having a variety of different L a groups and M groups:

[0526]

[0527] wherein M a -M dEach represents a different M moiety and the linking group contains functional groups (tetrazole, oxime, disulfide and ester; from left to right respectively), and the functional groups have different cleavage methods (oxime - acid hydrolysis; disulfide - reduction by TCEP (in vitro) or glutathione (in vivo); ester - esterase or base hydrolysis) or are non-cleavable (triazole).

[0528] The compounds of structure (I) can include multiple bioactive moieties (M groups). For example, the M groups can be selected based on complementary 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 conjugating the polymer-drug construct with targeting reagents such as antibodies, antibody fragments, proteins, sugar moieties, receptors, receptor ligands, prions, aptamers, enzymes, or other clinically relevant reagents provides utility for a variety of applications of interest, such as surface chemistry, assay development, etc.

[0529] Methods for preparing the compounds of structure (I) and / or (II) and methods for compound preparation using automated DNA synthesis techniques are described in PCT Publication Nos. WO 2015 / 027176, WO 2016 / 138461, and WO 2016 / 183185, which are hereby incorporated by reference in their entirety.

[0530] The following examples are provided for illustrative purposes and not for limitation.

[0531] Example

[0532] General methods

[0533] Mass spectrometry analysis was performed on a Waters / Micromass Quattro micro MS / MS system (in MS-only mode) using MassLynx 4.1 acquisition software. The mobile phase used for LC / MS on the dye was 100 mM 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), 8.6 mM triethylamine (TEA), pH 8. The phosphoramidites and precursor molecules were also analyzed using a Waters Acquity UHPLC system with a 2.1 mm × 50 mm Acquity BEH-C18 column maintained at 45 °C, using an acetonitrile / water mobile phase gradient. Using the Waters / Micromass Quattro micro MS / MS system (in MS-only mode) Tropylium cation infusion enhanced ionization was used to obtain the molecular weight of the monomeric intermediate. The excitation and emission properties experiments were recorded on a Cary Eclipse spectrophotometer.

[0534] Unless otherwise noted, all reactions were carried out in oven-dried glassware under a nitrogen atmosphere. Commercially available 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.

[0535] Example 1

[0536] NHS Activation

[0537]

[0538] The NHS-activated M moiety was synthesized using standard coupling conditions. That is, the M moiety containing a carboxyl group was dissolved in dichloromethane and N,N'-dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide (NHS) were added to the mixture. The final product was then purified if necessary and used in the next synthetic step. Alternatively, the M moiety can be modified to include a carboxyl group, for example, using the synthetic strategy shown in Example 3 below.

[0539] Example 2

[0540] Monomer Synthesis

[0541]

[0542] The NHS-activated M was reacted with an amine diol, followed by the addition of a trityl protecting group to obtain a trityl-protected intermediate. The trityl-protected intermediate was then reacted with 3-((chloro(diisopropylamino)phosphaneyl)oxy)propanenitrile to obtain the final phosphoramidite product. The final phosphoramidite product was then used in automated DNA synthesis to incorporate the moiety containing M (e.g., as a representative bioactive moiety or dye moiety) into an embodiment of the compound of structure (I).

[0543] Example 3

[0544] Synthesis of M-PEG-azide

[0545]

[0546] M-PEG-azide was synthesized according to the reaction sequence shown above. 2-(2-(2-Azidoethoxy)ethoxy)ethan-1-amine was reacted with dihydrofuran-2,5-dione to obtain the intermediate 4-((2-(2-(2-azidoethoxy)ethoxy)ethyl)amino)-4-oxobutanoic acid. This intermediate was reacted with perfluorophenol to obtain 4-((2-(2-(2-azidoethoxy)ethoxy)ethyl)amino)-4-oxobutanoate, which was coupled to M-amine to obtain the desired product, M-PEG-azide. The presence of the desired product was confirmed by LC-MS.

[0547] Example 4

[0548] Post-polymerization modification 1

[0549]

[0550] As shown in the above reaction sequence, an exemplary compound of structure (II) (which has 3 side-chain amine functional groups) was coupled to the NHS-activated M moiety (note - not all structural features of the compound of structure (II) are drawn for clarity). The reaction was carried out using a borate-buffered H 2 O / DMSO mixture (1:3) with magnesium chloride. The reaction successfully added the M moiety to each of the 3 amine functional groups to obtain a representative compound of structure (I), which was identified by LC-MS.

[0551] Example 5

[0552] Post-polymerization modification 2

[0553]

[0554] An exemplary compound of structure (II) having 3 side-chain alkynyl functional groups was coupled to M-PEG-azide. The reaction conditions included CuSO 4 , tris(3-hydroxypropyltriazolylmethyl)amine (THPTA), and sodium ascorbate. The reaction was carried out in a phosphate-buffered aqueous solvent containing 60% DMSO at pH 7.6. The reaction was carried out at room temperature and the presence of the desired product was confirmed by LC-MS. L a Represents a heteroalkyl linker.

[0555] Example 6

[0556] Activation and antibody conjugation

[0557]

[0558] The thiol protecting group of a representative compound of Structure (I) was removed using standard reducing conditions (i.e., TCEP), and the deprotected thiol was functionalized with 1,1'-(ethane-1,2-diyl)bis(1H-pyrrole-2,5-dione (bismaleimidoethane or “BMOE”) to afford 6-2. In parallel, the UCHT-1 antibody was treated with TCEP to reduce disulfide bonds. The reduced antibody was reacted with 6-2 (1.5 g) at a polymer:antibody molar ratio of 5:1.

[0559] Example 7

[0560] V AL -C IT Synthesis of -PABC(VCP) phosphoramidite monomer

[0561]

[0562] 4-Nitrophenol-activated Val-Cit-PABC carbonate was reacted with 3-(3-aminopropoxy)propane-1,2-diol (Step 1), followed by addition of a trityl protecting group to afford a trityl-protected intermediate (Step 2). The trityl-protected intermediate was then reacted with 3-((chloro(diisopropylamino)phosphoranyl)oxy)propanenitrile to afford the final phosphoramidite product. The final phosphoramidite product can then be used in synthesis to afford compounds of Structure (I).

[0563] Example 8

[0564] Synthesis of pyridyl disulfide phosphoramidite monomer

[0565]

[0566] N-Hydroxysuccinimide-activated pyridyl disulfide was reacted with 3-(3-aminopropoxy)propane-1,2-diol, followed by addition of a trityl protecting group to afford a trityl-protected intermediate. The trityl-protected intermediate was then reacted with 3-((chloro(diisopropylamino)phosphoranyl)oxy)propanenitrile to afford the final phosphoramidite product. The final phosphoramidite product can then be used in synthesis to afford compounds of Structure (I).

[0567] Example 9

[0568] Synthesis of ethylamino disulfide phosphoramidite monomer

[0569]

[0570] The trityl - protected pyridyl disulfide from Example 8 was reacted with cysteamine, and then the Fmoc protecting group was added to obtain a protected ethylamino disulfide intermediate. This intermediate was then reacted with 3 - ((chloro(diisopropylamino)phosphanyl)oxy)propanenitrile to obtain the final phosphoramidite product. The final phosphoramidite product can then be used in synthesis to obtain the compound of structure (I).

