Camptothecin Conjugates

Abstract

Antibody conjugates with camptothecin compounds are described along with methods of use and preparation. The present invention provides, inter alia, camptothecin conjugates, camptothecin-linker compounds and camptothecin compounds, methods of preparation and use thereof, and intermediates thereof. The camptothecin conjugates of the present invention are stable in the circulation and can induce cell death when the free drug is released from the conjugate in the vicinity of or within tumor cells.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Patent Application No. 63 / 321,105, filed March 17, 2022, and U.S. Patent Application No. 63 / 407,609, filed September 16, 2022, the disclosures of which are incorporated by reference in their entireties and for all purposes.

[0002] Reference to the electronic sequence listing The contents of the electronic sequence listing (761682009440SEQLIST.xml, size: 1,128,239 bytes, created on March 16, 2023) are incorporated herein by reference in their entirety. [Background technology]

[0003] Antibodies (mAbs) have been investigated for the targeted delivery of cytotoxic agents to tumor cells. While various drug classes have been evaluated for antibody-mediated targeted delivery, only a few classes of drugs have proven to be sufficiently active as antibody-drug conjugates while also possessing suitable toxicity profiles and other pharmacological properties to justify clinical development. One class of drug that has attracted interest is camptothecin. Designing antibody drug conjugates (ADCs) by attaching a cytotoxic agent to an antibody, typically via a linker, involves considering a variety of factors, including the presence of a conjugation handle on the drug for attachment to the linker, and linker technology for attaching the drug to the antibody in a conditionally stable manner. The conjugation handle of the parent compound in this class is a hydroxyl functionality at C20 to which a linker is attached through a carbonate functionality (see, e.g., Walker, MA et al. Bioorganic & Medicinal Chemistry Letters (2002) 12(2):217-219). However, the carbonate functionality typically suffers from hydrolytic instability, which can lead to premature release of the free drug into the systemic circulation, resulting in reduced ADC efficacy, poor immunological specificity of the conjugate, and increased toxicity. Thus, a need exists for engineered camptothecin conjugates that provide control over drug-linker stability to increase the amount of drug delivered to the desired site of action. The present invention addresses these and other needs. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Walker, MAet al.Bioorganic & Medicinal Chemistry Letters(2002)12(2):217-219 Summary of the Invention

[0005] The present invention provides, inter alia, camptothecin conjugates, camptothecin-linker compounds, and camptothecin compounds, methods for preparing and using the same, and intermediates thereof. The camptothecin conjugates of the present invention are stable in the circulation and, moreover, can induce cell death when the free drug is released from the conjugate near or within tumor cells.

[0006] In one embodiment, L-(QD) p or a salt thereof, wherein: L is a ligand unit, the subscript p is an integer from 1 to 16; Q is -ZA-, -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, ZAS * -W-, -ZAS * -W-RL-, -ZAB(S * )-RL-, -ZAB(S * )-W-, -ZAB(S * )-W-RL- and -ZAB(S * )-RL-Y- and a linker unit having a formula selected from the group consisting of: where Z is a stretching unit, A is a bond or linking unit, B is a parallel linked unit, S * is a partitioning agent, RL is a releasable linker, W is an amino acid unit, Y is a spacer unit, D is [ka] or a salt thereof, wherein: E is -OR b5 or -NR b5 R b5’ and R b1 is H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10Cycloalkyl, 3-10 membered heterocycloalkyl, (C6-C 12 aryl)-C2-C8 alkenyl-, C1-C8 hydroxyalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -OR a , -NR a R a’ and -SR a and each is selected from the group consisting of C1-C3 alkyl, -OR a , -NR a R a’ , -C(O)R a and -SR a optionally substituted with, or R b1 is R b2 , R b5 Or R b6 and together with the intervening atoms form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b2 is H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkyl-S(O)2-, C1-C8 aminoalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C1-C8 alkyl-NR a-C(O)-, C1-C8 alkyl-C(O)-NR a -, C1-C8 alkyl-NR a -C(O)O-, C1-C8 alkyl-OC(O)-NR a -, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -OR a , -NR a R a’ and -SR a and each is selected from the group consisting of: -OR a , -NR a R a’ and -SR a or optionally replaced by R b2 is R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring, or R b2 is R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered heterocycle fused to the 6-membered aryl; R b3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, -OR a , -NR a R a’ and -SR a is selected from the group consisting of R b4 is selected from the group consisting of H or halogen; Each R b5 and R b5’ are independently H, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C6 alkyl-O-C1-C6 alkyl-, C1-C8 aminoalkyl, (C1-C 4アルキルamino)-C1-C8 alkyl-, N,N-(C1-C4 hydroxyalkyl)(C1-C4 alkyl)amino-C1-C8 alkyl-, N,N-di(C1-C4 alkyl)amino-C1-C8 alkyl-, N-(C1-C4 hydroxyalkyl)-C1-C8 aminoalkyl-, C1-C8 alkyl-C(O)-, C1-C8 hydroxyalkyl-C(O)-, C1-C8 aminoalkyl-C(O)-, C3-C 10 Cycloalkyl, (C3-C 10 Cycloalkyl)-C1-C4 alkyl-, C3-C 10 Heterocycloalkyl, (C3-C 10 Heterocycloalkyl)-C 1- C4 alkyl-, C1-C6 hydroxyalkyl-heteroaryl-, phenyl, phenyl-C 1- C4 alkyl-, diphenyl-C1-C4 alkyl-, heteroaryl, heteroaryl-C1-C4 alkyl-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8 alkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, C1-C4 alkyl-SO2-C1-C8 alkyl-, NH2-SO2-C1-C8 alkyl-, (C3-C 10 Heterocycloalkyl)-C 1- C4 hydroxyalkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8 hydroxyalkyl-C3-C 10 heterocycloalkyl- or R b5 and R b5’ are, together with the nitrogen atom to which they are attached, independently halogen, C 1-forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -O-C1-C4 alkyl, -NH2, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, C1-C6 alkoxy-C(O)-NH-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, and C1-C8 aminoalkyl; or R b5’ is H and R b5 is R b1 and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring, R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ wherein the cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl, and heteroaryl portions are independently substituted with 0 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl-, -OH, -OC1-C4 alkyl, -NH2, -NHC1-C4 alkyl, and -N(C1-C4 alkyl)2; R b6 is H or R b1 and together with the intervening atoms form a carbocyclic or heterocyclic ring, R a and R a’ are each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C alkyl-S(O)-, C-C alkyl-C(O)-, C-C aminoalkyl-C(O)-, and C-C hydroxyalkyl-C(O)-; D is covalently bonded to Q through any suitable bonding site on D, and optionally, a hydroxyl, thiol, primary amine, or secondary amine hydrogen atom of D is replaced with a bond to Q, or a tertiary amine of D is quaternized to form a bond to Q.

[0007] Another embodiment as described above is a camptothecin-linker compound useful as an intermediate in preparing camptothecin conjugates, the camptothecin-linker compound being comprised of a camptothecin and a linker unit (Q), the linker unit being comprised of a stretcher unit precursor (Z') capable of forming a covalent bond to a targeting ligand to provide a ligand unit, and a releasable linker (RL), where RL is a glycoside unit (e.g., a glucuronide unit) in some embodiments of Q that do not have an amino acid unit.

[0008] In another aspect, the present invention provides a method of treating cancer, comprising administering to a subject in need thereof a camptothecin conjugate described herein.

[0009] In another aspect, the present invention provides a kit comprising a camptothecin conjugate described herein. [Brief explanation of the drawings]

[0010] [Figure 1A] 1 shows the mean tumor volume over time in the mouse model L540cy following administration of a single dose of camptothecin ADC with Ag4 antibody on day 12. [Figure 1B] 1 shows the mean tumor volume over time in the mouse model L540cy following administration of a single dose of camptothecin ADC with h00 antibody on day 12.

[0011] [Figure 2] 1 shows the mean tumor volume over time in the mouse model EBC-1 following administration of a single dose of glucuronide-based camptothecin ADC with Ag2 antibody on day 7.

[0012] [Figure 3] 1 shows the mean tumor volume over time in the mouse model OV-90 following administration of a single dose of glucuronide-based camptothecin ADC with the Ag3 antibody on day 17.

[0013] [Figure 4] 1 shows the mean tumor volume over time in mouse model 786-O following administration of a single dose of glucuronide-based camptothecin ADC with Ag5 antibody on day 15. DETAILED DESCRIPTION OF THE INVENTION

[0014] definition Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings: When a trade name is used herein, the trade name includes product formulations, generics, and the active pharmaceutical ingredient(s) of that trade name product unless the context indicates otherwise.

[0015] The term "antibody," as used herein, is used in the broadest sense and specifically encompasses intact monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments that exhibit the desired biological activity. Naturally occurring antibodies are tetramers, consisting of two identical pairs of immunoglobulin chains, each pair having one light chain and one heavy chain. Within each pair, the variable regions of the light and heavy chains (V L and V H), together are primarily responsible for binding to the antigen. The variable domains of the light and heavy chains consist of a framework region separated by three hypervariable regions, also called "complementarity-determining regions" or "CDRs." The constant regions can be recognized by and interact with the immune system (see, e.g., Janeway et al., 2001, Immunol. Biology, 5th Ed., Garland Publishing, New York). The antibody can be of any type (e.g., IgG, IgE, IgM, IgD, and IgA), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or subclass thereof. The antibody can be derived from any suitable species. In some embodiments, the antibody is of human or murine origin. The antibody can be, for example, a human antibody, a humanized antibody, or a chimeric antibody.

[0016] The term "monoclonal antibody," as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible natural mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method.

[0017] An "intact antibody" is an antibody that contains an antigen-binding variable region and a light chain constant domain (C L ) and a heavy chain constant domain, i.e., C depending on the antibody class. H 1. C H 2. C H 3 and C H 4. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof.

[0018] An "antibody fragment" includes a portion of an intact antibody that comprises the antigen-binding or variable region thereof. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, diabodies, triabodies, tetrabodies, linear antibodies, single-chain antibody molecules, scFv, scFv-Fc, multispecific antibody fragments formed from antibody fragment(s), fragment(s) produced by a Fab expression library, or epitope-binding fragments of any of the above that immunospecifically bind to a target antigen (e.g., a cancer cell antigen, a viral antigen, or a microbial antigen).

[0019] An "antigen" is an entity to which an antibody specifically binds.

[0020] The terms "specific binding" and "specifically bind" mean that an antibody or antibody derivative binds with high selectivity to the corresponding epitope of a target antigen and does not bind to numerous other antigens. Typically, the antibody or antibody derivative binds with a high selectivity to the corresponding epitope of a target antigen and does not bind to numerous other antigens. -7 M, preferably 10 -8 M~10 -9 M, 10 -10 M, 10 -11 M or 10 -12 M, which binds to a given antigen with an affinity that is at least two-fold higher than its affinity for binding to a nonspecific antigen other than the given antigen or a closely related antigen (e.g., BSA, casein).

[0021] The terms "inhibit" or "inhibition of" means to reduce by a measurable amount or to prevent completely.

[0022] The term "therapeutically effective amount" refers to an amount of a conjugate effective to treat a disease or disorder in a mammal. In the case of cancer, a therapeutically effective amount of a conjugate may reduce cancer cells, reduce tumor size, inhibit (i.e., slow to some extent, and preferably stop) cancer cell invasion into peripheral organs, inhibit (i.e., slow to some extent, and preferably stop) tumor metastasis, inhibit tumor growth to some extent, and / or alleviate to some extent one or more symptoms associated with cancer. To the extent the drug may inhibit the growth of and / or kill existing cancer cells, the drug may be cytostatic and / or cytotoxic. With respect to cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0023] The term "substantial" or "substantially" refers to the majority, i.e., greater than 50%, of a population, mixture, or sample, preferably greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the population.

[0024] The term "cytotoxic activity" refers to the cell-killing effect of a drug, or a camptothecin conjugate or an intracellular metabolite of a camptothecin conjugate. Cytotoxic activity is measured by the IC 50 It can be expressed as a value, which is the concentration (molar or mass concentration) at which half of the cells survive per unit volume.

[0025] The term "cytostatic activity" refers to the antiproliferative effect of a drug, or a camptothecin conjugate or an intracellular metabolite of a camptothecin conjugate.

[0026] The term "cytotoxic agent," as used herein, refers to a substance that has cytotoxic activity and causes destruction of cells. The term is intended to include chemotherapeutic agents as well as toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin, including synthetic analogs and derivatives thereof.

[0027] The term "cytostatic agent," as used herein, refers to a substance that inhibits cellular function, including cell growth or reproduction. Cytostatic agents include inhibitors such as protein inhibitors, e.g., enzyme inhibitors. Cytostatic agents have cytostatic activity.

[0028] The terms "cancer" and "cancerous" refer to or describe a physiological condition or disorder in mammals that is typically characterized by unregulated cell growth. A "tumor" contains one or more cancerous cells.

[0029] "Autoimmune disease," as used herein, refers to a disease or disorder caused by and directed against an individual's own tissues or proteins.

[0030] "Patient," as used herein, refers to a subject to which a camptothecin conjugate of the present invention is administered. Patients include, but are not limited to, humans, rats, mice, guinea pigs, non-human primates, pigs, goats, cows, horses, dogs, cats, birds, and poultry. Typically, the patient is a rat, mouse, dog, human, or non-human primate, more typically a human.

[0031] The terms "treat" or "treatment," unless otherwise indicated by context, refer to therapeutic treatment and prophylaxis, the purpose of which is to inhibit or slow (inhibit) the onset or spread of an undesirable physiological change or disorder, such as cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reduction in the extent of disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to developing the condition or disorder.

[0032] With respect to cancer, the term "treating" includes any or all of killing tumor cells, inhibiting the growth of tumor cells, cancer cells or tumors, inhibiting the replication of tumor cells or cancer cells, suppressing the overall tumor burden or reducing the number of cancerous cells, and ameliorating one or more symptoms associated with the disease.

[0033] With respect to autoimmune diseases, the term "treating" includes any or all of inhibiting the replication of cells associated with the autoimmune disease state (including, but not limited to, cells that produce autoimmune antibodies), suppressing the amount of autoimmune antibodies, and ameliorating one or more symptoms of the autoimmune disease.

[0034] The term "compound," as used herein, refers to the chemical compound per se (either named or represented by structure) and its salt forms (whether explicitly indicated or not, unless the context makes it clear that such salt form(s) should be excluded), and includes these compounds per se and their salt forms. The term "compound" also includes solvated forms of the compound, in which a solvent is non-covalently bound to the compound or reversibly covalently bound to the compound, such as when a carbonyl group of the compound is hydrated to form a gem-diol. Solvated forms include the compound per se and its salt form(s), including hemisolvates, monosolvates, and disolvates (including hydrates), and when a compound can bind to more than one solvent molecule, the two or more solvent molecules can be the same or different.

[0035] In some cases, the compounds of the invention include explicit reference to one or more of the above forms, e.g., salts and solvates; this reference does not imply any solid state form of the compound; however, this reference is for emphasis only and should not be construed as excluding any other form, as specified above. Furthermore, when salt and / or solvate forms of a compound or ligand drug conjugate composition are not explicitly mentioned, the omission should not be construed as excluding salt and / or solvate form(s) of the compound or conjugate, unless it is clear from the context that such salt and / or solvate forms should be excluded.

[0036] The phrase "salt thereof," as used herein, refers to a salt form of a compound (e.g., a drug, a drug-linker compound, or a ligand-drug conjugate compound). A salt form of a compound may be one or more intramolecular salt forms and / or involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. The counterion in a salt form of a compound is typically an organic or inorganic moiety that stabilizes the charge on the parent compound. A salt form of a compound has one or more charged atoms in its structure. When multiple charged atoms are part of the salt form, multiple counterions and / or multiple charged counterions are present. Thus, a salt form of a compound typically has one or more charged atoms and one or more counterions corresponding to those of the non-salt form of the compound. In some embodiments, the non-salt form of a compound contains at least one amino group or other basic moiety, and therefore, in the presence of an acid, an acid addition salt with the basic moiety is obtained. In other embodiments, the non-salt form of a compound contains at least one carboxylic acid group or other acidic moiety, and therefore, in the presence of a base, a carboxylate moiety or other anionic moiety is obtained. Exemplary salts include, but are not limited to, sulfate, trifluoroacetate, citrate, acetate, oxalate, hydrochloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0037] Pharmaceutically acceptable salts are salt forms of compounds suitable for administration to a subject as described herein, and in some embodiments include a countercation or counteranion, as described by P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002.

[0038] The linker unit is a bifunctional moiety that links camptothecin to the ligand unit in a camptothecin conjugate. The linker units of the present invention have several components (e.g., a extender unit, which in some embodiments has a basic unit, a linking unit that may or may not be present, a parallel linking unit that may or may not be present, a releasable linker, and a spacer unit that may or may not be present).

[0039] "PEG," "PEG unit," or "polyethylene glycol," as used herein, refers to an organic moiety composed of repeating ethylene-oxy subunits, which may be polydisperse, monodisperse, or discrete (i.e., having a discrete number of ethylene-oxy subunits). Polydisperse PEGs are a heterogeneous mixture of sizes and molecular weights, while monodisperse PEGs are typically purified from a heterogeneous mixture and therefore have a single chain length and molecular weight. Preferred PEG units are discrete PEGs, i.e., compounds that are synthesized stepwise rather than by a polymerization process. Discrete PEGs result in a single molecule with a defined and specified chain length.

[0040] The PEG units provided herein each comprise one or more polyethylene glycol chains composed of one or more ethyleneoxy subunits covalently bonded to one another. The polyethylene glycol chains can be linked together, for example, in a linear, branched, or star configuration. Typically, at least one of the polyethylene glycol chains is derivatized at one end with an alkyl moiety substituted with an electrophilic group for covalent attachment to the carbamate nitrogen (i.e., representing R) of the methylene carbamate unit prior to incorporation into the camptothecin conjugate. Typically, the terminal ethyleneoxy subunit of each polyethylene glycol chain that is not involved in covalent attachment to the remainder of the linker unit is modified with a PEG capping unit, typically H or an optionally substituted alkyl, such as -CH, -CHCH, or -CHCHCOH. Preferred PEG units have a single polyethylene glycol chain comprising 4 to 24 consecutive covalently bonded -CHCHO- subunits, terminating at one end with a PEG capping unit.

[0041] "Halogen," as that term is used herein, alone or in combination with another term, refers to fluorine, chlorine, bromine, or iodine, unless otherwise indicated or suggested by context, and is typically -F or -Cl.

[0042] Unless otherwise indicated, the term "alkyl," by itself or as part of another term, refers to a substituted or unsubstituted, straight or branched chain, saturated or unsaturated hydrocarbon having the indicated number of carbon atoms (e.g., "-C1-C8 alkyl" refers to 1 to 8 carbon atoms; "-C1-C 10 」(Alkyl refers to an alkyl group having 1 to 10 carbon atoms. When the number of carbon atoms is not specified, the alkyl group has 1 to 8 carbon atoms. Representative straight chain "C1-C8 alkyl" groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, and -n-octyl; branched chain -C3-C8 alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and -2-methylbutyl; unsaturated -C2-C8 alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and -2-methylbutyl. Examples of alkyl include, but are not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexyl, 2-hexyl, -3-hexyl, -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, and -3-methyl-1-butynyl. In some cases, the alkyl group is unsubstituted. The alkyl group can be substituted with one or more groups. In other embodiments, the alkyl group is saturated.

[0043] Unless otherwise indicated, "alkylene," alone or as part of another term, refers to a hydrocarbon radical, substituted or unsubstituted, saturated, branched or straight-chain, or cyclic, having the indicated number of carbon atoms, typically 1 to 10 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to, methylene (-CH-), 1,2-ethylene (-CHCH-), 1,3-propylene (-CHCHCH-), 1,4-butylene (-CHCHCHCH-), and the like. In preferred embodiments, the alkylene is a branched or straight-chain hydrocarbon (i.e., not a cyclic hydrocarbon).

[0044] "Alkenyl," as that term is used herein, alone or as part of another term, unless otherwise indicated or suggested by context, refers to an organic moiety, substituent, or group that contains one or more double bond functional groups (e.g., -CH=CH- moieties), or that contains 1, 2, 3, 4, 5, or 6 or more such functional groups, typically 1, 2, or 3, more typically 1 such functional group, and in some embodiments may be substituted (i.e., optionally substituted) with an aryl moiety or group, such as phenyl, or may contain non-aromatically bonded normal, secondary, tertiary, or cyclic carbon atoms, i.e., linear, branched, cyclic, or any combination thereof, as part of the base moiety, unless the alkenyl substituent, alkenyl moiety, or alkenyl group is a vinyl moiety (e.g., -CH=CH2 moiety). An alkenyl moiety, alkenyl group, or alkenyl substituent having multiple double bonds may have double bonds arranged consecutively (i.e., a 1,3-butadienyl moiety), may have double bonds arranged discontinuously with one or more intervening saturated carbon atoms, or a combination thereof, provided that the cyclic sequential arrangement of double bonds does not form a 4n+2 electron cyclic conjugated system (i.e., is not aromatic).

[0045] The alkenyl moiety, alkenyl group or alkenyl substituent is sp 2 sp carbon atoms that are divalent and double-bonded to another organic moiety or Markush structure to which the alkenyl is attached, or that are conjugated to each other 2 Contains at least two carbon atoms and their sp 2 One of the carbon atoms is monovalent and is single-bonded to another organic moiety or Markush structure to which the alkenyl is attached. Typically, when an alkenyl is used as a Markush group (i.e., a substituent), the alkenyl is bonded to the sp of the alkene functional group of the alkenyl moiety. 2The alkenyl is single-bonded through the carbon to the Markush group or another organic moiety to which it is attached. In some embodiments, when an alkenyl moiety is defined, the species corresponds to any of the optionally substituted alkyl or carbocyclyl groups, moieties, or substituents described herein, and the sp 2 One or more end double bonds where the carbon atom is monovalent and the sp of the parent alkene compound 2 and monovalent moieties derived by removing a hydrogen atom from carbon. Such monovalent moieties are exemplified by, but not limited to, vinyl (-CH=CH), allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, and cyclohexenyl. In some embodiments, the term alkenyl includes all of the above and / or other linear, cyclic, and branched carbon-containing moieties containing at least one double bond functionality, including sp 2 Carbon-containing moieties in which one of the carbon atoms is monovalent are included.

[0046] The number of carbon atoms in an alkenyl moiety is determined by the sp of the alkene functional group(s) that defines the moiety as an alkenyl substituent. 2 The number of carbon atoms and the sp 2It is defined by the total number of consecutive non-aromatic carbon atoms attached to each carbon, not including any carbon atoms from the other moiety or Markush structure to which the alkenyl moiety is a variable, and any optional substituents on the alkenyl moiety. When the double-bonded functional group is double-bonded to the Markush structure (e.g., =CH2), the number ranges from 1 to 50 or 1 to 30, typically 1 to 20 or 1 to 12, more typically 1 to 8, 1 to 6, or 1 to 4 carbon atoms; when the double-bonded functional group is single-bonded to the Markush structure (e.g., -CH=CH2), the number ranges from 2 to 50, typically 2 to 30, 2 to 20, or 2 to 12, more typically 2 to 8, 2 to 6, or 2 to 4 carbon atoms. For example, C2-C8 alkenyl or C2-C8 alkenyl refers to an alkenyl moiety containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms in which at least two are sp 2 carbon atoms and a moiety in which one of these carbon atoms is monovalent, C2-C6 alkenyl or C2-C6 alkenyl is an alkenyl moiety containing 2, 3, 4, 5 or 6 carbon atoms in which at least two are sp 2 In some embodiments, the alkenyl substituent or alkenyl group is a moiety consisting of 2 carbon atoms and one of the carbon atoms being monovalent. 2a C2-C6 alkenyl moiety or a C2-C4 alkenyl moiety having only two carbons, one of which is monovalent; in other aspects, the alkenyl moiety is unsubstituted or substituted with 1 to 4 or more, typically 1 to 3, more typically 1 or 2, independently selected moieties as disclosed herein, including substituents as defined herein for any substituent, excluding alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and any other moiety when the number of consecutive non-aromatic carbon atoms in the substituted alkenyl moiety is different from that of the unsubstituted alkenyl, and the substitution(s) are determined by the presence or absence of any of the consecutive sp 2 Carbon atoms and sp 3 When carbon atoms are present, they may be at any position on those atoms. Typically, alkenyl substituents are sp 2 A C2-C6 alkenyl moiety or a C2-C4 alkenyl moiety having only two carbons. When the number of carbon atoms is not specified, the alkenyl moiety has from 2 to 8 carbon atoms.

[0047] "Alkenylene," as that term is used herein, alone or as part of another term, unless otherwise indicated or suggested by context, includes one or more double-bonded moieties of the indicated number of carbon atoms, as described above for alkenyl, and in the parent alkene, the same sp of the alkene functional group. 2 carbon atom or two different sp 2 An alkenylene moiety refers to an organic moiety, substituent, or group having two radical centers derived by the removal of two hydrogen atoms from a carbon atom or two separate alkene functional groups. In some embodiments, an alkenylene moiety refers to a portion of an alkenyl radical, as described herein, that has the same sp of the double bond functional group of the alkenyl radical. 2 carbon atoms or different sp 2 sp from carbon atoms or from different double bond moieties 2It is the portion of an alkenyl radical in which a hydrogen atom is removed from a carbon to give a diradical. Typically, the alkenylene moiety has a -C=C- or -C=CX 1 Diradicals containing the structure -C=C-, wherein X 1 is absent or, as defined herein, optionally substituted saturated alkylene, which alkylene is typically a C1-C6 alkylene, more typically unsubstituted. The number of carbon atoms in an alkenylene moiety is determined by the sp of its alkene functional group(s) that defines the moiety as an alkenylene moiety. 2 The number of carbon atoms and their sp 2 The term "alkenyl" refers to an alkenyl moiety defined by the total number of consecutive non-aromatic carbon atoms attached to each carbon atom, not including any carbon atoms in other moieties or Markush structures where the alkenyl moiety exists as a variable. The number ranges from 2 to 50 or 2 to 30, typically 2 to 20 or 2 to 12, more typically 2 to 8, 2 to 6, or 2 to 4 carbon atoms, unless otherwise specified. For example, C2-C8 alkenylene or C2-C8 alkenylene refers to an alkenylene moiety containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms, at least two of which are sp 2 C2-C6 alkenylene or C2-C6 alkenylene means an alkenyl moiety containing 2, 3, 4, 5, or 6 carbon atoms, at least two of which are sp 2 In some embodiments, the alkenylene moiety is a group of two sp carbons, one of which is divalent or both of which are monovalent, and which are conjugated to each other. 2 C2-C6 alkenylene or C2-C4 alkenylene (both sp 2 Carbon atoms are monovalent) and in some embodiments are unsubstituted. When the number of carbon atoms is not specified, the alkenylene moiety has 2 to 8 carbon atoms and is unsubstituted or substituted in the same manner as described for the alkenyl moiety.

[0048] "Alkynyl," as that term is used herein, alone or as part of another term, unless otherwise indicated or suggested by context, refers to an organic moiety, organic substituent, or organic group that contains one or more triple bond functional groups (e.g., -C≡C- moieties) or that contains 1, 2, 3, 4, 5, or 6 or more such functional groups, typically 1, 2, or 3, more typically 1 such functional group, which in some embodiments may be substituted (i.e., optionally substituted) with an aryl moiety, e.g., phenyl, or, unless the alkynyl substituent, alkynyl moiety, or alkynyl group is -C≡CH, with an alkenyl moiety, or with linked normal, secondary, tertiary, or cyclic carbon atoms, i.e., linear, branched, cyclic, or combinations thereof. An alkynyl moiety, group, or substituent having multiple triple bonds may have the triple bonds arranged consecutively or non-consecutively with one or more intervening saturated or unsaturated carbon atoms, or a combination thereof, provided that the cyclic sequential arrangement of triple bonds does not form a 4n+2 electron cyclic conjugated system (i.e., is not aromatic).

[0049] An alkynyl moiety, alkynyl group, or substituent contains at least two sp carbon atoms, which are conjugated to each other, and one of the sp carbon atoms is single-bonded to another organic moiety or Markush structure to which the alkynyl is attached. When alkynyl is used as a Markush group (i.e., a substituent), the alkynyl is single-bonded to the Markush structure or another organic moiety to which the alkynyl is attached through the triple-bonded carbon (i.e., sp carbon) of the terminal alkyne functional group. In some embodiments, when an alkynyl moiety, alkynyl group, or alkynyl substituent is defined, the species includes any of the optionally substituted alkyl or carbocyclyl groups, moieties, or substituents described herein that have one or more endo triple bonds and a monovalent moiety derived by removing a hydrogen atom from an sp carbon of a parent alkyne compound. Such monovalent moieties are exemplified by, but not limited to, -C≡CH, -C≡C-CH3, and -C≡C-Ph.

[0050] The number of carbon atoms in an alkynyl substituent is defined by the number of sp carbon atoms in the alkene functional group that defines the group as an alkynyl substituent and the total number of consecutive non-aromatic carbon atoms attached to each of those sp carbons, not including any carbon atoms in other moieties or Markush structures in which the alkenyl moiety is a variable. This number can range from 2 to 50, typically 2 to 30, 2 to 20, or 2 to 12, more typically 2 to 8, 2 to 6, or 2 to 4 carbon atoms when triple-bonded functional groups are single-bonded to the Markush structure (e.g., -CH≡CH). For example, C2-C8 alkynyl or C2-C8 alkynyl refers to an alkynyl moiety containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms, at least two of which are sp carbon atoms conjugated together and one of which is monovalent, and C2-C6 alkynyl or C2-C6 alkynyl refers to an alkynyl moiety containing 2, 3, 4, 5, or 6 carbon atoms, at least two of which are sp carbon atoms conjugated together and one of which is monovalent. In some embodiments, the alkynyl substituent or group is a C2-C6 or C2-C4 alkynyl moiety having two sp carbon atoms conjugated together and one of which is monovalent, and in other embodiments, the alkynyl moiety is unsubstituted. When the number of carbon atoms is not specified, the alkynyl moiety, alkynyl group, or alkynyl substituent has from 2 to 8 carbon atoms. Alkynyl moieties can be substituted or unsubstituted in the same manner as described for alkenyl moieties, except that substitution at monovalent sp carbons is not permitted.

[0051] The term "prodrug," as used herein, refers to a compound that has low or no biological activity and is converted in the body to a more biologically active compound by a chemical or biological process (i.e., chemical reaction or enzymatic biotransformation). Typically, a biologically active compound is rendered less biologically active (i.e., converted to a prodrug) by chemically modifying the compound with a prodrug moiety. In some embodiments, the prodrug is a Type II prodrug, which is bioactivated extracellularly, e.g., in digestive fluids, or in the body's circulatory system, e.g., blood. Exemplary prodrugs are esters and β-D-glucopyranosides.

[0052] Unless otherwise indicated, "aryl," alone or as part of another term, means a substituted or unsubstituted monovalent carbocyclic aromatic hydrocarbon radical of the indicated number of carbon atoms, typically 6 to 20 carbon atoms, derived by removing one hydrogen atom from a carbon atom of a parent aromatic ring system. Some aryl groups are represented in the exemplary structures as "Ar." Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like. An exemplary aryl group is the phenyl group.

[0053] Unless otherwise indicated, an "arylene," alone or as part of another term, is an aryl group, as defined above, that has two covalent bonds (i.e., is divalent) and can be in the ortho, meta, or para positions, as shown in the structure below (with phenyl as an exemplary group). [ka]

[0054] Unless otherwise indicated, "C3-C8 heterocycle," alone or as part of another term, refers to a monovalent substituted or unsubstituted, aromatic or non-aromatic monocyclic or bicyclic ring system having 3 to 8 carbon atoms (also referred to as ring members) and 1 to 4 heteroatom ring members independently selected from N, O, P, or S, and derived by removing one hydrogen atom from a ring atom of a parent ring system. One or more N, C, or S atoms in the heterocycle can be oxidized. The ring containing the heteroatom can be aromatic or non-aromatic. A heterocycle in which all ring atoms participate in aromaticity is called heteroaryl, otherwise referred to as heterocarbocycle.

[0055] Unless otherwise specified, a heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Thus, a heteroaryl can be attached through an aromatic carbon atom in its aromatic ring system (referred to as a C-linked heteroaryl) or through a non-double-bonded N atom (i.e., an atom that is not =N-) in its aromatic ring system (referred to as an N-linked heteroaryl). That is, nitrogen-containing heterocycles can be C-linked or N-linked, and include pyrrole moieties such as pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked), and imidazole moieties such as imidazol-1-yl and imidazol-3-yl (both N-linked), as well as imidazol-2-yl, imidazol-4-yl, and imidazol-5-yl moieties (all C-linked).

[0056] Unless otherwise specified, a "C3-C8 heteroaryl" refers to an aromatic C3-C8 heterocycle, where the subscript indicates the total number of carbons in the ring system of the heterocycle or the total number of aromatic carbons in the aromatic ring system of the heteroaryl, not including the size of the ring system or whether or not it is fused. Representative examples of C3-C8 heterocycles include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, pyrrolyl, thiophenyl (thiophene), furanyl, thiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, isothiazolyl, and isoxazolyl.

[0057] Unless explicitly stated, the size of a heterocyclic or heteroaryl ring system is indicated by the total number of atoms in the ring. For example, a designation as a 5- or 6-membered heteroaryl indicates the total number of aromatic atoms (i.e., 5 or 6) in the heteroaromatic ring system of the heteroaryl, but does not imply the number of aromatic heteroatoms or aromatic carbons in the ring system. Fused heteroaryls are either explicitly stated or implied by the context, and are typically indicated by the number of aromatic atoms in each aromatic ring that is fused together to form the fused heteroaromatic ring system. For example, a 5,6-membered heteroaryl is a 5-membered aromatic ring fused to a 6-membered aromatic ring, in which one or both rings have aromatic heteroatom(s) or the two rings share a heteroatom.

[0058] A heterocycle fused to an aryl or heteroaryl, where the heterocycle remains non-aromatic and becomes part of a larger structure through bonding to the non-aromatic portion of the fused ring system, is an example of an optionally substituted heterocycle that is substituted by ring fusion with an aryl or heteroaryl. Similarly, an aryl or heteroaryl fused to a heterocycle or carbocycle that becomes part of a larger structure through bonding to the aromatic portion of the fused ring system is an example of an optionally substituted aryl or heterocycle that is substituted by ring fusion with the heterocycle or carbocycle.

[0059] Unless otherwise indicated, a "C3-C8 heterocycle," alone or as part of another term, refers to a C3-C8 heterocycle, as defined above, in which one of the heterocycle's hydrogen atoms has been replaced with a bond (i.e., it is divalent). Unless otherwise indicated, a "C3-C8 heteroarylene," alone or as part of another term, refers to a C3-C8 heteroaryl group, as defined above, in which one of the heteroaryl group's hydrogen atoms has been replaced with a bond (i.e., it is divalent).

[0060] Unless otherwise indicated, a "C3-C8 carbocycle," alone or as part of another term, is a 3-, 4-, 5-, 6-, 7-, or 8-membered monovalent substituted or unsubstituted, saturated or unsaturated, non-aromatic monocyclic or bicyclic carbocyclic ring derived by removing one hydrogen atom from a ring atom of a parent ring system. Representative -C3-C8 carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl, cyclooctyl, and cyclooctadienyl.

