Taxane-derived linker-payloads and uses thereof

Abstract

The present disclosure is directed to linker-payload compounds, and pharmaceutically acceptable salts, solvates, or stereoisomer thereof, comprising a structure of formula (I) 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 using the antibody-drug conjugates for the treatment of cancer.

Description

TAXANE-DERIVED LINKER-PAYLOADS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Patent Application Serial No. 63 / 725,240 filed November 26, 2024, the entire contents of which are incorporated by reference herein.FIELD OF THE DISCLOSURE

[0002] The present disclosure provides Linker-Payload Compounds which comprise a novel linker and a cytotoxic 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] The taxanes are a class of anticancer drugs that act by binding to tubulins / microtubules, which have a key role in cell division. The binding of taxanes to |3-tubulin promotes the assembly of microtubules and simultaneously inhibits disassembly, thereby stabilizing microtubule dynamics. Suppression of microtubule dynamics results in the blockade of cell mitosis, leading to apoptosis. Paclitaxel, a diterpenoid natural product, was discovered by Wall and Wani as the primary active component in extracts from the bark of the T. brevifolia Nutt. The chemical structure of paclitaxel was established in 1971. Injectable paclitaxel (Taxol) was approved by the US Food and Drug Administration (FDA) for the treatment of refractory ovarian cancer in 1992. refractory or anthracyclme-resistant breast cancer in 1994, Kaposi’s sarcoma in 1997, and non small cell lung cancer in 1998. Docetaxel (Taxotere), a semisynthetic analog of paclitaxel, exhibited excellent efficacy, better than paclitaxel in some cases. Docetaxel was approved by the FDA for the treatment of advanced breast cancer in 1996, non small cell lung cancer (NSCLC) in 1999, metastatic hormone-refractory prostate cancer (HRPC) in 2004, and head and neck cancer in 2006. Cabazitaxel, a member of the taxane class of drugs, was approved by the US Food and Drug Administration (FDA) for the treatment of hormone-refractory prostate cancer in 2010.

[0004] Antibody-drug conjugates represent an innovative therapeutic application that combines the unique, high speci ficity. properties, and anti-tumor activity of monoclonal antibodies (mAbs) that are tumor-specific but not sufficiently cytotoxic, with the potent cell-killing activity ofhighly 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):(I)or a pharmaceutically acceptable salt thereof,wherein:

[0008] D is selected from:or a taxane derivative;

[0009] A is selected from a bond, -(C(O)N(R9))r-, -(C(O)N(R9)CH2N(R9))-, - CH2CH2(OCH2CH2)rC(O)NH-, -(OCH2CH2)rC(O)NH-, -C(O)NH-(OCH2CH2).-CH2CH2-C(O)NH-, and -NHC(O)C(R8)2C(O)NH-;

[0010] X is a bond, or -(O-P(O)(OH)-O)r-;

[0011] each occurrence of Y is independently selected from -CH(R4)-, -CH(R4)-CH(R4)-, and -CH(R4)-CH(R4)-CH(R4)-, wherein R4can be the same or different when Y is -CH(R4)-CH(R4)-or -CH(R4)-CH(R4)-CH(R4)-;

[0012] Z is -CH(R2)- or -CH2CH2-;

[0013] R1is Br or maleimide or a bond;

[0014] R2is selected from H, Ci-Ce alky l, benzyl, -(Ci-Cs alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)S-CH3, -(CI-CS alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-NHC(O)-(CH2CH2O)s-(Ci-C3 alkylene)n-R7, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C3 alkylene)-R5, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C6alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkydene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), -(C1-C3 alkylene)-NHC(0)-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), and

[0015] R3is selected from H, Ci-Ce alky l, benzyl, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C4 alkylene)-NHC(O)-(6-membered monocyclic saccharide), — (Ci-C3 alkylene)-R5, -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-NHC(O)-(CH2CH2O)s-(Ci-C6alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH. -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-CH2CH2-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-(C1-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkyl ene)n-C(O)NH- (CH2CH2O)s-(Ci-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-Ce alkyl), and

[0016] each occurrence of R4is independently selected from H, Ci-Ce alkyl, benzyl, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C3 alkylene)-R3, -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6alkyl), -(C1-C3 alkylene)-NH-C(O)NH2, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, and

[0017] R5is selected from -OH, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), - NHC(O)NH2, -C(O)OH, -C(O)O-benzyl, -C(O)NH2, -C(O)NHCH2(CH(OH))tCH2OH. -C(O)NHCH2CH2N(CH3)2and -C(O)NHCH2CH2N+(CH3)3;

[0018] R7is selected from H, 5 or 6-membered heteroaryl.

[0019] wherein said 5 or 6-membered hctcroaryl group can be optionally substituted with a 6-membered monocyclic saccharide, and wherein said 6-membered monocyclic saccharide group can be optionally substituted with another 6-membered monocyclic saccharide, which can be the same or different;

[0020] each occurrence of R8is independently H or Ci-Ce alkyl, or both R8groups, together with the carbon atom to which they are attached, join to form a C3-C6 cycloalkyl group;

[0021] each occurrence of R9is independently H or Ci-Ce alkyl;

[0022] m is an integer from 0 to 2;

[0023] each occurrence of n is independently 0 or 1;

[0024] q is an integer from 0 to 6;

[0025] each occurrence of r is an integer from 1 to 3;

[0026] each occurrence of s is independently an integer from 1 to 20; and

[0027] each occurrence of t is independently an integer from 1 to 4.

[0028] The Compounds of Formula (I), or a pharmaceutically acceptable salt 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 by disrupting microtubule function.

[0029] 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). Further details are set forth in the accompanying detailed description below.

[0030] 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

[0031] This disclosure is directed to a class of Linker-Payload Compounds (the “Linker-Payload Compounds of the Present Disclosure”), wherein the linker structures contain a maleimide or bromo conjugation handle attached to a peptide linker, with variation on the amino acid sequence and the optional incorporation of PEG, saccharide, and polyol units and terminating with a connection to a cytotoxic 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 moi eties of the Linker-Payload Compounds.

[0032] 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 "alky l" applies to "alkyl" as well as the "alkyl" portions of "hydroxy alkyl," "haloalkyl," " -Ci-alky 1," etc.

[0033] As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the meanings set forth below'.

[0034] The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notw ithstanding 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 chemicalname 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.

[0035] As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0036] 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 anti cancer agent can be a hormone.

[0037] 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 1-99 and 199-203, as well as Linker-Payload Compounds comprising: (i) a Linker selected from the linkers numbered L-l through L-101, 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 100-198 and 204-208, which are collectively referred to herein as the “ADCs of the Present Disclosure.”

[0038] A “patient” is a human or non-human mammal. In one embodiment, a patient is a human.

[0039] 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.

[0040] The term “preventing,” as used herein with respect to a cellular proliferative disorder, refers to reducing the likelihood of a cellular proliferative disorder.

[0041] 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 used26113herein 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.

[0042] 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 plurality of ADC molecules. For a composition comprising an ADC of the Present Disclosure, the DAR for the composition is the average number of linker / drug moieties of all of the individual antibodydrug 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 10, 0 to 9, 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, 6 to 9, and 7 to 10. 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. 6 to 8, 7 to 9, and 8 to 10. 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, 7 to 8, 8 to 9, and 9 to 10. The term “composition” as used above, is understood to encompass pharmaceutical compositions.

[0043] 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 alkyd group contains from 1 to 10 carbon atoms (“Ci-Cio alkyl”) or from about 1 to about 6 carbon atoms (“Ci-Ce 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 may7be26113unsubstituted 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.

[0044] 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. Nonlimiting 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.

[0045] 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. Nonlimiting examples of alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. An alky nyl 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)-cycloalky 1, -C(O)OH and -C(O)O-alkyl. The term “C2-C10 alky nyl” refers to an alkynyl group having from 2 to 10 carbon atoms. Unless otherwise indicated, an alkynyl group is unsubstituted.

[0046] 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 “Ci-Ce alkylene” refers to an alkylene group having from 1 to 6 carbon atoms.

[0047] 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 alky lene 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.

[0048] 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 alky nylene group has from 2 to about 6 carbon atoms. In another embodiment, an alky nylene 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 alky nylene group having from 2 to 10 carbon atoms.

[0049] The term "aminoalkyl," as used herein, refers to an alkyl group as defined above, wherein one of the alky l group’s hydrogen atoms has been replaced with -NH2, -NH(CI-C6 alkyl), or -N(Ci-Ce 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 “Ci-Ce aminoalkyl” refers to an aminoalkyl group having from 1 to 6 carbon atoms.

[0050] 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 biologicalactivity 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 t pe (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.

[0051] The term "aryl," as used herein, refers to an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an aryl group contains from about 6 to about 10 carbon atoms (“Ce-Cio aryl”). An ar l 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 is phenyl. In another embodiment, an aryl group is napthalene. Unless otherwise indicated, an aryl group is unsubstituted.

[0052] 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:

[0053] 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 anyproduct 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 earner. 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.

[0054] 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 cycloalkyds include 1-decalinyl, norbomyl and adamantyl. A cycloalkyd 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 cycloalkyd group is unsubstituted. The term “3 to 7-membered monocyclic cycloalk d” refers to a monocyclic cycloalkyd 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.

[0055] 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 cycloalkyd group can be a spirocyclic cycloalkyd group having from 5 to 11 ring carbon atoms (“C5-C11 spirocyclic cycloalky d”). Illustrative examples of such a bicyclic cycloalkyl group include:

[0056] 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:

[0057] 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:

[0058] 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:

[0059] 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 cycloalkydene”). 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 cycloalky denes include the following:

[0060] 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.

[0061] 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:■r, and

[0062] 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,

[0063] 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. Nonlimiting 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.

[0064] The term ‘‘halo,” as used herein, means -F, -Cl, -Br or -I.26113

[0065] 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, -CH2CI and -CCh. The term “Ci-C6haloalkyl” refers to a haloalkyl group having from 1 to 6 carbon atoms.

[0066] 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 haloalky lene 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, -CH2CI and -CCh. The term ‘" Ci-Ce haloalkylene” refers to a haloalky lene group having from 1 to 6 carbon atoms.

[0067] 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 hydroxyalk l 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.

[0068] 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 0’9 or 10-membered bicyclic heteroaryl”). A heteroar l 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 any26113nitrogen 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 heleroar ls 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[l,2-a]pyridinyl, imidazo[2,l-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.

[0069] The term "heterocycloalkyl," as used herein, refers to a non-aromatic saturated monocyclic or multi cyclic 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,26113thiazolidinyL 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:

[0070] 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:H

[0071] A ring sulfur atom of a heterocycloalkyl group may also be functionalized as a sulfonyl group. An example of such a heterocycloalkyl group is:

[0072] In one embodiment, a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered monocyclic heterocycloalkyl.

[0073] 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 heterocycloalk l group can be a bicyclic spirocyclic heteroaryl group having from 1 to 11 ring atoms. Illustrative examples of such a bicyclic heterocycloalkyl group include:26113

[0074] In another embodiment, a heterocycloalkyl group can be a fused bicyclic heterocycloalkyl group having from 5 to 11 ring atoms (“5 to II -membered fused bicyclic heterocycloalkyl”). Illustrative examples of such a fused bicyclic heterocycloalkyl group include:

[0075] 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 heterocycloalky l group include:Art /

[0076] 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 heterocycloalky lene”). 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 heterocycloalky dene groups include:26113

[0077] 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:x-ZZ7

[0078] 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:HN—1-AZ

[0079] 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:< A / VandHi

[0080] 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 a26113carbonyl 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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).

[0085] Examples of "ring system substituents" include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl,-alkylene-heteroaryl,-alkenylene-26113heteroaryl, -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)2-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 Y1and Y2can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkyl ene-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:

[0086] When any substituent or variable (e.g., R\ 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.

[0087] As used herein, the term “composition’7is 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.

[0088] 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 lead26113to subtle or dramatic changes in potency, solubility, lack of off-target activity, packaging properties, and so on. (Diass, J. O. et al. Organometallics (2006) 25:1188-1198; Showell, G. A. et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558).

[0089] 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.

[0090] 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.

[0091] Pharmaceutically acceptable esters of the present compounds include the follow ing 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), aralky l (e g., benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (e.g., phenyl optionally substituted with, for example, halogen, Ci-4alkyl, -O-(Ci-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 (Cs-24)acyl glycerol.

[0092] One or more Compounds of the Present Disclosure may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as w ater, 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 of26113isolation, 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. Nonlimiting examples of solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate wherein the solvent molecule is water.

[0093] 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 PharmSciTech, 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).

[0094] 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.

[0095] Exemplary acid addition salts include acetates, ammonium, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates (also know n 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. 2ndRevised 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) 33 201-217; 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 their26113website). These disclosures are incorporated herein by reference thereto. In one embodiment, an acid salt is an ammonium salt or a di-ammonium salt.

[0096] 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 nitrogencontaining groups may be quartemized 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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 purecompounds 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.The following abbreviations are used below and have the following meanings:Ac AcylAcOH Acetic acidCTX CabazitaxelDap Diaminopropionic acidDAR Drug-to-antibody ratioDCM DichloromethaneDIPEA N. N-DiisopropylethylamineDMF DimethylformamideDMSO Dimethyl sulfoxideDTX Docetaxeleq. Equivalent(s)ESI Electrospray IonizationEtOAc Ethyl acetateEDTA Ethylenediaminetetraacetic acidFmoc Fluorenylmethyloxycarbonyl(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) HATUhr, h Hour(s)’H-WIR Proton nuclear magnetic resonanceHC1 Hydrochloric acidHPLC High performance liquid chromatographyLCMS Liquid chromatography-mass spectrometrya human prostate carcinoma cell line derived from a metastatic LNCap prostate cancer patient's lymph nodemAb Monoclonal antibodyParent mass minus cabazitaxel (fragmentation at hemiaminal M-CTX RHN-CH2— O-CTX bond)Parent mass minus two cabazitaxels (fragmentation at both M-2CTX hemiaminal RHN-CH2— O-CTX bonds)MgSO4Magnesium Sulfatemin Minute(s)MeCN AcetonitrileMeOH MethanolMS Mass spectrometrym / z Mass to charge ratioNaCl Sodium chlorideNa2SO4Sodium sulfateNHS N-hydroxysuccinimidePTX PaclitaxelPBS Phosphate-buffered salinePd PalladiumPd / C Palladium on carbonPEG Polyethylene glycolPolyethylene glycol moiety consisting of 3 ethylene glycol PEG3 groupsPSMA Prostate-specific membrane antigenRT Room temperatureTFA Trifluoroacetic acidTHF TetrahydrofuranTRIS TRIS-buffered salineThe Compounds of the Present Disclosure

[0110] Described are novel linker-payload compounds (the Compounds of Formula (I)) comprising a cytotoxic payload. The Compounds of Formula (I) are useful as a component of an antibody-drug conjugate, which is useful for the treatment and prevention of cancer. In addition, described herein are linker compounds which are useful as a component of an antibody-drug conjugate. Also described are antibody-drug conjugates comprising a Compound of Formula (I).26113compositions 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

[0111] In one aspect, the present disclosure provides Linker-Payload Compounds of Formula (I), or a pharmaceutically acceptable salt thereof, which comprise a cytotoxic payload, and a cleavable linker:or a pharmaceutically acceptable salt thereof,wherein A, D, X, Y, Z, R, R1, R3, R9, m and q are defined above for the Compounds of Formula (I).

[0112] In one embodiment, the Compounds of Formula (I) have the Formula (I’):(I’)or a pharmaceutically acceptable salt thereof,wherein:A is -C(O)NH-, -CH2CH2(OCH2CH2)rC(O)NH-, -(OCH2CH2)rC(O)NH-, -C(O)NH-(OCH2CH2)r-CH2CH2-C(O)NH-, or -NHC(O)C(R8)2C(O)NH<26113each occurrence of Y is independently selected from -CH(R4)-. -CH(R4)-CH(R4)-, and -CH(R4)-CH(R4)-CH(R4)-, wherein R4can be the same or different when Y is -CH(R4)-CH(R4)-or -CH(R4)-CH(R4)-CH(R4)-;Z is -CH(R2)- or -CH2CH2-;R1is Br or maleimide;R2is selected from H, Ci-Ce alkyl, benzyl, -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)S-CH3, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-NHC(O)-(CH2CH2O)s-(Ci-C3 alkylene)n-R7, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C3 alkylene)-R5, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), -(C1-C3 alkylene)-NHC(O)-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), andR3is selected fromH, Ci-Ce alkyl, benzyl. -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C4 alkylene)-NHC(O)-(6-membered monocyclic saccharide), -(Ci-C3 alkylene)-R5, -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-NHC(O)-(CH2CH2O)8-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-CH2CH2-C(O)NHCH2(CH(OH))tCH2OH, -(C 1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-(C1-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)n-C(O)NH- (CH2CH2O)s-(Ci-C3alkylene)-26113C(O)NH-R7. -(C1-C3 alkylene)-C(O)NH-(Ci-C? alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-Ce alkyl), andeach occurrence of R4is independently selected from H, Ci-Ce alkyl, benzyl, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C3 alkylene)-R3, -(C1-C3 alkydene)n-NHC(O)-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C6alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C3alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), -(C1-C3 alkylene)-NH-C(O)NH2, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, and

[0113] R5is selected from -OH, -(C1-C3 alkylene)-O-(6-membered monocyclic saccharide), - NHC(O)NH2, -C(O)OH, -C(O)O-benzyl, -C(O)NH2, -C(O)NHCH2(CH(OH))tCH2OH. -C(O)NHCH2CH2N(CH3)2and -C(O)NHCH2CH2N (CH3)3;R7is selected from H, 5 or 6-membered heteroaryl,26113NHHOwherein said 5 or 6-membered heteroaryl group can be optionally substituted with a 6-membered monocyclic saccharide, and wherein said 6-membered monocyclic saccharide group can be optionally substituted with another 6-membered monocyclic saccharide, which can be the same or different;each occurrence of R8is independently selected from H or Ci-Ce alkyl, or both R8groups, together with the carbon atom to which they are attached, join to form a C3-C6 cycloalkyl group;m is an integer from 0 to 2;each occurrence of n is independently 0 or 1;q is an integer from 1 to 4;r is an integer from 1 to 3;each occurrence of s is independently an integer from 1 to 20; andeach occurrence of t is independently an integer from 1 to 4.

[0114] In one embodiment, A is -C(O)NH-.

[0115] In another embodiment, A is a bond.26113

[0116] In still another embodiment, A is -(C(O)N(R9))r-.

[0117] In another embodiment, A is -(C(O)N(R9)CH2N(R9))-.

[0118] In another embodiment, A is (C(O)N(CH3)CH2N(CH3))-.