[0571] Example 10

[0572] Synthesis of N - hydroxyphthalimide phosphoramidite monomer

[0573]

[0574] N - Hydroxyphthalimide was reacted with (2,2 - dimethyl - 1,3 - dioxolan - 4 - yl)methanol under Mitsunobu conditions, and then deprotected under acidic conditions to obtain a diol intermediate. The diol intermediate was then reacted with DMTr - Cl and pyridine to protect the primary alcohol as a trityl derivative. Subsequent reaction with 3 - ((chloro(diisopropylamino)phosphanyl)oxy)propanenitrile gave the final phosphoramidite product. The final phosphoramidite product can then be used in synthesis to obtain the compound of structure (I).

[0575] Example 11

[0576] Synthesis of a representative compound of structure (II) (Synthesis 1)

[0577]

[0578] The Val - Cit - PABC phosphoramidite monomer described in Example 7 was reacted under appropriate conditions to obtain an Fmoc - protected polymer, which underwent a subsequent base - promoted deprotection step (e.g., with piperidine in DMF) to provide the compound of structure (II). As described, for example, in Example 4 above, the amine functional group can be coupled to the M moiety (not all structural features of the compound of structure (II) are drawn for clarity).

[0579] Example 12

[0580] Synthesis of a representative compound of structure (II) (Synthesis 2)

[0581]

[0582] Under appropriate conditions, the pyridyl disulfide phosphoramidite monomer described in Example 8 is reacted to obtain a pyridyl disulfide monomer. Reduction of this polymer (e.g., with TCEP) cleaves the disulfide, leaving a thiol group (-SH), which can be used for post-synthetic introduction of the M moiety, which is achieved by reaction with, for example, another thiol or maleimide group (for clarity, not all structural features of the compound of structure (II) are drawn).

[0583] Example 13

[0584] Synthesis of a representative compound of structure (II) (Synthesis 3)

[0585]

[0586] Under appropriate conditions, the ethylamino disulfide phosphoramidite monomer described in Example 9 is reacted to obtain an N-Fmoc protected polymer, which undergoes a subsequent base-promoted deprotection step (e.g., with piperidine in DMF) to provide a compound of the invention having an ethylamine-functionalized disulfide. The amine functional group can be coupled to the M moiety, as described, for example, in Example 4 above (for clarity, not all structural features of the compound of structure (II) are drawn).

[0587] Example 14

[0588] Synthesis of a representative compound of structure (II) (Synthesis 4)

[0589]

[0590] Under appropriate conditions, the N-hydroxyphthalimide phosphoramidite monomer described in Example 10 is reacted to obtain a phthalimide polymer derivative, which is reacted with hydrazine to form an alkoxyamine functional group. The alkoxyamine is reacted with a complementary group (e.g., an aldehyde or a ketone) to form an oxime linkage to the M moiety (for clarity, not all structural features of the compound of structure (II) are drawn).

[0591] Example 15

[0592] Exemplary synthesis of the polymer of structure (I)

[0593]

[0594] The DNA synthesis method can be applied to construct the compounds of structure (I). Monomers (e.g., phosphoramidite monomers) can be commercially available (e.g., from ChemGenes Corporation, Wilmington Mass.) or synthesized using the methods described herein (see, e.g., Examples 2 and 7-10). The introduction of the M moiety is accomplished as follows: during the DNA synthesis step, by including a moiety of the M moiety as a monomer, or in a post-polymerization modification step (e.g., as described in Examples 4-6 and 11-14). An exemplary DNA synthesis scheme is shown below.

[0595] Representative DNA synthesis cycle

[0596]

[0597] Oligomerization is typically initiated by removing a protecting group (e.g., dimethoxytrityl, DMTr) to expose the free -OH (hydroxyl) group (Step 1, detritylation). In the subsequent coupling step, a phosphoramidite monomer is introduced, which reacts with the free OH group, thereby forming a new covalent bond to phosphorus, accompanied by the loss of a diisopropylamine group (Step 2, coupling). The resulting phosphite triester is oxidized (e.g., with I 2 and pyridine) to a more stable phosphate ester (Step 3, oxidation), and the capping step renders any remaining free OH groups non-reactive (Step 4, capping). The new product phosphate ester oligomer contains a DMTr-protected OH group, which can be deprotected to restart the synthesis cycle so that another phosphoramidite monomer can be attached to the oligomer.

[0598] Customization occurs in Step 2 by selecting the phosphoramidite monomer. The properties of L, M, and G are selected such that the compounds of the desired structure (I) are synthesized. M and G can optionally be absent to incorporate a desired spacer between the M and / or G moieties. One of ordinary skill in the art can select a variety of monomer types to obtain the compounds of the present invention that contain multiple therapeutic agents and / or other moieties (e.g., dyes) and have differences simultaneously in the linker groups.

[0599] Example 16

[0600] Synthesis of monomethyl auristatin E PEG azide (MMAE-VAC-N 3 )

[0601]

[0602] The above compound was prepared using a similar synthesis method as shown in Example 3.

[0603] Example 17

[0604] Synthesis of NHS-activated auristatin F (AF-NHS)

[0605]

[0606] Using the standard coupling conditions indicated in the reaction scheme above, auristatin F was converted to the NHS-activated form.

[0607] Example 18

[0608] Synthesis of Compound II-5

[0609]

[0610] Compound II-3 was reacted with the product of Example 16 to give Compound I-4. Using a manual gradient elution of H 2 O / MeOH, the crude material was purified using a Waters C 18 Sep-Pak cartridge to give the desired Compound I-5. The product identity was confirmed by LC-MS; MW = 5052.8.

[0611] Compound I-4 was then reacted with the product of Example 17 to give Compound I-5. LC-MS analysis indicated that the desired product, Compound I-5, was obtained; MW = 5779.1.

[0612] Note: For clarity, the polymer structures are simplified. The complete structures can be found in Tables II and III as indicated.

[0613] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification, including U.S. Provisional Patent Application No. 62 / 832,728 filed on April 11, 2019 and U.S. Provisional Patent Application No. 62 / 877,160 filed on July 22, 2019, are hereby incorporated by reference in their entirety to the extent that they are not inconsistent with this specification.

[0614] It should be understood from the foregoing 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.