[0061] Unless otherwise indicated, "C3-C8 carbocycle," alone or as part of another term, refers to a C3-C8 carbocycle group, as defined above, in which another of the carbocycle group's hydrogen atoms has been replaced with a bond (i.e., is divalent).

[0062] Unless otherwise indicated, the term "heteroalkyl," alone or in combination with another term, means, unless otherwise indicated, a stable straight- or branched-chain hydrocarbon or combination thereof, which is fully saturated or has 1 to 3 degrees of unsaturation, and which consists of the indicated number of carbon atoms and 1 to 10, preferably 1 to 3, heteroatoms (selected from the group consisting of O, N, Si, and S), wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) O, N, and S may be located at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. The heteroatom Si may be located at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.

[0063] Examples of heteroalkyl include -CH-CH-O-CH, -CH-CH-NH-CH, -CH-CH-N(CH)-CH, -CH-S-CH-CH, -CH-CH-S(O)-CH, -NH-CH-CH-NH-C(O)-CH-CH, -CH-CH-S(O)-CH, -CH=CH-O-CH, -Si(CH), -CH-CH=NO-CH, and -CH=CH-N(CH)-CH. Up to two heteroatoms may be consecutive, such as, for example, -CH-NH-OCH and -CH-O-Si(CH). Typically, a C1-C4 heteroalkyl or heteroalkylene has 1 to 4 carbon atoms and 1 or 2 heteroatoms, and a C1-C3 heteroalkyl or heteroalkylene has 1 to 3 carbon atoms and 1 or 2 heteroatoms. In some embodiments, the heteroalkyl or heteroalkylene is saturated.

[0064] Unless otherwise stated, the term "heteroalkylene," alone or in combination with another term, means a divalent group derived from heteroalkyl (as discussed above), as exemplified by -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. In heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini. Furthermore, no orientation of the linking group is implied for alkylene and heteroalkylene linking groups.

[0065] Unless otherwise indicated, "aminoalkyl," alone or in combination with another term, refers to a heteroalkyl in which the alkyl moiety, as defined herein, is substituted with an amino, alkylamino, dialkylamino, or cycloalkylamino group. Exemplary non-limiting aminoalkyls are -CHNH, -CHCHNH, -CHCHNHCH, and -CHCHN(CH), and further include branched species, e.g., -CH(CH)NH and -C(CH)CHNH in either the (R) or (S) configuration. Alternatively, an aminoalkyl can refer to an alkyl moiety, alkyl group, or alkyl substituent, as defined herein, in which no sp carbon other than the radical carbon is present. 3 carbon is replaced by an amino or alkylamino moiety and at least one sp 3 Provided that carbon remains, sp of that part 3 The nitrogen is the sp of the alkyl 3 It is an alkyl moiety, alkyl group, or alkyl substituent replacing a carbon. When an aminoalkyl moiety is referred to as a substituent on a larger structure or another moiety, the aminoalkyl is covalently attached to that structure or moiety through a carbon radical of the alkyl portion of the aminoalkyl.

[0066] The term "hydroxyalkyl," as used herein, alone or in combination with another term, refers to an alkyl moiety, alkyl group, or alkyl substituent having a hydroxyl radical in place of one or more hydrogen atoms, unless otherwise indicated or suggested by context. In some embodiments, one or two hydrogen atoms in a hydroxyalkyl group are replaced with a hydroxyl substituent. Hydroxyalkyls are typically designated by the number of consecutive carbon atoms in the alkyl or alkylene portion thereof. Thus, a C hydroxyalkyl is exemplified by, but not limited to, -CH OH, and a C hydroxyalkyl is exemplified by, but not limited to, -CH CH OH or -CH (OH) CH .

[0067] The term "haloalkyl," as used herein, alone or in combination with another term, refers to an alkyl moiety, alkyl group, or alkyl substituent having a halogen in place of one or more hydrogen atoms, unless otherwise indicated or suggested by context. In some aspects, one or two hydrogen atoms in a haloalkyl group are replaced with a halogen. Haloalkyls are typically designated by the number of consecutive carbon atoms in its alkyl or alkylene portion. Thus, C haloalkyls are exemplified by, but not limited to, -CHF, -CHCl, -CHBr, or -CHI, and C haloalkyls are exemplified by, but not limited to, -CHCHF, -CHCHCl, -CHCHBr, -CHCHI, -CH(F)CH, -CH(Cl)CH, -CH(Br)CH, or -CH(I)CH. In some embodiments, the term "haloalkyl" refers to an alkyl moiety, alkyl group, or alkyl substituent having a halogen in place of two or more hydrogen atoms. For example, C1 haloalkyl is exemplified by, but not limited to, -CHF2, -CHCl2, -CHBr2, or -CHI2, and C2 haloalkyl is exemplified by, but not limited to, -CH2CHF2, -CH2CHCl2, -CH2CHBr2, -CH2CHI2, -CF2CH3, -CCl2CH3, -CBr2CH3, or -CI2CH3. In some embodiments, the term "haloalkyl" refers to an alkyl moiety, alkyl group, or alkyl substituent having halogens in place of all hydrogen atoms. In some embodiments, the term "haloalkyl" includes fully halogenated alkyl moieties, alkyl groups, or alkyl substituents. For example, C1 haloalkyl is exemplified by, but not limited to, -CF3, -CCl3, -CBr3, or -CI3.

[0068] Unless otherwise indicated, "alkylamino" and "cycloalkylamino," alone or in combination with another term, refer to an alkyl radical or cycloalkyl radical, as described herein, in which the radical carbon of the alkyl radical or cycloalkyl radical is replaced by a nitrogen radical, provided that at least one sp 3 " refers to an alkyl or cycloalkyl radical, provided that the carbon remains. When an alkylamino is substituted at the nitrogen with another alkyl moiety, the resulting substituted radical is sometimes referred to as a dialkylamino moiety, dialkylamino group, or dialkylamino substituent, where the alkyl moieties substituting the nitrogen are independently selected.

[0069] Exemplary, non-limiting amino, alkylamino, and dialkylamino substituents include those having the structure -N(R')2, where R' in these examples is independently hydrogen or C 1-6 In cycloalkylamines, which are heterocycloalkyls, both R', together with the nitrogen to which they are attached, define a heterocyclic ring. When both R' are hydrogen, the moiety is sometimes described as a primary amino group, or when both R' are alkyl, the moiety is sometimes described as a tertiary amine group. When one R' is hydrogen and the other is alkyl, the moiety is sometimes described as a secondary amino group. Primary and secondary alkylamino moieties are more reactive as nucleophiles toward electrophilic centers, including carbonyls, while tertiary amines are more basic.

[0070] "Substituted alkyl" refers to an alkyl in which one or more hydrogen atoms, typically one hydrogen atom, are each independently replaced with a substituent, and "substituted aryl" refers to an aryl in which one or more hydrogen atoms, typically one hydrogen atom, are each independently replaced with a substituent. Typical substituents include -X, -R', -OH, -OR', -SR', -N(R')2, -N(R')3, =NR', -CX3, -CN, -NO2, -NR'C(=O)R', and -C(=O)R. ’ , -C(=O)N(R ’ )2, -S(=O)2R ’ , -S(=O)2NR ’ , -S(=O)R ’ ,-OP(=O)(OR ’ )2, -P(=O)(OR ’ )2, -PO3 = , PO3H2, -C(=O)R ’ , -C(=S)R ’ , -CO2R ’ , -CO2 - , -C(=S)OR ’ , -C(=O)SR ’ , -C(=S)SR ’ , -C(=O)N(R ’ )2, -C(=S)N(R ’ )2 and -C(=NR)N(R ’ )2, wherein each X is independently selected from the group consisting of halogen, i.e., —F, —Cl, —Br, and —I; and each R ’ are independently -H, -C1-C 20 Alkyl, -C6-C 20 Aryl, -C3-C 14 It is selected from the group consisting of a heterocycle, a protecting group and a prodrug moiety.

[0071] More typically, the substituents are -X, -R', -OH, -OR', -SR', -N(R')2, -N(R')3, ═NR', -NR ’ C(=O)R ’ , -C(=O)R ’ , -C(=O)N(R ’ )2, -S(=O)2R’ , -S(=O)2NR ’ , -S(=O)R ’ , -C(=O)R ’ , -C(=S)R ’ , -C(=O)N(R ’ )2, -C(=S)N(R ’ )2 and -C(=NR)N(R ’ )2, wherein each X is independently selected from the group consisting of -F and -Cl, or selected from the group consisting of -X, -R', -OH, -OR', -N(R')2, -N(R')3, -NR'C(=O)R', -C(=O)N(R')2, -S(=O)2R', -S(=O)2NR', -S(=O)R', -C(=O)R', -C(=O)N(R')2, -C(=NR)N(R')2, protecting groups, and prodrug moieties; ’ are independently hydrogen, -C1-C 20 Alkyl, -C6-C 20 Aryl, -C3-C 14 It is selected from the group consisting of a heterocycle, a protecting group and a prodrug moiety.

[0072] In some embodiments, the alkyl substituent is —N(R ’ )2, -N(R ’ )3 and -C(=NR)N(R ’ )2, wherein R ’ is hydrogen and -C1-C 20 In another embodiment, the alkyl is substituted with a series of ethyleneoxy moieties to define the PEG unit. The alkylene, carbocycle, arylene, heteroalkyl, heteroalkylene, heterocycle, heteroaryl, and heteroarylene groups described above may also be similarly substituted.

[0073] "Protecting group," as used herein, means a moiety that prevents or reduces the ability of the atom or functional group to which it is attached to participate in undesired reactions. Typical protecting groups for atoms or functional groups are described in Greene (1999), "Protective Groups in Organic Synthesis, 3 rd Ed.”, Wiley Interscience. Protecting groups for heteroatoms, e.g., oxygen, sulfur, and nitrogen, are sometimes used to minimize or prevent undesired reactions of those atoms with electrophilic compounds. In other cases, protecting groups are used to reduce or eliminate the nucleophilicity and / or basicity of the unprotected heteroatom. Non-limiting examples of protected oxygens include -OR PR where R PR is a protecting group for hydroxyl, which is typically protected as an ester (e.g., acetate, propionate, or benzoate). Other protecting groups for hydroxyl avoid interference with the nucleophilicity of organometallic or other highly basic reagents, and the hydroxyl is typically protected as an ether, including alkyl or heterocycloalkyl ethers (e.g., methyl or tetrahydropyranyl ethers), alkoxymethyl ethers (e.g., methoxymethyl or ethoxymethyl ethers), optionally substituted aryl ethers and silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]-methylsilyl (SEM)). Nitrogen protecting groups include -NHR PR or -N(R PR )2-, for primary or secondary amines, where R PR at least one of R is a nitrogen atom protecting group, or both R PR Both include protecting groups.

[0074] A protecting group is suitable when it can prevent or avoid undesired side reactions or premature loss of the protecting group under the reaction conditions required to effect the desired chemical transformation elsewhere in the molecule, and, if desired, during purification of the newly formed molecule, and can be removed under conditions that do not adversely affect the structure or stereochemical integrity of the newly formed molecule. By way of example and not limitation, suitable protecting groups may include those already mentioned for protecting functional groups. Suitable protecting groups may also be those used in peptide coupling reactions.

[0075] "Electron-withdrawing group," as used herein, means a functional group or electronegative atom that draws electron density from the atom to which it is bonded, either inductively and / or through resonance (regardless of which is predominant) (i.e., the functional group or atom may inductively withdraw electrons, but may overall donate electrons through resonance), tending to stabilize the anion or electron-rich moiety. The electron-withdrawing effect is typically transmitted inductively, albeit in a damped form, to other atoms bonded to the bonded atom made electron-deficient by the electron-withdrawing group (EWG), thereby affecting the electrophilicity of more distant reactive centers. Exemplary electron-withdrawing groups include -C(=O), -CN, -NO, -CX, -X, -C(=O)OR. ’ , -C(=O)N(R ’ )2, -C(=O)R ’ , -C(=O)X, -S(=O)2R ’ , -S(=O)2OR ’ , -S(=O)2NHR ’ , -S(=O)2N(R ’ )2, -P(=O)(OR ’ )2, -P(=O)(CH3)NHR ’ , -NO, -N(R ’ )3 + wherein X is -F, -Br, -Cl, or -I; and R ’ In some embodiments, each independently represents hydrogen and C 1-6It is selected from the group consisting of alkyl, as well as certain O-linked moieties as described herein, such as acyloxy.

[0076] Exemplary EWGs can also include aryl groups (e.g., phenyl), depending on substitution, and certain heteroaryl groups (e.g., pyridine). That is, the term "electron-withdrawing group" also includes an aryl or heteroaryl that is further substituted with an electron-withdrawing group. Typically, electron-withdrawing groups on an aryl or heteroaryl are -C(=O), -CN, -NO2, -CX3, and -X, where independently selected X is a halogen, typically -F or -Cl. Depending on its substituents, the alkyl portion can also be an electron-withdrawing group.

[0077] As used herein, a "succinimide moiety" refers to an organic moiety comprised of a succinimide ring system present in one of the Drawer units (Z), which is typically further comprised of an alkylene-containing moiety attached to the imide nitrogen of the ring system. The succinimide moiety typically results from a Michael addition that adds a sulfhydryl group of a Ligand unit to the maleimide ring system of a Drawer unit precursor (Z'). Thus, the succinimide moiety is comprised of a thio-substituted succinimide ring system that, when present in a camptothecin conjugate, has its imide nitrogen substituted with the remainder of the Linker unit of the camptothecin conjugate, optionally substituted with the substituent(s) that were present on the maleimide ring system of Z'.

[0078] As used herein, "acid-amide moiety" refers to a succinic acid having an amide substituent resulting from the thio-substituted succinimide ring system of the succinimide moiety upon hydrolysis of one of its carbonyl-nitrogen bonds. Hydrolysis to provide the succinic acid-amide moiety results in a linker unit that is less likely to undergo premature loss of the attached Ligand unit through elimination of the antibody-thio substituent. Hydrolysis of the succinimide ring system of the thio-substituted succinimide moiety is expected to yield regiochemical isomers of the acid-amide moiety, due at least in part to the difference in reactivity of the two carbonyl carbons of the succinimide ring system resulting from either substituent present on the maleimide ring system of the Drawer unit precursor and the thio substituent introduced by the targeting ligand.

[0079] In many cases, the conjugates, linkers, and component assemblies described herein will refer to reactive groups. A "reactive group" or RG is a group containing a reactive site (RS) that can form a bond with either a component of a linker unit (i.e., A, W, Y) or camptothecin D. RS is a reactive site within the reactive group (RG). Non-limiting examples of reactive groups include sulfhydryl groups that form disulfide or thioether bonds, aldehyde, ketone, or hydrazine groups that form hydrazone bonds, carboxylic acid or amino groups that form peptide bonds, carboxylic acid or hydroxy groups that form ester bonds, sulfonic acids that form sulfonamide bonds, alcohols that form carbamate bonds, and amines that form sulfonamide or carbamate bonds.

[0080] The following table is illustrative of exemplary functional groups that may be formed after reaction of the reactive groups, reactive sites, and reactive sites. This table is not intended to be limiting. It will be apparent to one of skill in the art that the R' and R" moieties shown in the table are any valid organic moiety (e.g., alkyl, aryl, heteroaryl, substituted alkyl, substituted aryl, or substituted heteroaryl) that is compatible with the bond formation achieved upon conversion of RG to one of the exemplary functional groups. It will also be apparent that, as applied to embodiments of the present invention, R' may optionally represent one or more components of the self-stabilizing linker or optional second linker, and R" may optionally represent one or more components of the optional second linker, camptothecin, stabilizing unit, or detection unit. [Table 28]

[0081] Embodiment Numerous embodiments of the invention are described below, which are not intended to limit the invention in any way, and are followed by a more detailed discussion of the components that make up the conjugates of the invention. Those skilled in the art will understand that each of the conjugates defined, and any given embodiment thereof, is intended to include the full range of each component and linker.

[0082] Camptothecin conjugates In one embodiment, the present invention provides: L-(QD) p or a salt thereof, wherein: L is a Ligand unit; the subscript p is an integer from 1 to 16; Q is, -ZA-, -ZA-RL-, -ZA-RL-Y-, ZAS * -W-, -ZAS *-RL-, -ZAB(S * )-RL-, -ZAS * -W-RL-, -ZAS * -RL-Y- and -ZAB(S * )-RL-Y- wherein Z is a stretcher unit; A is a bond or linking unit; B is a parallel linked unit, S * is a partitioning agent, W is a peptide unit; RL is a releasable unit, Y is a spacer unit;

[0083] D is, [ka] or a salt thereof, wherein: E is -OR b5 or -NR b5 R b5’ and R b1 H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, (C6-C 12 aryl)-C2-C8 alkenyl-, C1-C8 hydroxyalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COORa , -OR a , -NR a R a’ and -SR a and R a , -OR a , -NR a R a’ , -C(O)R a and -SR a optionally substituted with, or R b1 But R b2 , R b5 Or R b6 and together with the intervening atoms form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b2 H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkyl-S(O)2-, C1-C8 aminoalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-NR a -, C1-C8 alkyl-NR a -C(O)O-, C1-C8 alkyl-OC(O)-NR a -, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -OR a , -NR a R a’ and -SR aand each is selected from the group consisting of: -OR a , -NR a R a’ and -SR a or optionally replaced by R b2 But R b1 Or R b3 and, together with the intervening atoms, form a 5- or 6-membered carbocyclic or heterocyclic ring; or R b2 But R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered heterocycle fused to the 6-membered aryl; R b3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, -OR a , -NR a R a’ and -SR a is selected from the group consisting of R b4 is selected from the group consisting of H or halogen; Each R b5 and R b5’ are independently H, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C6 alkyl-O-C1-C6 alkyl-, C1-C8 aminoalkyl, (C1-C4 alkylamino)-C1-C8 alkyl-, N,N-(C1-C4 hydroxyalkyl)(C1-C4 alkyl)amino-C1-C8 alkyl-, N,N-di(C1-C4 alkyl)amino-C1-C8 alkyl-, N-(C1-C4 hydroxyalkyl)-C1-C8 aminoalkyl-, C1-C8 alkyl-C(O)-, C1-C8 hydroxyalkyl-C(O)-, C1-C8 aminoalkyl-C(O)-, C3-C 10 Cycloalkyl, (C3-C 10 Cycloalkyl)-C1-C4 alkyl-, C3-C 10 Heterocycloalkyl, (C3-C 10 Heterocycloalkyl)-C 1- C4 alkyl, C1-C6 hydroxyalkyl, heteroaryl, phenyl, phenyl-C1- C4 alkyl-, diphenyl-C1-C4 alkyl-, heteroaryl, heteroaryl-C1-C4 alkyl-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8 alkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, C1-C4 alkyl-SO2-C1-C8 alkyl-, NH2-SO2-C1-C8 alkyl-, (C3-C 10 Heterocycloalkyl)-C 1- C4 hydroxyalkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8 hydroxyalkyl-C3-C 10 heterocycloalkyl- or R b5 and R b5’ are, in combination with the nitrogen atom to which they are attached, independently halogen, C 1- forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of C4 alkyl, C1-C6 hydroxyalkyl, -OH, -O-C4 alkyl, -NH2, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, C1-C6 alkoxy-C(O)-NH-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, and C1-C8 aminoalkyl; or R b5’ is H and R b5 But R b1 and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring, R b1 , R b2 , R b3 , R b4 , R b5 and R b5’wherein the cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl, and heteroaryl portions are independently substituted with 0 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, —OH, —OC1-C4 alkyl, —NH2, —NHC1-C4 alkyl, and —N(C1-C4 alkyl)2; R b6 is H or R b1 and together with the intervening atoms form a carbocyclic or heterocyclic ring, R a and R a’ are each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C alkyl-S(O)—, C-C alkyl-C(O)—, C-C aminoalkyl-C(O)—, and C-C hydroxyalkyl-C(O)—; A camptothecin conjugate in which D is covalently attached to Q through any suitable attachment site on D, and optionally a hydroxyl, thiol, primary amine, or secondary amine hydrogen atom of D is replaced with a bond to Q, or a tertiary amine of D is quaternized to form a bond to Q.

[0084] The present invention provides L-(QD) p or a salt thereof, wherein: L is a Ligand unit; the subscript p is an integer from 1 to 16; Q is, -ZA-, -ZA-RL-, -ZA-RL-Y-, ZAS * -W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL-, -ZAS * -RL-Y- and -ZAB(S * )-RL-Y- wherein Z is a stretcher unit; A is a bond or linking unit; B is a parallel linked unit, S * is a partitioning agent, W is a peptide unit; RL is a releasable unit, Y is a spacer unit; D is, [ka] or a salt thereof, wherein: R b1 is H, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, (C6-C 12 aryl)-C2-C8 alkenyl-, C1-C8 hydroxyalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -OR a , -NR a R a’ and -SR a and each is selected from the group consisting of: -OR a , -NR a R a’ and -SR a optionally substituted with, or R b1 But R b2 , R b5 Or R b6and together with the intervening atoms form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b2 H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkyl-S(O)2-, C1-C8 aminoalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-NR a -, C1-C8 alkyl-NR a -C(O)O-, C1-C8 alkyl-OC(O)-NR a -, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -OR a , -NR a R a’ and -SR a and each is selected from the group consisting of: -OR a , -NR a R a’ and -SR a optionally substituted with, or R b2 But R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring; R b3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, -OR a , -NR a Ra’ and -SR a is selected from the group consisting of R b4 is selected from the group consisting of H or halogen; Each R b5 and R b5’ are independently H, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 aminoalkyl, (C1-C4 alkylamino)-C1-C8 alkyl-, N,N-(C1-C4 hydroxyalkyl)(C1-C4 alkyl)amino-C1-C8 alkyl-, N,N-di(C1-C4 alkyl)amino-C1-C8 alkyl-, N-(C1-C4 hydroxyalkyl)-C1-C8 aminoalkyl-, C1-C8 alkyl-C(O)-, C1-C8 hydroxyalkyl-C(O)-, C1-C8 aminoalkyl-C(O)-, C3-C 10 Cycloalkyl, (C3-C 10 Cycloalkyl)-C1-C4 alkyl-, C3-C 10 Heterocycloalkyl, (C3-C 10 Heterocycloalkyl)-C 1- C4 alkyl-, phenyl, phenyl-C 1- C4 alkyl-, diphenyl-C1-C4 alkyl-, heteroaryl and heteroaryl-C1-C4 alkyl-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8 alkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, C1-C4 alkyl-SO2-C1-C8 alkyl-, NH2-SO2-C1-C8 alkyl-, (C3-C 10 Heterocycloalkyl)-C 1- C4 hydroxyalkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, phenyl-C(O)-, phenyl-SO2-, and C1-C8 hydroxyalkyl-C3-C 10heterocycloalkyl- or R b5 and R b5’ are, in combination with the nitrogen atom to which they are attached, independently halogen, C 1- forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of C4 alkyl, -OH, -O-C4 alkyl, -NH2, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, C1-C6 alkoxy-C(O)-NH-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, and C1-C8 aminoalkyl; or R b5’ is H and R b5 But R b1 and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring, R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ wherein the cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl, and heteroaryl portions are independently substituted with 0 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, —OH, —OC1-C4 alkyl, —NH2, —NHC1-C4 alkyl, and —N(C1-C4 alkyl)2; R b6 is H or R b1 and together with the intervening atoms form a carbocyclic or heterocyclic ring, R a and R a’ are each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C alkyl-S(O)—, C-C alkyl-C(O)—, C-C aminoalkyl-C(O)—, and C-C hydroxyalkyl-C(O)—; D is also a camptothecin conjugate in which D is covalently attached to Q through any suitable attachment site on D, and optionally a hydroxyl, thiol, primary amine, or secondary amine hydrogen atom of D is replaced with a bond to Q, or a tertiary amine of D is quaternized to form a bond to Q.

[0085] Provided herein are camptothecin conjugates comprising a Drug unit corresponding to formula D1, or any of its variations, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent and Q is attached to the Drug unit through an oxygen atom of the Drug unit.

[0086] In some embodiments of Formula D0, E is —NR b5 R b5’ In some embodiments of formula D0, E is -OR b5 In some embodiments, E is -OR b5 and R b1 is H and R b2 and R b3 together with the intervening atoms form a 5-membered heterocyclic ring, and R b4 , R b5 and R b6 Each of is H.

[0087] In some embodiments, R b1 , R b2 , R b3 and R b4 At least one of R is halogen. b1 , R b2 , R b3 and R b4 At least one of R is C-C alkyl. b1 , R b2 , R b3 and R b4 At least one of -OR a and R a is H or C1-C6 alkyl. In some embodiments, R b5 and R b5’ are H, respectively.

[0088] In some embodiments, the site of covalent attachment of D to the linker (e.g., second linker) of the drug linker moiety is represented by the formula D 1a Or D 1b , or any of their variations (e.g., D 1a -I~D 1a -X, D 1b -I~D 1b -X, etc., and are indicated by a dagger. It is also contemplated that in any of the formulas herein, D may be covalently attached to a linker (e.g., a second linker) of the drug-linker moiety at any site in D that is compatible with attachment to a linker (e.g., a second linker) (e.g., at any OH, NH, NHR, NR, SH, etc.), regardless of whether said site is marked with a dagger. In some embodiments, D is an alkyl group selected from the group consisting of R b5 is linked to the remainder of the drug-linker moiety through its OH or NH2 group.

[0089] In some embodiments, D is [ka] having a formula selected from the group consisting of:

[0090] In any of Formulas D1-I through D1-X and variations thereof, the variables may be defined according to Formula D0, or any of its variations, or according to Formula D1, or any of its variations. In some embodiments, D has a structure corresponding to any of Formulas D1-I through D1-X and variations thereof, where R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ does not exist.

[0091] In some embodiments, D is [ka] having a formula selected from the group consisting of: X and Y Bare independently O, S, S(O)2, and CR x R x’ or NR x and R x and R x’ are each independently selected from the group consisting of H, OH, C-C alkyl, C-C haloalkyl, C-C aminoalkyl-C(O)—, C-C alkyl-C(O)—, C-C hydroxyalkyl-C(O)—, C-C alkyl-NH—C(O)—, or C-C alkyl-S(O)—; m and n are each 1 or 2; Each R c1 , R c1’ , R c2 and R c2’ is independent, (i) H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -OR a , -NR a R a’ , -SR a , C1-C6 alkyl-C(O)-, C1-C6 alkyl-NR a -C(O)- and C1-C6 alkyl-S(O)2-; (ii)R b1 and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring, or (iii)R x’ and together with the intervening atoms form a 3- to 6-membered carbocyclic or heterocyclic ring, when m and n are both present, the sum of m+n is 2 or 3; The remaining variables are as defined in D1.

[0092] In some embodiments, D has a structure corresponding to any of formulas D1-IIa, D1-IIb, D1-IVa, or D1-IVb, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ does not exist.

[0093] In some embodiments, D is [ka] having a formula selected from the group consisting of: R d1 , R d1’ , R d2 and R d2’ are each independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NR a R a’ , -SR a , C1-C6 alkyl-C(O)-, C1-C6 alkyl-NR a -C(O)- and C1-C6 alkyl-S(O)2-; The remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, and D1-Xa. In some embodiments, D is [ka] having a formula selected from the group consisting of: Y 1 is a 5- or 6-membered heteroaryl optionally substituted with halogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, or C-C alkyl-S(O)-; The remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, and D1-Xa.

[0094] In some embodiments, D is [ka] having a formula selected from the group consisting of: Each R eare independently halogen, -OH, -NH, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C alkyl-S(O)-, and C-C alkyl-NR a -C(O)-; f is 0, 1, 2, 3, 4 or 5; The remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, and D1-Xa.

[0095] In some embodiments, D is [ka] having a formula selected from the group consisting of: R g is H, C1-C6 alkyl or 3-8 membered heterocyclyl; The remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, and D1-Xa. g is C1-C6 alkyl.

[0096] In some embodiments, D is [ka] having a formula selected from the group consisting of: R 3h , R 3h’ and R 3h’’ are each independently H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, -C(O)NH-C1-C6 alkyl, C6-C 10 Aryl, -C6-C 10 Aryl-C1-C6 alkyl and -C6-C 10 aryl-C1-C6 alkoxy, each of which is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NR aR a’ and -SR a is optionally replaced by The remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, and D1-Xa.

[0097] In some embodiments, D is [ka] wherein the variables are as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, and D1-Xa.

[0098] In some embodiments, D includes [ka] or a pharmaceutically acceptable salt thereof, wherein each R F and R F’ are independently -H, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 aminoalkyl, (C1-C4 alkylamino)-C1-C8 alkyl-, N,N-(C1-C4 hydroxyalkyl)(C1-C4 alkyl)amino-C1-C8 alkyl-, N,N-di(C1-C4 alkyl)amino-C1-C8 alkyl-, N-(C1-C4 hydroxyalkyl)-C1-C8 aminoalkyl, C1-C8 alkyl-C(O)-, C1-C8 hydroxyalkyl-C(O)-, C1-C8 aminoalkyl-C(O)-, C3-C 10 Cycloalkyl, (C3-C 10 Cycloalkyl)-C1-C4 alkyl-, C3-C 10 Heterocycloalkyl, (C3-C 10 Heterocycloalkyl)-C 1- C4 alkyl-, phenyl, phenyl-C 1-C4 alkyl-, diphenyl-C1-C4 alkyl-, heteroaryl and heteroaryl-C1-C4 alkyl-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8 alkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, C1-C4 alkyl-SO2-C1-C8 alkyl, NH2-SO2-C1-C8 alkyl, (C3-C 10 Heterocycloalkyl)-C 1- C4 hydroxyalkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl, phenyl-C(O)-, phenyl-SO2-, and C1-C8 hydroxyalkyl-C3-C 10 heterocycloalkyl, or R F and R F’ are, together with the nitrogen atom to which they are bonded, independently halogen, C 1- forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of C4 alkyl, -OH, -OC1-C4 alkyl, -NH2, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, C1-C6 alkoxy-C(O)-NH-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, and C1-C8 aminoalkyl; R F and R F’ The cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl portions of are independently substituted with 0 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, —OH, —O1-C4 alkyl, —NH2, —NHC1-C4 alkyl, and —N(C1-C4 alkyl)2.

[0099] In some embodiments, D includes [ka] or a pharmaceutically acceptable salt thereof, each R F and R F’ are independently -H, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C6-O-C1-C6 alkyl, C1-C8 aminoalkyl, (C1-C4 alkylamino)-C1-C8 alkyl-, N,N-(C1-C4 hydroxyalkyl)(C1-C4 alkyl)amino-C1-C8 alkyl-, N,N-di(C1-C4 alkyl)amino-C1-C8 alkyl-, N-(C1-C4 hydroxyalkyl)-C1-C8 aminoalkyl, C1-C8 alkyl-C(O)-, C1-C8 hydroxyalkyl-C(O)-, C1-C8 aminoalkyl-C(O)-, C3-C 10 Cycloalkyl, (C3-C 10 Cycloalkyl)-C1-C4 alkyl-, C3-C 10 Heterocycloalkyl, (C3-C 10 Heterocycloalkyl)-C 1- C4 alkyl-, heteroaryl-C1-C6 hydroxyalkyl, phenyl, phenyl-C 1- C4 alkyl-, diphenyl-C1-C4 alkyl-, heteroaryl and heteroaryl-C1-C4 alkyl-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8 alkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, C1-C4 alkyl-SO2-C1-C8 alkyl, NH2-SO2-C1-C8 alkyl, (C3-C 10 Heterocycloalkyl)-C 1- C4 hydroxyalkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl, phenyl-C(O)-, phenyl-SO2-, and C1-C8 hydroxyalkyl-C3-C 10 heterocycloalkyl, or RF and R F’ are, together with the nitrogen atom to which they are bonded, independently halogen, C 1- forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of C4 alkyl, -OH, C1-C6 hydroxyalkyl, -O-C1-C4 alkyl, -NH2, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, C1-C6 alkoxy-C(O)-NH-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, and C1-C8 aminoalkyl; R F and R F’ The cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl portions of are independently substituted with 0 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, —OH, —O1-C4 alkyl, —NH2, —NHC1-C4 alkyl, and —N(C1-C4 alkyl)2.

[0100] In some embodiments, D is [ka] where the dagger represents the point of covalent attachment of D to the linker (e.g., second linker) of the Drug Linker moiety. In some embodiments, the dagger represents the point of covalent attachment of D to the linker (e.g., second linker) of the Drug Linker moiety. b5 In another embodiment, the dagger indicates that the linker is attached directly to the nitrogen atom marked with the dagger (by substitution of the moiety). b5 In some embodiments, R F is C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8 alkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, C1-C4 alkyl-SO2-C1-C8 alkyl, NH2-SO2-C1-C8 alkyl, (C3-C 10Heterocycloalkyl)-C 1- C4 hydroxyalkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl, phenyl-C(O)-, phenyl-SO2- and C1-C8 hydroxyalkyl-C3-C 10 In some embodiments, R is selected from the group consisting of heterocycloalkyl. F’ is H. In some embodiments, R F’ is methyl. In some embodiments, R F and R F’ are taken together with the nitrogen atom to which each is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of C-C alkoxy-C(O)—NH—, C-C alkoxy-C(O)—C-C aminoalkyl-, and C-C aminoalkyl. In some embodiments, R F is C1-C6 alkyl-O-C1-C6 alkyl-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8 alkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, C1-C4 alkyl-SO2-C1-C8 alkyl, NH2-SO2-C1-C8 alkyl, (C3-C 10 Heterocycloalkyl)-C 1- C4 hydroxyalkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl, phenyl-C(O)-, phenyl-SO2- and C1-C8 hydroxyalkyl-C3-C 10 In some embodiments, R is selected from the group consisting of heterocycloalkyl. F’ is H. In some embodiments, R F’ is methyl. In some embodiments, R F and R F’are taken together with the nitrogen atom to which each is bonded to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of C-C alkoxy-C(O)—NH—, C-C alkoxy-C(O)—C-C aminoalkyl-, C-C hydroxyalkyl, and C-C aminoalkyl.

[0101] In some embodiments, D is [ka] or a salt thereof, wherein the dagger indicates the site of covalent attachment of D to Q, and the remaining variables are the same as defined in D1. In some embodiments, the remaining variables are the same as defined in D0. Formula D 1a In some embodiments, the dagger is (e.g., R b5 The linker is attached directly to the nitrogen marked with a dagger (by substitution of the moiety). 1a In another embodiment, the dagger is R b5 The linker is shown attached to an appropriate atom of the moiety (eg, a nitrogen atom or an oxygen atom).

[0102] Formula D 1a or formula D 1b In some embodiments of b1 , R b2 , R b3 and R b4 are hydrogen atoms.

[0103] Formula D 1a or formula D 1b In some embodiments of b1 , R b2 and R b4 is hydrogen and R b3 is halogen. In some embodiments, R b3 is fluoro.

[0104] Formula D 1a or formula D 1b In some embodiments ofb2 , R b3 and R b4 is hydrogen and R b3 is halogen. In some embodiments, R b1 is fluoro.

[0105] Formula D 1a or formula D 1b In some embodiments of b2 and R b4 is hydrogen and R b1 and R b3 and R are both halogen. b1 and R b3 are both fluoro.