[0119] In another embodiment, A is -CH2CH2(OCH2CH2)rC(O)NH-.

[0120] In yet another embodiment, A is -CH2CH2(OCH2CH2)2C(O)NH-.

[0121] In another embodiment, A is -NHC(O)C(R8)2C(O)NH-.

[0122] In a further embodiment, A is:O O

[0123] In one embodiment, D is:

[0125] In another embodiment, D is:26113

[0126] In still another embodiment, D is:

[0127] In a further embodiment, D is a taxane derivative.

[0128] In one embodiment, each occurrence of Y is -CH(R4)-.

[0129] In another embodiment, at least one occurrence of Y is -CH2CH2-.

[0130] In another embodiment, R is CH3.

[0131] n one embodiment, R1is maleimide.

[0132] In one embodiment, R1is Br.

[0133] In one embodiment, X is a bond.

[0134] In another embodiment, X is -(O-P(O)(OH)-O)r-.

[0135] In one embodiment, Z is -CH(R2)-.

[0136] In another embodiment, Z is -CH2CH2-.

[0137] In another embodiment, Z is -CH2-.

[0138] In still another embodiment, R1is Br, and Z is -CH2-.

[0139] In a further embodiment, R1is Br, Z is -CH(R2)-, and R2is selected from H,26113

[0140] In one embodiment, R3is selected from -CH3, -CH2OH,26113

[0141] In another embodiment, each occurrence of R4is independently selected from H, methyl, isopropyl, benzyl, -CH2COOH, -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2, -(CH2)3NHC(O)NH2. -CH2CH2C(O)NHCH2CH2N+(CH3)3,and

[0142] In one embodiment, m is 0.

[0143] In another embodiment, m is 1.

[0144] In another embodiment, m is 2.

[0145] In one embodiment, q is 0.

[0146] In another embodiment, q is 1.

[0147] In another embodiment, q is 2.

[0148] In still another embodiment, q is 3.

[0149] In another embodiment, q is 4.

[0150] In yet another embodiment, q is 5.

[0151] In still another embodiment, q is 6.

[0152] In another embodiment, r is 1.

[0153] In another embodiment, r is 2.

[0154] In still another embodiment, r is 3.

[0155] In one embodiment, at least one occurrence of s is 4.

[0156] In another embodiment, at least once occurrence of s is 8.

[0157] In another embodiment, at least one occurrence of s is 12.

[0158] In still another embodiment, at least one occurrence of s is 16.26113

[0159] In a further embodiment, each occurrence of s is independently selected from 8. 12 or 16.

[0160] In one embodiment, each occurrence of t is 4.

[0161] In one embodiment, the Compound of Formula (I) is a Compound of Formula (la):qor a pharmaceutically acceptable salt thereof, wherein A, D, X, Y, Z, R3, m and q are defined above for the Compounds of Formula (I).

[0162] In another embodiment, the Compound of Formula (I) is a Compound of Formula (lb):(lb)or a pharmaceutically acceptable salt thereof, wherein A, D, X, Y, Z, R3, m and q are defined above for the Compounds of Formula (I).

[0163] In one embodiment, for the compounds of formula (lb), Z is -CH2-.

[0164] In one embodiment, the Compound of Formula (la) is a Compound of Formula (la'):HO.O26113or a pharmaceutically acceptable salt thereof, wherein A, Y, Z, R3, m and q are defined above for the Compounds of Formula (I).

[0165] In another embodiment, the Compound of Formula (lb) is a Compound of Formula (Ib‘):(lb )or a pharmaceutically acceptable salt thereof, wherein A, Y, Z, R3, m and q are defined above for the Compounds of Formula (I).

[0166] In one embodiment, for the compounds of formula (lb’ ), Z is -CH2-.

[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-l through L-101), where the point of attachment of the Linker to the oxygen of the payload is denoted by:2611326113L-60 / H H II £ H IIHrj* ° Y OH° OH O^N 5 H^ / 6OHY0H—0H>o 5x< )b°TA T ° zi ^ / op / =i’ 0b / °°s'""IL-7 J \ / \ C D 3> c 3 O D o b iz o b iz^o=T T'b C>O 0 O O'' o o o oO O O O 1ZI ZI °o o o o (K ° °=o o o o >\,9 o"",;. „? A A S AA-'- o o o o o o ' ka=H< s ° or' Y° «^ o o 0 o 00 IZ’Y’V' ' o IZL-80 o o o ouIZ / \ _ p\ _ O O O x » \( o o= ZI(ZT- O \'- / ■ / / ' IZinJ Z IZz“W< o ZI L-9;zo zL- 10L- 11 / X0H fl fl Y H fl H 5 T - N ^ N Y i N Y O 0 / ■H H0 \Ho( OH OH I1 JL. OH YO^N Y )T °NH2HOH OH26113261132611326113261132611326113261132611326113261132611326113261132611326113

[0168] In one embodiment, the present disclosure provides linker-payload compounds comprising a linker moiety that is selected from L-1 through L-101, which is conjugated to an anticancer agent having a reactive -OH group.

[0169] In one embodiment, the present disclosure provides linker-payload compounds comprising a linker moiety that is selected from from L-1 through L-101. which is conjugated to an cytotoxic payload, which is a naturally-occurring taxane (e.g., taxotere, docetaxel, cabazitaxel, etc.) or ataxane derivative (i.e., a natural or synthetic derivative or analog of taxotere, docetaxel, or cabazitaxel).

[0170] In one embodiment, the Linker-Payload Compound of the Present Disclosure is in substantially purified form.

[0171] Non-limiting examples of the Linker-Payload Compounds of Formula (I) include Examples 1-99 and 199-203, or a pharmaceutically acceptable salt thereof.26113261132611326113261132611326113261132611326113261132611326113261132611326113261132611326113261132611326113Antibody-Drug Conjugates of the Present Disclosure

[0172] 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 “ADC(s) of the Present Disclosure”), which comprise a Linker-Payload of the Present Disclosure, joined to a ligand (e.g., an antibody).

[0173] Thus, an embodiment of the present disclosure is represented by an antibody-drug conjugate having a structural Formula (II):26113(II)or a pharmaceutically acceptable salt thereof,whereinL is a ligand;D is selected from:or a taxane derivative;

[0174] A is selected from a bond, -(C(O)N(R9))r-. -CH2CH2(OCH2CH2)rC(O)NH-. - (OCH2CH2)rC(O)NH-, -C(O)NH-(OCH2CH2)r-CH2CH2-C(O)NH-, and -NHC(O)C(R8)2C(O)NH-X is a bond, or -(O-P(O)(OH)-O)r-;26113each occurrence of Y is independently selected from -CH(R4)-, -CH(R4)-CH(R4)-, and -CH(R4)-CH(R4)-CH(R4)-, wherein R4can be the same or different when Y is -CH(R4)-CH(R4)-or -CH(R4)-CH(R4)-CH(R4)-;Z is -CH(R2)- or -CH2CH2-;R2is selected fromH, Ci-Ce alkyl, benzyl. -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)S-CH3, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-NHC(O)-(CH2CH2O)s-(Ci-C alkylene)n-R7, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C3 alkylene)-R5, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n- C(O)NH-CH2CH2-(CH2CH2O)s-(Ci-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci- C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), -(C1-C3 alkylene)-NHC(O)-(C 1-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), andR3is selected fromH, Ci-Ce alkyl, benzyl. -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C4 alkylene)-NHC(O)-(6-membered monocyclic saccharide), -(Ci-C3 alkylene)-R5, -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-NHC(O)-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-CH2CH2-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-(C1-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)n-C(O)NH- (CH2CH2O)S-(CI-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(C1-C6 alky l), and26113oeach occurrence of R4is independently selected from H, Ci-Cs alkyl, benzyl, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C3 alkylene)-R5, -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C3alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), -(C1-C3 alkylene)-NH-C(O)NH2, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, andR3is selected from -OH, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -NHC(O)NH2, -C(O)OH, -C(O)O-benzyl, -C(O)NH2, -C(O)NHCH2(CH(OH))tCH2OH, -C(O)NHCH2CH2N(CH3)2and -C(O)NHCH2CH2N+(CH3)3;R7is selected from H, 5 or 6-membered heteroaryl,26113wherein said 5 or 6-membered heteroaryl group can be optionally substituted with a 6-membered monocyclic saccharide, and wherein said 6-membered monocyclic saccharide group can be optionally substituted with another 6-membered monocyclic saccharide, which can be the same or different;each occurrence of R8is independently H or Ci-Ce alkyl, or both R8groups, together with the carbon atom to which they are attached, join to form a Ca-Ce cycloalkyl group; each occurrence of R9is independently H or Ci-Ce alkyl;m is an integer from 0 to 2;each occurrence of n is independently 0 or 1;p is an integer from 1 to 10;q is an integer from 0 to 6;each occurrence of r is an integer from 1 to 3;each occurrence of s is independently an integer from 1 to 20; andeach occurrence of t is independently an integer from 1 to 4.26113

[0175] In one embodiment, p is an integer from 1 to 8.

[0176] Another embodiment of the present disclosure is represented by an antibody-drug conjugate having a structural Formula (III):(III)or a pharmaceutically acceptable salt thereof,whereinL is a ligand;D is selected from:A is selected from a bond, -(C(O)N(R9))r-, -CH2CH2(OCH2CH2)rC(O)NH-, -(OCH2CH2)rC(O)NH-, -C(O)NH-(OCH2CH2)r-CH2CH2-C(O)NH-, and -NHC(O)C(R8)2C(O)NH-X is a bond, or -(O-P(O)(OH)-O)r-;26113each occurrence of Y is independently selected from -CH(R4)-, -CH(R4)-CH(R4)-, and -CH(R4)-CH(R4)-CH(R4)-, wherein R4can be the same or different when Y is -CH(R4)-CH(R4)-or -CH(R4)-CH(R4)-CH(R4)-;Z is -CH(R2)- or -CH2CH2-;R2is selected fromH, Ci-Ce alkyl, benzyl. -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)S-CH3, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-NHC(O)-(CH2CH2O)s-(Ci-C alkylene)n-R7, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C3 alkylene)-R5, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n- C(O)NH-CH2CH2-(CH2CH2O)s-(Ci-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci- C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), -(C1-C3 alkylene)-NHC(O)-(C 1-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), andR3is selected fromH, Ci-Ce alkyl, benzyl. -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C4 alkylene)-NHC(O)-(6-membered monocyclic saccharide), -(Ci-C3 alkylene)-R5, -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-NHC(O)-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-CH2CH2-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-(C1-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)n-C(O)NH- (CH2CH2O)S-(CI-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(C1-C6 alky l), and26113each occurrence of R4is independently selected from H, Ci-Ce alkyl, benzyl, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C3 alkylene)-R5, -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-(Ci-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6alkyl), -(C1-C3 alkylene)-NH-C(O)NH2, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, andR3is selected from -OH, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -NHC(O)NH2, -C(O)OH, -C(O)O-benzyl, -C(O)NH2, -C(O)NHCH2(CH(OH))tCH2OH, -C(O)NHCH2CH2N(CH3)2and -C(O)NHCH2CH2N+(CH3)3;R7is selected from H, 5 or 6-membered heteroaryl,26113wherein said 5 or 6-membered heteroaryl group can be optionally substituted with a 6-membered monocyclic saccharide, and wherein said 6-membered monocyclic saccharide group can be optionally substituted with another 6-membered monocyclic saccharide, which can be the same or different;each occurrence of R8is independently H or Ci-Ce alkyl, or both R8groups, together with the carbon atom to which they are attached, join to form a Ca-Ce cycloalkyl group; each occurrence of R9is independently H or Ci-Ce alkyl;m is an integer from 0 to 2;each occurrence of n is independently 0 or 1;p is an integer from 1 to 10;q is an integer from 0 to 6;each occurrence of r is an integer from 1 to 3;each occurrence of s is independently an integer from 1 to 20; andeach occurrence of t is independently an integer from 1 to 4.26113

[0177] In one embodiment, p is an integer from 1 to 8.

[0178] In one embodiment, the Compounds of Formula (II) have the structural Formula (Ila):or a pharmaceutically acceptable salt thereof,whereinA, Y, Z, R3, m, and q are as described herein for the Compounds of Formula (I); L is a ligand; andp is an integer from 1 to 10.

[0179] In one embodiment, p is an integer from 1 to 8.

[0180] In one embodiment, the Compounds of Formula (III) have the structural Formula (Illa):(Illa)wherein26113A, Y, Z, R3, m, and q are as described herein for the Compounds of Formula (I); L is a ligand; andp is an integer from 1 to 10.

[0181] In one embodiment, Z is -CH2-.

[0182] In another embodiment, p is an integer from 1 to 8.

[0183] In another embodiment, the ADC of the Present Disclosure is in substantially purified form.

[0184] Non-limiting examples of the ADCs of the Present Disclosure include Examples 1 GO- 198 and 204-208, or a pharmaceutically acceptable salt thereof, wherein L is the antibody Rosopatamab or Pelgifatamab (a humanized anti-PSMA IgGl monoclonal antibody), p is an integer from 1 to 8, and the linker / payload moiety, and point of attachment of the antibody (Ab) to the linker / payload moiety, is as indicated in the table below:Example Linker / Payload Point of Ab Example Linker / Payload Point of Ab No. moiety Attachment No. moiety Attachment to linker to linker 100 1 maleimide 156 57 maleimide 101 2 maleimide 157 58 maleimide 102 3 maleimide 158 59 maleimide 103 4 maleimide 159 60 maleimide 104 5 maleimide 160 61 maleimide 105 6 maleimide 161 62 maleimide 106 7 maleimide 162 63 maleimide 107 8 maleimide 163 64 maleimide 108 9 maleimide 164 65 maleimide 109 10 maleimide 165 66 maleimide 110 11 maleimide 166 67 maleimide 111 12 maleimide 167 68 maleimide 112 13 maleimide 168 69 maleimide 113 14 maleimide 169 70 maleimide 114 15 displacement of Br 170 71 maleimide group115 16 maleimide 171 72 maleimide 116 17 maleimide 172 73 maleimide 117 18 displacement of Br 173 74 maleimide group118 19 maleimide 174 75 maleimide 119 20 maleimide 175 76 maleimide 120 21 displacement of Br 176 77 maleimide group121 22 maleimide 177 78 maleimide122 23 maleimide 178 79 maleimide26113123 24 displacement of Br 179 80 maleimide group124 25 maleimide 180 81 maleimide 125 26 displacement of Br 181 82 maleimide group126 27 displacement of Br 182 83 maleimide group127 28 maleimide 183 84 maleimide 128 29 maleimide 184 85 maleimide 129 30 maleimide 185 86 maleimide 130 31 maleimide 186 87 maleimide 131 32 maleimide 187 88 maleimide 132 33 displacement of Br 188 89 displacement of Br group group 133 34 maleimide 189 90 maleimide 134 35 maleimide 190 91 maleimide 135 36 maleimide 191 92 displacement of Br group 136 37 maleimide 192 93 maleimide 137 38 maleimide 193 94 maleimide 138 39 maleimide 194 95 maleimide 139 40 maleimide 195 96 displacement of Br group 140 41 maleimide 196 97 maleimide 141 42 maleimide 197 98 displacement of Br group 142 43 maleimide 198 99 displacement of Br group 143 44 maleimide 204 199 maleimide 144 45 maleimide 205 200 maleimide 145 46 maleimide 206 201 maleimide 146 47 maleimide 207 202 maleimide 147 48 a to Br group 208 203 maleimide 148 49 maleimide149 50 a to Br group150 51 maleimide151 52 maleimide152 53 maleimide153 54 maleimide154 55 maleimide155 56 maleimide

[0185] 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.26113(c) The pharmaceutical composition of (a), further comprising a second therapeutic agent selected from the group consisting of anti cancer agents.(d) The pharmaceutical composition of (b), wherein the anticancer agent is an antihuman 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 subj ect 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).

[0186] 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 be26113employed in combination with one or more additional therapeutic agents selected from anticancer agents.

[0187] 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

[0188] 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 sulfonesubstituted pyridyl group on the linker.

[0189] 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. In one embodiment, the ligand is an antibody. In another embodiment, the ligand is a monoclonal antibody.

[0190] 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 grow th factors (“TGF”), such as TGF-a and TGF-β vaccinia growth factor (‘" VGF”), insulin and insulinlike grow th factors I and II, somatostatin, lectins and apoprotein from low density lipoprotein.

[0191] 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 immunized26113animals. 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.

[0192] 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.

[0193] 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.

[0194] 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 know n 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.26113

[0195] 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.

[0196] 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.

[0197] 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 DisclosureAs Intermediates for the Synthesis of ADCs

[0198] 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.

[0199] 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.26113For the Treatment and Prevention of Cancer

[0200] 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.

[0201] 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.

[0202] 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

[0203] Combinations with additional therapeutic agents are also contemplated in the instant methods. For example, combinations of the ADCs of the Present Disclosure with PPAR-y (i.e., PPAR-gamma) agonists and PPAR-5 (i.e., PPAR-delta) agonists are useful in the treatment of certain malignancies. PPAR-y and PPAR-8 are the nuclear peroxisome proliferator-activated26113receptors y and 5. PPAR-y 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-y agonists and PPAR- y / a agonists include, but are not limited to, thiazohdinediones (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-l,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.

[0204] Another embodiment of the instant disclosure is the use of the ADCs 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 Grow th and Dissemination in Mice," Gene Therapy. August 1998; 5(8): 1105-13), and interferon gamma (J. Immunol. 2000; 164:217-222).

[0205] The ADCs of the Present Disclosure may also be administered in combination with an inhibitor of inherent multi drug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins. Such MDR inhibitors include inhibitors of p-gly coprotein (P-gp), such as LY335979, XR9576, OC144-093. R101922, VX853 and PSC833 (valspodar), or a pharmaceutically acceptable salt thereof.

[0206] The ADCs of the Present Disclosure may also be administered with an immunologicenhancing drug, such as levamisole, isoprinosine and Zadaxin, or a pharmaceutically acceptable salt thereof.

[0207] The ADCs 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,- Ill -26113cyclobenzaprine. erythromycin, cocaine, furafyline, cimetidine, dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem, terfenadine, verapamil, cortisol, itraconazole, mibefradil, nefazodone and nelfinavir, or a pharmaceutically acceptable salt thereof.

[0208] The ADCs 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, Kol32, Kol34, Iressa, Imatnib mesylate, EKI-785, C11033, 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.

[0209] The ADCs 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.

[0210] The ADCs 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.

[0211] The ADCs of the Present Disclosure may also be useful for treating or preventing cancer in combination with siRNA therapeutics.

[0212] The ADCs of the Present Disclosure may also be administered in combination with y-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.

