Calicheamicin derivatives and antibody-drug conjugates thereof

Abstract

Disclosed herein, in part, are novel calicheamicin derivatives with novel chemical linkers that include cleavable moieties and conjugated to targeting antibodies.

Description

Atty. Docket No. SMO-OQ4WOCALICHEAMICIN DERIVATIVES AND ANTIBODY-DRUG CONJUGATES THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional PatentApplication No. 63 / 689,038, filed on August 30, 2024; the content of which is hereby incorporated by reference herein in its entirety.BACKGROUND

[0002] Antibody -drug conjugates (ADC’s) provide a mechanism for selective delivery of small molecule therapeutic pay loads to antigen-positive cancer cells, thereby attenuating systemic toxicity of cytotoxic drugs to antigen-negative normal cells. Three components of an ADC — the antibody, the cytotoxic payload, and the linker that joins them — are important in designing an effective therapeutic. Despite active development, challenges still exist, for example, toxicity due to the antibody binding to its target in normal tissue, and dispersion of the cytotoxic payload in normal tissue due to instability of the ADC linker. Thus, many ADC’s have not succeeded in clinical trials due to lack of safety and / or efficacy at tolerated doses.

[0003] The calicheamicins are a family of enediyne antitumor antibiotics isolated from the bacterium Micromonospora echinospora, with calicheamicin yl being a notable example. The calicheamicins are able to bind with DNA, particularly in the minor groove, whereupon the core undergoes a cyclization reaction analogous to form a diradical species. This diradical subsequently abstracts two hydrogen atoms from the deoxyribose (sugar) backbone of the DNA, ultimately leading to strand scission.

[0004] Calicheamicin antibody-drug conjugates (ADCs) are effective therapeutics for, e.g., leukemias. However, calicheamicin ADCs previously under clinical development have shown undesirable properties such as, e.g., being heterogeneous, aggregation-prone, and having a shortened half-life due to the instability of the acid- sensitive linker components in circulation.

[0005] Thus, there remains a need to develop further calicheamicin payloads and calicheamicin antibody-drug conjugates. Such compounds may have present properties which differ from those of calicheamicin derivatives studied to date, for example,1IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO advantageous chemical properties, physical properties, payload release characteristics, safety and tolerability profiles, and / or improved efficacy. Moreover, preferential delivery of calicheamicin payloads to diseased tissues through antibody-drug conjugates could lead to improved safety and efficacy, thereby providing therapeutic options for a larger number of patients and types of cancers.SUMMARY

[0006] The present disclosure relates to compounds useful for the treatment of cancer. For example, the present disclosure provides calicheamicin-based payloads, linkerpayloads, and antibody-drug conjugates. Further provided herein is the use of disclosed compounds as medicinal agents, processes for their preparation, and pharmaceutical compositions containing them as an active ingredient both alone or in combination with other agents, as well as provides for their use as medicaments and / or in the manufacture of medicaments for the treatment of cancer.

[0007] For example, disclosed herein is a compound, for example, a linker-payload represented by Formula (I):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is selected from the group consisting of2IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOY is-CH2-(OCH2CH2)m-* or -Cf h-CI b-fOCI bCf b)™-*; wherein * denotes the point of attachment to -NR4R5; orY is Ci-Ci2alkylene optionally substituted with -NRaC(=O)Rb;R1is selected from the group consisting of -Cs-Cealkyl, -CH(C3-Cecycloalkyl)2, -C3- C6alkylene-NRa(SO2)-Ci-C6alkyl, and -SCH3;R2is selected from the group consisting of Ci-Cialkyl and hydrogen;R3is selected from the group consisting of C 1 -Cialkyl and hydrogen;R4is selected from the group consisting of hydrogen and Ci -Chalky 1;R5is selected from the group consisting of hydrogen, -NH2,R4and R5, together with the nitrogen atom to which they are attached, may be joined together to form a 5-membered heterocyclyl selected from the group consisting of:Raand Rbare independently selected from the group consisting of hydrogen and Ci-C ialkyl; and3IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO m is 0-12.

[0008] Also disclosed herein is a compound, for example, a linker-payload represented by Formula (IA):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting of -Cs-Cealkyl, -CH(Cs-C6cycloalkyl)2, and - C3-C6alkylene-NRa(SO2)-C i -C6alky 1;R2is selected from the group consisting of C i -Cialkyl and hydrogen;R3is selected from the group consisting of C i -C ialkyl and hydrogen;Rais selected from the group consisting of hydrogen and Ci-Cralkyl; and m is 5, 6, or 7.

[0009] Further disclosed herein is a compound, for example a therapeutic payload, represented by Formula (II):4IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting of -C3-Cealkyl, -CH(C3-Cecycloalkyl)2, and - C3-C6alkylene-NRa(SO2)-Ci-C6alkyl;R2is selected from the group consisting of Ci-C3alkyl and hydrogen; andRais selected from the group consisting of hydrogen and Ci-C3alkyl.

[0010] In addition, disclosed herein is a compound, for example an antibody-drug conjugate, represented by Formula (III):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is selected from the group consisting ofZ is selected from the group consisting of:5IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO* denotes the point of attachment of Lig to Z by a thioether bond;** denotes the point of attachment of Lig to Z by an amide bond;Rzis selected from the group consisting of Ci -Chalky 1 and hydrogen;R1is selected from the group consisting of -Cs-Cealkyl, -CH(C3-C6cycloalkyl)2, -C3- C6alkylene-NRa(SO2)-Ci-C6alkyl, and -SCH3;R2is selected from the group consisting of Ci-C3alkyl and hydrogen;R3is selected from the group consisting of Ci-Csalkyl and hydrogen;Rais selected from the group consisting of hydrogen and C i-C3alkyl;Lig is a monoclonal antibody; m is 1, 2, 3, 4, 5, 6, or 7; p is 1, 2, 3, 4, 5, 6, or 7; q is 1, 2, 3, 4, 5, 6, or 7, and6IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO s is 1, 2, 3, 4, 5, 6, or 7.

[0011] Further disclosed herein is a compound, for example an antibody-drug conjugate, represented by Formula (IV):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is selected from the group consisting ofZ is selected from the group consisting of:7IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO* for each occurrence denotes a point of attachment of Lig to Z by a thioether bond;Rzis selected from the group consisting of Ci -Chalky 1 and hydrogen;R1is selected from the group consisting of -C3-Cealkyl, -CH(C3-Cecycloalkyl)2, -C3- C6alkylene-NRa(SO2)-Ci-C6alkyl, and -SCH3;R2is selected from the group consisting of Ci-C3alkyl and hydrogen;R3is selected from the group consisting of Ci-C3alkyl and hydrogen;Rais selected from the group consisting of hydrogen and Ci-C3alkyl;Lig is a monoclonal antibody; m is 1, 2, 3, 4, 5, 6, or 7; p is 3, 4, 5, or 6;8IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO q is 6, 7, 8, or 9; s is 3, 4, 5, or 6; and t is 3, 4, 5, or 6.

[0012] Methods of treating cancer are contemplated herein, comprising administering to a patient in need thereof an effective amount of a disclosed compound. For example, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed therapeutic payload, a disclosed linker-payload, or a disclosed antibody-drug conjugate. In some embodiments, the cancer is selected from the group consisting of, for example, blood cancer, lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, and esophageal cancer.

[0013] Pharmaceutical compositions comprising at least one disclosed compound, and a pharmaceutically acceptable carrier are additionally described herein. For example, provided herein is a pharmaceutically acceptable composition comprising a disclosed compound, e.g., a disclosed therapeutic payload, a disclosed linker-payload, or a disclosed antibody-drug conjugate and a pharmaceutically acceptable excipient. Also disclosed herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a disclosed therapeutic payload, a disclosed linker-payload, or a disclosed antibody-drug conjugate, and a pharmaceutically acceptable excipient.DETAILED DESCRIPTION

[0014] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.Definitions9IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0015] As used herein, the words “a” and “an” are meant to include one or more unless otherwise specified. For example, the term “an agent” encompasses both a single agent and a combination of two or more agents.

[0016] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci-ealkyl, Ci-4alkyl, and Ci-3alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -butyl, 3-methyl-2-butyl, 2-methyl-l -pentyl, 3-methyl-l -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l- butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0017] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C2-ealkenyl, and C3-4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0018] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-ealkynyl, and C3-ealkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0019] “Alkylene” means a straight or branched, saturated aliphatic divalent radical having the number of carbons indicated. “Cycloalkylene” refers to a divalent radical of carbocyclic saturated hydrocarbon group having the number of carbons indicated.

[0020] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as Ci-ealkoxy, and C2-6alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.10IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO

[0021] The term “carbonyl” as used herein refers to the radical -C(O)-. The term“cyano” as used herein refers to the radical -CN. The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I. The terms “hydroxy” and “hydroxyl” as used herein refer to the radical -OH. The term “oxo” as used herein refers to the radical =0.

[0022] The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as Cj-ecycloalkyl or C4-6cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

[0023] The terms “heteroaryl” or “heteroaromatic group” as used herein refers to a monocyclic aromatic 5-6 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine or pyrimidine etc.

[0024] The terms “heterocyclyl” or “heterocyclic group” are art-recognized and refer to e.g., saturated or partially unsaturated, 4-10 membered monocyclic or bicyclic ring structures, or e.g., 4-9 or 4-6 membered saturated ring structures, including bridged, fused or spirocyclic rings, and whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc.

[0025] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0026] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical11IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0027] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0028] “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the present disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).“Modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism.

[0029] “Treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[0030] In the present specification, the term “therapeutically effective amount” or“effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the present disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect, such as an amount which results in weight loss.

[0031] The term “pharmaceutically acceptable salt(s)” as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically12IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, -tolucnesull'onate and pamoate (i.e., 1 , 1 ’-methylene-£>w-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[0032] As will be understood by the skilled artisan, “H” is the symbol for hydrogen,“N” is the symbol for nitrogen, “S” is the symbol for sulfur, “O” is the symbol for oxygen. “Me” is an abbreviation for methyl. It will be appreciated that the present disclosure should be construed in congruity with the laws and principles of chemical bonding.

[0033] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0034] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol =z denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z’ or “E” configuration wherein the termsare13IPTS / 200111566.1Atty. Docket No. SMO-OQ4WO used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

[0035] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans,” where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.”

[0036] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For14IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0037] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the present disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0038] The present disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,1SN,18O,170,31P,32P,35S,18F, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0039] Certain isotopically labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon- 14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0040] Procedures for making compounds described herein are provided below in the working examples and may be supplemented or substituted by procedures known to those of skill in the art. Starting materials used in the working examples can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but would be apparent to those skilled in the art. Disclosed compounds, or any of the intermediates described herein,15IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO can be further derivatized by using one or more standard synthetic methods known to those skilled in the art.

[0041] Salts of compounds disclosed herein can be prepared by the reaction of a compound disclosed herein with an appropriate acid or base in a suitable solvent, or mixture of solvents (such as an ether, for example, diethyl ether, or an alcohol, for example ethanol, or an aqueous solvent) using conventional procedures. Salts of a compound disclosed herein can be exchanged for other salts by treatment using conventional ion-exchange chromatography procedures.Compounds

[0042] Disclosed herein, for example, is a compound, for example, a linker-payload, represented by Formula (I):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is selected from the group consisting ofY is-CH2-(OCH2CH2)m-* or -CH2-CH2-(OCH2CH2)m-*; wherein * denotes the point of attachment to -NR4R5; orY is Ci-C alkylene optionally substituted with -NRaC(=O)Rb;16IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOR1is selected from the group consisting of -Cs-Cealkyl, -CH(C3-C6cycloalkyl)2, -C3- C6alkylene-NRa(SO2)-Ci-C6alkyl, and -SCH3;R2is selected from the group consisting of Ci-C:ialkyl and hydrogen;R3is selected from the group consisting of C 1 -Cialkyl and hydrogen;R4is selected from the group consisting of hydrogen and Ci -Chalky I;R5is selected from the group consisting of hydrogen, -NH2,R4and R5, together with the nitrogen atom to which they are attached, may be joined together to form a 5-membered heterocyclyl selected from the group consisting of:Raand Rbare independently selected from the group consisting of hydrogen and Ci-Cutlkyl; and m is 0-12.17IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO

[0043] In some embodiments, for example, R5is selected from the group consisting of hydrogen,

[0044] In other embodiments, a compound of the present disclosure may be represented, for example, by Formula (IA):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is selected fromR1is selected from the group consisting of -Cs-Cealkyl, -CH / Cs-Cecycloalkylh, and - C3-C6alkylene-NRa(SO2)-Ci-C6alkyl;R2is selected from the group consisting of Ci-CFalkyl and hydrogen;R3is selected from the group consisting of Ci-Cialkyl and hydrogen;Rais selected from the group consisting of hydrogen and Ci-Csalkyl; and m is 5, 6, or 7.18IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO

[0045] In some embodiments, R2is selected from the group consisting of, for example, -CH2CH3, -CH(CH3h, -CH3, and hydrogen. For example, in certain embodiments R2is -CH2CH3. In other embodiments, for example, m is 6.

[0046] In some embodiments, a compound of the present disclosure may be represented, for example, by Formula (IB):

[0047] In additional embodiments, R3is selected from the group consisting of, or example, hydrogen and -CH3. In other embodiments, a compound of the present disclosure may be represented, for example, by Formula (IC):(IC).

[0048] In additional embodiments, R1is selected from the group consisting of, for example,19IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0049] In some embodiments, a compound of the present disclosure is selected from the group consisting of, for example:20IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO21IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO22IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO23IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO24IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO25IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO26IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO27IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO28IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO29IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof.

[0050] In further embodiments, a compound of the present disclosure is selected from the group consisting of, for example:30IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO31IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO32IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOand33IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof.

[0051] Also disclosed herein, for example, is compound, for example a therapeutic payload, represented by Formula (II):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting of -Cs-Cealkyl, -CH / Cs-Cecycloalkylh, and - C3-C6alkylene-NRa(SO2)-C i -C6alkyl;R2is selected from the group consisting of Ci-C <alkyl and hydrogen; andRais selected from the group consisting of hydrogen and C i-Cialkyl.

