Phosphoalkyl ribose polymers comprising biologically active compounds

Abstract

To provide compounds useful as biologically active compounds.SOLUTION: Compounds according to the present invention have the following structure (I) or a stereoisomer, tautomer or salt thereof, wherein R1, R2, R3, R4, R5, L, L1, L2, L3, L4, M, q, w and n are as defined herein. Methods associated with preparation and use of such compounds are also provided.SELECTED DRAWING: None

Description

[Technical field]

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

[0002] 2. Description of Related Art Targeted drug conjugates are intended to target only diseased cells and not harm healthy cells, unlike chemotherapy, for example.Conjugates are usually composed of a targeting molecule linked to a biologically active payload or drug.By combining the inherent targeting ability and therapeutic efficacy of biologically active drugs, conjugates can deliver drugs only to intended targets and minimize potential side effects. Antibody-drug conjugates (ADCs) are one of the classes of targeted drug conjugates that are of particular interest for cancer treatment. ADCs combine the targeting characteristics of monoclonal antibodies with the cancer-killing potential of cytotoxic agents, resulting in a therapy with several advantages over other chemotherapeutic agents. However, the complexity of ADC construction, specifically the challenges involved in the chemical linker between the antibody and the drug, make the development of new and effective therapeutic agents quite difficult. The first ADC was approved in 2001, but it took almost a decade for the next ADC to be approved. At present, only Adcetris® and Kadcyla® are commercially available worldwide (Zevalin® is only approved in China). Pioneer Pfizer / Wyeth withdrew Mylotarg® in 2010 after safety issues were observed during controlled clinical trials. Therefore, there is a need in the art for a potent targeted drug conjugate with a large therapeutic index.Ideally, such a drug conjugate should achieve fine discrimination between healthy tissue and diseased tissue (e.g., tumor cells).The present invention meets this need and achieves further related advantages. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Special Publication No. 2008-501319 Summary of the Invention [Means for solving the problem]

[0004] Briefly, embodiments of the present invention are generally directed to compounds useful as targeted drug conjugates, which may include fluorescent and / or colored dyes that allow selective delivery to targets such as tumor cells, as well as reagents for their preparation.Methods for preparing such molecules and methods for using the molecules to provide therapeutic treatment to patients in need thereof are also described. The presently disclosed compound embodiments include one or more biologically active moieties that are covalently linked by a linker ("L"). Advantageously, the present invention embodiments provide compounds that can be incorporated during polymer synthesis or attached post-synthetically. Furthermore, the embodiments described herein allow for the incorporation of multiple biologically active moieties within the same compound, and the optional inclusion of a targeting moiety. In one embodiment, a compound having the following structure (I): [ka] (I) Alternatively, a stereoisomer, tautomer or salt thereof is provided, wherein R 1 , R 2 , R 3 , R 4 , R 5 , L, L 1 , L 2 , L 3 , L 4 , M, q, w and n are as defined herein.) The compounds of structure (I) find utility in a number of applications, including use as therapeutic agents in a variety of treatment methods. In another embodiment, a method of treating a disease is provided 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 independently comprises a biologically active moiety effective to treat the disease. These and other aspects of the present invention will become evident upon reference to the following detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0006] With reference to the entire specification, the references to "one embodiment" or "an embodiment" mean that the particular features, structures, or properties described in connection with these embodiments are included in at least one embodiment of the invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or properties may be combined in any suitable manner in one or more embodiments. "Amino" means -NH 2 Refers to the base. "Carboxy" means -CO 2 Refers to the H group. "Cyano" refers to the group -CN. "Formyl" refers to the group -C(=O)H. "Hydroxy" or "hydroxyl" refers to the group --OH. "Imino" refers to the group =NH. "Nitro" means -NO 2 Refers to the base. "Oxo" refers to the =O substituent. "Sulfhydryl" refers to the -SH group. "Thioxo" refers to the group ═S.

[0007] "Alkyl" means an alkyl group containing no unsaturation and having 1 to 12 carbon atoms (C 1 -C 12 alkyl), 1 to 8 carbon atoms (C 1 -C 8 alkyl) or 1 to 6 carbon atoms (C 1 -C 6 "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless specifically stated otherwise in this specification, alkyl groups may be optionally substituted. "Alkylene" or "alkylene chain" refers to a divalent straight or branched hydrocarbon chain, containing no unsaturation and having 1 to 12 carbon atoms, consisting only of carbon and hydrogen, linking the remainder of the molecule to a radical group, e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless specifically stated otherwise in this specification, alkylene can be optionally substituted.

[0008] "Alkenylene" or "alkenylene chain" refers to a divalent straight or branched hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond and having 2-12 carbon atoms, linking the rest of the molecule to a radical group, e.g., ethenylene, propenylene, n-butenylene, etc. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, alkenylene may be substituted. "Alkynylene" or "alkynylene chain" refers to a divalent straight or branched hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond and having 2 to 12 carbon atoms, linking the rest of the molecule to a radical group, e.g., ethenylene, propenylene, n-butenylene, and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, alkynylene may be optionally substituted.

[0009] "Alkyl ether" refers to any alkyl group, as defined above, in which at least one carbon-carbon bond is replaced by a carbon-oxygen bond. The carbon-oxygen bond may be terminal (as in an alkoxy group) or the carbon-oxygen bond may be internal (i.e., COC). An alkyl ether contains at least one carbon-oxygen bond, but may contain more than one. For example, polyethylene glycol (PEG) is included within the meaning of alkyl ether. Unless specifically stated otherwise herein, alkyl ether groups may be substituted. For example, in some embodiments, an alkyl ether may be an alcohol or -OP(=R a )(R b )R c is replaced by Ra , R b and R c are each as defined for compounds of structures (I)-(XI).

[0010] "Alkylene ether" refers to any alkylene group, as defined above, in which at least one carbon-carbon bond is replaced by a carbon-oxygen bond. The carbon-oxygen bond may be terminal (as in an alkoxy group) or the carbon-oxygen bond may be internal (i.e., COC). An alkylene ether contains at least one carbon-oxygen bond, but may contain more than one (i.e., a "polyalkylene ether"). A PEG linking group is an example of a polyalkylene ether. "Hydroxyl polyalkylene ether" refers to a polyalkylene ether that contains at least one hydroxyl substituent. "Amino polyalkylene ether" refers to a polyalkylene ether that contains at least one amino (including alkylamino, arylamino, and aralkylamino) substituent. Unless otherwise specifically stated herein, alkylene ether, polyalkylene ether, hydroxyl polyalkylene ether, and amino polyalkylene ether groups may be substituted. "Aminoalkylene" refers to an alkylene as defined that contains one or more amino substituents. Unless stated otherwise specifically in the specification, the aminoalkylene group may be optionally substituted.

[0011] "Alkoxy" means a group of the formula -OR a R refers to the group a is an alkyl group, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted. "Alkylamino" means a group of the formula -NHR a or -NR a R a R refers to the group aare each independently an alkyl group, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted. "Alkoxyalkyl ether" means a group of the formula -OR a R b R refers to the group a is an alkylene group, as defined above, containing 1 to 12 carbon atoms, and Rb is an alkyl ether group, as defined herein. Unless otherwise specifically stated herein, an alkoxyalkyl ether group may be optionally substituted, for example, by an alcohol or -OP(=Ra)(Rb)Rc, where Ra, Rb, and Rc are each as defined for the compounds of structures (I)-(XI).

[0012] "Heteroalkyl" refers to an alkyl group, as defined above, that contains at least one heteroatom (e.g., Si, N, O, P, or S) within or at the terminus of the alkyl group. In some embodiments, the heteroatom is present within the alkyl group (i.e., a heteroalkyl has at least one carbon-[heteroatom] x -carbon bond, x is 1, 2 or 3). In other embodiments, the heteroatom is at the end of the alkyl group and thus serves to attach the alkyl group to the remainder of the molecule (e.g., M1-HA), where M1 is part of the molecule, H is the heteroatom, and A is the alkyl group. Unless otherwise specifically stated herein, heteroalkyl groups may be substituted. Exemplary heteroalkyl groups include ethylene oxide (e.g., polyethylene oxide), which may include a phosphorus-oxygen bond, such as a phosphodiester bond. "Heteroalkoxy" means a heteroalkoxy group of the formula -OR a R refers to the group a is a heteroalkyl group, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, a heteroalkoxy group may be optionally substituted.

[0013] "Heteroalkylene" refers to an alkylene group as defined above that contains at least one heteroatom (e.g., Si, N, O, P, or S) in the alkylene chain or at the end of the alkylene chain. In some embodiments, the heteroatom is in the alkylene chain (i.e., the heteroalkylene contains at least one carbon-[heteroatom]-carbon bond, and x is 1, 2, or 3). In other embodiments, the heteroatom is at the end of the alkylene and serves to bond the alkylene to the rest of the molecule (e.g., M1-HA-M2, where M1 and M2 are part of the molecule, H is a heteroatom, and A is an alkylene). Unless otherwise specifically stated herein, the heteroalkylene group may be substituted. Exemplary heteroalkylene groups include ethylene oxide (eg, polyethylene oxide), as well as the "C," "HEG," and "PEG 1K" linking groups illustrated below. [ka] Various embodiments of heteroalkylene linkers include multimers of the C-linkers, HEG linkers, and / or PEG 1K linkers described above. In some embodiments of the PEG 1K linker, n is 25. Multimers can have, for example, the following structure: [ka] (wherein x is 0 or an integer greater than 0, for example, x is in the range of 0 to 100 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). may include.

[0014] "Heteroalkenylene" is a heteroalkylene, as defined above, containing at least one carbon-carbon double bond. Unless stated otherwise specifically in the specification, a heteroalkenylene group may be optionally substituted. "Heteroalkynylene" is a heteroalkylene containing at least one carbon-carbon triple bond. Unless stated otherwise specifically in the specification, a heteroalkynylene group may be optionally substituted. "Heteroatom" in reference to a "heteroatom linker" refers to a linker group consisting of one or more heteroatoms. Exemplary heteroatom linkers include single atoms selected from the group consisting of Si, O, N, P, and S, as well as multiple heteroatoms, such as those of the formula -P(O - )(=O)O- or -OP(O - )(=O)O-- and multimers, and combinations thereof.

[0015] "Alkylphospho" means -RP(=O)(R a )R b R is an alkylene group; R a OH, O - OR c and R b is -Oalkyl or -Oalkylether, R c is the counter ion (e.g., Na + Unless otherwise specifically stated herein, an alkylphospho group may be optionally substituted. For example, in certain embodiments, the -Oalkyl or -Oalkylether moiety (R b ) may be optionally substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, or thiophosphoalkylether. An "Oalkylphospho" group is an alkylphospho group that is attached to the remainder of the molecule via an oxygen atom. Unless otherwise specifically stated herein, an Oalkylphospho group may be optionally substituted.

[0016] "Alkyetherphospho" means -RP(=O)(R a )R b R is an alkylene ether group; R aOH, O - OR c and R b is -Oalkyl or -Oalkylether, R c is the counter ion (e.g., Na + Unless otherwise specifically stated herein, the alkyl ether phospho group may be substituted. For example, in certain embodiments, the -Oalkyl or -Oalkyl ether moiety (R b ) may be optionally substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, or thiophosphoalkylether. An "O-alkyl ether phospho" is an alkyl ether phospho group that is attached to the remainder of the molecule via an oxygen atom. Unless otherwise specifically stated herein, an O-alkyl ether phospho group may be optionally substituted.

[0017] "Alkylthiophospho" means -P(=R a )(R b )R c R refers to the group a is O or S, and R b OH, O - , S - , OR d or S.R. d and R c is -Oalkyl or -Oalkylether, R d is a counter ion (e.g., Na+), where R a is S or R b is S - Or SR d or R a is S and R b is S - or S.R. dprovided that. Unless otherwise specifically stated herein, an alkylthiophospho group may be substituted. For example, in certain embodiments, the -Oalkyl or -Oalkylether moiety in an alkythiophospho group may be substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, or thiophosphoalkylether. An O-alkylthiophospho is an alkylthiophospho group that is attached to the remainder of the molecule via an oxygen atom. Unless otherwise specifically stated herein, an O-alkylthiophospho group may be substituted.

[0018] "Alkyl ether thiophospho" means -P(=R a )(R b )R c R refers to the group a is O or S, and R b OH, O - , S - , OR d or S.R. d and R c is -Oalkyl or -Oalkylether, R d is a counter ion (e.g., Na+), where R a is S or R b is S - Or SR d or R a is S and R b is S - or S.R. dprovided that: Unless otherwise specifically stated herein, an alkyl ether thiophospho group may be substituted. For example, in certain embodiments, the -O alkyl or -O alkyl ether moiety in an alkyl ether thiophospho group may be substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, or thiophosphoalkylether. An O alkyl ether thiophospho is an alkyl ether thiophospho group that is attached to the remainder of the molecule via an oxygen atom. Unless otherwise specifically stated herein, an O alkyl ether thiophospho group may be substituted.

[0019] "Phospho" means a divalent -OP(=O)(R a ) O-group, R a O - OR c and R c is the counter ion (e.g., H + , Na + etc.). "Phosphate" means -OP(=O)(R a )R b Group(R a OH, O - OR c and R b OH, O - , OR c ), a thiophosphate group or a further phosphate group (R c is the counter ion (e.g., Na + (etc.) "Phosphoalkyl" means -OP(=O)(R a )R b R refers to the group a OH, O - OR c and R b is -Oalkyl, and R c is the counter ion (e.g., Na +and the like. Unless otherwise specifically stated herein, a phosphoalkyl group may be substituted. For example, in certain embodiments, the -Oalkyl portion in a phosphoalkyl group may be substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether. "Phosphoalkylene" refers to a divalent -OP(=O)(R a )R b - refers to the group R a O - OR c and R b is -Oalkylene, and R c is a counterion (e.g., H+, Na+, etc.). Unless otherwise specifically stated herein, the phosphoalkylene group may be substituted. For example, in certain embodiments, the alkylene portion of the phosphoalkyl group may be substituted with one or more of hydroxyl, amino, sulfhydryl, or phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, or thiophosphoalkylether, and these substituents may be substituted.

[0020] "Phosphoalkyl ether" means -OP(=O)(R a )R b R refers to the group a OH, O - OR c and R b is -O alkyl ether, R c is the counter ion (e.g., Na +and the like. Unless otherwise specifically stated herein, a phosphoalkyl ether group may be substituted. For example, in certain embodiments, the -O alkyl ether moiety in a phosphoalkyl ether group may be substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether. "Thiophosphate" is -OP(=R a )(R b )R c Group(R a is O or S, and R b OH, O - , S - , OR d or S.R. d and R c OH, SH, O - , S - , OR d , S.R. d , a phosphate group or a further thiophosphate group, and R d is the counter ion (e.g., Na + etc.), where i) R a is S, and ii) R b is S - or S.R. d and iii) R c , SH, S - or S.R. d or iv) any combination of i), ii) and / or iii).

[0021] "Thiophospho" refers to the divalent -R d P(=R a )(R b )R c - refers to the group R a , R c and R d are each independently O or S; R b O - , S - , OR e or S.R. eand R e is the counter ion (e.g., H + , Na+, etc.), where R a is either S or R b is S - Or SR e or R c is S, or Rd is S, or a combination thereof. "Thiophosphoalkyl" means -OP(=R a )(R b )R c R refers to the group a is O or S, and R b OH, O - , S - , OR d or S.R. d and R c is -Oalkyl, and R d is the counter ion (e.g., Na + etc.), where i) R a is S, and ii) R b is S - or S.R. d or iii) R a is S and R b is S - or S.R. d Provided that. Unless otherwise specifically stated herein, a thiophosphoalkyl group may be substituted. For example, in certain embodiments, the -Oalkyl portion in a thiophosphoalkyl group may be substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether.

[0022] "Thiophosphoalkylene" refers to a divalent -R d P(=R a )(R b )R c - refers to the group R a and R d are each independently O or S; Rb O - , S - , OR e or S.R. e and R c is -Oalkylene or -Salkylene, R e is the counter ion (e.g., H + , Na + etc.), where R a is either S or R b is S - Or SR e or Rc is -S alkylene, or R d is S, or a combination thereof. Unless otherwise specifically stated herein, a thiophosphoalkylene group may be optionally substituted. For example, in certain embodiments, the alkylene moiety in a thiophosphoalkylene group may be optionally substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, or thiophosphoalkylether, and these substituents may be optionally substituted. "Thiophosphoalkyl ether" means -OP(=R a )(R b )R c R refers to the group a is O or S, and R b OH, O - , S - , OR d or S.R. d and R c is -O alkyl ether, R d is the counter ion (e.g., Na + etc.), where i) R a is S, and ii) R b is S - or S.R. d or iii) R a is S and R b is S - or S.R. dProvided that. Unless otherwise specifically stated herein, a thiophosphoalkyl ether group may be substituted. For example, in certain embodiments, the -O alkyl ether moiety in a thiophosphoalkyl group may be substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether.

