Automated synthesis of polymeric dual drugs

Abstract

Disclosed are compounds useful as biologically active compounds, with or without fluorescent or colored moieties. In some embodiments, the compounds have the following structure (I): JPEG2024537069000114.jpg30161(I) or a stereoisomer, tautomer or salt thereof (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 , M 1 , M 2 , M 3 , l, m, n, p, and q are as defined herein.) Additional compounds, methods of preparation, pharmaceutical compositions, and methods of treatment related to the compounds of structure (I) are also provided.

Description

[Technical field]

[0001] The present disclosure is generally directed to dimeric and polymeric biologically active compounds with spacing groups, with or without chromophore moieties (e.g., fluorescent dyes), compounds related thereto, and methods of treatment. [Background technology]

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

[0003] One embodiment is a compound having the following structure (I): [ka] (I) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 , M 1 , M 2 , M 3 , l, m, n, p, and q are as defined herein.

[0004] Another embodiment is a compound having the structure (Ia): [ka] (Ia) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 2 , L 3 , L 4 , L 6 , L 7 , L 9 , L 10 , L 11 , M 1 , M 2 , M 3, l, m, n, p, and q are as defined herein.

[0005] Another embodiment is a compound having the structure (Ib): [ka] (Ib) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 2 , R 3 , R 6 , R 7 , L 3 , L 10 , M 1 , M 2 , M 3 , l, m, n, p, and q are as defined herein.

[0006] Yet another embodiment is a compound having the structure (Ic): [ka] (I C) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 , L 3 , L 10 , M 1 , M 3 , l, m, n, p, and q are as defined herein.

[0007] Yet another embodiment is a compound having the structure (Id): [ka] (Id) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. . (In the formula, R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 , L 10 , M 3 , n, p, and q are as defined herein.

[0008] Yet another embodiment is a compound having the structure (Ie): [ka] (Ie) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 and n is as defined herein.

[0009] One embodiment is a compound having the following structure (III): [ka] (III) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 , M 1, M 2 , M 3 , l, m, n, p, and q are as defined herein.

[0010] Another embodiment is a compound having the structure (IIIa): [ka] (IIIa) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 2 , L 3 , L 4 , L 6 , L 7 , L 9 , L 10 , L 11 , M 1 , M 2 , M 3 , l, m, n, p, and q are as defined herein.

[0011] Another embodiment is a compound having the following structure (IIIb): [ka] (IIIb) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 2 , R 3 , R 6 , R 7 , L 3 , L 10 , M 1 , M 2 , M 3 , l, m, n, p, and q are as defined herein.

[0012] Yet another embodiment is a compound having the structure (IIIc): [ka] (IIIc) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 , L 3 , L 10 , M 1 , M 3 , l, m, n, p, and q are as defined herein.

[0013] Yet another embodiment is a compound having the structure (IIId): [ka] (IIId) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 , L 10 , M 3 , n, p, and q are as defined herein. These and other aspects of the present disclosure will become evident upon reference to the following detailed description. In the drawings, identical reference numbers identify similar elements. The sizes and relative positions of elements in the figures are not necessarily drawn to scale, and some of these elements have been arbitrarily enlarged and positioned to improve the legibility of the figures. Furthermore, the particular shapes of the depicted elements are not intended to convey any information regarding the actual shape of the particular elements, but have been selected solely for ease of recognition in the figures. [Brief description of the drawings]

[0014] [Figure 1] 1 shows the results of a Her2-negative cell proliferation assay in PC3. [Diagram 2] 1 shows the results of a Her2-negative cell proliferation assay in PC3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure. However, it will be understood by those skilled in the art that embodiments of the present disclosure may be practiced without these details. Unless the context requires otherwise, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in their open, inclusive sense, i.e., "including but not limited to." 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 those embodiments are included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout the 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.

[0016] "Amino" means -NH 2 Refers to the base. "Carboxy" means -CO 2 Refers to the H group. "Cyano" refers to the group -CN. "Formyl" refers to the group -C(=O)H. "Hydroxy" or "hydroxyl" refers to the group --OH. "Imino" refers to the group =NH. "Nitro" means -NO 2 Refers to the base. "Oxo" refers to the group ═O. "Sulfhydryl," "thiol," or "thio" refers to the --SH group. "Thioxo" refers to the group ═S. "Alkyl" means an alkyl group containing no unsaturation and having 1 to 12 carbon atoms (C 1 -C 12 alkyl), 1 to 8 carbon atoms (C 1 -C 8 alkyl) or 1 to 6 carbon atoms (C 1 -C 6 "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms attached to the remainder of the molecule by a single bond, such as 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.

[0017] "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. "Alkenylene" or "alkenylene chain" refers to a divalent straight or branched hydrocarbon chain, consisting only 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 specifically stated otherwise in this specification, alkenylene may be substituted.

[0018] "Alkynylene" or "alkynylene chain" refers to a divalent straight or branched hydrocarbon chain, consisting only 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, such as 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 this specification, alkynylene is optionally substituted. "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 R a , Rb and R c are each as defined for compounds of structure (I).

[0019] "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. "Heteroalkylene" refers to an alkylene group, as defined above, containing at least one heteroatom (e.g., Si, N, O, P, or S) within the alkylene chain or at a terminus of the alkylene chain. In some embodiments, the heteroatom is present within the alkylene chain (i.e., the heteroalkylene 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 alkylene and serves to attach the alkylene to the remainder of the molecule (e.g., M1-HA-M2, where M1 and M2 are part of the molecule, H is a heteroatom, and A is an alkylene). Unless stated otherwise specifically in the specification, heteroalkylene groups may be substituted. Exemplary heteroalkylene groups include ethylene oxide (e.g., polyethylene oxide), as well as the "C" and "HEG" linking groups shown below.

[0020] [ka] Various embodiments of heteroalkylene linkers include multimers of the C and HEG linkers described above. "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.

[0021] "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 O, N, P, and S, as well as multiple heteroatoms, such as those of the formula -P(O - )(=O)O- or -OP(O - )(=O)O-- and multimers, and combinations thereof. "Phosphate" means -OP(=O)(R a )R b Group (R a OH, O - OR c and R b OH, O - , OR c ), a thiophosphate group or a further phosphate group (R c refers to 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 + (e.g., phosphoalkyl groups). Unless otherwise specifically stated herein, phosphoalkyl groups 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.

[0022] "Phosphoalkyl ether" means -OP(=O)(R a )R b R refers to the group a OH, O - OR c and R bis -O alkyl ether, R c is the counter ion (e.g., Na + (e.g., phosphoalkyl ether groups). Unless otherwise specifically stated herein, a phosphoalkyl ether group may be substituted. For example, in certain embodiments, the -O alkyl ether portion of a phosphoalkyl ether group 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, R b OH, O - , S - , OR d or SR d and R c OH, SH, O - , S - , OR d , S.R. d , a phosphate group or a further thiophosphate group, R d is the counter ion (e.g., Na + etc.), where i) R a is S, and ii) R b is S - or SR d and iii) R c , SH, S - or SR d or iv) any combination of i), ii) and / or iii).

[0023] "Thiophosphoalkyl" means -OP(=R a )(R b )R c R refers to the group a is O or S, R b OH, O - , S - , OR d or SR d and Rc is -Oalkyl, and R d is a counter ion (e.g., Na+), where i) R a is S, and ii) R b is S - or SR d or iii) R a is S and R b is S - or SR d Unless otherwise specifically stated herein, a thiophosphoalkyl group may be optionally substituted. For example, in certain embodiments, the -Oalkyl portion in a thiophosphoalkyl group may be optionally substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether, or thiophosphoalkylether. "Thiophosphoalkyl ether" means -OP(=R a )(R b )R c R refers to the group a is O or S, R b OH, O - , S - , OR d or SR 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 SR d or iii) R a is S and R b is S - or SR dUnless otherwise specifically stated herein, a thiophosphoalkyl ether group may be substituted. For example, in certain embodiments, the -O alkyl ether portion of a thiophosphoalkyl group may be substituted with one or more of hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether.

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

[0025] "Aryl" refers to a ring system containing at least one carbocyclic aromatic ring. In some embodiments, an aryl contains 6 to 18 carbon atoms. The aryl ring may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aryl includes, but is not limited to, aryl derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated herein, an aryl group may be optionally substituted.

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

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

[0028] The suffix "-ene" refers to a particular structural feature (e.g., alkyl, aryl, heteroalkyl) that is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In other words, the suffix "-ene" refers to a particular structural feature having the description described herein that is a linker between the molecule and the radical group. The points of attachment of the "-ene" chain to the rest of the molecule and to the radical group can be through one atom or any two atoms within the chain. For example, alkyleneheteroalkylene refers to a linker that includes an alkylene portion and a heteroalkylene portion. "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. "Conjugation" refers to the overlap of one p orbital with another p orbital across an intervening sigma bond. Conjugation can occur in cyclic or acyclic compounds. "Degree of conjugation" refers to the overlap of at least one p orbital with another p orbital across an intervening sigma bond. For example, 1,3-butadiene has one degree of conjugation, while benzene and other aromatic compounds usually have multiple degrees of conjugation. Fluorescent and chromogenic compounds usually contain at least one degree of conjugation. "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.

[0029] "Colored" refers to molecules that absorb light within the color spectrum (ie, red, yellow, blue, etc.). "Linker" refers to a continuous chain of at least one atom, such as carbon, oxygen, nitrogen, sulfur, phosphorus, and combinations thereof, that connects one portion of a molecule to another portion of the same molecule, or to a different molecule, moiety, or solid support (e.g., a microparticle). The linker can be attached to the molecule through covalent bonds or other means, such as ionic or hydrogen bonding interactions. In some embodiments, the linker is a heteroatom linker (e.g., containing 1-10 Si, N, O, P, or S atoms), a heteroalkylene (e.g., containing 1-10 Si, N, O, P, or S atoms and an alkylene chain), or an alkylene linker (e.g., containing 1-12 carbon atoms). In some embodiments, the heteroalkylene linker has the following structure: [ka] (In the formula, x 9 and x 10 are each independently an integer greater than 0. In some embodiments, the heteroatom linker is -O-, -S-, or -OP(=O)O - In some embodiments, the heteroalkylene linker is -OP(=O)O - In some embodiments, the heteroalkylene linker comprises at least one S-S bond.