[0052] In some embodiments, a compound of the present disclosure may be represented, for example, by Formula (IIA):34IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO

[0053] In some embodiments, R2is selected from the group consisting of, for example, -CH2CH3, -CH(CH3)2, -CH3, and hydrogen. For example, in certain embodiments R2is -CH2CH3. In further embodiments, R1is selected from the group consisting of, for example:

[0054] In some embodiments, a compound of the present disclosure may be selected from the group consisting of, for example:35IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof

[0055] Further disclosed herein is a compound, for example and antibody-drug conjugate, represented by Formula (III):(III); or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is selected from the group consisting ofZ is selected from the group consisting of:36IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO* denotes the point of attachment of Lig to Z by a thioether bond;** denotes the point of attachment of Lig to Z by an amide bond;Rzis selected from the group consisting of Ci-Cialkyl and hydrogen;R1is selected from the group consisting of -Cs-Cealkyl, -CH(C3-Cecycloalkyl)2, -C3- C6alkylene-NRa(SO2)-Ci-C6alkyl, and -SCH3;R2is selected from the group consisting of Ci-Cialkyl and hydrogen;R3is selected from the group consisting of C 1 -CLalkyl and hydrogen;Rais selected from the group consisting of hydrogen and Ci-CLalkyl;Lig is a monoclonal antibody; m is 1, 2, 3, 4, 5, 6, or 7; p is 1, 2, 3, 4, 5, 6, or 7; q is 1, 2, 3, 4, 5, 6, or 7, and s is 1, 2, 3, 4, 5, 6, or 7.

[0056] In some embodiments, R2is selected from the group consisting of, for example, -CH2CH3, -CH(CH3h, -CH3, and hydrogen. For example, in certain embodiments R2is -CH2CH3. In other embodiments, for example, m is 6.37IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO

[0057] In some embodiments, a compound of the present disclosure may be represented, for example, by Formula (IIIA):(IIIA).

[0058] In other embodiments, R3is selected from the group consisting of hydrogen and -CH3. In further embodiments, a compound of the present disclosure may be represented, for example, by Formula (IIIB):(IIIB).

[0059] In further embodiments, R1is selected from the group consisting of, for example:38IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO

[0060] In some embodiments, for example, p is 3, 4, 5, or 6, q is 3, 4, 5, or 6, and s is 3, 4, 5, or 6. For example, in certain embodiments Z is selected from the group consisting of:

[0061] In some embodiments, Lig is selected from the group consisting of, for example, an anti-CD33 antibody, an anti-TROP2 antibody, an anti-EGFR antibody, and an anti-HER2 antibody.39IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0062] In some embodiments, a compound of the present disclosure may be represented, for example, by Formula (IIIC) or Formula (HID) :(HID); or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting ofZ is selected from the group consisting of40IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO* denotes the point of attachment of Lig to Z by a thioether bond;** denotes the point of attachment of Lig to Z by an amide bond; andLig is selected from the group consisting of an anti-CD33 antibody, an anti-TROP2 antibody, an anti-EGFR antibody, and an anti-HER2 antibody.

[0063] In some embodiments, a compound of the present disclosure may be selected, for example, from the group consisting of:41IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO42IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:Lig is selected from the group consisting of an anti-CD33 antibody, an anti-TROP2 antibody, an anti-EGFR antibody, and an anti-HER2 antibody.

[0064] Also disclosed herein is a compound, for example an antibody-drug conjugate, represented by Formula (IV):43IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is selected from the group consisting ofZ is selected from the group consisting of:44IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO* for each occurrence denotes a point of attachment of Lig to Z by a thioether bond;Rzis selected from the group consisting of C i -C ialkyl and hydrogen;R1is selected from the group consisting of -C3-Cealkyl, -CH(C3-Cecycloalkyl)2, -C3- C6alkylene-NRa(SO2)-Ci-C6alkyl, and -SCH3;R2is selected from the group consisting of C 1 -Cialkyl and hydrogen;R3is selected from the group consisting of Ci-C3alkyl and hydrogen;Rais selected from the group consisting of hydrogen and Ci-C3alkyl;Lig is a monoclonal antibody; m is 1, 2, 3, 4, 5, 6, or 7; p is 3, 4, 5, or 6; q is 6, 7, 8, or 9; s is 3, 4, 5, or 6; and t is 3, 4, 5, or 6.45IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO

[0065] In some embodiments, R2is selected from the group consisting of, for example, -CH2CH3, -CH(CH3h, -CH3, and hydrogen. For example, in certain embodiments R2is -CH2CH3. In other embodiments, for example, m is 6.

[0066] In some embodiments, a compound of the present disclosure may be represented, for example, by Formula (IVA):(IVA).

[0067] In other embodiments, R3is selected from the group consisting of hydrogen and -CH3. In further embodiments, a compound of the present disclosure may be represented, for example, by Formula (IVB):(IVB).

[0068] In further embodiments, R1is selected from the group consisting of, for example:46IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO

[0069] In some embodiments, for example, p is 4, q is 8, s is 4, and t is 4. For example, in certain embodiments Z is selected from the group consisting of:47IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO and

[0070] In some embodiments, Lig is selected from the group consisting of, for example, an anti-CD33 antibody, an anti-TROP2 antibody, an anti-EGFR antibody, and an anti-HER2 antibody.

[0071] In some embodiments, a compound of the present disclosure may be represented, for example, by Formula (IVC) or Formula (IVD):(IVD); or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:48IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOR1is selected from the group consisting ofZ is selected from the group consisting of:49IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO and* for each occurrence denotes a point of attachment of Lig to Z by a thioether bond; andLig is selected from the group consisting of an anti-CD33 antibody, an anti-TROP2 antibody, an anti-EGFR antibody, and an anti-HER2 antibody.

[0072] In some embodiments, a compound of the present disclosure may be selected, for example, from the group consisting of:50IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOand51IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:Lig is selected from the group consisting of an anti-CD33 antibody, an anti-TROP2 antibody, an anti-EGFR antibody, and an anti-HER2 antibody.

[0073] In other embodiments, for example, a disclosed compound, e.g., a therapeutic pay load or a linker-payload, is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof.52IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO53IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO54IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO55IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO56IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0074] In other embodiments, for example, a disclosed compound, e.g., a disclosed antibody-drug conjugate, is a compound identified in Table 2 below or a pharmaceutically acceptable salt thereof.Table 2.57IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO58IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO59IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO60IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO61IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO62IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO63IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO64IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO65IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO66IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO67IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO68IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO

[0075] In some embodiments, a contemplated Lig of any one of the compounds of the present disclosure is, for example, an anti-TROP2 antibody. In other embodiments, a contemplated Lig of any one of the compounds of the present disclosure is, for example, an anti-EGFR antibody, for example, Panitumumab, Nimotuzumab, Matuzumab, or Cetuximab. In still other embodiments, a contemplated Lig of any one of the compounds of the present disclosure is, for example, an anti-HER2 antibody. In certain embodiments, a contemplated Lig of any one of the compounds of the present disclosure is, for example, an anti-CD33 antibody. For example, contemplated targets and corresponding example antibodies of the present disclosure are provided in Table 3.Table 3.69IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO70IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOMethods71IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO

[0076] Disclosed herein, for example, is a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, for example, a disclosed payload. In some embodiments, the cancer is selected from the group consisting of, for example, blood cancer, lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, and esophageal cancer.

[0077] Also disclosed herein, for example, is a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a disclosed linker-payload. In some embodiments, the cancer is selected from the group consisting of, for example, blood cancer, lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, and esophageal cancer.

[0078] Further disclosed herein, for example, is a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a disclosed antibody-drug conjugate. In some embodiments, the cancer is selected from the group consisting of, for example, blood cancer, lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, and esophageal cancer.

[0079] In addition, disclosed herein is a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein, for example, a disclosed payload, a disclosed linker-payload, or a disclosed antibody-drug conjugate, and a pharmaceutically acceptable excipient. In some embodiments, the cancer is selected from the group consisting of, for example, blood cancer, lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, and esophageal cancer.

[0080] Also disclosed herein is a method of delivering a therapeutically effective amount of a therapeutic payload moiety to a patient in need thereof, comprising administering72IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO to the patient any one of the drug conjugates disclosed herein. In certain embodiments, the patient is a human.

[0081] In certain embodiments, administering a disclosed compound may comprise subcutaneous administration. In certain embodiments, administering a disclosed compound may comprise intravenous administration. In certain embodiments, administering a disclosed compound may comprise oral administration.

[0082] Provided methods of treatment may include administering a disclosed compound once, twice, or three times daily; about every other day (e.g., every 2 days); twice weekly (e.g., every 3 days, every 4 days, every 5 days, every 6 days, or e.g., administered with an interval of about 2 to about 3 days between doses); once weekly; three times weekly; every other week; twice monthly; once a month; every other month; or even less often.

[0083] Treatment can be continued for as long or as short a period as desired. A suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely. A treatment period can terminate when a desired result is achieved.

[0084] The compounds of the present disclosure may be administered to patients(animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. For treating clinical conditions and diseases noted herein, a compound of the present disclosure may be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Parenteral administration may include subcutaneous injections, intravenous or intramuscular injections or infusion techniques.

[0085] In certain instances, a compound described herein is administered in combination with a second therapeutic agent. In some embodiments, the benefit experienced by a patient is increased by administering a compound described herein with a second73IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO therapeutic agent that also has therapeutic benefit. In one specific embodiment, a compound described herein is co-administered with a second therapeutic agent wherein the compound described herein and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. The overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.

[0086] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g., the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

[0087] The compounds and compositions describe herein are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compositions described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a composition described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.

[0088] In particular, in certain embodiments, the present disclosure provides a method of treating one or more of the above medical indications comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein. In certain embodiments, the compound utilized by one or more of the methods disclosed herein is one of the generic, subgeneric, or specific compounds described herein.Pharmaceutical Compositions and Kits74IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO

[0089] Another aspect of the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and / or may be formulated for oral or subcutaneous administration.

[0090] For example, disclosed herein is a pharmaceutical composition comprising a therapeutic payload disclosed herein, and a pharmaceutically acceptable excipient. Also disclosed herein is a pharmaceutical composition comprising a linker-payload disclosed herein, and a pharmaceutically acceptable excipient. Further disclosed herein is a pharmaceutical composition comprising a drug conjugate disclosed herein, and a pharmaceutically acceptable excipient.

[0091] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more disclosed compounds, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual nontoxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0092] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these75IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0093] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0094] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0095] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use76IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0096] In another aspect, the present disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present invention.

[0097] Advantageously, the present disclosure also provides kits for use by e.g., a consumer in need of treatment of cancer. Such kits include a suitable dosage form such as those described herein and instructions describing the method of using such dosage form to77IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units.EXAMPLES

[0098] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. At least some of the compounds identified as “Intermediates” herein are contemplated as compounds of the present disclosure.Common Procedures for Preparation of Payloads and Linker- Payloads

[0099] Unless stated otherwise, all reactions were performed in heat gun-dried glassware under an argon atmosphere, using standard septa techniques. All commercially available starting building blocks were purchased from commercial vendors. Reactions were monitored by HPLC-MS analyses using a Shimadzu UFLC-MS-2020 system with ESI, and / or by thin-layer chromatography (TLC) using silica gel 60 F254 plates (Merck) and visualized by UV at 254 nm. Purifications were performed using automated flash chromatography system (ECOM), using prepacked column containing C18 or modified C18 silica gel (Interchim, PT-15C18AQ, 15 m Puriflash 200, 5 g, 12 g, or 25 g). Semipreparative HPLC were performed on ECOM HPLC system, using a modified Cl 8 semipreparative column (YMC-Actus, Triart Prep Cl 8, 250x20 mm, S-10 pm, 12nm). HPLC-MS analyses were performed on Shimadzu UFLC-MS-2020 system with ESI. Column: Acquity UPLC BEH Cl 8 1.7 pm, 2.1 x 50 mm. Solvent A: H2O 0.1 % HCOOH; Solvent B: MeCN + 0.1 % HCOOH. Total flow 0.6 ml / min. Total time of the method 10 min. Mass spectrum was78IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO recorded in range 100-3000 m / z both in positive and negative mode with event time 0.2 s. UV-Vis spectra were recorded with a Shimadzu SPD-M2OA Prominence diode array detector, in the range 200-800 nm. NMR spectra were recorded using > 99% deuterated solvents, on a 400 MHz Broker AVANCE III spectrometer (1H at 400 MHz) and / or on a Broker AVANCE 500 (1H at 500.0 MHz). Chemical shifts (in ppm, 5 scale) were solvent signal in 1H spectra. Intermediates and final products were freeze-dried using a Gregory instruments lyophilizer (model L4-110), from water or water mixtures of dioxane or acetonitrile.Common Procedures for Preparation of Antibody- Drug Conjugates and Assays:Common procedure XI: Removal of excess linker-drug from antibody-drug conjugate

[0100] Excess linker-drug was separated from respective antibody-drug conjugates by cation-exchange chromatography (Cytiva, HiTrap SP HP resin), composition of buffer A was 10% sucrose, 12.5 mM sodium acetate pH 5.0, 20 mM NaCl, and buffer B was 10% sucrose, 12.5 mM sodium acetate pH 5.0, IM NaCl. Antibody drug conjugate and unconjugated linker-drug mixture in lx PBS pH 7.4 were diluted in 10% sucrose, 12.5 mM Na-acetate pH 5.0, 0 mM NaCl buffer and loaded onto HiTrap SP HP resin column (Cytiva). Respective non-conjugated linker-drugs did not bind to the column, while respective antibody-drug conjugates bound to the column and were eluted in using A-B buffer gradient 0-42.5% B over 5 column volumes and 42.5%- 100% B over 5 column volumes. For reactions with transglutaminase, gradient elution was used and transglutaminase and ADC eluted as two distinct peaks using gradient 0-100% B over 53 column volumes. Analytical sizeexclusion chromatography (Cytiva, Superdex 200 10 / 300 in lx PBS, pH 6.0 buffer) showed that antibody drug conjugates were >90 % monomeric.Common Procedure X2: Evaluation of linker-drug conjugation using molecular weight shift using SDS-PAGE electrophoresis