[0106] Formula D 1a or formula D 1b In some embodiments of b1 is hydrogen and R b2 , R b3 and R b4 Each is a halogen. In some embodiments, R b2 , R b3 and R b4 are each fluoro.

[0107] Formula D 1a or formula D 1b In some embodiments of b1 , R b3 and R b4 is hydrogen and R b2 is C1-C6 alkyl, C1-C6 haloalkyl, halogen, -OR a or -SR a In some embodiments, R b2 is C1-C6 alkyl or halogen. In some embodiments, R b2 is C1-C6 alkyl. In some embodiments, R b2 is methyl. In some embodiments, R b2 is C1-C6 alkoxy. In some embodiments, R b2is methoxy. In some embodiments, R b2 is halogen. In some embodiments, R b2 is fluoro. In some embodiments, R b2 is chloro. In some embodiments, R b2 is bromo. In some embodiments, R b2 is C1-C6 haloalkyl. In some embodiments, R b2 is trifluoromethyl. In some embodiments, R b2 is C1-C6 haloalkylthio. In some embodiments, R b2 is trifluoromethylthio. In some embodiments, R b2 is a hydroxyl.

[0108] Formula D 1a or formula D 1b In some embodiments of b1 and R b4 is hydrogen and R b2 is C1-C6 alkyl, C1-C6 haloalkyl, halogen, -OR a or -SR a and R b3 is C1-C6 alkyl or halogen. In some embodiments, R b2 is C1-C6 alkyl, C1-C6 alkoxy, halogen or hydroxy, and R b3 is C1-C6 alkyl or halogen. In some embodiments, R b2 is C1-C6 alkyl. In some embodiments, R b2 is methyl. In some embodiments, R b2 is C1-C6 alkoxy. In some embodiments, R b2 is halogen. In some embodiments, R b2 is fluoro. In some embodiments, R b2 is methoxy. In some embodiments, R b2 is hydroxyl. In some embodiments, R b3is C1-C6 alkyl. In some embodiments, R b3 is methyl. In some embodiments, R b3 is halogen. In some embodiments, R b3 is fluoro. In some embodiments, R b2 is C1-C6 alkyl, and R b3 is halogen. In some embodiments, R b2 is methyl and R b3 is fluoro. In some embodiments, R b2 is C1-C6 alkoxy, and R b3 is halogen. In some embodiments, R b2 is methoxy and R b3 is fluoro. In some embodiments, R b2 and R b3 is halogen. In some embodiments, R b2 and R b3 and R are both fluoro. b2 is a halogen and R b3 is C1-C6 alkyl. In some embodiments, R b2 is fluoro and R b3 is methyl. In some embodiments, R b2 is hydroxyl and R b3 is halogen. In some embodiments, R b2 is hydroxyl and R b3 is fluoro.

[0109] Formula D 1a or formula D 1b In some embodiments of b2 is C1-C6 alkyl, C1-C6 haloalkyl, halogen, -OR a or -SR a and R b1 and R b3 are each independently selected from C1-C6 alkyl, halogen, C2-C6 alkenyl, (C6-C 12 Aryl)-C2-C6 alkenyl-(-ORa -OR a and R is selected from the group consisting of b4 is hydrogen. In some embodiments, R b2 is C1-C6 alkyl, C1-C6 haloalkyl, halogen, -OR a or -SR a and R b1 and R b3 are each independently selected from C1-C6 alkyl, halogen, C2-C6 alkenyl, (C6-C 12 aryl)-C2-C6 alkenyl (respectively, -OR a -OR a and R is selected from the group consisting of b4 is hydrogen. In some embodiments, R b1 is C1-C6 alkyl. In some embodiments, R b1 is methyl. In some embodiments, R b1 is halogen. In some embodiments, R b1 is fluoro. In some embodiments, R b1 is chloro. In some embodiments, R b1 is bromo. In some embodiments, R b1 is (C6-C 12 aryl)-C2-C6 alkenyl, -OR a In some embodiments, R b1 is 4-methoxystyryl. In some embodiments, R b1 is C-C alkenyl. In some embodiments, R b1 is vinyl. In some embodiments, R b1 is 1-methylvinyl. In some embodiments, R b1 is 1-methylvinyl. In some embodiments, R b2 is C1-C6 alkyl. In some embodiments, R b2 is methyl. In some embodiments, R b2is C1-C6 alkoxy. In some embodiments, R b2 is methoxy. In some embodiments, R b2 is hydroxyl. In some embodiments, R b3 is C1-C6 alkyl. In some embodiments, R b3 is methyl. In some embodiments, R b3 is ethyl. In some embodiments, R b3 is C1-C6 alkoxy. In some embodiments, R b3 is methoxy. In some embodiments, R b3 is halogen. In some embodiments, R b3 is fluoro. In some embodiments, R b3 is chloro. In some embodiments, R b3 is bromo. In some embodiments, R b2 is C1-C6 alkyl, and R b1 and R b3 is halogen. In some embodiments, R b2 is methyl and R b1 and R b3 and R are both fluoro. b2 is methyl and R b1 is fluoro and R b3 is bromo. In some embodiments, R b2 is methyl and R b1 is bromo and R b3 is fluoro. In some embodiments, R b2 is methyl and R b1 is chloro and R b3 is fluoro. In some embodiments, R b2 is methyl and R b1 is fluoro and R b3 is chloro. In some embodiments, R b2 is C1-C6 alkoxy, and R b1 and R b3is halogen. In some embodiments, R b2 is methoxy and R b1 and R b3 and R are both fluoro. b2 is methoxy and R b1 is bromo and R b3 is fluoro. In some embodiments, R b2 is methoxy and R b1 is fluoro and R b3 is bromo. In some embodiments, R b2 is hydroxyl and R b1 and R b3 is halogen. In some embodiments, R b2 is hydroxyl and R b1 and R b3 and R are both fluoro. b1 is a halogen and R b2 and R b3 are both C1-C6 alkyl. In some embodiments, R b1 is fluoro and R b2 and R b3 and R are both methyl. b1 is fluoro and R b2 is methyl and R b3 is ethyl. In some embodiments, R b1 and R b2 are both C1-C6 alkyl, and R b3 is halogen. In some embodiments, R b1 and R b2 are both methyl, and R b3 is fluoro.

[0110] In some embodiments, D is [ka] having a formula selected from the group consisting of:

[0111] Formula D 1a -I~D 1a In any of -X or any of its variations, the variables may be defined according to formula D0, or any of its variations, or according to formula D1, or any of its variations.

[0112] In some embodiments, D is [ka] having a formula selected from the group consisting of:

[0113] Formula D 1b -I~D 1b In any of -X or any of its variations, the variables may be defined according to formula D0, or any of its variations, or according to formula D1, or any of its variations. 1b -I~D 1b -IX and variations thereof, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ does not exist.

[0114] Formula D 1a or formula D 1b In some embodiments of b1 is R b2 and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring. In some embodiments, the drug has the formula D 1a / b -I, formula D 1a / b -II or Formula D 1a / b It has the structure of -III. [ka]

[0115] Formula D 1a or formula D 1b In some embodiments ofb2 is R b3 and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring, in which one or more hydrogens are optionally replaced with deuterium. In some embodiments, the drug has the formula D 1a / b -IV, D 1a / b -V, D 1a / b -VI, D 1a / b -VII, D 1a / b -VIII or D 1a / b It has the structure of -IX. [ka]

[0116] Formula D 1a / b -I~D 1 / ba In any of formulas D-IX or any of its variations, the variables may be defined according to formula D0, or any of its variations, or according to formula D1, or any of its variations. 1a / b -I~D 1a / b -X and variations thereof, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ does not exist.

[0117] In some embodiments of Formula D1, R b5 and R b5’ are both H. In some embodiments, R b5 is C1-C6 alkyl (e.g., methyl, ethyl), and R b5’ is H.

[0118] Formula D 1a or formula D 1b In some embodiments of b1 is R b5 and together with the intervening atoms form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring. In some embodiments, the drug has the formula D 1a / b -X structure. [ka]

[0119] In some embodiments, D is [ka] having a formula selected from the group consisting of: X and Y B are independently O, S, S(O)2, and CR x R x’ or NR x and R x and R x’ are each independently selected from the group consisting of H, OH, C-C alkyl, C-C haloalkyl, C-C aminoalkyl-C(O)—, C-C alkyl-C(O)—, C-C hydroxyalkyl-C(O)—, C-C alkyl-NH—C(O)—, or C-C alkyl-S(O)—; m and n are each 1 or 2; Each R c1 , R c1’ , R c2 and R c2’ is independent, (i) H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -OR a , -NR a R a’ , -SR a , C1-C6 alkyl-C(O)-, C1-C6 alkyl-NR a -C(O)- and C1-C6 alkyl-S(O)2-; (ii)R b1 and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring, or (iii)R x’ and together with the intervening atoms form a 3- to 6-membered carbocyclic or heterocyclic ring; or R c1 , Rc1’ , R c2 and R c2’ any two of these together form a 3- to 6-membered carbocyclic or heterocyclic ring, and R c1 , R c1’ , R c2 and R c2’ The remaining two are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NR a R a’ , -SR a , -C(O)-C1-C6 alkyl, -C(O)NR a selected from the group consisting of —C1-C6 alkyl and —S(O)2-C1-C6 alkyl; when m and n are both present, the sum of m+n is 2 or 3; The remaining variables are D 1a and D 1b This is the same as the definition in

[0120] In some embodiments, D has the formula D1a-IIa, where X is O. In some embodiments, D has the formula D1a-IIa, where X is S. In some embodiments, D has the formula D1a-IIa, where X is CR x R x’ In some embodiments, D has the formula D1a-IIa, wherein Y B is O. In some embodiments, D has the formula D1a-IIa, wherein Y B is S. In some embodiments, D has the formula D1a-IIa, wherein Y B is CR x R x’ In some embodiments, D has the formula D1a-IIa, where X is O and Y B is CR x R x’ In some embodiments, D has the formula D1a-IIa, where X is O and Y B is CR x R x’ and R x and R x’are both H. In some embodiments, D has formula D1a-IIa, wherein X is CR x R x’ and Y B is O. In some embodiments, D has the formula D1a-IIa, wherein X is CR x R x’ and Y B is O and R x and R x’ are both H. In some embodiments, D has the formula D1a-IIa, where X is S and Y B is CR x R x’ In some embodiments, D has the formula D1a-IIa, where X is S and Y B is CR x R x’ and R x and R x’ are both H. In some embodiments, D has formula D1a-IIa, wherein X is CR x R x’ and Y B is S. In some embodiments, D has the formula D1a-IIa, where X is CR x R x’ and Y B is S and R x and R x’ are both H. In some embodiments, D has formula D1a-IIa, where X and Y B are both CR x R x’ In some embodiments, D has the formula D1a-IIa, where X and Y B are both CR x R x’ and R x and R x’ are both H. In some embodiments, D has formula D1a-IIa, where X and Y B are both CR x R x’ and R b3In some embodiments, D has the formula D1a-IIa, where X and Y are B are both CR x R x’ and R x and R x’ are both H and R b3 In some embodiments, D has the formula D1a-IIa, where X and Y are B are both CR x R x’ and R x and R x’ are both H and R b3 In some embodiments, D has the formula D1a-IIa, where X and Y are fluoro. B are both CR x R x’ and R x and R x’ and are both H. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R b5 is H. In some embodiments, R b5’ is H. In some embodiments, R b5 and R b5’ are both H.

[0121] In some embodiments, D has the formula D1a-IIb, where X is O. In some embodiments, D has the formula D1a-IIb, where X is CR x R x’ In some embodiments, D has the formula D1a-IIb, where X is CR x R x’ and R x and R x’ are both H. In some embodiments, D has formula D1a-IIb, wherein X is CR x R x’ and R b3 In some embodiments, D has the formula D1a-IIb, wherein X is CRx R x’ and R x and R x’ are both H and R b3 In some embodiments, D has the formula D1a-IIb, wherein X is CR x R x’ and R x and R x’ are both H and R b3 is fluoro. In some embodiments, n is 1. In some embodiments, m is 1. In some embodiments, n and m are both 1. In some embodiments, R b5 is H. In some embodiments, R b5’ is H. In some embodiments, R b5 and R b5’ are both H.

[0122] In some embodiments, D has the formula D1a-IVa, where X is O. In some embodiments, D has the formula D1a-IVa, where X is S. In some embodiments, D has the formula D1a-IVa, where X is CR x R x’ In some embodiments, D has the formula D1a-IVa, where X is CR x R x’ and R x and R x’ are both H. In some embodiments, D has formula D1a-IVa, wherein X is CR x R x’ and R b1 In some embodiments, D has the formula D1a-IVa, where X is CR x R x’ and R x and R x’ are both H and R b1 In some embodiments, D has the formula D1a-IVa, where X is CR x R x’ and R x and Rx’ are both H and R b1 In some embodiments, D has the formula D1a-IVa, where X is O and R c1 is C1-C6 alkyl. In some embodiments, D has the formula D1a-IVa, where X is O and R c1 In some embodiments, n is 1. In some embodiments, n and m are both 1. In some embodiments, R b5 is H. In some embodiments, R b5’ is H. In some embodiments, R b5 and R b5’ are both H.

[0123] In some embodiments, D has the formula D1a-IVb, where X is O. In some embodiments, D has the formula D1a-IVb, where X is S. In some embodiments, D has the formula D1a-IVb, where X is CR x R x’ In some embodiments, D has the formula D1a-IVb, where X is CR x R x’ and R x and R x’ are both H. In some embodiments, D has formula D1a-IVb, wherein X is CR x R x’ and R b1 In some embodiments, D has the formula D1a-IVb, wherein X is CR x R x’ and R x and R x’ are both H and R b1 In some embodiments, D has the formula D1a-IVb, wherein X is CR x R x’ and R x and R x’ are both H and R b1In some embodiments, D has the formula D1a-IVb, where X is O and R c1 is C1-C6 alkyl. In some embodiments, D has the formula D1a-IVb, where X is O and R c1 In some embodiments, n is 1. In some embodiments, n and m are both 1. In some embodiments, R b5 is H. In some embodiments, R b5’ is H. In some embodiments, R b5 and R b5’ are both H.

[0124] In some embodiments, D has the formula D1a-Xa, where n is 1 or 2. In some embodiments, D has the formula D1a-Xa, where n is 1. In some embodiments, D has the formula D1a-Xa, where n is 2. In some embodiments, D has the formula D1a-Xa, where R b5’ is H. In some embodiments, D has the formula D1a-Xa, where n is 1 and R b5’ is H. In some embodiments, R b2 is OH. In some embodiments, R b3 is halo. In some embodiments, R b3 is fluoro. In some embodiments, R b2 is OH and R b3 is fluoro.

[0125] In some embodiments, D is [ka] wherein the variable group is D 1a , D 1b , D1a-IIa, D1a-IIb, D1a-IVa, D1a-IVb, and D1a-Xa. In some embodiments, D is of formula D 1a , D 1bD1a-IIa, D1a-IIb, D1a-IVa, and D1a-IVb, and variations thereof, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ does not exist.

[0126] In some embodiments, D has the formula D1b-IIa, where X is O. In some embodiments, D has the formula D1b-IIa, where X is S. In some embodiments, D has the formula D1b-IIa, where X is CR x R x’ In some embodiments, D has the formula D1b-IIa, wherein Y B is O. In some embodiments, D has the formula D1b-IIa, wherein Y B is S. In some embodiments, D has the formula D1b-IIa, wherein Y B is CR x R x’ In some embodiments, D has the formula D1b-IIa, where X is O and Y B is CR x R x’ In some embodiments, D has the formula D1b-IIa, where X is O and Y B is CR x R x’ where R x and R x’ are both H. In some embodiments, D has the formula D1b-IIa, wherein X is CR x R x’ and Y B is O. In some embodiments, D has the formula D1b-IIa, wherein X is CR x R x’ and Y B is O and R x and R x’ are both H. In some embodiments, D has the formula D1b-IIa, where X is S and Y B is CR x Rx’ In some embodiments, D has the formula D1b-IIa, where X is S and Y B is CR x R x’ and R x and R x’ are both H. In some embodiments, D has the formula D1b-IIa, wherein X is CR x R x’ and Y B is S. In some embodiments, D has the formula D1b-IIa, wherein X is CR x R x’ and Y B is S and R x and R x’ are both H. In some embodiments, D has the formula D1b-IIa, where X and Y B are both CR x R x’ In some embodiments, D has the formula D1b-IIa, where X and Y B are both CR x R x’ and R x and R x’ are both H. In some embodiments, D has the formula D1b-IIa, where X and Y B are both CR x R x’ and R b3 In some embodiments, D has the formula D1b-IIa, where X and Y are B are both CR x R x’ and R x and R x’ are both H and R b3 In some embodiments, D has the formula D1b-IIa, where X and Y are B are both CR x R x’ and R x and R x’ are both H and R b3In some embodiments, D has the formula D1b-IIa, where X and Y are fluoro. B are both CR x R x’ and R x and R x’ and are both H. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R b5 is H. In some embodiments, R b5’ is H. In some embodiments, R b5 and R b5’ are both H.

[0127] In some embodiments, D has the formula D1b-IIb, where X is O. In some embodiments, D has the formula D1b-IIb, where X is CR x R x’ In some embodiments, D has the formula D1b-IIb, where X is CR x R x’ and R x and R x’ are both H. In some embodiments, D has the formula D1b-IIb, wherein X is CR x R x’ and R b3 In some embodiments, D has the formula D1b-IIb, where X is CR x R x’ and R x and R x’ are both H and R b3 In some embodiments, D has the formula D1b-IIb, where X is CR x R x’ and R x and R x’ are both H and R b3 is fluoro. In some embodiments, n is 1. In some embodiments, m is 1. In some embodiments, n and m are both 1. In some embodiments, Rb5 is H. In some embodiments, R b5’ is H. In some embodiments, R b5 and R b5’ are both H.

[0128] In some embodiments, D has the formula D1b-IVa, where X is O. In some embodiments, D has the formula D1b-IVa, where X is S. In some embodiments, D has the formula D1b-IVa, where X is CR x R x’ In some embodiments, D has the formula D1b-IVa, where X is CR x R x’ and R x and R x’ are both H. In some embodiments, D has the formula D1b-IVa, wherein X is CR x R x’ and R b1 In some embodiments, D has the formula D1b-IVa, wherein X is CR x R x’ and R x and R x’ are both H and R b1 In some embodiments, D has the formula D1b-IVa, wherein X is CR x R x’ and R x and R x’ are both H and R b1 In some embodiments, D has the formula D1b-IVa, where X is O and R c1 is C1-C6 alkyl. In some embodiments, D has the formula D1b-IVa, where X is O and R c1 In some embodiments, n is 1. In some embodiments, n and m are both 1. In some embodiments, R b5 is H. In some embodiments, R b5’ is H. In some embodiments, Rb5 and R b5’ are both H.

[0129] In some embodiments, D has the formula D1b-IVb, where X is O. In some embodiments, D has the formula D1b-IVb, where X is S. In some embodiments, D has the formula D1b-IVb, where X is CR x R x’ In some embodiments, D has the formula D1b-IVb, where X is CR x R x’ and R x and R x’ are both H. In some embodiments, D has the formula D1b-IVb, wherein X is CR x R x’ and R b1 In some embodiments, D has the formula D1b-IVb, where X is CR x R x’ and R x and R x’ are both H and R b1 In some embodiments, D has the formula D1b-IVb, where X is CR x R x’ and R x and R x’ are both H and R b1 In some embodiments, D has the formula D1b-IVb, where X is O and R c1 is C1-C6 alkyl. In some embodiments, D has the formula D1b-IVb, where X is O and R c1 In some embodiments, n is 1. In some embodiments, n and m are both 1. In some embodiments, R b5 is H. In some embodiments, R b5’ is H. In some embodiments, R b5 and R b5’ are both H.

[0130] In some embodiments, D has the formula Dlb-Xa, where n is 1 or 2. In some embodiments, D has the formula Dlb-Xa, where n is 1. In some embodiments, D has the formula Dlb-Xa, where n is 2. In some embodiments, D has the formula Dlb-Xa, where R b5’ is H. In some embodiments, D has the formula D1b-Xa, where n is 1 and R b5’ is H. In some embodiments, R b2 is OH. In some embodiments, R b3 is halo. In some embodiments, R b3 is fluoro. In some embodiments, R b2 is OH and R b3 is fluoro.

[0131] In some embodiments, D is [ka] having a formula selected from the group consisting of: R d1 , R d1’ , R d2 and R d2’ are each independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NR a R a’ , -SR a , -C(O)-C1-C6 alkyl, -C(O)NR a selected from the group consisting of —C1-C6 alkyl and —S(O)2-C1-C6 alkyl; The remaining variables are D 1a and D 1b In some embodiments, D has a structure corresponding to any of formulas D1a-XI and D1b-XI and variations thereof, wherein the NH group is replaced with an OH group.

[0132] In some embodiments, D has the formula D1a-XI, where R b2 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a and -SR a and each R is selected from the group consisting of a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has the formula D1a-XI, where R b3 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a and -SR a and each R is selected from the group consisting of a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has the formula D1a-XI, where X is O, S, S(O), CR x R x’ or NR x and R x and R x’ are each independently selected from the group consisting of H, OH, C1-C6 alkyl, —C(O)—C1-C6 alkyl, —C(O)NH—C1-C6 alkyl, and —S(O)2—C1-C6 alkyl.

[0133] In some embodiments, D has the formula D1a-XI, where R b2 is C1-C6 alkyl. In some embodiments, D has the formula D1a-XI, where R b2 is methyl. In some embodiments, D has the formula D1a-XI, where R b3 In some embodiments, D has the formula D1a-XI, where R b3 In some embodiments, D has the formula D1a-XI, where R b2 is methyl and R b3is fluoro. In some embodiments, D has the formula D1a-XI, where n is 1 or 2. In some embodiments, D has the formula D1a-XI, where n is 1. In some embodiments, D has the formula D1a-XI, where n is 2. In some embodiments, D has the formula D1a-XI, where m is 1 or 2. In some embodiments, D has the formula D1a-XI, where m is 1. In some embodiments, D has the formula D1a-XI, where m is 2. In some embodiments, D has the formula D1a-XI, where n and m are both 1. In some embodiments, D has the formula D1a-XI, where n is 1 and m is 2. In some embodiments, D has the formula D1a-XI, where n is 2 and m is 1. In some embodiments, D has the formula D1a-XI, where X is O. In some embodiments, D has the formula D1a-XI, where X is CR x R x’ In some embodiments, D has the formula D1a-XI, where X is CR x R x’ and R x and R x’ are both H. In some embodiments, D has the formula D1a-XI, where X is NR x In some embodiments, D has the formula D1a-XI, where X is NR x and R x is C1-C6 alkyl. In some embodiments, D has the formula D1a-XI, where X is NR x and R x In some embodiments, D has the formula D1a-XI, where X is NR x and R xis methyl. In some embodiments, D has the formula D1a-XI where X is S. In some embodiments, D has the formula D1a-XI where X is S(O)2. In some embodiments, D has the formula D1a-XI where X is -S(O)2-C1-C6 alkyl. In some embodiments, D has the formula D1a-XI where X is -S(O)2-CH3.

[0134] In some embodiments, D has the formula D1b-XI, where R b2 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a and -SR a and each R is selected from the group consisting of a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has the formula D1b-XI, wherein R b3 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a and -SR a and each R is selected from the group consisting of a is independently selected from the group consisting of H, C-C alkyl, and C-C haloalkyl. In some embodiments, D has the formula Dlb-XI, where X is O, S, S(O), CR x R x’ or NR x and R x and R x’ are each independently selected from the group consisting of H, OH, C1-C6 alkyl, —C(O)—C1-C6 alkyl, —C(O)NH—C1-C6 alkyl, and —S(O)2—C1-C6 alkyl.

[0135] In some embodiments, D has the formula D1b-XI, where R b2 is C1-C6 alkyl. In some embodiments, D has the formula D1b-XI, where R b2is methyl. In some embodiments, D has the formula D1b-XI, where R b3 is halo. In some embodiments, D has the formula D1b-XI, where R b3 In some embodiments, D has the formula D1b-XI, where R b2 is methyl and R b3 is fluoro. In some embodiments, D has the formula Dlb-XI, where n is 1 or 2. In some embodiments, D has the formula Dlb-XI, where n is 1. In some embodiments, D has the formula Dlb-XI, where n is 2. In some embodiments, D has the formula Dlb-XI, where m is 1 or 2. In some embodiments, D has the formula Dlb-XI, where m is 1. In some embodiments, D has the formula Dlb-XI, where m is 2. In some embodiments, D has the formula Dlb-XI, where n and m are both 1. In some embodiments, D has the formula Dlb-XI, where n is 1 and m is 2. In some embodiments, D has the formula Dlb-XI, where n is 2 and m is 1. In some embodiments, D has the formula D1b-XI, where X is O. In some embodiments, D has the formula D1b-XI, where X is CR x R x’ In some embodiments, D has the formula D1b-XI, where X is CR x R x’ and R x and R x’ are both H. In some embodiments, D has the formula D1b-XI, where X is NR x In some embodiments, D has the formula D1b-XI, where X is NR x and R x is C1-C6 alkyl. In some embodiments, D has the formula D1b-XI, where X is NR x and R x is methyl. In some embodiments, D has the formula D1b-XI, where X is NRx and R x is methyl. In some embodiments, D has the formula Dlb-XI where X is S. In some embodiments, D has the formula Dlb-XI where X is S(O)2. In some embodiments, D has the formula Dlb-XI where X is -S(O)2-C1-C6 alkyl. In some embodiments, D has the formula Dlb-XI where X is -S(O)2-CH3.

[0136] In some embodiments, D is [ka] having a formula selected from the group consisting of: Y 1 is a 5- or 6-membered heteroaryl optionally substituted with halogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, or C-C alkyl-S(O)-; The remaining variables are D 1a and D 1b In some embodiments, D has a structure corresponding to any of formulas D1a-XII and D1b-XII and variations thereof, where the NH group is replaced with an OH group.

[0137] In some embodiments, D has formula D1a-XII, where R b2 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a and -SR a and each R is selected from the group consisting of a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1a-XII, wherein R b3 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a and -SRa and each R is selected from the group consisting of a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0138] In some embodiments, D has formula D1a-XII, where R b2 is C1-C6 alkyl. In some embodiments, D has formula D1a-XII, where R b2 In some embodiments, D has the formula D1a-XII, where R b3 In some embodiments, D has formula D1a-XII, where R b3 In some embodiments, D has the formula D1b-XI, where R b2 is methyl and R b3 In some embodiments, D has the formula D1a-XII, where Y is fluoro. 1 is a 5-membered heteroaryl optionally substituted with C-C alkyl, C-C hydroxyalkyl, or —S(O)—C-C alkyl. In some embodiments, D has the formula D1a-XII, wherein Y 1 is an unsubstituted 5-membered heteroaryl. In some embodiments, D has the formula D1a-XII, wherein Y 1 is unsubstituted thiophene. In some embodiments, D has formula D1a-XII, where Y 1 is unsubstituted thiophene and R b2 is methyl and R b3 In some embodiments, D has the formula D1a-XII, where Y is fluoro. 1 is a 5-membered heteroaryl and is substituted with C-C alkyl, C-C hydroxyalkyl, or —S(O)—C-C alkyl. In some embodiments, D has the formula D1a-XII, wherein Y 1is thiophene and is substituted with C-C alkyl, C-C hydroxyalkyl, or —S(O)—C-C alkyl. In some embodiments, D has the formula D1a-XII, wherein Y 1 is thiophene and is substituted with C1-C6 hydroxyalkyl. In some embodiments, D has the formula D1a-XII, wherein Y 1 is thiophene and is substituted with hydroxyethyl. In some embodiments, D has the formula D1a-XII, wherein Y 1 is a thiophene substituted with hydroxyethyl, and R b2 is methyl and R b3 In some embodiments, D has the formula D1a-XII, where Y is fluoro. 1 In some embodiments, D has the formula D1a-XII, where Y is furan. 1 is unsubstituted furan. In some embodiments, D has formula D1a-XII, wherein Y 1 In some embodiments, D has the formula D1a-XII, where Y is pyrrole. 1 is a substituted pyrrole. In some embodiments, D has formula D1a-XII, where Y 1 is pyrrole substituted with -S(O)2-C1-C6 alkyl. In some embodiments, D has the formula D1a-XII, where Y 1 is pyrrole substituted by -S(O)2-CH3. In some embodiments, D has the formula D1a-XII, where Y 1 In some embodiments, D has the formula D1a-XII, where Y is pyridine. 1 is unsubstituted pyridine. In some embodiments, D has the formula D1a-XII, where Y 1 In some embodiments, D has the formula D1a-XII, where Y is an isoxazole. 1 is an unsubstituted isoxazole. In some embodiments, D has the formula D1a-XII, wherein Y 1is an isoxazole substituted with one or more C1-C6 alkyl. In some embodiments, D has the formula D1a-XII, wherein Y 1 is an isoxazole substituted with one or more methyl. In some embodiments, D has the formula D1a-XII, wherein Y 1 is an isoxazole substituted with one methyl group. In some embodiments, D has the formula D1a-XII, where Y 1 is an isoxazole substituted with two methyl groups.

[0139] In some embodiments, D has formula D1b-XII, where R b2 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a and -SR a and each R is selected from the group consisting of a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has the formula D1b-XII, wherein R b3 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a and -SR a and each R is selected from the group consisting of a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0140] In some embodiments, D has formula D1b-XII, where R b2 is C1-C6 alkyl. In some embodiments, D has the formula D1b-XII, where R b2 In some embodiments, D has the formula D1b-XII, where R b3 In some embodiments, D has the formula D1b-XII, where R b3 In some embodiments, D has the formula D1b-XI, where Rb2 is methyl and R b3 In some embodiments, D has the formula D1b-XII, where Y 1 is a 5-membered heteroaryl optionally substituted with C-C alkyl, C-C hydroxyalkyl, or —S(O)—C-C alkyl. In some embodiments, D has the formula D1b-XII, wherein Y 1 is an unsubstituted 5-membered heteroaryl. In some embodiments, D has the formula D1b-XII, wherein Y 1 is unsubstituted thiophene. In some embodiments, D has the formula D1b-XII, where Y 1 is unsubstituted thiophene and R b2 is methyl and R b3 In some embodiments, D has the formula D1b-XII, where Y 1 is a 5-membered heteroaryl and is substituted with C-C alkyl, C-C hydroxyalkyl, or —S(O)—C-C alkyl. In some embodiments, D has the formula D1b-XII, wherein Y 1 is thiophene and is substituted with C-C alkyl, C-C hydroxyalkyl, or —S(O)—C-C alkyl. In some embodiments, D has the formula D1b-XII, wherein Y 1 is thiophene and is substituted with C1-C6 hydroxyalkyl. In some embodiments, D has the formula D1b-XII, wherein Y 1 is thiophene and is substituted with hydroxyethyl. In some embodiments, D has the formula D1b-XII, wherein Y 1 is a thiophene substituted with hydroxyethyl, and R b2 is methyl and R b3 In some embodiments, D has the formula D1b-XII, where Y 1 In some embodiments, D has the formula D1b-XII, where Y is furan. 1is unsubstituted furan. In some embodiments, D has the formula D1b-XII, wherein Y 1 In some embodiments, D has the formula D1b-XII, where Y is pyrrole. 1 is a substituted pyrrole. In some embodiments, D has the formula D1b-XII, where Y 1 is pyrrole substituted with -S(O)2-C1-C6 alkyl. In some embodiments, D has the formula D1b-XII, wherein Y 1 is pyrrole substituted by -S(O)2-CH3. In some embodiments, D has the formula D1b-XII, where Y 1 In some embodiments, D has the formula D1b-XII, where Y is pyridine. 1 is unsubstituted pyridine. In some embodiments, D has the formula D1b-XII, wherein Y 1 In some embodiments, D has the formula D1b-XII, where Y 1 is an unsubstituted isoxazole. In some embodiments, D has the formula D1b-XII, wherein Y 1 is an isoxazole substituted with one or more C1-C6 alkyl. In some embodiments, D has the formula D1b-XII, wherein Y 1 is an isoxazole substituted with one or more methyl. In some embodiments, D has the formula D1b-XII, wherein Y 1 is an isoxazole substituted with one methyl group. In some embodiments, D has the formula D1b-XII, where Y 1 is an isoxazole substituted with two methyl groups.

[0141] In some embodiments, D is [ka] having a formula selected from the group consisting of: Each R eare independently selected from the group consisting of halogen, —OH, —NH, C-C alkyl, C-C hydroxyalkyl, —S(O)—C-C alkyl, and —C(O)NH—C-C alkyl; f is 0, 1, 2, 3, 4 or 5; The remaining variables are D 1a and D 1b In some embodiments, D has a structure corresponding to any of formulas D1a-XIII and D1b-XIII and variations thereof, where the NH group is replaced with an OH group.

[0142] In some embodiments, D has formula D1a-XIII, where R b2 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a and -SR a and each R is selected from the group consisting of a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1a-XIII, wherein R b3 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a and -SR a and each R is selected from the group consisting of a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1a-XIII, wherein R eis selected from the group consisting of halogen, —OH, —NH, C-C alkyl, C-C hydroxyalkyl, —S(O)—C-C alkyl, and —C(O)NH—C-C alkyl. In some embodiments, D has the formula D1a-XIII, where f is 0, 1, 2, 3, 4, or 5. In some embodiments, D has the formula D1a-XIII, where f is 0. In some embodiments, D has the formula D1a-XIII, where f is 1. In some embodiments, D has the formula D1a-XIII, where f is 2. In some embodiments, D has the formula D1a-XIII, where f is 3. In some embodiments, D has the formula D1a-XIII, where f is 4. In some embodiments, D has the formula D1a-XIII, where f is 5.

[0143] In some embodiments, D has formula D1a-XIII, where R b2 is C1-C6 alkyl. In some embodiments, D has the formula D1a-XIII, where R b2 In some embodiments, D has the formula D1a-XIII, where R b3 In some embodiments, D has the formula D1a-XIII, where R b3 In some embodiments, D has the formula D1a-XIII, where R b2 is methyl and R b3 In some embodiments, D has the formula D1a-XIII, where R e In some embodiments, D has formula D1a-XIII, where R e is —OH and f is 1. In some embodiments, D has the formula D1a-XIII, where R e In some embodiments, D has the formula D1a-XIII, where R e In some embodiments, D has the formula D1a-XIII, where R eIn some embodiments, D has the formula D1a-XIII, where R e is —C(O)NH—C1-C6 alkyl.

[0144] In some embodiments, D has the formula D1b-XIII, where R b2 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a and -SR a and each R is selected from the group consisting of a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has the formula D1b-XIII, wherein R b3 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a and -SR a and each R is selected from the group consisting of a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has the formula D1b-XIII, wherein R e is selected from the group consisting of halogen, —OH, —NH, C-C alkyl, C-C hydroxyalkyl, —S(O)—C-C alkyl, and —C(O)NH—C-C alkyl. In some embodiments, D has the formula Dlb-XIII, where f is 0, 1, 2, 3, 4, or 5. In some embodiments, D has the formula Dlb-XIII, where f is 0. In some embodiments, D has the formula Dlb-XIII, where f is 1. In some embodiments, D has the formula Dlb-XIII, where f is 2. In some embodiments, D has the formula Dlb-XIII, where f is 3. In some embodiments, D has the formula Dlb-XIII, where f is 4. In some embodiments, D has the formula Dlb-XIII, where f is 5.