[0023] "Sulfhydrylalkyl" refers to an alkyl group that contains at least one sulfhydryl substituent. One or more -SH substituents may be present on a primary, secondary or tertiary carbon atom. Unless otherwise specifically stated herein, sulfhydrylalkyl groups may be substituted. "Sulfhydryl alkyl ether" refers to an alkyl ether group that contains at least one sulfhydryl substituent. The one or more -SH substituents may be present on a primary, secondary or tertiary carbon atom. Unless otherwise specifically stated herein, the sulfhydryl alkyl ether group may be substituted. "Sulfonate" is -OS(O) 2 R a R refers to the group a is alkyl or aryl. Unless stated otherwise specifically in the specification, a sulfonate group may be optionally substituted.

[0024] "Thioalkyl" means a group of the formula -SR a R refers to the group a is an alkyl group, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group may be optionally substituted. "Carbocyclic" refers to a stable 3- to 18-membered aromatic or non-aromatic ring containing 3 to 18 carbon atoms. Unless otherwise specifically stated herein, a carbocyclic ring can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems, and may be partially saturated or fully saturated. Non-aromatic carbocyclyl radicals include cycloalkyl, while aromatic carbocyclyl radicals include aryl. Unless otherwise specifically stated herein, a carbocyclic group may be optionally substituted.

[0025] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic carbocyclic ring, which may include saturated or unsaturated fused or bridged ring systems having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, attached to the remainder of the molecule by a single bond. Monocyclic cyclocalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo-[2.2.1]heptanyl, and the like. Unless otherwise specifically stated in the specification, cycloalkyl groups may be substituted. "Cycloalkylalkyl" means a group of the formula -R b R d R refers to the group b is an alkylene chain as defined above, and R d is a cycloalkyl group as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group may be optionally substituted. "Amide" means -NR a R b R refers to the radical a and R b is independently H, alkyl or aryl. Unless stated otherwise specifically in the specification, an amide group may be optionally substituted.

[0026] "Aryl" refers to a ring system containing at least one carbocyclic aromatic ring. In some embodiments, an aryl contains 6 to 18 carbon atoms. The aryl ring may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl includes, but is not limited to, aryl derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated herein, an aryl group may be substituted. "Aryloxy" means a group of the formula -OR a R refers to the group a is an aryl moiety as defined above, such as phenoxy, etc. Unless stated otherwise specifically in the specification, an aryloxy group may be optionally substituted.

[0027] "Aralkyl" means a group of the formula -R b -R c R refers to the group b is an alkylene chain as defined above, and R c is one or more aryl groups as defined above, e.g., benzyl, diphenylmethyl, etc. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted. "Oaralkyl" is an aralkyl group attached to the remainder of the molecule via an oxygen linking group. "ODMT" refers to dimethoxytrityl attached to the remainder of the molecule via an O atom. Unless otherwise specifically stated herein, Oaralkyl groups may be optionally substituted. "Cyanoalkyl" refers to an alkyl group that contains at least one cyano substituent. The one or more -CN substituents may be present on a primary, secondary or tertiary carbon atom. Unless otherwise specifically stated in the specification, a cyanoalkyl group may be optionally substituted.

[0028] "Heterocyclic" or "heterocyclyl" or "heterocyclic ring" refers to a stable 3-18 membered aromatic or non-aromatic ring containing 1-12 carbon atoms and 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless otherwise specifically stated herein, a heterocyclic ring may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems, the nitrogen, carbon or sulfur atoms in the heterocyclic ring may be oxidized, the nitrogen atoms may be quaternized, and the heterocyclic ring may be partially or fully saturated. Examples of aromatic heterocyclic rings are listed below in the definition of heteroaryl (i.e., heteroaryl is a subset of heterocyclic). Examples of non-aromatic heterocyclic rings include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, pyrazolopyrimidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclic group may be optionally substituted. "N-heterocyclyl" refers to a heterocyclyl group, as defined above, containing at least one nitrogen and where the point of attachment of the heterocyclyl group to the remainder of the molecule is through a nitrogen atom in the heterocyclyl group. Unless otherwise specifically stated in the specification, N-heterocyclyl groups may be optionally substituted.

[0029] "Heterocyclylalkyl" means a heterocyclyl group of the formula -R b R e R refers to the group bis an alkylene chain as defined above, and R e is a heterocyclyl group as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl group at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group may be optionally substituted.

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

[0031] "N-heteroaryl" refers to a heteroaryl group, as defined above, containing at least one nitrogen, where the point of attachment of the heteroaryl group to the remainder of the molecule is through a nitrogen atom in the heteroaryl group. Unless otherwise specifically stated in the specification, N-heteroaryl groups may be optionally substituted. "Heteroarylalkyl" means a heteroaryl group of the formula -R b R f R refers to the group b is an alkylene chain as defined above, and R f is a heteroaryl group as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group may be optionally substituted. "Hydroxylalkyl" refers to an alkyl group that contains at least one hydroxyl substituent. The one or more -OH substituents may be present on a primary, secondary or tertiary carbon atom. Unless otherwise specifically stated in the specification, a hydroxyalkyl group may be optionally substituted. "Hydroxylalkylene" refers to an alkylene group that contains at least one hydroxyl substituent. The one or more -OH substituents may be present on a primary, secondary or tertiary carbon atom. Unless otherwise specifically stated in the specification, a hydroxyalkylene group may be optionally substituted.

[0032] "Hydroxyl alkyl ether" refers to an alkyl ether group that contains at least one hydroxyl substituent. The one or more -OH substituents may be present on a primary, secondary or tertiary carbon atom. Unless otherwise specifically stated herein, a hydroxyalkyl ether group may be optionally substituted. "Polycyclic" refers to any molecule having more than one ring, which may be fused spirocyclic or separated by one or more atoms (e.g., joined via an acyclic linker). "Spirocyclic" refers to a polycyclic molecule in which two rings share a single carbon atom.

[0033] "Fused" refers to a ring system containing at least two rings, which share at least one common ring atom, e.g., two common ring atoms. When the fused ring is a heterocyclyl or heteroaryl ring, the common ring atom can be carbon or nitrogen. Fused rings include bicyclic, tricyclic, tertracyclic, etc. "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo. "Haloalkyl" refers to an alkyl group, as defined above, that is substituted with one or more halo groups, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

[0034] As used herein, the term "substituted" refers to any of the above groups (e.g., alkyl, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, alkoxy, alkyl ether, alkoxyalkyl ether, heteroalkyl, heteroalkoxy, phosphoalkyl, phosphoalkyl ether, thiophosphoalkyl, thiophosphoalkyl ether, carbocyclic, cycloalkyl, aryl, heterocyclic, and / or heteroaryl) in which at least one hydrogen atom (e.g., 1, 2, 3, or all hydrogen atoms) has been replaced with, but is not limited to, F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl, alkoxy and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfone, sulfonyl and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl and triarylsilyl groups; and bonds to non-hydrogen atoms such as other heteroatoms in various other groups. "Substituted" also refers to any of the above groups in which one or more hydrogen atoms are replaced by a higher bond (e.g., double or triple bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl and ester groups, and nitrogen in groups such as imine, oxime, hydrazone and nitrile. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced by a higher bond (e.g., double or triple bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl and ester groups, and nitrogen in groups such as imine, oxime, hydrazone and nitrile. g R h , -NR g C(=O)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 , -SRg , -SOR g , -SO 2 R g , -OSO 2 R g , -SO 2 OR g , =NSO 2 R g and -SO 2 NR g R h "Substituted" also includes any of the above groups in which one or more hydrogen atoms have been 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 In the above, R g and R h are the same or different and are independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. "Substituted" further refers to any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl group. In some embodiments, the optional substituents are -OP(=R a )(R b )R c and R a , R band R c are each as defined for compounds of structures (I)-(XI). Additionally, any of the aforementioned substituents may also be substituted with one or more of the aforementioned substituents.

[0035] "Conjugation" or "bioconjugation" refers to a chemical strategy that forms a stable covalent bond between two molecules. The term "bioconjugation" is generally used when one of the molecules is a biomolecule (e.g., an antibody). The product or compound that results from such a strategy is a conjugate, is conjugated, or a grammatical equivalent. "Fluorescent" refers to a molecule that can absorb light of a particular frequency and emit light of a different frequency. Fluorescence is well known to those of skill in the art. "Colored" refers to molecules that absorb light within the color spectrum (ie, red, yellow, blue, etc.).

[0036] "Linker" refers to a continuous chain of at least one atom, such as carbon, oxygen, nitrogen, sulfur, phosphorus, and combinations thereof, that connects one portion of a molecule to another portion of the same molecule or to a different molecule, moiety, or solid support (e.g., a microparticle). The linker can be attached to the molecule through covalent bonds or other means, such as ionic or hydrogen bonding interactions. "Analyte" or "analyte molecule" refers to a chemical species, substance, or chemical constituent that is being measured. In some embodiments, the analyte molecule is a biomolecule. Analyte molecules can include small molecules (e.g., organic compounds having a molecular weight less than 900 g / mol), drugs or drug metabolites (e.g., compounds known to regulate or result from biological processes, including alkaloids, glycosides, lipids, non-ribosomal peptides, phenazines, flavinols, polyketides, terpenes (including steroids), and tetrapyrroles), or pesticides.

[0037] The term "biomolecule" refers to any of a variety of biological substances, including nucleic acids, carbohydrates, amino acids, polypeptides, glycoproteins, hormones, aptamers, and mixtures thereof. More specifically, the term is intended to include, without limitation, RNA, DNA, oligonucleotides, modified or derivatized nucleotides, enzymes, receptors, prions, receptor ligands (including hormones), antibodies, antigens, and toxins, as well as bacteria, viruses, blood cells, and tissue cells. The visually detectable biomolecules of the present invention (e.g., compounds having a biomolecule linked to a compound) are prepared by contacting a biomolecule with the above-mentioned compounds having a reactive group that allows the binding of the biomolecule to the compound through any available atom or functional group, such as an amino, hydroxyl, carboxyl, or sulfhydryl group, on the biomolecule, as further described herein. A "reactive group" is a moiety that can react with a second reactive group (e.g., a "complementary reactive group") to form one or more covalent bonds, for example, by substitution, oxidation, reduction, addition, or cycloaddition reactions. Exemplary reactive groups are provided in Table 1 and include, for example, nucleophiles, electrophiles, dienes, dienophiles, aldehydes, oximes, hydrazones, alkynes, amines, azides, acyl azides, acyl halides, nitriles, nitrones, sulfhydryls, disulfides, sulfonyl halides, isothiocyanates, imidoesters, activated esters, ketones, α,β-unsaturated carbonyls, alkenes, maleimides, α-haloimides, epoxides, aziridines, tetrazines, tetrazoles, phosphines, biotins, thiiranes, and the like.

[0038] The terms "visible" and "visually detectable" are used herein to refer to substances observable by visual inspection without prior illumination or chemical or enzymatic activation. Such visually detectable substances absorb and emit light in the spectral region ranging from about 300 to about 900 nm. Preferably, such substances are intensely colored, preferably with a color intensity of at least about 40,000 nm. -1 cm -1 , more preferably at least about 50,000 M-1 cm -1 , and even more preferably at least about 60,000 M -1 cm -1 , and even more preferably at least about 70,000 M -1 cm -1 and most preferably at least about 80,000 M -1 cm -1 The compound embodiments of the present disclosure may be detected by naked eye observation or with the aid of optically-based detection devices, including, but not limited to, absorption spectrophotometers, transmitted light microscopes, digital cameras and scanners. Visually detectable substances are not limited to those that emit and / or absorb light in the visible spectrum. Also included within the scope of "visually detectable" substances are substances that emit and / or absorb light in the ultraviolet (UV) region (about 10 nm to about 400 nm), infrared (IR) region (about 700 nm to about 1 mm), and substances that emit and / or absorb in other regions of the electromagnetic spectrum.

[0039] For the purpose of the present invention, the term "photostable visible dye" refers to a chemical moiety that is visually detectable and does not significantly change or decompose when exposed to light, as defined herein above.Preferably, the photostable visible dye does not show significant decolorization or decomposition after exposure to light for at least 1 hour.More preferably, the visible dye is stable after exposure to light for at least 12 hours, even more preferably at least 24 hours, even more preferably at least 1 week, and most preferably at least 1 month.Non-limiting examples of photostable visible dyes suitable for use in the compounds and methods of the present invention include azo dyes, thioindigo dyes, quinacridone pigments, dioxazines, phthalocyanines, perinones, diketopyrrolopyrroles, quinophthalones, and trueycarboniums.

[0040] As used herein, the term "perylene derivative" is intended to include any substituted perylene that is visually detectable. However, the term is not intended to include perylene itself. The terms "anthracene derivative", "naphthalene derivative", and "pyrene derivative" are used similarly. In some preferred embodiments, the derivative (e.g., perylene, pyrene, anthracene, or naphthalene derivative) is an imide, bis-imide, or hydrazamimide derivative of perylene, anthracene, naphthalene, or pyrene. "Solid support" refers to any solid substrate known in the art for stationary phase support of molecules, for example, "microparticle" refers to any of a number of small particles useful for binding to compounds of the invention, including, but not limited to, glass beads, magnetic beads, polymeric beads, non-polymeric beads, etc. In certain embodiments, microparticles comprise polystyrene beads or controlled pore glass. "Solid support moiety" refers to a functional group that remains attached to a molecule once the molecule is cleaved from the solid support. Solid support moieties are known in the art and can be readily derivatized based on the structure of the solid support and the group linking the molecule to the solid support.

[0041] A "targeting moiety" is a moiety that selectively binds to or associates with a particular target, such as a tumor cell antigen. By "selectively" binds or associates, it is meant that the targeting moiety preferentially associates with or binds to a desired target over other targets. In some embodiments, the compounds disclosed herein include a linking group to the targeting moiety for the purpose of selectively binding or associating the compound with a tumor cell antigen (i.e., the target of the targeting moiety), thus enabling delivery of the biologically active moiety to the tumor cell. Exemplary targeting moieties include, but are not limited to, antibodies, antigens, nucleic acid sequences, enzymes, proteins, cell surface receptor antagonists, and the like. In some embodiments, the targeting moiety is a moiety, such as an antibody, that selectively binds to or associates with a targeting feature on or in a cell, such as a targeting feature on the cell membrane or other cell structure surface, thus enabling delivery of the biologically active moiety to or within the cell of interest. Small molecules that selectively bind to or associate with a desired biological target are also contemplated as targeting moieties in certain embodiments. Those of skill in the art will recognize other biological targets, and corresponding targeting moieties, that are useful in various embodiments.

[0042] A "physiologically cleavable linker" refers to a molecular linking group that can be split or separated in a defined manner to yield two or more separate molecules while present in the in vivo or in vitro environment of an organism or cellular system. In general, physiological conditions that include such cleavage or scission events can include temperatures in the range of about 20-40° C., atmospheric pressure of about 1 atm (101 kPa or 14.7 psi), pH of about 6-8, glucose concentration of about 1-20 mM, atmospheric oxygen concentration, and gravity of the Earth. In some embodiments, physiological conditions include enzymatic conditions (i.e., cleavage by an enzyme). Bond cleavage or scission can be homogeneous or heterogeneous cleavage. "Microparticle" is a type of solid support and refers to any of a number of small particles useful for binding to the compounds of the invention, including, but not limited to, glass beads, magnetic beads, polymeric beads, non-polymeric beads, etc. In certain embodiments, the microparticle comprises a polystyrene bead. "Base pairing moiety" refers to a heterocyclic moiety that can hybridize with a complementary heterocyclic moiety through hydrogen bonds (e.g., Watson-Crick type base pairing). Base pairing moieties include natural and unnatural bases. Non-limiting examples of base pairing moieties are RNA and DNA bases such as adenosine, guanosine, thymidine, cytosine and uridine, and their analogs.

[0043] The embodiments of the invention disclosed herein are also intended to encompass all compounds in which one or more atoms are isotopically labeled by replacement with an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include, respectively: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 Includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. Isotopically labeled compounds of structures (I)-(XI) may generally be prepared by conventional techniques known to those of skill in the art, or by methods analogous to those described below and in the Examples below, substituting appropriate isotopically labeled reagents in place of the non-labeled reagents previously used. "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances when said event or circumstance occurs as well as instances when it does not occur. For example, "optionally substituted alkyl" means that the alkyl group may be substituted or unsubstituted, and that the description includes both substituted and unsubstituted alkyl groups. "Salt" includes both acid addition salts and base addition salts.

[0044] "Acid addition salts" refers to salts of inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and salts of acids, such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, schizoic acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucous acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutamine ... It refers to salts formed with organic acids such as oleic acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0045] "Base addition salt" refers to a salt prepared from the addition of an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0046] Crystallization may produce solvates of the compounds described herein. The embodiments of the present invention include all solvates of the compounds described. As used herein, the term "solvate" refers to an aggregate that includes one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as corresponding solvate forms. The compounds of the present invention may be true solvates, while in other cases, the compounds of the present invention may simply retain incidental water or another solvent, or may be a mixture of water and some incidental solvent. The embodiments of the compounds of the present invention (e.g., compounds of structures (I)-(XI)), or salts, tautomers, or solvates thereof, may contain one or more stereocenters and may therefore give rise to enantiomers, diastereomers, and other stereoisomers that may be defined, with respect to absolute stereochemistry, as (R)- or (S)-, or, in the case of amino acids, (D)- or (L)-. The embodiments of the present invention 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 may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When a compound described herein contains an olefinic double bond, or other feature which results in geometric symmetry, unless otherwise specified, the compound is intended to include both E and Z geometric isomers, as well as all tautomers are also intended to be included.