[0615] Embodiments of the invention also include:

[0616] Embodiment 1. A compound having the following structure (I) or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof:

[0617]

[0618] Wherein:

[0619] M is independently, at each occurrence, a bioactive moiety or a fragment thereof, a prodrug of a bioactive moiety or a fragment thereof, a fluorescent dye, an imaging agent or a radioisotope binding site, provided that at least one occurrence of M is not a fluorescent dye;

[0620] L a is independently, at each occurrence, an optional physiologically cleavable linker and L b is independently, at each occurrence, an optional physiologically non-cleavable linker, provided that, L a and L b together have at least one occurrence containing more than 4 carbons;

[0621] L 1 and L 2 are independently, at each occurrence, an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene or heteroatom linker;

[0622] L 3 is independently, at each occurrence, a heteroalkylene, heteroalkenylene or heteroalkynylene linker having more than 3 atoms in length, wherein the heteroatoms in the heteroalkylene, heteroalkenylene and heteroalkynylene linkers are selected from O, N and S;

[0623] R 1 is independently, at each occurrence, H, alkyl or alkoxy;

[0624] R 2 and R 3 are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c 、Q or a protected form thereof or L';

[0625] R 4 is independently, at each occurrence, O - 、S - 、OZ, SZ or N(R 6 ) 2 , where Z is a cation and each R 6 is independently H or alkyl;

[0626] R 5 is independently, at each occurrence, oxo, thio or absent;

[0627] R a is O or S;

[0628] R b is OH, SH, O- , S - , OR d or SR d ;

[0629] R c is OH, SH, O - , S - , OR d , OL', SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphonylalkyl, thiophosphonylalkyl, phosphonylalkyl ether or thiophosphonylalkyl ether;

[0630] R d is a counterion;

[0631] Q is independently, each time it appears, a moiety containing a reactive group or a protected form thereof, which is capable of forming a covalent bond with a complementary reactive group Q' on the targeting moiety;

[0632] L' is independently, each time it appears, a linker containing a covalent bond with Q, a targeting moiety, a linker containing a covalent bond with the targeting moiety, a linker containing a covalent bond with a solid support, a linker containing a covalent bond with a solid support residue, a linker containing a covalent bond with a nucleoside, or a linker containing a covalent bond with another compound of structure (I);

[0633] m is independently, each time it appears, an integer of 0 or greater; and

[0634] n is an integer of 1 or greater.

[0635] Embodiment 2. A compound of the following structure (I) or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof:

[0636]

[0637] wherein:

[0638] M is independently, each time it appears, a bioactive moiety or a fragment thereof, a prodrug of a bioactive moiety or a fragment thereof, a fluorescent dye, an imaging agent or a radioactive isotope binding site, provided that at least one occurrence of M is not a fluorescent dye;

[0639] L a is independently, each time it appears, an optionally physiologically cleavable linker and L b is independently, each time it appears, an optionally physiologically non-cleavable linker;

[0640] L 1 and L 2is independently, at each occurrence, an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene or heteroatom linking group;

[0641] L 3 is independently, at each occurrence, a heteroalkylene, heteroalkenylene or heteroalkynylene linking group having more than 3 atoms in length, wherein the heteroatoms in said heteroalkylene, heteroalkenylene and heteroalkynylene linking groups are selected from O, N and S;

[0642] R 1 is independently, at each occurrence, H, alkyl or alkoxy;

[0643] R 2 and R 3 are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c , Q or a protected form thereof or L';

[0644] R 4 is independently, at each occurrence, O - 、S - 、OZ, SZ or N(R 6 ) 2 , where Z is a cation and each R 6 is independently H or alkyl;

[0645] R 5 is independently, at each occurrence, oxo, thioxo or absent;

[0646] R a is O or S;

[0647] R b is OH, SH, O - 、S - 、OR d or SR d ;

[0648] R c is OH, SH, O - 、S - 、OR d 、OL', SR d 、alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphonylalkyl, thiophosphonylalkyl, phosphonylalkyl ether or thiophosphonylalkyl ether;

[0649] R d is a counterion;

[0650] Q is independently, at each occurrence, a moiety containing a reactive group or a protected form thereof, which is capable of forming a covalent bond with a complementary reactive group Q' on a targeting moiety;

[0651] L' is independently, at each occurrence, a linker containing a covalent bond with Q, a targeting moiety, a linker containing a covalent bond with the targeting moiety, a linker containing a covalent bond with a solid support, a linker containing a covalent bond with a solid support residue, a linker containing a covalent bond with a nucleoside, or a linker containing a covalent bond with another compound of structure (I);

[0652] m is independently, at each occurrence, an integer of 0 or greater; and

[0653] n is an integer of 1 or greater,

[0654] provided that the occurrence of M does not have the following structure:

[0655] and

[0656] The compound of structure (I) does not have one of the following structures:

[0657]

[0658]

[0659] wherein:

[0660] q is an integer from 21 - 26;

[0661] D' has the following structure:

[0662]

[0663] AF has the following structure:

[0664] and

[0665] dT has the following structure:

[0666]

[0667] Embodiment 3. The compound according to Embodiment 1, wherein L 3 is independently, at each occurrence, a heteroalkyl linker.

[0668] Embodiment 4. The compound according to Embodiment 3, wherein L 3 is independently, at each occurrence, an alkylene oxide linker.

[0669] Embodiment 5. The compound according to Embodiment 1 or 2, L3 is polyethylene oxide, and the compound has the following structure (IA):

[0670]

[0671] where z is an integer from 2 to 100.

[0672] Embodiment 6. The compound according to embodiment 5, wherein z is an integer from 3 to 30.

[0673] Embodiment 7. The compound according to embodiment 5 or 6, wherein z is an integer from 3 to 6 or from 22 to 27.

[0674] Embodiment 8. The compound according to embodiment 1 or 2, L 3 is polyethylene oxide, and the compound has the following structure (IB):

[0675]

[0676] wherein:

[0677] z is an integer from 2 to 30;

[0678] x 1 and x 2 are each independently an integer from 0 to 6; and

[0679] x 3 and x 4 are independently an integer from 0 to 6 each time it appears.

[0680] Embodiment 9. The compound according to embodiment 8, wherein

[0681] x 1 and x 2 are each independently an integer from 0 to 3; and

[0682] x 3 and x 4 are independently an integer from 0 to 3 each time it appears.

[0683] Embodiment 10. The compound according to any one of embodiments 5 - 8, wherein for at least one occurrence of n, z is an integer from 3 to 6 and m is 3.

[0684] Embodiment 11. The compound according to any one of embodiments 5 - 8, wherein for at least one occurrence of m, z is an integer from 22 to 27.

[0685] Embodiment 12. The compound according to any one of embodiments 5 - 8, wherein for at least one occurrence of m, z is an integer from 44 to 54.

[0686] Embodiment 13. The compound according to any one of Embodiments 5-8, wherein for at least one occurrence of m, z is 3, and for at least one occurrence of n, m is 3.

[0687] Embodiment 14. The compound according to any one of Embodiments 5-8, wherein for at least one occurrence of m, z is 6, and for at least one occurrence of n, m is 3.

[0688] Embodiment 15. The compound according to any one of Embodiments 1-14, wherein L a has at least one occurrence.

[0689] Embodiment 16. The compound according to any one of Embodiments 1-15, wherein L a has at least one occurrence comprising 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 group, a nitro group, or a combination thereof.

[0690] Embodiment 17. The compound according to Embodiment 16, wherein L a comprises an amino acid sequence recognized by sortase.

[0691] Embodiment 18. The compound according to Embodiment 17, wherein the amino acid sequence is Leu-Pro-X-Thr-Gly, where X is any amino acid residue.

[0692] Embodiment 19. The compound according to any one of Embodiments 1-18, wherein L a has at least one occurrence that is a linker containing 3 or more carbons.