[0145] In some embodiments, D has the formula D1b-XIII, where R b2 is C1-C6 alkyl. In some embodiments, D has the formula D1b-XIII, where R b2 In some embodiments, D has the formula D1b-XIII, where R b3 In some embodiments, D has the formula D1b-XIII, where R b3 In some embodiments, D has the formula D1b-XIII, where R b2 is methyl and R b3 In some embodiments, D has the formula D1b-XIII, where R e In some embodiments, D has the formula D1b-XIII, where R e is —OH and f is 1. In some embodiments, D has the formula D1b-XIII, where R e In some embodiments, D has the formula D1b-XIII, where R e In some embodiments, D has the formula D1b-XIII, where R e In some embodiments, D has the formula D1b-XIII, where R e is —C(O)NH—C1-C6 alkyl.

[0146] In some embodiments, D is [ka] having a formula selected from the group consisting of: R g is H, C1-C6 alkyl or 3-8 membered heterocyclyl; The remaining variables are D 1a and D 1b In some embodiments, R gis C-C alkyl. In some embodiments, D has a structure corresponding to any of formulas D1a-XIV and D1b-XIV, and variations thereof, where the NH group is replaced with an OH group.

[0147] In some embodiments, D has formula D1a-XIV, where R b2 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1a-XIV, wherein R b3 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1a-XIV, wherein R g is H, C1-C6 alkyl or 3-8 membered heterocyclyl.

[0148] In some embodiments, D has formula D1a-XIV, where R b2 is C1-C6 alkyl. In some embodiments, D has formula D1a-XIV, where R b2 In some embodiments, D has the formula D1a-XIV, where R b3 In some embodiments, D has the formula D1a-XIV, where R b3 In some embodiments, D has formula D1a-XIV, where R b2 is methyl and R b3 In some embodiments, D has formula D1a-XIV, where R gis H. In some embodiments, D has formula D1a-XIV, where R g is C1-C6 alkyl. In some embodiments, D has formula D1a-XIV, where R g is a 3-8 membered heterocyclyl. In some embodiments, D has formula D1a-XIV, wherein R g is H and R b2 is methyl and R b3 is fluoro.

[0149] In some embodiments, D has formula D1b-XIV, where R b2 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1b-XIV, wherein R b3 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1b-XIV, wherein R g is H, C1-C6 alkyl or 3-8 membered heterocyclyl.

[0150] In some embodiments, D has formula D1b-XIV, where R b2 is C1-C6 alkyl. In some embodiments, D has the formula D1b-XIV, where R b2 is methyl. In some embodiments, D has the formula D1b-XIV, where R b3 In some embodiments, D has the formula D1b-XIV, where R b3In some embodiments, D has formula D1b-XIV, where R b2 is methyl and R b3 In some embodiments, D has formula D1b-XIV, where R g is H. In some embodiments, D has formula D1b-XIV, where R g is C1-C6 alkyl. In some embodiments, D has the formula D1b-XIV, where R g is a 3-8 membered heterocyclyl. In some embodiments, D has the formula D1b-XIV, wherein R g is H and R b2 is methyl and R b3 is fluoro.

[0151] In some embodiments, D is [ka] having a formula selected from the group consisting of: R 3h , R 3h’ and R 3h’’ are each independently H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -C(O)-C1-C6 alkyl, -C(O)O-C1-C6 alkyl, -C(O)NH-C1-C6 alkyl, C6-C 10 Aryl, -C6-C 10 Aryl-C1-C6 alkyl and -C6-C 10 aryl-C1-C6 alkoxy, each of which is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NR a R a’ and -SR a is optionally replaced by The remaining variables are D 1a and D 1bIn some embodiments, D has a structure corresponding to any of formulas D1a-XV and D1b-XV and variations thereof, where the NH group is replaced with an OH group.

[0152] In some embodiments, D has formula D1a-XV, where R b2 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1a-XV, wherein R b3 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0153] In some embodiments, D has formula D1a-XV, where R b2 is C1-C6 alkyl. In some embodiments, D has the formula D1a-XV, where R b2 In some embodiments, D has the formula D1a-XV, where R b2 In some embodiments, D has the formula D1a-XV, where R b2 In some embodiments, D has the formula D1a-XV, where R b2 In some embodiments, D has formula D1a-XV, where R b3 In some embodiments, D has the formula D1a-XV, where R b3 In some embodiments, D has formula D1a-XV, where R b2 is methyl and R b3In some embodiments, D has formula D1a-XV, where R b2 is H and R b3 In some embodiments, D has formula D1a-XV, where R b2 and R b3 and are both fluoro. In some embodiments, D has formula D1a-XV, where R b2 is -OH and R b3 is H. In some embodiments, D has formula D1a-XV, where R 3h , R 3h’ and R 3h’’ are each H. In some embodiments, D has formula D1a-XV, where R 3h and R 3h’ are both H and R 3h’’ is C1-C6 alkyl. In some embodiments, D has the formula D1a-XV, where R 3h and R 3h’ are both H and R 3h’’ In some embodiments, D has the formula D1a-XV, where R 3h and R 3h’ are both C1-C6 alkyl, and R 3h’’ is H. In some embodiments, D has formula D1a-XV, where R 3h and R 3h’ are both methyl, and R 3h’’ is H. In some embodiments, D has formula D1a-XV, where R 3h is H and R 3h’ and R 3h’’ and are both methyl. In some embodiments, D has formula D1a-XV, where R b2 is methyl and R b3 is fluoro and R 3h , R 3h’ and R 3h’’ are each H. In some embodiments, D has formula D1a-XV, where R b2 is methyl and R b3 is fluoro and R3h and R 3h’ are both H and R 3h’’ In some embodiments, D has the formula D1a-XV, where R 3h and R 3h’’ are both H and R 3h’ is -C6-C 10 It is aryl-C1-C6 alkoxy.

[0154] In some embodiments, D has the formula D1b-XV, where R b2 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has the formula D1b-XV, wherein R b3 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl.

[0155] In some embodiments, D has the formula D1b-XV, where R b2 is C1-C6 alkyl. In some embodiments, D has the formula D1b-XV, where R b2 is methyl. In some embodiments, D has the formula D1b-XV, where R b2 In some embodiments, D has the formula D1b-XV, where R b2 In some embodiments, D has the formula D1b-XV, where R b2 In some embodiments, D has the formula D1b-XV, where R b3 In some embodiments, D has the formula D1b-XV, where Rb3 In some embodiments, D has the formula D1b-XV, where R b2 is methyl and R b3 In some embodiments, D has the formula D1b-XV, where R b2 is H and R b3 In some embodiments, D has the formula D1b-XV, where R b2 and R b3 and are both fluoro. In some embodiments, D has the formula D1b-XV, where R b2 is -OH and R b3 is H. In some embodiments, D has the formula D1b-XV, where R 3h , R 3h’ and R 3h’’ are each H. In some embodiments, D has the formula D1b-XV, where R 3h and R 3h’ are both H and R 3h’’ is C1-C6 alkyl. In some embodiments, D has the formula D1b-XV, where R 3h and R 3h’ are both H and R 3h’’ is methyl. In some embodiments, D has the formula D1b-XV, where R 3h and R 3h’ are both C1-C6 alkyl, and R 3h’’ is H. In some embodiments, D has the formula D1b-XV, where R 3h and R 3h’ are both methyl, and R 3h’’ is H. In some embodiments, D has the formula D1b-XV, where R 3h is H and R 3h’ and R 3h’’ and are both methyl. In some embodiments, D has the formula D1b-XV, where R b2 is methyl and R b3 is fluoro and R 3h , R 3h’ and R 3h’’are each H. In some embodiments, D has the formula D1b-XV, where R b2 is methyl and R b3 is fluoro and R 3h and R 3h’ are both H and R 3h’’ is methyl. In some embodiments, D has the formula D1b-XV, where R 3h and R 3h’’ are both H and R 3h’ is -C6-C 10 It is aryl-C1-C6 alkoxy.

[0156] In some embodiments, D is [ka] wherein the variable group is D 1a and D 1b In some embodiments, D has a structure corresponding to any of formulas D1a-XVI and D1b-XVI and variations thereof, where R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ does not exist.

[0157] In some embodiments, D has formula D1a-XVI, where R b1 is H, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R b1 is H, halogen, -CN, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, -OR a , -NHR a or -SRa and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1a-XVI, wherein R b2 is H, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1a-XVI, wherein R b3 is H, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1a-XVI, wherein R b2 and R b3 together form a methylenedioxy moiety. In some embodiments, D has formula D1a-XVI, where R b6 is H or R b1 and together form a carbocyclic or heterocyclic ring. In some embodiments, D has formula D1a-XVI, where R b5’ is H, —C(O)—C1-C6 alkyl, or —C(O)—C1-C6 alkylamino.

[0158] In some embodiments, D has formula D1a-XVI, where R b1 In some embodiments, D has formula D1a-XVI, where R b1 In some embodiments, D has formula D1a-XVI, where R b1In some embodiments, D has formula D1a-XVI, where R b1 In some embodiments, D has the formula D1a-XVI, where R b1 In some embodiments, D has formula D1a-XVI, where R b1 is C1-C6 alkyl. In some embodiments, D has formula D1a-XVI, where R b1 is methyl.

[0159] In some embodiments, D has formula D1a-XVI, where R b2 is C1-C6 alkyl. In some embodiments, D has formula D1a-XVI, where R b2 In some embodiments, D has the formula D1a-XVI, where R b2 In some embodiments, D has formula D1a-XVI, where R b2 In some embodiments, D has the formula D1a-XVI, where R b2 In some embodiments, D has formula D1a-XVI, where R b2 In some embodiments, D has formula D1a-XVI, where R b2 is C1-C6 alkoxy. In some embodiments, D has the formula D1a-XVI, where R b2 In some embodiments, D has the formula D1a-XVI, where R b2 is C1-C6 hydroxyalkyl. In some embodiments, D has the formula D1a-XVI, where R b2 is C1-C6 haloalkyl. In some embodiments, D has formula D1a-XVI, wherein R b2 In some embodiments, D has the formula D1a-XVI, where R b2 In some embodiments, D has the formula D1a-XVI, where R b2is C2-C6 alkenyl. In some embodiments, D has formula D1a-XVI, wherein R b2 In some embodiments, D has formula D1a-XVI, where R b2 -SR a In some embodiments, D has formula D1a-XVI, where R b2 -SR a and R a is C1-C6 alkyl. In some embodiments, D has formula D1a-XVI, where R b2 -SR a and R a In some embodiments, D has the formula D1a-XVI, where R b2 -SR a and R a is C1-C6 haloalkyl. In some embodiments, D has formula D1a-XVI, wherein R b2 -SR a and R a In some embodiments, D has the formula D1a-XVI, where R b2 -SR a and R a is trifluoromethyl.

[0160] In some embodiments, D has formula D1a-XVI, where R b3 In some embodiments, D has formula D1a-XVI, where R b3 In some embodiments, D has the formula D1a-XVI, where R b3 In some embodiments, D has formula D1a-XVI, where R b3 In some embodiments, D has formula D1a-XVI, where R b3 is C1-C6 alkyl. In some embodiments, D has formula D1a-XVI, where R b3 In some embodiments, D has the formula D1a-XVI, where Rb3 In some embodiments, D has the formula D1a-XVI, where R b3 is C1-C6 alkoxy. In some embodiments, D has the formula D1a-XVI, where R b3 is methoxy.

[0161] In some embodiments, D has formula D1a-XVI, where R b2 and R b3 together with their intervening atoms form a 5-membered heterocycle fused to a 6-membered aryl. In some embodiments, D has formula D1a-XVI, wherein R b2 and R b3 taken together with their intervening atoms form 2,3-dihydrobenzofuranyl.

[0162] In some embodiments, D has formula D1a-XVI, where R b1 and R b6 are taken together with their intervening atoms to form a carbocyclic ring. In some embodiments, D has formula D1a-XVI, where R b1 and R b6 taken together with their intervening atoms form a 6-membered cycloalkyl.

[0163] In some embodiments, D has formula D1a-XVI, where R b5’ is H. In some embodiments, D has formula D1a-XVI, where R b5’ is H. In some embodiments, D has formula D1a-XVI, where R b5’ is —C(O)—C1-C6 alkyl. In some embodiments, D has the formula D1a-XVI, where R b5’ is —C(O)—C1-C6 alkylamino. In some embodiments, D has the formula D1a-XVI, where R b5’ is a 3-10 membered heteroaryl substituted with C1-C6 hydroxyalkyl. In some embodiments, D has the formula D1a-XVI, where R b5’is a 5-6 membered heteroaryl substituted with C1-C6 hydroxyalkyl. In some embodiments, D has the formula D1a-XVI, where R b5’ is pyridinyl substituted with -CH2OH.

[0164] In some embodiments, D has the formula D1b-XVI, where R b1 is H, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R b1 is H, halogen, -CN, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1b-XVI, wherein R b2 is H, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, -OR a , -NHR a or -SR a and each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1b-XVI, wherein R b3 is H, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, -OR a , -NHR a or -SR aand each R a is independently selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, D has formula D1b-XVI, wherein R b2 and R b3 together form a methylenedioxy moiety. In some embodiments, D has formula D1b-XVI, where R b6 is H or R b1 and together form a carbocyclic or heterocyclic ring. In some embodiments, D has formula D1b-XVI, where R b5’ is H, —C(O)—C1-C6 alkyl, or —C(O)—C1-C6 alkylamino.

[0165] In some embodiments, D has the formula D1b-XVI, where R b1 In some embodiments, D has the formula D1b-XVI, where R b1 In some embodiments, D has the formula D1b-XVI, where R b1 In some embodiments, D has the formula D1b-XVI, where R b1 In some embodiments, D has the formula D1b-XVI, where R b1 In some embodiments, D has the formula D1b-XVI, where R b1 is C1-C6 alkyl. In some embodiments, D has the formula D1b-XVI, where R b1 is methyl.

[0166] In some embodiments, D has the formula D1b-XVI, where R b2 is C1-C6 alkyl. In some embodiments, D has the formula D1b-XVI, where R b2 is methyl. In some embodiments, D has the formula D1b-XVI, where R b2 In some embodiments, D has the formula D1b-XVI, where R b2In some embodiments, D has the formula D1b-XVI, where R b2 In some embodiments, D has the formula D1b-XVI, where R b2 In some embodiments, D has the formula D1b-XVI, where R b2 is C1-C6 alkoxy. In some embodiments, D has the formula D1b-XVI, where R b2 In some embodiments, D has the formula D1b-XVI, where R b2 is C1-C6 haloalkyl. In some embodiments, D has the formula D1b-XVI, wherein R b2 is C1-C6 hydroxyalkyl. In some embodiments, D has the formula D1b-XVI, where R b2 In some embodiments, D has the formula D1b-XVI, where R b2 In some embodiments, D has the formula D1b-XVI, wherein R b2 is C2-C6 alkenyl. In some embodiments, D has formula D1b-XVI, wherein R b2 In some embodiments, D has the formula D1b-XVI, where R b2 -SR a In some embodiments, D has the formula D1b-XVI, where R b2 -SR a and R a is C1-C6 alkyl. In some embodiments, D has the formula D1b-XVI, where R b2 -SR a and R a is methyl. In some embodiments, D has the formula D1b-XVI, where R b2 -SR a and R a is C1-C6 haloalkyl. In some embodiments, D has the formula D1b-XVI, wherein R b2 -SR a and Ra In some embodiments, D has the formula D1b-XVI, where R b2 -SR a and R a is trifluoromethyl.

[0167] In some embodiments, D has the formula D1b-XVI, where R b3 In some embodiments, D has the formula D1b-XVI, where R b3 In some embodiments, D has the formula D1b-XVI, where R b3 In some embodiments, D has the formula D1b-XVI, where R b3 In some embodiments, D has the formula D1b-XVI, where R b3 is C1-C6 alkyl. In some embodiments, D has the formula D1b-XVI, where R b3 is methyl. In some embodiments, D has the formula D1b-XVI, where R b3 In some embodiments, D has the formula D1b-XVI, where R b3 is C1-C6 alkoxy. In some embodiments, D has the formula D1b-XVI, where R b3 is methoxy.

[0168] In some embodiments, D has the formula D1b-XVI, where R b2 and R b3 together with their intervening atoms form a 5-membered heterocycle fused to a 6-membered heteroaryl. In some embodiments, D has the formula D1b-XVI, wherein R b2 and R b3 taken together with their intervening atoms form 2,3-dihydrobenzofuranyl.

[0169] In some embodiments, D has the formula D1b-XVI, where R b1 and R b6are taken together with their intervening atoms to form a carbocyclic ring. In some embodiments, D has the formula D1b-XVI, where R b1 and R b6 taken together with their intervening atoms form a 6-membered cycloalkyl.

[0170] In some embodiments, D has the formula D1b-XVI, where R b5’ is H. In some embodiments, D has formula D1b-XVI, where R b5’ is H. In some embodiments, D has formula D1b-XVI, where R b5’ is —C(O)—C1-C6 alkyl. In some embodiments, D has the formula D1b-XVI, where R b5’ is —C(O)—C1-C6 alkylamino. In some embodiments, D has the formula D1b-XVI, where R b5’ is a 3-10 membered heteroaryl substituted with C1-C6 hydroxyalkyl. In some embodiments, D has the formula D1b-XVI, wherein R b5’ is a 5-6 membered heteroaryl substituted with C1-C6 hydroxyalkyl. In some embodiments, D has the formula D1b-XVI, where R b5’ is pyridinyl substituted with -CH2OH.

[0171] In another embodiment, L-(QD) p or a salt thereof, wherein: L is a Ligand unit; the subscript p is an integer from 1 to 16; Q is, -ZA-, -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, ZAS * -W-, -ZAS * -W-RL-, -ZAB(S *)-RL-, -ZAB(S * )-W-, -ZAB(S * )-W-RL- and -ZAB(S * )-RL-Y- and a linker unit having a formula selected from the group consisting of: wherein Z is a stretching unit; A is a bond or linking unit; B is a parallel linked unit, S * is a partitioning agent, RL is a releasable linker; W is an amino acid unit, Y is a spacer unit; D [ka] or a salt thereof, wherein: E is -OR b5 or -NR b5 R b5’ and R b1 H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, (C6-C 12 aryl)-C2-C8 alkenyl-, C1-C8 hydroxyalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -OR a , -NRa R a’ and -SR a and each is selected from the group consisting of C1-C3 alkyl, -OR a , -NR a R a’ , -C(O)R a and -SR a optionally substituted with, or R b1 But R b2 , R b5 Or R b6 and together with the intervening atoms form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b2 H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkyl-S(O)2-, C1-C8 aminoalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-NR a -, C1-C8 alkyl-NR a -C(O)O-, C1-C8 alkyl-OC(O)-NR a -, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -OR a , -NR a R a’ and -SR a and each is selected from the group consisting of: -OR a , -NR a Ra’ and -SR a or optionally replaced by R b2 But R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring, or R b2 But R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered heterocycle fused to the 6-membered aryl; R b3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, -OR a , -NR a R a’ and -SR a or is selected from the group consisting of R b3 But R b2 and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring, or a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl; R b4 is selected from the group consisting of H and halogen; Each R b5 and R b5’ are independently H, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C6 alkyl-O-C1-C6 alkyl-, C1-C8 aminoalkyl, (C1-C4 alkylamino)-C1-C8 alkyl-, N,N-(C1-C4 hydroxyalkyl)(C1-C4 alkyl)amino-C1-C8 alkyl-, N,N-di(C1-C4 alkyl)amino-C1-C8 alkyl-, N-(C1-C4 hydroxyalkyl)-C1-C8 aminoalkyl-, C1-C8 hydroxyalkyl-C(O)-, C3-C 10 Cycloalkyl, (C3-C 10 Cycloalkyl)-C1-C4 alkyl-, C3-C 10 Heterocycloalkyl, (C3-C 10 Heterocycloalkyl)-C 1-C4 alkyl-, heteroaryl-C1-C6 hydroxyalkyl, phenyl, phenyl-C 1- C4 alkyl-, diphenyl-C1-C4 alkyl-, heteroaryl, heteroaryl-C1-C4 alkyl-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8 alkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, C1-C4 alkyl-SO2-C1-C8 alkyl-, NH2-SO2-C1-C8 alkyl-, (C3-C 10 Heterocycloalkyl)-C 1- C4 hydroxyalkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8 hydroxyalkyl-C3-C 10 heterocycloalkyl- or R b5 and R b5’ are, in combination with the nitrogen atom to which they are attached, independently halogen, C 1- forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -O-C1-C4 alkyl, -NH2, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, C1-C6 alkoxy-C(O)-NH-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, and C1-C8 aminoalkyl; or R b5’ is H and R b5 But R b1 and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring, R b1 , R b2 , R b3 , R b4 , R b5 and R b5’wherein the cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl, and heteroaryl portions are independently substituted with 0 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, —OH, —OC1-C4 alkyl, —NH2, —NHC1-C4 alkyl, and —N(C1-C4 alkyl)2; R b6 is H or R b1 and together with the intervening atoms form a carbocyclic or heterocyclic ring, R a and R a’ are each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C alkyl-S(O)—, C-C alkyl-C(O)—, C-C aminoalkyl-C(O)—, and C-C hydroxyalkyl-C(O)—; a)R b2 But R b3 and when combined with the intervening atoms to form 1,3-dioxolane, R b5 is H and R b5’ is C1-C6 alkyl-O-C1-C6 alkyl-, or R b5 and R b5’ are, in combination with the nitrogen atom to which they are attached, independently halogen, C 1- forming a 5-, 6-, or 7-membered heterocycle having 0 to 3 substituents selected from the group consisting of C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -O-C1-C4 alkyl, -NH2, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, C1-C6 alkoxy-C(O)-NH-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, and C1-C8 aminoalkyl; b) When E is NH2, R b1 is -CN, 5-12 membered heteroaryl having at least one N in the ring, 3-10 membered heterocycloalkyl having at least one N in the ring, C1-C8 hydroxyalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a-C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -NR a R a’ and -SR a and each is selected from the group consisting of C1-C3 alkyl, -OR a , -NR a R a’ , -C(O)R a and -SR a optionally substituted with or R b1 But R b2 and together with the intervening atoms form a 5-, 6-, or 7-membered heterocyclic ring having at least one N in the ring, or a 5- or 6-membered heterocyclic ring fused with a 6-membered aryl; R b2 H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkyl-S(O)2-, C1-C8 aminoalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-NR a -, C1-C8 alkyl-NR a -C(O)O-, C1-C8 alkyl-OC(O)-NR a -, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NRa -C(O)-O-, -COOR a , -OR a , -NR a R a’ and -SR a and each is selected from the group consisting of: -OR a , -NR a R a’ and -SR a optionally replaced by, or R b2 But R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered heterocyclic ring having at least one N in the ring, or R b2 But R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered heterocycle fused to the 6-membered aryl; c)R b2 is —OH or methyl, and R b3 When F, R b1 But R b5 or R b5’ and the intervening atoms do not together form a ring, d) D is (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-7-ethyl-7-hydroxy-14-(morpholinomethyl)-1 0,13-Dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)piperazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione Pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminopiperidin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione -dione and tert-butyl (S)-(1-((7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)piperidin-4-yl)carbamate; D is covalently attached to Q through any suitable attachment site on D, and optionally a hydroxyl, thiol, primary amine, or secondary amine hydrogen atom of D is replaced with a bond to Q, or a tertiary amine of D is quaternized to provide a camptothecin conjugate that forms a bond to Q.

[0172] In some embodiments, D is represented by the formula D0-I: [ka] or a salt thereof, wherein R b1 ~R b6 are the same as those in D0.

[0173] In some embodiments, D is represented by the formula D0-II below: [ka] or a salt thereof, wherein R b1 is -CN, 5-12 membered heteroaryl having at least one N in the ring, 3-10 membered heterocycloalkyl having at least one N in the ring, C1-C8 hydroxyalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -NR a R a’ and -SR a and each is selected from the group consisting of C1-C3 alkyl, -OR a , -NR a R a’ , -C(O)R a and -SR a optionally replaced by, or R b1 is R b2 and together with the intervening atoms form a 5-, 6-, or 7-membered heterocyclic ring having at least one N in the ring, or a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl; R b2 is H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10Cycloalkyl, 3-10 membered heterocycloalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkyl-S(O)2-, C1-C8 aminoalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-NR a -, C1-C8 alkyl-NR a -C(O)O-, C1-C8 alkyl-OC(O)-NR a -, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -OR a , -NR a R a’ and -SR a and each is selected from the group consisting of: -OR a , -NR a R a’ and -SR a or optionally replaced by R b2は、 R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered heterocyclic ring having at least one N in the ring; or R b2 is R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered heterocycle fused to the 6-membered aryl; R b3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, -OR a , -NR a R a’ and -SR ais selected from the group consisting of R b4 is selected from the group consisting of H or halogen; R a and R a’ are each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C alkyl-S(O)-, C-C alkyl-C(O)-, C-C aminoalkyl-C(O)-, and C-C hydroxyalkyl-C(O)-; D is covalently bonded to Q through any suitable bonding site on D, and optionally, a hydroxyl, thiol, primary amine, or secondary amine hydrogen atom of D is replaced with a bond to Q, or a tertiary amine of D is quaternized to form a bond to Q.

[0174] In some embodiments, D is represented by the formula D0-III below: [ka] or a salt thereof, wherein R b1 , R b4 and R b6 are respectively, D 0a This is the same as the definition in

[0175] In some embodiments, D is represented by the formula D0-IV below: [ka] or a salt thereof, wherein R b1 , R b4 , R b5 , R b6 are respectively, D 0a In some embodiments, R b1 , R b4 , R b5 and R b6 are H, respectively.

[0176] In some embodiments, D is represented by the formula D0-V: [ka] or a salt thereof, wherein p2 is 2 to 6; R b5’’ is selected from the group consisting of H, C1-C6 alkyl, and C1-C6 haloalkyl; R b1 , R b4 , R b5’ , R b6 are respectively, D 0a In some embodiments, p2 is 2 and R b5’’ is methyl and R b1 , R b4 , R b5’ , R b6 are H, respectively.

[0177] In some embodiments, D is a group of the formula D0-VI: [ka] or a salt thereof, wherein R b2 , R b3 , R b4 , R b5 , R b5’ and R b6 are respectively, D 0a In some embodiments, R b2 is methyl and R b3 is F and R b5 , R b5’ and R b6 are H, respectively.

[0178] In some embodiments, D is represented by the formula D0-VII: [ka] or a salt thereof, wherein m and n are each 1 or 2, and when m and n are both present, m+n is 2 or 3; R b1’is C1-C3 alkyl or -C(O)R a and R b2 , R b3 , R b4 , R b5 , R b5’ and R b6 are respectively, D 0a This is the same as the definition in In some embodiments, m is 1, n is 2, and R b1’ is methyl and R b2 , R b3 , R b4 , R b5 , R b5’ , R b6 are each H. In some embodiments, m is 1, n is 2, and R b1’ is C(O)CH3 and R b2 , R b3 , R b4 , R b5 , R b5’ and R b6 are H, respectively.

[0179] In some embodiments, D is represented by the formula D0-VIII below: [ka] or a salt thereof, wherein n is 1, 2 or 3; R b5’’ is -C1-C6 hydroxyalkyl, R b1 , R b4 and R b6 are respectively, D 0a This is the same as the definition in In some embodiments, n is 1 and R b5’’ is -CHOH, and R b1 , R b4 and R b6 are H, respectively.

[0180] In some embodiments, D is one of the formulas D0-IX below: [ka] or a salt thereof, wherein R b1 , R b4 , R b5 , R b5’ and R b6 are respectively, D 0a In some embodiments, R b1 , R b4 , R b5 , R b5’ and R b6 are H, respectively.

[0181] In some embodiments, D is represented by the formula D0-X: [ka] or a salt thereof, wherein R b1 , R b4 , R b5 , R b5’ and R b6 are respectively, D 0a In some embodiments, R b1 , R b4 , R b5 , R b5’ and R b6 are H, respectively.

[0182] In some embodiments, D0 is D 0b Formula [ka] or a salt thereof, wherein E is -OR b5 or -NR b5 R b5’ and R b1 is H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10Cycloalkyl, 3-10 membered heterocycloalkyl, (C6-C 12 aryl)-C2-C8 alkenyl-, C1-C8 hydroxyalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -OR a , -NR a R a’ and -SR a and each is selected from the group consisting of C1-C3 alkyl, -OR a , -NR a R a’ , -C(O)R a and -SR a optionally substituted with, or R b1 is R b2 , R b5 Or R b6 and together with the intervening atoms form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b2 is H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkyl-S(O)2-, C1-C8 aminoalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C1-C8 alkyl-NR a-C(O)-, C1-C8 alkyl-C(O)-NR a -, C1-C8 alkyl-NR a -C(O)O-, C1-C8 alkyl-OC(O)-NR a -, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -OR a , -NR a R a’ and -SR a and each is selected from the group consisting of: -OR a , -NR a R a’ and -SR a or optionally replaced by R b2 is R b1 Or R b3 and, together with the intervening atoms, form a 5- or 6-membered carbocyclic or heterocyclic ring; or R b2 is R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered heterocycle fused to the 6-membered aryl; R b3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, -OR a , -NR a R a’ and -SR a is selected from the group consisting of R b4 is selected from the group consisting of H or halogen; Each R b5 and R b5’are independently H, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkyl-O-C1-C8 alkyl-, C1-C8 aminoalkyl, (C1-C4 alkylamino)-C1-C8 alkyl-, N,N-(C1-C4 hydroxyalkyl)(C1-C4 alkyl)amino-C1-C8 alkyl-, N,N-di(C1-C4 alkyl)amino-C1-C8 alkyl-, N-(C1-C4 hydroxyalkyl)-C1-C8 aminoalkyl-, C1-C8 alkyl-C(O)-, C1-C8 hydroxyalkyl-C(O)-, C1-C8 aminoalkyl-C(O)-, C3-C 10 Cycloalkyl, (C3-C 10 Cycloalkyl)-C1-C4 alkyl-, C3-C 10 Heterocycloalkyl, (C3-C 10 Heterocycloalkyl)-C 1- C4 alkyl-, C1-C6 hydroxyalkyl-heteroaryl-, phenyl, phenyl-C 1- C4 alkyl-, diphenyl-C1-C4 alkyl-, heteroaryl, heteroaryl-C1-C4 alkyl-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8 alkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, C1-C4 alkyl-SO2-C1-C8 alkyl-, NH2-SO2-C1-C8 alkyl-, (C3-C 10 Heterocycloalkyl)-C 1- C4 hydroxyalkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8 hydroxyalkyl-C3-C 10 heterocycloalkyl- or R b5 and R b5’ are, together with the nitrogen atom to which they are attached, independently halogen, C 1-forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -O-C1-C4 alkyl, -NH2, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, C1-C6 alkoxy-C(O)-NH-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, and C1-C8 aminoalkyl; or R b5’ is H and R b5 is R b1 and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring, R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ the cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl, and heteroaryl portions of are independently substituted with 0 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, —OH, —O1-C4 alkyl, —NH2, —NHC1-C4 alkyl, and —N(C1-C4 alkyl)2; R b6 is H or R b1 and together with the intervening atoms form a carbocyclic or heterocyclic ring, R a and R a’ are each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C alkyl-S(O)-, C-C alkyl-C(O)-, C-C aminoalkyl-C(O)-, and C-C hydroxyalkyl-C(O)-; a)R b2 But R b3 and together with the intervening atoms form 1,3-dioxolane, and E is -NR b5 R b5’ When b5 and R b5’ are independently H, C1-C8 alkyl-O-C1-C8 alkyl-, C1-C8 alkyl-C(O)(C3-C 10 Cycloalkyl)-C1-C4 alkyl-, C3-C10 Heterocycloalkyl, C1-C6 hydroxyalkyl-heteroaryl-, heteroaryl, heteroaryl-C1-C4 alkyl-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8 alkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, C1-C4 alkyl-SO2-C1-C8 alkyl-, NH2-SO2-C1-C8 alkyl-, (C3-C 10 Heterocycloalkyl)-C 1- C4 hydroxyalkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8 hydroxyalkyl-C3-C 10 heterocycloalkyl- or R b5 and R b5’ are, together with the nitrogen atom to which they are attached, independently halogen, C 1- forming a 5-, 6-, or 7-membered heterocycle having 0 to 3 substituents selected from the group consisting of C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -O-C1-C4 alkyl, -NH2, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, C1-C6 alkoxy-C(O)-NH-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, and C1-C8 aminoalkyl; or R b5’ is H and R b5 is R b1 and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring, R b1 , R b2 , R b3 , R b4 , R b5 and R b5’the cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl, and heteroaryl portions of are independently substituted with 0 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, —OH, —O1-C4 alkyl, —NH2, —NHC1-C4 alkyl, and —N(C1-C4 alkyl)2; b)R b2 But R b3 and when combined with the intervening atoms to form 1,3-dioxolane, E is not —OH, c)R b2 is methyl and R b3 When is F, then R b1 is R b6 and do not together with any intervening atoms form a ring, d) D is not selected from the group consisting of (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione and (S)-7-ethyl-7-hydroxy-14-(morpholinomethyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione.

[0183] In some embodiments, E is —NR b5 R b5’ In some embodiments, E is -OR b5 is.

[0184] In some embodiments, R b2 But R b3 and together with the intervening atoms form 1,3-dioxolane, and E is -NR b5 R b5’ When b5 and R b5’ are independently H, C1-C8 alkyl-O-C1-C8 alkyl-, C1-C8 alkyl-C(O)(C3-C 10Cycloalkyl)-C1-C4 alkyl-, C3-C 10 Heterocycloalkyl, C1-C6 hydroxyalkyl-heteroaryl-, heteroaryl, heteroaryl-C1-C4 alkyl-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8 alkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, C1-C4 alkyl-SO2-C1-C8 alkyl-, NH2-SO2-C1-C8 alkyl-, (C3-C 10 Heterocycloalkyl)-C 1- C4 hydroxyalkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8 hydroxyalkyl-C3-C 10 heterocycloalkyl- or R b5 and R b5’ are, together with the nitrogen atom to which they are attached, independently halogen, C 1- Form a 5-, 6-, or 7-membered heteroaryl having 0 to 3 substituents selected from the group consisting of C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -O-C1-C4 alkyl, -NH2, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, C1-C6 alkoxy-C(O)-NH-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, and C1-C8 aminoalkyl.

[0185] In some embodiments, D is D 0b -I formula [ka] or a salt thereof, and R b1 ~R b6 are respectively, D 0b is the same as the definition in Rb2 But R b3 and, when taken together with the intervening atoms to form a 5-, 6-, or 7-membered heterocycle, the heterocycle has no more than one O.