[0213] In one embodiment, specific anticancer agents useful in the present combination therapies include, but are not limited to: pembrolizumab (Keytruda®), abarelix (Plenaxisdepot®); 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 (Platino!®); 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 (Elliot'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®); geftinib (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 (Mesnextabs®); 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®); pahfermin (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 / 1-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (V el ban®); vincristine (Oncovin®); vinorelbine (Navelbine®); Olaparib (Lynparza®) vorinostat (Zolinza®), and zoledronate (Zometa®), or a pharmaceutically acceptable salt thereof.

[0214] Thus, the scope of the instant disclosure encompasses the use of the ADCs 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-y agonists, PPAR-8 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, y-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.

[0215] Y et 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 in combination with paclitaxel or trastuzumab.

[0216] 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 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 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.

[0217] 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 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-y agonist, a PPAR-8 agonist, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, y-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.

[0218] 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.

[0219] 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-L-1 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-L-1 antagonist is an anti-PD-L-1 antibody independently selected from atezolizumab, durvalumab and avelumab.26113

[0220] In one embodiments, the PD-1 antagonist is pembrolizumab. In particular subembodiments, 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.

[0221] 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.

[0222] In some embodiments, the PD-1 antagonist is nivolumab. In particular subembodiments, 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.

[0223] 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.

[0224] In some embodiments, the PD-1 antagonist is atezolizumab. In particular subembodiments, the method comprises administering 1200 mg of atezolizumab to the patient about every' three weeks.

[0225] In some embodiments, the PD-1 antagonist is durvalumab. In particular subembodiments, the method comprises administering 10 mg / kg of durvalumab to the patient about every' two weeks.

[0226] 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.

[0227] When the ADCs of the Present Disclosure are administered in combination with an antihuman 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. Either of the anti-human PD-1 antibody (or antigen-binding fragment thereof), and / or an ADC 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, and optionally other active agents will generally include a26113therapeutically 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).

[0228] In one embodiment, this disclosure provides an anti -human PD-1 antibody (or antigenbinding 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.

[0229] The disclosure also provides the use of an ADC 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.

[0230] 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, 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.

[0231] 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, 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), nodal26113marginal 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 / deltahepatosplenic 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.

[0232] 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.

[0233] 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).

[0234] In another embodiment, the present disclosure provides compositions comprising a compound of Formula IV, a pharmaceutically acceptable carrier, and pembrolizumab.

[0235] 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.

[0236] 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, or26113dronabinol. 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.

[0237] 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).

[0238] 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.

[0239] 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, y-radiation is preferred.

[0240] 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).

[0241] 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 / 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-y agonists. PPAR-3 agonists, an inhibitor of inherent multi drug 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, y-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.26113

[0242] 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

[0243] In one aspect, provided is a kit comprising a therapeutically effective amount of an ADC of the Present Disclosure or a pharmaceutically acceptable salt, solvate or ester of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.

[0244] In another aspect provided is a kit comprising an amount of an ADC 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, and the one or more additional therapeutic agents are provided in the same container. In one embodiment, the Compound of the Present Disclosure, and the one or more additional therapeutic agents are provided in separate containers.

[0245] In another aspect, provided is a kit comprising an ADC of the Present Disclosure, and an hyaluronan degrading enzyme.Compositions and Administration

[0246] 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).

[0247] 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).

[0248] 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 a26113pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carrier(s). diluent(s) or excipient(s).

[0249] 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.

[0250] 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.

[0251] In another embodiment, the compounds of the disclosure include those identified herein as Examples in the tables below, or a pharmaceutically acceptable salt thereof.

[0252] 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.

[0253] The ADCs of the Present Disclosure may be administered by oral, parenteral (e g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal 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.

[0254] 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.26113

[0255] Administration of the ADCs of the present disclosure can be by any suitable route, and can be facilitated by agents such as hyaluronan degrading enzymes, including hyaluronidases, including soluble PH20 polypeptides, and variants thereof. For systemic administration, the facilitating agents can be modified to increase pharmacological properties, such as serum halflife, by modifying the agents, such as with polymers. See. e.g., U. S. PatentNos.7,767,429. 8.431,380, 7,871,607, International Publication No. WO 2020 / 022791, U. S. Patent Publication No. US2006 / 0104968 and European Patent 1858926, and in numerous other patents and publications. Exemplary of such agents is the known agent PEGPH20 or rHuPH20. Accordingly, specific embodiments relate to pharmaceutical compositions comprising an ADC of the present disclosure, and any one of a hyaluronan degrading enzyme, hyaluronidase, soluble hyaluronidase, soluble PH20 polypeptide, or a variant of any of the foregoing. In particular embodiments, the pharmaceutical composition comprises [such agent] and a soluble PH20 polypeptide or a variant thereof.

[0256] In one embodiment, the hyaluronan degrading enzyme is a soluble hyaluronidase.

[0257] In another embodiment, the hyaluronan degrading enzyme is a soluble PH20.

[0258] 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, com 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 form26113osmotic 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.

[0259] 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.

[0260] 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 alky lene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxy cetanol, 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.

[0261] 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.

[0262] 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.

[0263] 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 be26113naturally- 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.

[0264] 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.

[0265] 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 anon-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.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] 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 to26113100 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.

[0270] 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.

[0271] 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

[0272] 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:

[0273] 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 AcOH modifier. Silica gel and reverse-phase flash column chromatography were conducted with commercially available pre-packed columns. Reversephase preparative HPLC purification was performed on preparative FIPLC instruments with UV26113and MS detection using a MeCN / water gradient with either TFA. formic acid, or AcOH 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 ECso data presented in tables refers to the cytotoxicity assays that are described in the Biological Assay section.SYNTHETIC SCHEMES, INTERMEDIATES, AND EXAMPLES

[0274] 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 CompoundsPreparation of Intermediate Compound iiStep AStep A - synthesis of compound ii

[0275] To a stirred mixture of (5)-3-amino-2-(2.5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)propanoic acid hydrochloride i (2.10 g, 9.52 mmol) and DIPEA (3.65 mL, 20.9 mmol) in DMF (16 mL) was added 2,5-dioxopyrrolidin-l-yl 2,5,8, 1 l,14,17,20,23-octaoxahexacosan-26-oate (4.85 g, 9.51 mmol) at room temperature. After 30 minutes, TFA (1.76 mL, 22.9 mmol) was added, and the mixture was then directly purified using reverse phase column chromatography (10-40% MeCN / water with 0.1% TFA modifier) to provide (S)-29-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-26-oxo-2, 5, 8,11,14,17, 20, 23-octaoxa-27-azatriacontan-30-oic acid ii. LCMS (ESI) m / z 579 [M+H]+.

[0276] The following intermediate compounds of the present disclosure were made using the method described above, and substituting the appropriate reactants and / or reagents:26113Compound Structure MS [M+H]+iii 9315 < D O DO O O iK ’o o oiv 0 721 O O OO o FmocHN^ / W^QHO O O C) HlMo o oo o o / <V \ 897 ' oZEvi 383 HN.M rovii o 525 FmocHN^^^QHHI\MPreparation of Intermediate Compound x26113Step A Step BStep A - synthesis of compound ix

[0277] To a stirred mixture of [3-lactose viii (300 mg, 0.88 mmol), sodium azide (399 mg, 6.13 mmol) and DIPEA (1.53 mL, 8.76 mmol) in water (9 mL) was added 2-chloro-l,3-dimethylimidazolinium chloride (444 mg, 2.63 mmol) at 0 °C. After 1 hour, the reaction mixture was directly purified using reverse phase column chromatography (0-50% MeCN / water with 0.1% formic acid modifier) to provide (2S,3R,4S.5R,6R)-2-(((2R,3S.4R,5R,6R)-6-azido-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol ix. LCMS (ESI) m / z: 390 [M+Na]+.Step B - synthesis of compound x

[0278] To a stirred mixture of Z-ascorbic acid (24.9 mg, 141 pmol), sodium Z-ascorbate (28.0 mg, 141 pmol) and 3-(4-((bz.ft( 1 -(tert-butyl)- 1 / 7-1, 2, 3-triazol-4-yl)methyl)amino)methyl)-17Z-l,2,3-triazol-l-yl)propan-l-ol (60.8 mg, 141 pmol) in water (5 mL) was added copper diacetate (25.7 mg, 141 pmol) at room temperature. After 2 minutes, this mixture was transferred to a separate vial containing (2S,3R,4S,5R,6R)-2-(((2R,3S,4R,5R,6R)-6-azido-4,5-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol ix (346 mg, 941 pmol) and (A)-16-(2,5-dioxo-2,5-dihydro-lI4-pyrrol-l-yl)-13-oxo-4,7,10-trioxa-14-azaheptadec-l-yn- 17-oic acid vi (300 mg, 785 pmol) in DMSO (2.5 mL) at room temperature. After 15 minutes, formic acid (88.8 pL, 2.35 mmol) was added, and the resulting mixture was directly purified using reverse phase column chromatography (0-40% MeCN / water with 0.1% formic acid modifier) to provide (S)-l-(l-((2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-26113pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)-lH-l,2,3-triazol-4-yl)-14-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-ll-oxo-2,5,8-trioxa-12-azapentadecan-15-oic acid x. LCMS (ESI) m / z 750 [M+H]+.

[0279] The following intermediate compounds of the present disclosure were made using the method described above, and substituting the appropriate reactants and / or reagents:Preparation of Intermediate Compound xyStep BStep A - synthesis of compound xiv26113

[0280] To a stirred mixture of (< S')-4-((((977-fluoren-9-yl)methoxy)carbonyl)amino)-5-(te / 'te butoxy)-5-oxopentanoic acid xiii (3.00 g, 7.05 mmol), DIPEA (3.68 mL, 21.2 mmol) and glucamine (1.79 g, 9.87 mmol) in DMF (17 mL) was added HATU (3.22 g, 8.46 mmol) at room temperature. After 1 hour, the reaction mixture was directly purified using reverse phase column chromatography (10-80% MeCN / water with 0.1% formic acid modifier) to provide tert-butyl N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N5-((2S,3R,4R,5R)-2, 3,4,5, 6-pentahydroxyhexyl)-Z-glutaminate xiv. LCMS (ESI) m z'. 589 [M+H]+.Step B - synthesis of compound xv

[0281] To a stirred mixture of tert-butyl N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N5-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-Z-glutaminate xiv (4.15 g, 7.05 mmol) in dioxane (14 mL) was added HC1 solution (4 M in dioxane, 17.6 mL, 70.1 mmol) at room temperature. After 4 hours, the mixture was concentrated in vacuo, and the resulting residue was purified using reverse phase column chromatography (10-70% MeCN / water with 0.1% formic acid modifier) to provide N2-(((9 / f-fluoren-9-yl)methoxy)carbonyl)-N5-((2S,3R,4R.5R)-2,3,4,5,6-pentahydroxyhexyl)-£-glutamine xv. LCMS (ESI) m z 533 [M+H]+.Preparation of Intermediate Compound xyiiStep A - synthesis of compound xvii

[0282] To a stirred mixture of 3-(2-(2-(3-((2,5-dioxopyrrolidin-l-yl)oxy)-3-oxopropoxy)ethoxy)ethoxy)propanoic acid (1.00 g, 2.88 mmol) and 6-amino-6-deoxy-P-cyclodextrin (3.27 g. 2.88 mmol) in DMF (7 mL) was added DIPEA (1.25 mL. 7.20 mmol) at26113room temperature. After 1 hour, HATU (1.10 g, 2.88 mmol), DIPEA (0.63 mL, 3.60 mmol) and (1S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-aminopropanoic acid xvi (939 mg, 2.88 mmol) was added at room temperature. After 45 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-70% MeCN / water with 0.1% formic acid modifier) to provide Fmoc-Dap(PEG3-P-cyclodextrin)-OH xvii. LCMS (ESI) m / z-. 1675 [M+H]+.Preparation of Intermediate Compound xxiiStep AStep A - synthesis of compound xix

[0283] To a stirred mixture of (S)-2-((((9E7-fluoren-9-yl)methoxy)carbonyl)amino)-5-(benzyloxy)-5 -oxopentanoic acid xviii (3.31 g, 7.21 mmol), 3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]propionic acid tert-butyl ester (2.00 g, 7.21 mmol) and DIPEA (3.14 mL, 18.0 mmol) in DMF (18 mL) was added HATU (2.74 g, 7.21 mmol) at room temperature. After 30 minutes, the reaction mixture was directly purified using normal phase column chromatography (10-100% EtOAc / hexanes) to provide 18-benzyl 1 -(tert-butyl) (S)-15-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-14-oxo-4,7,10-trioxa-13-azaoctadecanedioate xix. LCMS (ESI) m / z'. 719 [M+H]+.Step B - synthesis of compound xx

[0284] To a stirred mixture of 18-benzyl 1 -(tert-butyl) (S)-15-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-14-oxo-4,7,10-trioxa-13-azaoctadecanedioate xix (5.07 g, 7.05 mmol) in DCM (14 mL) was added TFA (5.43 mL, 70.5 mmol) at room temperature. After 2026113hours, the mixture was concentrated in vacuo to provide (S)-5-(3-(benzyloxy)-3-oxopropyl)-l-(9H-fluoren-9-yl)-3,6-dioxo-2,10,13,16-tetraoxa-4,7-diazanonadecan-19-oic acid xx, which was used directly without further purification. LCMS (ESI) m / z'. 663 [M+H]+.Step C - synthesis of compound xxi

[0285] To a stirred mixture of (S)-5-(3-(benzyloxy)-3-oxopropyl)-l-(9H-fluoren-9-yl)-3.6-di oxo-2, 10,13, 16-tetraoxa-4,7-di azanonadecan- 19-oic acid xx (2.00 g, 1.81 mmol), DIPEA (1.89 mL, 10.9 mmol) and glucamine (323 mg, 1.81 mmol) in DMF (4 mL) was added HATU (688 mg, 1.81 mmol) at room temperature. After 30 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-80% MeCN / water with 0.1% formic acid modifier) to provide 4S,21S,22R,23R,24R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-21,22, 23,24, 25-pentahydroxy-5, 18-dioxo-9, 12,15-trioxa-6, 19-diazapentacosanoic acid xxii. LCMS (ESI) mz 826 [M+H]+.Step D - synthesis of compound xxii

[0286] A mixture of benzyl (4S,21S.22R,23R.24R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-21,22, 23,24, 25-pentahydroxy-5, 18-dioxo-9, 12, 15-trioxa-6, 19-diazapentacosanoate xxi (820 mg, 0.99 mmol) and 10 wt% Pd / C (106 mg, 99.3 pmol Pd) in DCM (4 mL) and MeOH (2 mL) was stirred under ELQ. O atm) at room temperature. After 3 hours, the mixture was filtered through Celite diatomaceous earth, rinsed with MeOH and DCM, and concentrated in vacuo. The residue was purified using reverse phase column chromatography (10-80% MeCN / water with 0.1% TFA modifier) to provide (4S,21S,22R,23R,24R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-21,22,23, 24, 25-pentahy droxy-5, 18-dioxo-9, 12, 15-trioxa-6,19-diazapentacosanoic acid xxii. LCMS (ESI) m / z.- 736 [M+H]+.

[0287] The following intermediate compounds were made using the method described above, and substituting the appropriate reactants and / or reagents:2611326113Preparation of Intermediate Compound xxyiiiStep A Step BOHxxvii Step A - synthesis of compound xxvii

[0288] To a stirred mixture of Fmoc-L-Ser((Ac)4-beta-D-Glc)-OH xxvi (1.60 g, 2.43 mmol) in MeOH (12 mL) was added K2CO3 (673 mg. 4.87 mmol) at room temperature. After 4 hours, the mixture was acidified with aqueous 1 M HC1 solution (10 mL). and the organic solvent was removed in vacuo. The aqueous residue was washed with ether and the washed aqueous layer then was concentrated in vacuo to provide O-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-L-serine hydrochloride xxvii, which was used directly without further purification. LCMS (ESI) m / z'. 268 [M+H]+.Step B - synthesis of compound xxviii

[0289] To a stirred mixture of O-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hy droxymethyl)tetrahydro-2H-pyran-2-yl)-L-serine hy drochloride xxvii and DIPEA (1.06 mL, 6.08 mmol) in DMF (7 mL) and water (1 mL) was added Fmoc A-hydroxy succinimide ester (1.07 g, 3.16 mmol) at room temperature. After 16 hours, the reaction mixture was directly purified using reverse phase column chromatography (10-65% MeCN / water with 0.1% formic acid modifier) to provide A-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-((2R,3R,4S,5S,6R)-3, 4,5-26113trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-L-serine xxviii. LCMS (ESI) wZz: 512 [M+Na]+.Preparation of Intermediate Compound xxxiixxix xxxxxxii Step A - synthesis of compound xxx

[0290] To a stirred mixture of benzyl 4-hydroxybutanoate (500 mg, 2.57 mmol) in DCM (4 mL) was added chlorosulfonyl isocyanate 0.22 mL, 2.57 mmol) at room temperature. After 1 hour, amixture of 2,5,8,ll,14.17,20,23-octaoxapentacosan-25-amine xxix (1.09 g, 2.83 mmol) and triethylamine (1.10 mL, 7.89 mmol) in DCM (4 mL) was added at room temperature. After 1 hour, the mixture was concentrated in vacuo, and the resulting residue was purified using reverse phase column chromatography (10-95% MeCN / water with 0.1% formic acid modifier) to provide benzyl 4-(((N-(2, 5.8.11,14, 17,20, 23-octaoxapentacosan-25-yl)sulfamoyl)carbamoyl)oxy)butanoate xxx. LCMS (ESI) m / z 705Step B - synthesis of compound xxxi

[0291] A mixture of xxx (0.47 g, 0.69 mmol) and 10 wt% Pd / C (0.15 g, 0.14 mmol Pd) in DCM (1.5 mL) and MeOH (1.5 mL) was stirred under LLQ. O atm) at room temperature. After 5 hours, the mixture was filtered through Celite diatomaceous earth, rinsed with MeOH and DCM, and concentrated in vacuo to provide 4-(((N-(2,5,8,ll,14,17,20,23-octaoxapentacosan-25-yl)sulfamoyl)carbamoyl)oxy)butanoic acid xxxi, which was used directly without further purification. LCMS (ESI) m / z'. 593 [M+H]+.Step C - synthesis of compound xxxii

[0292] To a stirred mixture of xxxi (106 mg, 179 pmol), HATU (68.0 mg, 179 pmol) and DIPEA (62.3 pL, 358 pmol) in DMF (1 mL) was added (S)-3-amino-2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)propanoic acid hydrochloride i (39.5 mg, 179 pmol) at room temperature. After 15 minutes, formic acid (16.9 pL, 447 pmol) was added, and the reaction mixture was directly26113purified using reverse phase column chromatography (10-80% MeCN / water with 0.1% formic acid modifier) to provide (S)-3-(4-(((N-(2,5,8,ll,14,17,20,23-octaoxapentacosan-25-yl)sulfamoyl)carbamoyl)oxy)butanamido)-2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)propanoic acid xxxii. LCMS (ESI) m z 759 [M+H]+.Example 1Preparation of Linker-Payload 1Step A - synthesis of compound I-la