[0693] Embodiment 20. The compound according to any one of Embodiments 1-19, wherein L a has at least one occurrence that is a linker containing at least one nitrogen.

[0694] Embodiment 21. The compound according to any one of Embodiments 1-20, wherein L a has at least one occurrence comprising one of the following structures:

[0695]

[0696]

[0697] Embodiment 22. The compound according to any one of Embodiments 1-21, wherein L aEach occurrence of [[ ]] contains 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 group, a nitro group, or a combination thereof.

[0698] Embodiment 23. The compound according to any one of Embodiments 1-22, wherein each occurrence of L a is a linking group containing 3 or more carbons.

[0699] Embodiment 24. The compound according to any one of Embodiments 1-23, wherein each occurrence of L a is a linking group containing at least one nitrogen.

[0700] Embodiment 25. The compound according to any one of Embodiments 1-24, wherein each occurrence of L a contains one of the following structures:

[0701]

[0702] Embodiment 26. The compound according to any one of Embodiments 1-25, wherein at least one occurrence of L contains the following structure:

[0703]

[0704] Embodiment 27. The compound according to any one of Embodiments 1-26, wherein at least one occurrence of L contains one or more amino acid residues.

[0705] Embodiment 28. The compound according to Embodiment 27, wherein at least one occurrence of L a contains valine.

[0706] Embodiment 29. The compound according to any one of Embodiments 1-28, wherein at least one occurrence of L a contains one of the following structures:

[0707]

[0708] Embodiment 30. The compound according to any one of Embodiments 1-29, wherein each occurrence of L a contains the following structure:

[0709]

[0710] Embodiment 31. The compound according to any one of Embodiments 1-30, wherein each occurrence of L a contains one or more amino acid residues.

[0711] Embodiment 32. The compound according to embodiment 31, wherein each occurrence of L a contains valine.

[0712] Embodiment 33. The compound according to any one of embodiments 1-32, wherein each occurrence of L a contains one of the following structures:

[0713]

[0714] Embodiment 34. The compound according to any one of embodiments 1-33, wherein at least one occurrence of L a has one of the following structures:

[0715]

[0716] Embodiment 35. The compound according to any one of embodiments 1-34, wherein at least one occurrence of L b is present.

[0717] Embodiment 36. The compound according to any one of embodiments 1-35, wherein at least one occurrence of L b contains a thioether bond.

[0718] Embodiment 37. The compound according to any one of embodiments 1-36, wherein at least one occurrence of L b contains the following structure:

[0719]

[0720] Embodiment 38. The compound according to any one of embodiments 1-37, wherein at least one occurrence of L b contains one of the following structures:

[0721]

[0722] Embodiment 39. The compound according to any one of embodiments 1-38, wherein L b is present in each occurrence.

[0723] Embodiment 40. The compound according to any one of embodiments 1-39, wherein each occurrence of L b contains a thioether bond.

[0724] Embodiment 41. The compound according to any one of embodiments 1-40, wherein each occurrence of L b contains the following structure:

[0725]

[0726] Embodiment 42. The compound according to any one of embodiments 1-41, wherein L b each occurrence of which comprises one of the following structures:

[0727]

[0728] Embodiment 43. The compound according to any one of embodiments 1-42, wherein R 4 is independently OH, O - or OR d each time it occurs.

[0729] Embodiment 44. The compound according to any one of embodiments 1-43, wherein R 5 is oxo each time it occurs.

[0730] Embodiment 45. The compound according to any one of embodiments 1-44, wherein R 1 is H each time it occurs.

[0731] Embodiment 46. The compound according to any one of embodiments 1-45, wherein R 2 and R 3 are each independently H, OH or -OP(=R a )(R b )R c .

[0732] Embodiment 47. The compound according to any one of embodiments 1-45, wherein R 2 is H and R 3 is -OP(=R a )(R b )R c , Q or a linking group comprising a covalent bond with Q.

[0733] Embodiment 48. The compound according to any one of embodiments 1-47, wherein R 3 is -OP(=R a )(R b )R c or L'.

[0734] Embodiment 49. The compound according to embodiment 48, wherein R c is OL'.

[0735] Embodiment 50. The compound according to embodiment 48 or 49, wherein L' is a targeting moiety or a linking group to a targeting moiety.

[0736] Embodiment 51. The compound according to Embodiment 50, wherein L' is a linker to the targeting moiety, and the linker comprises an alkylene oxide or a phosphodiester moiety or a combination thereof.

[0737] Embodiment 52. The compound according to Embodiment 51, wherein L' has the following structure:

[0738]

[0739] wherein:

[0740] m” and n” are independently integers from 1 to 10;

[0741] R e is H, an electron pair or a counterion;

[0742] L” is a targeting moiety or a linker to the targeting moiety.

[0743] Embodiment 53. The compound according to Embodiment 52, wherein n” is 6.

[0744] Embodiment 54. The compound according to any one of Embodiments 1-53, wherein the targeting moiety is an antibody, a cell surface receptor antagonist or a cell surface receptor agonist.

[0745] Embodiment 55. The compound according to Embodiment 54, wherein the antibody, cell surface receptor antagonist or cell surface receptor agonist is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, folic acid or a MET inhibitor.

[0746] Embodiment 56. The compound according to Embodiment 54, wherein the targeting moiety is a monoclonal antibody.