[0030] A "physiologically cleavable linker" refers to a molecular linking group that can be cleaved 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 ranging from about 20 to 40° C., atmospheric pressure of about 1 atm (101 kPa or 14.7 psi), pH of about 6 to 8, glucose concentration of about 1 to 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. "Solid support" or "solid resin" refers to any solid substrate known in the art for stationary phase support of molecules, for example, "microparticle" refers to any of a number of small particles useful for binding to compounds of the present disclosure, including, but not limited to, glass beads, magnetic beads, polymeric beads, non-polymeric beads, etc. In certain embodiments, the microparticle comprises a polystyrene bead. In some embodiments, the solid support or solid resin is controlled pore glass or macroporous polystyrene.

[0031] "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. The embodiments disclosed herein are also meant to encompass all compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) that are isotopically labeled by replacing one or more atoms 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.

[0032] Isotopically labeled compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) can generally be prepared by processes similar to those described below and in the Examples below, by conventional techniques known to those of skill in the art, using the appropriate isotopically labeled reagent in place of the previously utilized non-labeled reagent. "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. "Salt" includes both acid addition salts and base addition salts.

[0033] "Acid addition salts" include salts of inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and salts of 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, glutaric acid, and the like. It refers to salts formed with organic acids such as 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.

[0034] "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, caffeine, and the like. Crystallization can produce solvates of the compounds described herein (e.g., compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId)). The embodiments of the present disclosure include all solvates of the compounds described. As used herein, the term "solvate" refers to an aggregate that includes one or more molecules of a compound of the present disclosure and one or more solvent molecules. The solvent can be water, in which case the solvate can be a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present disclosure can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as the corresponding solvate forms. The compounds of the present disclosure may be true solvates, while in other cases the compounds of the present disclosure may merely retain incidental water or another solvent, or may be a mixture of water and some incidental solvent.

[0035] Compound embodiments of the present disclosure (e.g., compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), ((III), (IIIa), (IIIb), (IIIc), or (IIId)), or salts, tautomers, or solvates thereof, can contain one or more stereocenters, which can thus give rise to enantiomers, diastereomers, and other stereoisomers that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or, with respect to amino acids, (D)- or (L)-. Embodiments of the present disclosure are intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- are also possible. -, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative), for example, using chiral high pressure liquid chromatography (HPLC). Where the compounds described herein contain olefinic double bonds or other features giving rise to other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomers are also intended to be included.

[0036] "Stereoisomers" refers to compounds composed of the same atoms joined by the same bonds but having different three-dimensional structures and which cannot be interconverted. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. "Tautomer" refers to a proton transfer from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the above compounds. Various tautomers of the compounds can be easily derived by one skilled in the art.

[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, but is not limited to, RNA, DNA, oligonucleotides, modified or derivatized nucleotides, enzymes, receptors, prions, receptor ligands (including hormones), antibodies, antigens, and toxins, as well as bacteria, viruses, blood cells, and tissue cells. Visually detectable biomolecules of the present disclosure (e.g., compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) having a biomolecule linked thereto) are prepared by contacting a biomolecule with a compound as described above having a reactive group that allows for attachment 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.

[0038] 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. "Bioconjugation" or "bioconjugate" and related variations refer to a chemical reaction strategy that forms a stable covalent bond between two molecules. The term "bioconjugation" is commonly used when one of the molecules is a biomolecule (e.g., an antibody), but can be used to describe forming a covalent bond with a non-biomolecule (e.g., a polymeric resin). The product or compound resulting from such a reaction strategy is a "conjugate," "bioconjugate," or grammatical equivalent.

[0039] 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 strongly colored and have a chromaticity of preferably at least about 40,000, more preferably at least about 50,000, even more preferably at least about 60,000, even more preferably at least about 70,000, and most preferably at least about 80,000 M. -1 cm -1The compounds of the present disclosure can be detected by naked eye observation or by using optical-based detection devices, including, but not limited to, absorption spectrophotometers, transmitted light microscopes, digital cameras, and scanners. Visually detectable substances are not limited to those that emit and / or absorb light in the visible spectrum. Substances that emit and / or absorb light in the ultraviolet (UV) region (about 10 nm to about 400 nm), infrared (IR) region (about 700 nm to about 1 mm), and substances that emit and / or absorb in other regions of the electromagnetic spectrum are also included within the scope of "visually detectable" substances. For the purposes of the present disclosure, 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 disclosure include azo dyes, thioindigo dyes, quinacridone pigments, dioxazines, phthalocyanines, perinones, diketopyrrolopyrroles, quinophthalones, and triarylcarboniums.

[0040] The polymeric compounds of various embodiments of the present disclosure are useful in a wide variety of analytical applications, such as biochemical and biomedical applications, in which it is necessary to determine the presence, location, spatial interaction, or amount of a particular analyte (e.g., a biomolecule). Thus, in another aspect, the present disclosure provides a method of visually detecting a biomolecule, comprising: (a) providing to a biological system a visually detectable biomolecule, including a compound of the embodiments disclosed herein (e.g., a compound of structure ((I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId)), linked to the biomolecule; and (b) detecting the biomolecule by its visual properties. For purposes of this disclosure, the phrase "detecting a biomolecule by its visual properties" refers to the detection of a biomolecule by the naked eye, or by any method, including, but not limited to, an absorption spectrophotometer, a transmitted light microscope, a digital camera, and a scanner, without illumination or chemical or enzymatic activation. It means that the biological system is observed using an optically-based detection device that is visually detectable. Densitometers can be used to quantify the amount of visually detectable biomolecules present. For example, the relative amounts of biomolecules in two samples can be determined by measuring the relative optical density. If the stoichiometry of dye molecules per biomolecule is known and the extinction coefficient of the dye molecules is known, the absolute concentration of the biomolecule can also be determined from the optical density measurements. As used herein, the term "biological system" is used to refer to any solution or mixture that contains one or more biomolecules in addition to visually detectable biomolecules. Non-limiting examples of such biological systems include cells, cell extracts, tissue samples, electrophoretic gels, assay mixtures, and hybridization reaction mixtures.

[0041] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that such a description includes instances when the 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. The chemical naming protocols and structure diagrams used herein are a modification of the IUPAC nomenclature system using the ACD / Nomenclature version 9.07 software program and / or the ChemDraw Ultra version 11.0 software naming program (CambridgeSoft). Common names familiar to those skilled in the art are also used.

[0042] For ease of illustration, various compounds of structure (I) or (III) that contain a phosphorus moiety (e.g., phosphate, etc.) may be present in an anionic state (e.g., -OPO(OH)O - , -OPO 3 2- ) as a charge. One of ordinary skill in the art will readily appreciate that the charge is pH dependent, and that uncharged (e.g., protonated or salts such as sodium or other cations) forms are also included within the scope of embodiments of the present disclosure. compound As mentioned above, in one embodiment of the present disclosure, compounds are provided that are useful as covalent linkers between biologically active moieties and targeting moieties. In another embodiment, the inclusion of one or more biologically active moieties (e.g., gemcitabine) in the backbone of the compound is provided. In other embodiments, the inclusion of one or more fluorescent dyes in compounds that are useful as covalent linkers between biologically active moieties and targeting moieties is provided. Furthermore, the inclusion of one or more fluorescent dyes in compounds allows visualization of the region to which the compound is bound. 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.

[0043] Numerous advantages are provided by the embodiments disclosed herein, including the ability to control the number of biologically active moieties attached to the polymer and then to any targeting moiety, the ability to control the type of biologically active moiety attached to the polymer and then to any targeting moiety, the ability to control the number of fluorescent dye moieties attached to the polymer and then to any targeting moiety, and the ability to control the order of the fluorescent dye moieties and biologically active moieties attached 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 backbone composition, the side chains can be selected to provide a basis for adjusting the solubility of the compounds disclosed herein. The monomer units of the polymer can be selected to incorporate various anti-cancer therapeutic agents during and as post-synthetic modifications after polymer synthesis (e.g., coupling of amine pendants to the polymer backbone using therapeutic agents with activated ester moieties). The composition of the polymer backbone can also be selected to achieve desired fluorescence properties, for example, by controlling the incorporation of fluorescent dye moieties (eg, number, frequency, spacing, etc.).

[0044] That is, embodiments disclosed herein also provide compounds that can advantageously include multiple therapeutic agents, for example, for complimentary or synergistic therapeutic strategies. Furthermore, embodiments of the present disclosure provide combinations of therapeutic agents, targeting moieties, and dye moieties (e.g., chromophores or fluorophores) that can be used for simultaneous targeting, treatment, and detection. The ease of coupling the polymer-drug constructs to targeting agents such as antibodies, antibody fragments, proteins, or other agents of clinical interest provides utility for a wide range of applications of interest (e.g., surface chemistry, assay development, etc.). Thus, in some embodiments, M 1 is a chromophore or fluorophore (e.g., FITC, 5-FAM, 6-FAM, etc.), and M 2 and / or M 3 is a therapeutic agent (eg, a drug moiety such as auristatin F or SN38), and the compounds disclosed herein have a gemcitabine moiety embedded in the polymer backbone.

[0045] 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 compounds to penetrate diseased cells / tissues and to be retained within them. These characteristics allow for effective delivery of bioactive agents through enhanced permeability, and increased efficacy through enhanced retention. Thus, in some embodiments, the compound has the following structure (I): [ka] (I) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 1 is independently at each occurrence H, alkyl or alkoxy; R 2 and R 3are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c , Q or a protected form thereof, L′; R a is O or S; R b OH, SH, O - , S - , OR d or SR d and R c OH, SH, O - , S - , OR d , O.L.', S.R. d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counterion, R 4 are independently represented by OH, SH, and O for each occurrence. - , S - , OR d , or S.R. d and; R 5 is independently at each occurrence oxo or thioxo; R 6 and R 7 is independently at each occurrence H, OH, or halo, with the proviso that R 6 or R 7 at least one of is OH or halo; L 3 and L 10 is, independently for each occurrence, a linker; L 1 , L 2 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , and L 11may, independently at each occurrence, be a direct bond or a substituted linker; M 1 is, independently for each occurrence, absent or a moiety that contains a fluorescent dye; M 2 is, independently for each occurrence, a chromophore; M 3 is, independently for each occurrence, a moiety that comprises an anticancer therapeutic agent; Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety; L' is, independently at each occurrence, a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a linker that includes a covalent bond to a solid support, a linker that includes a covalent bond to a solid support moiety, a solid support moiety, a linker that includes a covalent bond to a nucleoside, or a linker that includes a covalent bond to an additional compound of structure (I); l, independently at each occurrence, is an integer greater than or equal to 1; m, independently at each occurrence, is an integer equal to or greater than zero; n is an integer equal to or greater than 1, At least one occurrence of p is an integer greater than or equal to 1, and each remaining p is either 0 or an integer greater than or equal to 1; q is, independently for each occurrence, an integer equal to or greater than zero.