[0293] To a mixture of 97 / -fluoren-9-vlmelhyl A'-|2-| |(acet\ loxy (meth l |ammo|-2-oxoethyl] carbamate (991 mg, 2.69 mmol) and cabazitaxel (1.25 g, 1.49 mmol) in DCM (15 mL) was added lithium / c / V-butoxide (216 mg, 2.69 mmol) at room temperature. After 15 minutes, a further portion of lithium tert-butoxide (216 mg, 2.69 mmol) was added. After 15 minutes, the mixture was concentrated in vacuo, and the resulting residue was purified using reverse phase column chromatography (10-95% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((R)-10-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-l-(9H-fluoren-9-yl)-3,6-dioxo-2,9-dioxa-4,7-26113diazaundecan-ll-oyl)oxy)-l l-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate I-la. LCMS (ESI) m / z 1166 [M+Na]+.Step B - synthesis of compound I-lb

[0294] To a stirred solution of I-la (1.43 g, 1.25 mmol) in DMF (6 mL) was added triethylamine (1.22 mL, 8.75 mmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then a mixture ofN-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-L-serine xxviii (1.22 g, 2.50 mmol), HATU (950 mg. 2.50 mmol) and DIPEA (653 pL, 3.75 mmol) in DMF (4 mL) was added. After 15 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-95% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S, HS,12S,12aR,12bS)-12b-acetoxy-9-(((5S,13R)-13-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-l-(9H-fluoren-9-yl)-3,6,9-trioxo-5-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2, 12-dioxa-4,7, 10-tri azatetradecan- 14-oyl)oxy)- 11 -hy droxy-4,6-dimethoxy-4a,8, 13,13-tetramethy 1-5 -oxo-2a,3,4, 4a, 5, 6, 9, 10, 11, 12, 12a, 12b-dodecahy dro- 1H-7,11-methanocyclodeca[3, 4] benzo [l,2-b]oxet- 12-yl benzoate I-lb. LCMS (ESI) m / z: 1415 [M+Na]+. Step C - synthesis of compound I-lc

[0295] To a stirred solution of I-lb (397 mg, 0.29 mmol) in DMF (2 mL) was added triethylamine (318 pL, 2.28 mmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then a mixture of N-(9-fluorenylmethoxycarbonyl)-£-valine (126 mg, 0.37 mmol), HATU (141 mg, 0.37 mmol) and DIPEA (148 pL, 0.89 mmol) in DMF (1 mL) was added. After 15 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-95% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((5S,8S,16R)-16-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-l-(9H-fluoren-9-yl)-5-isopropyl-3,6,9,12-tetraoxo-8-((((2R,3R,4S.5S,6R)-3.4.5-trihydroxy-6-(hydroxymethy l)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2, 15-dioxa-4,7, 10,13-tetraazaheptadecan-17-oyl)oxy)-ll-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate I-lc. LCMS (ESI) m / z: 1514 [M+Na]+.Step D - synthesis of compound I-ld26113

[0296] To a stirred solution of I-lc (212 mg, 0.14 mmol) in DMF (1 mL) was added triethylamine (198 pL, 1.42 mmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then a mixture of 7V-[(97f-fluoren-9-ylmethoxy (carbonyl |- / i-alanine (57.5 mg, 0.19 mmol), HATU (70.2 mg, 0.19 mmol) and DIPEA (74.2 pL. 0.43 mmol) in DMF (0.5 mL) was added. After 15 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-95% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((9S,12S,20R)-20-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-l-(9H-fluoren-9-yl)-9-isopropyl-3,7, 10.13,16-pentaoxo- 12-((((2R,3R,4S,5S.6R)-3,4,5-trihy droxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2, 19-dioxa-4,8, 11,14,17-pentaazahenicosan-21-oyl)oxy)-ll-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate I-ld. LCMS (ESI) m z: 1585 [M+Na]+.Step E - synthesis of compound 1

[0297] To a stirred solution of I-ld (38.0 mg, 24.3 pmol) in DMF (0.5 mL) was added tri ethylamine (33.9 pL, 243 pmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then a mixture of (S)-53-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-50-oxo-2,5,8,ll,14,17.20,23,26,29,32.35,38,4L44,47-hexadecaoxa-51-azatetrapentacontan-54-oic acid iii (36.2 mg, 38.9 pmol), HATU (14.8 mg, 38.9 pmol) and DIPEA (12.7 pL, 72.9 pmol) in DMF (0.5 mL) was added. After 15 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-80% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((53S,60S,63S,71R)-71-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-53-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-60-isopropyl-50,54,58,61,64,67-hexaoxo-63-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,70-heptadecaoxa-5I,.55,.59,62,' 65,' 68-hexaazadoheptacontan-72-oyl)oxy)-l l-hydroxy-4,6-dimethoxy-4a.8.13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate 1. LCMS (ESI) m / z'. 1128 [M+2H]2+(m2). 1H NMR (500 MHz, DMSO- e) 5 8.72 - 8.59 (m. 1H), 8.20 - 8.01 (m, 2H), 8.01 - 7.84 (m, 4H), 7.77 - 7.66 (m, 1H), 7.66 - 7.55 (m. 2H), 7.47 - 7.35 (m, 3H), 7.31 (d, J = 7.2 Hz, 2H), 7.25 - 7.17 (m, 1H), 7.03 (s, 2H). 5.97 -5.84 (m, 1H), 5.38 (d, J = 6.9 Hz, 1H), 5.33 - 5.19 (m, 1H), 5.04 - 4.89 (m, 3H), 4.71 (s, 1H), 4.67 - 4.30 (m, 6H), 4.29 - 4.09 (m, 2H), 4.09 - 3.85 (m, 3H), 3.85 - 3.60 (m, 6H), 3.58 - 3.3826113(m. 63H), 3.38 - 3.27 (m, 9H), 3.27 - 2.91 (m, 11H), 2.75 - 2.57 (m. 1H), 2.44 - 2.12 (m, 7H), 2.08 - 1.68 (m, 6H), 1.61 - 1.42 (m, 4H), 1.34 (s, 8H), 1.23 (s, 1H), 1.01 (s, 3H), 0 JO. JO98 (s, 3H), 0.91 - 0.73 (m, 6H).

[0298] The following illustrative linker-payload compounds of the prese A nn^ o / t disclosure were d u i g h m t X A° X A°°°ma e s n t e e hods described in Example 1, and substituting thVe appropriate intermediates, o < / r ° "and other reactants and / or reagents. Linker-payloads with bromo o / = ao / c 'etamide conjugation handles y. i in. o / =were prepared via coupling of IV-hydroxysuccinimide bromoa )Oilll..ncetate to the corresponding Fmoc- v A >VV >\ T&e r t c e a > O=-d p o e t d mine in the final step. 7\ OK=- 'vO QExample Structu A O ° ~( z\ ir° zi~e MS ( ) o O O O ZT'=—" [M+H] 2 o o IZr y 1771V>°11X 4 ZI 's / j O O > O --"\zz A * °"( )( ( O O="'> \ IO O _ < ZI > > oT7o zi y z—oH o TZvZ-— ~3 178326113261137 1295\ >.o° [M+2H]2+ y= oy >■' (m / 2) A x A A X Ao°°°°°w w '? Vr? io / o / '11( TO=> M » T )v.\ ° °.o=\ / .! M M JCx °J"1>" / \\ X p T=: I:zX O\ ° ° ~ 8 < roZI z 1136^^ on., Q... / / K000°,-- \ / o b XZ iz [M+2Na] ° ° 2+ zi \? •°=X XZI / (m / 2)o11 ZIXM “ / \ o, P V' *.-px"IZ°„ r\ o ( o o — >~5W »'o o o o o o o o,,n. ^■o o o o9 o w wo O O 0 o o \l -0 9 1902 o o o o O'x^°M Mo o o o o 0 o o \ o o) CXNH 0 z>< ^_ _ o o MW_ p _\ p\ _ _ O O O c O O0 / M0 x 0HN OHOvMp°- HO" V"'^OHOH10 1089[M+2Na] 2i (m / 2)2611311 1686. O *0.o [M+Na]+X X ] X X=< XY \ n°X^ o / yf A A>°°°boyw / n? X Ar°?T°1xo X / Q. ' w?°TX o / => °..Q / \vM,°=I2. ( AGX^ °o° \ u.xZIo J-K- 12 X,5 „-^ Oc. °r ° ° ° 1104 ZI z iz ) >o oo 0== [M+2Na]2+ \xO ZT \— )o=y T\r.r ZI 'Z yX °°* (m / 2) oo TZ 0 b IZ '5 r r A; ZI11< TZ TZ °=J ^ ^ )\ ooO>==""X y\ f 2.0o~~ / \ / J T y z z z——J \\ \X\O=< r o o o o \ ) o o o oo13 o o 00 o o w 0 o O O wn " 1171[M+2Na] Mo o 2 00 o o o o X o MM + MM u yz- (m / 2) _ _ p\ _ p\\\ _ p _ p O O O X O14 1109[M- CTX]+2611315 1462 / ' \ CD co O □ o 3M o o c> o oIZ SI o o o o o oc o o>uiz / 4 U ' ZvUo'= o=.\..\ I I zz Q O ZI TZ416 y )z ooo„=- zz41}( O TZ O"" / 1168 —X [M+2Na]2+ X0 Vs< ° o =X- Qp ZT\< (( VO zi= / -"Mr~ / (m / 2) / ) ) OOo"*='4 <?"" ^ / V1o iz « y Q < III..^ \ V1\ 6 o z o 2°==-? ^O O== r\ZZ 1VZA < (.. ( / x.=.17,0 _ _ _0 _ _o= / O I o / 1110 [ o - o "si —o 9 9 0 ^^ > ^'O [M+2Na]Y Y° oO^NH o ¥ L °o- 2+ ll I Aozr(m / 2) ^^° C Ox °rxAXAh x<ycr erA - <> - A ° AA V-Ak oN^NA o oNA \ -Y ON-° O01AHO^NH218 1966[M+Na] '261132611321 \l -0 0 1448"^0 [M+2H]2+ O^NH O yPX (TM / 2) OY^0"'Br^Hu u YN>AN / ^ANJvhuNXrAN / VH iN_o Y ( A.S kH HA kH0NH OOY-OH0VAO) HO" Y OH"-OH-0Ho -rOH0H><. OHH0“ AM HO^Ay °h.i°< pH HO'' J.„, OHH°xH-OH "t,‘ O\JASSA^ / 0 "'-OH\OH22 k -o,9 / 1457'"' A [M+2H]2+ O^NH 0 JLPk? jf lA / Ao (m / 2) OPi °'' YjYH H U Y H 9 H 1 y-.U J \H H" <HoNH 0o^—oHOy%) HO" Y OH--OH-0H9: OHkO^M^ / ° ”'0H° N '■■!-< HO HO - -NoHr X... OH HO 1M / OH HOY.1S J.,, OH°. OH HO'' qfH0'-Q°HH0- S4Vy0\ ^OHOH26113261131402 [M+2H]2+ (m / 2)26113Example 2Preparation of Linker-Payload 2726113Step A - synthesis of compound l-27a

[0299] To a mixture of (< S)-1 l-benzyl-l-(9H-fluoren-9-yl)-3,6,9,12,15-pentaoxo-2-oxa-4,7,10,13,16-pentaazaheptadecan-17-yl acetate (1.36 g, 2.15 mmol) and cabazitaxel (1.00 g, 1.20 mmol) in DCM (12 mL) was added lithium te / 7-butoxide (172 mg, 2.15 mmol) at room temperature. After 25 minutes, the mixture was concentrated in vacuo, and the resulting residue was purified using reverse phase column chromatography (10-95% MeCN / water with 0.1% formic acid) to provide Fmoc-Gly-Gly-Phe-Gly-NH-CTh-cabazitaxel I-27a. LCMS (ESI) m / z 1428 [M+Na]+.Step B - synthesis of compound I-27b

[0300] To a stirred solution of I-27a (300 mg, 0.21 mmol) in DMF (1 mL) was added triethylamine (0.30 mL, 2.13 mmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then a mixture of Fmoc-Dap(PEG3-P-cyclodextrin)-OH xvii (357 mg, 0.21 mmol), HATU (89.3 mg, 0.24 mmol) and DIPEA (0.11 mL, 0.64 mmol) in DMF (1 mL) was added. After 15 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-80% MeCN / water with 0.1% formic acid modifier) to provide Fmoc-Dap(PEG3-P-cyclodextrin)-Gly-Gly-Phe-Gly-NH-CH2-cabazitaxel I-27b. LCMS (ESI) m / z: 1420 [M+2H]2+(w / 2).Step C - synthesis of compound I-27c

[0301] To a stirred solution of I-27b (164 mg, 57.7 pmol) in DMF (1 mL) was added triethylamine (80.5 pL, 577 pmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature and directly purified using reverse phase column chromatography (10-80% MeCN / water with 0.1% formic acid modifier) to provide H2N-Dap(PEG3-P-cyclodextrin)-Gly-Gly-Phe-Gly-NH-CH2-cabazitaxel formate l-27c. LCMS (ESI) m / z: 1309 [M+2H]2+(m / 2).Step D - synthesis of compound 27

[0302] To a stirred solution of I-27c (55 mg, 21 pmol) in DMF (0.5 mL) was added N-hydroxy succinimide bromoacetate (6.9 mg, 29 pmol) at room temperature. After 20 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-75% MeCN / water with 0.1% formic acid modifier) to provide BrAc-Dap(PEG3-P-cyclodextrin)-Gly-Gly-Phe-Gly-NH-CH2-cabazitaxel 27. LCMS (ESI) m / z: 1902 [M-CTX]+.JH NMR (500 MHz, DMSO-O 58.68 - 8.60 (m. 1H), 8.40 (d. J = 7.6 Hz. 1H), 8.37 - 8.31 (m, 1H), 8.31 - 8.23 (m, 1H), 8.14 - 8.07 (m, 1H), 8.05 - 8.00 (m, 1H), 8.00 - 7.93 (m, 2H), 7.93 - 7.87 (m, 1H), 7.73 -7.64 (m, 2H), 7.61 (t, J = 7.5 Hz, 2H), 7.48 - 7.42 (m, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.36 - 7.3026113(m. 2H), 7.29 - 7.15 (m. 6H), 5.97 - 5.89 (m. 1H), 5.84 - 5.60 (m, 12H). 5.38 (d, J = 6.9 Hz, 1H), 5.02 - 4.88 (m, 2H), 4.88 - 4.75 (m, 6H), 4.74 - 4.63 (m, 2H), 4.63 - 4.38 (m, 9H), 4.38 -4.30 (m, 1H), 4.01 (br s, 2H), 3.93 (br s, 2H), 3.82 - 3.51 (m, 34H), 3.51 - 3.42 (m, 9H), 3.42 - 3.19 (m, 30H), 3.16 (s. 3H), 3.13 - 3.03 (m, 1H), 2.85 - 2.72 (m, 1H), 2.66 - 2.54 (m, 1H), 2.43 - 2.23 (m, 6H), 1.99 - 1.70 (m, 4H). 1.55 - 1.42 (m, 4H). 1.34 (s. 9H), 1.01 (s. 3H), 0.97 (s, 3H).

[0303] The following illustrative linker-payload compounds of the present disclosure were made using the methods described in Example 2, and substituting the appropriate intermediates, and other reactants and / or reagents. Linker-payloads with bromo acetamide conjugation handles were prepared via coupling of / V-hydroxysuccinimide bromoacetate to the corresponding Fmoc-deprotected amine in the final step.Example Structure MS [M+H] 28 -0 p Y 791[M- QH QH O^NH O CTX]+~ L. OH OH kvJJ o=^ —2 u iHuH <u YAM,HoH<5 k A A0U29 OH 1947[M- 'O-< >. o, ro0HCTX] HO \— (+HO OH / O\ / OH HO*Y-^Q' OH HO' bk HO. 'HO^ / A^Oftu HO" Ao °HHO;°A...HNIH° A — O O OXA° X1 O^NH O k A2 H U H? r ALM.HSHS < H n \= / 0u261131071 [M+2Na] 2+ (m / 2) 31 1195[M+2Na] 2+ (m / 2)1158 [M- CTX]+2611326113Example 3Preparation of Linker-Payload 36l-36a l-36c26113Step A - synthesis of compound l-36b

[0304] To a stirred solution of Boc-Glu(OBzl)-Gly-OH I-36a (3.00 g, 7.61 mmol) in DCM (15 mL) was added TFA (5.9 mL, 76.1 mmol) at room temperature. After 2 hours, the mixture was concentrated in vacuo, and the resulting residue was purified using reverse phase column chromatography (10-70% MeCN / water with 0.1% TFA modifier) to provide (S)-(2-amino-5-(benzyloxy)-5-oxopentanoyl)glycine trifluoroacetate I-36b. LCMS (ESI) m / z 295 [M+H]+. Step B - synthesis of compound I-36c

[0305] To a stirred solution of I-36b (6.09 g, 14.9 mmol) and DIPEA (6.49 mL, 37.3 mmol) in DMF (15 mL) was added Fmoc-glycine N-hydroxysuccinimide ester (6.18 g. 15.7 mmol) at room temperature. After 18 hours, the reaction mixture was directly purified using reverse phase column chromatography (10-70% MeCN / water with 0.1% TFA modifier) to provide (S)-(2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetamido)-5-(benzyloxy)-5-oxopentanoyl)glycine I-36c. LCMS (ESI) m / z: 574 [M+H]+.Step C - synthesis of compound I-36d

[0306] To a stirred mixture of I-36c (6.35 g, 11.1 mmol), copper diacetate (603 mg, 3.32 mmol) and AcOH (2.53 mL, 44.3 mmol) in DMF (37 mL) was added lead tetraacetate (90% wt, 8.18 g, 16.6 mmol) and the resulting mixture was warmed to 70 °C. After 30 minutes, the mixture was cooled to room temperature and then was directly purified using reverse phase column chromatography (10-70% MeCN / water with 0.1% TFA modifier) to provide benzyl (S)-4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetamido)-5-((acetoxymethyl)amino)-5-oxopentanoate I-36d. LCMS (ESI) m / z: 528 [M-OAc]+.Step D - synthesis of compound I-36e