[0747] Embodiment 57. The compound according to embodiment 56, wherein the monoclonal antibody is abciximab, adalimumab, alemtuzumab, alirocumab, avibactam, basiliximab, benralizumab, beloterozemab, lintuzumab, brodalumab, broselezumab, canakinumab, caracizumab, pegolized siltuximab, daclizumab, denosumab, dupilumab, eculizumab, emicizumab, erenumab, evolocumab, rimegepant, galcanezumab, golimumab, guselkumab, ibalizumab, idarucizumab, infliximab, Itolizumab, Ixekizumab, lanadelumab, logivumab, mepolizumab, natalizumab, otosilumab, ocrelizumab, omalizumab, palivizumab, ranibizumab, reslizumab, rmab, rovilizumab, lurizumab, sarilumab, secukinumab, tezepelumab, thiomab, tocilizumab, ustekinumab, vedolizumab, avelumab, actoxumab, aducanumab, afasevikumab, afimoxifene, anifrolumab, anrukinzumab, anrukinzumab (IMA-638), aselizumab, atorolimumab, bapineuzumab, BCD-100, bavituximab, besilesomab, bispecific antibody, bimagrumab, bimekizumab, botezomib, brexucabtagene autoleucel, brentuximab vedotin, busotuzumab, bococizumab, brazikumab, brentuximab, broselezumab, caluximab, carotuximab, cilizumab, clazakizumab, crizanlizumab, conatumumab, cowuximab, CR6261, crenezumab, lizanlimab, crotedumab, depatuxizumab mafodotin, delotuzumab biosimilar, dizamizumab, divalumab, domalizumab, dusigitumab, emicizumab, epratuzumab, efalizumab, efungumab, edilizumab, elenumab, enokizumab, eptinezumab, erlizumab, etrolizumab, evisizumab, eweizumab, fanolesomab, faralimomab, faricimab, fasolizumab, panvilizumab, fezakinumab, farletuzumab, flecainide, futuximab, fantuzumab, fluvastatin, flosimab, flanurumab, gantinumab, gavrilumab, gevokizumab, ginsilumab, golisumab, gosuranemab, ilesizumab, inclacumab, inomumab, iomab-B, keliximab, lampalizumab, lanlizumab, laverximab, laukinumab, lenvervimab, ledermumab, leelizumab, livilizumab, ligelizumab, lodisizumab, pegolized lurizumab, matuzumab, mafrimumab, metuzumab,Mogamulizumab, Moxetumomab pasudotox, Muromonab-CD3, Namilumab, Nemolizumab, NEOD001, Nirsevimab, Odulimomab, Olokizumab, Oms721, OPN-305, Otilimab, Ocrelizumab, Ozanezumab, Olaratumab, Pexelizumab, Panobacumab, Pacrituzumab, Palivizumab, PDR001, Peregrizumab, Pectuzumab, Pralukizumab, Rozanolizumab, Ponatinib, Porgaviximab, Prasinezumab, Pritumumab, PRO 140, Quilizumab, Revilimab, Repotrectinib, Ranevetmab, Ravagalimab, Reflizumab, Rifanevizumab, Regavirumab, Relatlimab, Linvoseltamab, Risankizumab, Roledumab, Lomucizumab, Roledumab, SA237, Satralizumab, Sivulizumab, SHP647, Ofatumumab, Sintilimab, Cemiplimab, Sirukumab, Solanezumab, Sonepcizumab, Spartalizumab, Statilimab, Thalizumab, Sutrovimab, Sulimomab, Suvizumab, Sultomab, Tildrakizumab, Talizumab, Tanezumab, Teneliximab, Teprotumumab, Tezepelumab, Tebotelimab, Tocilizumab, Tralokinumab, Togalizumab, Tuvirumab, Ustekinumab, Ustekinumab, Valisovamab, Vepalimomab, Vesenocumab, Vepalimomab, Vobarilizumab, Azzalizumab, Trastuzumab, Gemtuzumab, Brentuximab, Vorsetuzumab, Lovatuzumab, Cantuzumab, Bivatuzumab mertansine or Vadastuximab talirine.,

[0748] Embodiment 58. The compound according to any one of Embodiments 1-57, wherein R 2 or R 3 has one of the following structures:

[0749]

[0750]

[0751] Embodiment 59. The compound according to any one of Embodiments 1-49, wherein R 3 has the following structure:

[0752]

[0753] Embodiment 60. The compound according to any one of embodiments 1-49, wherein R 2 or R 3 comprises one of the following structures:

[0754]

[0755]

[0756] Embodiment 61. The compound according to any one of embodiments 1-50, wherein R 3 comprises one of the following structures:

[0757]

[0758] Embodiment 62. The compound according to any one of embodiments 1-61, wherein at least one occurrence of m is an integer from 1 to 15.

[0759] Embodiment 63. The compound according to any one of embodiments 1-62, wherein at least one occurrence of m is an integer from 1 to 10.

[0760] Embodiment 64. The compound according to any one of embodiments 1-63, wherein at least one occurrence of m is an integer from 1 to 5.

[0761] Embodiment 65. The compound according to any one of embodiments 1-64, wherein each occurrence of m is an integer from 1 to 15.

[0762] Embodiment 66. The compound according to any one of embodiments 1-65, wherein each occurrence of m is an integer from 1 to 10.

[0763] Embodiment 67. The compound according to any one of embodiments 1-66, wherein each occurrence of m is an integer from 1 to 5.

[0764] Embodiment 68. The compound according to any one of embodiments 1-67, wherein n is an integer from 1 to 100.

[0765] Embodiment 69. The compound according to any one of embodiments 1-68, wherein n is an integer from 1 to 10.

[0766] Embodiment 70. The compound according to any one of embodiments 1-69, wherein at least one occurrence of M is an anti-neoplastic agent, enediyne antitumor antibiotic, maytansine compound, topoisomerase inhibitor, kinase inhibitor, anthracycline antibiotic, and EGFR inhibitor, or an alkylating agent.

[0767] Embodiment 71. The compound according to any one of Embodiments 1 - 70, wherein at least one occurrence of M is an anti - neoplastic agent, an enediyne antitumor antibiotic, a maytansine compound, a topoisomerase inhibitor, or an alkylating agent.

[0768] Embodiment 72. The compound according to any one of Embodiments 1 - 71, wherein each occurrence of M is independently an anti - neoplastic agent, an enediyne antitumor antibiotic, a maytansine compound, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline antibiotic, an EGFR inhibitor, or an alkylating agent.

[0769] Embodiment 73. The compound according to any one of Embodiments 1 - 72, wherein each occurrence of M is independently an enediyne antitumor antibiotic, a maytansine compound, a topoisomerase inhibitor, or an alkylating agent.

[0770] Embodiment 74. The compound according to any one of Embodiments 1 - 71, wherein at least one occurrence of M is selected from: auristatin F, monomethyl auristatin F, monomethyl auristatin E, paclitaxel, SN - 38, calicheamicin, anthramycin, abbeymycin, chelocarcin, DC - 81, methylanisomycin, neanisomycin A, neanisomycin B, porothramycin, prothracarcin, sibanomicin, sibiromycin, tomatomycin, DM1 cytotoxic, emtansine, irinotecan, camptothecin, topotecan, silatecan, cositecan, exatecan, letoecan, gemtuzumab, belotecan, and rubitecan.

[0771] Embodiment 75. The compound according to any one of Embodiments 1 - 74, wherein at least one occurrence of M has one of the following structures:

[0772]

[0773]

[0774] Embodiment 76. The compound according to any one of Embodiments 1 - 75, wherein each occurrence of M has one of the following structures:

[0775]

[0776]

[0777]

[0778] Embodiment 77. A compound selected from Table 2.

[0779] Embodiment 78. A composition comprising a compound according to any one of Embodiments 1-77 and a pharmaceutically acceptable carrier.

[0780] Embodiment 79. A method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of Embodiments 1-77 or a composition according to Embodiment 78, wherein at least one M is a bioactive moiety that is effective in treating the disease.

[0781] Embodiment 80. The method according to Embodiment 79, wherein each M is a bioactive moiety that is effective in treating the disease.

[0782] Embodiment 81. The method according to any one of Embodiments 79 or 80, wherein the disease is cancer.

[0783] Embodiment 82. The method according to Embodiment 81, wherein the cancer is breast cancer, non-Hodgkin 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 lymphoma, lymphoma, mesothelioma, non-small cell lung cancer, recurrent head and neck cancer, or a combination thereof.

[0784] Embodiment 83. The method according to any one of Embodiments 79-82, wherein the method further comprises administering an additional therapeutic agent selected from the group consisting of: anti-neoplastic agents, enediyne antitumor antibiotics, maytansinoids, topoisomerase inhibitors, kinase inhibitors, anthracycline antibiotics, and EGFR inhibitors, alkylating agents, and combinations thereof.