[0046] In a more specific embodiment, the occurring L 1 , L 5 , or L 8 At least one of the occurrences of L is alkylene. 1 , L 5 , or L 8 At least one of is methylene. In a more specific embodiment, the occurring L 1 , L 5 , or L 8 At least one of the occurrences of L is heteroalkylene. 1 , L 5 , or L 8At least one of comprises an alkylene oxide. Further, in some embodiments, the alkylene oxide is ethylene oxide. For example, the ethylene oxide is polyethylene oxide. In some embodiments, R 2 is L'. In some other embodiments, L' is a linker to the targeting moiety.

[0047] In some more specific embodiments, L' is a linker to the targeting moiety, which linker comprises an alkylene oxide or a phosphodiester moiety, or a combination thereof. In certain embodiments, L' has the following structure: [ka] has one of the following: (In the formula, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 and x 8 are independently an integer from 1 to 10, R b is H, an electron pair or a counterion, L″ is a targeting moiety or a linking group to a targeting moiety.

[0048] In some embodiments, the targeting moiety is an antibody or a cell surface receptor antagonist. In some more specific embodiments, the antibody or cell surface receptor antagonist is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, a folate or a MET inhibitor.

[0049] In some embodiments, the targeting moiety is selected from the group consisting of abciximab, adalimumab, alemtuzumab, alirocumab, avibactam, basiliximab, benralizumab, bezlotoxumab, blinatumomab, brodalumab, burosumab, canakinumab, caplacizumab, certolizumab pegol, daclizumab, denosumab, dupilumab, eculizumab, emicizumab, erenumab, evolocumab, fremanezumab, galcanezumab, golimumab, guselkumab, ibalizumab, idarucizumab, infliximab, itolizumab, ixekizumab, lanadelumab, Loxivetomab, Mepolizumab, Natalizumab, Oviltoxaximab, Ocrelizumab, Omalizumab, Palivizumab, Ranibizumab, Raxibacumab, Reslizumab, Ramucirumab (Rmab), Rovelizumab, Ruplizumab, Sarilumab, Secukinumab, Tildrakizumab, Thiomab, Tocilizumab, Ustekinumab, Vedolizumab, Abrilumab, Actoxumab, Aducanumab, Afasevicumab, Afelimomab, Anifrolumab, Anrukinzumab (IMA-638), Acelizumab, Atorlimumab, Bapineuzumab, BCD-100, Bedolizumab Rutilimumab, besilesomab, biciromab, bimagrumab, bimekizumab, virutamimab, bleselumab, brosozumab, bococizumab, brazikumab, briakinumab, brolucizumab, carlumab, carotuximab, cedelizumab, clazakizumab, crenoliximab, concizumab, cosfrobiximab, CR6261, crenezumab, crizanlizumab, clotidumab, depatuxizumab, mafodotin, dellotuximab-biotin, desamizumab, dilidabumab, domagurozumab, dusigitumab, ecloneximab, edovacomab, efazolin, Lizumab, efungumab, eldelumab, elezanumab, enokizumab, eptinezumab, elizumab, etrolizumab, evinacumab, exbivirumab, fanolesomab, faralimomab, faricimab, fasinumab, felvizumab, fezakinumab, framvotumab, fretikumab, flotetuzumab, fontolizumab, foravirumab, frobocimab, furanumab, gantenerumab, gavilimomab, gevokizumab, gimsilumab, gomilikimab, goslanemab, ianalumab, inlacumab, inolimomab, Iomab-B, keliximab,Lampalizumab, Landgrozumab, Ralcaviximab, Lebrikizumab, Lenvervimab, Lerdelimumab, Letolizumab, Ribivirumab, Ligelizumab, Roderucizumab, Lulizumab pegol, Marstacimab, Mavrilimumab, Metelimumab, Mirikizumab, Motavizumab, Muromonab CD3, Nevacumab, Nemolizumab, NEOD001, nirsevimab, odulimomab, orendalizumab, olokizumab, OMS721, opicinumab, olticumab, otelixizumab, otilimab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, panobacumab, pascolizumab, pateclizumab, PDR001, perakizumab, pexelizumab, plakmab, prozac Lizumab, ponezumab, polgabiximab, prasinezumab, priliximab, PRO140, kirusumab, rafivirumab, ralpancizumab, ranevetomab, ravagalimab, ravulizumab, refanezumab, regavirumab, relatorimab, linukumab, risankizumab, loredumab, romosozumab, rontalizumab, SA237, satralizumab, sevi lumab, SHP647, sifalimumab, simtuzumab, siplizumab, sirukumab, solanezumab, sonepcizumab, spartalizumab, stamulumab, sulesomab, sputabumab, stimulimab, subizumab, sublatoxumab, tadocizumab, talizumab, tamtubetomab, tanezumab, tefibazumab, terimomab alitox (Telimomab aritox, teneliximab, teplizumab, teprotumumab, tezepelumab, tiburizumab, toralizumab, tralokinumab, trevoglumab, tuvilumab, urocuplumab, urtoxazumab, valisacumab, vepalimomab, besencumab, visilizumab, bovalilizumab, zolimomab aritox, trastuzumab, gemtuzumab, brentuximab, borsetuzumab, lorvotuzumab, cantuzumab, bivatuzumab, inotuzumab, or vadastuximab.

[0050] In some embodiments, R 2 or R3 has the following structure: [ka] [ka] has one of the following: (In the formula, R a is H or a solid support.

[0051] In some more specific embodiments, R 2 has the following structure: [ka] has one of the following:

[0052] Further, in some more specific embodiments, R 3 has the following structure: [ka] has.

[0053] In some embodiments, the compound has the following structure (Ia): [ka] (Ia) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, z, independently at each occurrence, is an integer from 1 to 10.

[0054] In some embodiments, R 5 are independently expressed as OH, O - OR d In some other embodiments, R 4 Each occurrence is oxo. In some embodiments, the compound has the following structure (Ib): [ka] (Ib) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, x a , x b , x c , x d , x e , and x f is, independently for each occurrence, an integer from 0 to 6.

[0055] In some more specific embodiments, the compound has the following structure (Ic): [ka] (I C) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 8 is independently at each occurrence O, NH, or NR e and; R 9 is independently at each occurrence H, alkyl, or may be substituted alkyl; R 10 is, independently at each occurrence, H or F; R e is, independently at each occurrence, alkyl or substituted alkyl.

[0056] In certain embodiments, m is an integer equal to zero. In some more specific embodiments, the compound has the following structure (Id): [ka] (Id) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof.

[0057] In some more specific embodiments, the compound has the following structure (Ie): [ka] (Ie) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof.

[0058] In some embodiments, the compound has the following structure (III): [ka] (III) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 1 is independently at each occurrence H, alkyl or alkoxy; R 2 and R 3 are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a )(R b )R c , Q or a protected form thereof, L′; R a is O or S; R b OH, SH, O - , S - , OR d or SR d and R c OH, SH, O - , S - , OR d , O.L.', S.R. d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counterion, R 4 are independently represented by OH, SH, and O for each occurrence. - , S - , OR d , or S.R. d and; R5 is independently at each occurrence oxo or thioxo; R 6 and R 7 is independently at each occurrence H, OH, or halo, with the proviso that R 6 or R 7 at least one of is OH or halo; L 3 and L 10 is, independently for each occurrence, a linker; L 1 , L 2 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , and L 11 may, independently at each occurrence, be a direct bond or a substituted linker; M 1 is, independently for each occurrence, a moiety that contains a fluorescent dye that is not present; M 2 is, independently for each occurrence, a chromophore; M 3 is, independently for each occurrence, a moiety that comprises an anticancer therapeutic agent; Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety; L' is, independently at each occurrence, a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a linker that includes a covalent bond to a solid support, a linker that includes a covalent bond to a solid support moiety, a solid support moiety, a linker that includes a covalent bond to a nucleoside, or a linker that includes a covalent bond to an additional compound of structure (I); l, independently at each occurrence, is an integer greater than or equal to 1; m, independently at each occurrence, is an integer equal to or greater than zero; n is an integer equal to or greater than 1, At least one occurrence of p is an integer greater than or equal to 1, and each remaining p is either 0 or an integer greater than or equal to 1; q is, independently for each occurrence, an integer equal to or greater than zero.

[0059] In some more embodiments, the compound has the following structure (IIIa): [ka] (IIIa) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof.

[0060] In some more specific embodiments, the compound has the following structure (IIIb): [ka] (IIIb) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, x a , x b , x c , x d , x e , and x f is, independently for each occurrence, an integer from 0 to 6.

[0061] In some more specific embodiments, the compound has the following structure (IIIc): [ka] (IIIc) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 8 is independently at each occurrence O, NH, or NR e and; R 9 is independently at each occurrence H, alkyl, or may be substituted alkyl; R 10 is, independently at each occurrence, H or F; R eis, independently at each occurrence, alkyl or substituted alkyl.

[0062] In some more specific embodiments, the compound has the following structure (IIId): [ka] (IIId) or a pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof.

[0063] Various linkers and substituents (e.g., M) in compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) can be used. 1 , M 2 , M 3 , Q, R 1 , R 2 , R 3 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , or L 11) may be substituted with another substituent. For example, in some embodiments, optional substituents are selected to optimize the water solubility or other properties of the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), ((III), (IIIa), (IIIb), (IIIc), or (IIId). In certain embodiments, each alkyl, alkoxy, alkyl ether, alkoxyalkyl ether, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, and thiophosphoalkyl ether in the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) may be substituted with another substituent selected from the group consisting of hydroxyl, alkoxy, alkyl ether, alkoxyalkyl ether, sulfhydryl, amino, alkylamino, carboxyl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, and thiophosphoalkyl ether.