[0186] In some embodiments, D is D 0b -II formula [ka] or a salt thereof, wherein R b5 is H and R b5’ is H, C1-C8 alkyl-O-C1-C8 alkyl-, C1-C8 alkyl-C(O)(C3-C 10 Cycloalkyl)-C1-C4 alkyl-, C3-C 10 Heterocycloalkyl, C1-C6 hydroxyalkyl-heteroaryl-, heteroaryl, heteroaryl-C1-C4 alkyl-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8 alkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, C1-C4 alkyl-SO2-C1-C8 alkyl-, NH2-SO2-C1-C8 alkyl-, (C3-C 10 Heterocycloalkyl)-C 1- C4 hydroxyalkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8 hydroxyalkyl-C3-C 10 heterocycloalkyl- or R b5 and R b5’ are, together with the nitrogen atom to which they are attached, independently halogen, C 1-forming a 5-, 6-, or 7-membered heterocycle having 0 to 3 substituents selected from the group consisting of C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -O-C1-C4 alkyl, -NH2, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, C1-C6 alkoxy-C(O)-NH-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, and C1-C8 aminoalkyl; or R b5’ is R b1 and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring, R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ the cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl, and heteroaryl portions of are independently substituted with 0 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, —OH, —O1-C4 alkyl, —NH2, —NHC1-C4 alkyl, and —N(C1-C4 alkyl)2; R b1 and R b4 are respectively, D 0b This is the same as the definition in

[0187] In some embodiments, D is D 0b -III formula [ka] or a salt thereof, wherein R b1 , R b4 , R b5 and R b5’ are respectively, D 0b This is the same as the definition in

[0188] In some embodiments, D is D 0a -I formula [ka] or a salt thereof, wherein E is -ORb5 or -NR b5 R b5’ and R b1 is H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, (C6-C 12 aryl)-C2-C8 alkenyl-, C1-C8 hydroxyalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -OR a , -NR a R a’ and -SR a and each is selected from the group consisting of C1-C3 alkyl, -OR a , -NR a R a’ , -C(O)R a and -SR a optionally substituted with, or R b1 is R b2 , R b5 Or R b6 and together with the intervening atoms form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b2 is H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10Cycloalkyl, 3-10 membered heterocycloalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkyl-S(O)2-, C1-C8 aminoalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-NR a -, C1-C8 alkyl-NR a -C(O)O-, C1-C8 alkyl-OC(O)-NR a -, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -OR a , -NR a R a’ and -SR a and each is selected from the group consisting of: -OR a , -NR a R a’ and -SR a or optionally replaced by R b2 is R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring, or R b2 is R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered heterocycle fused to the 6-membered aryl; R b3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, -OR a , -NR a R a’ and -SR aor is selected from the group consisting of R b3 is R b2 and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring, or a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl; R b4 is selected from the group consisting of H and halogen; Each R b5 and R b5’ are independently H, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkyl-O-C1-C8 alkyl, C1-C8 aminoalkyl, (C1-C4 alkylamino)-C1-C8 alkyl-, N,N-(C1-C4 hydroxyalkyl)(C1-C4 alkyl)amino-C1-C8 alkyl-, N,N-di(C1-C4 alkyl)amino-C1-C8 alkyl-, N-(C1-C4 hydroxyalkyl)-C1-C8 aminoalkyl-, C1-C8 hydroxyalkyl-C(O)-, C3-C 10 Cycloalkyl, (C3-C 10 Cycloalkyl)-C1-C4 alkyl-, C3-C 10 Heterocycloalkyl, (C3-C 10 Heterocycloalkyl)-C 1- C4 alkyl-, heteroaryl-C1-C6 hydroxyalkyl, phenyl, phenyl-C 1- C4 alkyl-, diphenyl-C1-C4 alkyl-, heteroaryl, heteroaryl-C1-C4 alkyl-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8 alkyl-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-, C1-C6 alkoxy-C(O)-(C3-C 10 heterocycloalkyl)-C1-C8 alkyl-, C1-C4 alkyl-SO2-C1-C8 alkyl-, NH2-SO2-C1-C8 alkyl-, (C3-C 10 Heterocycloalkyl)-C 1- C4 hydroxyalkyl-, C1-C6 alkoxy-C(O)-(C3-C10 heterocycloalkyl)-C1-C8 alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8 hydroxyalkyl-C3-C 10 heterocycloalkyl- or R b5 and R b5’ are, together with the nitrogen atom to which they are attached, independently halogen, C 1- forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -O-C1-C4 alkyl, -NH2, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, C1-C6 alkoxy-C(O)-NH-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, and C1-C8 aminoalkyl; or R b5’ is H and R b5 is R b1 and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring, R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ the cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl, and heteroaryl portions of are independently substituted with 0 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, —OH, —O1-C4 alkyl, —NH2, —NHC1-C4 alkyl, and —N(C1-C4 alkyl)2; R b6 is H or R b1 and together with the intervening atoms form a carbocyclic or heterocyclic ring, R a and R a’ are each independently selected from the group consisting of H, C-C alkyl, C-C haloalkyl, C-C alkyl-S(O)-, C-C alkyl-C(O)-, C-C aminoalkyl-C(O)-, and C-C hydroxyalkyl-C(O)-; a)R b2 But R b3and together with the intervening atoms form 1,3-dioxolane, and E is -NR b5 R b5’ When b5 and R b5’ are independently H, C1-C8 alkyl-O-C1-C8 alkyl-, C1-C8 alkyl-C(O)(C3-C 10 Cycloalkyl)-C1-C4 alkyl-, C3-C 10 is selected from the group consisting of heterocycloalkyl, C1-C6 hydroxyalkyl-heteroaryl-, heteroaryl, heteroaryl-C1-C4 alkyl-, phenyl-C(O)-, and phenyl-SO2-; b5 and R b5’ are, together with the nitrogen atom to which they are attached, independently halogen, C 1- forming a 5-, 6-, or 7-membered heterocycle having 0 to 3 substituents selected from the group consisting of C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -O-C1-C4 alkyl, -NH2, -NH-C1-C4 alkyl, -N(C1-C4 alkyl)2, C1-C6 alkoxy-C(O)-NH-, C1-C6 alkoxy-C(O)-C1-C8 aminoalkyl-, and C1-C8 aminoalkyl; or R b5’ is H and R b5 is R b1 and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring, R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ the cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl, and heteroaryl portions of are independently substituted with 0 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, —OH, —O1-C4 alkyl, —NH2, —NHC1-C4 alkyl, and —N(C1-C4 alkyl)2; b)R b2 But R b3 and when combined with the intervening atoms to form 1,3-dioxolane, E is not —OH, c) When E is NH2, R b1 is -CN, 5-12 membered heteroaryl having at least one N in the ring, 3-10 membered heterocycloalkyl having at least one N in the ring, C1-C8 hydroxyalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -NR a R a’ and -SR a and each is selected from the group consisting of C1-C3 alkyl, -OR a , -NR a R a’ , -C(O)R a and -SR a optionally substituted with or R b1 is R b2 and together with the intervening atoms form a 5-, 6-, or 7-membered heterocyclic ring having at least one N in the ring, or a 5- or 6-membered heterocyclic ring fused with a 6-membered aryl; R b2 is H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5-12 membered heteroaryl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkyl-S(O)2-, C1-C8 aminoalkyl, C1-C8 alkyl-C(O)-C1-C8 aminoalkyl-, C1-C8 aminoalkyl-C(O)-C1-C8 alkyl-, C1-C8 alkyl-NR a -C(O)-, C1-C8 alkyl-C(O)-, C1-C8 alkyl-OC(O)-, C1-C8 alkyl-NR a-C(O)-, C1-C8 alkyl-C(O)-NR a -, C1-C8 alkyl-NR a -C(O)O-, C1-C8 alkyl-OC(O)-NR a -, C6-C 12 Aryl-C(O)-, C6-C 12 Aryl-OC(O)-NR a -, C6-C 12 Aryl-NR a -C(O)-O-, -COOR a , -OR a , -NR a R a’ and -SR a and each is selected from the group consisting of: -OR a , -NR a R a’ and -SR a optionally replaced by, or R b2は、 R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered heterocyclic ring having at least one N in the ring, or R b2 is R b1 Or R b3 and together with the intervening atoms form a 5- or 6-membered heterocycle fused to the 6-membered aryl; d)R b2 is -OH or methyl, and R b3 When is F, then R b1 is R b5 , R b5’ or R b6 and the intervening atoms do not together form a ring, e) D is (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-7-ethyl-7-hydroxy-14-(morpholinomethyl)-1 0,13-Dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)piperazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione Pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminopiperidin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione -dione and tert-butyl (S)-(1-((7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)piperidin-4-yl)carbamate; D is covalently bonded to Q through any suitable bonding site on D, optionally wherein a hydrogen atom of a hydroxyl, thiol, primary amine or secondary amine of D is replaced with a bond to Q, or a tertiary amine of D is quaternized to form a bond to Q.

[0189] In some embodiments, E is —NR b5 R b5’ In some embodiments, E is -OR b5 is.

[0190] In some embodiments, D has the formula D0-I' below: [ka] or a salt thereof, and R b1 ~R b6 are respectively, D 0a -I, and R b2 is R b3 and together with the intervening atoms form a 5-, 6-, or 7-membered heterocycle, which heterocycle has not more than one O.

[0191] In some embodiments, D is represented by the formula D0-III' below: [ka] or a salt thereof, wherein each R b1 ~R b4 、 R b5’ and R b6 are respectively, D 0a Defined as -I.

[0192] In some embodiments, D is a compound of Table I selected from the group consisting of: or a salt thereof. [Table I-1] [Table I-2] [Table I-3] [Table I-4] [Table I-5] [Table I-6] [Table I-7] [Table I-8]

Table I-9

Table I-10

Table I-11

Table I-12

Table I-13

Table I-14

Table I-15

Table I-16

Table I-17

Table I-18

Table I-19

Table I-20

Table I-21

Table I-22

Table I-23

Table I-24

Table I-25

[0193] In one group of embodiments, Q is -ZA-RL- and -ZA-RL-Y- wherein R is a releasable linker that is a glycoside unit (e.g., a glucuronide unit), and the groups Z, A, and Y have the meanings given above and in any one of the embodiments specifically set forth herein.

[0194] In one group of embodiments, Q is -ZAS * -RL- and -ZAS * -RL-Y- wherein R L is a releasable linker that is a glycoside unit (e.g., a glucuronide unit), and Z, A, S * and the radical Y have the meaning given above and in any one of the embodiments specifically given herein.

[0195] In one group of embodiments, Q is -ZAB(S * )-RL- and -ZAB(S * )-RL-Y- wherein R L is a releasable linker that is a glycoside unit (e.g., a glucuronide unit), and Z, A, S * The groups B and Y have the meanings given above and in any one of the embodiments specifically given herein.

[0196] In another group of embodiments, Q is -ZA- or -ZA-RL- wherein R is a releasable linker that is other than a glycoside unit (e.g., a glucuronide unit), and the groups Z and A have the meanings given above and in any one of the embodiments specifically set out herein.

[0197] In another group of embodiments, Q is -ZAS * -RL- and -ZAB(S * )-RL- wherein R L is a releasable linker that is other than a glycoside unit (e.g., a glucuronide unit), and Z, A, S * and the radicals B have the meanings given above and in any one of the embodiments specifically given herein.

[0198] In another group of embodiments, Q is -ZAS * -W- and -ZAB(S * )-W- wherein Z, A, S * The groups B and W have the meanings given above and in any one of the embodiments specifically given herein.

[0199] In another group of embodiments, Q is -ZAS * -W-RL- and -ZAB(S * )-W-RL- wherein R L is a releasable linker that is other than a glycoside unit (e.g., a glucuronide unit), and Z, A, S * The groups B and W have the meanings given above and in any one of the embodiments specifically given herein.

[0200] In one group of embodiments, Q is -ZA-RL-, -ZA-RL-Y-, -ZAS*-RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL- or -ZAB(S * A camptothecin conjugate having a formula of -R-R-Y- and comprised of a Drug unit having the formula D1 is [ka] [ka] wherein R is any one of the releasable linkers disclosed herein, preferably R is a glycoside unit (e.g., a glucuronide unit), and L, Z, A, S * The groups D, B, and Y have the meanings given above and in any one of the embodiments specifically set forth herein. Also provided herein are camptothecin conjugates corresponding to any of the formulas D1iN, D1iiN, D1iiiN, D1ivN, D1vN, or D1viN, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0201] In other embodiments, Q is -ZA-, -ZA-RL-, or -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- and -ZAB(S * A camptothecin conjugate having a formula of -W-RL- and comprised of a Drug unit having the formula D1 is [ka] wherein R is a releasable linker other than a glycoside unit (e.g., a glucuronide unit), and L, Z, A, S * The groups B and W have the meanings given above and in any one of the embodiments specifically given herein.

[0202] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having the Formula D1-I is [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S * The groups D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to formula D1IiN, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0203] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having the Formula D1-II is [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S *)-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S * The groups D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI have the meanings given above and in any one of the embodiments specifically set forth herein, and the remaining variables are as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI. 1I It is also a camptothecin conjugate corresponding to IiN, where R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0204] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having the Formula D1-III: [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S *The groups D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to formula D1IIIiN, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0205] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having Formula D1-IV is [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S * The groups D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to formula D1IViN, wherein Rb5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0206] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having the formula D1-V is [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S * The groups D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to the formula D1ViN, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0207] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having Formula D1-VI is [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S * The groups D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to formula D1VIiN, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0208] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having Formula D1-VII is [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS* -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S * The groups D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to formula D1VIIiN, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0209] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having Formula D1-VIII is [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S *The groups D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to formula D1VIIIiN, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0210] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having the formula D1-IX is [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S * The groups D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to the formula D1IXiN, wherein Rb5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0211] In another group of embodiments, camptothecin conjugates comprised of Drug units having the formula D1-X are [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S * The groups D1, B, R1 and Y have the meanings given above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI.

[0212] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having the Formula D1-IIa: [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S* )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S * The groups D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI have the meanings given above and in any one of the embodiments specifically set forth herein, and the remaining variables are as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI. 1- IIaiN, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0213] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having the Formula D1-IIb: [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS *-W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S * The groups D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to the formula D1-IIbiN, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0214] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having the Formula D1-IVa: [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S *The groups D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to the formula D1-IVaiN, wherein R b5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0215] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having Formula D1-IVb is [ka] wherein Q is Z-A-R-, -Z-A-R-Y-, -Z-AS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S * The groups D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to the formula D1-IVbiN, wherein Rb5’ The nitrogen atom bonded to R is replaced by an oxygen atom, b5’ is absent such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0216] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having the formula D1-Xa is [ka] wherein Q is Z-A-R-, -Z-A-R-Y-, -Z-AS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S * The groups D1, B, R1 and Y have the meanings given above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI.

[0217] In another group of embodiments, camptothecin conjugates comprised of Drug units having the formula D1-XI are [ka] wherein Q is Z-A-R-, -Z-A-R-Y-, -Z-AS * -RL-, -ZAS * -RL-Y-, -ZAB(S* )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S * The groups D, B, R, and Y have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to the formula D1-XIiN, wherein the nitrogen atom attached to Q is replaced with an oxygen atom and the hydrogen replacing said nitrogen atom is absent, such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0218] In another group of embodiments, camptothecin conjugates comprised of Drug units having Formula D1-XII are [ka] wherein Q is Z-A-R-, -Z-A-R-Y-, -Z-AS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S *)-W-RL-, where L, Z, A, S * The groups D1, B, R1, and Y have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to the formula D1-XIIiN, wherein the nitrogen atom attached to Q is replaced with an oxygen atom and the hydrogen replacing said nitrogen atom is absent, such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0219] In another group of embodiments, camptothecin conjugates comprised of Drug units having Formula D1-XIII are [ka] wherein Q is Z-A-R-, -Z-A-R-Y-, -Z-AS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S *The groups D1, B, R1, and Y have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to formula D1-XIIIiN, wherein the nitrogen atom attached to Q is replaced with an oxygen atom and the hydrogen replacing said nitrogen atom is absent, such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0220] In another group of embodiments, camptothecin conjugates comprised of Drug units having Formula D1-XIV are [ka] wherein Q is Z-A-R-, -Z-A-R-Y-, -Z-AS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S *The groups D1, B, R1, and Y have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to the formula D1-XIViN, wherein the nitrogen atom attached to Q is replaced with an oxygen atom and the hydrogen replacing said nitrogen atom is absent, such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0221] In another group of embodiments, camptothecin conjugates comprised of Drug units having Formula D1-XV are [ka] wherein Q is Z-A-R-, -Z-A-R-Y-, -Z-AS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S *The groups D, B, R, and Y have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to the formula D1-XViN, wherein the nitrogen atom attached to Q is replaced with an oxygen atom and the hydrogen replacing said nitrogen atom is absent, such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0222] In another group of embodiments, camptothecin conjugates comprised of Drug units having Formulas D1-XVI are [ka] wherein Q is Z-A-R-, -Z-A-R-Y-, -Z-AS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S *The groups D1, B, R1, and Y have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, and D1-XVI. Also provided herein are camptothecin conjugates corresponding to formula D1-XVIiN, wherein the nitrogen atom attached to Q is replaced with an oxygen atom and the hydrogen replacing said nitrogen atom is absent, such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0223] In another group of embodiments, a camptothecin conjugate comprised of a Drug unit having the formula D1-CPT6 is [ka] wherein Q is -ZA-RL-, -ZA-RL-Y-, -ZAS * -RL-, -ZAS * -RL-Y-, -ZAB(S * )-RL-, -ZAB(S * )-RL-Y-, -ZA-, -ZA-RL-, -ZAS * -W-, -ZAB(S * )-W-, -ZAS * -RL-, -ZAB(S * )-RL-, -ZAS * -W-RL- or -ZAB(S * )-W-RL-, where L, Z, A, S *The groups D, B, R, and Y have the meanings set forth above and in any one of the embodiments specifically set forth herein, and the remaining variables are the same as defined in D1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV, D1-XVI, and D1-CPT6. Also provided herein are camptothecin conjugates corresponding to the formula D1-CPT6iN, wherein the nitrogen atom attached to Q is replaced with an oxygen atom and the hydrogen replacing said nitrogen atom is absent, such that Q is attached to the Drug unit via an oxygen atom of the Drug unit.

[0224] Camptothecin molecules are known to undergo pH-dependent reversible hydrolysis between a ring-closed lactone form and a ring-opened carboxylate form. [ka] Without being bound by theory, it is believed that at acidic pH, the lactone form is preferred, while at physiological pH, the predominant form is the open-ring carboxylate. In biological systems, camptothecin free drug, or its drug-linker or conjugate, can exist as either the lactone or carboxylate form. Camptothecin-based antibody-drug conjugates (ADCs) have demonstrated activity against target cells regardless of the lactone state of the conjugated drug. Without being bound by theory, this effect is thought to be due to the processing of ADCs in acidic intracellular vesicles, where the equilibrium favors the active, closed-lactone form of camptothecin (Lau, UYet al. Mol. Pharmaceutics 2018, 15, 9, 4063-4072).

[0225] It is understood that the Drug Units of the present invention, as well as the Drug-Linkers and conjugates thereof, can form an equilibrium between the lactone and carboxylate forms. Therefore, it is also understood that the carboxylate forms of any lactone structures described herein are also within the scope of the present disclosure. It is understood that all carboxylate forms of camptothecin structures shown in lactone form, including the general formula, are included herein in the same context as the lactone forms, as if each lactone structure were specifically and individually included in its carboxylate form.

[0226] Camptothecin-Linker Compounds In some embodiments, when preparing the camptothecin conjugates of the present invention, it is desirable to synthesize the complete drug-linker combination prior to conjugation to a targeting agent. In such embodiments, the camptothecin-linker compounds as described herein are intermediate compounds. In these embodiments, the extender units in the camptothecin-linker compounds are not yet covalently attached to a ligand unit (i.e., are extender unit precursors Z') and therefore possess functional groups for conjugation to a targeting ligand. In one embodiment, the camptothecin-linker compounds are camptothecin compounds (referred to herein as having formula D1, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, D12, D13, D14, D15, D16, D17, D18, D19, D20, D21, D22, D23, D24, D25, D26, D27, D28, D29, D30, D31, D32, D33, D44, D45, D56, D57, D58, D59, D60, D61, D62, D63, D74, D75, D86, D97, D98, D109, D111, D121, D131, D142, D153, D154, D161, D172, D183, D194, D195, D215, D225, D231, D242, D254, D262, D273, D284, D295, D315, D296, D315, D297, D325, D298, D331, D299, D341, D342, D343, D344, D45, D46, D 1a , D 1b or any of these subformulas), and a linker unit (Q) comprising a glycoside unit (e.g., a glucuronide unit) as a releasable linker (RL) through which the Ligand unit is linked to the camptothecin.

[0227] In another embodiment, the camptothecin-linker compound has the formula D1, D 1a , D 1bor a camptothecin compound of any of these sub-formulas, and a Linker unit (Q) comprising a releasable linker (RL) that is other than a glycoside unit (e.g., a glucuronide unit) through which the Ligand unit is linked to the conjugated camptothecin compound. Thus, in any embodiment, the Linker unit comprises, in addition to RL, a Drawer unit precursor (Z') that comprises a functional group for conjugation to a targeting agent that is a precursor of the Ligand unit, thereby linking RL (directly or indirectly) to the Ligand unit. In some of these embodiments, a partitioning agent (S * ) as a side chain appendage, the parallel linking unit (B) is present. In any one of these embodiments, the linking unit (A) is present when it is desired to add additional distance between the drawer unit and the R L .

[0228] In one group of embodiments, the camptothecin-linker compound has the formula D1, D 1a , D 1b or any of these subformulas, and a linker unit (Q), wherein Q includes a releasable linker (RL) that is a glycoside unit (e.g., a glucuronide unit), and RL is attached either directly to the stretcher unit precursor (Z') or to an intervening component(s) of the linker unit of the camptothecin-linker compound (i.e., A, S). * and / or B(S * ))) indirectly linked to Z', where Z' is comprised of a functional group capable of forming a covalent bond to a targeting agent.

[0229] In another group of embodiments, the camptothecin-linker compound has the formula D1, D 1a , D 1b or any of these subformulas, and a linker unit (Q), where Q includes a releasable linker (RL) that is other than a glycoside unit (e.g., a glucuronide unit), and RL is attached either directly to the stretcher unit precursor (Z') or to an intervening component(s) of the linker unit of the camptothecin-linker compound (i.e., A, S, *and / or B(S * )) and is indirectly linked to Z', where Z' is comprised of a functional group capable of forming a covalent bond to a targeting agent.

[0230] In the context of the camptothecin conjugates and / or camptothecin-linker compounds of the present invention, the assembly is best described in terms of its constituent parts. While some procedures are described herein, the order of assembly and general conditions for preparing the conjugates and compounds will be well understood by those skilled in the art.

[0231] In some embodiments, the present invention provides a camptothecin-linker compound, the compound selected from the group consisting of the compounds in Table II. In some embodiments, the present invention provides a camptothecin conjugate, the conjugate comprising a ligand attached to a succinimide or succinic acid-amide moiety of a drug-linker moiety, the drug-linker moiety comprising a compound of Table II, with the maleimide moiety replaced by the succinimide or succinic acid-amide moiety. [Table II-1] [Table II-2] [Table II-3] [Table II-4] [Table II-5] [Table II-6] [Table II-7] [Table II-8] [Table II-9] [Table II-10]

[0232] Component Group Ligand unit: In some embodiments of the present invention, a Ligand unit is present. The Ligand unit (L-) is a targeting agent that specifically binds to a targeting moiety. In one group of embodiments, the Ligand unit specifically and selectively binds to a cellular component (cell-binding agent) or another target molecule of interest. The Ligand unit binds to camptothecin (e.g., a compound of formula D1, D2) in the presence of its targeting component or molecule. 1a , D 1b or one of any of these subformulas) to a specific target cell population that interacts with the Ligand unit, followed by release of the free drug at (i.e., intracellularly) or in the vicinity of (i.e., extracellularly) the target cell. Ligand units L include, but are not limited to, proteins, polypeptides, and peptides. Suitable Ligand units include, for example, antibodies, e.g., full-length antibodies and antigen-binding fragments thereof, interferons, lymphokines, hormones, growth factors, colony-stimulating factors, vitamins, nutrient-carrying molecules (such as, but not limited to, transferrin), or any other cell-binding molecule or substance. In some embodiments, the Ligand unit (L) is derived from an antibody or a protein targeting agent that is not an antibody.

[0233] In one group of embodiments, the Ligand unit is attached to Q (a Linker unit), which comprises a releasable glucuronide linker. As noted above, additional linking components may be present in the conjugates described herein to serve the purpose of providing additional space between the camptothecin drug compound and the Ligand unit (e.g., a Stretching unit and optionally a Linking unit A), or to provide solubility-enhancing properties to the composition (e.g., a Partitioning Agent S * ). In some of these embodiments, the Ligand unit is attached to the Linker unit, Z, via a heteroatom in the Ligand unit. Heteroatoms that may be present in the Ligand unit for such attachment include sulfur (in one embodiment, from a sulfhydryl group in the targeting ligand), oxygen (in one embodiment, from a carboxyl or hydroxyl group in the targeting ligand), and optionally substituted nitrogen (in one embodiment, from a primary or secondary amine functional group in the targeting ligand, or in another embodiment, from an optionally substituted amide nitrogen). These heteroatoms may be present in the targeting ligand in its native state, e.g., in a natural antibody, or may be introduced into the targeting ligand via chemical modification or biological engineering.

[0234] In one embodiment, a targeting agent that is a precursor to a Ligand unit has a sulfhydryl functional group such that the Ligand unit is attached to a Linker unit via the sulfhydryl functional sulfur atom.

[0235] In another embodiment, a targeting agent that is a precursor of a Ligand unit has one or more lysine residues that can react with an activated ester of a Drawer unit precursor of a camptothecin-Linker compound intermediate (such esters include, but are not limited to, N-hydroxysuccinimide, pentafluorophenyl, and p-nitrophenyl esters), resulting in an amide bond between a nitrogen atom of the Ligand unit and a C=O group of a Drawer unit of a Linker unit.

[0236] In yet another aspect, a targeting agent that is a precursor of a Ligand unit has one or more lysine residues that can be chemically modified to introduce one or more sulfhydryl groups. In these embodiments, the Ligand unit is covalently attached to a Linker unit via the sulfhydryl functional sulfur atom. Reagents that can be used to modify lysines in this manner include, but are not limited to, N-succinimidyl S-acetylthioacetate (SATA) and 2-iminothiolane hydrochloride (Traut's reagent).

[0237] In another embodiment, the targeting agent, which is the precursor of the Ligand unit, has one or more carbohydrate groups that can be modified to provide one or more sulfhydryl functional groups. The chemically modified Ligand unit in the camptothecin conjugate is attached to a Linker unit component (e.g., a Drawer unit) via the sulfhydryl functional sulfur atom.

[0238] In yet another embodiment, a targeting agent that is a precursor to a Ligand unit has one or more carbohydrate groups that can be oxidized to provide an aldehyde (—CHO) functional group (see, e.g., Laguzza, et al., 1989, J. Med. hem. 32(3):548-55). In these embodiments, the corresponding aldehyde interacts with a reactive site on the Drawer unit precursor to form a bond between the Drawer unit and the Ligand unit. Reactive sites on the Drawer unit precursor that can interact with the reactive carbonyl-containing functional group on the targeting Ligand unit include, but are not limited to, hydrazine and hydroxylamine. Other protocols for modifying proteins for the attachment of a Linker unit (Q) or related species are described in Coligan et al., Current Protocols in Protein Science, vol. 2, John Wiley & Sons (2002), incorporated herein by reference.

[0239] In some aspects, a targeting agent that is a precursor of a Ligand unit can form a bond by interacting with a reactive functional group of a Drawer unit precursor (Z') to form a covalent bond between the Drawer unit (Z) and a Ligand unit (whose structure corresponds to the targeting agent). The functional group of Z' that is capable of interacting with a targeting agent will depend on the nature of the targeting agent whose structure will correspond to the Ligand unit. In some embodiments, the reactive group is a maleimide (i.e., the maleimide moiety of the Drawer unit precursor) that is present on the Drawer unit prior to attachment to form the Ligand unit. The covalent attachment of the Ligand unit to the Drawer unit is through a sulfhydryl functional group of the targeting agent that is a precursor of a Ligand unit, which interacts with the maleimide functional group of Z' to form a thio-substituted succinimide. The sulfhydryl functional group can be present on the targeting agent in its native state, e.g., as a natural residue, or can be introduced into the targeting agent via chemical modification or biological engineering.

[0240] In yet another embodiment, the Ligand unit is derived from an antibody whose sulfhydryl groups are generated by reduction of the antibody's interchain disulfides. Thus, in some embodiments, the Linker unit is conjugated to a cysteine ​​residue derived from the reduced interchain disulfide(s).

[0241] In yet another embodiment, the Ligand unit is derived from an antibody and the sulfhydryl functionality is chemically introduced into the antibody, for example, by the introduction of a cysteine ​​residue. Thus, in some embodiments, the Linker unit (with or without a camptothecin bond) is conjugated to the Ligand unit through the introduced cysteine ​​residue of the Ligand unit.

[0242] It has been observed that the site of drug conjugation in bioconjugates can affect a number of parameters, including ease of conjugation, drug-linker stability, effects on the biophysical properties of the resulting bioconjugate, and in vitro cytotoxicity. With regard to drug-linker stability, the site of conjugation of the drug-linker moiety to the Ligand unit can affect the ability of the conjugated drug-linker moiety to undergo elimination reactions, potentially resulting in premature release of the free drug. Sites for conjugation of targeting agents include, for example, reduced interchain disulfides and designated cysteine ​​residues at engineered sites. In some embodiments, the conjugation methods for forming camptothecin conjugates described herein use thiol residues at engineered sites (e.g., position 239 according to the EU index as defined in Kabat) that are less susceptible to elimination reactions than conjugation methods that use thiol residues derived from reduced disulfide bonds. In other embodiments, the conjugation methods for forming camptothecin conjugates as described herein use thiol residues resulting from reduction of interchain disulfide bonds.

[0243] In some embodiments, a camptothecin conjugate comprises a non-immunoreactive protein, polypeptide, or peptide as its ligand unit. Thus, in some embodiments, the ligand unit is derived from a non-immunoreactive protein, polypeptide, or peptide. Examples include, but are not limited to, transferrin, epidermal growth factor ("EGF"), bombesin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, transforming growth factors ("TGF"), such as TGF-α and TGF-β, vaccinia growth factor ("VGF"), insulin and insulin-like growth factors I and II, somatostatin, lectins, and apoproteins derived from low-density lipoproteins.

[0244] Particularly preferred Ligand units are derived from antibodies. Thus, in any one of the embodiments described herein, the Ligand units are derived from antibodies. Useful polyclonal antibodies are heterogeneous populations of antibody molecules derived from the serum of immunized animals. Useful monoclonal antibodies are homogeneous populations of antibodies against a particular antigenic determinant (e.g., cancer cell antigens, viral antigens, microbial antigens, proteins, peptides, carbohydrate chains, chemicals, nucleic acids, or fragments thereof). In some embodiments, monoclonal antibodies (mAbs) against an antigen of interest are prepared by any technique known in the art that produces antibody molecules by continuous cell line culture.

[0245] Useful monoclonal antibodies include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, or human-mouse (or other species) chimeric monoclonal antibodies. These antibodies include full-length antibodies and antigen-binding fragments thereof. Human monoclonal antibodies can be produced by any of a number of techniques known in the art (e.g., Teng et al., 1983, Proc. Natl. Acad. Sci. USA. 80:7308-7312; Kozbor et al., 1983, Immunology Today 4:72-79; and Olsson et al., 1982, Meth. Enzymol. 92:3-16).

[0246] Antibodies useful in practicing the present invention are intact antibodies or functionally active fragments, derivatives, or analogs of antibodies, which antibodies or fragments thereof can immunospecifically bind to target cells (e.g., cancer cell antigens, viral antigens, or microbial antigens), or to other antibodies bound to tumor cells or tumor matrix. In this context, "functionally active" means that the fragment, derivative, or analog can immunospecifically bind to the target cell. To determine which CDR sequences bind to an antigen, synthetic peptides containing the CDR sequences in some embodiments are used in binding assays with the antigen using binding assays known in the art (e.g., Biacore™ assays) (see, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md.; Kabat E et al., 1980, J. Immunology 125(3):961-969).

[0247] Other useful antibodies include fragments of antibodies, such as, but not limited to, F(ab')2 fragments, Fab fragments, Fv, single chain antibodies, diabodies, triabodies, tetrabodies, scFv, scFv-Fv, or any other molecule with the same specificity as an antibody.

[0248] Additionally, recombinant antibodies containing both human and non-human portions, such as chimeric and humanized monoclonal antibodies, which in some embodiments are produced using standard recombinant DNA techniques, are useful antibodies. Chimeric antibodies are molecules in which different portions are derived from different animal species, such as a molecule having a variable region derived from a murine monoclonal and a human immunoglobulin constant region (see, e.g., U.S. Pat. Nos. 4,816,567 and 4,816,397, which are incorporated herein by reference in their entireties). Humanized antibodies are antibody molecules derived from a 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 in some embodiments can be prepared by recombinant DNA techniques known in the art, e.g., as described in International Publication No. WO 87 / 02671, European Patent Publication No. 0 184 187, European Patent Publication No. 0 171 496, European Patent Publication No. 0 173 494, International Publication No. WO 86 / 01533, U.S. Pat. No. 4,816,567, Berter et al., Science (1988) 240:1041-1043, Liu et al., Proc. Nat'l. Acad. Sci. USA (1987) 84:3439-3443, Liu et al., J. Immunol. (1987) 139:3521-3526, Sun et al. al.,Proc.Natl.Acad.Sci.USA(1987)84:214-218, Nishimura et al.,CancerRes.(1987)47: 999-1005,Wood et al.,Nature(1985)314:446-449,Shaw et al.,J.Natl.Cancer Inst. (1988) 80:1553-1559, Morrison, Science (1985) 229:1202-1207, Oi et al., BioTechniques (1986) 4:214-221, U.S. Patent No. 5,225,539, Jones et al. al., Nature (1986) 321:552-525, Verhoeyan et al. al., Science (1988) 239:1534-1536 and Beidler et al., J. Immunol. (1988) 141:4053-4060, each of which is incorporated herein by reference in its entirety.

[0249] In some cases (e.g., when immunogenicity to non-human or chimeric antibodies may arise), fully human antibodies are more desirable, and in some embodiments are produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chain genes, but which can express human heavy and light chain genes.

[0250] Antibodies include analogs and derivatives that are modified in any way, i.e., by the covalent attachment of any type of molecule, provided that such covalent attachment enables the antibody to retain its immunospecificity for binding to an antigen. For example, but not limited to, antibody derivatives and analogs include those that are further modified by, for example, glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, conjugation to cellular antibody units or other proteins, etc. In some embodiments, one or more of these numerous chemical modifications are performed by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis in the presence of tunicamycin, etc. In other embodiments, an antibody analog or derivative comprises one or more unnatural amino acids, optionally combined with one or more of the above chemical modifications.

[0251] In some embodiments, the antibody has one or more modifications (e.g., substitutions, deletions, or additions) to amino acid residues that interact with Fc receptors, including modifications in amino acid residues identified as being involved in the interaction of the anti-Fc domain with the FcRn receptor (see, e.g., International Publication No. WO 97 / 34631, which is incorporated herein by reference in its entirety).

[0252] In some embodiments, antibodies immunospecific for a cancer cell antigen are commercially available or produced by methods known to those of skill in the art, e.g., recombinant expression techniques. Nucleotide sequences encoding antibodies immunospecific for a cancer cell antigen are optionally obtained, for example, from GenBank or a similar database, published literature, or by routine cloning and sequencing.

