Antibody-conjugated drugs and uses thereof

Abstract

There is provided, inter alia, an antibody-conjugated drug (ADC) comprising a mutated antibody. Further disclosed are pharmaceutical compositions and methods for treating cancer using the ADCs provided herein.

Description

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 457,192, filed April 5, 2023, which is incorporated herein by reference for all purposes.

[0002] Throughout this application, various publications, patents, and / or patent applications have been cited. The disclosures of such publications, patents, and / or patent applications are hereby incorporated, in their entirety, by reference in order to more fully describe the current state of affairs in the fields covered by this disclosure. Technical Field

[0003] This disclosure relates to antibody-drug conjugates (ADCs) including antibodies comprising Fc variants and methods for preparing the same. Methods for treating cancer using the ADCs described herein are also provided.

[0004] Background Technology and Summary of the Invention Antibody-drug conjugates (ADCs) allow for the targeted delivery of drugs to tumors, and in some embodiments, allow for intracellular accumulation within them. Systemic administration of unconjugated drugs can lead to unacceptable levels of toxicity to normal cells (Polakis P. (2005), Recent Pharmacological Perspectives). Current Opinion in Pharmacology (5:382-387). ADCs are targeted chemotherapy molecules that combine the properties of both antibodies and cytotoxic drugs by targeting tumor cells expressing antigens with an effective cytotoxic drug (Teicher, BA (2009) "Current Cancer Drug Targets"). Current Cancer Drug Targets ( )》 9:982-1004), thereby enhancing the therapeutic index by maximizing efficacy and minimizing off-target toxicity (Carter, PJ and Senter PD (2008) Journal of Cancer ( ) The Cancer Journal .)》 14(3):154-169; Chari, RV (2008) "Review of Chemical Research" Acc. Chem. Res .)》 41:98-107.

[0005] This disclosure provides an ADC comprising a monoclonal antibody including an Fc variant comprising two amino acid substitutions for L234A and L235A (also referred to herein as the “LALA mutation”), which is conjugated to a camptothecin derivative toxin or a duostatin derivative toxin via a linker moiety. The monoclonal antibody is an anti-CD25 antibody, an anti-B7-H3 antibody, an anti-ROR1 antibody, an anti-Trop-2 antibody, or an anti-BCMA antibody. In one embodiment, the anti-CD25 antibody binds to cancer cells expressing CD25 and allows selective uptake of the ADC into the cancer cells. In another embodiment, the anti-B7-H3 antibody binds to cancer cells expressing B7-H3 and allows selective uptake of the ADC into the cancer cells. In yet another embodiment, the anti-ROR1 antibody binds to cancer cells expressing ROR1 and allows selective uptake of the ADC into the cancer cells. In yet another embodiment, the anti-Trop-2 antibody binds to cancer cells expressing Trop-2 and allows selective uptake of the ADC into the cancer cells. In yet another embodiment, the anti-BCMA antibody binds to cancer cells expressing BCMA and allows selective uptake of the ADC by the cancer cells. In its implementation, the ADCs provided herein selectively deliver effective amounts of camptothecin derivative toxins or sarsaparilla toxin derivative toxins to tumor tissues and reduce nonspecific toxicity associated with the relevant ADCs. The ADC compounds described herein comprise compounds with anticancer activity.

[0006] Camptothecin (CPT) is a compound derived from the camptotheca tree (Camptotheca acuminata). Camptotheca acuminta Camptothecin is a cytotoxic quinoline alkaloid isolated from a tree (a tree that grows naturally in China). CPT was discovered in the 1960s (Wall ME et al., 1966, *Journal of the American Chemical Society* 88:3888-3890). The antitumor activity of camptothecin depends on highly specific inhibition of topoisomerase-1 (TOPO 1). The enzyme TOPO 1 cleaves one strand of double-stranded DNA, partially unwinding the DNA, and then re-annealing the strand to relieve stress. Camptothecin and its derivatives bind to the TOPO 1 / DNA complex to prevent re-annealing, which can lead to cell death due to the accumulation of partially cleaved DNA (Hsiang YH et al., 1985, *Journal of Biochemistry* 260:14873-14878).

[0007] The clinical application of camptothecin is limited by its low solubility and serious side effects (Joerger M. et al., 2015, Br. J. Clin. Pharmacol. 80:128-138; Joerger M. et al., 2015, Invest. New Drugs 33:472-479). To overcome these drawbacks, several camptothecin derivatives have been developed to date, including topotecan (9-dimethylamino-10-hydroxycamptothecin; TPT) and irinotecan (7-ethyl-10-[4-(1-piperidinyl)-1-piperidinyl]carbonyloxycamptothecin; CPT-11) (Naumczuk B et al., 2017, Magn. Reason. Chem. 55:128-136; Hamilton G et al., 2014, Molecules 19:2077-2088). The US Food and Drug Administration has approved these CPT derivatives for the treatment of ovarian and colon cancer (Vladu et al., 2000, Molecular Pharmacology 57:243-251; Chazin et al., 2014, Mini Rev. Med. Chem. 14:953-962).

[0008] Another camptothecin derivative is exatecan, a water-soluble derivative of camptothecin (US Patent Nos. 10,195,288 and 8,575,188). Unlike irinotecan currently used in clinical settings, enzymatic activation is unnecessary. Dxd is another useful camptothecin derivative. Many camptothecin drugs are widely used clinically, primarily for bone cancer, prostate cancer, breast cancer, gastric cancer, pancreatic cancer, ovarian cancer, esophageal cancer, and endometrial cancer (Iqbal et al., 2014, *Molecular Biology International* 2014). Camptothecin drugs have short plasma half-lives, and maintaining efficacy in clinical use requires increased doses or frequency of administration, which may lead to tolerability issues in patients.

[0009] Sea haretoxins, such as the natural product sea haretoxin 10 and its synthetic derivatives monomethylreoxetine E (MMAE) and monomethylreoxetine F (MMAF), are products that exhibit potent antitumor and microtubule-inhibiting properties. Due to their high toxicity, direct use of sea haretoxins as therapeutic agents is ineffective. Instead, they are conjugated with antibodies for targeted delivery to kill cancer cells. On the one hand, this disclosure provides antibody-drug conjugates (ADCs) comprising monoclonal antibodies, said monoclonal antibodies comprising Fc variants, said Fc variants comprising two amino acid substitutions for L234A and L235A. On the other hand, this disclosure provides methods for preparing ADCs comprising monoclonal antibodies, said monoclonal antibodies comprising Fc variants, said Fc variants comprising two amino acid substitutions for L234A and L235A. Furthermore, this document provides methods for treating cancer using the ADCs disclosed herein.

[0010] On the one hand, this paper provides a formula (I) Formula (II) Or formula (III) The antibody-drug conjugate (ADC) or a pharmaceutically acceptable salt thereof, wherein Ab is a monoclonal antibody comprising an Fc variant comprising two amino acid substitutions for L234A and L235A; m is an integer from 1 to 8; L 1 It is a linker that binds to the monoclonal antibody; L 2 It is a bond, -C(O)-, -NH-, amino acid unit, -(CH2CH2O) n -、-(CH2) n -、-(4-aminobenzyloxycarbonyl)-、-(C(O)CH2CH2NH)-、-(C(O)N(R 2 )CH2CH2N(R 3 ))-, -O-, or any combination thereof; where n is an integer from 1 to 24; each R 2 and R 3 Independently, it is H or a substituted or unsubstituted alkyl group; L 3 It is a substituted or unsubstituted heterocyclic alkyl or a substituted or unsubstituted heteroaryl; or L 3 It is a substituted or unsubstituted -OCH2- (heterocyclic alkyl) or a substituted or unsubstituted -OCH2- (heteroaryl), wherein L 3 Through oxygen-D linkage; or L 3 It is a substituted or unsubstituted -CH2NCH2- (heteroaryl) or a substituted or unsubstituted -CH2NCH2- (heterocyclic alkyl), wherein L 3It is connected to D via -CH2- and to L via nitrogen. 2 Connection; R * It is a substituted or unsubstituted heterocyclic alkyl or a substituted or unsubstituted heteroaryl; D is ;D' is D' interacts with R through its amide group. * Connect and via oxygen and L 2 Connect; and D'' is or in: R 1 It is an H or -C1-C8 alkyl group; R 3 It includes H, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, and -OR. 3A -NR 3A R 3B -(CH2) v OR 6 Substituted or unsubstituted alkyl groups or substituted or unsubstituted heteroalkyl groups; R 4 It is H, halogen, -OR 4A -NR 4A R 4B Substituted or unsubstituted alkyl groups or substituted or unsubstituted heteroalkyl groups; V is N, O, or C; Z 1 It is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group; Z 2 It is a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, a substituted or unsubstituted cycloalkylene, or a substituted or unsubstituted heteroalkylene; R 6 It is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO(CH2CH2O) w CH2CH2M、-CONH(CH2CH2O) w CH2CH2M, Charged groups or sugar derivatives; v is an integer from 1 to 24; w is an integer from 1 to 24; M is -NH2, -OH, -COOH, or -OCH3; R 10 It is -OH, -OCH3, or -COOH; and Each R 3A R 3B R 4A and R 4B It is independently H or a substituted or unsubstituted alkyl group.

[0011] On one hand, this article provides a method for treating cancers expressing CD25, B7-H3, ROR1, Trop-2, or BCMA in subjects in need, the method comprising administering to the subject an ADC described herein (included in one aspect, implementation, table, example, or claim) or a pharmaceutically acceptable salt thereof.

[0012] On the one hand, this paper provides a preparative method (I) Formula (II) Or formula (III) A method for producing an antibody-drug conjugate (ADC) or a pharmaceutically acceptable salt thereof, said method comprising reacting a monoclonal antibody or a modified antibody with a product of formula (PI). Formula (P-II) Or formula (P-III) The molecule or its pharmaceutically acceptable salt reacts, wherein B is the reactive moiety capable of forming a bond with the monoclonal antibody; L 2 It is a bond, -C(O)-, -NH-, amino acid unit, -(CH2CH2O) n -、-(CH2) n -、-(4-aminobenzyloxycarbonyl)-、-O-、-(C(O)CH2CH2NH)-、-(C(O)N(R) 2 )CH2CH2N(R 3 ))- or any combination thereof; where n is an integer from 1 to 24; each R 2 and R 3 Independently, it is H or a substituted or unsubstituted alkyl group; L 3 It is a substituted or unsubstituted heterocyclic alkyl group, a substituted or unsubstituted heteroaryl group; or L 3 It is a substituted or unsubstituted -OCH2- (heterocyclic alkyl) or a substituted or unsubstituted -OCH2- (heteroaryl), wherein L 3 Through oxygen-D linkage; or L 3It is a substituted or unsubstituted -CH2NCH2- (heteroaryl) or a substituted or unsubstituted -CH2NCH2- (heterocyclic alkyl), wherein L 3 It is connected to D via -CH2- and to L via nitrogen. 2 Connection; R * It is a substituted or unsubstituted heterocyclic alkyl or a substituted or unsubstituted heteroaryl; D is ; and D' is D' interacts with R through its amide group. * Connect and via oxygen and L 2 Connect; and D'' is or in: R 1 It is an H or -C1-C8 alkyl group; R 3 It includes H, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, and -OR. 3A -NR 3A R 3B -(CH2) v OR 6 Substituted or unsubstituted alkyl groups or substituted or unsubstituted heteroalkyl groups; R 4 It is H, halogen, -OR 4A -NR 4A R 4B Substituted or unsubstituted alkyl groups or substituted or unsubstituted heteroalkyl groups; V is N, O, or C; Z 1 It is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group; Z 2 It is a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, a substituted or unsubstituted cycloalkylene, or a substituted or unsubstituted heteroalkylene; R 6 It is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO(CH2CH2O) w CH2CH2M、-CONH(CH2CH2O) w CH2CH2M, Charged groups or sugar derivatives; v is an integer from 1 to 24; w is an integer from 1 to 24; M is -NH2, -OH, -COOH, or -OCH3; R 10 It is -OH, -OCH3, or -COOH; and Each R 3A R 3B R 4A and R 4B It is independently H or a substituted or unsubstituted alkyl group.

[0013] On the one hand, this article provides a pharmaceutical composition comprising the ADC described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Attached Figure Description

[0014] Figure 1 The chemical structure of a linker-loador compound that can be used to prepare an ADC for in vitro and in vivo efficacy studies is shown.

[0015] Figure 2 illustrates the binding of wild-type (WT) and double-mutant (LALA) antibodies to various human cancer cell lines. The CD25-WT and CD25-LALA antibodies bind to the SU-DHL-1 cell line (CD25+). Figure 2A CD25-WT and CD25-LALA antibodies bind to Daudi cell line (CD25-). Figure 2B ). BCMA-WT and BCMA-LALA antibodies bind to the NCI-H929 cell line (BCMA+). Figure 2C ). BCMA-WT and BCMA-LALA antibodies bind to the K562 cell line (BCMA-). Figure 2D B7-H3-WT and B7-H3-LALA antibodies bind to the Panc-1 cell line (B7-H3+). Figure 2E B7-H3-WT and B7-H3-LALA antibodies bind to the A375 cell line (B7-H3+). Figure 2F B7-H3-WT and B7-H3-LALA antibodies bind to the A549 cell line (B7-H3+). Figure 2G ).

[0016] Figure 3 shows the in vitro efficacy study results of the ADC, including the anti-B7-H3 antibody or the anti-B7-H3-LALA antibody conjugated with L014-077, in the following cell types: PA-1 (B7-H3+) cells ( Figure 3A ) and NCI-H929 (B7-H3-) cells ( Figure 3BThe positive control is an anti-B7-H3 antibody conjugated with L014-077 by Daiichi or Macrogenics.

[0017] Figure 4 shows the in vitro efficacy study results of the ADC, including the anti-B7-H3 antibody or the anti-B7-H3-LALA antibody conjugated with L078-118, in the following cell types: PA-1 (B7-H3+) cells ( Figure 4A ) and NCI-H929 (B7-H3-) cells ( Figure 4B Positive controls were anti-B7-H3 coupled with SET0218 (Daiichi's linker-payload) and anti-B7-H3-LALA coupled with SET0218 linker-payload.

[0018] Figure 5 The results of in vitro binding studies using leukocytes from two donors are shown. The binding of wild-type (WT) and mutant antibodies (LALA) (anti-CD25, anti-B7-H3, and anti-BCMA) to monocytes, neutrophils, NK cells, T cells, and B cells is shown. The dashed line for 1000 binding antibodies indicates the limit of quantification.

[0019] Figure 6 The results of in vitro binding studies using leukocytes from two donors are shown. Binding of anti-B7-H3 wild-type (WT B7-H3) or mutant antibody (LALA B7-H3) to monocytes, neutrophils, NK cells, T cells, and B cells is shown. The dashed line for 1000 bound antibodies indicates the limit of quantification.

[0020] Figure 7A Results of an in vivo efficacy study of anti-B7-H3 antibodies or anti-B7-H3-LALA antibodies conjugated to L014-077 in PA-1 xenografts in Nu / Nu nude mice are presented, in which mice were treated once intravenously with 5 mg / kg ADC. Positive controls were anti-B7-H3 antibodies conjugated to L014-077 from Daiichi or Macrogenics.

[0021] Figure 7B Results of an in vivo efficacy study of anti-B7-H3 antibody or anti-B7-H3-LALA antibody conjugated to L078-118 in PA-1 xenografts in Nu / Nu nude mice are presented, in which mice were treated once intravenously with 10 mg / kg ADC. The positive control was anti-B7-H3-LALA conjugated to SET0218 (Daiichi's linker-payload). Figure 7C It shows in Figure 7B Results of mouse weight changes during in vivo studies of treated Nu / Nu nude mice as described in the paper.

