Camptothecin conjugates

Abstract

Conjugates of antibodies and camptothecin compounds, as well as methods of use and preparation, are set forth.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Application No. 63 / 321,105, filed on March 17, 2022, and U.S. Application No. 63 / 407,609, filed on September 16, 2022, the disclosures of which are hereby incorporated by reference in their entirety for all purposes.

[0003] References to Electronic Sequence Listings

[0004] The contents of the electronic Sequence Listing (761682009440SEQLIST.xml; size: 1,128,239 bytes; and creation date: March 16, 2023) are incorporated herein by reference in its entirety. Background Art

[0005] Antibodies (mAbs) have been studied for the targeted delivery of cytotoxic agents to tumor cells. Although various drug classes have been evaluated for targeted delivery of antibodies, only a few drug classes have been demonstrated to be sufficiently active as antibody-drug conjugates with an appropriate toxicity profile and other pharmacological properties to warrant clinical development. One drug class of interest is camptothecin.

[0006] Designing antibody drug conjugates (ADC) involves consideration of various factors, including the presence of a conjugated handle for connecting to a conjugate on a drug and a conjugate technology for connecting a drug to an antibody in a conditionally stable manner. The conjugated handle of the parent compound in the described category is a C20 hydroxyl functional group, wherein the conjugate is connected by a carbonate functional group (see, for example, Walker, MA et al. Bioorganic & Medicinal Chemistry Letters (2002) 12 (2): 217-219). However, the carbonate functional group is generally affected by hydrolytic instability, which causes premature release of free drug into the systemic circulation, thereby resulting in reduced ADC efficacy, insufficient immunospecificity of the conjugate, and increased toxicity. Therefore, it is necessary to engineer camptothecin conjugates to control drug-conjugate stability, thereby increasing the amount of the drug delivered to the desired site of action. The present invention addresses these and other needs. Summary of the invention

[0007] The present invention particularly provides camptothecin conjugates, camptothecin-linker compounds and camptothecin compounds, their preparation and use methods and their intermediates. The camptothecin conjugates of the present invention are relatively stable in circulation, but once free drugs are released from the conjugates near or inside tumor cells, they can cause cell death.

[0008] In one embodiment, a camptothecin conjugate having the formula:

[0009] L-(QD) p

[0010] or a salt thereof, wherein

[0011] L is a ligand unit;

[0012] Subscript p is an integer from 1 to 16;

[0013] Q is a linker unit having a formula selected from the group consisting of:

[0014] -ZA-、-ZA-RL-、-ZA-RL-Y-、-ZAS * -RL-, -ZAS * -RL-Y-,

[0015] ZAS * -W-, -ZAS * -W-RL-、-ZAB(S * )-RL-、-ZAB(S * )-W-、

[0016] -ZAB(S * )-W-RL- and -ZAB(S * )-RL-Y-,

[0017] Wherein Z is an extension subunit;

[0018] A is a bond or linker unit;

[0019] B is a parallel connection subunit;

[0020] S* is a separator;

[0021] RL is a releasable linker;

[0022] W is an amino acid unit;

[0023] Y is a Spacer unit; and

[0024] D is a drug unit having the formula

[0025]

[0026] or its salts; wherein;

[0027] E stands for -OR b5 or -NR b5 R b5’ ;

[0028] R b1 Selected from the group consisting of: 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- to 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-OC(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 optionally through C 1 -C 3 Alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or

[0029] R b1 With R b2 , R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring;

[0030] R b2 Selected from the group consisting of: H, halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkynyl, C 6 -C 12 Aryl, 5- to 12-membered heteroaryl, C 3 -C 10 Cycloalkyl, 3- to 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 -C12 Aryl-OC(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 optionally through -OR a 、-NR a R a’ and-SR a replace; or

[0031] R b2 With R b1 or R b3 and the intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring; or

[0032] R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group;

[0033] R b3 Selected from the group consisting of: 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 ;

[0034] R b4 selected from the group consisting of H or halogen;

[0035] Each R b5 and R b5’ Independently selected from the group consisting of: H, C 1 -C 8 Alkyl, C 1 -C 8 Hydroxyalkyl, C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl-, C 1 -C 8 Aminoalkyl, (C 1 -C 4 Alkylamino)-C 1 -C8 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 10Heterocycloalkyl)-, 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’ and the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of 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 aminoalkyl; or

[0036] Rb5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocyclic, heterocycloalkyl, heterocyclic, phenyl and heteroaryl moieties are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C 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 ;

[0037] R b6 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and

[0038] R a and R a’ Each independently selected from the group consisting of: 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)-,

[0039] wherein D is covalently linked to Q via any suitable linking site on D, optionally wherein a hydrogen atom of a hydroxyl, thiol, primary 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.

[0040] Other embodiments as described above are camptothecin-linker compounds useful as intermediates for preparing camptothecin conjugates, wherein the camptothecin-linker compound comprises camptothecin and a linker unit (Q), wherein the linker unit comprises an extender unit precursor (Z') capable of forming a covalent bond with a targeting ligand providing a ligand unit and a releasable linker (RL), wherein the releasable linker is a glycoside (e.g., a glucuronide) unit in some aspects where Q does not have an amino acid unit.

[0041] In another aspect, provided herein is a method of treating cancer comprising administering to a subject in need thereof a camptothecin conjugate described herein.

[0042] In another aspect, provided herein are kits comprising a camptothecin conjugate described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1A and Figure 1B It was shown that one dose of Ag4 antibody ( Figure 1A ) or h00 antibody ( Figure 1B ) in the case of camptothecin ADC in the L540cy mouse model over time.

[0044] Figure 2 Shown are mean tumor volumes over time in the EBC-1 mouse model with one dose of glucuronide-based camptothecin ADC with Ag2 antibody administered on day 7.

[0045] Figure 3 Shown are mean tumor volumes over time in the OV-90 mouse model with one dose of glucuronide-based camptothecin ADC with Ag3 antibody administered on day 17.

[0046] Figure 4 Shown are mean tumor volumes over time in the 786-O mouse model with one dose of glucuronide-based camptothecin ADC with Ag5 antibody administered on day 15. DETAILED DESCRIPTION

[0047] definition

[0048] Unless otherwise stated, the following terms and expressions as used herein are intended to have the following meanings.When a trade name is used herein, unless the context indicates otherwise, the trade name includes product formulations, generic drugs and one or more active pharmaceutical ingredients of the trade name product.

[0049] The term "antibody" as used herein is used in the broadest sense herein 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. The native form of an antibody is a tetramer and consists of two pairs of identical immunoglobulin chains, each pair having one light chain and one heavy chain. In each pair, the light chain and heavy chain variable regions (V L and V H ) are primarily responsible for binding to the antigen. The light and heavy chain variable domains consist of framework regions interspersed with 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, Immuno. Biology, 5th edition, Garland Publishing, New York). Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, and IgA), species (e.g., IgG 1 IgG 2 IgG 3 IgG 4 , IgA 1 and IgA 2 ) or its subclass. 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.

[0050] 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 naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific for a single antigenic site. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.

[0051] An "intact antibody" is one that contains an antigen-binding variable region and a light chain constant domain (C L ) and the heavy chain constant domain (C H 1. C H 2. C H 3 and C H 4) (optionally for antibody species) The constant domain may be a native sequence constant domain (eg, a human native sequence constant domain) or an amino acid sequence variant thereof.

[0052] "Antibody fragments" comprise a portion of an intact antibody, including its antigen binding or variable region. Examples of antibody fragments include Fab, Fab', F(ab'), 2and Fv fragments, diabodies, triabodies, tetrabodies, linear antibodies, single-chain antibody molecules, scFv, scFv-Fc, multispecific antibody fragments formed by one or more antibody fragments, one or more fragments produced by a Fab expression library, or an epitope binding fragment of any of the above.

[0053] An "antigen" is the entity to which an antibody specifically binds.

[0054] The terms "specific binding" and "specifically bind" mean that the antibody or antibody derivative will bind to its corresponding epitope of the target antigen in a highly selective manner and will not bind to many other antigens. Typically, the antibody or antibody derivative will bind to its corresponding epitope of the target antigen in a highly selective manner and will not bind to many other antigens. -7 M and preferably 10 -8 M to 10 -9 M, 10 -10 M, 10 -11 M or 10 -12 The invention relates to a novel antigen-binding protein that binds to the predetermined antigen with an affinity that is at least two times greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely related antigen.

[0055] The term "inhibit" or "inhibition of" means to reduce by a measurable amount or to prevent entirely.

[0056] The term "therapeutically effective amount" refers to an amount of a conjugate that is effective in treating a disease or condition in a mammal. In the case of cancer, a therapeutically effective amount of the conjugate can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow down to some extent and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with cancer to some extent. Insofar as the drug can inhibit the growth of existing cancer cells and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0057] The terms "substantial" or "essentially" refer to a majority of a population, mixture or sample, i.e., >50%, preferably greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of a population.

[0058] 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 can be expressed as IC 50The value is the concentration per unit volume (molar or mass) at which half of the cells survive.

[0059] The term "cytostatic activity" refers to the antiproliferative effect of the drug or camptothecin conjugate or the intracellular metabolite of the camptothecin conjugate.

[0060] As used herein, the term "cytotoxic agent" refers to a substance that has cytotoxic activity and causes cell destruction. The term is intended to include chemotherapeutic agents and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including synthetic analogs and derivatives thereof.

[0061] As used herein, the term "cytostatic agent" refers to a substance that inhibits cellular function, including cell growth or proliferation. Cytostatic agents include inhibitors such as protein inhibitors (e.g., enzyme inhibitors). Cytostatic agents have cytostatic activity.

[0062] The terms "cancer" and "cancerous" refer to or describe the physiological condition or disorder in mammals that is typically characterized by unregulated cell growth. A "tumor" contains one or more cancer cells.

[0063] As used herein, "autoimmune disease" refers to a disease or disorder arising from and directed against an individual's own tissues or proteins.

[0064] As used herein, "patient" refers to a subject to whom the 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, cattle, horses, dogs, cats, birds, and poultry. Typically, the patient is a rat, mouse, dog, human, or non-human primate, more typically a human.

[0065] Unless otherwise indicated by the context, the term "treat" or "treatment" refers to therapeutic treatment and preventive treatment, wherein the purpose is to inhibit or slow down (mitigate) undesirable physiological changes or conditions, such as the development or spread of cancer. For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, relieving symptoms, reducing the extent of the disease, stabilizing (i.e., not worsening) the disease state, delaying or slowing the progression of the disease, improving or alleviating the disease state, and alleviating (whether partially or completely), whether detectable or undetectable. "Treatment" also means extending survival compared to the expected survival when not receiving treatment. Those patients in need of treatment include those patients who have suffered from the disease or condition and those patients who are susceptible to the disease or condition.

[0066] In the context of cancer, the term "treat" includes any or all of the following: killing tumor cells; inhibiting the growth of tumor cells, cancer cells or tumors; inhibiting the replication of tumor cells or cancer cells; reducing the overall tumor burden or reducing the number of cancer cells; and ameliorating one or more symptoms associated with the disease.

[0067] In the context of autoimmune disease, 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 producing autoimmune antibodies), reducing the autoimmune antibody load, and ameliorating one or more symptoms of the autoimmune disease.

[0068] The term "compound" as used herein refers to and encompasses the chemical compound named or represented by the structure itself and one or more salt forms thereof, whether specified or not, unless the context clearly indicates the exclusion of such salt forms. The term "compound" also encompasses the solvate form of the compound, wherein a solvent is non-covalently associated with the compound or reversibly covalently associated with the compound when the carbonyl group of the compound is hydrated to form a geminal diol. Solvate forms include the form of the compound itself and one or more salt forms thereof and include hemisolvates, monosolvates, disolvates (including hydrates); and when a compound can be associated with two or more solvent molecules, the two or more solvent molecules may be the same or different.

[0069] In some cases, the compounds of the present invention will include explicit reference to one or more of the above forms (e.g., salts and solvates), which does not imply a solid state form of the compound; however, the reference is only for emphasis and should not be interpreted as excluding any other forms as identified above. In addition, when the salt and / or solvate form of a compound or ligand drug conjugate composition is not explicitly mentioned, the omission should not be interpreted as excluding one or more salt and / or solvate forms of the compound or conjugate, unless the context clearly indicates that such salt and / or solvate forms are excluded.

[0070] As used herein, the phrase "salt thereof" refers to a salt form of a compound (e.g., a drug, a drug linker compound, or a ligand drug conjugate compound). The salt form of a compound is one or more internal salt forms and / or involves including another molecule, such as an acetate ion, a succinate ion, or other counterions. The counterions of the salt form of a compound are generally organic or inorganic moieties that stabilize the charge on the parent compound. The salt form of a compound has one or more charged atoms in its structure. In examples where multiple charged atoms are part of the salt form, there are multiple counterions and / or multiple charged counterions. Therefore, the salt form of a compound generally has one or more charged atoms and one or more counterions corresponding to atoms of the non-salt form of the compound. In some aspects, the non-salt form of the compound contains at least one amino group or other basic moiety, and thus obtains an acid addition salt with a basic moiety in the presence of an acid. In other aspects, the non-salt form of the compound contains at least one carboxylic acid group or other acidic moiety, and thus obtains a carboxylate or other anionic moiety in the presence of a base. Exemplary salts include, but are not limited to, sulfate, trifluoroacetate, citrate, acetate, oxalate, chloride, 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)).

[0071] Pharmaceutically acceptable salts are salt forms of compounds suitable for administration to a subject as described herein, and in some aspects, include countercations or counteranions as described in PH Stahl and CG Wermuth, eds., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich: Wiley-VCH / VHCA, 2002.

[0072] The linker unit is a bifunctional moiety that links camptothecin to the ligand unit in the camptothecin conjugate. The linker unit of the present invention has several components (e.g., in some embodiments, there will be a stretcher unit with a basic unit; a linker unit that may be present or absent; a parallel linker unit that may also be present or absent; a releasable linker; and a spacer unit that may also be present or absent).

[0073] As used herein, "PEG," "PEG unit," or "polyethylene glycol" is an organic moiety comprising repeating ethylene-oxy subunits and can be polydisperse, monodisperse, or discrete (i.e., having a discrete number of ethylene-oxy subunits). Polydisperse PEGs are heterogeneous mixtures of size and molecular weight, whereas monodisperse PEGs are typically purified from a heterogeneous mixture and thus provide a single chain length and molecular weight. Preferably, the PEG unit is a discrete PEG, which is a compound synthesized in a stepwise manner rather than by a polymerization process. Discrete PEGs provide a single molecule with a defined and specified chain length.

[0074] The PEG units provided herein include one or more polyethylene glycol chains, each of which includes one or more ethyleneoxy subunits covalently linked to each other. The polyethylene glycol chains can be linked together, for example, in a linear, branched or star-shaped configuration. Typically, before being incorporated into the camptothecin conjugate, at least one polyethylene glycol chain is derivatized at one end with an alkyl moiety substituted with an electrophilic group for covalently linking to the carbamate nitrogen (i.e., an example representing R) of the methylene carbamate unit. Typically, the terminal ethyleneoxy subunit that does not participate in the covalent linking to the rest of the linker unit in each polyethylene glycol chain is modified with a PEG capping unit, which is typically H or an optionally substituted alkyl, such as -CH 3 、-CH 2 CH 3 or -CH 2 CH 2 CO 2 H. Preferably, the PEG unit has a single polyethylene glycol chain having 4 to 24 -CH 2 CH 2 O-subunit.

[0075]

[0043] Unless otherwise stated or implied by the context, the term "halogen" as used herein, by itself or in combination with another term, means fluorine, chlorine, bromine, or iodine and is typically -F or -Cl.

[0076] 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 (e.g., "-C 1 -C 8 Alkyl" or "-C 1 -C 10 "alkyl" refers to an alkyl group having 1 to 8 or 1 to 10 carbon atoms, respectively). When the number of carbon atoms is not indicated, the alkyl group has 1 to 8 carbon atoms. Representative straight chain "-C 1 -C 8"Alkyl" includes, but is not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, and -n-octyl; and branched-C 3 -C 8 Alkyl includes, but is not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl and -2-methylbutyl; unsaturated -C 2 -C 8 Alkyl includes, but is not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexyl, 2-hexyl, -3-hexyl, -ethynyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, and -3-methyl-1-butynyl. Sometimes the alkyl is unsubstituted. The alkyl may be substituted with one or more groups. In other aspects, the alkyl will be saturated.

[0077] Unless otherwise indicated, "alkylene" by itself or as part of another term refers to a substituted or unsubstituted saturated branched or straight chain or cyclic hydrocarbon radical having the stated number of carbon atoms, typically 1-10 carbon atoms, and having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylenes include, but are not limited to, methylene (-CH 2 -), 1,2-ethylene (-CH 2 CH 2 -), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc. In a preferred aspect, the alkylene group is a branched or straight chain hydrocarbon (ie, it is not a cyclic hydrocarbon).

[0078] Unless otherwise stated or implied by the context, the term "alkenyl" as used herein, by itself or as part of another term, refers to an organic moiety, substituent or group that contains one or more double bond functional groups (e.g., a -CH=CH- moiety), or 1, 2, 3, 4, 5 or 6 or more of such functional groups, typically 1, 2 or 3, more typically one such functional group, and unless the alkenyl substituent, moiety or group is a vinyl moiety (e.g., -CH=CH-), the alkenyl substituent, moiety or group is a vinyl moiety (e.g., -CH=CH-). 2moiety), may otherwise be substituted (i.e., optionally substituted) with an aryl moiety or group such as phenyl in some aspects, or may contain non-aromatic attached normal, secondary, tertiary or cyclic carbon atoms, i.e., straight chain carbon atoms, branched chain carbon atoms, cyclic carbon atoms, or any combination thereof, as part of the basic moiety. Alkenyl moieties, groups or substituents having multiple double bonds may have double bonds arranged continuously (i.e., 1,3-butadienyl moieties) or discontinuously, or a combination thereof, with one or more intervening saturated carbon atoms, provided that the cyclic continuous arrangement of the double bonds does not form a cyclic conjugated system of 4n+2 electrons (i.e., is not aromatic).

[0079] The alkenyl moiety, group or substituent contains at least one sp 2 A carbon atom, wherein the carbon atom is divalent and is double-bonded to another organic moiety or Markush structure associated therewith, or contains at least two sp 2 A carbon atom, one of which is sp 2 The carbon atom is monovalent and is single-bonded to another organic moiety or Markush structure associated therewith. Generally, when an alkenyl group is used as a Markush group (i.e., a substituent), the alkenyl group is located via the sp of the olefinic functional group of the alkenyl moiety. 2 The carbon is single-bonded to a Markush or another organic moiety to which it is associated. In some aspects, when an alkenyl moiety is specified, the species encompasses any of the optionally substituted alkyl or carbocyclyl groups, radicals, or substituents described herein having one or more internal double bonds, wherein its sp 2 carbon atom is monovalent), and the sp 2 A monovalent moiety derived from carbon by removing a hydrogen atom. Such monovalent moieties are exemplified by, but not limited to, vinyl (—CH═CH 2 ), allyl, 1-methylvinyl, butenyl, isobutenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl and cyclohexenyl. In some aspects, the term alkenyl encompasses those containing at least one double bond functional group and / or other linear, cyclic and branched carbon-containing moieties, wherein one sp 2 The carbon atom is univalent.

[0080] The number of carbon atoms in the alkenyl moiety is determined by the sp of the one or more olefin functional groups that define it as an alkenyl substituent. 2 The number of carbon atoms and the sp 2 The total number of adjacent non-aromatic carbon atoms of each of the alkenyl carbon atoms is defined by the total number of adjacent non-aromatic carbon atoms of each of the alkenyl carbon atoms, excluding any carbon atoms of the alkenyl moiety that are another part of a variable group or Markush structure and carbon atoms from any optional substituents of the alkenyl moiety. When the double bond functional group is double bonded to the Markush structure (e.g., =CH 2), the number is in the range of 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, or when the double bond functional group is bonded to the Markush structure (e.g., -CH=CH 2 ), the number is in the range of 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, C 2 -C 8 Alkenyl or C2-C8 alkenyl means an alkenyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms, at least two of which are sp conjugated to each other. 2 carbon atoms, wherein one of the carbon atoms is monovalent, and C 2 -C 6 Alkenyl or C2-C6 alkenyl means an alkenyl moiety containing 2, 3, 4, 5 or 6 carbon atoms, at least two of which are sp conjugated to each other. 2 Carbon, wherein one of the carbon atoms is monovalent. In some aspects, the alkenyl substituent or group is a substituent having only two sp 2 C of carbon 2 -C 6 or C 2 -C 4 An alkenyl moiety wherein at least one of the carbon atoms is monovalent, and 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 optional substituents, excluding alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and any other moiety when the substituted alkenyl differs in the number of adjacent non-aromatic carbon atoms relative to the unsubstituted alkenyl, wherein one or more substitutions may be located on adjacent sp of the alkenyl moiety. 2 Carbon and sp 3 Typically, an alkenyl substituent is a substituent having only two sp 2 C of carbon 2 -C 6 or C 2 -C 4 Alkenyl moieties. When the number of carbon atoms is not indicated, the alkenyl moiety has 2 to 8 carbon atoms.

[0081] Unless otherwise stated or implied by the context, the term "alkenylene" as used herein by itself or as part of another term refers to an organic moiety, substituent or group that contains one or more double bond moieties as previously described for alkenyl having the stated number of carbon atoms and having the same or two different sp 2In some aspects, the alkenylene moiety is a moiety of an alkenyl group as described herein, wherein the same or different sp atoms of the double bond functional groups of the alkenyl group have been removed from the same or different sp atoms of the double bond functional groups of the alkenyl group. 2 Carbon atoms or sp from different double bond bonding parts 2 The removal of a hydrogen atom from a carbon provides a diradical. Typically, the alkenylene moiety encompasses a -C=C- or -C=CX- 1 -C=C- structured diradical, where X 1 Absent or optionally substituted saturated alkylene as defined herein, which is typically C 1 -C 6 The number of carbon atoms in the alkenylene moiety is determined by the sp of the one or more olefinic functional groups that define the alkenylene moiety. 2 The number of carbon atoms and the sp attached to them 2 The total number of adjacent non-aromatic carbon atoms of each of the carbon atoms in the alkenyl group is defined as the total number of adjacent non-aromatic carbon atoms of each of the carbon atoms in the alkenyl group, not including any carbon atoms of another part or Markush structure present as a variable group of the alkenyl group. Unless otherwise specified, the number is in the range of 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. For example, C 2 -C 8 Alkenylene or C2-C8 alkenylene means an alkenylene moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms, at least two of which are sp conjugated to each other. 2 Carbon, one carbon atom is divalent or both carbon atoms are monovalent, and C 2 -C 6 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 conjugated to each other. 2 Carbon, at least two of which are sp 2 In some aspects, the alkenylene moiety is a sp having two conjugated carbon atoms. 2 C of carbon 2 -C 6 or C 2 -C 4 Alkenylene, two of which are sp 2 The carbon atoms are all monovalent, and in some aspects the alkenylene moiety is unsubstituted. When the number of carbon atoms is not indicated, the alkenylene moiety has 2 to 8 carbon atoms and is unsubstituted or substituted in the same manner as described for the alkenyl moiety.

[0082] Unless otherwise stated or implied by the context, the term "alkynyl" as used herein, by itself or as part of another term, refers to an organic moiety, substituent or group, which contains one or more triple bond functional groups (e.g., a -C≡C- moiety), or 1, 2, 3, 4, 5 or 6 or more of such functional groups, typically 1, 2 or 3, more typically one such functional group, and unless the alkynyl substituent, moiety or group is -C≡CH, it may be substituted (i.e., optionally substituted) with an aryl moiety such as phenyl in some aspects, or substituted with an alkenyl moiety or attached normal, secondary, tertiary or cyclic carbon atoms, i.e., straight-chain carbon atoms, branched carbon atoms, cyclic carbon atoms, or any combination thereof. Alkynyl moieties, groups or substituents having multiple triple bonds may have double bonds with one or more intervening saturated or unsaturated carbon atoms arranged continuously or discontinuously, or in combinations thereof, provided that the cyclic continuous arrangement of the triple bonds does not form a cyclic conjugated system of 4n+2 electrons (i.e., is not aromatic).

[0083] Alkynyl moieties, groups or substituents contain at least two sp carbon atoms, wherein the carbon atoms are conjugated to each other and one of the sp carbon atoms is single-bonded to another organic moiety or Markush structure associated therewith. When an alkynyl group is used as a Markush group (i.e., a substituent), the alkynyl group is single-bonded to the Markush formula or another organic moiety associated therewith through a triple-bonded carbon (i.e., sp carbon) of a terminal alkyne functional group. In some aspects, when an alkynyl moiety, group or substituent is specified, the species encompasses any of the optionally substituted alkyl or carbocyclic groups, groups, moieties or substituents described herein, which have one or more internal triple bonds, and a monovalent moiety derived from the sp carbon of a free parent alkyne compound by removing a hydrogen atom. Such monovalent moieties are exemplified by, but are not limited to, -C≡CH and -C≡C-CH 3 and -C≡C-Ph.

[0084] The number of carbon atoms in an alkynyl substituent is defined by the number of sp carbon atoms of the alkene functional group that defines it as an alkynyl substituent and the total number of adjacent non-aromatic carbon atoms attached to each of the sp carbons, excluding any carbon atoms where the alkene moiety is another part of a variable group or a Markush structure. When the triple bond functional group is bonded to the Markush structure (e.g., -CH≡CH) with a single bond, the number can vary 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, C 2 -C 8 Alkynyl or C2-C8 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms, at least two of which are sp carbon atoms conjugated to each other, wherein one of the carbon atoms is monovalent, and C 2 -C 6Alkynyl or C2-C6 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, or 6 carbon atoms, wherein at least two of the carbon atoms are sp carbons conjugated to each other, wherein one of the carbon atoms is monovalent. In some aspects, the alkynyl substituent or group is a C2-C6 alkynyl moiety having two carbon atoms conjugated to each other. 2 -C 6 or C 2 -C 4 Alkynyl moieties, wherein one of the carbon atoms is monovalent and in other aspects, the alkynyl moiety is unsubstituted. When the number of carbon atoms is not indicated, the alkynyl moiety, group or substituent has 2 to 8 carbon atoms. Alkynyl moieties may be substituted or unsubstituted in the same manner as described for alkenyl moieties, except that substitution at monovalent sp carbons is not permitted.

[0085] As used herein, the term "prodrug" refers to a less biologically active or inactive compound that is converted into a more biologically active compound in vivo by a chemical or biological process (i.e., a chemical reaction or an enzymatic biotransformation). Typically, a biologically active compound exhibits lower biological activity (i.e., is converted into a prodrug) by chemically modifying the compound with a prodrug moiety. In some aspects, the prodrug is a type II prodrug that is bioactivated extracellularly (e.g., in digestive fluids) or in the body's circulatory system (e.g., in the blood). Exemplary prodrugs are esters and β-D-pyranoglucosides.

[0086] Unless otherwise indicated, "aryl" by itself or as part of another term means a substituted or unsubstituted monovalent carbocyclic aromatic hydrocarbon radical having the stated number of carbon atoms (usually 6 to 20 carbon atoms) derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented as "Ar" in the exemplary structures. Typical aryl groups include, but are not limited to, groups derived from benzene, substituted benzenes, naphthalene, anthracene, biphenyl, and the like. An exemplary aryl group is phenyl.

[0087] Unless otherwise indicated, "arylene" by itself or as part of another term refers to an aryl group as defined above, which has two covalent bonds (i.e., it is divalent) and can be oriented in the ortho, meta, or para positions, as shown in the following structure with phenyl as an exemplary group:

[0088]

[0089] Unless otherwise indicated, “C 3 -C 8"Heterocycle" by itself or as part of another term refers to a monovalent substituted or unsubstituted aromatic or nonaromatic monocyclic or bicyclic ring system having 3 to 8 carbon atoms (also referred to as ring members) and one to four heteroatom ring members independently selected from N, O, P or S, and derived by removing one hydrogen atom from a ring atom of the parent ring system. One or more N, C or S atoms in the heterocycle may be oxidized. The ring including the heteroatom may be aromatic or nonaromatic. A heterocycle in which all the ring atoms are associated with aromaticity is called heteroaryl, otherwise known as heterocarbocycle.