[0101] Conjugation of linker-payload to antibody was evaluated by molecular weight shift of heavy and light chains of antibody drug conjugates towards higher molecular weights compared to unconjugated heavy and light chains using reduced, denaturing SDS- PAGE gel electrophoresis (4-12% Bis-Tris protein SDS-PAGE gels, ThermoFisherScientific). Drug to antibody ratio was estimated based on a fraction of heavy chain molecular weight (MW) species at higher MW compared to unconjugated heavy chain.79IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOFor ADC compounds that were generated using an intermediate species composed of antibody-linker, conjugation of linker-payload to antibody-linker intermediate was evaluated by molecular weight shift of heavy and light chains of antibody drug conjugates towards higher molecular weights compared to antibody-linker compound’s heavy and light chains using reduced, denaturing SDS-PAGE gel electrophoresis (4-12% Bis-Tris protein SDS- PAGE gels, ThermoFisherS cientific).Common Procedure X3: Determination of drug-linker to antibody ratio

[0102] Drug-linker to antibody ratio of antibody drug conjugates was determined using reverse phase liquid chromatography mass spectrometry (RPLC-MS) of antibody’s heavy and light chain subunit species using the approach known in the art (Zhu X. et al. 2020. J Pharm Anal. 10(3): 209-220; Firth D. et al. 2015 Analytical Biochemistry, 485, 34-42). Briefly, anti-HER2 and anti-EGFR antibody drug conjugates were deglycosylated using PNGase F treatment (New England Biolabs Rapid PNGAse). For anti-TROP2 and anti-CD33 antibody drug conjugate deglycosylation treatment was not needed as they contain mutations in Fc glycosylation sequence. Cysteine disulfide bridges were reduced to separate heavy and light chain subunits and sample analyzed by reverse phase liquid chromatography coupled to mass spectrometry (RPLC-MS). Following reduction of cysteine disulfide bridges and removal of N-linked glycans, the heavy and light chains eluted in distinct peaks. Electrospray ionization baseline subtracted spectra and deconvoluted mass spectra of RPLC eluted peaks were used to determine respective heavy and light chain masses and abundance (mass peak intensity) of antibody’s heavy and light chain subunit species conjugated to 0, 1, 2 or 3 linker-drug for heavy chain subunit (here referred to as Ho, Hi, H2, H3) cysteine residues, or 0 and 1 linker-drugs for heavy chain subunit conjugated to glutamine residues, and 0 or 1 linker-drug for light chain subunit (here referred to as LQ, LI) conjugated to cysteine residues. Data was used to determine the overall average linker-drug to antibody conjugate ratio (DAR) of each antibody drug conjugate. Reverse phase liquid chromatography condition was mobile phase A was 0.05% TFA in water, mobile phase B was 0.05% trifluoro acetic acid in acetonitrile. Gradient program was 10-20% of mobile phase B in 1 min, 20-50% mobile phase B in 9 min, flow rate 0.5 mL / min, post-column split, 2.1x50 mm Halo Diphenyl 2.7 um, 80°C. Mass spectrometer was Waters Xevo G2-XS QTof, with Acquity i-Class UPLC. Mass spectra data processing was performed by ProMass HR for MassLyxn software (Waters Limited).80IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0103] Average number of conjugated drug molecules to antibody was determined for each antibody drug conjugate using following formulas: Average linker pay load conjugated to light chain = (mass peak intensity of Lo x 0 / (1 x mass peak intensity of Li + 0 x mass peak intensity of Lo)) + (mass peak intensity of Li x 1 / (1 x mass peak intensity of Li + 0 x mass peak intensity of Lo)). Average linker payload conjugated to heavy chain = (mass peak intensity of Ho x 0 / (O x mass peak intensity of Ho + 1 x mass peak intensity of Hi + 2 x mass peak intensity of H2 + 3 x mass peak intensity of H3)) + (mass peak intensity of Hi x 1 / (0 x mass peak intensity of Ho + 1 x mass peak intensity of Hi + 2 x mass peak intensity of H2 + 3 x mass peak intensity of H3)) + (mass peak intensity of H2 x 2 / (O x mass peak intensity of Ho + 1 x mass peak intensity of Hi + 2 x mass peak intensity of H2 + 3 x mass peak intensity of H3)) + (mass peak intensity of H3 x 3 / (O x mass peak intensity of Ho + 1 x mass peak intensity of Hi + 2 x mass peak intensity of H2 + 3 x mass peak intensity of H3)). Average number of conjugated drug molecules to antibody composed of two light chain and two heavy chain subunits = (2x average linker payload conjugated to light chain + 2x average linker payload conjugated to heavy chain).

[0104] Observed mass of anti-TROP2 antibody heavy chain without linker-drug (Ho) was 49169Da (daltons) and observed mass of light chain without linker-drug (Lo) was 23332Da. Observed mass of anti-HER2 antibody heavy chain without linker-drug (Ho) was 49964 Da and observed light chain without linker-drug (Lo) was 23444 (Da). Observed mass of anti-EGFR antibody heavy chain without linker-drug (Ho) was 49769 (Da) and observed light chain without linker-drug (Lo) was 23259 (Da). Observed mass of anti-CD33antibody heavy chain without linker-drug (Ho) was 48608 (Da) and observed light chain without linker-drug (Lo) was 23829 (Da).

[0105] Observed respective masses of heavy chain with one linker-drug (Hi) was (Ho+ lx molecular weight of linker-drug), heavy chain with two linker-drug (H2) was (Ho + 2x molecular weight of linker-drug), heavy chain with three linker-drug (H3) was (Ho + 3x molecular weight of linker-drug). Observed respective masses of light chain with one linkerdrug (Li) was (Lo + lx molecular weight of linker-drug).Common procedure X4: Culturing cells

[0106] MDA-MB-468, FaDu, SW620, NCI-N87, U937 and MV411 cells were cultured in RPML1640 media (Gibco, Life Technologies) supplemented with 10% v / v heat inactivated FBS (Corning) at 37°C in a humidified incubator containing 5% CO2.81IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOCommon Procedure X5: Cytotoxicity assays

[0107] The viability of cancer cells in the presence of payloads or ADCs was measured in a series of in vitro assays. Cells were plated in 96-well white flat-bottomed plates (Grenier Bio-One) at 3.5 x 104per well in 100 pL culture medium.

[0108] Test compounds (payloads or ADCs) were added at a range of concentrations as nine-point serial dilution in quadruplicate for pay loads and duplicate or quadruplicate for ADCs. Following further incubation for 3 days for payloads and 3-5 days for antibody drug conjugates (ADC) in 37°C, 5% CO2, cell viability was assessed with the use of a CellTiter-Glo Luminescent Cell Viability Assay (Promega). Luminescence was measured using the SpectraMax iD3 plate reader (Molecular Devices). Luminescence values were plotted against log concentration of test compounds, and cell viability was calculated by dividing luminescence values at different payload or ADC concentrations by luminescence values at payload or ADC concentration of zero. IC50 values were calculated by GraphPad Prism as best-fit values using four parameter dose-response curve fit, with R squared ranging from 0.97-0.99. IC50 values and percent cell viability at indicated test compound concentration are shown in Tables 4-8.Synthesis of Synthetic Intermediates:Synthesis of Intermediate 1: Linker Fmoc-NH-PG6A-VCit-PABA-PFP:82IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOStep 1: Fmoc-NH-EVCit-PABA-OH

[0109] Commercially available dipeptide H2N-VCit-OH (2 g, 5.26 mmol) was dissolved in 20 mL of a 4: 1 DMF-water mixture, followed by the addition of Fmoc-E(OMe)- COOH (2 g, 5.27 mmol, 1 equiv.) and DMTMM (1.5 equiv., 7.90 mmol, 2.19 g). The resulting mixture was stirred at room temperature for 2 hours. DMF and water were evaporated under reduced pressure and the crude product was re-suspended in water (I L) and stirred for 2 hours at room temperature. After filtration, the solid was washed several times with water and dried under reduced pressure. Affording the product in high purity with no need of further purifications.Step 2: H2N-EVCit-PABA-OH.83IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WG

[0110] Fmoc-NH-EVCit-PABA-OH was dissolved in 3 mL of DMF and 1 mL of morpholine was added. After stirring at room temperature for 1 hour, the solvent and excess morpholine were evaporated under reduced pressure. The crude product was re-suspended in EtOAc (I L) and stirred for one hour at room temperature. After filtration, the solid was washed several times with EtOAc and dried under reduced pressure. Affording the product in high purity with no need of further purifications.Step 3: Fmoc-PG6A-EVCit-PABA-OH

[0111] H2N-EVCit-P ABA-OH (1 g, 1.91 mmol), Fmoc-PG6A-COOH (1.2 equiv.,2.29 mmol, 1.29 g) and DMTMM (1.5 equiv., 2.87 mmol, 793 mg) were dissolved in 5 mL of a 4:1 DMF / water mixture, diisopropylethylamine (2 equiv., 1.1 mL) was added and the resulting solution was stirred at room temperature for 1 hour. The crude reaction mixture was divided into 2 portions and purified by reverse-phase flash chromatography, using a column containing 40 g of diol-modified Cl 8 (AQ-C18, Interchim), and using a gradient of ACN in 0.1% TFA (0 to 100% ACN in H2O). Fractions containing the product were merged, recovering the desired product as a white powder, after lyophilization from water (1.65 g, 81 %). MS calc. for C53H76N7Oi6: 1066.53, found: 1066.75, [M+H]+.Step 4: Fmoc-PG6A-EVCit-PABA-PFP

[0112] Fmoc-PG6A-EVCit-P ABA-OH (300 mg, 0.28 mmol) and bis(pentaflorophenyl)carbonate (2 equiv., 0.56 mmol, 134 mg) were dissolved in 2 mL of DMF, and the resulting solution was stirred at room temperature for 30 min. The crude reaction mixture was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified Cl 8 (AQ-C18, Interchim), and using a gradient of ACN in 10 mM ammonium acetate (0 to 100% ACN in H2O). The desired product was obtained as a white powder after re-lyophilization from water / dioxane 1 :1 (207 mg, 58%). MS calc, for C6oH7SFsN7Oi8: 1276.51, found: 1276.00, [M+H]+.Synthesis of Intermediate 2: Linker Fmoc-NH-PG6A-Glr-N(Me)PHABA-PFP84IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOStep l: Glr-N(Me)PHABA-OH

[0113] (2S,3R,4S,5S,6S)-2-(2-Amino-4-(hydroxymethyl)phenoxy)-6- (methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (2.5 g, 5.50 mmol) was dissolved in 50 mL of MeOH. To the solution were added in the order formaldehyde (37 > in water, 548 pL) and formic acid (240 pL). The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of sodium cyanoborohydride (617 mg, 9.79 mmol, 1.8 equiv.). The crude reaction mixture was divided into 3 portions and purified by reverse-phase flash chromatography, using a column containing 40 g of diol-modified Cl 8 (AQ-C18, Interchim), and using a gradient of ACN in 0.1% TFA (0 to 100% ACN in H2O). Fractions containing the product were merged, recovering the desired product as a white powder, after lyophilization from water (2.1 g, 81 %). MS calc, for C21H28NO11: 470.17, found: 470.30, [M+H]+.Step 2: Glr-N(Me)PHABA-OTMS

[0114] Glr-N(Me)PHABA-OH (1.43 g, 3.05 mmol) was dissolved in 50 mL of DCM. After cooling at 0 °C, TMS-CI (2.2 equiv., 6.69 mmol, 865 pL) and85IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO diisopropylethylamine (3.5 equiv., 7.6 mmol, 1.27 mL) were added and the reaction mixture was let returning to room temperature stirred for 5 hours, until LCMS analysis confirmed full conversion to the product. The reaction mixture was diluted with 200 mL of DCM, washed with water (2 x 250 mL) and brine (250 mL). The reaction product (obtained as a yellow foam, 1.43 g, 87%) was used in the next step without any further purification.Step 3: Fmoc-NH-PG6A-Glr-N(Me)PHABA-OH

[0115] In a oven-dried round bottom flask were weighted Glr-N(Me)PHABA- OTMS (600 mg, 1.11 mmol), Fmoc-Nh-PG6A-COOH (1.1 equiv., 1.22 mmol, 685 mg) and COMU (CAS: 1075198-30-9, 1.5 equiv., 1.67 mmol, 713 mg). After 3 vacuum / argon cycles, 5 mL of anhydrous DMF were added and the resulting solution was stirred at room temperature overnight. Water (50 mL followed by TFA (1 mL) were added and the reaction mixture was stirred for 5 min at room temperature, followed by solvent removal under reduced pressure. The crude reaction mixture was purified by reverse-phase flash chromatography, using a column containing 40 g of diol-modified C18 (AQ-C18, Interchim), and using a gradient of ACN in 0. 1 % TFA (0 to 100% ACN in H2O). The desired product was obtained as a white powder after re-lyophilization from water / dioxane 1 : 1 (877 mg, 78%). MS calc, for C50H65N2O20: 1013.41, found: 1013.55, [M+H]+.Step 4: Fmoc-NH-PG6A-Glr-N(Me)PHABA-PFP

