BACKGROUND OF THE INVENTION

Many drugs, particularly cancer therapeutics, have a narrow therapeutic window, wherein their side effects limit their beneficial effects. Systemic administration of such drugs often results in a limited therapeutic effect because the dose required to elicit a more robust effect results in unacceptable side effects to the patient. This is particularly critical in the case of those drugs which possess a high cytotoxic potential, such as cytostatic agents, virostatic agents or immunosuppressive agents. Numerous research endeavors have looked into delivering a particular drug at a particular site of action. Often, this approach results in a higher concentration of the drug at the site of action than would be achieved by systemic administration, while limiting the side effects.

Drug delivery in oncology is of particular interest owing to the narrow therapeutic window of agents used in such indication. Numerous research efforts have concentrated on conjugating anticancer drugs with a wide spectrum of low- and high-molecular-weight carriers including sugars, growth factors, vitamins, peptides, antibodies, polysaccharides, lectins, serum proteins, and synthetic polymers. In most such drug delivery systems, the drug is bound to the carrier through a spacer that incorporates a pre-determined breaking point that allows the bound drug to be released at the cellular target site. (Kratz et al., ChemMedChem, 3:20-53 (2008)). Conjugates are known in which cytostatic agents are bound to serum proteins, predominantly to specific carrier molecules such as human serum albumin and human serum transferin, and then administered. In some instances, conjugates comprise a therapeutically effective substance, and, upon administration, result in the transport of the therapeutically effective substance to the target site where it is released (U.S. Pat. No. 7,387,771). In other instances, conjugates comprising a therapeutically effective substance, a spacer molecule and a protein-binding molecule, bind covalently to circulating serum albumin upon administration, which result in the transport of the therapeutically effective substance to the target site where it is released (U.S. Pat. No. 7,387,771). In yet other instances, antibody drug conjugates (ADC) can transport the drug to the target site for local release (Kratz et al., ChemMedChem, 3:20-53 (2008); Panowski et al., mAbs, 6, 34-45 (2014); Chari et al., Angewandte Chem. Int. Ed., 53, 3796-3827 (2014)).

However, when designing drug delivery systems, the appropriate balance should be struck between preserving the targeting properties of the drug carrier while enabling a controlled release of the drug. The drug delivery construct should have sufficient stability in the bloodstream, and yet allow effective release of the drug at the tumor site by enzymatic cleavage, reduction or, in a pH-dependent manner (Kratz et al., ChemMedChem, 3:20-53 (2008)). For example, Gemcitabine (Gemzar®) is an anticancer nucleoside chemotherapeutic agents that is widely used to treat solid tumors. Unfortunately, at its recommended dose of ˜1000 mg/m2approximately 90% are deactivated by cytidine deaminase to the inactive uridine metabolite and excreted in the urine. A further disadvantage resulting in chemo-resistance is the low expression level of the human equilibrative nucleoside transporter 1 (hENT1) on the cell surface of cancer cells thus preventing substantial uptake of gemcitabine.

Therefore, there is still a need for efficient drug delivery and release systems in order to achieve more effective and controlled delivery and release of the drug.

SUMMARY OF THE INVENTION

The present invention provides delivery systems for the effective and controlled delivery and release of therapeutic agents.

The present invention relates to a drug delivery system that comprises a hydrazone moiety that is cleaved in an acidic environment in a controlled manner, to provide controlled release of therapeutic agents. The present invention relates to a drug delivery system that comprises an amide bond, a carbamate bond, and/or an ester bond that is cleaved enzymatically, e.g., by esterases or amidases and/or hydrolytically, to provide controlled release of therapeutic agents. In some embodiments, the present invention relates to a drug delivery system that comprises an amide bond that is cleaved enzymatically, e.g., by esterases or amidases and/or hydrolytically, to provide controlled release of therapeutic agents. In other embodiments, the present invention relates to a drug delivery system that comprises a carbamate bond that is cleaved enzymatically and/or hydrolytically. In yet other embodiments, the present invention relates to a drug delivery system that comprises an ester bond that is cleaved enzymatically and/or hydrolytically.