[0047] "Stereoisomers" refers to compounds composed of identical atoms joined by the same bonds but having different three-dimensional structures and which cannot be interconverted. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. "Tautomer" refers to a proton transfer from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any of the above compounds. Various tautomers of the compounds can be easily derived by one skilled in the art. The chemical naming protocols and structure diagrams used herein are a modification of the IUPAC nomenclature system using the ACD / Nomenclature version 9.07 software program and / or the ChemDraw Ultra version 11.0 software naming program (CambridgeSoft). Common names familiar to those skilled in the art are also used.

[0048] As stated above, in one embodiment of the present invention, compounds are provided that are useful as covalent linkers between biologically active moieties and targeting moieties. In other embodiments, compounds are provided that are useful as synthetic intermediates for the preparation of compounds that include one or more biologically active moieties. In general terms, embodiments of the present invention are directed to polymers with biologically active moiety side chains. The biologically active moieties are linked by linkers that have phosphoalkyl or other linking groups that may include hydrophilic moieties at the pH at which the compounds are administered. Without wishing to be bound by theory, it is believed that the length and specific properties of the linker (e.g., hydrophilicity, charge, etc.) help to protect or withhold the biological activity until the drug is released at the desired target. In another aspect, the linker provides a link between the biologically active moiety and the targeting moiety that acts to increase the accumulation of the biologically active moiety at the desired target. That is, the biological activity is solely potentiated or increased in biological activity to accumulate at the intended target, which minimizes potential side effects of the treatment (e.g., cytotoxicity).

[0049] Thus, some embodiments include a compound having the following structure (I): [ka] (I) or a stereoisomer, pharma- ceutically acceptable salt, or tautomer thereof, wherein:

[0050] M is, independently at each occurrence, a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding moiety, provided that at least one occurrence of M is not a fluorescent dye; L is a physiologically cleavable linker; L 1 , L 2 , L 3 and L 4 is, independently at each occurrence, an optional alkylene linker or heteroalkylene linker; R 1 is independently at each occurrence H, alkyl or alkoxy;

[0051] R 2 is an electron pair, H, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfyhdryl alkyl ether, cyano alkyl, phospho, thio phospho, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, thio phosphoalkyl ether, Q or a protected form thereof, or L', wherein alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfyhdryl alkyl ether, cyano alkyl, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, and thio phosphoalkyl ether are optionally substituted with hydroxyl, amino, sulfhydryl, phosphate, thio phosphate, phosphoalkyl, thio phosphoalkyl, phosphoalkyl ether, or thio phosphoalkyl ether, or combinations thereof;

[0052] R 3 are H, OH, SH, -NH 2, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, -O aralkyl, phosphate, thiophosphate, alkyl phospho, alkyl thiophospho, -O alkyl phospho, -O alkyl thiophospho, alkyl ether phospho, alkyl ether thiophospho, -O alkyl ether phospho, -O alkyl ether thiophospho phosphoalkyl, phosphoalkyl ether, thiophosphoalkyl, thiophosphoalkyl ether, -O phosphoalkyl, -O phosphoalkyl ether, -O thiophosphoalkyl, -O thiophosphoalkyl ether, Q or a protected form thereof, or L'; the phosphoalkyl, phosphoalkylether, thiophosphoalkyl, thiophosphoalkylether, -Ophosphoalkyl, -Ophosphoalkylether, -Othiophosphoalkyl, -Othiophosphoalkylether may be substituted with hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether or combinations thereof;

[0053] R 4 independently for each occurrence, O - , S - , OZ, SZ or N(R 6 ) 2 Z is a cation and R 6 each is independently H or alkyl; R 5 is independently at each occurrence oxo, thioxo, or absent; Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety; L' is, independently at each occurrence, a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a solid support or a solid support moiety, a linker that includes a covalent bond to a solid support or a solid support moiety, or a linker that includes a covalent bond to an additional compound of structure (I); n is an integer equal to or greater than 1, q is an integer greater than or equal to 1 for at least one integer value of n; w is an integer greater than or equal to 0 for each integer value of n, provided that when n is greater than 1, at least one occurrence of L contains oxygen and no more than 3 carbons).

[0054] The various linkers and substituents in the compounds of structure (I) (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , L, L 1 , L 2 , L 3 , L 4, M, Q and L') may be further substituted with one more substituent. For example, in some embodiments, the optional substituents are selected to optimize the aqueous solubility, permeability, retention or other properties of the compounds of structure (I). In certain embodiments, the alkylene or heteroalkylene linker, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, phospho, thio phospho, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phospho alkyl, phospho alkyl ether, thio phospho alkyl, thio phospho alkyl ether, may be further substituted with one more substituent selected from the group consisting of hydroxyl, alkoxy, alkyl ether, alkoxy alkyl ether, sulfhydryl, amino, alkyl amino, carboxyl, phosphate, thio phosphate, phospho alkyl, thio phospho alkyl, phospho alkyl ether and thio phospho alkyl ether. In certain embodiments, the optional substituents are -OP(=R a )(R b )R c and R a is O or S, and R b OH, SH, O - , S - , OR d or S.R. d and R c OH, SH, O - , S - , OR d , S.R. d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is a counterion. In certain embodiments, the substituents are selected to increase cell or tissue penetration. In related embodiments, the substituents are selected to increase cell or tissue retention.

[0055] In certain embodiments, the compound has the following structure (Ia): [ka] (Ia) (In the formula,

[0056] M is, independently at each occurrence, a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding moiety, provided that at least one occurrence of M is not a fluorescent dye; L is a physiologically cleavable linker; L 1 and L 2 is, independently at each occurrence, an optional alkylene linker or heteroalkylene linker; R 1 is independently at each occurrence H, alkyl or alkoxy;

[0057] R 2is an electron pair, H, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, phospho, thio phospho, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, thio phosphoalkyl ether, Q or a protected form thereof, or L', wherein alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, and thio phosphoalkyl ether are optionally substituted with hydroxyl, amino, sulfhydryl, phosphate, thio phosphate, phosphoalkyl, thio phosphoalkyl, phosphoalkyl ether, or thio phosphoalkyl ether, or combinations thereof;

[0058] R 3 are H, OH, SH, -NH 2, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, -O aralkyl, phosphate, thiophosphate, alkyl phospho, alkyl thiophospho, -O alkyl phospho, -O alkyl thiophospho, alkyl ether phospho, alkyl ether thiophospho, -O alkyl ether phospho, -O alkyl ether thiophospho phosphoalkyl, phosphoalkyl ether, thiophosphoalkyl, thiophosphoalkyl ether, -O phosphoalkyl, -O phosphoalkyl ether, -O thiophosphoalkyl, -O thiophosphoalkyl ether, Q or a protected form thereof, or L'; the phosphoalkyl, phosphoalkylether, thiophosphoalkyl, thiophosphoalkylether, -Ophosphoalkyl, -Ophosphoalkylether, -Othiophosphoalkyl, -Othiophosphoalkylether may be substituted with hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether or combinations thereof; R 4 independently for each occurrence, O - , S - , OZ, SZ or N(R 6 ) 2 Z is a cation and R 6 each is independently H or alkyl; R 5 is independently at each occurrence oxo, thioxo, or absent; Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety; L' is, independently at each occurrence, a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a solid support or a solid support moiety, a linker that includes a covalent bond to a solid support or a solid support moiety, or a linker that includes a covalent bond to an additional compound of structure (I); and n is an integer from 1 to 10.

[0059] In some more specific embodiments of structure (Ia), when n is greater than 1, at least one occurrence of L contains oxygen and no more than 3 carbons. In some other embodiments, the compound has the following structure (Ib): [ka] (Ib) (In the formula, R 7 , R 8 , R 9 and R 10 is, independently at each occurrence, H or alkyl; x 1 and y 1 is independently an integer from 0 to 5 at each occurrence.

[0060] In different embodiments, the compound has one of the following structures (Ic), (Id), (Ie) or (If): [ka] has.

[0061] In some embodiments of the compound of structure (I), w is 1 for at least one integer value of n. In some embodiments, w is 1 for each occurrence. In some of these embodiments, the compound has the following structure (Ig): [ka] (Ig) (In the formula, R 7 , R 8 , R 9 and R 10 is, independently at each occurrence, H or alkyl; x 1 , x 2 , y 1 and y 2 is independently at each occurrence an integer from 0 to 5. In some embodiments, R 5 is oxo, R 4 O - Or OZ.

[0062] In certain embodiments, R 2 is H or an electron pair, and R 3 is L'. In a different embodiment, R 2 is L' or an electron pair, and R 3 is H. In other embodiments, R 2 is a hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, or sulfhydryl alkyl ether; R 3 is L'. In more specific embodiments, R 2 is one of the following structures: [ka] (In the formula, R 2a -OH, -NH 2 or -SH, and a is an integer of 1 to 10.

[0063] In other embodiments, R 3 is L', and R 2 is alkylphospho, alkylthiophospho, alkyletherphospho, alkyletherthiophospho, phosphoalkyl, phosphoalkylether, thiophosphoalkyl, or thiophosphoalkylether; R 2 -OH, -NH 2and -SH. In some of these embodiments, R 2 is one of the following structures: [ka] TIFF2024040167000011.tif167170 (in the formula, R 2a -OH, -SH, -NH 2 , phosphate or thiophosphate, R 4a and R 4b Independently, O - , S - , OZ or SZ, Z being a cation; R 5a and R 5b is independently oxo or thioxo; a, b, and c each independently represent an integer of 1 to 10.

[0064] In certain other embodiments, R 2 is L', and R 3 is OH or phosphate. In more specific embodiments, R 2 is L', and R 3 -OH, -NH 2 and -SH. In some embodiments, R is a phosphate, thiophosphate, phospho, thiophospho, -Oalkylphospho, -Oalkylthiophospho, -Oalkyletherphospho, -Oalkyletherthiophospho, -Ophosphoalkyl, -Ophosphoalkylether, -Othiophosphoalkyl, or -Othiophosphoalkylether, optionally substituted with a substituent selected from: 3 is one of the following structures: [ka] (In the formula, R 3a -OH, -SH, -NH 2 , phosphate or thiophosphate, R 4a and R 4b Independently, O - , S - , OZ or SZ, Z being a cation; R 5a and R 5b is independently oxo or thioxo; b and c each independently represent an integer of 1 to 10. has.

[0065] In some embodiments, at least one of a, b, or c is 2. In other embodiments, a, b, and c are each 2. In some embodiments, at least one of a, b, or c is 6. In some embodiments, a, b, and c are each 6. In some embodiments, R 4a and R 4b are respectively, O - and R 5a and R 5b Each is oxo. In other embodiments, R 4a and R 4b are respectively, O - and R 5a and R 5b Each is thioxo. In some embodiments, R 4a and R 4b are respectively, S - and R 5a and R 5b Each is thioxo. In certain embodiments, R 4a and R 4b are respectively, S - and R 5a and R 5b are each oxo.

[0066] In certain embodiments, n is an integer from 1 to 5. In some other embodiments, n is an integer from 2 to 15. In some embodiments, n is an integer from 2 to 10. In more specific embodiments, n is an integer from 2 to 5. One embodiment is a compound having the following structure (II): [ka] (II) or a stereoisomer, pharma- ceutically acceptable salt, or tautomer thereof, wherein: M is, independently at each occurrence, a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding moiety, provided that at least one occurrence of M is not a fluorescent dye; L is a physiologically cleavable linker; L 1 and L 2 is, independently at each occurrence, an optional alkylene linker or heteroalkylene linker;

[0067] R 1 is independently at each occurrence H, alkyl or alkoxy; R 2is an electron pair, H, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, phospho, thio phospho, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, thio phosphoalkyl ether, Q or a protected form thereof, or L', wherein alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, and thio phosphoalkyl ether are optionally substituted with hydroxyl, amino, sulfhydryl, phosphate, thio phosphate, phosphoalkyl, thio phosphoalkyl, phosphoalkyl ether, or thio phosphoalkyl ether, or combinations thereof;

[0068] R 3 are H, OH, SH, -NH 2, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, -O aralkyl, phosphate, thiophosphate, alkyl phospho, alkyl thiophospho, -O alkyl phospho, -O alkyl thiophospho, alkyl ether phospho, alkyl ether thiophospho, -O alkyl ether phospho, -O alkyl ether thiophospho phosphoalkyl, phosphoalkyl ether, thiophosphoalkyl, thiophosphoalkyl ether, -O phosphoalkyl, -O phosphoalkyl ether, -O thiophosphoalkyl, -O thiophosphoalkyl ether, Q or a protected form thereof, or L'; the phosphoalkyl, phosphoalkylether, thiophosphoalkyl, thiophosphoalkylether, -Ophosphoalkyl, -Ophosphoalkylether, -Othiophosphoalkyl, -Othiophosphoalkylether may be substituted with hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether or combinations thereof;

[0069] R 4 independently for each occurrence, O - , S - , OZ, SZ or N(R 6 ) 2 Z is a cation and R 6 each is independently H or alkyl; R 5 is independently at each occurrence oxo, thioxo, or absent; Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety; L' is, independently at each occurrence, a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a linker that includes a covalent bond to a solid support or a solid support residue, a linker that includes a covalent bond to a solid support or a solid support residue, or a linker that includes a covalent bond to an additional compound of structure (II); n is an integer equal to or greater than 1, q is an integer greater than or equal to 1 for at least one integer value of n. w is an integer greater than or equal to 0 for each integer value of n.

[0070] In some more specific embodiments of structure (II), when n is greater than 1, at least one occurrence of L contains oxygen and no more than 3 carbons. In some more specific embodiments, R 3 is L', and R 2 is alkylphospho, alkylthiophospho, alkyletherphospho, alkyletherthiophospho, phosphoalkyl, phosphoalkylether, thiophosphoalkyl, or thiophosphoalkylether; R 2 -OH, -NH 2 and -SH. In a related embodiment, R 2 is one of the following structures: [ka] TIFF2024040167000015.tif144170 (in the formula, R 2a -OH, -SH, -NH 2 , phosphate or thiophosphate, R 4a and R 4b Independently, O - , S - , OZ or SZ, Z being a cation; R 5a and R 5b is independently oxo or thioxo; a, b, and c each independently represent an integer of 1 to 10.

[0071] In some of the above embodiments, R 2 is L', and R 3 is OH or phosphate. In other embodiments, R 2 is L', and R 3 -OH, -NH 2 and -SH. In some of the above embodiments, R is phosphate, thiophosphate, phospho, thiophospho, -Oalkylphospho, -Oalkylthiophospho, -Oalkyletherphospho, -Oalkyletherthiophospho, -Ophosphoalkyl, -Ophosphoalkylether, -Othiophosphoalkyl, or -Othiophosphoalkylether, optionally substituted with a substituent selected from: 3 is one of the following structures: [ka] (In the formula, R 3a -OH, -SH, -NH 2 , phosphate or thiophosphate, R 4a and R 4b Independently, O - , S - , OZ or SZ, Z being a cation; R 5a and R 5b is independently oxo or thioxo; b and c each independently represent an integer of 1 to 10.

[0072] In some embodiments, R 2a or R 3a (or both) are -OH, -NH 2and -SH. For example, in some embodiments, R 2 or R 3 (or both) have the following structure: [ka] has.

[0073] In some embodiments, R 2 is H or an electron pair, and R 3 is a phosphate and the sum of q and w is at least 2. In some of these embodiments, q is greater than 1, e.g., greater than 2, greater than 3, greater than 4, greater than 5, greater than 6, or greater than 7. In other of these embodiments, L 1 and L 2 Each is an alkylene linker, e.g., methylene. In further embodiments, L 1 is an alkylene linker such as methylene, and L 2 does not exist (i.e., a direct bond). In some other embodiments, L 1 is a heteroalkylene linker, e.g., a heteroalkylene linker that includes an OPO bond, a S-S bond, or a combination thereof. In some of these embodiments, R 2 is H or an electron pair.

[0074] In certain particular embodiments of the above, for each occurrence, R 4 O - and R 5 In some embodiments of the above, L is oxo. 1 and L 2 Each L is an alkylene linker. 1 is an alkylene linker, L 2is not present. In some of these embodiments, alkylene is methylene. In some of the above embodiments, R 3 is -OH. In other embodiments, R 2 is H (H is therefore acidic, so at a certain pH value, the oxygen atom is negatively charged, i.e., R 2 becomes an electron pair).

[0075] In some embodiments of structure (II), L 2 and L 1 is, independently at each occurrence, an optional alkylene, phosphoalkylene, or phosphoalkylene ether linker. In some embodiments, L 2 Or L 1 In some embodiments, L 2 and L 1 may be, independently for each occurrence: [ka] TIFF2024040167000019.tif205170 (in the formula, R 2a -OH, -SH, -NH 2 , phosphate or thiophosphate, R 4a and R 4b Independently, O - , S - , OZ or SZ, Z being a cation; R 5a and R 5b is independently oxo or thioxo; a, b and c are each independently an integer of 1 to 10.