[0022] Figure 8 shows the results of in vivo efficacy studies of the following ADCs in SU-DHL-1 xenografts in Nu / Nu nude mice: anti-CD25 antibody or anti-CD25-LALA antibody conjugated with L078-118, wherein mice were treated once intravenously with 3 mg / kg ADC ( Figure 8A ); anti-CD25 antibody or anti-CD25-LALA antibody conjugated to L014-077, wherein mice were treated once intravenously with 3 mg / kg ADC ( Figure 8B ); anti-CD25-LALA antibodies conjugated to L078-118, L014-077, L078-182 or L078-120, wherein mice were treated once intravenously with 3 mg / kg ADC ( Figure 8C ). Detailed Implementation

[0023] definition: Unless otherwise defined, the technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art. Generally, terms relating to the techniques of cell and tissue culture, molecular biology, immunology, microbiology, genetics, transgenic cell production, protein chemistry and nucleic acid chemistry, and hybridization described herein are well known and commonly used in the art. Unless otherwise stated, the methods and techniques provided herein are generally performed according to routine procedures well known in the art and as described in the various general and more specific references cited and discussed herein. See, for example, Sambrook et al., *Molecular Cloning: A Laboratory Manual*, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989), and Ausubel et al., *Current Protocols in Molecular Biology*, Greene Publishing Associates (1992). Many foundational texts describe standard antibody production processes, including Borrebaeck (ed.), *Antibody Engineering*. Antibody Engineering ), 2nd edition, Freeman and Company, NY, 1995; McCafferty et al., Practical Methods for Antibody Engineering ( Antibody Engineering, A Practical Approach(Illegible text: "Antibody Engineering Protocols"), Oxford Press, Oxford, England, 1996; and Paul (1995), "Antibody Engineering Protocols" Antibody Engineering Protocols Humana Press, Towata, NJ, 1995; Paul (ed.), Basic Immunology Fundamental Immunology ), Raven Press, NY, 1993; Coligan (1991) *Contemporary Laboratory Immunology*, *Laboratory Guide to Immunology*. Current Protocols in Immunology Wiley / Greene, NY; Harlow and Lane (1989) *Antibodies: A Laboratory Manual* Antibodies: A Laboratory Manual *Basic and Clinical Immunology*, Cold Spring Harbor Press, NY; Stites et al. (editors). Basic and Clinical Immunology "Encoding Monoclonal Antibodies: Principles and Practice" (4th Edition), Lange Medical Publications, Los Altos, California, and the references cited therein; Coding Monoclonal Antibodies: Principles and Practice (2nd edition) Academic Press, New York, NY, 1986, and Kohler and Milstein's *Nature* (2nd edition). Nature (256: 495-497, 1975). All references cited herein are incorporated herein by reference in their entirety. Enzymatic reactions and enrichment / purification techniques are well known and are performed as commonly practiced in the art or as described herein according to the manufacturer's instructions. The terminology, laboratory procedures, and techniques used in conjunction with the analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry described herein are well known and commonly used in the art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical formulation, formulation and delivery, and the treatment of patients.

[0024] The headings provided herein are not intended to limit any aspect of this disclosure, which may be understood by referring to this specification in its entirety.

[0025] Unless the context otherwise requires, singular terms shall include plural meaning, and plural terms shall include singular meaning. Unless explicitly and definitively limited to one indicator, the singular forms “a,” “an,” and “the,” and any word used in the singular, shall include multiple indicators.

[0026] It should be understood that the use of "alternative" (e.g., "or") in this document is intended to refer to any one or two or any combination of the alternatives.

[0027] As used herein, the term “and / or” is to be construed as meaning that each of the specified features or components is explicitly disclosed with or without the other. For example, the term “and / or” as used herein in phrases such as “A and / or B” is intended to include “A and B”, “A or B”, “A” (alone), and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0028] As used herein, the term "about" refers to a value or composition within an acceptable margin of error for a specific value or composition, as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, according to practice in the art, "about" or "approximately" may mean within one or more standard deviations. Alternatively, depending on the limitations of the measurement system, "about" or "approximately" may mean a range of up to 10% (i.e., ±10%) or more. For example, about 5 mg may include any number between 4.5 mg and 5.5 mg. Furthermore, specifically referring to a biological system or process, the term may mean up to an order of magnitude or up to 5 times the value. When specific values ​​or compositions are provided in this disclosure, unless otherwise stated, the meaning of "about" or "approximately" should be assumed to be within an acceptable margin of error for said specific value or composition. In embodiments, about includes a specified value. Numerical ranges include the endpoints of the range. For example, "between 4.5 mg and 5.5 mg" includes 4.5 mg, 5.5 mg, and all values ​​greater than 4.5 mg and less than 5.5 mg.

[0029] In this disclosure, terms such as “comprises,” “comprising,” “containing,” and “having” may have the meanings assigned to them under U.S. patent law and may refer to “includes,” “including,” etc. “consisting essentially of” or “consistsessentially” also has the meanings assigned to it under U.S. patent law, and this term is open-ended, allowing for elements beyond what is described, provided that the essential or novel features described are not altered by elements beyond what is described, but excluding prior art embodiments.

[0030] The terms “polypeptide,” “peptide,” and “protein,” as well as other related terms used herein, are used interchangeably to refer to polymers of amino acid residues, wherein, in embodiments, the polymer may be coupled to a portion not composed of amino acids. The term applies to amino acid polymers in which one or more amino acid residues are artificial chemical mimics of corresponding naturally occurring amino acids, as well as to both naturally occurring and non-naturally occurring amino acid polymers. “Fusion protein” refers to a chimeric protein encoding two or more separate protein sequences recombinantly expressed as a single part. Polypeptides include mature molecules that have undergone cleavage. These terms encompass natural and artificial proteins, polypeptide analogs of protein fragments and sequences (such as mutant proteins, variants, chimeric proteins, and fusion proteins), and proteins that are covalently or non-covalently modified post-translationally or otherwise. Two or more polypeptides (e.g., three polypeptide chains) may associate with each other covalently and / or non-covalently to form multimeric polypeptide complexes (e.g., multispecific antigen-binding protein complexes). Association of polypeptide chains may also include peptide folding. Thus, polypeptide complexes can be dimers, trimers, tetramers, or higher-order complexes, depending on the number of polypeptide chains forming the complex.

[0031] As used herein, the terms “cancer,” “vesicle,” and “tumor” are used interchangeably and in singular or plural forms to refer to cells that have undergone malignant transformation, which makes them pathological to the host organism. Primary cancer cells can be readily distinguished from non-cancer cells using well-established techniques, particularly histological examination. As used herein, the definition of cancer cells includes not only primary cancer cells but also any cells derived from cancer cell ancestors. This includes metastatic cancer cells, as well as in vitro cultures and cell lines derived from cancer cells. When referring to a type of cancer that typically presents as a solid tumor, a “clinically detectable” tumor is defined as a tumor that is detectable based on tumor quality; for example, by procedures such as computed tomography (CT) scans, magnetic resonance imaging (MRI), X-rays, ultrasound, or physical examination palpation, and / or by the expression of one or more cancer-specific antigens in a sample obtainable from the patient. Tumors can be hematopoietic (or hematologic or hematological or blood-related) cancers, for example, cancers originating from blood cells or immune cells, which may be referred to as “liquid tumors.” Specific examples of clinical manifestations of hematologic malignancies include leukemia, such as chronic myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and acute lymphoblastic leukemia; plasma cell malignancies, such as multiple myeloma, MGUS, and Waldenstrom's macroglobulinemia; lymphomas, such as non-Hodgkin's lymphoma and Hodgkin's lymphoma; and so on.

[0032] The term “leukemia” broadly refers to a progressive malignant disease of the hematopoietic organs and is typically characterized by abnormal proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is usually classified clinically based on the following: (1) the duration and characteristics of the acute or chronic disease; (2) the type of cells involved; myeloid, lymphoid, or monocytic; and (3) the increase or non-increase in the number of abnormal cells in the hematologic-leukemic or non-leukemic (subleukemic) form. Exemplary leukemias that can be treated with the compounds or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocytic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, and hemocytoblastic leukemia. Leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloid leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia Leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0033] As used in this article, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphatic tissues. It begins with lymphocytes, blood cells primarily found in lymph nodes, spleen, thymus, and bone marrow. The two main types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the cancer's growth rate and the cell types involved. Aggressive (high-grade) and indolent (low-grade) types of NHL exist. Based on the cell types involved, there are B-cell and T-cell NHL. Exemplary B-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodular (monocyte-like B-cell) lymphoma, splenic lymphoma, diffuse large cell B-cell lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-cell lymphoblastic lymphoma. Exemplary T-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, pleomorphic large cell lymphoma, mycosis fungoides, and precursor T-cell lymphoblastic lymphoma.

[0034] The term "cancer" refers to all types of cancer, growths, or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinoma, and sarcoma. In the implementation, the ADCs and methods provided herein are useful for treating cancers expressing CD25, B7-H3, ROR1, Trop-2, or BCMA.

[0035] Exemplary cancers that can be treated with the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, head cancer, Hodgkin's disease, and non-Hodgkin's lymphomas. Exemplary cancers that can be treated with the compounds or methods provided herein include thyroid cancer, endocrine system cancers, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, rectal cancer, gastric cancer, and uterine cancer. Other examples include thyroid cancer, bile duct cancer, pancreatic cancer, malignant melanoma of the skin, colonic adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, squamous cell carcinoma of the head and neck, invasive breast cancer, lung adenocarcinoma, squamous cell carcinoma of the lung, non-small cell lung cancer, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocytosis, essential macroglobulinemia, primary brain tumor, malignant pancreatic islet tumor, malignant carcinoid tumor, urobladder cancer, precancerous skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, urogenital tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic tumors, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0036] The term “leukemia” broadly refers to a progressive malignant disease of the hematopoietic organs and is typically characterized by abnormal proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is usually classified clinically based on the following: (1) the duration and characteristics of the acute or chronic disease; (2) the type of cells involved; myeloid, lymphoid, or monocytic; and (3) the increase or non-increase in the number of abnormal cells in the hematologic-leukemic or non-leukemic (subleukemic) form. Exemplary leukemias that can be treated with the compounds or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocytic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, and hemocytoblastic leukemia. Leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloid leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia Leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0037] As used in this article, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphatic tissues. It begins with lymphocytes, blood cells primarily found in lymph nodes, spleen, thymus, and bone marrow. The two main types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the cancer's growth rate and the cell types involved. Aggressive (high-grade) and indolent (low-grade) types of NHL exist. Based on the cell types involved, there are B-cell and T-cell NHL. Exemplary B-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodular (monocyte-like B-cell) lymphoma, splenic lymphoma, diffuse large cell B-cell lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-cell lymphoblastic lymphoma. Exemplary T-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, pleomorphic large cell lymphoma, mycosis fungoides, and precursor T-cell lymphoblastic lymphoma.

[0038] The term "sarcoma" generally refers to a tumor composed of material similar to embryonic connective tissue and typically consists of tightly packed cells embedded in filamentous or homogeneous material. Sarcomas that can be treated with the compounds or methods provided in this article include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, botryoid sarcoma, green carcinosarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, and Kaposi's sarcoma. Sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant stromal sarcoma, extraperiosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or capillary dilatational sarcoma.

[0039] The term "melanoma" refers to a tumor caused by the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral lentigines melanoma, amelanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigines, malignant melanoma, nodular melanoma, subungual melanoma, or superficial diffuse melanoma.

[0040] The term "cancer" refers to malignant new growth composed of epithelial cells that tend to infiltrate surrounding tissues and cause metastasis. Exemplary cancers that can be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar cystic carcinoma, adenoid cystic carcinoma, adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basoid cell tumor, basal cell-like carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, brain carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine endometrial cancer, cribriform carcinoma, armored carcinoma, carcinoma cutaneum, columnar carcinoma, columnar cell carcinoma, tubular carcinoma, sclerosing carcinoma, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma, adenoid epithelial cell carcinoma, explant carcinoma, ulcerative carcinoma, fibrocarcinoma, colloid carcinoma, and gelatinous carcinoma. Carcinoma, giant cell carcinoma, adenocarcinoma, granular cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenal carcinoma, naive embryonal carcinoma, carcinoma in situ, intraepithelial carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma Carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucocellular carcinoma, mucoepidermoid carcinoma, mucinous mucosum, mucinous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossificans carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthosis nigra, pultaceous carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneider's carcinoma.Carcinoma, scleroderma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma, spherical cell carcinoma, spindle cell carcinoma, medullary carcinoma, squamous cell carcinoma, ligamentous carcinoma, angiomyodermal carcinoma, telangiectodes carcinoma, transitional cell carcinoma, tuberosum carcinoma, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[0041] As used herein, the terms “metastasis,” “metastatic,” and “metastatic cancer” are used interchangeably and refer to the spread of a proliferative disease or condition (e.g., cancer) from one organ to another non-adjacent organ or part of the body. “Metastatic cancer” is also referred to as “stage IV cancer.” Cancer begins at a site of origin, such as the breast, which is called the primary tumor, such as primary breast cancer. Some cancer cells in the primary tumor or site of origin acquire the ability to penetrate and infiltrate the surrounding normal tissue in the local area and / or penetrate the walls of the lymphatic or vascular systems that circulate systemically to other parts and tissues in the body. A second, clinically detectable tumor formed from the cancer cells of the primary tumor is called a metastatic or secondary tumor. When cancer cells metastasize, it is presumed that the metastatic tumor and its cells resemble the primary tumor. Therefore, if lung cancer metastasizes to the breast, the secondary tumor at the breast site consists of abnormal lung cells rather than abnormal breast cells. The secondary tumor in the breast is called metastatic lung cancer. Therefore, the phrase metastatic cancer refers to a disease in which the subject has or has had a primary tumor and has developed one or more secondary tumors. The phrase "non-metastatic cancer" or "subject with non-metastatic cancer" refers to a subject who has a primary tumor but not one or more secondary tumors. For example, metastatic lung cancer refers to a subject who has a primary lung tumor or a history of a primary lung tumor and has one or more secondary tumors in a second location, such as the breast.

[0042] The term "cutaneous metastasis" or "skin metastasis" refers to the secondary growth of malignant cells in the skin, where the malignant cells originate from a site of primary cancer (e.g., breast cancer). In cutaneous metastasis, cancer cells from a site of primary cancer can migrate to the skin, where these cells divide and cause lesions. Cutaneous metastasis can be caused by cancer cells migrating from a breast cancer tumor to the skin.

[0043] The term "visceral metastasis" refers to the secondary malignant cell growth in visceral organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), where the malignant cells originate from the site of the primary cancer (e.g., head and neck, liver, breast). In visceral metastasis, cancer cells from the site of the primary cancer can migrate to the skin, and within the visceral organ, these cells divide and cause lesions. Visceral metastasis can be caused by cancer cells migrating from liver cancer tumors or head and neck tumors to visceral organs.

[0044] In this implementation, the cancer is a metastatic cancer, a refractory cancer, or a recurrent cancer.

[0045] As used herein, “antibody” and “antibodies”, as well as related terms, refer to the complete immunoglobulin or its antigen-binding moiety that binds specifically to an antigen. The antigen-binding moiety can be generated by recombinant DNA technology or by enzymatic or chemical cleavage of the complete antibody. In particular, antigen-binding moieties include Fab, Fab', F(ab')2, Fv, domain antibodies (dAb) and complementarity-determining region (CDR) fragments, single-chain antibodies (scFv), chimeric antibodies, bifunctional antibodies, trifunctional antibodies, tetrafunctional antibodies, and polypeptides that include at least a portion sufficient to confer binding to a polypeptide-specific antigen.

[0046] Antibodies comprise recombinant antibodies and antigen-binding moieties. Antibodies include nonhuman antibodies, chimeric antibodies, humanized antibodies, and fully human antibodies. Antibodies include monospecific and multispecific antibodies (e.g., bispecific, trispecific, and higher-order specificities). Antibodies include tetrameric antibodies, light chain monomers, heavy chain monomers, light chain dimers, and heavy chain dimers. Antibodies include F(ab')2 fragments, Fab' fragments, and Fab fragments. Antibodies include single-domain antibodies, monovalent antibodies, single-chain antibodies, single-chain variable fragments (scFv), camelized antibodies, affinity antibodies, disulfide-linked Fv (sdFv), anti-idiotype antibodies (anti-Id), and microantibodies. Antibodies include monoclonal and polyclonal populations. This article describes anti-CD25 antibodies, anti-B7-H3 antibodies, anti-ROR1 antibodies, anti-Trop-2 antibodies, and anti-BCMA antibodies.

[0047] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, meaning that individual antibodies comprising the population are identical and / or bind to the same epitopes, except for possible variant antibodies, such as those comprising naturally occurring mutations or those generated during the production of the monoclonal antibody formulation, which are typically present in small quantities. In contrast to polyclonal antibody formulations, which typically comprise different antibodies targeting different determinants (epitopes), each monoclonal antibody in a monoclonal antibody formulation targets a single determinant on the antigen. Therefore, the modifier "monoclonal" indicates that the antibody is characterized by being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies to be used according to the invention can be prepared by a variety of techniques, including but not limited to hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals comprising all or part of human immunoglobulin loci, as described herein and other exemplary methods for preparing monoclonal antibodies.

[0048] As used herein, "epitope" and related terms refer to a portion of an antigen that binds via an antigen-binding protein (e.g., via an antibody or its antigen-binding portion). An epitope may include portions of two or more antigens that bind via an antigen-binding protein. An epitope may include discontinuous portions of one or two or more antigens (e.g., amino acid residues that are discontinuous in the primary sequence of the antigen but sufficiently close to each other in the context of the antigen's tertiary and quaternary structures to bind via an antigen-binding protein). Typically, the variable region of an antibody, specifically the CDR, interacts with the epitope. This article describes anti-CD25 antibodies that bind to the epitope of the CD25 peptide and their antigen-binding proteins. This article describes anti-B7-H3 antibodies that bind to the epitope of the B7-H3 peptide and their antigen-binding proteins. This article describes anti-ROR1 antibodies that bind to the epitope of the ROR1 peptide and their antigen-binding proteins. This article describes anti-Trop-2 antibodies that bind to the epitope of the Trop-2 peptide and their antigen-binding proteins. This article describes anti-BCMA antibodies that bind to the epitope of the BCMA peptide and their antigen-binding proteins.

