WO2025259682A1 - Enzyme-activated prodrugs with small molecule-mediated extended serum half-life - Google Patents

Enzyme-activated prodrugs with small molecule-mediated extended serum half-life

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Publication number
WO2025259682A1
WO2025259682A1 PCT/US2025/033019 US2025033019W WO2025259682A1 WO 2025259682 A1 WO2025259682 A1 WO 2025259682A1 US 2025033019 W US2025033019 W US 2025033019W WO 2025259682 A1 WO2025259682 A1 WO 2025259682A1
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prodrug
agonist
tuv
attorney docket
drug
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William W. Bachovchin
Hung-Sen Lai
Wengen Wu
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Tufts University
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Tufts University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the therapeutic index is the ratio between the Toxic Dose (TD or LD ), i.e., the dose that causes toxicity or is lethal in 50% of subjects, and the Effective Dose (ED ), i.e., the dose that produces the desired therapeutic effect in 50% of subjects.
  • TD Toxic Dose
  • ED Effective Dose
  • TI TD / ED .
  • a higher TI means there's a bigger margin between effective and harmful doses, which is ideal.
  • Many cancer drugs are inherently toxic, targeting rapidly dividing cells (which includes healthy ones like bone marrow or gut lining cells). The goal is to kill cancer cells while minimizing harm to healthy tissues. A drug with a low therapeutic index may still be used, but with careful monitoring (e.g., chemotherapy with regular blood tests).
  • FAP ⁇ Fibroblast Activation Protein Alpha
  • FAP is a type II integral membrane serine protease expressed on the surface of some types of tumor cells, but importantly on the surface of carcinoma-associated fibroblasts (CAFs) in the stroma of greater than 90% of solid tumors examined, but not on adjacent normal tissues.
  • Fibroblast-activation protein a also known as Seprase, is a type II integral membrane serine peptidase.
  • FAP belongs to the dipeptidyl peptidase IV family. It is a 170 kDa homodimer containing two N-glycosylated subunits with a large C-terminal extracellular domain, in which the enzyme's catalytic domain is located.
  • FAP in its glycosylated form, has -1- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 both post-prolyl dipeptidyl peptidase and gelatinase activities. Homologues of human FAP were found in several species, including mice and cynomolgus monkeys. FAP is a member of the dipeptidyl peptidase subfamily whose members are characterized by the ability to cleave the peptide bond following a proline residue. Normal adult tissues generally do not express detectable amounts of FAP.
  • FAP is expressed in reactive stromal fibroblasts of epithelial cancers, granulation tissue of healing wounds, and malignant cells of bone and soft tissue sarcomas.
  • FAP is thought to be involved in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis.
  • FAP is expressed selectively in reactive stromal fibroblasts of more than 90% of epithelial malignancies (primary and metastatic) examined, including lung, colorectal, bladder, ovarian and breast carcinomas, and in malignant mesenchymal cells of bone and soft tissue sarcomas, while it is generally absent from normal adult tissues (Bewed et al., Mol. Cancer Ther.
  • FAP is also expressed on certain malignant tumor cells.
  • most common types of epithelial cancers including more than 90 percent of breast, non-small cell lung, and colorectal carcinomas, contain FAP-expressing stromal fibroblasts. Scanlan et al. Proc Natl Acad Sci USA 91:5657-61 (1994).
  • FAP can provide target specificity to therapeutic agents. Due to its expression in many common cancers and its restricted expression in normal tissues, FAP has been considered a promising antigenic target for imaging, diagnosis and therapy of a variety of cancers.
  • Various approaches have been devised to exploit the selective expression of FAP in tumor stroma for clinical benefit, including monoclonal antibodies against FAP, small-molecule inhibitors of FAP enzymatic activity, FAP-activated prodrugs of cytotoxic compounds and FAP-specific CAR-T cells.
  • the present disclosure provides enzyme activated prodrugs represented by formula I or a pharmaceutically acceptable salt thereof: -2- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 HSA– L 1 – SRS – L 2 – D (I) wherein, D is a drug or an active pharmaceutical moiety; SRS represents a substrate recognition sequence which is enzymatically cleaved by a target enzyme; L 1 is a bond or a linker; L 2 is a bond or a self-eliminating linker which, after enzymatic cleavage of the substrate recognition sequence SRS by the target enzyme, is released from the prodrug to produce the pharmacologically active parent drug; and HSA is a moiety
  • the present disclosure provides pharmaceutical compositions comprising the prodrug disclosed herein and a pharmaceutically acceptable excipient.
  • the present disclosure provides methods for treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a prodrug disclosed herein, or a pharmaceutically acceptable salt thereof, to the subject.
  • the prodrug may be further characterized by one or more of the following features: • the prodrug has less than 50% of the therapeutic activity of the active form of the parent pharmacological agent, and more preferably less than 60%, 70%, 80%, 90%, 95%, or even 98%; • the prodrug has a therapeutic index that is at least 2 times greater than the therapeutic index of the parent pharmacological agent alone, and more preferably at least 5, 10, 50, 100, 250, 500, 1000, 5000, or even 10,000 times greater; • a larger percentage of the released pharmacological agent is localized in the target tissue, i.e., the tissue expressing the target enzyme, relative to administration of the parent pharmacological agent alone, when compared on an equivalent dose basis— i.e., the ratio of active agent localized to the target tissue relative to other tissue (such as blood, liver or heart) is at least 2 times greater for an equivalent dose of the prodrug relative to the agent alone, and preferably at least 5, 10, 100, or even 1000 times greater; -3
  • the pharmacologically active agent is a low-molecular agent, i.e., having a molecular weight less than 5000 amu, preferably less than 2500 amu and even more preferably less than 1500 amu.
  • the parent pharmacological agent comprises a free amine to which the substrate recognition sequence can be directly coupled by way of a covalent bond with the C-terminal carbonyl of the substrate recognition sequence moiety, so as to create an amide bond between the two moieties; or to which a self-eliminating linker can be coupled as a bridge between the substrate recognition sequence and the drug agent moiety.
  • the parent pharmacological agent moiety comprises a functional group other than an amine to which a self-eliminating linker can be coupled, or which can otherwise form a bond with the C-terminal carbonyl of the substrate recognition sequence, which resulting covalent bond can be cleaved by the target enzyme.
  • the invention provides a prodrug for fibroblast activation protein (FAP)-dependent release of an pharmacologically active agent, comprising an FAP substrate covalently linked to a drug agent via a bond or a self-eliminating linker. Upon cleavage by FAP of the FAP substrate, the drug agent is released in its active form or in a form that is readily metabolized to its active form.
  • FAP fibroblast activation protein
  • FIG. 1 shows a cell killing assay comparing the ability of 6707-PRO (see Synthetic Scheme 9), a ponatinib prodrug, to kill KCL22 cells in the presence of recombinant human FAP (rhFAP) – which activates – versus the presence of the selective FAP inhibitor 5057.
  • the assay is a cell titer-blue viability assay.
  • the EC50 for cell killing in the presence of the FAP -4- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 inhibitor was 110nM, while in the presence of rhFAP was more potent at 0.2nM.
  • the present disclosure provides enzyme activated prodrugs represented by formula I or a pharmaceutically acceptable salt thereof: HSA – L 1 – SRS – L 2 – D (I) wherein, D is a drug or an active pharmaceutical moiety; SRS represents a substrate recognition sequence which is enzymatically cleaved by a target enzyme; L 1 is a bond or a linker; L 2 is a bond or a self-eliminating linker which, after enzymatic cleavage of the substrate recognition sequence SRS by the target enzyme, is released from the prodrug to produce the parent drug; and HSA is a moiety that binds to human serum albumin with a K d of 1 x 10 -6 or less, has a mo
  • the parent pharmacological agent comprises a free amine to which the SRS moiety, such as a FAP substrate recognition sequence, can be directly coupled by way of a covalent bond with the C-terminal carbonyl of the SRS moiety, so as to create an amide bond between the two moieties; or to which a self-eliminating linker can be coupled as a bridge between the SRS moiety and agent moieties.
  • the parent pharmacological agent moiety comprises a functional group other than an amine to which a self-eliminating linker can be coupled, or which can otherwise form a bond with the C-terminal carbonyl of the SRS moiety, which resulting covalent bond can be cleaved by target enzyme.
  • a larger percentage of the released pharmacological agent is localized in the target tissue, i.e., the tissue expressing FAP or other target enzyme, relative to administration of the parent pharmacological agent alone, when compared on an equivalent dose basis—i.e., the ratio of active agent localized to the target tissue relative to other tissue (such as blood, liver or heart) is at least 2 times greater for an equivalent dose of the prodrug relative to the agent alone, and preferably at least 5, 10, 100, or even 1000 times greater; -5- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225
  • the SRS is a FAP substrate recognition sequence.
  • the FAP substrate recognition sequence can comprise a dipeptide represented in the general formula wherein A is a 5-7 membered heterocycle and R 1 is H or a lower alkyl (which may be straight chain or branched), and if a lower alkyl may be optionally substituted with a hydroxyl group.
  • the prodrug Upon cleavage by FAP of the FAP substrate recognition sequence, the prodrug releases the pharmacological agent as the pharmacologically active agent or in an intermediary form having one or more self-eliminating linkers that are readily metabolized to the pharmacologically active agent.
  • the FAP substrate recognition sequence contains a dipeptide represented in the general formula wherein: R 1 is as defined above; n is 1, 2, or 3; and each R 4 is independently H, (C 1 -C 6 ) alkyl, OH, —NH 2 , or halogen.
  • the FAP substrate recognition sequence which contains a dipeptide represented in the general formula -6- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 wherein R 1 , n and R 4 are as defined above.
  • the FAP substrate recognition sequence contains a (d)-Ala-Pro dipeptide represented in the general formula
  • the prodrug is an FAP-activated prodrug having a kcat/Km for cleavage by FAP at least 10-fold greater than for cleavage by prolyl endopeptidase (EC 3.4.21.26; PREP), and even more preferably at least 100-fold, 1000-fold, 5000-fold, or even 10,000-fold greater kcat/Km.
  • the prodrug is an FAP-activated prodrug having a kcat/Km, for cleavage by FAP at least 10-fold greater than for cleavage by at least one mammalian “DPP IV activity- and/or structure-homologues” (DASH) enzyme, such as DPP-2, DPP-4, DPP-7, DPP-8, and/or DPP-9, and even more preferably at least 50, 100, 250, 500, 1000, 5000, or even 10,000 times greater.
  • DASH mammalian “DPP IV activity- and/or structure-homologues”
  • the prodrug is an FAP-activated prodrug represented by formula IIa or a pharmaceutically acceptable salt thereof: IIa L 2 is a bond and -NH-L-D is the pharmacologically active agent, or -7- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 L 2 is a self-eliminating linker which, after FAP cleavage of the FAP substrate recognition sequence, is released from the prodrug to release D as the pharmacologically active agent; A is a 5-7 membered heterocycle; R 1 is H or alkyl (e.g., lower alkyl); B is C5-C8 monocyclic ring or a C8-C12 bicyclic ring; R 2 is H, -OH, or alkyl (e.g., lower alkyl); and each R a is, independently, H, alkyl, or aralkyl.
  • IIa L 2 is a bond and -NH-L-D is the pharma
  • the prodrug is an FAP-activated prodrug represented by formula IIb or a pharmaceutically acceptable salt thereof: n is 1, 2, or 3; and each R 4 is independently H, (C 1 -C 6 ) alkyl, —OH, —NH 2 , or halogen.
  • the prodrug is represented by formula II or a pharmaceutically acceptable salt thereof: -8- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 wherein, n is 1, 2, or 3; and each R 4 is independently H, (C 1 -C 6 ) alkyl, —OH, —NH 2 , or halogen.
  • R 1 is (C 1 -C 10 )alkyl (e.g., methyl). In other embodiments, R 1 is Ser. In yet other embodiments, R 1 is Thr. In yet other embodiments, R 1 is -alanine. In certain embodiments, In certain embodiments, In certain embodiments, R2 is the side chain of Arg or Lys. In certain embodiments, R2 is the side chain of homoarginine. In certain embodiments, R2 is a Dap-derived -guanidino acid arginine mimetics. In certain embodiments, Ra is H or methyl. In yet other embodiments, X is .
  • the prodrug is an FAP-activated prodrug represented by formula III or a pharmaceutically acceptable salt thereof: -9- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 wherein, n is 1, 2, or 3; and R 4 is absent or represents a (C 1 -C 6 ) alkyl, —OH, —NH 2 , or halogen.
  • L 1 is N-Succinimidyl 4-(2-pyridylthio) pentanoate, N- Succinimidyl 4-(N-maleimidomethyl) cyclohexane-1 carboxylate, or N-Succinimidyl (4-iodo- acetyl) aminobenzoate.
  • L 1 is a polyether.
  • L 1 is a poly(ethylene glycol).
  • L 1 is: ; and p is 1 to 100.
  • p is 6 to 50.
  • p is 6 to 12. 1
  • L is represented by: ; and p is 1 to 20.
  • the prodrug is represented by formula IIa or a pharmaceutically acceptable salt thereof:
  • IIa A is a 5-7 membered heterocycle;
  • R 1 is H or alkyl (e.g., lower alkyl);
  • B is C5-C8 monocyclic ring or a C8-C12 bicyclic ring;
  • R 2 is H, -OH, or alkyl (e.g., lower alkyl); and each is independently R a is H, alkyl, or aralkyl.
  • the prodrug is represented by formula IIb or a pharmaceutically acceptable salt thereof: -11- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 IIb wherein, n is 1, 2, or 3; and each R 4 is independently H, (C 1 -C 6 ) alkyl, —OH, —NH 2 , or halogen.
  • the prodrug is represented by formula II or a pharmaceutically acceptable salt thereof: wherein, n is 1, 2, or 3; and each R 4 is independently H, (C 1 -C 6 ) alkyl, —OH, —NH 2 , or halogen.
  • R 1 is (C 1 -C 10 )alkyl (e.g., methyl). In other embodiments, R 1 is Ser. In yet other embodiments, R 1 is Thr. In yet other embodiments, R 1 is -alanine. -12- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225
  • R 2 is the side chain of Arg or Lys. In certain embodiments, R 2 is the side chain of homoarginine. In certain embodiments, R 2 is a Dap-derived -guanidino acid arginine mimetics. In certain embodiments, R a is H or methyl. In yet other embodiments, X is .
  • the prodrug is represented by formula III or a pharmaceutically acceptable salt thereof: wherein, n is 1, 2, or 3; and R 4 is absent or represents a (C 1 -C 6 ) alkyl, —OH, —NH 2 , or halogen.
  • L 1 is N-Succinimidyl 4-(2-pyridylthio) pentanoate, N- Succinimidyl 4-(N-maleimidomethyl) cyclohexane-1 carboxylate, or N-Succinimidyl (4-iodo- acetyl) aminobenzoate.
  • L 1 is a polyether.
  • L 1 -13- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 ; and p is 1 to 100. In certain embodiments, p is 6 to 50. In certain embodiments, p is 6 to 12. In certain embodiments, L 1 is represented by: ; and p is 1 to 20. In certain embodiments, p is 1 to 4. In certain embodiments, HSA is -14- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In yet other embodiments, HSA is . In certain embodiments, the prodrug is represented by formula IVa or a pharmaceutically acceptable salt thereof: IVa.
  • the prodrug is represented by formula IVb or a pharmaceutically acceptable salt thereof: IVb. -15- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225
  • the prodrug is represented by formula IVc or a pharmaceutically acceptable salt thereof: IVc.
  • the prodrug is represented by formula IVd or a pharmaceutically acceptable salt thereof: IVd.
  • the drug is an immunomodulator.
  • the drug is an immune activating agent.
  • the immunomodulator induces an innate immunity pathway.
  • the immunomodulator is an immuno-DASH inhibitor that inhibits the enzymatic activity of DPP8 and DPP9 and induces macrophage pyroptosis.
  • the immunomodulator is a STING agonist.
  • the immunomodulator is a RIG-1 agonist.
  • the immunomodulator is a Toll-like receptor (TLR) agonist, such as a TLR1/2 agonist, a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR6/2 agonist, a TLR7 agonist, a TLR7/8 agonist, a TLR7/9 agonist, a TLR8 agonist, a -16- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 TLR9 agonist, and a TLR11 agonist, preferably selected from the group consisting of a TLR3 agonist, a TLR7 agonist, a TLR7/8 agonist, and a TLR9 agonist.
  • TLR Toll-like receptor
  • the drug is cytotoxic to cancer associated fibroblasts (CAFs).
  • CAFs cancer associated fibroblasts
  • the drug polarizes tumor associated macrophage towards M1 macrophage or inhibits M2 macrophage immunosuppressive activity.
  • the drug accelerates T-cell priming and/or dendritic cell trafficking.
  • the drug inhibits or depletes Treg cells, such as by blocking immunosuppressive function or migration to lymph nodes and/or the tumor microenvironment.