[0076] In certain particular embodiments, L 1 or L 2 is one of the following structures: [ka] (wherein b is an integer of 2 to 10).

[0077] In some other embodiments of any of the above-mentioned compounds of structure (IV), each occurrence of L 3 In some of these embodiments, one or more of R is a heteroalkylene linker, e.g., a heteroalkylene linker that includes an OPO bond, a S-S bond, or a combination thereof. 2 is H or an electron pair. For example, in some embodiments, an occurring L 3 At least one of the following structures: [ka] has.

[0078] A specific embodiment is a compound having the following structure (III): [ka] (III) or a stereoisomer, pharma- ceutically acceptable salt, or tautomer thereof, wherein: M is a biologically active moiety or a fragment thereof, a prodrug of a biologically active moiety or a fragment thereof; L is a physiologically cleavable linker; R 1 is H, alkyl or alkoxy, R 2 is H, an electron pair, a cation or L', R 3 is H, phosphate, OH or L'; R 4 O - , S - , OZ or SZ, Z being a cation; R 5 is oxo or thioxo, R 7 , R 8 , R 9 and R 10is, independently at each occurrence, H or alkyl; x and y are each independently an integer of 0 to 5.

[0079] In some embodiments of structure (III), when n is greater than 1, at least one occurrence of L contains oxygen and no more than 3 carbons. In some embodiments, x and y are each 1. In some embodiments, x is 0 and each y is 1.

[0080] One embodiment is a compound having the following structure (IV): [ka] (IV) or a stereoisomer, tautomer or salt thereof, wherein M is, independently at each occurrence, a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding moiety, provided that at least one occurrence of M is not a fluorescent dye;

[0081] A represents a cyclic moiety; L is a physiologically cleavable linker; L 1 , L 2 , L 3 and L 4 is, independently at each occurrence, an optional linker that comprises an atom selected from carbon, oxygen, sulfur, nitrogen, and phosphorus; R 1 is independently at each occurrence H, alkyl or alkoxy; R 2is an electron pair, H, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, phospho, thio phospho, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, thio phosphoalkyl ether, Q or a protected form thereof, or L', wherein alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, and thio phosphoalkyl ether are optionally substituted with hydroxyl, amino, sulfhydryl, phosphate, thio phosphate, phosphoalkyl, thio phosphoalkyl, phosphoalkyl ether, or thio phosphoalkyl ether, or combinations thereof;

[0082] R 3 are H, OH, SH, -NH 2, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, -O aralkyl, phosphate, thiophosphate, alkyl phospho, alkyl thiophospho, -O alkyl phospho, -O alkyl thiophospho, alkyl ether phospho, alkyl ether thiophospho, -O alkyl ether phospho, -O alkyl ether thiophospho phosphoalkyl, phosphoalkyl ether, thiophosphoalkyl, thiophosphoalkyl ether, -O phosphoalkyl, -O phosphoalkyl ether, -O thiophosphoalkyl, -O thiophosphoalkyl ether, Q or a protected form thereof, or L'; the phosphoalkyl, phosphoalkylether, thiophosphoalkyl, thiophosphoalkylether, -Ophosphoalkyl, -Ophosphoalkylether, -Othiophosphoalkyl, -Othiophosphoalkylether may be substituted with hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether or combinations thereof;

[0083] Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety; L' is, independently at each occurrence, a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a solid support or a solid support moiety, a linker that includes a covalent bond to a solid support or a solid support moiety, or a linker that includes a covalent bond to an additional compound of structure (IV); n is an integer equal to or greater than 1, q is an integer greater than or equal to 1 for at least one integer value of n. w is an integer greater than or equal to 0 for each integer value of n.

[0084] In some embodiments of structure (IV), when n is greater than 1, at least one occurrence of L contains oxygen and no more than 3 carbons. In some embodiments, n is an integer from 1-10, or from 2-10. In certain embodiments, L 2 In another embodiment, L 4 contains a phosphorus-oxygen bond. In certain particular embodiments of compound (I) or (IV), w is 0 at each occurrence. For example, in certain embodiments, the compound has the following structure (V): [ka] (V) or a stereoisomer, tautomer or salt thereof, wherein M is, independently at each occurrence, a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding moiety, provided that at least one occurrence of M is not a fluorescent dye;

[0085] L is a physiologically cleavable linker; L 1 and L 2 is, independently at each occurrence, an optional linker that comprises an atom selected from carbon, oxygen, sulfur, nitrogen, and phosphorus; R 1 is independently at each occurrence H, alkyl or alkoxy; R 2is an electron pair, H, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, phospho, thio phospho, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, thio phosphoalkyl ether, Q or a protected form thereof, or L', wherein alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, and thio phosphoalkyl ether are optionally substituted with hydroxyl, amino, sulfhydryl, phosphate, thio phosphate, phosphoalkyl, thio phosphoalkyl, phosphoalkyl ether, or thio phosphoalkyl ether, or combinations thereof;

[0086] R 3 are H, OH, SH, -NH 2, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, -O aralkyl, phosphate, thiophosphate, alkyl phospho, alkyl thiophospho, -O alkyl phospho, -O alkyl thiophospho, alkyl ether phospho, alkyl ether thiophospho, -O alkyl ether phospho, -O alkyl ether thiophospho phosphoalkyl, phosphoalkyl ether, thiophosphoalkyl, thiophosphoalkyl ether, -O phosphoalkyl, -O phosphoalkyl ether, -O thiophosphoalkyl, -O thiophosphoalkyl ether, Q or a protected form thereof, or L'; the phosphoalkyl, phosphoalkylether, thiophosphoalkyl, thiophosphoalkylether, -Ophosphoalkyl, -Ophosphoalkylether, -Othiophosphoalkyl, -Othiophosphoalkylether may be substituted with hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether or combinations thereof;

[0087] Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety; L' is, independently at each occurrence, a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a solid support or a solid support moiety, a linker that includes a covalent bond to a solid support or a solid support moiety, or a linker that includes a covalent bond to an additional compound of structure (V); where n is an integer greater than or equal to 1.

[0088] In some more specific embodiments of structure (V), when n is greater than 1, at least one occurrence of L contains oxygen and no more than 3 carbons. In still other embodiments, at least one occurrence of w is 1. For example, in some embodiments, the compound has the following structure (VI): [ka] (VI) or a stereoisomer, tautomer or salt thereof, wherein

[0089] M is, independently at each occurrence, a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding moiety, provided that at least one occurrence of M is not a fluorescent dye; L is a physiologically cleavable linker; L 1 , L 2 , L 3 and L 4 is, independently at each occurrence, an optional linker that comprises an atom selected from carbon, oxygen, sulfur, nitrogen, and phosphorus; R 1 is independently at each occurrence H, alkyl or alkoxy;

[0090] R 2is an electron pair, H, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, phospho, thio phospho, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, thio phosphoalkyl ether, Q or a protected form thereof, or L', wherein alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, and thio phosphoalkyl ether are optionally substituted with hydroxyl, amino, sulfhydryl, phosphate, thio phosphate, phosphoalkyl, thio phosphoalkyl, phosphoalkyl ether, or thio phosphoalkyl ether, or combinations thereof;

[0091] R 3 are H, OH, SH, -NH 2, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, -O aralkyl, phosphate, thiophosphate, alkyl phospho, alkyl thiophospho, -O alkyl phospho, -O alkyl thiophospho, alkyl ether phospho, alkyl ether thiophospho, -O alkyl ether phospho, -O alkyl ether thiophospho phosphoalkyl, phosphoalkyl ether, thiophosphoalkyl, thiophosphoalkyl ether, -O phosphoalkyl, -O phosphoalkyl ether, -O thiophosphoalkyl, -O thiophosphoalkyl ether, Q or a protected form thereof, or L'; the phosphoalkyl, phosphoalkylether, thiophosphoalkyl, thiophosphoalkylether, -Ophosphoalkyl, -Ophosphoalkylether, -Othiophosphoalkyl, -Othiophosphoalkylether may be substituted with hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether or combinations thereof;

[0092] R 4 independently for each occurrence, O - , S - , OZ, SZ or N(R 6 ) 2 Z is a cation and R 6 each is independently H or alkyl; R 5 is independently at each occurrence oxo, thioxo, or absent; Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety; L' is, independently at each occurrence, a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a solid support or a solid support moiety, a linker that includes a covalent bond to a solid support or a solid support moiety, or a linker that includes a covalent bond to an additional compound of structure (VI); n is an integer equal to or greater than 1, w is an integer greater than or equal to 1 for at least one integer value of n; q is an integer greater than or equal to 0 for each integer value of n.

[0093] In some more specific embodiments of structure (VI), when n is greater than 1, at least one occurrence of L contains oxygen and no more than 3 carbons. Yet another embodiment is a compound having the following structure (VII): [ka] (VII) (In the formula, M is, independently at each occurrence, a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding moiety, provided that at least one occurrence of M is not a fluorescent dye; L is a physiologically cleavable linker; R 1 , H, C 1 -C 6 is alkyl or alkoxy; R 2 is cyanoalkyl or L', R 3 is H, -Oaralkyl or L', R 6 is C 1 -C 6 is alkyl, R 7 , R8 , R 9 and R 10 is, independently at each occurrence, H or alkyl; x and y are, independently at each occurrence, an integer from 0 to 5.

[0094] In some more specific embodiments of structure (VII), when n is greater than 1, at least one occurrence of L contains oxygen and no more than 3 carbons. In some embodiments of the compound of structure (VII), R 6 Each is isopropyl. In another embodiment, R 2 is 2-cyanoethyl. In a further embodiment, R 3 is -Oaralkyl, for example -O-dimethoxytrityl (-ODMT). In different embodiments of compound (VII), x and y are each 1. In other embodiments, x is 0 and y is 1.

[0095] Another embodiment is a compound having the following structure (VIII): [ka] (VIII) (In the formula, M is, independently at each occurrence, a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding moiety, provided that at least one occurrence of M is not a fluorescent dye; L is a physiologically cleavable linker; R 1 , H, C 1 -C 6 is alkyl or alkoxy; R 2 is cyanoalkyl or L', R 6 is C 1 -C 6 is alkyl, L 2is an optional alkylene linker or heteroalkylene linker.

[0096] In some embodiments of the compound of compound (VIII), R 6 Each is isopropyl. In some embodiments, R 2 is 2-cyanoethyl. In another embodiment, R 2 is 2-cyanoethyl. In yet another embodiment, R 1 is H. In a further embodiment, L 2 is an alkylene linker, such as a methylene linker. In some more specific embodiments of structure (VIII), when n is greater than 1, at least one occurrence of L contains oxygen and no more than 3 carbons. Other embodiments include disulfide dimers having the following structure (IX): [ka] (IX) or a salt or stereoisomer thereof, M is, independently at each occurrence, a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding moiety, provided that at least one occurrence of M is not a fluorescent dye; L is a physiologically cleavable linker; R 11 is independently H, phosphate, alkyl phosphate, C 1 -C 6 Alkyl or C 1 -C 6 is a hydroxyl alkyl; x', y' and z' are each independently an integer of 0 to 10.

[0097] In some more specific embodiments of structure (IX), when n is greater than 1, at least one occurrence of L contains oxygen and no more than 3 carbons. In various embodiments, each y' is 0. In some different embodiments, each z' is 1. In further embodiments of the above, each x' is independently an integer from 2 to 6. In some other different embodiments, R 11 is phosphate, CH 2 OPO 3 2- or CH 2 It is OH.

[0098] In various other embodiments, the compound has the following structure (X): [ka] (X) or a salt or stereoisomer thereof, wherein L, L', M and Q are as defined for structure (I); R 11 is independently H, phosphate, phosphate, C 1 -C 6 Alkyl or C 1 -C 6 is an alkyl substituted with a hydroxyl alkyl; x', y' and z' are each, independently at each occurrence, an integer from 0 to 10.

[0099] In some more specific embodiments of structure (X), when n is greater than 1, at least one occurrence of L contains oxygen and no more than 3 carbons. In some embodiments, Q is -SH. In various embodiments, each y' is 0. In some different embodiments, each z' is 1. In further embodiments of the above, each x' is independently an integer from 2 to 6. In some other different embodiments, R 11 is phosphate, CH 2 OPO 3 2- or CH 2 It is OH. Another embodiment is a disulfide dimer having the structure (XI): [ka] (XI) or a salt or stereoisomer thereof, wherein M is, independently at each occurrence, a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding moiety, provided that at least one occurrence of M is not a fluorescent dye; L is a physiologically cleavable linker; R 11 is independently H, phosphate, phosphate, C 1 -C 6 Alkyl or C 1 -C 6 is an alkyl substituted with a hydroxyl alkyl; x', y' and z' are each, independently at each occurrence, an integer from 0 to 10.

[0100] In some more specific embodiments of structure (XI), when n is greater than 1, at least one occurrence of L contains oxygen and no more than 3 carbons. In various embodiments, each y' is 0. In some different embodiments, each z' is 1. In further embodiments of the above, each x' is independently an integer from 2 to 6. In some other different embodiments, R 11 is phosphate, CH 2 OPO 3 2- or CH 2 It is OH.

[0101] The linker L may be used as a point of attachment of the M moiety to the remainder of the compound. For example, in some embodiments, a synthetic precursor to a compound of structure (I)-(XI) is prepared, and the M moiety is attached to the synthetic precursor using any number of readily available methods known in the art, such as those referred to as "click chemistry." For this purpose, any of a number of rapid and substantially irreversible reactions may be used to attach M to the synthetic precursor for forming a compound of structure (I)-(XI). Exemplary reactions include the copper-catalyzed reaction of an azide with an alkyne to form a triazole (Huisgen 1,3-dipolar cycloaddition), the reaction of a diene with a dienophile (Diels-Alder), strain-promoted alkyne-nitrone cycloaddition, the reaction of a strained alkene with an azide, tetrazine or tetrazole, the [3+2] cycloaddition of an alkene with an azide, the inverse demand Diels-Alder of an alkene with a tetrazine, the photoreaction of an alkene with a tetrazole, and various substitution reactions such as the replacement of a leaving group by a nucleophilic attack on an electrophilic atom. Exemplary substitution reactions include reactions of amines with activated esters (e.g., N-hydroxysuccinimide esters), isocyanates, isothiocyanates, etc. In some embodiments, the reaction to form L may be carried out in an aqueous environment.

[0102] Thus, in some embodiments, L, for each occurrence, is a linker that includes a functional group formable by reaction of two complementary reactive groups, e.g., a functional group that is the product of one of the "click" reactions described above. In various embodiments, for at least one occurrence of L, the functional group can be formed by reaction of an aldehyde, oxime, hydrazone, alkyne, amine, azide, acyl azide, acyl halide, nitrile, nitrone, sulfhydryl, disulfide, sulfonyl halide, isothiocyanate, imidoester, activated ester (e.g., N-hydroxysuccinimide ester), ketone, α,β-unsaturated carbonyl, alkene, maleimide, α-haloimide, epoxide, aziridine, tetrazine, tetrazole, phosphine, biotin, or thiirane functional group with a complementary reactive group, e.g., reaction of an amine with an N-hydroxysuccinimide ester or an isothiocyanate. In some embodiments, each occurrence of L has the following structure: [ka] has.

[0103] In other embodiments, for at least one occurrence of L, the functional group may be formed by reaction of an alkyne and an azide. In other embodiments, for at least one occurrence of L, the functional group may be formed by reaction of an amine (e.g., a primary amine) and an N-hydroxysuccinimide ester or an isothiocyanate. In further embodiments, for at least one occurrence of L, the functional group comprises an alkene, ester, amide, thioester, disulfide, carbocyclic, heterocyclic or heteroaryl group. In further embodiments, for at least one occurrence of L, the functional group comprises an alkene, ester, amide, thioester, thiourea, disulfide, carbocyclic, heterocyclic or heteroaryl group. In other embodiments, the functional group comprises an amide or thiourea. In some further specific embodiments, for at least one occurrence of L, L is a linker comprising a triazolyl functional group. In other embodiments, for at least one occurrence of L, L is a linker comprising an amide or thiourea functional group. Some embodiments provide L that is cleavable under appropriate conditions (e.g., physiological conditions). Thus, in some embodiments, L comprises an amide bond, an ester bond, a disulfide bond, a hydrazone, a phosphotriester, a diester, a β-glucuronide, a double bond, a triple bond, an ether bond, a ketone or oxo, diol, cyano, nitro, or a combination thereof.

[0104] In some embodiments, L comprises tert-butyloxycarbonyl, paramethoxybenzyl, dialkyl or diaryldialkoxysilane, orthoester, acetal, β-thiopropionate, ketal, phosphoramidate, hydrazone, vinyl ether, imine, aconityl, trityl, polyketal, bisarylhydrazone, diazobenzene, bivinaldiol, pyrophosphate diester, or valine citrulline. In certain embodiments, L, independently at each occurrence, is a linker that is cleavable at a pH in the range of 6 to 8. For example, in some embodiments, L is a linker that is cleavable at pH 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, or 8.0.