The present invention relates to a drug delivery system that comprises (i) a hydrazone moiety that is cleaved in an acidic environment in a controlled manner, and optionally (ii) an amide bond, a carbamate bond, and/or an ester bond that is cleaved enzymatically, e.g., by esterases or amidases and/or hydrolytically, to provide controlled release of therapeutic agents. In some embodiments, the present invention relates to a drug delivery system that comprises a (i) hydrazone moiety that is cleaved in an acidic environment in a controlled manner, and optionally (ii) an amide bond that is cleaved enzymatically, e.g., by esterases or amidases and/or hydrolytically, to provide controlled release of therapeutic agents. In some embodiments, the present invention relates to a drug delivery system that comprises a (i) hydrazone moiety that is cleaved in an acidic environment in a controlled manner, and optionally (ii) a carbamate bond that is cleaved enzymatically and/or hydrolytically, to provide controlled release of therapeutic agents. In some embodiments, the present invention relates to a drug delivery system that comprises a (i) hydrazone moiety that is cleaved in an acidic environment in a controlled manner, and optionally (ii) an ester bond that is cleaved enzymatically and/or hydrolytically, to provide controlled release of therapeutic agents. In some embodiments, the present invention relates to a drug delivery system that comprises (i) a hydrazone moiety that is cleaved in an acidic environment in a controlled manner, and optionally (ii) an amide bond that is selectively cleaved by carboxylesterase 1 and/or 2, to provide controlled release of therapeutic agents. In some embodiments, the present invention relates to a drug delivery system that comprises a (i) hydrazone moiety that is cleaved in an acidic environment in a controlled manner, and (ii) an amide bond that is selectively cleaved by carboxylesterase 2, to provide controlled release of therapeutic agents.

The present invention provides a compound having the structure represented by Formula (I):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein:

Agent is selected from the group consisting of a cytostatic agent, a cytotoxic agent, a cytokine, an immunosuppressive agent, an antirheumatic, an antiphlogistic, an antibiotic, an analgesic, a virostatic agent, an anti-inflammatory agent, an antimicotic agent, a transcription factor inhibitor, a cell cycle modulator, an MDR modulator, a proteasome or protease inhibitor, an apoptosis modulator, an enzyme inhibitor, a signal transduction inhibitor, a protease inhibitor, an angiogenesis inhibitor, a hormone or hormone derivative, an antibody or a fragment thereof, a therapeutically or diagnostically active peptide, a radioactive substance, a light emitting substance, a light absorbing substance, and a derivative of any of the foregoing;

Spacer is absent,



n is 0 or 1;

X is selected from the group consisting of: optionally substituted C1-C18alkyl wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—; optionally substituted C1-C18alkyl-NH—C(O)—R5— wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—; optionally substituted C1-C18alkyl-C(O)—NH—R5— wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—; optionally substituted aryl; optionally substituted heteroaryl; and optionally substituted cycloalkyl;

R5is selected from the group consisting of an optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl;

Y is absent or selected from the group consisting of optionally substituted C1-C6alkyl, —NH—C(O)—, —C(O)—NH—, —C(O)—O—, and —O—C(O)—;

R1is absent or selected from the group consisting of optionally substituted C1-C18alkyl wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—; optionally substituted C1-C18alkyl-NH—C(O)R5— wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—; and optionally substituted C1-C18alkyl-C(O)—NH—R5— wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—,

or R1is a naturally or non-naturally occurring amino acid,

or R1has the following formula:



wherein:

is absent, or is selected from the group consisting of:



R is:OPO3M1wherein M1=Mg2+, 2 Na+, 2K+, 2H+, 2NH4+orSO3M2wherein M2=Na+, K+, H+, NH4+

R2is selected from the group consisting of optionally substituted C1-C12alkyl, optionally substituted aryl, and optionally substituted heteroaryl;

Z1, Z2, Z3and Z4are each independently selected from the group consisting of —H, an electron-withdrawing group, and a water-soluble group;

PBG is a protein-binding group selected from the group consisting of an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridylthio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group, an optionally substituted acetylene group, an optionally substituted N-hydroxysuccinimide ester group, an antibody or fragment thereof, and a derivatized antibody of derivatized fragment thereof;

wherein when Spacer is absent, Agent is linked to the nitrogen adjacent to Spacer by a double bond; and

wherein at least one of Z1, Z2, Z3and Z4is an electron-withdrawing group.

In some embodiments, PBG is a protein-binding group selected from the group consisting of an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridylthio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group, an optionally substituted acetylene group, and an optionally substituted N-hydroxysuccinimide ester group.