[0116] Fmoc-NH-PG6A-Glr-N(Me)PHABA-OH (410 mg, 0.41 mmol) and bis(pentaflorophenyl)carbonate (2 equiv., 0.82 mmol, 394 mg) were dissolved in 2 mL of DMF, and the resulting solution was stirred at room temperature for 30 min. The crude reaction mixture was purified by reverse-phase flash chromatography, using a column containing 40 g of diol-modified Cl 8 (AQ-C18, Interchim), and using a gradient of ACN in 10 mM ammonium acetate (0 to 100% ACN in H2O). The desired product was obtained as a white powder after re-lyophilization from water / dioxane 1 :1 (331 mg, 66%). MS calc, for C57H64F5N2O22: 1223.39, found: 1223.05, [M+H]+.Synthesis of Intermediate 3: MI-PG6-LLQGP-NH286IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0117] To a solution of H-LLQGP-NH2.TFA (1.05 equiv. 21 mg, 0.032 mmol) and Mal-PEG6-NHS ester (1.0 equiv., 17.4 mg, 0.031 mmol) in DMF (1.5 ml) was added diisopropylethylamine (2.1 equiv., 11.4 11 L, 0.065 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by reverse-phase flash chromatography using semipreparative column (diol-modified C18, 060 % ACN / H2O), offering the product MI-PG6-LLQGP-NH2 as a white solid after lyophilization (19 mg, 65 %). MS calc, for C43H73N8O15: 941.52, found: 941.45, [M+H]+. ’H NMR (600 MHz, DMSO- de) 5: 7.97 (d, 7 = 8.1 Hz, 1H), 7.92 - 7.84 (m, 3H), 7.26 (s, 1H), 7.20 (s, 1H), 7.02 (s, 2H), 6.92 (s, 1H), 6.73 (s, 1H), 4.35 - 4.22 (m, 3H), 4.20 (dd, J = 8.8, 2.9 Hz, 1H), 3.98 (dd, J = 17.1, 5.6 Hz, 1H), 3.89 - 3.79 (m, 1H), 3.63 - 3.53 (m, 4H), 3.53 - 3.39 (m, 22H), 2.53 - 2.49 (m, 2H, overlapping with DMSO signal), 2.40 (dt, J = 13.9, 6.8 Hz, 1H), 2.32 (dt, J = 14.3, 6.3 Hz, 1H), 2.22 - 2.14 (m, 1H), 2.13 - 2.06 (m, 2H), 2.06 - 1.92 (m, 1H), 1.91 - 1.67 (m, 4H), 1.64 - 1.53 (m, 2H), 1.52 - 1.37 (m, 4H), 0.87 (d, J = 6.6 Hz, 6H), 0.83 (d, J = 6.5 Hz, 6H).Additional Synthetic Intermediates87IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOExample 1: Synthesis of Compound C10188IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0118] Calicheamicin (104 mg, 0.076 mmol) was dissolved in acetonitrile (6 mL) and the solution was cooled at -20 °C. Triethylamine (53 pL), EDC hydrochloride (15 mg, 1 equiv.) and propane-2-thiol (18 pL, 0.23 mmol, 3 equiv.) were added in the order, and the reaction mixture was stirred overnight at -20 °C. The crude reaction mixture was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified Cl 8 (AQ-C18, Interchim), and using a gradient of ACN in 10 mM ammonium acetate (0 to 100% ACN in H2O). The desired product was recovered as a white powder, after lyophilization from water (68 mg, 66 %). MS calc, for C57H79IN3O21S3: 1364.33, found: 1364.40, [M+H]+. ’H NMR (400 MHz, DMSO-76) 5 6.21 - 6.16 (m, OH), 6.15 (d, J= 9.4 Hz, 1H), 6.10 - 6.00 (m, 1H), 5.55 - 5.49 (m, 2H), 5.41 - 5.35 (m, 2H), 5.09 (d, 7 = 4.8 Hz, 1H), 5.06 (d, 7 = 5.4 Hz, 1H), 4.89 (d, 7 = 10.0 Hz, 1H), 4.47 (d, 7 = 7.7 Hz, 1H), 4.22 (dt, 7 = 4.9, 2.6 Hz, 1H), 4.06 (s, 1H), 4.03 - 3.91 (m, 1H), 3.91 - 3.82 (m, 1H), 3.75 (d, 7 = 19.8 Hz, 5H), 3.53 (s, 7H), 3.37 (s, 4H), 2.45 - 2.36 (m, 3H), 2.24 (s, 3H), 1.22 (dd, 7= 6.1, 2.8 Hz, 6H), 1.15 (d, 7 = 6.7 Hz, 2H), 1.10 (dd, 7 = 6.4, 3.6 Hz, 5H), 0.96 (t, 7 = 7.1 Hz, 2H).Example 2: Synthesis of Compound C102

[0119] Calicheamicin (35 mg, 0.025 mmol) was dissolved in acetonitrile (2 mL) and the solution was cooled at -20 °C. Triethylamine (25 ,11 L), EDC hydrochloride (5 mg, 1 equiv.) and propane-2-thiol (6 pL, 0.08 mmol, 3 equiv.) were added in the order, and the reaction mixture was stirred overnight at -20 °C. The crude reaction mixture was purified by89IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO reverse-phase flash chromatography, using a column containing 25 g of diol-modifled Cl 8 (AQ-C18, Interchim), and using a gradient of ACN in 10 mM ammonium acetate (0 to 100% ACN in H2O). The desired product was recovered as a white powder, after lyophilization from water (20 mg, 58 %). MS calc, for C61H83IN3O21S3: 1416.37, found: 1416.40, [M+H]+. ’H NMR (400 MHz, DMSO-4fc) 5 6.93 (s, 1H), 6.81 (s, 1H), 6.24 (dd, J= 9.4, 5.3 Hz, 1H), 6.14 (d, J = 9.5 Hz, 1H), 6.10 - 6.00 (m, 2H), 5.53 - 5.46 (m, 1H), 5.44 - 5.34 (m, 2H), 5.07 (dd, 7 = 13.4, 5.1 Hz, 2H), 4.88 (d, J = 10.1 Hz, 1H), 4.46 (d, 7 = 7.7 Hz, 1H), 4.23 (dt, 7 = 5.0, 2.7 Hz, 1H), 4.06 (t, 7= 5.1 Hz, 2H), 4.06 - 3.92 (m, 1H), 3.92 - 3.82 (m, 1H), 3.72 (s, 3H), 3.73 - 3.62 (m, 1H), 3.53 (s, 3H), 3.57 - 3.47 (m, 4H), 3.45 - 3.31 (m, 2H), 2.90 (d, 7 = 17.6 Hz, 1H), 2.21 (s, 2H), 2.19 - 2.06 (m, 1H), 1.83 (t, 7= 9.0 Hz, 1H), 1.63 (t, 7 = 11.2 Hz, 1H), 1.42 (t, 7 = 11.3 Hz, 1H), 1.22 (t, 7 = 6.0 Hz, 6H), 1.10 (d, 7 = 6.2 Hz, 3H), 1.00 - 0.85 (m, 2H), 0.52 - 0.44 (m, 4H), 0.29 (dq, 7 = 11.0, 6.6, 6.0 Hz, 4H).Example 3: Synthesis of Compound C103

[0120] Calicheamicin (45 mg, 0.033 mmol) was dissolved in acetonitrile (4 mL) and the solution was cooled at -20 °C. Triethylamine (23 pL), EDC hydrochloride (6.3 mg, 1 equiv.) and A-(3-mercaptobutyl)methanesulfonamide (23.6 mg, 3.8 equiv.) were added in the order, and the reaction mixture was stirred overnight at -20 °C. The crude reaction mixture was purified by reverse-phase flash chromatography, using a column containing 25 g of diol- modifled C18 (AQ-C18, Interchim), and using a gradient of ACN in 10 mM ammonium90IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO acetate (0 to 100% ACN in H2O). The desired product was recovered as a white powder, after lyophilization from water (27 mg, 57 %). MS calc, for C59H84IN4O23S4: 1469.47, found: 1469.40, [M-H]’. H NMR (400 MHz, DMSO-J6) 5 6.93 (d, J = 14.0 Hz, 2H), 6.83 (s, 1H), 6.22 - 6.18 (m, OH), 6.15 (dd, J = 9.5, 1.2 Hz, 1H), 6.08 (s, 1H), 6.04 (dt, 7 = 9.5, 1.6 Hz, 1H), 5.50 (d, J = 3.8 Hz, 2H), 5.40 (d, 7 = 5.9 Hz, 1H), 5.37 (d, 7 = 1.9 Hz, 1H), 5.09 (d, 7 = 4.8 Hz, 1H), 5.06 (d, 7 = 5.4 Hz, 1H), 4.89 (d, 7= 10.0 Hz, 1H), 4.47 (d, 7 = 7.7 Hz, 1H), 4.25 - 4.19 (m, 1H), 4.O7 (s, 1H), 3.97 (dd, 7 = 9.4, 6.1 Hz, 1H), 3.87 (dd, 7 = 10.7, 6.2 Hz, 1H), 3.69 - 3.58 (m, 1H), 3.53 (s, 12H), 3.42 - 3.38 (m, 1 H), 2.94 (d, 7 = 3.4 Hz, OH), 2.89 (t, 7= 3.6 Hz, OH), 2.39 (d, 7= 6.1 Hz, OH), 2.16 (q, 7 = 9.6, 7.2 Hz, 2H), 1.87 (s, 1H), 1.82 - 1.76 (m, OH), 1.66 - 1.56 (m, 2H), 1.42 (t, 7 = 12.1 Hz, 1H), 1.22 - 1.15 (m, 5H), 1.11 (d, 7 = 0.9 Hz, OH), 0.96 (td, 7 = 7.1, 2.3 Hz, 3H).Example 4: Synthesis of Compound Cl 04

[0121] Calicheamicin (30 mg, 0.023 mmol) was dissolved in acetonitrile (4 mL) and the solution was cooled at -20 °C. Triethylamine (15 pL), EDC hydrochloride (4.2 mg, 1 equiv.) and dicyclobutylmethanethiol (11 mg, 2.5 equiv.) were added in the order, and the reaction mixture was stirred overnight at -20 °C. The crude reaction mixture was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified Cl 8 (AQ-C18, Interchim), and using a gradient of ACN in 10 mM ammonium acetate (0 to 100% ACN in H2O). The desired product was recovered as a white powder, after lyophilization91IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO from water (18 mg, 55 %). MS calc, for C63H87IN3O21S3: 1445.47, found: 1444.5, [M+H]+.]H NMR (400 MHz, DMSO-76) 5 6.94 (s, 1H), 6.82 (s, 1H), 6.25 (dd, J = 9.0, 6.2 Hz, 1H), 6.15 (d, J = 9.5 Hz, 1H), 6.12 (s, 1H), 6.09 - 6.00 (m, 1H), 5.53 - 5.48 (m, 3H), 5.44 (d, J = 5.6 Hz, 1H), 5.37 (d, J = 1 .9 Hz, 2H), 5.09 (d, J = 4.8 Hz, 2H), 5.06 (d, J = 5.4 Hz, 2H), 4.89 (d, 7 = 9.8 Hz, 2H), 4.48 (d, 7 = 7.8 Hz, 1H), 4.23 (dt, 7 = 5.0, 2.4 Hz, 2H), 4.06 (s, 2H), 3.97 (dq, 7 = 9.0, 6. 1 Hz, 2H), 3.87 (dd, 7 = 10.5, 6.2 Hz, 1H), 3.77 (d, 7 = 1.2 Hz, 6H), 3.72 (s, 6H), 3.61 - 3.57 (m, OH), 3.50 (d, 7 = 3.0 Hz, 1H), 3.46 - 3.39 (m, 2H), 3.28 - 3.22 (m, 15H), 2.66 - 2.56 (m, 1H), 2.47 - 2.34 (m, 6H), 2.24 (d, 7 = 1.5 Hz, 6H), 2.13 (t, 7 = 10.0 Hz, 1H), 1.92 - 1.55 (m, 17H), 1.25 - 1.16 (m, 12H), 1.10 (d, 7= 6.2 Hz, 6H), 0.96 (t, 7 = 7.0 Hz, 4H).Example 5: Synthesis of Compound C105 and Compound C10692IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOStep 1:

[0122] Fmoc-NH-PG6A-Glr-N(Me)PHABA-PFP (75 mg, 0.06 mmol) was dissolved in 3 mL of a 1 :1 mixture of acetonitrile and dioxane, followed by the addition of triethylamine (8 pL, 1 equiv.) and hydroxybenzotriazole (HOBt, 1 equiv., 8.4 mg). The prepared solution of the OBt activated carbonate linker was added in 3 portions (one portion per day) to a previously prepared solution of Compound C102 (50 mg, 0.037 mmol) in acetonitrile (2 mL) and the resulting mixture was stirred at room temperature for 3 further days (after the last addition). The crude reaction mixture was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified C 18 (AQ-C18, Interchim), and using a gradient of ACN in 0.1% TFA (0 to 100% ACN in H2O). (82 mg, 81 % yield with respect of Cl).Step 2: Compound Cl 0593IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0123] The product of Step 1 (82 mg) was dissolved in 3 mL of 1:1 water / THF mixture. LiOH (8 mg, 10 equiv.) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of 100 pL of acetic acid and the crude reaction product was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified C18 (AQ-C18, Interchim), and using a gradient of ACN in 0.1% acetic acid (0 to 100% ACN in H2O). Compound C105 was obtained as a white powder after lyophilization from water (10 mg). MS calc, for C90H127IN5O37S3: 2092.64, found: 1047.3, [(M+H) / 2]2+.Step 3: Compound Cl 06

[0124] Compound C105 (10 mg) was dissolved in 0.5 mL of DMF. Diisopropyl ethylamine (1 pL, 1.2 equiv.) was added, followed by the TCO NHS ester (1.6 mg, 1.2 equiv.) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by reverse-phase flash chromatography, using on semipreparative column (Triart YMC) using a gradient of ACN in 10 mM ammonium acetate. Compound 106 was obtained as a white powder after lyophilization from water (3.5 mg recovered). MS calc, for C99H139IN5O39S3: 2244.73, found: 1259,30 [(M+H) / 2]2+.Example 6: Synthesis of Compound C10794IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOStep 1:

[0125] Compound C102 (126 mg, 0.089 mmol) was dissolved in 10 mL of acetonitrile and the linker Fmoc-PG6A-EVCit-PABA-PFP (3.5 equiv. in total, 397 mg) was added in three portions (1 equiv. every 3 days). The reaction was stirred for 5 additional days after the last addition of linker. The crude reaction mixture was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified C18 (AQ-C18, Interchim), and using a gradient of ACN in 0.2 % formic acid (0 to 100% ACN in H2O), and repurified on semipreparative column (Triart YMC) using a gradient of ACN in 0.2 % acetic acid. The desired product was obtained as a white powder after lyophilization from water (126 mg, 61% yield with respect of Compound C102).Step 2: Compound C107

