EP4637748A2

EP4637748A2 - Pnu anthracycline-derived linker-payloads, pharmaceutical compositions, and uses thereof

Info

Publication number: EP4637748A2
Application number: EP23908261.3A
Authority: EP
Inventors: Manoj B. CHARATI; Juana DU REGENS; John A. Flygare; Rebecca Elizabeth JOHNSON; Simon B. LANG; Christian L. MORALES; Ryan QUIROZ; W. Michael SEGANISH; Ling Tong; Nancy S. ZEPEDA
Original assignee: Merck Sharp and Dohme LLC
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2022-12-22
Filing date: 2023-12-18
Publication date: 2025-10-29
Also published as: CN120615015A; AU2023408438A1; WO2024137502A2; JP2025542248A; KR20250123203A; MX2025007337A; WO2024137502A3

Abstract

The present disclosure is directed to linker-payloads, and pharmaceutically acceptable salts, solvates, or stereoisomer thereof, comprising a structure of formula (I). The disclosure is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds, intermediates thereof, and compositions in the prevention or treatment of cancers and/or tumors.

Description

PNU ANTHRACYCLINE-DERIVED LINKER-PAYLOADS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Application No. 63/434,520, filed December 22, 2022, and U.S. Provisional Application No.63/496,986, filed April 19, 2023, the disclosures of which is incorporated herein by their entirety. FIELD OF THE DISCLOSURE [0002] The present disclosure provides Linker-Payload Compounds which comprise a PNU anthracycline payload, and which are useful as a component of antibody-drug conjugates. The disclosure also provides antibody-drug conjugates comprising the linker-payload compounds, compositions thereof, and methods of use thereof for the treatment of cancer. BACKGROUND OF THE DISCLOSURE [0003] Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from Streptomyces bacterium, and are among the most effective anticancer treatments ever developed, demonstrating efficacy against more types of cancer than any other class of chemotherapeutic agents. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder cancer, and lung cancers. The usefulness of anthracyclines, however, is limited by their toxicity, due to which, only a small number of anthracyclines or related DNA intercalating agents are available for clinical use. [0004] Antibody-drug conjugates represent an innovative therapeutic application that combines the unique, high specificity, properties, and anti-tumor activity of monoclonal antibodies (mAbs) that are tumor-specific but not sufficiently cytotoxic, with the potent cell-killing activity of highly cytotoxic small molecule drugs, such as anthracyclines, that are unsuitable for systemic administration alone. [0005] The antibody-drug conjugate is a three-component system, comprised of a cytotoxic payload linked to an antibody via a biodegradable linker. The antibody first binds to specific markers (antigens or receptors) at the surface of a cancer cell, then the intact antibody-drug conjugate is internalized within the cancer cell, where the linker is degraded, and the payload is released. [0006] Advances in linker technology are needed to provide for improved control over drug pharmacokinetics, and improve the delivery and release of the cytotoxic payload in cancer cells. The present disclosure addresses that need. SUMMARY OF THE DISCLOSURE [0007] In one aspect, provided are Compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein: R¹ is selected from -X-Y-Z-R³, when R² is H or C₁-C₆ alkyl; R² is H or C1-C6 alkyl, or R¹ and R² join to form a 4 to 6-membered monocyclic heterocycloalkylene group, or a 5 to 11-membered bicyclic spirocyclic heterocycloalkylene group, each of which is substituted on a ring carbon atom with -X-Y-Z-R³; R³ is selected from: X is selected from –(CH2)n-N(R⁴)-, -R⁵-N(R⁴)-, -(CH2)n-N(R⁴)-C(O)R⁵-, -(CH2)n-N(R⁴)- (C₁-C₆ alkylene)-N(R⁴)-, 5 or 6-membered monocyclic heterocycloalkylene, –(CH₂)_n-R⁵-N(R⁴)-, 5 to 11-membered bicyclic spirocyclic heterocycloalkylene, –(CH₂)_n-R⁵-, –(CH₂)_n-R⁵- N(R⁴)C(O)O-(CH2)nR⁵-N(R⁴)-, -(CH2)n-NHC(O)O-(CH2)n-R⁵-N(R⁴)-, –(CH2)n-R⁵-O-C(O)- N(R⁴)-(C₁-C₆ alkylene)-N(R⁴)-, -R⁵-NHC(O)CH₂OCH₂N(R⁴)C(O)CH₂N(R⁴)-, -(CH₂)_n- N(R⁴)C(O)NH-N(R⁴)-, -R⁵-N(R⁴)C(O)CH2N(R⁴)-, –(CH2)n-N(R⁴)-(CH2)n-N(R⁴)-, and -R⁵-O- CH₂N(R⁴)-; Y is a bond or -C(O)C(R⁴)(R⁶)NH-; Z is -C(O)CH(R⁷)NHC(O)CH(R⁸)NH-; R⁴ is H, C_1-6 alkyl, or R⁵ is selected from C6-C10 arylene, 4 to 6-membered monocyclic heterocycloalkylene, 5 to 11-membered bicyclic spirocyclic heterocycloalkylene, C₃-C₇ monocyclic cycloalkylene, C₅- C11 bridged bicyclic cycloalkylene, -NH-NH-, and -NHC(O)NH-, wherein said 4 to 6-membered monocyclic heterocycloalkylene can be optionally substituted on a ring carbon atom with an oxo group; R⁶, R⁷ and R⁸ are each independently selected from H, -CH₂CH₂CH₂NHC(O)NH_2, benzyl, and a naturally occurring amino acid side chain; R⁹ is -CH₂NHC(O)-(CH₂CH₂O)_q-CH₃; m is 0, 1, or 2; each occurrence of n is independently an integer from 0 to 4; and q is selected from 4, 8, 10, and 12. [0008] The Compounds of Formula (I), and pharmaceutically acceptable salts thereof, can be useful as components of antibody-drug conjugates, which are useful for the treatment and prevention of cancer. Without being bound by any specific theory, it is believed that the payload moieties of the Compounds of Formula (I), act as inhibitors of topoisomerases. [0009] Accordingly, provided herein are antibody-drug conjugates comprising a Compound of Formula (I) as the payload/linker moiety. Also provides are methods for treating or preventing cancer in a patient, comprising administering to the patient an effective amount of at least one antibody-drug conjugate, comprising a Compound of Formula (I). [0010] Further details are set forth in the accompanying detailed description below. [0011] Although any methods and materials similar to those described herein can be used in the practice or testing of the Compounds of Formula (I) or antibody-drug conjugates comprising a Compound of Formula (I), illustrative methods and materials are now described. Other embodiments, aspects and features are either further described in or will be apparent from the ensuing description, examples and appended claims. DETAILED DESCRIPTION OF THE DISCLOSURE [0012] This disclosure is directed to a class of PNU anthracycline-derived Linker-Payload Compounds (the “Linker-Payload Compounds of the Present Disclosure”), wherein the linker structures contain a maleimide group, or a sulfone-substituted pyridyl group attached to a peptide linker, with variation on the amino acid sequence and the optional incorporation of PEG units and terminating with a connection to a PNU anthracycline-derived payload. An embodiment of the disclosure relates to the Linker-Payload Compounds. Another embodiment of the disclosure relates to antibody-drug conjugates comprising the Linker-Payload Compounds of the Present Disclosure (the “ADCs of the Present Disclosure”). Yet another embodiment relates to the novel linker moieties of the Linker-Payload Compounds. [0013] The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding, and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name and an ambiguity exists between the structure and the name, it is to be understood that the structure predominates. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl," "-O-alkyl," etc... [0014] As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the meanings set forth below. [0015] The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name and an ambiguity exists between the structure and the name, it is to be understood that the structure predominates. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl," "-O-alkyl," etc... [0016] As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: [0017] The term "anticancer agent" refers to a chemical compound that can be used to treat cancer. This definition also includes antihormonal agents that act to modulate, reduce, block, or inhibit the effects of hormones that promote cancer growth, which are often in the form of systemic or holistic therapy. An anticancer agent can be a hormone. [0018] The term "Compound(s) of the Present Disclosure" refers to chemical compounds disclosed herein. Included in the definition of “Compound(s) of the Present Disclosure” are Linker-Payload Compounds of Formulas (I) through (XXII), Linker-Payload Compounds of Examples 1-36, as well as Linker-Payload Compounds comprising: (i) a Linker selected from the linkers numbered L-1 through L-12, and (ii) a payload of formula (XVI), all of which are collectively referred herein to as the “Linker-Payload Compounds of the Present Disclosure”. Also included in the definition of “Compound(s) of the Present Disclosure” are antibody-drug conjugates disclosed herein, including, but not limited to, the compounds of Formulas (XXIII) through (LVII), and the antibody-drug conjugates of Examples 37-72, which are collectively referred to herein as the “ADCs of the Present Disclosure.” [0019] A “patient” is a human or non-human mammal. In one embodiment, a patient is a human. [0020] The term "effective amount" as used herein, refers to the amount of the subject compound, and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered. In the combination therapies described herein, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount. [0021] The term “preventing,” as used herein with respect to a cellular proliferative disorder, refers to reducing the likelihood of a cellular proliferative disorder. [0022] The terms “treating” or “treatment” (of, e.g., a disease, disorder, or conditions or associated symptoms, which together or individually may be referred to as “indications”) as used herein include: inhibiting the disease, disorder or condition, i.e., arresting or reducing the development of the disease or its biological processes or progression or clinical symptoms thereof; or relieving the disease, i.e., causing regression of the disease or its biological processes or progression and/or clinical symptoms thereof. “Treatment” as used herein also refers to control, amelioration, or reduction of risks to the subject afflicted with a disease, disorder or condition in which a tumor is involved. The terms “preventing” or “prevention” or “prophylaxis” of a disease, disorder or condition as used herein includes: impeding the development or progression of clinical symptoms of the disease, disorder, or condition in a mammal that may be exposed to or predisposed to the disease, disorder or condition but does not yet experience or display symptoms of the disease, and the like. [0023] The term “DAR” or “Drug Antibody Ratio,” as used herein, refers to the average number of linker/drug moieties attached to an antibody in a composition comprising a pluraility of ADCs of the Present Disclosure. For a composition comprising an ADC of the Present Disclosure, the DAR for the composition is the average of the DARs of all of the individual antibody-drug conjugate molecules present in said composition, and this average is expressed as a decimal. As such, in some embodiments for a composition comprising an ADC of the Present Disclosure, the DAR of the composition is a decimal from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, and from 0 to 1. In additional embodiments, for a composition comprising an ADC of the Present Disclosure, the DAR of the composition is a decimal from 1 to 4, 2 to 5, 3 to 6, 4 to 7, 5 to 8, and 6 to 8. In other embodiments, for a composition comprising an ADC of the Present Disclosure, the DAR of the composition is a decimal from 1 to 3, 2 to 4, 3 to 5, 4 to 6, 5 to 7, and 6 to 8. In further embodiments, for a composition comprising an ADC of the Present Disclosure, the DAR of the composition is a decimal from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, and 7 to 8. The term “composition” as used above, is understood to encompass pharmaceutical compositions. [0024] The term "alkyl,” as used herein, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond. An alkyl group may be straight or branched and contain from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 10 carbon atoms. In different embodiments, an alkyl group contains from 1 to 10 carbon atoms (“C1-C10 alkyl”) or from about 1 to about 6 carbon atoms (“C1-C6 alkyl”). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. An alkyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH₂, -NH(alkyl), -N(alkyl)₂, NH(cycloalkyl), -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)- cycloalkyl, -C(O)OH and –C(O)O-alkyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted. [0025] The term "alkenyl,” as used herein, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having one of its hydrogen atoms replaced with a bond. An alkenyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 10 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2- enyl, n-pentenyl, octenyl and decenyl. An alkenyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH₂, -NH(alkyl), -N(alkyl)₂, - NH(cycloalkyl), -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(O)OH and –C(O)O-alkyl. The term “C₂-C₁₀ alkenyl” refers to an alkenyl group having from 2 to 10 carbon atoms. Unless otherwise indicated, an alkenyl group is unsubstituted. [0026] The term "alkynyl,” as used herein, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and having one of its hydrogen atoms replaced with a bond. An alkynyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkynyl group contains from about 2 to about 10 carbon atoms. In another embodiment, an alkynyl group contains from about 2 to about 6 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyl. An alkynyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, - O-aryl, -alkylene-O-alkyl, alkylthio, -NH₂, -NH(alkyl), -N(alkyl)₂, -NH(cycloalkyl), -O-C(O)- alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(O)OH and –C(O)O-alkyl. The term “C2-C10 alkynyl” refers to an alkynyl group having from 2 to 10 carbon atoms. Unless otherwise indicated, an alkynyl group is unsubstituted. [0027] The term "alkylene,” as used herein, refers to an alkyl group, as defined above, wherein one of the alkyl group’s hydrogen atoms has been replaced with a bond. Non-limiting examples of alkylene groups include –CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂-, - CH(CH3)CH2CH2-, -CH(CH3)- and -CH2CH(CH3)CH2-. In one embodiment, an alkylene group has from 1 to about 10 carbon atoms. In another embodiment, an alkylene group has from 1 to about 6 carbon atoms. In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is -CH2-. The term “C₁-C₆ alkylene” refers to an alkylene group having from 1 to 6 carbon atoms. [0028] The term "alkenylene,” as used herein, refers to an alkenyl group, as defined above, wherein one of the alkenyl group’s hydrogen atoms has been replaced with a bond. Non-limiting examples of alkylene groups include -CH=CH-, -CH=CHCH2-, -CH2CH2CH=CH-, and - CH₂(CH₃)C=CH-. In one embodiment, an alkenylene group has from 2 to about 6 carbon atoms. In one embodiment, an alkenylene group has from 2 to about 10 carbon atoms. In another embodiment, an alkenylene group is branched. In another embodiment, an alkenylene group is linear. The term “C2-C6 alkenylene” refers to an alkenylene group having from 2 to 6 carbon atoms. [0029] The term "alkynylene,” as used herein, refers to an alkynyl group, as defined above, wherein one of the alkynyl group’s hydrogen atoms has been replaced with a bond. Non- limiting examples of alkylene groups include -C≡C-, -C≡CCH2-, and -C≡CCH(CH3)2-. In one embodiment, an alkynylene group has from 2 to about 6 carbon atoms. In another embodiment, an alkynylene group has from 2 to about 10 carbon atoms. In another embodiment, an alkynylene group is branched. In another embodiment, an alkynylene group is linear. The term “C2-C6 alkynylene” refers to an alkynylene group having from 2 to 6 carbon atoms. The term “C2-C10 alkynylene” refers to an alkynylene group having from 2 to 10 carbon atoms. [0030] The term "aminoalkyl," as used herein, refers to an alkyl group as defined above, wherein one of the alkyl group’s hydrogen atoms has been replaced with -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2. In one embodiment, an aminoalkyl group has from 1 to 6 carbon atoms. Non-limiting examples of aminoalkyl groups include –CH2NH2, -CH2N(CH3)2, - CH₂CH₂NH₂, and -CH₂NH(CH)₃. The term “C₁-C₆ aminoalkyl” refers to an aminoalkyl group having from 1 to 6 carbon atoms. [0031] The term “antibody” as used herein is used in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments that exhibit the desired biological activity provided that the antibody fragment have the requisite number of attachment sites for a drug-linker. The native form of an antibody is a tetramer and consists of two identical pairs of immunoglobulin chains, each pair having one light chain and one heavy chain. In each pair, the light and heavy chain variable regions (VL and VH) are together primarily responsible for binding to an antigen. The light chain and heavy chain variable domains consist of a framework region interrupted by three hypervariable regions, also called “complementarity determining regions” or “CDRs.” The constant regions may be recognized by and interact with the immune system, (see, e.g., Janeway et al., 2001, Immuno. Biology, 5th Ed., Garland Publishing, New York). An antibody can be of any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass. The antibody can be derived from any suitable species. In some aspects, the antibody is of human or murine origin. An antibody can be, for example, human, humanized or chimeric. [0032] The term "aryl," as used herein, refers to an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon. In one embodiment, an aryl group contains from about 6 to about 10 carbon atoms (“C₆-C₁₀ aryl”). An aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. In one embodiment, an aryl group can be optionally fused to a cycloalkyl or cycloalkanoyl group. Non-limiting examples of aryl groups include phenyl and naphthyl. An example of an aryl group fused to a cycloalkyl ring includes: . In one embodiment, an aryl group is phenyl. In another embodiment, an aryl group is napthalene. Unless otherwise indicated, an alkyl group is unsubstituted. [0033] The term "arylene," as used herein, refers to an aryl group as defined above, wherein one of the aryl group’s hydrogen atoms has been replaced with a bond. Non-limiting examples of arylene groups include: . [0034] In one embodiment, an alkylene group has from 1 to about 10 carbon atoms. In another embodiment, an alkylene group has from 1 to about 6 carbon atoms. In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is -CH2-. The term “C1-C6 alkylene” refers to an alkylene group having from 1 to 6 carbon atoms. [0035] The term "composition" as used herein is intended to encompass a product comprising an ADC of the Present Disclosure or a pharmaceutically acceptable salt thereof, together with one or more additional specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to a pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), which include an ADC of the Present Disclosure or a pharmaceutically acceptable salt thereof, optionally together with one or more additional active ingredients, and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the Present Disclosure encompass any composition made by admixing an ADC of the Present Disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. [0036] The term "cycloalkyl," as used herein, refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 11 ring carbon atoms. In one embodiment, a cycloalkyl contains from about 5 to about 11 ring carbon atoms. In another embodiment, a cycloalkyl is monocyclic, and contains from about 3 to about 7 ring atoms. In another embodiment, a cycloalkyl is monocyclic, and contains from about 5 to about 6 ring atoms. In another embodiment, a cycloalkyl is bicyclic and contains about 4 to 10 ring atoms. Non- limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Non-limiting examples of multicyclic cycloalkyls include 1-decalinyl, norbornyl and adamantyl. A cycloalkyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. Unless otherwise indicated, cycloalkyl group is unsubstituted. In one embodiment, a cycloalkyl group is unsubstituted. The term “3 to 7-membered monocyclic cycloalkyl” refers to a monocyclic cycloalkyl group having from 3 to 7 ring carbon atoms. The term “5 to 11-membered bicyclic cycloalkyl group” refers to a bicyclic cycloalkyl group having from 5 to 11 ring carbon atoms. [0037] A multicyclic cycloalkyl group may have rings that are fused, rings that are joined in a spirocyclic manner, and rings that are bridged. In one embodiment, a cycloalkyl group can be a spirocyclic cycloalkyl group having from 5 to 11 ring carbon atoms (“C5-C11 spirocyclic cycloalkyl”). Illustrative examples of such a bicyclic cycloalkyl group include: . [0038] In another embodiment, a cycloalkyl group can be a fused bicyclic cycloalkyl group having from 5 to 11 ring carbon atoms (“C₅-C₁₁ fused bicyclic cycloalkyl”). Illustrative examples of such a fused bicyclic cycloalkyl group include: . [0039] In another embodiment, a cycloalkyl group can be a bridged bicyclic cycloalkyl group having from 5 to 11 ring carbon atoms (“C₅-C₁₁ bridged bicyclic cycloalkyl”), or a bridged tricyclic cycloalkyl group having from 6 to 14 ring carbon atoms. Illustrative examples of such bridged bicyclic and tricyclic heterocycloalkyl groups include: . [0040] A ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group. An illustrative example of such a cycloalkyl group (also referred to herein as a “cycloalkanoyl” group) includes, but is not limited to, cyclobutanoyl: . [0041] The term "cycloalkylene," as used herein, refers to a cycloalkyl group, as defined above, wherein one of the cycloalkyl group’s hydrogen atoms has been replaced with a bond. In one embodiment, a cycloalkylene is monocyclic, and contains from about 3 to about 7 ring carbon atoms (“C3-C7 monocyclic cycloalkylene”). In another embodiment, a cycloalkylene is In another embodiment, a cycloalkyl is bicyclic and contains about 5 to 10 ring atoms (C5-C10 bicyclic cycloalkylene”). Non-limiting examples of monocyclic cycloalkylenes include the following: . [0042] A cycloalkylene group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. Unless otherwise indicated, a cycloalkylene group is unsubstituted. In one embodiment, a cycloalkylene group is unsubstituted. [0043] Multicyclic cycloalkylene group may have rings that are fused, rings that are joined in a spirocyclic manner, and rings that are bridged. In one embodiment, a cycloalkylene group can be a bridged bicyclic cycloalkylene group having from 5 to 11 ring carbon atoms. Illustrative examples of such a bridged bicyclic heterocycloalkyl group includes, but is not limited to: , . [0044] A ring carbon atom of a cycloalkylene group may be functionalized as a carbonyl group. An illustrative example of such a cycloalkylene group includes, but is not limited to, . [0045] The term "cycloalkenyl," as used herein, refers to a non-aromatic mono- or multicyclic ring system comprising from about 4 to about 10 ring carbon atoms and containing at least one endocyclic double bond. In one embodiment, a cycloalkenyl contains from about 4 to about 7 ring carbon atoms. In another embodiment, a cycloalkenyl contains 5 or 6 ring atoms. Non- limiting examples of monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. A cycloalkenyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. A ring carbon atom of a cycloalkylene group may be functionalized as a carbonyl group. In one embodiment, a cycloalkenyl group is cyclopentenyl. In another embodiment, a cycloalkenyl group is cyclohexenyl. The term “4 to 6-membered cycloalkenyl” refers to a cycloalkenyl group having from 4 to 6 ring carbon atoms. [0046] The term “halo,” as used herein, means –F, -Cl, -Br or -I. [0047] The term "haloalkyl," as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group’s hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has from 1 to 10 carbon atoms. In another embodiment, a haloalkyl group has from 1 to 6 carbon atoms. In another embodiment, a haloalkyl group is substituted with from 1 to 6 F atoms. In a class of this embodiment, the haloalkyl group is substituted with from 1 to 3 F atoms. Non-limiting examples of haloalkyl groups include - CH2CHF2, –CH2F, -CHF2, -CF3, -CH2Cl and -CCl3. The term “C1-C6 haloalkyl” refers to a haloalkyl group having from 1 to 6 carbon atoms. [0048] The term "haloalkylene," as used herein, refers to a haloalkyl group as defined above, wherein one or more of the haloalkyl group’s hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkylene group has from 1 to 10 carbon atoms. In another embodiment, a haloalkylene group has from 1 to 6 carbon atoms. In another embodiment, a haloalkylene group is substituted with from 1 to 6 F atoms. In a class of this embodiment, the haloalkylene group is substituted with from 1 to 3 F atoms. Non-limiting examples of haloalkylene groups include -CH2CHF2, –CH2F, -CHF2, -CF3, -CH2Cl and -CCl3. The term “C1- C6 haloalkylene” refers to a haloalkylene group having from 1 to 6 carbon atoms. [0049] The term "hydroxyalkyl," as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group’s hydrogen atoms has been replaced with an –OH group. In one embodiment, a hydroxyalkyl group has from 1 to 10 carbon atoms. In another embodiment, a hydroxyalkyl group has from 1 to 6 carbon atoms. Non-limiting examples of hydroxyalkyl groups include –CH₂OH, -CH₂CH₂OH, -CH₂CH₂CH₂OH and -CH₂CH(OH)CH₃. The term “C₁-C₁₀ hydroxyalkyl” refers to a hydroxyalkyl group having from 1 to 10 carbon atoms. [0050] The term "heteroaryl,” as used herein, refers to an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms (“5 or 6-membered monocyclic heteroaryl”). In another embodiment, a heteroaryl group is bicyclic and had 8 to 10 ring atoms (“8 to 10-membered bicyclic heteroaryl”). In still another embodiment, a heteroaryl group is bicyclic and has 9 or 10 ring atoms (“9 or 10-membered bicyclic heteroaryl”). A heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below. A heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. The term “heteroaryl” also encompasses a heteroaryl group, as defined above, which is fused to a benzene ring. Non-limiting examples of heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1- b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like, and all isomeric forms thereof. The term “heteroaryl” also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. In one embodiment, a heteroaryl group is a 5-membered heteroaryl. In another embodiment, a heteroaryl group is a 6-membered heteroaryl, such as pyridyl. [0051] In one embodiment, an 8 to 10-membered bicyclic heteroaryl group comprises a fused bicyclic heterocyclic group in which one of the two fused rings is phenyl or monocyclic heteroaryl, such as: . [0052] A “9 to 14-membered tricyclic heteroaryl” comprises an 8 to 10-membered bicyclic heteroaryl group, wherein a third ring is fused to one of the rings of the 8 to 10-membered bicyclic heteroaryl group. Such third ring can be a cycloalkyl, heterocycloalkyl, or heteroaryl ring. Examples of a 9 to 14-membered tricyclic heteroaryl group include: . . [0053] The term "heterocycloalkyl," as used herein, refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S, N or Si, and the remainder of the ring atoms are carbon atoms. A heterocycloalkyl group can be joined via a ring carbon, ring silicon atom or ring nitrogen atom. In one embodiment, a heterocycloalkyl group is monocyclic. In one embodiment, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms (“3 to 7-membered monocyclic heterocycloalkyl”). In another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms (“5 or 6-membered monocyclic heterocycloalkyl”). In one embodiment, a heterocycloalkyl group is bicyclic. In another embodiment, a heterocycloalkyl group is bicyclic and has from about 5 to about 11 ring atoms (“5 to 11-membered bicyclic heterocycloalkyl”). In another embodiment, a heterocycloalkyl group is tricyclic and has from about 10 to about 14 ring atoms (“10 to 14-membered tricyclic heterocycloalkyl”). There are no adjacent oxygen and/or sulfur atoms present in the ring system. Any –NH group in a heterocycloalkyl ring may exist protected such as, for example, as an - N(BOC), -N(CBz), -N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of the Present Disclosure. A heterocycloalkyl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below. The nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone, silacyclopentane, silapyrrolidine and the like, and all isomers thereof. Non-limiting illustrative examples of a silyl-containing heterocycloalkyl group include: . [0054] A ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group. Illustrative examples of such a heterocycloalkyl group include, but are not limited to: . [0055] A ring sulfur atom of a heterocycloalkyl group may also be functionalized as a sulfonyl group. An example of such a heterocycloalkyl group is: . [0056] In one embodiment, a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered monocyclic heterocycloalkyl. [0057] A multicyclic heterocycloalkyl group may have rings that are fused, rings that are joined in a spirocyclic manner, and rings that are bridged. In one embodiment, a heterocycloalkyl group can be a bicyclic spirocyclic heteroaryl group having from 1 to 11 ring atoms. Illustrative examples of such a bicyclic heterocycloalkyl group include: . [0058] In another embodiment, a heterocycloalkyl group can be a fused bicyclic heterocycloalkyl group having from 5 to 11 ring atoms (“5 to 11-membered fused bicyclic heterocycloalkyl”). Illustrative examples of such a fused bicyclic heterocycloalkyl group include: . [0059] In another embodiment, a heterocycloalkyl group can be a bridged heterocycloalkyl group having from 5 to 11 ring atoms (“5 to 11-membered bridged bicyclic heterocycloalkyl”). Illustrative examples of such a bridged bicyclic heterocycloalkyl group include: . [0060] The term "heterocycloalkylene," as used herein, refers to a heterocycloalkyl group, as defined above, wherein one of the heterocycloalkyl group’s hydrogen atoms has been replaced with a bond. A heterocycloalkylene group can be joined via a ring carbon or ring nitrogen atom. In one embodiment, a heterocycloalkylene group has from 4 to 6 ring atoms (“4 to 6-membered heterocycloalkylene”). In another embodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heterocycloalkenyl group is bicyclic and has from 5 to 10 ring atoms (“5 to 10-membered bicyclic heterocycloalkylene”). A heterocycloalkylene group can optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocycloalkylene can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S- dioxide. A ring carbon atom of a heterocycloalkylene group may be functionalized as a carbonyl group. Non-limiting examples of monocyclic heterocycloalkylene groups include: . [0061] A multicyclic heterocycloalkylene group may have rings that are fused, rings that are joined in a spirocyclic manner, and rings that are bridged. In one embodiment, a heterocycloalkylene group can be a bicyclic spirocyclic heterocycloalkylene group having from 5 to 11 ring atoms (“5 to 11-membered bicyclic spirocyclic heterocycloalkylene”). Illustrative examples of such a bicyclic spirocyclic heterocycloalkylene group include: . [0062] In another embodiment, a heterocycloalkylene group can be a fused bicyclic heterocycloalkylene group having from 5 to 11 ring atoms (“5 to 11-membered fused bicyclic heterocycloalkylene”). Illustrative examples of such a fused bicyclic heterocycloalkylene group include: . [0063] In another embodiment, a heterocycloalkylene group can be a bridged heterocycloalkylene group having from 5 to 11 ring atoms (“5 to 11-membered bridged bicyclic heterocycloalkylene”). Illustrative examples of such a bridged bicyclic heterocycloalkylene group include: . [0064] The term "heterocycloalkenyl," as used herein, refers to a heterocycloalkyl group, as defined above, wherein the heterocycloalkyl group contains from 4 to 10 ring atoms, and at least one endocyclic carbon-carbon or carbon-nitrogen double bond. A heterocycloalkenyl group can be joined via a ring carbon or ring nitrogen atom. In one embodiment, a heterocycloalkenyl group has from 4 to 6 ring atoms. In another embodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heterocycloalkenyl group is bicyclic. A heterocycloalkenyl group can optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. A ring carbon atom of a heterocycloalkenyl group may be functionalized as a carbonyl group. Non-limiting examples of heterocycloalkenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H- pyranyl, dihydrofuranyl, fluoro-substituted dihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like and the like. In one embodiment, a heterocycloalkenyl group is a 5-membered heterocycloalkenyl. In another embodiment, a heterocycloalkenyl group is a 6-membered heterocycloalkenyl. The term “4 to 6-membered heterocycloalkenyl” refers to a heterocycloalkenyl group having from 4 to 6 ring atoms. [0065] The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By “stable compound’ or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. [0066] The term "in substantially purified form,” as used herein, refers to the physical state of a compound after the compound is isolated from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof. The term "in substantially purified form,” also refers to the physical state of a compound after the compound is obtained from a purification process or processes described herein or well-known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well-known to the skilled artisan. [0067] It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. [0068] When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, Greene et al., Protective Groups in Organic Synthesis, Wiley-Interscience, New York, (1999). [0069] Examples of "ring system substituents" include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl,-alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, - C(O)- aryl, halo, -NO₂, -CN, -SF₅, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, - S(O)-alkyl, -S(O)2-alkyl, -S(O)-aryl, -S(O)2-aryl, -S(O)-heteroaryl, -S(O)z-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkyleneheteroaryl, -S(O)₂-alkylene-aryl, -S(O)₂- alkylene-heteroaryl, -Si(alkyl)2, -Si(aryl)2, Si(heteroaryl)2 -Si(alkyl)( aryl), - Si(alkyl)(cycloalkyl), -Si(alkyl)(heteroaryl), cycloalkyl, heterocycloalkyl, -O-C(O)-alkyl, -O- C(O)-aryl, -O-C(O)-cycloalkyl, -C(=N-CN)-NH₂, -C(=NH)-NH₂, -C(=NH)-NH(alkyl), - N(Y¹)(Y²), -alkylene-N(Y¹)(Y²), -C(O)N(Y¹)(Y²), and -S(O)2N(Y¹)(Y²), wherein Y¹ and Y² can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylenedioxy, ethylenedioxy, -C(CH₃)₂- and the like which form moieties such as, for example: . [0070] When any substituent or variable (e.g., R⁵, n, etc.) occurs more than one time in any constituent or in Formula (I), its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated. [0071] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results from combination of the specified ingredients in the specified amounts. [0072] It is understood that one or more silicon (Si) atoms can be incorporated into the compounds of the instant disclosure in place of one or more carbon atoms by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. Carbon and silicon differ in their covalent radius leading to differences in bond distance and the steric arrangement when comparing analogous C-element and Si-element bonds. These differences lead to subtle changes in the size and shape of silicon-containing compounds when compared to carbon. One of ordinary skill in the art would understand that size and shape differences can lead to subtle or dramatic changes in potency, solubility, lack of off-target activity, packaging properties, and so on. (Diass, J. O. et al. Organometallics (2006) 5:1188-1198; Showell, G.A. et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558). [0073] It is understood that substituents and substitution patterns on the compounds of the instant disclosure can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase “optionally substituted with one or more substituents” should be understood as meaning that the group in question is either unsubstituted or may be substituted with one or more substituents. [0074] Where optional substitution of a moiety is described (e.g., "optionally substituted") the term means that if substituents are present, one or more of the enumerated substituents for the specified substrate can be present on the substrate in a bonding position normally occupied by the default substituent normally occupying that position. For example, a default substituent on the carbon atoms of an alkyl moiety is a hydrogen atom, an optional substituent can replace the default substituent. [0075] Pharmaceutically acceptable esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy group of a hydroxyl compound, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (e.g., phenyl optionally substituted with, for example, halogen, C_1-4alkyl, -O-(C_1-4alkyl) or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol. [0076] One or more Compounds of the Present Disclosure may exist in unsolvated as well as solvated 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. "Solvate" means a physical association of a Compound of the Present Disclosure with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate wherein the solvent molecule is water. [0077] One or more Compounds of the Present Disclosure may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTechours. , 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than room temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example IR spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate). [0078] The Linker-Payload Compounds can form salts which are also within the scope of the Present Disclosure. As used herein, the term "pharmaceutically acceptable salts" or “salts,” refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Salts in the solid form may exist in more than one crystal structure and may also be in the form of hydrates. [0079] Exemplary acid addition salts include acetates, ammonium, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates (also known as mesylates), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates), and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, ^{Selection and Use. 2nd} _{Revised Ed. (2011) Zurich: Wiley-VCH; S. Berge et al, Journal of} Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto. In one embodiment, an acid salt is an ammonium salt or a di-ammonium salt. [0080] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen- containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. [0081] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the Present Disclosure and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the Present Disclosure. [0082] The compounds of the disclosure may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this disclosure. Unless a specific stereochemistry is indicated, the present disclosure is meant to encompass all such isomeric forms of these compounds. [0083] The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined, amongst other methods, by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well-known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques. Also, some of the Linker-Payload Compounds may be atropisomers (e.g., substituted biaryls), and are considered as part of the Present Disclosure. Enantiomers can also be directly separated using chiral chromatographic techniques. [0084] It is also possible that the Linker-Payload Compounds may exist in different tautomeric forms, and all such forms are embraced within the scope of the Present Disclosure. For example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure. [0085] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of the Present Disclosure. If a Linker- Payload Compound incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the Present Disclosure. [0086] In all cases, compound name(s) accompany the structure drawn and are intended to capture each of the stereochemical permutations that are possible for a given structural isomer based on the synthetic operations employed in its preparation. Lists of discrete stereoisomers that are conjoined using or indicate that the presented compound (e.g. ‘Example number’) was isolated as a single stereoisomer, and that the identity of that stereoisomer corresponds to one of the possible configurations listed. Lists of discrete stereoisomers that are conjoined using and indicate that the presented compound was isolated as a racemic mixture or diastereomeric mixture. [0087] A specific absolute configuration is indicated by use of a wedged-bolded or wedged- hashed line. Unless a specific absolute configuration is indicated, the present disclosure is meant to encompass all such stereoisomeric forms of these compounds. [0088] In this specification, where there are multiple oxygen and/or sulfur atoms in a ring system, there cannot be any adjacent oxygen and/or sulfur present in said ring system. [0089] Individual stereoisomers of the Compounds of the Present Disclosure may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the Present Disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", “ester”, "prodrug" and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds. [0090] In the Compounds of Formula (I), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (¹H), and deuterium (²H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched Compounds of Formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. In one embodiment, a Compound of Formula (I) has one or more of its hydrogen atoms replaced with deuterium. [0091] Polymorphic forms of the Linker-Payload Compounds, and of the salts, solvates, hydrates, esters and prodrugs of the Linker-Payload Compounds, are intended to be included in the present disclosure. [0092] For all embodiments described herein, any variable not explicitly defined in the embodiment is as defined in Formula (I). In each of the embodiments described herein, each variable is selected independently of the other unless otherwise noted. [0093] The following abbreviations are used below and have the following meanings: The Compounds of the Present Disclosure [0094] Described are novel linker-payload compounds (the Compounds of Formula (I)) comprising a PNU Anthracycline payload. The Compounds of Formula (I) are useful as components of antibody-drug conjugates, which are useful for the treatment and prevention of cancer. Also described are antibody-drug conjugates comprising a Compound of Formula (I), compositions comprising such antibody-drug conjugates, and the use of such antibody-drug conjugates for the treatment or prevention of cancer. Linker-Payload Compounds of the Present Disclosure [0095] In one aspect, the present disclosure provides Linker-Payload Compounds of Formula (I), and pharmaceutically acceptable salts thereof, which comprise a PNU anthracycline payload, and a cleavable linker: wherein R¹ and R² are defined above. [0096] In one embodiment, R¹ is selected from -X-Y-Z-R³. [0097] In one embodiment, R² is H. [0098] In another embodiment, R² is C₁-C₆ alkyl. [0099] In a specific embodiment, R² is H. [0100] In a specific embodiment, R² is methyl. [0101] In one embodiment, R¹ is -X-Y-Z-R³, and R² is H or C₁-C₆ alkyl. [0102] In one embodiment, R¹ and R² join to form a 4 to 6-membered monocyclic heterocycloalkylene group, which is substituted on a ring carbon atom with -X-Y-Z-R³. [0103] In another embodiment, R¹ and R² join to form a 5 to 11-membered bicyclic heterocycloalkylene group, which is substituted on a ring carbon atom with -X-Y-Z-R³. [0104] In a specific embodiment, R¹ and R² join to form: . [0105] In one embodiment, R³ is: . [0106] In another embodiment, R³ is: . [0107] In another embodiment, R³ is: . [0108] In still another embodiment, R³ is: . [0109] In a specific embodiment, R³ is: . [0110] In another specific embodiment, R³ is: . [0111] In another specific embodiment, R³ is: . [0112] In another specific embodiment, R³ is: . [0113] In still another specific embodiment, R³ is: . [0114] In still another specific embodiment, R³ is: . [0115] In another specific embodiment, R³ is: . [0116] In another specific embodiment, R³ is: . [0117] In one embodiment, X is -(CH₂)_n-N(R⁴)-. [0118] In another embodiment, X is -(CH2)n-NH- and n is 1 or 2. [0119] In another embodiment, X is -(CH2)n-N(CH3)-, and n is 1 or 2. [0120] In one embodiment, X is -NH-. [0121] In another embodiment, X is -R⁵-NH-. [0122] In one embodiment, X is -(CH₂)_n-N(R⁴)-C(O)R⁵-. [0123] In another embodiment, X is -(CH2)n-N(R⁴)-(C1-C6 alkylene)-NH(R⁴)-. [0124] In another embodiment, X is -(CH₂)_n-N(R⁴)-C(O)O(CH₂)_n-R⁵-N(R⁴)- [0125] In another embodiment, X is -(CH2)3-NH-(CH2)3-NH-. [0126] In another embodiment, X is 5 or 6-membered monocyclic heterocycloalkylene. [0127] In a specific embodiment, X is: . [0128] In another embodiment, X is -(CH₂)_n-R⁵-. [0129] In a specific embodiment, X is -CH2-R⁵-. [0130] In another specific embodiment, X is: . [0131] In yet another embodiment, X is -(CH₂)_n-R⁵-NH(R⁴)-. [0132] In another embodiment, X is 5 to 11-membered bicyclic spirocyclic heterocycloalkylene. [0133] In a specific embodiment, X is: . [0134] In still another embodiment, X is -(CH2)n-R⁵-NHC(O)O-R⁵NH(R⁴)-. [0135] In a further embodiment, X is -(CH₂)_n-NHC(O)O-(CH₂)_n-R⁵-NH(R⁴). [0136] In another embodiment, X is –(CH₂)_n-R⁵-O-C(O)-NH(R⁴)-(C₁-C₆ alkylene)-NH(R⁴)-. [0137] In one embodiment, X is -R⁵-NHC(O)CH2OCH2N(R⁴)C(O) CH2N(R⁴)-. [0138] In a specific embodiment, X is: . [0139] In another embodiment, X is -(CH2)n-N(R⁴)C(O)NH-N(R⁴)-. [0140] In a specific embodiment, X is: -CH2CH2NHC(O)NHNH-. [0141] In another embodiment, X is -R⁵-N(R⁴)C(O)CH₂N(R⁴)-. [0142] In a specific embodiment, X is: . [0143] In still another embodiment, X is –(CH2)n-N(R⁴)-(CH2)n-N(R⁴)-. [0144] In a specific embodiment, X is: -CH2CH2NH-CH2CH2NH-. [0145] In a further embodiment, -R⁵-O-CH₂N(R⁴)-. [0146] In a specific embodiment, X is: . [0147] In one embodiment, Y is a bond. [0148] In another embodiment, Y is -C(O)C(R⁴)(R⁶)NH-. [0149] In another embodiment, Y is -C(O)C(R⁴)(R⁶)NH-, wherein R⁶ is H or isopropyl, and R⁴ is H or methyl. [0150] In one embodiment, Z is -C(O)CH(R⁷)NHC(O)CH(R⁸)NH-, wherein R⁷ and R⁸ are each independently selected from H, methyl, isopropyl, and -CH2CH2CH2NHC(O)NH2. [0151] In one embodiment, R⁵ is C₆-C₁₀ aryl. [0152] In another embodiment, R⁵ is C3-C7 monocyclic cycloalkylene. [0153] In another embodiment, R⁵ is C₅-C₁₁ bicyclic cycloalkylene. [0154] In another embodiment, R⁵ is -NHC(O)NH-. [0155] In another embodiment, R⁵ is -NH-NH-. [0156] In a specific embodiment, R⁵ is selected from -NH-NH-, -NHC(O)NH-, . [0157] In one embodiment, X is selected from -(CH2)n-N(R⁴)-, -R⁵-N(R⁴)-, -(CH2)n-N(R⁴)- C(O)R⁵-, -(CH₂)_n-N(R⁴)-(C₁-C₆ alkylene)-N(R⁴)-, -(CH₂)_n-R⁵-N(R⁴)-, -(CH₂)_n-R⁵-, -(CH₂)_n-R⁵- NHC(O)O-(CH2)nR⁵-N(R⁴)-, -(CH2)n-NHC(O)O-(CH2)n-R⁵-N(R⁴)-, -(CH2)n-R⁵-O-C(O)-N(R⁴)- (C₁-C₆ alkylene)-N(R⁴)-, -R⁵-NHC(O)CH₂OCH₂N(R⁴)C(O) CH₂N(R⁴)-, -R⁵- N(R⁴)C(O)CH2N(R⁴)-, –(CH2)n-N(R⁴)-CH2-N(R⁴)-, and -R⁵-O-CH2N(R⁴)-; each occurrence of R⁴ is independently H, methyl, or Fmoc; and each occurrence of R⁵ is independently selected from -NH-NH-, -NHC(O)NH, . [0158] In one embodiment, the group -X-Y-Z-R³ is selected from: , ,