[0064] In some embodiments, L 3 Or L 10 may, independently at each occurrence, be a direct bond or a substituted linker. In some embodiments, L 3 Or L 10 is independently at each occurrence an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatom linker. 3 Or L 10 is a linker that includes a functional group that can be formed by reaction of two complementary reactive groups (e.g., an azide and an alkyne). In some embodiments, L 3 Or L 10is independently at each occurrence optionally selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, alkyleneheteroarylenealkylene, alkyleneheterocyclylenealkylene, alkylenecarbocyclylenealkylene, heteroalkyleneheteroarylenealkylene, heteroalkyleneheterocyclylenealkylene, heteroalkylenecarbocyclylenealkylene, heteroalkyleneheteroaryleneheteroalkylene, heteroalkyleneheterocyclyleneheteroalkylene, heteroalkylenecarbocyclyleneheteroalkylene, alkyleneheteroaryleneheteroalkylene, alkyleneheterocyclyleneheteroalkylene, alkylenecarbocyclyleneheteroalkylene, heteroarylene, heterocyclylene, carbocyclylene, alkyleneheteroarylene, alkyleneheterocyclylene, heteroarylenealkylene, alkylenecarbocyclylene, carbocyclylenealkylene, heteroalkyleneheteroarylene, heteroalkyleneheterocyclylene, heteroaryleneheteroalkylene, heteroalkylenecarbocyclylene, carbocyclyleneheteroalkylene, or a heteroatom linker. 3 Or L 10 may be substituted.

[0065] In some embodiments, the linker L 3 Or L 10 is the M to the remainder of the compound 1 and M 3 In certain embodiments, L 3 Or L 10 In some embodiments, L is absent. 3 Or L 10 In some more specific embodiments, L 3 Or L 10 Each occurrence of L, if present, is independently alkylene or heteroalkylene. 3 Or L 10 In some more specific embodiments, at least one of the occurrences of L is heteroalkylene.3 Or L 10 At least one of the occurrences of L 3 Or L 10 At least one of the following structures: [ka] has. (In the formula, x 9 and x 10 are each independently an integer greater than 0)

[0066] In some embodiments, x 9 is 1, 2, 3, or 4. In certain embodiments, x 10 is 2, 3, 4, or 5. In some specific embodiments, x 9 is 1 or 2, and x 10 is 2, 3, or 4. In certain specific embodiments, L 3 Or L 10 Each occurrence of is heteroalkylene. In some more specific embodiments, L 3 Or L 10 Each occurrence of L includes oxygen. In certain more specific embodiments, L 3 Or L 10 For each occurrence, the following structure: [ka] has. (In the formula, x 9 and x 10 are each independently an integer greater than 0)

[0067] In some embodiments, x 9 is 1, 2, 3, or 4. In certain embodiments, x 10 is 2, 3, 4, or 5. In more specific embodiments, x 9 is 1 or 2, and x 10 is 2, 3, or 4. In certain other embodiments, the L 3 Or L10 At least one of the following structures: [ka] Includes. (In the formula, x 9 and x 10 are each independently an integer greater than 0)

[0068] In certain embodiments, L 3 Or L 10 In a more specific embodiment, the occurring L 3 Or L 10 At least one of the occurring L comprises an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence comprising one or more amino acid residues, a ketone, a diol, a cyano, a nitro, or a combination thereof. 3 Or L 10 At least one of the following structures: [ka] Contains one of the following:

[0069] In certain embodiments, L 3 Or L 10 Each occurrence of L includes an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence, a ketone, a diol, a cyano, a nitro, or a combination thereof. 3 Or L 10 For each occurrence, the following structure:

[0070] [ka] Contains one of the following:

[0071] In a more specific embodiment, the occurring L 3Or L 10 At least one of the following structures: [ka] has one of the following: In some specific embodiments, L 3 Or L 10 For each occurrence, the following structure: [ka] has one of the following:

[0072] In some embodiments, L 1 , L 5 , or L 9 At each occurrence, independently, comprises a phosphodiester. In certain embodiments, each occurrence of L 1 , L 5 , or L 9 In a more specific embodiment, at least one of the occurrences of L 1 , L 5 , or L 9 At least one of the following structures: [ka] Contains one of the following: (In the formula, g is an integer ranging from 1 to 10; z' is an integer ranging from 1 to 30.

[0073] In some of the foregoing embodiments, z' is 3, 6, or 11 to 28. In some embodiments, g is in the range of 2 to 5. In other more specific embodiments, each occurrence of L 1 , L 5 , or L 9 At least one of the following structures: [ka] Includes.

[0074] In certain embodiments, L1 , L 5 , or L 9 For each occurrence, the following structure: [ka] Includes.

[0075] In various other embodiments, R 2 and R 3 are each independently OH or -OP(=R a )(R b )R c In some different embodiments, R 2 or R 3 is OH or -OP(=R a )(R b )R c and R 2 or R 3 The other is a linker that includes a covalent bond to Q or Q. In some embodiments, R 2 and R 3 are each independently -OP(=R a )(R b )R c In some specific embodiments, R c is OL'. In some of these embodiments, L' is a heteroalkylene linker to Q, a targeting moiety, an analyte molecule, a solid support, a solid support residue, a nucleoside, or an additional compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), ((III), (IIIa), (IIIb), (IIIc), or (IIId). In some embodiments, L' comprises an alkylene oxide or phosphodiester moiety, or a combination thereof. In certain embodiments, L' has the following structure: [ka] has. (In the formula, m″ and n″ are independently an integer from 1 to 10; R e is H, an electron pair or a counterion, L” is Re or Q is a direct bond or linkage to a targeting moiety, an analyte molecule, a solid support, a solid support residue, a nucleoside, or a further compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId).

[0076] 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 (e.g., controlled pore glass or polystyrene beads). 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 a moiety that includes a reactive group capable of forming a covalent bond with a complementary reactive group, Q', on an additional compound of (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) (e.g., R 2 or R 3 and Q and Q' contain complementary reactive groups such that reaction of a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) occurs with a further compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) to result in a covalently linked dimer of a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId). Multimeric compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId), and combinations thereof, can also be prepared in an analogous manner and are included within the scope of embodiments of the present disclosure.

[0077] The type of Q group and its attachability to the remainder of a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) are not particularly limited, so long as Q contains a moiety that has the appropriate reactivity to form the desired bond. In certain embodiments, Q is a moiety that is not susceptible to hydrolysis under aqueous conditions, yet is sufficiently reactive to form a bond with a corresponding group on an analyte molecule (e.g., a biomolecule) or a solid support (e.g., an amine, azide, or alkyne). Certain embodiments of the compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), and / or (IIId) include a Q group commonly used in the field of bioconjugation. For example, in some embodiments, Q includes a nucleophilic reactive group, an electrophilic reactive group, or a cycloaddition reactive group. In some more specific embodiments, Q includes a sulfhydryl, a disulfide, an activated ester, an isothiocyanate, an azide, an alkyne, an alkene, a diene, a dienophile, an acid halide, a sulfonyl halide, a phosphine, an α-haloamide, a biotin, an amino, or a maleimide functional group. In some embodiments, the activated ester is an N-succinimide ester, an imido ester, or a polyflourophenyl ester. In other embodiments, the alkyne is an alkyl azide or an acyl azide. In some embodiments, Q comprises a maleimide functional group.

[0078] Exemplary Q moieties are shown in Table I below. [Table 1-1] [Table 1-2] [Table 1-3]

[0079] 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 on another compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId). Thus, some embodiments include compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) that are in the form of a disulfide dimer, with the disulfide bond coming from the SH Q group. In some other embodiments, R 2 Or R 3 One of the groups is OH or -OP(=R a )(R b )R c and R 2 Or R 3 the other is a linker comprising a covalent bond to the analyte molecule or a linker comprising a covalent bond to the solid support. For example, in some embodiments, the analyte molecule is a nucleic acid or polymer thereof, or an amino acid or polymer thereof. In other embodiments, the analyte molecule is an enzyme, a receptor, a receptor ligand, an antibody, a glycoprotein, an aptamer, or a prion. In yet other embodiments, the solid support is a polymeric bead or a non-polymeric bead. In some embodiments, the targeting moiety is an antibody or a cell surface receptor antagonist.

[0080] In certain specific embodiments, R 2 Or R 3 has the following structure: [ka] [ka] has one of the following:

[0081] In some embodiments, R 2 Or R 3 One of the groups is OH or -OP(=Ra )(R b )R c and R 2 Or R 3 The other has the following structure: [ka] Includes.

[0082] In some embodiments, the occurring M 3 At least one of is an alkylating agent, antimetabolite, microtubule inhibitor, topoisomerase inhibitor, or cytotoxic antibiotic. 3 are, by their occurrence, alkylating agents, antimetabolites, microtubule inhibitors, topoisomerase inhibitors, or cytotoxic antibiotics.

[0083] In certain embodiments, the occurring M 3 At least one of the occurring M is a nitrogen mustard, a nitrosourea, a tetrazine, an aziridine, cisplatin or a cisplatin derivative, or a non-classical alkylating agent. 3 At least one of is mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide, busulfan, N-nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU), semustine (MeCCNU), fotemustine, streptozotocin, dacarbazine, mitozolomide, temozolomide, thiotepa, mytomycin, diaziquone (AZQ), cisplatin, carboplatin, oxaliplatin, procarbazine, or hexamethylmelamine. 3 At least one of the occurring M 3At least one of is methotrexate, pemetrexed, fluorouracil, capecitabine, cytarabine, gemcitabine, decitabine, azacitidine, fludarabine, nelarabine, cladribine, clofarabine, pentostatin, thioguanine, and mercaptopurine. 3 At least one of the occurring M is an auristatin, a vinca alkaloid, or a taxane. 3 At least one of is auristatin F, auristatin E, vincristine, vinblastine, vinorelbine, vindesine, vinflunine, paclitaxel, docetaxel, etoposide, or teniposide. 3 At least one of is irinotecan, SN38, topotecan, camptothecin, doxorubicin, mitoxantrone, teniposide, novobiocin, mervalone, or aclarubicin. 3 At least one of the occurring M 3 At least one of the occurring M is doxorubicin, daunorubicin, epirubicin, idarubicin, pirarubicin, aclarubicin, or mitoxantrone. 3 At least one of is auristatin F, monomethylauristatin F, monomethylauristatin E, paciltaxol, SN-38, calicheamicin, anthramycin, aveimicin, ticamycin, DC-81, mazethramycin, neothramycin A, neothramycin B, polothramycin, prothracarcin, sivanomycin, sibiromycin, tomamycin, mertansine, emtansine, irinotecan, camptothecin, topotecan, ciratecan, cositecan, exatecan, rutotecan, gimatecan, belotecan, and rubitecan. 3are, by occurrence, auristatin F, monomethylauristatin F, monomethylauristatin E, paciltaxol, SN-38, calicheamicin, anthramycin, aveimicin, ticamycin, DC-81, mazethramycin, neothramycin A, neothramycin B, polothramycin, prothracarcin, sivanomycin, sibiromycin, tomamycin, mertansine, emtansine, irinotecan, camptothecin, topotecan, ciratecan, cositecan, exatecan, lutotecan, gimatecan, belotecan, and rubitecan.