[0090] Unless otherwise indicated, the heterocycle is connected to its side group at any heteroatom or carbon atom that produces a stable structure. Therefore, the heteroaryl group can be bonded by the aromatic carbon of its aromatic ring system, which is called C-connected heteroaryl, or by the non-double bonded N atom (i.e., non-=N-) bonding in its aromatic ring system, which is called N-connected heteroaryl. Therefore, the nitrogen-containing heterocycle can be C-connected or N-connected and include pyrrole moieties, such as pyrrole-1-yl (N-connected) and pyrrole-3-yl (C-connected); and imidazole moieties, such as imidazole-1-yl and imidazole-3-yl (both of which are N-connected), and imidazole-2-yl, imidazole-4-yl and imidazole-5-yl moieties (which are all C-connected).

[0091] Unless otherwise indicated, “C 3 -C 8 "Heteroaryl" is an aromatic C 3 -C 8 Heterocycle, wherein the subscript indicates the total number of carbons in the cyclic ring system of the heterocycle or the total number of aromatic carbons in the aromatic ring system of the heteroaryl and does not imply the size of the ring system or the presence or absence of ring fusion. 3 -C 8 Representative examples of heterocycles include, but are not limited to, pyrrolidinyl, azetidinyl, hexahydropyridinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, pyrrolyl, thienyl (thiophene), furanyl, thiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, isothiazolyl, and isoxazolyl.

[0092] When explicitly given, the size of the heterocycle or heteroaryl ring system is indicated by the total number of atoms in the ring. For example, a designation of a 5-membered or 6-membered heteroaryl indicates the total number of aromatic atoms in the heteroaromatic ring system of the heteroaryl (i.e., 5 or 6), but does not imply the number of aromatic heteroatoms or aromatic carbons in the ring system. A fused heteroaryl is one that is explicitly stated or implied by the context, and is generally 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 an aromatic 5-membered ring fused to an aromatic 6-membered ring, wherein one or both rings have one or more aromatic heteroatoms or wherein one heteroatom is shared between the two rings.

[0093] A heterocycle fused to an aryl or heteroaryl group such that the heterocycle remains non-aromatic and is part of a larger structure by attachment to the non-aromatic portion of the fused ring system is an example of an optionally substituted heterocycle wherein the heterocycle is substituted by fusion to an aryl or heteroaryl ring. Likewise, an aryl or heteroaryl group fused to a heterocycle or carbocycle which is part of a larger structure by attachment to the aromatic portion of the fused ring system is an example of an optionally substituted aryl or heterocycle wherein the aryl or heterocycle is substituted by ring fusion to a heterocycle or carbocycle.

[0094] Unless otherwise indicated, “C 3 -C 8 "Heterocyclyl" by itself or as part of another term refers to a C 3 -C 8 A heterocyclic ring wherein one of the hydrogen atoms of the heterocyclic ring is replaced by a bond (ie, it is divalent). Unless otherwise indicated, "C 3 -C 8 "Heteroarylene" by itself or as part of another term refers to a C 3 -C 8 Heteroaryl wherein one of the hydrogen atoms of the heteroaryl is replaced by a bond (ie, it is divalent).

[0095] Unless otherwise indicated, “C 3 -C 8 "Carbocycle" by itself 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 carbon ring derived by removing one hydrogen atom from a ring atom of a parent ring system. Representative -C 3 -C 8 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.

[0096] Unless otherwise indicated, “C 3 -C 8 "Carbocycle" by itself or as part of another term means a C 3 -C 8 A carbocyclic group wherein another hydrogen atom of the carbocyclic group is replaced by a bond (ie, it is divalent).

[0097] Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term, unless otherwise stated, means a stable straight or branched hydrocarbon or combination thereof (fully saturated or containing 1 to 3 degrees of unsaturation) consisting of the stated number of carbon atoms and 1 to 10, preferably 1 to 3, heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. One or more heteroatoms O, N and S may be placed at any interior position of the heteroalkyl or at the position where the alkyl is attached to the rest of the molecule. The heteroatom Si may be placed at any position of the heteroalkyl, including the position where the alkyl is attached to the rest of the molecule.

[0098] Examples of heteroalkyl groups include -CH 2 -CH 2 -O-CH 3 、-CH 2 -CH 2 -NH-CH 3 、-CH 2 -CH 2 -N(CH 3 )-CH 3 、-CH 2 -S-CH 2 -CH 3 、-CH 2 -CH 2 -S(O)-CH 3 、-NH-CH 2 -CH 2 -NH-C(O)-CH 2 -CH 3 、-CH 2 -CH 2 -S(O) 2 -CH 3 、-CH=CH-O-CH 3 、-Si(CH 3 ) 3 、-CH 2 -CH=NO-CH 3 and -CH=CH-N(CH 3 )-CH 3 Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3 Usually, C 1 To C 4 A heteroalkyl or heteroalkylene group has 1 to 4 carbon atoms and 1 or 2 heteroatoms and C 1To C 3 The heteroalkyl or heteroalkylene group has 1 to 3 carbon atoms and 1 or 2 heteroatoms. In some aspects, the heteroalkyl or heteroalkylene group is saturated.

[0099] Unless otherwise indicated, the term "heteroalkylene," by itself or in combination with another term, means a divalent radical derived from a heteroalkyl group (as discussed above), such as by a -CH 2 -CH 2 -S-CH 2 -CH 2 -and-CH 2 -S-CH 2 -CH 2 -NH-CH 2 - exemplified. For heteroalkylene, heteroatoms may also occupy either or both of the chain termini. In addition, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.

[0100] Unless otherwise indicated, "aminoalkyl" by itself or in combination with another term means a heteroalkyl group in which the alkyl portion, as defined herein, is substituted with amino, alkylamino, dialkylamino, or cycloalkylamino. Exemplary non-limiting aminoalkyl groups are -CH 2 NH 2 、-CH 2 CH 2 NH 2 、-CH 2 CH 2 NHCH 3 and -CH 2 CH 2 N(CH 3 ) 2 Also included are branched species such as -CH(CH 3 )NH 2 and -C(CH 3 )CH 2 NH 2 Alternatively, aminoalkyl is an alkyl moiety, group or substituent as defined herein, wherein sp 3 The carbon has been replaced by an amino or alkylamino moiety, wherein its sp 3 Nitrogen replaces the sp 3 Carbon, provided that at least one sp 3 The carbon remains. When the aminoalkyl moiety is referred to as a substituent of a larger structure or another moiety, the aminoalkyl group is covalently attached to the structure or moiety through the carbon radical of the alkyl portion of the aminoalkyl group.

[0101] Unless otherwise stated or implied by the context, the term "hydroxyalkyl" as used herein, by itself or in combination with another term, refers to an alkyl moiety, group, or substituent having a hydroxy group replacing one or more hydrogen atoms. In some aspects, one or two hydrogen atoms are replaced by a hydroxy substituent in the hydroxyalkyl group. Hydroxyalkyl groups are typically represented by the number of adjacent carbon atoms of their alkyl or alkylene moieties. Thus, C 1 Hydroxyalkyl is exemplified by but not limited to -CH 2 OH, and C 2 Hydroxyalkyl is exemplified by but not limited to -CH 2 CH 2 OH or -CH 2 (OH)CH 3 .

[0102] Unless otherwise stated or implied by the context, the term "haloalkyl" as used herein, by itself or in combination with another term, refers to an alkyl moiety, group, or substituent having a halogen replacing one or more hydrogen atoms. In some aspects, one or two hydrogen atoms are replaced by the halogen in the haloalkyl. A haloalkyl group is typically represented by the number of adjacent carbon atoms of its alkyl or alkylene moiety. Thus, C 1 Haloalkyl is exemplified by but not limited to -CH 2 F, -CH 2 Cl, -CH 2 Br or -CH 2 I, and C 2 Haloalkyl is exemplified by but not limited to -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CH 2 Br, -CH 2 CH 2 I. -CH(F)CH 3 、-CH(Cl)CH 3 、-CH(Br)CH 3 or -CH(I)CH 3 In some embodiments, the term "haloalkyl" refers to an alkyl moiety, group, or substituent having halogens replacing two or more hydrogen atoms. For example, C 1 Haloalkyl is also exemplified by but not limited to -CHF 2 , -CHCl 2 , -CHBr 2 or -CHI 2 , and C 2 Haloalkyl is exemplified by but not limited to -CH 2 CHF 2 、-CH 2CHCl 2 、-CH 2 CHBr 2 、-CH 2 CHI 2 , -CF 2 CH 3 , -CCl 2 CH 3 , -CBr 2 CH 3 or -CI 2 CH 3 In some embodiments, the term "haloalkyl" refers to an alkyl moiety, group, or substituent having halogens replacing all hydrogen atoms. In some embodiments, the term "haloalkyl" encompasses fully halogenated alkyl moieties, groups, or substituents. For example, C 1 Haloalkyl is also exemplified by, but not limited to, -CF 3 , -CCl 3 , -CBr 3 or -CI 3 .

[0103] Unless otherwise indicated, "alkylamino" and "cycloalkylamino" by themselves or in combination with another term mean an alkyl or cycloalkyl group as described herein, wherein a radical carbon of the alkyl or cycloalkyl group has been replaced by a nitrogen group, provided that at least one sp 3 The carbon remains. In those instances where an alkylamino group is substituted at its nitrogen with another alkyl moiety, the resulting substituted group is sometimes referred to as a dialkylamino moiety, group or substituent, wherein the alkyl moieties replacing the nitrogen are independently selected.

[0104] Exemplary and non-limiting amino, alkylamino, and dialkylamino substituents include amino groups having -N(R') 2 Those substituents of the structure, wherein R' in said example is independently selected from hydrogen or C 1-6 Alkyl, usually selected from hydrogen or methyl, and in cycloalkylamines included in heterocycloalkyl, R' and the nitrogen to which it is attached together define the heterocycle. When both R' are hydrogen or alkyl, the moieties are sometimes described as primary and tertiary amino groups, respectively. When one R' is hydrogen and the other is alkyl, the moieties are sometimes described as secondary amino groups. Primary and secondary alkylamino moieties are more reactive as nucleophiles towards electrophilic centers containing carbonyl groups, while tertiary amines are more basic.

[0105] "Substituted alkyl" and "substituted aryl" refer to alkyl and aryl groups, respectively, in which one or more hydrogen atoms (usually one) are each independently replaced with a substituent. Typical substituents include, but are not limited to, -X, -R', -OH, -OR', -SR', -N(R'), 2 、-N(R') 3、=NR'、-CX 3 、-CN、-NO 2 , -NR'C(=O)R', -C(=O)R', -C(=O)N(R') 2 、-S(=O) 2 R', -S(=O) 2 NR', -S(=O)R', -OP(=O)(OR') 2 、-P(=O)(OR') 2 ,-PO 3 ＝ ,PO 3 H 2 , -C(=O)R', -C(=S)R', -CO 2 R', -CO 2 - , -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: -F, -Cl, -Br and -I; and wherein each R' is independently selected from the group consisting of: -H, -C 1 -C 20 Alkyl, -C 6 -C 20 Aryl, -C 3 -C 14 Heterocycles, protecting groups and prodrug moieties.

[0106] More typically, the substituents are selected from the group consisting of: -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) 2 R', -S(=O) 2 NR', -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) 2 R', -S(=O) 2 NR', -S(=O)R', -C(=O)R', -C(=O)N(R') 2 、-C(=NR)N(R') 2 , protecting groups and prodrug moieties, wherein each X is -F; and wherein each R' is selected from the group consisting of: hydrogen, -C 1 -C 20 Alkyl, -C 6 -C 20 Aryl, -C 3 -C 14 Heterocycles, protecting groups and prodrug moieties.

[0107] In some aspects, the alkyl substituent is selected from -N(R') 2 、-N(R') 3 and -C(=NR)N(R') 2 The group consisting of, wherein R' is selected from hydrogen and -C 1 -C 20 In other aspects, the alkyl group is substituted with a series of ethyleneoxy moieties to define the PEG unit. Alkylene, carbocycle, carbocyclyl, arylene, heteroalkyl, heteroalkylene, heterocycle, heterocyclyl, heteroaryl, and heteroarylene as described above may also be similarly substituted.

[0108] As used herein, "protecting group" means a moiety that prevents or reduces the ability of the atom or functional group to which it is attached to participate in an undesired reaction. Typical protecting groups for atoms or functional groups are described in Greene (1999), "Protective groups". ROTECTIVE G ROUPS I N O RGANIC S YNTHESIS , 3rd edition", given in Wiley Interscience. In some instances, protecting groups for heteroatoms such as oxygen, sulfur, and nitrogen are used to minimize or avoid undesired reactions with electrophilic compounds. In other instances, protecting groups are used to reduce or eliminate the nucleophilicity and / or basicity of unprotected heteroatoms. A non-limiting example of protected oxygen is through -OR PR Given, where R PRis a protecting group for hydroxyl, where hydroxyl is usually protected as an ester (e.g., acetate, propionate, or benzoate). Other protecting groups for hydroxyl avoid interfering with the nucleophilicity of organometallic reagents or other highly basic reagents, where hydroxyl is usually protected in the form of ethers, including alkyl or heterocycloalkyl ethers (e.g., methyl or tetrahydropyranyl ether), alkoxymethyl ethers (e.g., methoxymethyl or ethoxymethyl ether), 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 for primary or secondary amines such as -NHR PR or -N(R PR ) 2 - those nitrogen protecting groups in which at least one R PR is a nitrogen atom protecting group or two R PR Together they form a protecting group.

[0109] The blocking group is suitable when it is capable of preventing or avoiding premature loss of undesired side reactions or blocking groups under the reaction conditions required for achieving the desired chemical transformation elsewhere in the molecule and during purification of the newly formed molecule when desired, and can be removed under conditions that do not adversely affect the structural or stereochemical integrity of the newly formed molecule. As an example and not limitation, suitable blocking groups may include those described above for the protective functional group. Suitable blocking groups are sometimes the blocking groups used in peptide coupling reactions.

[0110] As used herein, "electron withdrawing group" means a functional group or electronegative atom that pulls electron density away from the atom to which it is bonded, either inductively and / or by resonance, whichever is more dominant (i.e., the functional group or atom can withdraw electrons inductively but can donate electrons by resonance as a whole), and tends to stabilize anions or electron-rich moieties. The electron-withdrawing effect is typically transmitted inductively (albeit in a weakened form) to other atoms connected to the bonded atom that has been rendered electron-deficient by the electron-withdrawing group (EWG), thereby affecting the electrophilicity of more distal reactive centers. Exemplary electron-withdrawing groups include, but are not limited to, -C(=O), -CN, -NO 2 、-CX 3 , -X, -C(=O)OR', -C(=O)N(R') 2 , -C(=O)R', -C(=O)X, -S(=O) 2 R', -S(=O) 2 OR', -S(=O) 2NHR', -S(=O) 2 N(R') 2 、-P(=O)(OR') 2 、-P(=O)(CH 3 )NHR'、-NO、-N(R') 3 + , wherein X is -F, -Br, -Cl or -I, and R' in some aspects is independently selected at each occurrence from the group consisting of: hydrogen and C 1-6 Alkyl, as well as certain O-linked moieties as described herein, such as acyloxy.

[0111] Exemplary EWGs may also include aryl groups (e.g., phenyl), depending on substitution, and certain heteroaryl groups (e.g., pyridine). Thus, the term "electron withdrawing group" also includes aryl or heteroaryl groups further substituted with electron withdrawing groups. Typically, the electron withdrawing group on the aryl or heteroaryl group is -C(=O), -CN, -NO 2 、-CX 3 and -X, wherein independently selected X is a halogen, typically -F or -Cl. Depending on its substituents, the alkyl portion may also be an electron withdrawing group.

[0112] As used herein, "succinimide moiety" refers to an organic moiety comprising a succinimide ring system, which is present in a type of stretcher unit (Z), which typically also comprises an alkylene-containing moiety bonded to the imide nitrogen of the ring system. The succinimide moiety is typically generated by Michael addition of a sulfhydryl group of a ligand unit to the maleimide ring system of a stretcher unit precursor (Z'). Thus, the succinimide moiety comprises a sulfur-substituted succinimide ring system and, when present in a camptothecin conjugate, has its imide nitrogen substituted by the remainder of the linker unit of the camptothecin conjugate and optionally by one or more substituents present on the maleimide ring system of Z'.

[0113] As used herein, "acid-amide moiety" refers to succinic acid with an amide substituent, which is produced by subjecting the sulfur-substituted succinimide ring system of the succinimide moiety to cleavage of one of its carbonyl-nitrogen bonds by hydrolysis. The hydrolysis that produces the succinic acid-amide moiety provides a linker unit that is less likely to suffer premature loss of the ligand unit to which it is bonded by eliminating the antibody-sulfur substituent. It is expected that hydrolysis of the succinimide ring system of the sulfur-substituted succinimide moiety provides regiochemical isomers of the acid-amide moiety due to differences in the reactivity of the two carbonyl carbons of the succinimide ring system, which differences can be at least partially attributed to any substituent present in the maleimide ring system of the extender unit precursor and to the sulfur substituent introduced by the targeting ligand.

[0114] In many examples, the conjugates, linkers, and assemblies of components described herein will be referred to as reactive groups. A "reactive group" or RG is a group containing a reactive site (RS) that is capable of forming a bond with a component of a linker unit (i.e., A, W, Y) or camptothecin D. RS is a reactive site within a reactive group (RG). Non-limiting examples of reactive groups include sulfhydryls that form disulfide or thioether bonds; aldehydes, ketones, or hydrazine groups that form hydrazone bonds; carboxylic acid groups or amino groups that form peptide bonds; carboxylic acid groups or hydroxyl groups that form ester bonds; sulfonic acids that form sulfonamide bonds; alcohols that form carbamate bonds; and amines that form sulfonamide or carbamate bonds.

[0115] The following table illustrates reactive groups, reactive sites, and exemplary functional groups that may be formed following reaction at the reactive sites. The table is not intended to be limiting. One skilled in the art will appreciate that the R' and R" moieties noted in the table are in fact any organic moieties (e.g., alkyl, aryl, heteroaryl; or substituted alkyl, aryl, or heteroaryl) that are compatible with the bond formation provided in converting RG to one of the exemplary functional groups. It will also be appreciated that when applied to embodiments of the present invention, R' may represent one or more components of a self-stabilizing linker or an optional second linker, and R" may represent one or more components of an optional second linker, a camptothecin, a stabilizing unit, or a detection unit, as appropriate.

[0116]

[0117] Implementation

[0118] The following describes various embodiments of the present invention, which are not intended to limit the present invention in any way, followed by a more detailed discussion of the components that make up the conjugates. It will be appreciated by those skilled in the art that each of the identified conjugates and any of the selected embodiments thereof is intended to include the full scope of each component and linker.

[0119] Camptothecin conjugate

[0120] In one embodiment, provided herein is a camptothecin conjugate having the formula:

[0121] L-(QD) p

[0122] or a salt thereof, wherein

[0123] L is a ligand unit;

[0124] Subscript p is an integer from 1 to 16;

[0125] Q is a linker unit having a formula selected from the group consisting of:

[0126] -ZA-;-ZA-RL-;-ZA-RL-Y-;ZAS * -W-;-ZAS * -RL-;-ZAB(S * )-RL-;

[0127] -ZAS * -W-RL-;-ZAS * -RL-Y-; and -ZAB(S * )-RL-Y-;

[0128] Wherein Z is an extension subunit,

[0129] A is a bond or linker unit;

[0130] B is a parallel connection subunit;

[0131] As a separator;

[0132] W is a peptide unit;

[0133] RL is a releasable unit;

[0134] Y is a Spacer unit; and

[0135] D is a drug unit having the formula

[0136]

[0137] or its salt; wherein

[0138] E stands for -OR b5 or -NR b5 R b5’ ;

[0139] R b1 Selected from the group consisting of: 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- to 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 -C8 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-OC(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 optionally through R a 、-OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or

[0140] R b1 With R b2 , R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring;

[0141] R b2 Selected from the group consisting of: H, halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkynyl, C 6 -C 12 Aryl, 5- to 12-membered heteroaryl, C 3 -C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, C 1 -C 8 Haloalkyl, C 1 -C8 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-OC(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 optionally through -OR a 、-NR a R a’ and-SR a replace; or

[0142] R b2 With R b1 or R b3 and the intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring; or

[0143] R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group;

[0144] R b3 Selected from the group consisting of: 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 ;

[0145] R b4 selected from the group consisting of H or halogen;

[0146] Each R b5 and R b5’ Independently selected from the group consisting of: H, C 1 -C 8 Alkyl, C 1 -C 8 Hydroxyalkyl, C 1 -C 6 Alkyl-OC 1 -C 6 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 8Hydroxyalkyl-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-, C1 -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’ and the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C 4 Alkyl, C 1 -C 6 Hydroxyalkyl, -OH, -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 aminoalkyl; or

[0147] R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocyclic, heterocycloalkyl, heterocyclic, phenyl and heteroaryl moieties are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 Alkyl, -OH, -OC 1 -C 4 Alkyl, -NH 2 、-NHC 1 -C 4 Alkyl and -N(C1 -C 4 alkyl) 2 ;

[0148] R b6 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and

[0149] R a and R a’ Each independently selected from the group consisting of: 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)-,

[0150] wherein D is covalently linked to Q via any suitable linking site on D, optionally wherein a hydrogen atom of a hydroxyl, thiol, primary 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.

[0151] Also provided herein are camptothecin conjugates having the formula:

[0152] L-(QD) p

[0153] or a salt thereof, wherein

[0154] L is a ligand unit;

[0155] Subscript p is an integer from 1 to 16;

[0156] Q is a linker unit having a formula selected from the group consisting of:

[0157] -ZA-;-ZA-RL-;-ZA-RL-Y-;ZAS * -W-;-ZAS * -RL-;-ZAB(S * )-RL-;

[0158] -ZAS * -W-RL-;-ZAS * -RL-Y-; and -ZAB(S * )-RL-Y-;

[0159] Wherein Z is an extension subunit,

[0160] A is a bond or linker unit;

[0161] B is a parallel connection subunit;

[0162] As a separator;

[0163] W is a peptide unit;

[0164] RL is a releasable unit;

[0165] Y is a Spacer unit; and

[0166] D is a drug unit having the formula

[0167]

[0168] or its salt; wherein

[0169] R b1 Selected from the group consisting of: H, halogen, 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- to 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)-, C6 -C 12 Aryl-C(O)-, C 6 -C 12 Aryl-OC(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 optionally through -OR a 、-NR a R a’ and-SR a replace; or

[0170] R b1 With R b2 , R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring;

[0171] R b2 Selected from the group consisting of: H, halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkynyl, C 6 -C 12 Aryl, 5- to 12-membered heteroaryl, C 3 -C 10 Cycloalkyl, 3- to 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 8Alkyl-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-OC(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 optionally through -OR a 、-NR a R a’ and-SR a replace; or

[0172] R b2 With R b1 or R b3 and intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring;

[0173] R b3 Selected from the group consisting of: 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 ;

[0174] R b4 selected from the group consisting of H or halogen;

[0175] Each R b5 and R b5’Independently selected from the group consisting of: H, C 1 -C 8 Alkyl, C 1 -C 8 Hydroxyalkyl, 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-, phenyl, phenyl-C 1- C 4 Alkyl-, diphenyl-C 1 -C 4 Alkyl-, heteroaryl- and 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-(C1 -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’ and the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C 4 Alkyl, -OH, -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)-C1 -C 8 Aminoalkyl- and C 1 -C 8 aminoalkyl; or

[0176] R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocyclic, heterocycloalkyl, heterocyclic, phenyl and heteroaryl moieties are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C 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 ;

[0177] R b6 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and

[0178] R a and R a’ Each independently selected from the group consisting of: 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)-,

[0179] wherein D is covalently linked to Q via any suitable linking site on D, optionally wherein a hydrogen atom of a hydroxyl, thiol, primary 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.

[0180] Also provided herein are compositions corresponding to the formula D1 or any variation thereof of a drug unit, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0181] In formula D 0 In some embodiments, E is -NR b5 R b5’ In formula D 0 In some embodiments, E is -OR b5 In some embodiments, E is -OR b5 , R b1 For H, R b2 and R b3 are combined with the intervening atoms to form a 5-membered heterocyclic ring, and R b4 , R b5 and R b6 Each of them is H.

[0182] In some embodiments, R b1 , R b2 , R b3 and R b4 In some embodiments, at least one of R b1 , R b2 , R b3 and R b4 At least one of them is C 1 -C 6 In some embodiments, R b1 , R b2 , R b3 and R b4 At least one of -OR a , and R a H or C 1 -C 6 In some embodiments, R b5 and R b5’ Each is H.

[0183] In some embodiments, the site of covalent attachment of D to a linker (eg, a second linker) of a drug linker moiety is represented by the formula D 1a or D 1b or any variation thereof (e.g., D 1a -I to D 1a -X, D 1b -I to D 1b -X, etc.). It is also contemplated that D may be at any position in D that is compatible with attachment to a linker (e.g., a second linker) (e.g., at any OH, NH2 , NHR, NR 2 SH, etc.) is covalently attached to a linker (e.g., a second linker) of a drug linker moiety, whether or not the site is marked by a dagger in any formula herein. In some embodiments, D is connected to a linker (e.g., a second linker) of a drug linker moiety via R b5 OH or NH 2 The group is linked to the remainder of the drug-linker moiety.

[0184] In some embodiments, D has a formula selected from the group consisting of

[0185]

[0186]

[0187] For formula D 1 -I to D 1 -X and any of its variations, the variables can be based on the formula D 0 or any of its variations, or it can be defined according to formula D 1 In some embodiments, D has a formula corresponding to 1 -I to D 1 -X and any of its variants, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ Missing.

[0188] In some embodiments, D has a formula selected from the group consisting of

[0189]

[0190] in

[0191] X and Y B Each independently is O, S, S(O) 2 , CR x R x’ or NR x ;

[0192] R x and R x’ Each is independently selected from the group consisting of: 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 -C6 Hydroxyalkyl-C(O)-, C 1 -C 6 Alkyl-NH-C(O)- or C 1 -C 6 Alkyl-S(O) 2 -;and

[0193] m and n are each 1 or 2;

[0194] Each R c1 , R c1’ , R c2 and R c2’ Independently

[0195] (i) selected from the group consisting of: 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’ and-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

[0196] (ii) with R b1 Together with the intervening atoms, they form a 5- to 7-membered carbocyclic or heterocyclic ring; or

[0197] (iii) with R x’ Together with the intervening atoms, they form a 3- to 6-membered carbocyclic or heterocyclic ring;

[0198] When both m and n are present, the sum of m+n is 2 or 3; and

[0199] The remaining variables are as for D 1 defined.

[0200] In some embodiments, D has a structure corresponding to any of Formula D1-IIa, D1-IIb, D1-IVa, or D1-IVb, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ Missing.

[0201] In some embodiments, D has a formula selected from the group consisting of

[0202]

[0203] in

[0204] R d1 , R d1’ , R d2 and R d2’ Each independently selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NR a R a’ and-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 -;and

[0205] The remaining variables are as for D 1 In some embodiments, D has a formula selected from the group consisting of

[0206]

[0207] in

[0208] Y 1 is a 5-membered or 6-membered heteroaryl group, which is optionally substituted by 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 - replace; and

[0209] The remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb and D1-Xa.

[0210] In some embodiments, D has a formula selected from the group consisting of

[0211]

[0212] in

[0213] Each R e independently selected from the group consisting of 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)-; f is 0, 1, 2, 3, 4 or 5; and

[0214] The remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb and D1-Xa.

[0215] In some embodiments, D has a formula selected from the group consisting of

[0216]

[0217] in

[0218] R g H, C 1 -C 6 alkyl or a 3- to 8-membered heterocyclic group; and

[0219] The remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb and D1-Xa. In some embodiments, R g C 1 -C 6 alkyl.