, ,

, , , and [0159] In one embodiment, the Compound of Formula (I) is a Compounds of Formula (I’):

and pharmaceutically acceptable salts thereof, wherein: R¹ is selected from -X-Y-Z-R³, when R² is H or C₁-C₆ alkyl; R² is H or C1-C6 alkyl, or R¹ and R² join to form a 4 to 6-membered monocyclic heterocycloalkylene group, or a 5 to 11-membered bicyclic spirocyclic heterocycloalkylene group, each of which is substituted on a ring carbon atom with -X-Y-Z-R³; R³ is selected from: , and X is selected from –(CH2)n-N(R⁴)-, -R⁵-N(R⁴)-, -(CH2)n-N(R⁴)-C(O)R⁵-, -(CH2)n-N(R⁴)- (C₁-C₆ alkylene)-N(R⁴)-, 5 or 6-membered monocyclic heterocycloalkylene, –(CH₂)_n-R⁵-N(R⁴)-, 5 to 11-membered bicyclic spirocyclic heterocycloalkylene, –(CH2)n-R⁵-NHC(O)O-(CH2)nR⁵- N(R⁴)-, -(CH2)n-NHC(O)O-(CH2)n-R⁵-N(R⁴)-, and –(CH2)n-R⁵-O-C(O)-N(R⁴)-(C1-C6 alkylene)- N(R⁴)-; Y is a bond or -C(O)C(R⁴)(R⁶)NH-; Z is -C(O)CH(R⁷)NHC(O)CH(R⁸)NH-; R⁴ is H, C1-6 alkyl, or R⁵ is selected from C6-C10 arylene, 4 to 6-membered monocyclic heterocycloalkylene, 5 to 11-membered bicyclic spirocyclic heterocycloalkylene, C₃-C₇ monocyclic cycloalkylene, C₅- C11 bicyclic cycloalkylene, and -NHC(O)NH-, wherein said 4 to 6-membered monocyclic heterocycloalkylene can be optionally substituted on a ring carbon atom with an oxo group; R⁶, R⁷ and R⁸ are each independently selected from H, -CH2CH2CH2NHC(O)NH2, and a naturally occurring amino acid side chain; m is 0, 1, or 2; and each occurrence of n is independently an integer from 0 to 4. In one embodiment, the Compound of Formula (I) is represented by Formula (II): (II) wherein R², X, Y, Z, and m are as described herein for the Compounds of Formula (I). [0160] In another embodiment, the Compound of Formula (I) is represented by Formula (III): wherein X, Y, Z, and m are as described herein; and A is a 4 or 6-membered monocyclic heterocycloalkylene group. [0161] In another embodiment, the Compound of Formula (I) is represented by Formula (IV): wherein R², X, Y, Z, and m are as described herein. [0162] In still another embodiment, the Compound of Formula (I) is represented by Formula (V): wherein X, Y, Z, and m are as described herein; and A is a 4 or 6-membered monocyclic heterocycloalkylene group. [0163] In a further embodiment, the Compound of Formula (I) is represented by Formula (VI):

wherein R², X, Y, Z, and m are as described herein. [0164] In another embodiment, the Compound of Formula (I) is represented by Formula (VII): wherein X, Y, Z, and m are as described herein; and A is a 4 or 6-membered monocyclic heterocycloalkylene group. [0165] In another embodiment, the Compound of Formula (I) is represented by Formula (VIII): wherein R², R⁹, X, Y, Z, and m are as described herein. [0166] In another embodiment, the Compound of Formula (I) is represented by Formula (IX): wherein R⁹, X, Y, Z, and m are as described herein; and A is a 4 or 6-membered monocyclic heterocycloalkylene group. [0167] In another embodiment, it may be desirable to synthesize the linker prior to conjugation to the drug or targeting moiety to provide antibody-drug conjugates. In such embodiments, the linker compounds may act as intermediate compounds. Illustrative linkers of the Present Disclosure, include, but are not limited to the following Linker fragments (L-1 to L-12), where the point of attachment to the payload to the Linker is denoted by :