  • the Therapeutic Index of the prodrug is at least 5 times greater than the Therapeutic Index for the free drug when given systemically, more preferably at least 10, 20, 30, 40, 50, 75 or even 100 times greater.
  • the drug has a molecular weight less than 5000 amu, preferably less than 2500 amu.
  • the drug is Val-boroPro.
  • the prodrug is selected from the group consisting of , -17- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 , a pharmaceutically acceptable salt thereof.
  • the prodrug is selected from the group consisting of , , and -18- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 ; or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides pharmaceutical compositions comprising the prodrug disclosed herein and a pharmaceutically acceptable excipient.
  • the present disclosure provides methods for treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a prodrug disclosed herein, or a pharmaceutically acceptable salt thereof, to the subject.
  • the cancer is acute myeloid leukemia (AML).
  • the prodrug includes a parent drug with from 2 to 5 HSA/SRS containing moieties appended thereto, preferably 2 or 3, and more preferably 2.
  • such prodrugs can be represented by formula or a pharmaceutically acceptable salt thereof: wherein, D, SRS, L 1 , L 2 and HSA are as defined above, and q is an integer from 2-5.
  • q is 2.
  • the SRS can be an FAP substrate recognition sequences and the prodrug can be represented by the general formula wherein D, A, R 1 , L 1 , L 2 , X and HSA are as defined above, and q is an integer from 2-5. In certain embodiments, q is 2.
  • the prodrug can be represented by the general formula -19- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 wherein D, R 1 , R 4 , L 1 , L 2 , X, HSA and n are as defined above, and q is an integer from 2-5. In certain embodiments, q is 2. In certain embodiments, R 1 is CH 3 and n is 1.
  • the HSA moiety is one which confers serum half-life extension to the prodrug (relative to the parent drug) by functioning as a serum albumin binding moiety.
  • the serum albumin binding moiety is a moiety that binds to human serum albumin with a Kd of 500 micromolar or less, and more preferably a Kd for human serum albumin binding of less than 250 micromolar, 100 micromolar, 10 micromolar, 1 micromolar, 100 nanomolar or even 10 nanomolar.
  • the serum albumin binding moiety has a molecular weight of 3000 amu or less.
  • the serum albumin binding moiety increases the serum half-life of the prodrug by 10-fold or more relative to the pharmacologically active agent, and even more preferably by more than 20-fold, 50-fold, 100-fold, 500-fold, 1000-fold or even 10000-fold.
  • HSA is a serum albumin binder comprising an Evans blue moiety (or analog thereof), such as may be selected from: ; -20- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 .
  • HSA is a serum albumin binder comprising an iodophenyl, preferably a p-iodophenyl, such as may be selected from: .
  • HSA is a serum albumin binding macrocyclic, such as -21- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225
  • HSA is a serum albumin binding peptide, such as
  • the HSA moiety is selected from: -22- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 .
  • the Therapeutic Index of the prodrug is at least 5 times greater than the Therapeutic Index for the free drug when given systemically, more preferably at least 10, 20, 30, 40, 50, 75 or even 100 times greater.
  • the drug has a molecular weight less than 5000 amu, preferably less than 2500 amu.
  • a wide range of drug entities can be used as the pharmacologically active moiety of the subject prodrugs.
  • the pharmacologically active moiety can be selected from a chemotherapeutic agent, a toxin, a cytokine, a growth inhibitory agent, a protein degrader, a peptide, a radionuclide, a hormone, an anti-viral agent, an anti-bacterial agent, an immunoregulatory agent, a fluorophore, a dye, or a contrast agent.
  • the pharmacologically active agent is an immunomodulator – which includes drug moieties acting as immune activating agents and/or inducers of an innate immunity pathway response.
  • the pharmacologically active agent induces the production of IFN- .
  • the pharmacologically active agent induces the production of proinflammatory cytokines.
  • the pharmacologically active agent induces the production of IL-1 ⁇ .
  • the pharmacologically active agent induces the production of IL-18.
  • the pharmacologically active agent promotes the expansion and survival of effector cells including NK, T, and CD8+ T cells.
  • the pharmacologically active agent is an immuno-DASH inhibitor that inhibits the enzymatic activity of DPP8 and DPP9, and induces macrophage pyroptosis in vitro and/or in vivo.
  • the pharmacologically active agent is a damage-associated molecular pattern molecule.
  • the pharmacologically active agent is a pathogen-associated molecular pattern molecule.
  • the pharmacologically active agent is a STING agonist.
  • the pharmacologically active agent is a RIG-1 agonist.
  • the pharmacologically active agent is a Toll-like receptor (TLR) agonist, such as a selected from the group consisting of a TLR1/2 agonist, a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR6/2 agonist, a TLR7 agonist, a TLR7/8 agonist, a TLR7/9 agonist, a TLR8 agonist, a TLR9 agonist, and a TLR11 agonist, preferably selected from the group consisting of a TLR3 agonist, a TLR7 agonist, a TLR7/8 agonist, and a TLR9 agonist.
  • TLR Toll-like receptor
  • the pharmacologically active agent is a cyclic dinucleotide. In certain embodiments, the pharmacologically active agent is ADU-S100. In certain embodiments, the pharmacologically active agent is a RIG-I agonist, wherein the RIG-I agonist is KIN700, KIN1148, KIN600, KIN500, KIN100, KIN101, KIN400, KIN2000, or SB-9200.
  • the pharmacologically active agent is selected from a group consisting of: S-27609, CL307, UC-IV150, imiquimod, gardiquimod, resiquimod, motolimod, VTS-1463GS-9620, GSK2245035, TMX-101, TMX-201, TMX-202, isatoribine, AZD8848, MEDI9197, 3M-051, 3M-852, 3M-052, 3M-854A, S-34240, KU34B, or CL663.
  • the pharmacologically active agent is cytotoxic to cancer associated fibroblasts (CAFs).
  • the pharmacologically active agent polarizes tumor associated macrophage populations towards M1 macrophage and/or inhibits M2 macrophage immunosuppressive activity. In certain embodiments, the pharmacologically active agent accelerates T-cell priming and/or dendritic cell trafficking. In certain embodiments, the pharmacologically active agent inhibits or depletes Treg cells, such as by blocking immunosuppressive function or migration to lymph nodes and/or the tumor microenvironment. -24- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In certain embodiments, the pharmacologically active agent is an IAP Inhibitor agent(s).
  • Exemplary IAP Inhibitors include LCL161 Inhibitor, AZD5582, SM-164, BV6, Xevinapant, GDC-0152, ASTX660, CUDC-427, Embelin (or Embelic acid), MX69, MV1, Polygalacin D, UC-112, HY-125378m Tolinapant (ASTX660) and SBP-0636457.
  • the pharmacologically active agent is a BACE inhibitor.
  • the pharmacologically active agent is an FAK inhibitor.
  • the pharmacologically active agent is a VEGR inhibitor.
  • the pharmacologically active agent is an AKT inhibitor.
  • the pharmacologically active agent is a TAK1 inhibitor.
  • TAK1 inhibitors include 5Z-7-oxozeaenol, dehydroabietic acid, NG25, sarsasapogenin, takinib, TAK1-IN1, minnelide and triptolide.
  • the pharmacologically active agent is a RET inhibitor.
  • the pharmacologically active agent is a FLT3 inhibitor.
  • the pharmacologically active agent is a BCR/ABL inhibitor.
  • the pharmaceutical moiety D is an immuno-DASH inhibitor, i.e., an agent which inhibits the enzymatic activity of DPP9 (preferably inhibitors both DPP9 and DPP8 activity), and induces macrophage pyroptosis in vitro and/or in vivo.
  • an immuno-DASH inhibitor i.e., an agent which inhibits the enzymatic activity of DPP9 (preferably inhibitors both DPP9 and DPP8 activity), and induces macrophage pyroptosis in vitro and/or in vivo.
  • the immuno-DASH inhibitor for use in the method of the present invention are represented by the general formula; wherein R’ 1 is a small hydrophobic group, e.g., a lower alkyl or a halogen, or a cyclic or bicyclic of 4 to 10 carbons, which may be substituted or unsubstituted; R’4 is absent, or represents (independently) or a small hydrophobic group, such as a lower alkyl or a halogen; and n is an integer of 1, 2 or 3 (and is preferably 1).
  • R’ 1 is a small hydrophobic group, e.g., a lower alkyl or a halogen, or a cyclic or bicyclic of 4 to 10 carbons, which may be substituted or unsubstituted
  • R’4 is absent, or represents (independently) or a small hydrophobic group, such as a lower alkyl or a halogen
  • n is an integer of 1, 2 or 3 (and
  • the immuno-DASH inhibitor is represented by: -25- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225
  • the immuno-DASH inhibitor is one of the following:
  • the immuno-DASH inhibitor is a dipeptide boronic acid of valine and proline (Val-boroPro), and is preferably (d)-Ala-boroPro having the structure
  • Exemplary immuno-DASH prodrugs include , -26- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 , and pharmaceutically acceptable salts thereof.
  • the pharmaceutical moiety D is a STING agonist.
  • the STING agonist is represented in one of the following structures: Still another STING agonist that can be used as Drug Moiety in the present binder conjugates is Still other exemplary STING agonists that can be readily adapted for use as the Drug Moiety in the conjugates of the present invention are taught, merely to illustrate, in PCT -27- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 Publications WO2017123669A1, WO2015077354A1 and US Patent Publication US20150056224A1, which are incorporated by reference.
  • the STING agonist can be coupled to the linker though functional groups other than amines as shown above, such as through free hydroxyl groups for example.
  • TLR Toll-like receptor
  • TLR Toll-like receptor
  • TLR Toll-like receptor
  • TLR include, but are not limited to, TLR1/2 agonists, TLR2 agonists, TLR3 agonists (e.g., PolyI:C), TLR4 agonists (e.g., S-type lipopolysaccharide, paclitaxel, lipid A, and monophosphoryl lipid A), TLR5 agonists (e.g., flagellin), TLR6/2 agonists (e.g., MALP-2), TLR7 agonist, TLR7/8 agonists (e.g., gardiquimod, imiquimod, loxoribine, and resiquimod (R848)), TLR7/9 agonists (e.g., hydroxychloroquine sulfate), TLR8 agonists (e.g., motolimod (VTX-2337)), TLR9 agonists (e.g., CpG-ODN), and TLR11 agonist
  • Exemplary agonists of TRLs include: -28- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 -29- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225
  • the TRL agonist is a TRL7/8 agonist such as one of P ublication Nos. WO2008135791 ⁇ WO2016141092, which are incorporated by reference, also describe classes of imidazoquinoline compounds having immuno-modulating properties which act via TLR7.
  • TRL agonists that be readily adapted for use as the Drug Moiety of the binder conjugates of the present invention are disclosed in, for example, Yoo et al. “Structure–activity relationships in Toll-like receptor 7 agonistic 1H-imidazo[4,5-c]pyridines” Org. Biomol. Chem., 2013, 11, 6526-6545; Fletcher et al. “Masked oral prodrugs of Toll-like receptor 7 agonists: a new approach for the treatment of infectious disease”, 2006 Current opinion in investigational drugs (London, England). 7. 702-708; and Pryde et al. “The discovery of a novel prototype small molecule TLR7 agonist for the treatment of hepatitis C virus infection” Med.
  • the TRL agonists can be coupled to the linker though functional groups other than amines as shown above, such as through free hydroxyl groups for example.
  • the pharmaceutical moiety D is a RIG-1 agonist.
  • Retinoic acid- inducible gene I (RIG-1) agonists are used to induce innate immune responses.
  • RIG-I is responsible for the type-1 interferon (IFNI) response.
  • RIG-I Upon its activation, RIG-I activates its RIG-I inflammasome, which leads to pyroptosis, an immunogenic mechanism of programmed -30- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 cell death as well as the induction of pro-inflammatory cyotkines (Elion et al., Oncotarget. 2018; 9(48): 29007-29017). Pyroptosis results in the formation of pores in the plasma membrane, leading to hypotonic cell swelling and leakage of intracellular contents, including danger associated molecular patterns (DAMPs). The DAMPs and cytokines lead to a local acute inflammatory immune response.
  • DAMPs danger associated molecular patterns
  • RIG-I agonists examples include KIN700, KIN1148, KIN600, KIN500, KIN100, KIN101, KIN400, KIN2000, RGT100, and SD-9200.
  • RIG-I agonists for use in accordance with the present disclosure are described in International Publication No. WO 2019/236567, published December 12, 2019, incorporated by reference herein (v) Exemplary Anthracyclines
  • the pharmaceutical moiety D is an anthracycline or derivative thereof, preferably doxorubicin or other analogs that are able to induce immunogenic cell death of tumor cells.
  • Anthracyclines and analogs thereof specifically include, without limitation, doxorubicin, daunorubicin, epirubicin, idarubicin, pirarubicin, valrubicin, aclarubicin, mitoxantrone, actinomycin, bleomycin, plicamycin, and mitomycin.
  • the anthracycline moiety can be represented by the formula wherein, R c represents (C1-C6)alkyl, (C1-C6)hydroxyalkyl, or (C1-C6)alkanoyloxy(C1-C6)alkyl, in particular methyl, hydroxymethyl, diethoxyacetoxymethyl, or butyryloxymethyl; R d represents hydrogen, hydroxyl, or (C 1 -C 6 )alkoxy, in particular methoxy; -31- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 one of R e and R f represents a hydrogen atom; and the other represents a hydrogen atom or a hydroxy or tetrahydropyrany-2-yloxy (OTHP) group.
  • R c represents (C1-C6)alkyl, (C1-C6)hydroxyalkyl, or (C1-C6)alkanoyloxy(C1-C6)alkyl, in particular methyl, hydroxymethyl,
  • the pharmaceutical moiety D is a proteasome inhibitor.
  • Exemplary proteasome inhibitors include -32- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225
  • Exemplary proteasome prodrugs include ; -33- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 ; and pharmaceutically acceptable salts thereof.
  • Taxanes/Taxoids In certain embodiments, the pharmaceutical moiety D is a taxane. Taxanes are a class of diterpenes. The principal mechanism of action of the taxane class of drugs is the disruption of microtubule function.
  • Taxanes are essential to cell division, and taxanes stabilize GDP- bound tubulin in the microtubule, thereby inhibiting the process of cell division as depolymerization is prevented.
  • taxanes are mitotic inhibitors.
  • the vinca alkaloids prevent mitotic spindle formation through inhibition of tubulin -34- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 polymerization. Both taxanes and vinca alkaloids are, therefore, named spindle poisons or mitosis poisons, but they act in different ways. Taxanes are also thought to be radiosensitizing.
  • the pharmaceutical moiety D is a platinum-based agent.
  • Platinum-based antineoplastic drugs (informally called platins) are chemotherapeutic agents typically used to treat cancer. Platinum-based antineoplastic agents cause crosslinking of DNA as monoadduct, interstrand crosslinks, intrastrand crosslinks or DNA protein crosslinks. Usually they act on the adjacent N-7 position of guanine, forming a 1, 2 intrastrand crosslink. The resultant crosslinking inhibits DNA repair and/or DNA synthesis in cancer cells.
  • Platinum- based antineoplastic agents are sometimes described as "alkylating-like" due to similar effects as alkylating antineoplastic agents, although they do not have an alkyl group.
  • platinum-based agents include oxaliplatin, cisplatin, carboplatin, nedaplatin, picoplatin, phenanthriplatin, triplatin, spiroplatin, satraplatin, iproplatin, and satraplatin.
  • Exemplary platinum-based prodrugs include (ix) Exemplary BCR/ABL Kinases Inhibitors
  • the pharmaceutical moiety D is an inhibitor of ABL kinase inhibitor, and may be a BCR-ABL kinase inhibitor.
  • the pharmaceutical moiety D is a pan-inhibitor of ABL kinase inhibitor, and it may be a pan-BCR-ABL kinase inhibitor.
  • Exemplary pan-inhibitors include imatinib, nilotinib, dasatinib, bosutinib and ponatinib.
  • the BCR-ABL kinase inhibitor is a FMS-like tyrosine kinase 3 (FLT3) inhibitor such as quizartinib (AC220), crenolanib (CP-868596), midostaurin (PKC-412), lestaurtinib (CEP-701), 4SC-203, TTT- 3002, sorafenib (Bay-43-0006), Ponatinib (AP-24534), sunitinib (SU-11248) or tandutinib (MLN-0518).
  • FLT3 FMS-like tyrosine kinase 3
  • Exemplary BCR-ABL kinase inhibitor prodrugs include FAP-activated ponatinib prodrugs such as ; ; ; ; -36- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 .
  • An example of an FAP-activated sorafenib prodrugs is (x) Exemplary TAK1 Inhibitors
  • the pharmaceutical moiety D is a TAK1 inhibitor.
  • TAK1 inhibitors include 5Z-7-oxozeaenol, dehydroabietic acid, NG25, sarsasapogenin, takinib, TAK1-IN1, minnelide and triptolide, or a pharmaceutically acceptable salt or mixture thereof.
  • the ESO Regenerative agent is a RET inhibitor.