[0126] The product of Step 1 (138 mg, 0.054 mmol) was dissolved in 4 mL of 1 :1 water / THF mixture. LiOH (9 mg, 10 equiv.) was added and the reaction mixture was stirred at room temperature for 1 hour. Piperidine, 20 p L was added and the reaction mixture was stirred one further hour at room temperature. The reaction was quenched by the addition of 100 pL of acetic acid and the crude reaction product was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified C18 (AQ-C18, Interchim), and using a gradient of ACN in 0.2% formic acid (0 to 100% ACN in H2O). The product was further re-purified twice on semipreparative column (Triart YMC) using a gradient of ACN in 10 mM ammonium acetate, and a gradient of ACN in 5 mM ammonium acetate for the second purification. The desired product was obtained as a white powder after lyophilization from water (14 mg). MS calc, for C99H143IN10O36S3: 2272.35, found: 1137.4, [M / 2+H]+. *H NMR (400 MHz, DMSO-cfc) 8 10.05 (s, 1H), 8.37 (s, 1H), 8.01 (dd, J = 21.7, 8.5 Hz, 1H),95IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO7.56 (d, 7 = 7.9 Hz, 2H), 7.24 (s, 2H), 6.94 (s, 1H), 5.99 (s, 1H), 5.53 (s, 2H), 5.37 (d, 7 = 1.9 Hz, 1H), 5.06 (s, 1H), 4.96 (s, 2H), 4.89 (d, 7 = 9.9 Hz, 1H), 4.32 (d, J = 7.2 Hz, 1H), 4.23 (s, 1H), 4.18 (s, 1H), 4.07 (s, 1H), 3.97 (dd, 7 = 9.3, 6.2 Hz, 1H), 3.87 (s, 2H), 3.75 (d, 7 = 19.4 Hz, 4H), 3.56 (dd, 7 = 7.6, 4.8 Hz, 2H), 3.53 (s, 1H), 3.56 - 3.40 (m, 12H), 3.21 - 3.14 (m, 1H), 2.94 (s, 2H), 2.82 (t, 7 = 5.5 Hz, 1H), 2.24 (s, 2H), 2.13 (s, 2H), 2.07 (s, 1H), 1.99 (d, 7 = 7.7 Hz, 1H), 1.85 (s, 1H), 1.81 (s, 2H), 1.64 (s, 2H), 1.44 (s, 1H), 1.36 (s, 2H), 1.25 - 1.18 (m, 5H), 1.10 (d, 7 = 6.2 Hz, 2H), 0.97 (s, 3H), 0.80 (dd, 7 = 10.4, 6.8 Hz, 6H), 0.46 (t, 7 = 8.6 Hz, 1 H), 0.40 (s, 5H), 0.25 (s, 1H).Example 7: Synthesis of Compound C10896IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOStep 1:

[0127] Fmoc-NH-PG6A-Glr-N(Me)PHABA-PFP (134 mg, 0.11 mmol) was dissolved in 4 mL of a 1 :1 mixture of acetonitrile and dioxane, followed by the addition of triethylamine (15 pL, 1 equiv.) and hydroxybenzotriazole (HOBt, 1 equiv., 15.5 mg). The prepared solution of the OBt activated carbonate linker was added in 3 portions (one portion per day) to a previously prepared solution of Compound C101 (100 mg, 0.073 mmol) in acetonitrile (2 mL) and the resulting mixture was stirred at room temperature for 5 further days (after the last addition). The crude reaction mixture was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified C18 (AQ-C18, Interchim), and using a gradient of ACN in 0.1% TFA (0 to 100% ACN in H2O), and repurified on semipreparative column (Triart YMC) using a gradient of ACN in 10 mM ammonium acetate. The desired product was obtained as a white powder after lyophilization from water (81 mg, 53% yield with respect of Compound C101).Step 2: Compound Cl 08

[0128] The product of Step 1 (81 mg) was dissolved in 4 mL of 1:1 water / THF mixture. LiOH (8 mg, 10 equiv.) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of 100 pL of acetic acid and the crude reaction product was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified C18 (AQ-C18, Interchim), and using a gradient of ACN in 0.1% acetic acid (0 to 100% ACN in H2O). The desired product was obtained as a white powder after lyophilization from water (60 mg, 87%). MS calc, for C86H122IN5O37S3: 2041.00, found: 1021.1.05, [M+2H]2+. H NMR (400 MHz, DMSO-6) 5 7.30 (s, 1H), 7.23 (s, 3H), 6.94 (s, 1H), 6.14 (d, J = 5.9 Hz, 1H), 6.00 (d, J = 9.4 Hz, 1H), 5.93 (s, 1H), 5.52 (s,97IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO1H), 5.37 (d, 7 = 2.0 Hz, 1H), 5.30 (s, 1H), 5.08 (dd, 7 = 13.9, 5.0 Hz, 2H), 4.99 (s, 4H), 4.90 (d, 7 = 9.3 Hz, 1H), 4.53 (s, OH), 4.23 (s, 1H), 4.07 (s, 1H), 4.03 - 3.91 (m, 1H), 3.86 (s, 1H), 3.75 (d, 7 = 19.2 Hz, 5H), 3.74 (s, 3H), 3.58 - 3.53 (m, 1H), 3.53 (s, 10H), 3.52 - 3.39 (m, 12H), 3.37 (s, 3H), 3.17 (s, 6H), 3.04 (d, 7 = 5.0 Hz, 3H), 2.90 (dt, 7 = 10.4, 5.9 Hz, 3H), 2.24 (s, 2H), 1.83 (d, 7 = 12.5 Hz, 1H), 1.64 (t, 7 = 11.1 Hz, 1H), 1.36 (s, 1H), 1.21 (dd, 7= 8.7, 5.3 Hz, 2H), 1.19 (s, 9H), 1.11 (dd, 7 = 10.1, 6.4 Hz, 4H), 0.99 (t, 7 = 6.8 Hz, 1H).Example 8: Synthesis of Compound C109Step 1:98IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0129] Compound C101 (66 mg, 0.048 mmol) was dissolved in 15 mL of acetonitrile and the linker Fmoc-PG6A-EVCit-PABA-PFP (3 equiv. in total, 0.145 mmol, 185 mg) was added in three portions (1 equiv. every 2 days). The reaction was stirred for 7 additional days after the last addition of linker. The crude reaction mixture was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified Cl 8 (AQ-C18, Interchim), and using a gradient of ACN in 0.2 % formic acid (0 to 100% ACN in H2O), and repurified on semipreparative column (Triart YMC) using a gradient of ACN in 0.2 % acetic acid. The desired product was obtained as a white powder after lyophilization from water (42 mg, 35% yield with respect of Compound C101).Step 2: Compound Cl 09

[0130] The product of Step 1 (42 mg) was dissolved in 4 mL of 1 : 1 water / THF mixture. LiOH (4 mg, 10 equiv.) was added and the reaction mixture was stirred at room temperature for 1 hour. Piperidine, 20 p L was added and the reaction mixture was stirred one further hour at room temperature. The reaction was quenched by the addition of 100 p L of acetic acid and the crude reaction product was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified C18 (AQ-C18, Interchim), and using a gradient of ACN in 0.2% formic acid (0 to 100% ACN in H2O). The desired product was obtained as a white powder after lyophilization from water (23 mg recovered). MS calc, for C95H139IN10O36S3: 2220.28, found: 1111.10, [M / 2+H]+.]H NMR (400 MHz, DMSO-6) 5 10.05 (s, 1H), 8.00 (s, 1H), 7.59 - 7.52 (m, 2H), 7.24 (s, 2H), 6.93 (s, 1H), 5.99 (d, 7 = 13.7 Hz, 1H), 5.52 (s, 2H), 5.36 (s, 1H), 5.10 (s, 1H), 4.95 (s, 2H), 4.90 (s, 1H), 4.33 (s, 2H), 4.22 (s, 1H), 4.17 (s, 1H), 4.06 (s, 1H), 3.87 (s, 2H), 3.77 (s, 2H), 3.72 (s, 2H), 3.59 - 3.43 (m, 18H), 2.84 (t, 7 = 5.5 Hz, 1H), 2.23 (s, 2H), 2.06 (d, 7 = 6.9 Hz, 1H), 1.81 (s, 2H),I.62 (s, 2H), 1.25 - 1.17 (m, 5H), 1.13 - 1.02 (m, 5H), 0.98 (d, 7 = 7.1 Hz, 1H), 0.80 (dd, 7 =I I .1 , 6.6 Hz, 6H).Example 9: Synthesis of Compound C11099IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0131] Compound C108 (6.4 mg) was dissolved in 0.5 mL of DMF and diisopropylethylamine (2.5 pL) was added followed by the Bis Sulfone NHS ester (2.8 mg, 1.5 equiv.). The reaction mixture was stirred at room temperature for 4 hours and directly purified by reverse-phase HPLC, using a semipreparative column (Triart YMC) using a gradient of ACN in 10 mM ammonium acetate. The desired product was obtained as a white powder after lyophilization from water (2.3 mg, 53% purity). MS calc, for C 11 1 H144IN5O43S5: 2523.57, found: 1262.9, [M+2H]2+.Example 10: Synthesis of Compound Clll100IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOStep 1:

[0132] Compound C103 (34.5 mg, 0.023 mmol) was dissolved in 5 mL of acetonitrile and 1 mL of dioxane and the linker Fmoc-PG6A-EVCit-PABA-PFP (3.5 equiv. in total, 0.07 mmol, 89 mg) was added in three portions. The reaction was stirred for 7 additional days after the last addition of linker. The crude reaction mixture was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified Cl 8 (AQ-C18, Interchim), and using a gradient of ACN in 0.2 % formic acid (0 to 100% ACN in H2O), and repurified on semipreparative column (Triart YMC) using a gradient of ACN in101IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO0.2 % acetic acid. The desired product was obtained as a white powder after lyophilization from water (14.2 mg).Step 2: Compound Cl 11

[0133] The product of Step 1 (14 mg) was dissolved in 2 mL of 1:1 water / THF mixture. LiOH (0.4 mg, 3 equiv.) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of 30 pL of acetic acid and the crude reaction product was purified by reverse-phase flash chromatography, using on semipreparative column (Triart YMC) using a gradient of ACN in 10 mM ammonium acetate. The desired product was obtained as a white powder after lyophilization from water (23 mg recovered). MS calc, for C97H145IN11O38S4: 2326.77, found: 1164,30 [(M+H) / 2]2+.Example 11: Synthesis of Compound C112 and Compound C113102IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOStep 1:

[0134] Fmoc-NH-PG6A-Glr-N(Me)PHABA-PFP (50 mg, 0.06 mmol) was dissolved in 2 mL of a 1 :1 mixture of acetonitrile and dioxane, followed by the addition of triethylamine (5 ,uL, 1 equiv.) and hydroxybenzotriazole (HOBt, 1 equiv., 5.6 mg). The prepared solution of the OBt activated carbonate linker was added in 3 portions (one portion per day) to a previously prepared solution of Compound C104 (42 mg, 0.032 mmol) in acetonitrile (2 mL) and the resulting mixture was stirred at room temperature for 3 further days (after the last addition). The crude reaction mixture was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified C 18 (AQ-C18, Interchim), and using a gradient of ACN in 0.1% TFA (0 to 100% ACN in H2O). (82 mg, 24% yield with respect of Compound Cl 04).Step 2: Compound Cl 12103IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0135] The product of Step 1 (21 mg) was dissolved in 4 mL of 1:1 water / THF mixture. LiOH (2 mg, 10 equiv.) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of 100 pL of acetic acid and the crude reaction product was purified by reverse-phase flash chromatography, using a column containing 25 g of diol-modified C18 (AQ-C18, Interchim), and using a gradient of ACN in 0.1% acetic acid (0 to 100% ACN in H2O). The desired product was obtained as a white powder after lyophilization from water (7 mg). MS calc, for C92H131IN5O37S3: 2120.67, found: 1061.6, [(M+H) / 2]2+.Step 3: Compound Cl 13

[0136] Compound Cl 12 (6.3 mg) was dissolved in 0.5 mL of DMF.Diisopropylethylamine (0.62 pL, 1.2 equiv.) was added, followed by the TCO NHS ester (1 mg, 1.25 equiv.) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by reverse-phase flash chromatography, using on semipreparative column (Triart YMC) using a gradient of ACN in 10 mM ammonium acetate. The desired product was obtained as a white powder after lyophilization from water (2.4 mg recovered). MS calc, for C101H143IN5O39S3: 2272.76, found: 1137,2 [(M+H) / 2]2+. HPLC purity 96%.Example 12: Synthesis of Compound C114104IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0137] Compound Cl 08 (8 mg) was dissolved in 0.3 mL of DMF.Diisopropylethylamine (0.85 pL, 1.25 equiv.) was added, followed by the TCO NHS ester (1.3 mg, 1.25 equiv.) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by reverse-phase flash chromatography, using on semipreparative column (Triart YMC) using a gradient of ACN in 10 mM ammonium acetate. The desired product was obtained as a white powder after lyophilization from water (3.4 mg recovered). MS calc, for C95H135IN5O39S3: 2192.69, found: 1096.30 [(M+H) / 2]2+.Example 13: Synthesis of Compound C115105IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0138] Compound C107 (4.5 mg) was dissolved in 0.5 mL of DMF. Diisopropyl ethylamine (0.42 pL, 1 .25 equiv.) was added, followed by the TCO NHS ester (0.65 mg, 1 .25 equiv.) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by reverse-phase flash chromatography, using on semipreparative column (Triart YMC) using a gradient of ACN in 10 mM ammonium acetate. The desired product was obtained as a white powder after lyophilization from water (2.1 mg recovered). MS calc, for CiosHiselNioChsSs: 2423.88, found: 1213,20 [(M+H) / 2]2+. HPLC purity 99%.Example 14: Synthesis of Compound C116106IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0139] Compound C 109 (12 mg) was dissolved in 0.5 mL of DMF. Diisopropyl ethylamine (1.2 pL, 1.25 equiv.) was added, followed by the TCO NHS ester (1.8 mg, 1.25 equiv.) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was directly purified by reverse-phase flash chromatography, using on semipreparative column (Triart YMC) using a gradient of ACN in 10 mM ammonium acetate. The desired product was obtained as a white powder after lyophilization from water (2.1 mg recovered). MS calc, for C104H152IN10O38S3: 2371.85, found: 1 186.7 [(M+H) / 2]2+. HPLC purity 70%.Example 15: Generation of antibodies