In some embodiments, the PBG is associated with an antibody or fragment thereof. In some embodiments, the PBG is covalently bound to an antibody or fragment thereof. In some embodiments, the PBG is associated with albumin. In other embodiments, the PBG is covalently bound to endogenous or exogeneous albumin. In other embodiments, the PGB is covalently bound to the cysteine-34 of endogenous or exogenous albumin.

The present invention provides a compound having the structure represented by Formula (I):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof; wherein

Agent is selected from the group consisting of a cytostatic agent, a cytotoxic agent, a cytokine, an immunosuppressive agent, an antirheumatic, an antiphlogistic, an antibiotic, an analgesic, a virostatic agent, an anti-inflammatory agent, an antimicotic agent, a transcription factor inhibitor, a cell cycle modulator, an MDR modulator, a proteasome or protease inhibitor, an apoptosis modulator, an enzyme inhibitor, a signal transduction inhibitor, a protease inhibitor, an angiogenesis inhibitor, a hormone or hormone derivative, an antibody or a fragment thereof, a therapeutically or diagnostically active peptide, a radioactive substance, a light emitting substance, a light absorbing substance, and a derivative of any of the foregoing;

Spacer is absent,



n is 0 or 1;

X is selected from the group consisting of optionally substituted C1-C18alkyl wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—; optionally substituted C1-C18alkyl-NH—C(O)—R5— wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—, optionally substituted C1-C18alkyl-C(O)—NH—R5— wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—; optionally substituted aryl; optionally substituted heteroaryl; and optionally substituted cycloalkyl;

R5is selected from the group consisting of from an optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl;

Y is absent or selected from the group consisting of optionally substituted C1-C6alkyl, —NH—C(O)—, —C(O)—NH—, —C(O)—O—, and —O—C(O)—;

R1is absent or selected from the group consisting of optionally substituted C1-C18alkyl wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—; optionally substituted C1-C18alkyl-NH—C(O)R5— wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—, and optionally substituted C1-C18alkyl-C(O)—NH—R5— wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—;

R2is selected from the group consisting of —H, optionally substituted C1-C12alkyl, optionally substituted aryl, and optionally substituted heteroaryl;

Z1, Z2, Z3and Z4are each independently selected from the group consisting of —H or an electron-withdrawing group;

PBG is a protein-binding group selected from the group consisting of an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridylthio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group, an optionally substituted acetylene group, an optionally substituted N-hydroxysuccinimide ester group, and an antibody or fragment thereof;

wherein when Spacer is absent, Agent is linked to the nitrogen adjacent to Spacer by a double bond; and

wherein at least one of Z1, Z2, Z3and Z4is an electron-withdrawing group.

In some embodiments, PBG is a protein-binding group selected from the group consisting of an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridylthio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group, an optionally substituted acetylene group, and an optionally substituted N-hydroxysuccinimide ester group.

In some embodiments, the PBG is associated with an antibody or fragment thereof. In some embodiments, the PBG is covalently bound to an antibody or fragment thereof. In some embodiments, the PBG is associated with albumin. In other embodiments, the PBG is covalently bound to endogenous or exogenous albumin. In other embodiments, the PGB is covalently bound to the cysteine-34 of endogenous or exogenous albumin.

In certain embodiments, the invention provides a compound represented by Formula (II):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;

wherein Agent, PBG, Y, R1, Z1, Z2, Z3and Z4are as defined for a compound of Formula (I).

In certain embodiments, the invention provides a compound having the structure represented by Formula (III):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;

wherein Agent, Spacer, PBG, Y, R1, Z2, Z3and Z4are as defined for a compound of Formula (I); and

wherein Z1is an electron withdrawing group.

In certain embodiments, the invention provides a compound having the structure represented by Formula (IV):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;

wherein Agent, PBG, Y, R1, Z2, Z3and Z4are as defined for a compound of Formula (I); and

wherein Z1is an electron withdrawing group.

In certain embodiments, the invention provides a compound having the structure represented by Formula (V):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;

wherein Agent, PBG, n, Y, R1, R2, Z1, Z2, Z3and Z4are as defined for a compound of Formula (I).

In certain embodiments, the invention provides a compound having the structure represented by Formula (VI):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein:

M is a pyrimidine or purine group that contains at least one primary or secondary amino group and optionally contains one or more substituents selected from halogen.