[0105] In certain embodiments, L, independently at each occurrence, is a linker that is cleavable at a temperature in the range of 20° C. to 40° C., 25° C. to 35° C., 30° C. to 35° C., 30° C. to 37° C., 35° C. to 37° C., 35° C. to 40° C., or 32° C. to 38° C. In certain embodiments, L, independently at each occurrence, is a linker that is cleavable at a temperature in the range of about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., about 25° C., about 26° C., about 27° C., about 28° C., about 29° C., about 30° C., about 31° C., about 32° C., about 33° C., about 34° C., about 35° C., about 36° C., about 37° C., about 38° C., about 39° C., or about 40° C. In certain embodiments, L is, independently at each occurrence, a linker that is cleavable by an enzyme. For example, in some embodiments, the enzyme is a hydrolase, oxidoreductase, or lyase. In certain embodiments, the enzyme is an EC4.1 (e.g., EC4.1.1, EC4.1.2, EC4.1.3, or EC4.1.99), EC4.2, EC4.3, EC4.4, EC4.5, EC4.6, or EC4.99 enzyme.

[0106] In certain embodiments, L is one of the following structures: [ka] (In the formula, R is H, methyl, ethyl, isopropyl, tert-butyl or phenyl; X is O or CH 2 and n is an integer greater than 0.

[0107] In yet other embodiments, for at least one occurrence of L, LM has the following structure: [ka] (In the formula, L 1a and L 1b are each independently an optional linker.

[0108] In a different embodiment, for at least one occurrence of L, LM has the following structure: [ka] (In the formula, L 1a and L 1b are each independently an optional linker. In the various embodiments described above, L 1a Or L 1b , or both are absent. 1a Or L 1b , or both are present.

[0109] In some embodiments, L 1a or L 1b Each occurrence, if any, is independently alkylene or heteroalkylene. For example, in some embodiments, L 1a or L 1b is, if present, independently one of the following structures: [ka] has.

[0110] In yet another embodiment of structure (I), L is, independently at each occurrence, an optional alkylene or heteroalkylene linker. In certain embodiments, L is one of the following structures: [ka] has.

[0111] In some specific embodiments, at least one occurrence of L is one of the following structures: [ka] has.

[0112] In some embodiments, L is one of the following structures: [ka] where one occurrence of L contains oxygen and has 3 or fewer carbons.

[0113] In a further embodiment, L 2 and L 3 is expressed independently for each occurrence as C 1 -C 6 Alkylene, C 2 -C 6 Alkenylene or C 2 -C 6 It is alkynylene. In other embodiments, R 2 and R 3 are each independently -OP(=R a )(R b ) OL', where L' is an alkylene or heteroalkylene linker to Q, a targeting moiety, an analyte (e.g., an analyte molecule), a solid support, a solid support residue, an amino acid, a nucleoside, or an additional compound of structure (I). 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 an additional compound of structure (I) to the compound of structure (I). Advantageously, certain embodiments include the use of an L' moiety that is selected to increase or optimize the aqueous solubility of the compound. In certain embodiments, L' is a heteroalkylene moiety. In some other certain embodiments, L' includes an alkylene oxide or phosphodiester moiety, or a combination thereof.

[0114] In some embodiments, L' comprises a divalent functional group selected from the group consisting of polyalkylene ether, hydroxyl alkylene, amino alkylene, hydroxyl polyalkylene ether, amino polyalkylene ether, phospho, thiophospho, phosphoalkylene, or thiophosphoalkylene. In certain embodiments, L' has the structure: [ka] (In the formula, m" and n" are independently an integer from 1 to 10; R e is H, an electron pair or a counterion, L″ comprises a targeting moiety or a linking group to a targeting moiety (e.g., an antibody).

[0115] In some embodiments, m" is an integer from 4 to 10, such as 4, 6, or 10. In other embodiments, n" is an integer from 3 to 6, such as 3, 4, 5, or 6. In various embodiments, L' includes polyalkylene ethers, phospho and phosphoalkylene. For example, in some embodiments, L' has one of the following structures: [ka] (wherein a is an integer from 1 to 6 and b is an integer from 2 to 10). In some embodiments, a is 2. In some embodiments, a is 1, 3, 4, 5, or 6. In some embodiments, b is 6. In certain particular embodiments, b is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0116] In some embodiments, L' is a linker comprising a covalent bond to Q, where Q is a sulfhydryl, disulfide, activated ester, isothiocyanate, azide, alkyne, alkene, diene, dienophile, acid halide, sulfonyl halide, phosphine, α-haloamide, biotin, amino, or maleimide. In certain embodiments, L' is a linker that comprises a covalent bond to a solid support. In some such embodiments, the solid support is a polymeric or non-polymeric bead.

[0117] In certain other embodiments, L' is a targeting moiety or a linker to a targeting moiety. In certain embodiments, the targeting moiety is an antibody or a cell surface receptor antagonist. In related embodiments, the antibody or cell surface receptor antagonist is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, a folate or a MET inhibitor. In certain embodiments, the antibody or cell surface receptor antagonist is a tyrosine kinase inhibitor (e.g., gefitinib, erlotinib), lapatinib, vandetanib, neratinib, osimertinib, tovantinib (ARQ197), crizotinib, cabozantinib, tyrphostins (e.g., AG538, AG1024), pyrrolo(2,3-d)-pyrimidine derivatives (e.g., NVP-AEW541), monoclonal antibodies (e.g., Figitumab), These include rituximab, cetuximab, panitumumab, necitumumab, ganitumab, cixutumumab, dalotuzumab, lobatumumab, onartuzumab, K1, labetuzumab, milatuzumab, lorvotuzumab, inotuzumab), BMS-777607, PF-02341066, PF-04217903, AMG-458, MK-2461, JNJ-38877605, GSK1363089 (foretinib), XL880, XL184, ARQ197, E7050, or INCB28060.

[0118] In certain embodiments, the antibody or cell surface receptor antagonist targets EGFR (e.g., EGFRvIII), HER2, folate receptor, CD19, CD20, CD22, CD27L, CD30, CD33, CD37, CD56, CD66e, CD70, CD74, CD79b, CA6, CD138, CA6, mesothelin, nectin 4, STEAP1, MUC16, MaPi2b, GCC, Trop-2, AGS-5, ENPP3, carbonic anhydrase IX, GPNMB, PDMA. In some other embodiments, L" is an alkylene or heteroalkylene moiety. In certain other embodiments, L" comprises an alkylene oxide, a phosphodiester moiety, a peptidyl linker, a sulfhydryl, a disulfide, or a maleimide moiety, or a combination thereof. In other further specific embodiments of any of the above-mentioned compounds of structure (I), R 2 or R 3 is one of the following structures: [ka] I have TIFF2024040167000042.tif180170.

[0119] Certain embodiments of the compounds of structure (I)-(XI) can be prepared following solid phase synthesis methods similar to those known in the art for the preparation of peptides. Thus, in some embodiments, L' is a linking group to a solid support or solid support residue. A variety of solid supports (e.g., polystyrene, polyamide, PEG-based), protecting groups (e.g., Fmoc, Boc, triphenylmethyl), activating groups (e.g., carbodiimide, triazole), and other materials are readily available and can be used in some embodiments to prepare compounds of structure (I). The solid support residue can be removed or modified after synthesis.

[0120] In yet other embodiments, Q, independently at each occurrence, is a moiety that includes a reactive group capable of forming a covalent bond with an analyte molecule or a solid support. In other embodiments, Q, independently at each occurrence, is a moiety that includes a reactive group capable of forming a covalent bond with a complementary reactive group, Q'. For example, in some embodiments, Q' is present in an additional compound of structures (I)-(XI) (e.g., R 2 or R 3Positions (Q, Q'), Q and Q' contain complementary reactive groups such that reaction of a compound of structure (I)-(XI) with an additional compound of structure (I)-(XI) results in a covalent dimerization of the compound of structure (I)-(XI). Multimeric compounds of structure (I)-(XI) can also be prepared in an analogous manner and are included within the scope of embodiments of the present invention.

[0121] The type of Q group and its attachability to the remainder of the compounds of structures (I)-(XI) are not particularly limited, provided that Q contains a moiety having appropriate reactivity to form the desired bond. In certain embodiments, Q is a moiety (e.g., an amine, azide, or alkyne) that is not susceptible to hydrolysis under aqueous conditions, yet is sufficiently reactive to form a bond with a corresponding group on the analyte molecule or solid support. Certain embodiments of the compounds of structures (I)-(XI) include Q groups commonly used in the field of bioconjugation. For example, in some embodiments, Q includes a nucleophilic reactive group, an electrophilic reactive group, or a cycloaddition reactive group. In some more specific embodiments, Q includes a sulfhydryl, disulfide, activated ester, isothiocyanate, azide, alkyne, alkene, diene, dienophile, acid halide, sulfonyl halide, phosphine, α-haloamide, biotin, amino, or maleimide functionality. In some embodiments, the activated ester is an N-succinimide ester, an imido ester, or a polyfluorophenyl ester. In other embodiments, the alkyne is an alkyl azide or an acyl azide.

[0122] Q groups can be conveniently provided in protected forms that enhance storage stability or other desired properties, and the protecting groups can then be removed at the appropriate time for coupling, for example, with a targeting moiety or analyte. Thus, Q groups include "protected forms" of reactive groups, including any of the reactive groups listed above and in Table 1 below. A "protected form" of Q refers to a moiety that has a lower reactivity under a given reaction condition relative to Q, but can be converted to Q under conditions that preferably do not decompose or react with other moieties of the compounds of structures (I)-(XI). Those skilled in the art can derive an appropriate protected form of Q based on the particular Q and the desired end use and storage conditions. For example, if Q is -SH, the protected form of Q includes a disulfide that can be reduced using common known techniques and reagents (e.g., TCEP) to reveal an -SH moiety.

[0123] Exemplary Q moieties are provided in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3]

[0124] In some embodiments, Q comprises a sulfhydryl, an isothiocyanate, an imidoester, an acyl azide, an activated ester, a sulfonyl halide, a maleimide, an α-haloimide, a disulfide, a phosphine, an azide, an alkyne, a diene, an alkene or a dienophile, an amino, or a combination thereof. In some embodiments, Q is a sulfhydryl, an isothiocyanate, an imidoester, an acyl azide, an activated ester, a sulfonyl halide, a maleimide, an α-haloimide, a disulfide, a phosphine, an azide, an alkyne, a diene, an alkene or a dienophile, an amino, or a combination thereof. In some embodiments, Q comprises biotin. In some embodiments, Q is biotin. In some embodiments, Q comprises an affinity tag (e.g., a peptide sequence to which the analyte protein binds). In some embodiments, the affinity tag comprises one or more histidine moieties.

[0125] It should be noted that in some embodiments, when Q is -SH, the -SH moiety tends to form a disulfide bond with another sulfhydryl group of another compound of structures (I)-(XI), for example. Thus, some embodiments include compounds of structures (I)-(XI) in the form of a disulfide dimer, where the disulfide bond is derived from the Q group that is -SH. In other embodiments, the Q moiety is conveniently hidden (e.g., protected) as a disulfide moiety, which can be subsequently reduced to provide an activated Q moiety for conjugation to a desired targeting moiety. For example, the Q moiety has the following structure: [ka] where R is an optionally substituted alkyl group. For example, in some embodiments, Q can be masked as a disulfide having the following structure: [ka] wherein n' is an integer from 1 to 10, for example 6.

[0126] Similarly, compounds of structures (I)-(XI) are included within the scope of certain embodiments, where R 2 and R 3 One or both of R 2 and R 3 One or both of -OP(=R a )(R b )R c and R cis OL', where L' is a linker comprising a covalent bond to an additional compound of structure (I)-(XI). Such compounds can be prepared, for example, by preparing a first compound of structure (I)-(XI) having about 10 "M" moieties (i.e., n=9) and having a suitable "Q" for reaction with a complementary Q' group on a second compound of structure (I)-(XI). In this manner, compounds of structure (I)-(XI) having any number of "M" moieties, for example 100 or more, can be prepared without the need to sequentially couple each monomer. An exemplary embodiment of such a compound of structure (I) is the following structure (I"): [ka] (I'') (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , L, L 1 , L 2 , L 3 , L 4 , M, q, w and n are, independently at each occurrence, as defined for compounds of structure (I); L″ is a linker that contains a functional group resulting from reaction of a Q moiety with the corresponding Q′ moiety; and α is an integer greater than 1, for example, 1 to 100, or 1 to 10.

[0127] Other compounds of structures (II)-(VIII) can be derived in a similar manner by one of skill in the art For example, such compounds can be synthesized by dimerizing or polymerizing combinations of compounds of structures (I)-(XI) provided herein. In some other embodiments, R 2 or R 3 One of the groups is OH or -OP (=R a )(R b )R c and R 2 or R 3The other is a linker that includes a covalent bond to the targeting moiety or a linker that includes a covalent bond to the solid support. For example, in some embodiments, the targeting moiety is an antibody or a cell surface receptor antagonist. In yet another embodiment, the solid support is a polymeric bead or a non-polymeric bead. The value for m is another variable that can be selected based on the desired solubility, osmotic activity, or therapeutic use. In some embodiments, m is, independently at each occurrence, an integer from 1 to 20. In some embodiments, m is, independently at each occurrence, an integer from 1 to 10. In other embodiments, m is, independently at each occurrence, an integer from 1 to 5, e.g., 1, 2, 3, 4, or 5. The solubility, permeability or retention can also be adjusted by selecting different values ​​of n. In certain embodiments, n is an integer between 1 and 100. In other embodiments, n is an integer between 1 and 10. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[0128] Tumor cell antigens include tumor-specific and tumor-associated antigens, such as EGFR, HER2, folate receptor, CD20, CD33, oncofetal antigens (e.g., alpha-fetoprotein, carcinoembryonic antigen, immature laminin receptor, TAG-72), CA-125, MUC-1, epithelial tumor antigens, tyrosinase, melanoma-associated antigens (MAGE), and aberrant products of RAS or p53. Tumor cell antigens can also include antigens characterized as oncofetal, oncoviral (e.g., HPV E6, E7), overexpressed / accumulated (e.g., BING-4, calcium activated chloride channel 2, 9D7, Ep-CAM, EphA3, HER2, telomerase, mesothelin, SAP-1, survivin), cancer testis (e.g., BAGE family, CAGE family, GAGE ​​family, MAGE family, SAGE family, XAGE family), lineage restricted, mutated, post-translationally modified, idiotypic, CT9 or CT10 (e.g., NY-ESO-1 / LAGE-1, PRAME). In some embodiments, M is, independently at each occurrence, an NSAID, a kinase inhibitor, an anthracycline, an EGFR inhibitor, or an alkylating agent.

[0129] In some embodiments, at least one M is an anti-cancer drug. In certain particular embodiments, each occurrence of M is independently an anti-cancer drug, and the targeting moiety is an antibody specific for a tumor cell antigen. In some embodiments, the tumor cell antigen is EGFR, HER2, folate receptor, CD20, or CD33. In some specific embodiments, at least one occurrence of M has one of the following structures: [ka] has.

[0130] In certain embodiments, M, for each occurrence, is one of the following structures: [ka] has. In some more specific embodiments, M has each occurrence of the following structure: [ka] has.

[0131] In certain more specific embodiments, each occurrence of M has the structure: [ka] has. Anticancer drugs, as used herein, include derivatives, which are anticancer drugs that have been modified or derivatized, such that the drug may be conjugated or attached to another molecule (e.g., to include a Q moiety). For example, maytansine is a cancer drug and maytansinoids are derivatives of cancer drugs.

[0132] In certain embodiments, the anticancer drug is an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor (such as irinotecan or such as etoposide or such as doxorubicin), a taxane (such as an anti-microtubule agent, including paclitaxel and docetaxel), an antimetabolite agent (such as 5-FU or such as gemcitabine), an alkylating agent (such as cisplatin or such as cyclophosphamide), or a taxane. Anti-cancer drugs that may be modified and incorporated into compound embodiments of the present disclosure include, for example, auristatin F, auristatin E, maytansine, calicheamicin, paclitaxel, doxorubicin, cryptophycin; erlotinib, CC-1065, carzelesin, SJG-136, DSB-120, afatinib, Iressa, or methotrexate.