[0307] To a mixture of I-36d (1.20 g, 2.03 mmol) and cabazitaxel (1.00 g, 1.20 mmol) in DCM (12 mL) was added lithium tert-butoxide (182 mg, 2.27 mmol) at room temperature. After 25 minutes, the mixture was concentrated in vacuo, and the resulting residue was purified using reverse phase column chromatography (10-95% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S.4aS,6R.9S, 11 S.12S, 12aR, 12bS)- 12b-acetoxy-9-(((8S.13R)-8-(3-(benzyloxy)-3-oxopropyl)-13-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-l-(9H-fluoren-9-yl)-3,6,9-trioxo-2,12-dioxa-4,7,10-triazatetradecan-14-oyl)oxy)-ll-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethy 1-5 -oxo-2a,3,4, 4a, 5, 6, 9, 10, 11, 12, 12a, 12b-dodecahy dro- 1H-7, 11 -methanocyclodeca[3, 4] benzo [l,2-b]oxet- 12-yl benzoate I-36e. LCMS (ESI) m / z: 1386 [M+Na]+. Step E - synthesis of compound I-36f26113

[0308] To a stirred solution of I-36e (1.29 g, 0.95 mmol) in DMF (5 mL) was added triethylamine (1.06 mL, 7.58 mmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then a mixture of Fmoc-Val-OH (418 mg, 1.23 mmol), HATU (468 mg, 1.23 mmol) and DIPEA (0.50 mL, 2.84 mmol) in DMF (1 mL) was added. After 15 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-95% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((5S,llS,16R)-ll-(3-(benzyloxy)-3-oxopropyl)-16-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-l-(9H-fluoren-9-yl)-5-isopropyl-3,6,9,12-tetraoxo-2,15-dioxa-4,7,10,13-tetraazaheptadecan-17-oyl)oxy)-l 1-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,l l,12,12a,12b-dodecahydro-lH-7,1 l-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate I-36f. LCMS (ESI) m / z'. 1463 [M+H]+.Step F - synthesis of compound I-36g

[0309] To a stirred solution of I-36f (250 mg, 171 pmol) in DMF (1 mL) was added triethylamine (238 pL, 1.71 mmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then a mixture of (4S,20S,26S,27R,28R,29R)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-26,27,28,29,30-pentahydroxy-5,18,23-trioxo-20-(((2S,3R.4R.5R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl)-9,12,15-trioxa-6,19,24-triazatriacontanoic acid xxv (211 mg, 205 pmol), HATU (78.0 mg, 205 pmol) and DIPEA (89.3 pL, 513 pmol) in DMF (1 mL) was added. After 15 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-85% MeCN / water with 0.1% formic acid modifier) to provide(2aR,4S,4aS,6R,9S,l! S.12S,12aR,12bS)-9-(((2R.7S,13S.18S,34S,40S.41R,42R.43R)-18-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-7-(3-(benzyloxy)-3-oxopropyl)-2-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-40,41,42,43,44-pentahydroxy-13-isopropyl-6,9,12,15,19,32,37-heptaoxo-34-(((2S,3R,4R,5R)-2,3,4,5.6-pentahydroxyhexyl)carbamoyl)-3,23,26,29-tetraoxa-5,8,ll,14.20,33.38-heptaazatetratetracontanoyl)oxy)-12b-acetoxy-ll-hydroxy-4,6-dimethoxy-4a,8, I3,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9, I0, H,12,12a, I2b-dodecahydro-IH-7,ll-methanocyclodeca[3,4]benzo[I,2-b]oxet-I2-yl benzoate I-36g. LCMS (ESI) m / z-. 1415 [M-CTX]+.Step G - synthesis of compound I-36h

[0310] A mixture of I-36g (96.0 mg, 42.7 pmol) and 10 wt% Pd / C (13.6 mg, 12.8 pmol Pd) in DCM (0.4 mL), MeOH (0.4 mL) and water (0.1 mL) was stirred under H2(1.0 atm) at room26113temperature. After 3 hours, the mixture was filtered through Cehte diatomaceous earth, rinsed with MeOH and DCM, and concentrated in vacuo to provide (4S,10S,15S,31S,37S,38R,39R,40R)-15-((((9H-fhioren-9-yl)methoxy)carbonyl)amino)-4-(((((2R,3S)-l-(((2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-12-(benzoyloxy)-ll-hydroxy-4.6-dimethoxy-4a,8,13.13-tetramethyl-5-oxo-2a.3.4.4a,5,6,9,10.1 l,12,12a,12b-dodecahydro-lH-7,1 l-methanocyclodeca[3,4]benzo[l,2-b]oxet-9-yl)oxy)-3-((tert-butoxy carbonyl)amino)-l-oxo-3-phenylpropan-2-yl)oxy)methyl)carbamoyl)-37, 38, 39, 40,41-pentahydroxy-10-isopropyl-6,9,12,16,29,34-hexaoxo-31-(((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl)-20,23,26-trioxa-5,8,ll,17,30.35-hexaazahentetracontanoic acid I-36h, which was used directly without further purification. LCMS (ESI) m / z'. 1325 [M-CTX]+. Step H - synthesis of compound 36

[0311] To a stirred solution of I-36h (92.0 mg, 42.6 pmol) in DMF (1 mL) was added triethylamine (59.4 pL, 426 pmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then a mixture of (S)-29-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-26-oxo-2,5,8,l 1,14,17, 20, 23-octaoxa-27-azatriacontan-30-oic acid ii (34.5 mg, 59.6 pmol), HATU (22.7 mg, 59.6 pmol) and DIPEA (22.3 pL, 128 pmol) in DMF (0.5 mL) was added. After 15 minutes, formic acid (32.1 pL, 852 pmol) was added and the reaction mixture was directly purified using reverse phase column chromatography (10-75% MeCN / water with 0.1% formic acid modifier) to provide (29S,32S,37S,43S)-43-(((((2R,3S)-l-(((2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-12-(benzoyloxy)-ll-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-9-yl)oxy)-3-((tert-butoxycarbonyl)amino)-l-oxo-3-phenylpropan-2-yl)oxy)methyl)carbamoyl)-29-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-37-isopropyl-26, 30, 35,38, 41-pentaoxo-32-(((14S,20S,21R,22R,23R)-20, 21, 22,23, 24-pentahydroxy-12,17-dioxo-14-(((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl)-3,6,9-trioxa-13,18-diazatetracosyl)carbamoyl)-2,5,8,ll,14,17,20.23-octaoxa-27,31,36,39,42-pentaazahexatetracontan-46-oic acid 36. LCMS (ESI) m / z'. 1272 [M+2Na]2t(m / 2). 'H NMR (500 MHz, DMSO-rfc) 5 12.10 (br s, 1H), 8.90 - 8.70 (m, 1H), 8.35 - 8.16 (m, 2H), 8.10 - 7.83 (m, 6H), 7.78 - 7.66 (m, 3H), 7.66 - 7.52 (m, 2H), 7.48 - 7.35 (m, 3H), 7.35 - 7.25 (m, 2H), 7.25 -7.13 (m, 1H), 7.09 (s, OH), 7.02 (s, 1H), 6.03 - 5.89 (m, 1H), 5.40 (d, J = 6.9 Hz, 1H), 5.07 -4.91 (m, 2H), 4.79 - 4.59 (m, 4H). 4.59 - 4.49 (m, 2H). 4.49 - 4.42 (m, 2H), 4.42 - 4.17 (m. 7H), 4.16 - 4.08 (m, 2H), 4.03 (s, 2H), 3.88 - 3.68 (m, 4H), 3.68 - 3.54 (m, 9H), 3.54 - 3.36 (m, 40H), 3.36 - 3.26 (m, 17H), 3.26 - 3.13 (m, 8H), 3.12 - 2.93 (m, 2H), 2.74 - 2.60 (m, 1H), 2.4626113- 2.32 (m, 3H), 2.28 (s, 3H). 2.25 - 2.14 (m, 4H). 2.14 - 2.05 (m. 3H). 2.03 - 1.93 (m. 2H), 1.93 - 1.78 (m, 7H), 1.78 - 1.56 (m, 3H), 1.57 - 1.43 (m, 4H), 1.34 (s, 8H), 1.28 - 1.17 o.o (m, 1H), 1.03 (s, 3H), 0.99 (s O D Q D, 3H), 0.91 - 0.77 (m, 6H).iy i T n^ o o / MM o o o o X X X Ao°°

[0312] The following illustrative linker-payload compoundswere m w yrMS? b b / / ??ad11e using the methods described in Example 3, and o o o o substituting the appropriate intermed o / of=—iates, and other reactants and / or...reagents. Linker-payloads wi MMth bromo acetamide conjugatioo o o o y An > > i, / .. ha"ndles were prepared via coupling of JV-hydroxysuccinimide bromoacetate to the correspond / \xin=IZg Fmoc-deprotected amine in the ^OXU °° “final step., A iZTZI' 'A ( o o= Example ( S °=tru >cture MS IZ1® / AOo \ [M+H 37 MH=X " ]z zz\ ro~ A 1000 \ j / i y &—— [M+2NH \\ \ r / ~ 4] \< yo=2+o o o o o o o o zz- (m / 2) o o o MM < Q.i.o o o o o ° zMMo o o o o o o oYY° o38 MM A u M° 1064 _ _ _ _ oo o o ' 'OX °yM< [M+2H]2+ ' o(w2)39 1025[M+H]2+(m / 2)26113 41 42 432611345 1459OH -^0 J k [M+Na]+.. r\i_ 1 xiXHO O^NH o^1 0= 00 (V Jx HO^Q^ 11 i " / K-> V _ / Y J. \\ / °^^ OH | L II ^O"'X JXS5 -O>°°'Vc -ox H=OW Y° ° C° )r Co Q1= / — ) AO O 2= - H AMH X A X A°o°° \o ^o^ / - y yrr?0 / )1b -z^——..?O V / 0 o b b / / 46 O zi OHO zi 1623 k ^OH K.. K.. ° ° [M+Na]+^ < O O.=,,_ ).o o= L J3H J<fOHH0| 0^^H0 / / ','| / \-''°H h0''> R^% | v” OOyo zi^- NHxV<o= ziY OH V < / ?'■■< <...8 1H8 20=(T^ 1H0 0 0 47 W v 1502[M+Na]+X(y48 1485[M+Na]+261132611326113Example 4Preparation of Linker-Payload 51Step A - synthesis of compound I-51a26113

[0313] To a mixture of (5S,8S)-l-(9H-fluoren-9-yl)-5,8-dimethyl-3,6,9-trioxo-2-oxa-4,7.10-triazaundecan-ll-yl acetate (1.09 g, 2.39 mmol) and cabazitaxel (1.00 g, 1.20 mmol) in DCM (12 mL) was added lithium / e / 7-buto\ide (172 mg, 2.15 mmol) at room temperature. After 20 minutes, the mixture was concentrated in vacuo, and the resulting residue was purified using reverse phase column chromatography (10-95% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S, HS,12S,12aR,12bS)-12b-acetoxy-9-(((5S,8S,13R)-13-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-l -(9H-fluoren-9-yl)-5,8-dimethyl-3,6,9-trioxo-2, 12-dioxa-4,7, 10-triazatetradecan- 14-oyl)oxy)- 11 -hy droxy-4,6-dimethoxy-4a,8, 13, 13-tetramethyl-5-oxo-2a,3.4.4a,5,6,9,10,l l,12,12a,12b-dodecahydro-lH-7.1 l-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate I-51a. LCMS (ESI) m / z'. 1252 [M+Na]+.Step B - synthesis of compound 1-5 lb

[0314] To a stirred solution of I-51a (664 mg, 540 pmol) in DMF (5 mL) was added triethylamine (0.75 mL, 5.40 mmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then a mixture ofN-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-L-serine xxviii (317 mg 648 pmol), HATU (246 mg, 648 pmol) and DIPEA (282 pL, 1.62 mmol) in DMF (2 mL) was added. After 15 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-80% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S, HS,12S,12aR,12bS)-12b-acetoxy-9-(((5S,8S,llS,16R)-16-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-l-(9H-fluoren-9-yl)-8,ll-dimethyl-3,6,9,12-tetraoxo-5-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2,15-dioxa-4,7,10,13-tetraazaheptadecan-17-oyl)oxy)- 11 -hydroxy-4, 6-dimethoxy-4a,8, 13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate I-51b. LCMS (ESI) m / z 1501 [M+Na]+.Step C - synthesis of compound I-51c

[0315] To a stirred solution of I-51b (466 mg, 315 pmol) in DMF (2 mL) was added triethylamine (571 pL, 4.10 mmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then 2,5-dioxopyrrolidin-l-yl 1 -(9H-fluoren-9-yl)-3-oxo-2,7,10-trioxa-4-azatridecan-13-oate (172 mg, 347 pmol) was added. After 1 hour, the reaction mixture was directly purified using reverse phase column chromatography (10-80% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((15S,18S,21S,26R)-26-((S)-((tert-26113butoxy carbony l)amino)(pheny l)methy 1)- 1 -(9H-fluoren-9-yl)- 18,21 -dimethyl -3, 13, 16, 19,22-pentaoxo-15-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2,7,10,25-tetraoxa-4,14,17,20,23-pentaazaheptacosan-27-oyl)oxy)-ll-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3.4]benzo[l,2-b]oxet-12-yl benzoate I-51c. LCMS (ESI) mZz: 1660 [M+Na]+.Step D - synthesis of compound 51

[0316] To a stirred solution of I-51c (180 mg, 98.9 pmol) in DMF (0.8 mL) was added triethylamine (138 pL, 989 pmol). and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then a mixture of (S)-53-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-50-oxo-2,5,8,ll,14,17,20,23,26,29,32,35,38,41,44,47-hexadecaoxa-51-azatetrapentacontan-54-oic acid iii (120 mg, 129 pmol), HATU (48.9 mg, 129 pmol) and DIPEA (51.7 pL, 297 pmol) in DMF (0.5 mL) was added. After 15 minutes, formic acid (74.6 pL, 1.98 mmol) was added and the reaction mixture was directly purified using reverse phase column chromatography (10-75% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((53S,66S,69S,72S,77R)-77-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-53-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-69,72-dimethyl-50,54,64.67,70,73-hexaoxo-66-((((2R,3R.4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2,5,8,ll,14,17,20,23,26,29,32,35,38,41,44,47,58,61,76-nonadecaoxa-51,55,65,68,71,74-hexaazaoctaheptacontan-78-oyl)oxy)-ll-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12.12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate 51. LCMS (ESI) m / z 1493 [M-CTX]+. 'H NMR (500 MHz, DMSO-de) 5 8.73 -8.59 (m, 1H), 8.16 - 8.05 (m, 2H), 8.05 - 7.94 (m, 3H), 7.94 - 7.83 (m, 2H), 7.74 - 7.65 (m, 1H), 7.65 - 7.53 (m, 2H), 7.43 - 7.26 (m, 5H), 7.26 - 7.16 (m, 1H), 7.03 (s, 2H), 6.01 - 5.89 (m, 1H), 5.39 (d, J = 7.0 Hz, 1H), 5.04 - 4.86 (m, 4H), 4.76 - 4.65 (m, 2H), 4.62 - 4.52 (m, 2H), 4.52 -4.45 (m, 2H), 4.45 - 4.37 (m, 1H). 4.37 - 4.24 (m, 1H). 4.24 - 4.12 (m, 2H), 4.03 (s. 2H), 3.98 -3.84 (m, 1H), 3.84 - 3.73 (m, 2H), 3.73 - 3.54 (m, 7H), 3.54 - 3.26 (m, 72H), 3.26 - 3.09 (m, 10H), 3.09 - 2.91 (m, 2H), 2.72 - 2.61 (m, 1H), 2.46 - 2.35 (m, 2H), 2.35 - 2.22 (m, 4H), 2.22 - 2.12 (m, 1H), 2.04 - 1.91 (m, 1H), 1.91 - 1.74 (m, 4H), 1.58 - 1.44 (m, 4H), 1.33 (s, 9H), 1.26 - 1.12 (m, 7H), 1.03 (s, 3H). 0.98 (s, 3H).