[0168] The linker fragments of L-1 to L-12 can be joined to a payload using the following reactants L-1’ to L-12’ respectively, wherein Q is -OH or -Cl:

[0169] In one aspect, the present disclosure provides Linker-Payload Compounds having structural Formulas (X)-(XXI), wherein D is an anticancer agent: [0170] In one embodiment, the present disclosure provides linker-payload compounds comprising a linker moiety that is selected from L-1, L-2, L-1, L-4, L-5, L-6, L-7, L-8, L-9, L- 10, L-11, and L-12, which is conjugated to an anticancer agent having a reactive -OH group. [0171] In one embodiment, the present disclosure provides linker-payload compounds comprising a linker moiety that is selected from L-1, L-2, L-1, L-4, L-5, L-6, L-7, L-8, L-9, L- 10, L-11, and L-12, which is conjugated to an anticancer agent which is a PNU anthracycline. [0172] In a specific embodiment, the present disclosure provides linker-payload compounds comprising: (i) a linker (L) that is selected from L-1, L-2, L-1, L-4, L-5, L-6, L-7, L-8, L-9, L- 10, L-11, and L-12; and (ii) a payload that is a PNU anthracycline compound of formula (XXII): (XXII) or a pharmaceutically acceptable salt thereof, wherein: R^1’ is H or C_1-6 alkyl; R^2’ is a linker chosen from linkers L-1 to L-12; alternatively, R¹ and R², taken together with the common nitrogen atom to which they are each attached, join to form: (i) a 3 to 7-membered monocyclic heterocycloalkyl group, (ii) a 5 to 11-membered bridged bicyclic heterocycloalkyl group, (iii) a 5 to 11-membered fused bicyclic heterocycloalkyl group, or (iv) a 5 to 11-membered spirocyclic heterocycloalkyl group, wherein said 3 to 7-membered monocyclic heterocycloalkyl group, said 5 to 11-membered bicyclic heterocycloalkyl group, said 5 to 11-membered fused heterocycloalkyl group, and said 5 to 11- membered spirocyclic heterocycloalkyl group can each be optionally and independently substituted with one or more R^A groups, and wherein a linker chosen from linkers L-1 to L-12 attaches to a ring atom of (i), (ii), (iii), or (iv); each occurrence of R^A is independently selected from C1-6 alkyl, halo, -CN, -OR³, - N(R³)₂, C₁-C₆ aminoalkyl, -(C₁-C₆ alkylene)-NHC(O)-(C₁-C₆ aminoalkyl), -O-(C_1-6 alkyl), - NHC(O)CH2OH, and -(C1-C6 alkylene)-(3 to 7-membered monocyclic heterocycloalkyl), wherein a 3 to 7-membered monocyclic heterocycloalkyl group can be optionally and independently substituted with one or more R^B groups; and each occurrence of R^B is independently selected from C1-6 alkyl, halo, -CN, -OR³, - N(R³)₂, C₁-C₆ aminoalkyl, -O-(C_1-6 alkyl), -NHC(O)-(C₁-C₆ aminoalkyl), -(C₁-C₆ alkylene)- NHC(O)-(C1-C6 aminoalkyl), C1-6 alkyl, halo, -CN, -OR³, -N(R³)2, -O-(C1-6 alkyl), and -NHC(O)CH₂OH. [0173] The payload of Formula (XVI) can be joined to the linkers of formula L-1, L-2, L-1, L- 4, L-5, L-6, L-7, L-8, L-9, L-10, L-11, and L-12, using the methods described herein, or methods well-known in synthetic organic chemistry. [0174] In one embodiment, the Linker-Payload Compound of the Present Disclosure is in substantially purified form. [0175] Non-limiting examples of the Linker-Payload Compounds of Formula (I) include Examples 1-36, and pharmaceutically acceptable salts thereof. 20 28 ADCs of the Present Disclosure [0176] The Linker-Payload Compounds of the Present Disclosure have utility for conjugation to antibodies or other targeting moieties to generate antibody-drug conjugates, or other targeting ligand conjugates, for oncology indications. Accordingly, in one aspect, the present disclosure provides antibody-drug conjugates (the “ADCs of the Present Disclosure”), which comprise a Linker-Payload of the Present Disclosure, joined to a ligand (e.g., an antibody). [0177] Thus, an embodiment of the Present Disclosure is represented by an antibody-drug conjugate having a structural Formula (XXIII): (XXIII) wherein R², R⁹, X, Y, and Z are described above herein for the Compounds of Formula (I); p is an integer from 1 to 8; L is a ligand, such as an antibody, or other targeting moiety; and R^3’ is selected from: , , , and wherein ** indicates the point of attachment of R^3’ to L. [0178] In one embodiment, L is an antibody, and R^3’ is attached to the sulfur atom of a cysteine residue of said antibody. [0179] Another embodiment of the Present Disclosure is represented by an antibody-drug conjugate having a structural Formula (XXIV): wherein X, Y, and Z are as described herein; A is a 4 or 6-membered monocyclic heterocycloalkylene group; p is an integer from 1 to 8; L is a ligand, such as an antibody, or other targeting moiety; and R^3’ is selected from: , , , and , wherein ** indicates the point of attachment of R^3’ to L. [0180] In one embodiment, L is an antibody, and R^3’ is attached to the sulfur atom of a cysteine residue of said antibody. [0181] Another embodiment of the Present Disclosure is represented by an antibody-drug conjugate having a structural Formula (XXV): (XXV) wherein R², X, Y, Z, and m are as described herein; p is an integer from 1 to 8; and L is a ligand, such as an antibody, or other targeting moiety. [0182] Still another embodiment of the Present Disclosure is represented by an antibody-drug conjugate having a structural Formula (XXVI): wherein X, Y, Z, and m are as described herein; A is a 4 or 6-membered monocyclic heterocycloalkylene group; p is an integer from 1 to 8; and L is a ligand, such as an antibody, or other targeting moiety. [0183] A further embodiment of the Present Disclosure is represented by an antibody-drug conjugate having a structural Formula (XXVII): (XXVII) wherein R², X, Y, Z, and m are as described herein; p is an integer from 1 to 8; and L is a ligand, such as an antibody, or other targeting moiety. [0184] Another embodiment of the Present Disclosure is represented by an antibody-drug conjugate having a structural Formula (XXVIII): (XXVIII) wherein X, Y, Z, and m are as described herein; A is a 4 or 6-membered monocyclic heterocycloalkylene group; p is an integer from 1 to 8; and L is a ligand, such as an antibody, or other targeting moiety. [0185] Yet another embodiment of the Present Disclosure is represented by an antibody-drug conjugate having a structural Formula (XXIX): wherein R², X, Y, Z, and m are as described herein, p is an integer from 1 to 8, and L is a ligand, such as an antibody, or other targeting moiety. [0186] Another embodiment of the Present Disclosure is represented by an antibody-drug conjugate having a structural Formula (XXX):

wherein X, Y, Z, and m are as described herein; A is a 4 or 6-membered monocyclic heterocycloalkylene group; p is an integer from 1 to 8; and L is a ligand, such as an antibody, or other targeting moiety. [0187] Another embodiment of the Present Disclosure is represented by an antibody-drug conjugate having a structural Formula (XXXI): wherein R², R⁹, X, Y, and Z are as described herein; p is an integer from 1 to 8; and L is a ligand, such as an antibody, or other targeting moiety. [0188] Another embodiment of the Present Disclosure is represented by an antibody-drug conjugate having a structural Formula (XXXII):

(XXXII) wherein R⁹, X, Y, and Z, are as described herein; A is a 4 or 6-membered monocyclic heterocycloalkylene group; p is an integer from 1 to 8; and L is a ligand, such as an antibody, or other targeting moiety. [0189] In one embodiment, for the compounds of formulas (XXIII) through (XXXII), L is an antibody, and the linker is attached to the sulfur atom of a cysteine group of said antibody. [0190] In one embodiment, the antibody-drug conjugates of the Present Disclosure include the following Compounds having a structural formula of (XXXIII) through (LVII):

and ( V) wherein L is a ligand, and p is an integer from 0 to 8. [0191] In one embodiment, the antibody-drug conjugate of the Present Disclosure is in substantially purified form. [0192] Non-limiting examples of the antibody-drug conjugates of the Present Disclosure include Examples 37-72, and pharmaceutically acceptable salts thereof, wherein L is Sacituzumab (S365C), and p is an integer from 1 to 8:

O N O p O 65

71 , and [0193] Other embodiments include the following: (a) A composition comprising a mixture of an ADC of the Present Disclosure, wherein the DAR of the composition is a decimal from 0 to 8. (b) A pharmaceutical composition comprising an effective amount of an ADC of the Present Disclosure, and a pharmaceutically acceptable carrier. (c) The pharmaceutical composition of (a), further comprising a second therapeutic agent selected from the group consisting of anticancer agents. (d) The pharmaceutical composition of (b), wherein the anticancer agent is an anti- human PD-1 antibody (or antigen-binding fragment thereof). (e) A pharmaceutical combination that comprises: (i) an ADC of the Present Disclosure, and (ii) a second therapeutic agent selected from the group consisting of anticancer agents, wherein the ADC of the Present Disclosure, and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting replication of cancer cells, or for treating cancer and/or reducing the likelihood or severity of symptoms of cancer. (f) The combination of (e), wherein the second therapeutic agent is an anti-human PD-1 antibody (or antigen-binding fragment thereof). (g) A method of inhibiting cancer cell replication in a subject in need thereof which comprises administering to the subject an effective amount of an ADC of the Present Disclosure. (h) A method of treating cancer and/or reducing the likelihood or severity of symptoms of cancer in a subject in need thereof which comprises administering to the subject an effective amount of an ADC of the Present Disclosure. (i) The method of (h), wherein the ADC of the Present Disclosure is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of anticancer agents. (j) The method of (i), wherein the second therapeutic agent is an anti-human PD-1 antibody (or antigen-binding fragment thereof). (k) A method of inhibiting cancer cell replication in a subject in need thereof which comprises administering to the subject the composition of (a); the pharmaceutical composition of (b), (c) or (d) or the combination of (e) or (f). (l) A method of treating cancer and/or reducing the likelihood or severity of symptoms of cancer in a subject in need thereof which comprises administering to the subject the composition of (a); the pharmaceutical composition of (b), (c) or (d) or the combination of (e) or (f). [0194] Also described herein are ADCs of the Present Disclosure for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) medicine; (b) inhibiting cancer cell replication, or (c) treating cancer and/or reducing the likelihood or severity of symptoms of cancer. In these uses, the ADC of the Present Disclosure can optionally be employed in combination with one or more additional therapeutic agents selected from anticancer agents. [0195] It is further to be understood that the embodiments of compositions and methods provided as (a) through (k) above are understood to include all embodiments of the compounds, including such embodiments as result from combinations of embodiments. The Ligand [0196] In one embodiment, the Linker-Payload Compounds of the Present Disclosure can be conjugated to a Ligand, such as an antibody, to provide antibody-drug conjugates (ADCs of the Present Disclosure). In these antibody-drug conjugates, the ligand joins to the linker via a bond formed between a moiety on the Ligand and either the maleimide group or the sulfone- substituted pyridyl group on the linker. [0197] The ligand can be any moiety with a free sulfur atom including, but not limited to, antibodies, proteins, peptides, polypeptides, or engineered antibodies modified to provide a free cysteine. An aspect of this is realized when the ligand is an antibody, preferably an intact antibody. The Ligand acts to target and present the drug to the particular target cell population with which the ligand interacts. Suitable Ligands include, for example, antibodies, e.g., full- length antibodies and antigen binding fragments thereof, interferons, lymphokines, hormones, growth factors and colony-stimulating factors, vitamins, nutrient transport molecules (such as, but not limited to, transferrin), or any other cell binding molecule or substance, including small molecules and peptides. The ligand can be, for example, a non-antibody protein targeting agent. [0198] When the conjugates comprise non-immunoreactive protein, polypeptide, or peptide Ligands instead of an antibody, useful non-immunoreactive protein, polypeptide, or peptide Ligands include, but are not limited to, transferrin, epidermal growth factors (“EGF”), bombesin, gastrin, gastrin releasing peptide, platelet-derived growth factor, IL-2, IL-6, transforming growth factors (“TGF”), such as TGF-α and TGF-β, vaccinia growth factor (“VGF”), insulin and insulinlike growth factors I and II, somatostatin, lectins and apoprotein from low density lipoprotein. [0199] Particularly preferred ligands are antibodies, including intact antibodies. In fact, in any of the embodiments described herein, the ligand can be an antibody. Useful polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of immunized animals. Useful monoclonal antibodies are homogeneous populations of antibodies to a particular antigenic determinant (e.g., a cancer cell antigen, a viral antigen, a microbial antigen, a protein, a peptide, a carbohydrate, a chemical, nucleic acid, or fragments thereof). A monoclonal antibody (mAb) to an antigen-of-interest can be prepared by using any technique known in the art which provides for the production of antibody molecules by continuous cell lines in culture. In one embodiment, the Ligand is an antibody, and joins to the linker via a cysteine group. [0200] Additionally, recombinant antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which can be made using standard recombinant DNA techniques, are useful antibodies. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as for example, those having a variable region derived from a murine monoclonal and human immunoglobulin constant regions. (See, e.g, U.S. Pat. Nos.4,816,567; and 4,816,397, which are incorporated herein by reference in their entirety.) Humanized antibodies are antibody molecules from non- human species having one or more complementarity determining regions (CDRs) from the non-human species and a framework region from a human immunoglobulin molecule. (See, e.g, U.S. Pat. No.5,585,089, which is incorporated herein by reference in its entirety.) Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in International Publication No. WO 87/02671, and European Patent Publication No.0184187, each of which is incorporated herein by reference in its entirety. [0201] Completely human antibodies are particularly desirable and can be produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes. Antibodies include analogs and derivatives that are either modified, i.e. by the covalent attachment of any type of molecule as long as such covalent attachment permits the antibody to retain its antigen binding immunospecificity. For example, but not by way of limitation, derivatives and analogs of the antibodies include those that have been further modified, e.g. by glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular antibody or other protein, etc. Any of numerous chemical modifications can be carried out by known techniques including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis in the presence of tunicamycin, etc. Additionally, the analog or derivative can contain one or more unnatural amino acids. [0202] In a specific embodiment, known antibodies for the treatment of cancer can be used. Antibodies immunospecific for a cancer cell antigen can be obtained commercially or produced by any method known to one of skill in the art such as, e.g., recombinant expression techniques. The nucleotide sequence encoding antibodies immunospecific for a cancer cell antigen can be obtained, e.g., from the GenBank database or a database like it, the literature publications, or by routine cloning and sequencing. [0203] In another specific embodiment, antibodies for the treatment of an autoimmune disease are used in accordance with the compositions and methods of the disclosure. Antibodies immunospecific for an antigen of a cell that is responsible for producing autoimmune antibodies can be obtained from any organization (e.g., a university scientist or a company) or produced by any method known to one of skill in the art such as, e.g., chemical synthesis or recombinant expression techniques. [0204] In another embodiment, it may be desirable to conjugate components of the linker to the ligand (e.g., antibody) prior to attaching the payload component of an antibody-drug conjugate. For example, in embodiments where a thiol containing substituent, e.g., cysteine, is being used to attach the payload component, it may be desirable to conjugate components of the linker to the ligand (e.g., antibody) prior to attaching the payload component of the antibody-drug conjugate. Uses of the Compound of the Present Disclosure As Intermediates for the Synthesis of ADCs [0205] The Linker-Payload Compounds of the Present Disclosure are useful as a component of antibody-drug conjugates. In one embodiment, a Linker-Payload Compound of the Present Disclosure can be conjugated to a Ligand (i.e., an antibody or antibody fragment) to make an ADC of the Present Disclosure. The maleimide group or sulfone-substituted pyridyl group of a Linker-Payload Compound of the Present Disclosure can serve as a conjugation handle, and point of attachment of a Ligand to a Linker-Payload Compound of the Present Disclosure. In a specific embodiment an antibody is attached to a Linker-Payload Compound of the Present Disclosure via a sulfur atom of a cysteine residue on the antibody. [0206] In a specific embodiment, one or more engineered cysteine groups on an antibody are reduced to provide free thiol group(s) which can then undergo a conjugation reaction with a maleimide group or sulfone-substituted pyridyl group on a Linker-Payload Compound of the Present Disclosure and thereby attach the antibody to the Linker moiety of the Linker-Payload Compound of the Present Disclosure, and form an ADC of the Present Disclosure. For the Treatment and Prevention of Cancer [0207] As noted above, additional embodiments of the Present Disclosure are each directed to a method for the treatment a disease, disorder, or condition, or one or more symptoms thereof (“indications”) which method comprises administering to a subject in need of such treatment a therapeutically effective amount of an ADC of the Present Disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or salt thereof. [0208] One such embodiment provides a method of treating or preventing a cancer selected from breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, stomach cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer (for example, small cell lung cancer and non-small cell lung cancer) colon cancer, rectal cancer, colorectal cancer, leukemia (for example, acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, pancreatic cancer, and lymphoma (for example, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, or recurrent anaplastic large cell lymphoma) in a subject in need thereof, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of an ADC of the Present Disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising said compound, salt or solvate thereof. In one such embodiment, the subject is a human. [0209] Another aspect of the disclosure relates to a method for treating and/or preventing a tumor, comprising administering to a patient in need thereof a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition comprising the compound according to the present disclosure. Combination Therapies [0210] Combinations with additional therapeutic agents are also contemplated in the instant methods. For example, combinations of the ADCs of the Present Disclosure of the Present Disclosure with PPAR- ^ (i.e., PPAR-gamma) agonists and PPAR- ^ (i.e., PPAR-delta) agonists are useful in the treatment of certain malignancies. PPAR- ^ and PPAR- ^ are the nuclear peroxisome proliferator-activated receptors ^ and ^. PPAR- ^ agonists have been shown to inhibit the angiogenic response to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice (Arch. Ophthamol.2001; 119:709-717). Examples of PPAR- ^ agonists and PPAR- ^/ ^ agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionic acid (disclosed in USSN 09/782,856), and 2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy) phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid (disclosed in USSN 60/235,708 and 60/244,697), or a pharmaceutically acceptable salt thereof. [0211] Another embodiment of the instant disclosure is the use of the ADCs of the Present Disclosure of the Present Disclosure in combination with gene therapy for the treatment of cancer. For an overview of genetic strategies to treating cancer see Hall et al., (Am. J. Hum. Genet.61:785-789, 1997), and Kufe et al., (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000). Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus- mediated gene transfer (see U.S. Patent No.6,069,134, for example), a uPA/uPAR antagonist ("Adenovirus-Mediated Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis- Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August 1998;5(8):1105- 13), and interferon gamma (J. Immunol.2000;164:217-222). [0212] The ADCs of the Present Disclosure may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins. Such MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar), or a pharmaceutically acceptable salt thereof. [0213] The ADCs of the Present Disclosure of the Present Disclosure may also be administered with an immunologic-enhancing drug, such as levamisole, isoprinosine and Zadaxin, or a pharmaceutically acceptable salt thereof. [0214] The ADCs of the Present Disclosure of the Present Disclosure may also be useful for treating or preventing cancer in combination with P450 inhibitors including: xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine, methyrapone, caffeine, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafyline, cimetidine, dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem, terfenadine, verapamil, cortisol, itraconazole, mibefradil, nefazodone and nelfinavir, or a pharmaceutically acceptable salt thereof. [0215] The ADCs of the Present Disclosure of the Present Disclosure may also be useful for treating or preventing cancer in combination with Pgp and/or BCRP inhibitors including: cyclosporin A, PSC833, GF120918, cremophorEL, fumitremorgin C, Ko132, Ko134, Iressa, Imatnib mesylate, EKI-785, Cl1033, novobiocin, diethylstilbestrol, tamoxifen, resperpine, VX- 710, tryprostatin A, flavonoids, ritonavir, saquinavir, nelfinavir, omeprazole, quinidine, verapamil, terfenadine, ketoconazole, nifidepine, FK506, amiodarone, XR9576, indinavir, amprenavir, cortisol, testosterone, LY335979, OC144-093, erythromycin, vincristine, digoxin and talinolol, or a pharmaceutically acceptable salt thereof. [0216] The ADCs of the Present Disclosure of the Present Disclosure may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates, including but not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof. [0217] The ADCs of the Present Disclosure of the Present Disclosure may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors. Examples of aromatase inhibitors include but are not limited to: anastrozole, letrozole and exemestane, or a pharmaceutically acceptable salt thereof. [0218] The ADCs of the Present Disclosure of the Present Disclosure may also be useful for treating or preventing cancer in combination with siRNA therapeutics. [0219] The ADCs of the Present Disclosure of the Present Disclosure may also be administered in combination with γ-secretase inhibitors and/or inhibitors of NOTCH signaling. Such inhibitors include compounds described in WO 01/90084, WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO 03/093264, WO 03/093251, WO 03/093253, WO 2004/039800, WO 2004/039370, WO 2005/030731, WO 2005/014553, USSN 10/957,251, WO 2004/089911, WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137, WO 2004/031139, WO 2004/031138, WO 2004/101538, WO 2004/101539 and WO 02/47671 (including LY-450139), or a pharmaceutically acceptable salt thereof. [0220] In one embodiment, specific anticancer agents useful in the present combination therapies include, but are not limited to: pembrolizumab (Keytruda^®), abarelix (Plenaxis _depot ^® _{); aldesleukin (Prokine} ^® _{); Aldesleukin (Proleukin} ^® _{); Alemtuzumabb (Campath} ^® _); _{alitretinoin (Panretin} ^® _{); allopurinol (Zyloprim} ^® _{); altretamine (Hexalen} ^® _{); amifostine} _(Ethyol ^® _{); anastrozole (Arimidex} ^® _{); arsenic trioxide (Trisenox} ^® _{); asparaginase (Elspar} ^® _); _{azacitidine (Vidaza} ^® _{); bevacuzimab (Avastin} ^® _{); bexarotene capsules (Targretin} ^® _{); bexarotene} _{gel (Targretin} ^® _{); bleomycin (Blenoxane} ^® _{); bortezomib (Velcade} ^® _{); busulfan intravenous} _(Busulfex ^® _{); busulfan oral (Myleran} ^® _{); calusterone (Methosarb} ^® _{); capecitabine (Xeloda} ^® _); _{carboplatin (Paraplatin} ^® _{); carmustine (BCNU} ^® _{, BiCNU} ^® _{); carmustine (Gliadel} ^® _{); carmustine} _{with Polifeprosan 20 Implant (Gliadel Wafer} ^® _{); celecoxib (Celebrex} ^® _{); cetuximab (Erbitux} ^® _); _{chlorambucil (Leukeran} ^® _{); cisplatin (Platinol} ^® _{); cladribine (Leustatin} ^® _{, 2-CdA} ^® _{); clofarabine} _(Clolar ^® _{); cyclophosphamide (Cytoxan} ^® _{, Neosar} ^® _{); cyclophosphamide (Cytoxan Injection} ^® _); _{cyclophosphamide (Cytoxan Tablet} ^® _{); cytarabine (Cytosar-U} ^® _{); cytarabine liposomal} _(DepoCyt ^® _{); dacarbazine (DTIC-Dome} ^® _{); dactinomycin, actinomycin D (Cosmegen} ^® _); _{Darbepoetin alfa (Aranesp} ^® _{); daunorubicin liposomal (DanuoXome} ^® _{); daunorubicin,} _{daunomycin (Daunorubicin} ^® _{); daunorubicin, daunomycin (Cerubidine} ^® _{); Denileukin diftitox} _(Ontak ^® _{); dexrazoxane (Zinecard} ^® _{); docetaxel (Taxotere} ^® _{); doxorubicin (Adriamycin PFS} ^® _); _{doxorubicin (Adriamycin} ^® _{, Rubex} ^® _{); doxorubicin (Adriamycin PFS Injection} ^® _{); doxorubicin} _{liposomal (Doxil} ^® _{); dromostanolone propionate (Dromostanolone} ^® _{); dromostanolone} propionate (Masterone injection^®); Elliott's B Solution (Elliott's B Solution^®); epirubicin _(Ellence ^® _{); Epoetin alfa (epogen} ^® _{); erlotinib (Tarceva} ^® _{); estramustine (Emcyt} ^® _{); etoposide} _{phosphate (Etopophos} ^® _{); etoposide, VP-16 (Vepesid} ^® _{); exemestane (Aromasin} ^® _{); Filgrastim} _(Neupogen ^® _{); floxuridine (intraarterial) (FUDR} ^® _{); fludarabine (Fludara} ^® _{); fluorouracil, 5-FU} _(Adrucil ^® _{); fulvestrant (Faslodex} ^® _{); gefitinib (Iressa} ^® _{); gemcitabine (Gemzar} ^® _{); gemtuzumab} _{ozogamicin (Mylotarg} ^® _{); goserelin acetate (Zoladex Implant} ^® _{); goserelin acetate (Zoladex} ^® _); _{histrelin acetate (Histrelin implant} ^® _{); hydroxyurea (Hydrea} ^® _{); Ibritumomab Tiuxetan} _(Zevalin ^® _{); idarubicin (Idamycin} ^® _{); ifosfamide (IFEX} ^® _{); imatinib mesylate (Gleevec} ^® _); _{interferon alfa 2a (Roferon A} ^® _{); Interferon alfa-2b (Intron A} ^® _{); irinotecan (Camptosar} ^® _); _{lenalidomide (Revlimid} ^® _{); letrozole (Femara} ^® _{); leucovorin (Wellcovorin} ^® _{, Leucovorin} ^® _); _{Leuprolide Acetate (Eligard} ^® _{); levamisole (Ergamisol} ^® _{); lomustine, CCNU (CeeBU} ^® _); _{meclorethamine, nitrogen mustard (Mustargen} ^® _{); megestrol acetate (Megace} ^® _{); melphalan, L-} _{PAM (Alkeran} ^® _{); mercaptopurine, 6-MP (Purinethol} ^® _{); mesna (Mesnex} ^® _{); mesna (Mesnex} _tabs ^® _{); methotrexate (Methotrexate} ^® _{); methoxsalen (Uvadex} ^® _{); mitomycin C (Mutamycin} ^® _); _{mitotane (Lysodren} ^® _{); mitoxantrone (Novantrone} ^® _{); nandrolone phenpropionate (Durabolin-} ₅₀ ^® _{); nelarabine (Arranon} ^® _{); Nofetumomab (Verluma} ^® _{); Oprelvekin (Neumega} ^® _{); oxaliplatin} _(Eloxatin ^® _{); paclitaxel (Paxene} ^® _{); paclitaxel (Taxol} ^® _{); paclitaxel protein-bound particles} _(Abraxane ^® _{); palifermin (Kepivance} ^® _{); pamidronate (Aredia} ^® _{); pegademase (Adagen} _{(Pegademase Bovine)} ^® _{); pegaspargase (Oncaspar} ^® _{); Pegfilgrastim (Neulasta} ^® _{); pemetrexed} _{disodium (Alimta} ^® _{); pentostatin (Nipent} ^® _{); pipobroman (Vercyte} ^® _{); plicamycin, mithramycin} _(Mithracin ^® _{); porfimer sodium (Photofrin} ^® _{); procarbazine (Matulane} ^® _{); quinacrine} _(Atabrine ^® _{); Rasburicase (Elitek} ^® _{); Rituximab (Rituxan} ^® _{); Ridaforolimus; sargramostim} _(Leukine ^® _{); Sargramostim (Prokine} ^® _{); sorafenib (Nexavar} ^® _{); streptozocin (Zanosar} ^® _); _{sunitinib maleate (Sutent} ^® _{); talc (Sclerosol} ^® _{); tamoxifen (Nolvadex} ^® _{); temozolomide} _(Temodar ^® _{); teniposide, VM-26 (Vumon} ^® _{); testolactone (Teslac} ^® _{); thioguanine, 6-TG} _(Thioguanine ^® _{); thiotepa (Thioplex} ^® _{); topotecan (Hycamtin} ^® _{); toremifene (Fareston} ^® _); _{Tositumomab (Bexxar} ^® _{); Tositumomab/I-131 tositumomab (Bexxar} ^® _{); Trastuzumab} _(Herceptin ^® _{); tretinoin, ATRA (Vesanoid} ^® _{); Uracil Mustard (Uracil Mustard Capsules} ^® _); _{valrubicin (Valstar} ^® _{); vinblastine (Velban} ^® _{); vincristine (Oncovin} ^® _{); vinorelbine} _(Navelbine ^® _{); Olaparib (Lynparza} ^® _{) vorinostat (Zolinza} ^® _{), and zoledronate (Zometa} ^® _{), or a} pharmaceutically acceptable salt thereof. [0221] Thus, the scope of the instant disclosure encompasses the use of the ADCs of the Present Disclosure of the Present Disclosure in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR- ^ agonists, PPAR- ^ agonists, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, γ-secretase and/or NOTCH inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint, and any of Therapeutic agents listed above. [0222] Yet another example of the disclosure is a method of treating cancer that comprises administering a therapeutically effective amount of an ADC of the Present Disclosure of the Present Disclosure in combination with paclitaxel or trastuzumab. [0223] Therapeutic combination disclosed herein may be used in combination with one or more other active agents, including but not limited to, other anti-cancer agents that are used in the prevention, treatment, control, amelioration, or reduction of risk of a particular disease or condition (e.g., cell-proliferation disorders). In one embodiment, an ADC of the Present Disclosure of the Present Disclosure is combined with one or more other anti-cancer agents for use in the prevention, treatment, control amelioration, or reduction of risk of a particular disease or condition for which the ADCs of the Present Disclosure of the Present Disclosure are useful. Such other active agents may be administered, by a route and in an amount commonly used therefor, prior to, contemporaneously, or sequentially with an ADC of the Present Disclosure. [0224] The instant disclosure also includes a pharmaceutical composition useful for treating or preventing cancer that comprises a therapeutically effective amount of ADCs of the Present Disclosure of the Present Disclosure and a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR- ^ agonist, a PPAR- ^ agonist, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, γ-secretase and/or NOTCH inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint, and any of Therapeutic agents listed above. [0225] The disclosure further relates to a method of treating cancer in a human patient comprising administration of an and a PD-1 antagonist to the patient. The compound of the disclosure and the PD-1 antagonist may be administered concurrently or sequentially. [0226] In particular embodiments, the PD-1 antagonist is an anti-PD-1 antibody, or antigen binding fragment thereof. In alternative embodiments, the PD-1 antagonist is an anti-PD-L1 antibody, or antigen binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody, independently selected from pembrolizumab, nivolumab, cemiplimab, sintilimab, tislelizumab, atezolizumab (MPDL3280A), camrelizumab and toripalimab. In other embodiments, the PD-L1 antagonist is an anti-PD-L1 antibody independently selected from atezolizumab, durvalumab and avelumab. [0227] In one embodiments, the PD-1 antagonist is pembrolizumab. In particular sub- embodiments, the method comprises administering 200 mg of pembrolizumab to the patient about every three weeks. In other sub-embodiments, the method comprises administering 400 mg of pembrolizumab to the patient about every six weeks. [0228] In further sub-embodiments, the method comprises administering 2 mg/kg of pembrolizumab to the patient about every three weeks. In particular sub-embodiments, the patient is a pediatric patient. [0229] In some embodiments, the PD-1 antagonist is nivolumab. In particular sub- embodiments, the method comprises administering 240 mg of nivolumab to the patient about every two weeks. In other sub-embodiments, the method comprises administering 480 mg of nivolumab to the patient about every four weeks. [0230] In some embodiments, the PD-1 antagonist is cemiplimab. In particular embodiments, the method comprises administering 350 mg of cemiplimab to the patient about every 3 weeks. [0231] In some embodiments, the PD-1 antagonist is atezolizumab. In particular sub- embodiments, the method comprises administering 1200 mg of atezolizumab to the patient about every three weeks. [0232] In some embodiments, the PD-1 antagonist is durvalumab. In particular sub- embodiments, the method comprises administering 10 mg/kg of durvalumab to the patient about every two weeks. [0233] In some embodiments, the PD-1 antagonist is avelumab. In particular sub-embodiments, the method comprises administering 800 mg of avelumab to the patient about every two weeks. [0234] When the ADCs of the Present Disclosure of the Present Disclosure are administered in combination with an anti-human PD-1 antibody (or antigen-binding fragment thereof), the anti- human PD-1 antibody (or antigen-binding fragment thereof) may be administered either simultaneously with, or before or after, the ADCs of the Present Disclosure of the Present Disclosure. Either of the anti-human PD-1 antibody (or antigen-binding fragment thereof), and/or an ADC of the Present Disclosure of the Present Disclosure, or a pharmaceutically acceptable salt thereof, may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agent(s). The weight ratio of the anti-human PD-1 antibody (or antigen-binding fragment thereof) to an ADC of the Present Disclosure, may be varied and will depend upon Therapeutically effective dose of each agent. Generally, a therapeutically effective dose of each will be used. Combinations including at least one anti-human PD-1 antibody (or antigen-binding fragment thereof), an ADC of the Present Disclosure of the Present Disclosure, and optionally other active agents will generally include a therapeutically effective dose of each active agent. In such combinations, the anti-human PD-1 antibody (or antigen-binding fragment thereof), the ADCs of the Present Disclosure, and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent with, or subsequent to the administration of other agent(s). [0235] In one embodiment, this disclosure provides an anti-human PD-1 antibody (or antigen- binding fragment thereof), and/or a compound of Formula IV, and at least one other active agent as a combined preparation for simultaneous, separate or sequential use in treating cancer. [0236] The disclosure also provides the use of an ADC of the Present Disclosure of the Present Disclosure, for treating cancer, where the patient has previously (e.g., within 24-hours) been treated with an anti-human PD-1 antibody (or antigen-binding fragment thereof). The disclosure also provides the use of an anti-human PD-1 antibody (or antigen-binding fragment thereof) for treating a cellular proliferative disorder, where the patient has previously (e.g., within 24-hours) been treated with an antibody-linker-payload compound (antibody-drug conjugate) an ADC of the Present Disclosure of the Present Disclosure. [0237] The present disclosure further relates to methods of treating cancer, said method comprising administering to a subject in need thereof a combination therapy that comprises (a) an ADC of the Present Disclosure of the Present Disclosure, and (b) an anti-human PD-1 antibody (or antigen-binding fragment thereof); wherein the anti-human PD-1 antibody (or antigen-binding fragment thereof) is administered once every 21 days. [0238] Additionally, the present disclosure relates to methods of treating cancer, said method comprising administering to a subject in need thereof a combination therapy that comprises: (a) an ADC of the Present Disclosure of the Present Disclosure, and (b) an anti-human PD-1 antibody (or antigen-binding fragment thereof. In specific embodiments, the cancer occurs as one or more solid tumors or lymphomas. In further specific embodiments, the cancer is selected from the group consisting of advanced or metastatic solid tumors and lymphomas. In still further specific embodiments, the cancer is selected from the group consisting of malignant melanoma, head and neck squamous cell carcinoma, MSI-H cancer, MMR deficient cancer, non-small cell lung cancer, urothelial carcinoma, gastric or gastroesophageal junction adenocarcinoma, breast adenocarcinoma, and lymphomas. In additional embodiments, the lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (malt), nodal marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Burkitt lymphoma, anaplastic large cell lymphoma (primary cutaneous type), anaplastic large cell lymphoma (systemic type), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma/leukemia, nasal type extranodal NK/T-cell lymphoma, enteropathy-associated T-cell lymphoma, gamma/delta hepatosplenic T- cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, and Hodgkin lymphoma. In particular embodiments, the cellular proliferative disorder is a cancer that has metastasized, for example, a liver metastases from colorectal cancer. In additional embodiments, the cellular proliferative disorder is a cancer is classified as stage III cancer or stage IV cancer. In instances of these embodiments, the cancer is not surgically resectable. [0239] In embodiments of the methods disclosed herein, the anti-human PD-1 antibody (or antigen binding fragment thereof) is administered by intravenous infusion or subcutaneous injection. [0240] In one embodiment, the present disclosure provides compositions comprising an ADC of the Present Disclosure, a pharmaceutically acceptable carrier, and an anti-human PD-1 antibody (or antigen-binding fragment thereof). [0241] In another embodiment, the present disclosure provides compositions comprising a compound of Formula IV, a pharmaceutically acceptable carrier, and pembrolizumab. [0242] In one embodiment, the present disclosure provides compositions comprising a compound of Formula IV, a pharmaceutically acceptable carrier, and two additional therapeutic agents, one of which is an anti-human PD-1 antibody (or antigen-binding fragment thereof), and the other of which is independently selected from the group consisting of anticancer agents. [0243] An ADC of the Present Disclosure may be employed in conjunction with anti-emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of an ADC of the Present Disclosure, alone or with radiation therapy. For the prevention or treatment of emesis, an ADC of the Present Disclosure may be used in conjunction with other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Patent Nos.2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, an antidopaminergic, such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide, aprepitant, fosaprepitant, or dronabinol. In another example, conjunctive therapy with an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosed for the treatment or prevention of emesis that may result upon administration of the ADCs of the Present Disclosure. [0244] The ADCs of the Present Disclosure may also be administered with an agent useful in the treatment of anemia. Such an anemia treatment agent is, for example, a continuous erythropoiesis receptor activator (such as epoetin alfa). [0245] The ADCs of the Present Disclosure may also be administered with an agent useful in the treatment of neutropenia. Such a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF). Examples of a G-CSF include filgrastim. [0246] The ADCs of the Present Disclosure may be useful when co-administered with other treatment modalities, including but not limited to, radiation therapy, surgery, and gene therapy. Accordingly, in one embodiment, the methods of treating cancer described herein, unless stated otherwise, can optionally include the administration of an effective amount of radiation therapy. For radiation therapy, γ-radiation is preferred. [0247] The methods of treating cancers described herein can optionally include the administration of an effective amount of radiation (i.e., the methods of treating cancers described herein optionally include the administration of radiation therapy). [0248] The methods of treating cancer described herein include methods of treating cancer that comprise administering a therapeutically effective amount of an ADC of the Present Disclosure in combination with radiation therapy and/or in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/ytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR- ^ agonists, PPAR- ^ agonists, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, γ-secretase and/or NOTCH inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint, and any of the additional therapeutic agents listed herein. [0249] Additional embodiments of the disclosure include the pharmaceutical compositions, combinations, uses and methods set forth in above, wherein it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination is consistent with the description of the embodiments. It is further to be understood that the embodiments provided above are understood to include all embodiments, including such embodiments as result from combinations of embodiments. Kits [0250] In one aspect, provided is a kit comprising a therapeutically effective amount of an ADC of the Present Disclosure of the Present Disclosure or a pharmaceutically acceptable salt, solvate or ester of said compound and a pharmaceutically acceptable carrier, vehicle or diluent. [0251] In another aspect provided is a kit comprising an amount of an ADC of the Present Disclosure of the Present Disclosure, and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more active ingredients result in a desired therapeutic effect. In one embodiment, the Compound of the Present Disclosure of the Present Disclosure, and the one or more additional therapeutic agents are provided in the same container. In one embodiment, the Compound of the Present Disclosure of the Present Disclosure, and the one or more additional therapeutic agents are provided in separate containers. Compositions and Administration [0252] An aspect of this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an ADC of the Present Disclosure or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable carrier(s), diluent(s) or excipients(s). [0253] Another aspect of this disclosure relates to a composition comprising an ADC of the Present Disclosure, or a pharmaceutically acceptable salt thereof, having a DAR that is a decimal from 0 to 8. In one aspect, this composition is a pharmaceutical composition, and comprises one or more pharmaceutically acceptable carrier(s), diluent(s) or excipients(s). [0254] Another aspect of the disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of an ADC of the Present Disclosure as described herein, or a tautomer, mesomere, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier(s), diluent(s) or excipient(s). [0255] Another aspect of the disclosure relates to an ADC of the Present Disclosure as described herein, or a tautomer, mesomere, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof for use as a drug or drug component. [0256] Another aspect of the disclosure relates to an ADC of the Present Disclosure as described herein, or a tautomer, mesomere, racemate, enantiomer, diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in the preparation of a medicament for treating or preventing a tumor. [0257] In another embodiment, the compounds of the disclosure include those identified herein as Examples in the tables below, and pharmaceutically acceptable salts thereof. [0258] In another embodiment, the present disclosure is directed to a method for the manufacture of a medicament for use in a subject comprising combining an ADC of the Present Disclosure, or a pharmaceutically acceptable salt thereof, with a pharmaceutical carrier or diluent. [0259] The ADCs of the Present Disclosure may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, buccal or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals the compounds of the disclosure are effective for use in humans. [0260] The pharmaceutical compositions for the administration of the compounds of this disclosure may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. [0261] The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, solutions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Oral tablets may also be formulated for immediate release, such as fast melt tablets or wafers, rapid dissolve tablets or fast dissolve films. [0262] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. [0263] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. [0264] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or acetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. [0265] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. [0266] The pharmaceutical compositions of the disclosure may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. [0267] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. [0268] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. [0269] The ADCs of the Present Disclosure may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature, and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. [0270] For topical use, creams, ointments, jellies, solutions or suspensions and the like, containing the ADCs of the Present Disclosure are employed. Similarly, transdermal patches may also be used for topical administration. [0271] The pharmaceutical composition and method of the Present Disclosure may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above-mentioned pathological conditions. [0272] In the treatment, prevention, control, amelioration, or reduction of risk of the conditions disclosed herein an appropriate dosage level of the compounds of this disclosure will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0.20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day or may be administered once or twice per day. [0273] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. [0274] Methods for preparing the compounds of this disclosure are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein. Preparative Examples [0275] The Compounds of the Present Disclosure can be prepared according to the following schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. It is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in detail. The general procedures for making the compounds claimed in this disclosure can be readily understood by one skilled in the art from viewing the following schemes and descriptions. General Experimental Information: [0276] Unless otherwise noted, all reactions were magnetically stirred. All reagents and solvents were purchased from commercial sources and used as is unless otherwise noted. Reaction progress and synthetic intermediate analysis were assessed by LCMS (UV detection with ESI, APCI, or other mass detection) when applicable using a MeCN/water gradient with either TFA, formic acid, or NH4HCO3 modifier. Silica gel and reverse-phase flash column chromatography were conducted with commercially available pre-packed columns. Reverse- phase preparative HPLC purification was performed on preparative HPLC instruments with UV and MS detection using a MeCN/water gradient with either TFA, formic acid, or NH₄OH modifier.¹H NMR spectra were collected at room temperature, and chemical shifts are reported in ppm relative to the residual proteo-solvent signals, and multiplicities, coupling constants (where applicable), and signal integrations are listed parenthetically. Unless otherwise noted, all EC₅₀ data presented in tables refers to the cytotoxicity assays that are described in the Biological Assay section. SYNTHETIC SCHEMES, INTERMEDIATES, AND EXAMPLES [0277] The compounds of the disclosure may be prepared by methods known in the art of organic synthesis as set forth in part by the following general synthetic schemes and specific preparative examples. Starting materials are available commercially or may be prepared by known methods. Preparation of Intermediate Compounds Preparation of Intermediate Compound i Step A – synthesis of compound ii [0278] To a stirred mixture of (9H-fluoren-9-yl)methyl hydrazinecarboxylate (i, 3.00 g, 11.8 mmol) in DMF (50.0 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (3.02 g, 11.8 mmol), and the resulting reaction was allowed to stir at 25 °C for 1 hour. The reaction was monitored using TLC (DCM:CH3OD = 10:1). The reaction mixture, which contains 1-((9H- fluoren-9-yl)methyl) 2-(2,5-dioxopyrrolidin-1-yl) hydrazine-1,2-dicarboxylate (ii, 4.66 g, 11.8 mmol) in DMF, was used without further purification. Step B – synthesis of compound iii [0279] To a stirred mixture of ii (4.66 g, 11.8 mmol) in DMF (50.0 ml) was added tert-butyl (2-aminoethyl)carbamate (1.89 g, 11.8 mmol), and the resulting reaction was allowed to stir at 25 °C for 16 hours. Water (50.0 mL) was added, and the mixture was extracted with ethyl acetate (2 x 40.0 mL). The combined organic extracts were washed with brine (50.0 mL), dried over Na₂SO₄, filtered, concentrated in vacuo. The residue obtained was purified using flash silica gel chromatography (5% MeOH/DCM) to provide (9H-fluoren-9-yl)methyl 11,11-dimethyl-4,9- dioxo-10-oxa-2,3,5,8-tetraazadodecanoate (iii, 3.7 g, 8.40 mmol) as a solid. LCMS: MS (ESI) m/z: 441.3 [M+H]⁺. Step C – synthesis of compound iv [0280] To a stirred mixture of iii (3.0 g, 6.8 mmol) in DMF (10 mL) was added piperidine (1.0 mL, 10 mmol), and the resulting reaction was allowed to stir at 25 °C for 30 minutes. The reaction mixture was monitored using TLC (DCM:CH3OD = 10: 1). The reaction mixture was concentrated in vacuo, and the resulting residue was purified using silica gel column flash chromatography (eluting with 0-10% MeOH/DCM) to provide tert-butyl (2- (hydrazinecarboxamido)ethyl)carbamate iv (1.10 g, 5.04 mmol) as an oil.¹H NMR (500 MHz, CD3OD) δ = 3.28 - 3.19 (m, 2H), 3.18 - 3.11 (m, 2H), 1.50 - 1.36 (m, 9H) Exchangeable protons not reported. Preparation of Intermediate Compound vi Step A – synthesis of compound vi [0281] To a solution of tert-butyl (4-hydroxybenzyl)carbamate (v, 300 mg, 1.344 mmol) in DCM (10 mL) at 0 °C was added DIEA (0.235 mL, 1.34 mmol), and trichloromethyl chloroformate (0.380 g, 1.92 mmol). The resulting reaction was allowed to stir for 30 minutes at 0 °C and for 2 hours at 20 °C. The reaction mixture was concentrated in vacuo to provide 4- (((tert-butoxycarbonyl)amino)methyl)phenyl carbonochloridate vi (300 mg, 1.050 mmol) which was used without further purification. Preparation of Intermediate Compound x Step A – synthesis of compound viii [0282] To a solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-proline (vii, 3.4 g, 10 mmol), and HATU (3.83 g, 10.1 mmol) in DMF (30 mL) at 0 °C was added a solution of tert-butyl (2- aminoethyl)carbamate (1.61 g, 10.1 mmol), and DIEA (5.28 mL, 30.2 mmol). The mixture was allowed to stir at 0 °C for 4 hours and then at 25 °C for another 17 hours. The crude 9H-fluoren- 9-yl)methyl (S)-2-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl) pyrrolidine-1-carboxylate (viii, 5g, 5.73 mmol) was used directly without further purification. Step B – synthesis of compound ix [0283] To a solution of viii (4.0 g, 8.3 mmol) in DMF (10 mL) was added piperidine (1.0 mL, 8.3 mmol), and the resulting mixture was allowed to stir at 20 °C for 1 hour. The mixture was concentrated in vacuo, and diluted with DCM (10 mL), filtered, and lyophilized to provide crude tert-butyl (S)-(2-(pyrrolidine-2-carboxamido)ethyl)carbamate (ix, 2.4 g, 6.5 mmol) as an oil which was used without further purification. Step C – synthesis of compound x [0284] To a solution of (((9H-fluoren-9-yl)methoxy)carbonyl)glycylglycine (2.70 g, 7.62 mmol), and HATU (4.35 g, 11.4 mmol) in DMF (10 mL) was added ix (1.96 g, 7.62 mmol) followed by DIEA (3.99 mL, 22.9 mmol). The resulting reaction was allowed to stir at 0 °C for 4 hours and then at room temperature for 17 hours, then concentrated in vacuo to provide _{compound x, which was used without further purification. LCMS (ESI) m/z: 616.3 [M+Na} ⁺ _]. Preparation of Intermediate Compound xiv Step A – synthesis of compound xiii [0285] To a stirred mixture of benzyl azetidin-3-ylcarbamate (xi, 500 mg, 2.42 mmol) in DCM (20 mL) was added triethylamine (736 mg, 7.27 mmol), sodium triacetoxyborohydride (771 mg, 3.64 mmol), and tert-butyl 3-formylazetidine-1-carboxylate (xii, 539 mg, 2.91 mmol) at room temperature under argon atmosphere. The resulting mixture was allowed to stir for 16 hours. The reaction mixture was concentrated in vacuo, and the residue obtained was purified using flash silica gel column chromatography (0-100% EtOAc/petroleum ether) to provide tert-butyl 3-((3- (((benzyloxy)carbonyl)amino)azetidin-1-yl)methyl)azetidine-1-carboxylate xiii as an oil. MS: m/z = 376.25 [M+H]⁺. Step B – synthesis of compound xiv [0286] To a stirred mixture of xiii (490 mg, 1.31 mmol) in MeOH (10 mL) was added 10% Pd/C (139 mg, 0.131 mmol) at room temperature under a hydrogen atmosphere. The resulting mixture was allowed to stir for 1 hour, then the reaction mixture was filtered, and washed with MeOH (20 mL). The filtrate was concentrated in vacuo to provide tert-butyl 3-((3- aminoazetidin-1-yl)methyl)azetidine-1-carboxylate xiv as a solid. MS: m/z = 242.25 [M + H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 2H) 3.46 - 3.42 (m, 4H), 2.59 -2.56 (m, 2H), 1.84 (s, 4H), 1.36 (s, 9H). Preparation of Intermediate Compound xviii Step A – synthesis of compound xvi [0287] To a solution of (S)-2-amino-2,3-dimethylbutanoic acid (xv, 400 mg, 3.05 mmol) in THF (10 mL) was added a solution of potassium carbonate (843 mg, 6.10 mmol) in water (5 mL), followed by (9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (1.54 g, 4.57 mmol). The resulting reaction was allowed to stir at 20 °C for 17 hours, then the reaction mixture was concentrated in vacuo, and acidified to pH=2 to form a suspension which was then filtered to provide the compound (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2,3- dimethylbutanoic acid xvi as a solid, which was used without further purification. LCMS (ESI) _{m/z: 354.3 [M+H]} ⁺ _. Step B – synthesis of compound xvii [0288] To a solution of xvi (800 mg, 1.36 mmol) in DMF (5 mL) was added HATU (775 mg, 2.04 mmol) followed by tert-butyl (2-(methylamino)ethyl)carbamate (237 mg, 1.36 mmol), and DIEA (0.712 mL, 4.07 mmol). The reaction mixture was allowed to stir at 20 °C for 1 hour, then concentrated in vacuo. The residue obtained was purified using silica gel column chromatography (eluting with 0 to 50% EtOAc/petroleum ether) to provide (9H-fluoren-9- yl)methyl (S)-(1-((2-((tert-butoxycarbonyl)amino)ethyl)(methyl)amino)-2,3-dimethyl-1- oxobutan-2-yl)carbamate xvii as a solid. LCMS (ESI) m/z: 532.3 [M+Na]⁺. Step C – synthesis of compound xviii [0289] To a solution of xvii (400 mg, 0.785 mmol) in DMF (5 mL) was added piperidine (0.50 mL, 0.79 mmol), and the reaction mixture was allowed to stir at 20 °C for 1 hour. The crude mixture was concentrated in vacuo, and purified using HPLC (Boston Green ODS 150 x 30 mm x 5 um, eluting with 15% to 35% MeCN/water (with 0.5% TFA as modifier)) to provide the compound tert-butyl (S)-(2-(2-amino-N,2,3-trimethylbutanamido)ethyl) carbamate xviii as a solid. LCMS (ESI) m/z: 288.2 [M+H]⁺. Preparation of Intermediate Compound xxiv Step A – synthesis of compound xx [0290] To a stirred mixture of 3-aminopyrrolidin-2-one (xix, 50.0 mg, 0.499 mmol), and Boc2O (0.174 mL, 0.749 mmol) in MeOH (2 mL) was added TEA (0.209 mL, 1.50 mmol), and the resulting reaction was allowed to stir at 70 °C for 16 hours. The reaction was monitored using TLC (DCM:CH3OD = 10:1). The solvent was removed in vacuo, and the resulting residue was purified using flash silica gel chromatography (0-100% EtOAc/Petroleum ether) to provide tert-butyl (2-oxopyrrolidin-3-yl)carbamate xx. MS (ESI) m/z: 201.3 [M+H]⁺ Step B – synthesis of compound xxi [0291] To a stirred suspension of NaH (24 mg, 0.60 mmol) in THF (1 mL) was added xx (100 mg, 0.499 mmol) at 0 °C and the resulting reaction was allowed to stir at 25 °C for 30 minutes under N₂ atmosphere. A solution of 2-bromoacetonitrile (71.9 mg, 0.599 mmol), and TBAI (36.9 mg, 0.100 mmol) in THF (1 mL) was added, and the resulting reaction was allowed to stir at 25 °C for 3 hours. The reaction was monitored using TLC (EtOAc). Water (30 mL) was added, and the resulting solution was extracted with ethyl acetate (100 mL × 2). The combined organic extracts were washed with brine (100 mL × 2), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue obtained was purified using flash silica gel chromatography (0-100% EtOAc/Petroleum) to provide tert-butyl (1-(cyanomethyl)-2-oxopyrrolidin-3-yl)carbamate xxi. Step C – synthesis of compound xxii [0292] To a stirred mixture of xxi (1.3 g, 5.4 mmol) in EtOH (15 mL) was added platinum(IV) oxide (0.247 g, 1.09 mmol), and the resulting reaction was allowed to stir at 25 °C for 16 hours under H2 atmosphere. The reaction was monitored using TLC (EtOAc). The mixture was filtered, and the filter cake was washed with ethanol (10 mL). The filtrate was concentrated in vacuo, and the residue obtained was purified using preparative HPLC (Welch Xtimate C18150 x 25 mm x 5 um, 8 to 100% ACN:water (with TFA as modifier)), and the solution was lyophilized to provide tert-butyl (1-(2-aminoethyl)-2-oxopyrrolidin-3-yl)carbamate xxii. MS (ESI) m/z: 244.2 [M+H]⁺. Step D – synthesis of compound xxiii [0293] To a solution of xxii (400 mg, 1.64 mmol) in DCM (5 mL) was added TFA (1.0 mL, 13 mmol), and the resulting reaction was allowed to stir at 0 °C for 1 hour. The reaction mixture was filtered, concentrated in vacuo, and the residue obtained was lyophilized to provide 3- amino-1-(2-aminoethyl)pyrrolidin-2-one xxiii. LCMS (ESI) m/z: 144.1 [M+H]⁺. Step E – synthesis of compound xxiv [0294] To a solution of xxiii (200 mg, 1.40 mmol) in DCM (10 mL) was added TEA (0.389 mL, 2.79 mmol) followed by Boc2O (0.259 mL, 1.12 mmol) in DCM (10 mL) at 0 °C, then the mixture was allowed to stir at 0 °C for 4 hours. The crude mixture was concentrated in vacuo to provide the crude compound tert-butyl (2-(3-amino-2-oxopyrrolidin-1-yl)ethyl)carbamate xxiv which was used in next step without further purification. LCMS (ESI) m/z: 244.4 [M+H]⁺. Preparation of Intermediate Compound xxvii Step A – synthesis of compound xxvi [0295] To a solution of (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- methylbutanamido)-5-ureidopentanoic acid (xxv, 500 mg, 1.01 mmol) in DMF (5 mL) was added tert-butyl (4-aminobenzyl)carbamate (224 mg, 1.01 mmol), TCFH (339 mg, 1.21 mmol), and 1-methylimidazole (248 mg, 3.02 mmol). The resulting reaction was allowed to stir at 20 °C for 18 hours, then the reaction mixture was concentrated in vacuo. The residue obtained was purified using preparative HPLC (Boston Green ODS 150 x 30 mm x 5 um, eluting with 48% to 78% acetonitrile/ water (with 0.1% TFA as modifier)) to provide (9H-fluoren-9-yl)methyl ((S)- 1-(((S)-1-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2- yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (xxvi). LCMS (ESI) m/z: 701.4 [M+H] ⁺. Step B – synthesis of compound xxvii [0296] To a solution of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(((tert- butoxycarbonyl)amino)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1- oxobutan-2-yl)carbamate (xxvi, 260 mg, 0.371 mmol) in DMF (4 mL) was added piperidine (0.4 mL, 0.4 mmol). The resulting reaction was allowed to stir at 20 °C for 1 hour, then the reaction mixture was concentrated in vacuo to provide compound xxvii, which was used without purification. LCMS (ESI) m/z: 479.3 [M+H⁺]. Preparation of Intermediate Compound xxxi Step A – synthesis of compound xxix [0297] To a solution of ((benzyloxy)carbonyl)-L-valyl-L-alanine (xxviii, 1.0 g, 3.1 mmol) in DMF (5 mL) was added HATU (1.30 g, 3.41 mmol). The mixture was allowed to stir for 5 minutes at room temperature, and tert-butyl (4-aminobenzyl)carbamate (0.690 g, 3.10 mmol) was added. After stirring for another 5 minutes at room temperature, DIEA (1.63 mL, 9.31 mmol) was added, and the reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was purified using preparative HPLC (Boston Uni C18150 x 40 mm x 5 um, eluting with 42% to 72% acetonitrile/water (with 0.1% TFA as modifier)) to provide benzyl ((S)-1-(((S)-1-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)-1-oxopropan-2- yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (xxix). LCMS (ESI) m/z: 527.3 [M+H] ⁺. Step B – synthesis of compound xxx [0298] To a stirred mixture of xxix (550 mg, 1.044 mmol) in trifluoroethanol (15 mL) was added Pd-C (300 mg, 10% Pd), and the resulting reaction was allowed to stir at 25 °C for 18 hours under a hydrogen atmosphere. The mixture was concentrated in vacuo to provide tert- butyl (4-((S)-2-((S)-2-amino-3-methylbutanamido)propanamido)benzyl)carbamate (xxx). LCMS (ESI) m/z: 393.4 [M+H] ⁺ Step C – synthesis of compound xxxi [0299] To a solution of 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid (164 mg, 0.968 mmol) in DMF (4 mL) was added HATU (405 mg, 1.07 mmol). After stirring for 5 minutes, xxx (380 mg, 0.968 mmol), and DIEA (0.507 mL, 2.90 mmol) were added, and the resulting reaction was allowed to stir at 20 °C for 2 hours. The residue obtained was purified using preparative HPLC (Boston Green ODS 150 x 30 mm x 5 um, eluting with 30% to 60% acetonitrile/water (with 0.1% TFA as modifier)) to provide tert-butyl (4-((S)-2-((S)-2-(3-(2,5- dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3- methylbutanamido)propanamido)benzyl)carbamate (xxxi). LCMS (ESI) m/z: 544.3 [M+H] ⁺. [0300] The following intermediate Compound of the Present Disclosure was made using the methods described above, and substituting the appropriate reactants and/or reagents: Preparation of Intermediate Compound xli