  • the drug moiety D is SM1-71, a potent multi-targeted acrylamide-modified TAK1 inhibitor, having a structure: -37- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225
  • An exemplary FAP-activated SM1-71 prodrug is: (xi) Exemplary Topoisomerase Inhibitors
  • the pharmaceutical moiety D is a topoisomerase inhibitor.
  • the drug moiety D is a topoisomerase I inhibitor.
  • Exemplary topoisomerase I inhibitor from which D may be selected include the group consisting of exatecan, lurtotecan, diflomotecan, gimatecan, lurtotecan, belotecan, edotecarin, topovale, rosettacin, cositecan, 9-aminocamptothecin, 10-hydroxy-camptothecin (HOCPT), silatecan, elmotecan, irinotecan (CPT-11; Camptosar), and topotecan.
  • the topoisomerase I inhibitor is camptothecin or an analog thereof, such as irinotecan, topotecan, silatecan, cositecan, exatecan, deruxtecan, lurtotecan, gimatecan, belotecan or rubitecan.
  • the topoisomerase I inhibitor is an active metabolite of camptothecin or an analog thereof, such as SN-38.
  • the drug moiety D is exatecan, having a structure .
  • An exemplary FAP-activated exatecan is represented in the formula: -38- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 .
  • the drug moiety D is topotecan, having a structure .
  • the drug moiety D is irinotecan, having a structure
  • the drug moiety D is SN-38, having a structure .
  • -39- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225
  • An exemplary topoisomerase I inhibitor prodrug is an FAP-activated exatecan, such as shown in the formula below.
  • the drug moiety D is a DNA topoisomerase II inhibitor.
  • Exemplary DNA topoisomerase II inhibitor include ones selected from the group consisting of etoposide, teniposide, and tafluposide.
  • the pharmaceutical moiety D is a chemotherapeutic agent, i.e., is a chemical compound useful in the treatment of cancer.
  • chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); delta-9- tetrahydrocannabinol (dronabinol, MARINOL); beta-lapachone; lapac
  • calicheamicin especially calicheamicin gamma1I and calicheamicin omegaI1 (see, e.g., Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33: 183-186 -40- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 (1994)); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-
  • the therapeutic moiety is a chemotherapeutic drug moiety.
  • chemotherapeutic drug moieties include, but are not limited to, platinum-based drugs (e.g., oxaliplatin, cisplatin, carboplatin, spiroplatin, iproplatin, satraplatin, etc.), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, and nitrosoureas), anti-metabolites (e.g., 5- fluorouracil (5-FU), azathioprine, methotrexate, leucovorin, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, pemetrexed, and raltitrexed), plant alkaloids (e.g., vincristine, vin
  • the agent is an anti-cancer agent.
  • the anti-cancer agent is selected from the group comprising anthracyclines, vinca drugs, vincristine, vinblastine, etoposide, mitomycins, bleomycins, folic acid derivatives, aminopterin, methotrexate, dichloromethotrexate, cytotoxic nucleoside analogs, 5-fluorouracil, gemcitabine, 5-azacytidine, the pteridine family of drugs, diynenes, podophyllotoxins, antiandrogens, biscalutamide, flutamide, nilutamide, cyproterone acetate, antifolates, topoisomerase inhibitors, topotecan, irinotecan, alkylating agents, cyclophosphamide, cisplatin
  • the pharmacological agent is a toxin, such as may be selected from the group consisting of maytansines, hemiasterlins, amanitins, camptothecans, exatecans, anthracyclines, pyrrolobenzodiazepines, and auristatins.
  • the FAP-activated prodrug releases a cyclin-dependent kinase (CDK) inhibitor upon cleavage by FAP.
  • CDK cyclin-dependent kinase
  • An exemplary CDK inhibitor is dinaciclib (MK-7965, SCH 727965), an inhibitor of CDK1, CDK2, CDK5, and CDK9.
  • CDK inhibitors are known.
  • flavopiridol is a non-selective CDK inhibitor that is undergoing human clinical trials for chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • Additional examples of CDK inhibitors include BAY1000394 (See WO 2013/139734 to Bayer Intellectual Property GmbH), compounds disclosed in WO 2014/078637 to Merck Patent GmbH, P276-00, (R)- roscovitine (also known as seliciclib), and alvocidib.
  • the FAP-activated prodrug releases a phosphatidylinositol 3- kinase (PI3K) inhibitor upon cleavage by FAP.
  • PI3K phosphatidylinositol 3- kinase
  • An exemplary PI3K inhibitor is buparlisib, also known as BKM120, an orally bioavailable specific oral inhibitor of the pan-class I phosphatidylinositol 3-kinase (PI3K) family of lipid kinases with potential antineoplastic activity.
  • PI3K inhibitor BKM120 specifically inhibits class I PIK3 in the PI3K/AKT kinase (or protein kinase B) signaling pathway in an ATP-competitive manner, thereby inhibiting the production of the secondary messenger phosphatidylinositol-3,4,5-trisphosphate and activation of the PI3K signaling pathway. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis.
  • An exemplary PI3K inhibitor prodrug is an FAP-activated buparlisib prodrugs such as .
  • the FAP-activated prodrug releases a mitogen-activated protein kinase (MEK) inhibitor upon cleavage by FAP.
  • MEK mitogen-activated protein kinase
  • An exemplary MEK inhibitor is TAK- 733, an orally bioavailable small-molecule inhibitor of MEK1 and MEK2 (MEK1/2) with potential antineoplastic activity.
  • MEK inhibitor TAK-733 selectively binds to and inhibits the activity of MEK1/2, preventing the activation of MEK1/2-dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling and tumor cell proliferation.
  • MEK1/2 (MAP2K1/K2) are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types.
  • the FAP-activated prodrug releases a B-Raf kinase (BRAF) inhibitor upon cleavage by FAP.
  • BRAF B-Raf kinase
  • An exemplary BRAF inhibitor is dabrafenib mesylate (GSK 2118436).
  • HDAC histone deacetylase
  • An exemplary HDAC inhibitor is entinostat, also known as SNDX-275 and MS-275.
  • the pharmacological agent is a toxin, such as may be selected from pyrrolobenzodiazepine compounds or derivatives thereof (e.g., PBD), auristatin compounds or derivatives thereof (e.g., MMAE, MMAF), maytansinoid compounds or derivatives thereof (e.g., maytansine, DM1, DM4, DM21), duocarmycin or derivatives thereof, nicotinamide phosphoribosyltransferase (NAMPT) inhibitors or derivatives thereof, tubulysin compounds or derivatives thereof, enediyne compounds or derivatives thereof (e.g., calicheamicin), anthracycline compounds or derivatives thereof (e.g., doxorubicin), pyrrole-based kinesin spindle protein (KSP) inhibitors or derivatives thereof, cryptophycin compounds or derivatives thereof (e.g., cryptophycin 52), drug efflux pump inhibitors or derivatives
  • PBD
  • the FAP-activated prodrugs of the invention can employ a heterocyclic self- eliminating moiety covalently linked to the drug moiety and the cleavable Substrate -44- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 Recongition Sequence moiety.
  • a self-eliminating moiety may be defined as a bifunctional chemical group which is capable of covalently linking together two spaced chemical moieties into a normally stable molecule, releasing one of said spaced chemical moieties from the molecule by means of enzymatic cleavage; and following said enzymatic cleavage, spontaneously cleaving from the remainder of the bifunctional chemical group to release the other of said spaced chemical moieties.
  • the self- eliminating moiety is covalently linked at one of its ends, directly or indirectly through a Spacer unit, to the ligand by an amide bond and covalently linked at its other end to a chemical reactive site (functional group) pending from the drug.
  • the derivatization of the drug moiety with the self-eliminating moiety may render the drug less pharmacologically active (e.g. less toxic) or not active at all until the drug is cleaved.
  • the FAP-activated prodrug is generally stable in circulation, or at least that should be the case in the absence of an enzyme capable of cleaving the amide bond between the substrate recognition sequence and the self-eliminating moiety.
  • the amide bond is cleaved initiating a spontaneous self- eliminating reaction resulting in the cleavage of the bond covalently linking the self- eliminating moiety to the drug, to thereby effect release of the pharmacologically active agent in its underivatized or pharmacologically active form.
  • the self-eliminating moiety in conjugates of the invention either incorporate one or more heteroatoms and thereby provides improved solubility, improves the rate of cleavage and decreases propensity for aggregation of the conjugate.
  • L 2 is a benzyloxycarbonyl group.
  • L 2 is wherein R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl.
  • R 1 is hydrogen.
  • R 1 is methyl.
  • L 2 is selected from
  • the self-eliminating moiety L 2 is selected from wherein U is O, S or NR 6 ; Q is CR 4 or N; V 1 , V 2 and V 3 are independently CR 4 or N provided that for formula II and III at least one of Q, V 1 and V 2 is N; T is NH, NR 6 , O or S pending from said drug moiety; R 1 , R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, —N(R 5 ) 2 , —N(R 5 ) 3 + , C 1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, —SO2R5, —S( O)R5, — SR5, —SO2N(R5)2, —C( O)R5, —CO2R5, —C( O)N(R5)2, —CN, —N
  • T when T is NH, it is derived from a primary amine (—NH2) pending from the drug moiety (prior to coupling to the self-eliminating moiety) and when T is N, it is derived from a secondary amine (—NH—) from the drug moiety (prior to coupling to the self-eliminating moiety).
  • T when T is O or S, it is derived from a hydroxyl (—OH) or sulfhydryl (—SH) group respectively pending from the drug moiety prior to coupling to the self-eliminating moiety.
  • the self-eliminating linker L 2 is p-aminobenzyloxycarbonyl (PABC).
  • PABC p-aminobenzyloxycarbonyl
  • the self-eliminating linker L 2 is 2,4- bis(hydroxymethyl)aniline.
  • Other exemplary self-eliminating linkers that are readily adapted for use in the present invention are taught in, for example, US Patent US7754681, WO2012074693A1, US9089614, EP1732607A2, WO2015038426A1, Walther et al.
  • a FAP-activated prodrug is formulated with a pharmaceutically acceptable excipient to form a composition.
  • a molecule or other substance/agent is considered “pharmaceutically acceptable” if it is approved or approvable by a regulatory agency of the Federal government or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans.
  • An excipient may be any inert (inactive), non-toxic agent, administered in combination with an FAP-activated prodrug.
  • Pharmaceutically acceptable excipients comprise a variety of materials known in the art, including but not limited to saccharides (such as glucose, lactose, and the like), preservatives such as antimicrobial agents, reconstitution aids, colorants, saline (such as phosphate buffered saline), and buffers.
  • an FAP-activated prodrug or composition is administered to a subject.
  • a subject may be any animal (e.g., a mammal), including, but not limited to, humans, non-human primates, canines, felines, and rodents.
  • a “subject” refers to a human subject.
  • the subject has a diseased tissue, such as a cancer. Therefore, a FAP-activated prodrug or composition may be administered to a subject to treat a diseased tissue, such as cancer.
  • a FAP-activated prodrug is used to manufacture a medicament for the treatment of a diseased tissue (e.g., cancer).
  • Non- limiting examples of cancers include skin cancer (e.g., melanoma or non-melanoma, such as basal cell or squamous cell), lung cancer, prostate cancer, breast cancer, colorectal cancer, kidney (renal) cancer, bladder cancer, non-Hodgkin’s lymphoma, thyroid cancer, endometrial cancer, exocrine cancer, and pancreatic cancer.
  • skin cancer e.g., melanoma or non-melanoma, such as basal cell or squamous cell
  • lung cancer e.g., prostate cancer, breast cancer, colorectal cancer, kidney (renal) cancer, bladder cancer, non-Hodgkin’s lymphoma, thyroid cancer, endometrial cancer, exocrine cancer, and pancreatic cancer.
  • treat refers to the process of alleviating at least one symptom associated with a disease (e.g., cancer).
  • a symptom may be a physical, mental, or pathological manifestation of a disease.
  • a FAP-activated prodrug as provided herein should be administered in an effective amount, which can be any amount used to treat or prevent the condition.
  • an effective amount is an amount used to alleviate a symptom associated with the particular disease being treated.
  • Methods are known for determining effective amounts of various therapeutic molecules, for example. -48- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 Routes of administration include intravenous, intramuscular, intratumoral, intraperitoneal, intranasal, and subcutaneous. Other routes of administration are encompassed by the present disclosure.
  • the FAP-activated prodrugs of the present disclosure may be formulated for intravenous, intramuscular, intratumoral, intraperitoneal, intranasal, or subcutaneous administration.
  • FAP-activated prodrugs of the present disclosure may be formulated for intravenous, intramuscular, intratumoral, intraperitoneal, intranasal, or subcutaneous administration.
  • Certain Definitions Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art.
  • agent is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or -49- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 animal (particularly mammalian) cells or tissues.
  • Agents include, for example, agents whose structure is known, and those whose structure is not known.
  • drug means a medicine or other substance which has a physiological effect when ingested or otherwise introduced into the body.
  • a drug is a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or a condition.
  • active pharmaceutical moiety means the core molecule or ion of a drug (i.e., the drug molecule without certain appendages) that is responsible for the physiological or pharmacological action of a drug substance.
  • a “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal.
  • Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • the term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • administering or “administration of” a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and -50- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 transdermally (by absorption, e.g., through a skin duct).
  • a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods. Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and/or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity).
  • a compound or an agent is administered orally, e.g., to a subject by ingestion.
  • the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
  • a therapeutically effective amount may be administered in one or more administrations.
  • the precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.
  • the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
  • “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.
  • the term “alkyl” refers to saturated aliphatic groups, including but not limited to C 1 -C 10 straight-chain alkyl groups or C 1 -C 10 branched-chain alkyl groups.
  • the “alkyl” group refers to C 1 -C 6 straight-chain alkyl groups or C 1 -C 6 branched- chain alkyl groups.
  • alkyl refers to C 1 -C 4 straight-chain alkyl groups or C 1 -C 4 branched-chain alkyl groups.
  • alkyl include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl and the like.
  • alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkyl refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted -52- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 cycloalkyl groups, and cycloalkyl-substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C 1- 30 for straight chains, C 3-30 for branched chains), and more preferably 20 or fewer.
  • alkyl as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2- trifluoroethyl, etc.
  • C x-y or “C x -C y ”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • C 0 alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • a C 1-6 alkyl group for example, contains from one to six carbon atoms in the chain.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • alkylS- refers to a group , wherein R 9 and R 10 each independently represent a hydrogen or hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by , wherein R 9 , R 10 , and R 10 ’ each independently represent a hydrogen or a hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7-membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • carbamate is art-recognized and refers to a group , wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • the term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct- 3-ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H- indene and bicyclo[4.1.0]hept-3-ene.
  • Carbocycles may be substituted at any one or more positions capable of bearing a hydrogen atom.
  • carbonate is art-recognized and refers to a group -OCO 2 -.
  • cycloalkyl includes substituted or unsubstituted non-aromatic single ring structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings.
  • cycloalkyl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is cycloalkyl and the substituent (e.g., R 100 ) is attached to the cycloalkyl ring, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, and the like.
  • esteer refers to a group -C(O)OR 9 wherein R 9 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-.
  • Ethers may be either symmetrical or unsymmetrical.
  • ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle.
  • Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • halo and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
  • heteroalkyl and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • -55- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”.
  • rings e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls
  • TUV-18225 of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • sulfate is art-recognized and refers to the group –OSO 3 H, or a pharmaceutically acceptable salt thereof.
  • sulfonamido is art-recognized and refers to the group represented by the general formulae , wherein R 9 and R 10 independently represents hydrogen or hydrocarbyl.
  • sulfoxide is art-recognized and refers to the group–S(O)-.
  • sulfonate is art-recognized and refers to the group SO 3 H, or a pharmaceutically acceptable salt thereof.
  • sulfone is art-recognized and refers to the group –S(O) 2 -.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(O)SR 9 or –SC(O)R 9 wherein R 9 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
  • urea is art-recognized and may be represented by the general formula , wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl.
  • modulate as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.
  • pharmaceutically acceptable is art-recognized.
  • the term includes compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.
  • pharmaceutically acceptable acid addition salt means any non-toxic organic or inorganic salt of any base compounds represented by Formula I.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sul
  • the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection of the appropriate salt will be known to one skilled in the art.
  • Other non- pharmaceutically acceptable salts e.g., oxalates, may be used, for example, in the isolation of -58- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable basic addition salt as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.
  • Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in an R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30.
  • the disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726. Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (ent ought) isomers. In each instance, the disclosure includes both mixture and separate individual isomers.
  • Prodrug or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example, hydrolyzed or oxidized, in the host after administration to form the physiologically active “drug” or “active pharmaceutical moiety.”
  • Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.
  • prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference.
  • the prodrugs of this disclosure are metabolized to produce a compound of Formula I.
  • the present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, -59- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.
  • the term “Log of solubility”, “LogS” or “logS” as used herein is used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption.
  • LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol/liter.