X1and X2are each independently selected from the group consisting of —H, —OH, C1-C6alkyl, halogen, and —N3.

X3and X4are each independently, as valence permits, absent or selected from the group consisting of —H, —OH, C1-C6alkyl, halogen, and —N3.

R′ is —R3or —CH2R3;

wherein each occurrence of R3is independently selected from the group consisting of —OH, —CH3, —OP(O)(OH)2, —P(O)(OH)OP(O)(OH)2, —OP(O)(OH)OP(O)(OH)OP(O)(OH)2, —OP(O)(OH)(NH2), an amino acid, an acyl group, and a pharmaceutically acceptable salt thereof, wherein the salt contains an alkali metal ion, an alkaline metal ion, an ammonium or an alkyl substituted ammonium ion; and

wherein X, n, Z1, Z2, Z3, Z4, Y, R1, R2and PBG are as defined for a compound of Formula (V).

In certain embodiments, the invention provides a compound having the structure represented by Formula (VI):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof; wherein

M is a pyrimidine or purine group that contains at least one primary or secondary amino group.

X1and X2are each independently selected from the group consisting of —H, —OH, C1-C6alkyl, halogen, and —N3.

X3and X4are each independently, as valence permits, absent or selected from the group consisting of —H, —OH, C1-C6alkyl, halogen, and —N3.

R3is selected from —OH, —OP(O)(OH)2, —P(O)(OH)OP(O)(OH)2, —OP(O)(OH)OP(O)(OH)OP(O)(OH)2, —OP(O)(OH)(NH2), an amino acid, an acyl group, and a pharmaceutically acceptable salt thereof, wherein the salt contains an alkali metal ion, an alkaline metal ion, an ammonium or an alkyl substituted ammonium ion; and wherein X, n, Z1, Z2, Z3, Z4, Y, R1, R2and PBG are as defined for a compound of Formula (V).

In certain embodiments, the invention provides a compound having the structure represented by Formula (VII):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;

wherein R′ is —R3or —CH2R3; and X, X1, X2, X3, X4, n, Y, R1, R2, R3, Z1, Z2, Z3, Z4and PBG are as defined for a compound of Formula (VI).

In certain embodiments, the invention provides a compound having the structure represented by Formula (VII):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;

wherein X, X1, X2, X3, X4, n, Y, R1, R2, R3, Z1, Z2, Z3, Z4and PBG are as defined for a compound of Formula (V).

In certain embodiments, the invention provides a compound having a structure represented by Formula (VIII):


or pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof; wherein

Z1is an electron withdrawing group; and

wherein Agent, X, n, R2, PBG, Y, R1, Z2, Z3and Z4are as defined for a compound of Formula (V).

In certain embodiments, the invention provides a compound having the structure represented by Formula (IX):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein:

M is a pyrimidine or purine group that contains at least one primary or secondary amino group and optionally contains one or more substituents selected from halogen;

X1and X2are each independently selected from the group consisting of —H, —OH, C1-C6alkyl, halogen, and —N3;

X3and X4are each independently, as valence permits, absent or selected from the group consisting of —H, —OH, C1-C6alkyl, halogen, and —N3;

R′ is —R3or —CH2R3;

wherein each occurence of R3is independently selected from the group consisting of —OH, —CH3, —OP(O)(OH)2, —P(O)(OH)OP(O)(OH)2, —OP(O)(OH)OP(O)(OH)OP(O)(OH)2, —OP(O)(OH)(NH2), an amino acid, an acyl group, and a pharmaceutically acceptable salt thereof, wherein the salt contains an alkali metal ion, an alkaline metal ion, an ammonium or an alkyl substituted ammonium ion; and

wherein X, n, Y, Z1, Z2, Z3, Z4, R1, R2and PBG are as defined for a compound of Formula (VIII).

In certain embodiments, the invention provides a compound having the structure represented by Formula (IX):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof; wherein

M is a pyrimidine or purine group that contains at least one primary or secondary amino group;

X1and X2are each independently selected from the group consisting of —H, —OH, C1-C6alkyl, halogen, and —N3;

X3and X4are each independently, as valence permits, absent or selected from the group consisting of —H, —OH, C1-C6alkyl, halogen, and —N3;

R3is selected from —OH, —OP(O)(OH)2, —P(O)(OH)OP(O)(OH)2, —OP(O)(OH)OP(O)(OH)OP(O)(OH)2, —OP(O)(OH)(NH2), an amino acid, an acyl group, and a pharmaceutically acceptable salt thereof, wherein the salt contains an alkali metal ion, an alkaline metal ion, an ammonium or an alkyl substituted ammonium ion; and wherein X, n, Y, Z1, Z2, Z3, Z4, R1, R2and PBG are as defined for a compound of Formula (VIII).