[0317] The following illustrative linker-payload compounds were made using the methods described in Example 4, and substituting the appropriate intermediates, and other reactants and / or26113reagents. Linker-payloads with bromo acetamide conjugation handles were prepared via coupling of V-hydroxysuccinimide bromoacetate to the corresponding Fmoc-deprotected am oine in the final step. _ / A X \A n VV’X1Example Structure A°° MS X A°°o / ' fM+H] 52 2() \. iuio / < ' °= 960 o / = [M+2H] ) 9 / \ IMM P=. JV >2+ TL VX °° (m / 2) Kk O Z1" 'AM x. M O_ °°ZI IZ zz IZ / M f.jo=53 r\~ 1451 \l —o 9 2y...o X 2.^- OH OH, o o o, O^NH 0i i H II “K / A Mo o o oo o o ozzo0Ho o o o yy% / Ho M ■ AK MM o o o oo o o o^NJYN-XNJYN-0O VIHS =Hs_ _ o o o oM^ $ 054 1 142[M+2H]2+ (m / 2)55 M _oo oz1129[M+2Na] OH OH,, M A T 1HO2 ^A ITA I / HNY O^ NH O + ° (m / 2) °H / O°H / U i °HOOAAo y o:oHN5o-^ / o'^'o-^°\261132611359\l -o 9 686[M- CTX] n OH OH O^N -H 0 || kA+— 7k ✓ r\°°M00 J OH OH L J =H°o= / —9 9 \ H H 9 I H i / As 00V— k 0 0=O0 A60 00 / \ 1839 / AA o\ / \ I [M+Na] X \ z z——+V / 0C>..-0 / I IQ O IZ> <.>°? 61 X"" O^ ° °v \ V< 0= zz- " J -0 9 / 1779 OH ■' XJ < / ?'■ O(iiiiin>i<>' [M+Na]+HO*.^ >° z / 1 1OH O NH 0 Q / ✓>< *HO'' rrV0''n H 9N-^?N-\ f° HN_A?NJ IYHN_O 100VJ J j H H n£H n 05:\ a=- / p OH QH crJk AyOHO N JHOH OH261132611326113149570 1448[M- CTX]+71 1078[M+2Na] 2+ (m / 2) 1573 [M+Na]+1143 [M+2Na] 2+ (m / 2)26113OHOH2611378 1437 ^\C o □ O 0>= / ^ 0=o o o o°A c ° w w -. )O O O= - o o o o y' ' O IZ — - / / ?$ h ' ):cb ' / z—— o o o o.< < ) < ° X _1\ ( ) { )Oo o Q;"= —' #T'< ZI Q O O O iz|" - - 7 / i y \ ' \1 Tb / 'o zi 1' 1111— ■.79O a==\\ ZE 1954 b111> ° ° °ZIZT / T\ / / < Q Q i ■TT_ [M+Na]+) (* ) (1o oo o o o -■; --== — — / ( ' O IZ) — — / X X / / b b )T)T' ' t ■?————- ^O °(1;x^ o o \-< y o= zi— ZI ZI / V 1 lll.«- bfY <j?" ° s / = >o \ Q.< yi on=. zi— TZ IZ< °? / ' / ^^~o^O b. ° °. ° V=. O“ / v\<, yo zi=- ° < / qr?" / ■ o / ...Q Q / / .Y°L ° Y°Y o ~O o °\ °\y <y <80 1969[M+Na]+81 1939[M+Na]+2611382 1186-O JO.0 [M+2H]2+ '' o 0 o DX A XYX (TM / 2) X A°°°°O O O O X A?°°XX '1w?1 / o o o o 5 X.o o o o / \^\,2 0 X>ZI °=2:° °"XIX / \L_. W X WIZ= °° A83X 'x. ZIZ 186 \ o ^o° LX| U5.'Y Q ° ° “ ° 0 O|. / — x) ( )xO p Q= — ^)^ \. ZI=^ °TZTZ / 'Tb -T— >.^ °TIZzzIZ I I > M r° tn / ■ I X >z—° r\ r\ i°z■ Q~— 'Ir\ r 5o o / o Q\ x= —~ ' ' 4 »T? qo O.\ ) p ° ''"1'£.,;> zzzzo o Jso o X “o p« «. \< vo zi=-,84 u o oo o 1139 o o000 o Qo t [M- X X CTX] o o o o+o o o ozYu Y°O\ _ _ _ O oD O ( uj _ j^^ oo oo^ OXX °x85 1186[M+2Na] 2+ (m / 2)26113261132611392 \l -o,9 1508OH [M+2Na] I-OK TA YX^,, H " A \ iOH O-^N 0 Yl A-A\ 2+ L A?1 bS-- / k\ Y no'' V 'rR (m / 2) o L J iHOnJ )—Br^fHN^A 9N^o^o^?lNl rhN^A?N1 IhN_0 fA n £hH n = H g \= / NH1 ^OHV? OH*x XoyA' Y< HTOHHC / Y\QOH HU<0H HOV '"X°HH°xH.0HHOHS / )X-<0\HOH'- / Y0^0-ozkf°e0" OH\OH93 1450\Jl -o,9on [M+2Na], Jx. A \ 1 2+ y YOHO NH O ✓>< *(m / 2) oH0' I0VNHHOHoWS / ohr < / °>-""°. < \.9 I J / -OH0'' |T OHHOOH ) \\? OHH0Y p°> O^S '^HI tl J 1 HHQ°, P b]f Y T)H \ _ TO / "'r / A V / OHH noV / . r oT" C c h OH0\^: A >""0' / ‘"'O"" \ JHO^* °^\HO261132611326113Example 5Preparation of Linker-Payload 9726113Step A - synthesis of compound l-97a

[0318] To a stirred mixture of Fmoc-Dap(PEG3-P-cyclodextrin)-OH xvii (373 mg, 223 pmol), HATU (84.7 mg, 223 pmol) and DIPEA (155 pL, 891 pmol) in DMF (1 mL) was added N-(amino-PEG3)- / V- / iA(PEG3-acid) hydrochloride (150 mg, pmol) at room temperature. After 15 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-80% MeCN / water with 0.1% formic acid modifier) to provide Fmoc-Dap(PEG3-P-cyclodextrin)-PEG3-A- / iA(PEG3-OH) I-97a. LCMS (ESI) m / z: 1129 [M+2H]2+(m / 2).Step B - synthesis of compound I-97b

[0319] To a stirred solution of I-51b (80.0 mg, 54.0 pmol) in DMF (1 mL) was added triethylamine (98.0 pL, 0.70 mmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then a mixture of Fmoc-Dap(PEG3-P-cyclodextrin)-PEG3-A- / iA(PEG3-OH) I-97a (61.0 mg, 27.0 pmol), HATU (23.0 mg, 60.0 pmol) and DIPEA (38.0 pL, 0.22 mmol) in DMF (0.5 mL) was added. After 15 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-80% MeCN / water with 0.1% formic acid modifier) to provide Fmoc-Dap(PEG3-P-cyclodextrin)-PEG3-jV- / ? A[PEG3-Ser(Glc)-Ala-Ala-NH-CH2-cabazitaxel] I-97b. LCMS (ESI) m / z: 1531 [M-2CTX]2+(m / 2, double hemiaminal fragment)'Step C - synthesis of compound 97

[0320] To a stirred solution of I-97b (95.0 mg, 20.0 pmol) in DMF (1 mL) was added tri ethylamine (42.0 pL, 0.30 mmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then maleimidoacetic acid N-hydroxysuccinimide ester (7.6 mg, 30.0 pmol) was added. After 30 minutes, formic acid (30 pL.0.80 mmol) was added and the reaction mixture was directly purified using reverse phase column chromatography (10-90% MeCN / water with 0.1% formic acid modifier) to provide MalCl-Dap(PEG3-P-cyclodextrin)-PEG3- / V- / iz '[PEG3-Ser(Glc)-Ala-Ala-NH-CH2-cabazitaxel] 97. LCMS (ESI) m / z: 1489 [M-2CTX]2+(m / 2, double hemiaminal fragment).1H NMR (500 MHz. DMSO- L) 58.75 - 8.62 (m. 2H), 8.14 - 8.05 (m. 2H), 8.05 - 7.88 (m, 8H), 7.74 - 7.65 (m, 3H), 7.65 - 7.57 (m, 4H), 7.45 - 7.28 (m, 9H), 7.28 - 7.17 (m, 2H), 7.10 (s, 2H), 6.01 - 5.93 (m, 2H), 5.88 - 5.58 (m, 12H), 5.40 (d, J = 6.8 Hz, 2H), 5.09 - 4.88 (m, 7H), 4.88 - 4.78 (m, 7H), 4.77 -4.64 (m, 5H), 4.63 - 4.38 (m, 13H), 4.38 - 4.27 (m, 4H), 4.27 - 4.13 (m, 4H), 4.10 (d, J = 7.8 Hz. 1H), 4.07 - 3.98 (m, 4H), 3.98 - 3.85 (m, 3H), 3.80 - 3.74 (m, 3H), 3.74 - 3.53 (m, 37H), 3.53 - 3.41 (m, 42H), 3.41 - 3.25 (m, 33H), 3.25 - 3.19 (m, 10H), 3.19 - 3.11 (m, 4H), 3.11 -2.94 (m, 4H), 2.75 - 2.63 (m, 8H), 2.47 - 2.38 (m, 5H), 2.38 - 2.20 (m, 9H), 2.06 - 1.93 (m, 2H),261131.93 - 1.75 (m. 8H). 1.60 - 1.44 (m. 8H), 1.34 (s. 18H). 1.28 - 1.13 (m, 13H), 1.04 (s. 6H), 0.99 (s, 6H).Example 6Preparation of Linker-Payload 200Step F200Step A - synthesis of compound I-200a26113

[0321] To a mixture of cabazitaxel (646 mg, 0.773 mmol), sodium iodide (116 mg, 0.773 mmol) and di-tert-butyl (chloromethyl) phosphate (200 mg, 0.773 mmol) in DCM (6 mL) was added lithium terf-butoxide (0.351 ml, 0.773 mmol) at room temperature. After 18 hours, the mixture was concentrated in vacuo, and the resulting residue was purified using reverse phase column chromatography (50-85% MeCN / water with 0.1% TFA modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((2R,3S)-3-((tert-butoxycarbonyl)amino)-2-(((di-tert-butoxyphosphoryl)oxy)methoxy)-3-phenylpropanoyl)oxy)-ll-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3.4]benzo[l,2-b]oxet-12-yl benzoate I-200a. LCMS (ESI) m / z: 1058 [M+H]+.Step B - synthesis of compound I-200b

[0322] A mixture of I-200a (214 mg, 0.202 mmol) in MeCN / H₂O / TFA= 5:5:1 (8 mL) was stirred at room temperature. After 18 hours, the mixture was directly lyophilized to provide (2aR,4S,4aS,6R,9S,l IS,12S, I2aR, I2bS)-12b-acetoxy-9-(((2R,3S)-3-amino-3-phenyl-2-((phosphonooxy)methoxy)propanoyl)oxy)-ll-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate I-200b. LC / MS: MS (ESI) m / z: 846 [M+H]+.Step C - synthesis of compound I-200c

[0323] To a mixture of (9H-fluoren-9-yl)methyl (2-((hydroxy(lH-imidazol-l-yl)phosphoryl)oxy)ethyl)carbamate (64.5 mg, 0.156 mmol), zinc chloride (1.559 ml, 1.559 mmol, 1 M solution in THF) in DMF (3 mL) was added I-200b (165 mg, 0.156 mmol) at room temperature. After 1.5 hours, the reaction mixture was directly purified using reverse phase column chromatography (30-60% MeCN / water with 0.1% TFA modifier) to provide (2aR,4S,4aS,6R,9S, HS,12S,12aR,12bS)-9-(((2R,3S)-2-((((((2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)(hydroxy)phosphoryl)oxy)(hydroxy)phosphoryl)oxy)methox y)-3-amino-3-phenylpropanoyl)oxy)-12b-acetoxy-ll-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethy 1-5 -oxo-2a,3,4,4a.5.6.9.10, 11, 12, 12a.12b-dodecahy dro- 1 H-7, 11 -methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate I-200c. LCMS (ESI) m / z: 1191 [M+H]L Step D - synthesis of compound I-200d

[0324] To a mixture of I-200c (178 mg, 0.149 mmol) in DCM (3 mL), was added di-te / 7-butyl dicarbonate (65.2 mg, 0.299 mmol) and triethylamine (0.062 ml, 0.448 mmol) at room temperature. After 18 hours, the mixture was concentrated in vacuo, and the resulting residue was purified using reverse phase column chromatography (27-57% MeCN / water with 10 mM26113NH4HCO3 modifier) to provide (2aR,4S,4aS,6R,9S. HS,12S.12aR.12bS)-9-(((2R,3S)-2-((((((2-((((9H-fluoren-9yl)methoxy)carbonyl)amino)ethoxy)(hydroxy)phosphoiyl)oxy)(hydroxy) phosphoryl) oxy)methoxy)-3-((tert-butoxycarbonyl)amino)-3-phenylpropanoyl)oxy)-12b-acetoxy-1 l-hydroxy-4.6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,l 1, 12.12a, 12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[ L2-b]oxet-12-yl benzoate I-200d. LCMS (ESI) m / z: 1291 [M+H]+.Step E - synthesis of compound I-200e

[0325] To a mixture of I-200d (75 mg, 0.058 mmol) in DMF (2 rnL), was added TEA (0.4 ml, 2.87 mmol) at room temperature. After stirring for 4 hours, the mixture was directly purified using reverse phase column chromatography (13-43% MeCN / water with 10 mM NH4HCO3 modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((2R,3S)-2-((((((2-aminoethoxy)(hydroxy)phosphoryl)oxy)(hydroxy)phosphoryl)oxy)methoxy)-3-((tert-butoxycarbonyl)amino)-3-phenylpropanoyl)oxy)-ll-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethy 1-5 -oxo-2a,3,4,4a,5,6,9, 10, 11, 12, 12a, 12b-dodecahy dro- 1 H-7, 11 -methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate I-200e. LCMS (ESI) m / z: 1069 |M+H|. Step F - synthesis of compound 200

[0326] To a mixture of (< S)-29-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-26-oxo- 2.5.8.11.14.17.20.23-octaoxa-27-azatriacontan-30-oic acid ii (10.8 mg, 0.019 mmol) in DMF (2 mL), was sequentially added HATU (10.67 mg, 0.028 mmol), I-200e (20 mg, 0.019 mmol) and DIPEA (9.80 pl, 0.056 mmol) at room temperature. After 1.5 hours, the reaction mixture was directly purified using reverse phase column chromatography (14-44% MeCN / water with 7 mM HCOONH4 modifier) to provide (S)-29-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-26,30-dioxo- 2.5.8.11.14.17.20.23-octaoxa-27,31-diazatritriacontan-33-yl dihydrogen diphosphate-CEb-cabazitaxel 200. LCMS (ESI) m / z: 1630 [M+H]+. 'H NMR (400 MHz, DMSO-r / 6) 5 = 8.17 - 8.04 (m, 1H), 8.01 - 7.88 (m, 2H), 7.79 - 7.59 (m, 3H), 7.38 - 7.22 (m, 10H), 7.15 - 7.11 (m, 1H), 6.94 (s, 1H), 5.91 - 5.72 (m, 1H), 5.39 - 5.25 (m, 1H), 5.21 (s, 1H), 4.96 - 4.91 (m, 1H), 4.77 (br d, J = 19.6 Hz, 2H), 4.68 (s, 1H). 4.52 (br s, 2H), 3.98 (br s. 2H), 3.91 - 3.70 (m, 4H), 3.58 (br dd, J = 2.7, 6.9 Hz, 2H), 3.51 - 3.48 (m, 28H), 3.46 (br d, J = 5.4 Hz, 3H), 3.42 (br d, J = 5.0 Hz, 5H), 3.41 (br s, 1H), 3.27 (s, 3H), 3.23 (s, 3H), 3.20 (s, 2H), 2.20 (br s, 4H), 1.77 (br s, 3H), 1.48 (s, 3H), 1.32 (br s. 9H), 1.03 - 0.90 (m, 6H).26113Example 7Preparation of Linker-Payload 201Step A - synthesis of compound 1-201 a26113

[0327] To a mixture of (5S,8S)-l-(9H-fluoren-9-yl)-5,8-dimethyl-3,6,9-trioxo-2-oxa-4,7.10-triazaundecan-ll-yl acetate (2.00 g, 4.41 mmol) and paclitaxel (2.64 g, 3.09 mmol) in DCM (70 mL) was added lithium / e / 7-buto\ide (353 mg, 4.41 mmol) at room temperature. After 1 hour, the mixture was concentrated in vacuo, and the resulting residue was purified using reverse phase column chromatography (10-95% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S, HS,12S,12aR,12bS)-9-(((5S,8S,13R)-13-((S)-benzamido(phenyl)methyl)-l-(9H-fluoren-9-yl)-5,8-dimethyl-3,6,9-trioxo-2,12-dioxa-4,7,10-triazatetradecan-14-oyl)oxy)-12-(benzoyloxy)-4,ll-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-3,4,4a,5,6,9,10,ll,12,12a-decahydro-lH-7.1 l-methanocyclodeca[3,4]benzo[l,2-b]oxete-6,12b(2aH)-diyl diacetate I-209a.LCMS (ESI)wZz: 1248 [M+H]+.Step B - synthesis of compound I-201b

[0328] To a stirred solution of I-201a (550 mg, 441 pmol) in DMF (4 mL) was added triethylamine (0.62 mL, 4.41 mmol), and the resulting mixture was warmed to 50 °C. After 1 hour, the mixture was cooled to room temperature, then a mixture ofN-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-L-serine xxviii (324 mg, 661 pmol), HATU (251 mg, 661 pmol) and DIPEA (230 pL, 1.32 mmol) in DMF (2 mL) was added. After 15 minutes, the reaction mixture was directly- purified using reverse phase column chromatography (10-80% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S, HS,12S,12aR,12bS)-9-(((5S,8S, HS,16R)-16-((S)-benzamido(phenyl)methyl)- 1 -(9H-fluoren-9-y l)-8, 11 -dimethyl-3,6,9, 12-tetraoxo-5-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2,15-dioxa-4,7,10,13-tetraazaheptadecan-17-oyl)oxy)-12-(benzoyloxy)-4,ll-dihydroxy-4a, 8, 13,13-tetramethyl-5-oxo-3,4,4a,5,6,9, 10,11,12, 12a-decahy dro- 1H-7, 11-methanocyclodeca[3,4]benzo[l,2-b]oxete-6,12b(2aH)-diyl diacetate I-201b. LCMS (ESI) ffi / z: 1519 [M+Na]+.Step C - synthesis of compound I-201c

[0329] To a stirred solution of I-201b (416 mg, 278 pmol) in DMF (2 mL) was added tri ethylamine (387 pL, 2.78 mmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then 2,5-dioxopyrrolidin-l-yl 1 -(9H-fluoren-9-yl)-3-oxo-2,7,10-trioxa-4-azatridecan-13-oate (179 mg, 361 pmol) was added. After 20 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-90% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-9-(((15S,18S,21S,26R)-26-((S)-26113benzamido(pheny l)methyl)- 1 -(9H-fluoren-9-y 1)- 18,21 -dimethy 1-3,13,16,19,22-pentaoxo- 15 -((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2,7,10,25-tetraoxa-4,14,17,20,23-pentaazaheptacosan-27 -oyl)oxy)-12-(benzoyloxy)-4,ll-dihydroxy-4a,8,13.13-tetramethyl-5-oxo-3,4,4a,5,6,9,10,ll,12,12a-decahydro-lH-7,ll-methanocyclodeca[3,4]benzo[ l,2-b]oxete-6,12b(2aH)-diyl diacetate I-201c. LCMS (ESI) m / z'.1678 [M+Na]+.Step D - synthesis of compound 201

[0330] To a stirred solution of I-201c (120 mg, 98.9 pmol) in DMF (0.8 mL) was added triethylamine (101 pL, 725 pmol). and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then a mixture of (S)-53-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-50-oxo-2,5,8,ll,14,17,20,23,26,29,32,35,38,41,44,47-hexadecaoxa-51-azatetrapentacontan-54-oic acid iii (101 mg, 109 pmol), HATU (41.3 mg, 109 pmol) and DIPEA (37.9 pL, 217 pmol) in DMF (0.5 mL) was added. After 15 minutes, formic acid (54.7 pL, 1.45 mmol) was added and the reaction mixture was directly purified using reverse phase column chromatography (10-75% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-9-(((53S,66S,69S,72S,77R)-77-((S)-benzamido(phenyl)methyl)-53-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-69,72-dimethyl-50,54,64.67,70,73-hexaoxo-66-((((2R.3R.4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2,5,8,ll,14,17,20,23,26,29,32,35,38,41,44,47,58,61,76-nonadecaoxa-51,55,65,68,71,74-hexaazaoctaheptacontan-78-oyl)oxy)-12-(benzoyloxy)-4,ll-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-3, 4, 4a.5.6.9.10, 11,12, 12a-decahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxete-6,12b(2aH)-diyl diacetate 201. LCMS (ESI) m z 1196 [M+2Na]2+(m / 2). 'H NMR (500 MHz. DMSO-O 58.90 - 8.80 (m, 1H), 8.80 - 8.70 (m, 1H), 8.16 - 7.81 (m, 10H), 7.70 (t, J= 7.4 Hz, 1H), 7.61 (t, J= 7.6 Hz, 2H), 7.54 (t, J= 7.4 Hz, 1H), 7.49 - 7.36 (m, 7H), 7.30 - 7.22 (m, 1H), 7.04 (s.2H), 6.33 (s, 1H), 6.03 - 5.93 (m, 1H), 5.65 - 5.56 (m, 1H), 5.45 (d, J = 7.0 Hz, 1H), 5.03 - 4.86 (m. 4H), 4.82 - 4.71 (m. 2H), 4.71 - 4.54 (m. 3H), 4.54 - 4.46 (m, 2H), 4.38 - 4.09 (m, 4H), 4.09 - 4.00 (m, 2H), 4.00 - 3.83 (m, 1H), 3.83 - 3.75 (m, 1H), 3.75 - 3.63 (m, 2H), 3.63 - 3.55 (m, 3H), 3.55 - 3.42 (m, 65H), 3.42 - 3.34 (m, 3H), 3.24 (s, 3H), 3.22 - 3.10 (m, 4H), 3.10 - 2.91 (m, 2H), 2.47 - 2.24 (m, 8H), 2.24 - 2.15 (m, 2H), 2.15 - 2.01 (m, 4H), 1.94 - 1.78 (m.4H), 1.72 - 1.58 (m, 1H), 1.52 (s, 3H), 1.28 - 1.10 (m, 6H), 1.04 (s, 6H).26113Example 8Preparation of Linker-Payload 202Step A - synthesis of compound I-202a26113