[0049] As used herein, the terms “antibody fragment,” “antibody moiety,” “antigen-binding fragment of an antibody,” or “antigen-binding portion of an antibody,” and other related terms, refer to molecules that include, in addition to the intact antibody, a portion of the intact antibody that binds to the antigen bound by the intact antibody. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; Fd; and Fv fragments, as well as dAb; bifunctional antibodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and polypeptides comprising at least a portion sufficient to confer binding to a polypeptide-specific antigen. Antigen-binding portions of antibodies can be generated by recombinant DNA technology or by enzymatic or chemical cleavage of the intact antibody. Antigen-binding portions particularly include Fab, Fab', F(ab')2, Fv, domain-specific antibodies (dAbs) and complementarity-determining region (CDR) fragments, chimeric antibodies, bifunctional antibodies, trifunctional antibodies, tetrafunctional antibodies, and polypeptides comprising at least a portion of an immunoglobulin sufficient to confer antigen-binding properties to the antibody fragment. This document describes an antigen-binding fragment of an anti-CD25 antibody. This document describes an antigen-binding fragment of an anti-B7-H3 antibody. This article describes the antigen-binding fragment of the anti-ROR1 antibody. This article describes the antigen-binding fragment of the anti-Trop-2 antibody. This article describes the antigen-binding fragment of the anti-BCMA antibody.

[0050] Antigen-binding proteins can have structures such as immunoglobulins. In one embodiment, "immunoglobulin" refers to a tetrameric molecule. Each tetrameric molecule consists of two pairs of identical polypeptide chains, each pair having a "light" chain (approximately 25 kDa) and a "heavy" chain (approximately 50-70 kDa). The N-terminus of each chain defines a variable region, having approximately 100 to 110 or more amino acids, primarily responsible for antigen recognition. The C-terminal portion of each chain defines a constant region, primarily responsible for effector function. Human light chains are classified as κ or λ light chains. Heavy chains are classified as μ, δ, γ, α, or ε, and antibody isotypes are defined as IgM, IgD, IgG, IgA, and IgE, respectively. Within the light and heavy chains, the variable and constant regions are linked by a "J" region having approximately 12 or more amino acids, wherein the heavy chain also includes a "D" region having approximately 10 or more amino acids. See Chapter 7 of *Basic Immunology* (Paul, W., ed., 2nd ed., Raven Press, New York (1989)) (the cited literature is incorporated herein by reference in its entirety for all purposes). The variable region of each light / heavy chain pair forms an antibody-binding site, resulting in a complete immunoglobulin having two antigen-binding sites. In one embodiment, the antigen-binding protein can be a synthetic molecule having a structure different from that of the tetrameric immunoglobulin molecule but still binding to a target antigen or to two or more target antigens. For example, synthetic antigen-binding proteins may include antibody fragments, 1-6 or more polypeptide chains, asymmetric combinations of polypeptides, or other synthetic molecules. The terms "variable heavy chain," "V," and "V" are used interchangeably. H "VH" or "variable region" refers to the variable region of the immunoglobulin heavy chain, including Fv, scFv, dsFv, or Fab; while the terms "variable light chain" and "VH" refer to the variable regions of the immunoglobulin heavy chain. L"VL" or "variable region" refers to the variable region of the immunoglobulin light chain, including Fv, scFv, dsFv, or Fab. "Variable region" or "variable domain" refers to the domain of the antibody heavy or light chain involved in antibody-antigen binding. The variable domains (VH and VL, respectively) of the heavy and light chains of natural antibodies typically have similar structures, with each domain comprising four conserved frame regions (FRs) and three hypervariable regions (HVRs). (See, for example, Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., p. 91 (2007).) A single VH or VL domain can be sufficient to confer antigen-binding specificity. Furthermore, antibodies binding to a specific antigen can be isolated from antibodies that bind to the antigen to screen for complementary VL or VH domains, respectively, using the VH or VL domain. See, for example, Portolano et al., Journal of Immunology. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991). This article describes antigen-binding proteins with immunoglobulin-like properties that specifically bind to CD25, B7-H3, ROR1, Trop-2, or BCMA.

[0051] Examples of antibody functional fragments include, but are not limited to, intact antibody molecules, antibody fragments such as Fv, single-chain Fv (scFv), complementarity-determining regions (CDRs), VL (light chain variable regions), VH (heavy chain variable regions), Fab, F(ab)2', and any combination thereof, or any other functional portion of an immunoglobulin peptide capable of binding to a target antigen (see, for example, *Basic Immunology* (edited by Paul, 4th edition, 2001)). As will be understood by those skilled in the art, various antibody fragments can be obtained through a variety of methods, such as digesting intact antibodies with an enzyme (e.g., pepsin); or synthesizing them de novo. Antibody fragments are typically synthesized de novo using chemical methods or recombinant DNA methods. Therefore, as used herein, the term antibody includes antibody fragments generated by modifying intact antibodies, or antibody fragments synthesized de novo using recombinant DNA methods (e.g., single-chain Fv), or antibody fragments identified using phage display libraries (see, for example, McCafferty et al., (1990) *Nature*). 348:552). The term "antibody" also includes bivalent or bispecific molecules, bifunctional antibodies, trifunctional antibodies, and tetrafunctional antibodies. Bivalent and bispecific molecules are described in the following literature: e.g., Kostelny et al. (1992) Journal of Immunology 148:1547; Pack and Pluckthun (1992) Biochemistry ( Biochemistry)》 31:1579; Hollinger et al. (1993), Proceedings of the National Academy of Sciences of the United States of America (PNAS) PNAS. USA )》 90:6444; Zuckermann et al. (1994) Journal of Immunology 152:5368; Zhu et al. (1997) (Protein Science) Protein Sci .)》 6:781, Hu et al. (1996) Cancer Research ( Cancer Res .)》 56:3055; Adams et al. (1993) Cancer Research 53:4026; and McCartney et al. (1995) Protein Engineering ( Protein Eng .)》 8:301.

[0052] As used herein, the terms “antigen-binding protein,” “antigen-binding domain,” “antigen-binding region,” or “antigen-binding site,” and related terms, refer to a protein comprising a portion that binds to an antigen, and optionally a scaffold or framework portion that adopts a conformation that facilitates the binding of the antigen-binding protein to the antigen. Examples of antigen-binding proteins include antibodies, antibody fragments (e.g., the antigen-binding portion of an antibody), antibody derivatives, and antibody analogs. Antigen-binding proteins may include, for example, alternative protein scaffolds or artificial scaffolds having a transplanted CDR or a CDR derivative. Such scaffolds include, but are not limited to, antibody-derived scaffolds comprising, for example, introducing mutations to stabilize the three-dimensional structure of the antigen-binding protein, and fully synthetic scaffolds comprising, for example, biocompatible polymers. See, for example, Korndorfer et al., 2003, Proteins: Structure, Function, and Bioinformatics, Vol. 53, No. 1: 121-129; Roque et al., 2004, Biotechnol. Prog. 20: 639-654. Alternatively, peptide antibody mimics (“PAMs”) and scaffolds based on antibody mimics utilizing fibronectin components as a scaffold can be used. This article describes antigen-binding proteins that bind to CD25, B7-H3, ROR1, Trop-2, or BCMA.

[0053] In one implementation, the dissociation constant (K) DThis can be measured using BIACORE surface plasmon resonance (SPR) assays. Surface plasmon resonance refers to the optical phenomena that allow for the analysis of real-time interactions by detecting changes in protein concentration within a biosensor matrix, for example, using the BIACORE system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0054] As used throughout this application with respect to CD25, B7-H3, ROR1, Trop-2, or BCMA antigen-binding proteins, "specific binding" means that the antigen-binding protein binds to human CD25 (hCD25), B7-H3 (hB7-H3), ROR1 (hROR1), Trop-2 (hTrop-2), or BCMA (hBCMA), respectively, but not to other human proteins or binds only minimally. However, this terminology does not preclude the fact that the antigen-binding proteins of the present invention may also be cross-reactive with other forms of CD25, B7-H3, ROR1, Trop-2, or BCMA (e.g., primate CD25, B7-H3, ROR1, Trop-2, or BCMA). In one embodiment, if the antibody is at 10... -5 M or smaller, or 10 -6 M or smaller, or 10 -7 M or smaller, or 10 -8 M or smaller, or 10 -9 M or smaller or 10 -10 M or a smaller dissociation constant K D When an antibody binds to an antigen, it specifically binds to the target antigen.

[0055] As used herein, the term "Fc" or "Fc region" refers to a portion of the constant region of an antibody heavy chain that begins in or after the hinge region and ends at the C-terminus of the heavy chain. The Fc region includes at least a portion of the CH and CH3 regions and may or may not include a portion of the hinge region. Two polypeptide chains, each carrying a half-Fc region, may dimerize to form the Fc region. The Fc region can bind to Fc cell surface receptors and some proteins of the immune complement system. The Fc region exhibits effector functions, including any one activity or any combination of two or more activities, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent phagocytosis (ADP), opsonization, and / or cell binding. The Fc region can bind to Fc receptors, including FcγRI (e.g., CD64), FcγRII (e.g., CD32), and / or FcγRIII (e.g., CD16a). In embodiments, the Fc region may include mutations that increase or decrease any one or any combination of these functions (e.g., an effector-negative Fc region).

[0056] In embodiments, the antigen-binding protein is an IgG, IgA, IgD, IgE, or IgM antibody having one or more mutations in its Fc region (e.g., one or more mutations that reduce antibody-dependent enhancement (ADE) and / or one or more mutations that increase antibody half-life). Mutations that reduce or eliminate the interaction of the Fc region of such antibodies with their receptors (e.g., FcγR) on cells can reduce or eliminate ADE. For example, the antigen-binding protein provided herein may be an IgG1 or IgG4 antibody having an ADE-reducing mutation in its Fc region (such as the LALA mutation), or it may be a single-chain antibody (ScFv) optionally including an ADE-reducing mutation, such as the LALA mutation (the leucine residues at positions 234 and 235 in the EU index shown in Kabat are mutated to alanine residues). In other embodiments, the antigen-binding protein provided herein may be a Fab, Fab', or F(ab')2 antibody fragment.

[0057] This disclosure provides an ADC comprising a monoclonal antibody, said monoclonal antibody including an Fc region mutation (LA mutation) selected from L234A and L235A. In embodiments, the mutation in the Fc region may include mutations in both L234A and L235A (LALA). In embodiments, the mutation in the Fc region is an LA mutation or two LALA mutations. In embodiments, the LALA mutation in the Fc region reduces the effector function of the monoclonal antibody compared to a monoclonal antibody without an LALA mutation in the Fc region.

[0058] Unless otherwise stated, as used herein, the term "CD25" refers to any naturally occurring CD25 from any vertebrate source, including mammals such as primates (e.g., humans, cynomolgus monkeys, and rodents (e.g., mice and rats)). The term encompasses "full-length" untreated CD25 as well as any form of CD25 produced by cellular processing. The term also encompasses variants of naturally occurring CD25, such as splice variants, allelic variants, and isotypes. An exemplary amino acid sequence of the human CD25 protein is shown in SEQ ID NO: 70.

[0059] Unless otherwise stated, as used herein, the term "B7-H3" refers to any naturally occurring B7-H3 from any vertebrate source, including mammals such as primates (e.g., humans, cynomolgus monkeys, and rodents (e.g., mice and rats)). The term covers "full-length" untreated B7-H3 as well as any form of B7-H3 produced by cellular processing. The term also covers variants of naturally occurring B7-H3, such as splice variants, allelic variants, and isotypes. An exemplary amino acid sequence of the human B7-H3 protein is shown in SEQ ID NO: 71.

[0060] Unless otherwise stated, as used herein, the term "ROR1" refers to any native ROR1 from any vertebrate source, including mammals such as primates (e.g., humans, cynomolgus monkeys, and rodents (e.g., mice and rats)). The term covers "full-length" untreated ROR1 as well as any form of ROR1 produced by cellular processing. The term also covers variants of naturally occurring ROR1, such as splice variants, allelic variants, and isotypes. An exemplary amino acid sequence of the human ROR1 protein is shown in SEQ ID NO: 72.

[0061] Unless otherwise stated, as used herein, the term "Trop-2" refers to any native Trop-2 from any vertebrate source, including mammals such as primates (e.g., humans, cynomolgus monkeys, and rodents (e.g., mice and rats)). The term covers "full-length" untreated Trop-2 as well as any form of Trop-2 produced by cellular processing. The term also covers variants of naturally occurring Trop-2, such as splice variants, allelic variants, and isotypes. An exemplary amino acid sequence of the human Trop-2 protein is shown in SEQ ID NO: 73.

[0062] Unless otherwise specified, as used herein, the term "BCMA" means any native BCMA from any vertebrate source, including mammals such as primates (e.g., humans, cynomolgus monkeys, and rodents (e.g., mice and rats)). The term covers "full-length" untreated BCMA as well as any form of BCMA produced by cellular processing. The term also covers variants of naturally occurring BCMA, such as splice variants, allelic variants, and isotypes. An exemplary amino acid sequence of the human BCMA protein is shown in SEQ ID NO: 74.

[0063] The term "CD25-expressing cancer" refers to cancer comprising cells that express CD25 on their surface. In an embodiment, the term "CD25-expressing cancer" refers to cancer comprising cells that internalize CD25 into their cells. The term "B7-H3-expressing cancer" refers to cancer comprising cells that express B7-H3 on their surface. In an embodiment, the term "B7-H3-expressing cancer" refers to cancer comprising cells that internalize B7-H3 into their cells. The term "ROR1-expressing cancer" refers to cancer comprising cells that express ROR1 on their surface. In an embodiment, the term "ROR1-expressing cancer" refers to cancer comprising cells that internalize ROR1 into their cells. The term "Trop-2-expressing cancer" refers to cancer comprising cells that express Trop-2 on their surface. In an embodiment, the term "Trop-2-expressing cancer" refers to cancer comprising cells that internalize Trop-2 into their cells. The term "BCMA-expressing cancer" refers to cancer comprising cells that express BCMA on their surface. In implementation, the term "BCMA-expressing cancer" refers to cancers that include cells that internalize BCMA into their cells.

[0064] The terms "anti-CD25 antibody" and "CD25-binding antibody" refer to antibodies capable of binding to CD25 with sufficient affinity, making the antibody useful as a therapeutic agent targeting CD25. In one embodiment, the anti-CD25 antibody binds to less than about 10% of the antibody's binding to CD25, as measured, for example, by radioimmunoassay (RIA). In some embodiments, the dissociation constant (Kd) of the CD25-binding antibody is ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 5 nM, ≤ 4 nM, ≤ 3 nM, ≤ 2 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10 μM). -8 M or smaller, such as 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13M). In some implementations, the anti-CD25 antibody binds to an epitope of CD25 that is conserved in CD25 from different species.

[0065] The terms "anti-B7-H3 antibody" and "antibody that binds to B7-H3" refer to antibodies capable of binding to B7-H3 with sufficient affinity, making the antibody useful as a therapeutic agent targeting B7-H3. In one embodiment, the anti-B7-H3 antibody binds to less than about 10% of the antibody's binding to B7-H3, as measured, for example, by radioimmunoassay (RIA). In some embodiments, the dissociation constant (Kd) of the antibody binding to B7-H3 is ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 5 nM, ≤ 4 nM, ≤ 3 nM, ≤ 2 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10 μM). -8 M or smaller, such as 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 M). In some implementations, the anti-B7-H3 antibody binds to epitopes of B7-H3 that are conserved in B7-H3 from different species.

[0066] The terms "anti-ROR1 antibody" and "ROR1-binding antibody" refer to antibodies capable of binding to ROR1 with sufficient affinity, making the antibody useful as a therapeutic agent targeting ROR1. In one embodiment, the anti-ROR1 antibody binds to less than about 10% of the antibody's binding to ROR1, as measured, for example, by radioimmunoassay (RIA). In some embodiments, the dissociation constant (Kd) of the ROR1-binding antibody is ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 5 nM, ≤ 4 nM, ≤ 3 nM, ≤ 2 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10 μM). -8 M or smaller, such as 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 M). In some implementations, the anti-ROR1 antibody binds to an epitope of ROR1 that is conserved in ROR1 from different species.

[0067] The terms "anti-Trop-2 antibody" and "antibody that binds to Trop-2" refer to antibodies capable of binding to Trop-2 with sufficient affinity, making the antibody useful as a therapeutic agent in targeting Trop-2. In one embodiment, the anti-Trop-2 antibody binds to less than about 10% of the unrelated non-Trop-2 protein, as measured, for example, by radioimmunoassay (RIA). In some embodiments, the dissociation constant (Kd) of the antibody that binds to Trop-2 is ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 5 nM, ≤ 4 nM, ≤ 3 nM, ≤ 2 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10 μM). -8 M or smaller, such as 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 M). In some implementations, the anti-Trop-2 antibody binds to an epitope of Trop-2 that is conserved in Trop-2 from different species.