[0220] In some embodiments, D has a formula selected from the group consisting of

[0221]

[0222] in

[0223] R 3h , R 3h’and R 3h” Each independently selected from the group consisting of: 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)OC 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 optionally C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NR a R a’ and-SR a replace; and

[0224] The remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb and D1-Xa.

[0225] In some embodiments, D has a formula selected from the group consisting of

[0226]

[0227] Where the variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb and D1-Xa.

[0228] In some embodiments, D is incorporated into a camptothecin having the structure

[0229]

[0230] or a pharmaceutically acceptable salt thereof, wherein each R F and R F’ Independently selected from the group consisting of: -H, C 1-C 8 Alkyl, C 1 -C 8 Hydroxyalkyl, 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-, phenyl, phenyl-C 1- C 4 Alkyl-, diphenyl-C 1 -C 4 Alkyl-, heteroaryl-, and 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-C1 -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 F and R F’ Combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C 4 Alkyl, -OH, -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 C1 -C 8 aminoalkyl; wherein R F and R F’ The cycloalkyl, heterocycloalkyl, phenyl and heteroaryl portions of the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl groups are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C 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 .

[0231] In some embodiments, D is incorporated into a camptothecin having the structure

[0232]

[0233] or a pharmaceutically acceptable salt thereof, wherein each R F and R F’ Independently selected from the group consisting of: -H, C 1 -C 8 Alkyl, C 1 -C 8 Hydroxyalkyl, C 1 -C 6 -OC 1 -C 6 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 -C8 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-, heteroaryl-C 1 -C 6 Hydroxyalkyl, phenyl, phenyl-C 1- C 4 Alkyl-, diphenyl-C 1 -C 4 Alkyl-, heteroaryl-, and 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-, C1 -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 F and R F’ Combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of 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 aminoalkyl; wherein R F and R F’ The cycloalkyl, heterocycloalkyl, phenyl and heteroaryl portions of the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl groups are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C 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 .

[0234] In some embodiments, D has the formula

[0235]

[0236] Wherein the dagger indicates the point of covalent attachment of D to a linker (e.g., a second linker) of the drug linker moiety. In some embodiments, the dagger indicates a direct attachment of the linker to the nitrogen bearing the dagger (e.g., via R b5 In other embodiments, the dagger indicates that the linker and R b5 In some embodiments, R F Selected from the group consisting of: 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 In some embodiments, R F’ is -H. In some embodiments, RF’ In some embodiments, R F and R F’ Combined with the nitrogen atom to which they are attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of: 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 In some embodiments, R F Selected from the group consisting of: C 1 -C 6 Alkyl-OC 1 -C 6 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 10Heterocycloalkyl)-C 1 -C 8 Alkyl, Phenyl-C(O)-, Phenyl-SO 2 - and C 1 -C 8 Hydroxyalkyl-C 3 -C 10 In some embodiments, R F’ is -H. In some embodiments, R F’ In some embodiments, R F and R F’ Combined with the nitrogen atom to which they are attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of: C 1 -C 6 Alkoxy-C(O)-NH-, C 1 -C 6 Alkoxy-C(O)-C 1 -C 8 Aminoalkyl-, C 1 -C 6 Hydroxyalkyl and C 1 -C 8 Aminoalkyl.

[0237] In some embodiments, D is a Drug unit having a formula selected from the group consisting of

[0238]

[0239] or a salt thereof, wherein the sword indicates the site of covalent attachment of D to Q and the remaining variables are as for D 1 In some embodiments, the remaining variables are as defined for D 0 In formula D 1a In some embodiments, the dagger indicates a direct attachment of the linker to the nitrogen bearing the dagger (e.g., via R b5 Partial replacement). In formula D 1a In other embodiments, the dagger indicates that the linker and R b5 The attachment of a suitable atom of the moiety (e.g., a nitrogen or oxygen atom) may be accomplished by bonding.

[0240] In formula D 1a Or D 1b In some embodiments, R b1 , R b2 , R b3 and R b4 Each is hydrogen.

[0241] In formula D 1a Or D 1b In some embodiments, Rb1 , R b2 and R b4 is hydrogen, and R b3 In some embodiments, R b3 For fluorine.

[0242] In formula D 1a Or D 1b In some embodiments, R b2 , R b3 and R b4 is hydrogen, and R b3 In some embodiments, R b1 For fluorine.

[0243] In formula D 1a Or D 1b In some embodiments, R b2 and R b4 is hydrogen, and R b1 and R b3 Both are halogen. In some embodiments, R b1 and R b3 Both are fluorine.

[0244] In formula D 1a Or D 1b In some embodiments, R b1 is hydrogen, and R b2 , R b3 and R b4 In some embodiments, R b2 , R b3 and R b4 Each is fluorine.

[0245] In formula D 1a Or D 1b In some embodiments, R b1 , R b3 and R b4 is hydrogen, and R b2 C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, halogen, -OR a or -SR a In some embodiments, R b2 C 1 -C 6 In some embodiments, R b2 C 1 -C 6 In some embodiments, R b2In some embodiments, R b2 C 1 -C 6 In some embodiments, R b2 In some embodiments, R b2 In some embodiments, R b2 In some embodiments, R b2 In some embodiments, R b2 In some embodiments, R b2 C 1 -C 6 In some embodiments, R b2 In some embodiments, R b2 C 1 -C 6 In some embodiments, R b2 In some embodiments, R b2 It is hydroxyl.

[0246] In formula D 1a Or D 1b In some embodiments, R b1 and R b4 is hydrogen, R b2 C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, halogen, -OR a or -SR a ; and R b3 C 1 -C 6 In some embodiments, R b2 C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, halogen or hydroxy, and R b3 C 1 -C 6 In some embodiments, R b2 C 1 -C 6 In some embodiments, R b2 In some embodiments, R b2 C 1 -C 6 In some embodiments, R b2 In some embodiments, Rb2 In some embodiments, R b2 In some embodiments, R b2 In some embodiments, R b3 C 1 -C 6 In some embodiments, R b3 In some embodiments, R b3 In some embodiments, R b3 In some embodiments, R b2 C 1 -C 6 Alkyl and R b3 In some embodiments, R b2 is methyl and R b3 In some embodiments, R b2 C 1 -C 6 Alkoxy and R b3 In some embodiments, R b2 is methoxy and R b3 In some embodiments, R b2 and R b3 In some embodiments, R b2 and R b3 In some embodiments, R b2 is a halogen and R b3 C 1 -C 6 In some embodiments, R b2 is fluorine and R b3 In some embodiments, R b2 is hydroxyl and R b3 In some embodiments, R b2 is hydroxyl and R b3 For fluorine.

[0247] In formula D 1a Or D 1b In some embodiments, R b2 C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, halogen, -OR a or -SR a ; R b1 and R b3 Both are independently selected from the group consisting of: C 1 -C 6Alkyl, halogen, C 2 -C 6 Alkenyl, (C 6 -C 12 Aryl)-C 2 -C 6 Alkenyl-, the group is optionally substituted by -OR a AND-OR a Replace; and R b4 In some embodiments, R b2 C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, halogen, -OR a or -SR a ; R b1 and R b3 Both are independently selected from the group consisting of: C 1 -C 6 Alkyl, halogen, C 2 -C 6 Alkenyl, (C 6 -C 12 Aryl)-C 2 -C 6 Alkenyl-, each optionally substituted with -OR a AND-OR a Replace; and R b4 In some embodiments, R b1 C 1 -C 6 In some embodiments, R b1 In some embodiments, R b1 In some embodiments, R b1 In some embodiments, R b1 In some embodiments, R b1 In some embodiments, R b1 For optionally -OR a Replaced (C 6 -C 12 Aryl)-C 2 -C 6 In some embodiments, R b1 In some embodiments, R b1 C 2 -C 6 In some embodiments, R b1 In some embodiments, R b1 In some embodiments, Rb1 In some embodiments, R b2 C 1 -C 6 In some embodiments, R b2 In some embodiments, R b2 C 1 -C 6 In some embodiments, R b2 In some embodiments, R b2 In some embodiments, R b3 C 1 -C 6 In some embodiments, R b3 In some embodiments, R b3 In some embodiments, R b3 C 1 -C 6 In some embodiments, R b3 In some embodiments, R b3 In some embodiments, R b3 In some embodiments, R b3 In some embodiments, R b3 In some embodiments, R b2 C 1 -C 6 Alkyl and R b1 and R b3 In some embodiments, R b2 is methyl and R b1 and R b3 In some embodiments, R b2 is methyl, R b1 is fluorine and R b3 In some embodiments, R b2 is methyl, R b1 is bromine and R b3 In some embodiments, R b2 is methyl, R b1 is chlorine and R b3 In some embodiments, R b2 is methyl, R b1 is fluorine and R b3 In some embodiments, R b2 C 1 -C 6 Alkoxy and R b1 and R b3In some embodiments, R b2 is methoxy and R b1 and R b3 In some embodiments, R b2 is methoxy, R b1 is bromine and R b3 In some embodiments, R b2 is methoxy, R b1 is fluorine and R b3 In some embodiments, R b2 is hydroxyl and R b1 and R b3 In some embodiments, R b2 is hydroxyl and R b1 and R b3 In some embodiments, R b1 is a halogen and R b2 and R b3 Both are C 1 -C 6 In some embodiments, R b1 is fluorine and R b2 and R b3 In some embodiments, R b1 is fluorine, R b2 is methyl and R b3 In some embodiments, R b1 and R b2 Both are C 1 -C 6 Alkyl and R b3 In some embodiments, R b1 and R b2 Both are methyl and R b3 For fluorine.

[0248] In some embodiments, D has a formula selected from the group consisting of

[0249]

[0250]

[0251] For formula D 1a -I to D 1a -X or any of its variant forms, the variables can be based on the formula D 0 or any of its variations, or it can be defined according to formula D 1 or any variation thereof.

[0252] In some embodiments, D has a formula selected from the group consisting of

[0253]

[0254] For formula D 1b -I to D 1b -X or any of its variant forms, the variables can be based on the formula D 0 or any of its variations, or it can be defined according to formula D 1 In some embodiments, D has a formula corresponding to 1b -I to D 1b -IX and any of its variants, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ Missing.

[0255] In formula D 1a Or D 1b In some embodiments, R b1 With R b2 and intervening atoms to form a 5-membered or 6-membered carbocyclic or heterocyclic ring. In some embodiments, the drug has the following formula D 1a / b -I, Formula D 1a / b -II or Formula D 1a / b -III structure:

[0256]

[0257] In formula D 1a Or D 1b In some embodiments, R b2 With R b3 and intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring; wherein one or more hydrogens are optionally replaced by deuterium. In some embodiments, the drug has the following 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 -IX structure:

[0258]

[0259] For formula D 1a / b -I to D 1 / ba -IX or any of its variant forms, the variables may be according to formula D 0 or any of its variations, or it can be defined according to formula D 1In some embodiments, D has a formula corresponding to 1a / b -I to D 1a / b -X and any of its variants, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ Missing.

[0260] In formula D 1 In some embodiments, R b5 and R b5’ Both are H. In some embodiments, R b5 C 1 -C 6 alkyl (e.g., methyl, ethyl), and R b5’ For H.

[0261] In formula D 1a Or D 1b In some embodiments, R b1 With R b5 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring. In some embodiments, the drug has the following formula D 1a / b -X structure:

[0262]

[0263] In some embodiments, D has a formula selected from the group consisting of

[0264]

[0265] in

[0266] X and Y B Each independently is O, S, S(O) 2 , CR x R x’ or NR x ;

[0267] R x and R x’ Each is independently selected from the group consisting of: 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 -C6 Alkyl-NH-C(O)- or C 1 -C 6 Alkyl-S(O) 2 -;and

[0268] m and n are each 1 or 2;

[0269] Each R c1 , R c1’ , R c2 and R c2’ Independently

[0270] (i) selected from the group consisting of: 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’ and-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

[0271] (ii) with R b1 Together with the intervening atoms, they form a 5- to 7-membered carbocyclic or heterocyclic ring; or

[0272] (iii) with R x’ Together with the intervening atoms, they form a 3- to 6-membered carbocyclic or heterocyclic ring; or

[0273] R c1 , R c1’ , R c2 and R c2’ Any two of the c1 , R c1’ , R c2 and R c2’ The remaining two of are independently selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NRa R a’ and-SR a 、-C(O)-C 1 -C 6 Alkyl, -C(O)NR a -C 1 -C 6 Alkyl and -S(O) 2 -C 1 -C 6 alkyl;

[0274] When both m and n are present, the sum of m+n is 2 or 3; and

[0275] The remaining variables are as for D 1a and D 1b defined.

[0276] In some embodiments, D has the formula D1a-IIa, wherein X is O. In some embodiments, D has the formula D1a-IIa, wherein X is S. In some embodiments, D has the formula D1a-IIa, wherein 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 CR x R x’ In some embodiments, D has the formula D1a-IIa, wherein X is O and Y B CR x R x’ In some embodiments, D has the formula D1a-IIa, wherein X is O and Y B CR x R x’ , where R x and R x’ Both are H. In some embodiments, D has the formula D1a-IIa, wherein X is CR x R x’ And Y B In some embodiments, D has the formula D1a-IIa, wherein X is CR x R x’ And Y B is O, where R x and R x’ Both are H. In some embodiments, D has the formula D1a-IIa, wherein X is S and Y B CRx R x’ In some embodiments, D has the formula D1a-IIa, wherein X is S and Y B CR x R x’ , where R x and R x’ Both are H. In some embodiments, D has the formula D1a-IIa, wherein X is CR x R x’ And Y B is S. In some embodiments, D has the formula D1a-IIa, wherein X is CR x R x’ And Y B is S, where R x and R x’ Both are H. In some embodiments, D has the formula D1a-IIa, wherein X and Y B Both are CR x R x’ In some embodiments, D has the formula D1a-IIa, wherein X and Y B Both are CR x R x’ , where R x and R x Both are H. In some embodiments, D has the formula D1a-IIa, wherein X and Y B Both are CR x R x’ , and R b3 In some embodiments, D has the formula D1a-IIa, wherein X and Y B Both are CR x R x’ , R x and R x’ Both are H, and R b3 In some embodiments, D has the formula D1a-IIa, wherein X and Y B Both are CR x R x’ , R x and R x’ Both are H, and R b3 In some embodiments, D has the formula D1a-IIa, wherein X and Y B Both are CR x R x’ , where R x and R x’Both are 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’ Both are H.

[0277] In some embodiments, D has the formula D1a-IIb, wherein X is O. In some embodiments, D has the formula D1a-IIb, wherein X is CR x R x’ In some embodiments, D has the formula D1a-IIb, wherein X is CR x R x’ , where R x and R x’ Both are H. In some embodiments, D has the 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 CR x R x’ , R x and R x’ Both are H, and R b3 In some embodiments, D has the formula D1a-IIb, wherein X is CR x R x’ , R x and R x’ Both are H, and R b3 is fluorine. In some embodiments, n is 1. In some embodiments, m is 1. In some embodiments, both n and m are 1. In some embodiments, R b5 is H. In some embodiments, R b5’ is H. In some embodiments, R b5 and R b5’ Both are H.

[0278] In some embodiments, D has the formula D1a-IVa, wherein X is O. In some embodiments, D has the formula D1a-IVa, wherein X is S. In some embodiments, D has the formula D1a-IVa, wherein X is CR x R x’ In some embodiments, D has the formula D1a-IVa, wherein X is CR x R x’ , where R x and R x’Both are H. In some embodiments, D has the formula D1a-IVa, wherein X is CR x R x’ And R b1 In some embodiments, D has the formula D1a-IVa, wherein X is CR x R x’ , R x and R x’ Both are H, and R b1 In some embodiments, D has the formula D1a-IVa, wherein X is CR x R x’ , R x and R x’ Both are H, and R b1 In some embodiments, D has the formula D1a-IVa, wherein X is O and R c1 C 1 -C 6 In some embodiments, D has the formula D1a-IVa, wherein X is O and R c1 is methyl. In some embodiments, n is 1. In some embodiments, both n and m are 1. In some embodiments, R b5 is H. In some embodiments, R b5’ is H. In some embodiments, R b5 and R b5’ Both are H.

[0279] In some embodiments, D has the formula D1a-IVb, wherein X is O. In some embodiments, D has the formula D1a-IVb, wherein X is S. In some embodiments, D has the formula D1a-IVb, wherein X is CR x R x’ In some embodiments, D has the formula D1a-IVb, wherein X is CR x R x’ , where R x and R x’ Both are H. In some embodiments, D has the 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’ , R x and R x’ Both are H, and R b1 In some embodiments, D has the formula D1a-IVb, wherein X is CR xR x’ , R x and R x’ Both are H, and R b1 In some embodiments, D has the formula D1a-IVb, wherein X is O and R c1 C 1 -C 6 In some embodiments, D has the formula D1a-IVb, wherein X is O and R c1 is methyl. In some embodiments, n is 1. In some embodiments, both n and m are 1. In some embodiments, R b5 is H. In some embodiments, R b5’ is H. In some embodiments, R b5 and R b5’ Both are H.

[0280] In some embodiments, D has the formula D1a-Xa, wherein n is 1 or 2. In some embodiments, D has the formula D1a-Xa, wherein n is 1. In some embodiments, D has the formula D1a-Xa, wherein n is 2. In some embodiments, D has the formula D1a-Xa, wherein R b5’ is H. In some embodiments, D has the formula D1a-Xa, wherein n is 1 and R b5’ is H. In some embodiments, R b2 In some embodiments, R b3 In some embodiments, R b3 In some embodiments, R b2 OH and R b3 For fluorine.

[0281] In some embodiments, D has a formula selected from the group consisting of

[0282]

[0283] Where the variables are as for D 1a , D 1b In some embodiments, D has a formula corresponding to D 1a , D 1b , D1a-IIa, D1a-IIb, D1a-IVa and D1a-IVb and their variations, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ Missing.

[0284] In some embodiments, D has the formula D1b-IIa, wherein X is O. In some embodiments, D has the formula D1b-IIa, wherein X is S. In some embodiments, D has the formula D1b-IIa, wherein 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 CR x R x’ In some embodiments, D has the formula D1b-IIa, wherein X is O and Y B CR x R x’ In some embodiments, D has the formula D1b-IIa, wherein X is O and Y B CR x R x’ , where R x and R x’ Both are H. In some embodiments, D has the formula D1b-IIa, wherein X is CR x R x’ And Y B In some embodiments, D has the formula D1b-IIa, wherein X is CR x R x’ And Y B is O, where R x and R x’ Both are H. In some embodiments, D has the formula D1b-IIa, wherein X is S and Y B CR x R x’ In some embodiments, D has the formula D1b-IIa, wherein X is S and Y B CR x R x’ , where R x and R x’ Both are 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, where R x and R x’Both are H. In some embodiments, D has the formula D1b-IIa, wherein X and Y B Both are CR x R x’ In some embodiments, D has the formula D1b-IIa, wherein X and Y B Both are CR x R x’ , where R x and R x’ Both are H. In some embodiments, D has the formula D1b-IIa, wherein X and Y B Both are CR x R x’ , and R b3 In some embodiments, D has the formula D1b-IIa, wherein X and Y B Both are CR x R x’ , R x and R x’ Both are H, and R b3 In some embodiments, D has the formula D1b-IIa, wherein X and Y B Both are CR x R x’ , R x and R x’ Both are H, and R b3 In some embodiments, D has the formula D1b-IIa, wherein X and Y B Both are CR x R x’ , where R x and R x’ Both are 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’ Both are H.

[0285] In some embodiments, D has the formula D1b-IIb, wherein X is O. In some embodiments, D has the formula D1b-IIb, wherein X is CR x R x’ In some embodiments, D has the formula D1b-IIb, wherein X is CR x R x’ , where R x and R x’Both are 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, wherein X is CR x R x’ , R x and R x’ Both are H, and R b3 In some embodiments, D has the formula D1b-IIb, wherein X is CR x R x’ , R x and R x’ Both are H, and R b3 is fluorine. In some embodiments, n is 1. In some embodiments, m is 1. In some embodiments, both n and m are 1. In some embodiments, R b5 is H. In some embodiments, R b5’ is H. In some embodiments, R b5 and R b5’ Both are H.

[0286] In some embodiments, D has the formula D1b-IVa, wherein X is O. In some embodiments, D has the formula D1b-IVa, wherein X is S. In some embodiments, D has the formula D1b-IVa, wherein X is CR x R x’ In some embodiments, D has the formula D1b-IVa, wherein X is CR x R x’ , where R x and R x’ Both are 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’ , R x and R x’ Both are H, and R b1 In some embodiments, D has the formula D1b-IVa, wherein X is CR x R x’ , R x and R x’ Both are H, and R b1 In some embodiments, D has the formula D1b-IVa, wherein X is O and Rc1 C 1 -C 6 In some embodiments, D has the formula D1b-IVa, wherein X is O and R c1 is methyl. In some embodiments, n is 1. In some embodiments, both n and m are 1. In some embodiments, R b5 is H. In some embodiments, R b5’ is H. In some embodiments, R b5 and R b5’ Both are H.

[0287] In some embodiments, D has the formula D1b-IVb, wherein X is O. In some embodiments, D has the formula D1b-IVb, wherein X is S. In some embodiments, D has the formula D1b-IVb, wherein X is CR x R x’ In some embodiments, D has the formula D1b-IVb, wherein X is CR x R x’ , where R x and R x’ Both are 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, wherein X is CR x R x’ , R x and R x’ Both are H, and R b1 In some embodiments, D has the formula D1b-IVb, wherein X is CR x R x’ , R x and R x’ Both are H, and R b1 In some embodiments, D has the formula D1b-IVb, wherein X is O and R c1 C 1 -C 6 In some embodiments, D has the formula D1b-IVb, wherein X is O and R c1 is methyl. In some embodiments, n is 1. In some embodiments, both n and m are 1. In some embodiments, R b5 is H. In some embodiments, R b5’ is H. In some embodiments, R b5 and R b5’ Both are H.

[0288] In some embodiments, D has the formula D1b-Xa, wherein n is 1 or 2. In some embodiments, D has the formula D1b-Xa, wherein n is 1. In some embodiments, D has the formula D1b-Xa, wherein n is 2. In some embodiments, D has the formula D1b-Xa, wherein R b5’ is H. In some embodiments, D has the formula D1b-Xa, wherein n is 1 and R b5’ is H. In some embodiments, R b2 In some embodiments, R b3 In some embodiments, R b3 In some embodiments, R b2 OH and R b3 For fluorine.

[0289] In some embodiments, D has a formula selected from the group consisting of

[0290]

[0291] in

[0292] R d1 , R d1’ , R d2 and R d2’ Each independently selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NR a R a’ and-SR a 、-C(O)-C 1 -C 6 Alkyl, -C(O)NR a -C 1 -C 6 Alkyl and S(O) 2 -C 1 -C 6 Alkyl; and

[0293] The remaining variables are as for D 1a and D 1b In some embodiments, D has a structure corresponding to any one of Formulae D1a-XI and D1b-XI and variations thereof, wherein NH 2 The group is replaced by an OH group.

[0294] In some embodiments, D has the formula D1a-XI, wherein R b2Selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a and-SR a , where each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1a-XI, wherein R b3 Selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a and-SR a , where each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1a-XI, wherein X is O, S, S(O) 2 , CR x R x’ or NR x ; where R x and R x’ Each is independently selected from the group consisting of: H, OH, C 1 -C 6 Alkyl, -C(O)-C 1 -C 6 Alkyl, -C(O)NH-C 1 -C 6 Alkyl and S(O) 2 -C 1 -C 6 alkyl.

[0295] In some embodiments, D has the formula D1a-XI, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1a-XI, wherein R b2 In some embodiments, D has the formula D1a-XI, wherein R b3In some embodiments, D has the formula D1a-XI, wherein R b3 In some embodiments, D has the formula D1a-XI, wherein R b2 is methyl and R b3 is fluorine. In some embodiments, D is of formula D1a-XI, wherein n is 1 or 2. In some embodiments, D is of formula D1a-XI, wherein n is 1. In some embodiments, D is of formula D1a-XI, wherein n is 2. In some embodiments, D is of formula D1a-XI, wherein m is 1 or 2. In some embodiments, D is of formula D1a-XI, wherein m is 1. In some embodiments, D is of formula D1a-XI, wherein m is 2. In some embodiments, D is of formula D1a-XI, wherein both n and m are 1. In some embodiments, D is of formula D1a-XI, wherein n is 1 and m is 2. In some embodiments, D is of formula D1a-XI, wherein n is 2 and m is 1. In some embodiments, D is of formula D1a-XI, wherein X is O. In some embodiments, D is of formula D1a-XI, wherein X is CR x R x’ In some embodiments, D has the formula D1a-XI, wherein X is CR x R x’ , and R x and R x’ Both are H. In some embodiments, D has the formula D1a-XI, wherein X is NR x In some embodiments, D has the formula D1a-XI, wherein X is NR x , where R x C 1 -C 6 In some embodiments, D has the formula D1a-XI, wherein X is NR x , where R x In some embodiments, D has the formula D1a-XI, wherein X is NR x , where R x In some embodiments, D has the formula D1a-XI, wherein X is S. In some embodiments, D has the formula D1a-XI, wherein X is S(O) 2 In some embodiments, D has the formula D1a-XI, wherein X is -S(O) 2 -C 1 -C 6 In some embodiments, D has the formula D1a-XI, wherein X is -S(O) 2 -CH 3 .

[0296] In some embodiments, D has the formula D1b-XI, wherein R b2 Selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a and-SR a , where each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1b-XI, wherein R b3 Selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a and-SR a , where each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1b-XI, wherein X is O, S, S(O) 2 , CR x R x’ or NR x ; where R x and R x’ Each is independently selected from the group consisting of: H, OH, C 1 -C 6 Alkyl, -C(O)-C 1 -C 6 Alkyl, -C(O)NH-C 1 -C 6 Alkyl and S(O) 2 -C 1 -C 6 alkyl.

[0297] In some embodiments, D has the formula D1b-XI, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1b-XI, wherein R b2 In some embodiments, D has the formula D1b-XI, wherein Rb3 In some embodiments, D has the formula D1b-XI, wherein R b3 In some embodiments, D has the formula D1b-XI, wherein R b2 is methyl and R b3 is fluorine. In some embodiments, D has the formula D1b-XI, wherein n is 1 or 2. In some embodiments, D has the formula D1b-XI, wherein n is 1. In some embodiments, D has the formula D1b-XI, wherein n is 2. In some embodiments, D has the formula D1b-XI, wherein m is 1 or 2. In some embodiments, D has the formula D1b-XI, wherein m is 1. In some embodiments, D has the formula D1b-XI, wherein m is 2. In some embodiments, D has the formula D1b-XI, wherein both n and m are 1. In some embodiments, D has the formula D1b-XI, wherein n is 1 and m is 2. In some embodiments, D has the formula D1b-XI, wherein n is 2 and m is 1. In some embodiments, D has the formula D1b-XI, wherein X is O. In some embodiments, D has the formula D1b-XI, wherein X is CR x R x’ In some embodiments, D has the formula D1b-XI, wherein X is CR x R x’ , and R x and R x’ Both are H. In some embodiments, D has the formula D1b-XI, wherein X is NR x In some embodiments, D has the formula D1b-XI, wherein X is NR x , where R x C 1 -C 6 In some embodiments, D has the formula D1b-XI, wherein X is NR x , where R x In some embodiments, D has the formula D1b-XI, wherein X is NR x , where R x In some embodiments, D has the formula D1b-XI, wherein X is S. In some embodiments, D has the formula D1b-XI, wherein X is S(O) 2 In some embodiments, D has the formula D1b-XI, wherein X is -S(O) 2 -C 1 -C 6 In some embodiments, D has the formula D1b-XI, wherein X is -S(O) 2 -CH 3 .

[0298] In some embodiments, D has a formula selected from the group consisting of

[0299]

[0300] in

[0301] Y 1 is a 5- or 6-membered heteroaryl group, which is optionally substituted by 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 - replace; and

[0302] The remaining variables are as for D 1a and D 1b In some embodiments, D has a structure corresponding to any one of Formulas D1a-XII and D1b-XII and variations thereof, wherein NH 2 The group is replaced by an OH group.