Step A – synthesis of compound xxxiv [0301] To a solution of 2-chloro-6-methylnicotinonitrile (xxxiii, 10 g, 66 mmol) in sulfuric acid (70.0 mL, 1310 mmol) was added chromic anhydride (19.7 g, 197 mmol) portionwise over a 2-hour period while the reaction mixture was kept at 0 °C. After stirring at room temperature for 18 hours, the mixture was poured into ice-water, and the resulting solid was collected by filtration to provide the crude 6-chloro-5-(aminocarbonyl)-2-picolinic acid xxxiv. Step B – synthesis of compound xxxv [0302] A mixture of xxxiv was dissolved in POCl3 (50 mL, 536 mmol), and the reaction mixture was heated to 115 °C, and allowed to stir at this temperature for 30 minutes. The mixture was then concentrated in vacuo, and the resulting residue was diluted with ice water. The resulting solution was filtered, and the collected solid was dried to provide 6-chloro-5- cyanopicolinic acid xxxv as a solid. LC/MS: MS (ESI) m/z: 183.2 [M+H]⁺. Step C – synthesis of compound xxxvi [0303] To a stirred mixture of xxxv (5.60 g, 30.7 mmol) in DMF (50 mL) was added sodium methanethiolate (2.15 g, 30.7 mmol). The mixture was allowed to stir at 20 °C for 15 hours. The mixture was concentrated in vacuo, and purified using flash silica gel column chromatography (0-50% MeOH/DCM) to provide 5-cyano-6-(methylthio)picolinic acid xxxvi as a solid. LCMS (ESI) m/z: 195.2 [M+H]⁺. Step D – synthesis of compound xxxvii ^[0304] _{To a stirred mixture of xxxvi (200 mg, 1.03 mmol) in THF (5 mL) was added HATU} (470 mg, 1.24 mmol), DIPEA (0.540 mL, 3.09 mmol), and tert-butyl 3-aminopropanoate (150 mg, 1.03 mmol). The mixture was allowed to stir at 20 °C for 15 hours. The mixture was concentrated in vacuo, and purified using flash silica gel column chromatography (0-100% Petroleum ether/EtOAc) to provide tert-butyl 3-(5-cyano-6-(methylthio)picolinamido)propanoate _{xxxvii as an oil. LCMS (ESI): 266.2 [M-56+H]} ⁺ _. Step E – synthesis of compound xxxviii ^[0305] _{To a stirred mixture of xxxvii (218 mg, 0.678 mmol) in DCM (5 mL) were added m-} CPBA (468 mg, 2.71 mmol). The mixture was allowed to stir at 20 °C for 18 hours. The mixture was concentrated in vacuo, and purified using flash silica gel column chromatography (0-100% petroleum ether/EtOAc) to provide tert-butyl 3-(5-cyano-6- _{(methylsulfonyl)picolinamido)propanoate xxxviii as a solid. LCMS (ESI): 298.2 [M-56+H]} ⁺ _. Step F – synthesis of compound xxxix [0306] A solution of xxxviii (1.2 g, 3.4 mmol) in DCM (18 mL), and TFA (6 mL) was allowed to stir at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to provide 3-(5-cyano-6-(methylsulfonyl)picolinamido)propanoic acid xxxix as a solid which was used without further purification. LCMS (ESI) m/z: 298.2 [M+H]⁺. Step G – synthesis of compound xl [0307] To a stirred mixture of xxxix (300 mg, 1 mmol) in DCM (6 mL) were added EDC (232 mg, 1.21 mmol), and N-hydroxysuccinamide (151 mg, 1.31 mmol). The mixture was allowed to stir at 20 °C for 5 hours. The solution was concentrated to provide 2,5-dioxopyrrolidin-1-yl 3- (5-cyano-6-(methylsulfonyl)picolinamido)propanoate xl as a soild which was used without further purification. LCMS (ESI) m/z: 395.0 [M+H]⁺ . Step H – synthesis of compound xli [0308] To a solution of xl (400 mg, 1 mmol) in DMF (10 mL) was added L-alanyl-L-alanine (179 mg, 1.12 mmol), and TEA (0.566 mL, 4.06 mmol). The resulting reaction was allowed to stir at 25 °C for 2 hours, then the reaction mixture was concentrated in vacuo to provide (methyl (3-(5-cyano-6-(methylsulfonyl)picolinamido)propanoyl)-L-alanyl-L-alaninate xli as a solid which was used without purification. LCMS (ESI) m/z: 440.0 [M+H]⁺. Preparation of Intermediate Compound xlviii