[0068] The terms "anti-BCMA antibody" and "BCMA-binding antibody" refer to antibodies capable of binding to BCMA with sufficient affinity such that the antibody can be used as a therapeutic agent in targeting BCMA. In one embodiment, the anti-BCMA antibody binds to less than about 10% of the unrelated non-BCMA protein, as measured, for example, by radioimmunoassay (RIA). In some embodiments, the dissociation constant (Kd) of the BCMA-binding antibody is ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 5 nM, ≤ 4 nM, ≤ 3 nM, ≤ 2 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10 μM). -8 M or smaller, such as 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 M). In some implementations, the anti-BCMA antibody binds to epitopes of BCMA that are conserved in BCMA from different species.

[0069] As used herein, the term "chimeric antibody" and related terms refer to an antibody comprising one or more regions from a first antibody and one or more regions from one or more other antibodies. In one embodiment, one or more CDRs are derived from a human antibody. In another embodiment, all CDRs are derived from a human antibody. In yet another embodiment, CDRs from more than one human antibody are mixed and matched in the chimeric antibody. For example, the chimeric antibody may include CDR1 from the light chain of a first human antibody, CDR2 and CDR3 from the light chain of a second human antibody, and CDRs from the heavy chain of a third antibody. In another instance, the CDRs are derived from different species, such as humans and mice, or humans and rabbits, or humans and goats. Those skilled in the art will understand that other combinations are possible.

[0070] Additionally, the framework region may originate from one of the same antibodies, from one or more different antibodies such as a human antibody, or from a humanized antibody. In one example of a chimeric antibody, a portion of the heavy and / or light chain is identical, homologous, or derived from an antibody of a specific species or belonging to a specific antibody class or subclass, while the remainder of the chain is identical, homologous, or derived from an antibody of another species or belonging to another antibody class or subclass. Fragments of such antibodies exhibiting the desired biological activity (i.e., the ability to specifically bind to a target antigen) are also included. Chimeric antibodies can be prepared from portions of any of the anti-CD25, anti-B7-H3, anti-ROR1, anti-Trop-2, or anti-BCMA antibodies described herein.

[0071] "Effective functions" are those biological activities attributable to the Fc region of an antibody that vary with antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

[0072] As used herein, the term "variant" polypeptide and "variant" of a polypeptide refers to a polypeptide comprising an amino acid sequence having one or more amino acid residues inserted, deleted, and / or substituted into an amino acid sequence relative to a reference polypeptide sequence. Polypeptide variants include fusion proteins. In the same manner, variant polynucleotides comprise a nucleotide sequence having one or more nucleotides inserted, deleted, and / or substituted into a nucleotide sequence relative to another polynucleotide sequence. Polynucleotide variants include fusion polynucleotides.

[0073] As used herein, the term "derivative" of a polypeptide is a polypeptide (e.g., an antibody) that has been chemically modified, for example, by coupling, phosphorylation, and glycosylation with another chemical moiety such as polyethylene glycol, albumin (e.g., human serum albumin). Unless otherwise indicated, the term "antibody" includes its derivatives, variants, fragments, and mutant proteins, in addition to antibodies comprising two full-length heavy chains and two full-length light chains, examples of which are described below.

[0074] The term "hinge" refers to an amino acid segment typically found between two domains of a protein, which imparts flexibility to the entire structure and allows one or both domains to move relative to each other. Structurally, the hinge region comprises about 10 to about 100 amino acids, such as about 15 to about 75 amino acids, about 20 to about 50 amino acids, or about 30 to about 60 amino acids. In embodiments, the length of the hinge region is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 amino acids. The hinge region may be derived from the hinge region of a naturally occurring protein (such as the CD8 hinge region or a fragment thereof, the CD8α hinge region or a fragment thereof), the hinge region of an antibody (e.g., IgG, IgA, IgM, IgE, or IgD antibody), or the hinge region connecting the constant structural domains CH1 and CH2 of an antibody. The hinge region may be derived from an antibody and may or may not include one or more constant regions of the antibody, or the hinge region may include the hinge region of the antibody and the CH3 constant region of the antibody, or the hinge region may include the hinge region of the antibody and the CH2 and CH3 constant regions of the antibody, or the hinge region may be a non-naturally occurring peptide, or the hinge region may be located between the C-terminus of the scFv and the N-terminus of the transmembrane structural domain. In one embodiment, the hinge region includes any one region or any combination of two or more regions, said region including an upper hinge sequence, a core hinge sequence, or a lower hinge sequence from an IgG1, IgG2, IgG3, or IgG4 immunoglobulin molecule. In one embodiment, the hinge region includes the IgG1 hinge sequence EPKSCDKTHT (SEQ ID NO: 108). In another embodiment, the hinge region includes the IgG1 core hinge sequence CP. X CP, among which XIt is P, R, or S (SEQ ID NO: 109). In one embodiment, the hinge region includes the lower hinge sequence APELLGGP (SEQ ID NO: 110). In one embodiment, the hinge is connected to an Fc region (CH2) having the amino acid sequence SVFLFPPKPKDT (SEQ ID NO: 111). In one embodiment, the hinge region includes the amino acid sequence of the upper hinge, core hinge, or lower hinge and includes EPKSCDKTHTCPPCPAPELLGGP (SEQ ID NO: 112). In one embodiment, the hinge region includes one, two, three, or more cysteine ​​residues that can form at least one, two, three, or more interchain disulfide bonds.

[0075] As used herein, the term "labeled antibody" or related terms refer to a labeled antibody or antibody linked to a detectable label or portion for detection, and its antigen-binding portion thereof, wherein the detectable label or portion is radioactive, colorimetric, antigenic, enzymatic, detectable beads (such as magnetic or electron-dense (e.g., gold) beads), biotin, streptavidin, or protein A. A variety of labels may be used, including but not limited to radionuclides, fluorescent agents, enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, and ligands (e.g., biotin, haptens). Any anti-B7-H3 antibodies, antigen-binding proteins, and antibody fragments described herein may be unlabeled or may be linked to a detectable label or portion.

[0076] "Humanized antibody" refers to an antibody having a sequence that differs from that of an antibody derived from a non-human species through substitution, deletion, and / or addition of one or more amino acids, such that, compared to a non-human species antibody, the humanized antibody is less likely to induce an immune response and / or induce a less severe immune response when administered to a human subject. In one embodiment, certain amino acids in the framework and constant domains of the heavy and / or light chains of the non-human species antibody are mutated to produce a humanized antibody. In another embodiment, a constant domain from a human antibody is fused with a variable domain from a non-human species. In yet another embodiment, one or more amino acid residues in one or more CDR sequences of a non-human antibody are altered to reduce the potential immunogenicity of the non-human antibody when administered to a human subject, wherein the altered amino acid residues are not critical for the immune-specific binding of the antibody to its antigen, or the alteration to the amino acid sequence is a conserved alteration such that the binding of the humanized antibody to the antigen is not significantly worse than that of the non-human antibody to the antigen. Examples of how to prepare humanized antibodies can be found in U.S. Patents 6,054,297, 5,886,152 and 5,877,293.

[0077] The term "human antibody" refers to an antibody having one or more variable and constant regions derived from a human immunoglobulin sequence. In one embodiment, all variable and constant domains are derived from a human immunoglobulin sequence (e.g., a fully human antibody). These antibodies can be prepared in various ways, examples of which are described below, including by recombinant methods or by immunization with a mouse antigen of interest, said antigen of interest being genetically modified to express an antibody derived from a human heavy chain and / or light chain encoding gene. Fully human anti-CD25 antibodies, anti-B7-H3 antibodies, anti-ROR1 antibodies, anti-Trop-2 antibodies, and anti-BCMA antibodies, as well as their antigen-binding proteins, are described herein. This definition of a human antibody explicitly excludes humanized antibodies that include non-human antigen-binding residues.

[0078] The term "isolated" means "artificially" altered in its natural state, or changed or removed from its original environment, or both. When the term "isolated" is applied to nucleic acids or proteins, it means that the nucleic acid or protein is substantially free of other cellular components associated with it in its natural state. It may be, for example, in a homogeneous state and may be in a dry state or in an aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis, high-performance liquid chromatography, or mass spectrometry. Proteins that are the dominant species present in a formulation are substantially purified. For example, polynucleotides or polypeptides naturally present in living organisms are not "isolated," but the same polynucleotides or polypeptides isolated from their native coexisting substances are "isolated," including but not limited to when such polynucleotides or polypeptides are reintroduced into cells, even if the cells are of the same species or type as the cells from which the polynucleotides or polypeptides were isolated.

[0079] “CDR” is defined as the complementarity-determining region (CDR) amino acid sequence of an antibody, which is a hypervariable domain of the heavy and light chains of an immunoglobulin. Three heavy chain and three light chain CDRs (or CDR regions) exist in the variable portion of an immunoglobulin. Therefore, as used herein, “CDR” can refer to all three heavy chain CDRs or all three light chain CDRs (if appropriate, or both).

[0080] CDRs provide most of the contact residues for antibody-antigen or epitope binding. The CDRs of interest in this invention are derived from the variable heavy and light chain sequences of the donor antibody and include analogs of naturally occurring CDRs that also share or retain the same antigen-binding specificity and / or neutralizing capacity as the donor antibody from which they are derived.

[0081] The CDR sequence of an antibody can be determined using the Kabat numbering system (Kabat et al.; Sequences of proteins of Immunological Interest, NIH, 1987); alternatively, the sequence can be determined using the Chothia numbering system (Al-Lazikani et al., (1997) Journal of Molecular Biology (JMB) 273, 927-948), the contact definition method (MacCallum RM, and Martin ACR and Thornton J. M, (1996) Journal of Molecular Biology, 262(5), 732-745) or any other established method known to those skilled in the art for numbering residues in antibodies and determining CDRs.

[0082] Other numbering conventions for CDR sequences available to technicians include the "AbM" (University of Bath) and "Contact" (University College London) methods. The minimum overlapping area can be determined using at least two of the Kabat, Chothia, AbM, and Contact methods to provide a "minimum binding unit." The minimum binding unit can be a sub-part of the CDR.

[0083] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of molecule X for its partner Y can typically be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0084] "Affinity-mature" antibodies are those that have one or more alterations in one or more hypervariable regions (HVRs) compared to parental antibodies that do not have such alterations, resulting in improved antibody affinity for antigens.

[0085] As used herein, the term "domain" refers to a folded protein structure having a tertiary structure independent of the rest of the protein. Typically, domains are responsible for discrete functional properties of a protein and, in many cases, can be added to, removed from, or transferred to other proteins without loss of the remaining protein and / or the domain's function. "Antibody single variable domain" is a folded polypeptide domain that includes the sequence characteristics of an antibody variable domain. The term therefore includes fully variable antibody domains and modified variable domains, such as those in which one or more loops have been replaced (which is not a characteristic of antibody variable domains), or antibody variable domains that have been truncated or include N-terminal or C-terminal extensions, as well as folded fragments of variable domains that at least retain the binding activity and specificity of the full-length domain.

[0086] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cell function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., 211 At、 131 I, 125 I, 90 Y、 186 Re、 188 Re、 153 Sm、 212 Bi、 32 P, 212 Radioactive isotopes of Pb and Lu; chemotherapeutic agents or drugs (e.g., methotrexate, doxorubicin, vinblastine alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitors; enzymes and their fragments, such as nucleolysins; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including their fragments and / or variants; and the various antitumor or anticancer agents disclosed below.

[0087] Chemotherapy agents are chemical compounds that can be used to treat cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; azacyclopropanes such as benzodopa, carboquone, meturedopa, and uredopa; ethylene imines and methylamelamins. es), including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (especially bullatacin and bullatacinone); delnabinol (MARINOL®); beta-lapachone; and laparol. Colchicine; betulinic acid; camptothecin (including synthetic analogues topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®, acetylcamptothecin, scopolectin, and 9-aminocamptothecin)); lichenin; callystatin; CC-1065 (including its adozelesin and carboxylic acid). Synthetic analogs of carzelesin and bizelesin; podophyllotoxin; podophyllin; teniposide; nostocin (specifically nostocin 1 and nostocin 8); saurustoxin; duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin;Nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, and mechlorethamine oxide. Hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, trofosfamide; nitrosurea, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1 and calicheamicin ω1 (see, for example, *Agnew, Chem Intl. Ed. Engl.*, 33: 183-186 (1994)); dynemicin, including dynemicin A; esperamicin;In addition to new carcinogen chromophores and related chromogenin-based anti-cancer chromophores), aclacinomysins, actinomycin, autramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, and chromomycins. Dactinomycin, daunorubicin, detorubicin, 6-diaza-5-oxo-L-leucine, doxorubicin (including morpholino-duxorubicin, cyanomorpholino-duxorubicin, 2-pyrrolino-duxorubicin, and deoxyduxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, and mycophenolic acid. Acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil. Pyridines (5-FU); folic acid analogs, such as folate, methotrexate, pteroxate, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thioimidazoline, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azouridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fluorouridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone.Anti-adrenergic drugs, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as frolinic acid; aceglucan lactone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate); epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansine alkaloids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazine; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oregon) OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecene (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vindesine (ELDISINE®, FILDESIN®); dacarbazine;Mannomustine; mitobronitol; mitolactal; pipobroman; gacytosine; arabinoside (“Ara-C”); thiotepa; taxanes, such as paclitaxel (TAXOL®; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANETM paclitaxel nanoparticle formulations without levofloxacin (American Pharmaceutical Partners, Schaumberg, Illinois), and docetaxel (TAXOTERE®; Rhône-Poulenc Rorer, Antony, France). France); chloranbucil; gemcitabine (GEMZAR®); 6-thioguanine; mecaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; VELBAN®; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; ONCOVIN®; oxaliplatin; leucovovin; NAVELBINE®; novantrone; edaltraza; daunomycin; aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; capecitabine (XELODA®); pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above, such as CHOP, an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; CVP, an abbreviation for combination therapy of cyclophosphamide, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen of oxaliplatin (ELOXATINTM) combined with 5-FU and leucovorin.

[0088] "Antibody-drug conjugate" or "ADC" is an antibody conjugated to one or more heterologous molecules (including but not limited to cytotoxic agents).

[0089] As used herein, the term "coupled" when referring to two parts means that the two parts are bonded together, wherein the bond connecting the two parts can be covalent or non-covalent. In embodiments, the two parts are covalently bonded to each other (e.g., directly or through a covalently bonded intermediate). In embodiments, the two parts are non-covalently bonded (e.g., through ionic bonds, van der Waals bonds / interactions, hydrogen bonds, polar bonds, or combinations or mixtures thereof).

[0090] "Individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., human and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject is a person. In some embodiments, the subject is an adult, adolescent, child, or infant. In some embodiments, the terms "individual" or "patient" are used and are intended to be used interchangeably with "subject."

[0091] The "percentage of amino acid sequence identity (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to those in the reference polypeptide sequence after sequence alignment and the introduction of vacancies (if necessary) to achieve the maximum percentage of sequence identity. Sequence alignment for determining the percentage of amino acid sequence identity can be performed in a variety of ways within the scope of the art, for example, by means of the local homology algorithm of Smith and Waterman, 1981, Advances in Applied Mathematics (Ads App. Math.) 2, 482; by means of the local homology algorithm of Needleman and Wunsch, 1970, Journal of Molecular Biology 48, 443; by means of the similarity search algorithm of Pearson and Lipman, 1988, Proceedings of the National Academy of Sciences 88, 2444; or by means of computer programs using said algorithms (e.g., EMBOSS Needle or EMBOSS Water, available at www.ebi.ac.uk / Tools / psa / ). Those skilled in the art can determine the appropriate parameters for sequence alignment, including any algorithm required to achieve maximum alignment across the full length of the sequences being compared. As used herein, “sequence identity percentage” or “[sequence] identity percentage (%)” is determined by comparing two optimally locally aligned sequences over a comparison window defined by the local alignment length between the two sequences. (This can also be considered as a percentage of homology or “percentage of homology (%)”.) The amino acid sequence in the comparison window may include additions or deletions (e.g., vacancies or overhangs) for optimal alignment of the two sequences compared to a reference sequence. Local alignment between two sequences includes only segments of each sequence deemed sufficiently similar according to criteria depending on the algorithm used for the alignment (e.g., EMBOSS Water). "Identical" or "percentage of identity" means that two or more sequences or subsequences are identical or have the same specified percentage of amino acid residues or nucleotides (i.e., approximately 60% identity within a specified region when performing maximum correspondence comparisons and alignments within a comparison window or specified region, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher). Percentage identity is calculated by determining the number of positions in the two sequences where the same nucleic acid bases or amino acid residues appear to generate a number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window, and multiplying the result by 100.The optimal alignment of sequences for comparison can be determined using: Smith and Waterman's local homology algorithm (Advances in Applied Mathematics 2:482, 1981), Needleman and Wunsch's global homology alignment algorithm (Journal of Molecular Biology 48:443, 1970), Pearson and Lipman's similarity search method (Proceedings of the National Academy of Sciences 85:2444, 1988), or by inspection. As another example, GAP and BESTFIT can be used to determine the optimal alignment of two sequences that have been identified for comparison. Typically, a default value of 5.00 is used for the gap weight and a default value of 0.30 for the gap weight length.