In some embodiments, X1, X2, X3, and X4are each independently selected from the group consisting of —H, —OH, —CH3, —F, —Cl, —Br, —I, and —N3.

In certain embodiments, the invention provides a compound having the structure represented by Formula (X):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;

wherein R′ is —R3or —CH2R3; and X1, X2, X3, X4, R3, X, n, Y, Z1, Z2, Z3, Z4, R1and R2are as defined for a compound of Formula (IX).

In certain embodiments, the invention provides a compound having the structure represented by Formula (X):


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;

wherein X1, X2, X3, X4, R3, X, n, Y, Z1, Z2, Z3, Z4, R1and R2are as defined for a compound of Formula (IX).

In some embodiments, Agent is selected from the group consisting of N-nitrosoureas; doxorubicin, 2-pyrrolpyrrolinoanthracycline, morpholinoanthracycline, diacetatoxyalkylanthracycline, daunorubicin, epirubicin, idarubicin, nemorubicin, PNU-159682, mitoxantrone; ametantrone; chlorambucil, bendamustine, melphalan, oxazaphosphorines; 5-fluorouracil, 5′-deoxy-5-fluorocytidine, 2′-deoxy-5-fluoridine, cytarabine, cladribine, fludarabine, pentostatine, gemcitabine, 4-amino-1-(((2S,3R,4S,5R)-3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)methyl)-5-fluoropyrimidin-2(1H)-one, thioguanine; methotrexate, raltitrexed, pemetrexed, plevitrexed; paclitaxel, docetaxel; topotecan, irinotecan, SN-38, 10-hydroxycamptothecin, GG211, lurtotecan, 9-aminocamptothecin, camptothecin, 7-formylcamptothecin, 7-acetylcamptothecin, 9-formylcamptothecin, 9-acetylcamptothecin, 9-formyl-10-hydroxycamptothecin, 10-formylcamptothecin, 10-acetylcamptothecin, 7-butyl-10-aminocamptothecin, 7-butyl-9-amino-10,11-methylenedioxocamptothecin; vinblastine, vincristine, vindesine, vinorelbine; calicheamicins; maytansine, maytansinol; auristatin (including but not limited to auristatin D, auristatin E, auristatin F, monomethyl auristatin D, monomethyl auristatin E, monomethyl auristatin F, monomethyl auristatin F methylester, auristatin PYE auristatin PHE, the related natural product dolastatin 10, and derivatives thereof); amatoxins (including but not limited to α-amanitin, β-amanitin, γ-amanitin, ε-amanitin, amanin, amaninamide, amanullin, and amanullinic acid and derivatives thereof); duocarmycin A, duocarmycin B1, duocarmycin B2, duocarmycin C, duocarmycin SA, CC1065, adozelesin, bizelesin, carzelesin; eribulin; trabectedin; pyrrolobenzodiazepine, anthramycin, tomaymycin, sibiromycin, DC-81, DSB-120; epothilones; bleomycin; dactinomycin; plicamycin, miromycin C, and cis-configured platinum(II) complexes; or a derivative of any of the foregoing.

In some embodiments, Agent is selected from the group consisting of N-nitrosoureas;

doxorubicin, 2-pyrrolpyrrolinoanthracycline, morpholinoanthracycline, diacetatoxyalkylanthracycline, daunorubicin, epirubicin, idarubicin, nemorubicin, PNU-159682, mitoxantrone; ametantrone; chlorambucil, bendamustine, melphalan, oxazaphosphorines; 5-fluorouracil, 2′-deoxy-5-fluoridine, cytarabine, cladribine, fludarabine, pentostatine, gemcitabine, 4-amino-1-(((2S,3R,4S,5R)-3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)methyl)-5-fluoropyrimidin-2(1H)-one, thioguanine; methotrexate, raltitrexed, pemetrexed, plevitrexed; paclitaxel, docetaxel; topotecan, irinotecan, SN-38, 10-hydroxycamptothecin, GG211, lurtotecan, 9-aminocamptothecin, camptothecin, 7-formylcamptothecin, 9-formylcamptothecin, 9-formyl-10-hydroxycamptothecin, 7-butyl-10-aminocamptothecin, 7-butyl-9-amino-10,11-methylenedioxocamptothecin; vinblastine, vincristine, vindesine, vinorelbine; calicheamicins; maytansinoids; auristatins; epothilones; bleomycin, dactinomycin, plicamycin, miromycin C, and cis-configured platinum(II) complexes; or a derivative of any of the foregoing.