[0785] Embodiment 84. The method according to any one of Embodiments 79-82, wherein the method further comprises administering an additional therapeutic agent selected from the group consisting of: anti-neoplastic agents, enediyne antitumor antibiotics, maytansinoids, topoisomerase inhibitors, kinase inhibitors, anthracycline antibiotics, and EGFR inhibitors, alkylating agents, and combinations thereof.

[0786] Embodiment 85. The method according to embodiment 83, wherein the additional therapeutic agent comprises auristatin F, monomethyl auristatin F, monomethyl auristatin E, paclitaxel, SN-38, calicheamicin, anthramycin, abbeymycin, chelocarcin, DC-81, methylanisomycin, neanisomycin A, neanisomycin B, porothramycin prothracarcin, sibiromycin, siberomycin, thomamycin, DM1 cytotoxic, emtansine, irinotecan, camptothecin, topotecan, silatecan, cositecan, exatecan, letolecan, gemitecan, belotecan, and rubitecan.

[0787] Embodiment 86. The method according to any one of embodiments 79 or 80, wherein the disease bioactivity partially degrades proteins.

[0788] Embodiment 87. The method according to embodiment 86, wherein the protein is amyloid protein or tau protein.

[0789] Embodiment 88. The method according to any one of embodiments 79, 80, 86, or 87, wherein the disease is amyloidosis or Alzheimer's disease.

[0790] Embodiment 89. The method according to any one of embodiments 79, 80, 86, or 87, wherein the disease is prostate cancer, pancreatic cancer, or breast cancer.

[0791] Embodiment 90. The method according to any one of embodiments 79, 80, 86, or 87, wherein the disease is a tumor disease, a cardiovascular disease, a kidney disease, a metabolic disease, or a respiratory disease.

[0792] Embodiment 91. The method according to any one of embodiments 79, 80, 86, or 87, wherein the disease is a lung disease or a central nervous system disease.

[0793] Embodiment 92. The method according to any one of embodiments 79, 80, 86, or 87, wherein the disease is metastatic castration-resistant prostate cancer or metastatic breast cancer.

Claims

1. A compound having the following structure (I), or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof: Wherein: M, each occurrence independently, is a bioactive moiety or a fragment thereof, a prodrug of a bioactive moiety or a fragment thereof, a fluorescent dye, an imaging agent or a radioisotope binding site, provided that at least one occurrence of M is not a fluorescent dye, and at least one occurrence of M is an anti-neoplastic agent, an enediyne antitumor antibiotic, a maytansine compound, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline antibiotic and an EGFR inhibitor or an alkylating agent; L a is independently, at each occurrence, a physiologically cleavable linker and L b is independently, at each occurrence, an optional physiologically non-cleavable linker, provided that L a and L b together contain more than 4 carbons in at least one occurrence; L 1 and L 2 is independently, at each occurrence, an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene or heteroatom linking group; L 3 independently at each occurrence is a heteroalkyl, heteroalkenyl or heteroalkynyl linking group having more than 3 atom lengths, wherein the heteroatoms in the heteroalkyl, heteroalkenyl and heteroalkynyl linking groups are selected from O, N and S; R 1 is independently H, alkyl or alkoxy each time it appears; R 2 and R 3 each independently is H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c , Q or a protected form thereof or L'; R 4 is independently O at each occurrence - 、S - 、OZ, SZ or N(R 6 ) 2 , where Z is a cation and each R 6 is independently H or an alkyl group; R 5 is independently oxo, thioxo or absent at each occurrence; R a is O or S; R b is OH, SH, O - , S - , OR d or SR d ; R c is OH, SH, O - , S - , OR d , OL', SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether or thiophosphoalkyl ether; R d is a counter ion; Q, each occurrence independently, is a moiety containing a reactive group or a protected form thereof, which is capable of forming a covalent bond with a complementary reactive group Q' on a targeting moiety; L', each occurrence independently, is a linker containing a covalent bond with Q, a targeting moiety, a linker containing a covalent bond with a targeting moiety, a linker containing a covalent bond with a solid support, a linker containing a covalent bond with a solid support residue, a linker containing a covalent bond with a nucleoside or a linker containing a covalent bond with another compound of structure (I); m, each occurrence independently, is an integer of 0 or greater; and n is an integer of 1 or greater.

2. A compound having the following structure (I), or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof: Wherein: M, each occurrence independently, is a bioactive moiety or a fragment thereof, a prodrug of a bioactive moiety or a fragment thereof, a fluorescent dye, an imaging agent or a radioisotope binding site, provided that at least one occurrence of M is not a fluorescent dye, and at least one occurrence of M is an anti-neoplastic agent, an enediyne antitumor antibiotic, a maytansine compound, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline antibiotic and an EGFR inhibitor or an alkylating agent; L a is independently, at each occurrence, a physiologically cleavable linker and L b is independently, at each occurrence, an optional physiologically non-cleavable linker; L 1 and L 2 is independently, at each occurrence, an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene or heteroatom linking group; L 3 independently at each occurrence is a heteroalkyl, heteroalkenyl or heteroalkynyl linking group having more than 3 atom lengths, wherein the heteroatoms in said heteroalkyl, heteroalkenyl and heteroalkynyl linking groups are selected from O, N and S; R 1 is independently H, alkyl or alkoxy each time it appears; R 2 and R 3 each independently is H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c , Q or a protected form thereof or L'; R 4 is independently O at each occurrence - 、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 oxo, thioxo or absent at each occurrence; R a is O or S; R b is OH, SH, O - , S - , OR d or SR d ; R c is OH, SH, O - , S - , OR d , OL', SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphonylalkyl, thiophosphonylalkyl, phosphonylalkyl ether or thiophosphonylalkyl ether; R d is a counter ion; Q, each occurrence independently, is a moiety containing a reactive group or a protected form thereof, which is capable of forming a covalent bond with a complementary reactive group Q' on a targeting moiety; L', each occurrence independently, is a linker containing a covalent bond with Q, a targeting moiety, a linker containing a covalent bond with a targeting moiety, a linker containing a covalent bond with a solid support, a linker containing a covalent bond with a solid support residue, a linker containing a covalent bond with a nucleoside or a linker containing a covalent bond with another compound of structure (I); m, each occurrence independently, is an integer of 0 or greater; and n is an integer of 1 or greater, provided that the occurrence of M does not have the following structure: The compound of structure (I) does not have one of the following structures: Wherein: q is an integer from 21 - 26; D' has the following structure: AF has the following structure: and dT have the following structure:

3. The compound according to claim 1, wherein L 3 is, independently at each occurrence, a heteroalkyl linking group.

4. The compound according to claim 3, wherein L 3 is independently an alkylene oxide linking group each time it appears.

5. The compound according to claim 1, L 3 is polyethylene oxide, and the compound has the following structure (IA): Wherein z is an integer from 2 - 100.

6. The compound according to claim 5, wherein z is an integer from 3 - 30.

7. The compound according to claim 5, wherein z is an integer from 3 - 6 or 22 - 27.

8. The compound according to claim 1, L 3 is polyethylene oxide, and the compound has the following structure (IB): Wherein: z is an integer from 2 - 30; x 1 and x 2 each independently is an integer from 0 to 6; and x 3 and x 4 is independently an integer from 0 to 6 at each occurrence.