[0253] In a specific embodiment, a known antibody for the treatment of cancer is used.

[0254] In another specific embodiment, antibodies for the treatment of autoimmune diseases are used in accordance with the compositions and methods of the invention.

[0255] In certain embodiments, useful antibodies bind to a receptor or receptor complex expressed on activated lymphocytes, which receptor or receptor complex is, in some embodiments, an immunoglobulin gene superfamily member, a TNF receptor superfamily member, an integrin, a cytokine receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a complement control protein.

[0256] In some embodiments, the antibody incorporated into the camptothecin conjugate will specifically bind to CD19, CD30, CD33, CD70, or LIV-1.

[0257] Exemplary antigens are shown below, with exemplary antibodies that bind to the indicated antigens shown in parentheses.

[0258] In some embodiments, the antigen is a tumor-associated antigen. In some embodiments, the tumor-associated antigen is a transmembrane protein. For example, the following antigens are recognized: ANTXR1, BAFF-R, CA9 (exemplary antibodies include girentuximab), CD147 (exemplary antibodies include gavilimomab and metuzumab), CD19, CD20 (exemplary antibodies include divodilimab and ibritumomab tiuxetan), CD274, also known as PD-L1 (exemplary antibodies include adebulimab, atezolizumab, garivulimab, durvalumab, and avelumab), CD30 (exemplary antibodies include iratumumab and brentuximab), CD33 (exemplary antibodies include lintuzumab), CD352, CD45 (exemplary antibodies include rituximab, ... Exemplary antibodies include apamistamab), CD47 (exemplary antibodies include letaplimab and magrolimab), CLPTM1L, DPP4, EGFR, ERVMER34-1, FASL, FSHR, FZD5, FZD8, GUCY2C (exemplary antibodies include indusatumab), IFNAR1 (exemplary antibodies include faralimomab), IFNAR2, LMP2, MLANA, SIT1, TLR2 / 4 / 1 (exemplary antibodies include tomalalimab), TM4SF5, TMEM132A, TMEM40, UPK1B, VEGF, and VEFGR2 (exemplary antibodies include gentuximab) are transmembrane proteins.

[0259] In some embodiments, the tumor-associated antigen is a transmembrane transport protein, for example, the following antigens: ASCT2 (an exemplary antibody is idactamab), MFSD13A, Mincle, NOX1, SLC10A2, SLC12A2, SLC17A2, SLC38A1, SLC39A5, SLC39A6, also known as LIV1 (an exemplary antibody is ladiratuzumab), SLC44A4, SLC6A15, SLC6A6, SLC7A11, and SLC7A5 are transmembrane transport proteins.

[0260] In some embodiments, the tumor-associated antigen is a transmembrane or membrane-bound glycoprotein, such as the following antigens: CA-125, CA19-9, CAMPATH-1 (exemplary antibodies include alemtuzumab), carcinoembryonic antigen (exemplary antibodies include arcitumomab, sergituzumab, amunaleukin, and labetuzumab), CD112, CD155, CD24, CD247, CD37 (exemplary antibodies include rilotomab), CD38 (exemplary antibodies include ferzalta), and the like. felzartamab), CD3D, CD3E (exemplary antibodies include foralumab and teplizumab), CD3G, CD96, CDCP1, CDH17, CDH3, CDH6, CEACAM1, CEACAM6, CLDN1, CLDN16, CLDN18.1 (exemplary antibodies include zolbetuximab), CLDN18.2 (exemplary antibodies include zolbetuximab), CLDN19, CLDN 2, CLEC12A (an exemplary antibody includes tepoditamab), DPEP1, DPEP3, DSG2, endosialin (an exemplary antibody includes ontuxizumab), ENPP1, EPCAM (an exemplary antibody includes adecatumumab), FN, FN1, Gp100, GPA33, gpNMB (an exemplary antibody includes glembatumumab), ICAM1, L1CAM, LAMP1, MELTF, also known as CD228, NCAM1, Nectin-4 (an exemplary antibody includes enfortumab), PDPN, PMSA, PROM1, PSCA, PSMA, Siglec1-16, SIRPa, SIRPg, TACSTD2, TAG-72, tenascin, tissue factor, also known as TF (an exemplary antibody includes tisotumumab), and ULBP1 / 2 / 3 / 4 / 5 / 6 are transmembrane or membrane-bound glycoproteins.

[0261] In some embodiments, the tumor-associated antigen is a transmembrane or membrane-bound receptor kinase. For example, the following antigens are transmembrane or membrane-bound receptor kinases: ALK, Axl (an exemplary antibody is tilvestamab), BMPR2, DCLK1, DDR1, EPHA receptor, EPHA2, ERBB2, also known as HER2 (an exemplary antibody is trastuzumab, bevacizumab, pertuzumab, and marjetuximab), ERBB3, FLT3, PDGFR-B (an exemplary antibody is linucumab), PTK7 (an exemplary antibody is cofetuzumab), RET, ROR1 (an exemplary antibody is cirmtuzumab), ROR2, ROS1, and Tie3.

[0262] In some embodiments, the tumor-associated antigen is a membrane-bound or membrane-localized protein.For example, the following antigens are membrane-bound or membrane-localized proteins: ALPP, ALPPL2, ANXA1, FOLR1 (an exemplary antibody is farletuzumab), IL13Ra2, IL1RAP (an exemplary antibody is nidanilimab), NT5E, OX40, Ras mutant, RGS5, RhoC, SLAMF7 (an exemplary antibody is elotuzumab), and VSIR.

[0263] In some embodiments, the tumor-associated antigen is a transmembrane G protein-coupled receptor (GPCR). For example, the following antigens are GPCRs: CALCR, CD97, GPR87, and KISS1R.

[0264] In some embodiments, the tumor-associated antigen is a cell surface-bound or cell surface receptor, such as the following antigens: B7-DC, BCMA, CD137, CD244, CD3 (exemplary antibodies include otelixizumab and visilizumab), CD48, CD5 (exemplary antibodies include zolimoab alitox), CD70 (exemplary antibodies include cusatuzumab and borsetuzumab), CD74 (exemplary antibodies include milatuzumab), CD79A, CD-262 (exemplary antibodies include tigatuzumab), DR4 (exemplary antibodies include mapatumumab), FAS, FGFR1, FGFR2 (exemplary antibodies include apriutuzumab), FG FR3 (exemplary antibodies include vofatamab), FGFR4, GITR (exemplary antibodies include ragifilimab), Gpc3 (exemplary antibodies include ragifilimab), HAVCR2, HLA-E, HLA-F, HLA-G, LAG-3 (exemplary antibodies include encelimab), LY6G6D, LY9, MICA, MICB, MSLN, MUC1, MUC5AC, NY-ESO-1, OY-TES1, PVRIG, Sialyl-Thomsen-Nouveau antigen, sperm protein 17, TNFRSF12, and uPAR are cell surface associated and / or cell surface receptors.

[0265] In some embodiments, the tumor-associated antigen is a chemokine receptor or a cytokine receptor. For example, the following antigens are chemokine receptors: CD115 (exemplary antibodies include axatilimab, cabilalizumab, and emactuzumab), CD123, CXCR4 (exemplary antibodies include ulocuplumab), IL-21R, and IL-5R (exemplary antibodies include benralizumab).

[0266] In some embodiments, the tumor-associated antigen is a costimulatory surface-expressed protein. For example, the following antigens are costimulatory surface-expressed proteins: B7-H3 (exemplary antibodies include enoblituzumab and omburtamab), B7-H4, B7-H6, and B7-H7.

[0267] In some embodiments, the tumor-associated antigen is a transcription factor or a DNA-binding protein. For example, the following antigens are transcription factors: ETV6-AML, MYCN, PAX3, PAX5, and WT1. The following protein is a DNA-binding protein: BORIS.

[0268] In some embodiments, the tumor-associated antigen is an integral membrane protein, for example, the following antigens: SLITRK6 (an exemplary antibody is sirtratumab), UPK2, and UPK3B.

[0269] In some embodiments, the tumor-associated antigen is an integrin, for example, the following antigens are integrin antigens: alpha v beta 6, ITGAV (exemplary antibodies include abituzumab), ITGB6, and ITGB8.

[0270] In some embodiments, the tumor-associated antigen is a glycolipid, for example, the following are glycolipid antigens: FucGM1, GD2 (an exemplary antibody is dinutuximab), GD3 (an exemplary antibody is mitumomab), GloboH, GM2, and GM3 (an exemplary antibody is racotumomab).

[0271] In some embodiments, the tumor-associated antigen is a cell surface hormone receptor. For example, the following antigens are cell surface hormone receptors: AMHR2 and androgen receptor.

[0272] In some embodiments, the tumor-associated antigen is a transmembrane or membrane-bound protease, for example, the following antigens: ADAM12, ADAM9, TMPRSS11D, and metalloproteinases are transmembrane or membrane-bound proteases.

[0273] In some embodiments, the tumor-associated antigen is aberrantly expressed in an individual with cancer. For example, the following antigens may be aberrantly expressed in individuals with cancer: AFP, AGR2, AKAP-4, ARTN, BCR-ABL, C5 complement, CCNB1, CSPG4, CYP1B1, De2-7 EGFR, EGF, Fas-associated antigen 1, FBP, G250, GAGE, HAS3, HPV E6 E7, hTERT, IDO1, LCK, legumain, LYPD1, MAD-CT-1, MAD-CT-2, MAGEA3, MAGEA4, MAGEC2, MerTk, ML-IAP, NA17, NY-BR-1, p53, p53 mutant, PAP, PLAVI, polysialic acid, PR1, PSA, sarcoma translocation breakpoint, SART3, sLe, SSX2, survivin, Tn, TRAIL, TRAIL1, TRP-2, and XAGE1.

[0274] In some embodiments, the antigen is an immune cell-associated antigen. In some embodiments, the immune cell-associated antigen is a transmembrane protein. For example, the following antigens are identified: BAFF-R, CD163, CD19, CD20 (exemplary antibodies include rituximab, ocrelizumab, divodilimab, and ibritumomab tiuxetan), CD25 (exemplary antibodies include basiliximab), CD274, also known as PD-L1 (exemplary antibodies include adebulerimab, atezolizumab, garivulimab, durvalumab, and avelumab), CD30 (exemplary antibodies include iratumumab and brentuximab), CD33 (exemplary antibodies include lintuzumab), CD352, and CD45 (exemplary antibodies include apamistadenomatous leukemia). ipamistamab), CD47 (exemplary antibodies include letaplimab and magrolimab), CTLA4 (exemplary antibodies include ipilimumab), FASL, IFNAR1 (exemplary antibodies include faralimomab), IFNAR2, LAYN, LILRB2, LILRB4, PD-1 (exemplary antibodies include ipilimumab, nivolumab, pembrolizumab, balstilimab, budigalimab, geptanolimab, toripalimab, and pidilizumab), SIT1, and TLR2 / 4 / 1 (exemplary antibodies include tomalalimab) are transmembrane proteins.

[0275] In some embodiments, the immune cell-associated antigen is a transmembrane transport protein, for example, Mincle is a transmembrane transport protein.

[0276] In some embodiments, the immune cell-associated antigen is a transmembrane or membrane-bound glycoprotein. For example, the following antigens are transmembrane or membrane-bound glycoproteins: CD112, CD155, CD24, CD247, CD28, CD30L, CD37 (an exemplary antibody is rilotomab), CD38 (an exemplary antibody is felzartamab), CD3D, CD3E (an exemplary antibody is foralamuab and teplizumab), CD3G, CD44, CLEC12A (an exemplary antibody is tepoditamab), DCIR, DCSIGN, Dectin-1, Dectin-2, ICAM1, LAMP1, Siglec1-16, SIRPa, SIRPg, and ULBP1 / 2 / 3 / 4 / 5 / 6.

[0277] In some embodiments, the immune cell-associated antigen is a transmembrane or membrane-bound receptor kinase, for example, the following antigens: Axl (an exemplary antibody is tilvestamab) and FLT3 are transmembrane or membrane-bound receptor kinases.

[0278] In some embodiments, the immune cell-associated antigen is a membrane-bound or membrane-localized protein, for example, the following antigens: CD83, IL1RAP (an exemplary antibody is nidanilimab), OX40, SLAMF7 (an exemplary antibody is elotuzumab), and VSIR.

[0279] In some embodiments, the immune cell-associated antigen is a transmembrane G protein-coupled receptor (GPCR). For example, the following antigens are GPCRs: CCR4 (exemplary antibodies include mogamulizumab-kpkc), CCR8, and CD97.

[0280] In some embodiments, the immune cell-associated antigen is a cell surface-bound or cell surface receptor, such as the following antigens: B7-DC, BCMA, CD137, CD2 (exemplary antibodies include siplizumab), CD244, CD27 (exemplary antibodies include varlilumab), CD278 (exemplary antibodies include feraZilimab and vopratelimab), CD3 (exemplary antibodies include otelixizumab and visilizumab), CD40 (exemplary antibodies include dacetuzumab and lucatumumab), CD48, CD5 (exemplary antibodies include zolimoab alitox), CD70 (exemplary antibodies include cusatuzumab and borsetuzumab), CD74 (exemplary antibodies include riboZymoab and riboZymoab), and CD5 (exemplary antibodies include riboZymoab and riboZymoab). Exemplary antibodies include milatuzumab), CD79A, CD-262 (exemplary antibodies include tigatuzumab), DR4 (exemplary antibodies include mapatumumab), GITR (exemplary antibodies include ragifilimab), HAVCR2, HLA-DR, HLA-E, HLA-F, HLA-G, LAG-3 (exemplary antibodies include encelimab), MICA, MICB, MRC1, PVRIG, Sialyl-Thomsen-Nouveau antigen, TIGIT (exemplary antibodies include etigilimab), Trem2, and uPAR are cell surface bound and / or cell surface receptors.

[0281] In some embodiments, the immune cell-associated antigen is a chemokine receptor or a cytokine receptor. For example, the following antigens are chemokine receptors or cytokine receptors: CD115 (exemplary antibodies include axatilimab, cabilalizumab, and emactuzumab), CD123, CXCR4 (exemplary antibodies include urocuprumab), IL-21R, and IL-5R (exemplary antibodies include benralizumab).

[0282] In some embodiments, the immune cell-associated antigen is a costimulatory surface-expressed protein. For example, the following antigens are costimulatory surface-expressed proteins: B7-H3 (exemplary antibodies include enoblituzumab and omburtamab), B7-H4, B7-H6, and B7-H7.

[0283] In some embodiments, the immune cell-associated antigen is a peripheral membrane protein, for example, the following antigens: B7-1 (exemplary antibodies include galiximab) and B7-2.

[0284] In some embodiments, the immune cell-associated antigen is aberrantly expressed in individuals with cancer. For example, the following antigens may be aberrantly expressed in individuals with cancer: complement C5, IDO1, LCK, MerTk, and Tyrol.

[0285] In some embodiments, the antigen is a stromal cell-associated antigen. In some embodiments, the stromal cell-associated antigen is a transmembrane or membrane-bound protein. For example, the following antigens are transmembrane or membrane-bound proteins: FAP (an exemplary antibody is sibrotuzumab), IFNAR1 (an exemplary antibody is faralimomab), and IFNAR2.

[0286] In some embodiments, the antigen is CD30. In some embodiments, the antibody is an antibody or antigen-binding fragment that binds to CD30, such as those described in International Publication No. WO 02 / 43661. In some embodiments, the anti-CD30 antibody is cAC10, which is described in International Publication No. WO 02 / 43661. cAC10 is also known as brentuximab. In some embodiments, the anti-CD30 antibody comprises the CDRs of cAC10. In some embodiments, the CDRs are as defined by the Kabat numbering system. In some embodiments, the CDRs are as defined by the Chothia numbering system. In some embodiments, the CDRs are as defined by the IMGT numbering system. In some embodiments, the CDRs are as defined by the AbM numbering system. In some embodiments, the anti-CD30 antibody comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD30 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10, and a light chain comprising the amino acid sequence of SEQ ID NO: 11.

[0287] In some embodiments, the antigen is CD70. In some embodiments, the antibody is an antibody or antigen-binding fragment that binds to CD70, such as those described in International Publication No. WO 2006 / 113909. In some embodiments, the antibody is the anti-CD70 antibody h1F6, which is described in International Publication No. WO 2006 / 113909. h1F6 is also known as borsetuzumab. In some embodiments, the anti-CD70 antibody comprises a heavy chain variable region comprising the three CDRs of SEQ ID NO: 12 and a light chain variable region comprising the three CDRs of SEQ ID NO: 13. In some embodiments, the CDRs are as defined by the Kabat numbering system. In some embodiments, the CDRs are as defined by the Chothia numbering system. In some embodiments, the CDRs are as defined by the IMGT numbering system. In some embodiments, the CDRs are as defined by the AbM numbering system. In some embodiments, the anti-CD70 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 12, and a light chain variable region comprising an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-CD30 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 14 and a light chain comprising the amino acid sequence of SEQ ID NO: 15.

[0288] In some embodiments, the antigen is interleukin-1 receptor accessory protein (IL1RAP). IL1RAP is a co-receptor for the IL1 receptor (IL1R1) and is required for interleukin-1 (IL1) signaling. IL1 has been implicated in resistance to certain chemotherapy regimens. IL1RAP is overexpressed in various solid tumors, both on cancer cells and within the tumor microenvironment, but expression on normal cells is low. IL1RAP is also overexpressed in hematopoietic stem and progenitor cells, making it a potential target for chronic myeloid leukemia (CML). IL1RAP has also been shown to be overexpressed in acute myeloid leukemia (AML). Binding of antibodies to IL1RAP may block intracellular signaling from IL-1 and IL-33, allowing NK cells to recognize tumor cells and subsequently kill them by antibody-dependent cellular cytotoxicity (ADCC).

[0289] In some embodiments, the antigen is ASCT2. ASCT2 is also known as SLC1A5. ASCT2 is a ubiquitously expressed, broad-specificity, sodium-dependent neutral amino acid exchanger. ASCT2 is involved in glutamine transport. ASCT2 is overexpressed in various cancers and is closely associated with poor prognosis. Downregulation of ASCT2 has been shown to suppress intracellular glutamine levels and downstream glutamine metabolism (including glutathione production). Due to its high expression in many cancers, ASCT2 is a potential therapeutic target. These effects attenuate growth and proliferation, increase apoptosis and autophagy, and increase oxidative stress and suppression of the mTORC1 pathway in head and neck squamous cell carcinoma (HNSCC). In addition, silencing ASCT2 improved response to cetuximab in HNSCC.

[0290] In some embodiments, an antibody-drug conjugate provided herein binds to TROP2. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 17, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 18, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 19, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23. In some embodiments, the antibody of the antibody drug conjugate is sacituzumab. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 24, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 25, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 26, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 27, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 28, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 29. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 30 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the antibody of the antibody drug conjugate is datopotamab.

[0291] In some embodiments, an antibody-drug conjugate provided herein binds to MICA. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 32, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 33, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 34, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 35, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 38 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments, the antibody of the antibody drug conjugate is h1D5v11 hIgG1K. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 40, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 41, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 42, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 43, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 44, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 46 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the antibody of the antibody drug conjugate is MICA.36 hIgG1K G236A. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 48, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 49, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 50, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 51, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 52, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 53. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 54 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55. In some embodiments, the antibody of the antibody drug conjugate is h3F9 H1L3 hIgG1K.In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 56, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 57, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 58, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 59, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 60, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 61. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 62 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 63. In some embodiments, the antibody of the antibody drug conjugate is CM33322 Ab28 hIgG1K.

[0292] In some embodiments, an antibody-drug conjugate provided herein binds to CD24. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 64, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 65, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 66, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 67, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 68, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 69. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 70 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 71. In some embodiments, the antibody of the antibody drug conjugate is SWA11.

[0293] In some embodiments, the antibody-drug conjugates provided herein bind to ITGav. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 72, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 73, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 74, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 75, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 76, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 77. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 78 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 79. In some embodiments, the antibody of the antibody drug conjugate is intetumumab. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 80, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 81, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 82, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 83, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 84, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 85. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 86 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 87. In some embodiments, the antibody of the antibody drug conjugate is abituzumab.

[0294] In some embodiments, an antibody-drug conjugate provided herein binds to gpA33. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 88, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 89, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 90, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 91, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 92, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 93. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 94 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 95.

[0295] In some embodiments, an antibody-drug conjugate provided herein binds to IL1Rap. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 96, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 97, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 98, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 99, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 100, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 101. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 102 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 103. In some embodiments, the antibody of the antibody drug conjugate is nidanilimab.

[0296] In some embodiments, an antibody-drug conjugate provided herein binds to EpCAM. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 104, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 105, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 106, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 107, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 108, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 109. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 110 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 111. In some embodiments, the antibody of the antibody drug conjugate is adecatumumab. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 112, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 113, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 114, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 115, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 116, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 117. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 118 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 119. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 118 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1182. In some embodiments, the antibody of the antibody drug conjugate is Ep157305. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 120, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 121, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 122, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 123, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 124, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 125. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 126 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127.In some embodiments, the antibody of the antibody drug conjugate is Ep3-171. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 128, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 129, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 130, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 131, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 132, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 134 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 135. In some embodiments, the antibody of the antibody drug conjugate is Ep3622w94. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 136, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 137, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 138, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 139, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 140, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 141. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 142 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 143. In some embodiments, the antibody of the antibody drug conjugate is EpING1. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 144, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 145, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 146, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 147, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 148, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 149. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 150 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 151. In some embodiments, the antibody of the antibody drug conjugate is EpAb2-6.In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 104, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 105, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 1181, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 107, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 108, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 109. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1181.

[0297] In some embodiments, an antibody-drug conjugate provided herein binds to CD352. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 152, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 153, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 154, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 155, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 156, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 157. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 158 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 159. In some embodiments, the antibody of the antibody drug conjugate is h20F3.

[0298] In some embodiments, an antibody-drug conjugate provided herein binds to CS1. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 160, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 161, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 162, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 163, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 164, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 165. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 166 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 167. In some embodiments, the antibody of the antibody drug conjugate is elotuzumab.

[0299] In some embodiments, an antibody-drug conjugate provided herein binds to CD38. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 168, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 169, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 170, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 171, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 172, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 173. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 174 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 175. In some embodiments, the antibody of the antibody drug conjugate is daratumumab.

[0300] In some embodiments, an antibody-drug conjugate provided herein binds to CD25. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 176, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 177, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 178, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 179, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 180, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 181. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 182 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 183. In some embodiments, the antibody of the antibody drug conjugate is daclizumab.

[0301] In some embodiments, an antibody-drug conjugate provided herein binds to ADAM9. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 184, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 185, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 186, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 187, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 188, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 189. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 190 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 191. In some embodiments, the antibody of the antibody drug conjugate is chMAbA9-A. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 192, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 193, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 194, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 195, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 196, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 197. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 198 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 199. In some embodiments, the antibody of the antibody drug conjugate is hMAbA9-A. In some embodiments, the antibody-drug conjugates provided herein bind to ADAM9. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1183, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 185, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 186, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 187, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 188, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 189. In some embodiments, an antibody-drug conjugate provided herein binds to ADAM9. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1183.In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1184, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 193, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 194, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1185, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 196, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 197. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1184. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1185.

[0302] In some embodiments, the antibody-drug conjugates provided herein bind to CD59. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 200, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 201, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 202, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 203, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 204, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 205. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 206 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 207. In some embodiments, the antibody-drug conjugates provided herein bind to CD59. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1186, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 1187, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 202, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 203, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 204, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 205. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1186. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 1187. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1188 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 207.

[0303] In some embodiments, the antibody-drug conjugates provided herein bind to CD25. In some embodiments, the antibody of the antibody drug conjugate is Clone123.

[0304] In some embodiments, the antibody-drug conjugates provided herein bind to CD229, hi some embodiments, the antibody of the antibody drug conjugate is h8A10.

[0305] In some embodiments, an antibody-drug conjugate provided herein binds to CD 19. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 208, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 209, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 210, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 211, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 212, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 213. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 214 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 215. In some embodiments, the anti-CD19 antibody comprises a heavy chain comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1175, and a light chain comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1176. In some embodiments, the antibody of the antibody drug conjugate is denintuzumab, also known as hBU12. See WO2009052431.

[0306] In some embodiments, the antibody-drug conjugates provided herein bind to CD70. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 216, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 217, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 218, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 219, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 220, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 221. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 222 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 223. In some embodiments, the antibody of the antibody-drug conjugate is borsetuzumab. Optionally, the antibodies provided herein bind to CD70. In some such cases, the antibody comprises a CDR-H1 sequence that has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1169; a CDR-H2 sequence that has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1170; a CDR-H3 sequence that has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1171; a CDR-H3 sequence, a CDR-L1 sequence that has at least 80%, at least 85%, at least 90% or at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1172, a CDR-L2 sequence that has at least 80%, at least 85%, at least 90% or at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1173, and a CDR-L3 sequence that has at least 80%, at least 85%, at least 90% or at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1174.In some cases, the antibody comprises a CDR-H1 sequence comprising at most one mutation relative to the amino acid sequence of SEQ ID NO: 1169, a CDR-H2 sequence comprising at most one mutation relative to the amino acid sequence of SEQ ID NO: 1170, a CDR-H3 sequence comprising at most one mutation relative to the amino acid sequence of SEQ ID NO: 1171, a CDR-L1 sequence comprising at most one mutation relative to the amino acid sequence of SEQ ID NO: 1172, a CDR-L2 sequence comprising at most one mutation relative to the amino acid sequence of SEQ ID NO: 1173, and a CDR-L3 sequence comprising at most one mutation relative to the amino acid sequence of SEQ ID NO: 1174.

[0307] In some embodiments, an antibody-drug conjugate provided herein binds to B7H4. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 224, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 225, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 226, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 227, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 228, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 229. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 230 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 231. In some embodiments, the antibody of the antibody drug conjugate is mirzotamab.

[0308] In some cases, the antibodies provided by the present invention bind to B7H4. In some cases, the antibodies comprise a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively), each of which is set forth in SEQ ID NOs: 77-82, 91-96, 99-104, 985-990, 993-998, 1001-128, 1009-1014, 1017-1022, 1025-1030, 1033-1038, 1041-1046, 1049-1050, 1051-1052, 1053-1054, 1055-1056, 1057-1058, 1059-1060, 1061-1062, 1063-1064, 1065-1066, 1067-1068, 1069-1070, 1071-1072, 1073-1074, 1075-1076, 1077-1078, 1079-1080, 1081-1082, 1083-1084, 1085-1086, 1087-1088, 1089-1090, 1091-1092, 1093-1094, 1095-1096, 1097-1098, 1098-2000, 1099-2001, 1099-2002, 1099-2003, 10 054, SEQ ID NOs: 1057 to 1062, SEQ ID NOs: 1065 to 1070, SEQ ID NOs: 1073 to 1078, SEQ ID NOs: 1081 to 1086, SEQ ID NOs: 1089 to 1094, SEQ ID NOs: 1097 to 1102, SEQ ID NOs: 1105 to 1110, SEQ ID NOs: 1113 to 1118 and SEQ ID NOs: 1121 to 1126. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively), each of which is set forth in SEQ ID NOs: 77-82, 91-96, 99-104, 985-990, 993-998, 1001-1006, 1009-1014, 1017-1022, 1025-1030, 1033-1034, 1035-1036, 1037-1038, 1039-1040, 1041-1042, 1043-1044, 1045-1046, 1047-1048, 1049-1050, 1051-1052, 1053-1054, 1055-1056, 1057-1058, 1059-1060, 1061-1062, 1063-1064, 1065-1066, 1067-1068, 1069-1070, 1071-1072, 1073-1074, 1075-1076, 1077-1078, 1079-1080, 1081-1082, 1083-1084, 1085-1086, 1087-1088, 1089-1090, 1091-1092, 1900-1903, 1904-1905, 1906-190 038, SEQ ID NOs: 1041 to 1046, SEQ ID NOs: 1049 to 1054, SEQ ID NOs: 1057 to 1062, SEQ ID NOs: 1065 to 1070, SEQ ID NOs: 1073 to 1078, SEQ ID NOs: 1081 to 1086, SEQ ID NOs: 1089 to 1094, SEQ ID NOs: 1097 to 1102, SEQ ID NOs: 1105 to 1110, SEQ ID NOs: 1113 to 1118 and SEQ ID NOs: 1121 to 1126.In some cases, the anti-B7H4 antibodies are selected from the group consisting of SEQ ID NOs:963 and 87, SEQ ID NOs:964 and 87, SEQ ID NOs:966 and 90, SEQ ID NOs:967 and 90, SEQ ID NOs:1129 and 1130, SEQ ID NOs:1131, 1132, 1131 and 1132, SEQ ID NOs:1133 and 1134, SEQ ID NOs:1135 and 1136, SEQ ID NOs:1137 and 1138, SEQ ID NOs:1139 and 1140, SEQ ID NOs:1141 and 1142, SEQ ID NOs:1143 and 1144, SEQ ID NOs:1145 and 1146, SEQ ID NOs:1147 and 1148, SEQ ID NOs:1149 and 1150, SEQ ID NOs:1151 and 1152, SEQ ID NOs:1153 and 1154, SEQ ID NOs:1155 and 1156, 156, SEQ ID NOs:1157 and 1158, SEQ ID NOs:1159 and 1160, SEQ ID NOs:1161 and 1162, SEQ ID NOs:1163 and 1164, SEQ ID NOs:1165 and 1166 or SEQ ID NOs:1167 and 1168. In some embodiments, the anti-B7H4 antibodies are selected from the group consisting of SEQ ID NOs:961 and 962, SEQ ID NOs:975 and 98, SEQ ID NOs:983 and 984, SEQ ID NOs:991 and 992, SEQ ID NOs:999 and 1000, SEQ ID NOs:1007 and 1008, SEQ ID NOs:1015 and 1016, SEQ ID NOs:1031 and 1032, SEQ ID NOs:1039 and 1040, SEQ ID NOs:1047 and 1048, SEQ ID NOs:1055 and 1056, SEQ ID NOs:1063 and 1064, and SEQ ID NOs:1071 and 1072, respectively. , SEQ ID NOs: 1079 and 1080, SEQ ID NOs: 1087 and 1088, SEQ ID NOs: 1095 and 1096, SEQ ID NOs: 1103 and 1104, SEQ ID NOs: 1111 and 1112, SEQ ID NOs: 1119 and 1120, or SEQ ID NOs: 1127 and 1128.

[0309] In some embodiments, an antibody-drug conjugate provided herein binds to CD138. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 232, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 233, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 234, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 235, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 236, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 237. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 238 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 239. In some embodiments, the antibody of the antibody drug conjugate is indatuxumab.

[0310] In some embodiments, an antibody-drug conjugate provided herein binds to CD166. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 240, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 241, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 242, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 243, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 244, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 245. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 246 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 247. In some embodiments, the antibody of the antibody drug conjugate is pralzatamab.

[0311] In some embodiments, an antibody-drug conjugate provided herein binds to CD51. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 248, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 249, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 250, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 251, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 252, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 253. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 254 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 255. In some embodiments, the antibody of the antibody drug conjugate is intetumumab.

[0312] In some embodiments, an antibody-drug conjugate provided herein binds to CD56. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 256, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 257, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 258, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 259, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 260, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 261. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 262 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 263. In some embodiments, the antibody of the antibody drug conjugate is lorvotuzumab.

[0313] In some embodiments, an antibody-drug conjugate provided herein binds to CD74. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 264, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 265, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 266, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 267, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 268, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 269. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 270 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 271. In some embodiments, the antibody of the antibody drug conjugate is milatuzumab.

[0314] In some embodiments, an antibody-drug conjugate provided herein binds to CEACAM5. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 272, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 273, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 274, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 275, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 276, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 277. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 278 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 279. In some embodiments, the antibody of the antibody drug conjugate is labetuzumab.

[0315] In some embodiments, an antibody-drug conjugate provided herein binds to CanAg. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 280, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 281, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 282, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 283, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 284, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 285. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 286 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 287. In some embodiments, the antibody of the antibody drug conjugate is cantuzumab.

[0316] In some embodiments, an antibody-drug conjugate provided herein binds to DLL-3. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 288, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 289, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 290, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 291, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 292, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 293. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 294 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 295. In some embodiments, the antibody of the antibody drug conjugate is rovalpituzumab.

[0317] In some embodiments, an antibody-drug conjugate provided herein binds to DPEP-3. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 296, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 297, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 298, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 299, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 300, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 301. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 302 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 303. In some embodiments, the antibody of the antibody drug conjugate is tamrintamab.

[0318] In some embodiments, an antibody-drug conjugate provided herein binds to EGFR. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 304, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 305, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 306, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 307, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 308, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 309. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 310 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 311. In some embodiments, the antibody of the antibody drug conjugate is laprituximab. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 312, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 313, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 314, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 315, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 316, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 317. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 318 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 319. In some embodiments, the antibody of the antibody drug conjugate is rosatuxizumab. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 320, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 321, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 322, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 323, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 324, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 325. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 326 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 327. In some embodiments, the antibody of the antibody drug conjugate is cercultamab.In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 328, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 329, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 330, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 331, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 332, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 333. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 334 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 335. In some embodiments, the antibody of the antibody drug conjugate is cetuximab.

[0319] In some embodiments, an antibody-drug conjugate provided herein binds to FRa. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 336, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 337, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 338, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 339, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 340, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 341. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 342 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 343. In some embodiments, the antibody of the antibody drug conjugate is mirvetuximab. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 344, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 345, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 346, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 347, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 348, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 349. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 350 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 351. In some embodiments, the antibody of the antibody drug conjugate is farletuzumab.

[0320] In some embodiments, an antibody-drug conjugate provided herein binds to MUC-1. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 352, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 353, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 354, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 355, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 356, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 357. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 358 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 359. In some embodiments, the antibody of the antibody drug conjugate is gatipotuzumab.

[0321] In some embodiments, an antibody-drug conjugate provided herein binds to mesothelin. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 360, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 361, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 362, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 363, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 364, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 365. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 366 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 367. In some embodiments, the antibody of the antibody drug conjugate is anetumab.

[0322] In some embodiments, an antibody-drug conjugate provided herein binds to ROR-1. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 368, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 369, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 370, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 371, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 372, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 373. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 374 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 375. In some embodiments, the antibody of the antibody drug conjugate is zilovertamab.

[0323] In some embodiments, the antibody-drug conjugates provided herein bind to ASCT2. In some embodiments, the antibody-drug conjugates provided herein bind to B7H4. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 376, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 377, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 378, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 379, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 380, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 381. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 382 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 383. In some embodiments, the antibody of the antibody-drug conjugate is 20502. See WO2019040780.