[0084] In certain embodiments, the occurring M 3 At least one of the following structures: [ka] has. In some specific embodiments, M 3 For each occurrence, the following structure: [ka] has.

[0085] In certain embodiments, the -L 10 -M 3 At least one of the following structures: [ka] has.

[0086] In certain embodiments, -L 10 -M 3 For each occurrence, the following structure: [ka] has.

[0087] In certain embodiments, the occurring M 3 At least one of the following structures: [ka] has. In some specific embodiments, M 3 For each occurrence, the following structure: [ka] has.

[0088] In certain embodiments, the -L 10 -M 3 At least one of the following structures: [ka] has.

[0089] In certain embodiments, -L 10 -M 3 For each occurrence, the following structure: [ka] has.

[0090] In still other embodiments of any of the above, M 1 independently at each occurrence, includes two or more aryl or heteroaryl rings, or combinations thereof, such as three or more, or four or more aryl or heteroaryl rings, or combinations thereof, or even five or more aryl or heteroaryl rings, or combinations thereof. 1 independently at each occurrence, contains six aryl or heteroaryl rings, or a combination thereof. In further embodiments, the rings are fused. For example, in some embodiments, M 1 independently at each occurrence, includes 2 or more fused rings, 3 or more fused rings, 4 or more fused rings, 5 or more fused rings, or even 6 or more fused rings. 1 independently at each occurrence includes fused polycyclic aryl moieties that contain at least two fused rings.

[0091] In certain specific embodiments, M 1 is independently selected from the group consisting of 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, and ter-naphthyl moieties.

[0092] In some embodiments, M 1 is independently selected from the group consisting of p-terphenyl, perylene, azobenzene, phenazine, phenanthroline, acridine, thioxanthrene, chrysene, rubrene, coronene, cyanine, perylene imide, perylene amide, and derivatives thereof. 1 is independently selected from the group consisting of coumarin dyes, resorufin dyes, dipyrrometheneboron difluoride dyes, ruthenium bipyridyl dyes, thiazole orange dyes, polymethines, and N-aryl-1,8-naphthalimide dyes. 1 , M 2 , or M 3 is independently selected at each occurrence from the group consisting of coumarin dyes, boron dipyrromethenes, rhodamines, cyanines, pyrenes, perylenes, perylene monoimides, 6-FAM, 5-FAM, 6-FITC, 5-FITC, and derivatives thereof. 1 may, independently for each occurrence, have the structure: [ka] has one of the following:

[0093] In some more specific embodiments, the M 1At least one of the following structures: [ka] has.

[0094] In some more specific embodiments, M 1 For each occurrence, the following structure: [ka] has.

[0095] In some more specific embodiments, the -L 3 -M 1 At least one of the following structures: [ka] has.

[0096] In some more specific embodiments, -L 3 -M 1 For each occurrence, the following structure: [ka] has.

[0097] The compounds of the present disclosure (e.g., compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId)) are useful, in part, because they can be conjugated to a targeting molecule (e.g., an antibody or fragment thereof). Such conjugation can be accomplished by reducing the disulfide bond of a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) with a suitable reagent (e.g., TCEP) and coupling the resulting molecule to a suitable linker reagent (e.g., 1,1'-(ethane-1,2-diyl)bis(1H-pyrrole-2,5-dione), commonly known as bis-maleimidoethane or "BMOE"). The resulting product can then be coupled to a targeting molecule (eg, an antibody or fragment thereof) bearing a free thiol (-SH) group (eg, present via reduction of a disulfide bond in the targeting molecule).

[0098] Thus, in some embodiments, R 2 has the following structure: [ka] Includes. (In the formula, L a is a direct bond or C 1 -C 6 In some embodiments, L is alkylene. a is a direct bond)

[0099] In some embodiments, R 2 further comprises a covalent bond to an antibody (e.g., a monoclonal antibody such as brentuximab, gemtuzumab, trastuzumab, inotuzumab, polatuzumab, enfortumab, trastuzumab, sacituzumab, belantamab, moxetuzumab, etc.) or a fragment thereof. For example, in some embodiments, R 2 has the following structure: [ka] Includes. (In the formula, A is an antibody (e.g., a monoclonal antibody, such as brentuximab, gemtuzumab, trastuzumab, inotuzumab, polatuzumab, enfortumab, trastuzumab, sacituzumab, belantamab, or moxetumomab). a is a direct bond. In some embodiments, R 2 has the following structure: [ka] has. (In the formula, x 13 is 0 or an integer greater than 0 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12)

[0100] In some embodiments, the compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) have m between 0 and 10. In certain embodiments, the compounds of structure (I), (Ia), (Ib), (Ic), (Id), or (Ie) have m between 0, 1, 2, 3, 4, or 5. In some embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) has n=1, 2, 3, or 4. In certain embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) has n=1 or 2.

[0101] In some embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) has p=1, 2, 3, or 4. In certain embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) has p=1 or 2. In some more specific embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) has m 0, n 1, and p 2. In some more specific embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) has m 1, n 1, and p 2. In some more specific embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) has m 5, n 1, and p 2.

[0102] In some more specific embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is 6 or R 7 is F. In certain embodiments, a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) has at least one occurrence of R 6 and R 7 Each of these is F. In some more specific embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is 6 or R 7 At least each of is F and R 8is O and R 9 is H and R 10 is H. In some more specific embodiments, the compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) are 6 or R 7 is H, and at least each of R 8 is O and R 9 is C(=O)OCH 2 CH 2 CH 2 CH 2 CH 3 and R 10 is F.

[0103] In some more specific embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is x a , x b , x c , x d , x e , and x f is, independently at each occurrence, an integer of 0 or 1. In some more specific embodiments, the compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) have q being 0 or 1. In some embodiments, a method of treating a disease or disorder is disclosed, comprising administering a therapeutically effective amount of a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId), or a pharmaceutical composition of a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) to a subject in need thereof. In some more specific embodiments, the disease or disorder is cancer, including breast cancer, gastric cancer, lung cancer, ovarian cancer, lymphoma, and bladder cancer. In some embodiments, a compound of structure (III) has a switched auristatin F moiety (labeled "AF") and a gemcitabine moiety compared to structures (I), (Ia), (Ib), (Ic), or (Id). For example, a compound of structure (III) with a switched AF and gemcitabine moieties is shown in Table 2 as compound I-13 and can be prepared according to the procedures described in this disclosure. In some specific embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is a compound selected from Table 2. The compounds of Tables 2 and 3 were prepared according to the procedures described in the Examples. [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]

[0104] Pharmaceutical Compositions One embodiment provides a composition comprising a compound according to any one of the embodiments disclosed herein (e.g., a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId)) and a pharma- ceutically acceptable carrier. Other embodiments are directed to pharmaceutical compositions. The pharmaceutical compositions include any one (or more) of the compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical compositions are formulated for oral administration. In other embodiments, the pharmaceutical compositions are formulated for injection. In further embodiments, the pharmaceutical compositions include the compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) 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.

[0105] In certain embodiments, the compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) 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, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and selectively taken up by the organ. In yet other embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is provided in the form of an immediate release formulation, a sustained release formulation, or an intermediate release formulation. In yet other embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is administered locally.

[0106] The compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) are effective over a wide dosage range. For example, in the treatment of adult humans, dosages of 0.01-1000 mg per day, 0.5-100 mg per day, 1-50 mg per day, and 5-40 mg per day are examples of dosages that may be used in certain embodiments. An exemplary dosage is 10-30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the weight of the subject being treated, and the preference and experience of the attending physician. In some embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is administered in a single dose. Typically, such administration will be by injection, for example intravenous injection, to rapidly introduce the drug. However, other routes may be used if appropriate. A single dose of the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) may also be used to treat acute conditions.

[0107] In some embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is administered in multiple doses. In some embodiments, administration is about once, twice, three times, four times, five times, six times, or more per day. In other embodiments, administration is about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) and another agent are administered together about once a day to about six times a day. In other embodiments, administration of compounds and agents of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) continues for less than about 7 days. In yet other embodiments, 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.

[0108] Administration of a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) may be continued for as long as necessary. In some embodiments, a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is administered continuously over an extended period of time, e.g., for long-term acting treatment. In some embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is administered at a dosage. It is known in the art that due to subject-to-subject variability in the pharmacokinetics of compounds, individualization of dosing regimens is necessary for optimal treatment. Dosing for the compounds of the present disclosure can be found by routine experimentation in light of the present disclosure.

[0109] In some embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is formulated into a pharmaceutical composition. In a specific embodiment, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants, that facilitate the processing of the active compound into a medicament that can be used. The appropriate 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).

[0110] Provided herein is a pharmaceutical composition comprising a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) and a pharma- ceutically acceptable diluent, excipient, or carrier. In certain embodiments, the described compounds are administered as pharmaceutical compositions in which the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is mixed with other active ingredients, as in combination therapy. All combinations of active agents described in the combination therapy section below and throughout this disclosure are encompassed herein. In specific embodiments, the pharmaceutical composition comprises one or more compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId).