[0303] In some embodiments, D has D1a-XII, wherein R b2 Selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a and-SR a , where each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1a-XII, wherein R b3 Selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a and-SR a , where each R a Independently selected from the group consisting of: H, C 1 -C6 Alkyl and C 1 -C 6 Halogenated alkyl.

[0304] In some embodiments, D has the formula D1a-XII, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1a-XII, wherein R b2 In some embodiments, D has the formula D1a-XII, wherein R b3 In some embodiments, D has the formula D1a-XII, wherein R b3 In some embodiments, D has the formula D1b-XI, wherein R b2 is methyl and R b3 In some embodiments, D has the formula D1a-XII, wherein Y 1 is optionally C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl or -S(O) 2 -C 1 -C 6 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 an unsubstituted thiophene. In some embodiments, D has the formula D1a-XII, wherein Y 1 is unsubstituted thiophene; and R b2 is methyl and R b3 In some embodiments, D has the formula D1a-XII, wherein Y 1 It is C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl or -S(O) 2 -C 1 -C 6 In some embodiments, D has the formula D1a-XII, wherein Y 1 It is C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl or -S(O) 2 -C 1 -C 6In some embodiments, D has the formula D1a-XII, wherein Y 1 It is C 1 -C 6 In some embodiments, D has the formula D1a-XII, wherein Y 1 is a thiophene substituted with hydroxyethyl. In some embodiments, D has the formula D1a-XII, wherein Y 1 is thiophene substituted with hydroxyethyl; and R b2 is methyl and R b3 In some embodiments, D has the formula D1a-XII, wherein Y 1 is furan. In some embodiments, D has the formula D1a-XII, wherein Y 1 is an unsubstituted furan. In some embodiments, D has the formula D1a-XII, wherein Y 1 In some embodiments, D has the formula D1a-XII, wherein Y 1 is a substituted pyrrole. In some embodiments, D has the formula D1a-XII, wherein Y 1 It is composed of -S(O) 2 -C 1 -C 6 In some embodiments, D has the formula D1a-XII, wherein Y 1 It is composed of -S(O) 2 -CH 3 In some embodiments, D has the formula D1a-XII, wherein Y 1 In some embodiments, D has the formula D1a-XII, wherein Y 1 is an unsubstituted pyridine. In some embodiments, D has the formula D1a-XII, wherein Y 1 isoxazole. In some embodiments, D has the formula D1a-XII, wherein Y 1 is an unsubstituted isoxazole. In some embodiments, D has the formula D1a-XII, wherein Y 1 is composed of one or more C 1 -C 6 In some embodiments, D has the formula D1a-XII, wherein Y 1 is an isoxazole substituted with one or more methyl groups. In some embodiments, D has the formula D1a-XII, wherein Y 1 isoxazole substituted with one methyl group. In some embodiments, D has the formula D1a-XII, wherein Y 1 It is an isoxazole substituted with two methyl groups.

[0305] In some embodiments, D has the formula D1b-XII, wherein R b2 Selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a and-SR a , where each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1b-XII, wherein R b3 Selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a and-SR a , where each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 Halogenated alkyl.

[0306] In some embodiments, D has the formula D1b-XII, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1b-XII, wherein R b2 In some embodiments, D has the formula D1b-XII, wherein R b3 In some embodiments, D has the formula D1b-XII, wherein R b3 In some embodiments, D has the formula D1b-XI, wherein R b2 is methyl and R b3 In some embodiments, D has the formula D1b-XII, wherein Y 1 is optionally C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl or -S(O) 2 -C 1 -C 6In 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 an unsubstituted thiophene. In some embodiments, D has the formula D1b-XII, wherein Y 1 is unsubstituted thiophene; and R b2 is methyl and R b3 In some embodiments, D has the formula D1b-XII, wherein Y 1 It is C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl or -S(O) 2 -C 1 -C 6 In some embodiments, D has the formula D1b-XII, wherein Y 1 It is C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl or -S(O) 2 -C 1 -C 6 In some embodiments, D has the formula D1b-XII, wherein Y 1 It is C 1 -C 6 In some embodiments, D has the formula D1b-XII, wherein Y 1 is a thiophene substituted with hydroxyethyl. In some embodiments, D has the formula D1b-XII, wherein Y 1 is thiophene substituted with hydroxyethyl; and R b2 is methyl and R b3 In some embodiments, D has the formula D1b-XII, wherein Y 1 is furan. In some embodiments, D has the formula D1b-XII, wherein Y 1 is an unsubstituted furan. In some embodiments, D has the formula D1b-XII, wherein Y 1 In some embodiments, D has the formula D1b-XII, wherein Y 1 is a substituted pyrrole. In some embodiments, D has the formula D1b-XII, wherein Y 1 It is composed of -S(O) 2 -C 1 -C 6In some embodiments, D has the formula D1b-XII, wherein Y 1 It is composed of -S(O) 2 -CH 3 In some embodiments, D has the formula D1b-XII, wherein Y 1 is pyridine. In some embodiments, D has the formula D1b-XII, wherein Y 1 is an unsubstituted pyridine. In some embodiments, D has the formula D1b-XII, wherein Y 1 isoxazole. In some embodiments, D has the formula D1b-XII, wherein Y 1 is an unsubstituted isoxazole. In some embodiments, D has the formula D1b-XII, wherein Y 1 is composed of one or more C 1 -C 6 In some embodiments, D has the formula D1b-XII, wherein Y 1 is an isoxazole substituted with one or more methyl groups. In some embodiments, D has the formula D1b-XII, wherein Y 1 isoxazole substituted with one methyl group. In some embodiments, D has the formula D1b-XII, wherein Y 1 It is an isoxazole substituted with two methyl groups.

[0307] In some embodiments, D has a formula selected from the group consisting of

[0308]

[0309] in

[0310] Each R e independently selected from the group consisting of halogen, -OH, -NH 2 , C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, -S(O) 2 -C 1 -C 6 Alkyl and -C(O)NH-C 1 -C 6 alkyl;

[0311] f is 0, 1, 2, 3, 4, or 5; and

[0312] The remaining variables are as for D 1a and D 1bIn some embodiments, D has a structure corresponding to any one of Formulae D1a-XIII and D1b-XIII and variations thereof, wherein NH 2 The group is replaced by an OH group.

[0313] In some embodiments, D has D1a-XIII, wherein R b2 Selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a and-SR a , where each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1a-XIII, wherein R b3 Selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a and-SR a , where each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1a-XIII, wherein R e Selected from the group consisting of halogen, -OH, -NH 2 , C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, -S(O) 2 -C 1 -C 6 Alkyl and -C(O)NH-C 1 -C 6In some embodiments, D has the formula D1a-XIII, wherein f is 0, 1, 2, 3, 4, or 5. In some embodiments, D has the formula D1a-XIII, wherein f is 0. In some embodiments, D has the formula D1a-XIII, wherein f is 1. In some embodiments, D has the formula D1a-XIII, wherein f is 2. In some embodiments, D has the formula D1a-XIII, wherein f is 3. In some embodiments, D has the formula D1a-XIII, wherein f is 4. In some embodiments, D has the formula D1a-XIII, wherein f is 5.

[0314] In some embodiments, D has the formula D1a-XIII, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1a-XIII, wherein R b2 In some embodiments, D has the formula D1a-XIII, wherein R b3 In some embodiments, D has the formula D1a-XIII, wherein R b3 In some embodiments, D has the formula D1a-XIII, wherein R b2 is methyl and R b3 In some embodiments, D has the formula D1a-XIII, wherein R e In some embodiments, D has the formula D1a-XIII, wherein R e is -OH and f is 1. In some embodiments, D has the formula D1a-XIII, wherein R e In some embodiments, D has the formula D1a-XIII, wherein R e In some embodiments, D has the formula D1a-XIII, wherein R e For -NH 2 In some embodiments, D has the formula D1a-XIII, wherein R e -C(O)NH-C 1 -C 6 alkyl.

[0315] In some embodiments, D has the formula D1b-XIII, wherein R b2 Selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a and-SR a, where each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1b-XIII, wherein R b3 Selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a and-SR a , where each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1b-XIII, wherein R e Selected from the group consisting of halogen, -OH, -NH 2 , C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl, -S(O) 2 -C 1 -C 6 Alkyl and -C(O)NH-C 1 -C 6 In some embodiments, D has the formula D1b-XIII, wherein f is 0, 1, 2, 3, 4, or 5. In some embodiments, D has the formula D1b-XIII, wherein f is 0. In some embodiments, D has the formula D1b-XIII, wherein f is 1. In some embodiments, D has the formula D1b-XIII, wherein f is 2. In some embodiments, D has the formula D1b-XIII, wherein f is 3. In some embodiments, D has the formula D1b-XIII, wherein f is 4. In some embodiments, D has the formula D1b-XIII, wherein f is 5.

[0316] In some embodiments, D has the formula D1b-XIII, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1b-XIII, wherein R b2 In some embodiments, D has the formula D1b-XIII, wherein R b3In some embodiments, D has the formula D1b-XIII, wherein R b3 In some embodiments, D has the formula D1b-XIII, wherein R b2 is methyl and R b3 In some embodiments, D has the formula D1b-XIII, wherein R e In some embodiments, D has the formula D1b-XIII, wherein R e is -OH and f is 1. In some embodiments, D has the formula D1b-XIII, wherein R e In some embodiments, D has the formula D1b-XIII, wherein R e In some embodiments, D has the formula D1b-XIII, wherein R e For -NH 2 In some embodiments, D has the formula D1b-XIII, wherein R e -C(O)NH-C 1 -C 6 alkyl.

[0317] In some embodiments, D has a formula selected from the group consisting of

[0318]

[0319] in

[0320] R g H, C 1 -C 6 alkyl or a 3- to 8-membered heterocyclic group; and

[0321] The remaining variables are as for D 1a and D 1b In some embodiments, R g C 1 -C 6 In some embodiments, D has a structure corresponding to any one of Formulas D1a-XIV and D1b-XIV and variations thereof, wherein NH 2 The group is replaced by an OH group.

[0322] In some embodiments, D has the formula D1a-XIV, wherein R b2 H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a; Each R a Independently selected from H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1a-XIV, wherein R b3 H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1a-XIV, wherein R g H, C 1 -C 6 An alkyl group or a 3- to 8-membered heterocyclic group.

[0323] In some embodiments, D has the formula D1a-XIV, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1a-XIV, wherein R b2 In some embodiments, D has the formula D1a-XIV, wherein R b3 In some embodiments, D has the formula D1a-XIV, wherein R b3 In some embodiments, D has the formula D1a-XIV, wherein R b2 is methyl and R b3 In some embodiments, D has the formula D1a-XIV, wherein R g is H. In some embodiments, D has the formula D1a-XIV, wherein R g C 1 -C 6 In some embodiments, D has the formula D1a-XIV, wherein R g is a 3- to 8-membered heterocyclyl. In some embodiments, D has the formula D1a-XIV, wherein R g For H, R b2 is methyl, and R b3 For fluorine.

[0324] In some embodiments, D has the formula D1b-XIV, wherein Rb2 H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1b-XIV, wherein R b3 H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1b-XIV, wherein R g H, C 1 -C 6 An alkyl group or a 3- to 8-membered heterocyclic group.

[0325] In some embodiments, D has the formula D1b-XIV, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1b-XIV, wherein R b2 In some embodiments, D has the formula D1b-XIV, wherein R b3 In some embodiments, D has the formula D1b-XIV, wherein R b3 In some embodiments, D has the formula D1b-XIV, wherein R b2 is methyl and R b3 In some embodiments, D has the formula D1b-XIV, wherein R g is H. In some embodiments, D has the formula D1b-XIV, wherein R g C 1 -C 6 In some embodiments, D has the formula D1b-XIV, wherein R gis a 3- to 8-membered heterocyclyl. In some embodiments, D has the formula D1b-XIV, wherein R g For H, R b2 is methyl, and R b3 For fluorine.

[0326] In some embodiments, D has a formula selected from the group consisting of

[0327]

[0328] in

[0329] R 3h , R 3h’ and R 3h” Each independently selected from the group consisting of: 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)OC 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 optionally C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NR a R a’ and-SR a Replace; and the remaining variables are as for D 1a and D 1b In some embodiments, D has a structure corresponding to any one of Formulas D1a-XV and D1b-XV and variations thereof, wherein NH 2 The group is replaced by an OH group.

[0330] In some embodiments, D has the formula D1a-XV, wherein R b2 H, halogen, C 1-C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1a-XV, wherein R b3 H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from H, C 1 -C 6 Alkyl and C 1 -C 6 A group consisting of haloalkyl.

[0331] In some embodiments, D has the formula D1a-XV, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1a-XV, wherein R b2 In some embodiments, D has the formula D1a-XV, wherein R b2 In some embodiments, D has the formula D1a-XV, wherein R b2 In some embodiments, D has the formula D1a-XV, wherein R b2 In some embodiments, D has the formula D1a-XV, wherein R b3 In some embodiments, D has the formula D1a-XV, wherein R b3 In some embodiments, D has the formula D1a-XV, wherein R b2 is methyl and R b3 In some embodiments, D has the formula D1a-XV, wherein R b2 H and R b3 In some embodiments, D has the formula D1a-XV, wherein R b2 and R b3 In some embodiments, D has the formula D1a-XV, wherein R b2is -OH and R b3 is H. In some embodiments, D has the formula D1a-XV, wherein R 3h , R 3h’ and R 3h” Each is H. In some embodiments, D has the formula D1a-XV, wherein R 3h and R 3h’ Both are H and R 3h” C 1 -C 6 In some embodiments, D has the formula D1a-XV, wherein R 3h and R 3h’ Both are H and R 3h” In some embodiments, D has the formula D1a-XV, wherein R 3h and R 3h’ Both are C 1 -C 6 Alkyl and R 3h” is H. In some embodiments, D has the formula D1a-XV, wherein R 3h and R 3h’ Both are methyl and R 3h” is H. In some embodiments, D has the formula D1a-XV, wherein R 3h is H, and R 3h’ and R 3h” In some embodiments, D has the formula D1a-XV, wherein R b2 is methyl, R b3 is fluorine, and R 3h , R 3h’ and R 3h” Each is H. In some embodiments, D has the formula D1a-XV, wherein R b2 is methyl, R b3 is fluorine, R 3h and R 3h’ Both are H, and R 3h” In some embodiments, D has the formula D1a-XV, wherein R 3h and R 3h” Both are H, and R 3h’ For -C 6 -C 10 Aryl-C 1 -C 6 Alkoxy.

[0332] In some embodiments, D has the formula D1b-XV, wherein R b2 H, halogen, C 1 -C 6 Alkyl, C1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1b-XV, wherein R b3 H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from H, C 1 -C 6 Alkyl and C 1 -C 6 A group consisting of haloalkyl.

[0333] In some embodiments, D has the formula D1b-XV, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1b-XV, wherein R b2 In some embodiments, D has the formula D1b-XV, wherein R b2 In some embodiments, D has the formula D1b-XV, wherein R b2 In some embodiments, D has the formula D1b-XV, wherein R b2 In some embodiments, D has the formula D1b-XV, wherein R b3 In some embodiments, D has the formula D1b-XV, wherein R b3 In some embodiments, D has the formula D1b-XV, wherein R b2 is methyl and R b3 In some embodiments, D has the formula D1b-XV, wherein R b2 H and R b3 In some embodiments, D has the formula D1b-XV, wherein R b2 and R b3 In some embodiments, D has the formula D1b-XV, wherein R b2 is -OH and R b3is H. In some embodiments, D has the formula D1b-XV, wherein R 3h , R 3h’ and R 3h” Each is H. In some embodiments, D has the formula D1b-XV, wherein R 3h and R 3h’ Both are H and R 3h” C 1 -C 6 In some embodiments, D has the formula D1b-XV, wherein R 3h and R 3h’ Both are H and R 3h” In some embodiments, D has the formula D1b-XV, wherein R 3h and R 3h’ Both are C 1 -C 6 Alkyl and R 3h” is H. In some embodiments, D has the formula D1b-XV, wherein R 3h and R 3h’ Both are methyl and R 3h” is H. In some embodiments, D has the formula D1b-XV, wherein R 3h is H, and R 3h’ and R 3h” In some embodiments, D has the formula D1b-XV, wherein R b2 is methyl, R b3 is fluorine, and R 3h , R 3h’ and R 3h” Each is H. In some embodiments, D has the formula D1b-XV, wherein R b2 is methyl, R b3 is fluorine, R 3h and R 3h’ Both are H, and R 3h” In some embodiments, D has the formula D1b-XV, wherein R 3h and R 3h” Both are H, and R 3h’ For -C 6 -C 10 Aryl-C 1 -C 6 Alkoxy.

[0334] In some embodiments, D has a formula selected from the group consisting of

[0335]

[0336] Where the variables are as for D1a and D 1b In some embodiments, D has a structure corresponding to any one of Formulae D1a-XVI and D1b-XVI and variations thereof, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ Missing.

[0337] In some embodiments, D has the formula D1a-XVI, wherein R b1 H, halogen, -OH, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, R b1 H, halogen, -CN, -OH, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b2 H, halogen, -OH, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b3 H, halogen, -OH, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b2 and R b3 Together they form a methylenedioxy moiety. In some embodiments, D has the formula D1a-XVI, wherein R b6 H or R b1 Together they form a carbocyclic or heterocyclic ring. In some embodiments, D has the formula D1a-XVI, wherein R b5’ H, -C(O)-C 1 -C 6 Alkyl or -C(O)-C 1 -C 6 Alkylamino.

[0338] In some embodiments, D has the formula D1a-XVI, wherein R b1 In some embodiments, D has the formula D1a-XVI, wherein R b1 In some embodiments, D has the formula D1a-XVI, wherein R b1In some embodiments, D has the formula D1a-XVI, wherein R b1 In some embodiments, D has the formula D1a-XVI, wherein R b1 In some embodiments, D has the formula D1a-XVI, wherein R b1 C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b1 It is methyl.

[0339] In some embodiments, D has the formula D1a-XVI, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b2 In some embodiments, D has the formula D1a-XVI, wherein R b2 In some embodiments, D has the formula D1a-XVI, wherein R b2 In some embodiments, D has the formula D1a-XVI, wherein R b2 In some embodiments, D has the formula D1a-XVI, wherein R b2 In some embodiments, D has the formula D1a-XVI, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b2 In some embodiments, D has the formula D1a-XVI, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b2 In some embodiments, D has the formula D1a-XVI, wherein R b2 In some embodiments, D has the formula D1a-XVI, wherein R b2 C 2 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b2 In some embodiments, D has the formula D1a-XVI, wherein R b2 For-SRa In some embodiments, D has the formula D1a-XVI, wherein R b2 For-SR a , where R a C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b2 For-SR a , where R a In some embodiments, D has the formula D1a-XVI, wherein R b2 For-SR a , where R a C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b2 For-SR a , where R a In some embodiments, D has the formula D1a-XVI, wherein R b2 For-SR a , where R a It is trifluoromethyl.

[0340] In some embodiments, D has the formula D1a-XVI, wherein R b3 In some embodiments, D has the formula D1a-XVI, wherein R b3 In some embodiments, D has the formula D1a-XVI, wherein R b3 In some embodiments, D has the formula D1a-XVI, wherein R b3 In some embodiments, D has the formula D1a-XVI, wherein R b3 C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b3 In some embodiments, D has the formula D1a-XVI, wherein R b3 In some embodiments, D has the formula D1a-XVI, wherein R b3 C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b3 It is a methoxy group.

[0341] In some embodiments, D has the formula D1a-XVI, wherein R b2 and R b3Together with its intervening atoms, it forms a 5-membered heterocyclic ring fused to a 6-membered aryl group. In some embodiments, D has the formula D1a-XVI, wherein R b2 and R b3 Together with its intervening atoms it forms 2,3-dihydrobenzofuranyl.

[0342] In some embodiments, D has the formula D1a-XVI, wherein R b1 and R b6 Together with their intervening atoms, they form a carbocyclic ring. In some embodiments, D has the formula D1a-XVI, wherein R b1 and R b6 Together with its intervening atoms, it forms a 6-membered cycloalkyl.

[0343] In some embodiments, D has the formula D1a-XVI, wherein R b5’ is H. In some embodiments, D has the formula D1a-XVI, wherein R b5’ is H. In some embodiments, D has the formula D1a-XVI, wherein R b5’ -C(O)-C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b5’ -C(O)-C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b5’ For C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b5’ For C 1 -C 6 In some embodiments, D has the formula D1a-XVI, wherein R b5’ For the classics-CH 2 OH substituted pyridinyl.

[0344] In some embodiments, D has the formula D1b-XVI, wherein R b1 H, halogen, -OH, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -OR a、-NHR a or -SR a ; Each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, R b1 H, halogen, -CN, -OH, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b2 H, halogen, -OH, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b3 H, halogen, -OH, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, -OR a 、-NHR a or -SR a ; Each R a Independently selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b2 and R b3 together form a methylenedioxy moiety. In some embodiments, D has the formula D1b-XVI, wherein R b6 H or R b1 Together they form a carbocyclic or heterocyclic ring. In some embodiments, D has the formula D1b-XVI, wherein R b5’ H, -C(O)-C 1 -C 6 Alkyl or -C(O)-C 1 -C 6 Alkylamino.

[0345] In some embodiments, D has the formula D1b-XVI, wherein R b1 In some embodiments, D has the formula D1b-XVI, wherein R b1 In some embodiments, D has the formula D1b-XVI, wherein R b1 In some embodiments, D has the formula D1b-XVI, wherein R b1 In some embodiments, D has the formula D1b-XVI, wherein R b1 In some embodiments, D has the formula D1b-XVI, wherein R b1 C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b1 It is methyl.

[0346] In some embodiments, D has the formula D1b-XVI, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b2 In some embodiments, D has the formula D1b-XVI, wherein R b2In some embodiments, D has the formula D1b-XVI, wherein R b2 In some embodiments, D has the formula D1b-XVI, wherein R b2 In some embodiments, D has the formula D1b-XVI, wherein R b2 In some embodiments, D has the formula D1b-XVI, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b2 In some embodiments, D has the formula D1b-XVI, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b2 C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b2 In some embodiments, D has the formula D1b-XVI, wherein R b2 In some embodiments, D has the formula D1b-XVI, wherein R b2 C 2 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b2 In some embodiments, D has the formula D1b-XVI, wherein R b2 For-SR a In some embodiments, D has the formula D1b-XVI, wherein R b2 For-SR a , where R a C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b2 For-SR a , where R a In some embodiments, D has the formula D1b-XVI, wherein R b2 For-SR a , where R a C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b2 For-SR a , where R aIn some embodiments, D has the formula D1b-XVI, wherein R b2 For-SR a , where R a It is trifluoromethyl.

[0347] In some embodiments, D has the formula D1b-XVI, wherein R b3 In some embodiments, D has the formula D1b-XVI, wherein R b3 In some embodiments, D has the formula D1b-XVI, wherein R b3 In some embodiments, D has the formula D1b-XVI, wherein R b3 In some embodiments, D has the formula D1b-XVI, wherein R b3 C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b3 In some embodiments, D has the formula D1b-XVI, wherein R b3 In some embodiments, D has the formula D1b-XVI, wherein R b3 C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b3 It is a methoxy group.

[0348] In some embodiments, D has the formula D1b-XVI, wherein R b2 and R b3 Together with their intervening atoms, they form a 5-membered heterocyclic ring fused to a 6-membered heteroaryl. In some embodiments, D has the formula D1b-XVI, wherein R b2 and R b3 Together with its intervening atoms it forms 2,3-dihydrobenzofuranyl.

[0349] In some embodiments, D has the formula D1b-XVI, wherein R b1 and R b6 Together with their intervening atoms, they form a carbocyclic ring. In some embodiments, D has the formula D1b-XVI, wherein R b1 and R b6 Together with its intervening atoms, it forms a 6-membered cycloalkyl.

[0350] In some embodiments, D has the formula D1b-XVI, wherein R b5’ is H. In some embodiments, D has the formula D1b-XVI, wherein R b5’is H. In some embodiments, D has the formula D1b-XVI, wherein R b5’ -C(O)-C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b5’ -C(O)-C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b5’ For C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b5’ For C 1 -C 6 In some embodiments, D has the formula D1b-XVI, wherein R b5’ For the classics-CH 2 OH substituted pyridinyl.

[0351] In another embodiment, a camptothecin conjugate having the formula:

[0352] L-(QD) p

[0353] or a salt thereof, wherein

[0354] L is a ligand unit;

[0355] Subscript p is an integer from 1 to 16;

[0356] Q is a linker unit having a formula selected from the group consisting of:

[0357] -ZA-、-ZA-RL-、-ZA-RL-Y-、-ZAS * -RL-, -ZAS * -RL-Y-,

[0358] ZAS * -W-, -ZAS * -W-RL-、-ZAB(S * )-RL-、-ZAB(S * )-W-、

[0359] -ZAB(S * )-W-RL- and -ZAB(S * )-RL-Y-,

[0360] Wherein Z is an extension subunit;

[0361] A is a bond or linker unit;

[0362] B is a parallel connection subunit;

[0363] S* is a separator;

[0364] RL is a releasable linker;

[0365] W is an amino acid unit;

[0366] Y is a Spacer unit; and

[0367] D is a drug unit having the formula

[0368]

[0369] or its salts; wherein;

[0370] E stands for -OR b5 or -NR b5 R b5’ ;

[0371] R b1 Selected from the group consisting of: 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- to 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)-, C1 -C 8 Alkyl-OC(O)-, C 6 -C 12 Aryl-C(O)-, C 6 -C 12 Aryl-OC(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 optionally through C 1 -C 3 Alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or

[0372] R b1 With R b2 , R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring;

[0373] R b2 Selected from the group consisting of: H, halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkynyl, C 6 -C 12 Aryl, 5- to 12-membered heteroaryl, C 3 -C 10 Cycloalkyl, 3- to 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 8Alkyl-, 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-OC(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 optionally through -OR a 、-NR a R a’ and-SR a replace; or

[0374] R b2 With R b1 or R b3 and the intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring; or

[0375] R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group;

[0376] R b3 Selected from the group consisting of: H, halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 1 -C 6Haloalkyl, -OR a 、-NR a R a’ and-SR a ;or

[0377] R b3 With R b2 and intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring or a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group;

[0378] R b4 selected from the group consisting of H and halogen;

[0379] Each R b5 and R b5’ Independently selected from the group consisting of: H, C 1 -C 8 Alkyl, C 1 -C 8 Hydroxyalkyl, C 1 -C 6 Alkyl-OC 1 -C 6 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’and the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of 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 aminoalkyl; or

[0380] R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocyclic, heterocycloalkyl, heterocyclic, phenyl and heteroaryl moieties are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C 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 ;

[0381] R b6 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and

[0382] R a and R a’ Each independently selected from the group consisting of: H, C 1 -C 6 Alkyl, C1 -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)-,

[0383] a) When R b2 With R b3 When combined with the intervening atoms to form 1,3-dioxolane, R b5 H and R b5’ C 1 -C 6 Alkyl-OC 1 -C 6 Alkyl-, or R b5 and R b5’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of 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 aminoalkyl;

[0384] b) When E is NH 2 When R b1 is selected from the group consisting of: -CN, a 5- to 12-membered heteroaryl group having at least one cyclic N, a 3- to 10-membered heterocycloalkyl group having at least one cyclic N, a C 1 -C 8 Hydroxyalkyl, C 1 -C 8Alkyl-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-OC(O)-NR a -、C 6 -C 12 Aryl-NR a -C(O)-O-, -COOR a 、-NR a R a’ and-SR a ; Each optionally through C 1 -C 3 Alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a Substitution, or R b1 With R b2 and intervening atoms combine to form a 5-, 6-, or 7-membered heterocyclic ring having at least one cyclic N or a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group; R b2 Selected from the group consisting of: H, halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkynyl, C 6 -C 12 Aryl, 5- to 12-membered heteroaryl, C 3 -C 10 Cycloalkyl, 3- to 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, C1 -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-OC(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 optionally through -OR a 、-NR a R a’ and-SR a replace; or

[0385] R b2 With R b1 or R b3 and intervening atoms to form a 5- or 6-membered heterocyclic ring having at least one cyclic N, or R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group;

[0386] c) When Rb2 is -OH or methyl and R b3 When F, R b1 Not with R b5 or R b5’ together with the intervening atoms form a ring; and

[0387] d) D is not selected from the group consisting of: (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol-[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]dioxol-[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)hexahydropyrazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3 ]dioxol[4,5-g]pyrano[3',4':6,7]indoleazino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminohexahydropyridin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol[4,5-g]pyrano[3',4':6,7]indole Azino[1,2-b]quinoline-8,11(7H)-dione and (S)-tert-butyl(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

[0388] wherein D is covalently linked to Q via any suitable linking site on D, optionally wherein a hydrogen atom of a hydroxyl, thiol, primary 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.