[0331] To a mixture of (5S,8S)-l-(9H-fluoren-9-yl)-5,8-dimethyl-3,6,9-trioxo-2-oxa-4,7.10-triazaundecan-11-yl acetate (2.00 g, 4.41 mmol) and docetaxel (2.49 g, 3.09 mmol) in DCM (70 mL) was added lithium / e / 7-buto\ide (353 mg, 4.41 mmol) at room temperature. After 1 hour, the mixture was concentrated in vacuo, and the resulting residue was purified using reverse phase column chromatography (10-95% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S, HS,12S,12aR,12bS)-12b-acetoxy-9-(((5S,8S,13R)-13-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-l -(9H-fluoren-9-yl)-5,8-dimethyl-3,6,9-trioxo-2, 12-dioxa-4,7, 10-tri azatetradecan- 14-oyl)oxy)-4,6, 11 -trihydroxy-4a,8, 13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12.12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate I-202a. LCMS (ESI) m / z'. 1201 [M+H]+.Step B - synthesis of compound I-202b

[0332] To a stirred solution of I-202a (500 mg, 441 pmol) in DMF (4 mL) was added triethylamine (0.58 mL, 4.16 mmol), and the resulting mixture was warmed to 50 °C. After 1 hour, the mixture was cooled to room temperature, then a mixture ofN-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-L-serine xxviii (306 mg, 624 pmol), HATU (237 mg, 624 pmol) and DIPEA (217 pL, 1.25 mmol) in DMF (2 mL) was added. After 15 minutes, the reaction mixture was directly- purified using reverse phase column chromatography (10-80% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S, HS,12S,12aR,12bS)-12b-acetoxy-9-(((5S,8S,llS,16R)-16-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-l-(9H-fluoren-9-yl)-8,ll-dimethyl-3,6,9,12-tetraoxo-5-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2,15-dioxa-4,7,10,13-tetraazaheptadecan-17-oyl)oxy)-4,6,ll-trihydroxy-4a,8.13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate I-202b. LCMS (ESI) m / z 1473 [M+Na]+.Step C - synthesis of compound I-202c

[0333] To a stirred solution of I-202b (469 mg, 323 pmol) in DMF (2 mL) was added triethylamine (451 pL, 3.23 mmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then 2,5-dioxopyrrolidin-l-yl 1 -(9H-fluoren-9-yl)-3-oxo-2,7,10-trioxa-4-azatridecan-13-oate (209 mg, 420 pmol) was added. After 20 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-90% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((15S,18S,21S,26R)-26-((S)-((tert-26113butoxy carbony l)amino)(pheny l)methy 1)- 1 -(9H-fluoren-9-yl)- 18,21 -dimethyl -3, 13, 16, 19,22-pentaoxo-15-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2,7,10,25-tetraoxa-4,14,17,20,23-pentaazaheptacosan-27 -oyl)oxy)-4,6,ll-trihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3.4]benzo[l,2-b]oxet-12-yl benzoate I-202c. LCMS (ESI) m / z: 1632 [M+Na]+.Step D - synthesis of compound 202

[0334] To a stirred solution of I-202c (120 mg, 98.9 pmol) in DMF (0.8 mL) was added triethylamine (101 pL, 725 pmol). and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then a mixture of (S)-53-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-50-oxo-2,5,8,ll,14,17,20,23,26,29,32,35,38,41,44,47-hexadecaoxa-51-azatetrapentacontan-54-oic acid iii (104 mg, 112 pmol), HATU (42.5 mg, 112 pmol) and DIPEA (39.0 pL, 224 pmol) in DMF (0.5 mL) was added. After 15 minutes, formic acid (56.3 pL, 1.49 mmol) was added and the reaction mixture was directly purified using reverse phase column chromatography (10-75% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((53S,66S,69S,72S,77R)-77-((S)-((tert-butoxycarbonyl)amino)(phenyl)methyl)-53-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-69,72-dimethyl-50,54,64.67,70,73-hexaoxo-66-((((2R,3R.4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2,5,8,ll,14,17,20,23,26,29,32,35,38,41,44,47,58,61,76-nonadecaoxa-51,55,65,68,71,74-hexaazaoctaheptacontan-78-oyl)oxy)-4,6,ll-trihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12.12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl benzoate 202. LCMS (ESI) m / z 1173 [M+2Na]2+(m / 2). 'H NMR (500 MHz, DMSO) 5 8.73 - 8.59 (m, 1H), 8.17 - 7.83 (m, 6H), 7.75 - 7.67 (m, 1H), 7.67 - 7.57 (m, 2H), 7.43 - 7.26 (m, 4H), 7.24 - 7.17 (m, 1H), 7.04 (s, 2H), 5.98 - 5.86 (m, 1H), 5.43 (d, J= 6.8 Hz, 1H), 5.17 - 5.08 (m, 1H), 5.06 - 4.89 (m, 6H). 4.78 - 4.69 (m, 1H), 4.62 - 4.55 (m, 1H), 4.55 - 4.45 (m, 3H), 4.45 - 4.38 (m. 1H), 4.38 - 4.25 (m. 1H), 4.25 - 4.13 (m. 2H), 4.12 - 4.00 (m, 3H), 4.00 - 3.85 (m, 1H), 3.85 - 3.75 (m, 1H), 3.75 - 3.63 (m, 2H), 3.63 - 3.55 (m, 4H), 3.55 - 3.41 (m, 68H), 3.41 - 3.34 (m, 3H), 3.24 (s, 3H), 3.22 - 3.09 (m, 4H), 3.09 - 2.93 (m, 2H), 2.48 - 2.34 (m, 4H), 2.34 - 2.23 (m, 5H), 2.23 - 2.13 (m, 2H), 1.88 - 1.76 (m, 4H), 1.71 - 1.59 (m, 1H), 1.53 (s, 3H), 1.34 (s, 9H), 1.26 - 1.12 (m, 6H), 1.07 - 0.96 (m, 6H).26113Example 9Preparation of Linker-Payload 203Step A - synthesis of compound I-203b

[0335] To a mixture of (5S,8S)-l-(9H-fluoren-9-yl)-5,8-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazaundecan-ll-yl acetate (478 mg, 1.05 mmol) and (2aR,4S,4aS,6R,9S,l! S,12S,12aR,12bS)-12b-acetoxy-9-(((2R,3S)-3-((tert-butoxycarbonyl)amino)-5,5-difluoro-2-hydroxypent-4-26113enoyl)oxy)-l 1 -hydroxy-4.6-dimelhoxy-4a.8. l3.l3-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl 3-(difluoromethoxy)benzoate I-203a (made using the method described in Bioorg. Chem.2022, 119, 105578) (520 mg, 586 pmol) in DCM (2 mL) and THF (4 mL) was added lithium / e / 7-butoxide (84.4 mg, 1.05 mmol) at room temperature. After 10 minutes, the mixture was concentrated in vacuo, and the resulting residue was purified using reverse phase column chromatography (10-95% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((5S,8S,13R)-13-((S)-l-((tert-butoxycarbonyl)amino)-3,3-difluoroallyl)-l-(9H-fluoren-9-yl)-5,8-dimethyl-3,6,9-trioxo-2,12-dioxa-4,7, 10-triazatetradecan-14-oyl)oxy)- 11 -hy droxy-4,6-dimethoxy-4a,8, 13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl 3-(difluoromethoxy)benzoate I-203b. LCMS (ESI) m / z: 1282 [M+H]+Step B - synthesis of compound I-203c

[0336] To a stirred solution of I-203b (565 mg, 441 pmol) in DMF (4 mL) was added triethylamine (0.49 mL, 3.53 mmol), and the resulting mixture was warmed to 50 °C. After 1.5 hours, the mixture was cooled to room temperature, then a mixture ofN-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-L-serine xxviii (345 mg, 706 pmol), HATU (268 mg. 706 pmol) and DIPEA (230 pL, 1.325 mmol) in DMF (2 mL) was added. After 15 minutes, the reaction mixture was directly purified using reverse phase column chromatography (10-95% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S, HS,12S,12aR,12bS)-12b-acetoxy-9- (((5 S, 8S, 11 S, 16R)- 16-((S)- 1 -((tert-butoxy carbony l)amino)-3.3 -difluoroallyl)- 1 -(9H-fluoren-9-yl)-8,ll-dimethyl-3,6,9,12-tetraoxo-5-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2, 15-dioxa-4,7, 10,13-tetraazaheptadecan-17-oyl)oxy)-ll-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl 3-(difluoromethoxy)benzoate I-203c. LCMS (ESI) m / z: 1531 [M+H]+.Step C - synthesis of compound I-203d

[0337] To a stirred solution of I-203c (540 mg, 353 pmol) in DMF (3.5 mL) was added triethylamine (492 pL, 3.53 mmol), and the resulting mixture was warmed to 50 °C. After 2 hours, the mixture was cooled to room temperature, then 2,5-dioxopyrrolidin-l-yl 1 -(9H-fluoren-9-yl)-3-oxo-2,7,10-trioxa-4-azatridecan-13-oate (193 mg, 388 pmol) was added. After 20 minutes, the reaction mixture was directly purified using reverse phase column chromatography26113(10-90% MeCN / water with 0.1% formic acid modifier) to provide (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((15S,18S,21S,26R)-26-((S)-l-((tert-butoxycarbonyl)amino)-3,3-difluoroallyl)-l-(9H-fluoren-9-yl)-18,21-dimethyl-3,13,16,19,22-pentaoxo-15-((((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-2,7,10.25-tetraoxa-4,14.17,20,23-pentaazaheptacosan-27-oyl)oxy)-l 1-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,l l,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl 3-(difluoromethoxy)benzoate I-203d. LCMS (ESI) m / z: 1712 [M+Na]+.Step D - synthesis of compound 203

[0338] To a stirred solution of I-203d (170 mg, 101 pmol) in DMF (1.0 mL) was added tri ethylamine (140 pL. 1.01 mmol), and the resulting mixture was warmed to 50 °C. After 1 hour, the mixture was cooled to room temperature, then a mixture of (S)-53-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-50-oxo-2,5,8,l l,14,17,20,23,26,29,32,35,38,41,44.47-hexadecaoxa-51-azatetrapentacontan-54-oic acid iii (141 mg, 151 pmol). HATU (57.4 mg, 151 pmol) and DIPEA (52.6 pL, 302 pmol) in DMF (0.5 mL) was added. After 15 minutes, formic acid (75.9 pL, 2.01 mmol) was added and the reaction mixture was directly purified using reverse phase column chromatography (10-75% MeCN / water with 0.1% formic acid modifier) to provide (2aR.4S,4aS.6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-9-(((53S,66S,69S.72S,77R)-77-((S)-l-((tert-butoxycarbonyl)amino)-3,3-difluoroallyl)-53-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-69,72-dimethyl-50,54,64,67,70,73-hexaoxo-66-((((2R,3R,4S,5S,6R)-3,4,5-tnhydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)- 2,5,8,1 l,14,17,20,23,26,29,32.35,38,41,44,47.58,61,76-nonadecaoxa-51,55,65.68,71,74-hexaazaoctaheptacontan-78-oyl)oxy)- 11 -hy droxy-4,6-dimethoxy-4a,8, 13, 13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-12-yl 3-(difluoromethoxy)benzoate 203. LCMS (ESI) m / z'. 1213 [M+2Na]2+(m / 2).'H NMR (500 MHz, DMSO) 5 8.78 - 8.64 (m, 1H). 8.17 - 7.84 (m, 6H), 7.78 (s, 1H), 7.67 -7.57 (m, 1H), 7.54 - 7.48 (m, 1H). 7.31 (t. J = 73.5 Hz, 1H), 7.16 - 7.07 (m, 1H), 7.04 (s, 2H).6.05 - 5.95 (m, 1H), 5.43 (d, J= 6.8 Hz, 1H), 5.06 - 4.91 (m, 3H), 4.83 - 4.66 (m, 5H), 4.66 -4.42 (m, 4H), 4.41 - 4.08 (m, 5H), 4.03 (d, J= 7.7 Hz, 1H), 3.99 - 3.85 (m, 1H), 3.86 - 3.68 (m, 4H), 3.68 - 3.55 (m, 4H), 3.55 - 3.40 (m, 66H), 3.40 - 3.35 (m, 3H), 3.27 - 3.21 (m, 8H), 3.21 -3.10 (m, 4H), 3.10 - 2.93 (m, 2H). 2.78 - 2.62 (m, 2H). 2.47 - 2.39 (m, 2H), 2.39 - 2.14 (m. 8H), 1.92 (s, 3H), 1.59 - 1.44 (m, 4H), 1.31 (s, 9H), 1.28 - 1.18 (m, 6H), 1.07 (s, 3H), 1.02 (s, 3H).26113Example 10Antibody Conjugation Protocol to Prepare Antibody-Drug Conjugate Examples 100-198 and 204-208

[0339] Illustrative Linker-Payload Compounds of the Present Disclosure were conjugated to an anti-PSMA antibody, using the following conjugation protocol:

[0340] For maleimide conjugations: An aqueous 10 mM solution of 3,3',3"-phosphanetriyltripropionic acid hydrochloride (6 eq., 49 pL, 0.49 pmol) was added to the antibody (Rosopatamab or Pelgifatamab, 12 mg), and the mAb was reduced for 2 h at 23 °C. DMSO (100 pL) was added, followed by a 10 mM DMSO solution of 1 (41 pL, 5 eq.). After 30 minutes, a second portion of 10 mM DMSO solution of 1 (41 pL, 5 eq.) was added, and the resulting reaction was mixed at 23 °C overnight.

[0341] The mixture was then purified via SEC column (AKTA™ chromatography sy stem, PBS mobile phase, monitoring at 280 nm), and the resulting conjugate is exchanged into 10 mM pH 6.0 histidine buffer, followed by addition of 9% sucrose to provide ADC example 100. The solution was characterized by LCMS (Agilent PLRP-S column, 1000 A, 5 pm, 15-90% MeCN / H2O with 0.1% formic acid, 80 °C column temperature) and SEC (Acquity UPLC Protein BEH SEC, 200 A, 1.7 pm. 100 mM sodium phosphate, 200 mM NaCl, 0.02% azide, 5% IPA added to mobile phase for hydrophobic ADCs).

[0342] For bromo acetamide conjugations: The antibody (Rosopatamab or Pelgifatamab, 12 mg) was exchanged into PBS (10 mM pH 7.4) and taken to a concentration of 10 mg / mL in PBS (1500 pL) and Tns / EDTA (400 pL) (10% v / v 500 mM pH 8 TRIS / 90% 25 mM EDTA). An aqueous 10 mM solution of 3,3',3"-phosphanetriyltripropionic acid hydrochloride (6 eq., 49 pL, 0.49 pmol) was added, and the mAh was reduced for 2 h at 23 °C. DMSO (100 pL) was added, followed by a 10 mM DMSO solution of 1 (41 pL, 5 eq.). After 30 minutes, a second portion of 10 mM DMSO solution of 1 (41 pL. 5 eq.) was added, and the resulting reaction was mixed at 23 °C overnight.

[0343] The mixture was then purified via SEC column (AKTA™ chromatography system, PBS mobile phase, monitoring at 280 nm), and the resulting conjugate is exchanged into 10 mM pH 6.0 histidine buffer, followed by addition of 9% sucrose to provide ADC example 100. The solution was characterized by LCMS (Agilent PLRP-S column, 1000 A, 5 pm, 15-90% MeCN / H2O with 0.1% formic acid, 80 °C column temperature) and SEC (Acquity UPLC Protein26113BEH SEC, 200 Å, 1.7 μm, 100 mM sodium phosphate, 200 mM NaCl, 0.02% azide, 5% IPA added to mobile phase for hydrophobic ADCs).