[0092] Sequence comparisons and the determination of the percentage of identity between two polypeptide sequences or two polynucleotide sequences can be accomplished using mathematical algorithms. For example, the “percentage of identity” or “percentage of homology” between two polypeptide or two polynucleotide sequences can be determined by comparing sequences using the GAP computer program (GCG Wisconsin Package, version 10.3, Accelrys, San Diego, California) with its default parameters. Expressions such as “includes a sequence having at least X% identity with Y” regarding the test sequence mean that when aligned with sequence Y as described above, the test sequence includes at least X% of the residues identical to those in Y.

[0093] In one embodiment, the amino acid sequence of the test antibody may be similar to, but not identical to, any amino acid sequence of a polypeptide constituting the multispecific antigen-binding protein complex described herein. The similarity between the test antibody and the polypeptide may be at least 95%, or at least 96%, 97%, 98%, or 99% identical to any polypeptide constituting the multispecific antigen-binding protein complex described herein. In one embodiment, the similar polypeptide may include amino acid substitutions within the heavy chain and / or light chain. In one embodiment, amino acid substitutions include one or more conserved amino acid substitutions. A “conserved amino acid substitution” is an amino acid substitution in which an amino acid residue is replaced by another amino acid residue having a side chain (R group) having similar chemical properties (e.g., charge or hydrophobicity). Generally, conserved amino acid substitutions do not substantially alter the functional properties of the protein. Where two or more amino acid sequences differ from each other due to conserved substitutions, the percentage of sequence identity or degree of similarity may be adjusted upwards to correct the conservatism of the substitution. Methods for making such adjustments are well known to those skilled in the art. See, for example, Pearson (1994) Methods in Molecular Biology 24: 307-331, which is incorporated herein by reference in its entirety. Examples of amino acid groups with side chains having similar chemical properties include: (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; (2) aliphatic-hydroxy side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartic acid and glutamic acid; and (7) sulfur-containing side chains are cysteine ​​and methionine.

[0094] Antibodies can be obtained from sources such as serum or plasma, which contain immunoglobulins with various antigen specificities. These antibodies can be enriched for specific antigen specificity by affinity purification. Such enriched antibody formulations typically consist of less than about 10% antibodies with specific binding activity against a particular antigen. Performing several rounds of affinity purification on these formulations can increase the proportion of antibodies with specific binding activity against the antigen. Antibodies prepared in this manner are often referred to as "monospecific." Monospecific antibody formulations can consist of approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 99.9% antibodies with specific binding activity against a particular antigen. Antibodies can be generated using recombinant nucleic acid techniques described below.

[0095] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is attached. This term includes vectors that are self-replicating nucleic acid structures, as well as vectors incorporated into the genome of a host cell into which they have been introduced. Some vectors are capable of directing the expression of the nucleic acid to which they are operatively attached. Such vectors are referred to herein as "expression vectors."

[0096] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells in which exogenous nucleic acids have been introduced, including progeny cells of such cells. Host cells include “transformants” and “transformed cells,” which include primary transformed cells and their derived progeny, regardless of passage number. The nucleic acid content of progeny cells may not be exactly the same as that of the parent cells, but may include mutations. This document includes mutant progeny cells with the same function or biological activity as those screened or selected from the original transformed cells.

[0097] The term "pharmaceutically acceptable salt" is intended to include salts of active compounds prepared with a relatively non-toxic acid or base using specific substituents found on the compounds described herein. When the compounds of this disclosure include relatively acidic functional groups, a base addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired base (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this disclosure include relatively basic functional groups, an acid addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired acid (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid; and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, and methanesulfonic acid. Also included are salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., “Pharmaceutical Salts”, *Journal of Pharmaceutical Science*). Journal of Pharmaceutical Science )》, 1977, 66 (1-19). Certain specific compounds disclosed herein include both basic and acidic functional groups that allow the compound to be converted into a base addition salt or an acid addition salt.

[0098] Therefore, the compounds of this disclosure can exist in the form of salts (such as those having a pharmaceutically acceptable acid). This disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts containing amino acids (such as glutamic acid) and quaternary ammonium salts (e.g., iodomethane, iodoethane, etc.). These salts can be prepared by methods known to those skilled in the art.

[0099] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in some physical properties, such as solubility in polar solvents.

[0100] In addition to salt form, this disclosure also provides compounds in prodrug form. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of this disclosure. The prodrugs of the compounds described herein can be converted in vivo after administration. Alternatively, the prodrugs can be converted into the compounds of this disclosure in an in vitro environment (e.g., upon contact with suitable enzymes or chemical reagents) by chemical or biochemical methods.

[0101] Some compounds of this disclosure may exist in both unsolvable and solvable forms (including hydrated forms). Generally, solvable forms are equivalent to unsolvable forms and are covered within the scope of this disclosure. Some compounds of this disclosure may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by this disclosure and are intended to be within the scope of this disclosure.

[0102] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate administration of the active agent to a subject and facilitate absorption by the subject, and said substances may be included in the compositions of this disclosure without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, lactated Ringer's solution, plain sucrose, plain glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), fatty acid esters, carboxymethyl cellulose, polyvinylpyrrolidone, and pigments, etc. Such formulations can be sterilized and, if desired, can be mixed with adjuvants (such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring substances, and / or aromatic substances, etc.), which do not react adversely with the compounds of this disclosure. Those skilled in the art will recognize that other pharmaceutical excipients are useful in this disclosure.

[0103] The term "drug formulation" refers to a preparation which is in a form that allows the biological activity of the active ingredient contained therein to be effective and does not contain any additional components that would cause unacceptable toxicity to a subject who will administer the formulation.

[0104] The terms “administering,” “administered,” and grammatical variations refer to the physical introduction of a pharmaceutical agent into a subject using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral administration routes, such as by injection or infusion. As used herein, the phrase “parenteral administration” means any mode of administration other than enteral and local administration (typically by injection), and includes, but is not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions, as well as in vivo electroporation. In some embodiments, the formulation is administered via a non-gastrointestinal route (e.g., orally). Other non-parenteral routes include local, epidermal, or mucosal application, such as intranasal, vaginal, rectal, sublingual, or topical. Application may also be performed, for example, once, multiple times, and / or over one or more extended periods.

[0105] The term "effective amount" of a pharmaceutical preparation, such as a drug formulation, refers to the amount that, in doses, effectively achieves the desired therapeutic or preventative outcome within the required time period.

[0106] The abbreviations used in this article have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described in this article are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0107] The description of the compounds disclosed herein is limited by the principles of chemical bonding known to those skilled in the art. Therefore, where a group can be substituted by one or more of a plurality of substituents, such substitution is chosen to conform to the principles of chemical bonding and to obtain compounds that are not inherently unstable and / or, as known to those skilled in the art, may be unstable under environmental conditions (e.g., aqueous, neutral, and several known physiological conditions). For example, heterocyclic alkyl or heteroaryl groups are linked to the remainder of the molecule via cyclic heteroatoms according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0108] When a substituent is specified by its conventional chemical formula (written from left to right), the substituent equally covers the chemically identical substituents produced when the structure is written from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0109] The term sugar refers to carbohydrates (or sugars). In some embodiments, sugars are monosaccharides. In others, sugars are polysaccharides. The most basic unit of sugar is the monomer of a carbohydrate. The general formula is C2. n H 2n O n The term sugar derivative refers to a sugar molecule modified with substituents other than the hydroxyl group. Examples include glycosylamines, sugar phosphates, and sugar esters. Other sugar derivatives include, for example, β-D-glucuronic acid, D-galactosyl, and D-glucosyl.

[0110] The term "charged group" refers to a chemical group carrying a positive or negative charge, such as phosphates, phosphonates, sulfates, sulfonates, nitrates, carboxylates, carbonates, etc. In some embodiments, at least 50% of the charged groups are ionized in at least one aqueous solution with a pH in the range of 5-9. In some embodiments, the charged group is anionicly charged.

[0111] Unless otherwise stated, the term "alkyl," either on its own or as part of another substituent, means a straight (i.e., unbranched) or branched carbon chain (or carbon) or combination thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and may include monovalent, divalent, and polyvalent groups. Alkyl groups may include a specified number of carbons (e.g., C1-C1). 10(This refers to one to ten carbon atoms). An alkyl group is an uncyclic chain. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, methyl, and homologues and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Unsaturated alkyl groups are alkyl groups having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propynyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and higher homologues and isomers. An alkoxy group is an alkyl group connected to the rest of the molecule via an oxygen linker (-O-). The alkyl moiety can be an alkenyl moiety. The alkyl moiety can be an alkynyl moiety. The alkyl moiety can be fully saturated. An alkenyl group may include more than one double bond and / or one or more triple bonds in addition to the one or more double bonds. An alkynyl group may include more than one triple bond and / or one or more double bonds in addition to the one or more triple bonds.

[0112] Unless otherwise stated, the term "alkylene", either on its own or as part of another substituent, refers to a divalent group derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) will have 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred herein. "Lower alkyl" or "lower alkylene" is a short-chain alkyl or alkylene group that typically has eight or fewer carbon atoms. Unless otherwise stated, the term "alkenyl", either on its own or as part of another substituent, refers to a divalent group derived from an olefin.

[0113] Unless otherwise stated, the term "heteroalkyl," either alone or in combination with another term, means a stable straight or branched chain or combination thereof comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, or S), wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom (e.g., O, N, S, Si, or P) may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is attached to the rest of the molecule. The heteroalkyl group is an uncyclic chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-S-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. At most two or three heteroatoms can be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P). Unless otherwise stated, the term "heteroalkenyl," either alone or in combination with another term, means a heteroalkyl group comprising at least one double bond. In addition to the one or more double bonds mentioned above, a heteroalkenyl group may optionally include more than one double bond and / or one or more triple bonds. Unless otherwise stated, the term "heteroyneyl," either alone or in combination with another term, means a heteroalkyl group comprising at least one triple bond. A heteroyneyl group may optionally include more than one triple bond and / or one or more double bonds other than the one or more triple bonds mentioned above.

[0114] Similarly, unless otherwise stated, the term "heteroalkylene," either on its own or as part of another substituent, refers to a divalent group derived from a heteroalkylene group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom can also occupy any one or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Further still, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, and as used herein, heteroalkylene groups include those groups linked to the remainder of the molecule by a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SO2R'. When the term "heteroalkyl" is used, followed by a specific heteroalkyl group (such as -NR'R'', etc.), it should be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is used to increase clarity. Therefore, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'', etc.

[0115] Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl," either alone or in combination with other terms, refer to the cyclic form of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, the heteroatom may occupy the position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, etc. "Cycloalkylene" and "heterocycloalkylene" refer, alone or as part of another substituent, to divalent groups derived from cycloalkylene and heterocycloalkylene, respectively.

[0116] In embodiments, the term "cycloalkyl" refers to monocyclic, bicyclic, or polycyclic cycloalkyl ring systems. In embodiments, a monocyclic ring system is a cyclic hydrocarbon group comprising 3 to 8 carbon atoms, wherein such groups may be saturated or unsaturated, but are not aromatic. In embodiments, the cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic or fused bicyclic rings. In embodiments, a bridged monocyclic ring includes a monocyclic cycloalkyl ring, wherein two non-adjacent carbon atoms of the monocyclic ring are connected by an alkylene bridge of one to three additional carbon atoms (i.e., in the form of (CH2)). w The bridging group, where w is 1, 2, or 3). Representative examples of bicyclic systems include, but are not limited to, bicyclic [3.1.1]heptane, bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, bicyclic [3.2.2]nonane, bicyclic [3.3.1]nonane, and bicyclic [4.2.1]nonane. In embodiments, the fused bicyclic cycloalkyl ring system comprises a monocyclic cycloalkyl ring fused to a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclic, or monocyclic heteroaryl group. In embodiments, the bridging or fused bicyclic cycloalkyl group is partially connected to the parent molecule via any carbon atom included within the monocyclic cycloalkyl ring. In embodiments, the cycloalkyl group is optionally substituted with one or both groups that are independently oxo or thio. In embodiments, the fused bicyclic cycloalkyl group is a 5- or 6-membered monocyclic cycloalkyl ring fused with a benzene ring, a 5- or 6-membered monocyclic cycloalkyl group, a 5- or 6-membered monocyclic cycloalkenyl group, a 5- or 6-membered monocyclic heterocyclic group, or a 5- or 6-membered monocyclic heteroaryl group, wherein the fused bicyclic cycloalkyl group is optionally substituted by one or two groups that are independently oxo or thio. In embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused with: (i) a ring system selected from the group consisting of: bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (ii) two other ring systems independently selected from the group consisting of: phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclic groups. In embodiments, the polycyclic cycloalkyl group is partially connected to the parent molecule via any carbon atom included within the base ring. In embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused with: (i) a ring system selected from the group consisting of: bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (ii) two other ring systems independently selected from the group consisting of: phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclic groups. Examples of polycyclic cycloalkyl groups include, but are not limited to, tetradecahydrophenanthrenyl, perhydrophenanthiazin-1-yl, and perhydrophenoxazin-1-yl.

[0117] In embodiments, cycloalkyl is cycloalkenyl. The term "cycloalkenyl" is used according to its common, general meaning. In embodiments, cycloalkenyl is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. In embodiments, a monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group comprising 3 to 8 carbon atoms, wherein such a group is unsaturated (i.e., includes at least one cyclic carbon-carbon double bond) but is not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, a bicyclic cycloalkenyl ring is a bridged monocyclic or fused bicyclic ring. In embodiments, a bridged monocyclic ring includes a monocyclic cycloalkenyl ring, wherein two non-adjacent carbon atoms of the monocyclic ring are connected by an alkylene bridge of one to three additional carbon atoms (i.e., in the form of (CH2)). w The bridging group, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyl groups include, but are not limited to, norbornenyl and bicyclic [2.2.2]octyl-2-enyl. In embodiments, the fused bicyclic cycloalkenyl ring system comprises a monocyclic cycloalkenyl ring fused to a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclic, or monocyclic heteroaryl group. In embodiments, the bridged or fused bicyclic cycloalkenyl group is partially connected to the parent molecule via any carbon atom included within the monocyclic cycloalkenyl ring. In embodiments, the cycloalkenyl group is optionally substituted by one or both groups that are independently oxo or thio. In embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused with: (i) a ring system selected from the group consisting of: bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (ii) two ring systems independently selected from the group consisting of: phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclic groups. In embodiments, the polycyclic cycloalkenyl group is partially connected to the parent molecule via any carbon atom included within the base ring. In embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused with: (i) a ring system selected from the group consisting of: bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (ii) two ring systems independently selected from the group consisting of: phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclic groups.

[0118] In embodiments, heterocyclic alkyl groups are heterocyclic groups. As used herein, the term "heterocyclic group" means monocyclic, bicyclic, or polycyclic heterocycle. A heterocyclic monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring comprising at least one heteroatom independently selected from the group consisting of O, N, and S, wherein the ring is saturated or unsaturated, but not aromatic. A 3- or 4-membered ring comprises one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring may comprise zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6- or 7-membered ring comprises zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The heterocyclic monocyclic heterocycle is partially connected to the parent molecule via any carbon or nitrogen atom included within the heterocyclic monocyclic heterocycle. Representative examples of heterocyclic monocyclic heterocycles include, but are not limited to, azahexacyclobutyl, azahexacycloheptyl, aziridinyl, diazacycloheptyl, 1,3-dioxacyclohexyl, 1,3-dioxapentyl, 1,3-dithiopentyl, 1,3-dithiaalkyl, imidazolinyl, imidazolinyl, isothiazolinyl, isothiazolinyl, isoxazolyl, isoxazolyl, morpholinyl, oxadiazolinyl, oxadiazolyl, oxazolinyl, oxazolyl, piperazine, piperidinyl, pyranyl, pyrazolinyl, thiazolinyl, pyrrololinyl, pyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiadiazolinyl, thiadiazolinyl, thiazolinyl, tetrahydrothiazolinyl, thiomorpholinyl, 1,1-oxothiomorpholinyl (thiomorpholinone), thiopyranyl, and trithiaalkyl. A heterocyclic bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl group. The heterocyclic bicyclic heterocycle is connected to the parent molecule via any carbon or nitrogen atom included within the monocyclic heterocyclic portion of the bicyclic system. Representative examples of bicyclic heterocycles include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indol-1-yl, indol-2-yl, indol-3-yl, 2,3-dihydrobenzothiophene-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In embodiments, the heterocyclic group is optionally substituted with one or both groups that are independently oxo or thio. In some embodiments, the bicyclic heterocyclic group is a 5- or 6-membered monocyclic heterocyclic ring fused with a benzene ring, a 5- or 6-membered monocyclic cycloalkyl group, a 5- or 6-membered monocyclic cycloalkenyl group, a 5- or 6-membered monocyclic heterocyclic group, or a 5- or 6-membered monocyclic heteroaryl group, wherein the bicyclic heterocyclic group is optionally substituted by one or two groups that are independently oxo or thio.A polycyclic heterocyclic ring system is a monocyclic heterocyclic ring (base ring) fused with the following: (i) a ring system selected from the group consisting of: bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic groups; or (ii) two other ring systems independently selected from the group consisting of: phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclic groups. The polycyclic heterocyclic group is connected to the parent molecule portion via any carbon or nitrogen atom included within the base ring. In embodiments, the polycyclic heterocyclic ring system is a monocyclic heterocyclic ring (base ring) fused with the following: (i) a ring system selected from the group consisting of: bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclic; or (ii) two other ring systems independently selected from the group consisting of: phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclic. Examples of polycyclic heterocyclic groups include, but are not limited to, 10H-phenthiazin-10-yl, 9,10-dihydroacryl-9-yl, 9,10-dihydroacryl-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azapheno-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinoline-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazole-9-yl.