[0389] In some embodiments, D has D 0 -I formula

[0390]

[0391] or its salt; wherein R b1 -R b6 As for D 0 defined.

[0392] In some embodiments, D has D0 -II

[0393]

[0394] or its salts; wherein;

[0395] R b1 is selected from the group consisting of: -CN, a 5- to 12-membered heteroaryl group having at least one cyclic N, a 3- to 10-membered heterocycloalkyl group having at least one cyclic N, a 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-OC(O)-NR a -、C 6 -C 12 Aryl-NR a -C(O)-O-, -COOR a 、-NR a R a’ and-SR a ; Each optionally through C 1 -C 3 Alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or

[0396] R b1 With R b2 and intervening atoms to form a 5-, 6-, or 7-membered heterocyclic ring having at least one cyclic N, or a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group;

[0397] R b2 Selected from the group consisting of: H, halogen, C1 -C 8 Alkyl, C 2 -C 8 Alkynyl, C 6 -C 12 Aryl, 5- to 12-membered heteroaryl, C 3 -C 10 Cycloalkyl, 3- to 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-OC(O)-NR a -、C 6 -C 12 Aryl-NR a -C(O)-O-, -COOR a 、-OR a 、-NR a Ra’ and-SR a ; each optionally through -OR a 、-NR a R a’ and-SR a replace; or

[0398] R b2 With R b1 or R b3 and intervening atoms combine to form a 5- or 6-membered heterocyclic ring having at least one cyclic N, or

[0399] R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group;

[0400] R b3 Selected from the group consisting of: 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 ;

[0401] R b4 is selected from the group consisting of H or halogen; and

[0402] R a and R a’ Each independently selected from the group consisting of: 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)-,

[0403] wherein D is covalently linked to Q via any suitable linking site on D, optionally wherein a hydrogen atom of a hydroxyl, thiol, primary 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.

[0404] In some embodiments, D has D 0 -III Formula

[0405]

[0406] or its salt; wherein R b1 , R b4 and R b6 As for D 0a defined.

[0407] In some embodiments, D has D 0 -IV formula

[0408]

[0409] or its salt; wherein R b1 , R b4 , R b5 , R b6 As for D 0a In some embodiments, R b1 , R b4 , R b5 and R b6 Each is H.

[0410] In some embodiments, D has D 0 -V

[0411]

[0412] or a salt thereof; wherein:

[0413] p2 is 2 to 6;

[0414] R b5” Selected from the group consisting of: H, C 1 -C 6 Alkyl and C 1 -C 6 haloalkyl; and

[0415] R b1 , R b4 , R b5’ , R b6 As for D 0a In some embodiments, p2 is 2, R b5” is methyl, and R b1 , R b4 , R b5’ , R b6 Each is H.

[0416] In some embodiments, D has D 0 -VI formula

[0417]

[0418] or its salt; wherein R b2 , R b3 , R b4 , R b5 , R b5’ and R b6 As for D 0a In some embodiments, R b2 is methyl, R b3 is F, and R b5 , R b5’ and R b6 Each is H.

[0419] In some embodiments, D has D 0 -VII formula

[0420]

[0421] or its salts; wherein;

[0422] m and n are each 1 or 2, and when both m and n are present, m+n is 2 or 3;

[0423] R b1’ C 1 -C 3 Alkyl or -C(O)R a ;and

[0424] R b2 , R b3 , R b4 , R b5 , R b5’ and R b6 As for D 0a defined.

[0425] In some embodiments, m is 1, n is 2, R b1’ is methyl, and R b2 , R b3 , R b4 , R b5 , R b5’ , R b6 Each is H. In some embodiments, m is 1, n is 2, R b1’ C(O)CH 3 , and R b2 , R b3 , R b4 , R b5 , R b5’ and R b6 Each is H.

[0426] In some embodiments, D has D 0 -VIII

[0427]

[0428] or a salt thereof; wherein:

[0429] n is 1, 2 or 3;

[0430] R b5” For -C 1 -C 6 hydroxyalkyl; and

[0431] R b1 , R b4 and R b6 As for D 0a defined.

[0432] In some embodiments, n is 1, R b5” -CH 2 OH, and R b1 , R b4 and R b6 Each is H.

[0433] In some embodiments, D has D 0 -IX formula

[0434]

[0435] or its salt; wherein R b1 , R b4 , R b5 , R b5’ and R b6 As for D 0a In some embodiments, R b1 , R b4 , R b5 , R b5’ and R b6 Each is H.

[0436] In some embodiments, D has D 0 -X

[0437]

[0438] or its salt; wherein R b1 , R b4 , R b5 , R b5’ and R b6 As for D 0aIn some embodiments, R b1 , R b4 , R b5 , R b5’ and R b6 Each is H.

[0439] In some embodiments, D 0 With D 0b Style

[0440]

[0441] or its salts; wherein;

[0442] E stands for -OR b5 or -NR b5 R b5’ ;

[0443] R b1 Selected from the group consisting of: 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- to 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)-, C6 -C 12 Aryl-OC(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 optionally through C 1 -C 3 Alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or

[0444] R b1 With R b2 , R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring;

[0445] R b2 Selected from the group consisting of: H, halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkynyl, C 6 -C 12 Aryl, 5- to 12-membered heteroaryl, C 3 -C 10 Cycloalkyl, 3- to 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 -C8 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-OC(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 optionally through -OR a 、-NR a R a’ and-SR a replace; or

[0446] R b2 With R b1 or R b3 and the intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring; or

[0447] R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group;

[0448] R b3 Selected from the group consisting of: 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 ;

[0449] R b4 selected from the group consisting of H or halogen;

[0450] Each R b5 and R b5’ Independently selected from the group consisting of: H, C 1 -C 8 Alkyl, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkyl-OC 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- C4 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’ and the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C 4 Alkyl, -OH, -C1 -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 aminoalkyl; or

[0451] R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocyclic, heterocycloalkyl, heterocyclic, phenyl and heteroaryl moieties are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C 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 ;

[0452] R b6 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and

[0453] R a and R a’ Each independently selected from the group consisting of: H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkyl-S(O) 2 -、C1 -C 6 Alkyl-C(O)-, C 1 -C 6 Aminoalkyl-C(O)- and C 1 -C 6 Hydroxyalkyl-C(O)-,

[0454] a) When R b2 With R b3 and the intervening atoms to form 1,3-dioxolane and E is -NR b5 R b5’ When each R b5 and R b5’ are independently selected from the group consisting of: H, C 1 -C 8 Alkyl-OC 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 -C8 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’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of 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 aminoalkyl; or

[0455] R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’The cycloalkyl, carbocyclic, heterocycloalkyl, heterocyclic, phenyl and heteroaryl moieties are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C 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 ;

[0456] b) When R b2 With R b3 When combined with the intervening atom to form 1,3-dioxolane, E is not -OH;

[0457] c) When R b2 is methyl and R b3 When F, R b1 Not with R b6 Together with the intervening atoms, they form a ring, and

[0458] d) D is not selected from the group consisting of: (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol[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]dioxol[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione.

[0459] In some embodiments, E is -NR b5 R b5’ In some embodiments, E is -OR b5 .

[0460] In some embodiments, when R b2 With R b3 and the intervening atoms to form 1,3-dioxolane and E is -NR b5 R b5’ When each R b5 and R b5’ are independently selected from the group consisting of: H, C 1 -C 8 Alkyl-OC 1 -C 8 Alkyl-, C1 -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 10Heterocycloalkyl-, or R b5 and R b5’ The 5-, 6- or 7-membered heteroaryl group is combined with the nitrogen atom to which it is attached to form a 5-, 6- or 7-membered heteroaryl group having 0 to 3 substituents independently selected from the group consisting of 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 Aminoalkyl.

[0461] In some embodiments, D has D 0b -I formula

[0462]

[0463] or its salt; R b1 -R b6 As for D 0b defined; and where R b2 With R b3 When combined with intervening atoms to form a 5-, 6-, or 7-membered heterocyclic ring, the heterocyclic ring has no more than one O.

[0464] In some embodiments, D has D 0b -II

[0465]

[0466] or its salts; wherein;

[0467] R b5 H and R b5’ Selected from the group consisting of: H, C 1 -C 8 Alkyl-OC 1 -C 8 Alkyl-, C 1 -C 8 Alkyl-C(O)(C3 -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’is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of 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 aminoalkyl; or

[0468] R b5’ With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocyclic, heterocycloalkyl, heterocyclic, phenyl and heteroaryl moieties are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C 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

[0469] R b1 and R b4 As for D 0b As defined, the premise is

[0470] In some embodiments, D has D 0b -III Formula

[0471]

[0472] or its salt; wherein R b1 , R b4 , R b5 and R b5’ As for D 0b defined.

[0473] In some embodiments, D has D 0a -I formula

[0474]

[0475] or its salts; wherein;

[0476] E stands for -OR b5 or -NR b5 R b5’ ;

[0477] R b1 Selected from the group consisting of: 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- to 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)-, C6 -C 12 Aryl-OC(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 optionally through C 1 -C 3 Alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or

[0478] R b1 With R b2 , R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring;

[0479] R b2 Selected from the group consisting of: H, halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkynyl, C 6 -C 12 Aryl, 5- to 12-membered heteroaryl, C 3 -C 10 Cycloalkyl, 3- to 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 -C8 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-OC(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 optionally through -OR a 、-NR a R a’ and-SR a replace; or

[0480] R b2 With R b1 or R b3 and the intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring; or

[0481] R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group;

[0482] R b3 Selected from the group consisting of: 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

[0483] R b3 With R b2 and intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring or a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group;

[0484] R b4 selected from the group consisting of H and halogen;

[0485] Each R b5 and R b5’ Independently selected from the group consisting of: H, C 1 -C 8 Alkyl, C 1 -C 8 Hydroxyalkyl, C 1 -C 8 Alkyl-OC 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-C1- 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’ and the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C 4Alkyl, -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 aminoalkyl; or

[0486] R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocyclic, heterocycloalkyl, heterocyclic, phenyl and heteroaryl moieties are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C 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 ;

[0487] R b6 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and

[0488] R a and R a’ Each independently selected from the group consisting of: 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)-,

[0489] a) When R b2 With R b3 and the intervening atoms combine to form 1,3-dioxolane, and E is -NR b5 R b5’ When each R b5 and R b5’ are independently selected from the group consisting of: H, C 1 -C 8 Alkyl-OC 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’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of 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 8Aminoalkyl- and C 1 -C 8 aminoalkyl; or

[0490] R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocyclic, heterocycloalkyl, heterocyclic, phenyl and heteroaryl moieties are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C 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 ;

[0491] b) When R b2 With R b3 When combined with the intervening atom to form 1,3-dioxolane, E is not -OH;

[0492] c) When E is NH 2 When R b1 is selected from the group consisting of: -CN, a 5- to 12-membered heteroaryl group having at least one cyclic N, a 3- to 10-membered heterocycloalkyl group having at least one cyclic N, a 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 12Aryl-C(O)-, C 6 -C 12 Aryl-OC(O)-NR a -、C 6 -C 12 Aryl-NR a -C(O)-O-, -COOR a 、-NR a R a’ and-SR a ; Each optionally through C 1 -C 3 Alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a Substitution, or R b1 With R b2 and intervening atoms combine to form a 5-, 6-, or 7-membered heterocyclic ring having at least one cyclic N or a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group; R b2 Selected from the group consisting of: H, halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkynyl, C 6 -C 12 Aryl, 5- to 12-membered heteroaryl, C 3 -C 10 Cycloalkyl, 3- to 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)-, C1 -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-OC(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 optionally through -OR a 、-NR a R a’ and-SR a replace; or

[0493] R b2 With R b1 or R b3 and intervening atoms to form a 5- or 6-membered heterocyclic ring having at least one cyclic N, or R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to the 6-membered aryl group; and

[0494] d) When R b2 is -OH or methyl and R b3 When F, R b1 Not with R b5 , R b5’ or R b6 together with the intervening atoms form a ring; and

[0495] e) D is not selected from the group consisting of: (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol-[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]dioxol-[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)hexahydropyrazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3 ]dioxol[4,5-g]pyrano[3',4':6,7]indolizine[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminohexahydropyridin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol[4,5-g]pyrano[3',4':6,7]indolizine and (S)-tert-butyl(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.

[0496] wherein D is covalently linked to Q via any suitable linking site on D, optionally wherein a hydrogen atom of a hydroxyl, thiol, primary 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.

[0497] In some embodiments, E is -NR b5 R b5’ In some embodiments, E is -OR b5 .

[0498] In some embodiments, D has D 0 -I'

[0499]

[0500] or its salt; R b1 -R b6 As for D 0a -I defined; and when R b2 With R b3 When combined with intervening atoms to form a 5-, 6-, or 7-membered heterocyclic ring, the heterocyclic ring has no more than one O.

[0501] In some embodiments, D has D 0 -III'

[0502]

[0503] or a salt thereof; wherein each R b1 -R b4 , R b5’ and R b6 Each as D 0a -I defined.

[0504] In some embodiments, D is a compound of Table I or a salt thereof selected from the group consisting of:

[0505] Table I

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530] In one group of embodiments, Q has a formula selected from the group consisting of:

[0531] -ZA-RL- and -ZA-RL-Y-,

[0532] wherein RL is a releasable linker that is a glycoside (eg, glucuronide) unit, and the groups Z, A and Y have the meanings provided above and in any of the embodiments specifically recited herein.

[0533] In one group of embodiments, Q has a formula selected from the group consisting of:

[0534] -ZAS * -RL- and -ZAS * -RL-Y-,

[0535] wherein RL is a releasable linker that is a glycoside (e.g., glucuronide) unit, and the groups Z, A, S * and Y have the meanings provided above and in any of the embodiments specifically recited herein.

[0536] In one group of embodiments, Q has a formula selected from the group consisting of:

[0537] -ZAB(S * )-RL- and -ZAB(S * )-RL-Y-,

[0538] wherein RL is a releasable linker that is a glycoside (e.g., glucuronide) unit, and the groups Z, A, S * , B and Y have the meanings provided above and in any of the embodiments specifically enumerated herein.

[0539] In another group of embodiments, Q has a formula selected from the group consisting of:

[0540] -ZA- or -ZA-RL-,

[0541] wherein RL is a releasable linker other than a glycoside (eg, glucuronide) unit, and groups Z and A have the meanings provided above and in any of the embodiments specifically recited herein.

[0542] In another group of embodiments, Q has a formula selected from the group consisting of:

[0543] -ZAS * -RL- and -ZAB(S * )-RL-,

[0544] wherein RL is a releasable linker other than a glycoside (e.g., a glucuronide) unit, and the groups Z, A, S * and B have the meanings provided above and in any of the embodiments specifically recited herein.

[0545] In another group of embodiments, Q has a formula selected from the group consisting of:

[0546] -ZAS * -W- and -ZAB(S * )-W-,

[0547] Among them, groups Z, A, S * , B and W have the meanings provided above and in any of the embodiments specifically enumerated herein.

[0548] In another group of embodiments, Q has a formula selected from the group consisting of:

[0549] -ZAS * -W-RL- and -ZAB(S * )-W-RL-,

[0550] wherein RL is a releasable linker other than a glycoside (e.g., a glucuronide) unit, and the groups Z, A, S * , B and W have the meanings provided above and in any of the embodiments specifically enumerated herein.

[0551] In one group of embodiments, wherein Q has the formula -ZA-RL-, -ZA-RL-Y-, -ZAS*-RL-, -ZAS*-RL-Y-, -ZAB(S*)-RL-, or -ZAB(S*)-RL-Y- and comprises a compound having the formula D 1 The camptothecin conjugates of the drug units are represented by the following formulae:

[0552]

[0553]

[0554]

[0555] wherein RL is any of the releasable linkers disclosed herein, preferably RL is a glycoside (e.g., a glucuronide) unit, and the groups L, Z, A, S * , B and Y have the meanings provided above and in any of the embodiments specifically recited herein. Also provided herein is a 1 iN、D 1 iiN、D 1 iiiN、D 1 ivN、D 1 vN or D 1 viN camptothecin conjugate of any one of the following, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0556] In other embodiments, wherein Q is of the formula -ZA-, -ZA-RL-, -ZAS*-W-, -ZAB(S*)-W-, -ZAS*-RL-, -ZAB(S*)-RL-, -ZAS*-W-RL-, and -ZAB(S*)-W-RL- and comprises a compound of the formula D 1 The camptothecin conjugates of the drug units are represented by the following formulae:

[0557]

[0558] wherein RL is a releasable linker other than a glycoside (e.g., a glucuronide) unit and the groups L, Z, A, S * , B and W have the meanings provided above and in any of the embodiments specifically enumerated herein.

[0559] In another group of embodiments, the camptothecin conjugates comprising a drug unit having formula D1-I are represented by the following formulae:

[0560]

[0561] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 IiN camptothecin conjugate, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0562] In another group of embodiments, the camptothecin conjugates comprising a drug unit having formula D1-II are represented by the following formulae:

[0563]

[0564] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1I IiN camptothecin conjugate, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0565] In another group of embodiments, the camptothecin conjugates comprising drug units having formula D1-III are represented by the following formulae, respectively:

[0566]

[0567] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 IIIiN camptothecin conjugate, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0568] In another group of embodiments, the camptothecin conjugates comprising a drug unit having formula D1-IV are represented by the following formulae, respectively:

[0569]

[0570] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 Camptothecin conjugate of IViN, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0571] In another group of embodiments, the camptothecin conjugates comprising a drug unit having formula D1-V are represented by the following formulae, respectively:

[0572]

[0573] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 Camptothecin conjugate of ViN, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0574] In another group of embodiments, the camptothecin conjugates comprising a drug unit having formula D1-VI are represented by the following formulae, respectively:

[0575]

[0576] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 VIiN camptothecin conjugate, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0577] In another group of embodiments, the camptothecin conjugates comprising drug units having formula D1-VII are represented by the following formulae, respectively:

[0578]

[0579] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 Camptothecin conjugate of VIIiN, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and Rb5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0580] In another group of embodiments, the camptothecin conjugates comprising drug units having formulae D1-VIII are represented by the following formulae, respectively:

[0581]

[0582] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 VIIIiN camptothecin conjugate, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0583] In another group of embodiments, the camptothecin conjugates comprising a drug unit having formula D1-IX are represented by the following formulae, respectively:

[0584]

[0585] where Q has -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-; groups L, Z, A, S *, B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 Camptothecin conjugate of IXiN, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0586] In another group of embodiments, the camptothecin conjugates comprising a drug unit having formula D1-X are represented by the following formulae:

[0587]

[0588] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined.

[0589] In another group of embodiments, the camptothecin conjugates comprising a drug unit having formula D1-IIa are represented by the following formulae:

[0590]

[0591] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1- IIaiN camptothecin conjugate, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0592] In another group of embodiments, the camptothecin conjugates comprising a drug unit having Formula D1-IIb are represented by the following formulae:

[0593]

[0594] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 -IIbiN camptothecin conjugate, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and Rb5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0595] In another group of embodiments, the camptothecin conjugates comprising a drug unit having Formula D1-IVa are represented by the following formulae:

[0596]

[0597] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 -IVaiN camptothecin conjugate, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0598] In another group of embodiments, the camptothecin conjugates comprising a drug unit having Formula D1-IVb are represented by the following formulae:

[0599]

[0600] where Q has -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-; groups L, Z, A, S *, B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 -IVbiN camptothecin conjugate, wherein R b5’ The bound nitrogen atom is replaced by an oxygen atom and R b5’ is missing, such that Q is attached to the Drug unit through the oxygen atom of the Drug unit.

[0601] In another group of embodiments, the camptothecin conjugates comprising a drug unit having formula D1-Xa are represented by the following formulae:

[0602]

[0603] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined.

[0604] In another group of embodiments, the camptothecin conjugates comprising a drug unit having formula D1-XI are represented by the following formulae, respectively:

[0605]

[0606] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 -XIiN camptothecin conjugate, wherein the nitrogen atom to which Q is bound is replaced by an oxygen atom and replaces the hydrogen deficiency of the nitrogen atom, so that Q is linked to the drug unit through the oxygen atom of the drug unit.

[0607] In another group of embodiments, the camptothecin conjugates comprising a drug unit having formula D1-XII are represented by the following formulae, respectively:

[0608]

[0609] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 -XIIIiN camptothecin conjugate, wherein the nitrogen atom to which Q is bound is replaced by an oxygen atom and replaces the hydrogen deficiency of the above nitrogen atom, so that Q is linked to the drug unit through the oxygen atom of the drug unit.

[0610] In another group of embodiments, the camptothecin conjugates comprising drug units having formula D1-XIII are represented by the following formulae, respectively:

[0611]

[0612] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 -XIIIiN camptothecin conjugate, wherein the nitrogen atom to which Q is bound is replaced by an oxygen atom and replaces the hydrogen deficiency of the above nitrogen atom, so that Q is linked to the drug unit through the oxygen atom of the drug unit.

[0613] In another group of embodiments, the camptothecin conjugates comprising a drug unit having formula D1-XIV are represented by the following formulae, respectively:

[0614]

[0615] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1, D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 -XIViN camptothecin conjugate, wherein the nitrogen atom to which Q is bound is replaced by an oxygen atom and replaces the hydrogen deficiency of the nitrogen atom, so that Q is linked to the drug unit through the oxygen atom of the drug unit.

[0616] In another group of embodiments, the camptothecin conjugates comprising a drug unit having Formula D1-XV are represented by the following formulae, respectively:

[0617]

[0618] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 -XViN camptothecin conjugate, wherein the nitrogen atom to which Q is bound is replaced by an oxygen atom and replaces the hydrogen deficiency of the above nitrogen atom, so that Q is linked to the drug unit through the oxygen atom of the drug unit.

[0619] In another group of embodiments, the camptothecin conjugates comprising a drug unit having Formula D1-XVI are represented by the following formulae, respectively:

[0620]

[0621] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , D1-IIa, D1-IIb, D1-IVa, D1-IVb, D1-Xa, D1-XI, D1-XII, D1-XIII, D1-XIV, D1-XV and D1-XVI are defined herein. 1 -XVIiN camptothecin conjugate, wherein the nitrogen atom to which Q is bound is replaced by an oxygen atom and replaces the hydrogen deficiency of the nitrogen atom, so that Q is linked to the drug unit through the oxygen atom of the drug unit.

[0622] In another group of embodiments, the camptothecin conjugates comprising a drug unit having the formula D1-CPT6 are represented by the following formulae:

[0623]

[0624] where Q has -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-; groups L, Z, A, S * , B, RL and Y have the meanings provided above and in any of the embodiments specifically recited herein; and the remaining variables are as for D 1 , 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. 1-CPT6iN camptothecin conjugate, wherein the nitrogen atom to which Q is bound is replaced by an oxygen atom and replaces the hydrogen deficiency of the nitrogen atom, so that Q is linked to the drug unit through the oxygen atom of the drug unit.

[0625] Camptothecin molecules are known to undergo pH-dependent reversible hydrolysis between the ring-closed lactone form and the ring-opened carboxylate salt.

[0626]

[0627] Without being limited by theory, it is believed that at acidic pH, the lactone form is favorable, and at physiological pH, the main form is an open-loop carboxylate. In biological systems, drugs or drug-linkers or their conjugates without camptothecin can exist in lactone or carboxylate form. It has been confirmed that the activity of antibody drug conjugates (ADCs) based on camptothecin to target cells is not limited to theory. Regardless of the state of the lactone of the drug combined. It is believed that the effect is attributed to ADC processing in acidic intracellular vesicles, which is conducive to balancing to the active closed lactone form of camptothecin (Lau, UY et al. Mol. Pharmaceutics 2018, 15, 9, 4063-4072).

[0628] It should be understood that the drug units herein as well as drug-linkers and conjugates thereof may undergo an equilibrium between the lactone and carboxylate forms. Therefore, for any lactone structure described herein, the carboxylate form should also be understood to be within the scope of the present disclosure. All carboxylate forms of camptothecin structures depicted in lactone form, including the general formula, should be understood to be included herein in the same context as the lactone form, as if each lactone structure is explicitly and individually included in the carboxylate form.

[0629] Camptothecin-Linker Compounds

[0630] In some embodiments, when preparing a camptothecin conjugate, it will be desirable to synthesize the complete drug-linker combination prior to conjugation to a targeting agent. In such embodiments, the camptothecin-linker compound as described herein is an intermediate compound. In those embodiments, the Stretcher unit in the camptothecin-linker compound has not yet been covalently linked to a Ligand unit (i.e., is a Stretcher unit precursor Z'), and therefore has a functional group for conjugation to a targeting ligand. In one embodiment, the camptothecin-linker compound comprises a camptothecin compound (shown herein as Formula D 1 , D 1a , D 1b or any subformula thereof) and a Linker unit (Q) comprising a glycoside (eg, glucuronide) unit as a releasable Linker (RL) through which the Ligand unit is attached to the Camptothecin.

[0631] In another embodiment, the camptothecin-linker compound comprises formula D 1 , D 1a , D 1b Or a camptothecin compound of any subformula thereof and a linker unit (Q) comprising a releasable linker (RL) other than a glycoside (e.g., glucuronide) unit, through which the ligand unit is linked to the conjugated camptothecin compound. Therefore, in any embodiment, in addition to RL, the linker unit also comprises an extension unit precursor (Z'), which comprises a functional group for conjugating with a targeting agent (which is a precursor of the ligand unit) and is therefore capable of linking RL (directly or indirectly) to the ligand unit. In some embodiments of those embodiments, when it is desired to add a spacer (S*) as a side chain attachment, there is a parallel linker unit (B). In any of those embodiments, when it is desired to increase more distance between the extension unit and the RL, there is a linker unit (A).

[0632] In one group of embodiments, the camptothecin-linker compound comprises a compound having the formula D 1 , D 1a , D 1b or a camptothecin compound of any subformula thereof and a linker unit (Q), wherein Q comprises a releasable linker (RL) that is a glycoside (e.g., a glucuronide) unit, said RL being directly linked to a stretcher unit precursor (Z') or through one or more intervening components (i.e., A, S, or S) of a linker unit of a camptothecin-linker compound. * and / or B(S * )) is indirectly linked to Z', wherein Z' comprises a functional group capable of forming a covalent bond with the targeting agent.

[0633] In another group of embodiments, the camptothecin-linker compound comprises a compound having the formula D 1 , D 1a , D 1b or a camptothecin compound of any subformula thereof and a linker unit (Q), wherein Q comprises a releasable linker (RL) other than a glycoside (e.g., glucuronide) unit (RL), said RL being directly linked to a stretcher unit precursor (Z') or via one or more intervening components (i.e., A, S, S, etc.) of a linker unit of a camptothecin-linker compound. * and / or B(S * )) is indirectly linked to Z', wherein Z' comprises a functional group capable of forming a covalent bond with the targeting agent.

[0634] In the context of camptothecin conjugates and / or camptothecin-linker compounds, assembly is best described in terms of its component groups. Although some procedures are described herein, those skilled in the art will fully understand the order of assembly and the general conditions for preparing conjugates and compounds.

[0635] In some embodiments, provided herein are camptothecin-linker compounds, wherein the compound is selected from the group consisting of compounds in Table II. In some embodiments, provided herein are camptothecin conjugates, wherein the conjugate comprises a ligand attached to a succinimide moiety or a succinic acid-amide moiety of a drug-linker moiety, wherein the drug-linker moiety comprises a compound of Table II, wherein the maleimide moiety is replaced by a succinimide or succinic acid-amide moiety.