  • carbon atoms or hydrogen atoms in alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more elements selected from the group consisting of 0, S, N or with groups containing one or more elements selected from the group consisting of 0, S, N.
  • Embodiments include alkoxy, cycloalkoxy, arykoxy, aralkoxy, alkenyloxy, cycloalkenyloxy, alkynyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, alkenylthio, cycloalkenylthio, alkynylthio, alkylamino, cycloalkylamino, arylamino, aralkylamino, alkenylamino, cycloalkenylamino, alkynylamino radicals.
  • hydrogen atoms in alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more halogen atoms.
  • One radical is the trifluoromethyl radical.
  • a wording defining the limits of a range oflength such as, e. g., "from 1 to 6" means any integer from 1 to 6, i.e. 1, 2, 3, 4, 5 and 6.
  • any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.
  • linker refers to any chemically suitable linker.
  • linker are not or only slowly cleaved under physiological conditions.
  • the linker does not comprise recognition sequences for proteases or recognition structures for other degrading enzymes. Since it is preferred that the compounds of the invention are administered systemically to allow broad access to all compartments of the body and subsequently enrichment of the compounds of the invention wherever in the body the tumor is -60- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 located, it is preferred that the linker is chosen in such that it is not or only slowly cleaved in blood.
  • Suitable linkers comprises or consists of optionally substituted alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, aralkyl, heteroaralyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, sulfonyl, amines, ethers, thioethers phosphines, phosphoramidates, carboxamides, esters, imidoesters, amidines, thioesters, sulfonamides, 3-thiopyrrolidine-2,5-dion, carbamates, ureas, guanidines, thioureas, disulfides, oximes, hydrazines, hydr
  • the linker comprises or consists of 1,4-piperazine, 1,3-propane and a phenolic ether or combinations thereof.
  • amino acid refers to any organic acid containing one or more amino substituents, e.g. ⁇ -, ⁇ - or ⁇ -amino, derivatives of aliphatic carboxylic acids.
  • conventional amino acid refers to the twenty naturally occurring amino acids, and encompasses all stereometric isoforms, i.e. D, L-, D- and L-amino acids thereof.
  • H 2 /Pd-C MeOH
  • vii. 4-Aminobenzyl alcohol, HATU, DIEA, DMF
  • viii. 4- Nitrophenyl chloroformate, DIEA, Py-ACN; ix. 2, 5, TEA, DMF; x. TFA-TIPS-DCM; xi. 7- (tert-Butoxy)-7-oxoheptanoic acid, COMU, DIEA, DMF; xii. TFA-TIPS-DCM (80:4:16); xiii. 8, HATU, DIEA, DMF; xiv. PhB(OH) 2 , TBME-H 2 O.
  • TFA-TIPS-DCM ix.7-(tert-Butoxy)-7-oxoheptanoic acid, COMU, DIEA, DMF; x. TFA- TIPS-DCM (80:4:16); xi. 8, HATU, DIEA, DMF. -66- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 VI. Synthetic Scheme for Compound EB-6323 Synthetic Scheme 6. i. L-boroPro-pn.HCl, HATU, DIEA, DMF; ii. 4N HCl in dioxane; iii. 2- Chlorotrityl Chloride Resin, DIPEA, DCM; iv.
  • Synthetic Scheme for Compound 7894E-BV Synthetic Scheme 11 i. NBS, PPh3, THF; ii. PON, NaI, THF, 65'C; iii. TFA-TIPS-DCM; iv. N-Boc-4-AMB-OH, HATU, DIEA, DMF; v. TFA-TIPS-DCM; vi. EB-P, HATU, DIEA, DMF. INCORPORATION BY REFERENCE All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually -71- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 indicated to be incorporated by reference.

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Abstract

Disclosed are prodrugs activated by fibroblast-activation protein a (FAP) and other tumor-microenvironment proteases, and methods of use thereof.

Description

Attorney Docket No.: TUV-18225 Enzyme-Activated Prodrugs with Small Molecule-Mediated Extended Serum Half-Life RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application Number 63/819,295, filed June 6, 2025; and U.S. Provisional Application Number 63/658,177, filed June 10, 2024. The contents of each of the aforementioned applications is incorporated by reference. BACKGROUND The therapeutic index (TI) is critically important in the development of cancer drugs because it helps determine how safe and effective a drug is. The therapeutic index is the ratio between the Toxic Dose (TD or LD ), i.e., the dose that causes toxicity or is lethal in 50% of subjects, and the Effective Dose (ED ), i.e., the dose that produces the desired therapeutic effect in 50% of subjects. TI = TD / ED . A higher TI means there's a bigger margin between effective and harmful doses, which is ideal. Many cancer drugs are inherently toxic, targeting rapidly dividing cells (which includes healthy ones like bone marrow or gut lining cells). The goal is to kill cancer cells while minimizing harm to healthy tissues. A drug with a low therapeutic index may still be used, but with careful monitoring (e.g., chemotherapy with regular blood tests). If a drug has a narrow TI, doctors may need to personalize dosages based on the patient’s weight, metabolism, or genetic factors to reduce the risk of toxicity. In cancer treatment, the therapeutic index is essential because it defines how safely a drug can be used to maximize tumor-killing effects while limiting damage to the patient. It's a key factor in selecting, dosing, and monitoring anti-cancer therapies. More recently, researchers in the field have designed and developed a Fibroblast Activation Protein Alpha (herein “FAPα” or “FAP”)-activated prodrugs. FAP is a type II integral membrane serine protease expressed on the surface of some types of tumor cells, but importantly on the surface of carcinoma-associated fibroblasts (CAFs) in the stroma of greater than 90% of solid tumors examined, but not on adjacent normal tissues. Fibroblast-activation protein a (FAP), also known as Seprase, is a type II integral membrane serine peptidase. FAP belongs to the dipeptidyl peptidase IV family. It is a 170 kDa homodimer containing two N-glycosylated subunits with a large C-terminal extracellular domain, in which the enzyme's catalytic domain is located. FAP, in its glycosylated form, has -1- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 both post-prolyl dipeptidyl peptidase and gelatinase activities. Homologues of human FAP were found in several species, including mice and cynomolgus monkeys. FAP is a member of the dipeptidyl peptidase subfamily whose members are characterized by the ability to cleave the peptide bond following a proline residue. Normal adult tissues generally do not express detectable amounts of FAP. In contrast, FAP is expressed in reactive stromal fibroblasts of epithelial cancers, granulation tissue of healing wounds, and malignant cells of bone and soft tissue sarcomas. FAP is thought to be involved in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis. FAP is expressed selectively in reactive stromal fibroblasts of more than 90% of epithelial malignancies (primary and metastatic) examined, including lung, colorectal, bladder, ovarian and breast carcinomas, and in malignant mesenchymal cells of bone and soft tissue sarcomas, while it is generally absent from normal adult tissues (Brennen et al., Mol. Cancer Ther. 11 (2): 257-266 (2012); Garin-Chesa et al., Proc Natl Acad Sci USA 87, 7235-7239 (1990); Rettig et al., Cancer Res. 53:3327-3335 (1993); Rettig et al., Proc Natl Acad Sci USA 85, 3110-3114 (1988)). FAP is also expressed on certain malignant tumor cells. Significantly, most common types of epithelial cancers, including more than 90 percent of breast, non-small cell lung, and colorectal carcinomas, contain FAP-expressing stromal fibroblasts. Scanlan et al. Proc Natl Acad Sci USA 91:5657-61 (1994). Because in adults its expression is restricted to pathologic sites, including cancer, fibrosis, arthritis, wounding, and inflammation, FAP can provide target specificity to therapeutic agents. Due to its expression in many common cancers and its restricted expression in normal tissues, FAP has been considered a promising antigenic target for imaging, diagnosis and therapy of a variety of cancers. Various approaches have been devised to exploit the selective expression of FAP in tumor stroma for clinical benefit, including monoclonal antibodies against FAP, small-molecule inhibitors of FAP enzymatic activity, FAP-activated prodrugs of cytotoxic compounds and FAP-specific CAR-T cells. In the quest for developing FAP-activated prodrugs providing higher therapeutic indexes relative to the parent drug molecule, finding FAP-substrates which are selectively activated in the body only by FAP and not by other enzymes is paramount. SUMMARY OF THE INVENTION In one aspect, the present disclosure provides enzyme activated prodrugs represented by formula I or a pharmaceutically acceptable salt thereof: -2- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 HSA– L1 – SRS – L2 – D (I) wherein, D is a drug or an active pharmaceutical moiety; SRS represents a substrate recognition sequence which is enzymatically cleaved by a target enzyme; L1 is a bond or a linker; L2 is a bond or a self-eliminating linker which, after enzymatic cleavage of the substrate recognition sequence SRS by the target enzyme, is released from the prodrug to produce the pharmacologically active parent drug; and HSA is a moiety that binds to human serum albumin with a Kd of 1 x 10-6 or less, has a molecular weight of 2000 amu or less, and confers an increase in serum half-life of the prodrug by 10-fold or more relative to parent drug D. In another aspect, the present disclosure provides pharmaceutical compositions comprising the prodrug disclosed herein and a pharmaceutically acceptable excipient. In yet another aspect, the present disclosure provides methods for treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a prodrug disclosed herein, or a pharmaceutically acceptable salt thereof, to the subject. In certain embodiments, the prodrug may be further characterized by one or more of the following features: • the prodrug has less than 50% of the therapeutic activity of the active form of the parent pharmacological agent, and more preferably less than 60%, 70%, 80%, 90%, 95%, or even 98%; • the prodrug has a therapeutic index that is at least 2 times greater than the therapeutic index of the parent pharmacological agent alone, and more preferably at least 5, 10, 50, 100, 250, 500, 1000, 5000, or even 10,000 times greater; • a larger percentage of the released pharmacological agent is localized in the target tissue, i.e., the tissue expressing the target enzyme, relative to administration of the parent pharmacological agent alone, when compared on an equivalent dose basis— i.e., the ratio of active agent localized to the target tissue relative to other tissue (such as blood, liver or heart) is at least 2 times greater for an equivalent dose of the prodrug relative to the agent alone, and preferably at least 5, 10, 100, or even 1000 times greater; -3- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 • the maximum tolerated dose of the prodrug is at least 2 times greater than the maximum tolerated dose of the pharmacological agent if administered as the parent agent, and even more preferably at least 5, 10, 100, or even 1000 times greater; • the cell permeability of the prodrug is at least 50% less than the cell permeability of the parent pharmacological agent, and even more preferably at least 60%, 70%, 80%, 90%, 95%, 98%, 99%, or even 99.9% less; • the circulating half-life of the prodrug is at least 25% longer than the circulating half-life of the parent pharmacological agent alone, and even more preferably at least 50%, 75%, 100%, 150%, 200%, 500%, 750%, or even 1000% longer; and/or • the circulating half-life of the prodrug is at least 5 hours, and more preferably at least 10, 20, 30, 40, 48, 60, 72 or even at least 100 hours. In certain embodiments, the pharmacologically active agent is a low-molecular agent, i.e., having a molecular weight less than 5000 amu, preferably less than 2500 amu and even more preferably less than 1500 amu. In certain embodiments, the parent pharmacological agent comprises a free amine to which the substrate recognition sequence can be directly coupled by way of a covalent bond with the C-terminal carbonyl of the substrate recognition sequence moiety, so as to create an amide bond between the two moieties; or to which a self-eliminating linker can be coupled as a bridge between the substrate recognition sequence and the drug agent moiety. In other embodiments, the parent pharmacological agent moiety comprises a functional group other than an amine to which a self-eliminating linker can be coupled, or which can otherwise form a bond with the C-terminal carbonyl of the substrate recognition sequence, which resulting covalent bond can be cleaved by the target enzyme. In certain embodiments, the invention provides a prodrug for fibroblast activation protein (FAP)-dependent release of an pharmacologically active agent, comprising an FAP substrate covalently linked to a drug agent via a bond or a self-eliminating linker. Upon cleavage by FAP of the FAP substrate, the drug agent is released in its active form or in a form that is readily metabolized to its active form. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows a cell killing assay comparing the ability of 6707-PRO (see Synthetic Scheme 9), a ponatinib prodrug, to kill KCL22 cells in the presence of recombinant human FAP (rhFAP) – which activates – versus the presence of the selective FAP inhibitor 5057. The assay is a cell titer-blue viability assay. The EC50 for cell killing in the presence of the FAP -4- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 inhibitor was 110nM, while in the presence of rhFAP was more potent at 0.2nM. Expressed as a “prodrug activation ratio”, 6707-PRO had an FAP activation ratio of 550. FIG. 2 shows the serum half-life for 6707-PRO for each of human and mouse serum. DETAILED DESCRIPTION OF THE INVENTION In one aspect, the present disclosure provides enzyme activated prodrugs represented by formula I or a pharmaceutically acceptable salt thereof: HSA – L1 – SRS – L2 – D (I) wherein, D is a drug or an active pharmaceutical moiety; SRS represents a substrate recognition sequence which is enzymatically cleaved by a target enzyme; L1 is a bond or a linker; L2 is a bond or a self-eliminating linker which, after enzymatic cleavage of the substrate recognition sequence SRS by the target enzyme, is released from the prodrug to produce the parent drug; and HSA is a moiety that binds to human serum albumin with a Kd of 1 x 10-6 or less, has a molecular weight of 2000 amu or less, and increases the serum half-life of D by 10- fold or more relative to parent D. In certain embodiments, the parent pharmacological agent comprises a free amine to which the SRS moiety, such as a FAP substrate recognition sequence, can be directly coupled by way of a covalent bond with the C-terminal carbonyl of the SRS moiety, so as to create an amide bond between the two moieties; or to which a self-eliminating linker can be coupled as a bridge between the SRS moiety and agent moieties. In other embodiments, the parent pharmacological agent moiety comprises a functional group other than an amine to which a self-eliminating linker can be coupled, or which can otherwise form a bond with the C-terminal carbonyl of the SRS moiety, which resulting covalent bond can be cleaved by target enzyme. In certain embodiments, a larger percentage of the released pharmacological agent is localized in the target tissue, i.e., the tissue expressing FAP or other target enzyme, relative to administration of the parent pharmacological agent alone, when compared on an equivalent dose basis—i.e., the ratio of active agent localized to the target tissue relative to other tissue (such as blood, liver or heart) is at least 2 times greater for an equivalent dose of the prodrug relative to the agent alone, and preferably at least 5, 10, 100, or even 1000 times greater; -5- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In certain embodiments, the SRS is a FAP substrate recognition sequence. For example, the FAP substrate recognition sequence can comprise a dipeptide represented in the general formula wherein A is a 5-7 membered heterocycle and R1 is H or a lower alkyl (which may be straight chain or branched), and if a lower alkyl may be optionally substituted with a hydroxyl group. Upon cleavage by FAP of the FAP substrate recognition sequence, the prodrug releases the pharmacological agent as the pharmacologically active agent or in an intermediary form having one or more self-eliminating linkers that are readily metabolized to the pharmacologically active agent. In certain embodiments, the FAP substrate recognition sequence contains a dipeptide represented in the general formula wherein: R1 is as defined above; n is 1, 2, or 3; and each R4 is independently H, (C1-C6) alkyl, OH, —NH2, or halogen. In certain embodiments, the FAP substrate recognition sequence which contains a dipeptide represented in the general formula -6- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 wherein R1, n and R4 are as defined above. In certain embodiments, the FAP substrate recognition sequence contains a (d)-Ala-Pro dipeptide represented in the general formula In certain embodiments, the prodrug is an FAP-activated prodrug having a kcat/Km for cleavage by FAP at least 10-fold greater than for cleavage by prolyl endopeptidase (EC 3.4.21.26; PREP), and even more preferably at least 100-fold, 1000-fold, 5000-fold, or even 10,000-fold greater kcat/Km. In certain embodiments, the prodrug is an FAP-activated prodrug having a kcat/Km, for cleavage by FAP at least 10-fold greater than for cleavage by at least one mammalian “DPP IV activity- and/or structure-homologues” (DASH) enzyme, such as DPP-2, DPP-4, DPP-7, DPP-8, and/or DPP-9, and even more preferably at least 50, 100, 250, 500, 1000, 5000, or even 10,000 times greater. In certain embodiments, the prodrug is an FAP-activated prodrug represented by formula IIa or a pharmaceutically acceptable salt thereof: IIa L2 is a bond and -NH-L-D is the pharmacologically active agent, or -7- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 L2 is a self-eliminating linker which, after FAP cleavage of the FAP substrate recognition sequence, is released from the prodrug to release D as the pharmacologically active agent; A is a 5-7 membered heterocycle; R1 is H or alkyl (e.g., lower alkyl); B is C5-C8 monocyclic ring or a C8-C12 bicyclic ring; R2 is H, -OH, or alkyl (e.g., lower alkyl); and each Ra is, independently, H, alkyl, or aralkyl. In certain embodiments, the prodrug is an FAP-activated prodrug represented by formula IIb or a pharmaceutically acceptable salt thereof: n is 1, 2, or 3; and each R4 is independently H, (C1-C6) alkyl, —OH, —NH2, or halogen. In certain embodiments, the prodrug is represented by formula II or a pharmaceutically acceptable salt thereof: -8- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 wherein, n is 1, 2, or 3; and each R4 is independently H, (C1-C6) alkyl, —OH, —NH2, or halogen. In certain embodiments, R1 is (C1-C10)alkyl (e.g., methyl). In other embodiments, R1 is Ser. In yet other embodiments, R1 is Thr. In yet other embodiments, R1 is -alanine. In certain embodiments, In certain embodiments, In certain embodiments, R2 is the side chain of Arg or Lys. In certain embodiments, R2 is the side chain of homoarginine. In certain embodiments, R2 is a Dap-derived -guanidino acid arginine mimetics. In certain embodiments, Ra is H or methyl. In yet other embodiments, X is . In certain embodiments, the prodrug is an FAP-activated prodrug represented by formula III or a pharmaceutically acceptable salt thereof: -9- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 wherein, n is 1, 2, or 3; and R4 is absent or represents a (C1-C6) alkyl, —OH, —NH2, or halogen. In certain embodiments, L1 is N-Succinimidyl 4-(2-pyridylthio) pentanoate, N- Succinimidyl 4-(N-maleimidomethyl) cyclohexane-1 carboxylate, or N-Succinimidyl (4-iodo- acetyl) aminobenzoate. In certain embodiments, L1 is a polyether. In certain embodiments, L1 is a poly(ethylene glycol). In certain embodiments, L1 is: ; and p is 1 to 100. In certain embodiments, p is 6 to 50. In certain embodiments, p is 6 to 12. 