[0133] Other non-limiting examples of anti-cancer drugs include Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib) and adriamycin, alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethylenediaminetetraacetate, ... melamine and methylmelamine (including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine); chlorambucil, chlornaphazine, clophosfamide, estramustine, ifosamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicin, phenesterine, prednimustine, trofosfamide, nitrogen mustards such as uracil mustard; carmustine, chlorozotocin, fotemustine, lomustine, Nitrosoureas such as mustine, nimustine, and ranimustine; aclacinomycins, actinomycin, ausramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex®, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenone Antibiotics such as folate, nogalamycin, olivomycins, peplomycin, potfilomycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine;Pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as florinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomitine; elliptinium acetate; etoglucide; nitrate Gallium; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenameth; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK.RTM; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2"-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Taxanes, such as paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, NJ), and docetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicin or capecitabine. Also, for example, tamoxifen (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxyphene, keoxyphene, LY117018, onapristone and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C;Suitable cancer drugs include anti-hormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens including mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeroda; ibandronate; camptothecin-11 (CPT-11); the topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO);

[0134] In certain embodiments, at least one M is selected from the group consisting of tyrosine kinase inhibitors (e.g., gefitinib, erlotinib), lapatinib, vandetanib, neratinib, osimertinib, tovantinib (ARQ197), crizotinib, cabozantinib, tyrphostins (e.g., AG538, AG1024), pyrrolo(2,3-d)-pyrimidine derivatives (e.g., NVP-AEW541), monoclonal antibodies (e.g., figitumumab, cetuximab, panitumumab, ribavirinib ... tuzumab, necitumumab, ganitumab, cixutumumab, dalotuzumab, lobatuzumab, onartuzumab, K1, labetuzumab, milatuzumab, lorvotuzumab, inotuzumab), BMS-777607, PF-02341066, PF-04217903, AMG-458, MK-2461, JNJ-38877605, GSK1363089 (foretinib), XL880, XL184, ARQ197, E7050 or INCB28060.

[0135] Where desired, embodiments of the disclosed compounds or compositions may be used in combination with other agents such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, avicin, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharazine, alvocidib, 3-aryl ... minopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic agents, antitumor herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, biricoderm, brostallicin, bryostatin, buthionine sulfoxime, CBV (chemotherapy), calyculin, cell cycle nonspecific antineoplastic agents, dichloroacetic acid, discodermolide, elsamitrucin, eno Citabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferginol, holodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, ranicuidar, larotaxel, lenalidomide, lucantone, lurtotecan, mefosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, progesterone, It may be used in combination with commonly prescribed anticancer drugs such as roteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaprofin, taliquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126 or zosquidar.

[0136] M is selected based on desired therapeutic and / or optical properties, for example, treatment of a particular disease or condition (e.g., cancer), or generation of a particular color and / or fluorescent emission wavelength. In some embodiments, M is the same at each occurrence. However, it is important to note that each occurrence of M need not be the same M, and certain embodiments include compounds in which M is not the same at each occurrence. For example, in some embodiments, M is not the same at each occurrence, and different M moieties are selected to have different therapeutic properties (e.g., cytotoxicity and anti-inflammatory). In some embodiments, M is not the same at each occurrence, and different M moieties are selected to have the same or similar therapeutic properties (e.g., cytotoxicity). In certain embodiments, M is each of the following:

[0137] [ka] Selected independently from TIFF2024040167000054.tif67150.

[0138] For ease of illustration, specific points of attachment to the remainder of the molecule (i.e., [ka] Although the M moiety is illustrated having a bond (attachment point) at the end of the bond, the M moiety may be attached via any available point. One of skill in the art can determine the appropriate attachment point.

[0139] In certain embodiments, LM has the following structure: [ka] TIFF2024040167000057.tif221170. In further embodiments of any of the above, M are the same. In other embodiments, each M is different. In further embodiments, one or more M are the same and one or more M are different.

[0140] In some embodiments, the selected occurrences of M are not the same, and different M moieties are selected to have absorbance and / or emission for use in fluorescence resonance energy transfer (FRET) methods. For example, in such embodiments, different M moieties are selected so that the absorbance of radiation at one wavelength causes the emission of radiation at a different wavelength by FRET mechanism. Exemplary M moieties can be appropriately selected by those skilled in the art based on the desired end use. Exemplary M moieties for FRET methods include fluorescein and 5-TAMRA (5-carboxytetramethylrhodamine, succinimidyl ester) dyes. M may be attached to the remainder of the molecule from any position (i.e., atom) on M. Those of skill in the art will recognize means by which M can be attached to the remainder of the molecule. Exemplary methods include the "click" reaction described herein.

[0141] In some embodiments, at least one M is a fluorescent or chromogenic moiety. Any fluorescent and / or chromogenic moiety may be used, such as those known in the art and commonly used in colorimetric, UV and / or fluorescent assays. Examples of M moieties useful in various embodiments of the invention include, but are not limited to, xanthene derivatives (e.g., fluorescein, rhodamine, Oregon Green, eosin, or Texas Red); cyanine derivatives (e.g., cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, or merocyanine); squaraine derivatives and ring-substituted squaraines (including Seta, SeTau, and Squara dyes); naphthalene derivatives (e.g., dansyl and polodan derivatives); coumarin derivatives; oxadiazole derivatives (e.g., pyridyloxazole, nitro benzoxadiazoles or benzoxadiazoles); anthracene derivatives (e.g., anthraquinones, including DRAQ5, DRAQ7, and CyTRAK orange); pyrene derivatives such as cascade blue; oxazine derivatives (e.g., Nile red, Nile blue, cresyl violet, oxazine 170); acridine derivatives (e.g., proflavine, acridine orange, acridine yellow); arylmethine derivatives: auramine, crystal violet, malachite green; and telapyrrole derivatives (e.g., porphine, phthalocyanine, or bilirubin). Other exemplary M moieties include cyanine dyes, xanthate dyes (e.g., Hex, Vic, Nedd, Joe, or Tet); Yakima yellow, Redmond red; Tamura; Texas red, and alexa fluor® dyes. A variety of dye molecules can be incorporated into the compound embodiments disclosed herein, for example, the dye compounds disclosed in U.S. Pat. Nos. 6,218,108; 6,140,480; 6,479,650; 6,670,193 and 7,423,133, each of which is incorporated by reference in its entirety.

[0142] In still other embodiments of any of the above, at least one M comprises three or more aryl or heteroaryl rings, or a combination thereof, for example, four or more aryl or heteroaryl rings, or a combination thereof, or even five or more aryl or heteroaryl rings, or a combination thereof.In some embodiments, at least one M comprises six aryl or heteroaryl rings, or a combination thereof.In further embodiments, the rings are fused.For example, in some embodiments, at least one M comprises three or more fused rings, four or more fused rings, five or more fused rings, or even six or more fused rings.

[0143] In some embodiments, at least one M is cyclic. For example, in some embodiments, at least one M is carbocyclic. In other embodiments, at least one M is heterocyclic. In still other embodiments described above, at least one M, independently at each occurrence, comprises an aryl moiety. In some of these embodiments, the aryl moiety is polycyclic. In other further embodiments, the aryl moiety is a fused polycyclic aryl moiety, for example, the fused polycyclic aryl moiety can include at least three, at least four, or even more than four aryl rings. In other embodiments of any of the above-mentioned compounds of structures (I)-(XI), at least one M comprises at least one heteroatom. For example, in some embodiments, the heteroatom is nitrogen, oxygen, or sulfur. In further embodiments of any of the above, at least one M comprises at least one substituent, for example, in some embodiments, the substituent is a fluoro, chloro, bromo, iodo, amino, alkylamino, arylamino, hydroxy, sulfhydryl, alkoxy, aryloxy, phenyl, aryl, methyl, ethyl, propyl, butyl, isopropyl, t-butyl, carboxy, sulfonate, amido, or formyl group.

[0144] In some more specific embodiments of the above, at least one M is a dimethylaminostilbene, quinacridone, fluorophenyl-dimethyl-BODIPY, his-fluorophenyl-BODIPY, acridine, terylene, sexiphenyl, porphyrin, benzopyrene, (fluorophenyl-dimethyl-difluorobora-diaza-indacene)phenyl, (bis-fluorophenyl-difluorobora-diaza-indacene)phenyl, quaterphenyl, bi-benzothiazole, ter-benzothiazole, bi-naphthyl, bi-anthracyl, squaraine, squarylium, 9,10-ethynylanthracene, or ter-naphthyl moiety. In other embodiments, at least one M is p-terphenyl, perylene, azobenzene, phenazine, phenanthroline, acridine, thioxanthrene, chrysene, rubrene, coronene, cyanine, perylene imide, or perylene amide, or a derivative thereof. In further embodiments, at least one M is a coumarin dye, a resorufin dye, a dipyrrometheneboron difluoride dye, a ruthenium bipyridyl dye, an energy transfer dye, a thiazole orange dye, a polymethine, or an N-aryl-1,8-naphthalimide dye. In some embodiments, at least one M is pyrene, perylene, perylene monoimide or 6-FAM, or a derivative thereof. In some other embodiments, at least one M has the following structure: [ka] has one of the following: The M moiety containing the carboxylic acid group can be used in the anionic form (CO 2 - ), but one of skill in the art will appreciate that this will vary with pH and that the protonated form (CO 2 It will be appreciated that H) is included in various embodiments.

[0145] In certain embodiments, M is not a purine or pyrimidine base, such as, but not limited to, guanine, cytosine, thymidine, and adenine. In other embodiments, M is not a porphyrin. In other embodiments, M is the following: [ka] Not one of them.

[0146] In other embodiments, one or more occurrences of M are base pair moieties. In some of these embodiments, the base pair moieties are purines, pyrimidines, dihydropyrimidines or derivatives thereof. In further embodiments, the base pair moieties have one of the following structures: [ka] has.

[0147] In some specific embodiments, the compound is a compound selected from Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] As used in Table 2 and throughout this application, R 2 , R 3 , L, Q and M have the definitions provided for the compounds of structure (I) unless otherwise indicated. In some embodiments, M is, independently at each occurrence, F, F', F", E, Y, N', I', D' or D", provided that at least one M is N', I', D' or D". F, F' and F'' can be any of the following structures: [ka] Each of the above refers to a fluorescein moiety having the following structure:

[0148] "E" has the following structure: [ka] Refers to...

[0149] "Y" has the following structure: [ka] Refers to... "N'" refers to the following structure: [ka] Refers to...

[0150] "I'" refers to the following structure: [ka] Refers to... "D'" refers to the following structure: [ka] Refers to...

[0151] "D" means the following structure: [ka] Refers to...

[0152] "dT" has the following structure: [ka] (In the formula, R is H or a direct bond. In some embodiments, L′, R 2 or R 3 In a more specific embodiment, R 2 In some embodiments, R 3 comprises dT. In some embodiments, L' comprises dT.

[0153] Some embodiments include any of the compounds presented in Table 2 and described above, including specific compounds conjugated to a targeting moiety such as an antibody. In some embodiments, one of the compounds of structure (I) is conjugated to an antibody. In some embodiments, one to two compounds of structure (I) are conjugated to an antibody. In some embodiments, two compounds of structure (I) are conjugated to an antibody. In some embodiments, three compounds of structure (I) are conjugated to an antibody. In some embodiments, four compounds of structure (I) are conjugated to an antibody. In some embodiments, five compounds of structure (I) are conjugated to an antibody. In some embodiments, five or fewer compounds of structure (I) are conjugated to an antibody.

[0154] An additional embodiment is a compound having the structure: [ka] (In the formula, R 2 , R 3 , L and M have the definitions given for the compound of structure (I).

[0155] In various embodiments, reactive polymers can be used to prepare compounds of structure (I)-(XI). In certain embodiments, these reactive polymers are synthetic intermediates that contain moieties useful for reacting with a complementary moiety to form a covalent bond between M and the reactive polymer by any number of synthetic methodologies (e.g., the "click" reaction described above), thus forming compounds of structure (I)-(XI). Thus, in various embodiments, compounds of structure (I) can be prepared by reacting a reactive polymer having the following structure (I'): [ka] (I') or a stereoisomer, salt or tautomer thereof,

[0156] G is, independently at each occurrence, a moiety that contains a reactive group or a protected analogue thereof that is capable of forming a covalent bond with a complementary reactive group; L 1a , L 1 , L 2 , L 3 and L 4 is, independently at each occurrence, an optional alkylene linker or heteroalkylene linker; R 1 is independently at each occurrence H, alkyl or alkoxy;

[0157] R 2 is an electron pair, H, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, phospho, thio phospho, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, thio phosphoalkyl ether, Q or a protected form thereof, or L', wherein alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, alkyl phospho, alkyl thio phospho, alkyl ether phospho, alkyl ether thio phospho, phosphoalkyl, phosphoalkyl ether, thio phosphoalkyl, and thio phosphoalkyl ether are optionally substituted with hydroxyl, amino, sulfhydryl, phosphate, thio phosphate, phosphoalkyl, thio phosphoalkyl, phosphoalkyl ether, or thio phosphoalkyl ether, or combinations thereof;

[0158] R 3 are H, OH, SH, -NH 2, alkyl, alkyl ether, hydroxyl alkyl, amino alkyl, hydroxyl alkyl ether, sulfhydryl alkyl, sulfhydryl alkyl ether, cyano alkyl, -O aralkyl, phosphate, thiophosphate, alkyl phospho, alkyl thiophospho, -O alkyl phospho, -O alkyl thiophospho, alkyl ether phospho, alkyl ether thiophospho, -O alkyl ether phospho, -O alkyl ether thiophospho phosphoalkyl, phosphoalkyl ether, thiophosphoalkyl, thiophosphoalkyl ether, -O phosphoalkyl, -O phosphoalkyl ether, -O thiophosphoalkyl, -O thiophosphoalkyl ether, Q or a protected form thereof, or L'; the phosphoalkyl, phosphoalkylether, thiophosphoalkyl, thiophosphoalkylether, -Ophosphoalkyl, -Ophosphoalkylether, -Othiophosphoalkyl, -Othiophosphoalkylether may be substituted with hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether or combinations thereof; R 4 independently for each occurrence, O - , S - , OZ, SZ or N(R 6 ) 2 Z is a cation and R 6 each is independently H or alkyl; R 5 is independently at each occurrence oxo, thioxo, or absent; Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety; L' is, independently at each occurrence, a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a linker that includes a covalent bond to a solid support or a solid support moiety, a linker that includes a covalent bond to a solid support or a solid support moiety, or a linker that includes a covalent bond to an additional compound of structure (I'); n is an integer equal to or greater than 1, q and w are, independently at each occurrence, an integer greater than or equal to 0.

[0159] In certain other related embodiments, compounds of structures (II)-(VIII) are prepared in an analogous manner. In some embodiments, the reactive polymer is selected from Table 3 below. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] In various embodiments, G in the compounds of Table 3 is alkynyl, such as ethynyl. In other embodiments, G in the compounds of Table 3 is azide. In other embodiments, G in the compounds of Table 3 is amino (NH2 In other embodiments, G in the compounds of Table 3 is an isothiocyanate. In other embodiments, G in the compounds of Table 3 is an activated ester, such as an ester of N-hydroxysuccinimide. Certain embodiments are directed to therapeutically effective fluorescent compounds, with the proviso that at least one of the occurrences of M is not a fluorescent dye, and at least one of the occurrences of M is a fluorescent dye. Therapeutically effective fluorescent compounds include compounds that contain at least one biologically active moiety or fragment thereof, or a prodrug of a biologically active moiety or fragment thereof, which emit a fluorescent signal when excited by light, such as ultraviolet light.

[0160] composition Also provided is a composition comprising any one of the claimed compounds and a targeting moiety. The presently disclosed compound embodiments are "tunable," meaning that by appropriate selection of variables in any of the compounds described above, one of skill in the art can arrive at a compound with a desired molar fluorescence and / or a given molar fluorescence (molar brightness). The "tunability" of certain embodiments of the compounds allows the user to easily arrive at a compound with a desired fluorescence and / or color for use in a particular assay. While all variables can affect the molar fluorescence of certain embodiments of the compounds disclosed herein, the following variables are not limited to M, L, and / or β-aminobutyric acid. 1 It is believed that the appropriate selection of m, n and n plays an important role in the molar fluorescence of the disclosed compound embodiments. Thus, in one embodiment, a method for obtaining a compound with a desired molar fluorescence comprises the steps of selecting an M moiety with known fluorescence, preparing a compound of structure (I)-(XI) that includes an M moiety, and adjusting L to reach the desired molar fluorescence. 1 , m and n.

[0161] For ease of illustration, various compounds that contain phosphorus moieties (e.g., phosphate, etc.) can be present in an anionic state (e.g., -OPO(OH)O - , -OPO 3 2- ) as a charge. One of ordinary skill in the art will readily appreciate that the charge is pH dependent, and that uncharged (e.g., protonated or salts such as sodium or other cations) forms are also included within the scope of embodiments of the present invention. Compositions comprising any of the above-mentioned compounds and one or more targeting moieties (e.g., antibodies or cell surface receptor antagonists) are provided in various other embodiments. Also provided in some embodiments is the use of such compositions in a method for treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structure (I)-(XI) or a composition comprising a compound of structure (I)-(XI), wherein each M is independently a biologically active moiety effective to treat the disease.

[0162] Pharmaceutical Compositions One embodiment provides a composition comprising a compound according to any one of the embodiments disclosed herein and a pharma- ceutically acceptable carrier. Another embodiment provides a composition comprising a plurality of conjugates comprising the compound of claim 1 covalently attached to an antibody by a single linking group, wherein the plurality of conjugates have at least 90% structural homogeneity. "Structural homogeneity" means a compound having the same structure, including the point of attachment to the antibody. 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. Other embodiments are directed to pharmaceutical compositions. The pharmaceutical compositions include any one (or more) of the compounds described above and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions are formulated for oral administration. In other embodiments, the pharmaceutical compositions are formulated for injection. In further embodiments, the pharmaceutical compositions include the compounds disclosed herein and an additional therapeutic agent (e.g., an anti-cancer agent). Non-limiting examples of such therapeutic agents are described herein below. Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal and topical administration. Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic and intranasal injection.