[0636] Table II

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646] Component Group Ligand unit:

[0647] 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 target 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 is used to bind camptothecin (such as Formula D 1 , D 1a , D 1bor any of its subformulas) is targeted and presented to a specific target cell population, and the Ligand unit interacts with the target cell population due to the presence of the component or molecule it targets and allows free drug to be subsequently released within the target cell (i.e., intracellularly) or near the target cell (i.e., extracellularly). The Ligand unit L includes, but is 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, lymphohormones, hormones, growth factors, colony stimulating factors, vitamins, nutrient transport molecules (such as, but not limited to transferrin), or any other cell binding molecule or substance. In some embodiments, the Ligand unit (L) is from an antibody or non-antibody protein targeting agent.

[0648] In one set of embodiments, the Ligand unit is bonded to Q (Linker unit) comprising a glucuronide-releasable Linker. As described above, additional linking components may be present in the conjugates described herein to provide additional space between the camptothecin drug compound and the Ligand unit (e.g., a Stretcher unit and optionally a Linker unit, A) or to provide composition properties to increase solubility (e.g., a Spacer, S). * ) purpose. In some of those embodiments, the Ligand unit is bonded to Z of the Linker unit through a heteroatom of the Ligand unit. Heteroatoms that may be present on the Ligand unit for such bonding include sulfur (in one embodiment, from a thiol group of the Targeting Ligand), oxygen (in one embodiment, from a carboxyl or hydroxyl group of the Targeting Ligand), and optionally substituted nitrogen (in one embodiment, from a primary or secondary amine functional group of the Targeting Ligand, or in another embodiment, from an optionally substituted amide nitrogen). Those heteroatoms may be present on the Targeting Ligand in its native state (e.g., in a naturally occurring antibody), or may be introduced into the Targeting Ligand by chemical modification or bioengineering.

[0649] In one embodiment, the precursor targeting agent as a Ligand unit has a thiol functional group, such that the Ligand unit is bonded to the Linker unit through the sulfur atom of the thiol functional group.

[0650] In another embodiment, the targeting agent as a precursor of the Ligand unit has one or more lysine residues that are capable of reacting with an activated ester of a Stretcher unit precursor of the camptothecin-Linker compound intermediate (such esters include but are not limited to N-hydroxysuccinimide, pentafluorophenyl and p-nitrophenyl esters) and thereby providing an amide bond consisting of the nitrogen atom of the Ligand unit and the C=O group of the Stretcher unit of the Linker unit.

[0651] In yet another aspect, the targeting agent as a precursor of the Ligand unit has one or more lysine residues that can be chemically modified to introduce one or more sulfhydryl groups. In those embodiments, the Ligand unit is covalently linked to the Linker unit via the sulfur atom of the sulfhydryl functional group. Reagents that can be used to modify lysine in the manner described include, but are not limited to, S-acetylthioacetic acid N-succinimidyl ester (SATA) and 2-imidothiolane hydrochloride (Traut's Reagent).

[0652] In another embodiment, the targeting agent as a precursor of the Ligand unit has one or more carbohydrate groups that can be modified to provide one or more thiol functional groups. The chemically modified Ligand unit in the camptothecin conjugate is bonded to the Linker unit component (e.g., Extender unit) through the sulfur atom of the thiol functional group.

[0653] In yet another embodiment, the targeting agent as a precursor of the 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. Chem. 32(3):548-55). In such embodiments, the corresponding aldehyde interacts with a reactive site on the Extender unit precursor to form a bond between the Extender unit and the Ligand unit. Reactive sites on the Extender unit precursor that can interact with a reactive carbonyl-containing functional group on the Targeting Ligand unit include, but are not limited to, hydrazine and hydroxylamine. Other schemes for modifying proteins to attach a Linker unit (Q) or related substances are described in Coligan et al., Current Protocols in Protein Science, Vol. 2, John Wiley & Sons (2002) (incorporated herein by reference).

[0654] In some aspects, the targeting agent as a precursor of the ligand unit can interact with the reactive functional group on the extension unit precursor (Z') to form a covalent bond between the extension unit (Z) and the ligand unit corresponding to the structure of the targeting agent. The functional group of Z' with the ability to interact with the targeting agent will depend on the properties of the targeting agent whose structure corresponds to the ligand unit. In some embodiments, the reactive group is maleimide, which is present on the extension unit (i.e., the maleimide part of the extension unit precursor) before it is connected to form the ligand unit. The covalent connection of the ligand unit to the extension unit is realized by the sulfhydryl functional group of the targeting agent as a precursor of the ligand unit and the maleimide functional group of Z' to form a sulfur-substituted succinimide. The sulfhydryl functional group may be present on the targeting agent in the native state of the targeting agent (e.g., in a naturally occurring residue), or may be introduced into the targeting agent by chemical modification or by bioengineering.

[0655] In yet another embodiment, the Ligand unit is from an antibody and the sulfhydryl groups are generated by reduction of interchain disulfides of the antibody. Thus, in some embodiments, the Linker unit is conjugated to a cysteine ​​residue from one or more reduced interchain disulfides.

[0656] In yet another embodiment, the Ligand unit is derived from an antibody and the sulfhydryl functional group is chemically introduced into the antibody, e.g., by the introduction of a cysteine ​​residue. Thus, in some embodiments, the Linker unit (with or without the attached camptothecin) is conjugated to the Ligand unit via the introduced cysteine ​​residue of the Ligand unit.

[0657] For bioconjugates, it has been observed that the site of drug conjugation can affect many parameters, including the ease of conjugation, drug-linker stability, the effect on the biophysical properties of the resulting bioconjugate and in vitro cytotoxicity. Regarding drug-linker stability, the conjugation site of the drug-linker portion and the ligand unit can affect the ability of the conjugated drug-linker portion to undergo elimination reactions in some examples to cause premature release of free drugs. Sites for conjugation on the targeting ligand include, for example, reduced interchain disulfides and selected cysteine ​​residues at engineered sites. In some embodiments, the conjugation method for forming a camptothecin conjugate as described herein uses a genetically engineered site (e.g., according to the position 239 of the EU index listed in Kabat) that is less prone to elimination reactions than the conjugation method using thiol residues from reduced disulfide bonds. In other embodiments, the conjugation method for forming a camptothecin conjugate as described herein uses thiol residues generated by reduction of interchain disulfide bonds.

[0658] In some embodiments, the camptothecin conjugate comprises a non-immunoreactive protein, polypeptide or peptide as its ligand unit. Therefore, in some embodiments, the ligand unit is 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 factor ("TGF") (such as TGF-α and TGF-β), vaccinia virus growth factor ("VGF"), insulin and insulin-like growth factor I and II, somatostatin, lectin and apoproteins from low-density lipoprotein.

[0659] Particularly preferred ligand units are from antibodies. Therefore, in any embodiment described herein, the ligand unit is from an antibody. Available polyclonal antibodies are heterogeneous populations of antibody molecules derived from the serum of immune animals. Available monoclonal antibodies are homogeneous populations of antibodies directed against specific antigenic determinants (e.g., cancer cell antigens, viral antigens, microbial antigens, proteins, peptides, carbohydrates, chemicals, nucleic acids or fragments thereof). In some embodiments, monoclonal antibodies (mAbs) directed against antigens of interest are prepared by using any technology known in the art, which provides antibody molecules produced by continuous cell lines in culture.

[0660] Available monoclonal antibodies include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, or chimeric human-mouse (or other species) monoclonal antibodies. Antibodies include full-length antibodies and antigen-binding fragments thereof. Human monoclonal antibodies can be prepared 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).

[0661] Antibodies useful in practicing the present invention are intact antibodies or functionally active fragments, derivatives or analogs of antibodies, wherein the antibody or its fragment is capable of immunospecific binding to a target cell (e.g., a cancer cell antigen, a viral antigen, or a microbial antigen), or to other antibodies of a tumor cell or matrix. In this context, "functional activity" means that the fragment, derivative or analog is capable of immunospecific binding to a target cell. To determine which CDR sequences bind to an antigen, in some embodiments, the binding assay is performed by any binding assay known in the art (e.g., Biacore TM Assays) use synthetic peptides containing CDR sequences in antigen binding assays (see, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th ed., National Institute of Health, Bethesda, Md.; Kabat E et al., 1980, J. Immunology 125(3):961-969).

[0662] Other useful antibodies include antibody fragments such as, but not limited to, F(ab') 2 fragment, Fab fragment, Fv, single-chain antibody, diabody, triabody, tetrabody, scFv, scFv-FV or any other molecule with the same specificity as an antibody.

[0663] In addition, in some embodiments, recombinant antibodies (such as chimeric and humanized monoclonal antibodies) comprising both human and non-human parts prepared using standard recombinant DNA techniques are available antibodies. Chimeric antibodies are molecules in which different parts are derived from different animal species, such as, for example, those molecules having variable regions derived from mouse monoclonals and human immunoglobulin constant regions. (See, for example, U.S. Patent No. 4,816,567; and U.S. Patent No. 4,816,397, which are incorporated herein by reference in their entirety). Humanized antibodies are antibody molecules from non-human species having one or more complementary determining regions (CDRs) from non-human species and framework regions from human immunoglobulin molecules. (See, e.g., U.S. Pat. No. 5,585,089, the entire contents of which are incorporated herein by reference.) In some embodiments, such chimeric and humanized monoclonal antibodies are produced by recombinant DNA techniques known in the art, for example, using the methods 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 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 No. 86 / 01533; U.S. Patent 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., Proc. Natl. Acad. Sci. USA (1987) 84:214-218; Nishimura et al., Cancer. Res. (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. Pat. No. 5,225,539; Jones et al., Nature (1986) 321: 552-525; Verhoeyan et 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.

[0664] Fully human antibodies are more desirable in some instances (e.g., when immunogenicity to non-human or chimeric antibodies might arise) and are generated in some embodiments using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chain genes but are capable of expressing human heavy and light chain genes.

[0665] Antibodies include modified analogs and derivatives, i.e., analogs and derivatives modified by covalent attachment of any type of molecule, as long as such covalent attachment allows the antibody to retain its antigen binding immunospecificity. For example, but not by way of limitation, derivatives and analogs of antibodies include those that have been further modified, for example, by glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization by known protection / blocking groups, proteolytic cleavage, linkage to cell antibody units or other proteins, etc. In some embodiments, one or more of those many 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, analogs or derivatives of antibodies contain one or more unnatural amino acids that are sometimes used in combination with one or more of the above chemical modifications.

[0666] In some embodiments, the antibodies have one or more modifications (e.g., substitutions, deletions, or additions) in amino acid residues that interact with Fc receptors. Those modifications include modifications in amino acid residues identified as being involved in the interaction between the anti-Fc domain and the FcRn receptor (see, e.g., International Publication No. WO 97 / 34631, which is incorporated herein by reference in its entirety).

[0667] In some embodiments, antibodies with immunospecificity to cancer cell antigens are commercially available or produced by methods known to those skilled in the art (such as recombinant expression techniques). Nucleotide sequences encoding antibodies with immunospecificity to cancer cell antigens are sometimes obtained, for example, from the GenBank database or a database similar thereto, literature publications, or by conventional cloning and sequencing.

[0668] In specific embodiments, known antibodies used to treat cancer are used.

[0669] In another specific embodiment, the compositions and methods according to the invention use antibodies for the treatment of autoimmune diseases.

[0670] In certain embodiments, useful antibodies bind to a receptor or receptor complex expressed on activated lymphocytes. In some embodiments, the receptor or receptor complex is a member of the immunoglobulin gene superfamily, a member of the TNF receptor superfamily, an integrin, a cytokine receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a complement control protein.

[0671] In some embodiments, the antibody incorporated into the camptothecin conjugate will specifically bind CD19, CD30, CD33, CD70, or LIV-1.

[0672] Exemplary antigens are provided below. Exemplary antibodies that bind the indicated antigens are shown in parentheses.

[0673] 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 transmembrane proteins: ANTXR1, BAFF-R, CA9 (exemplary antibodies include girentuximab), CD147 (exemplary antibodies include gavilimomab and metuzumab), CD19, CD20 (exemplary antibodies include divozilimab and ibritumomab tiuxetan), CD274 (also known as PD-L1) (exemplary antibodies include adebrelimab, atezolizumab, garivulimab, durvalumab, and avelumab), CD30 (exemplary antibodies include iratumumab and brentuximab), CD33 (exemplary antibodies include lintuzumab), and CD40 (exemplary antibodies include lintuzumab). intuzumab), CD352, CD45 (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 tomaralimab), TM4SF5, TMEM132A, TMEM40, UPK1B, VEGF, and VEFGR2 (exemplary antibodies include gentuximab).

[0674] In some embodiments, the tumor-associated antigen is a transmembrane transport protein. For example, the following antigens are transmembrane transport proteins: ASCT2 (exemplary antibodies include idactamab), MFSD13A, Mincle, NOX1, SLC10A2, SLC12A2, SLC17A2, SLC38A1, SLC39A5, SLC39A6 (also known as LIV1) (exemplary antibodies include laditratuzumab), SLC44A4, SLC6A15, SLC6A6, SLC7A11, and SLC7A5.

[0675] In some embodiments, the tumor-associated antigen is a transmembrane or membrane-associated glycoprotein. For example, the following antigens are transmembrane or membrane-associated glycoproteins: CA-125, CA19-9, CAMPATH-1 (exemplary antibodies include alemtuzumab), carcinoembryonic antigen (exemplary antibodies include arcitumomab, cergutuzumab, amunaleukin and labetuzumab), CD112, CD155, CD24, CD247, CD37 ( Exemplary antibodies include lilotomab), CD38 (exemplary antibodies include felzartamab), CD3D, CD3E (exemplary antibodies include foralumab and teplizumab), CD3G, CD96, CDCP1, CDH17, CDH3, CDH6, CEACAM1, CEACAM6, CLDN1, CLDN16, CLDN1 8.1 (exemplary antibodies include zolbetuximab), CLDN18.2 (exemplary antibodies include zolbetuximab), CLDN19, CLDN2, CLEC12A (exemplary antibodies include tepoditamab), DPEP1, DPEP3, DSG2, endosialin (exemplary antibodies include ontuxizumab), ENPP1, EPCAM (exemplary antibodies include adecatumumab), FN, FN1, Gp100, GPA33, gpNMB (exemplary antibodies include glembatumumab), ICAM1, L1CAM, LAMP1, MELTF also known as CD228, NCAM1, connexin-4 (exemplary antibodies include enfortumab), PDPN, PMSA, PROM1, PSCA, PSMA, Siglec 1-16, SIRPa, SIRPg, TACSTD2, TAG-72, tenascin, tissue factor (also known as TF) (exemplary antibodies include tisotumab), and ULBP1 / 2 / 3 / 4 / 5 / 6.

[0676] In some embodiments, the tumor-associated antigen is a transmembrane or membrane-associated receptor kinase. For example, the following antigens are transmembrane or membrane-associated receptor kinases: ALK, Axl (exemplary antibodies include tilvestamab), BMPR2, DCLK1, DDR1, EPHA receptor, EPHA2, ERBB2 (also known as HER2) (exemplary antibodies include trastuzumab, bevacizumab, pertuzumab, and margetuximab), ERBB3, FLT3, PDGFR-B (exemplary antibodies include rinucumab), PTK7 (exemplary antibodies include cofetuzumab), RET, ROR1 (exemplary antibodies include cirmtuzumab), ROR2, ROS1, and Tie3.

[0677] In some embodiments, the tumor-associated antigen is a membrane-associated or membrane-localized protein. For example, the following antigens are membrane-associated or membrane-localized proteins: ALPP, ALPPL2, ANXA1, FOLR1 (exemplary antibodies include farletuzumab), IL13Ra2, IL1RAP (exemplary antibodies include nidanilimab), NT5E, OX40, Ras mutants, RGS5, RhoC, SLAMF7 (exemplary antibodies include elotuzumab), and VSIR.

[0678] 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.

[0679] In some embodiments, the tumor-associated antigen is a cell surface-associated receptor or a cell surface receptor. For example, the following antigens are cell surface-associated receptors and / or cell surface receptors: B7-DC, BCMA, CD137, CD 244, CD3 (exemplary antibodies include otelixizumab and visilizumab), CD48, CD5 (exemplary antibodies include zolimomab aritox), CD70 (exemplary antibodies include cusatuzumab and vorsetuzumab), CD74 (exemplary antibodies include milatuzumab), CD79A, CD-262 (exemplary antibodies include tigatuzumab), DR4 (exemplary antibodies include mapatumumab), FAS, FGFR1, FGFR2 (exemplary antibodies include aprutumab), FGFR3 (exemplary antibodies include vofatamab), FG FR4, 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.

[0680] In some embodiments, the tumor-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, cabiralizumab, and emactuzumab), CD123, CXCR 4 (exemplary antibodies include ulocuplumab), IL-21R, and IL-5R (exemplary antibodies include benralizumab).

[0681] In some embodiments, the tumor-associated antigen is a co-stimulatory surface-expressed protein. For example, the following antigens are co-stimulatory surface-expressed proteins: B7-H3 (exemplary antibodies include enoblituzumab and omburtamab), B7-H4, B7-H6, and B7-H7.

[0682] 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 proteins are DNA binding proteins: BORIS.

[0683] In some embodiments, the tumor-associated antigen is an integral membrane protein. For example, the following antigens are integral membrane proteins: SLITRK6 (exemplary antibodies include sirtratumab), UPK2, and UPK3B.

[0684] In some embodiments, the tumor-associated antigen is an integrin. For example, the following antigens are integrin antigens: αvβ6, ITGAV (exemplary antibodies include abituzumab), ITGB6, and ITGB8.

[0685] In some embodiments, the tumor-associated antigen is a glycolipid. For example, the following are glycolipid antigens: FucGM1, GD2 (exemplary antibodies include dinutuximab), GD3 (exemplary antibodies include mitumomab), GloboH, GM2 and GM3 (exemplary antibodies include racotumomab).

[0686] 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.

[0687] In some embodiments, the tumor-associated antigen is a transmembrane or membrane-associated protease. For example, the following antigens are transmembrane or membrane-associated proteases: ADAM12, ADAM9, TMPRSS11D, and metalloproteinases.

[0688] In some embodiments, the tumor-associated antigen is abnormally expressed in an individual with cancer. For example, the following antigens may be abnormally expressed in an individual with cancer: AFP, AGR2, AKAP-4, ARTN, BCR-ABL, C5 complement, CCNB1, CSPG4, CYP1B1, De2-7 EGFR, EGF, Fas-related antigen 1, FBP, G250, GAGE, HAS3, HPV E6 E7, hTERT, IDO1, LCK, legumin, LYPD1, MAD-CT-1, MAD-CT-2, MAGEA3, MAGEA4, MAGEC2, MerTk, ML-IAP, NA17, NY-BR-1, p53, p53 mutant, PAP, PLAV I, polysialic acid, PR1, PSA, sarcoma translocation breakpoints, SART3, sLe, SSX2, survivin, Tn, TRAIL, TRAIL1, TRP-2, and XAGE1.

[0689] 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 transmembrane proteins: BAFF-R, CD163, CD19, CD20 (exemplary antibodies include rituximab, ocrelizumab, devolimumab; ibritumomab tiuxetan), CD25 (exemplary antibodies include basiliximab), CD274 also known as PD-L1 (exemplary antibodies include adebelimumab, atezolizumab, galivlimab, durvalumab and avelumab), CD30 (exemplary antibodies include itumumab and briximab), CD33 (exemplary antibodies include lintuzumab), CD352, CD45 (exemplary antibodies include apamizumab), CD47 (exemplary antibodies include leplizumab and magrolimab), CT LA4 (exemplary antibodies include ipilimumab), FASL, IFNAR1 (exemplary antibodies include faramoxizumab), 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 toralimumab).

[0690] In some embodiments, the immune cell-associated antigen is a transmembrane transport protein. For example, Mincle is a transmembrane transport protein.

[0691] In some embodiments, the immune cell-associated antigen is a transmembrane or membrane-associated glycoprotein. For example, the following antigens are transmembrane or membrane-associated glycoproteins: CD112, CD155, CD24, CD247, CD28, CD30L, CD37 (exemplary antibodies include rilotomab), CD38 (exemplary antibodies include feztomax), CD3D, CD3E (exemplary antibodies include forarucumab and telizumab), CD3G, CD44, CLEC12A (exemplary antibodies include teditumab), DCIR, DCSIGN, Dectin 1, Dectin 2, ICAM1, LAMP1, Siglec 1-16, SIRPa, SIRPg, and ULBP1 / 2 / 3 / 4 / 5 / 6.

[0692] In some embodiments, the immune cell-associated antigen is a transmembrane or membrane-associated receptor kinase. For example, the following antigens are transmembrane or membrane-associated receptor kinases: Axl (exemplary antibodies include tetuzumab) and FLT3.

[0693] In some embodiments, the immune cell-associated antigen is a membrane-associated or membrane-localized protein. For example, the following antigens are membrane-associated or membrane-localized proteins: CD83, IL1RAP (exemplary antibodies include nidalizumab), OX40, SLAMF7 (exemplary antibodies include elotuzumab), and VSIR.

[0694] 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.

[0695] In some embodiments, the immune cell-associated antigen is a cell surface-associated receptor or a cell surface receptor. For example, the following antigens are cell surface-associated receptors and / or cell surface receptors: B7-DC, BCMA, CD137, CD2 (exemplary antibodies include siplizumab), CD 244, CD27 (exemplary antibodies include varlilumab), CD278 (exemplary antibodies include feladilimab and vopratelimab), CD3 (exemplary antibodies include oxicizumab and visilizumab), CD40 (exemplary antibodies include dacetuzumab and lucatumumab), CD48, CD5 (exemplary antibodies include atozumab), CD70 (exemplary antibodies include gustuzumab and vopratelimab), CD74 (exemplary antibodies include milatuzumab), CD79A, CD-262 (exemplary antibodies include tegtuzumab), DR4 (exemplary antibodies include mapatumumab), GITR (exemplary antibodies include ragavulimab), HAVCR2, HLA-DR, HLA-E, HLA-F, HLA-G, LAG-3 (exemplary antibodies include ansarizumab), MICA, MICB, MRC1, PVRIG, sialyl-Thomson-neoantigen, TIGIT (exemplary antibodies include etigilimab), Trem2 and uPAR.

[0696] 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 iklizumab, cabilizumab and imituzumab), CD123, CXCR4 (exemplary antibodies include ulurumab), IL-21R and IL-5R (exemplary antibodies include benralizumab).

[0697] In some embodiments, the immune cell-associated antigen is a co-stimulatory surface-expressed protein. For example, the following antigens are co-stimulatory surface-expressed proteins: B7-H 3 (exemplary antibodies include enoxaparin and obinutuzumab), B7-H4, B7-H6, and B7-H7.

[0698] In some embodiments, the immune cell-associated antigen is a membrane peripheral protein. For example, the following antigens are membrane peripheral proteins: B7-1 (exemplary antibodies include galiximab) and B7-2.

[0699] 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: C5 complement, IDO1, LCK, MerTk, and Tyrol.

[0700] In some embodiments, the antigen is a stromal cell-associated antigen. In some embodiments, the stromal cell-associated antigen is a transmembrane or membrane-associated protein. For example, the following antigens are transmembrane or membrane-associated proteins: FAP (exemplary antibodies include sibrotuzumab), IFNAR1 (exemplary antibodies include faramotuzumab), and IFNAR2.

[0701] 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 Patent Publication No. WO 02 / 43661. In some embodiments, the anti-CD30 antibody is cAC10, which is described in International Patent Publication No. WO 02 / 43661. cAC10 is also known as bricilimab. In some embodiments, the anti-CD30 antibody comprises the CDRs of cAC10. In some embodiments, the CDRs are as defined by the Kabat numbering scheme. In some embodiments, the CDRs are as defined by the Chothia numbering scheme. In some embodiments, the CDRs are as defined by the IMGT numbering scheme. In some embodiments, the CDRs are as defined by the AbM numbering scheme. In some embodiments, the anti-CD30 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, wherein the CDRs comprise the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is 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 that is 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.

[0702] 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 Patent Publication No. WO 2006 / 113909. In some embodiments, the antibody is h1F6 anti-CD70 antibody, which is described in International Patent Publication No. WO 2006 / 113909. h1F6 is also known as vorsetuzumab. In some embodiments, the anti-CD70 antibody includes a heavy chain variable region comprising three CDRs of SEQ ID NO: 12 and a light chain variable region comprising three CDRs of SEQ ID NO: 13. In some embodiments, the CDRs are as defined by the Kabat numbering scheme. In some embodiments, the CDRs are as defined by the Chothia numbering scheme. In some embodiments, the CDRs are as defined by the IMGT numbering scheme. In some embodiments, the CDRs are as defined by the AbM numbering scheme. In some embodiments, the anti-CD70 antibody comprises a heavy chain variable region comprising an amino acid sequence that is 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 that is 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.

[0703] In some embodiments, the antigen is interleukin-1 receptor accessory protein (IL1RAP). IL1RAP is a coreceptor of the IL1 receptor (IL1R1) and is required for interleukin-1 (IL1) signaling. IL1 is associated with resistance to certain chemotherapy regimens. IL1RAP is overexpressed in various solid tumors, both on cancer cells and in the tumor microenvironment, but has low expression on normal cells. IL1RAP is also overexpressed in hematopoietic stem cells and progenitor cells, making it a candidate for targeting chronic myeloid leukemia (CML). IL1RAP has also been shown to be overexpressed in acute myeloid leukemia (AML). Antibody binding to IL1RAP can block signal transduction from IL-1 and IL-33 to cells, and allow NK cells to recognize tumor cells and subsequently kill through antibody-dependent cellular cytotoxicity (ADCC).

[0704] In some embodiments, the antigen is ASCT2. ASCT2 is also known as SLC1A5. ASCT2 is a ubiquitously expressed, broadly specific, sodium-dependent neutral amino acid exchanger. ASCT2 is involved in glutamine transport. ASCT2 is overexpressed in different cancers and is associated with poor prognosis. Downregulation of ASCT2 has been shown to suppress intracellular glutamine levels and downstream glutamine metabolism, including glutathione production. Due to the high expression of ASCT2 in many cancers, it is a potential therapeutic target. The effect weakens growth and proliferation in head and neck squamous cell carcinoma (HNSCC), increases apoptosis and autophagy, and increases oxidative stress and mTORC1 pathway inhibition. In addition, silencing ASCT2 improves the response of HNSCC to cetuximab.

[0705] In some embodiments, the antibody-drug conjugates provided herein bind to TROP2. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 16, 17, 18, 19, 20 and 21, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 22 and a light chain variable region comprising an 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 24, 25, 26, 27, 28 and 29, respectively. 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.

[0706] In some embodiments, the antibody-drug conjugates provided herein bind to MICA. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 32, 33, 34, 35, 36 and 37, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 40, 41, 42, 43, 44 and 45, respectively. In some embodiments, the antibody of the antibody drug conjugate includes a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 46 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 47. In some embodiments, the antibody of the antibody drug conjugate is MICA.36hIgG1K G236A. In some embodiments, the antibody of the antibody drug conjugate includes CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs include the amino acid sequences of SEQ ID NO: 48, 49, 50, 51, 52 and 53, respectively. In some embodiments, the antibody of the antibody drug conjugate includes a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 54 and a light chain variable region comprising an 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 56, 57, 58, 59, 60 and 61, respectively. 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 CM33322Ab28 hIgG1K.

[0707] In some embodiments, the antibody-drug conjugates provided herein bind to CD24. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 64, 65, 66, 67, 68 and 69, respectively. 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.

[0708] In some embodiments, the antibody-drug conjugates provided herein bind to ITGav. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO:72, 73, 74, 75, 76 and 77, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO:80, 81, 82, 83, 84 and 85, respectively. 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.

[0709] In some embodiments, the antibody-drug conjugates provided herein bind to gpA33. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 88, 89, 90, 91, 92 and 93, respectively. 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.

[0710] In some embodiments, the antibody-drug conjugates provided herein bind to IL1Rap. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 96, 97, 98, 99, 100 and 101, respectively. 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 nidalizumab.