Step A – Synthesis of compound xliii [0309] A solution of 5-bromo-6-hydroxypyridine-3-carboxylic acid (xlii, 600 g, 2.59 mol), and cuprous cyanide (231 g, 2.59 mol) in DMF (3.6 L) was allowed to stir for 12 hours at 125 ^oC under a N2 atmosphere. The reaction mixture was cooled to room temperature and quenched with water (5.0 L). The resultant mixture was filtered and the filter cake was dried under reduced pressure to provide 5-cyano-6-hydroxypyridine-3-carboxylic acid (xliii). LCMS: (ESI, m/z): [M- H]- = 163 Step B – Synthesis of compound xliv [0310] A solution of xliii (600 g, 3.37 mol), and phosphorus oxychloride (1.8 L) was allowed to stir for 1 hour at 110 ^oC. The reaction was monitored using LCMS, and then concentrated in vacuo. The crude product was quenched with water that was pre-cooled to 10°C and the mixture was extracted with EtOAc (3 x 500 mL). The organic layer was washed with brine (500 mL) and dried over sodium sulfate. The mixture was filtered and concentrated in vacuo,and the residue obtained was purified using reverse phase flash chromatography (silica gel, 25% to 100% petroleum ether/EtOAc) to provide 6-chloro-5-cyanopyridine-3-carboxylic acid (xliv). LCMS: (ESI, m/z): [M-H]- = 181 Step C – Synthesis of compound xlv [0311] Into a 500 mL three-necked bottle was added dimethylformamide (115.5 mL), and xliv (7.7 g, 42 mmol) at 25 °C. The reaction was cooled to 10 °C and (Methylsulfanyl)sodium (7.39 g, 105 mmol) was added in portions. The resulting reaction was allowed to stir for 8 hours at 25°C, then the reaction mixture was slowly transferred to H₂O (1200 mL), then extracted with ethyl acetate (1 x 700 mL). The pH value of the aqueous layer was adjusted to 2-3 with 1 M HCl, and the resulting solution was filtered to provide 5-cyano-6-(methylsulfanyl)pyridine-3- carboxylic acid (xlv) as a solid. LCMS: (ESI, m/z): [M-H]- = 193 Step D – Synthesis of compound xlvi [0312] To a solution of xlv (7.4 g, 38 mmol) in DCM (185 mL) was added m-CPBA (26.3 g, 152 mmol), and the resulting reaction was allowed to stir for 24 hours at 45 ^oC under nitrogen atmosphere. The reaction was quenched with saturated sodium bisulfite at 0 °C and concentrated in vacuo. To the resulting residue was added 2-methyltetrahydrofuran, and the t mixture was filtered, and concentrated in vacuo. The residue obtained was purified using silica gel column chromatography (eluting with DCM/MeOH) to provide compound xlvi. LCMS: (ESI, m/z): [M+H]⁺ = 227.05. Step E – Synthesis of compound xlvii [0313] Intermediate xlvi (0.57 g, 2.5 mmol), and HATU (1.0 g, 2.7 mmol) were dissolved in 10 mL DMF and the resulting solution was stirred for 30 minutes at 25 ℃. tert-butyl 3-(5-cyano-6- (methylsulfonyl)nicotinamido)propanoate (0.65 g, 1.8 mmol) was added, and the resulting reaction was cooled to 10 ℃. DIPEA (0.873 mL, 5.00 mmol) was added dropwise into the reaction mixture at 10 ^oC, and the reaction was allowed to stir at 25 ℃ for 2 hours, then diluted with water, and extracted with EtOAc (3 x 10 mL). The combined organic extracts were concentrated in vacuo, and the resulting residue was purified using silica gel column chromatography (eluting with 2:1 to 1:1 hexanes:EtOAc) to provide compound xlvii.¹H NMR (500 MHz, CD₃OD) δ 8.49 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 4.12 (s, 3H), 2.92 (t, J = 6.9 Hz, 2H), 1.88 (t, J = 6.9 Hz, 2H), 0.74 (s, 9H). Step F – Synthesis of compound xlviii [0314] Compound xlvii (80 g, 0.226 mmol) was dissolved in 1,4-dioxane (160 mL), and to the resulting mixture was added a solution of 4 M HCl in 1,4-dioxane (480 mL). The resulting reaction was allowed to stir at 25 ℃ for 12 hours, then the reaction mixture was filtered, and concentrated in vacuo to provide compound xlviii, which was used without further purification. ¹H NMR (500 MHz, CD3OD) δ 9.22 (d, J = 1.9 Hz, 1H), 8.80 (d, J = 1.9 Hz, 1H), 3.66 (t, J = 5.8 Hz, 2H), 3.44 (s, 3H), 2.67 (t, J = 6.8 Hz, 2H). Preparation of Intermediate Compound l Step A – synthesis of compound xlix ^[0315] _{To a stirred mixture of 3-(5-cyano-6-(methylsulfonyl)picolinamido)propanoic acid} (xxxix, 1 g, 3 mmol) in THF (5 mL) was added HATU (1.54 g, 4.04 mmol), DIPEA (1.76 mL, 10.1 mmol), and tert-butyl glycylglycinate (0.633 g, 3.36 mmol). The reaction was allowed to stir at 20 °C for 15 hours, then the reaction mixture was concentrated in vacuo, and the residue obtained was purified using flash silica gel column chromatography (0-100% petroleum ether/EtOAc) to provide tert-butyl (3-(5-cyano-6-(methylsulfonyl)picolinamido) _{propanoyl)glycylglycinate xlix as a solid. LCMS (ESI): 468.2 [M+H]} ⁺ Step B – synthesis of compound l [0316] A solution of xlix (1.2 g, 2.6 mmol) in DCM (18 mL), and TFA (6 mL) was allowed to stir at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to provide (3-(5-cyano-6-(methylsulfonyl)picolinamido)propanoyl)glycylglycine l as a solid, which was used without further purification. LCMS (ESI) m/z: 412.1 [M+H]⁺. Preparation of Intermediate Compound liv Step A – synthesis of compound lii [0317] To a solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-alanyl-L-alanine (li, 1.5 g, 3.9 mmol) in DMF (30 mL) was added HATU (1.49 g, 3.92 mmol), and the resulting solution was allowed to stir for 10 minutes at room temperature. tert-butyl 3-(aminomethyl)azetidine-1- carboxylate (0.80 g, 4.3 mmol) was added, and the reacion was allowed to stir for an additional 10 minutes. DIPEA (2.06 mL, 11.8 mmol) was added, and the reaction was allowed to stir at 20 °C for another 3 hours. The reaction mixture was concentrated in vacuo, and the residue obtained was purified using preparative HPLC (Boston Uni C1840 x 150 x 5 um, eluting with acetonitrile/water (with 0.1% TFA as modifier) from 40% to 70% of acetonitrile) to provide tert- butyl 3-((5S,8S)-1-(9H-fluoren-9-yl)-5,8-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazaundecan-11- yl)azetidine-1-carboxylate (lii). LCMS (ESI) m/z: 551.2 [M+H] ⁺. Step B – synthesis of compound liii [0318] To a solution of lii (2.37 g, 4.30 mmol) in DMF (15 mL), was added piperidine (1.5 mL, 15.15 mmol), and the resulting reaction was allowed to stir at 25 °C for 3 hours. The reaction mixture was dried using lyophilization to provide tert-butyl 3-(((S)-2-((S)-2- aminopropanamido) propanamido)methyl)azetidine-1-carboxylate (liii), which was used without _{further purification. LCMS (ESI): 329.2 [M+H]} ⁺ _. Step C – synthesis of compound liv [0319] To a solution of 3-(5-cyano-6-(methylsulfonyl)picolinamido)propanoic acid (xxxix, 400 mg, 1.35 mmol) in DMF (1.5 mL) was added HATU (767 mg, 2.02 mmol), and DIPEA (0.470 mL, 2.69 mmol), and the reaction was allowed to stir for 10 minutes at room temperature. Compound liii (803 mg, 1.35 mmol) (55%) was added, and the reaction was allowed to stir at 20 °C for an additional 30 minutes. The reaction mixture was concentrated in vacuo, and the residue obtained was purified using preparative HPLC (Boston Uni C1840 x 150 x 5 um, eluting with acetonitrile/water (with 0.1% TFA as modifier) from 15% to 45% acetonitrile) to provide tert-butyl 3-((4S,7S)-13-(5-cyano-6-(methylsulfonyl)pyridin-2-yl)-4,7-dimethyl-3,6,9,13- tetraoxo-2,5,8,12-tetraazatridecyl)azetidine-1-carboxylate (liv). LCMS (ESI): 608.2 [M+H]⁺. [0320] The following intermediate Compounds of the Present Disclosure were made using the methods described above, and substituting the appropriate reactants and/or reagents:

Preparation of Intermediate Compound lxv Step A – synthesis of compound lxiii [0321] To a solution of (3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoyl)-L-alanyl-L- alanine (lxii, 700 mg, 2.25 mmol) in DCM (10 mL), and MeOH (10 mL) was added (4- aminophenyl)methanol (332 mg, 2.70 mmol), followed by EEDQ (834 mg, 3.37 mmol). The resulting reaction was cooled to 20 °C, and allowed to stir at this temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue obtained was purified using silica gel chromatography (0 to 10% MeOH in DCM) to provide 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol- 1-yl)-N-((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1- _{oxopropan-2-yl)propanamide (lxiii). LCMS (ESI) m/z: 439.3 [M+Na]} ⁺ _. Step B – synthesis of compound lxiv [0322] To a solution of lxiii (200 mg, 0.48 mmol) in DMF (5 mL) was added bis(4- nitrophenyl) carbonate (161 mg, 0.528 mmol), and DIEA (0.109 mL, 0.624 mmol), and the resulting reaction was cooled to 20 °C, and allowed to stir at this temperature for 18 hours. The reaction mixture was diluted with water (30 mL), and the resulting solution concentrated using lyophilization to provide 4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanamido)propanamido)propanamido)benzyl (4-nitrophenyl) carbonate (lxiv). LCMS (ESI) m/z: 582.3 [M+H] ⁺. Step C – synthesis of compound lxv [0323] To a solution of lxiv (200 mg, 0.344 mmol) in DMF (5 mL) was added tert-butyl 3- (aminomethyl)azetidine-1-carboxylate (64.1 mg, 0.344 mmol), and the resulting reaction was allowed to stir at 20 °C for 1 hour. The reaction mixture was directly purified using prep-HPLC (Boston Green ODS 150 x 30 mm x 5 um, eluting with 40% to 60% MeCN/water (with 0.01% TFA as modifier)) to provide tert-butyl 3-(((((4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)propanamido)propanamido)propanamido)benzyl)oxy) carbonyl)amino)methyl)azetidine-1-carboxylate (lxv). LCMS (ESI) m/z: 529.3 [M+H⁺-Boc]. Preparation of Intermediate Compound lxxi Step A – synthesis of compound lxvii [0324] To a solution of (4-aminophenyl)methanol (lxvi, 6.44 g, 52.3 mmol) in DCM/MeOH (2:1) (60 mL) was added a stirred mixture of EEDQ (4.85 g, 19.6 mmol), and (((9H-fluoren-9- yl)methoxy)carbonyl)-L-alanyl-L-alanine (5.0 g, 13 mmol) at room temperature. The resulting reaction was allowed to stir at room temperature for 18 hours, then the reaction mixture was concentrated in vacuo. The residue obtained was suspended in TBME (80 mL), and stirred for 30 minutes, then mixture was filtered, and the filter cake was washed with TBME (20 mL). The combined filtrate and washing was concentrated in vacuo to provide (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2- yl)carbamate (lxvii). Step B – synthesis of compound lxviii [0325] DIPEA (0.143 mL, 0.820 mmol) was added to a stirred mixture of bis(4-nitrophenyl) carbonate (0.150 g, 0.492 mmol), and lxvii (0.2 g, 0.410 mmol) in DMF (2 mL) at room temperature, and the resulting reaction was allowed to stir at room temperature for 2 hours. The reaction mixture was poured into H₂O (40 mL), and the resulting mixture was filtered. The filter cake was washed with water (10 mL), then dried under vacuum with toluene to provide (9H- fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy) methyl)phenyl)amino)- 1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (lxviii). LCMS (ESI) m/z: 675.3 [M+H] ⁺. Step C – synthesis of compound lxix [0326] A solution of lxviii (2 g, 3.06 mmol), tert-butyl (2-(hydrazinecarboxamido) ethyl)carbamate (0.803 g, 3.68 mmol), and HOBt (0.141 g, 0.919 mmol) in DMF (20 mL) at room temperature was allowed to stir for 5 minutes. Pyridine (0.496 mL, 6.13 mmol) was added, the resulting reaction was allowed to stir for 18 hours at room temperature, and the reaction mixture was then concentrated in vacuo. The resulting residue was purified using silica gel column flash chromatography (DCM/MeOH 0 to 30%) to provide 4-((S)-2-((S)-2-((((9H- fluoren-9-yl)methoxy)carbonyl)amino)propanamido)propanamido)benzyl 11,11-dimethyl-4,9- dioxo-10-oxa-2,3,5,8-tetraazadodecanoate (lxix). LCMS (ESI) m/z: 732.4 [M+H] ⁺. Step D – synthesis of compound lxx [0327] Diethylamine (0.50 mL, 4.9 mmol) was added to a stirred mixture of lxix (1.1 g, 1.5 mmol) in DMF (10 mL) at room temperature, and the resulting reaction was allowed to stir for 2 hours. The reaction mixture was then concentrated in vacuo to provide 4-((S)-2-((S)-2- aminopropanamido)propanamido)benzyl 11,11-dimethyl-4,9-dioxo-10-oxa-2,3,5,8- tetraazadodecanoate (lxx), which was used without further purification. Step E – synthesis of compound lxxi [0328] DIPEA (0.679 mL, 3.89 mmol) was added to a stirred mixture of 2,5-dioxopyrrolidin-1- yl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoate (414 mg, 1.55 mmol), and lxx (660 mg, 1.30 mmol) in DMF (8 mL) at room temperature, and the resulting reaction was allowed to stir for 2 hours. The reaction mixture was directly purified using preparative HPLC (Boston Uni C1850 x 40 mm x 5 um eluting with 19% to 49% acetonitrile/water (with 0.1% TFA as modifier)), to provide 4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanamido)propanamido)propanamido)benzyl 11,11-dimethyl-4,9-dioxo-10-oxa-2,3,5,8- tetraazadodecanoate (lxxi). LCMS (ESI) m/z: 661.3 [M+H] ⁺. Preparation of Intermediate Compound lxxv Step A – synthesis of compound lxxiii [0329] To a solution of (3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanoyl)glycylglycylglycine (lxxii, 0.50 g, 1.5 mmol) in DMF (5 mL) was added HATU (0.670 g, 1.76 mmol). The resulting solution was allowed to stir for 10 minutes at room temperature, then a solution of tert-butyl methyl(2-(methylamino)ethyl)carbamate (0.304 g, 1.616 mmol) in DMF (0.1 mL) was added, and the resulting reaction was allowed to stir for 10 minutes at room temperature. DIEA (0.770 mL, 4.41 mmol) was added, and the reaction was allowed to stir at room temperature for 1 hour. The reaction mixture was directly purified using reverse-phase HPLC (Boston Green ODS 150 x 30 mm x 5 um, 23% to 53% acetonitrile/water (with 0.1% TFA as modifier)), and concentrated in vacuo to provide tert-butyl (15-(2,5-dioxo- 2,5-dihydro-1H-pyrrol-1-yl)-3-methyl-4,7,10,13-tetraoxo-3,6,9,12- tetraazapentadecyl)(methyl)carbamate (lxxiii, 0.5 g, 0.979 mmol). Step B – synthesis of compound lxxiv [0330] Compound lxxiii (200 mg, 0.392 mmol) was taken up in a 3:1 mixture of DCM:TFA (4 mL), and the solution obtained was allowed stir at 20 °C for 1 hour. The reaction mixture was concentrated in vacuo to provide 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(5-methyl-6,9,12- trioxo-2,5,8,11-tetraazatridecan-13-yl)propanamide (lxxiv), which was used without further purification. Step C – synthesis of compound lxxv [0331] To a solution of lxxiv (100 mg, 0.244 mmol) in DCM (10 mL) was added DIEA (0.032 mL, 0.184 mmol), and 4-(((tert-butoxycarbonyl)amino)methyl)phenyl carbonochloridate (35 mg, 0.12 mmol). The resulting reaction was cooled to 0 °C, and allowed to stir at this temperature for 30 minutes. The reaction mixture was allowed to warm to room temperature, then was allowed to stir for an additional 1 hour. The reaction mixture was concentrated in vacuo, and the residue obtained was purified using reverse phase HPLC (Boston Green ODS 150 x 30 mm x 5 um, 23% to 53% acetonitrile/water (with 0.1% TFA as modifier)), and concentrated to provide 4-(((tert- butoxycarbonyl)amino)methyl)phenyl (15-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3-methyl- 4,7,10,13-tetraoxo-3,6,9,12-tetraazapentadecyl)(methyl) carbamate (lxxv). LCMS (ESI) m/z: 660.3 [M+H] ⁺. Preparation of Intermediate Compound lxxxiv Step A – synthesis of compound lxxvii [0332] To a solution of lxxvi (10 g, 28 mmol) in THF (100 mL) and toluene (40 mL) was added lead tetraacetate (17.5 g, 39.5 mmol) and the resulting reaction was heated to 85 ^oC, and allowed to stir at this temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue obtained was purified using silica gel flash chromatography (EtOAc/petroleum ether 30 to 50 %) to provide lxxvii (11.2 g, 21.3 mmol) as a solid. LCMS (ESI) m/z: 391.2 [M+Na] ⁺. Step B – synthesis of compound lxxviii [0333] To a solution of lxxvii (2.5 g, 6.8 mmol) in DCM (30 mL) was added TFA (1.05 mL, 13.6 mmol) and tert-butyl 2-hydroxyacetate (4.48 g, 33.9 mmol). The resulting reaction was allowed to stir at 25 °C for 18 hours, then the reaction mixture was diluted with sat. aq. NaHCO₃ (10 mL) and extracted with DCM (3 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo, and the resulting residue was purified using silica gel column chromatography (EtOAc/petroleum ether 5 to 9%) to provide lxxviii (1.02 g, 1.852 mmol) as a solid. LCMS (ESI) m/z: 463.1 [M+Na] ⁺. Step C – synthesis of compound lxxix [0334] To a solution of lxxviii (1.5 g, 3.4 mmol) in DCM (9 mL), was added TFA (3.0 mL, 39 mmol), and the resulting reaction was allowed to stir at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to provide lxxix (1.2 g, 2.2 mmol) as an oil which was used without further purification. LCMS (ESI) m/z: 407.1 [M+H⁺]. Step D – synthesis of compound lxxx [0335] To a solution of lxxix (1.0 g, 2.6 mmol) in DMF (10 mL) was added HATU (1.19 g, 3.12 mmol), and the resulting solution was allowed to stir at room tempearature for 5 minutes. tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.671 g, 3.38 mmol) and DIEA (1.36 mL, 7.80 mmol) were added, and the reaction was allowed to stir at 20 °C for 2 hours. The reaction mixture was concentrated in vacuo, and the residue obtained was purified using preparative HPLC (Boston Uni C18150 mm x 40 mm x 5 um, eluting with acetonitrile/water (0.1% TFA) eluting from 37% to 67% at a flow rate of 60 mL/min) to provide lxxx (680 mg, 1.148 mmol) as a solid. LCMS (ESI) m/z: 565.4 [M+H]⁺. Step E – synthesis of compound lxxxi [0336] To a solution of lxxx (370 mg, 0.655 mmol) in DMF (4 mL) was added piperidine (0.40 mL, 0.66 mmol). The resulting reaction was allowed to stir at 20 °C for 1 hour, then the reaction mixture was concentrated in vacuo to provide lxxxi (360 mg, 0.526 mmol) as a solid, which was used without further purification. LCMS (ESI) m/z: 343.2 [M+H]⁺. Step F – synthesis of compound lxxxii [0337] To a solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-phenylalanine (407 mg, 1.05 mmol) in DMF (5 mL) was added HATU (300 mg, 0.789 mmol), and the resulting solution was allowed to stir at room temperature for 5 minutes. Compound lxxvi (360 mg, 0.526 mmol) and DIEA (0.275 mL, 1.58 mmol) were added, and the resulting reaction was allowed to stir at 20 °C for 1 hour. The reaction mixture was directly purified using preparative HPLC (Boston Uni C18 150 mm x 40 mm x 5 um 45% to 75% MeCN/water (0.1% TFA) at a flow rate of 60 mL/min) to provide lxxxii (180 mg, 0.253 mmol) as a solid. LCMS (ESI) m/z: 712.3 [M+H]⁺. Step F – synthesis of compound lxxxiii [0338] To a solution of lxxxii (180 mg, 0.253 mmol) in DMF (2 mL) was added piperidine (0.20 mL, 0.25 mmol). The resulting reaction was allowed to stir at 20 °C for 30 minutes, then the reaction mixture was concentrated in vacuo to provide lxxxiii (150 mg, 0.184 mmol) as a solid, which was used without further purification. LCMS (ESI) m/z: 490.2 [M+H]⁺. Step G – synthesis of compound lxxxiv [0339] To a solution of (3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoyl)glycylglycine (226 mg, 0.797 mmol) in DMF (2 mL) was added HATU (202 mg, 0.531 mmol), and the resulting reaction was allowed to stir at room temperature for 5 minutes. Compound lxxxiii (130 mg, 0.266 mmol) and DIEA (0.139 mL, 0.797 mmol) were added, and the resulting reaction was allowed to stir at 20 °C for 2 hours. The reaction mixture was then concentrated in vacuo, and the residue obtained was purified using preparative HPLC (Boston Prime C18150 mm x 40 mm x 5 um, eluting with MeCN/Water (0.1% TFA) 20% to 40% at a flow rate of 25 mL/min) to provide lxxxiv (80 mg, 0.079 mmol) as a solid. LCMS (ESI) m/z: 755.3 [M+H]⁺. Preparation of Intermediate Compound lxxxvii Step A – synthesis of compound lxxxvi [0340] To a solution of lxxxv (420 mg, 1.02 mmol) in DMF (7 mL) was added HATU (466 mg, 1.23 mmol), and the resulting solution was allowed to stir at room temperature for 5 minutes. tert-Butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (202 mg, 1.02 mmol) and DIEA (0.535 mL, 3.06 mmol) were added, and the resulting reaction was allowed to stir at 20 °C for 2 hours. The reaction mixture was concentrated in vacuo to provide lxxxvi (600 mg, 0.608 mmol) as a solid, which was used without further purification. LCMS (ESI) m/z: 592.3 [M+H]⁺. Step B – synthesis of compound lxxxvii [0341] To a solution of lxxxvi (600 mg, 1.01 mmol) in DMF (6 mL) was added piperidine (0.60 mL, 1.0 mmol), and the resulting reaction was allowed to stir at 20 °C for 1 hour. The reaction mixture was concentrated in vacuo, and the residue obtained was purified using preparative HPLC (Boston Prime C18150 mm x 40 mm x 5 um, eluting with MeCN/water (0.1% TFA) 5% to 35% at a flow rate of 25 mL/min) to provide lxxxvii (400 mg, 0.974 mmol) as a solid. LCMS (ESI) m/z: 370.3 [M+H]⁺. Preparation of Intermediate Compound xciii B H Step A – synthesis of compound lxxxix [0342] To a solution of lxxxviii (3.5 g, 17 mmol) in AcOH (30 mL) was added furan-2,5-dione (1.68 g, 17.1 mmol). The resulting reaction was allowed to stir at 20 °C for 18 hours, then the reaction mixture was concentrated in vacuo to provide lxxxix (5 g, 16.50 mmol) as a solid, which was used without further purification. LCMS (ESI) m/z: 203.2 [M+H-Boc]⁺. Step B – synthesis of compound xc [0343] To a solution of lxxxix (5.0 g, 16 mmol) in toluene (40 mL) was added dimethyl acetamide (2 mL) and triethylamine (6.92 mL, 49.6 mmol). The resulting reaction was heated to 110 °C, and allowed to stir at this temperature for 18 hours, then the reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue obtained was purified using preparative HPLC (Boston Green ODS 150 mm x 30 mm x 5 um eluting with MeCN/water (0.1% TFA) 20% to 40% at a flow rate of 25 mL/min) to provide xc (3.08 g, 7.32 mmol) as a solid. LCMS (ESI) m/z: 229.1 [M+H-56]⁺. Step C – synthesis of compound xci [0344] To a solution of xc (3.08 g, 10.8 mmol) in DCM (15 mL) was added TFA (5.0 mL, 65 mmol) and the resulting reaction was allowed to stir at 25 °C for 3 hours. The reaction mixture was concentrated in vacuo to provide xci (2.4 g) as an oil which was used without further purification. LCMS (ESI) m/z: 185.2 [M+H]⁺. Step D – synthesis of compound xcii [0345] To a solution of xci (0.542 g, 2.94 mmol) in DMF (10 mL) was added 2,5- dioxopyrrolidin-1-yl 2,5,8,11,14,17,20,23-octaoxahexacosan-26-oate (1.5 g, 2.9 mmol) followed by NMM (0.596 g, 5.89 mmol), and the resulting reaction was allowed to stir at 20 °C for 18 hours. The reacopm mixture was directly purified using preparative HPLC (Boston Uni C18150 mm x 40 mm x 5 um eluting with MeCN/water (0.1% TFA) 5% to 35% at a flow rate of 60 mL/min) to provide xcii (730 mg, 1.26 mmol) as an oil. LCMS (ESI) m/z: 579.3 [M+H]⁺. Step E – synthesis of compound xciii [0346] To a solution of xcii (0.20 g, 0.35 mmol) and lxxxvii (0.153 g, 0.415 mmol) in DMF (2 mL) was added NMM (0.105 g, 1.04mmol), at 0 °C, was slowly added HATU (0.131 g, 0.346 mmol). The resulting reaction was allowed to stir at 0 ^oC for 3 hours, then the reaction mixture was concentrated in vacuo. The residue obtained was purified using preparative HPLC (Boston Prime C18150 mm x 40 mm x 5 um, eluting with MeCN/water(0.1% TFA) 15% to 45% at a flow rate of 25 mL/min) to provide xciii (130 mg, 0.119 mmol) as a powder. LCMS (ESI) m/z: 930.7 [M+H]⁺. Preparation of Intermediate Compound xcviii Step A – synthesis of compound xciv [0347] To a solution of ((benzyloxy)carbonyl)glycylglycine (1.0 g, 3.8 mmol) and N- hydroxysuccinimide (0.52 g, 4.5 mmol) in dioxane (7 mL) was slowly added a solution of DCC (0.930 g, 4.51 mmol) in dry dioxane (7 mL). The reaction mixture was allowed to stir at 20 °C for 12 hours, then the reaction mixture was concentrated in vacuo to provide xciv (1.3 g, 2.147 mmol) as a solid, which was used without further purification. LCMS (ESI) m/z: 364.2 [M+H]⁺. Step B – synthesis of compound xcv [0348] A stirred mixture of xciv (1.3 g, 3.6 mmol) and sodium bicarbonate (0.361 g, 4.29 mmol) in water (10 mL) was added to a solution of L-phenylalanylglycine (0.954 g, 4.29 mmol) in dioxane (20 mL). The resulting reaction was allowed to stir at 20 °C for 18 hours, then the reaction mixture was concentrated in vacuo. The resulting residue was purified using preparative HPLC (Boston Uni C18150 mm x 40 mm x 5 um, eluting with acetonitrile/water (0.1% TFA) from 15% to 45% at a flow rate of 60 mL/min) to provide xcv (1.3 g, 2.76 mmol) as a solid. LCMS (ESI) m/z: 471.3 [M+H]⁺. Step C – synthesis of compound xcvi [0349] To a solution of xcv (500 mg, 1.06 mmol) in DMF (7 mL) was added HATU (445 mg, 1.17 mmol), and the resulting solution was allowed to stir for 5 minutes at room temperature. tert-Butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (211 mg, 1.06 mmol) and Hunig’s base (0.557 mL, 3.19 mmol) were added, and the resulting reaction was allowed to stir at 20 °C for 2 hours. The reaction mixture was concentrated in vacuo, and the residue obtained was purified using preparative HPLC (Boston Green ODS 150 mm x 30 mm x 5 um, eluting with acetonitrile/ water (0.1% TFA) from 30% to 60% at a flow rate of 25 mL/min) to provide xcvi (645 mg, 0.991 mmol) as a solid. LCMS (ESI) m/z: 651.3 [M+H]⁺. Step D – synthesis of compound xcvii [0350] To a mixture of xcvi (645 mg, 0.991 mmol) in trifluoroethanol (15 mL) was added 10% Pd/C (300 mg) and the mixture was allowed to stir at 25 °C for 18 hours under 1 atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to provide xcvii (544 mg, 0.769 mmol) as an oil. LCMS (ESI) m/z: 517.3 [M+H]⁺. Step E – synthesis of compound xcviii [0351] To a solution of 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid (49.1 mg, 0.290 mmol) in DMF (2 mL) was added HATU (121 mg, 0.319 mmol), and the resulting solution was allowed to stir at room temperature for 5 minutes. Compound xcvii (150 mg, 0.290 mmol) and Hunig’s base (0.152 mL, 0.871 mmol) were added, and the resulting reaction was allowed to stir at 20 °C for 2 hours, then the reaction mixture was concentrated in vacuo. The residue obtained was purified using preparative HPLC (Boston Green ODS 150 mm x 30 mm x 5 um, eluting with 23% to 53% acetonitrile/water (0.1% TFA) at a flow rate of 25 mL/min) to provide xcviii (70 mg, 0.101 mmol) as a solid. LCMS (ESI) m/z: 668.3 [M+H]⁺. Preparation of Intermediate Compound xcx [0352] To a solution of (8S,10S)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-10- (((1S,3R,4aS,9S,9aR, 10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4',3':4,5]oxazolo[2,3- c][1,4]oxazin-3-yl)oxy)-7,8,9,10-tetrahydrotetracene-5,12-dione (xcix, 200 mg, 0.312 mmol) in methanol (5 mL), and water (5 mL) was added a solution of sodium periodate (80 mg, 0.37 mmol) in water (1 mL), and the resulting reaction was allowed to stir at room temperature for 30 minutes. The solvent was gradually removed from the reaction mixture in vacuo at 25 °C over 18 hours, and the resulting residue xcx was used without further purification. LCMS (ESI) m/z: 628.6 [M+H]⁺. Example 1 Preparation of Linker-Payload 1 Step A – synthesis of compound I-1b [0353] To a stirred solution of L-alanyl-L-alanine (I-1a, 1.00 g, 6.24 mmol), and TEA (1.74 mL, 12.5 mmol) in DCM (2 mL) was added 2,5-dioxopyrrolidin-1-yl 3-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)propanoate (2.09 g, 7.87 mmol) at 25 °C. The mixture was allowed to stir at 25 °C for 18 hours. The mixture was concentrated in vacuo, and purified using prep-HPLC (YMC- Triart Prep C18150 x 40 mm x 7 um, eluting with 7% to 37% acetonitrile/water (with 0.1% TFA as modifier)) to provide (3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoyl)-L-alanyl-L- alanine as solid I-1b. LCMS (ESI) m/z: 312.1 [M+H]⁺. Step B – synthesis of compound I-1c [0354] To a stirred mixture of I-1b (300 mg, 0.964 mmol) in DMF (4 mL) was added HATU (733 mg, 1.93 mmol), and the resulting reaction was allowed to stir at 25 °C for 10 minutes. Then tert-butyl (2-aminoethyl)carbamate (154 mg, 0.964 mmol) in DMF (1 mL), and DIPEA (0.505 mL, 2.89 mmol) were added to the above mixture, and the mixture was allowed to stir at 25 °C for 25 minutes. The solution was purified using Prep-HPLC (Boston Uni C1840 x 150 x 5 um, 8% to 100% acetonitrile/water (with 0.1% TFA as modifier)), and lyophilized to provide tert-butyl (2-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanamido)propanamido)propanamido)ethyl)(methyl)carbamate I-1c as an oil. LCMS (ESI) m/z: 490.0 [M+Na]⁺. Step C – synthesis of compound I-1d [0355] The solution of I-1c (300 mg, 0.642 mmol), and TFA (2 mL, 0.642 mmol) in DCM (6 mL) was allowed to stir at 0 °C for 1 hour. The reaction was monitored using LCMS, and the resulting reaction was concentrated in vacuo at 0 °C to provide the compound 3-(2,5-dioxo-2,5- dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-((2-(methylamino)ethyl)amino)-1-oxopropan-2- yl)amino)-1-oxopropan-2-yl)propanamide I-1d as an oil, which was used in next step without further purification. LCMS (ESI) m/z: 368.0 [M+H]⁺. Step D – synthesis of compound 1 [0356] To a solution of xcx (150 mg, 0.239 mmol) in DMF (2 mL) was added HATU (182 mg, 0.478 mmol). After the reaction mixture was allowed to stir for 10 minutes, I-1d (88 mg, 0.24 mmol) in DMF (0.5 mL) was added, and the resulting reaction was allowed to stir for 10 minutes. DIPEA (0.125 mL, 0.717 mmol) was added, and the reaction mixture was allowed to stir at 20 °C for another 1 hour. The crude mixture was purified using preparative HPLC (YMC- Triart Prep C18150 x 40 mm x 7 um, eluting with 25% to 55% acetonitrile/water (using 7 mM ammonium formate as modifier)) to provide (2S,4S)-N-(2-((S)-2-((S)-2-(3-(2,5-dioxo-2,5- dihydro-1H-pyrrol-1-yl)propanamido)propanamido) propanamido)ethyl)-2,5,12-trihydroxy-7- methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-N-methyl-6,11-dioxo-1,2,3,4,6,11- hexahydrotetracene-2-carboxamide 1 as a solid.¹H NMR (400 MHz, CDCl₃) δ 13.94 (br s, 1H), 13.37 (br s, 1H), 8.03 (d, J=7.58 Hz, 1H), 7.78 (t, J=8.07 Hz, 1H), 7.39 (d, J=8.31 Hz, 1H), 7.00- 7.12 (m, 1H), 6.77 (br d, J=7.34 Hz, 1H), 6.69 (s, 2H), 6.17-6.33 (m, 1H), 5.53 (br s, 1H), 5.27- 5.40 (m, 1H), 4.70 (s, 1H), 4.47 (s, 1H), 4.21-4.44 (m, 2H), 3.99-4.13 (m, 5H), 3.78-3.96 (m, 3H), 3.54-3.72 (m, 2H), 3.36-3.50 (m, 8H), 2.93-3.11 (m, 2H), 2.67-2.85 (m, 2H), 2.30-2.65 (m, 4H), 1.66-1.84 (m, 7H), 1.38 (br d, J=6.36 Hz, 6H), LCMS (ESI) m/z: 977.3 [M+H]⁺. [0357] The following illustrative Linker-Payload Compounds of the Present Disclosure were made using the methods described in Example 1, and substituting the appropriate intermediates, and other reactants and/or reagents:

[0358] The following illustrative Examples of the Present Disclosure were made using the methods described in Example 1 (Steps B, C, and D), and substituting the appropriate intermediates, reactants and/or reagents:

[0359] The following illustrative Examples of the Present Disclosure were made using the methods described in Example 1 (Steps C and D), and substituting the appropriate intermediates, reactants and/or reagents:

[0360] To a solution of Compound 19 (80 mg, 0.058 mmol) in DMF (0.3 mL) was added piperidine (0.010 mL, 0.058 mmol), and the resulting reaction was allowed to stir at 0 °C for 10 minutes. The reaction mixture was purified using preparative HPLC (C18-1150 x 30 mm x 5 um, eluting with 25% to 56% acetonitrile/water (with 8 mM ammonium formate as modifier)) to provide 5-cyano-N-((12S,15S)-12,15-dimethyl-1,11,14,17-tetraoxo-1-((2S,4S)-2,5,12- trihydroxy-7-methoxy-4-(((1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H- pyrano[4',3':4,5]oxazolo[2,3-c][1,4]oxazin-3-yl)oxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen- 2-yl)-2,6,10,13,16-pentaazanonadecan-19-yl)-6-(methylsulfonyl)picolinamide 34 as a solid.¹H NMR (400 MHz, CD3OD) δ = 8.50 (dd, J=8.1, 10.3 Hz, 1H), 8.39 (s, 2H), 8.29 (dd, J=3.8, 8.1 Hz, 1H), 7.88 (dd, J=2.1, 7.4 Hz, 1H), 7.81 - 7.73 (m, 1H), 7.50 (d, J=8.6 Hz, 1H), 5.31 (q, J=5.0 Hz, 1H), 5.14 - 5.06 (m, 1H), 4.59 (s, 1H), 4.31 (s, 1H), 4.16 - 4.03 (m, 3H), 3.96 (s, 4H), 3.77 (td, J=6.1, 11.9 Hz, 1H), 3.63 - 3.55 (m, 2H), 3.47 (br d, J=11.7 Hz, 1H), 3.42 - 3.36 (m, 5H), 3.33 (s, 3H), 3.31 - 3.25 (m, 2H), 3.10 - 2.98 (m, 3H), 2.95 (br d, J=6.9 Hz, 4H), 2.65 (br s, 2H), 2.57 - 2.46 (m, 2H), 2.28 (br s, 2H), 1.93 - 1.77 (m, 5H), 1.77 - 1.58 (m, 2H), 1.31 - 1.20 (m, 9H). LCMS (ESI) m/z: 1162.3 [M+H]⁺. [0361] The following illustrative Linker-Payload Compound of the Present Disclosure was made using the methods described in the Example above, and substituting the appropriate intermediates, reactants and/or reagents: Example 3 Preparation of Linker-Payload Compound 36

Step A – synthesis of compound I-36b [0362] To a solution of (2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetamido)methyl acetate (669 mg, 1.82 mmol)) in DCM (10 mL), was added TFA (0.466 mL, 6.05 mmol), and 3- aminobicyclo[1.1.1]pentan-1-ol (I-36a, 120 mg, 1.21 mmol). The resulting reaction was allowed to stir at 25 °C for 18 hours, then the reaction mixture was concentrated in vacuo, and the residue obtained was purified using preparative HPLC (Boston Prime C18150 mm x 40 mm x 5 um, eluting with 15% to 45% acetonitrile/water (0.1 % TFA) at a flow rate of 25 mL/min) to provide I-36b (230 mg, 0.524 mmol) as a solid. LCMS (ESI) m/z: 408.3 [M+H]⁺. Step B – synthesis of compound I-36c [0363] To a solution of xcx (200 mg, 0.319 mmol) in DMF (4 mL) was added HATU (145 mg, 0.382 mmol), and the resulting solution was allowed to stir at room temperature for 10 minutes. A solution of Compound I-36b (130 mg, 0.319 mmol) in DMF (0.4 mL) was added, the resulting solution was allowed to stir at room temperature for 10 minutes. Hunig’s base (124 mg, 0.956 mmol) was added, and the resulting reaction was allowed to stir at room temperature for 20 minutes. The reaction mixture, which contains compound I-36c (300 mg, 0.147 mmol) in DMF was used without further purification. Step C – synthesis of compound I-36d [0364] To a solution of I-36c (300 mg, 0.147 mmol) in DMF (4.4 mL) was added piperidine (0.4 mL, 4.04 mmol), and the resulting reaction was allowed to stir at 20 °C for 10 minutes. The reaction mixture was directly purified using preparative HPLC (Phenomenex Gemini-NX 150 mm x 30 mm x 5 um; 23% to 53% acetonitrile/water (7 mM HCOONH₄) at a flow rate of 25 mL/min) to provide I-36d (50 mg, 0.057 mmol) as a solid. LCMS (ESI) m/z: 795.5[M+H]⁺. Step D – synthesis of compound 36 [0365] To a solution of (3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoyl)glycylglycine (27 mg, 0.094 mmol) in DMF (0.2 mL) was added HATU (47.8 mg, 0.126 mmol), and the resulting solution was allowed to stir at room temperature for 10 minutes. Compound I-36d (50 mg, 0.063 mmol) was added, the mixture was stirred for 10 minutes at room temperature, then Hunig’s base (0.033 mL, 0.189 mmol) was added, and the resulting reaction was allowed to stir at 25 °C for 30 minutes. The reaction mixture was directly purified using preparative HPLC (Phenomenex Gemini-NX 150 mm x 30 mm x 5 um; 23% to 53% acetonitrile/water (7 mM HCOONH₄) at a flow rate of 25 mL/min) to provide 36 (14.7 mg, 0.014 mmol) as a solid.¹H NMR (400MHz, DMSO-d₆) δ = 8.49 - 8.38 (m, 2H), 8.20 (br s, 1H), 8.06 (br s, 2H), 7.86 (br s, 2H), 7.60 (br s, 1H), 6.93 (s, 2H), 5.31 (br s, 1H), 5.19 (br s, 1H), 4.94 (br s, 1H), 4.51 (br s, 3H), 4.16 (br s, 1H), 4.05 (br s, 1H), 3.93 (br s, 4H), 3.71 - 3.50 (m, 10H), 3.44 (m, 2H), 2.97 - 2.77 (m, 2H), 2.61 (br s, 1H), 2.35 (br s, 4H), 2.28 - 2.18 (m, 3H), 2.06 (br s, 6H), 1.60 (br s, 2H), 1.14 (m, 3H). LCMS (ESI) m/z: 1060.6 [M+H⁺]. Example 4 Antibody Conjugation Protocol to Prepare Antibody-Drug Conjugate Examples 37-68 [0366] Illustrative Linker-Payload Compounds of the Present Disclosure were conjugated to an anti-TROP2 antibody, using the following conjugation protocol: [0367] The antibody (Humanized x [TACSTD2_H] mAb (sacituzumab (S375C)) IgG1 / Kappa) (20 mg) was used as received in Hist (10mM pH 6.5) 9% sucrose. The antibody was diluted to ~7 mg/ml in a 90% buffer / 10% DMSO. A 10 mM solution of linker-payload compound (3.1 eq.) in DMSO was added, and the resulting conjugation reaction was allowed to stir for 2 hours at room temperature. The reaction mixture was then purifiedby exchanging into 10 mM histidine pH 6.5 with a desalting column on a AKTA chromatography system followed by the addition of 9% sucrose. Using this methodology, the following antibody-drug conjugates of the Present Disclosure were made:

Example 5 Antibody Conjugation Protocol to Prepare Antibody-Drug Conjugate Examples 69-70. [0368] Illustrative Linker-Payload Compounds of the Present Disclosure were conjugated to an anti-TROP2 antibody, to provide Antibody-Drug Conjugate Examples 69-71, respectively, using the following conjugation protocol: [0369] The antibody (Humanized x [TACSTD2_H] mAb (sacituzumab (S375C)) IgG1 / Kappa) (20 mg) was exchanged into 40mM Tris-Acetate, 1mM EDTA, pH 8.3. The antibody was diluted to ~10 mg/ml in a 90% buffer / 10% DMF. A 10 mM solution of an illustrative linker-payload compound (5.5 Eq) in DMF was added, and the resulting conjugation reaction was allowed to stir overnight at room temperature. The reaction mixture was then purified using exchanging into 10 mM histidine pH 6.5 with a desalting column on a AKTA chromatography system followed by the addition of 9% sucrose. [0370] Using this methodology, the following antibody-drug conjugates of the prese Using this methodology, the following antibody-drug conjugates of the Present Disclosure were made: Example 6 TROP2 BxPC-3 Cytotoxicity Assay Protocol for Examples 37-41, 43-52, 57-58, and 60-70 [0371] Illustrative TROP2 antibody-drug conjugates of the Present Disclosure (Examples 37- 41, 43-53, 57-58, 60-68) were subjected to a cell-based cytotoxicity assay (BxPC-3 cells, CellTiter-Glo® 2.0 Cytotoxicity Assay) utilizing the following protocol: [0372] BxPC-3 cells were cultured in RPMI 1640 medium (Gibco^TM 72400-047) supplemented with 10% FBS (Gibco^TM 26140-079) on T75 flasks. Cells were washed once with PBS (without calcium or magnesium), then 2 mL of 0.25% Trypsin-EDTA (Thermo Fisher^TM catalog # 25200056) was added, and the flask was incubated at 37 ºC for ~3 minutes. Next 10 mL of cell culture medium was added, and pipetted up and down a few times to dissociate cells. The mixture of cells was transferred to a 15-mL conical tube and centrifuged at 300 g for 5 minutes. The cell pellet was resuspended in 2 mL of cell culture medium, and cells were counted with a Vi-CELL. Cells were seeded onto 96-well plates (Corning^TM catalog # 3904) in 90 µl of cell culture medium per well (3,000 cells per well). After 24 hours, a serial dilution of small molecules and antibody-drug conjugates in cell culture medium was prepared and 10 µL of dilutes was added into each well (total volume is 100 µL per well). Only the inner 60 wells on the plate were used for drug treatment and no-treatment controls. The plates were incubated in a cell culture incubator for 96 hours, then equilibrated at room temperature for approximately 30 minutes. The CellTiter-Glo^TM Buffer was thawed and allowed to equilibrate to room temperature. The appropriate volume of CellTiter-Glo^TM Buffer was transferred into the amber bottle containing CellTiter-Glo^TM Substrate to reconstitute the lyophilized enzyme/substrate mixture (Promega^TM catalog #G7573). Next, 100 µl of CellTiter-Glo^TM Reagent were added to each well, and the contents were mixed for 2 minutes on an orbital shaker to induce cell lysis. The plate was allowed to incubate at room temperature for 10 minutes to stabilize luminescent signal. Luminescence was recorded on PerkinElmer Multimode Plate Reader EnVision^TM. The data was analyzed with GraphPad Prism 8 [four-parameter non-linear regression, y=Bottom + (Top-Bottom)/(1+(IC50/x)^HillSlope)]. [0373] Illustrative Examples of the Present Disclosure were tested, and results are provided below: Example 7 TROP2 BxPC-3 Cytotoxicity Assay Protocol for Examples 42, 54, and 59 [0374] Illustrative TROP2 antibody-drug conjugates of the Present Disclosure (Examples 31, 41, and 46) were subjected to a cell-based cytotoxicity assay (BxPC-3 cells, CellTiter-Glo® 2.0 Cytotoxicity Assay) utilizing the following protocol: Step 1: Seed 384-well Plates for Assay (45 μL per well) on day 0 [0375] BxPC-3 cells (in sample vials) were quickly thawed in a cryo-vial by incubation in a 37°C water bath for <1 min until only a small bit of ice was left in the sample vial. The vial was removed from the water bath and wiped down with 70% ethanol. The cells were transferred from the vial to a sterile centrifuge tube containing 8 mL of pre-warmed cell culture medium (RPMI- 1640 (Cat#30-2001) + 10% FBS + 1% P/S). The vial was flushed with an additional 1 mL of medium to ensure complete transfer of cells to the centrifuge tube. The cells were then centrifuged (150 x g) for 5 minutes. The supernatant was aspirated, and the cell pellet was resuspended in 10-20 mL cell culture medium (RPMI-1640 (Cat#30-2001) + 10% FBS + 1% P/S). Cells were counted using Vi-cell and prepared 1500 cells/well (in 45 μL of media). Then 45μL/well of cells were put into Corning® 384-well Low Flange White Flat Bottom Polystyrene TC-treated Microplates (Corning, Cat#3570) using Standard Cassette Combi. The plates were spun down in a centrifuge (150 x g) for 30 seconds. Step 2: Add antibody-drug conjugates on day 1 [0376] Centrifuge tubes containing the illustrative antibody-drug conjugate, and reference stock, were taken out and allowed to thaw at room temperature. The tubes were then centrifuged (2000 x g) for 30 seconds.10X Intermediate assay plates (Waters plate, Cat# 186002632) were prepared using a Bravo liquid handler, using proper buffer (10mM pH 6.5 histidine 9% sucrose buffer) to make serial dilutions. Media (no cells) was used for Max_E. Then 5 μL of 10X stock from the intermediate plate were added to an assay plate using a Bravo liquid handler (employing a very slow speed so as not to disturb the cell monolayer). The plates were then spun down in a centrifuge (150 x g) for 30 seconds. Step 3: CellTiter-Glo 2.0 Assay (Promega, Cat#G9242) on day 5 (TROP2) [0377] CellTiter-Glo^TM 2.0 Reagent was thawed at 4°C overnight (the reagent was not exposed to temperatures above 25 °C during this time). The kit was equilibrated to room temperature for 30 minutes, then 20μl of CellTiter-Glo^TM 2.0 Reagent was added to 50 μl of medium containing cells using Standard Cassette Combi. The contents were mixed for 2-3 minutes on an orbital shaker to induce cell lysis, and the plates were spun down (150 x g) for 30 seconds. The plates were then allowed to incubate at room temperature for 5 minutes to stabilize the luminescent signal. The luminescence was recorded to calculate an EC50 value, using an integration time of 0.25–1 second per well as a guideline. [0378] Illustrative Examples of the Present Disclosure were tested, and results are provided below:

Claims

WHAT IS CLAIMED: 1. A compound having a structural Formula I: and pharmaceutically acceptable salts thereof, wherein: R¹ is selected from -X-Y-Z-R³, when R² is H or C₁-C₆ alkyl; R² is H or C1-C6 alkyl, or R¹ and R² join to form a 4 to 6-membered monocyclic heterocycloalkylene group, or a 5 to 11-membered bicyclic spirocyclic heterocycloalkylene group, each of which is substituted on a ring carbon atom with -X-Y-Z-R³; R³ is selected from: , , , and X is selected from –(CH2)n-N(R⁴)-, -R⁵-N(R⁴)-, -(CH2)n-N(R⁴)-C(O)R⁵-, -(CH2)n-N(R⁴)- (C₁-C₆ alkylene)-N(R⁴)-, 5 or 6-membered monocyclic heterocycloalkylene, –(CH₂)_n-R⁵-N(R⁴)-, 5 to 11-membered bicyclic spirocyclic heterocycloalkylene, –(CH2)n-R⁵-, –(CH2)n-R⁵- N(R⁴)C(O)O-(CH₂)_nR⁵-N(R⁴)-, -(CH₂)_n-NHC(O)O-(CH₂)_n-R⁵-N(R⁴)-, –(CH₂)_n-R⁵-O-C(O)- N(R⁴)-(C1-C6 alkylene)-N(R⁴)-, -R⁵-NHC(O)CH2OCH2N(R⁴)C(O)CH2N(R⁴)-, -(CH2)n-

N(R⁴)C(O)NH-N(R⁴)-, -R⁵-N(R⁴)C(O)CH₂N(R⁴)-, –(CH₂)_n-N(R⁴)-(CH₂)_n-N(R⁴)-, and -R⁵-O- CH2N(R⁴)-; Y is a bond or -C(O)C(R⁴)(R⁶)NH-; Z is -C(O)CH(R⁷)NHC(O)CH(R⁸)NH-; R⁴ is H, C_1-6 alkyl, or R⁵ is selected from C₆-C₁₀ arylene,

4 to 6-membered monocyclic heterocycloalkylene, 5 to 11-membered bicyclic spirocyclic heterocycloalkylene, C3-C7 monocyclic cycloalkylene, C5- C₁₁ bridged bicyclic cycloalkylene, -NH-NH-, and -NHC(O)NH-, wherein said 4 to 6-membered monocyclic heterocycloalkylene can be optionally substituted on a ring carbon atom with an oxo group; R⁶, R⁷ and R⁸ are each independently selected from H, -CH2CH2CH2NHC(O)NH2, benzyl, and a naturally occurring amino acid side chain; R⁹ is -CH2NHC(O)-(CH2CH2O)q-CH3; m is 0, 1, or 2; each occurrence of n is independently an integer from 0 to 4; and q is selected from 4, 8, 10, and 12. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is: . 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is: or 4. The compound according to claim 2 or 3, wherein m is 1.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R¹ is -X-Y-Z-R³, and R² is H or C1-C6 alkyl.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² join to form a 4 to 6-membered monocyclic heterocycloalkylene group, or a 5 to 11-membered bicyclic spirocyclic heterocycloalkylene group, each of which is substituted on a ring carbon atom with -X-Y-Z-R³.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R² is H.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein X is 5 or 6-membered monocyclic heterocycloalkylene or 5 to 11-membered bicyclic spirocyclic heterocycloalkylene.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, X is selected from -(CH2)n-N(R⁴)-, -R⁵-N(R⁴)-, -(CH2)n-N(R⁴)-C(O)R⁵-, -(CH2)n-N(R⁴)- (C₁-C₆ alkylene)-N(R⁴)-, -(CH₂)_n-R⁵-N(R⁴)-, -(CH₂)_n-R⁵-, -(CH₂)_n-R⁵-NHC(O)O-(CH₂)_nR⁵- N(R⁴)-, -(CH2)n-NHC(O)O-(CH2)n-R⁵-N(R⁴)-, -(CH2)n-R⁵-O-C(O)-N(R⁴)-(C1-C6 alkylene)- N(R⁴)-, R⁵-NHC(O)CH₂OCH₂N(R⁴)C(O)CH₂N(R⁴)-, -(CH₂)_n-N(R⁴)C(O)NH-N(R⁴)-, -R⁵- N(R⁴)C(O)CH2N(R⁴)-, –(CH2)n-N(R⁴)-CH2-N(R⁴)-, and -R⁵-O-CH2N(R⁴)-; each occurrence of R⁴ is independently H, methyl, or Fmoc; and each occurrence of R⁵ is independently selected from -NH-NH-, -NHC(O)NH,

.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein Y is a bond.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein Y is -C(O)C(R⁴)(R⁶)NH-, wherein R⁶ is H, benzyl, or isopropyl, and R⁴ is H or methyl.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)CH(R⁷)NHC(O)CH(R⁸)NH-, and R⁷ and R⁸ are each independently selected from H, methyl, isopropyl, and -CH₂CH₂CH₂NHC(O)NH₂.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein the group -X-Y-Z-R³ is selected from: , ,

, ,

, , , and .

14. A compound, or a pharmaceutically acceptable salt thereof, selected from:

and

15. An antibody-drug conjugate having a structural Formula (XXIII): (XXIII) or a pharmaceutically acceptable salt thereof, wherein: L is an antibody; R² is H or C1-C6 alkyl; R^3’ is selected from: , and ; wherein ** indicates the point of attachment of R^3’ to L; X is selected from –(CH2)n-N(R⁴)-, -R⁵-N(R⁴)-, -(CH2)n-N(R⁴)-C(O)R⁵-, -(CH2)n-N(R⁴)- (C₁-C₆ alkylene)-N(R⁴)-, 5 or 6-membered monocyclic heterocycloalkylene, –(CH₂)_n-R⁵-N(R⁴)-, 5 to 11-membered bicyclic spirocyclic heterocycloalkylene, –(CH2)n-R⁵-, –(CH2)n-R⁵- N(R⁴)C(O)O-(CH₂)_nR⁵-N(R⁴)-, -(CH₂)_n-NHC(O)O-(CH₂)_n-R⁵-N(R⁴)-, –(CH₂)_n-R⁵-O-C(O)- N(R⁴)-(C1-C6 alkylene)-N(R⁴)-, -R⁵-NHC(O)CH2OCH2N(R⁴)C(O) CH2N(R⁴)-, -(CH2)n- N(R⁴)C(O)NH-N(R⁴)-, -R⁵-N(R⁴)C(O)CH₂N(R⁴)-, –(CH₂)_n-N(R⁴)-CH₂-N(R⁴)-, and -R⁵-O- CH2N(R⁴)-; Y is a bond or -C(O)C(R⁴)(R⁶)NH-; Z is -C(O)CH(R⁷)NHC(O)CH(R⁸)NH-; R⁴ is H, C_1-6 alkyl, or R⁵ is selected from C₆-C₁₀ arylene, 4 to 6-membered monocyclic heterocycloalkylene, 5 to 11-membered bicyclic spirocyclic heterocycloalkylene, C3-C7 monocyclic cycloalkylene, C5- C₁₁ bridged bicyclic cycloalkylene, -NH-NH-, and -NHC(O)NH-, wherein said 4 to 6-membered monocyclic heterocycloalkylene can be optionally substituted on a ring carbon atom with an oxo group; R⁶, R⁷ and R⁸ are each independently selected from H, -CH2CH2CH2NHC(O)NH2, benzyl, and a naturally occurring amino acid side chain; R⁹ is -CH2NHC(O)-(CH2CH2O)q-CH3; m is 0, 1, or 2; each occurrence of n is independently an integer from 0 to 4; and q is selected from 4, 8, 10, and 12.

16. An antibody-drug conjugate having a structural Formula (XXIV): or a pharmaceutically acceptable salt thereof, wherein: A is 4 to 6-membered monocyclic heterocycloalkylene or 5 to 11-membered bicyclic spirocyclic heterocycloalkylene; L is an antibody; R^3’ is selected from: , and wherein ** indicates the point of attachment of R^3’ to L; X is selected from –(CH2)n-N(R⁴)-, -R⁵-N(R⁴)-, -(CH2)n-N(R⁴)-C(O)R⁵-, -(CH2)n-N(R⁴)- (C₁-C₆ alkylene)-N(R⁴)-, 5 or 6-membered monocyclic heterocycloalkylene, –(CH₂)_n-R⁵-N(R⁴)-, 5 to 11-membered bicyclic spirocyclic heterocycloalkylene, –(CH2)n-R⁵-, –(CH2)n-R⁵- N(R⁴)C(O)O-(CH2)nR⁵-N(R⁴)-, -(CH2)n-NHC(O)O-(CH2)n-R⁵-N(R⁴)-, –(CH2)n-R⁵-O-C(O)- N(R⁴)-(C1-C6 alkylene)-N(R⁴)-, -R⁵-NHC(O)CH2OCH2N(R⁴)C(O)CH2N(R⁴)-, -(CH2)n- N(R⁴)C(O)NH-N(R⁴)-, -R⁵-N(R⁴)C(O)CH2N(R⁴)-, –(CH2)n-N(R⁴)-CH2-N(R⁴)-, and -R⁵-O- CH₂N(R⁴)-; Y is a bond or -C(O)C(R⁴)(R⁶)NH-; Z is -C(O)CH(R⁷)NHC(O)CH(R⁸)NH-; R⁴ is H, C1-6 alkyl, or ; R⁵ is selected from C₆-C₁₀ arylene, 4 to 6-membered monocyclic heterocycloalkylene, 5 to 11-membered bicyclic spirocyclic heterocycloalkylene, C3-C7 monocyclic cycloalkylene, C5- C₁₁ bridged bicyclic cycloalkylene, -NH-NH-, and -NHC(O)NH-, wherein said 4 to 6-membered monocyclic heterocycloalkylene can be optionally substituted on a ring carbon atom with an oxo group; R⁶, R⁷ and R⁸ are each independently selected from H, -CH₂CH₂CH₂NHC(O)NH_2, benzyl, and a naturally occurring amino acid side chain; R⁹ is -CH₂NHC(O)-(CH₂CH₂O)_q-CH₃; m is 0, 1, or 2; each occurrence of n is independently an integer from 0 to 4; and q is selected from 4, 8, 10, and 12.

17. The antibody-drug conjugate of claim 15, which is selected from: , and

or a pharmaceutically acceptable salt thereof, wherein: X is selected from –(CH₂)_n-N(R⁴)-, -R⁵-N(R⁴)-, -(CH₂)_n-N(R⁴)-C(O)R⁵-, -(CH₂)_n-N(R⁴)- (C1-C6 alkylene)-N(R⁴)-, 5 or 6-membered monocyclic heterocycloalkylene, –(CH2)n-R⁵-N(R⁴)-, 5 to 11-membered bicyclic spirocyclic heterocycloalkylene, –(CH₂)_n-R⁵-, –(CH₂)_n-R⁵- N(R⁴)C(O)O-(CH2)nR⁵-N(R⁴)-, -(CH2)n-NHC(O)O-(CH2)n-R⁵-N(R⁴)-, –(CH2)n-R⁵-O-C(O)- N(R⁴)-(C₁-C₆ alkylene)-N(R⁴)-, -R⁵-NHC(O)CH₂OCH₂N(R⁴)C(O)CH₂N(R⁴)-, -(CH₂)_n- N(R⁴)C(O)NH-N(R⁴)-, -R⁵-N(R⁴)C(O)CH2N(R⁴)-, –(CH2)n-N(R⁴)-CH2-N(R⁴)-, and -R⁵-O- CH₂N(R⁴)-; Y is a bond or -C(O)C(R⁴)(R⁶)NH-; Z is -C(O)CH(R⁷)NHC(O)CH(R⁸)NH-; R⁴ is H, C_1-6 alkyl, or ; R⁵ is selected from C6-C10 arylene, 4 to 6-membered monocyclic heterocycloalkylene, 5 to 11-membered bicyclic spirocyclic heterocycloalkylene, C₃-C₇ monocyclic cycloalkylene, C₅- C11 bridged bicyclic cycloalkylene, -NH-NH-, and -NHC(O)NH-, wherein said 4 to 6-membered monocyclic heterocycloalkylene can be optionally substituted on a ring carbon atom with an oxo group; R⁶, R⁷ and R⁸ are each independently selected from H, -CH₂CH₂CH₂NHC(O)NH_2, benzyl, and a naturally occurring amino acid side chain; R⁹ is -CH2NHC(O)-(CH2CH2O)q-CH3; m is 0, 1, or 2; each occurrence of n is independently an integer from 0 to 4; and q is selected from 4, 8, 10, and 12.

18. The antibody-drug conjugate of claim 16, which is selected from:

or a pharmaceutically acceptable salt thereof, wherein: A is 4 to 6-membered monocyclic heterocycloalkylene or 5 to 11-membered bicyclic spirocyclic heterocycloalkylene; X is selected from –(CH2)n-N(R⁴)-, -R⁵-N(R⁴)-, -(CH2)n-N(R⁴)-C(O)R⁵-, -(CH2)n-N(R⁴)- (C₁-C₆ alkylene)-N(R⁴)-, 5 or 6-membered monocyclic heterocycloalkylene, –(CH₂)_n-R⁵-N(R⁴)-, 5 to 11-membered bicyclic spirocyclic heterocycloalkylene, –(CH2)n-R⁵-, (CH2)n-R⁵- N(R⁴)C(O)O-(CH₂)_nR⁵-N(R⁴)-, -(CH₂)_n-NHC(O)O-(CH₂)_n-R⁵-N(R⁴)-, –(CH₂)_n-R⁵-O-C(O)- N(R⁴)-(C1-C6 alkylene)-N(R⁴)-, -R⁵-NHC(O)CH2OCH2N(R⁴)C(O)CH2N(R⁴)-, -(CH2)n- N(R⁴)C(O)NH-N(R⁴)-, -R⁵-N(R⁴)C(O)CH₂N(R⁴)-, –(CH₂)_n-N(R⁴)-CH₂-N(R⁴)-, and -R⁵-O- CH2N(R⁴)-; Y is a bond or -C(O)CH(R⁷)NH-; Z is -C(O)CH(R⁶)NHC(O)CH(R⁷)NH-; R² is H or C1-C6 alkyl; R⁴ is H or C1-6 alkyl; R⁵ is selected from C6-C10 arylene, 4 to 6-membered monocyclic heterocycloalkylene, C₃-C₇ monocyclic cycloalkylene, C₅-C₁₁ bridged bicyclic cycloalkylene, -NH-NH-, and - NHC(O)NH-; R⁶, R⁷ and R⁸ are each independently selected from H, -CH₂CH₂CH₂NHC(O)NH_2, benzyl, and a naturally occurring amino acid side chain; R⁹ is -CH₂NHC(O)-(CH₂CH₂O)_q-CH₃; m is 0, 1, or 2; each occurrence of n is independently an integer from 0 to 4; and q is selected from 4, 8, 10, and 12.

19. The antibody-drug conjugate of any of claims 15-18, wherein L is an antibody.

20. A linker-payload compound comprising: (i) a payload that is a compound of formula (XXII): or a pharmaceutically acceptable salt thereof, wherein: R^1’ is H or C_1-6 alkyl; R^2’ is a linker chosen from linkers L-1 to L-12; alternatively, R¹ and R², taken together with the common nitrogen atom to which they are each attached, join to form: (i) a 3 to 7-membered monocyclic heterocycloalkyl group, (ii) a 5 to 11-membered bridged bicyclic heterocycloalkyl group, (iii) a 5 to 11-membered fused bicyclic heterocycloalkyl group, or (iv) a 5 to 11-membered spirocyclic heterocycloalkyl group, wherein said 3 to 7-membered monocyclic heterocycloalkyl group, said 5 to 11-membered bicyclic heterocycloalkyl group, said 5 to 11-membered fused heterocycloalkyl group, and said 5 to 11- membered spirocyclic heterocycloalkyl group can each be optionally and independently substituted with one or more R^A groups, and wherein a linker chosen from linkers L-1 to L-12 attaches to a ring atom of (i), (ii), (iii), or (iv); each occurrence of R^A is independently selected from C1-6 alkyl, halo, -CN, -OR³, - N(R³)₂, C₁-C₆ aminoalkyl, -(C₁-C₆ alkylene)-NHC(O)-(C₁-C₆ aminoalkyl), -O-(C_1-6 alkyl), - NHC(O)CH2OH, and -(C1-C6 alkylene)-(3 to 7-membered monocyclic heterocycloalkyl), wherein a 3 to 7-membered monocyclic heterocycloalkyl group can be optionally and independently substituted with one or more R^B groups; and each occurrence of R^B is independently selected from C1-6 alkyl, halo, -CN, -OR³, - N(R³)₂, C₁-C₆ aminoalkyl, -O-(C_1-6 alkyl), -NHC(O)-(C₁-C₆ aminoalkyl), -(C₁-C₆ alkylene)- NHC(O)-(C1-C6 aminoalkyl), C1-6 alkyl, halo, -CN, -OR³, -N(R³)2, -O-(C1-6 alkyl), and -NHC(O)CH₂OH; and Ĩii) a linker that is selected from the following:

and wherein said linker joins to the R² group of said payload, and the point of attachment on the linker is denoted by .

21. A linker-payload compound having a formula selected from:

or a pharmaceutically acceptable salt thereof, wherein D is a payload that is selected from anticancer agents.

22. A pharmaceutical composition comprising: (a) an antibody-drug conjugate of any of claims 15-19, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier.

23. Use of: (a) an antibody-drug conjugate of any of claims 15-19, or a pharmaceutically acceptable salt thereof, or (b) the pharmaceutical composition of claim 22, for the manufacture of a medicament for the treatment or prevention of cancers or tumors.

24. A method of treating or preventing a cancer selected from breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, stomach cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer (for example, small cell lung cancer and non-small cell lung cancer) colon cancer, rectal cancer, colorectal cancer, leukemia (for example, acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, pancreatic cancer, and lymphoma (for example, Hodgkin’s lymphoma, non- Hodgkin’s lymphoma, or recurrent anaplastic large cell lymphoma) in a subject in need thereof, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of: (a) an antibody-drug conjugate of any of claims 15-19, or a pharmaceutically acceptable salt thereof, or (b) a pharmaceutical composition of claim 22.