[0140] Anti-HER2, anti-TROP2, anti-EGFR, and anti-CD33 light chain and heavy chain protein sequences were generated by gene synthesis and codon optimized for expression in mammalian cells (GeneUniversal and ATUM). The heavy and light chain genes were cloned into separate mammalian expression vectors and then transiently cotransfected in EXPI293F cells (ThermoFisher). Antibody expression was carried out in EXPI293F expression medium (ThermoFisher) and supernatant harvested 5 days post transfection. Respective antibodies were purified using M AB SELECT Sure Resin (Cytiva) and buffer exchanged into lx phosphate buffer saline pH 7.0. Analytical size-exclusion chromatography (Cytiva, Superdex 200 10 / 300) data indicated that respective antibodies were approximately >95% monomer.Anti-TROP2 mAbAnti-TROP2 heavy chain, SEQ ID NO: 1107IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0141] QVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYAQGFTGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARGGY GSSYWYFDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGAnti-TROP2 light chain, SEQ ID NO: 2

[0142] DIQMTQSPSSLSASVGDRVTITCQASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQHYITPLTFGGGTKVEIK RTVAAPS VFIFPPSDEQLKS GTAS VVCLLNNFYPREAKVQWKVDNALQS GNS QES VT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECAnti-CD33 mAb

[0143] Anti-CD33 antibody amino acid sequence was based on heavy and light chain variable domain gemtuzumab amino acid sequence KEGG database entry D03259.Anti-CD33 heavy chain, SEQ ID NO: 3

[0144] EVQLVQSGAEVKKPGSSVKVSCKASGYTITDSNIHWVRQAPGQSLEWIGYIYPYNGGTDYNQKFKNRATLTVDNPTNTAYMELSSLRSEDTAFYYCVNGNPW LAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALG APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPAnti-CD33 light chain, SEQ ID NO: 4

[0145] DIQLTQSPSTLSASVGDRVTITCRASESLDNYGIRFLTWFQQKPGKAP KLLMYAASNQGSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQTKEVPWSFGQG108IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOTKVEVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECAnti-HER2 mAb

[0146] Anti-HER2 antibody amino acid sequence was based on heavy and light chain variable domain trastuzumab amino acid sequence KEGG database entry D03257.Anti-HER2 light chain, SEQ ID NO: 5

[0147] DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECAnti-HER2 IgGl heavy chain, SEQ ID NO: 6

[0148] EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGG DGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGLLQGAnti-EGFR mAh

[0149] Anti-EGFR antibody amino acid sequence was based on heavy and light chain variable domain panitumumab amino acid sequence KEGG database entry D05350.Anti-EGFR heavy chain, SEQ ID NO: 7

[0150] QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEW1GH1YYSGNTNYNPSLKSRLT1SIDTSKTQFSLKLSSVTAADTA1YYCVRDRVTGAF DIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW109IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GLLQGAnti-EGFR light chain, SEQ ID NO: 8

[0151] DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIK RTVAAPS VFIFPPSDEQLKS GTAS VVCLLNNFYPREAKVQWKVDNALQS GNS QES VT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECExample 16: General procedure for generation of antibody drug conjugateMethod PM2

[0152] In order to generate an antibody drug conjugate where linker-drug was conjugated to glutamine 295 residue on antibody, the antibody drug conjugates were produced by first reacting amine-tetrazine linker to glutamine residue 295 using enzyme transglutaminase (TG). Reaction resulted in isopeptide bond formation between glutamine residue 295 and amine residue in linker. Second, antibody-linker tetrazine intermediate was reacted with linker-drug comprising a / ra / i.s-cyclooctene (TCO) moiety using “click” chemistry. This method was utilized to generate ADC compounds C205, C207, C208, C212, C213, C214, C215, C216, and C217. A schematic of the method is shown below.

[0153] In some embodiments, contemplated herein is a bioorthogonal click chemistry system employing methyl-phenyl tetrazine and / ran.v-cyclooctene (TCO) as a110IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO reactive pair, wherein TCO may be positioned at the terminal end of the linker-payload moiety. In other embodiments, the configuration is reversed, for example, with tetrazine conjugated to the linker-payload. In additional embodiments, the reactive pair is not limited to tetrazine and TCO. For example, in certain embodiments tetrazine may be substituted with other strained dienophiles or nitrogen heterocycles such as, for example, triazine, triazinium, or azide. In further embodiments, TCO may be replaced with other strained alkynes or cycloalkenes including but not limited to, for example, dibenzocyclooctyne (DBCO) or bicyclononyne (BCN).Method PM3

[0154] In order to generate an antibody drug conjugate where linker-drug is conjugated to heavy-heavy and heavy-light interchain cysteines of the antibody, the antibodydrug conjugates were produced by a two-step sequence. In a first step, a linker comprising a transglutaminase (TG) recognition sequence and a maleimide moiety was reacted with the reduced cysteine residues of the antibody to form thioether bonds. The linker’s maleimide moiety was reacted with antibody’s reduced cysteines to form a thioether bond. In a subsequent step, the glutamine residue within the TG recognition sequence of the antibodylinker intermediate was reacted, via TG-catalyzed transamidation, with an amine-PEG- containing linker-drug to generate an isopeptide bond. This method was utilized to generate ADC compounds C201 and C202. A schematic of the method is shown below.Method PM6

[0155] In order to generate an antibody drug conjugate where linker-drug is conjugated to heavy-heavy and heavy-light interchain cysteines of the antibody, the antibodydrug conjugates were produced by reacting a linker-drug compound with an antibody in a two-step sequence. In a first step, linker comprising bis-sulfone moiety formed thioether111IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO bonds at both cysteine residues of reduced disulfide crosslinking light and heavy chain antibody subunits and / or heavy and heavy chain antibody subunits, and / or a thioether bond at one cysteine residue. In step two, tetrazine moiety from antibody-linker intermediate was reacted with linker-drug comprising a / ran.v-cyclooctene (TCO) moiety to ligate tetrazine and TCO using “click” chemistry. This method was utilized to generate ADC compounds C211, C221, and C222. A schematic of the method is shown below.Method PM7

[0156] In order to generate an antibody drug conjugate where linker-drug is conjugated to heavy-heavy and heavy-light interchain cysteines of the antibody, the antibodydrug conjugates were produced by reacting a linker-drug compound with an antibody in a two step sequence. In a first step, linker comprising active-mono-sulfone moiety formed thioether bonds at both of cysteine residues of reduced disulfide crosslinking light and heavy chain antibody subunits and / or heavy and heavy chain antibody subunits, and / or a thioether bond at one cysteine residue. In step two, tetrazine moiety from antibody-linker intermediate was reacted with linker-drug comprising a / ra -cyclooctene (TCO) moiety to ligate tetrazine and TCO using “click” chemistry. This method was utilized to generate ADC compounds C210 and C218. A schematic of the method is shown below.112IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOMethod PM9

[0157] In order to generate an antibody drug conjugate where linker-drug is conjugated to heavy-heavy and heavy-light interchain cysteines of the antibody, the antibody drug conjugate was produced in one step reaction by reacting a linker-drug compound comprising bis-sulfone moiety that reacted with one and / or two reduced cysteine residues forming disulfide bond sites present between light and heavy chain antibody subunits and heavy and heavy chain antibody subunits respectively to form thioether bond at one of the two cysteine residues of reduced disulfides, and two of the cysteine residues of reduced disulfides forming re-bridging conjugation between light and heavy chain antibody subunits and / or heavy and heavy chain antibody subunits respectively. This method was utilized to generate ADC compound C204. A schematic of the method is shown below.113IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOMethod PM10

[0158] In order to generate an antibody drug conjugate where linker-drug is conjugated to heavy-heavy and heavy-light interchain cysteines of the antibody, the antibodydrug conjugates were produced by reacting a linker-drug compound with an antibody in two step sequence. In a first step, linker comprising di-bromo maleimide moiety formed thioether bonds at both cysteine residues of reduced disulfide crosslinking light and heavy chain antibody subunits and / or heavy and heavy chain antibody subunits respectively, and / or a thioether bond at one reduced cysteine residue. In step two, tetrazine moiety present in linker conjugated to antibody-linker intermediate was reacted with linker-drug comprising a trans- cyclooctene (TCO) moiety to ligate tetrazine and TCO using “click” chemistry. This method was utilized to generate ADC compound C209. A schematic of this method is shown below.114IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOMethod PM15

[0159] In order to generate an antibody drug conjugate where linker-drug was conjugated to glutamine residue on antibody in one step reaction, the antibody drug conjugates were produced by reacting antibody comprising glutamine moiety in transglutaminase tag peptide expressed on C-terminus of antibody heavy chain with linkerdrug comprising amine moiety using enzyme transglutaminase. Reaction resulted in isopeptide bond formation between glutamine on antibody and amine residue in linker. This method was utilized to generate ADC compounds C203 and C206. A schematic of the method is shown below.Example 17: Synthesis of compound C203

[0160] Compound C203 was generally prepared according to Method PM 15. Specifically, Compound C203 was prepared using 20 molar equivalents of linker payload compound C108 to 1.4 mg / ml anti-EGFR IgGl monoclonal antibody in 26 mM Tris, 270 mM NaCl, pH 7.5, 5% DMSO and 1.5 % (wt / v) transglutaminase (Ajinomoto) and incubation at 19 °C for 18 hr with nutation. Antibody drug conjugate was separated from unconjugated linker-payload and transglutaminase according to Common Procedure X2. Percent monomer was 91%. Linker-drug conjugation efficiency was confirmed by molecular weight shift of heavy chain compared to unconjugated antibody by electrophoresis (reduced SDS-PAGE) and ADC DAR estimated ~ 1.4. Reduced RPLC-MS ADC DAR was -1.2.DAR estimated based on SDS-PAGE electrophoresis was - 1.4.Example 18: Synthesis of compound C206115IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO

[0161] Compound C206 was generally prepared according to Method PM15.Specifically, compound C206 was prepared using 30 molar equivalents of linker payload compound C108 to 1.4 mg / ml anti-HER2 IgGl monoclonal antibody in 26 mM Tris, 322 mM NaCl, pH 7.5, 5% DMSO and 1.5 % (wt / v) transglutaminase (Ajinomoto) and incubation at 19 °C for 12 hr with nutation. Antibody drug conjugate was separated from unconjugated linker-payload and transglutaminase according to Common Procedure X2. Percent monomer was 100%. Linker-drug conjugation efficiency was confirmed by molecular weight shift of heavy chain compared to unconjugated antibody by electrophoresis (reduced SDS-PAGE) and ADC DAR estimated ~ 0.7.Example 19: Synthesis of compound C204

[0162] Compound C204 was generally prepared according to Method PM9. Specifically, compound C204 was prepared by first reducing inter-chain Cys by incubating anti-TROP2 antibody at 5 mg / ml in lx PBS pH 7.0 with 40 mole equivalent excess of TCEP for 1 hr, 19 °C. Excess TCEP was removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Then 33 mole excess equivalent of linker-payload compound Cl 10 and 10% (v / v) DMSO were added to the reduced 3.8 mg / ml antibody solution and reaction incubated at 19 °C for 20 hr. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 89%. Linkerdrug conjugation efficiency was confirmed by molecular weight shift of heavy and light chains consistent with re-bridging of heavy-heavy and heavy-light Cys-Cys interchain bonds compared to unconjugated antibody by electrophoresis (reduced SDS-PAGE).Example 20: Synthesis of compound C205116IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0163] Compound C205 was generally prepared according to Method PM2. Specifically, compound C205 was prepared by first generating intermediate 1-20 by reacting 3 mg / ml anti-TROP2 antibody and 30 mole excess over antibody of Intermediate 4 in 13 mM Tris, 150 mM NaCl, pH 7.5, 1.5% Transglutaminase (wt / v) (Ajinomoto), and 5% (v / v) DMSO for 20 hr at 19 °C with nutation. Excess linker and transglutaminase were removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, to generate compound C205, linker-payload compound C 106 was added at 20 mole excess over 2.5 mg / ml of intermediate 1-20 and DMSO was added to 10% (v / v) and reaction incubated for 20 hr at 33 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 100%. Linker-drug conjugation was confirmed by molecular weight shift of heavy chain compared to intermediate 1-20 by electrophoresis (reduced SDS-PAGE) and ADC DAR estimated - 1.3. Reduced RP-LCMS ADC DAR was ~ 1.8.Example 21: Synthesis of compound C207117IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0164] Compound C207 was generally prepared according to Method PM2.Specifically, Compound C207 was prepared by first generating intermediate 1-21 by reacting 3 mg / ml anti-TROP2 antibody and 40 mole excess over antibody of Intermediate 5 in 13mM Tris, 150mM NaCl, pH 7.5, 1.5% Transglutaminase (wt / v) (Ajinomoto), and 5% (v / v) DMSO for 20 hr at 19°C with nutation. Excess linker and transglutaminase were removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, to generate compound C207, linker-payload compound Cl 13 was added at 1 1 mole excess over 2.2 mg / ml of intermediate 1-21 and DMSO was added to 10% (v / v) and reaction incubated for 20 hr at 19 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 100%. Linker-drug conjugation was confirmed by molecular weight shift of heavy chain compared to intermediate 1-21 by electrophoresis (reduced SDS-PAGE) and ADC DAR estimated ~ 1.5. Reduced RP-LCMS ADC DAR ~ 1.8.Example 22: Synthesis of compound C208