[0324] In some embodiments, an antibody-drug conjugate provided herein binds to B7-H3. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 384, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 385, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 386, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 387, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 388, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 389. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 390 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 391. In some embodiments, the antibody of the antibody drug conjugate is chAb-A(BRCA84D). In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 392, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 393, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 394, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 395, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 396, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 397. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 398 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 399. In some embodiments, the antibody of the antibody drug conjugate is hAb-B. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 400, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 401, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 402, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 403, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 404, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 405. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 406 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 407. In some embodiments, the antibody of the antibody drug conjugate is hAb-C.In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 408, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 409, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 410, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 411, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 412, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 413. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 414 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 415. In some embodiments, the antibody of the antibody drug conjugate is hAb-D. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 416, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 417, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 418, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 419, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 420, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 421. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 422 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 423. In some embodiments, the antibody of the antibody drug conjugate is chM30. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 424, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 425, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 426, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 427, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 428, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 429. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 430 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 431. In some embodiments, the antibody of the antibody drug conjugate is hM30-H1-L4.In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 432, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 433, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 434, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 435, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 436, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 437. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 438 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 439. In some embodiments, the antibody of the antibody drug conjugate is AbV_huAb18-v4. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 440, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 441, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 442, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 443, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 444, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 445. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 446 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 447. In some embodiments, the antibody of the antibody drug conjugate is AbV_huAb3-v6. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 448, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 449, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 450, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 451, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 452, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 453. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 454 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 455. In some embodiments, the antibody of the antibody drug conjugate is AbV_huAb3-v2.6.In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 456, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 457, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 458, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 459, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 460, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 461. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 462 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 463. In some embodiments, the antibody of the antibody drug conjugate is AbV_huAb13-v1-CR. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 464, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 465, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 466, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 467, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 468, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 469. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 470 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 471. In some embodiments, the antibody of the antibody drug conjugate is 8H9-6m. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 472 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 473. In some embodiments, the antibody of the antibody drug conjugate is m8517. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 474, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 475, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 476, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 477, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 478, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 479. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 480 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 481.In some embodiments, the antibody of the antibody drug conjugate is TPP-5706. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 482 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 483. In some embodiments, the antibody of the antibody drug conjugate is TPP-6642. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 484 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 485. In some embodiments, the antibody of the antibody drug conjugate is TPP-6850. In some embodiments, the antibody-drug conjugates provided herein bind to B7-H3. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 384, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 1189, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 1190, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1191, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 1192, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 1193. In some embodiments, an antibody-drug conjugate provided herein binds to B7-H3. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 1189. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 1190. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1191. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 1192. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 1193. In some embodiments, the antibody of the antibody drug conjugate is chAb-A(BRCA84D).In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1194, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 1195, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 1196, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1197, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 396, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 397. In some embodiments, the antibody of the antibody drug conjugate is chAb-A(BRCA84D). In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1194. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 1195. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 1196. In some embodiments, the antibody of the antibody drug conjugate is a chAb-A(BRCA84D). In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 400, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 401, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 402, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 403, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 404, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 1198. In some embodiments, the antibody of the antibody drug conjugate is an hAb-B. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 1198. In some embodiments, the antibody of the antibody drug conjugate is an hAb-C. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1199, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 1200, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 1201, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1202, a CDR-L2 comprising the amino acid sequence of SEQ ...

Claims

1. L-(Q-D) ｐ or a salt thereof, wherein L is a targeting agent, in particular a ligand unit derived from an antibody that selectively binds to a cancer cell antigen; the subscript p is an integer ranging from 1 to 16; Q, -Z-A-, -Z-A-RL-, -Z-A-RL-Y-, -Z-A-S ＊ -RL-, -Z-A-S ＊ -RL-Y-, -Z-A-S ＊ -W-, -Z-A-S ＊ -W-RL-, -Z-A-B(S ＊ )-RL-, -Z-A-B(S ＊ )-W-, -Z-A-B(S ＊ )-W-RL- and -Z-A-B(S ＊ )-RL-Y- is a linker unit having a formula selected from the group consisting of: In the formula, Z is a stretching unit, A is a bond or a linking unit; B is a parallel linked unit; S ＊ is a partitioning agent, R is a releasable linker; W is an amino acid unit, Y is a spacer unit; D is the following D ０ｂ Formula 【Chemical 227】 or a salt thereof, wherein E is -OR ｂ５ Or -NR ｂ５ R ｂ５’ and R ｂ１ H, halogen, -CN, C １ -C ８ Alkyl, C １ -C ８ Haloalkyl, C ２ -C ８ Alkenyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ cycloalkyl, 3- to 10-membered heterocycloalkyl, (C ６ -C １２ Aryl)-C ２ -C ８ Alkenyl-, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ Each of the compounds is selected from the group consisting of １ -C ３ Alkyl, -OR ａ , -NR ａ R ａ’ , -C(O)R ａ and -SR ａ or R ｂ１ But, R ｂ２ , R ｂ５ Or R ｂ６ and together with the intervening atoms form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring; R ｂ２ H, halogen, C １ -C ８ Alkyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ Cycloalkyl, 3-10 membered heterocycloalkyl, C １ -C ８ Haloalkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-S(O) ２ -, C １ -C ８ Aminoalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-NR ａ -, C １ -C ８ Alkyl-NR ａ -C(O)O-, C １ -C ８ Alkyl-OC(O)-NR ａ -, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ and each is selected from the group consisting of: ａ , -NR ａ R ａ’ and -SR ａ or optionally replaced by R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring; or R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered heterocycle fused to a 6-membered aryl; R ｂ３ H, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Haloalkyl, -OR ａ , -NR ａ R ａ’ and -SR ａ is selected from the group consisting of R ｂ４ is selected from the group consisting of H or halogen; Each R ｂ５ and R ｂ５’ are independent, H, C １ -C ８ Alkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl-, C １ -C ８ Aminoalkyl, (C １ -C ４ alkylamino)-C １ -C ８ Alkyl-, N,N-(C １ -C ４ Hydroxyalkyl) (C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, N,N-di(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, N-(C １ -C ４ Hydroxyalkyl)-C １ -C ８ Aminoalkyl-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Hydroxyalkyl-C(O)-, C １ -C ８ Aminoalkyl-C(O)-, C ３ -C １０ Cycloalkyl, (C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl, C ３ -C １０ Heterocycloalkyl, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Alkyl-, C １ -C ６ Hydroxyalkyl-heteroaryl-, phenyl, phenyl-C １－ C ４ Alkyl-, diphenyl-C １ -C ４ Alkyl-, Heteroaryl, Heteroaryl-C １ -C ４ Alkyl-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ６ Alkoxy-C(O)-N-(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, C １ -C ４ Alkyl-SO ２ -C １ -C ８ Alkyl-, NH ２ -SO ２ -C １ -C ８ Alkyl-, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Hydroxyalkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, phenyl-C(O)-, phenyl-SO ２ - and C １ -C ８ Hydroxyalkyl-C ３ -C １０ heterocycloalkyl- or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ is H, and R ｂ５ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: R ｂ６ is H or R ｂ１ and together with the intervening atoms form a carbocyclic or heterocyclic ring, R ａ and R ａ’ are each independently H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl-S(O) ２ -, C １ -C ６ Alkyl-C(O)-, C １ -C ６ Aminoalkyl-C(O)- and C １ -C ６ hydroxyalkyl-C(O)-; a) R ｂ２ But, R ｂ３ and together with the intervening atoms form a 1,3-dioxolane, and E is -NR ｂ５ R ｂ５’ When ｂ５ and R ｂ５’ are independent, H, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-C(O)(C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl-, C ３ -C １０ Heterocycloalkyl, C １ -C ６ Hydroxyalkyl-heteroaryl-, heteroaryl, heteroaryl-C １ -C ４ Alkyl-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ６ Alkoxy-C(O)-N-(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, C １ -C ４ Alkyl-SO ２ -C １ -C ８ Alkyl-, NH ２ -SO ２ -C １ -C ８ Alkyl-, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Hydroxyalkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, phenyl-C(O)-, phenyl-SO ２ - and C １ -C ８ Hydroxyalkyl-C ３ -C １０ heterocycloalkyl- or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ is H, and R ｂ５ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: b) R ｂ２ But, R ｂ３ and when combined with the intervening atoms to form 1,3-dioxolane, E is not -OH, c) R ｂ２ is methyl, R ｂ３ When is F, R ｂ１ But, R ｂ６ and does not form a ring together with the intervening atoms, d) D is not (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione or (S)-7-ethyl-7-hydroxy-14-(morpholinomethyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, or a salt of any of the above; The camptothecin conjugate or salt thereof, wherein D is covalently attached to Q through any suitable attachment site on D, and optionally a hydrogen atom of a hydroxyl, thiol, primary amine or secondary amine of D is replaced with a bond to Q, or a tertiary amine of D is quaternized to form a bond to Q.

2. D. 【Chemical 228】 or a salt thereof, wherein the dagger indicates the site of covalent attachment of D to Q, or R ｂ５ a hydrogen atom of a hydroxyl, thiol, primary amine or secondary amine of is replaced by a bond to Q, or R ｂ５ The camptothecin conjugate of claim 1 , wherein the tertiary amine of is quaternized to form a bond to Q.

3. D. 【Chemical 229】 【Chemistry 230】 or a salt thereof, wherein the dagger indicates the site of covalent attachment of D to Q, or R ｂ５ a hydrogen atom of a hydroxyl, thiol, primary amine or secondary amine of is replaced by a bond to Q, or R ｂ５ The camptothecin conjugate of claim 2 , wherein the tertiary amine of is quaternized to form a bond to Q.

4. D. 【Chemistry 231】 or a salt thereof, wherein X and Y Ｂ are each independently O, S, or S(O) ２ , C.R. ｘ R ｘ’ Or N.R. ｘ and R ｘ and R ｘ’ are each independently H, OH, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Aminoalkyl-C(O)-, C １ -C ６ Alkyl-C(O)-, C １ -C ６ Hydroxyalkyl-C(O)-, C １ -C ６ Alkyl-NH-C(O)- or C １ -C ６ Alkyl-S(O) ２ - selected from the group consisting of m and n are each 1 or 2; Each R ｃ１ , R ｃ１’ , R ｃ２ and R ｃ２’ became independent, (i) H, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, -OR ａ , -NR ａ R ａ’ , -SR ａ , C １ -C ６ Alkyl-C(O)-, C １ -C ６ Alkyl-NR ａ -C(O)- and C １ -C ６ Alkyl-S(O) ２ - or is selected from the group consisting of (ii) R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; or (iii) R ｘ’ and together with the intervening atoms form a 3- to 6-membered carbocyclic or heterocyclic ring, when m and n are both present, the sum of m+n is 2 or 3; The dagger symbol indicates the site of covalent attachment of D to Q or R ｂ５ a hydrogen atom of a hydroxyl, thiol, primary amine or secondary amine of is replaced by a bond to Q, or R ｂ５ The camptothecin conjugate of claim 2 , wherein the tertiary amine of is quaternized to form a bond to Q.

5. D. 【Chemistry 232】 or a salt thereof, wherein R ｄ１ , R ｄ１’ , R ｄ２ and R ｄ２’ are each independently H, a halogen, or C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ａ , -NR ａ R ａ’ , -SR ａ , C １ -C ６ Alkyl-C(O)-, C １ -C ６ Alkyl-NR ａ -C(O)- and C １ -C ６ Alkyl-S(O) ２ - selected from the group consisting of 3. The camptothecin conjugate of claim 2, wherein the dagger indicates the site of covalent attachment of D to Q.

6. D. 【Chemistry 233】 or a salt thereof, wherein Y １ is a 5- or 6-membered heteroaryl; halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl or C １ -C ６ Alkyl-S(O) ２ is optionally substituted with -, 3. The camptothecin conjugate of claim 2, wherein the dagger indicates the site of covalent attachment of D to Q.

7. D. 【Chemical 234】 or a salt thereof, wherein Each R ｅ are independently halogen, —OH, —NH ２ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Alkyl-S(O) ２ - and C １ -C ６ Alkyl-NR ａ -C(O)-, where f is 0, 1, 2, 3, 4 or 5; 3. The camptothecin conjugate of claim 2, wherein the dagger indicates the site of covalent attachment of D to Q.

8. D. 【Chemistry 235】 or a salt thereof, wherein R ｇ But, H, C １ -C ６ alkyl or a 3- to 8-membered heterocycle; 3. The camptothecin conjugate of claim 2, wherein the dagger indicates the site of covalent attachment of D to Q.

9. D. 【Chemistry 236】 or a salt thereof, wherein R ３ｈ , R ３ｈ’ and R ３ｈ’’ are each independently H, C １ -C ６ Alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, —C(O)—C １ -C ６ Alkyl, —C(O)O—C １ -C ６ Alkyl, -C(O)NH-C １ -C ６ Alkyl, C ６ -C １０ Aryl, -C ６ -C １０ Aryl-C １ -C ６ Alkyl and -C ６ -C １０ Aryl-C １ -C ６ alkoxy, each of which is selected from the group consisting of C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ａ , -NR ａ R ａ’ and -SR ａ is optionally replaced by 3. The camptothecin conjugate of claim 2, wherein the dagger indicates the site of covalent attachment of D to Q.

10. D. 【Chemical 237】 3. The camptothecin conjugate of claim 2, having a formula selected from the group consisting of: or a salt thereof, wherein the dagger indicates the site of covalent attachment of D to Q.

11. D is the following D ０ｂ -I formula 【Chemical 238】 or a salt thereof, wherein R ｂ２ But, R ｂ３ and when combined with the intervening atoms to form a 5-, 6-, or 7-membered heterocycle, said heterocycle has no more than one O.

12. D is the following D ０ｂ Formula II 【Chemical 239】 or a salt thereof, wherein R ｂ５ is H, and R ｂ５’ But, H, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl, C １ -C ８ Alkyl-C(O)(C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl, C ３ -C １０ Heterocycloalkyl, C １ -C ６ Hydroxyalkyl-heteroaryl-, heteroaryl, heteroaryl-C １ -C ４ Alkyl-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ６ Alkoxy-C(O)-N-(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, C １ -C ４ Alkyl-SO ２ -C １ -C ８ Alkyl-, NH ２ -SO ２ -C １ -C ８ Alkyl-, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Hydroxyalkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, phenyl-C(O)-, phenyl-SO ２ - and C １ -C ８ Hydroxyalkyl-C ３ -C １０ heterocycloalkyl- or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ with the proviso that D is not (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione or (S)-7-ethyl-7-hydroxy-14-(morpholinomethyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, or a salt of any of the foregoing.

13. D is the following D ０ｂ Formula III 【Chemistry 240】 2. The camptothecin conjugate of claim 1, having the formula:

14. D is the following D ０ａ -I formula 【Chemical 241】 or a salt thereof, wherein E is -OR ｂ５ Or -NR ｂ５ R ｂ５’ and R ｂ１ H, halogen, -CN, C １ -C ８ Alkyl, C １ -C ８ Haloalkyl, C ２ -C ８ Alkenyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ cycloalkyl, 3- to 10-membered heterocycloalkyl, (C ６ -C １２ Aryl)-C ２ -C ８ Alkenyl-, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ Each of the compounds is selected from the group consisting of １ -C ３ Alkyl, -OR ａ , -NR ａ R ａ’ , -C(O)R ａ and -SR ａ or R ｂ１ But, R ｂ２ , R ｂ５ Or R ｂ６ and together with the intervening atoms form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring; R ｂ２ H, halogen, C １ -C ８ Alkyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ Cycloalkyl, 3-10 membered heterocycloalkyl, C １ -C ８ Haloalkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-S(O) ２ -, C １ -C ８ Aminoalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-NR ａ -, C １ -C ８ Alkyl-NR ａ -C(O)O-, C １ -C ８ Alkyl-OC(O)-NR ａ -, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ and each is selected from the group consisting of: ａ , -NR ａ R ａ’ and -SR ａ or optionally replaced by R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring, or R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered heterocycle fused to a 6-membered aryl; R ｂ３ H, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Haloalkyl, -OR ａ , -NR ａ R ａ’ and -SR ａ or R ｂ３ But, R ｂ２ and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring, or a 5-membered heterocyclic ring fused to a 6-membered aryl; R ｂ４ is selected from the group consisting of H and halogens; Each R ｂ５ and R ｂ５’ are independent, H, C １ -C ８ Alkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl, C １ -C ８ Aminoalkyl, (C １ -C ４ alkylamino)-C １ -C ８ Alkyl-, N,N-(C １ -C ４ Hydroxyalkyl) (C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, N,N-di(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, N-(C １ -C ４ Hydroxyalkyl)-C １ -C ８ Aminoalkyl-, C １ -C ８ Hydroxyalkyl-C(O)-, C ３ -C １０ Cycloalkyl, (C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl, C ３ -C １０ Heterocycloalkyl, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Alkyl-, Heteroaryl-C １ -C ６ Hydroxyalkyl, phenyl, phenyl-C １－ C ４ Alkyl-, diphenyl-C １ -C ４ Alkyl-, Heteroaryl, Heteroaryl-C １ -C ４ Alkyl-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ６ Alkoxy-C(O)-N-(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, C １ -C ４ Alkyl-SO ２ -C １ -C ８ Alkyl-, NH ２ -SO ２ -C １ -C ８ Alkyl-, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Hydroxyalkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, phenyl-C(O)-, phenyl-SO ２ - and C １ -C ８ Hydroxyalkyl-C ３ -C １０ heterocycloalkyl- or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ is H, and R ｂ５ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: R ｂ６ is H or R ｂ１ and together with the intervening atoms form a carbocyclic or heterocyclic ring, R ａ and R ａ’ are each independently H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl-S(O) ２ -, C １ -C ６ Alkyl-C(O)-, C １ -C ６ Aminoalkyl-C(O)- and C １ -C ６ hydroxyalkyl-C(O)-; a) R ｂ２ But, R ｂ３ and together with the intervening atoms form a 1,3-dioxolane, and E is -NR ｂ５ R ｂ５’ When ｂ５ and R ｂ５’ are independent, H, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-C(O)(C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl-, C ３ -C １０ Heterocycloalkyl, C １ -C ６ Hydroxyalkyl-heteroaryl-, heteroaryl, heteroaryl-C １ -C ４ Alkyl-, phenyl-C(O)- and phenyl-SO ２ -, or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ is H, and R ｂ５ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: b) R ｂ２ But, R ｂ３ and when combined with the intervening atoms to form 1,3-dioxolane, E is not -OH, c) E is NH ２ When R ｂ１ is -CN, 5-12 membered heteroaryl having at least one N in the ring, 3-10 membered heterocycloalkyl having at least one N in the ring, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -NR ａ R ａ’ and -SR ａ Each of the compounds is selected from the group consisting of １ -C ３ Alkyl, -OR ａ , -NR ａ R ａ’ , -C(O)R ａ and -SR ａ or R ｂ１ But, R ｂ２ and together with the intervening atoms form a 5-, 6-, or 7-membered heterocycle having at least one N in the ring, or a 5-membered heterocycle fused to a 6-membered aryl; R ｂ２ H, halogen, C １ -C ８ Alkyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ Cycloalkyl, 3-10 membered heterocycloalkyl, C １ -C ８ Haloalkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-S(O) ２ -, C １ -C ８ Aminoalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-NR ａ -, C １ -C ８ Alkyl-NR ａ -C(O)O-, C １ -C ８ Alkyl-OC(O)-NR ａ -, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ and each is selected from the group consisting of: ａ , -NR ａ R ａ’ and -SR ａ optionally replaced by, or R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered heterocyclic ring having at least one N in the ring, or R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered heterocycle fused to a 6-membered aryl; d) R ｂ２ is —OH or methyl, and R ｂ３ When is F, R ｂ１ But, R ｂ５ , R ｂ５’ Or R ｂ６ does not, together with the intervening atoms, form a ring; e) D is (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-7-ethyl-7-hydroxy-14-(morpholinomethyl)-10,13-dihydro- 11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)piperazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[ 1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminopiperidin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione and tert-butyl(S)-(1-((7-ethyl- 2. The camptothecin conjugate of claim 1, which is not selected from the group consisting of 7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)piperidin-4-yl)carbamate, or a salt of any of the above.

15. D is the following D ０ Formula of -I' 【Chemical Formula 242】 or a salt thereof, In the formula, R ｂ２ But, R ｂ３ and when combined with the intervening atoms to form a 5-, 6-, or 7-membered heterocycle, said heterocycle has no more than one O.

16. D is the following D ０ Formula III' 【Chemical Formula 243】 or a salt thereof, wherein R ｂ１ H, halogen, -CN, C １ -C ８ Alkyl, C １ -C ８ Haloalkyl, C ２ -C ８ Alkenyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ cycloalkyl, 3- to 10-membered heterocycloalkyl, (C ６ -C １２ Aryl)-C ２ -C ８ Alkenyl-, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ Each of the compounds is selected from the group consisting of １ -C ３ Alkyl, -OR ａ , -NR ａ R ａ’ , -C(O)R ａ and -SR ａ or R ｂ１ But, R ｂ５ Or R ｂ６ and together with the intervening atoms form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring; R ｂ４ is selected from the group consisting of H or halogen; R ｂ５ is H, and R ｂ５’ But, C １ -C ８ Alkyl-O-C １ -C ８ alkyl or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: R ｂ６ is H or R ｂ１ and together with the intervening atoms form a carbocyclic or heterocyclic ring, R ａ and R ａ’ are each independently H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl-S(O) ２ -, C １ -C ６ Alkyl-C(O)-, C １ -C ６ Aminoalkyl-C(O)- and C １ -C ６ hydroxyalkyl-C(O)-, wherein D is selected from the group consisting of (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-7-ethyl-7-hydroxy-14- (Morpholinomethyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)piperazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4' :6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminopiperidin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione and tert-butyl(S)-(1-((7-ethyl) 2. The camptothecin conjugate of claim 1, provided that the camptothecin conjugate is not selected from the group consisting of: 1,3-dihydro-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)piperidin-4-yl)carbamate; or a salt of any of the above.

17. L-(Q-D) ｐ or a salt thereof, wherein L is a targeting agent, in particular a ligand unit derived from an antibody that selectively binds to a cancer cell antigen; the subscript p is an integer ranging from 1 to 16; Q, -Z-A-, -Z-A-RL-, -Z-A-RL-Y-, -Z-A-S ＊ -RL-, -Z-A-S ＊ -RL-Y-, -Z-A-S ＊ -W-, -Z-A-S ＊ -W-RL-, -Z-A-B(S ＊ )-RL-, -Z-A-B(S ＊ )-W-, -Z-A-B(S ＊ )-W-RL- and -Z-A-B(S ＊ )-RL-Y- is a linker unit having a formula selected from the group consisting of: In the formula, Z is a stretching unit, A is a bond or a linking unit; B is a parallel linked unit; S ＊ is a partitioning agent, R is a releasable linker; W is an amino acid unit, Y is a spacer unit; The camptothecin conjugate or salt thereof, wherein D is a drug unit D, D comprises a compound selected from Table I, or a salt thereof, and D is covalently attached to Q through any suitable attachment site on D, and optionally a hydrogen atom of a hydroxyl, thiol, primary amine or secondary amine of D is replaced with a bond to Q, or a tertiary amine of D is quaternized to form a bond to Q.

18. Q, -Z-ARL-, -Z-ARL-Y-, -Z-AS ＊ -RL-, -Z-AB(S ＊ )-RL-, -Z-AS ＊ -RL-Y- and -Z-AB(S ＊ )-RL-Y- is a linker unit having a formula selected from the group consisting of:

18. The camptothecin conjugate of any one of claims 1 to 17, wherein A is a linking unit and R L is a glycoside unit (e.g. a glucuronide unit).

19. The glycoside unit (e.g., glucuronide unit) is 【Chemical formula 244】 having the formula: Su is the hexose form of a monosaccharide; O' represents an oxygen atom of a glycosidic bond that can be cleaved by a glycosidase; A single asterisk ( ＊ ) indicates the site of covalent attachment to D; Two asterisks ( ＊＊ ) indicates the site of covalent attachment of Q to the remainder, Optionally, the glycoside unit (e.g., glucuronide unit) is 【Chemistry 245】 or Optionally, the glycoside unit (e.g., glucuronide unit) is 【Chemical formula 246】 20. The camptothecin conjugate of claim 18 having the formula:

20. The camptothecin conjugate of claims 1-16, wherein RL is present and is a peptide comprising 2-8 amino acids.

21. 21. The camptothecin conjugate of claim 20, wherein R L is a dipeptide.

22. 22. The camptothecin conjugate of claim 20 or 21, wherein R is val-ala, val-cit or val-lys.

23. Q is -Z-A-RL-Y-, -Z-A-S ＊ -RL-Y- or -Z-A-B(S ＊ )-RL-Y-, The spacer unit (Y) is 【Chemical 247】 where EWG is an electron withdrawing group; O ＊ represents the oxygen atom from the hydroxy substituent of D; the wavy line adjacent to the nitrogen atom indicates the site of covalent attachment to the carbonyl carbon atom of the glycosidic unit (e.g., a glucuronide unit); O ＊ The wavy line adjacent to indicates the site of covalent attachment of D to the remainder of the group, or The spacer unit (Y) is 【Chemical 248】 having the formula: EWG is an electron withdrawing group; the wavy line adjacent to the nitrogen atom indicates the site of a covalent bond to the carbonyl carbon atom of the glycosidic unit (e.g., a glucuronide unit); 20. The camptothecin conjugate of claim 18, wherein the wavy line adjacent to the carbonyl carbon atom indicates the site of the covalent bond to the nitrogen atom of the amino substituent of D.

24. 23. The camptothecin conjugate of claims 1-17 or 20-22, wherein Y is present and has the formula: 【Chemical 249】

25. Q, -Z-A-,-Z-A-S ＊ -W- and -Z-A-B(S ＊ )-W- wherein A is a linking unit; or Q, -Z-ARL-, -Z-AS ＊ -RL-, -Z-AB(S ＊ )-RL-, -Z-AS ＊ -W-RL- and -Z-AB(S ＊ )-W-RL- wherein A is a linking unit and R L is a releasable linker other than a glycoside unit (e.g. a glucuronide unit).

26. Q is -Z-A-RL-, -Z-A-S ＊ -RL- and -Z-A-S ＊ -W-RL-, wherein R.L. 【Chemistry 250】 having the formula: Two asterisks ( ＊＊ ) indicates the site of covalent attachment to D; A single asterisk ( ＊ The wavy lines with the letters A and S ＊ or W.

27. -Q-D is -Z-A-S ＊ -W-RL-D, wherein D is covalently bonded to Q via the nitrogen atom of the amine functional group of D; W is an amino acid unit selected from the group consisting of N-methyl-glycine (sarcosine), N-methyl-alanine, N-methyl-β-alanine, valine, N-methyl-valine; or D is covalently bonded to Q via the oxygen atom of a hydroxyl substituent on the lactone ring of D; 27. The camptothecin conjugate of claim 25 or 26, wherein W is an amino acid unit selected from the group consisting of glutamic acid or lysine.

28. -ZA- comprises a succinimide-alkanoyl moiety, or a succinimide moiety and a triazole moiety, each optionally having a succinimide ring in hydrolyzed form as a succinamide moiety, or a succinamide moiety derivable from the mDPR of a camptothecin-linker compound; or -Z-A-, 【Chemistry 251】 and optionally having a succinimide ring in hydrolyzed form as the succinamide moiety, wherein two asterisks ( ＊＊ The wavy line with the letter S ＊ The site of covalent binding to the ＊＊＊ 28. The camptothecin conjugate of claim 27, wherein the wavy line with the dashed line indicates the point of covalent attachment of L to the sulfur atom.

29. Q is -Z-A-S ＊ -RL- and -Z-A-S ＊ -W-RL-, wherein S ＊ but, 【Chemistry 252】 where subscript n is an integer ranging from 1 to 36; The wavy line adjacent to the nitrogen atom indicates the site of the covalent bond to the carbonyl carbon atom of A, and the dashed line adjacent to the carbonyl carbon atom indicates -Z-A-S. ＊ -RL-RL or -Z-A-S ＊ indicates the site of the covalent bond to the nitrogen atom of the amine functional group of W in -W-RL-; In particular, -Z A- in any of the formulas of Q is 【Chemistry 253】 where two asterisks ( ＊＊ The wavy line with the letter S ＊ indicates the site of the covalent bond to the nitrogen atom of the amine functional group of ＊＊＊ 16. The camptothecin conjugate of claim 15, wherein the wavy line with a dash () indicates the point of covalent attachment of L to the sulfur atom.

30. Q is a group represented by the formula -Z-A-S ＊ -W- or -Z-A-S-W-RL- linker unit, ＊ -W-, 【Chemical 254】 and optionally having a succinimide ring in hydrolyzed form as the succinamide moiety, where the subscript n is an integer ranging from 2 to 10, preferably an integer ranging from 2 to 4, and where the subscript n is an integer ranging from 2 to 4, and where the subscript n is an integer ranging from 2 to 4, and where the subscript n is an integer ranging from 2 to 4, ＊＊ ) indicates the covalent binding site to D or RL, and three asterisks ( ＊＊＊ 26. The camptothecin conjugate of claim 25, wherein the wavy line with the dashed dot ( ) indicates the point of covalent attachment of L to the sulfur atom.

31. (i) Z'-A-RL-D, (ii) Z'-A-RL-Y-D, (iii)Z’-A-S ＊ -RL-D、 (iv)Z’-A-S ＊ -RL-Y-D、 (v)Z’-A-B(S ＊ )-RL-D、 (vi)Z’-A-B(S ＊ )-RL-Y-D、 (vii) Z'-A-D, ( )) ＊ ____、 ())]'_______________ ＊ )? (x) Z'-A-S ＊ -W-RL-D and (xi)Z’-A-B(S ＊ )-W-RL-D A camptothecin-linker compound having a formula selected from the group consisting of: Z' is a stretch unit precursor; A is a bond or a linking unit; B is a parallel linked unit; S ＊ is a partitioning agent, R is a releasable linker; Y is a spacer unit; D is the following D ０ｂ Formula 【255】 or a salt thereof, wherein E is -OR ｂ５ Or -NR ｂ５ R ｂ５’ and R ｂ１ H, halogen, -CN, C １ -C ８ Alkyl, C １ -C ８ Haloalkyl, C ２ -C ８ Alkenyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ cycloalkyl, 3- to 10-membered heterocycloalkyl, (C ６ -C １２ Aryl)-C ２ -C ８ Alkenyl-, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ Each of the compounds is selected from the group consisting of １ -C ３ Alkyl, -OR ａ , -NR ａ R ａ’ , -C(O)R ａ and -SR ａ or R ｂ１ But, R ｂ２ , R ｂ５ Or R ｂ６ and together with the intervening atoms form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring; R ｂ２ H, halogen, C １ -C ８ Alkyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ Cycloalkyl, 3-10 membered heterocycloalkyl, C １ -C ８ Haloalkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-S(O) ２ -, C １ -C ８ Aminoalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-NR ａ -, C １ -C ８ Alkyl-NR ａ -C(O)O-, C １ -C ８ Alkyl-OC(O)-NR ａ -, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ and each is selected from the group consisting of: ａ , -NR ａ R ａ’ and -SR ａ or optionally replaced by R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring; or R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered heterocycle fused to a 6-membered aryl; R ｂ３ H, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Haloalkyl, -OR ａ , -NR ａ R ａ’ and -SR ａ is selected from the group consisting of R ｂ４ is selected from the group consisting of H or halogen; Each R ｂ５ and R ｂ５’ are independent, H, C １ -C ８ Alkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl, C １ -C ８ Aminoalkyl, (C １ -C ４ alkylamino)-C １ -C ８ Alkyl-, N,N-(C １ -C ４ Hydroxyalkyl) (C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, N,N-di(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, N-(C １ -C ４ Hydroxyalkyl)-C １ -C ８ Aminoalkyl-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Hydroxyalkyl-C(O)-, C １ -C ８ Aminoalkyl-C(O)-, C ３ -C １０ Cycloalkyl, (C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl-, C ３ -C １０ Heterocycloalkyl, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Alkyl-, C １ -C ６ Hydroxyalkyl-heteroaryl-, phenyl, phenyl-C １－ C ４ Alkyl-, diphenyl-C １ -C ４ Alkyl-, Heteroaryl, Heteroaryl-C １ -C ４ Alkyl-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ６ Alkoxy-C(O)-N-(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, C １ -C ４ Alkyl-SO ２ -C １ -C ８ Alkyl-, NH ２ -SO ２ -C １ -C ８ Alkyl-, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Hydroxyalkyl, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, phenyl-C(O)-, phenyl-SO ２ - and C １ -C ８ Hydroxyalkyl-C ３ -C １０ heterocycloalkyl- or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ is H, and R ｂ５ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: R ｂ６ is H or R ｂ１ and together with the intervening atoms form a carbocyclic or heterocyclic ring, R ａ and R ａ’ are each independently H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl-S(O) ２ -, C １ -C ６ Alkyl-C(O)-, C １ -C ６ Aminoalkyl-C(O)- and C １ -C ６ hydroxyalkyl-C(O)-; a) R ｂ２ But, R ｂ３ and together with the intervening atoms form a 1,3-dioxolane, and E is -NR ｂ５ R ｂ５’ When ｂ５ and R ｂ５’ are independent, H, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-C(O)(C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl-, C ３ -C １０ Heterocycloalkyl, C １ -C ６ Hydroxyalkyl-heteroaryl-, heteroaryl, heteroaryl-C １ -C ４ Alkyl-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ６ Alkoxy-C(O)-N-(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, C １ -C ４ Alkyl-SO ２ -C １ -C ８ Alkyl-, NH ２ -SO ２ -C １ -C ８ Alkyl-, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Hydroxyalkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, phenyl-C(O)-, phenyl-SO ２ - and C １ -C ８ Hydroxyalkyl-C ３ -C １０ heterocycloalkyl- or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ is H, and R ｂ５ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: b) R ｂ２ But, R ｂ３ and when combined with the intervening atoms to form 1,3-dioxolane, E is not -OH, c) R ｂ２ is methyl, R ｂ３ When is F, R ｂ１ But, R ｂ６ and does not form a ring together with the intervening atoms, d) D is not (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione or (S)-7-ethyl-7-hydroxy-14-(morpholinomethyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, or a salt of any of the above; The camptothecin-linker compound wherein D is covalently attached to the remainder of the camptothecin-linker compound through any suitable attachment site on D, and optionally a hydrogen atom of a hydroxyl, thiol, primary amine or secondary amine of D is replaced with a bond to the remainder of the camptothecin-linker compound, or a tertiary amine of D is quaternized to form a bond to the remainder of the camptothecin-linker compound.

32. D. 【256】 or a salt thereof, wherein the dagger indicates the site of covalent attachment of D to the remainder of the camptothecin-linker compound, or R ｂ５ a hydrogen atom of a hydroxyl, thiol, primary amine or secondary amine of R is replaced by a bond to the remainder of the camptothecin-linker compound, or ｂ５ is quaternized to form a bond to the remainder of the camptothecin-linker compound.

33. D. 【Chemistry 257】 【Chemistry 258】 or a salt thereof, wherein the dagger indicates the site of covalent attachment of D to the remainder of the camptothecin-linker compound, or R ｂ５ a hydrogen atom of a hydroxyl, thiol, primary amine or secondary amine of R is replaced by a bond to the remainder of the camptothecin-linker compound, or ｂ５ is quaternized to form a bond to the remainder of the camptothecin-linker compound.