[0711] In some embodiments, the antibody-drug conjugates provided herein bind to EpCAM. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 104, 105, 106, 107, 108 and 109, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 110 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 111. In some embodiments, the antibody of the antibody drug conjugate is adelimumab. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 112, 113, 114, 115, 116 and 117, respectively. In some embodiments, the antibody of the antibody drug conjugate includes a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 118 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 119. In some embodiments, the antibody of the antibody drug conjugate includes a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 118 and a light chain variable region comprising an 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 includes CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs include amino acid sequences of SEQ ID NO: 120, 121, 122, 123, 124 and 125, respectively. In some embodiments, the antibody of the antibody drug conjugate includes a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 126 and a light chain variable region comprising an 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 128, 129, 130, 131, 132 and 133, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 136, 137, 138, 139, 140 and 141, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 144, 145, 146, 147, 148 and 149, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 104, 105, 1181, 107, 108 and 109, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, and the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 1181.

[0712] In some embodiments, the antibody-drug conjugates provided herein bind to CD352. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 152, 153, 154, 155, 156 and 157, respectively. 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.

[0713] In some embodiments, the antibody-drug conjugates provided herein bind to CS1. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 160, 161, 162, 163, 164, and 165, respectively. 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.

[0714] In some embodiments, the antibody-drug conjugates provided herein bind to CD38. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 168, 169, 170, 171, 172 and 173, respectively. 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.

[0715] In some embodiments, the antibody-drug conjugates provided herein bind to CD25. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 176, 177, 178, 179, 180 and 181, respectively. 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.

[0716] In some embodiments, the antibody-drug conjugates provided herein bind to ADAM9. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 184, 185, 186, 187, 188 and 189, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 190 and a light chain variable region comprising an 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 192, 193, 194, 195, 196 and 197, respectively. 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-drug conjugate is hMAbA9-A. In some embodiments, the antibody-drug conjugate provided herein binds to ADAM9. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 1183, 185, 186, 187, 188 and 189, respectively. In some embodiments, the antibody-drug conjugate provided herein binds to ADAM9. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, and the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 1183. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, and the CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 1184, 193, 194, 1185, 196 and 197, respectively. 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.

[0717] In some embodiments, the antibody-drug conjugates provided herein bind to CD59. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 200, 201, 202, 203, 204 and 205, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 1186, 1187, 202, 203, 204 and 205, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, and the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 1186. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H2, and the CDR-H2 comprises 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.

[0718] In some embodiments, the antibody-drug conjugates provided herein bind to CD25. In some embodiments, the antibody of the antibody drug conjugate is clone 123.

[0719] In some embodiments, the antibody-drug conjugates provided herein bind to CD229. In some embodiments, the antibody of the antibody drug conjugate is h8A10.

[0720] In some embodiments, the antibody-drug conjugates provided herein bind to CD 19. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 208, 209, 210, 211, 212 and 213, respectively. 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.

[0721] In some embodiments, the antibody-drug conjugates provided herein bind to CD70. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 216, 217, 218, 219, 220 and 221, respectively. 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 vorsetuzumab. In some cases, the antibodies provided herein bind to CD70. In some such cases, the antibody comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1169, 1170, 1171, 1172, 1173, and 1174, respectively. In some cases, the antibody comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1169, 1170, 1171, 1172, 1173, and 1174, respectively.

[0722] In some embodiments, the antibody-drug conjugates provided herein bind to B7H4. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 224, 225, 226, 227, 228 and 229, respectively. 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.

[0723] In some cases, the antibodies provided herein bind to B7H4. 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), wherein each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95% or 100% sequence identity to an amino acid sequence from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 77-82, SEQ ID NOs: 91-96, SEQ ID NOs: 99-104, SEQ ID NOs: 985-990, SEQ ID NOs: 993-998, SEQ ID NOs: 1001-128, SEQ ID NOs: 1009-1014, SEQ ID NOs: 1017-1022, SEQ ID NOs: 1025-1030, SEQ ID NOs: 1033-1038, SEQ ID NOs: 1041-1046, SEQ ID NOs: NO:1049-1054, SEQ ID NO:1057-1062, SEQ ID NO:1065-1070, SEQ ID NO:1073-1078, SEQ ID NO:1081-1086, SEQ ID NO:1089-1094, SEQ ID NO:1097-1102, SEQ ID NO:1105-1110, SEQ ID NO:1113-1118 and SEQ ID NO:1121-1126.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 comprises at most one mutation relative to an amino acid sequence from an amino acid sequence selected from the group consisting of SEQ ID NOs: 77-82, SEQ ID NOs: 91-96, SEQ ID NOs: 99-104, SEQ ID NOs: 985-990, SEQ ID NOs: 993-998, SEQ ID NOs: 1001-1006, SEQ ID NOs: 1009-1014, SEQ ID NOs: 1017-1022, SEQ ID NOs: 1025-1030, SEQ ID NOs: 1033-1038, SEQ ID NOs: 1041-1046, SEQ ID NOs: 1049-1054, SEQ ID NOs: 1057-1062, SEQ ID NOs: 1063-1064, SEQ ID NOs: 1065-1070, SEQ ID NOs: 1071-1072, SEQ ID NOs: 1073-1074, SEQ ID NOs: 1075-1076, SEQ ID NOs: 1080-1081 NO:1065-1070, SEQ ID NO:1073-1078, SEQ ID NO:1081-1086, SEQ ID NO:1089-1094, SEQ ID NO:1097-1102, SEQ ID NO:1105-1110, SEQ ID NO:1113-1118 and SEQ ID NO:1121-1126.In some cases, the anti-B7H4 antibody comprises a heavy chain and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequence 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 11321131 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: NO:1145 and 1146, SEQ ID NO:1147 and 1148, SEQ ID NO:1149 and 1150, SEQ ID NO:1151 and 1152, SEQ ID NO:1153 and 1154, SEQ ID NO:1155 and 1156, SEQ ID NO:1157 and 1158, SEQ ID NO:1159 and 1160, SEQ ID NO:1161 and 1162, SEQ ID NO:1163 and 1164, SEQ ID NO:1165 and 1166, or SEQ ID NO:1167 and 1168.In some embodiments, the anti-B7H4 antibody comprises a heavy chain variable region and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the following amino acid sequences, respectively: 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, SEQ ID NOs: 1071 and 1072, SEQ ID NOs: 1073 and 1074, NO: 1079 and 1080, SEQ ID NO: 1087 and 1088, SEQ ID NO: 1095 and 1096, SEQ ID NO: 1103 and 1104, SEQ ID NO: 1111 and 1112, SEQ ID NO: 1119 and 1120, or SEQ ID NO: 1127 and 1128.

[0724] In some embodiments, the antibody-drug conjugates provided herein bind to CD138. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 232, 233, 234, 235, 236 and 237, respectively. 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.

[0725] In some embodiments, the antibody-drug conjugates provided herein bind to CD166. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 240, 241, 242, 243, 244 and 245, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 246 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 247. In some embodiments, the antibody of the antibody drug conjugate is praluzatamab.

[0726] In some embodiments, the antibody-drug conjugates provided herein bind to CD51. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 248, 249, 250, 251, 252 and 253, respectively. 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 intumumab.

[0727] In some embodiments, the antibody-drug conjugates provided herein bind to CD56. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 256, 257, 258, 259, 260 and 261, respectively. 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.

[0728] In some embodiments, the antibody-drug conjugates provided herein bind to CD74. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 264, 265, 266, 267, 268 and 269, respectively. 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.

[0729] In some embodiments, the antibody-drug conjugates provided herein bind to CEACAM5. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 272, 273 274, 275, 276 and 277, respectively. 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.

[0730] In some embodiments, the antibody-drug conjugates provided herein are bound to CanAg. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 280, 281, 282, 283, 284 and 285, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 286 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 287. In some embodiments, the antibody of the antibody drug conjugate is cantuzumab.

[0731] In some embodiments, the antibody-drug conjugates provided herein bind to DLL-3. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 288, 289, 290, 291, 292 and 293, respectively. 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.

[0732] In some embodiments, the antibody-drug conjugates provided herein bind to DPEP-3. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 296, 297, 298, 299, 300 and 301, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 302 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 303. In some embodiments, the antibody of the antibody drug conjugate is tamrintamab.

[0733] In some embodiments, the antibody-drug conjugates provided herein bind to EGFR. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO:304, 305, 306, 307, 308 and 309, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 312, 313, 314, 315, 316 and 317, respectively. 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 losatuxizumab. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 320, 321, 322, 323, 324 and 325, respectively. In some embodiments, the antibody of the antibody drug conjugate includes a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 326 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 327. In some embodiments, the antibody of the antibody drug conjugate is serclutamab. In some embodiments, the antibody of the antibody drug conjugate includes CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs include the amino acid sequences of SEQ ID NO: 328, 329, 330, 331, 332 and 333, respectively. In some embodiments, the antibody of the antibody drug conjugate includes a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 334 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 335. In some embodiments, the antibody of the antibody drug conjugate is cetuximab.

[0734] In some embodiments, the antibody-drug conjugates provided herein bind to FRα. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO:336, 337, 338, 339, 340 and 341, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs respectively comprise the amino acid sequences of SEQ ID NOs: 344, 345, 346, 347, 348 and 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 farizumab.

[0735] In some embodiments, the antibody-drug conjugates provided herein bind to MUC-1. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 352, 353, 354, 355, 356 and 357, respectively. 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.

[0736] In some embodiments, the antibody-drug conjugates provided herein bind to mesothelin. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 360, 361, 362, 363, 364 and 365, respectively. 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.

[0737] In some embodiments, the antibody-drug conjugates provided herein bind to ROR-1. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 368, 369, 370, 371, 372 and 373, respectively. 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.

[0738] 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO:376, 377, 378, 379, 380 and 381, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO:382 and a light chain variable region comprising an amino acid sequence of SEQ ID NO:383. In some embodiments, the antibody of the antibody drug conjugate is 20502. See WO2019040780.

[0739] In some embodiments, the antibody-drug conjugates provided herein bind to B7-H3. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO:384, 385, 386, 387, 388 and 389, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 392, 393, 394, 395, 396 and 397, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 400, 401, 402, 403, 404 and 405, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 408, 409, 410, 411, 412 and 413, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 416, 417, 418, 419, 420 and 421, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 424, 425, 426, 427, 428 and 429, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 430 and a light chain variable region comprising an 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 432, 433, 434, 435, 436 and 437, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 438 and a light chain variable region comprising an 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 440, 441, 442, 443, 444 and 445, respectively. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 448, 449, 450, 451, 452 and 453, respectively.In some embodiments, the antibody of the antibody drug conjugate includes a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 454 and a light chain variable region comprising an 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 includes CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs include amino acid sequences of SEQ ID NO: 456, 457, 458, 459, 460 and 461, respectively. In some embodiments, the antibody of the antibody drug conjugate includes a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 462 and a light chain variable region comprising an 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 464, 465, 466, 467, 468 and 469, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 470 and a light chain variable region comprising an 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 an amino acid sequence of SEQ ID NO: 472 and a light chain variable region comprising an 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 474, 475, 476, 477, 478 and 479, respectively. 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 conjugate provided herein binds to B7-H3. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 384, 1189, 1190, 1191, 1192 and 1193, respectively. In some embodiments, the antibody-drug conjugate provided herein binds to B7-H3. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H2, and the CDR-H2 comprises 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 1194, 1195, 1196, 1197, 396 and 397, respectively. 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 CDR-H1, and the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 1194. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H2, and the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 1195. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H3, and the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 1196.In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 1197. In some embodiments, the antibody of the antibody drug conjugate is hAb-B. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 400, 401, 402, 403, 404 and 1198, respectively. 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-L3 comprising an amino acid sequence of SEQ ID NO: 1198. In some embodiments, the antibody of the antibody drug conjugate is hAb-C. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 1199, 1200, 1201, 1202, 1203 and 1204, respectively. In some embodiments, the antibody of the antibody drug conjugate is hAb-C. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, and the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 1199. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H2, and the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 1200. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H3, and the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 1201. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 1202. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 1203. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 1204. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 1205, 433, 434, 435, 436 and 437, respectively.In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 1205. 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 heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 438 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 1206. In some embodiments, the antibody of the antibody drug conjugate is AbV_huAbl8-v4. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise amino acid sequences of SEQ ID NO: 1207, 441, 1208, 443, 444 and 445, respectively. In some embodiments, the antibody of the antibody drug conjugate is AbV_huAbl8-v4. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 1207. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 1208. 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, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3, wherein the CDRs comprise the amino acid sequences of SEQ ID NO: 1209, 449, 450, 451, 452, and 453, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 1209. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 454 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 1210. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 1211, 457, 458, 459, 460 and 461, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, and the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 1211.In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 462 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 1212. 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 CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 464, 1213, 466, 467, 468 and 1214, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H2, and the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 1213. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-l3, and the CDR-l3 comprises the amino acid sequence of SEQ ID NO: 1214.

[0740] In some embodiments, the antibody-drug conjugates provided herein bind to CDCP1. In some embodiments, the antibody of the antibody drug conjugate is 10D7.

[0741] In some embodiments, the antibody-drug conjugates provided herein bind to HER3. In some embodiments, the antibody of the antibody drug conjugate includes a heavy chain comprising an amino acid sequence of SEQ ID NO: 486 and a light chain comprising an amino acid sequence of SEQ ID NO: 487. In some embodiments, the antibody of the antibody drug conjugate is patritumab. In some embodiments, the antibody of the antibody drug conjugate includes a heavy chain comprising an amino acid sequence of SEQ ID NO: 488 and a light chain comprising an amino acid sequence of SEQ ID NO: 489. In some embodiments, the antibody of the antibody drug conjugate is seribantumab. In some embodiments, the antibody of the antibody drug conjugate includes a heavy chain comprising an amino acid sequence of SEQ ID NO: 490 and a light chain comprising an amino acid sequence of SEQ ID NO: 491. In some embodiments, the antibody of the antibody drug conjugate is elgemtumab. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 492 and a light chain comprising the amino acid sequence of SEQ ID NO: 493. In some embodiments, the antibody of the antibody drug conjugate is lumretuzumab.

[0742] In some embodiments, the antibody-drug conjugates provided herein bind to RON. In some embodiments, the antibody of the antibody drug conjugate is Zt / g4.

[0743] In some embodiments, the antibody-drug conjugates provided herein bind to Claudin-2.

[0744] In some embodiments, the antibody-drug conjugates provided herein bind to HLA-G.

[0745] In some embodiments, the antibody-drug conjugates provided herein bind to PTK7. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 494, 495, 496, 497, 498 and 499, respectively. 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: 500 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 501. In some embodiments, the antibody of the antibody drug conjugate is PTK7 mab1. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 502, 503, 504, 505, 506 and 507, respectively. 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: 508 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 509. In some embodiments, the antibody of the antibody drug conjugate is PTK7 mab 2. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 510, 511, 512, 513, 514 and 515, respectively. 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: 516 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 517. In some embodiments, the antibody of the antibody drug conjugate is PTK7 mab 3.

[0746] In some embodiments, the antibody-drug conjugates provided herein bind to LIV1. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NO: 518, 519, 520, 521, 522 and 523, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 524 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 525. In some embodiments, the antibody of the antibody drug conjugate is ladituzumab, which is also called hLIV22 and hglg. See WO2012078668.

[0747] In some embodiments, the antibody-drug conjugates provided herein bind to avb6. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 526, 527, 528, 529, 530 and 531, respectively. 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: 532 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 533. In some embodiments, the antibody of the antibody drug conjugate is h2A2. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, and the CDRs comprise the amino acid sequences of SEQ ID NOs: 534, 535, 536, 537, 538 and 539, respectively. 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: 540 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 541. In some embodiments, the antibody of the antibody drug conjugat...

Claims

1. A camptothecin conjugate having the formula L-(Q-D) p or a salt thereof, wherein L is a Ligand unit from a targeting agent, specifically from an antibody that selectively binds to a cancer cell antigen; The subscript p is an integer ranging from 1 to 16; Q is a linker unit having a formula selected from the group consisting of: -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- Wherein Z is an extension subunit; A is a bond or linker unit; B is a parallel connection subunit; S * As a separator; RL is a releasable linker; W is an amino acid unit; Y is a Spacer unit; and D is D 0b The drug unit D of the formula or a salt thereof, wherein; E stands for -OR b5 or -NR b5 R b5’ ; R b1 Selected from the group consisting of: H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, (C6-C 12 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 ; Each optionally through C1-C3 alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or R b1 With R b2 , R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b2 Selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 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 ; each optionally through -OR a 、-NR a R a’ and-SR a replace; or R b2 With R b1 or R b3 and the intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring; or R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group; R b3 Selected from the group consisting of: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, -OR a 、-NR a R a’ and-SR a ; R b4 selected from the group consisting of H or halogen; Each R b5 and R b5’ independently selected from the group consisting of: 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-C8alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8hydroxyalkyl-C3-C 10 Heterocycloalkyl-, or R b5 and R b5’ and the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently 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 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and R a and R a’ each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-S(O)2-, C1-C6 alkyl-C(O)-, C1-C6 aminoalkyl-C(O)- and C1-C6 hydroxyalkyl-C(O)-, a) When R b2 With R b3 and the intervening atoms to form 1,3-dioxolane and E is -NR b5 R b5’ When each R b5 and R b5’ are independently selected from the group consisting of: 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-C8aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8alkyl-, 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-C8alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8hydroxyalkyl-C3-C 10 Heterocycloalkyl-, or R b5 and R b5’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, -OH, -OC1-C4 alkyl, -NH2, -NHC1-C4 alkyl and -N(C1-C4 alkyl)2; b) When R b2 With R b3 When combined with the intervening atom to form 1,3-dioxolane, E is not -OH; and c) When R b2 is methyl and R b3 When F, R b1 Not with R b6 Together with the intervening atoms, they form a ring, and d) D is not (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol-[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]dioxol-[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; wherein D is covalently linked to Q via any suitable linking site on D, optionally wherein a hydrogen atom of a hydroxyl, thiol, primary 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. The camptothecin conjugate of claim 1, wherein D has a formula selected from the group consisting of or a salt thereof, wherein the sword indicates the covalent attachment site of D to Q, or wherein R b5 The hydrogen atom of a hydroxyl group, thiol, primary amine or secondary amine is replaced by a bond with Q, or R b5 The tertiary amine of is quaternized to form a bond with Q.

3. The camptothecin conjugate of claim 2, wherein D has a formula selected from the group consisting of or a salt thereof, wherein the sword indicates the covalent attachment site of D to Q, or wherein R b5 The hydrogen atom of a hydroxyl group, thiol, primary amine or secondary amine is replaced by a bond with Q, or R b5 The tertiary amine of is quaternized to form a bond with Q.

4. The camptothecin conjugate of claim 2, wherein D has a formula selected from the group consisting of or a salt thereof, wherein X and Y B Each independently is O, S, S(O)2, CR x R x’ or NR x ; R x and R x’ Each is independently selected from the group consisting of H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl-C(O)-, C1-C6 alkyl-C(O)-, C1-C6 hydroxyalkyl-C(O)-, C1-C6 alkyl-NH-C(O)- or C1-C6 alkyl-S(O)2-; and m and n are each 1 or 2; Each R c1 , R c1’ , R c2 and R c2’ Independently (i) selected from the group consisting of: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -OR a 、-NR a R a’ and-SR a 、C1-C6 alkyl-C(O)-、C1-C6 alkyl-NR a -C(O)- and C1-C6 alkyl-S(O)2-; or (ii) with R b1 Together with the intervening atoms, they form a 5- to 7-membered carbocyclic or heterocyclic ring; or (iii) with R x’ Together with the intervening atoms, they form a 3- to 6-membered carbocyclic or heterocyclic ring; and When both m and n are present, the sum of m+n is 2 or 3; wherein the sword indicates the covalent attachment site of D and Q, or wherein R b5 The hydrogen atom of a hydroxyl group, thiol, primary amine or secondary amine is replaced by a bond with Q, or R b5 The tertiary amine of is quaternized to form a bond with Q.

5. The camptothecin conjugate of claim 2, wherein D has a formula selected from the group consisting of or a salt thereof, wherein R d1 , R d1’ , R d2 and R d2’ Each is independently selected from the group consisting of: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-NR a R a’ and-SR a 、C1-C6 alkyl-C(O)-、C1-C6 alkyl-NR a -C(O)- and C1-C6 alkyl-S(O)2-; The dagger indicates the covalent attachment site of D and Q.

6. The camptothecin conjugate of claim 2, wherein D has a formula selected from the group consisting of or a salt thereof, wherein Y 1 is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 alkyl-S(O)2-; The dagger indicates the covalent attachment site of D and Q.

7. The camptothecin conjugate of claim 2, wherein D has a formula selected from the group consisting of or a salt thereof, wherein Each R e independently selected from the group consisting of halogen, -OH, -NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl-S(O)2- and C1-C6 alkyl-NR a -C(O)-; and f is 0, 1, 2, 3, 4 or 5; The dagger indicates the covalent attachment site of D and Q.

8. The camptothecin conjugate of claim 2, wherein D has a formula selected from the group consisting of or a salt thereof, wherein R g is H, C1-C6 alkyl or 3 to 8 membered heterocycle; The dagger indicates the covalent attachment site of D and Q.

9. The camptothecin conjugate of claim 2, wherein D has a formula selected from the group consisting of or a salt thereof, wherein R 3h , R 3h’ and R 3h” Each independently selected from the group consisting of: 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 optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-NR a R a’ and-SR a replace; The dagger indicates the covalent attachment site of D and Q.

10. The camptothecin conjugate of claim 2, wherein D has a formula selected from the group consisting of or a salt thereof; wherein the sword indicates the covalent attachment site of D and Q.

11. The camptothecin conjugate of claim 1, wherein D has D 0b -I formula or its salt; wherein R b2 With R b3 When combined with intervening atoms to form a 5-, 6-, or 7-membered heterocyclic ring, the heterocyclic ring has no more than one O.

12. The camptothecin conjugate of claim 1, wherein D has D 0b -II or a salt thereof, wherein; R b5 H and R b5’ Selected from the group consisting of: 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-C8aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8alkyl-, 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-C8alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8hydroxyalkyl-C3-C 10 Heterocycloalkyl-, or R b5 and R b5’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ wherein the cycloalkyl, carbocyclic, heterocyclic, phenyl and heteroaryl moieties are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, -OH, -OC1-C4 alkyl, -NH2, -NHC1-C4 alkyl and -N(C1-C4 alkyl)2, provided that D is not (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1, 3]dioxol and [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]dioxol and [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. The camptothecin conjugate of claim 1, wherein D has D 0b -III or a salt thereof.

14. The camptothecin conjugate of claim 1, wherein D has D 0a -I formula or a salt thereof, wherein; E stands for -OR b5 or -NR b5 R b5’ ; R b1 Selected from the group consisting of: H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, (C6-C 12 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 ; Each optionally through C1-C3 alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or R b1 With R b2 , R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b2 Selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 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 ; each optionally through -OR a 、-NR a R a’ and-SR a replace; or R b2 With R b1 or R b3 and the intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring; or R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group; R b3 Selected from the group consisting of: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, -OR a 、-NR a R a’ and-SR a ;or R b3 With R b2 and intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring or a 5-membered heterocyclic ring fused to a 6-membered aryl group; R b4 selected from the group consisting of H and halogen; Each R b5 and R b5’ independently selected from the group consisting of: 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-C 10 heterocycloalkyl)-C1-C8alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8hydroxyalkyl-C3-C 10 Heterocycloalkyl-, or R b5 and R b5’ and the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently 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 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and R a and R a’ each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-S(O)2-, C1-C6 alkyl-C(O)-, C1-C6 aminoalkyl-C(O)- and C1-C6 hydroxyalkyl-C(O)-, a) When R b2 With R b3 and the intervening atoms combine to form 1,3-dioxolane, and E is -NR b5 R b5’ When each R b5 and R b5’ are independently selected from the group consisting of: 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-, phenyl-C(O)- and phenyl-SO2-, or R b5 and R b5’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, -OH, -OC1-C4 alkyl, -NH2, -NHC1-C4 alkyl and -N(C1-C4 alkyl)2; b) When R b2 With R b3 When combined with the intervening atom to form 1,3-dioxolane, E is not -OH; c) When E is NH2, R b1 Selected from the group consisting of: -CN, 5- to 12-membered heteroaryl with at least one cyclic N, 3- to 10-membered heterocycloalkyl with at least one cyclic N, 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 ; Each optionally through C1-C3 alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a Substitution, or R b1 With R b2 and intervening atoms combine to form a 5-, 6-, or 7-membered heterocyclic ring having at least one cyclic N or a 5-membered heterocyclic ring fused to a 6-membered aryl group; R b2 Selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 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 ; each optionally through -OR a 、-NR a R a’ and-SR a replace; or R b2 With R b1 or R b3 and intervening atoms to form a 5- or 6-membered heterocyclic ring having at least one cyclic N, or R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to the 6-membered aryl group; and d) When R b2 is -OH or methyl and R b3 When F, R b1 Not with R b5 , R b5’ or R b6 together with the intervening atoms form a ring; and e) D is not selected from the group consisting of: (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol-[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol-[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)hexahydropyrazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol-1,1-dioxolane-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1 Penta[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminohexahydropyridin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol ... ]quinoline-8,11(7H)-dione and (S)-tert-butyl(1-((7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxol[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.

15. The camptothecin conjugate of claim 1, wherein D has the formula D0-I' or a salt thereof, When R b2 With R b3 When combined with intervening atoms to form a 5-, 6-, or 7-membered heterocyclic ring, the heterocyclic ring has no more than one O.

16. The camptothecin conjugate of claim 1, wherein D has the formula D0-III' or a salt thereof, wherein; R b1 Selected from the group consisting of: H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, (C6-C 12 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 ; Each optionally through C1-C3 alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or R b1 With R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b4 selected from the group consisting of H or halogen; R b5 H and R b5’ is C1-C8 alkyl-O-C1-C8 alkyl, or R b5 and R b5’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently 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 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and R a and R a’ each independently selected from the group consisting of: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-S(O)2-, C1-C6 alkyl-C(O)-, C1-C6 aminoalkyl-C(O)-, and C1-C6 hydroxyalkyl-C(O)-, provided that D is not selected from the group consisting of: (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3] dioxol [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] dioxol [4,5-g] pyrano [3',4':6,7] indolizino [1,2-b] quinoline-8,11 (7H) -dione, (S) -14-((4-(2-amino (S)-14-((4-aminohexahydropyridin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol-[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminohexahydropyridin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol-[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 and (S)-tert-butyl(1-((7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolino[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.

17. A camptothecin conjugate having the formula L-(Q-D) p or a salt thereof, wherein L is a Ligand unit from a targeting agent, specifically from an antibody that selectively binds to a cancer cell antigen; The subscript p is an integer ranging from 1 to 16; Q is a linker unit having a formula selected from the group consisting of: -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- Wherein Z is an extension subunit; A is a bond or linker unit; B is a parallel connection subunit; S * As a separator; RL is a releasable linker; W is an amino acid unit; Y is a Spacer unit; and D is a drug unit D, wherein D comprises a compound selected from Table I or a salt thereof, wherein D is covalently linked to Q through any suitable attachment 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.

18. The camptothecin conjugate of any one of claims 1 to 17, wherein Q is a linker unit having a subunit selected from the group consisting of: -Z-A-RL-;-Z-A-RL-Y-;-Z-A-S * -RL-;-Z-A-B(S * )-RL-; -Z-A-S * -RL-Y-; and -Z-A-B(S * )-RL-Y-, wherein A is a linker unit and RL is a glycoside (eg, glucuronide) unit.

19. The camptothecin conjugate of claim 18, wherein the glycoside (eg, glucuronide) unit has the formula: in Su is the hexose form of a monosaccharide; O' represents the oxygen atom of the glycosidic bond that can be cleaved by glycosidase; The wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and The wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the rest of Q, Optionally wherein the glycoside (eg, glucuronide) unit has the formula: Optionally wherein the glycoside (eg, glucuronide) unit has the formula:

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

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

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

23. The camptothecin conjugate according to claim 18, wherein Q is a linker unit having the formula -ZA-RL-Y-, -ZAS*-RL-Y-, or -ZAB(S*)-RL-Y-; and The Spacer unit (Y) has the following formula: Where EWG is the electron withdrawing group; O* represents the oxygen atom from the hydroxyl 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 (eg, glucuronide) unit; and The wavy line adjacent to O* indicates the site of covalent attachment to the rest of D, or The spacer unit (Y) has the following formula: in EWG is an electron withdrawing group; The wavy line adjacent to the nitrogen atom indicates the site of covalent attachment to the carbonyl carbon atom of the glycosidic (e.g., glucuronide) unit; and The wavy line adjacent to the carbonyl carbon atom indicates the site of covalent attachment to the nitrogen atom of the amino substituent of D.