9. The compound according to claim 8, wherein x 1 and x 2 are each independently an integer from 0 to 3; and x 3 and x 4 is independently an integer from 0 to 3 each time it appears.

10. The compound according to claim 5 or 8, wherein for at least one occurrence of n, z is an integer from 3 - 6 and m is 3.

11. The compound according to claim 5 or 8, wherein for at least one occurrence of m, z is an integer from 22 to 27.

12. The compound according to claim 5 or 8, wherein for at least one occurrence of m, z is an integer from 44 to 54.

13. The compound according to claim 5 or 8, wherein for at least one occurrence of m, z is 3, and for at least one occurrence of n, m is 3.

14. The compound according to claim 5 or 8, wherein for at least one occurrence of m, z is 6, and for at least one occurrence of n, m is 3.

15. The compound according to claim 5 or 8, wherein at least one occurrence of L a is present.

16. The compound according to claim 5 or 8, wherein at least one occurrence of L a 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 group, a nitro group, or a combination thereof.

17. The compound according to claim 16, wherein L a comprises an amino acid sequence recognized by sortase.

18. The compound according to claim 17, wherein the amino acid sequence is Leu - Pro - X - Thr - Gly, where X is any amino acid residue.

19. The compound according to claim 5 or 8, wherein at least one occurrence of L a is a linking group containing 3 or more carbons.

20. The compound according to claim 5 or 8, wherein at least one occurrence of L a is a linking group containing at least one nitrogen.

21. The compound according to claim 5 or 8, wherein at least one occurrence of L a comprises one of the following structures:

22. The compound according to claim 5 or 8, wherein each occurrence of L a 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 group, a nitro group, or a combination thereof.

23. The compound according to claim 5 or 8, wherein each occurrence of L a is a linking group containing 3 or more carbons.

24. The compound according to claim 5 or 8, wherein each occurrence of L a is a linking group containing at least one nitrogen.

25. The compound according to claim 5 or 8, wherein each occurrence of L a comprises one of the following structures:

26. The compound according to claim 5 or 8, wherein at least one occurrence of L a comprises one or more amino acid residues.

27. The compound according to claim 26, wherein at least one occurrence of L a comprises valine.

28. The compound according to claim 5 or 8, wherein at least one occurrence of L a comprises one of the following structures:

29. The compound according to claim 5 or 8, wherein each occurrence of L a comprises one or more amino acid residues.

30. The compound according to claim 29, wherein each occurrence of L a comprises valine.

31. The compound according to claim 5 or 8, wherein each occurrence of L a comprises one of the following structures:

32. The compound according to claim 5 or 8, wherein at least one occurrence of L a has one of the following structures:

33. The compound according to claim 5 or 8, wherein at least one occurrence of L b is present.

34. The compound according to claim 5 or 8, wherein at least one occurrence of L b comprises a thioether bond.

35. The compound according to claim 5 or 8, wherein at least one occurrence of L b comprises the following structure:

36. The compound according to claim 5 or 8, wherein at least one occurrence of L b comprises one of the following structures:

37. The compound according to claim 5 or 8, wherein L b is present at each occurrence.

38. The compound according to claim 5 or 8, wherein each occurrence of L b comprises a thioether bond.

39. The compound according to claim 5 or 8, wherein each occurrence of L b comprises the following structure:

40. The compound according to claim 5 or 8, wherein each occurrence of L b comprises one of the following structures:

41. The compound according to claim 5 or 8, wherein R 4 is independently OH, O - or OR d each time it appears.

42. The compound according to claim 5 or 8, wherein R 5 is oxo at each occurrence.

43. The compound according to claim 5 or 8, wherein R 1 is H each time it appears.

44. A compound according to claim 5 or 8, wherein R 2 and R 3 are each independently H, OH or -OP(=R a )(R b )R c .

45. The compound according to claim 5 or 8, wherein R 2 is H and R 3 is -OP(=R a )(R b )R c 、Q or a linking group containing a covalent bond with Q.

46. The compound according to claim 5 or 8, wherein R 3 is -OP(=R a )(R b )R c or L'.

47. The compound according to claim 46, wherein R c is OL'.

48. The compound according to claim 47, wherein L' is a targeting moiety or a linker to a targeting moiety.

49. The compound according to claim 48, wherein L' is a linker to a targeting moiety, and the linker comprises an alkylene oxide or a phosphodiester moiety or a combination thereof.

50. The compound according to claim 49, wherein L' has the following structure: Wherein: 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 linker to a targeting moiety.

51. The compound according to claim 50, wherein n” is 6.

52. The compound according to claim 5 or 8, wherein the targeting moiety is an antibody, a cell surface receptor antagonist, or a cell surface receptor agonist.

53. The compound according to claim 52, wherein the antibody, cell surface receptor antagonist, or cell surface receptor agonist is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin - like growth factor receptor (IGFR) inhibitor, folic acid, or a MET inhibitor.

54. The compound according to claim 52, wherein the targeting moiety is a monoclonal antibody.

55. The compound according to claim 54, wherein the monoclonal antibody is abciximab, adalimumab, alemtuzumab, alirocumab, avibactam, basiliximab, benralizumab, besilesomab, lintuzumab, brodalumab, brositumab, canakinumab, caracizumab, pegolized siltuximab, daclizumab, denosumab, dupilumab, eculizumab, emicizumab, erenumab, evolocumab, rimegepant, galcanezumab, golimumab, guselkumab, ibalizumab, idarucizumab, infliximab, Itolizumab, Ixekizumab, lanadelumab, lodavilimab, mepolizumab, natalizumab, otoselixizumab, ocrelizumab, omalizumab, palivizumab, ranibizumab, reslizumab, rmab, rovilizumab, lumiliximab, sarilumab, secukinumab, teclistamab, thiomab, tocilizumab, ustekinumab, vedolizumab, avelumab, actoxumab, aducanumab, afasevikumab, afimoxifene, anifrolumab, anrukinzumab, anrukinzumab (IMA-638), aselizumab, atorolimumab, bapineuzumab, BCD-100, bavituximab, besoab, bispecific antibody, bimagrumab, bimekizumab, botelimumab, brentuximab, busotuzumab, bococizumab, brazikumab, brexanolone, broseptumab, caluximab, carotuximab, cilgavimab, clazakizumab, crizanlizumab, conatumumab, cowxizumab, CR6261, crenezumab, leqembi, crotedumab, depatuxizumab mafodotin, delotuzumab biosimilar, dizamizumab, dovitinib, domalizumab, dusigitumab, emicizumab, epratuzumab, efalizumab, efungumab, edrucizumab, elotuzumab, enokizumab, eptinezumab, erlizumab, etrolizumab, evinacumab, evorpacept, fanolesomab, faricimab, faricimab, fasudil, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, 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faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimab, faricimabMovocizumab, Muromonab-CD3, Nebacumab, Nemolizumab, NEOD001, Nirsevimab, Odulimab, Olokizumab, Olozumab, OMS721, OPN-001, Otesivimab, Ocrelizumab, Otilimab, Oselumab, Ozanezumab, Olizumab, Pascolizumab, Panobacumab, Pacrituzumab, Palivizumab, PDR001, Peregrizumab, Pexelizumab, Pralukizumab, Rozanolizumab, Ponezumab, Porgaviximab, Prasinezumab, Priliximab, PRO 140, Quilizumab, Revilimab, Repotrectinib, Ranevetmab, Ravagalimab, Reflizumab, Rifanevimab, Regavirumab, Relatlimab, Linuzumab, Risankizumab, Roledumab, Lomucizumab, Rolizumab, SA237, Satralizumab, Siveramab, SHP647, Ofatumumab, Sintilimab, Cilimumab, Sirukumab, Solanezumab, Sonepcizumab, Spartalizumab, Statilimab, Thiosolumab, Sutrovimab, Sulimomab, Suvizumab, Sultomab, Tadalizumab, Talizumab, Tanezumab, Tenelizumab, Teflonimab, Atimomab, Tenecimab, Telizumab, Tovetumab, Tezelizumab, Telbivizumab, Tolizumab, Trofoluzumab, Troglumomab, Tovevimab, Ulorotuzumab, Ustekinumab, Valilizumab, Vepalimomab, Vesenizumab, Vicilizumab, Vobarilizumab, Azomomab, Trastuzumab, Gemtuzumab, Brentuximab, Vorsetuzumab, Lovatuzumab, Cantuzumab, Bivatuzumab, Boronatuzumab, or Vadastuximab.