[0119] Unless otherwise stated, the term "halogen" or "halogen," either on its own or as part of another substituent, refers to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "halogenated alkyl" refer to both monohalogenated and polyhalogenated alkyl groups. For example, the term "halogenated (C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0120] Unless otherwise stated, the term "acyl" means -C(O)R, where R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0121] Unless otherwise stated, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent, which can be a monocyclic or fused together (i.e., a fused-ring aryl) or a plurality of covalently linked rings (preferably 1 to 3 rings). A fused-ring aryl refers to a plurality of fused rings, wherein at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to an aryl (or ring) comprising at least one heteroatom (such as N, O, or S), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl (i.e., a plurality of fused rings, wherein at least one of the fused rings is a heteroaromatic ring). 5,6-fused-ring heteroaryl refers to two fused rings, one ring having a 5-membered ring and the other having a 6-membered ring, and wherein at least one of the rings is a heteroaryl ring. Similarly, 6,6-fused-ring heteroaryl refers to two fused rings, one ring having a 6-membered ring and the other having a 6-membered ring, and wherein at least one of the rings is a heteroaryl ring. Furthermore, 6,5-fused-ring heteroaryl refers to two fused rings, one of which has 6 members and the other has 5 members, and at least one of these rings is a heteroaryl ring. The heteroaryl group can be attached to the rest of the molecule via a carbon atom or a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thiopheneyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiaphenyl, isoquinolinyl, quinoxalinyl, quinolinyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl. The substituents in the aryl and heteroaryl ring systems mentioned above are selected from the group of acceptable substituents described below. "Arylidene" and "heteroarylidene" refer, alone or as part of another substituent, to divalent groups derived from aryl and heteroaryl groups, respectively. Heteroaryl substituents can be -O- bonded to a nitrogen atom in a cyclic heteroatom.

[0122] A fused-ring heterocyclic alkyl-aryl group is an aryl group fused with a heterocyclic alkyl group. A fused-ring heterocyclic alkyl-heteroaryl group is a heteroaryl group fused with a heterocyclic alkyl group. A fused-ring heterocyclic alkyl-heteroalkyl group is a heterocyclic alkyl group fused with a cycloalkyl group. A fused-ring heterocyclic alkyl-heteroalkyl group is a heterocyclic alkyl group fused with another heterocyclic alkyl group. Fused-ring heterocyclic alkyl-aryl, fused-ring heterocyclic alkyl-heteroaryl, fused-ring heterocyclic alkyl-cycloalkyl, or fused-ring heterocyclic alkyl-heteroalkyl groups may each be independently unsubstituted or substituted with one or more of the substituents described herein.

[0123] A spirocycle is a group of two or more rings in which adjacent rings are connected by a single atom. Individual rings within a spirocycle can be the same or different. Individual rings within a spirocycle can be substituted or unsubstituted and can have substituents different from other individual rings within a group of spirocycles. Possible substituents for individual rings within a spirocycle are possible substituents of the same ring when not part of the spirocycle (e.g., substituents of cycloalkyl or heteroalkyl rings). A spirocycle can be a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heteroalkyl, or a substituted or unsubstituted heteroalkylene, and the individual ring within the spirocycle group can be any ring in the immediately preceding list, including all rings of one type (e.g., all rings of substituted heteroalkylene, where each ring can be the same or different substituted heteroalkylene). When referring to spirocycle systems, heterocyclic spirocycles mean spirocycles in which at least one ring is a heterocycle and each ring can be a different ring. When referring to spirocyclic systems, a substituted spirocycle means that at least one ring is substituted and each substituent may optionally be different.

[0124] symbol" (The wavy line) indicates the point where the chemical part connects to the rest of the molecule or chemical formula.

[0125] As used in this article, the term "oxo" refers to oxygen bonded to a carbon atom in a double bond.

[0126] As used herein, the term "alkylsulfonyl" means having the formula -S(O2)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' may have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").

[0127] The term "alkylarylene" refers to an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene has the formula: or .

[0128] The alkylarylene moiety may be substituted (e.g., substituted with substituents) at the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with the following: halogen, oxo, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl groups, or substituted or unsubstituted 2- to 5-membered heteroalkyl groups. In embodiments, the alkylarylene group is unsubstituted.

[0129] Each of the terms above (e.g., "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl", and "heteroaryl") includes both the substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of group are provided below.

[0130] Substituents in alkyl and heteroalkyl groups (including those commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, ynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) may be one or more groups selected from, but not limited to, the following groups: -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR''C(O)R''', -NR''C(O) 2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', with the number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in this group. R, R', R'', R''', and R'''' each preferably independently refers to hydrogen, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl (e.g., an aryl substituted with 1-3 halogens), a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkyl, an alkoxy or thioalkoxy, or an aralkyl. When the compounds described herein include more than one R group, each of the R groups is independently selected, for example, as each R' group, R'' group, R''' group, and R'''' group is independently selected when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion of substituents, those skilled in the art will understand that the term "alkyl" is intended to include groups comprising a carbon atom bonded to a group other than a hydrogen group, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0131] Similar to the substituents described for alkyl groups, the substituents for aryl and heteroaryl groups are varied and selected from, for example: -OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R'', -NR''C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', - ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy and fluoro(C1-C4)alkyl, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'', in the range of zero to the total number of open valences on the aromatic ring system; and wherein R', R'', R''' and R'''' are preferably independently selected independently from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When the compounds described herein include more than one R group, each R group among the R groups is selected independently, for example, as if each R' group, R'' group, R''' group and R'''' group were selected independently when more than one of these groups are present.

[0132] Substituents on a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) can be described as substituents on the ring rather than on a specific atom of the ring (often referred to as floating substituents). In this case, the substituent can be attached to any ring atom (following the valence rules), and in the case of fused or spirocyclic rings, the substituent described as associating with a single atom of the fused or spirocyclic ring (floating substituents on a single ring) can be a substituent on any of the fused or spirocyclic rings (floating substituents on multiple rings). When the substituent is attached to the ring rather than a specific atom (floating substituent) and the substituent's subscript is an integer greater than one, multiple substituents can be located on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent can optionally be different. Where the connection point between the ring and the rest of the molecule is not limited to a single atom (floating substituent), the connection point can be any atom of the ring, and in the case of fused or spirocyclic rings, it can be any atom of any of the fused or spirocyclic rings while following the valence rules. In the case where a ring, fused ring, or spirocyclic ring comprises one or more cyclic heteroatoms, and the ring, fused ring, or spirocyclic ring is shown having more than one floating substituent (including, but not limited to, connection points with the rest of the molecule), the floating substituent may bond to the heteroatom. In the case where the cyclic heteroatom is shown bonded to one or more hydrogen atoms in a structure or formula having a floating substituent (e.g., a cyclic nitrogen having two bonds bonded to a ring atom and a third bond bonded to a hydrogen atom), when the heteroatom bonds to the floating substituent, the substituent will be understood as replacing hydrogen while following the rules of chemical valence.

[0133] Two or more substituents may optionally be linked to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called cycloforming substituents are found to be typically (though not necessarily) linked to a cyclic base structure. In one embodiment, the cycloforming substituent is linked to an adjacent element of the base structure. For example, two cycloforming substituents linked to an adjacent element of the cyclic base structure produce a fused ring structure. In another embodiment, the cycloforming substituent is linked to a single element of the base structure. For example, two cycloforming substituents linked to a single element of the cyclic base structure produce a spirocyclic structure. In yet another embodiment, the cycloforming substituent is linked to a non-adjacent element of the base structure.

[0134] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form the formula -TC(O)-(CRR'). p A -U- ring, where T and U are independently -NR-, -O-, -CRR'-, or single bonds, and p is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -A-(CH2). rThe substituents of -B- are substituted, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or single bonds, and r is an integer from 1 to 4. One of the single bonds in the newly formed ring may optionally be substituted with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with the formula -(CRR'-). s -X'-(C''R''R''') d The substituents are substituted, wherein s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0135] As used herein, the term “heteroatom” or “cyclic heteroatom” is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0136] As used herein, "substituent" means a group selected from the following: (A) Oxygenated, Halogenated, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OC F3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C... 10 Aryl, C 10Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (B) An alkyl group substituted with at least one of the following substituents: (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), or aryl (e.g., C6-C4 alkyl). 10 Aryl, C 10 Aryl or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl): (i) Oxygenated, halogenated, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OC F3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C... 10 Aryl, C 10 Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (ii) An alkyl group substituted with at least one of the following substituents: (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-C...10 Aryl, C 10 Aryl or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl): (a) Oxygenated, Halogenated, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OC F3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C... 10 Aryl, C 10 Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (b) an alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), a heteroalkyl group (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), a cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), a heterocycloalkyl group (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), or an aryl group substituted with at least one of the following substituents (e.g., C6-C4 alkyl). 10 Aryl, C 10Aryl or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl): oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)O H, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C... 10 Aryl, C 10 (aryl or phenyl) or unsubstituted heteroaryl (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl or 5 to 6-membered heteroaryl).

[0137] As used herein, “size-limited substituent” or “size-limited substituent group” means a group selected from all the substituents described above for “substituent”, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C2 group. 20 Alkyl groups, each substituted or unsubstituted heteroalkyl group being a substituted or unsubstituted 2- to 20-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group being a substituted or unsubstituted C3-C8 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group being a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group being a substituted or unsubstituted C6-C8 cycloalkyl group. 10 Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10-membered heteroaryl.

[0138] As used herein, “lower substituent” or “lower substituent group” means a group selected from all the substituents described above for “substituent”, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3- to 7-membered cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, each substituted or unsubstituted aryl group is a substituted or unsubstituted phenyl group, and each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 6-membered heteroaryl group.

[0139] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-restricted substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0140] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl group may be a substituted or unsubstituted C1-C2 group. 20 Alkyl groups, each substituted or unsubstituted heteroalkyl group being a substituted or unsubstituted 2- to 20-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group being a substituted or unsubstituted C3-C8 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group being a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group being a substituted or unsubstituted C6-C8 cycloalkyl group. 10 The aryl group, and / or each substituted or unsubstituted heteroaryl group, is a substituted or unsubstituted 5- to 10-membered heteroaryl group. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C1-C... 20Alkylenes, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 3- to 8-membered heteroalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10 The aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5 to 10-membered heteroaryl group.

[0141] In some embodiments, each substituted or unsubstituted alkyl group may be a substituted or unsubstituted C1-C8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C7 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkyl group. 10 The aryl group and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 9-membered heteroaryl group. In some embodiments, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C1-C8 alkylene group, each substituted or unsubstituted heteroalkylene group is a substituted or unsubstituted 2- to 8-membered heteroalkylene group, each substituted or unsubstituted cycloalkylene group is a substituted or unsubstituted C3-C7 cycloalkylene group, each substituted or unsubstituted heteroalkylene group is a substituted or unsubstituted 3- to 7-membered heteroalkylene group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 alkylene group. 10 The aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 9-membered heteroaryl group. In some embodiments, the compound is a chemical species set forth in the following examples section, figures, or tables.

[0142] In the embodiments, the substituted or unsubstituted portions (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene and / or substituted or unsubstituted heteroaryl) are unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene and / or unsubstituted heteroaryl). In the embodiments, the substituted or unsubstituted portions (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene and / or substituted or unsubstituted heteroaryl) are substituted (e.g., respectively substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene and / or substituted heteroaryl).

[0143] In embodiments, the substituted portion (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, wherein if the substituted portion is substituted with multiple substituents, each substituent may optionally be different. In embodiments, if the substituted portion is substituted with multiple substituents, each substituent is different.

[0144] In embodiments, the substituted portion (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-restricted substituent, wherein if the substituted portion is substituted with multiple size-restricted substituents, each size-restricted substituent may optionally be different. In embodiments, if the substituted portion is substituted with multiple size-restricted substituents, each size-restricted substituent is different.

[0145] In embodiments, the substituted portion (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent, wherein if the substituted portion is substituted with multiple lower substituents, each lower substituent may optionally be different. In embodiments, if the substituted portion is substituted with multiple lower substituents, each lower substituent is different.

[0146] In embodiments, the substituted portion (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, a size-restricted substituent, or a lower substituent; wherein if the substituted portion is substituted with a plurality of groups selected from substituents, size-restricted substituents, and lower substituents, each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In embodiments, if the substituted portion is substituted with a plurality of groups selected from substituents, size-restricted substituents, and lower substituents, each substituent, size-restricted substituent, and / or lower substituent is different.

[0147] Certain compounds disclosed herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds; in absolute stereochemistry, enantiomers, racemates, diastereomers, tautomers, geometric isomers, and stereoisomers, which can be defined as amino acids and individual isomers, are included within the scope of this disclosure. The compounds disclosed herein do not include compounds known in the art that are too unstable to be synthesized and / or isolated. This disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein involve olefinic bonds or other geometrically asymmetric centers, and unless otherwise specified, the compounds are expected to include both E and Z geometric isomers.

[0148] As used herein, the term "isomer" refers to a compound that has the same number and type of atoms and therefore the same molecular weight, but differs in the structural arrangement or configuration of the atoms.

[0149] As used in this paper, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily transformed from one isomer to another.

[0150] It will be apparent to those skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of this disclosure.

[0151] Unless otherwise stated, the structures described herein are intended to include all stereochemical forms of the structures; that is, the R and S configurations of each asymmetric center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers and diastereomers, are all within the scope of this disclosure.

[0152] It should be noted that throughout this application, alternatives are written in the Markush group, for example, at each amino acid position including more than one possible amino acid. By special consideration, each member of the Markush group should be considered individually, thereby including another implementation, and the Markush group should not be construed as a single unit.

[0153] A "linker" refers to a chemical portion comprising a covalent bond or atomic chain that covalently links an antibody to a drug moiety. In various embodiments, the linker comprises a divalent group. In various embodiments, the linker may comprise one or more amino acid residues. In some embodiments, the linker is an incleavable linker. In some embodiments, the linker is an enzyme-cleavable linker (e.g., a Val-Cit or Val-Cit-PAB linker).

[0154] The "amino acid unit" has the formula , where R 0 It is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(═NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(═NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, phenyl or cyclohexyl. In various embodiments, the amino acid unit includes not only naturally occurring amino acids, but also minor amino acids and non-naturally occurring amino acid analogs, such as citrulline, oroleucine, selenomethionine, β-alanine, N-dimethyllysine, etc. The amino acid unit can be represented by its standard three-letter code for the amino acid (e.g., Ala, Cys, Asp, Glu, Val, Phe, Lys, etc.).

[0155] As used herein, the terms “bioconjugate” and “bioconjugate linker” refer to the association that occurs between atoms or molecules of a “bioconjugate reactive group” or a “bioconjugate reactive moiety.” Association can be direct or indirect. For example, the coupling between a first bioconjugate reactive group (e.g., -NH2, -C(O)OH, -N-hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., thiol, sulfur-containing amino acid, amine, amine side chain of an amino acid, or carboxylate) can occur directly, for example, through a covalent bond or linker (e.g., the first linker of the second linker), or indirectly, for example, through non-covalent bonds (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (π effect), hydrophobic interactions, etc.). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., association of two bioconjugate reactive groups), which includes, but is not limited to, nucleophilic substitution (e.g., reactions of amines and alcohols with acyl halides, reactive esters), electrophilic substitution (e.g., enamine reactions), and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in the following literature: for example, March, *Advanced Organic Chemistry*, 3rd ed., John Wiley & Sons, New York, 1985; Hermanson, *Bioconjugate Technologies*, Academic Press, San Diego, 1996; and Feeney et al., *Modification of Proteins*, Progress in Chemistry Series, Vol. 198, American Chemical Society, Washington, DC, 1982. In embodiments, the first bioconjugate reactive group (e.g., the maleimide moiety) is covalently linked to the second bioconjugate reactive group (e.g., a thiol). In one embodiment, a first bioconjugate reactive group (e.g., a haloacetyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a thiol). In another embodiment, a first bioconjugate reactive group (e.g., a pyridyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a thiol).In one embodiment, a first bioconjugate reactive group (e.g., an -N-hydroxysuccinimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., an amine). In another embodiment, the first bioconjugate reactive group (e.g., a fluorophenyl ester moiety) reacts with the second bioconjugate reactive group (e.g., an amine) to form a covalent bond. In yet another embodiment, the first bioconjugate reactive group (e.g., an -sulfonyl-N-hydroxysuccinimide moiety) reacts with the second bioconjugate reactive group (e.g., an amine) to form a covalent bond.