24. The camptothecin conjugate of claims 1-17 or 20-22, wherein Y exists and has the formula:

25. The camptothecin conjugate according to any one of claims 1 to 17, wherein Q is a linker unit having a formula selected from the group consisting of: -Z-A-; -Z-A-S * -W- and -Z-A-B(S * )-W- Where A is a linker unit, or Q is a linker unit having a formula selected from the group consisting of: -Z-A-RL-、-Z-A-S * -RL-; -Z-A-B(S * )-RL-, -Z-A-S * -W-RL- and -Z-A-B(S * )-W-RL-, wherein A is a linker unit and RL is a releasable linker other than a glycoside (eg, glucuronide) unit.

26. The camptothecin conjugate of claim 25, wherein Q is a linker unit having a formula selected from the group consisting of: -ZA-RL-, -ZAS*-RL-, and -ZAS*-W-RL-, wherein RL has the formula: in The wavy line marked with a double asterisk (**) indicates the site of covalent attachment to D; and Wavy lines marked with a single asterisk (*) indicate points of covalent attachment to A, S*, or W.

27. The camptothecin conjugate according to claim 25 or 26, wherein -QD has the formula -ZAS*-W-RL-D, where D is covalently linked to Q via the nitrogen atom of the amine functional group of D; and 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 linked to Q via the oxygen atom of the hydroxy substituent on the lactone ring of D; and W is an amino acid unit selected from the group consisting of glutamic acid or lysine.

28. The camptothecin conjugate of claim 27, wherein -ZA- comprises a succinimidyl-alkanoyl moiety or a succinimidyl and triazole moiety, each optionally having a succinimidyl ring in hydrolyzed form as the succinamide moiety, or a succinamide moiety derivable from the mDPR of a camptothecin-linker compound, or Wherein -ZA- has the following formula: It optionally has a hydrolyzed succinimide ring as the succinamide part, wherein a wavy line marked with double asterisks (**) indicates a covalent attachment site to S*; and a wavy line marked with triple asterisks (***) indicates a covalent attachment point to the sulfur atom of L.

29. The camptothecin conjugate of claim 15, wherein Q is a linker unit having a formula selected from the group consisting of: -ZAS*-RL- and -ZAS*-W-RL-, wherein S* has the following formula: Wherein the subscript n is an integer ranging from 1 to 36, The wavy line adjacent to the nitrogen atom indicates the covalent attachment site to the carbonyl carbon atom of A, and the wavy line adjacent to the carbonyl carbon atom indicates the covalent attachment site to the nitrogen atom of the amine functional group of RL of -ZAS*-RL- or W of -ZAS*-W-RL-, Specifically, -Z A- in any formula of Q has the formula: The wavy line marked with double asterisks (**) indicates the site of covalent attachment to the nitrogen atom of the amine functional group of S*; and the wavy line marked with triple asterisks (***) indicates the point of covalent attachment to the sulfur atom of L.

30. The camptothecin conjugate of claim 25, wherein Q is a linker unit having the formula -ZAS*-W- or -ZASW-RL-, wherein -ZAS*-W- in any of the formulas has the following formula: It optionally has a hydrolyzed succinimide ring as the succinic acid amide portion, wherein the subscript n is an integer in the range of 2 to 10, preferably in the range of 2 to 4; the wavy line marked with a double asterisk (**) indicates a covalent bonding site with D or RL; and the wavy line marked with a triple asterisk (***) indicates a covalent bonding point with the sulfur atom of L.

31. A camptothecin-linker compound having a formula selected from the group consisting of: (i) Z'-A-RL-D; (ii) Z'-A-RL-YD; (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'-AD (viii) Z'-AS*-WD (ix)Z'-AB(S*)-WD (x) Z'-AS*-W-RL-D; and (xi)Z'-AB(S*)-W-RL-D in Z' is the elongation subunit precursor; A is a bond or linker unit; B is a parallel connection subunit; S * As a separator; RL is a releasable linker; Y is a Spacer unit; and D is D 0b The drug unit D of the formula or its salts; wherein; E stands for -OR b5 or -NR b5 R b5’ ; R b1 Selected from the group consisting of: H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, (C6-C 12 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 ; Each optionally through C1-C3 alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or R b1 With R b2 , R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b2 Selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 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 ; each optionally through -OR a 、-NR a R a’ and-SR a replace; or R b2 With R b1 or R b3 and the intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring; or R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group; R b3 Selected from the group consisting of: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, -OR a 、-NR a R a’ and-SR a ; R b4 selected from the group consisting of H or halogen; Each R b5 and R b5’ independently selected from the group consisting of: 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-C8alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8hydroxyalkyl-C3-C 10 Heterocycloalkyl-, or R b5 and R b5’ and the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently 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 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and R a and R a’ each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-S(O)2-, C1-C6 alkyl-C(O)-, C1-C6 aminoalkyl-C(O)- and C1-C6 hydroxyalkyl-C(O)-, a) When R b2 With R b3 and the intervening atoms to form 1,3-dioxolane and E is -NR b5 R b5’ When each R b5 and R b5’ are independently selected from the group consisting of: 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-C8aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8alkyl-, 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-C8alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8hydroxyalkyl-C3-C 10 Heterocycloalkyl-, or R b5 and R b5’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, -OH, -OC1-C4 alkyl, -NH2, -NHC1-C4 alkyl and -N(C1-C4 alkyl)2; b) When R b2 With R b3 When combined with the intervening atom to form 1,3-dioxolane, E is not -OH; and c) When R b2 is methyl and R b3 When F, R b1 Not with R b6 Together with the intervening atoms, they form a ring, and d) D is not (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol-[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]dioxol-[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; wherein D is covalently linked to the remainder of the camptothecin-linker compound via any suitable linking site on D, optionally wherein a hydrogen atom of a hydroxyl, thiol, primary 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. The camptothecin-linker compound of claim 31, wherein D has a formula selected from the group consisting of or a salt thereof, wherein the sword indicates the site of covalent attachment of D to the remainder of the camptothecin-linker compound, or wherein R b5 A hydrogen atom of a hydroxyl, thiol, primary or secondary amine of R is replaced by a bond to the rest of the camptothecin-linker compound, or R b5 The tertiary amine of is quaternized to form a bond to the rest of the camptothecin-linker compound.

33. The camptothecin-linker compound of claim 32, wherein D has a formula selected from the group consisting of or a salt thereof; wherein the sword indicates the site of covalent attachment of D to the remainder of the camptothecin-linker compound, or wherein R b5 A hydrogen atom of a hydroxyl, thiol, primary or secondary amine of R is replaced by a bond to the rest of the camptothecin-linker compound, or R b5 The tertiary amine of is quaternized to form a bond to the rest of the camptothecin-linker compound.

34. The camptothecin-linker compound of claim 32, wherein D has a formula selected from the group consisting of or a salt thereof, wherein X and Y B Each independently is O, S, S(O)2, CR x R x’ or NR x ; R x and R x’ Each is independently selected from the group consisting of H, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl-C(O)-, C1-C6 alkyl-C(O)-, C1-C6 hydroxyalkyl-C(O)-, C1-C6 alkyl-NH-C(O)- or C1-C6 alkyl-S(O)2-; and m and n are each 1 or 2; Each R c1 , R c1’ , R c2 and R c2’ Independently (i) selected from the group consisting of: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, -OR a 、-NR a R a’ and-SR a 、C1-C6 alkyl-C(O)-、C1-C6 alkyl-NR a -C(O)- and C1-C6 alkyl-S(O)2-; or (ii) with R b1 Together with the intervening atoms, they form a 5- to 7-membered carbocyclic or heterocyclic ring; or (iii) with R x’ Together with the intervening atoms, they form a 3- to 6-membered carbocyclic or heterocyclic ring; and When both m and n are present, the sum of m+n is 2 or 3; wherein the sword indicates the site of covalent attachment of D to the rest of the camptothecin-linker compound, or wherein R b5 A hydrogen atom of a hydroxyl, thiol, primary or secondary amine of R is replaced by a bond to the rest of the camptothecin-linker compound, or R b5 The tertiary amine of is quaternized to form a bond to the rest of the camptothecin-linker compound.

35. The camptothecin-linker compound of claim 32, wherein D has a formula selected from the group consisting of or a salt thereof, wherein R d1 , R d1’ , R d2 and R d2’ Each is independently selected from the group consisting of: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-NR a R a’ and-SR a 、C1-C6 alkyl-C(O)-、C1-C6 alkyl-NR a -C(O)- and C1-C6 alkyl-S(O)2-; The dagger indicates the site of covalent attachment of D to the rest of the camptothecin-linker compound.

36. The camptothecin-linker compound of claim 32, wherein D has a formula selected from the group consisting of or a salt thereof, wherein Y 1 is a 5-membered or 6-membered heteroaryl group, which is optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 alkyl-S(O)2-; The dagger indicates the site of covalent attachment of D to the rest of the camptothecin-linker compound.

37. The camptothecin-linker compound of claim 31, wherein D has a formula selected from the group consisting of or a salt thereof, wherein Each R e independently selected from the group consisting of halogen, -OH, -NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl-S(O)2- and C1-C6 alkyl-NR a -C(O)-; and f is 0, 1, 2, 3, 4 or 5; The dagger indicates the site of covalent attachment of D to the rest of the camptothecin-linker compound.

38. The camptothecin-linker compound of claim 32, wherein D has a formula selected from the group consisting of or a salt thereof, wherein R g is H, C1-C6 alkyl or 3 to 8 membered heterocyclic group; The dagger indicates the site of covalent attachment of D to the rest of the camptothecin-linker compound.

39. The camptothecin-linker compound of claim 32, wherein D has a formula selected from the group consisting of or a salt thereof, wherein R 3h , R 3h’ and R 3h” Each independently selected from the group consisting of: 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 optionally substituted by C1-C6 alkyl, C1-C6 haloalkyl, -OR a 、-NR a R a’ and-SR a replace; The dagger indicates the site of covalent attachment of D to the rest of the camptothecin-linker compound.

40. The camptothecin-linker compound of claim 32, wherein D has a formula selected from the group consisting of or its salts; The dagger indicates the site of covalent attachment of D to the rest of the camptothecin-linker compound.

41. The camptothecin-linker compound of claim 31, wherein D has D 0b -I formula or a salt thereof; and wherein R b2 With R b3 When combined with intervening atoms to form a 5-, 6-, or 7-membered heterocyclic ring, the heterocyclic ring has no more than one O.

42. The camptothecin-linker compound of claim 31, wherein D has D 0b -II or a salt thereof, wherein; R b5’ Selected from the group consisting of: 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-C8aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8alkyl-, 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-C8alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8hydroxyalkyl-C3-C 10 Heterocycloalkyl-, or R b5 and R b5’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ wherein the cycloalkyl, carbocyclic, heterocyclic, phenyl and heteroaryl moieties are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, -OH, -OC1-C4 alkyl, -NH2, -NHC1-C4 alkyl and -N(C1-C4 alkyl)2, provided that D is not (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1, 3]dioxol and [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]dioxol and [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. The camptothecin-linker compound of claim 31, wherein D has D 0b -III or a salt thereof.

44. The camptothecin-linker compound of claim 31, wherein D has D 0a -I formula or a salt thereof, wherein; E stands for -OR b5 or -NR b5 R b5’ ; R b1 Selected from the group consisting of: H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, (C6-C 12 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 ; Each optionally through C1-C3 alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or R b1 With R b2 , R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b2 Selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 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 ; each optionally through -OR a 、-NR a R a’ and-SR a replace; or R b2 With R b1 or R b3 and the intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring; or R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group; R b3 Selected from the group consisting of: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, -OR a 、-NR a R a’ and-SR a ;or R b3 With R b2 and intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring or a 5-membered heterocyclic ring fused to a 6-membered aryl group; R b4 selected from the group consisting of H and halogen; Each R b5 and R b5’ independently selected from the group consisting of: 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-C 10 heterocycloalkyl)-C1-C8alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8hydroxyalkyl-C3-C 10 Heterocycloalkyl-, or R b5 and R b5’ and the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently 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 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and R a and R a’ each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-S(O)2-, C1-C6 alkyl-C(O)-, C1-C6 aminoalkyl-C(O)- and C1-C6 hydroxyalkyl-C(O)-, a) When R b2 With R b3 and the intervening atoms combine to form 1,3-dioxolane, and E is -NR b5 R b5’ When each R b5 and R b5’ are independently selected from the group consisting of: 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-, phenyl-C(O)- and phenyl-SO2-, or R b5 and R b5’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, -OH, -OC1-C4 alkyl, -NH2, -NHC1-C4 alkyl and -N(C1-C4 alkyl)2; b) When R b2 With R b3 and the intervening atoms to form 1,3-dioxolane, E is not -OH; c) when E is NH2, R b1 Selected from the group consisting of: -CN, 5- to 12-membered heteroaryl with at least one cyclic N, 3- to 10-membered heterocycloalkyl with at least one cyclic N, 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 ; Each optionally through C1-C3 alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a Substitution, or R b1 With R b2 and intervening atoms combine to form a 5-, 6-, or 7-membered heterocyclic ring having at least one cyclic N or a 5-membered heterocyclic ring fused to a 6-membered aryl group; R b2 Selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 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 ; each optionally through -OR a 、-NR a R a’ and-SR a replace; or R b2 With R b1 or R b3 and intervening atoms to form a 5- or 6-membered heterocyclic ring having at least one cyclic N, or R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to the 6-membered aryl group; and d) When R b2 is -OH or methyl and R b3 When F, R b1 Not with R b5 , R b5’ or R b6 together with the intervening atoms form a ring; and e) D is not selected from the group consisting of: (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol-[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol-[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)hexahydropyrazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol-1,1-dioxolane-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1 Penta[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminohexahydropyridin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol ... ]quinoline-8,11(7H)-dione and (S)-tert-butyl(1-((7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxol[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. The camptothecin-linker compound of claim 31, wherein D has the formula D0-I' or a salt thereof, wherein R b2 With R b3 When combined with intervening atoms to form a 5-, 6-, or 7-membered heterocyclic ring, the heterocyclic ring has no more than one O. 45a. The camptothecin-linker compound of claim 31, wherein D has the formula D0-III' or a salt thereof, wherein; R b1 Selected from the group consisting of: H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, (C6-C 12 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 ; Each optionally through C1-C3 alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or R b1 With R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b4 selected from the group consisting of H or halogen; R b5’ is C1-C8 alkyl-O-C1-C8 alkyl, or R b5 and R b5’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5 is H and Rb5' and R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently 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 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and R a and R a’ Each is independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-S(O)2-, C1-C6 alkyl-C(O)-, C1-C6 aminoalkyl-C(O)- and C1-C6 hydroxyalkyl-C(O)-; Provided that D is not selected from the group consisting of: (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol-[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol-[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)hexahydropyrazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol-1,1-dioxolane-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1 Penta[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminohexahydropyridin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol ... ]quinoline-8,11(7H)-dione and (S)-tert-butyl(1-((7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxol[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. ​​A camptothecin-linker compound having the formula (i) Z'-A-RL-D; (ii) Z'-A-RL-YD; (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'-AD (viii) Z'-AS*-WD (ix)Z'-AB(S*)-WD (x) Z'-AS*-W-RL-D; and (xi)Z'-AB(S*)-W-RL-D in Z' is the elongation subunit precursor; A is a bond or linker unit; B is a parallel connection subunit; S * As a separator; RL is a releasable linker; Y is a Spacer unit; and D is a drug unit D, wherein D comprises a compound selected from Table I or a salt thereof, wherein D is covalently linked to the remainder of the camptothecin-linker compound through any suitable attachment site on D, optionally wherein a hydrogen atom of a hydroxyl, thiol, primary 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 camptothecin-linker compound as described in any one of claims 31-46, which has 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 linker unit; and RL is a glycoside (e.g., a glucuronide) unit, optionally wherein the glycoside unit has the following formula: Optionally wherein the glycoside unit has the formula: The wavy lines marked with a single asterisk (*) indicate the covalent attachment site to D or to the spacer unit (Y); and the wavy lines marked with a double asterisk (**) indicate the covalent attachment site to A, B or S. * covalent attachment point.

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

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

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

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

52. The camptothecin-linker compound of any one of claims 31-46, having formula (ii), formula (iv) or formula (vi), wherein The spacer unit (Y) has the following formula: Where EWG is the electron withdrawing group; O* represents the oxygen atom from the hydroxyl functional group of D; The wavy line adjacent to the nitrogen atom indicates the site of covalent attachment to the carbonyl carbon atom of the glycosidic (e.g., glucuronide) unit; and The wavy line adjacent to O* indicates the site of covalent attachment to the rest of D, or The spacer unit (Y) has the following formula: in EWG is an electron withdrawing group; The wavy line adjacent to the nitrogen atom indicates the site of covalent attachment to the carbonyl carbon atom of the glycosidic (e.g., glucuronide) unit; and The wavy line adjacent to the carbonyl carbon atom indicates the site of covalent attachment to the nitrogen atom of the amine functionality of D.

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

54. A camptothecin-linker compound as described in any of claims 31-46, which has formula (vii), formula (viii) or formula (ix), wherein A is a linker unit, or it has formula (i), formula (iii), formula (x) or formula (xi), wherein A is a linker unit and RL is a releasable linker other than a glycoside (e.g., a glucuronide) unit.

55. The camptothecin-linker compound of claim 54, having formula (i), formula (iii) or formula (x), wherein RL has the formula: in The wavy line marked with a double asterisk (**) indicates the site of covalent attachment to D; and Wavy lines marked with a single asterisk (*) indicate points of covalent attachment to A, S*, or W.

56. The camptothecin-linker compound of claim 55, having 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. The camptothecin-linker compound of any one of claims 54-56, wherein Z'-A- comprises a maleimido-alkanoyl moiety or mDPR, the basic nitrogen atom of which is optionally protonated or protected with an acid labile protecting group.

58. The camptothecin-linker compound of any one of claims 54-56, having formula (iii) or formula (x), wherein Z'-A- has a formula selected from the group consisting of: The wavy line marked with a double asterisk (**) indicates the site of covalent attachment to S*.

59. The camptothecin-linker compound of any one of claims 54-56, having formula (iii) or formula (x), wherein S* has the following formula: The subscript n is an integer in the range of 1 to 36.

60. The camptothecin-linker compound of claim 54 or 55, having formula (viii) or formula (x), wherein Z'-AS*-W- has the formula: wherein the subscript n is an integer in the range of 2 to 10, preferably in the range of 2 to 4; the wavy line marked with a double asterisk (**) indicates the covalent attachment site to D or RL.

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

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

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

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

65. Type D 0b Compounds or a salt thereof, wherein; E stands for -OR b5 or -NR b5 R b5’ ; R b1 Selected from the group consisting of: H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, (C6-C 12 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 ; Each optionally through C1-C3 alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or R b1 With R b2 , R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b2 Selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 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 ; each optionally through -OR a 、-NR a R a’ and-SR a replace; or R b2 With R b1 or R b3 and the intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring; or R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group; R b3 Selected from the group consisting of: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, -OR a 、-NR a R a’ and-SR a ; R b4 selected from the group consisting of H or halogen; Each R b5 and R b5’ independently selected from the group consisting of: 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-C8alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8hydroxyalkyl-C3-C 10 Heterocycloalkyl-, or R b5 and R b5’ and the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently 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 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and R a and R a’ each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-S(O)2-, C1-C6 alkyl-C(O)-, C1-C6 aminoalkyl-C(O)- and C1-C6 hydroxyalkyl-C(O)-, a) When R b2 With R b3 and the intervening atoms to form 1,3-dioxolane and E is -NR b5 R b5’ When each R b5 and R b5’ are independently selected from the group consisting of: 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-C8aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8alkyl-, 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-C8alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8hydroxyalkyl-C3-C 10 Heterocycloalkyl-, or R b5 and R b5’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, -OH, -OC1-C4 alkyl, -NH2, -NHC1-C4 alkyl and -N(C1-C4 alkyl)2; b) When R b2 With R b3 When combined with the intervening atom to form 1,3-dioxolane, E is not -OH; and c) When R b2 is methyl and R b3 When F, R b1 Not with R b6 together with the intervening atoms form a ring; and d) D is not (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol[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]dioxol[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.

66. The compound of claim 65, wherein the compound has D 0b -I formula or a salt thereof; and wherein R b2 With R b3 When combined with intervening atoms to form a 5-, 6-, or 7-membered heterocyclic ring, the heterocyclic ring has no more than one O.

67. The compound of claim 65, wherein D has D 0b -II or a salt thereof, wherein; R b5 H and R b5’ Selected from the group consisting of: 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-C8aminoalkyl-, C1-C6 alkoxy-C(O)-N-(C1-C4 alkyl)amino-C1-C8alkyl-, 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-C8alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8hydroxyalkyl-C3-C 10 Heterocycloalkyl-, or R b5 and R b5’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ wherein the cycloalkyl, carbocyclic, heterocyclic, phenyl and heteroaryl moieties are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, -OH, -OC1-C4 alkyl, -NH2, -NHC1-C4 alkyl and -N(C1-C4 alkyl)2; provided that D is not (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1, 3]dioxol and [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]dioxol and [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 compound of claim 65, wherein the compound has D 0b -III or a salt thereof.

69. The compound of claim 65, wherein the compound has D 0a -I formula or a salt thereof, wherein; E stands for -OR b5 or -NR b5 R b5’ ; R b1 Selected from the group consisting of: H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, (C6-C 12 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 ; Each optionally through C1-C3 alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or R b1 With R b2 , R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b2 Selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 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 ; each optionally through -OR a 、-NR a R a’ and-SR a replace; or R b2 With R b1 or R b3 and the intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring; or R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to a 6-membered aryl group; R b3 Selected from the group consisting of: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, -OR a 、-NR a R a’ and-SR a ;or R b3 With R b2 and intervening atoms to form a 5- or 6-membered carbocyclic or heterocyclic ring or a 5-membered heterocyclic ring fused to a 6-membered aryl group; R b4 selected from the group consisting of H and halogen; Each R b5 and R b5’ independently selected from the group consisting of: 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-C 10 heterocycloalkyl)-C1-C8alkyl-, phenyl-C(O)-, phenyl-SO2- and C1-C8hydroxyalkyl-C3-C 10 Heterocycloalkyl-, or R b5 and R b5’ and the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently 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 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and R a and R a’ each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-S(O)2-, C1-C6 alkyl-C(O)-, C1-C6 aminoalkyl-C(O)- and C1-C6 hydroxyalkyl-C(O)-, a) When R b2 With R b3 and the intervening atoms combine to form 1,3-dioxolane, and E is -NR b5 R b5’ When each R b5 and R b5’ are independently selected from the group consisting of: 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-, phenyl-C(O)- and phenyl-SO2-, or R b5 and R b5’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ H and R b5 With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, -OH, -OC1-C4 alkyl, -NH2, -NHC1-C4 alkyl and -N(C1-C4 alkyl)2; b) When R b2 With R b3 and the intervening atoms to form 1,3-dioxolane, E is not -OH; c) when E is NH2, R b1 Selected from the group consisting of: -CN, 5- to 12-membered heteroaryl with at least one cyclic N, 3- to 10-membered heterocycloalkyl with at least one cyclic N, 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 ; Each optionally through C1-C3 alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a Substitution, or R b1 With R b2 and intervening atoms combine to form a 5-, 6-, or 7-membered heterocyclic ring having at least one cyclic N or a 5-membered heterocyclic ring fused to a 6-membered aryl group; R b2 Selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 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 ; each optionally through -OR a 、-NR a R a’ and-SR a replace; or R b2 With R b1 or R b3 and intervening atoms to form a 5- or 6-membered heterocyclic ring having at least one cyclic N, or R b2 With R b1 or R b3 and the intervening atoms combine to form a 5- or 6-membered heterocyclic ring fused to the 6-membered aryl group; and d) When R b2 is -OH or methyl and R b3 When F, R b1 Not with R b5 , R b5’ or R b6 together with the intervening atoms form a ring; and e) D is not selected from the group consisting of: (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol-[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3]dioxol-[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-(2-aminoethyl)hexahydropyrazin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol-1,1-dioxolane-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1,1-dioxol-1 Penta[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminohexahydropyridin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol ... ]quinoline-8,11(7H)-dione and (S)-tert-butyl(1-((7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxol[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 of claim 65, wherein the compound has the formula D0-I' or a salt thereof, When R b2 With R b3 When combined with intervening atoms to form a 5-, 6-, or 7-membered heterocyclic ring, the heterocyclic ring has no more than one O.

71. The compound of claim 65, wherein the compound has the formula D0-III' or a salt thereof, wherein; R b1 Selected from the group consisting of: H, halogen, -CN, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, C3-C 10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, (C6-C 12 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 ; Each optionally through C1-C3 alkyl, -OR a 、-NR a R a’ 、-C(O)R a and-SR a replace; or R b1 With R b5 or R b6 and intervening atoms to form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R b4 selected from the group consisting of H or halogen; R b5’ is C1-C8 alkyl-O-C1-C8 alkyl, or R b5 and R b5’ is combined with the nitrogen atom to which it is attached to form a 5-, 6-, or 7-membered heterocyclic ring having 0 to 3 substituents independently selected from the group consisting of halogen, C 1- C4 alkyl, -OH, -C1-C6 hydroxyalkyl, -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; or R b5’ With R b1 and intervening atoms to form a 5- to 7-membered carbocyclic or heterocyclic ring; wherein R b1 , R b2 , R b3 , R b4 , R b5 and R b5’ The cycloalkyl, carbocycle, heterocycloalkyl, heterocycle, phenyl and heteroaryl portions are substituted with 0 to 3 substituents independently 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 H, or with R b1 together with the intervening atoms form a carbocyclic or heterocyclic ring; and R a and R a’ each independently selected from the group consisting of: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-S(O)2-, C1-C6 alkyl-C(O)-, C1-C6 aminoalkyl-C(O)-, and C1-C6 hydroxyalkyl-C(O)-, provided that D is not selected from the group consisting of: (S)-7-ethyl-7-hydroxy-14-((4-methylhexahydropyrazin-1-yl)methyl)-10,13-dihydro-11H-[1,3] dioxol [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] dioxol [4,5-g] pyrano [3',4':6,7] indolizino [1,2-b] quinoline-8,11 (7H) -dione, (S) -14-((4-(2-amino (S)-14-((4-aminohexahydropyridin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol-[4,5-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione, (S)-14-((4-aminohexahydropyridin-1-yl)methyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxol-[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 and (S)-tert-butyl(1-((7-ethyl-7-hydroxy-8,11-dioxo-7,8,11,13-tetrahydro-10H-[1,3]dioxolino[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 group consisting of a compound of Table I or a salt thereof.

73. A compound having the formula: or a salt thereof.

74. A compound having the formula or a salt thereof.

75. A compound having the formula or a salt thereof.

76. A camptothecin-linker compound having the formula or a salt thereof.

77. A compound having the formula or a salt thereof.

78. A compound having the formula or a salt thereof.

79. A compound having the formula or a salt thereof.

80. A compound having the formula or a salt thereof.

81. A compound having the formula or a salt thereof.

82. A camptothecin-linker compound, wherein the compound is a compound of Table II or a salt thereof.

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

84. The compound of claim 65, wherein the compound has the formula DO-I" or a salt thereof, When R b2 With R b3 When combined with intervening atoms to form a 5-, 6-, or 7-membered heterocyclic ring, the heterocyclic ring has no more than one O.

85. The camptothecin conjugate of claim 1, wherein D has the formula D0-I" or a salt thereof, When R b2 With R b3 When combined with intervening atoms to form a 5-, 6-, or 7-membered heterocyclic ring, the heterocyclic ring has no more than one O.

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