[0165] Compound C208 was generally prepared according to Method PM2.Specifically, compound C208 was prepared by first generating intermediate 1-22 by reacting 3 mg / ml anti-CD33 antibody and 40 mole excess over antibody of Intermediate 5 in 20 mM Tris, 180 mM NaCl, pH 7.5, 1.5% Transglutaminase (wt / v) (Ajinomoto), and 5% (v / v) DMSO for 20 hr at 19 °C with nutation. Excess linker and transglutaminase were removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. To generate compound C208, linker-payload compound Cl 13 was added to 1.9 mg / ml of Intermediate 1-22 at 11 mole excess over antibody and DMSO was added to 10% (v / v) and reaction incubated for 20 hr at 19 °C. Antibody drug conjugate was separated from unconjugated linker-payload according118IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO to Common Procedure X2. Percent monomer was 96%. Linker-drug conjugation was confirmed by molecular weight shift of heavy chain compared to Intermediate 1-22 by electrophoresis (reduced SDS-PAGE) and DAR estimated - 1.4. Reduced ADC RP-LCMS DAR - 1.4.Example 23: Synthesis of compound C212

[0166] Compound C212 was generally prepared according to Method PM2. Specifically, compound C212 was prepared by first reacting 4.3 mg / ml anti-CD33 antibody and 70 mole excess over antibody of Intermediate 5 in 5.5 mM Tris, 110 mM NaCl, pH 7.5, 1.5% Transglutaminase (wt / v) (Ajinomoto), and 5% (v / v) DMSO for 20 hr at 19 °C with nutation. Excess linker and transglutaminase were removed from antibody using sizeexclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, to generate compound C212, linker-payload compound Cl 14 was added at 22 mole excess over 1.6 mg / ml of intermediate 1-23 and DMSO was added to 10% (v / v) and reaction incubated for 14 hr at 33 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was -100%. Linker-drug conjugation was confirmed by molecular weight shift of heavy chain compared to intermediate 1-23 by electrophoresis (reduced SDS- PAGE) and ADC DAR estimated - 1.2.Example 24: Synthesis of compound C213119IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0167] Compound C213 was generally prepared according to Method PM2. Specifically, compound C213 was prepared by first reacting 3.3 mg / ml anti-CD33 antibody and 40 mole excess over antibody of Intermediate 5 in 18 mM Tris, 180 mM NaCl, pH 7.5, 1.5% Transglutaminase (wt / v) (Ajinomoto), and 5% (v / v) DMSO for 20 hr at 19 °C with nutation. Excess linker and transglutaminase were removed from antibody using sizeexclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, to generate compound C213, linker-payload compound C106 was added at 22 mole excess over 2.8 mg / ml of intermediate 1-24 and DMSO was added to 10% (v / v) and reaction incubated for 20 hr at 33 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 95%. Linker-drug conjugation was confirmed by molecular weight shift of heavy chain compared to intermediate 1-24 by electrophoresis (reduced SDS- PAGE) and ADC DAR estimated ~ 1.2 Reduced RP-LCMC ADC DAR was ~ 1.8.Example 25: Synthesis of compound C214

[0168] Compound C214 was generally prepared according to Method PM2.Specifically, compound C214 was prepared by first reacting 3.3 mg / ml anti-CD33 antibody120IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO and 40 mole excess over antibody of Intermediate 5 in 18 mM Tris, 180 mM NaCl, pH 7.5, 1.5% Transglutaminase (wt / v) (Ajinomoto), and 5% (v / v) DMSO for 20 hr at 19 °C with nutation. Excess linker and transglutaminase were removed from antibody using sizeexclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, to generate compound C214, linker-payload compound Cl 15 was added at 22 mole excess over 2.8 mg / ml intermediate 1-25 and DMSO was added to 10% (v / v) and reaction incubated for 20 hr at 33 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 98%. Linker-drug conjugation was confirmed by molecular weight shift of heavy chain compared to intermediate 1-25 by electrophoresis (reduced SDS-PAGE) and DAR estimated ~ 1.3. Reduced RP-LCMS ADC DAR ~ 1.7.Example 26: Synthesis of compound C215

[0169] Compound C215 was generally prepared according to Method PM2. Specifically, compound C215 was prepared by first reacting 3.3 mg / ml anti-TROP2 antibody and 40 mole excess over antibody of Intermediate 5 in 10 mM Tris, 150 mM NaCl, pH 7.5, 1.5% Transglutaminase (wt / v) (Ajinomoto), and 5% (v / v) DMSO for 20 hr at 19 °C with nutation. Excess linker and transglutaminase were removed from antibody using sizeexclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, to generate compound #C215, linker-payload compound Cl 16 was added at 30 mole excess over 2.9 mg / ml of intermediate 1-26 and DMSO was added to 10% (v / v) and reaction incubated for 20 hr at 33 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 100%. Linker-drug conjugation was confirmed by molecular121IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO weight shift of heavy chain compared to intermediate 1-26 by electrophoresis (reduced SDS- PAGE) and ADC DAR estimated ~ 0.6.Example 27: Synthesis of compound C216

[0170] Compound C216 was generally prepared according to Method PM2. Specifically, compound C216 was prepared by first reacting 2 mg / ml anti-TROP2 antibody and 70 mole excess over antibody of Intermediate 5 in 5.5 mM Tris, 110 mM NaCl, pH 7.5, 1.5% Transglutaminase (wt / v) (Ajinomoto), and 5% (v / v) DMSO for 20 hr at 19 °C with nutation. Excess linker and transglutaminase were removed from antibody using sizeexclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, to generate compound C216, linker-payload compound Cl 14 was added at 22 mole excess over 1.6 mg / ml of Intermediate 1-27 and DMSO was added to 10% (v / v) and reaction incubated for 20 hr at 33 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 99%. Linker-drug conjugation was confirmed by molecular weight shift of heavy chain compared to intermediate 1-27 by electrophoresis (reduced SDS- PAGE) and ADC DAR estimated ~ 1.3.Example 28: Synthesis of compound C217122IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0171] Compound C217 was generally prepared according to Method PM2. Specifically, compound C217 was prepared by first reacting 3.3 mg / ml anti-TROP2 antibody and 40 mole excess over antibody of Intermediate 5 in 10 mM Tris, 150 mM NaCl, pH 7.5, 1.5% Transglutaminase (wt / v) (Ajinomoto), and 5% (v / v) DMSO for 20 hr at 19 °C with nutation. Excess linker and transglutaminase were removed from antibody using sizeexclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, to generate compound C217, linker-payload compound Cl 15 was added at 22 mole excess over 2.9 mg / ml of intermediate 1-28 and DMSO was added to 10% (v / v) and reaction incubated for 20 hr at 33 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 100%. Linker-drug conjugation was confirmed by molecular weight shift of heavy chain compared to intermediate 1-28 by electrophoresis (reduced SDS- PAGE) and DAR estimated ~ 1.3. Reduced RP-LCMS ADC DAR ~ 1.7.Example 29: Synthesis of compound C201123IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0172] Compound C201was generally prepared according to Method PM3. Specifically, compound C201 was prepared by first reducing inter-chain Cys by incubating 5.5 mg / ml anti-CD33 antibody in lx PBS pH 7.0, 10% sucrose and 20 mM EDTA or anti- CD33 antibody in 40 mM Tris 130 mM NaCl, pH 7.5 with 40 mole equivalent excess of TCEP for 1 hr at 19 °C. Second, 30 mole excess equivalent of Intermediate 3 and 5% (v / v) DMSO were added to the reduced antibody solution and reaction incubated at 19 °C for 2-3 hr. Excess linker was removed from antibody using size-exclusion chromatography HiTrap Desalt (Cytiva) in 40mM Tris-HCl, 300 mM NaCl, pH 7.5 buffer. Third, linker-payload compound Cl 08 was added to 0.8 mg / ml of intermediate 1-29 at 30 molar excess over antibody, transglutaminase was added at 1.5% (wt / v) and DMSO was added to 5% (v / v) final, and reaction incubated for 12 hr at 19 °C. Antibody drug conjugate was separated from unconjugated linker-payload and transglutaminase according to Common Procedure X2. Percent monomer was 95%. Linker-drug conjugation efficiency was confirmed by molecular weight shift by electrophoresis compared to intermediate 1-29 (reduced SDS-PAGE).Reduced RP-LCMS ADC DAR ~ 1.9.Example 30: Synthesis of compound C202

[0173] Compound C202 was generally prepared according to Method PM3.Specifically, compound C202 was prepared by first reducing inter-chain Cys by incubating 3.9 mg / ml anti-TROP2 antibody in lx PBS pH 7.0, 10% sucrose and 20 mM EDTA with 40 mole equivalent excess of TCEP for 1 hr at 19 °C. Second, 30 mole excess equivalent of Intermediate 3 and 5% (v / v) DMSO was added to the reduced antibody solution and reaction124IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO incubated at 19 °C for 2-3 hr. Excess linker was removed from antibody using size-exclusion chromatography HiTrap Desalt (Cytiva) in 40 mM Tris, 300 mM NaCl, pH 7.5 buffer Third, linker-payload compound Cl 08 was added to 1.2 mg / ml of intermediate 1-30 at 30 molar excess over antibody, transglutaminase was added at 1.5% (wt / v) and DMSO was added to 5% (v / v) final, and reaction incubated for 12 hr at 19 °C. Antibody drug conjugate was separated from unconjugated linker-payload and transglutaminase according to Common Procedure X2. Percent monomer was 97%. Linker-drug conjugation efficiency was confirmed by molecular weight shift compared to intermediate 1-30 by electrophoresis (reduced SDS-PAGE). Reduced RP-LCMS ADC DAR ~ 3.Example 31: Synthesis of compound C209

[0174] Compound C209 was generally prepared according to Method PM 10. Specifically, compound C209 was prepared by first reducing inter-chain Cys by incubating 5 mg / ml anti-TROP2 antibody in lx PBS pH 7.0 with 40 mole equivalent excess of TCEP for 1 hr at 19 °C. Excess TCEP was removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, 30 mole excess equivalent of Intermediate 6 and 5% (v / v) DMSO were added to the 2.4 mg / ml reduced antibody solution and reaction incubated at 19 C for 18-20 hr. Excess linker was removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Third, linker-payload compound Cl 14 was added to 1.6 mg / ml of intermediate 1-31 at 25 molar excess over antibody and DMSO was added to 10% (v / v) final, and reaction incubated for 20125IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO hr at 33 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 98%. Linker-drug conjugation efficiency was confirmed by molecular weight shift compared to intermediate 1-31 by electrophoresis (reduced SDS-PAGE).Example 32: Synthesis of compound C210

[0175] Compound C210 was generally prepared according to Method PM7. Specifically, compound C210 was prepared by first reducing inter-chain Cys by incubating 5 mg / ml anti-TROP2 antibody in lx PBS pH 7.0 with 40 mole equivalent excess of TCEP for 1 hr at 19 °C. Excess TCEP was removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, 30 mole excess equivalent of Intermediate 7 and 5% (v / v) DMSO were added to the 2.4 mg / ml reduced antibody solution and reaction incubated at 19 °C for 18-20 hr. Excess linker was removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Third, linker-payload compound Cl 14 was added to 1.8 mg / ml of intermediate 1-32 at 25 molar excess over antibody and DMSO was added to 10% (v / v) final, and reaction incubated for 20 hr at 33 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 100%. Linker-drug conjugation efficiency was confirmed by molecular weight shift compared to intermediate 1-32 by electrophoresis (reduced SDS-PAGE).Example 33: Synthesis of compound C218126IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0176] Compound C218 was generally prepared according to Method PM7. Specifically, compound C218 was prepared by first reducing inter-chain Cys by incubating 7 mg / ml anti-CD33 antibody in lx PBS pH 7.0 with 40 mole equivalent excess of TCEP for 1 hr at 19 °C. Excess TCEP was removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, 25 mole excess equivalent of Intermediate 7 and 5% (v / v) DMSO were added to the 5 mg / ml reduced antibody solution and reaction incubated at 19 °C for 20 hr. Excess linker was removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Third, linker-payload compound Cl 14 was added to 3.6 mg / ml of intermediate 1-33 at 20 molar excess over antibody and DMSO was added to 10% (v / v) final, and reaction incubated for 20 hr at 19 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 100%. Linker-drug conjugation efficiency was confirmed by molecular weight shift compared to intermediate 1-33 by electrophoresis (reduced SDS-PAGE).Example 34: Synthesis of compound C211127IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0177] Compound C211 was generally prepared according to Method PM6. Specifically, compound C211 was prepared by first reducing inter-chain Cys by incubating 5 mg / ml anti-TROP2 antibody in lx PBS pH 7.0 with 40 mole equivalent excess of TCEP for 1 hr at 19 °C. Excess TCEP was removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, 30 mole excess equivalent of Intermediate 8 and 5% (v / v) DMSO were added to the 2.4 mg / ml reduced antibody solution and reaction incubated at 19 C for 18-20 hr. Excess linker was removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Third, linker-payload compound Cl 14 was added to 1.4 mg / ml of intermediate 1-34 at 25 molar excess over antibody and DMSO was added to 10% (v / v) final, and reaction incubated for 20 hr at 33 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 100%. Linker-drug conjugation efficiency was confirmed by molecular weight shift compared to intermediate 1-34 species by electrophoresis (reduced SDS-PAGE).Example 35: Synthesis of compound C221128IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0178] Compound C221 was generally prepared according to Method PM6. Specifically, compound C221 was prepared by first reducing inter-chain Cys by incubating 7 mg / ml anti-CD33 antibody in lx PBS pH 7.0 with 40 mole equivalent excess of TCEP for 1 hr at 19 °C. Excess TCEP was removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, 25 mole excess equivalent of Intermediate 8 and 5% (v / v) DMSO were added to the 5 mg / ml reduced antibody solution and reaction incubated at 19 °C for 20 hr. Excess linker was removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Third, linker-payload compound C106 was added to 3.6 mg / ml of intermediate 1-35 at 20 molar excess over antibody and DMSO was added to 10% (v / v) final, and reaction incubated for 20 hr at 19 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 100%. Linker-drug conjugation efficiency was confirmed by molecular weight shift compared to intermediate 1-35 by electrophoresis (reduced SDS-PAGE).Example 36: Synthesis of compound C222129IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO

[0179] Compound C222 was generally prepared according to Method PM7. Specifically, compound C222 was prepared by first reducing inter-chain Cys by incubating 5 mg / ml anti-TROP2 antibody in lx PBS pH 7.0 with 40 mole equivalent excess of TCEP for 1 hr at 19 °C. Excess TCEP was removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Second, 25 mole excess equivalent of Intermediate 7 and 5% (v / v) DMSO were added to the 4 mg / ml reduced antibody solution and reaction incubated at 19 °C for 20 hr. Excess linker was removed from antibody using size-exclusion chromatography (Zeba Spin Desalting Column, 40K MWCO, Thermo Fisher Scientific) in lx PBS pH 7.4 buffer. Third, linker-payload compound Cl 16 was added to 3.3 mg / ml of intermediate 1-36 at 20 molar excess over antibody and DMSO was added to 10% (v / v) final, and reaction incubated for 20 hr at 19 °C. Antibody drug conjugate was separated from unconjugated linker-payload according to Common Procedure X2. Percent monomer was 100%.Example 37: Payloads (as small molecules) effectively kill cancer cell lines

[0180] To determine the relative cell-killing potency of disclosed payloads, cellkilling assays were run on multiple human cancer cells lines, MV411 (BAL (biphenotypic B- myelomonocytic leukemia) cell line), U937 (non- Hodgkin’s lymphoma cell line), MDA-MB- 468 (Triple Negative Breast Cancer cell line), FaDu (hypopharyngeal tumor of a squamous cell carcinoma cell line) following Common Procedure X4 and Common Procedure X5.