[0156] Useful bioconjugate reactivity sections for the bioconjugate chemistry used in this article include, for example: (a) Carboxyl groups and their various derivatives, including but not limited to N-hydroxysuccinimide esters, N-hydroxybenzotriazole esters, acid halides, acylimidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) Hydroxyl group, which can be converted into ester, ether, aldehyde, etc.

[0157] (c) Haloalkyl, wherein the halide may subsequently be replaced by a nucleophilic group such as an amine, carboxylate anion, thiol anion, carbanion or alkoxy ion, thereby resulting in the new group being covalently attached at the site of the halogen atom; (d) a dienophile group, which is capable of participating in the Diels-Alder reaction, such as a maleimide group or a maleimide group; (e) an aldehyde or ketone group, wherein the aldehyde or ketone group allows for subsequent derivatization by the formation of a carbonyl derivative (e.g., an imine, hydrazone, hemicarbazone, or oxime) or by mechanisms such as Grignard addition or alkyllithium addition. (f) a sulfonyl halide group, which is used for subsequent reaction with an amine, for example, to form a sulfonamide; (g) Thiol group, which can be converted into a disulfide, react with an acyl halide, or bond with a metal such as gold, or react with maleimide; (h) An amine or thiol group (e.g., present in cysteine), which may be, for example, acylated, alkylated or oxidized; (i) An olefin, which may undergo, for example, cycloaddition, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphorous amide and other standard functional groups that can be used in nucleic acid synthesis; (l) Metal-silicon oxide bonding; and (m) forms a metallic bond with a reactive phosphorus group (e.g., phosphine) to form, for example, a phosphate diester bond.

[0158] (n) Azides coupled with alkynes using copper-catalyzed cycloaddition click chemistry.

[0159] (o) Biotin conjugates can react with avidin or strepavidin to form avidin-biotin complex or strepavidin-biotin complex.

[0160] The reactive groups of bioconjugates can be selected such that they do not participate in or interfere with the chemical stability of the conjugates described herein. Alternatively, the presence of protecting groups can protect the reactive functional groups from participating in cross-linking reactions. In embodiments, bioconjugates comprise molecular entities derived from the reaction of unsaturated bonds such as maleimide with thiol groups.

[0161] The term "analog" or "analogue" is used according to its ordinary, general meaning in chemistry and biology, and refers to a chemical compound that is structurally similar but compositionally different from another compound (i.e., the so-called "reference" compound) for example, in the substitution of one atom by a different element, or in the presence of a particular functional group, or in the absolute stereochemistry of one or more chiral centers of a reference compound. Thus, an analog is a compound that is similar or equivalent to a reference compound in function and appearance, but dissimilar or not equivalent in structure or origin.

[0162] As used in this article, the common organic and cell type abbreviations are defined as follows: Composition Antibody-drug conjugates On the one hand, this article provides an antibody-drug conjugate (ADC) comprising a monoclonal antibody (Ab), a drug moiety (D), and a linker moiety covalently linking the monoclonal antibody to the drug moiety.

[0163] On the other hand, this paper provides an ADC of formula (I), formula (II), or formula (III): Or its pharmaceutically acceptable salt, wherein: Ab is a monoclonal antibody, which includes an Fc variant comprising two amino acid substitutions for L234A and L235A; m is an integer from 1 to 8; L 1It is a linker that binds to the monoclonal antibody; L 2 It is a bond, -C(O)-, -NH-, amino acid unit, -(CH2CH2O) n -、-(CH2) n -、-O-、-(4-aminobenzyloxycarbonyl)-、-(C(O)CH2CH2NH)-、-(C(O)N(R 2 )CH2CH2N(R 5 ))- or any combination thereof; where n is an integer from 1 to 24; Each R 2 and R 5 It is independently H or a substituted or unsubstituted alkyl group; L 3 It is a substituted or unsubstituted heterocyclic alkyl group, a substituted or unsubstituted heteroaryl group; or L 3 It is a substituted or unsubstituted -OCH2- (heterocyclic alkyl) or a substituted or unsubstituted -OCH2- (heteroaryl), wherein L 3 Through oxygen-D linkage; or L 3 It is a substituted or unsubstituted -CH2NCH2- (heteroaryl) or a substituted or unsubstituted -CH2NCH2- (heterocyclic alkyl), wherein L 3 It is connected to D via -CH2- and to L via nitrogen. 2 connect; R * It is a substituted or unsubstituted heterocyclic alkyl or a substituted or unsubstituted heteroaryl; D is ;D' is D' interacts with R through its amide group. * Connect and via oxygen and L 2 Connect; and D'' is or in: R 1 It is an H or -C1-C8 alkyl group; R 3 It includes H, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, and -OR. 3A -NR 3A R 3B -(CH2) v OR 6Substituted or unsubstituted alkyl groups or substituted or unsubstituted heteroalkyl groups; R 4 It is H, halogen, -OR 4A -NR 4A R 4B Substituted or unsubstituted alkyl groups or substituted or unsubstituted heteroalkyl groups; V is N, O, or C; Z 1 It is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group; Z 2 It is a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, a substituted or unsubstituted cycloalkylene, or a substituted or unsubstituted heteroalkylene; R 6 It is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO(CH2CH2O) w CH2CH2M、-CONH(CH2CH2O) w CH2CH2M, Charged groups or sugar derivatives; v is an integer from 1 to 24; w is an integer from 1 to 24; M is -NH2, -OH, -COOH, or -OCH3; R 10 It is -OH, -OCH3, or -COOH; and Each R 3A R 3B R 4A and R 4B It is independently H or a substituted or unsubstituted alkyl group.

[0164] In the implementation, D'' is in: R 1 It is an H or -C1-C8 alkyl group; R 3 It is H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 4 It is H, halogen, or substituted or unsubstituted alkyl; V is N; and Z 2 It is a substituted or unsubstituted aryl group.

[0165] In the implementation, D'' is: , , , or .

[0166] In the implementation, D'' is .

[0167] In this implementation, m is an integer from 1 to 8. In this implementation, m is 1. In this implementation, m is 2. In this implementation, m is 3. In this implementation, m is 4. In this implementation, m is 5. In this implementation, m is 6. In this implementation, m is 7. In this implementation, m is 8.

[0168] In the implementation, n is an integer from 1 to 24. In the implementation, n is an integer from 1 to 4. In the implementation, n is 1. In the implementation, n is 2. In the implementation, n is 3. In the implementation, n is 4. In the implementation, n is 5. In the implementation, n is 6. In the implementation, n is 7. In the implementation, n is 8. In the implementation, n is 9. In the implementation, n is 10. In the implementation, n is 11. In the implementation, n is 12. In the implementation, n is 13. In the implementation, n is 14. In the implementation, n is 15. In the implementation, n is 16. In the implementation, n is 17. In the implementation, n is 18. In the implementation, n is 19. In the implementation, n is 20. In the implementation, n is 21. In the implementation, n is 22. In the implementation, n is 23. In the implementation, n is 24.

[0169] In one embodiment, the monoclonal antibody is a modified antibody. In another embodiment, the modified antibody binds to a transmembrane protein, such as the extracellular domain of a transmembrane protein. In another embodiment, the transmembrane protein is a transmembrane receptor, such as a transmembrane receptor kinase. In yet another embodiment, the transmembrane receptor kinase is a transmembrane receptor tyrosine kinase. In yet another embodiment, the modified antibody binds to a tyrosine kinase.

[0170] In the implementation, L 1 It is a linker that binds to monoclonal antibodies. In the implementation, L 1 It is a linker that binds to one or two sulfur or nitrogen atoms of a monoclonal antibody. In the embodiment, L 1 It is a linker that binds to a sulfur atom of a monoclonal antibody. In the implementation, L 1 It is a linker that binds to two sulfur atoms of a monoclonal antibody. In the implementation, L 1 It is a linker that binds to a nitrogen atom of a monoclonal antibody. In the implementation, L1 It is a linker that binds to the two nitrogen atoms of a monoclonal antibody.

[0171] In the implementation, L 1 It is a linker that binds to modified monoclonal antibodies.

[0172] In the implementation, L 1 It is a linker that binds to a cysteine ​​molecule of a monoclonal antibody. In the embodiment, L 1 It is a linker that binds to two cysteine ​​molecules of a monoclonal antibody. In the embodiment, L 1 It is a linker that binds to a lysine molecule of a monoclonal antibody. In the embodiment, L 1 It is a linker that binds to two lysine molecules of a monoclonal antibody.

[0173] In the implementation, L 1 It is a linker that binds to modified monoclonal antibodies.

[0174] In this embodiment, the monoclonal antibody is an anti-CD25 antibody, an anti-B7-H3 antibody, an anti-ROR1 antibody, an anti-Trop-2 antibody, or an anti-BCMA antibody.

[0175] In one embodiment, the monoclonal antibody is an anti-CD25 antibody. In another embodiment, the monoclonal antibody is an anti-B7-H3 antibody. In another embodiment, the monoclonal antibody is an anti-ROR1 antibody. In another embodiment, the monoclonal antibody is an anti-Trop-2 antibody. In another embodiment, the monoclonal antibody is an anti-BCMA antibody.

[0176] In the implementation, L 1 yes , , , , , , , , , , , or .

[0177] In the implementation, L 1 yes or .

[0178] In the implementation, L 1 yes In the implementation method, L 1 yes In the implementation method, L1 yes In the implementation method, L 1 yes In the implementation method, L 1 yes In the implementation method, L 1 yes In the implementation method, L 1 yes In the implementation method, L 1 yes In the implementation method, L 1 yes In the implementation method, L 1 yes In the implementation method, L 1 yes In the implementation method, L 1 yes In the implementation method, L 1 yes In the implementation method, L 1 yes .

[0179] In L 1 yes In this case, the two CH2 moieties shown on the right side of the structure can each bind to different cysteine ​​residues of the anti-CD25 antibody via thiol groups. In L... 1 yes In this case, the two olefinic carbons displayed at the bottom of the structure can each bind to different cysteine ​​residues of the anti-CD25 antibody via a thiol group. In L... 1 yes In this case, carbon can bind to the cysteine ​​residue of the anti-CD25 antibody via a thiol group.

[0180] In the implementation, L 2 It is a bond, -C(O)-, -NH-, -Val-, -Phe-, -Lys-, -Gly-, -O-, -(4-aminobenzyloxycarbonyl)-, -(C(O)N(R 2 )CH2CH2N(R 5 -, -Ser-, -Thr-, -Ala-, -β-Ala-, -citrulline-(Cit), -(CH2) n -、-(CH2CH2O) n -, N-dimethyllysine or any combination thereof.

[0181] In the implementation, each R 2 and R 5Independently, it is H or a substituted or unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, each R 2 and R 5 H is independent. In the implementation, each R 2 and R 5 Independently, it is a substituted or unsubstituted alkyl group. In the embodiments, each R 2 and R 5 Independently, it is a substituted or unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, each R 2 and R 5 Independently, it is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, each R 2 and R 5 It is independently a substituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0182] In the implementation, each R 2 and R 5 Independently, it is H or a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, each R 2 and R 5 Independently, it is a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl group. In embodiments, each R 2 and R 5 Independently, it is a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, each R 2 and R 5 Independently, it is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, each R 2 and R 5 It is independently a substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0183] In the implementation, each R 2 and R 5Independently, it is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, or hexyl. In the embodiments, each R 2 and R 5 Independently, it is methyl. In the embodiments, each R 2 and R 5 Independently, it is ethyl. In the embodiments, each R 2 and R 5 Independently, it is propyl. In the implementation, each R... 2 and R 5 It is butyl alone.

[0184] In the implementation, L 2 The following are some common carboxyl groups: -C(O)-, -NH-, -Val-, -Phe-, -Lys-, -Gly-, -(4-aminobenzyloxycarbonyl)-, -(C(O)N(CH3)CH2CH2N(CH3))-, -Ser-, -Thr-, -Ala-, -β-Ala-, -O-, -citrulline-(Cit), -(CH2) n -、-(CH2CH2O) n -, N-dimethyllysine or any combination thereof.

[0185] In the implementation, L 2 The following are possible combinations: -C(O)-, -NH-, -Val-, -Gly-, -Cit-, -Ala-, -O-, -(4-aminobenzyloxycarbonyl)-, -(CH2). n -、-(CH2CH2O) n -, -(C(O)N(CH3)CH2CH2N(CH3))-, N-dimethyllysine or any combination thereof.

[0186] In the implementation, L 2 It is -C(O)-, -NH-, -Gly-, -(CH2) n -、-(CH2CH2O) n - or any combination thereof.

[0187] In the implementation, L 2 It is -C(O)-, -NH-, -Val-, -Cit-, -(CH2CH2O) n -、-(4-aminobenzyloxycarbonyl)-、-(CH2) n -, -(C(O)N(CH3)CH2CH2N(CH3))-, N-dimethyllysine or any combination thereof.

[0188] In the implementation, L 2The following are possible combinations: -C(O)-, -NH-, -Val-, -(4-aminobenzyloxycarbonyl)-, -Gly-, -citrulline-(-Cit-), -(CH2). n -、-(CH2CH2O) n -, N-dimethyllysine or any combination thereof.

[0189] In the implementation, L 2 yes: , , , , , , , , , , , , , , , , , , , , , , , ,or .

[0190] In the implementation, L 2 yes , , or .

[0191] In the implementation, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes In the implementation method, L 2 yes .

[0192] In the implementation, L 2 It is a key. In the implementation, L 2 It is -C(O)-. In the implementation, L 2 It is -NH-. In the implementation, L 2 It is -Val-. In the implementation, L 2 Yes -Phe-. In the implementation, L 2 It is -Lys-. In the implementation, L 2 It is -(4-aminobenzyloxycarbonyl)-. In the embodiments, L 2 It is -(CH2) n - In the implementation, L 2 It is -(CH2CH2O) n - In the implementation, L 2 It is -Gly-. In the implementation, L 2 Yes -Ser-. In the implementation, L 2 Yes -Thr-. In the implementation, L2 It is -Ala-. In the implementation, L 2 It is -β-Ala-. In the implementation, L 2 Yes -Cit-. In the implementation, L 2 Yes -O-. In the implementation, L 2 It is N-dimethyllysine.

[0193] In the implementation, -L 1 -L 2 -yes , , , , , , , , , , , , , , , , , , , or .

[0194] In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes The two CH2 moieties shown on the left side of the structure can each bind to a single sulfur atom of the anti-CD25 antibody. In the embodiment, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes The two olefinic carbons shown at the bottom of the structure can each bind to a separate sulfur atom of the anti-CD25 antibody. In this embodiment, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2-yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes In the implementation, -L 1 -L 2 -yes .

[0195] In the implementation, L 3This refers to substituted (e.g., substituted with a substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), substituted (e.g., substituted with a substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl groups, 5- to 9-membered heteroaryl groups, or 5- to 6-membered heteroaryl groups), substituted (e.g., substituted with a substituent, size-restricted substituent, or lower substituent) or unsubstituted -OCH2-(heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups)), substituted (e.g., substituted with a substituent, size-restricted substituent, or lower substituent)). The -OCH2-(heteroaryl group (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl)) is substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2-(heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl group, 3- to 6-membered heterocyclic alkyl group, or 5- to 6-membered heterocyclic alkyl group)) or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2-(heteroaryl group (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl)). In embodiments, L 3 It is replaced by one or more substituents. In the implementation, L 3 It is replaced by one or more size-restricted substituents. In the implementation, L 3 It is replaced by one or more lower substituents.

[0196] In the implementation, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl) or substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2-(heterocyclic alkyl (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl)). In embodiments, L 3 It is replaced by one or more substituents. In the implementation, L 3 It is replaced by one or more size-restricted substituents. In the implementation, L 3 It is replaced by one or more lower substituents.

[0197] In the implementation, L 3It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkylene (e.g., 3- to 8-membered heterocyclic alkylene, 3- to 6-membered heterocyclic alkylene, or 5- to 6-membered heterocyclic alkylene). In the embodiments, L 3 It is replaced by one or more substituents. In the implementation, L 3 It is replaced by one or more size-restricted substituents. In the implementation, L 3 It is replaced by one or more lower substituents.