[0163] In certain embodiments, the compounds described herein are administered locally rather than systemically, for example, by injecting the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, a long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to the organ and taken up selectively by the organ. In still other embodiments, the compounds described herein are provided in the form of a fast-release formulation, a sustained-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds described herein are administered locally.

[0164] The compounds according to embodiments of the present invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages of 0.01-1000 mg per day, 0.5-100 mg, 1-50 mg per day, and 5-40 mg per day are examples of dosages that may be used in certain embodiments. An exemplary dosage is 10-30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the weight of the subject being treated, and the preference and experience of the attending physician. In some embodiments, the compound of the present invention is administered in a single dose.Usually, such administration will be by injection, for example intravenous injection, to rapidly introduce the drug.However, if appropriate, other routes are used.A single dose of the compound of the present invention may also be used to treat acute conditions. In some embodiments, the compound of the present invention is administered in multiple doses. In some embodiments, administration is about once, twice, three times, four times, five times, six times, or more per day. In other embodiments, administration is about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compound of the present invention and another agent are administered together about once a day to about six times a day. In another embodiment, administration of the compound of the present invention and the agent continues for less than about 7 days. In yet another embodiment, administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous dosing is achieved and maintained for as long as necessary.

[0165] Administration of the compound embodiment of the present invention may continue as long as necessary. In some embodiments, the compound of the present invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compound of the present invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compound of the present invention is administered continuously for an extended period of time, for example, for long-term treatment. In some embodiments, the compound of the present invention is administered in a dosage.It is known in the art that due to subject-to-subject variability in the pharmacokinetics of compounds, individualization of dosage regimen is necessary for optimal treatment.Dosage for the embodiment of the compound of the present invention can be found by routine experimentation in light of this disclosure.

[0166] In some embodiments, the compound described herein is formulated into pharmaceutical composition.In specific embodiments, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliary agents, which facilitate the processing of active compound into medicament-usable preparations.Suitable formulation depends on the route of administration selected. Any pharma- ceutical acceptable techniques, carriers, and excipients may be used to formulate the pharmaceutical compositions described herein, as appropriate: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999). Provided herein are pharmaceutical compositions comprising a compound of structure (I)-(XI) and a pharma- ceutically acceptable diluent, excipient, or carrier. In certain embodiments, the described compounds are administered as pharmaceutical compositions in which the compounds of structure (I)-(XI) are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of active agents described in the combination therapy section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions comprise one or more compounds of structure (I)-(XI).

[0167] Pharmaceutical composition, as used herein, refers to a mixture of a compound of structure (I)-(XI) with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments of practicing the methods of treatment or methods of use provided herein, a therapeutically effective amount of a compound of structure (I)-(XI) provided herein is administered in a pharmaceutical composition to a mammal having the disease, disorder, or medical condition to be treated. In a specific embodiment, the mammal is a human. In certain embodiments, the therapeutically effective amount will vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds described herein are used singly or as components of mixtures in combination with one or more therapeutic agents. In one embodiment, one or more compounds of structure (I)-(XI) are formulated in an aqueous solution. In a specific embodiment, the aqueous solution is selected from physiologically compatible buffers such as, by way of example only, Hank's solution, Ringer's solution, or saline buffer. In other embodiments, one or more compounds of structure (I)-(XI) are formulated for transmucosal administration. In a specific embodiment, the transmucosal formulation includes a penetrant appropriate for the barrier to be permeated. In yet other embodiments, when the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In a specific embodiment, such solutions include physiologically compatible buffers and / or excipients. In another embodiment, the compounds described herein are formulated for oral administration.The compounds described herein are formulated by combining active compounds with, for example, pharma-ceutically acceptable carriers or excipients.In various embodiments, the compounds described herein are formulated in oral dosage forms, including, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc.

[0168] In certain embodiments, pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, grinding the resulting mixture, and then processing the mixture of granules to obtain tablet or dragee cores, after adding suitable auxiliary agents if desired.Suitable excipients are sugars, including lactose, sucrose, mannitol or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or fillers such as polyvinylpyrrolidone (PVP or povidone) or others such as calcium phosphate.In specific embodiments, disintegrants can be added.Disintegrants include, by way of example only, cross-linked sodium croscarmellose, polyvinylpyrrolidone, agar or alginic acid or its salts, such as sodium alginate.

[0169] In one embodiment, dosage forms such as dragee cores and tablets are coated with one or more suitable coatings. In a specific embodiment, a concentrated sugar solution is used to coat the dosage form. The sugar solution may contain additional components such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes and / or pigments may be added to the coating for identification purposes. Furthermore, dyes and / or pigments may be utilized to characterize different combinations of active compound doses.

[0170] In certain embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. In specific embodiments, the push-fit capsules contain the active ingredient in a mixture with one or more fillers. The fillers include, by way of example only, binders such as lactose, starch, and / or lubricants such as talc or magnesium stearate, and may also include stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. In other embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated for oral or sublingual administration. Formulations suitable for oral or sublingual administration include, by way of example only, tablets, lozenges, or gels. In yet other embodiments, the compounds described herein are formulated for parental administration, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, the injectable formulations are provided in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives may be added to the injectable formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles. Parenteral injection formulations may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. In additional embodiments, suspensions of the active compounds (e.g., compounds of structures (I)-(XI)) are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. The suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0171] In yet another embodiment, the compounds of structures (I)-(XI) are administered topically. The compounds described herein are formulated into various compositions that can be administered topically, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compositions may contain solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0172] In yet other embodiments, the compounds of structures (I)-(XI) are formulated for transdermal administration. In specific embodiments, transdermal formulations can be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in polymers or adhesives using transdermal delivery devices and transdermal delivery patches. In various embodiments, such patches are constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents. In additional embodiments, transdermal delivery of the compounds of structures (I)-(XI) is achieved by iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of the compounds of structures (I)-(XI). In specific embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharma- ceutically acceptable solvents that aid in passage through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage that includes a backing member, a reservoir containing the compound (which may include a carrier), optionally a rate-controlling barrier for delivering the compound to the host's skin at a controlled and predetermined rate over an extended period of time, and a means for securing the device to the skin.

[0173] In other embodiments, the compounds of structures (I)-(XI) are formulated to be administered by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders. Any pharmaceutical composition of the compounds of structures (I)-(XI) is conveniently delivered in the form of an aerosol spray supply from a pressurized pack or nebulizer with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In a specific embodiment, the dosage unit of the pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules or cartridges, such as, by way of example only, gelatin, for use in an inhaler or insufflator are formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0174] In yet other embodiments, the compounds of structures (I)-(XI) are formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories or retention enemas containing a conventional suppository base such as cocoa butter or other glycerides, and a synthetic polymer such as polyvinylpyrrolidone, PEG, etc. In suppository forms of the composition, a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is melted first. In certain embodiments, the pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries, which facilitate the processing of the active compounds into medicament-usable preparations. The appropriate formulation depends on the route of administration selected. Any pharma-ceutically acceptable techniques, carriers, and excipients may be used, if appropriate. The pharmaceutical compositions containing the compounds of structures (I)-(XI) are prepared in a conventional manner, such as, by way of example only, conventional mixing, dissolving, granulating, dragee making, wet milling, emulsifying, encapsulating, entrapping, or compressing processes.

[0175] The pharmaceutical compositions comprise at least one pharma- ceutically acceptable carrier, diluent or excipient, and as an active ingredient, at least one compound of structure (I)-(XI) as described herein. The active ingredient is in free acid or free base form, or in a pharma- ceutically acceptable salt form. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds provided herein. Additionally, the compounds described herein include unsolvated forms and solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds provided herein are also considered to be disclosed herein. Additionally, the pharmaceutical compositions may include other medicinal or pharmaceutical agents, carriers, preservatives, stabilizing agents, wetting or emulsifying agents, solution promoters, adjuvants such as salts for regulating osmotic pressure, buffering agents, and / or therapeutically valuable substances.

[0176] The method of preparing a composition comprising the compound described herein includes formulating the compound with one or more inert pharma- ceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compound disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The forms of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquid before use, or emulsions. These compositions may also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like. In some embodiments, pharmaceutical compositions comprising at least one compound of structure (I)-(XI) are illustratively in the form of a liquid in which the drug is in solution, in suspension, or both. Typically, when the composition is administered as a solution or suspension, a first portion of the drug is in solution and a second portion of the drug is in particulate form in suspension in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous. In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents.Useful polymers include water-soluble polymers such as cellulose polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers.Some pharmaceutical compositions described herein include mucoadhesive polymers, e.g., selected from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0177] Useful pharmaceutical compositions may also include solubilizing agents to aid in the dissolution of the compounds of structures (I)-(XI). The term "solubilizing agent" generally includes agents that result in the formation of a micellar or true solution of the drug. Certain acceptable non-ionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers. In addition, useful pharmaceutical compositions may contain one or more pH adjusting or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid, bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane, and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition in an acceptable range.

[0178] In addition, useful compositions may also contain one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions, with suitable salts including sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. Other useful pharmaceutical compositions may contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal, stabilized chlorine dioxide, and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride. Still other useful compositions contain one or more surfactants to enhance physical stability or for other purposes.Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil, and polyoxyethylene alkyl ethers and alkyl phenyl ethers, such as octoxynol 10, octoxynol 40.

[0179] Still other useful compositions optionally contain one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite. In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case it is customary to include a preservative in the composition. In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In additional embodiments, the compounds described herein are delivered using sustained release systems, such as semi-transparent matrices of solid hydrophobic polymers containing therapeutic agents. A variety of sustained release materials are useful herein. In some embodiments, sustained release capsules release compounds for several weeks up to 100 days. Depending on the chemical nature and biological stability of therapeutic reagents, additional strategies for protein stabilization are used.

[0180] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizing agents. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc, or (n) combinations thereof. In some embodiments, the concentration of one or more compounds provided in the pharmaceutical composition is 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.1%. %, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v or v / v.

[0181] In some embodiments, the concentration of one or more compounds is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 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 higher than 0.0001% w / w, w / v or v / v.

[0182] In some embodiments, the concentration of the one or more compounds is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 100%, from about 0.09% to about 120%, from about 0.10% to about 130%, from about 0.11% to about 140%, from about 0.12% to about 150%, from about 0.13% to about 160%, from about 0.14% to about 170%, from about 0.15% to about 180%, from about 0.16% to about 190%, from about 0.18% to about 200%, from about 0.19% to about 210%, from about 0.19% to about 220%, from about 0.19% to about 230%, from about 0.19% to about 240%, from about 0.19% to about 250%, from about 0.19% to about 260%, from about 0.19% to about 250%, from about 0.19% to about 220%, from about 0.19% to about 230%, from about 0.19% to about 240%, from about 0.19% to about 25 ... about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v or v / v. In some embodiments, the concentration of the one or more compounds is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v or v / v.

[0183] In some embodiments, the amount of one or more compounds is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g.

[0184] In some embodiments, the amount of one or more compounds is 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.004 ... g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.00 75g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0 .085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5 g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or more than 10g. In some embodiments, the amount of one or more compounds is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0185] 1. Treatment method In yet another embodiment, the compound is useful for various methods of treating disease or condition.Therefore, one embodiment provides a method of treating disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of the embodiments disclosed herein or the composition according to any one of the embodiments disclosed herein, wherein each M is independently an effective biologically active moiety for treating the disease.In some embodiments, the disease is cancer, and each M is independently an anticancer drug. For example, in certain embodiments, the disclosure provides methods of treating solid tumors, multiple myeloma, glioma, clear cell renal cell carcinoma, prostate cancer, ovarian cancer, non-small cell lung cancer, GI malignancies, acute lymphoblastic leukemia, acute myeloid leukemia, renal cell carcinoma, colorectal cancer, epithelial cancer, pancreatic and gastric cancer, renal cell carcinoma, non-Hodgkin's lymphoma, metastatic renal cell carcinoma, malignant mesothelioma, adenocarcinoma of the pancreas, ovary and / or lung, B-cell malignancies, breast cancer, melanoma, recurrent multiple myeloma, small cell lung cancer, CD22 positive B-cell malignancies, Hodgkin's lymphoma / anaplastic large cell lymphoma, or HER2 positive breast cancer.

[0186] Certain embodiments also relate to a method of treating a hyperproliferative disorder in a mammal (e.g., a human), comprising administering to the mammal a therapeutically effective amount of a compound or a pharma- ceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.In some embodiments, the method relates to a method for treating acute myeloid leukemia, adolescent cancer, adrenocortical carcinoma of childhood, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoid, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer. , colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic bile duct carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer , liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of unknown primary site, midline canal carcinoma, cancer of the mouth, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma for the treatment of cancers such as bronchial carcinoma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, chorioepithelial tumor, rare cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer or virus-induced cancer.In some embodiments, the methods relate to the treatment of non-cancerous hyperproliferative disorders such as benign hyperplasia of the skin (eg, psoriasis), restenosis or the prostate (eg, benign prostatic hyperplasia (BPH)).

[0187] Certain specific embodiments provide a method of treating lung cancer, comprising administering to a subject in need thereof an effective amount of any of the above compounds (or pharmaceutical compositions comprising same). In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung carcinoma, or large cell lung carcinoma. In other embodiments, the lung cancer is small cell lung carcinoma. Other lung cancers treatable by the disclosed compounds include, but are not limited to, adenoma, carcinoid tumor, and undifferentiated carcinoma.

[0188] Thus, in some embodiments of the above-described method, R 2 is a linker that includes a covalent linking group to a targeting moiety, such as an antibody or cell surface receptor antagonist, for example, an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, a folate or a MET inhibitor. In a further embodiment, the method further comprises inducing apoptosis. Thus, embodiments of the present compounds find use in any number of methods, including, but not limited to, drug delivery, quantification of apoptosis, qualifying the delivery of therapeutic agents, quantification of apoptosis, and the diagnosis and treatment of diseases such as hematological cancers.

[0189] In addition to the methods described above, embodiments of the compounds of structures (I)-(XI) find utility in a variety of fields and methods including, but not limited to, cancer treatment and imaging, and / or drug delivery, by including targeting moieties in the compounds of structures (I)-(XI), such as antibodies or sugars, or other moieties that preferentially bind to cancer cells. In some embodiments, the method of treatment includes treating a tumor having tumor cells with a tumor cell receptor. In some embodiments, the tumor cells have receptors in the range of 1,000-100,000, 1,000-50,000, 1,000-25,000, 1,000-10,000 receptors per cell. For example, in some embodiments, the tumor cells have about 1,000, about 10,000 receptors, or less than 100,000 receptors per cell.

[0190] Preparation method

[0033] Embodiments of the compounds of structure (I) above, as well as the variable factor R in the compounds of structures (I)-(XI) above, 1 , R 2 , R 3 , R 4 , R 5 , L, L 1 , L 2 , L 3 , L 4 It is understood that any specific choices described herein for M, q, w and / or n may be independently combined with other embodiments and / or variables of the compounds of structures (I)-(XI) to form embodiments of the invention not specifically described above. Additionally, optimal listings may be combined with any specific R in a particular embodiment and / or claim. 1 , R 2 , R 3 , R 4 , R 5 , L, L 1 , L 2 , L 3 , L 4 In the cases listed with respect to the variables M, q, w and / or n, it is understood that each individual selection may be excluded from the scope of particular embodiments and / or claims, and that the most suitable remaining listings are considered to be within the scope of the present invention. It is understood that in this description, combinations of substituents and / or variables of the depicted formulae are permissible if such contributions result in stable compounds.

[0191] It will also be appreciated by those skilled in the art that in the processes described herein, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R" (wherein R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups can be added or removed according to standard techniques known to those skilled in the art and described herein. The use of protecting groups is described in detail in Green, TW and PGM Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As will be appreciated by those skilled in the art, these protecting groups can also be polymeric resins such as Wang resin, Rink resin or 2-chlorotrityl chloride resin. Additionally, all compounds of the invention that exist in free base or free acid form can be converted to their salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of compounds of the invention can be converted to their free base or acid form by standard techniques.

[0192] The following reaction scheme illustrates an exemplary method for making the compounds of the present invention. It is understood that a person skilled in the art may be able to make these compounds by analogous methods or by combining other methods known to a person skilled in the art. Methods for preparing the embodiments of the compounds disclosed herein (e.g., structures (I)-(XI)) can be found, for example, in PCT Publication Nos. WO2015 / 027176 and WO2016 / 138461, which are incorporated herein by reference in their entirety. It is also understood that a person skilled in the art may be able to make other compounds of structures (I)-(XI) that are not specifically exemplified below by analogous methods as described below, by using appropriate starting components and modifying synthetic parameters as necessary. Generally, the starting components can be obtained from commercial sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or can be synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)), or can be prepared as described herein.