34. D. 【Chemical 259】 or a salt thereof, wherein X and Y Ｂ are each independently O, S, or S(O) ２ , C.R. ｘ R ｘ’ Or N.R. ｘ and R ｘ and R ｘ’ are each independently H, OH, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Aminoalkyl-C(O)-, C １ -C ６ Alkyl-C(O)-, C １ -C ６ Hydroxyalkyl-C(O)-, C １ -C ６ Alkyl-NH-C(O)- or C １ -C ６ Alkyl-S(O) ２ - selected from the group consisting of m and n are each 1 or 2; Each R ｃ１ , R ｃ１’ , R ｃ２ and R ｃ２’ became independent, (i) H, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, -OR ａ , -NR ａ R ａ’ , -SR ａ , C １ -C ６ Alkyl-C(O)-, C １ -C ６ Alkyl-NR ａ -C(O)- and C １ -C ６ Alkyl-S(O) ２ - or is selected from the group consisting of (ii) together with Rb1 and the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; or (iii) R ｘ’ and together with the intervening atoms form a 3- to 6-membered carbocyclic or heterocyclic ring, when m and n are both present, the sum of m+n is 2 or 3; The dagger indicates the site of covalent attachment of D to the remainder of the camptothecin-linker compound, or R ｂ５ a hydrogen atom of a hydroxyl, thiol, primary amine or secondary amine of R is replaced by a bond to the remainder of the camptothecin-linker compound, or ｂ５ is quaternized to form a bond to the remainder of the camptothecin-linker compound.

35. D. 【Chemistry 260】 or a salt thereof, wherein R ｄ１ , R ｄ１’ , R ｄ２ and R ｄ２’ are each independently H, a halogen, or C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ａ , -NR ａ R ａ’ , -SR ａ , C １ -C ６ Alkyl-C(O)-, C １ -C ６ Alkyl-NR ａ -C(O)- and C １ -C ６ Alkyl-S(O) ２ - selected from the group consisting of 33. The camptothecin-linker compound of claim 32, wherein the dagger indicates the site of covalent attachment of D to the remainder of the camptothecin-linker compound.

36. D. 【Chemical 261】 or a salt thereof, wherein Y １ is a 5- or 6-membered heteroaryl; halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl or C １ -C ６ Alkyl-S(O) ２ is optionally substituted with -, 33. The camptothecin-linker compound of claim 32, wherein the dagger indicates the site of covalent attachment of D to the remainder of the camptothecin-linker compound.

37. D. 【Chemical 262】 or a salt thereof, wherein Each R ｅ are independently halogen, —OH, —NH ２ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Alkyl-S(O) ２ - and C １ -C ６ Alkyl-NR ａ -C(O)-, where f is 0, 1, 2, 3, 4 or 5; 32. The camptothecin-linker compound of claim 31, wherein the dagger indicates the site of covalent attachment of D to the remainder of the camptothecin-linker compound.

38. D. 【Chemical 263】 or a salt thereof, wherein R ｇ But, H, C １ -C ６ alkyl or 3-8 membered heterocyclyl; 33. The camptothecin-linker compound of claim 32, wherein the dagger indicates the site of covalent attachment of D to the remainder of the camptothecin-linker compound.

39. D. 【Chemical Formula 264】 or a salt thereof, wherein R ３ｈ , R ３ｈ’ and R ３ｈ’’ are each independently H, C １ -C ６ Alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, —C(O)—C １ -C ６ Alkyl, —C(O)O—C １ -C ６ Alkyl, -C(O)NH-C １ -C ６ Alkyl, C ６ -C １０ Aryl, -C ６ -C １０ Aryl-C １ -C ６ Alkyl and -C ６ -C １０ Aryl-C １ -C ６ alkoxy, each of which is selected from the group consisting of C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ａ , -NR ａ R ａ’ and -SR ａ is optionally replaced by 33. The camptothecin-linker compound of claim 32, wherein the dagger indicates the site of covalent attachment of D to the remainder of the camptothecin-linker compound.

40. D. 【Chemistry 265】 or a salt thereof, 33. The camptothecin-linker compound of claim 32, wherein the dagger indicates the site of covalent attachment of D to the remainder of the camptothecin-linker compound.

41. D is the following D ０ｂ -I formula 【Chemical 266】 or a salt thereof, wherein R ｂ２ But, R ｂ３ and, when combined with the intervening atoms to form a 5-, 6-, or 7-membered heterocycle, said heterocycle has no more than one O.

42. D is the following D ０ｂ Formula II 【Chemical 267】 or a salt thereof, wherein R ｂ５’ But, H, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-C(O)(C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl-, C ３ -C １０ Heterocycloalkyl, C １ -C ６ Hydroxyalkyl-heteroaryl-, heteroaryl, heteroaryl-C １ -C ４ Alkyl-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ６ Alkoxy-C(O)-N-(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, C １ -C ４ Alkyl-SO ２ -C １ -C ８ Alkyl-, NH ２ -SO ２ -C １ -C ８ Alkyl-, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Hydroxyalkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, phenyl-C(O)-, phenyl-SO ２ - and C １ -C ８ Hydroxyalkyl-C ３ -C １０ heterocycloalkyl- or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ with the proviso that D is not (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione or (S)-7-ethyl-7-hydroxy-14-(morpholinomethyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, or a salt of any of the foregoing.

43. D is the following D ０ｂ Formula III 【Chemical 268】 32. The camptothecin-linker compound of claim 31 , comprising:

44. D is the following D ０ａ -I formula 【Chemical 269】 or a salt thereof, wherein E is -OR ｂ５ Or -NR ｂ５ R ｂ５’ and R ｂ１ H, halogen, -CN, C １ -C ８ Alkyl, C １ -C ８ Haloalkyl, C ２ -C ８ Alkenyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ cycloalkyl, 3- to 10-membered heterocycloalkyl, (C ６ -C １２ Aryl)-C ２ -C ８ Alkenyl-, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ Each of the compounds is selected from the group consisting of １ -C ３ Alkyl, -OR ａ , -NR ａ R ａ’ , -C(O)R ａ and -SR ａ or R ｂ１ But, R ｂ２ , R ｂ５ Or R ｂ６ and together with the intervening atoms form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring; R ｂ２ H, halogen, C １ -C ８ Alkyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ Cycloalkyl, 3-10 membered heterocycloalkyl, C １ -C ８ Haloalkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-S(O) ２ -, C １ -C ８ Aminoalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-NR ａ -, C １ -C ８ Alkyl-NR ａ -C(O)O-, C １ -C ８ Alkyl-OC(O)-NR ａ -, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ and each is selected from the group consisting of: ａ , -NR ａ R ａ’ and -SR ａ or optionally replaced by R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring, or R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered heterocycle fused to a 6-membered aryl; R ｂ３ H, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Haloalkyl, -OR ａ , -NR ａ R ａ’ and -SR ａ or R ｂ３ But, R ｂ２ and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring, or a 5-membered heterocyclic ring fused to a 6-membered aryl; R ｂ４ is selected from the group consisting of H and halogens; Each R ｂ５ and R ｂ５’ are independent, H, C １ -C ８ Alkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl, C １ -C ８ Aminoalkyl, (C １ -C ４ alkylamino)-C １ -C ８ Alkyl-, N,N-(C １ -C ４ Hydroxyalkyl) (C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, N,N-di(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, N-(C １ -C ４ Hydroxyalkyl)-C １ -C ８ Aminoalkyl-, C １ -C ８ Hydroxyalkyl-C(O)-, C ３ -C １０ Cycloalkyl, (C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl, C ３ -C １０ Heterocycloalkyl, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Alkyl-, Heteroaryl-C １ -C ６ Hydroxyalkyl, phenyl, phenyl-C １－ C ４ Alkyl-, diphenyl-C １ -C ４ Alkyl-, Heteroaryl, Heteroaryl-C １ -C ４ Alkyl-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ６ Alkoxy-C(O)-N-(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, C １ -C ４ Alkyl-SO ２ -C １ -C ８ Alkyl-, NH ２ -SO ２ -C １ -C ８ Alkyl-, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Hydroxyalkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, phenyl-C(O)-, phenyl-SO ２ - and C １ -C ８ Hydroxyalkyl-C ３ -C １０ heterocycloalkyl- or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ is H, and R ｂ５ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: R ｂ６ is H or R ｂ１ and together with the intervening atoms form a carbocyclic or heterocyclic ring, R ａ and R ａ’ are each independently H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl-S(O) ２ -, C １ -C ６ Alkyl-C(O)-, C １ -C ６ Aminoalkyl-C(O)- and C １ -C ６ hydroxyalkyl-C(O)-; a) R ｂ２ But, R ｂ３ and together with the intervening atoms form a 1,3-dioxolane, and E is -NR ｂ５ R ｂ５’ When ｂ５ and R ｂ５’ are independent, H, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-C(O)(C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl-, C ３ -C １０ Heterocycloalkyl, C １ -C ６ Hydroxyalkyl-heteroaryl-, heteroaryl, heteroaryl-C １ -C ４ Alkyl-, phenyl-C(O)- and phenyl-SO ２ -, or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ is H, and R ｂ５ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: b) R ｂ２ But, R ｂ３ and, when combined with the intervening atoms to form 1,3-dioxolane, E is not -OH; and c) E is NH ２ When R ｂ１ is -CN, 5-12 membered heteroaryl having at least one N in the ring, 3-10 membered heterocycloalkyl having at least one N in the ring, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -NR ａ R ａ’ and -SR ａ Each of the compounds is selected from the group consisting of １ -C ３ Alkyl, -OR ａ , -NR ａ R ａ’ , -C(O)R ａ and -SR ａ or R ｂ１ But, R ｂ２ and together with the intervening atoms form a 5-, 6-, or 7-membered heterocycle having at least one N in the ring, or a 5-membered heterocycle fused to a 6-membered aryl; R ｂ２ H, halogen, C １ -C ８ Alkyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ Cycloalkyl, 3-10 membered heterocycloalkyl, C １ -C ８ Haloalkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-S(O) ２ -, C １ -C ８ Aminoalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-NR ａ -, C １ -C ８ Alkyl-NR ａ -C(O)O-, C １ -C ８ Alkyl-OC(O)-NR ａ -, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ and each is selected from the group consisting of: ａ , -NR ａ R ａ’ and -SR ａ optionally replaced by, or R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered heterocyclic ring having at least one N in the ring, or R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered heterocycle fused to a 6-membered aryl; d) R ｂ２ is —OH or methyl, and R ｂ３ When is F, R ｂ１ But, R ｂ５ , R ｂ５’ Or R ｂ６ does not, together with the intervening atoms, form a ring; e) D is (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-7-ethyl-7-hydroxy-14-(morpholinomethyl)-10,13-dihydro-1 1H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)piperazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1 ,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminopiperidin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione and tert-butyl(S)-(1-((7-ethyl-7- 32. The camptothecin-linker compound of claim 31, which is not selected from the group consisting of hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)piperidin-4-yl)carbamate, or a salt of any of the foregoing.

45. D is the following D ０ Formula of -I' 【Chemistry 270】 or a salt thereof, ｂ２ But, R ｂ３ and, when combined with the intervening atoms to form a 5-, 6-, or 7-membered heterocycle, said heterocycle has no more than one O.

45. [Claim 45a] D is the following D ０ Formula III' 【Chemistry 271】 or a salt thereof, wherein R ｂ１ H, halogen, -CN, C １ -C ８ Alkyl, C １ -C ８ Haloalkyl, C ２ -C ８ Alkenyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ cycloalkyl, 3- to 10-membered heterocycloalkyl, (C ６ -C １２ Aryl)-C ２ -C ８ Alkenyl-, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ Each of the compounds is selected from the group consisting of １ -C ３ Alkyl, -OR ａ , -NR ａ R ａ’ , -C(O)R ａ and -SR ａ or R ｂ１ But, R ｂ５ Or R ｂ６ and together with the intervening atoms form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring; R ｂ４ is selected from the group consisting of H or halogen; R ｂ５’ But, C １ -C ８ Alkyl-O-C １ -C ８ alkyl or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５ is H, and Rb5′ is R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: R ｂ６ is H or R ｂ１ and together with the intervening atoms form a carbocyclic or heterocyclic ring, R ａ and R ａ’ are each independently H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl-S(O) ２ -, C １ -C ６ Alkyl-C(O)-, C １ -C ６ Aminoalkyl-C(O)- and C １ -C ６ hydroxyalkyl-C(O)-; provided that D is (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-7-ethyl-7-hydroxy-14-(morpholinomethyl)-10,13-dihydro-1 1H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)piperazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2- b]quinoline-8,11(7H)-dione, (S)-14-((4-aminopiperidin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione and tert-butyl(S)-(1-((7-ethyl-7-hydroxy 32. The camptothecin-linker compound of claim 31, provided that the camptothecin-linker compound is not selected from the group consisting of: -8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)piperidin-4-yl)carbamate, or a salt of any of the foregoing.

46. (i) Z'-A-RL-D, (ii) Z'-A-RL-Y-D, (iii)Z’-A-S ＊ -RL-D、 (iv)Z’-A-S ＊ -RL-Y-D、 (v)Z’-A-B(S ＊ )-RL-D、 (vi)Z’-A-B(S ＊ )-RL-Y-D、 (vii) Z'-A-D, ( )) ＊ ____、 ())]'_______________ ＊ )? (x) Z'-A-S ＊ -W-RL-D and (xi)Z’-A-B(S ＊ )-W-RL-D A camptothecin-linker compound of the formula: Z' is a stretch unit precursor; A is a bond or a linking unit; B is a parallel linked unit; S ＊ is a partitioning agent, R is a releasable linker; Y is a spacer unit; D is a Drug unit D, D comprises a compound selected from Table I or a salt thereof, D is covalently attached to the remainder of the camptothecin-linker compound through any suitable attachment site on D, and optionally, a hydrogen atom of a hydroxyl, thiol, primary amine or secondary amine of D is replaced with a bond to the remainder of the camptothecin-linker compound or a tertiary amine of D is quaternized to form a bond to the remainder of the camptothecin-linker compound.

47. A compound having a formula selected from the group consisting of formula (i), formula (ii), formula (iii), formula (iv), formula (v) and formula (vi), wherein A is a linking unit and R is a glycoside unit (e.g., a glucuronide unit), and optionally the glycoside unit is 【Chemical 272】 or optionally, the glycosidic unit has the formula: 【Chemical 273】 where in the formula is an asterisk ( ＊ ) indicates the site of covalent attachment to a D or spacer unit (Y), and two asterisks ( ＊＊ The wavy lines with the letters A, B, or S ＊ 47. A camptothecin-linker compound according to any one of claims 31 to 46, exhibiting a point of covalent attachment to:

48. The camptothecin-linker compound of claims 31-46, wherein RL is present and is a peptide containing from 2 to 8 amino acids.

49. 49. The camptothecin-linker compound of claim 48, wherein R L is a dipeptide.

50. 50. The camptothecin-linker compound of claim 48 or 49, wherein R L is val-ala, val-cit, or val-lys.

51. Formula (iii), formula (iv), formula (v) and formula (vi), wherein ＊ The camptothecin-linker compound of any one of claims 31 to 46, wherein is a PEG group.

52. having the formula (ii), (iv) or (vi), The spacer unit (Y) is 【Chemical 274】 where EWG is an electron withdrawing group; O ＊ represents an oxygen atom derived from a hydroxy functional group of D, the wavy line adjacent to the nitrogen atom indicates the site of a covalent bond to the carbonyl carbon atom of the glycosidic unit (e.g., a glucuronide unit); O ＊ The wavy line adjacent to indicates the site of covalent attachment of D to the remainder of the group, or The spacer unit (Y) is 【Chemistry 275】 having the formula: EWG is an electron withdrawing group; the wavy line adjacent to the nitrogen atom indicates the site of a covalent bond to the carbonyl carbon atom of the glycosidic unit (e.g., a glucuronide unit); 47. The camptothecin-linker compound of any one of claims 31 to 46, wherein the wavy line adjacent to the carbonyl carbon atom indicates the site of the covalent bond to the nitrogen atom of the amine functionality of D.

53. 51. The camptothecin-linker compound of any one of claims 31-46 or 48-50, wherein Y is present and has the formula: 【Chemical 276】

54. 47. The camptothecin-linker compound of any one of claims 31 to 46, having formula (vii), (viii) or (ix) where A is a linking unit, or having formula (i), (iii), (x) or (xi) where A is a linking unit and R L is a releasable linker other than a glycoside unit (e.g. a glucuronide unit).

55. having the formula (i), (iii) or (x), RL has the formula 【Chemical 277】 During the ceremony, Two asterisks ( ＊＊ ) indicates the site of covalent attachment to D; A single asterisk ( ＊ The wavy lines with the letters A and S ＊ or W.

56. 56. The camptothecin-linker compound of claim 55, having the formula (x), wherein W is an amino acid unit selected from the group consisting of N-methyl-glycine (sarcosine), N-methyl-alanine, N-methyl-β-alanine, valine, and N-methyl-valine.

57. 57. The camptothecin-linker compound of any one of claims 54 to 56, wherein Z'-A- is composed of a maleimido-alkanoyl moiety or mDPR, the basic nitrogen atom of which is optionally protonated or protected by an acid-labile protecting group.

58. having the formula (iii) or formula (x), Z'-A- is 【Chemical 278】 wherein the formula is selected from the group consisting of: ＊＊ The wavy line with the letter S ＊ 57. The camptothecin-linker compound of any one of claims 54 to 56, which exhibits a site of covalent attachment to

59. having the formula (iii) or formula (x), S ＊ but, 【Chemical 279】 57. The camptothecin-linker compound of any one of claims 54 to 56, having the formula:

60. A camptothecin-linker compound of formula (viii) or formula (x), ＊ -W-, 【Chemistry 280】 wherein the subscript n is an integer ranging from 2 to 10, preferably an integer ranging from 2 to 4, and two asterisks ( ＊＊ 56. The camptothecin-linker compound of claim 54 or 55, wherein the wavy line with the dashed dash (+) indicates the site of covalent attachment to D or RL.

61. 31. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a camptothecin conjugate according to any one of claims 1 to 30, optionally wherein the cancer is selected from the group consisting of lymphoma, leukemia and solid tumors, optionally lymphoma or leukemia.

62. 31. Use of a camptothecin conjugate according to any one of claims 1 to 30 in the preparation of a medicament for treating cancer in a subject, optionally wherein the cancer is selected from the group consisting of lymphoma, leukemia and solid tumors, optionally lymphoma or leukemia.

63. A pharma- ceutically acceptable composition comprising the camptothecin conjugate of any one of claims 1 to 30 and at least one pharma- ceutically acceptable excipient.

64. 31. A composition for treating cancer in a subject in need thereof, said composition comprising an effective amount of a camptothecin conjugate according to any one of claims 1 to 30, optionally wherein the cancer is selected from the group consisting of lymphoma, leukemia and solid tumors, optionally lymphoma or leukemia.

65. The following formula D ０ｂ 【Chemistry 281】 or a salt thereof, wherein E is -OR ｂ５ Or -NR ｂ５ R ｂ５’ and R ｂ１ H, halogen, -CN, C １ -C ８ Alkyl, C １ -C ８ Haloalkyl, C ２ -C ８ Alkenyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ cycloalkyl, 3- to 10-membered heterocycloalkyl, (C ６ -C １２ Aryl)-C ２ -C ８ Alkenyl-, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ Each of the compounds is selected from the group consisting of １ -C ３ Alkyl, -OR ａ , -NR ａ R ａ’ , -C(O)R ａ and -SR ａ or R ｂ１ But, R ｂ２ , R ｂ５ Or R ｂ６ and together with the intervening atoms form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring; R ｂ２ H, halogen, C １ -C ８ Alkyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ Cycloalkyl, 3-10 membered heterocycloalkyl, C １ -C ８ Haloalkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-S(O) ２ -, C １ -C ８ Aminoalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-NR ａ -, C １ -C ８ Alkyl-NR ａ -C(O)O-, C １ -C ８ Alkyl-OC(O)-NR ａ -, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ and each is selected from the group consisting of: ａ , -NR ａ R ａ’ and -SR ａ or optionally replaced by R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring; or R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered heterocycle fused to a 6-membered aryl; R ｂ３ H, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Haloalkyl, -OR ａ , -NR ａ R ａ’ and -SR ａ is selected from the group consisting of R ｂ４ is selected from the group consisting of H or halogen; Each R ｂ５ and R ｂ５’ are independent, H, C １ -C ８ Alkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl, C １ -C ８ Aminoalkyl, (C １ -C ４ alkylamino)-C １ -C ８ Alkyl-, N,N-(C １ -C ４ Hydroxyalkyl) (C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, N,N-di(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, N-(C １ -C ４ Hydroxyalkyl)-C １ -C ８ Aminoalkyl-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Hydroxyalkyl-C(O)-, C １ -C ８ Aminoalkyl-C(O)-, C ３ -C １０ Cycloalkyl, (C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl-, C ３ -C １０ Heterocycloalkyl, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Alkyl-, C １ -C ６ Hydroxyalkyl-heteroaryl-, phenyl, phenyl-C １－ C ４ Alkyl-, diphenyl-C １ -C ４ Alkyl-, Heteroaryl, Heteroaryl-C １ -C ４ Alkyl, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ６ Alkoxy-C(O)-N-(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, C １ -C ４ Alkyl-SO ２ -C １ -C ８ Alkyl-, NH ２ -SO ２ -C １ -C ８ Alkyl-, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Hydroxyalkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, phenyl-C(O)-, phenyl-SO ２ - and C １ -C ８ Hydroxyalkyl-C ３ -C １０ heterocycloalkyl- or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ is H, and R ｂ５ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: R ｂ６ is H or R ｂ１ and together with the intervening atoms form a carbocyclic or heterocyclic ring, R ａ and R ａ’ are each independently H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl-S(O) ２ -, C １ -C ６ Alkyl-C(O)-, C １ -C ６ Aminoalkyl-C(O)- and C １ -C ６ hydroxyalkyl-C(O)-; a) R ｂ２ But, R ｂ３ and together with the intervening atoms form a 1,3-dioxolane, and E is -NR ｂ５ R ｂ５’ When ｂ５ and R ｂ５’ are independent, H, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-C(O)(C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl-, C ３ -C １０ Heterocycloalkyl, C １ -C ６ Hydroxyalkyl-heteroaryl-, heteroaryl, heteroaryl-C １ -C ４ Alkyl-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ６ Alkoxy-C(O)-N-(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, C １ -C ４ Alkyl-SO ２ -C １ -C ８ Alkyl-, NH ２ -SO ２ -C １ -C ８ Alkyl-, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Hydroxyalkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, phenyl-C(O)-, phenyl-SO ２ - and C １ -C ８ Hydroxyalkyl-C ３ -C １０ heterocycloalkyl- or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl and C １ -C ８ forming a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ is H, and R ｂ５ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: b) R ｂ２ But, R ｂ３ and when combined with the intervening atoms to form 1,3-dioxolane, E is not -OH, c) R ｂ２ is methyl, R ｂ３ When is F, R ｂ１ But, R ｂ６ and does not form a ring together with the intervening atoms, d) The compound or a salt thereof, wherein D is not (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione or (S)-7-ethyl-7-hydroxy-14-(morpholinomethyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, or any salt thereof.

66. The compound is represented by the following formula D ０ｂ -I formula 【Chemical 282】 or a salt thereof, wherein R ｂ２ But, R ｂ３ and, together with the intervening atoms, form a 5-, 6-, or 7-membered heterocycle, said heterocycle having no more than one O.

67. D is the following D ０ｂ Formula II 【Chemistry 283】 or a salt thereof, wherein R ｂ５ is H, and R ｂ５’ But, H, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-C(O)(C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl, C ３ -C １０ Heterocycloalkyl, C １ -C ６ Hydroxyalkyl-heteroaryl-, heteroaryl, heteroaryl-C １ -C ４ Alkyl-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ６ Alkoxy-C(O)-N-(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, C １ -C ４ Alkyl-SO ２ -C １ -C ８ Alkyl-, NH ２ -SO ２ -C １ -C ８ Alkyl-, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Hydroxyalkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, phenyl-C(O)-, phenyl-SO ２ - and C １ -C ８ Hydroxyalkyl-C ３ -C １０ heterocycloalkyl- or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ with the proviso that D is not (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione or (S)-7-ethyl-7-hydroxy-14-(morpholinomethyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, or a salt of any of the foregoing.

68. The following D ０ｂ Formula III 【Chemical 284】 66. The compound of claim 65, having the formula:

69. The compound is represented by the following formula D ０ａ -I formula 【Chemistry 285】 or a salt thereof, wherein E is -OR ｂ５ Or -NR ｂ５ R ｂ５’ and R ｂ１ H, halogen, -CN, C １ -C ８ Alkyl, C １ -C ８ Haloalkyl, C ２ -C ８ Alkenyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ cycloalkyl, 3- to 10-membered heterocycloalkyl, (C ６ -C １２ Aryl)-C ２ -C ８ Alkenyl-, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ Each of the compounds is selected from the group consisting of １ -C ３ Alkyl, -OR ａ , -NR ａ R ａ’ , -C(O)R ａ and -SR ａ or R ｂ１ But, R ｂ２ , R ｂ５ Or R ｂ６ and together with the intervening atoms form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring; R ｂ２ H, halogen, C １ -C ８ Alkyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ Cycloalkyl, 3-10 membered heterocycloalkyl, C １ -C ８ Haloalkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-S(O) ２ -, C １ -C ８ Aminoalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-NR ａ -, C １ -C ８ Alkyl-NR ａ -C(O)O-, C １ -C ８ Alkyl-OC(O)-NR ａ -, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ and each is selected from the group consisting of: ａ , -NR ａ R ａ’ and -SR ａ or optionally replaced by R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring, or R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered heterocycle fused to a 6-membered aryl; R ｂ３ H, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C １ -C ６ Haloalkyl, -OR ａ , -NR ａ R ａ’ and -SR ａ or R ｂ３ But, R ｂ２ and together with the intervening atoms form a 5- or 6-membered carbocyclic or heterocyclic ring, or a 5-membered heterocyclic ring fused to a 6-membered aryl; R ｂ４ is selected from the group consisting of H and halogens; Each R ｂ５ and R ｂ５’ are independent, H, C １ -C ８ Alkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl, C １ -C ８ Aminoalkyl, (C １ -C ４ alkylamino)-C １ -C ８ Alkyl-, N,N-(C １ -C ４ Hydroxyalkyl) (C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, N,N-di(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, N-(C １ -C ４ Hydroxyalkyl)-C １ -C ８ Aminoalkyl-, C １ -C ８ Hydroxyalkyl-C(O)-, C ３ -C １０ Cycloalkyl, (C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl-, C ３ -C １０ Heterocycloalkyl, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Alkyl-, Heteroaryl-C １ -C ６ Hydroxyalkyl, phenyl, phenyl-C １－ C ４ Alkyl-, diphenyl-C １ -C ４ Alkyl-, Heteroaryl, Heteroaryl-C １ -C ４ Alkyl, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ６ Alkoxy-C(O)-N-(C １ -C ４ Alkyl)amino-C １ -C ８ Alkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, C １ -C ４ Alkyl-SO ２ -C １ -C ８ Alkyl-, NH ２ -SO ２ -C １ -C ８ Alkyl-, (C ３ -C １０ Heterocycloalkyl)-C １－ C ４ Hydroxyalkyl-, C １ -C ６ Alkoxy-C(O)-(C ３ -C １０ Heterocycloalkyl)-C １ -C ８ Alkyl-, phenyl-C(O)-, phenyl-SO ２ - and C １ -C ８ Hydroxyalkyl-C ３ -C １０ heterocycloalkyl- or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ is H, and R ｂ５ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: R ｂ６ is H or R ｂ１ and together with the intervening atoms form a carbocyclic or heterocyclic ring, R ａ and R ａ’ are each independently H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl-S(O) ２ -, C １ -C ６ Alkyl-C(O)-, C １ -C ６ Aminoalkyl-C(O)- and C １ -C ６ hydroxyalkyl-C(O)-; a) R ｂ２ But, R ｂ３ and together with the intervening atoms form a 1,3-dioxolane, and E is -NR ｂ５ R ｂ５’ When ｂ５ and R ｂ５’ are independent, H, C １ -C ８ Alkyl-O-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-C(O)(C ３ -C １０ Cycloalkyl)-C １ -C ４ Alkyl-, C ３ -C １０ Heterocycloalkyl, C １ -C ６ Hydroxyalkyl-heteroaryl-, heteroaryl, heteroaryl-C １ -C ４ Alkyl-, phenyl-C(O)- and phenyl-SO ２ -, or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ is H, and R ｂ５ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: b) R ｂ２ But, R ｂ３ and, when combined with the intervening atoms to form 1,3-dioxolane, E is not -OH; and c) E is NH ２ When R ｂ１ is -CN, 5-12 membered heteroaryl having at least one N in the ring, 3-10 membered heterocycloalkyl having at least one N in the ring, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -NR ａ R ａ’ and -SR ａ Each of the compounds is selected from the group consisting of １ -C ３ Alkyl, -OR ａ , -NR ａ R ａ’ , -C(O)R ａ and -SR ａ or R ｂ１ But, R ｂ２ and together with the intervening atoms form a 5-, 6-, or 7-membered heterocycle having at least one N in the ring, or a 5-membered heterocycle fused to a 6-membered aryl; R ｂ２ H, halogen, C １ -C ８ Alkyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ Cycloalkyl, 3-10 membered heterocycloalkyl, C １ -C ８ Haloalkyl, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-S(O) ２ -, C １ -C ８ Aminoalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-NR ａ -, C １ -C ８ Alkyl-NR ａ -C(O)O-, C １ -C ８ Alkyl-OC(O)-NR ａ -, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ and each is selected from the group consisting of: ａ , -NR ａ R ａ’ and -SR ａ optionally replaced by, or R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered heterocyclic ring having at least one N in the ring, or R ｂ２ But, R ｂ１ Or R ｂ３ and together with the intervening atoms form a 5- or 6-membered heterocycle fused to a 6-membered aryl; d) R ｂ２ is —OH or methyl, and R ｂ３ When is F, R ｂ１ But, R ｂ５ , R ｂ５’ Or R ｂ６ does not, together with the intervening atoms, form a ring; e) D is (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-7-ethyl-7-hydroxy-14-(morpholinomethyl)-10,13-dihydro 11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)piperazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione dolidino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminopiperidin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione and tert-butyl(S)-(1-( 66. The compound of claim 65, which is not selected from the group consisting of (7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)piperidin-4-yl)carbamate, or a salt of any of the foregoing.

70. The compound is represented by the following formula D ０ Formula of -I' 【Chemistry 286】 or a salt thereof, In the formula, R ｂ２ But, R ｂ３ and, when combined with the intervening atoms to form a 5-, 6-, or 7-membered heterocycle, said heterocycle has no more than one O.

71. The compound is represented by the following formula D ０ Formula III' 【Chemistry 287】 or a salt thereof, wherein R ｂ１ H, halogen, -CN, C １ -C ８ Alkyl, C １ -C ８ Haloalkyl, C ２ -C ８ Alkenyl, C ２ -C ８ Alkynyl, C ６ -C １２ Aryl, 5-12 membered heteroaryl, C ３ -C １０ cycloalkyl, 3- to 10-membered heterocycloalkyl, (C ６ -C １２ Aryl)-C ２ -C ８ Alkenyl-, C １ -C ８ Hydroxyalkyl, C １ -C ８ Alkyl-C(O)-C １ -C ８ Aminoalkyl-, C １ -C ８ Aminoalkyl-C(O)-C １ -C ８ Alkyl-, C １ -C ８ Alkyl-NR ａ -C(O)-, C １ -C ８ Alkyl-C(O)-, C １ -C ８ Alkyl-OC(O)-, C ６ -C １２ Aryl-C(O)-, C ６ -C １２ Aryl-O—C(O)—NR ａ -, C ６ -C １２ Aryl-NR ａ -C(O)-O-, -COOR ａ , -OR ａ , -NR ａ R ａ’ and -SR ａ Each of the compounds is selected from the group consisting of １ -C ３ Alkyl, -OR ａ , -NR ａ R ａ’ , -C(O)R ａ and -SR ａ or R ｂ１ But, R ｂ５ Or R ｂ６ and together with the intervening atoms form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring; R ｂ４ is selected from the group consisting of H or halogen; R ｂ５’ But, C １ -C ８ Alkyl-O-C １ -C ８ alkyl or R ｂ５ and R ｂ５’ are, together with the nitrogen atom to which they are attached, independently a halogen, C １－ C ４ Alkyl, -OH, -C １ -C ６ Hydroxyalkyl, -OC １ -C ４ Alkyl, -NH ２ , -NH-C １ -C ４ Alkyl, -N(C １ -C ４ Alkyl) ２ , C １ -C ６ Alkoxy-C(O)-NH-, C １ -C ６ Alkoxy-C(O)-C １ -C ８ Aminoalkyl- and C １ -C ８ forming a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents selected from the group consisting of aminoalkyl; R ｂ５’ But, R ｂ１ and together with the intervening atoms form a 5- to 7-membered carbocyclic or heterocyclic ring; R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ and R ｂ５’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl moieties of １ -C ４ Alkyl, -OH, -OC １ -C ４ Alkyl, -NH ２ , -NHC １ -C ４ Alkyl and -N(C １ -C ４ Alkyl) ２ and is substituted with 0 to 3 substituents selected from the group consisting of: R ｂ６ is H or R ｂ１ and together with the intervening atoms form a carbocyclic or heterocyclic ring, R ａ and R ａ’ are each independently H, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkyl-S(O) ２ -, C １ -C ６ Alkyl-C(O)-, C １ -C ６ Aminoalkyl-C(O)- and C １ -C ６ hydroxyalkyl-C(O)-, where D is selected from the group consisting of (S)-7-ethyl-7-hydroxy-14-((4-methylpiperazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, ... 4-(morpholinomethyl)-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)piperazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[ 3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminopiperidin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione and tert-butyl(S)-(1 -((7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-14-yl)methyl)piperidin-4-yl)carbamate, or a salt of any of the foregoing.

72. A compound selected from the compounds of Table I, or a salt thereof. 【Request 73】 【Chemical 288】 or a salt thereof. 【Request 74】 【Chemical 289】 or a salt thereof. 【Request 75】 【Chemical 290】 or a salt thereof. 【Request 76】 【Chemical 291】 【Chemical 292】 【Chemical 293】 or a salt thereof. 【Request 77】 【Chemical 294】 or a salt thereof. 【Request 78】 【Chemical 295】 or a salt thereof. 【Request 79】 【Chemical 296】 【Chemical 297】 【Chemical Formula 298】 【Chemical 299】 【Chemistry 300】 【Chemistry 301】 【Chemistry 302】 or a salt thereof. 【Request 80】 【Chemical 303】 【Chemistry 304】 or a salt thereof.

81. 【Chemical 305】 or a salt thereof.

82. A camptothecin-linker compound which is a compound of Table II or a salt thereof.

83. A camptothecin conjugate, the conjugate comprising a ligand attached to a succinimide or succinic acid-amide moiety of a camptothecin-linker moiety, the camptothecin-linker moiety comprising a compound of Table II, wherein a maleimide moiety of the camptothecin-linker moiety is replaced with the succinimide or succinic acid-amide moiety.

84. The compound is represented by the following formula D ０ -I″ formula 【Chemistry 306】 or a salt thereof, In the formula, R ｂ２ But, R ｂ３ and, when combined with the intervening atoms to form a 5-, 6-, or 7-membered heterocycle, said heterocycle has no more than one O.

85. D is the following D ０ -I″ formula 【Chemistry 307】 or a salt thereof, In the formula, R ｂ２ But, R ｂ３ and when combined with the intervening atoms to form a 5-, 6-, or 7-membered heterocycle, said heterocycle has no more than one O.

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