[0111] Pharmaceutical composition, as used herein, refers to a mixture of a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) 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 carrying out the methods of treatment or methods of use provided herein, a therapeutically effective amount of a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) provided herein is administered in a pharmaceutical composition to a mammal having a disease, disorder, or medical condition to be treated. In a specific embodiment, the mammal is a human. In certain embodiments, the therapeutically effective amount 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. Compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) are used alone or in combination with one or more therapeutic agents, as components of mixtures. In one embodiment, one or more compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) 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), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) 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.

[0112] In another embodiment, the compounds described herein are formulated for oral administration.The compounds described herein are formulated by combining the active compound with, for example, a pharma- ceutically acceptable carrier or excipient.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, and the like. In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and then processing the mixture of granules to obtain tablet or dragee cores, after adding suitable auxiliary agents, in particular.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 may be added.Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or its salts, such as sodium alginate.

[0113] In one embodiment, dosage forms such as dragee cores and tablets are provided with one or more suitable coatings. In a specific embodiment, concentrated sugar solutions are used to coat the dosage forms. The sugar solutions 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. For identification purposes, dyes and / or pigments may be added to the coating. Furthermore, dyes and / or pigments may be utilized to characterize different combinations of active compound doses.

[0114] In certain embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. In a specific embodiment, 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.

[0115] In other embodiments, a therapeutically effective amount of at least one of the compounds described herein is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In 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 structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId)) 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.

[0116] In yet another embodiment, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is administered topically. The compounds described herein are formulated into various compositions that can be administered topically, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compositions may contain solubilizers, stabilizers, tonicity enhancers, buffering agents, and preservatives. In yet other embodiments, the compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) are formulated for transdermal administration. In specific embodiments, the transdermal formulations can be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in polymers or adhesives using transdermal delivery devices and transdermal delivery patches. In various embodiments, such patches are constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents. In additional embodiments, transdermal delivery of the compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is achieved by iontophoretic patches, and the like. In certain embodiments, the transdermal patch provides controlled delivery of the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId). In specific embodiments, the absorption rate is slowed by using a rate-controlling membrane or by trapping the compound within a polymer matrix or gel. In alternative embodiments, an absorption enhancer is used to increase absorption. The absorption enhancer or carrier comprises an absorbable pharma- ceutically acceptable solvent that aids 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 (which may include a carrier) containing the compound, 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 fixing the device to the skin.

[0117] In other embodiments, the compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is 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 compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) 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 of, 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.

[0118] In yet other embodiments, the compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) are formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG, etc. Suppository forms of the composition may contain a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, which may be combined with melted cocoa butter. In certain embodiments, the pharmaceutical composition is formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries, which facilitate the processing of the active compound into a medicament that can be used pharma- ceutically. The appropriate formulation depends on the route of administration selected. Any pharma- ceutically acceptable techniques, carriers, and excipients may be used, if appropriate. Pharmaceutical compositions containing compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) are prepared in a conventional manner, such as by conventional mixing, dissolving, granulating, dragee making, wet milling, emulsifying, encapsulating, entrapping, or compressing processes, by way of example only.

[0119] 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), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) 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. In addition, the pharmaceutical compositions may contain other medicinal or pharmaceutical agents, carriers, preservatives, stabilizing agents, wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure, adjuvants such as buffers, and / or substances of therapeutic value.

[0120] Methods for preparing compositions containing the compounds described herein include formulating the compounds with one or more inert pharma- ceutically acceptable excipients or carriers to form solids, semi-solids, or liquids. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The forms of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to use, or emulsions. These compositions may also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like. In some embodiments, the pharmaceutical composition comprising at least one compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) is 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.

[0121] In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulose polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein include mucoadhesive polymers, e.g., selected from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran. Useful pharmaceutical compositions may also include solubilizing agents that aid in the dissolution of the compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId). 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.

[0122] In addition, useful pharmaceutical compositions may include 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. Further useful compositions may also contain one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions, with suitable salts including sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0123] Other useful pharmaceutical compositions may include 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 non-ionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil, and polyoxyethylene alkyl ethers and alkyl phenyl ethers, such as octoxynol 10, octoxynol 40. Still other useful compositions optionally contain one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite. In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case it is customary to include a preservative in the composition.

[0124] 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 the therapeutic reagent, additional strategies for protein stabilization are used. 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.

[0125] In some embodiments, the concentration of the 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.

[0126] 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 greater than 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.

[0127] 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 within 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.

[0128] 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.

[0129] 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 ranges from 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0130] Treatment Certain compounds of the present disclosure are useful for treating diseases (i.e., compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId)). The compounds disclosed herein provide a targeted approach to drug delivery strategies. Thus, in one embodiment, a method of treating a disease (or a symptom thereof) is provided comprising administering to a mammal (e.g., a human) in need thereof a therapeutically effective amount of a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId). 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.

[0131] In some of the foregoing embodiments, the disease is cancer. For example, in certain embodiments, the cancer is breast cancer, non-Hodgkin's lymphoma, acute myeloid leukemia, multiple myeloma, gastric cancer, renal cell carcinoma, solid tumors, ovarian cancer, prostate cancer, colorectal cancer, pancreatic cancer, small cell lung cancer, diffuse large B-cell lymphoma, neoplasms, urothelial carcinoma, ALL, CLL, glioblastoma, Hodgkin's lymphoma, lymphoma, mesothelioma, non-small cell lung cancer, recurrent head and neck cancer, or a combination thereof.

[0132] 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 of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId), or a pharma- ceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.In some embodiments, the method is directed to 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 cancer Cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of unknown primary, midline canal carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma 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, paraneoplastic syndrome, For the treatment of cancers such as ganglionoma, 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)).

[0133] 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 compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) above (or a pharmaceutical composition 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 cancer. Other lung cancers treatable by the disclosed compounds include, but are not limited to, adenoma, carcinoid tumor, and undifferentiated carcinoma.

[0134] Thus, in some embodiments of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId), A is an antibody or a cell surface receptor antagonist, such as an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, a folate, a MET inhibitor, or an antibody such as trastuzumab. In a further embodiment, the method further comprises inducing apoptosis. 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. Additional therapeutic agents that can be combined with the compounds of the present disclosure can be found in "The Pharmacological Basis of Therapeutics," 10th Edition, by Goodman and Gilman, edited by Hardman, Limbird and Gilman, or the Physician's Desk Reference, both of which are incorporated herein by reference in their entireties.

[0135] The compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId) described herein can be used in combination with the agents disclosed herein or other suitable agents depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered simultaneously or separately with the second agent. This combined administration can include co-administration of the two agents in the same dosage form, co-administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the agents described above can be formulated together in the same dosage form and administered at the same time. Alternatively, the compounds of the present disclosure and any of the agents described above can be administered at the same time, with both agents being in separate formulations. In another alternative, any of the agents described above can be administered immediately after administration of the compounds of the present disclosure, or vice versa. In some embodiments of the separate administration protocol, a compound of the disclosure and any of the agents described above are administered minutes apart, or hours apart, or days apart.

[0136] In some embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of an anti-tumor agent, an enediyne anti-tumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and an EGFR inhibitor or alkylating agent, and combinations thereof. In some more specific embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of an anti-tumor agent, an enediyne anti-tumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and an EGFR inhibitor or alkylating agent, and combinations thereof. In certain embodiments, the additional therapeutic agent comprises auristatin F, monomethylauristatin F, monomethylauristatin E, paciltaxol, SN-38, calicheamicin, anthramycin, aveimicin, ticamycin, DC-81, mazethramycin, neothramycin A, neothramycin B, polothramycin, prothracarcin, sivanomycin, sibiromycin, tomamycin, mertansine, emtansine, irinotecan, camptothecin, topotecan, ciratecan, cositecan, exatecan, lutotecan, gimatecan, belotecan, and rubitecan.

[0137] The examples and preparations provided below further describe and illustrate the compounds of the present disclosure and the methods of preparing such compounds. It should be understood that the scope of the present disclosure is in no way limited by the scope of the following examples and preparations. In the following examples and throughout the specification and claims, molecules and moieties that have a single stereocenter are present as racemic mixtures unless otherwise specified. Molecules and moieties that contain two or more stereocenters are present as racemic mixtures of diastereomers unless otherwise specified. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art. For ease of illustration, various compounds that contain phosphorus moieties (e.g., phosphate, etc.) can be present in an anionic state (e.g., -OPO(OH)O - , -OPO 3 2- ) as a charge. One of ordinary skill in the art will readily appreciate that the charge is pH dependent, and that uncharged (e.g., protonated or salts such as sodium or other cations) forms are also included within the scope of embodiments of the present disclosure. Compositions comprising any of the above-mentioned compounds and one or more analyte molecules (e.g., biomolecules) are provided in various other embodiments. In some embodiments, the use of such compositions in analytical methods for detecting one or more analyte molecules is also provided.

[0138] In some embodiments of the aforementioned method, R 2 is a linker that includes a covalent bond to an analyte molecule, such as a biomolecule. For example, a nucleic acid or polymer thereof, or an amino acid or polymer thereof (e.g., a polynucleotide or a polypeptide). In further embodiments, the biomolecule is an enzyme, a receptor, a receptor ligand, an antibody, a glycoprotein, an aptamer, or a prion. In yet another embodiment of the aforementioned method, R 2 is a linker that includes a covalent bond to a solid support, such as a microparticle (e.g., a controlled pore glass or polystyrene bead). For example, in some embodiments, the microparticle is a polymeric or non-polymeric bead. In addition to the methods described above, embodiments of compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), and (IIId) find utility in a variety of fields and methods, including, but not limited to, imaging for the identification of cancerous and other tissues in endoscopic procedures; single cell and / or single molecule analytical methods, e.g., detection of polynucleotides with little or no amplification; cancer imaging, e.g., by conjugating compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), and (IIId) to antibodies or sugars or other moieties that preferentially bind to cancer cells; imaging in surgery; histone binding for the identification of various diseases; drug delivery in dental and other procedures.

[0139]

[0033] Embodiments of the compounds of structures (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), and (IIId) above, and the variable factor R in the compounds of structures (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), and (IIId) above, 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 , M 1 , M 2 , M 3 It is understood that any specific choices described herein for l, m, n, p, and / or q may be independently combined with other embodiments and / or variables of the compounds of structures (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), and (IIId) to form embodiments of the disclosure not specifically set forth above. Additionally, the list of choices may be combined with any specific R in a particular embodiment and / or claim. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 , M 1 , M 2 , M3 , l, m, n, p, and / or q variables, it is understood that each individual selection may be excluded from the scope of a particular embodiment and / or claim, and that the remaining listing of selections is considered to be within the scope of the 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.