[0344] The following table demonstrates average DAR and percent aggregation for Rosopatamab or Pelgifatamab ADCs utilizing the illustrative compounds of the present disclosure and the aforementioned conjugation protocol:Linker- ADC Avg.Payload %AggregationExample DARExample100 1 8.0 1.5101 2 7.7 8.4102 3 8.0 6.9103 4 8.0 9.5104 5 8.0 1.6105 6 7.6 2.5106 7 2.4 6.9107 8 8.0 1.1108 9 8.0 2.0109 10 7.7 1110 11 8.0 50.0111 12 8.0 1.6112 13 8.0 0.8113 14 8.0 3.3114 15 6.1 5.6115 16 8.0 2.5116 17 7.9 1.8117 18 4.8 1.9118 19 8.0 1119 20 7.9 2.8120 21 8.0 0.3121 22 8.0 2.5122 23 8.0 100123 24 8.0 25124 25 8.0 6.5125 26 8.0 2.2126 27 8.0 3.2127 28 8.0 16.3128 29 8.0 3.2129 30 7.9 1.8130 31 7.6 1.2131 32 8.0 100132 33 8.0 1.526113133 34 8.0 3.2 134 35 8.0 100 135 36 8.0 1.3 136 37 7.9 1.0 137 38 8.0 0.9 138 39 3.1 2.7 139 40 8.0 10.5 140 41 7.7 4.2 141 42 8.0 3.1 142 43 6.7 4.7 143 44 7.9 0.9 144 45 8.0 4.6 145 46 7.9 4.5 146 47 8.0 3.7 147 48 8.0 3.1 148 49 8.0 0.7 149 50 8.0 1.6 150 51 8.0 1.6 151 52 3.1 7.0 152 53 5.4 3.8 153 54 7.0 2.4 154 55 7.3 3.2 155 56 7.5 8.7 156 57 7.9 8.4 157 58 8.0 12.0 158 59 6.0 28.0 159 60 8.0 7.6 160 61 7.6 19.8 161 62 8.0 2.3 162 63 3.4 6.0 163 64 8.0 10.5 164 65 8.0 23.0 165 66 8.0 15.0 166 67 2.6 3.8 167 68 6.9 6.7 168 69 7.9 6.6 169 70 8.0 1.8 170 71 7.6 7.3 171 72 7.9 38.0 172 73 8.0 1.1 173 74 8.0 1.6 174 75 7.0 1.1175 76 8.0 50.026113176 77 7.4 4.4177 78 7.0 50.0178 79 7.1 8.7179 80 5.7 3.2180 81 7.6 4.0181 82 7.5 3.5182 83 7.3 10.0183 84 7.3 40.0184 85 8.0 3.2185 86 8.0 1.0186 87 8.0 1.4187 88 8.0 2.7188 89 8.0 2.6189 90 7.8 3.5190 91 7.8 1.2191 92 7.8 0.4192 93 8.0 0.4193 94 8.0 4.3194 95 8.0 2.2195 96 8.0 100196 97 10.0 48197 98 8.0 0.3198 99 8.0 1.3204 199 8.0 10.9205 200 7.5 0.1206 201 7.8 0.5207 202 7.8 0.5208 203 7.8 0.7Example 11LNCaP Cytotoxicity Assay Protocol for Selected ADCs of the Present Disclosure

[0345] Illustrative Rosopatamab or Pelgifatamab antibody-drug conjugates of the Present Disclosure (Examples 100-198 and 204-208) were subjected to a cell-based cytotoxicity assay (LNCaP cells, CellTiter-Glo® 2.0 Cytotoxicity7Assay) utilizing the following protocol:

[0346] Prostate carcinoma cells LNCaP clone FGC were pre-characterized for PSMA cell surface expressions. LNCaP cells had average PSMA copy number 82,187, and served as PSMA high-expressing target cells in the assay. LNCap cell line was cultured in RPMI 1640 medium (Gibco™ 11875-093) supplemented with 10% Heat Inactivated Fetal Bovine Serum (Gibco™ A56708-01), 2mM L-Glutamine (Corning™ 25-0050CV), and 1% of Pen Strep(Gibco™ 15140-26113122) in T75 flasks. Medium was aspirated when cells reached about 80% confluency. Five (5) mL of TrypLE Express(Gibco™ 12604-013) was added into each flask and incubated at 37 °C for 5 minutes to dissociate cells. Next 5 mL of cell culture medium was added into the flask containing dissociated cells, and pipetted up and down a few times to break the cell clumps. The cell suspension 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 LNCaP cells were filtered through 30 / / m Pre-separation Filters (Miltenyi 130-041-407). Cells were counted with Vi-CELL, then plated into 96-well flat bottom plates (Costar™ 3610) in 50 gL of cell culture medium with seeding density of 5000 LNCaP cells per well. A 10-step 1 to 5 serial dilution of antibody -drug conjugates in cell culture medium was prepared starting from 1330 nM as the highest concentration. 50 / / L of dilutes was added into each well that was pre-plated with target cells (100 / zL total volume per well and 665 nM as the highest final concentration). The plates were incubated in a 37°C cell culture incubator for 120 hours. At the end of the incubation, CellTiter-Glo™ One Solution was thawed and allowed to equilibrate to room temperature, and 100 / / L was added into each well. Plates were put on an orbital shaker at speed 300 rpm for 5 minutes to stabilize luminescent signal. Luminescence was recorded on PerkinElmer Multimode Plate Reader EnVision™. Percent of proliferation was calculated using raw readings of each well divided by average luminescence of wells containing cells without ADC treatment from each corresponding plate. Half-maximal inhibitory concentration for Proliferation IC50 (nM) was calculated with GraphPad Prism 10 [four-parameter non-linear regression with constraints set as bottom>0% & top<20%],

[0347] Illustrative Examples of the Present Disclosure were tested, and results are provided below:ADC LNCaP ADC LNCaPExample EC5O (nM) Example EC5O (nM)100 2.3 156 88.9101 2.1 157 2.4102 29.5 158 NA103 2.0 159 8.3104 2.6 160 8.8105 2.9 161 41.3106 10.2 162 66.5107 13.3 163 37.5108 1.5 164 25.9109 1.4 165 NA110 NA 166 9.826113111 7.5 167 20.2 112 10.4 168 2.8 113 9.2 169 2.0 114 5.8 170 2.5 115 9.3 171 NA 116 2.0 172 2.7 117 10.2 173 2.7 118 4 174 2.8 119 3.2 175 NA 120 3 176 2.6 121 4.2 177 NA 122 NA 178 6.2 123 NA 179 4.3 124 5 180 3.4 125 8.5 181 4.6 126 1.3 182 3.3 127 13.7 183 NA 128 1.1 184 4.7 129 2.6 185 5.2 130 3.3 186 7.4 131 NA 187 8.7 132 2 188 3.7 133 1.6 189 3.7 134 NA 190 5.1 135 2.6 191 5.5 136 65.9 192 15.7 137 41.4 193 4.9 138 119.0 194 5.8 139 6.3 195 NA 140 5.5 196 NA 141 2.3 197 2.2 142 7.4 198 2.7 143 12.5 204 2.0 144 3.5 205 0.6 145 4.3 206 95.1 146 5.9 207 0.7 147 3 208 0.3 148 1.3149 3150 3.0151 NA152 4.7153 60.326113154 69.6155 43.4 NA = Not available

Claims

1. WHAT IS CLAIMED:

1. A compound comprising structural Formula I:

4.

5. (I) or a pharmaceutically acceptable salt thereof,6.wherein:7.D is selected from:

9. 11.or a taxane derivative;12.A is selected from a bond, -(C(O)N(R9))r-, -(C(O)N(R9)CH2N(R9))-, -CH2CH2(OCH2CH2)rC(O)NH-, -(OCH2CH2)rC(O)NH-. -C(O)NH-(OCH2CH2),-CH2CH2-C(O)NH-, and -NHC(O)C(R8)2C(O)NH-;13.X is a bond, or -(O-P(O)(OH)-O)r each occurrence of Y is independently selected from -CH(R4)-. -CH(R4)-CH(R4)-, and -CH(R4)-CH(R4)-CH(R4)-, wherein R4can be the same or different when Y is -CH(R4)-CH(R4)-or -CH(R4)-CH(R4)-CH(R4)-;14.Z is -CH(R2)- or -CH2CH2-;15.R1is Br or maleimide or a bond;16.R2is selected from H, Ci-Ce alkyl, benzyl, -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)S-CH3, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-NHC(O)-(CH2CH2O)s-(Ci-C3 alkylene)n-R7, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C3 alkylene)-R5, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), -(C1-C3 alkylene)-NHC(O)-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), and17.OH HO HO19. 21.R3is selected fromH, Ci-Ce alkyl, benzyl. -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C4 alkylene)-NHC(O)-(6-membered monocyclic saccharide), — (Ci-C3 alkylene)-R5, -(C1-C3 alky lene)n-NHC(O)-CH2CH2-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-NHC(O)-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-CH2CH2-C(O)NHCH2(CH(OH))tCH2OH, -(C 1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-(C1-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)n-C(O)NH- (CH2CH2O)s-(Ci-C3 alkylene)- C(O)NH-R7. -(C1-C3 alkylene)-C(O)NH-(Ci-C? alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-Ce alkyl), and23. 25.each occurrence of R4is independently selected from H, Ci-Ce alkyl, benzyl, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C3 alkylene)-R3, -(C1-C3 alkydene)n-NHC(O)-CH2CH2-(CH2CH2O)S-(CI-C6alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C6alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C3alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), -(C1-C3 alkylene)-NH-C(O)NH2, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, and27.

28. o29.R5is selected from -OH, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -NHC(O)NH2, -C(O)OH. -C(O)O-benzyl, -C(O)NH2, -C(O)NHCH2(CH(OH))tCH2OH. -C(O)NHCH2CH2N(CH3)2and -C(O)NHCH2CH2N+(CH3)3;30.R7is selected from H, 5 or 6-membered heteroaryl, NH32.

33. HO34.wherein said 5 or 6-membered heteroaryl group can be optionally substituted with a 6-membered monocyclic saccharide, and wherein said 6-membered monocyclic saccharide group can be optionally substituted with another 6-membered monocyclic saccharide, which can be the same or different;35.each occurrence of R8is independently H or Ci-Ce alkyl, or both R8groups, together with the carbon atom to which they are attached, join to form a O-C > cycloalkyl group;36.each occurrence of R9is independently H or Ci-Ce alkyl;37.m is an integer from 0 to 2;38.each occurrence of n is independently 0 or 1;39.q is an integer from 0 to 6;40.each occurrence of r is an integer from 1 to 3;41.each occurrence of s is independently an integer from 1 to 20; and42.each occurrence of t is independently an integer from 1 to 4. 261132. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is Br, and Z is -CH2-.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is maleimide, and Z is -CH(R2)- or -CH2CH2-.

4. The compound according to claim 1, which is a compound of Formula (la’):

47.

48. (la')49.or a pharmaceutically acceptable salt thereof, wherein A, Y, Z, R3, m, and q are as defined in claim 1.

5. The Compound according to claim 1, of Formula (lb’):

52. 54.(lb )55.or a pharmaceutically acceptable salt thereof, wherein A, Y, Z, R3, m, and q are as defined in claim 1.

6. The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein R2is selected from H,57.

7. The compound of any of claims 1-4, and 6, or a pharmaceutically acceptable salt thereof, wherein R3is selected from -CH3, -CH2OH,o o o60.

61. 2611362.OH64.

8. The compound of any one of claims 1-4, 6 or 7, or a pharmaceutically acceptable salt thereof, wherein each occurrence of R4is independently selected from H, methyl, isopropyl, benzyl. -CH2COOH. -CH2CH2COOH, -CH2C(O)NH2, -CH2CH2C(O)NH2. -(CH2)3NHC(O)NH2, -CH2CH2C(O)NHCH2CH2N (CH3)3,67.and69.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein each occurrence of s is independently selected from 8, 12 or 16.2611310. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein each occurrence of t is 4.

11. The compound of any one of claims 1-10 wherein D is:

75.

12. The compound of any one of claims 1-10 wherein D is:

79.

13. The compound of any one of claims 1-10 wherein D is:

83.

14. The compound of any one of claims 1-10 wherein D is:2611387.

15. A compound of claim 1, or a pharmaceutically acceptable salt thereof, being any of the compounds numbered 1-99 and 199-203 in the above specification.

16. An antibody-drug conjugate comprising structural Formula (II):

92.

93. (II)94.or a pharmaceutically acceptable salt thereof,95.wherein96.L is a ligand;97.D is selected from:

98. 100.or a taxane derivative;101.A is selected from a bond, -(C(O)N(R9))r-, -CH2CH2(OCH2CH2)rC(O)NH-, -(OCH2CH2)rC(O)NH-, -C(O)NH-(OCH2CH2)r-CH2CH2-C(O)NH-, and -NHC(O)C(R8)2C(O)NH-102.X is a bond, or -(O-P(O)(OH)-O)r-;103.each occurrence of Y is independently selected from -CH(R4)-, -CH(R4)-CH(R4)-, and -CH(R4)-CH(R4)-CH(R4)-, wherein R4can be the same or different when Y is -CH(R4)-CH(R4)-or -CH(R4)-CH(R4)-CH(R4)-;104.Z is -CH(R2)- or -CH2CH2-;105.R2is selected from H, Ci-Ce alkyl, benzyl, -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)S-CH3, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-NHC(O)-(CH2CH2O)s-(Ci-C3 alkylene)n-R7, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C3 alkylene)-R5, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7. -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-(Ci-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci- C3alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), -(C1-C3 alkylene)-NHC(0)-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), and107. 109.R3is selected from H, Ci-Ce alkyl, benzyl, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C4 alkylene)-NHC(O)-(6-membered monocyclic saccharide), -(Ci-C3 alkylene)-R5, -(C1-C3 alkylene)., -NHC(O)-CH2CH2-(CH2CH2O)s-(Ci-C alkylene)-R7, -(C1-C3 alkylene)n-NHC(O)-(CH2CH2O)s-(Ci-C6alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C6alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-CH2CH2-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-(C1-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)n-C(O)NH- (CH2CH2O)S-(CI-C3alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-Ce alkyl), and111. 113.each occurrence of R4is independently selected fromH, Ci-Ce alkyl, benzyl, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C3 alkylene)-R5, -(C1-C3 alkylene)n- NHC(O)-CH2CH2-(CH2CH2O)S-(CI-C6alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 aJkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), -(C1-C3 alkylene)-NH-C(O)NH2, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, and115. 117.R5is selected from -OH, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -NHC(O)NH2, -C(O)OH, -C(O)O-benzyl, -C(O)NH2, -C(O)NHCH2(CH(OH))tCH2OH, -C(O)NHCH2CH2N(CH3)2and -C(O)NHCH2CH2N+(CH3)3;118.R7is selected from H, 5 or 6-membered heteroaryl,120.

122. 124.wherein said 5 or 6-membered heteroaryl group can be optionally substituted with a 6-membered monocyclic saccharide, and wherein said 6-membered monocyclic saccharide group can be optionally substituted with another 6-membered monocyclic saccharide, which can be the same or different;125.each occurrence of R8is independently H or Ci-Ce alkyl, or both R8groups, together with the carbon atom to which they are attached, join to form a C3-C6 cycloalkyl group; each occurrence of R9is independently H or Ci-Ce alkyl;126.m is an integer from 0 to 2;127.each occurrence of n is independently 0 or 1;128.p is an integer from 1 to 10;129.q is an integer from 0 to 6;130.each occurrence of r is an integer from 1 to 3;131.each occurrence of s is independently an integer from 1 to 20; and132.each occurrence of t is independently an integer from 1 to 4.

17. An antibody-drug conjugate having a structural Formula (III):

135.

136. (III) 26113137.or a pharmaceutically acceptable salt thereof,138.wherein139.L is a ligand;140.D is selected from:

142. 144.or a taxane derivative;145.A is selected from a bond, -(C(O)N(R9))r-, -CH2CH2(OCH2CH2)rC(O)NH-, -(OCH2CH2)rC(O)NH-, -C(O)NH-(OCH2CH2)r-CH2CH2-C(O)NH-, and -NHC(O)C(R8)2C(O)NH-146.X is a bond, or -(O-P(O)(OH)-O)r-;147.each occurrence of Y is independently selected from -CH(R4)-, -CH(R4)-CH(R4)-, and -CH(R4)-CH(R4)-CH(R4)-, wherein R4can be the same or different when Y is -CH(R4)-CH(R4)-or -CH(R4)-CH(R4)-CH(R4)-;148.Z is -CH(R2)- or -CH2CH2-;149.R2is selected fromH, Ci-Ce alkyl, benzyl. -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)S-CH3, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-NHC(O)-(CH2CH2O)s-(Ci-C alkylene)n-R7, -(C1-C3 alkylene)n-O-(6-membered 26113150.monocyclic saccharide), -(C1-C3 alkylene)-R5, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), -(C1-C3 alkylene)-NHC(O)-(Ci-Cs alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), and152. 154.R3is selected from H, Ci-Ce alkyl, benzyl, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C4 alkylene)-NHC(O)-(6-membered monocyclic saccharide), -(Ci-C3 alkylene)-R5, -(C1-C3 alk\'lene)n-NHC(O)-CH2CH2-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3155. 157.alkylene)n-NHC(O)-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-(Ci-C6 alkylene)-R7, -(C1-C3 alkylene)„-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)„-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-(CH2CH2O)s-CH2CH2-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-(C1-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)n-C(O)NH- (CH2CH2O)S-(CI-C3 alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-Ce alkyl), and 26113159.

160. o161.each occurrence of R4is independently selected from H, Ci-Cs alkyl, benzyl, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -(C1-C3 alkylene)-R5, -(C1-C3 alkylene)n-NHC(O)-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(C1-C6 alkylene)-R7, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)s-C(O)NHCH2(CH(OH))tCH2OH, -(C1-C3 alkylene)n-C(O)NH-CH2CH2-(CH2CH2O)S-(CI-C3alkylene)-C(O)NH-R7, -(C1-C3 alkylene)-C(O)NH-(Ci-C3 alkylene)-OC(O)NHS(O)2-NH-(CH2CH2O)s-(Ci-C6 alkyl), -(C1-C3 alkylene)-NH-C(O)NH2, -(C1-C3 alkylene)n-C(O)NHCH2(CH(OH))tCH2OH, and163. 165.R3is selected from -OH, -(C1-C3 alkylene)n-O-(6-membered monocyclic saccharide), -NHC(O)NH2, -C(O)OH, -C(O)O-benzyl, -C(O)NH2, -C(O)NHCH2(CH(OH))tCH2OH, -C(O)NHCH2CH2N(CH3)2and -C(O)NHCH2CH2N+(CH3)3;166.R7is selected from H, 5 or 6-membered heteroaryl, 26113168. 170.wherein said 5 or 6-membered heteroaryl group can be optionally substituted with a 6-membered monocyclic saccharide, and wherein said 6-membered monocyclic saccharide group can be optionally substituted with another 6-membered monocyclic saccharide, which can be the same or different;171.each occurrence of R8is independently H or Ci-Ce alkyl, or both R8groups, together with the carbon atom to which they are attached, join to form a Ca-Ce cycloalkyl group; each occurrence of R9is independently H or Ci-Ce alkyl;172.m is an integer from 0 to 2;173.each occurrence of n is independently 0 or 1;174.p is an integer from 1 to 10;175.q is an integer from 0 to 6;176.each occurrence of r is an integer from 1 to 3;177.each occurrence of s is independently an integer from 1 to 20; and178.each occurrence of t is independently an integer from 1 to 4. 2611318. The antibody-drug conjugate of claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein L is an antibody.

19. An antibody-drug conjugate, or a pharmaceutically acceptable salt thereof, being any of the antibody-drug conjugates numbered 100-198 and 204-208 in the above specification.

20. A pharmaceutical composition comprising: (a) an antibody-drug conjugate of any of claims 16-19, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier.

21. Use of: (a) an antibody-drug conjugate of any of claims 16-19, or a pharmaceutically acceptable salt thereof, or (b) the pharmaceutical composition of claim 20, for the manufacture of a medicament for the treatment or prevention of cancers or tumors.

22. 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 16-19, or a pharmaceutically acceptable (b) salt thereof, or (b) a pharmaceutical composition of claim 20.

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