56. The compound according to claim 5 or 8, wherein R 2 or R 3 has one of the following structures:

57. The compound according to claim 5 or 8, wherein R 3 has the following structure:

58. The compound according to claim 5 or 8, wherein R 2 or R 3 comprises one of the following structures:

59. The compound according to claim 5 or 8, wherein R 3 comprises one of the following structures:

60. The compound according to claim 5 or 8, wherein at least one occurrence of m is an integer from 1 to 15.

61. The compound according to claim 5 or 8, wherein at least one occurrence of m is an integer from 1 to 10.

62. The compound according to claim 5 or 8, wherein at least one occurrence of m is an integer from 1 to 5.

63. The compound according to claim 5 or 8, wherein each occurrence of m is an integer from 1 to 15.

64. The compound according to claim 5 or 8, wherein each occurrence of m is an integer from 1 to 10.

65. The compound according to claim 5 or 8, wherein each occurrence of m is an integer from 1 to 5.

66. The compound according to claim 5 or 8, wherein n is an integer from 1 to 100.

67. The compound according to claim 5 or 8, wherein n is an integer from 1 to 10.

68. The compound according to claim 5 or 8, wherein at least one occurrence of M is an anti - neoplastic agent, an enediyne antitumor antibiotic, a maytansine - like compound, a topoisomerase inhibitor, or an alkylating agent.

69. The compound according to claim 5 or 8, wherein M is independently, upon each occurrence, an antineoplastic agent, enediyne antitumor antibiotic, maytansine compound, topoisomerase inhibitor, kinase inhibitor, anthracycline antibiotic, and EGFR inhibitor, or an alkylating agent.

70. The compound according to claim 5 or 8, wherein M is independently, upon each occurrence, an enediyne antitumor antibiotic, maytansine compound, topoisomerase inhibitor, or an alkylating agent.

71. The compound according to claim 5 or 8, wherein at least one occurrence of M is selected from: auristatin F, monomethyl auristatin F, monomethyl auristatin E, paclitaxel, SN-38, calicheamicin, anthramycin, abbeymycin, chelocarcin, DC-81, methylanisomycin, neanisomycin A, neanisomycin B, porothramycin, prothracarcin, sibamiycin, sibiromycin, thomamycin, DM1 cytotoxin, emtansine, irinotecan, camptothecin, topotecan, silatecan, cositecan, exatecan, leotecan, gemitecan, belotecan, and rubitecan.

72. The compound according to claim 5 or 8, wherein at least one occurrence of M has one of the following structures:

73. The compound according to claim 5 or 8, wherein each occurrence of M has one of the following structures:

74. A compound having one of the following structures: wherein R 2 is wherein R 2 is wherein R 2 is wherein R 2 is and MMAE-VAC is where R 2 is MMAE-VAC is and AF is or where R 2 is R 3 is and MMAE-VAC is 75. A composition comprising the compound according to any one of claims 1-74 and a pharmaceutically acceptable carrier.

76. Use of the compound according to any one of claims 1-74 or the composition according to claim 75 in the manufacture of a medicament for the treatment of a disease, wherein at least one M is a bioactive moiety effective in treating the disease.

77. The use according to claim 76, wherein each M is a bioactive moiety effective in treating the disease.

78. The use according to any one of claims 76 or 77, wherein the disease is cancer.

79. The use according to claim 78, wherein the cancer is breast cancer, non-Hodgkin 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 lymphoma, lymphoma, mesothelioma, non-small cell lung cancer, recurrent head and neck cancer, or a combination thereof.

80. The use according to claim 76, wherein the method further comprises administering an additional therapeutic agent selected from: antineoplastic agents, enediyne antitumor antibiotics, maytansine compounds, topoisomerase inhibitors, kinase inhibitors, anthracycline antibiotics, and EGFR inhibitors, alkylating agents, and combinations thereof.

81. The use according to claim 76, wherein the method further comprises administering an additional therapeutic agent selected from the group consisting of: anti-neoplastic agents, enediyne antitumor antibiotics, maytansinoids, topoisomerase inhibitors, kinase inhibitors, anthracycline antibiotics and EGFR inhibitors, alkylating agents, and combinations thereof.

82. The use according to claim 80, wherein the additional therapeutic agent comprises auristatin F, monomethyl auristatin F, monomethyl auristatin E, paclitaxel, SN-38, calicheamicin, anthramycin, abbeymycin, cactinomycin, DC-81, methylanamycin, neothramycins A and B, porothramycin, prothracarcin, sibanomicin, sibiromycin, tomatomycin, DM1 cytotoxic, emtansine, irinotecan, camptothecin, topotecan, silatecan, cositecan, exatecan, leotecan, gemitecan, belotecan, and rubitecan.

83. The use according to any one of claims 76 or 77, wherein the disease bioactively degrades proteins.

84. The use according to claim 83, wherein the protein is amyloid or tau protein.

85. The use according to any one of claims 76, 77 or 84, wherein the disease is amyloidosis or Alzheimer's disease.

86. The use according to any one of claims 76, 77 or 84, wherein the disease is prostate cancer, pancreatic cancer or breast cancer.

87. The use according to any one of claims 76, 77 or 84, wherein the disease is a tumor disease, a cardiovascular disease, a renal disease, a metabolic disease or a respiratory disease.

88. The use according to any one of claims 76, 77 or 84, wherein the disease is a pulmonary disease or a central nervous system disease.

89. The use according to any one of claims 76, 77 or 84, wherein the disease is metastatic castration-resistant prostate cancer or metastatic breast cancer.

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