[0140] It will also be appreciated by those skilled in the art that in the processes described herein, the functional groups of intermediate compounds may need to be protected with 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 one of skill in the art will appreciate, these protecting groups can also be polymeric resins such as Wang resin, Rink resin, or 2-chlorotrityl chloride resin.

[0141] Additionally, all compounds of the present disclosure that exist in free base or free acid form can be converted to their salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of compounds of the present disclosure can be converted to their free base or acid form by standard techniques. The following reaction schemes illustrate exemplary methods for making the compounds of the present disclosure. It is understood that those skilled in the art may be able to make these compounds by similar methods or by combining other methods known to those skilled in the art. It is also understood that those skilled in the art may be able to make other compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc) and (IIId) that are not specifically exemplified below by similar methods as described below, by using appropriate starting components and modifying synthesis parameters as necessary. In general, the starting components can be obtained from 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 in the present disclosure.

[0142] DNA synthesis methodology can be applied to construct compounds of structures (I) and (III). Monomers (e.g., phosphoramidite monomers) can be purchased commercially (e.g., from ChemGenes Corporation, Wilmington Mass.) or can be synthesized using methods described herein (see, e.g., Examples 1-3). Introduction of the desired moiety can be achieved during the DNA synthesis process by including the desired moiety as part of the monomer (e.g., G of General Reaction Scheme I).1 (See, for example.) An exemplary DNA synthesis scheme is shown below.

[0143] A typical DNA synthesis cycle [ka]

[0144] Oligomerization is usually initiated by removing a protecting group (e.g., dimethoxytrityl group, DMTr) to reveal a free -OH (hydroxyl) group (step 1, detritylation). In a subsequent coupling step, a phosphoramidite monomer is introduced which reacts with the free OH group to form a new covalent bond with phosphorus with concomitant loss of a diisopropylamine group (step 2, coupling). The resulting phosphite triester (e.g., I 2 and pyridine) to the more stable phosphate ester (step 3, oxidation), and a capping step renders the remaining free OH group unreactive (step 4, capping). The new product, the phosphate oligomer, contains a DMTr-protected OH group that can be deprotected to restart the synthesis cycle, thus allowing another phosphoramidite monomer to be added to the oligomer. Customization is performed in step 2 by the selection of phosphoramidite monomers. The nature of L (i.e., linker group) and M (i.e., chemotherapeutic agent) in the above scheme are selected to synthesize the desired compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), and (IIId). M may be absent to incorporate the desired spacing between the M moieties. One skilled in the art can select multiple monomer types and vary the linker group simultaneously to arrive at compounds of the present disclosure containing multiple therapeutic agents and / or other moieties (e.g., fluorophores or chromophores).

[0145] General reaction scheme 1 (phosphoramidites) [ka]

[0146] Reaction Scheme I illustrates a method for the preparation of a phosphoramidite intermediate useful for the preparation of a compound of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), or (IIId). Referring to Reaction Scheme I, G 1 represents the desired moiety containing a carboxylic acid functionality (e.g., a drug moiety such as auristatin F, gemcitabine, capecitabine, or SN38), L represents a divalent linker moiety (e.g., alkylene, or alkylene ether), X represents a leaving group (e.g., halo, such as Cl), and PG represents a protecting group (e.g., 4,4'-dimethoxytriphenylmethyl). Step 1 of Reaction Scheme I begins with activation of the carboxylic acid functionality of the first compound shown using known reagents under basic conditions (e.g., HATU and DIPEA in DMF). The activated acid is then reacted with an amine to provide the reaction product of step 1. The resulting diol is then protected under standard conditions (e.g., 4,4'-dimethoxytriphenylmethyl chloride and pyridine). Diols such as gemcitabine begin with step 2. The protected product is then reacted with 3-((chloro(diisopropylamino)phosphanyl)oxy)propanenitrile (or other appropriate reagent) to provide the desired compound of structure (II) shown above.

[0147] The resulting compound of structure (II) can then be used to synthesize the desired compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), and (IIId) by reaction under well-known (automated) DNA synthesis conditions. In addition to the compound of structure (II), additional repeat units can be incorporated to achieve the final compounds of structure (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), and (IIId). Generally, the following structures are used:

[0148] [ka] Compounds having the formula: (In the formula, L is a desired linker moiety (e.g., including PEG or a dye-containing moiety).

[0149] In some specific embodiments, the synthesis of compounds of structures (I), (Ia), (Ib), (Ic), (Id), (Ie), (III), (IIIa), (IIIb), (IIIc), and (IIId) may include the following compounds: [ka] can be used. EXAMPLES

[0150] General method Mass spectral analysis was performed on a Waters / Micromass Quattro micro MS / System MS (MS mode only) using MassLynx 4.1 acquisition software. The mobile phase used for LC / MS was 100 mM 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), 8.6 mM triethylamine (TEA), pH 8. Phosphoramidites and precursor molecules were also analyzed using an acetonitrile / water mobile phase gradient held at 45° C. on a 2.1 mm x 50 mm Acquity BEH-C. 18 The analysis is performed using a Waters Acquity UHPLC system equipped with a 1000 .mu.m column. The molecular weights of the monomer intermediates are obtained on a Waters / Micromass Quattro micro MS / system MS (MS mode only) using tropylium cation injection enhanced ionization. Excitation and emission profile experiments are recorded on a Cary Eclipse spectrophotometer.

[0151] All reactions are carried out in oven-dried glassware under a nitrogen atmosphere unless otherwise noted. Commercially available 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.

[0152] Example 1 Synthesis of DMT-protected gemcitabine compounds [ka]

[0153] Gemcitabine (0.5057 mmol theoretical) is added to a dry round-bottom flask under an inert gas blanket containing a magnetic stir bar, followed by anhydrous pyridine (5.06 mL). The reaction flask is then transferred to an ice-water bath (0° C.) and allowed to cool with mixing until homogenized (approximately 10 min). 4,4'-dimethoxytrityl chloride (0.257 g, 0.759 mmol) is then added to the cooled mixture with continuous mixing under inert gas. The reaction mixture is allowed to warm to room temperature and then sampled for TLC analysis. Once the reaction is confirmed to be complete, any remaining unreacted 4,4'-dimethoxytrityl chloride is quenched by adding methanol to the reaction mixture (0.160 g, 5.06 mmol). The solvent is removed by rotary evaporation under vacuum (10 mbar) and with heating (55° C.). The concentrated residue is then suspended in toluene (5.06 mL) and the toluene is removed by rotary evaporation under vacuum (10 mbar) and heating (55° C.); repeat twice. The crude product is dissolved in dichloromethane (5.06 mL), washed with sodium bicarbonate (5.06 mL, saturated aqueous solution) and separated. This process is repeated once. The separated organic phase is washed with sodium chloride (5.06 mL, saturated aqueous solution) and separated. The separated organic phase is dried over anhydrous sodium sulfate and the sodium sulfate is filtered off. The product containing organic phase is sampled for TLC and LC-UV / MS analysis. The solvent is removed by rotary evaporation to obtain crude DMT-protected gemcitabine.

[0154] This crude material is then combined with the crude material from the small scale pilot reaction. The combined crude material is purified by silica gel flash chromatography, dichloromethane / methanol mobile phase, product-containing fractions are pooled, the solvent is removed by rotary evaporation, and then placed on a vacuum line for at least 24 hours to give DMT-protected gemcitabine.

[0155] Example 2 Synthesis of DMT-protected gemcitabine phosphoramidites [ka]

[0156] Purified DMT-protected gemcitabine (0.226 mmol), dried under vacuum for at least 24 hours, is dissolved in dichloromethane (2.26 mL) under an inert gas blanket, containing a magnetic stir bar, followed by the addition of DIPEA (0.117 g) followed by Cl-Phos (0.107 g). The reaction is mixed for approximately 15 minutes and then sampled for TLC analysis (TLC indicated completion of the reaction). Once the reaction is confirmed to be complete, the reaction mixture is washed by adding directly to sodium bicarbonate (2.26 mL, saturated aqueous solution), the organic phase is separated, and this is repeated once. The organic phases are combined and dried over anhydrous sodium sulfate, and the sodium sulfate is then filtered off. The product containing organic phase is sampled for TLC and LC-UV / MS analysis. The dichloromethane is then removed by rotary evaporation and proceeded to purification without crude weight. This crude material is then combined with the crude material from the small scale pilot reaction. The combined crude material is purified by silica gel solid phase extraction, dichloromethane / methanol / triethylamine mobile phase, and product-containing fractions are pooled. The mobile phase is removed by rotary evaporation, then placed on a vacuum line for at least 24 hours to obtain the DMT-protected gemcitabine phosphoramidite. Alternatively, the DMT-protected gemcitabine phosphoramidite can be purchased from Glen Research and used as is without further purification.

[0157] Example 3 Synthesis of Compound I-1 Preparation of stock solutions Borate buffer prepared at 250 mM, pH 10 Fluorescein-NHS solution prepared at 350 mM (300 mg in 1.35 mL DMSO:acetonitrile 25:75) solid phase synthesis Compound I-1 is prepared on a DNA synthesizer using standard DNA synthesis techniques (i.e., DMT-protected 2-cyanoethyl phosphoramidite) on a solid support. The polymer is removed from the solid support with ammonium hydroxide and lyophilized to a paste. A 250 mg aliquot is reconstituted in water. A small aliquot is removed and reconstituted in 100 mM NaCO, pH 9 to determine concentration (A263ε=10,000). 3 Prepare serial dilutions in 100 mM NaCl. The final stock concentration is found to be 14.5 mM.