In some embodiments, Z1, Z2, Z3and Z4are each independently selected from the group consisting of —H, halogen, —C(O)OH, —C(O)O—C1-C6alkyl, —NO2, haloalkyl, —S(O)2—C1-C6alkyl, and —CN. In some embodiments, Z1, Z2, Z3and Z4are each independently selected from the group consisting of —H, —Cl, —Br, —I, —F, —C(O)OH, —NO2, —CF3, and —CN. In some embodiments, Z1, Z2, Z3and Z4are each independently selected from the group consisting of —H, —Cl, —F, —NO2, and —CF3. In some embodiments, Z1, Z2, Z3and Z4are each independently selected from the group consisting of —OP(O)(OH)2, —P(O)(OH)OP(O)(OH)2, —OP(O)(OH)OP(O)(OH)OP(O)(OH)2, —OP(O)(OH)(NH2), —P(O)(OH)2, —SO3H, and a pharmaceutically acceptable salt thereof. In some embodiments, at least one of Z1, Z2, Z3and Z4is not —H.

In some embodiments, Z1, Z2, Z3and Z4are each independently selected from the group consisting of —H, halogen, —C(O)OH, —C(O)O—C1-C6alkyl, —NO2, haloalkyl, —S(O)2—C1-C6alkyl, and —CN. In some embodiments, Z1, Z2, Z3and Z4are each independently selected from the group consisting of —H, —Cl, —Br, —I, —F, —C(O)OH, —NO2, —CF3, and —CN. In some embodiments, Z1, Z2, Z3and Z4are each independently selected from the group consisting of —H, —Cl, —F, —NO2, and —CF3. In some embodiments, at least one of Z1, Z2, Z3and Z4is not —H.

In some embodiments, Z1is selected from the group consisting of halogen, —C(O)OH, —C(O)O—C1-C6alkyl, —NO2, haloalkyl, —S(O)2—C1-C6alkyl, and —CN; and Z2, Z3and Z4are each independently selected from the group consisting of —H, halogen, —C(O)OH, —C(O)O—C1-C6alkyl, —NO2, haloalkyl, —S(O)2—C1-C6alkyl, and —CN. In some embodiments, Z1is selected from the group consisting of —Cl, —Br, —I, —F, —C(O)OH, —NO2, —CF3, and —CN; and Z2, Z3and Z4are each independently selected from the group consisting of —H, —Cl, —Br, —I, —F, —C(O)OH, —NO2, —CF3, and —CN. In some embodiments, Z1is selected from the group consisting of —Cl, —F, and —NO2; and Z2, Z3and Z4are each independently selected from the group consisting of —H, —Cl, —F, —NO2, and —CF3.

In some embodiments, the


moiety of a compound of the invention is selected from the group consisting of:



In some embodiments, the


moiety of a compound of the invention is selected from the group consisting of:



In some embodiments, Y is —C(O)—NH—. In some embodiments, Y is —C(O)—O—. In some embodiments, Y is absent.

In some embodiments, R1is selected from the group consisting of optionally substituted C1-C18alkyl wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—; optionally substituted C1-C18alkyl-NH—C(O)—R5— wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—; and optionally substituted C1-C18alkyl-C(O)—NH—R5— wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—.

In some embodiments, R1is selected from the group consisting of



In some embodiments, R1is absent.

In some embodiments, PBG is an optionally substituted maleimide group. In some embodiments, PBG is



In some embodiments, the


moiety of a compound of the invention is selected from the group consisting of:



In some embodiments, Spacer is


n is 0 or 1; and X is selected from the group consisting of optionally substituted C1-C18alkyl wherein optionally up to six carbon atoms in said C1-C18alkyl are each independently replaced with —OCH2CH2—; optionally substituted aryl; optionally substituted heteroaryl; and optionally substituted cycloalkyl; and R2is as defined for Formula I.