1 In certain embodiments, L is represented by: ; and p is 1 to 20. In certain embodiments, p is 1 to 4. -10- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In certain embodiments, L2 is selected from the group consisting of —NH—(CH2)4— C(=O)—, —NH—(CH2)3—C(=O)—, p-aminobenzyloxycarbonyl (PABC), and 2,4- bis(hydroxymethyl)aniline. In certain embodiments, the prodrug is represented by formula IIa or a pharmaceutically acceptable salt thereof: IIa A is a 5-7 membered heterocycle; R1 is H or alkyl (e.g., lower alkyl); B is C5-C8 monocyclic ring or a C8-C12 bicyclic ring; R2 is H, -OH, or alkyl (e.g., lower alkyl); and each is independently Ra is H, alkyl, or aralkyl. In certain embodiments, the prodrug is represented by formula IIb or a pharmaceutically acceptable salt thereof: -11- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 IIb wherein, n is 1, 2, or 3; and each R4 is independently H, (C1-C6) alkyl, —OH, —NH2, or halogen. In certain embodiments, the prodrug is represented by formula II or a pharmaceutically acceptable salt thereof: wherein, n is 1, 2, or 3; and each R4 is independently H, (C1-C6) alkyl, —OH, —NH2, or halogen. In certain embodiments, R1 is (C1-C10)alkyl (e.g., methyl). In other embodiments, R1 is Ser. In yet other embodiments, R1 is Thr. In yet other embodiments, R1 is -alanine. -12- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In certain embodiments, R2 is the side chain of Arg or Lys. In certain embodiments, R2 is the side chain of homoarginine. In certain embodiments, R2 is a Dap-derived -guanidino acid arginine mimetics. In certain embodiments, Ra is H or methyl. In yet other embodiments, X is . In certain embodiments, the prodrug is represented by formula III or a pharmaceutically acceptable salt thereof: wherein, n is 1, 2, or 3; and R4 is absent or represents a (C1-C6) alkyl, —OH, —NH2, or halogen. In certain embodiments, L1 is N-Succinimidyl 4-(2-pyridylthio) pentanoate, N- Succinimidyl 4-(N-maleimidomethyl) cyclohexane-1 carboxylate, or N-Succinimidyl (4-iodo- acetyl) aminobenzoate. In certain embodiments, L1 is a polyether. In certain embodiments, L1 -13- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 ; and p is 1 to 100. In certain embodiments, p is 6 to 50. In certain embodiments, p is 6 to 12. In certain embodiments, L1 is represented by: ; and p is 1 to 20. In certain embodiments, p is 1 to 4. In certain embodiments, HSA is -14- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In yet other embodiments, HSA is . In certain embodiments, the prodrug is represented by formula IVa or a pharmaceutically acceptable salt thereof: IVa. In certain embodiments, the prodrug is represented by formula IVb or a pharmaceutically acceptable salt thereof: IVb. -15- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In certain embodiments, the prodrug is represented by formula IVc or a pharmaceutically acceptable salt thereof: IVc. In certain embodiments, the prodrug is represented by formula IVd or a pharmaceutically acceptable salt thereof: IVd. In certain embodiments, the drug is an immunomodulator. In certain embodiments, the drug is an immune activating agent. In certain embodiments, the immunomodulator induces an innate immunity pathway. In certain embodiments, the immunomodulator is an immuno-DASH inhibitor that inhibits the enzymatic activity of DPP8 and DPP9 and induces macrophage pyroptosis. In certain embodiments, the immunomodulator is a STING agonist. In certain embodiments, the immunomodulator is a RIG-1 agonist. In certain embodiments, the immunomodulator is a Toll-like receptor (TLR) agonist, such as a TLR1/2 agonist, a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR6/2 agonist, a TLR7 agonist, a TLR7/8 agonist, a TLR7/9 agonist, a TLR8 agonist, a -16- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 TLR9 agonist, and a TLR11 agonist, preferably selected from the group consisting of a TLR3 agonist, a TLR7 agonist, a TLR7/8 agonist, and a TLR9 agonist. In certain embodiments, the drug is cytotoxic to cancer associated fibroblasts (CAFs). In certain embodiments, the drug polarizes tumor associated macrophage towards M1 macrophage or inhibits M2 macrophage immunosuppressive activity. In certain embodiments, the drug accelerates T-cell priming and/or dendritic cell trafficking. In certain embodiments, the drug inhibits or depletes Treg cells, such as by blocking immunosuppressive function or migration to lymph nodes and/or the tumor microenvironment. In certain embodiments, the Therapeutic Index of the prodrug is at least 5 times greater than the Therapeutic Index for the free drug when given systemically, more preferably at least 10, 20, 30, 40, 50, 75 or even 100 times greater. In certain embodiments, the drug has a molecular weight less than 5000 amu, preferably less than 2500 amu. In certain embodiments, the drug is Val-boroPro. In certain embodiments, L2 is selected from the group consisting of —NH—(CH2)4— C(=O)—, p-aminobenzyloxycarbonyl (PABC), and 2,4- bis(hydroxymethyl)aniline. In certain embodiments, the prodrug is selected from the group consisting of , -17- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 , a pharmaceutically acceptable salt thereof. In certain embodiments, the prodrug is selected from the group consisting of , , and -18- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 ; or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides pharmaceutical compositions comprising the prodrug disclosed herein and a pharmaceutically acceptable excipient. In yet another aspect, the present disclosure provides methods for treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a prodrug disclosed herein, or a pharmaceutically acceptable salt thereof, to the subject. In certain embodiments, the cancer is acute myeloid leukemia (AML). In another embodiment, the prodrug includes a parent drug with from 2 to 5 HSA/SRS containing moieties appended thereto, preferably 2 or 3, and more preferably 2. For instance, such prodrugs can be represented by formula or a pharmaceutically acceptable salt thereof: wherein, D, SRS, L1, L2 and HSA are as defined above, and q is an integer from 2-5. In certain embodiments, q is 2. For example, the SRS can be an FAP substrate recognition sequences and the prodrug can be represented by the general formula wherein D, A, R1, L1, L2, X and HSA are as defined above, and q is an integer from 2-5. In certain embodiments, q is 2. In certain embodiments, the prodrug can be represented by the general formula -19- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 wherein D, R1, R4, L1, L2, X, HSA and n are as defined above, and q is an integer from 2-5. In certain embodiments, q is 2. In certain embodiments, R1 is CH3 and n is 1. The HSA moiety is one which confers serum half-life extension to the prodrug (relative to the parent drug) by functioning as a serum albumin binding moiety. In certain embodiments, the serum albumin binding moiety is a moiety that binds to human serum albumin with a Kd of 500 micromolar or less, and more preferably a Kd for human serum albumin binding of less than 250 micromolar, 100 micromolar, 10 micromolar, 1 micromolar, 100 nanomolar or even 10 nanomolar. In certain embodiments, the serum albumin binding moiety has a molecular weight of 3000 amu or less. In certain embodiments, the serum albumin binding moiety increases the serum half-life of the prodrug by 10-fold or more relative to the pharmacologically active agent, and even more preferably by more than 20-fold, 50-fold, 100-fold, 500-fold, 1000-fold or even 10000-fold. In certain embodiments, HSA is a serum albumin binder comprising an Evans blue moiety (or analog thereof), such as may be selected from: ; -20- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 . In certain embodiments, HSA is a serum albumin binder comprising an iodophenyl, preferably a p-iodophenyl, such as may be selected from: . In other embodiments, HSA is a serum albumin binding macrocyclic, such as -21- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In still other embodiments, HSA is a serum albumin binding peptide, such as In still other embodiments, the HSA moiety is selected from: -22- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 . A. Exemplary Pharmacologically Active Agents In certain embodiments, the Therapeutic Index of the prodrug is at least 5 times greater than the Therapeutic Index for the free drug when given systemically, more preferably at least 10, 20, 30, 40, 50, 75 or even 100 times greater. In certain embodiments, the drug has a molecular weight less than 5000 amu, preferably less than 2500 amu. A wide range of drug entities can be used as the pharmacologically active moiety of the subject prodrugs. For instance, the pharmacologically active moiety can be selected from a chemotherapeutic agent, a toxin, a cytokine, a growth inhibitory agent, a protein degrader, a peptide, a radionuclide, a hormone, an anti-viral agent, an anti-bacterial agent, an immunoregulatory agent, a fluorophore, a dye, or a contrast agent. In certain embodiments, the pharmacologically active agent is an immunomodulator – which includes drug moieties acting as immune activating agents and/or inducers of an innate immunity pathway response. In certain embodiments, the pharmacologically active agent induces the production of IFN- . In certain embodiments, the pharmacologically active agent induces the production of proinflammatory cytokines. In certain embodiments, the pharmacologically active agent induces the production of IL-1β. In certain embodiments, the pharmacologically active agent induces the production of IL-18. In certain embodiments, the pharmacologically active agent promotes the expansion and survival of effector cells including NK, T, and CD8+ T cells. -23- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In certain embodiments, the pharmacologically active agent is an immuno-DASH inhibitor that inhibits the enzymatic activity of DPP8 and DPP9, and induces macrophage pyroptosis in vitro and/or in vivo. In certain embodiments, the pharmacologically active agent is a damage-associated molecular pattern molecule. In certain embodiments, the pharmacologically active agent is a pathogen-associated molecular pattern molecule. In certain embodiments, the pharmacologically active agent is a STING agonist. In certain embodiments, the pharmacologically active agent is a RIG-1 agonist. In certain embodiments, the pharmacologically active agent is a Toll-like receptor (TLR) agonist, such as a selected from the group consisting of a TLR1/2 agonist, a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR6/2 agonist, a TLR7 agonist, a TLR7/8 agonist, a TLR7/9 agonist, a TLR8 agonist, a TLR9 agonist, and a TLR11 agonist, preferably selected from the group consisting of a TLR3 agonist, a TLR7 agonist, a TLR7/8 agonist, and a TLR9 agonist. In certain embodiments, the pharmacologically active agent is a cyclic dinucleotide. In certain embodiments, the pharmacologically active agent is ADU-S100. In certain embodiments, the pharmacologically active agent is a RIG-I agonist, wherein the RIG-I agonist is KIN700, KIN1148, KIN600, KIN500, KIN100, KIN101, KIN400, KIN2000, or SB-9200. In certain embodiments, the pharmacologically active agent is selected from a group consisting of: S-27609, CL307, UC-IV150, imiquimod, gardiquimod, resiquimod, motolimod, VTS-1463GS-9620, GSK2245035, TMX-101, TMX-201, TMX-202, isatoribine, AZD8848, MEDI9197, 3M-051, 3M-852, 3M-052, 3M-854A, S-34240, KU34B, or CL663. In certain embodiments, the pharmacologically active agent is cytotoxic to cancer associated fibroblasts (CAFs). In certain embodiments, the pharmacologically active agent polarizes tumor associated macrophage populations towards M1 macrophage and/or inhibits M2 macrophage immunosuppressive activity. In certain embodiments, the pharmacologically active agent accelerates T-cell priming and/or dendritic cell trafficking. In certain embodiments, the pharmacologically active agent inhibits or depletes Treg cells, such as by blocking immunosuppressive function or migration to lymph nodes and/or the tumor microenvironment. -24- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In certain embodiments, the pharmacologically active agent is an IAP Inhibitor agent(s). Exemplary IAP Inhibitors include LCL161 Inhibitor, AZD5582, SM-164, BV6, Xevinapant, GDC-0152, ASTX660, CUDC-427, Embelin (or Embelic acid), MX69, MV1, Polygalacin D, UC-112, HY-125378m Tolinapant (ASTX660) and SBP-0636457. In certain embodiments, the pharmacologically active agent is a BACE inhibitor. In certain embodiments, the pharmacologically active agent is an FAK inhibitor. In certain embodiments, the pharmacologically active agent is a VEGR inhibitor. In certain embodiments, the pharmacologically active agent is an AKT inhibitor. In certain embodiments, the pharmacologically active agent is a TAK1 inhibitor. Exemplary TAK1 inhibitors include 5Z-7-oxozeaenol, dehydroabietic acid, NG25, sarsasapogenin, takinib, TAK1-IN1, minnelide and triptolide. In certain embodiments, the pharmacologically active agent is a RET inhibitor. In certain embodiments, the pharmacologically active agent is a FLT3 inhibitor. In certain embodiments, the pharmacologically active agent is a BCR/ABL inhibitor. (i) Exemplary immuno-DASH Inhibitors In certain embodiments, the pharmaceutical moiety D is an immuno-DASH inhibitor, i.e., an agent which inhibits the enzymatic activity of DPP9 (preferably inhibitors both DPP9 and DPP8 activity), and induces macrophage pyroptosis in vitro and/or in vivo. In certain embodiments, the immuno-DASH inhibitor for use in the method of the present invention are represented by the general formula; wherein R’1 is a small hydrophobic group, e.g., a lower alkyl or a halogen, or a cyclic or bicyclic of 4 to 10 carbons, which may be substituted or unsubstituted; R’4 is absent, or represents (independently) or a small hydrophobic group, such as a lower alkyl or a halogen; and n is an integer of 1, 2 or 3 (and is preferably 1). In some embodiments, the immuno-DASH inhibitor is represented by: -25- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In some embodiments, the immuno-DASH inhibitor is one of the following: In certain preferred embodiments, the immuno-DASH inhibitor is a dipeptide boronic acid of valine and proline (Val-boroPro), and is preferably (d)-Ala-boroPro having the structure Exemplary immuno-DASH prodrugs include , -26- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 , and pharmaceutically acceptable salts thereof. (ii) Exemplary STING Agonists In certain embodiments, the pharmaceutical moiety D is a STING agonist. In certain embodiments, the STING agonist is represented in one of the following structures: Still another STING agonist that can be used as Drug Moiety in the present binder conjugates is Still other exemplary STING agonists that can be readily adapted for use as the Drug Moiety in the conjugates of the present invention are taught, merely to illustrate, in PCT -27- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 Publications WO2017123669A1, WO2015077354A1 and US Patent Publication US20150056224A1, which are incorporated by reference. It will also be appreciated by those skilled in the art that, particularly with the use of a self-eliminating linker, the STING agonist can be coupled to the linker though functional groups other than amines as shown above, such as through free hydroxyl groups for example. (iii) Exemplary TLR Agonists In certain embodiments, the pharmaceutical moiety D is Toll-like receptor (TLR) agonist. Examples of the “Toll-like receptor (TLR) agonist” include, but are not limited to, TLR1/2 agonists, TLR2 agonists, TLR3 agonists (e.g., PolyI:C), TLR4 agonists (e.g., S-type lipopolysaccharide, paclitaxel, lipid A, and monophosphoryl lipid A), TLR5 agonists (e.g., flagellin), TLR6/2 agonists (e.g., MALP-2), TLR7 agonist, TLR7/8 agonists (e.g., gardiquimod, imiquimod, loxoribine, and resiquimod (R848)), TLR7/9 agonists (e.g., hydroxychloroquine sulfate), TLR8 agonists (e.g., motolimod (VTX-2337)), TLR9 agonists (e.g., CpG-ODN), and TLR11 agonists (e.g., profilin). Exemplary TRL agonists that can be used as the Drug Moiety in the binder conjugates of the present invention include S-27609, CL307, UC-IV150, imiquimod, gardiquimod, resiquimod, motolimod, VTS-1463GS-9620, GSK2245035, TMX-101, TMX-201, TMX-202, isatoribine, AZD8848, MEDI9197, 3M-051, 3M-852, 3M-052, 3M-854A, S-34240, KU34B, or CL663, or as appropriate, analogs thereof with appropriate functional groups for directed linkage and release from the substrate recognition sequence or by linkage to a self-eliminating linker. Exemplary agonists of TRLs, particularly TRL7 agonists, TRL8 agonists and TRL7/8 agonists include: -28- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 -29- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In other embodiments, the TRL agonist is a TRL7/8 agonist such as one of Publication Nos. WO2008135791 ̧ WO2016141092, which are incorporated by reference, also describe classes of imidazoquinoline compounds having immuno-modulating properties which act via TLR7. Other exemplary TRL agonists that be readily adapted for use as the Drug Moiety of the binder conjugates of the present invention are disclosed in, for example, Yoo et al. “Structure–activity relationships in Toll-like receptor 7 agonistic 1H-imidazo[4,5-c]pyridines” Org. Biomol. Chem., 2013, 11, 6526-6545; Fletcher et al. “Masked oral prodrugs of Toll-like receptor 7 agonists: a new approach for the treatment of infectious disease”, 2006 Current opinion in investigational drugs (London, England). 