[0158] Dye Coupling Reaction In a 50 mL centrifuge tube equipped with a magnetic stir bar, add water (1.110 μL), borate buffer (1.800 μL), compound I-1 polymer solution (466 μL), acetonitrile (137.5 μL), triethylamine (313 μL), and fluorescein-NHS solution (675 μL). Wrap the tube in aluminum foil and stir the mixture at room temperature overnight. Size Exclusion Filtration Add 1 mL of water to an Amicon Ultra-15 centrifugal filter (Millipore UFC900324, molecular weight cutoff = 3000). Add the crude reaction mixture (4.5 mL) from the dye coupling reaction to the filtration apparatus. Rinse the reaction vessel twice with 4 mL of 100 mM NaOH and transfer the rinse to the filtration apparatus. Centrifuge the filtration apparatus at maximum speed (3220 g, swinging bucket, 30 min). Remove the filtrate and treat the retentate with an additional 10 mL of 100 mM NaOH. Centrifuge the filtration apparatus as before. Remove the filtrate again and add a third 10 mL aliquot of 100 mM NaOH to the retentate. Centrifuge the apparatus as before and remove the filtrate. Add a fourth 10 mL aliquot of 100 mM NaOH to the retentate and centrifuge as before. Remove the filtrate and add 10 mL of water to the filtration apparatus. Centrifuge the mixture as before. The retentate is removed and the filter vessel is washed with water and rinse is added to final volume (3.5 mL). The desired product is confirmed by LC-MS and the concentration is determined using absorbance.

[0159] analyticalLC-UV 495nm The chromatogram showed 62% of the target product I-2 by total peak area or related peak areas identified by MS (given expected molecular weight of 10755.1 and observed molecular weight of 70760.7). analyticalLC-UV 495nm The chromatogram showed 65% of the target product I-6 by total peak area or related peak areas identified by MS (expected molecular weight 5730.7 and observed molecular weight 5734.1). analyticalLC-UV 266nm The chromatogram showed 22% of the target product I-10 by total peak area or related peak areas identified by MS (given expected molecular weight of 8722.8 and observed molecular weight of 8730.1). analyticalLC-UV 266nm The chromatogram showed 59% of the target product I-4 by total peak area or related peak areas identified by MS (given expected molecular weight of 4818.9 and observed molecular weight of 4822.1).

[0160] Example 4 Activation of Compound I-1 and Antibody Conjugates [ka]

[0161] Maleimide-functionalized compound I-1 is prepared according to the method described in Example 1. In parallel, trastuzumab antibody is treated with bis-maleimidoethane ("BMOE") to reduce disulfide bonds. The reduced antibody is reacted with compound I-1 at a polymer to antibody molar ratio of 5:1. This reaction results in a final product with a polymer to antibody ratio of 1:1, as detected by size exclusion chromatography. In some embodiments, anti-CD33, anti-CD70, or anti-CD123 can be used with bismaleimidoethane ("BMOE") to reduce disulfide bonds. I-2, I-6, and I-9 ADCs are prepared according to the procedure in Example 4 and are shown below:

[0162] Compound I-9ADC [ka] Compound I-6ADC [ka] Compound I-2ADC [ka] Other compounds disclosed herein (I-1, I-3 to I-5, I-7 to I-8, and I-10 to I-22) can be conjugated to antibodies by the same methods described above to generate other ADCs. The antibody trastuzumab is used in Example 4 to demonstrate conjugation between the compounds disclosed herein and antibodies, but this is used for illustration purposes only and other antibodies may be included, such as brentuximab, gemtuzumab, trastuzumab, inotuzumab, polatuzumab, enfortumab, trastuzumab, sacituzumab, belantamab, or moxetuzumab.

[0163] Example 5 Cell proliferation assay Compounds I-2, I-6, and I-9 were prepared on a DNA synthesizer as disclosed in this disclosure. Compounds I-2, I-6, and I-9 were activated and conjugated to the commercially available antibody trastuzumab. As shown in Figures 1-2, compound I-2 ADC (labeled "ADC:073-128-R3a") was more potent and cytotoxic than other ADCs (I-9 ADC labeled "ADC:073-128-R1" and I-6 ADC labeled "ADC:073-128-R2") and its constituent moieties including auristatin F alone (labeled "AF") and trastuzumab alone (labeled "Herceptin"). Compound I-2 ADC was found to be potent and selective for cell lines expressing the Her2 antigen. Compound I-2ADC (labeled "ADC:073-128-R3a") and compound I-2ADC (labeled "ADC:073-128-R3b") differ in the average number of polymers conjugated per antibody (degree of labeling, or DOL). ADC:073-128-R3a has a DOL of 1.7 and ADC:073-128-R3b has a DOL of 0.9.

[0164] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification and / or listed in the Application Data Sheets, including U.S. Provisional Patent Application No. 63 / 250,931, filed September 30, 2021, and U.S. Provisional Patent Application No. 63 / 253,071, filed October 6, 2021, are incorporated by reference herein in their entirety to the extent not inconsistent with this description. If necessary, aspects of the embodiments can be modified to employ concepts from the various patents, applications, and publications to provide still further embodiments. From the foregoing it will be appreciated that, although specific embodiments of the present disclosure have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the present disclosure. Accordingly, the present disclosure is not to be limited except as by the appended claims.

Claims

1. A compound having the following structure (I): 【Chemical 1】 (I) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 1 is independently at each occurrence H, alkyl, or alkoxy; R 2 and R 3 are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a ) (R b ) R c , Q or a protected form thereof, L′, or a combination of one or more thereof; R a is O or S, R b OH SH O - , S - , OR d or SR d and R c OH SH O - , S - , OR d ,OL',SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counterion, R 4 are independently expressed as OH, SH, and O for each occurrence. - , S - , OR d , or SR d and R 5 is independently at each occurrence oxo or thioxo; R 6 and R 7 is independently at each occurrence H, OH, or halo, with the proviso that R 6 or R 7 at least one of is OH or halo; L 3 and L 10 is, independently at each occurrence, a linker; L 1 , L 2 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , and L 11 may, independently at each occurrence, be a direct bond or a substituted linker; M 1 is, independently for each occurrence, a moiety containing a fluorescent dye that is absent; M 2 is, independently at each occurrence, a chromophore; M 3 is, independently at each occurrence, a moiety that comprises an anticancer therapeutic agent; Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety; L′ is, independently at each occurrence, a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a linker that includes a covalent bond to a solid support, a linker that includes a covalent bond to a solid support residue, a solid support residue, a linker that includes a covalent bond to a nucleoside, or a linker that includes a covalent bond to an additional compound of structure (I); l is, independently at each occurrence, an integer greater than or equal to 1; m is, independently at each occurrence, an integer greater than or equal to zero; n is an integer of 1 or more, at least one occurrence of p is an integer greater than or equal to 1, and each remaining p is either 0 or an integer greater than or equal to 1; q is, independently at each occurrence, an integer greater than or equal to zero.

2. Appearing L 1 , L 5 , or L 8 The compound of claim 1 , wherein at least one of is heteroalkylene.

3. L' is a group having the following structure: 【Chemistry 2】 2. The compound of claim 1, comprising one of: (In the formula, x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 and x 8 are independently an integer from 1 to 10, R b is H, an electron pair or a counterion, L" is a targeting moiety or a linking group to a targeting moiety.

4. The compound of claim 1 , wherein the targeting moiety is an antibody or a cell surface receptor antagonist.

5. R 2 or R 3 but has the following structure: 【Chemistry 3-1】 【Chemistry 3-2】 2. The compound of claim 1, having one of: (In the formula, R a is H or a solid support)

6. The following structure (Ib): 【Chemistry 4】 (Ib) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, x a , x b , x c , x d , x e , and x f is independently an integer from 0 to 6 at each occurrence.

7. Appearing L 3 or L 10 at least one of which has the following structure: 【Chemistry 5】 2. The compound of claim 1, comprising one of:

8. L 3 or L 10 8. The compound of claim 7, wherein each occurrence of comprises an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence, a ketone, a diol, a cyano, a nitro, or a combination thereof.

9. Q has the following structure: 【Chemistry 6】 or -NH ２ 2. The compound of claim 1 having the formula:

10. Appearing M 3 10. The compound of claim 1, wherein at least one of is an alkylating agent, antimetabolite, microtubule inhibitor, topoisomerase inhibitor, or cytotoxic antibiotic.

11. Appearing M 3 2. The compound of claim 1, wherein at least one of is an antifolate, a fluoropyrimidine, a deoxynucleoside analog, or a thiopurine.

12. The compound of claim 1, wherein m is an integer from 0 to 10.

13. 2. The compound of claim 1, wherein n is 1, 2, 3, or 4.

14. 2. The compound of claim 1, wherein p is 1, 2, 3, or 4.

15. x a , x b , x c , x d , x e , and x f 7. The compound of claim 6, wherein each occurrence is independently an integer of 0 or 1.

16. 10. The compound of claim 1 having one of the structures in Table 2, or a salt or tautomer thereof.

17. The compound of claim 1 , wherein q is 0 or 1.

18. 10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.

19. 19. A method for treating a disease or disorder, comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 18 to a subject in need thereof.

20. The following structure (III): 【Chemistry 7】 (III) a compound having or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. (In the formula, R 1 is independently at each occurrence H, alkyl, or alkoxy; R 2 and R 3 are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R a ) (R b ) R c , Q or a protected form thereof, L′, or a combination of one or more thereof; R a is O or S; R b OH SH O - , S - , OR d or SR d and R c OH SH O - , S - , OR d ,OL',SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether; R d is the counterion, R 4 are independently expressed as OH, SH, and O for each occurrence. - , S - , OR d , or SR d and R 5 is independently at each occurrence oxo or thioxo; R 6 and R 7 is independently at each occurrence H, OH, or halo, with the proviso that R 6 or R 7 at least one of is OH or halo; L 3 and L 10 is, independently at each occurrence, a linker; L 1 , L 2 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , and L 11 may, independently at each occurrence, be a direct bond or a substituted linker; M 1 is, independently for each occurrence, a moiety containing a fluorescent dye that is absent; M 2 is, independently at each occurrence, a chromophore; M 3 is, independently at each occurrence, a moiety that comprises an anticancer therapeutic agent; Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety; L′ is, independently at each occurrence, a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a linker that includes a covalent bond to a solid support, a linker that includes a covalent bond to a solid support residue, a solid support residue, a linker that includes a covalent bond to a nucleoside, or a linker that includes a covalent bond to an additional compound of structure (I); l is, independently at each occurrence, an integer greater than or equal to 1; m is, independently at each occurrence, an integer greater than or equal to zero; n is an integer of 1 or more, at least one occurrence of p is an integer greater than or equal to 1, and each remaining p is either 0 or an integer greater than or equal to 1; q is, independently at each occurrence, an integer greater than or equal to zero.

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