In some embodiments, Spacer is


wherein R2is selected from the group consisting of: —H, optionally substituted C1-C12alkyl, optionally substituted aryl, and optionally substituted heteroaryl; W1, W2, W3and W4are each independently selected from the group consisting of: —H, halogen, —C(O)OH, —C(O)O—C1-C6alkyl, —NO2, haloalkyl, —S(O)2—C1-C6alkyl, and —CN. In some embodiments, W1, W2, W3and W4are each independently selected from the group consisting of: —H, —Cl, —Br, —I, —F, —C(O)OH, —NO2, —CF3, and —CN. In some embodiments, W1, W2, W3and W4are each independently selected from the group consisting of: —H, —Cl, —F, —NO2, and —CF3. In some embodiments, W1, W2, W3and W4are each independently selected from the group consisting of: a phenoxy group, a primary, secondary or tertiary amine group, an ether group, a phenol group, an amide group, an ester group, an alkyl group, a substituted alkyl group, a phenyl group, and a vinyl group. In some embodiments, W1, W2, W3and W4are each independently selected from the group consisting of: —OP(O)(OH)2, —P(O)(OH)OP(O)(OH)2, —OP(O)(OH)OP(O)(OH)OP(O)(OH)2, —OP(O)(OH)(NH2), —P(O)(OH)2, —SO3H, and a pharmaceutically acceptable salt thereof. In some embodiments, at least one of W1, W2, W3and W4is not —H.

In some embodiments, W1is selected from the group consisting of: halogen, —C(O)OH, —C(O)O—C1-C6alkyl, —NO2, haloalkyl, —S(O)2—C1-C6alkyl, and —CN; and W2, W3and W4are each independently selected from the group consisting of: —H, halogen, —C(O)OH, —C(O)O—C1-C6alkyl, —NO2, haloalkyl, —S(O)2—C1-C6alkyl, and —CN. In some embodiments, W1is selected from the group consisting of: —Cl, —Br, —I, —F, —C(O)OH, —NO2, —CF3, and —CN; and W2, W3and W4are each independently selected from the group consisting of: —H, —Br, —I, —F, —C(O)OH, —NO2, —CF3, and —CN. In some embodiments, W1is selected from the group consisting of: —Cl, —F, and —NO2; and Z2, Z3and Z4are each independently selected from the group consisting of: —H, —Cl, —F, —NO2, and —CF3.

In some embodiments, Spacer is


wherein R2is selected from the group consisting of —H, optionally substituted C1-C12alkyl, optionally substituted aryl, and optionally substituted heteroaryl.

In some embodiments, Spacer is



In some embodiments, Spacer is


and m is 1, 2, 3, 4, 5, or 6.

In some embodiments, Spacer is



In some embodiments, the compound of the invention is selected from the group consisting of:


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof,
wherein:


is absent, or is selected from the group consisting of:



R isOPO3M1wherein M1=Mg2+, 2 Na+, 2K+, 2H+, 2NH4+, Na+, K+, NH4+, and/or H+orSO3M2wherein M2=Na+, K+, H+, and/or NH4+.

In some embodiments, the compound of the invention is selected from the group consisting of:


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.

In some embodiments, Agent is α-amanitin, and the compound of the present invention is selected from the group consisting of:


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.

In some embodiments, Agent is an auristatin or derivative thereof and the compound of the present invention is selected from the group consisting of:


or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.

In certain embodiments, the invention provides a pharmaceutical composition comprising a compound as disclosed herein, and a pharmaceutically acceptable carrier.

In certain embodiments, the invention provides a method for treating a disease or condition selected from the group consisting of a cancer, a virus disease, autoimmune disease, acute or chronic inflammatory disease, and a disease caused by bacteria, fungi, or other micro-organisms, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutical composition described herein.

In some embodiments, the invention provides compounds and compositions for use as a medicament. In some embodiments, the invention provides compounds and compositions for use in treating a disease or condition selected from the group consisting of a cancer, a virus disease, an autoimmune disease, an acute or chronic inflammatory disease, and a disease caused by bacteria, fungi, or other micro-organisms.

In some embodiments, the compound disclosed herein may be used in the manufacture or preparation of a medicament for the treatment of a disease or condition selected from the group consisting of a cancer, a virus disease, an autoimmune disease, an acute or chronic inflammatory disease, and a disease caused by bacteria, fungi, or other micro-organisms.