7. 702-708; and Pryde et al. “The discovery of a novel prototype small molecule TLR7 agonist for the treatment of hepatitis C virus infection” Med. Chem. Commun., 2011, 2, 185-189. It will also be appreciated by those skilled in the art that, particularly with the use of a self-eliminating linker, the TRL agonists can be coupled to the linker though functional groups other than amines as shown above, such as through free hydroxyl groups for example. (iv) Exemplary RIG-1 Agonists In certain embodiments, the pharmaceutical moiety D is a RIG-1 agonist. Retinoic acid- inducible gene I (RIG-1) agonists are used to induce innate immune responses. RIG-I is responsible for the type-1 interferon (IFNI) response. Upon its activation, RIG-I activates its RIG-I inflammasome, which leads to pyroptosis, an immunogenic mechanism of programmed -30- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 cell death as well as the induction of pro-inflammatory cyotkines (Elion et al., Oncotarget. 2018; 9(48): 29007-29017). Pyroptosis results in the formation of pores in the plasma membrane, leading to hypotonic cell swelling and leakage of intracellular contents, including danger associated molecular patterns (DAMPs). The DAMPs and cytokines lead to a local acute inflammatory immune response. Examples of RIG-I agonists include KIN700, KIN1148, KIN600, KIN500, KIN100, KIN101, KIN400, KIN2000, RGT100, and SD-9200. Other non-limiting examples of RIG-I agonists for use in accordance with the present disclosure are described in International Publication No. WO 2019/236567, published December 12, 2019, incorporated by reference herein (v) Exemplary Anthracyclines In certain embodiments, the pharmaceutical moiety D is an anthracycline or derivative thereof, preferably doxorubicin or other analogs that are able to induce immunogenic cell death of tumor cells. Anthracyclines and analogs thereof specifically include, without limitation, doxorubicin, daunorubicin, epirubicin, idarubicin, pirarubicin, valrubicin, aclarubicin, mitoxantrone, actinomycin, bleomycin, plicamycin, and mitomycin. For example, the anthracycline moiety can be represented by the formula wherein, Rc represents (C1-C6)alkyl, (C1-C6)hydroxyalkyl, or (C1-C6)alkanoyloxy(C1-C6)alkyl, in particular methyl, hydroxymethyl, diethoxyacetoxymethyl, or butyryloxymethyl; Rd represents hydrogen, hydroxyl, or (C1-C6)alkoxy, in particular methoxy; -31- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 one of Re and Rf represents a hydrogen atom; and the other represents a hydrogen atom or a hydroxy or tetrahydropyrany-2-yloxy (OTHP) group. (vi) Exemplary Proteasome Inhibitors In certain embodiments, the pharmaceutical moiety D is a proteasome inhibitor. Exemplary proteasome inhibitors include -32- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 Exemplary proteasome prodrugs include ; -33- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 ; and pharmaceutically acceptable salts thereof. (vii) Taxanes/Taxoids In certain embodiments, the pharmaceutical moiety D is a taxane. Taxanes are a class of diterpenes. The principal mechanism of action of the taxane class of drugs is the disruption of microtubule function. Microtubules are essential to cell division, and taxanes stabilize GDP- bound tubulin in the microtubule, thereby inhibiting the process of cell division as depolymerization is prevented. Thus, in essence, taxanes are mitotic inhibitors. In contrast to the taxanes, the vinca alkaloids prevent mitotic spindle formation through inhibition of tubulin -34- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 polymerization. Both taxanes and vinca alkaloids are, therefore, named spindle poisons or mitosis poisons, but they act in different ways. Taxanes are also thought to be radiosensitizing. Non-limiting examples of taxanes include paclitaxel, docetaxel, and cabazitaxel. (viii) Platinum-Based Agents In certain embodiments, the pharmaceutical moiety D is a platinum-based agent. Platinum- based antineoplastic drugs (informally called platins) are chemotherapeutic agents typically used to treat cancer. Platinum-based antineoplastic agents cause crosslinking of DNA as monoadduct, interstrand crosslinks, intrastrand crosslinks or DNA protein crosslinks. Mostly they act on the adjacent N-7 position of guanine, forming a 1, 2 intrastrand crosslink. The resultant crosslinking inhibits DNA repair and/or DNA synthesis in cancer cells. Platinum- based antineoplastic agents are sometimes described as "alkylating-like" due to similar effects as alkylating antineoplastic agents, although they do not have an alkyl group. Non-limiting examples of platinum-based agents include oxaliplatin, cisplatin, carboplatin, nedaplatin, picoplatin, phenanthriplatin, triplatin, spiroplatin, satraplatin, iproplatin, and satraplatin. Exemplary platinum-based prodrugs include (ix) Exemplary BCR/ABL Kinases Inhibitors In certain embodiments, the pharmaceutical moiety D is an inhibitor of ABL kinase inhibitor, and may be a BCR-ABL kinase inhibitor. In certain embodiments, the pharmaceutical moiety D is a pan-inhibitor of ABL kinase inhibitor, and it may be a pan-BCR-ABL kinase inhibitor. Exemplary pan-inhibitors include imatinib, nilotinib, dasatinib, bosutinib and ponatinib. In certain embodiments, the BCR-ABL kinase inhibitor is a FMS-like tyrosine kinase 3 (FLT3) inhibitor such as quizartinib (AC220), crenolanib (CP-868596), midostaurin (PKC-412), lestaurtinib (CEP-701), 4SC-203, TTT- 3002, sorafenib (Bay-43-0006), Ponatinib (AP-24534), sunitinib (SU-11248) or tandutinib (MLN-0518). -35- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 Exemplary BCR-ABL kinase inhibitor prodrugs include FAP-activated ponatinib prodrugs such as ; ; ; ; -36- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 . An example of an FAP-activated sorafenib prodrugs is (x) Exemplary TAK1 Inhibitors In certain embodiments, the pharmaceutical moiety D is a TAK1 inhibitor. Exemplary TAK1 inhibitors include 5Z-7-oxozeaenol, dehydroabietic acid, NG25, sarsasapogenin, takinib, TAK1-IN1, minnelide and triptolide, or a pharmaceutically acceptable salt or mixture thereof. In certain embodiments, the ESO Regenerative agent is a RET inhibitor. In certain embodiments, the drug moiety D is SM1-71, a potent multi-targeted acrylamide-modified TAK1 inhibitor, having a structure: -37- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 An exemplary FAP-activated SM1-71 prodrug is: (xi) Exemplary Topoisomerase Inhibitors In certain embodiments, the pharmaceutical moiety D is a topoisomerase inhibitor. In certain preferred embodiments, the drug moiety D is a topoisomerase I inhibitor. Exemplary topoisomerase I inhibitor from which D may be selected include the group consisting of exatecan, lurtotecan, diflomotecan, gimatecan, lurtotecan, belotecan, edotecarin, topovale, rosettacin, cositecan, 9-aminocamptothecin, 10-hydroxy-camptothecin (HOCPT), silatecan, elmotecan, irinotecan (CPT-11; Camptosar), and topotecan. In certain embodiments, the topoisomerase I inhibitor is camptothecin or an analog thereof, such as irinotecan, topotecan, silatecan, cositecan, exatecan, deruxtecan, lurtotecan, gimatecan, belotecan or rubitecan. In certain embodiments, the topoisomerase I inhibitor is an active metabolite of camptothecin or an analog thereof, such as SN-38. In certain embodiments, the drug moiety D is exatecan, having a structure . An exemplary FAP-activated exatecan is represented in the formula: -38- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 . In certain embodiments, the drug moiety D is topotecan, having a structure . In certain embodiments, the drug moiety D is irinotecan, having a structure In certain embodiments, the drug moiety D is SN-38, having a structure . -39- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 An exemplary topoisomerase I inhibitor prodrug is an FAP-activated exatecan, such as shown in the formula below. In certain embodiments, the drug moiety D is a DNA topoisomerase II inhibitor. Exemplary DNA topoisomerase II inhibitor include ones selected from the group consisting of etoposide, teniposide, and tafluposide. (xii) Other Exemplary Pharmacological Drug Entities In certain embodiments, the pharmaceutical moiety D is a chemotherapeutic agent, i.e., is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); delta-9- tetrahydrocannabinol (dronabinol, MARINOL); beta-lapachone; lapachol; colchicines; betulinic acid; a camptothecin (including the synthetic analogue topotecan (HYCAMTIN), CPT-11 (irinotecan, CAMPTOSAR), acetylcamptothecin, scopolectin, and 9- aminocamptothecin); bryostatin; pemetrexed; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); podophyllotoxin; podophyllinic acid; teniposide; cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; TLK-286; CDP323, an oral alpha-4 integrin inhibitor; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e. g., calicheamicin, especially calicheamicin gamma1I and calicheamicin omegaI1 (see, e.g., Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33: 183-186 -40- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 (1994)); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, doxorubicin (including ADRIAMYCIN, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin HCl liposome injection (DOXIL) and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate, gemcitabine (GEMZAR), tegafur (UFTORAL), capecitabine (XELODA), an epothilone, and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, and imatinib (a 2-phenylaminopyrimidine derivative), as well as other c-Kit inhibitors; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2 ,2 -trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine (ELDISINE, FILDESIN); dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); thiotepa; taxoids, e.g., paclitaxel (TAXOL), albumin-engineered nanoparticle formulation of paclitaxel (ABRAXANE), and doxetaxel (TAXOTERE); chloranbucil; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine (VELBAN); platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine (ONCOVIN); oxaliplatin; leucovovin; vinorelbine (NAVELBINE); novantrone; edatrexate; daunomycin; aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluorometlhylornithine (DMFO); retinoids such as retinoic acid; pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an -41- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN) combined with 5-FU and leucovovin. In still other embodiments, the therapeutic moiety is a chemotherapeutic drug moiety. Examples of chemotherapeutic drug moieties include, but are not limited to, platinum-based drugs (e.g., oxaliplatin, cisplatin, carboplatin, spiroplatin, iproplatin, satraplatin, etc.), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, and nitrosoureas), anti-metabolites (e.g., 5- fluorouracil (5-FU), azathioprine, methotrexate, leucovorin, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, pemetrexed, and raltitrexed), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel (taxol), and docetaxel), topoisomerase inhibitors (e.g., irinotecan (CPT-11; Camptosar), topotecan, amsacrine, etoposide (VP16), etoposide phosphate, and teniposide), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, and plicamycin), tyrosine kinase inhibitors (e.g., gefltinib (IRESSA®), sunitinib (SUTENT®; SU11248), erlotinib (TARCEVA®; OSI-1774), lapatinib (GW572016; GW2016), canertinib (Cl 1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY 43-9006), imatinib (GLEEVEC®; STI571), dasatinib (BMS-354825), leflunomide (SU101), vandetanib (ZACTIMA™; ZD6474), pharmaceutically acceptable salts thereof, stereoisomers thereof, derivatives thereof, analogs thereof, and combinations thereof. Other non-limiting examples of therapeutic moieties are provided in WO 2019/236567, incorporated herein by reference. `In certain embodiments, the agent is an anti-cancer agent. In certain embodiments, the anti-cancer agent is selected from the group comprising anthracyclines, vinca drugs, vincristine, vinblastine, etoposide, mitomycins, bleomycins, folic acid derivatives, aminopterin, methotrexate, dichloromethotrexate, cytotoxic nucleoside analogs, 5-fluorouracil, gemcitabine, 5-azacytidine, the pteridine family of drugs, diynenes, podophyllotoxins, antiandrogens, biscalutamide, flutamide, nilutamide, cyproterone acetate, antifolates, topoisomerase inhibitors, topotecan, irinotecan, alkylating agents, cyclophosphamide, cisplatin, carboplatin, ifosfamide, nitrogen mustard alkylating agents, melphalan, taxanes, paclitaxel, docetaxel), naphthalimides, amonafide, tirapazamine (SR- 4233). -42- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In certain embodiments, the pharmacological agent is a toxin, such as may be selected from the group consisting of maytansines, hemiasterlins, amanitins, camptothecans, exatecans, anthracyclines, pyrrolobenzodiazepines, and auristatins. In certain embodiments, the FAP-activated prodrug releases a cyclin-dependent kinase (CDK) inhibitor upon cleavage by FAP. An exemplary CDK inhibitor is dinaciclib (MK-7965, SCH 727965), an inhibitor of CDK1, CDK2, CDK5, and CDK9. A Phase I trial on the effect of dinaciclib in combination with aprepitant was performed in patients with advanced malignancies. Other CDK inhibitors are known. For example, flavopiridol is a non-selective CDK inhibitor that is undergoing human clinical trials for chronic lymphocytic leukemia (CLL). Senderowicz et al. J. Clin. Oncol. 16(9): 2986-2999 (1998). Additional examples of CDK inhibitors include BAY1000394 (See WO 2013/139734 to Bayer Intellectual Property GmbH), compounds disclosed in WO 2014/078637 to Merck Patent GmbH, P276-00, (R)- roscovitine (also known as seliciclib), and alvocidib. In certain embodiments, the FAP-activated prodrug releases a phosphatidylinositol 3- kinase (PI3K) inhibitor upon cleavage by FAP. An exemplary PI3K inhibitor is buparlisib, also known as BKM120, an orally bioavailable specific oral inhibitor of the pan-class I phosphatidylinositol 3-kinase (PI3K) family of lipid kinases with potential antineoplastic activity. PI3K inhibitor BKM120 specifically inhibits class I PIK3 in the PI3K/AKT kinase (or protein kinase B) signaling pathway in an ATP-competitive manner, thereby inhibiting the production of the secondary messenger phosphatidylinositol-3,4,5-trisphosphate and activation of the PI3K signaling pathway. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis. An exemplary PI3K inhibitor prodrug is an FAP-activated buparlisib prodrugs such as . -43- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In certain embodiments, the FAP-activated prodrug releases a mitogen-activated protein kinase (MEK) inhibitor upon cleavage by FAP. An exemplary MEK inhibitor is TAK- 733, an orally bioavailable small-molecule inhibitor of MEK1 and MEK2 (MEK1/2) with potential antineoplastic activity. MEK inhibitor TAK-733 selectively binds to and inhibits the activity of MEK1/2, preventing the activation of MEK1/2-dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling and tumor cell proliferation. MEK1/2 (MAP2K1/K2) are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types. In certain embodiments, the FAP-activated prodrug releases a B-Raf kinase (BRAF) inhibitor upon cleavage by FAP. An exemplary BRAF inhibitor is dabrafenib mesylate (GSK 2118436). In certain embodiments, the FAP-activated prodrug releases a histone deacetylase (HDAC) inhibitor upon cleavage by FAP. An exemplary HDAC inhibitor is entinostat, also known as SNDX-275 and MS-275. In certain embodiments, the pharmacological agent is a toxin, such as may be selected from pyrrolobenzodiazepine compounds or derivatives thereof (e.g., PBD), auristatin compounds or derivatives thereof (e.g., MMAE, MMAF), maytansinoid compounds or derivatives thereof (e.g., maytansine, DM1, DM4, DM21), duocarmycin or derivatives thereof, nicotinamide phosphoribosyltransferase (NAMPT) inhibitors or derivatives thereof, tubulysin compounds or derivatives thereof, enediyne compounds or derivatives thereof (e.g., calicheamicin), anthracycline compounds or derivatives thereof (e.g., doxorubicin), pyrrole-based kinesin spindle protein (KSP) inhibitors or derivatives thereof, cryptophycin compounds or derivatives thereof (e.g., cryptophycin 52), drug efflux pump inhibitors or derivatives thereof, sandramycin or derivatives thereof, amanitin compounds or derivatives thereof, or camptothecin compounds or derivatives thereof (e.g., SN-38, belotecan, exatecan, deruxtecan) In certain embodiments, the pharmacological agent is a toxin, such as may be selected from the group consisting of maytansines, hemiasterlins, amanitins, camptothecans, exatecans, anthracyclines, pyrrolobenzodiazepines, and auristatins. B. Exemplary Self-Eliminating Linkers The FAP-activated prodrugs of the invention can employ a heterocyclic self- eliminating moiety covalently linked to the drug moiety and the cleavable Substrate -44- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 Recongition Sequence moiety. A self-eliminating moiety may be defined as a bifunctional chemical group which is capable of covalently linking together two spaced chemical moieties into a normally stable molecule, releasing one of said spaced chemical moieties from the molecule by means of enzymatic cleavage; and following said enzymatic cleavage, spontaneously cleaving from the remainder of the bifunctional chemical group to release the other of said spaced chemical moieties. In accordance with the present invention, the self- eliminating moiety is covalently linked at one of its ends, directly or indirectly through a Spacer unit, to the ligand by an amide bond and covalently linked at its other end to a chemical reactive site (functional group) pending from the drug. The derivatization of the drug moiety with the self-eliminating moiety may render the drug less pharmacologically active (e.g. less toxic) or not active at all until the drug is cleaved. The FAP-activated prodrug is generally stable in circulation, or at least that should be the case in the absence of an enzyme capable of cleaving the amide bond between the substrate recognition sequence and the self-eliminating moiety. However, upon exposure of the FAP- activated prodrug to a suitable enzyme, the amide bond is cleaved initiating a spontaneous self- eliminating reaction resulting in the cleavage of the bond covalently linking the self- eliminating moiety to the drug, to thereby effect release of the pharmacologically active agent in its underivatized or pharmacologically active form. The self-eliminating moiety in conjugates of the invention either incorporate one or more heteroatoms and thereby provides improved solubility, improves the rate of cleavage and decreases propensity for aggregation of the conjugate. These improvements of the heterocyclic self-eliminating linker constructs of the present invention over non-heterocyclic, PAB-type linkers may result in surprising and unexpected biological properties such as increased efficacy, decreased toxicity, and more desirable pharmacokinetics. In certain embodiments, L2 is a benzyloxycarbonyl group. In certain embodiments, L2 is wherein R1 is hydrogen, unsubstituted or substituted C1-3 alkyl, or unsubstituted or substituted heterocyclyl. -45- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 In certain embodiments, R1 is hydrogen. In certain instances, R1 is methyl. In certain embodiments, L2 is selected from In certain embodiments, the self-eliminating moiety L2 is selected from wherein U is O, S or NR6; Q is CR4 or N; V1, V2 and V3 are independently CR4 or N provided that for formula II and III at least one of Q, V1 and V2 is N; T is NH, NR6, O or S pending from said drug moiety; R1, R2, R3 and R4 are independently selected from H, F, Cl, Br, I, OH, —N(R5)2, —N(R5)3 +, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, —SO2R5, —S( O)R5, — SR5, —SO2N(R5)2, —C( O)R5, —CO2R5, —C( O)N(R5)2, —CN, —N3, —NO2, C1- C8 alkoxy, C1-C8 halosubstituted alkyl, polyethyleneoxy, phosphonate, phosphate, C1- -46- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 C8 alkyl, C1-C8 substituted alkyl, C2-C8 alkenyl, C2-C8 substituted alkenyl, C2- C8 alkynyl, C2-C8 substituted alkynyl, C6-C20 aryl, C6-C20 substituted aryl, C1- C20 heterocycle, and C1-C20 substituted heterocycle; or when taken together, R2 and R3form a carbonyl ( O), or spiro carbocyclic ring of 3 to 7 carbon atoms; and R5 and R6 are independently selected from H, C1-C8 alkyl, C1-C8substituted alkyl, C2- C8 alkenyl, C2-C8 substituted alkenyl, C2-C8alkynyl, C2-C8 substituted alkynyl, C6- C20 aryl, C6-C20 substituted aryl, C1-C20 heterocycle, and C1-C20 substituted heterocycle; where C1-C8 substituted alkyl, C2-C8 substituted alkenyl, C2-C8substituted alkynyl, C6- C20 substituted aryl, and C2-C20 substituted heterocycle are independently substituted with one or more substituents selected from F, Cl, Br, I, OH, —N(R5)2, —N(R5)3 +, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, C1-C8 alkylsulfonate, C1- C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, — SO2R5, —S( O)R5, —SR5, —SO2N(R5)2, —C( O)R5, —CO2R5, —C( O)N(R5)2, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C3- C12 carbocycle, C6-C20 aryl, C2-C20 heterocycle, polyethyleneoxy, phosphonate, and phosphate. It will be understood that when T is NH, it is derived from a primary amine (—NH2) pending from the drug moiety (prior to coupling to the self-eliminating moiety) and when T is N, it is derived from a secondary amine (—NH—) from the drug moiety (prior to coupling to the self-eliminating moiety). Similarly, when T is O or S, it is derived from a hydroxyl (—OH) or sulfhydryl (—SH) group respectively pending from the drug moiety prior to coupling to the self-eliminating moiety. In certain embodiments, the self-eliminating linker L2 is —NH—(CH2)4—C(=O)— or —NH—(CH2)3—C(=O)—. In certain embodiments, the self-eliminating linker L2 is p-aminobenzyloxycarbonyl (PABC). In certain embodiments, the self-eliminating linker L2 is 2,4- bis(hydroxymethyl)aniline. Other exemplary self-eliminating linkers that are readily adapted for use in the present invention are taught in, for example, US Patent US7754681, WO2012074693A1, US9089614, EP1732607A2, WO2015038426A1, Walther et al. “Prodrugs in medicinal chemistry and enzyme prodrug therapies” Adv Drug Deliv Rev.2017 Sep 1;118:65-77, and Tranoy-Opalinski et al. “Design of self-eliminating linkers for tumour-activated prodrug therapy”, Anticancer -47- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 Agents Med Chem. 2008 Aug;8(6):618-37; the teachings of which are each incorporated by reference herein. D. Therapeutic Compositions and Methods of Use In some embodiments, a FAP-activated prodrug is formulated with a pharmaceutically acceptable excipient to form a composition. A molecule or other substance/agent is considered “pharmaceutically acceptable” if it is approved or approvable by a regulatory agency of the Federal government or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans. An excipient may be any inert (inactive), non-toxic agent, administered in combination with an FAP-activated prodrug. Pharmaceutically acceptable excipients comprise a variety of materials known in the art, including but not limited to saccharides (such as glucose, lactose, and the like), preservatives such as antimicrobial agents, reconstitution aids, colorants, saline (such as phosphate buffered saline), and buffers. In some embodiments, an FAP-activated prodrug or composition is administered to a subject. A subject may be any animal (e.g., a mammal), including, but not limited to, humans, non-human primates, canines, felines, and rodents. A “subject” refers to a human subject. In some embodiments, the subject has a diseased tissue, such as a cancer. Therefore, a FAP-activated prodrug or composition may be administered to a subject to treat a diseased tissue, such as cancer. In some embodiments, a FAP-activated prodrug is used to manufacture a medicament for the treatment of a diseased tissue (e.g., cancer). Non- limiting examples of cancers include skin cancer (e.g., melanoma or non-melanoma, such as basal cell or squamous cell), lung cancer, prostate cancer, breast cancer, colorectal cancer, kidney (renal) cancer, bladder cancer, non-Hodgkin’s lymphoma, thyroid cancer, endometrial cancer, exocrine cancer, and pancreatic cancer. Other cancers are contemplated herein. The term treat, as known in the art, refers to the process of alleviating at least one symptom associated with a disease (e.g., cancer). A symptom may be a physical, mental, or pathological manifestation of a disease. Symptoms associated with various diseases are known. To treat or prevent a particular condition, a FAP-activated prodrug as provided herein should be administered in an effective amount, which can be any amount used to treat or prevent the condition. Thus, in some embodiments, an effective amount is an amount used to alleviate a symptom associated with the particular disease being treated. Methods are known for determining effective amounts of various therapeutic molecules, for example. -48- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 Routes of administration include intravenous, intramuscular, intratumoral, intraperitoneal, intranasal, and subcutaneous. Other routes of administration are encompassed by the present disclosure. Thus, the FAP-activated prodrugs of the present disclosure may be formulated for intravenous, intramuscular, intratumoral, intraperitoneal, intranasal, or subcutaneous administration. E. Certain Definitions Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art. The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000). Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985). All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control. The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or -49- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known. The term “drug” means a medicine or other substance which has a physiological effect when ingested or otherwise introduced into the body. A drug is a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or a condition. The term “active pharmaceutical moiety” means the core molecule or ion of a drug (i.e., the drug molecule without certain appendages) that is responsible for the physiological or pharmacological action of a drug substance. A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats). “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount. “Administering” or “administration of” a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and -50- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods. Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and/or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents. A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation. As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted. -51- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. As used herein, the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O- alkyl, -OP(O)(O-alkyl)2 or –CH2-OP(O)(O-alkyl)2. Preferably, “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted. As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C1-C10 branched-chain alkyl groups. Preferably, the “alkyl” group refers to C1-C6 straight-chain alkyl groups or C1-C6 branched- chain alkyl groups. Most preferably, the “alkyl” group refers to C1-C4 straight-chain alkyl groups or C1-C4 branched-chain alkyl groups. Examples of “alkyl” include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl and the like. The “alkyl” group may be optionally substituted. The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-. The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-. The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-. The term “alkoxy” refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like. The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl. The term “alkyl” refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted -52- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1- 30 for straight chains, C3-30 for branched chains), and more preferably 20 or fewer. Moreover, the term “alkyl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2- trifluoroethyl, etc. The term “Cx-y” or “Cx-Cy”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. C0alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. A C1-6alkyl group, for example, contains from one to six carbon atoms in the chain. The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group. The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-. The term “amido”, as used herein, refers to a group , wherein R9 and R10 each independently represent a hydrogen or hydrocarbyl group, or R9 and R10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by , wherein R9, R10, and R10’ each independently represent a hydrogen or a hydrocarbyl group, or R9 and R10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group. -53- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group. The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. The term “carbamate” is art-recognized and refers to a group , wherein R9 and R10 independently represent hydrogen or a hydrocarbyl group. The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group. The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct- 3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H- indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom. The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group. The term “carbonate” is art-recognized and refers to a group -OCO2-. -54- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 The term “carboxy”, as used herein, refers to a group represented by the formula -CO2H. The term “cycloalkyl” includes substituted or unsubstituted non-aromatic single ring structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings. The term “cycloalkyl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is cycloalkyl and the substituent (e.g., R100) is attached to the cycloalkyl ring, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, and the like. The term “ester”, as used herein, refers to a group -C(O)OR9 wherein R9 represents a hydrocarbyl group. The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl. The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo. The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group. The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur. -55- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group. The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent, and typically has at least one carbon- hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof. The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group. The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent). The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each -56- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7. The term “sulfate” is art-recognized and refers to the group –OSO3H, or a pharmaceutically acceptable salt thereof. The term “sulfonamido” is art-recognized and refers to the group represented by the general formulae , wherein R9 and R10 independently represents hydrogen or hydrocarbyl. The term “sulfoxide” is art-recognized and refers to the group–S(O)-. The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof. The term “sulfone” is art-recognized and refers to the group –S(O)2-. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. -57- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group. The term “thioester”, as used herein, refers to a group -C(O)SR9 or –SC(O)R9 wherein R9 represents a hydrocarbyl. The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur. The term “urea” is art-recognized and may be represented by the general formula , wherein R9 and R10 independently represent hydrogen or a hydrocarbyl. The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity. The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients. The term “pharmaceutically acceptable acid addition salt” as used herein means any non-toxic organic or inorganic salt of any base compounds represented by Formula I. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non- pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of -58- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art. Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in an R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726. Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers. “Prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example, hydrolyzed or oxidized, in the host after administration to form the physiologically active “drug” or “active pharmaceutical moiety.” Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of this disclosure are metabolized to produce a compound of Formula I. The present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985. The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, -59- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use. The term “Log of solubility”, “LogS” or “logS” as used herein is used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption. LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol/liter. In certain embodiments, carbon atoms or hydrogen atoms in alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more elements selected from the group consisting of 0, S, N or with groups containing one or more elements selected from the group consisting of 0, S, N. Embodiments include alkoxy, cycloalkoxy, arykoxy, aralkoxy, alkenyloxy, cycloalkenyloxy, alkynyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, alkenylthio, cycloalkenylthio, alkynylthio, alkylamino, cycloalkylamino, arylamino, aralkylamino, alkenylamino, cycloalkenylamino, alkynylamino radicals. Other embodiments include hydroxyalkyl, hydroxycycloalkyl, hydroxyaryl, hydroxyaralkyl, hydroxyalkenyl, hydroxycycloalkenyl, hydroxyalinyl, mercaptoalkyl, mercaptocycloalkyk, mercaptoaryl, mercaptoaralkyl, mercaptoalkenyl, mercaptocycloalkenyl, mercaptoalkynyl, aminoalkyl, aminocycloalkyl, aminoaryl, aminoaralkyl, aminoalkenyl, aminocycloalkenyl, aminoalkynyl radicals. In certain embodiments, hydrogen atoms in alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more halogen atoms. One radical is the trifluoromethyl radical. As used herein a wording defining the limits of a range oflength such as, e. g., "from 1 to 6" means any integer from 1 to 6, i.e. 1, 2, 3, 4, 5 and 6. In other words, any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range. The term "linker" as used herein refers to any chemically suitable linker. Preferably, linker are not or only slowly cleaved under physiological conditions. Thus, it is preferred that the linker does not comprise recognition sequences for proteases or recognition structures for other degrading enzymes. Since it is preferred that the compounds of the invention are administered systemically to allow broad access to all compartments of the body and subsequently enrichment of the compounds of the invention wherever in the body the tumor is -60- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 located, it is preferred that the linker is chosen in such that it is not or only slowly cleaved in blood. The cleavage is considered slowly, if less than 50% of the linkers are cleaved 2 h after administration of the compound to a human patient. Suitable linkers, for example, comprises or consists of optionally substituted alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, aralkyl, heteroaralyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, sulfonyl, amines, ethers, thioethers phosphines, phosphoramidates, carboxamides, esters, imidoesters, amidines, thioesters, sulfonamides, 3-thiopyrrolidine-2,5-dion, carbamates, ureas, guanidines, thioureas, disulfides, oximes, hydrazines, hydrazides, hydrazones, diaza bonds, triazoles, triazolines, tetrazines, platinum complexes and amino acids, or combinations thereof. Preferably, the linker comprises or consists of 1,4-piperazine, 1,3-propane and a phenolic ether or combinations thereof. As used herein, the term "amino acid" refers to any organic acid containing one or more amino substituents, e.g. α-, β- or γ-amino, derivatives of aliphatic carboxylic acids. The term "conventional amino acid" refers to the twenty naturally occurring amino acids, and encompasses all stereometric isoforms, i.e. D, L-, D- and L-amino acids thereof. EXAMPLES The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention. Synthesis of Exemplary Compounds of the Disclosure I. Synthetic Scheme for Compound EB-3996 -61- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 Synthetic Scheme 1. i. L-boroLeu-pn.HCl, HATU, DIEA, DMF; ii.4N HCl in dioxane; iii.2- Chlorotrityl Chloride Resin, DIPEA, DCM; iv. 20% piperidine in DMF; v. Fmoc-D-Ala-OH, HATU, DIEA, DMF; vi. 20% piperidine in DMF; vii. Fmoc-L-Ser(OtBu)-OH, HATU, DIEA, DMF; viii.20% piperidine in DMF; ix. Succinic acid mono-benzyl ester, HATU, DIEA, DMF; x. 1%TFA in DCM; xi. HATU, DIEA; xii. H2/Pd-C, MeOH; xiii.7, PyBop, DIEA, DMF; xiv. TFA-TIPS-DCM; xv. PhB(OH)2, TBME-H2O. -62- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 II. Synthetic Scheme for Compound EB-P-3996 Synthetic Scheme 2. i. L-boroLeu-pn.HCl, HATU, DIEA, DMF; ii. 4N HCl in dioxane; iii. Boc-D-Ala-OH, HATU, DIEA, DMF; iv. H2/Pd-C, MeOH; v. HATU, DIEA; vi. 4N HCl in dioxane; vii. 7-(tert-Butoxy)-7-oxoheptanoic acid, COMU, DIEA, DMF; viii. TFA-TIPS- DCM (80:4:16); ix. 8, HATU, DIEA, DMF; x. PhB(OH)2, TBME-H2O. -63- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 III. Synthetic Scheme for Compound EB-S-3996 Synthetic Scheme 3. i. L-boroLeu-pn.HCl, HATU, DIEA, DMF; ii.4N HCl in dioxane; iii.2- Chlorotrityl Chloride Resin, DIPEA, DCM; iv. 20% piperidine in DMF; v. Fmoc-D-Ala-OH, HATU, DIEA, DMF; vi. 20% piperidine in DMF; vii. mono-tert-Butyl succinate, HATU, DIEA, DMF; viii. 1%TFA in DCM; ix. HATU, DIEA; x. TFA-TIPS-DCM; xi. 7, PyBop, DIEA, DMF; xii. PhB(OH)2, TBME-H2O. -64- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 IV. Synthetic Scheme for Compound EB-2727D Synthetic Scheme 4. i. L-boroLeu-pn.HCl, HATU, DIEA, DMF; ii. 4N HCl in dioxane; iii. Boc-D-Ala-OH, HATU, DIEA, DMF; iv. 4N HCl in dioxane; v. Boc-4-AMB-OH, HATU, DIEA; vi. H2/Pd-C, MeOH; vii. 4-Aminobenzyl alcohol, HATU, DIEA, DMF; viii. 4- Nitrophenyl chloroformate, DIEA, Py-ACN; ix. 2, 5, TEA, DMF; x. TFA-TIPS-DCM; xi. 7- (tert-Butoxy)-7-oxoheptanoic acid, COMU, DIEA, DMF; xii. TFA-TIPS-DCM (80:4:16); xiii. 8, HATU, DIEA, DMF; xiv. PhB(OH)2, TBME-H2O. -65- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 V. Synthetic Scheme for Compound EB-MMAE Synthetic Scheme 5. i. Boc-D-Ala-OH, HATU, DIEA, DMF; ii. 4N HCl in dioxane; iii. Boc- 4-AMB-OH, HATU, DIEA; iv. H2/Pd-C, MeOH; v. 4-Aminobenzyl alcohol, HATU, DIEA, DMF; vi. 4-Nitrophenyl chloroformate, DIEA, Py-ACN; vii. MMAE, HOBt, DIEA, Py-DMF; viii. TFA-TIPS-DCM; ix.7-(tert-Butoxy)-7-oxoheptanoic acid, COMU, DIEA, DMF; x. TFA- TIPS-DCM (80:4:16); xi. 8, HATU, DIEA, DMF. -66- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 VI. Synthetic Scheme for Compound EB-6323 Synthetic Scheme 6. i. L-boroPro-pn.HCl, HATU, DIEA, DMF; ii. 4N HCl in dioxane; iii. 2- Chlorotrityl Chloride Resin, DIPEA, DCM; iv. 20% piperidine in DMF; v. Fmoc-D-Ala-OH, HATU, DIEA, DMF; vi. 20% piperidine in DMF; vii. Fmoc-L-Ser(OtBu)-OH, HATU, DIEA, DMF; viii.20% piperidine in DMF; ix. Fmoc-NH-PEG(8)-CO2H (CAS:756526-02-0), HATU, DIEA, DMF; x. 20% piperidine in DMF; xi. Succinic acid mono-benzyl ester, HATU, DIEA, DMF; xii. 1%TFA in DCM; xiii. 2, 4, HATU, DIEA; xiv. H2/Pd-C, MeOH; xv. 7, PyBop, DIEA, DMF; xvi. TFA-TIPS-DCM; xvii. PhB(OH)2, TBME-H2O. -67- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 VII. Synthetic Scheme for Compound EB-6325 Synthetic Scheme 7. i. L-boroPro-pn.HCl, HATU, DIEA, DMF; ii. 4N HCl in dioxane; iii. 2- Chlorotrityl Chloride Resin, DIPEA, DCM; iv. 20% piperidine in DMF; v. Fmoc-D-Ala-OH, HATU, DIEA, DMF; vi. 20% piperidine in DMF; vii. Fmoc-L-Ser(OtBu)-OH, HATU, DIEA, DMF; viii.20% piperidine in DMF; ix. Fmoc-NH-PEG(8)-CO2H (CAS:756526-02-0), HATU, DIEA, DMF; x. 1%TFA in DCM; xi. 2, 4, HATU, DIEA; xii. 20% piperidine in DMF; xiii.7- (tert-Butoxy)-7-oxoheptanoic acid, COMU, DIEA, DMF; xiv. TFA-TIPS-DCM (80:4:16); xv. 8, HATU, DIEA, DMF; xvi. TFA-TIPS-DCM; xvii. PhB(OH)2, TBME-H2O. -68- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 VIII. Synthetic Scheme for Compound 6707-GFP Synthetic Scheme 8. i. Fmoc-Pro(4R-F)-PAB-Br,THF,Ponatinib; ii.10%Pyrrolidine/DMF; iiiBoc-Gly-OH, HATU, DIEA, DMF; iv.TFA-DCM; v.HATU, DIEA, DMF. -69- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 IX. Synthetic Scheme for Compound 6707-PRO Synthetic Scheme 9: i. Fmoc-D-Ala-Pro-PAB-Br,THF,Ponatinib; ii.10%Pyrrolidine/DMF; iii.6-(3-(4-(Boc)Piperazin-1-yl)Propoxy)Quinolin(CAS 2370952-96-6), HATU, DIEA, DMF; iv.TFA-DCM; v.HATU, DIEA, DMF. -70- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 X. Synthetic Scheme for Compound 7894-E-B Synthetic Scheme 10: i. ii. HATU, DIEA, DMF. XI. Synthetic Scheme for Compound 7894E-BV Synthetic Scheme 11: i. NBS, PPh3, THF; ii. PON, NaI, THF, 65'C; iii. TFA-TIPS-DCM; iv. N-Boc-4-AMB-OH, HATU, DIEA, DMF; v. TFA-TIPS-DCM; vi. EB-P, HATU, DIEA, DMF. INCORPORATION BY REFERENCE All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually -71- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. -72- FoleyHoagUS12920586.2

Claims

Attorney Docket No.: TUV-18225 We claim: 1. An enzyme activated prodrug represented by formula I or a pharmaceutically acceptable salt thereof: HSA– L1 – SRS – L2 – D (I) wherein, D is a parent drug; SRS represents a substrate recognition sequence which is enzymatically cleaved by a target enzyme; L1 is a bond or a linker; L2 is a bond or a self-eliminating linker which, after enzymatic cleavage of the substrate recognition sequence SRS by the target enzyme, is released from the prodrug to produce the pharmacologically active parent drug; and HSA is a moiety that binds to human serum albumin with a Kd of 1 x 10-6 or less, has a molecular weight of 2000 amu or less, and confers an increase in serum half-life of the prodrug by 10-fold or more relative to parent drug D. 2. The prodrug of claim 1, wherein the prodrug has less than 50% of the therapeutic activity of the parent drug. 3. The prodrug of claim 1 or 2, wherein the target enzyme is Fibroblast Activation Protein alpha (FAPα). 4. The prodrug of claim 3, wherein SRS is represented in the general formula wherein A is a 5-7 membered heterocycle, and R1 is H or a lower alkyl (which may be straight chain or branched), and if a lower alkyl may be optionally substituted with a hydroxyl group. -73- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 5. The prodrug of claim 3 or 4, wherein the prodrug has a kcat/Km for cleavage by FAP at least 10-fold greater than for cleavage by prolyl endopeptidase (EC 3.4.21.26; PREP). 6. The prodrug of any of the preceding claims, wherein cell permeability of the prodrug is at least 50% less than cell permeability of the parent drug D upon cleavage from the prodrug. 7. The prodrug of any of the preceding claims, wherein the prodrug has a therapeutic index that is at least 2 times greater than the therapeutic index of the parent drug D. 8. The prodrug of any of the preceding claims, wherein prodrug has a maximum tolerated dose at least 2 times greater than the maximum tolerated dose of the parent drug D. 9. The prodrug of any of the preceding claims, wherein prodrug has a circulating half- life at least 25% longer than the circulating half-life of the parent drug D. 10. The prodrug of any of the preceding claims, wherein the parent drug D is a drug moiety, which may be, optionally, a cytotoxic, cytostatic or epigenetic moiety or a radioisotope containing moiety. 11. The prodrug of any of the preceding claims, wherein the parent drug D is an imaging agent. 12. The prodrug of any of the preceding claims, represented in the general formula: wherein L2 is a bond and -NH-L-D is the pharmacologically active agent, or -74- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 L2 is a self-eliminating linker which, after FAP cleavage of the FAP substrate recognition sequence, is released from the prodrug to release D as the pharmacologically active agent; A is a 5-7 membered heterocycle; R1 is H or alkyl (e.g., lower alkyl); B is C5-C8 monocyclic ring or a C8-C12 bicyclic ring; R2 is H, -OH, or alkyl (e.g., lower alkyl); and each Ra is, independently, H, alkyl, or aralkyl. 13. The prodrug of any of the preceding claims, wherein the serum albumin binding moiety is a moiety that binds to human serum albumin with a Kd of 500 micromolar or less, has a molecular weight of 3000 amu or less, and increases the serum half-life of the prodrug by 10 fold or more relative to the pharmacologically active agent. 14. The prodrug of claim 13, wherein the serum albumin binding moiety is selected from: ; -75- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 . 15. The prodrug of claim 13, wherein the serum albumin binding moiety is selected from: . 16. The prodrug of any one of the preceding claims, in form of a pharmaceutically acceptable salt. 17. Use of the prodrug of any one of the preceding claims in the manufacture of a medicament for the treatment of a diseased tissue, optionally a cancer. -76- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 18. A composition comprising the prodrug of any one of claims 1-16 and a pharmaceutically acceptable excipient. 19. A method comprising administering to a subject in need thereof an effective amount of the prodrug of any one of the preceding claims. 20. A method comprising administering to a subject in need thereof an effective amount of the prodrug of any one of the preceding claims, wherein the subject has a diseased tissue, optionally a cancer. 21. An enzyme activated prodrug represented by formula I or a pharmaceutically acceptable salt thereof: HSA – L1 – SRS – L2 – D I wherein, D is a drug or an active pharmaceutical moiety; SRS represents a substrate recognition sequence which is enzymatically cleaved by a target enzyme; L1 is a bond or a linker; L2 is a bond or a self-eliminating linker which, after enzymatic cleavage of the substrate recognition sequence SRS by the target enzyme, is released from the prodrug to produce the parent drug; and HSA is a moiety that binds to human serum albumin with a Kd of 1 x 10-6 or less, has a molecular weight of 2000 amu or less, and increases the serum half-life of D by 10- fold or more relative to parent D. 22. The prodrug of claim 21, wherein the prodrug is represented by formula IIa or a pharmaceutically acceptable salt thereof: -77- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 IIa A is a 5-7 membered heterocycle; R1 is H or alkyl (e.g., lower alkyl); B is C5-C8 monocyclic ring or a C8-C12 bicyclic ring; R2 is H, -OH, or alkyl (e.g., lower alkyl); and each is independently Ra is H, alkyl, or aralkyl. 23. The prodrug of claim 21, wherein the prodrug is represented by formula IIb or a pharmaceutically acceptable salt thereof: wherein, n is 1, 2, or 3; and each R4 is independently H, (C1-C6) alkyl, —OH, —NH2, or halogen. -78- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 24. The prodrug of claim 21, wherein the prodrug is represented by formula II or a pharmaceutically acceptable salt thereof: wherein, n is 1, 2, or 3; and each R4 is independently H, (C1-C6) alkyl, —OH, —NH2, or halogen. 25. The prodrug of any one of claims 22-24, wherein R1 is (C1-C10)alkyl (e.g., methyl). 26. The prodrug of any one of claims 22-24, wherein R1 is Ser. 27. The prodrug of any one of claims 22-24, wherein R1 is Thr. 28. The prodrug of any one of claims 22-24, wherein R1 is -alanine. 29. The prodrug of any one of claims 22-28, wherein 30. The prodrug of any one of claims 22-28, wherein . 31. The prodrug of any one of claims 22-30, wherein R2 is the side chain of Arg or Lys. -79- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 32. The prodrug of any one of claims 22-30, wherein R2 is the side chain of homoarginine. 33. The prodrug of any one of claims 22-30, wherein R2 is a Dap-derived -guanidino acid arginine mimetics 34. The prodrug of any one of claims 22-30, wherein Ra is H or methyl. 35. The prodrug of any one of claims 22-28, wherein X is . 36. The prodrug of any one of claims 21-35, wherein the prodrug is represented by formula III or a pharmaceutically acceptable salt thereof: III wherein, R4 is absent or represents a (C1-C6) alkyl, —OH, —NH2, or halogen. 37. The prodrug of any one of claims 21-36, wherein L1 is N-Succinimidyl 4-(2- pyridylthio) pentanoate, N- Succinimidyl 4-(N-maleimidomethyl) cyclohexane-1 carboxylate, or N-Succinimidyl (4-iodo-acetyl) aminobenzoate. 38. The prodrug of any one of claims 21-36, wherein L1 is a polyether. 39. The prodrug of any one of claims 21-36, wherein L1 is a poly(ethylene glycol). 40. The prodrug of any one of claims 21-39, wherein: -80- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 p is 1 to 100. 41. The prodrug of claim 40, wherein p is 6 to 50. 42. The prodrug of claim 40, wherein p is 6 to 12. 43. The prodrug of any one of claims 21-39 wherein: p is 1 to 20. 44. The prodrug of claim 23, wherein p is 1 to 4. 45. The prodrug of any one of claims 21-44, wherein HSA is . -81- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 46. The prodrug of any one of claims 21-44, wherein HSA is . 47. The prodrug of any one of claims 21-44, wherein HSA is . 48. The prodrug of any one of claims 21-24, wherein the prodrug is represented by formula IVa or a pharmaceutically acceptable salt thereof: IVa. 49. The prodrug of any one of claims 21-44, wherein the prodrug is represented by formula IVb or a pharmaceutically acceptable salt thereof: -82- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 IVb. 50. The prodrug of any one of claims 21-44, wherein the prodrug is represented by formula IVc or a pharmaceutically acceptable salt thereof: IVc. 51. The prodrug of any one of claims 21-44, wherein the prodrug is represented by formula IVd or a pharmaceutically acceptable salt thereof: -83- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 IVd. 52. The prodrug of any one of claims 21-51, wherein the drug is an immunomodulator. 53. The prodrug of claim 52, wherein the drug is an immune activating agent. 54. The prodrug of claim 52, wherein the immunomodulator induces an innate immunity pathway. 55. The prodrug of any one of claims 52-54, wherein the immunomodulator is an immuno-DASH inhibitor that inhibits the enzymatic activity of DPP8 and DPP9 and induces macrophage pyroptosis. 56. The prodrug of any one of claims 52-54, wherein the immunomodulator is a STING agonist. 57. The prodrug of any one of claims 52-54, wherein the immunomodulator is a RIG-1 agonist. 58. The prodrug of any one of claims 52-54, wherein the immunomodulator is a Toll-like receptor (TLR) agonist, such as a TLR1/2 agonist, a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR6/2 agonist, a TLR7 agonist, a TLR7/8 agonist, a TLR7/9 agonist, a TLR8 agonist, a TLR9 agonist, and a TLR11 agonist, preferably selected from the group consisting of a TLR3 agonist, a TLR7 agonist, a TLR7/8 agonist, and a TLR9 agonist. 59. The prodrug of any one of claims 21-58, wherein the drug is cytotoxic to cancer associated fibroblasts (CAFs). 60. The prodrug of any one of claims 21-59, wherein the drug polarizes tumor associated macrophage towards M1 macrophage or inhibits M2 macrophage immunosuppressive activity. 61. The prodrug of any one of claims 21-60, wherein the drug accelerates T-cell priming and/or dendritic cell trafficking. -84- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 62. The prodrug of any one of claims 21-61, wherein the drug inhibits or depletes Treg cells, such as by blocking immunosuppressive function or migration to lymph nodes and/or the tumor microenvironment. 63. The prodrug of any one of claims 21-62, wherein the Therapeutic Index of the prodrug is at least 5 times greater than the Therapeutic Index for the free drug when given systemically, more preferably at least 10, 20, 30, 40, 50, 75 or even 100 times greater. 64. The prodrug of any claims 21-63, wherein the drug has a molecular weight less than 5000 amu, preferably less than 2500 amu. 65. The prodrug of any claims 21-51, wherein the drug is Val-boroPro. 66. The prodrug of any one of claims 21-65, wherein L2 is selected from the group consisting of —NH—(CH2)4—C(=O)—, —NH—(CH2)3—C(=O)—, p- aminobenzyloxycarbonyl (PABC), and 2,4-bis(hydroxymethyl)aniline. 67. The prodrug of claim 21, wherein the prodrug is selected from the group consisting of , -85- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 , ; or a pharmaceutically acceptable salt thereof. 68. The prodrug of claim 21, wherein the prodrug is selected from the group consisting of , and -86- FoleyHoagUS12920586.2 Attorney Docket No.: TUV-18225 ; or a pharmaceutically acceptable salt thereof. 69. A pharmaceutical composition comprising the prodrug of any one of claims 1-68 and a pharmaceutically acceptable excipient. 70. A method for treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a prodrug of any one of claims 1-68, or a pharmaceutically acceptable salt thereof, to the subject. 71. The method of claim 70, wherein the cancer is acute myeloid leukemia (AML). -87- FoleyHoagUS12920586.2
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