[0193] Reaction Scheme I [ka] Reaction Scheme I shows the reaction 1 , L 1a , L 1 , L 2 and M is as defined above, R 2 and R 3 is as defined above or a protected variation thereof; L 1a’FIG. 1 illustrates exemplary methods for preparing intermediates useful in the preparation of compounds of structures (I)-(XI) in which, when taken together with the adjacent carbon to which it is attached, is L as defined above. Referring to Reaction Scheme 1, compounds of structure a can be purchased or prepared by methods well known to those skilled in the art. Reaction with MX (X is a halogen, such as bromo) under Suzuki coupling conditions known in the art provides compounds of structure b. Compounds of structure b can be used in the preparation of compounds of structures (I)-(XI), as described below.

[0194] Reaction Scheme II [ka] Reaction Scheme II illustrates an alternative method for the preparation of intermediate compounds useful in the preparation of compounds of structures (I)-(XI). 1 , L, L 1a , L 1 , L 2 and M is as defined above, R 2 and R 3 Referring to Reaction Scheme II, where M is as defined above or a protected variant thereof, a compound of structure c, which can be purchased or prepared by well-known techniques, is reacted with M-G' to produce a compound of structure d, where G and G' represent functional groups with complementary reactivity (i.e., functional groups that react to form a covalent bond). G' can be M or part of the structural backbone of M, e.g., a side chain to a cyclic anhydride. G can be any number of functional groups, such as amino.

[0195] In certain embodiments, the compounds of structures (I)-(XI) are oligomers containing 2-100 repeat units. Such oligomers can be prepared using methods similar to well-known automated DNA synthesis methods. DNA synthesis methods are well-known in the art. Briefly, two alcohol groups, such as R in intermediates b or d above, are 2 and R 3are functionalized with a dimethoxytrityl (DMT) group and a 2-cyanoethyl-N,N-diisopropylamino phosphoramidite group, respectively. The phosphoramidite group is usually attached to an alcohol group in the presence of an activating agent such as tetrazole, followed by oxidation of the phosphorus atom with iodine. The dimethoxytrityl group can be removed with an acid (e.g., chloroacetic acid) to expose the free alcohol, which can be reacted with the phosphoramidite group. The 2-cyanoethyl group can be removed after oligomerization by treatment with aqueous ammonia. The preparation of phosphoramidites used in oligomerization methods is also well known in the art. For example, primary alcohols (e.g., R 3 ) can be protected as a DMT group by reaction with DMT-Cl. A secondary alcohol (e.g., R 2 ) is functionalized as a phosphoramidite by reaction with a suitable reagent such as 2-cyanoethyl N,N-diisopropylchlorophosphoramidite. Methods for the preparation of phosphoramidites and their oligomerization are well known in the art.

[0196] Oligomers of intermediates b or d are prepared according to the well-known phosphoramidite chemistry described above. The desired number of repeat units m is determined by coupling the phosphoramidite to a suitable intermediate, such as an intermediate having the following structure: [ka] This is repeated a desired number of times to incorporate the compound into the molecule. The following examples are offered by way of illustration and not by way of limitation. EXAMPLES

[0197] General method 1 H and 31 P NMR spectra are obtained on a JEOL 400 MHz spectrometer. 31 P NMR spectra were referenced to 85% aqueous phosphoric acid.1 H NMR is referenced to TMS. Reversed-phase HPLC dye analysis was performed using a 2.1 mm × 50 mm Acquity BEH-C NMR spectrometer maintained at 45 °C. 18 LC / MS is performed using a Waters Acquity UHPLC system equipped with a column. Mass spectral analysis is performed on a Waters / Micromass Quattro micro MS / system MS (MS mode only) using MassLynx 4.1 acquisition software. The mobile phase used for LC / MS is 100 mM 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), 8.6 mM triethylamine (TEA), pH 8. Phosphoramidites and precursor molecules are analyzed using an Agilent Infinity 1260 UHPLC system equipped with a diode array detector and high performance autosampler using an Aapptec © Spirit™ peptide C18 column (4.6 mm x 100 mm, 5 μm particle size). Excitation and emission profile experiments are recorded on a Cary Eclipse spectrophotometer.

[0198] All reactions were carried out in oven-dried glassware under a nitrogen atmosphere unless otherwise noted. Commercial DNA synthesis reagents are purchased from Glen Research (Sterling, VA). Anhydrous pyridine, toluene, dichloromethane, diisopropylethylamine, triethylamine, acetic acid, pyridine and THF are purchased from Aldrich. All other chemicals are purchased from Aldrich or TCI and used as is without further purification. All oligomeric (i.e., dimers or higher) compounds are synthesized on an ABI394 DNA synthesizer using standard protocols for phosphoramidite-based coupling procedures. The chain assembly cycles for oligomeric synthesis are: (i) detritylation, 3% trichloroacetic acid in dichloromethane, 1 min, (ii) coupling, 0.1 M phosphoramidites and 0.45 M tetrazole in acetonitrile, 10 min, (iii) 0.5 M acetic anhydride in THF / lutidine, 1 / 1, 15 sec, (iv) oxidation, 0.1 M iodine in THF / pyridine / water, 10 / 10 / 1, 30 sec. The chemical steps in this cycle are followed by washing with acetonitrile and bubbling with dry argon for 0.2-0.4 min. Cleavage resulting from support and removal of the base and phosphoramidate protecting groups is achieved by treatment with ammonia for 1 h at room temperature. The oligomeric dyes are then analyzed by reversed-phase HPLC as described above.

[0199] Example 1 Synthesis of Ibuprofen-NHS and Naproxen-NHS [ka] Ibuprofen-NHS and naproxen-NHS were synthesized using standard coupling conditions: ibuprofen and naproxen were dissolved separately in dichloromethane, and to this mixture was added N,N'-dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide (NHS). The product was then purified as necessary and used in the next synthetic step. Ibuprofen-NHS is easily synthesized in one step on a multigram scale.

[0200] Example 2 Synthesis of ibuprofen polymers [ka] As shown in the reaction sequence above, an exemplary polymer (e.g., with amine functional side chains) is coupled with ibuprofen-NHS. This reaction is carried out in borate buffered H2SO4 containing magnesium chloride. 2 This reaction is carried out using an O / DMSO mixture and successfully adds an ibuprofen moiety to each of the amine functional groups to give the desired product.

[0201] Example 3 Synthesis of naproxen polymers [ka] As shown in the reaction sequence above, an exemplary polymer (e.g., with amine functional side chains) is coupled to naproxen-NHS. This reaction is carried out in borate buffered H2O containing magnesium chloride. 2 This reaction is carried out using an O / DMSO mixture and successfully adds an ibuprofen moiety to each of the amine functional groups to give the desired product.

[0202] Example 4 Synthesis of doxorubicin-NHS [ka] Doxorubicin is reacted with dihydrofuran-2,5-dione to give a carboxylic acid-containing intermediate, which is activated using TFA-NHS and pyridine to give doxorubicin-NHS.

[0203] Example 5 Synthesis of doxorubicin polymers [ka] The exemplary polymer is linked to doxorubicin-NHS. The reaction conditions require experimentation using different solvent mixtures due to the limited solubility of the doxorubicin derivative. Alternative reaction conditions include increasing the content of organic solvent, increasing the reaction temperature, and adding sodium dodecyl sulfate (SDS) to support the reaction.

[0204] Example 6 Synthesis of doxorubicin-PEG-azide [ka]

[0205] Doxorubicin-PEG-azide was synthesized on a 50 mg scale following the reaction sequence shown above. Azide 6-1 was reacted with dihydrofuran-2,5-dione to give intermediate 6-2, which was reacted with perfluorophenol to give intermediate 6-3. Intermediate 6-3 was coupled to doxorubicin to give the desired product, doxorubicin-PEG-azide, in good yield (74%). The presence of the desired product was confirmed by LC-MS.

[0206] Example 7 Synthesis of doxorubicin polymers [ka] An exemplary alkynyl-containing polymer is linked to doxorubicin-PEG-azide. The reaction conditions are: CuSO 4 , tris(3-hydroxypropyltriazolylmethyl)amine (THPTA) and sodium ascorbate. The reaction is carried out in an aqueous phosphate buffer containing 60% DMS at pH 7.6. The reaction is carried out at room temperature and the presence of the desired product is confirmed by LC-MS.

[0207] Example 8 Synthesis of ibuprofen phosphoramidite [ka]

[0208] Expandable derivatives of ibuprofen were synthesized according to the reactions shown above as representative derivatives that will be incorporated into the compound embodiments described herein. Ibuprofen-NHS was reacted with 8-1 (2-amino-1,3-propanediol) and then trityl protecting group was added to give intermediate 2-3. The protected product 8-3 was then reacted with 8-4 to give the final product 8-5, ibuprofen-phosphoramidite (79%). The ibuprofen-phosphoramidite was then used in automated DNA synthesis to incorporate ibuprofen as a representative biologically active moiety into the compound embodiments described herein. Alternatively, ibuprofen-NHS was derivatized according to the reaction procedure shown above by reacting with 4-(aminomethoxy)butane-1,2,-diol. The resulting final product of this reaction sequence resulted in an alternative ibuprofen phosphoramidite with an extended linker compared to the ibuprofen-phosphoramidite shown above.

[0209] Example 9 Synthesis of naproxen phosphoramidite [ka]

[0210] Naproxen-phosphoramidite (9-5) was synthesized using similar reaction conditions and reagents described for the synthesis of ibuprofen-phosphoramidite, shown in Example 8. The desired product was obtained in good yield (79%) and was incorporated into compound embodiments of the present disclosure as a representative biologically active moiety. Alternatively, naproxen-NHS was derivatized according to the reaction procedure shown above by reacting with 4-(aminomethoxy)butane-1,2,-diol. The resulting final product of this reaction sequence resulted in an alternative naproxen phosphoramidite with an extended linker compared to the naproxen phosphoramidite shown above.

[0211] Example 10 Exemplary compounds prepared using automated DNA synthesis methods The polymer sequences are prepared using ibuprofen-phosphoramidites and / or naproxen-phosphoramidites, as described in Examples 8 and 9, respectively. The sequences are successfully prepared using automated DNA synthesis techniques known in the art. Compounds synthesized according to this strategy are homogeneous (i.e., contain only one biologically active moiety), while other compounds are heterogeneous (i.e., contain a combination of two). Other advantageous structural features are included in the embodiments synthesized according to this method. For example, fluorescein is easily and conveniently included as part of the construct. The compounds synthesized contain a protected thiol moiety (C6SS), which is then used for binding to a targeting moiety (e.g., an antibody) as described herein.

[0212] Numerous advantages are provided by the embodiments disclosed herein, including the ability to control the number of bioactive or fluorescent dye moieties that are linked to the polymer and then to any targeting moiety.The composition of the polymer backbone can also be selected to achieve desired solubility properties, for example, by controlling the incorporation of charge moieties (e.g., number, frequency, spacing, etc.).In addition to the properties provided by the composition of the backbone, the side chains can be selected to provide a basis for adjusting the solubility of the compounds disclosed herein.

[0213] The embodiments disclosed herein also provide compounds that can advantageously include multiple therapeutic agents, for example, for complimentary or synergistic therapeutic strategies.Furthermore, the embodiments of the present disclosure provide combinations of therapeutic agents, targeting moieties and dye moieties (e.g., fluorophores) that can be used for targeting, treatment and detection simultaneously.The ease of coupling the polymer-drug constructs to targeting agents such as antibodies, antibody fragments, proteins or other agents of clinical interest makes them useful for a wide range of applications of interest (e.g., surface chemistry, assay development, etc.).

[0214] The compounds of certain embodiments also achieve other desirable properties, including enhanced permeability and retention. In addition to achieving the necessary solubility, the chemical characteristics of the compound embodiments can be adjusted to modulate the ability of the compound to penetrate and be retained within diseased cells / tissues. These characteristics allow for effective delivery of bioactive agents through enhanced permeability, and increased efficacy through enhanced retention.

[0215] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referred to in this specification are hereby incorporated by reference in their entirety to the extent inconsistent with the present disclosure, including U.S. Provisional Patent Application No. 62 / 616,672, filed January 12, 2018. From the foregoing it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

1. Compounds having the following structure (VI): 【Chemistry 1】 or having stereoisomers, tautomers, or salts thereof (wherein the formula, M is a biologically active moiety that is independently selected from NSAIDs, kinase inhibitors, anthracyclines, epidermal growth factor receptor (EGFR) inhibitors, alkylating agents, and anticancer drugs each time it appears. L is a physiologically cleavable heteroalkylene linker, L 1 and L 3 Each instance is independently either an alkylene or heteroalkylene linker, or it is absent. L 2 and L 4 Each instance is independently a heteroalkylene linker containing a phosphodiester bond. R 1 Each instance is independently H, alkyl, or alkoxy. R 2 This is an alkylene or heteroalkylene to a target-directed moiety selected from an electron pair, H, alkyl, alkyl ether, hydroxylalkyl, aminoalkyl, hydroxylalkyl ether, sulfhydrylalkyl, sulfidylalkyl ether, cyanoalkyl, phospho, thiophospho, alkylphospho, alkylthiophospho, alkyl etherphospho, alkyl etherthiophospho, phosphoalkyl, phosphoalkyl ether, thiophosphoalkyl, thiophosphoalkyl ether, or an alkylene or heteroalkylene to a target-directed moiety selected from antibodies and cell surface receptor antagonists. R 3 is -OP(=Ra)(Rb)OL', L' is a nucleoside or a nucleoside to which a linker having the following structure is attached, 【Chemistry 2】 (In the formula, m'' and n'' are independent integers from 1 to 10, Re is H, an electron pair, or a counterion. Ra is either O or S. Rb is OH, O-, S-, ORd, or SRd. Rd is the counterion, n is an integer between 1 and 10. w is an integer greater than or equal to 1 for at least one integer value of n. q is a non-negative integer for each integer value of n.

2. The compound according to claim 1, wherein the heteroalkylene linker containing the phosphodiester bond is selected from the following structures. 【Transformation 3】

3. The compound according to claim 1 or 2, wherein R3 comprises dT having the following structure. 【Chemistry 4】 (In the formula, (R is either H or a direct bond.)

4. The compound according to any one of claims 1 to 3, wherein L is cleavable by hydrolase, oxidoreductase, or lyase.

5. The compound according to any one of claims 1 to 4, wherein L is a linker that independently contains an amide bond, an ester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a ketone, a diol, a cyano, a nitro, or a combination thereof, each time it appears.

6. L is a compound according to any one of claims 1 to 5, selected from the following structures. 【Transformation 5】 (In the formula, L1a or L1b, in each instance, is either an alkylene or a heteroalkylene linker, or it is absent.

7. The compound according to claim 6, wherein L1a or L1b, if present, independently has one of the following structures. 【Transformation 6】

8. L is a compound according to any one of claims 1 to 5, selected from the following structures. 【Transformation 7】 (In the formula, R is H, methyl, ethyl, isopropyl, tert-butyl, or phenyl. X is either O or CH₂, n is an integer greater than 0.

9. R 2 The compound according to any one of claims 1 to 8, having one of the following structures. 【Chemistry 8-1】 【Chemistry 8-2】 (In the formula, R 2a is -OH, -SH, -NH 2 , phosphate, thiophosphate or L', and R 4a and R 4b O - S - It is either OZ or SZ, where Z is a cation. R 5a and R 5b They are independently oxo or thioxo. a, b, and c are each independent integers between 1 and 10.

10. R2 is the compound according to any one of claims 1 to 9, having the following structure. 【Chemistry 9-1】 【Chemistry 9-2】

11. R 3 The compound according to any one of claims 1 to 10, having one of the following structures. 【Chemistry 10】 (In the formula, R 3a -OH, -SH, -NH 2 , phosphate, thiophosphate or L', L' is a nucleoside, R 4a and R 4b O - S - It is either OZ or SZ, where Z is a cation. R 5a and R 5b They are independently oxo or thioxo. (b and c are each independent integers between 1 and 10.)

12. At least one of the M that appears is one of the following structures: 【Chemistry 11】 A compound according to any one of claims 1 to 11, having the following characteristics.

13. Each time M appears, it is one of the following structures: 【Chemistry 12】 A compound according to any one of claims 1 to 11, having the following characteristics.

14. R2 is an alkylene or heteroalkylene to a target-directing moiety selected from antibodies and cell surface receptor antagonists, The compound according to any one of claims 1 to 13, wherein the target-directing portion is an antibody specific to tumor cell antigens.

15. The compound according to claim 14, wherein the tumor cell antigen is EGFR, HER2, folate receptor, CD20, or CD33.

16. A compound according to any one of claims 1 to 15, used for selective delivery to target cells.

17. A composition comprising a compound according to any one of claims 1 to 16, and a pharmaceutically acceptable carrier.

18. A composition comprising a plurality of conjugates, each containing a compound according to any one of claims 1 to 16, which is covalently bound to an antibody by a single linking group, wherein the plurality of conjugates have at least 90% structural homogeneity.

19. The composition according to claim 18, wherein the multiple conjugates have at least 95% structural homogeneity.

20. The composition according to claim 18, wherein the multiple conjugates have structural homogeneity exceeding 99%.

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