[0181] Shown IC50 values were calculated by GraphPad Prism as best-fit values using four parameter dose-response curve fit, with R squared ranging from 0.97-0.99. IC50 values are shown in Table 4. Calicheamicin (MedChemExpress) was used as control.130IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOTable 4. Cell Toxicity Data of PayloadsExample 38: Antibody-Drug Conjugates Effectively Kill Cognate Cells expressing HER2, TROP2, EGFR and CD33

[0182] To determine the relative cell-killing potency of ADCs of the present disclosure compared to a similar ADC (DXD), cell-killing assays were run on multiple cells lines expressing HER2, TROP2 and EGFR following Common Procedure X4 and Common Procedure X5.

[0183] For testing anti-HER-2 ADCs, NCI-N87 and FaDu cell lines were used as they express HER2 (Dokter et al., 2015, Mol Cancer Therapy, (3) :692-703, Naveed et al 2022). For testing anti-TROP2 ADCs, MDA-MB-468 and FaDu cell lines were used since they express TROP2 (Strop et al., 2016, Mol Cancer Therapy, (11): 2698-2708). For testing anti-EGFR ADCs, MDA-MB-468, FaDu and SW620 cell lines were used as they express EGFR (Wong et al., 2018, Oncotarget, (71):33446-33458, Wollman et al. 2022)). For testing anti-CD33 ADCs, MV411 and U937 cell lines were used as they express CD33(Krupka et al. 2014, Perez-Oliva et al. 2011)

[0184] Shown IC50 were calculated by GraphPad Prism as best-fit values using four parameter dose-response curve fit, with R squared ranging from 0.97-0.99. IC50 values and average percent cell viability are shown in Tables 5-8.Table 5. Cell Toxicity Data EGFR-ADC131IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOTable 6. Cell Toxicity Data HER2-ADCTable 7. Cell Toxicity Data TR0P2-ADC132IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOTable 8. Cell Toxicity Data CD33-ADC133IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOINCORPORATION BY REFERENCE

[0185] All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.EQUIVALENTS

[0186] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0187] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.134IPTS / 2001 1 1566.1

Claims

1. Atty. Docket No. SMO-OQ4WOCLAIMSWhat is claimed is:

1. A compound represented by Formula (I):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is selected from the group consisting ofY is-CH2-(OCH2CH2)m-* or -CH2-CH2-(OCH2CH2)m-*; wherein * denotes the point of attachment to -NR4R5; orY is Ci-Ci2alkylene optionally substituted with -NRaC(=O)Rb;R1is selected from the group consisting of -C3-Cealkyl, -CH(C3-C6cycloalkyl)2, -C3- C6alkylene-NRa(SO2)-Ci-C6alkyl, and -SCH3;R2is selected from the group consisting of Ci-C3alkyl and hydrogen;R3is selected from the group consisting of Ci-C3alkyl and hydrogen;R4is selected from the group consisting of hydrogen and Ci-C3alkyl;Rsis selected from the group consisting of hydrogen, -NH2,135IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOR4and R5, together with the nitrogen atom to which they are attached, may be joined together to form a 5-membered heterocyclyl selected from the group consisting of:Raand Rbare independently selected from the group consisting of hydrogen and Ci-C alkyl; and m is 0-12.

2. The compound of claim 1 , wherein R5is selected from the group consisting of hydrogen,3. The compound of claim 1 or 2, wherein the compound is represented by Formula (IA):136IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting of -Cs-Cealkyl, -CH(C3-C6cycloalkyl)2, and - C3-C6alkylene-NRa(SO2)-C 1 -C6alkyl;R2is selected from the group consisting of Ci-Cialkyl and hydrogen;R3is selected from the group consisting of Ci-C3alkyl and hydrogen;Rais selected from the group consisting of hydrogen and Ci -Chalky I; and m is 5, 6, or 7.

4. The compound of any one of claims 1-3, wherein R2is selected from the group consisting of -CH2CH3, -CH(CH3)2, -CH3, and hydrogen.

5. The compound of any one of claims 1-4, wherein R2is -CH2CH3.

6. The compound of any one of claims 1-5, wherein m is 6.

7. The compound of any one of claims 1-6, wherein the compound is represented by Formula (IB):137IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO8. The compound of any one of claims 1-7, wherein R3is selected from the group consisting of hydrogen and -CH3.

9. The compound of any one of claims 1-6, wherein the compound is represented by Formula (IC):(IC).

10. The compound of any one of claims 1-9, wherein R1is selected from the group consisting of11. The compound of claim 1 , wherein the compound is selected from the group consisting of:138IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO139IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO140IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO141IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO142IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO143IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO144IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO145IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO146IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO147IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO148IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof.

12. The compound of claim 1, wherein the compound is selected from the group consisting of:149IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO150IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO151IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO152IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO andor a pharmaceutically acceptable salt and / or a stereoisomer thereof.

13. A compound represented by Formula (II):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting of -Cs-Cealkyl, -CH / Cs-Cecycloalkylh, and - C3-C6alkylene-NRa(SO2)-C i -C6alkyl;R2is selected from the group consisting of Ci-Cialkyl and hydrogen; andRais selected from the group consisting of hydrogen and Ci-Cvtlkyk14. The compound of claim 13, wherein the compound is represented by Formula (IIA):153IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO15. The compound of claim 13 or 14, wherein R2is selected from the group consisting of - CH2CH3, -CH(CH3)2, -CH3, and hydrogen.

16. The compound of any one of claims 13-15, wherein R2is -CH2CH3.

17. The compound of any one of claims 13-16, wherein R1is selected from the group consisting of18. The compound of claim 13, wherein the compound is selected from the group consisting of154IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOor a pharmaceutically acceptable salt and / or a stereoisomer thereof19. A compound represented by Formula (III):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is selected from the group consisting ofZ is selected from the group consisting of:155IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO* denotes the point of attachment of Lig to Z by a thioether bond;** denotes the point of attachment of Lig to Z by an amide bond;Rzis selected from the group consisting of Ci-Cialkyl and hydrogen;R1is selected from the group consisting of -Cs-Cealkyl, -CH(C3-Cecycloalkyl)2, -C3- C6alkylene-NRa(SO2)-Ci-C6alkyl, and -SCH3;R2is selected from the group consisting of Ci-Cialkyl and hydrogen;R3is selected from the group consisting of C 1 -CLalkyl and hydrogen;Rais selected from the group consisting of hydrogen and Ci-CLalkyl;Lig is a monoclonal antibody; m is 1, 2, 3, 4, 5, 6, or 7; p is 1, 2, 3, 4, 5, 6, or 7; q is 1, 2, 3, 4, 5, 6, or 7, and s is 1, 2, 3, 4, 5, 6, or 7.

20. The compound of claim 19, wherein R2is selected from the group consisting of - CH2CH3, -CH(CH3)2, -CH3, and hydrogen.

21. The compound of claim 19 or 20, wherein R2is -CH2CH3.156IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO22. The compound of any one of claims 19-21, wherein m is 6.

23. The compound of any one of claims 19-22, wherein the compound is represented by Formula (III A):(IIIA).

24. The compound of any one of claims 19-23, wherein R3is selected from the group consisting of hydrogen and -CHa.

25. The compound of any one of claims 19-22, wherein the compound is represented by Formula (IIIB):(IIIB).

26. The compound of any one of claims 19-25, wherein R1is selected from the group consisting of157IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO27. The compound of any one of claims 19-26, wherein p is 3, 4, 5, or 6, q is 3, 4, 5, or 6, and s is 3, 4, 5, or 6.

28. The compound of any one of claims 19-27, wherein Z is selected from the group consisting of29. The compound of any one of claims 19-28, wherein Lig is selected from the group consisting of an anti-CD33 antibody, an anti-TROP2 antibody, an anti-EGFR antibody, and an anti-HER2 antibody.158IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO30. The compound of any one of claims 19-29, wherein the compound is represented by Formula (IIIC) or Formula (IIID):(IIID); or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting ofZ is selected from the group consisting of159IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO* denotes the point of attachment of Lig to Z by a thioether bond;** denotes the point of attachment of Lig to Z by an amide bond; andLig is selected from the group consisting of an anti-CD33 antibody, an anti-TROP2 antibody, an anti-EGFR antibody, and an anti-HER2 antibody.

31. The compound of any one of claims 19-30, wherein the compound is selected from the group consisting of:160IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOwherein Lig is an anti-CD33 antibody;wherein Lig is an anti-TROP2 antibody;161IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOwherein Lig is an anti-EGFR antibody;wherein Lig is an anti-TROP2 antibody;162IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOwherein Lig is an anti-HER2 antibody;wherein Lig is an anti-TROP2 antibody;163IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOwherein Lig is an anti-CD33 antibody;wherein Lig is an anti-CD33 antibody;164TPTS / 2001 1 1566 1Atty. Docket No. SMO-OQ4WOwherein Lig is an anti-CD33 antibody;wherein Lig is an anti-CD33 antibody;165IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOwherein Lig is an anti-TR0P2 antibody;wherein Lig is an anti-TROP2 antibody; and166IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOwherein Lig is an anti-TR0P2 antibody; or a pharmaceutically acceptable salt and / or a stereoisomer thereof.

32. A compound represented by Formula (IV):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is selected from the group consisting ofZ is selected from the group consisting of:167IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO* for each occurrence denotes a point of attachment of Lig to Z by a thioether bond;Rzis selected from the group consisting of Ci -Chalky 1 and hydrogen;168IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOR1is selected from the group consisting of -Cs-Cealkyl, -CH(C3-C6cycloalkyl)2, -C3- C6alkylene-NRa(SO2)-Ci-C6alkyl, and -SCH3;R2is selected from the group consisting of Ci-Cialkyl and hydrogen;R3is selected from the group consisting of Ci-CTalkyl and hydrogen;Rais selected from the group consisting of hydrogen and Ci-C^alkyl;Lig is a monoclonal antibody; m is 1, 2, 3, 4, 5, 6, or 7; p is 3, 4, 5, or 6; q is 6, 7, 8, or 9; s is 3, 4, 5, or 6; and t is 3, 4, 5, or 6.

33. The compound of claim 32, wherein R2is selected from the group consisting of - CH2CH3, -CH(CH3)2, -CH3, and hydrogen.

34. The compound of claim 32 or 33, wherein R2is -CH2CH3.

35. The compound of any one of claims 32-34, wherein m is 6.

36. The compound of any one of claims 32-35, wherein the compound is represented by Formula (IVA):(IVA).

37. The compound of any one of claims 32-36, wherein R3is selected from the group consisting of hydrogen and -CH3.169IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO38. The compound of any one of claims 32-35, wherein the compound is represented by Formula (IVB):(IVB).

39. The compound of any one of claims 32-38, wherein R1is selected from the group consisting of40. The compound of any one of claims 32-39, wherein p is 4, q is 8, s is 4, and t is 4.

41. The compound of any one of claims 32-40, wherein Z is selected from the group consisting of170IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO42. The compound of any one of claims 32-41, wherein Lig is selected from the group consisting of an anti-CD33 antibody, an anti-TROP2 antibody, an anti-EGFR antibody, and an anti-HER2 antibody.

43. The compound of any one of claims 32-42, wherein the compound is represented by Formula (IVC) or Formula (IVD):171IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WO(IVC) or(IVD); or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting ofZ is selected from the group consisting of:172IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WO* for each occurrence denotes a point of attachment of Lig to Z by a thioether bond; andLig is selected from the group consisting of an anti-CD33 antibody, an anti-TROP2 antibody, an anti-EGFR antibody, and an anti-HER2 antibody.

44. The compound of any one of claims 32-43, wherein the compound is selected from the group consisting of:173IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOwherein Lig is an anti-TROP2 antibody;wherein Lig is an anti-TROP2 antibody;174IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOwherein Lig is an anti-TR0P2 antibody;wherein Lig is an anti-TROP2 antibody;175IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOwherein Lig is an anti-CD33 antibody;wherein Lig is an anti-TROP2 antibody;176IPTS / 2001 1 1566.1Atty. Docket No. SMO-004WOwherein Lig is an anti-TROP2 antibody;wherein Lig is an anti-CD33 antibody; and\T1IPTS / 2001 1 1566.1Atty. Docket No. SMO-OQ4WOwherein Lig is an anti-TROP2 antibody; or a pharmaceutically acceptable salt and / or a stereoisomer thereof.

45. A pharmaceutical composition comprising a compound of any one of claims 1-43, or a pharmaceutically acceptable salt and / or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

46. A method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 -43, or the pharmaceutical composition of claim 44.

47. The method of claim 46, wherein the cancer is selected from the group consisting of blood cancer, lung cancer, kidney cancer, urothelial cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, and esophageal cancer.178IPTS / 2001 1 1566.1