[0198] In the implementation, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) heterocyclic alkylene (e.g., 3- to 8-membered heterocyclic alkylene, 3- to 6-membered heterocyclic alkylene, or 5- to 6-membered heterocyclic alkylene). In embodiments, L 3 It is an unsubstituted heterocyclic alkyl group (e.g., a 3- to 8-membered heterocyclic alkyl group, a 3- to 6-membered heterocyclic alkyl group, or a 5- to 6-membered heterocyclic alkyl group). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) heteroaryl group (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiment, L 3 It is an unsubstituted heteroaryl group (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiment, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl group, 3- to 6-membered heterocyclic alkyl group, or 5- to 6-membered heterocyclic alkyl group)). In embodiments, L 3 It is an unsubstituted -OCH2- (heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl group, 3- to 6-membered heterocyclic alkyl group, or 5- to 6-membered heterocyclic alkyl group)). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) OCH2-(heteroaryl (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl)). In embodiments, L 3 It is an unsubstituted -OCH2- (heteroaryl (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl)). In the embodiment, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (heterocyclic alkyl (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl)). In embodiments, L 3It is an unsubstituted -CH2NCH2- (heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl group, 3- to 6-membered heterocyclic alkyl group, or 5- to 6-membered heterocyclic alkyl group)). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl)). In embodiments, L 3 It is an unsubstituted -CH2NCH2-(heteroaryl (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl or 5 to 6-membered heteroaryl)).

[0199] In the implementation, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 3- to 8-membered heterocyclic alkyl group. In embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) 3- to 8-membered heterocyclic alkyl group. In embodiments, L 3 It is an unsubstituted 3- to 8-membered heterocyclic alkyl group. In the embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (3 to 8-membered heterocyclic alkyl group). In embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (3 to 8-membered heterocyclic alkyl). In embodiments, L 3 It is an unsubstituted -CH2NCH2- (3 to 8-membered heterocyclic alkyl group). In the embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (3 to 8-membered heterocyclic alkylene). In embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (3 to 8-membered heterocyclic alkylene). In embodiments, L 3 It is an unsubstituted -OCH2- (3 to 8-membered heterocyclic alkyl group).

[0200] In the implementation, L 3 It is a 3- to 8-membered heterocyclic alkyl group that is substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted.

[0201] In the implementation, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 3- to 6-membered heterocyclic alkylene compounds. In embodiments, L3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) 3- to 6-membered heterocyclic alkylene group. In embodiments, L 3 It is an unsubstituted 3- to 6-membered heterocyclic alkyl group. In the embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (3 to 6-membered heterocyclic alkyl group). In embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (3 to 6-membered heterocyclic alkyl). In embodiments, L 3 It is an unsubstituted -CH2NCH2- (3 to 6-membered heterocyclic alkyl group). In the embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (3 to 6-membered heterocyclic alkylene). In embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (3 to 6-membered heterocyclic alkylene). In embodiments, L 3 It is an unsubstituted -OCH2- (3 to 6-membered heterocyclic alkyl group).

[0202] In the implementation, L 3 It is a 3- to 6-membered heterocyclic alkyl group that is substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted.

[0203] In the implementation, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic butyl, heterocyclic pentyl, or heterocyclic hexyl. In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) heterocyclic butyl, heterocyclic pentyl, or heterocyclic hexyl. In the embodiment, L 3 It is an unsubstituted heterocyclic butyl, heterocyclic pentyl, or heterocyclic hexyl group. In the embodiment, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (heterocyclic butyl, heterocyclic pentyl, or heterocyclic hexyl). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (heterocyclic butyl, heterocyclic pentyl, or heterocyclic hexyl). In the embodiment, L 3It is unsubstituted -CH2NCH2- (heterocyclic butyl, heterocyclic pentyl, or heterocyclic hexyl). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (heterocyclic butylene, heterocyclic pentylene, or heterocyclic hexylene). In the embodiment, L 3 It is substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (heterocyclic butylene, heterocyclic pentylene, or heterocyclic hexylene). In embodiments, L 3 It is unsubstituted -OCH2- (heterocyclic butyl, heterocyclic pentyl, or heterocyclic hexyl).

[0204] In the implementation, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclobutyl, heterocyclopentyl, or heterocyclohexyl.

[0205] In the implementation, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic butyl. In the embodiment, L 3 It is a heterocyclic butyl group that has been substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, L 3 It is an unsubstituted heterocyclic butyl group. In the implementation, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (heterocyclic butyl). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (heterocyclic butyl). In the embodiment, L 3 It is an unsubstituted -CH2NCH2- (heterocyclic butyl). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (heterocyclic butyl). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (heterocyclic butyl). In the embodiment, L 3 It is unsubstituted -OCH2- (heterocyclic butyl).

[0206] In the implementation, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclopentyl group. In the embodiment, L 3It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) heterocyclopentyl group. In the embodiment, L 3 It is an unsubstituted heterocyclopentyl group. In the embodiment, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (heterocyclopentyl). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (heterocyclopentyl). In the embodiment, L 3 It is an unsubstituted -CH2NCH2- (heterocyclic pentyl). In the embodiment, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (heterocyclopentyl). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (heterocyclopentyl). In the embodiment, L 3 It is the unsubstituted -OCH2- (heterocyclopentyl).

[0207] In the implementation, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclohexyl group. In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) heterocyclohexyl group. In the embodiment, L 3 It is an unsubstituted heterocyclohexyl group. In the implementation, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (heterocyclohexyl). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (heterocyclohexyl). In the embodiment, L 3 It is the unsubstituted -CH2NCH2- (heterocyclohexyl). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (heterocyclohexyl). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (heterocyclohexyl). In the embodiment, L 3 It is unsubstituted -OCH2- (heterocyclohexyl).

[0208] In the implementation, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5- to 10-membered heteroaryl group. In an embodiment, L 3 It is a 5- to 10-membered heteroaryl group that has been substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In an embodiment, L 3 It is an unsubstituted 5- to 10-membered heteroaryl group. In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (5 to 10-membered heteroaryl). In embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (5 to 10-membered heteroaryl). In embodiments, L 3 It is an unsubstituted -CH2NCH2- (5 to 10-membered heteroaryl). In the embodiment, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (5 to 10-membered heteroaryl). In the embodiment, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (5 to 10-membered heteroaryl). In the embodiment, L 3 It is an unsubstituted -OCH2- (5 to 10 methyl aryl group).

[0209] In the implementation, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5- to 9-membered heteroaryl group. In an embodiment, L 3 It is a 5- to 9-membered heteroaryl group that has been substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In an embodiment, L 3 It is an unsubstituted 5- to 9-membered heteroaryl group. In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (5 to 9 membered heteroaryl). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (5 to 9 membered heteroaryl). In the embodiment, L 3 It is an unsubstituted -CH2NCH2- (5 to 9-membered heteroaryl). In the embodiment, L 3It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (5 to 9-membered heteroaryl). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (5 to 9 membered heteroaryl). In the embodiment, L 3 It is an unsubstituted -OCH2- (5 to 9 nucleotide heteroaryl groups).

[0210] In the implementation, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5- to 6-membered heteroaryl group. In an embodiment, L 3 It is a 5- to 6-membered heteroaryl group that has been substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In an embodiment, L 3 It is an unsubstituted 5- to 6-membered heteroaryl group. In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (5 to 6-membered heteroaryl). In embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (5 to 6-membered heteroaryl). In embodiments, L 3 It is an unsubstituted -CH2NCH2- (5 to 6-membered heteroaryl). In the embodiment, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (5 to 6-membered heteroaryl). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (5 to 6-membered heteroaryl). In the embodiment, L 3 It is an unsubstituted -OCH2- (5 to 6-membered heteroaryl).

[0211] In the implementation, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted furanyl, pyrrolyl, pyridyl, pyranyl, imidazolyl, thiophene, oxazolyl, or thiazolyl group. In the embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) furanyl, pyrrolyl, pyridinyl, pyranyl, imidazolyl, thiophene, oxazolyl, or thiazolyl group. In the embodiments, L 3It is an unsubstituted furanyl, pyrrolyl, pyridinyl, pyranyl, imidazolyl, thiophene, oxazolyl, or thiazolyl group. In the embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (furanyl, pyrroleyl, pyridinyl, pyranyl, imidazolyl, thiopheneyl, oxazolyl, or thiazolyl). In embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (furanyl, pyrroleyl, pyridyl, pyranyl, imidazolyl, thiopheneyl, oxazolyl, or thiazolyl). In embodiments, L 3 It is an unsubstituted -CH2NCH2- (furanyl, pyrroleyl, pyridyl, pyranyl, imidazolyl, thiophenyl, oxazolyl, or thiazolyl). In the embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (furanyl, pyrrolyl, pyridyl, pyranyl, imidazolyl, thiophenyl, oxazolyl, or thiazolyl). In embodiments, L 3 It is substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (furanyl, pyrrolyl, pyridinyl, pyranyl, imidazolyl, thiophenyl, oxazolyl, or thiazolyl). In embodiments, L 3 It is an unsubstituted -OCH2- (furanyl, pyrrolyl, pyridinyl, pyranyl, imidazolyl, thiophenyl, oxazolyl, or thiazolyl).

[0212] In the implementation, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted furanyl group. In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) furanyl group. In the embodiment, L 3 It is an unsubstituted furanyl group. In the implementation, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (furanyl). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (furanyl). In the embodiment, L 3 It is an unsubstituted -CH2NCH2- (furanyl). In the embodiments, L 3It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (furanyl). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (furanyl). In the embodiment, L 3 It is the unsubstituted -OCH2- (furanyl).

[0213] In the implementation, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyridine group. In the embodiment, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) pyridine group. In the embodiment, L 3 It is an unsubstituted pyridine group. In the implementation, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (pyrrole). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (pyrrole). In the embodiment, L 3 It is an unsubstituted -CH2NCH2- (pyrrole). In the embodiment, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (pyridine group). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (pyridine group). In the embodiment, L 3 It is unsubstituted -OCH2- (pyridine).

[0214] In the implementation, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyridyl group. In the embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) pyridyl group. In embodiments, L 3 It is an unsubstituted pyridyl group. In the embodiments, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (pyridyl). In embodiments, L 3It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (pyridyl). In embodiments, L 3 It is an unsubstituted -CH2NCH2- (pyridyl). In the embodiments, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (pyridylene). In embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (pyridylene). In the embodiment, L 3 It is the unsubstituted -OCH2- (pyridylene).

[0215] In the implementation, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyranyl group. In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) pyranyl group. In the embodiment, L 3 It is an unsubstituted pyranyl group. In the implementation, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (pyranyl). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (pyranyl). In the embodiment, L 3 It is an unsubstituted -CH2NCH2- (pyranyl). In the embodiment, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (pyranyl group). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (pyranyl group). In the embodiment, L 3 It is the unsubstituted -OCH2- (pyranyl group).

[0216] In the implementation, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted imidazolidinyl group. In the embodiment, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) imidazole group. In the embodiment, L 3 It is an unsubstituted imidazolyl group. In the implementation method, L 3It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (imidazolium). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (imidazolium). In the embodiment, L 3 It is an unsubstituted -CH2NCH2- (imidazolium group). In the embodiments, L 3 It is either substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (imidazolyl). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (imidazolyl). In the embodiment, L 3 It is the unsubstituted -OCH2- (imidazolyl).

[0217] In the implementation, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted thiazolyl group. In the embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) imidazolate group. In the embodiment, L 3 It is an unsubstituted thiazole group. In the embodiments, L 3 It is either substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (thiazolyl). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (thiazolyl). In the embodiments, L 3 It is an unsubstituted -CH2NCH2- (thiazolyl). In the embodiments, L 3 It is either substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (thiazolyl). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (thiazolyl). In the embodiment, L 3 It is the unsubstituted -OCH2- (thiazolyl).

[0218] In the implementation, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted thiophene group. In the embodiment, L 3It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) thiophene group. In the embodiment, L 3 It is an unsubstituted thiophene group. In the implementation, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (thiophene group). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (thiophene group). In the embodiment, L 3 It is an unsubstituted -CH2NCH2- (thienyl). In the embodiment, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (thiophene group). In the embodiment, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (thiophene group). In the embodiment, L 3 It is unsubstituted -OCH2- (thienyl group).

[0219] In the implementation, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted imoxazole group. In the embodiments, L 3 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) imidazolidinyl group. In the embodiment, L 3 It is an unsubstituted imidazolidinyl group. In the implementation, L 3 It is an unsubstituted imidazolidinyl group. In the implementation, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -CH2NCH2- (oxazolyl). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -CH2NCH2- (oxazolyl). In the embodiment, L 3 It is an unsubstituted -CH2NCH2- (oxazolyl). In the embodiments, L 3 It is either substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted -OCH2- (imoxazolyl). In the embodiments, L 3 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) -OCH2- (imoxazolyl). In the embodiment, L 3 It is the unsubstituted -OCH2- (imoxazolyl).

[0220] In the implementation, R * It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl) or a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R * It is replaced by one or more substituents. In the implementation, R * It is replaced by one or more size-restricted substituents. In the implementation, R * It is replaced by one or more lower substituents.

[0221] In the implementation, R * It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl). In the embodiments, R * It is an unsubstituted heterocyclic alkyl group (e.g., a 3- to 8-membered heterocyclic alkyl group, a 3- to 6-membered heterocyclic alkyl group, or a 5- to 6-membered heterocyclic alkyl group). In the embodiments, R * It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) heteroaryl group (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiment, R * It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl or 5 to 6-membered heteroaryl).

[0222] In the implementation, R * It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 3- to 8-membered heterocyclic alkyl group. In embodiments, R * It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) 3- to 8-membered heterocyclic alkyl group. In embodiments, R * It is an unsubstituted 3- to 8-membered heterocyclic alkyl group.

[0223] In the implementation, R * It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 3- to 6-membered heterocyclic alkyl group. In embodiments, R * It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) 3- to 6-membered heterocyclic alkyl group. In embodiments, R * It is an unsubstituted 3- to 6-membered heterocyclic alkyl group.

[0224] In the implementation, R * It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic butyl, heterocyclic pentyl, or heterocyclic hexyl. In the embodiment, R * It is a heterocyclic butyl, heterocyclic pentyl, or heterocyclic hexyl group that has been substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, R * It is an unsubstituted heterocyclic butyl, heterocyclic pentyl, or heterocyclic hexyl.

[0225] In the implementation, R * It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic butyl. In the embodiment, R * It is a heterocyclic butyl group that has been substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, R * It is an unsubstituted heterocyclic butyl.

[0226] In the implementation, R * It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclopentyl group. In the embodiment, R * It is a heterocyclic pentyl group that has been substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, R * It is an unsubstituted heterocyclic pentyl group.

[0227] In the implementation, R * It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclohexyl group. In the embodiment, R * It is a heterocyclohexyl group that has been substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, R * It is an unsubstituted heterocyclohexyl group.

[0228] In the implementation, R * It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5- to 10-membered heteroaryl group. In an embodiment, R * It is a 5- to 10-membered heteroaryl group that has been substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In an embodiment, R * It is an unsubstituted 5 to 10-membered heteroaryl group.

[0229] In the implementation, R *It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5- to 9-membered heteroaryl group. In an embodiment, R * It is a 5- to 9-membered heteroaryl group that has been substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In an embodiment, R * It is an unsubstituted 5 to 9-membered heteroaryl group.

[0230] In the implementation, R * It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5- to 6-membered heteroaryl group. In an embodiment, R * It is a 5- to 6-membered heteroaryl group that has been substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In an embodiment, R * It is an unsubstituted 5- to 6-membered heteroaryl group.

[0231] In the implementation, R * It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted furanyl, pyrroleyl, pyridyl, pyranyl, imidazoleyl, or thiazolyl group. In the embodiments, R * It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) furanyl, pyrroleyl, pyridyl, pyranyl, imidazoyl, or thiazoyl group. In the embodiments, R * It is an unsubstituted furanyl, pyrroleyl, pyridyl, pyranyl, imidazolyl, or thiazolyl group.

[0232] In the implementation, R * It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted furanyl group. In the embodiment, R * It is a substituted furanyl group (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, R * It is an unsubstituted furanyl group.

[0233] In the implementation, R * It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyrrole group. In the embodiment, R * It is a substituted pyrrole group (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, R * It is an unsubstituted pyrrole group.

[0234] In the implementation, R *It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyridinyl group. In the embodiments, R * It is a substituted pyridyl group (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, R * It is an unsubstituted pyridinyl group.

[0235] In the implementation, R * It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyranyl group. In the embodiment, R * It is a substituted pyranyl group (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, R * It is an unsubstituted pyranyl group.

[0236] In the implementation, R * It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted imidazole group. In the embodiment, R * It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) imidazole group. In the embodiment, R * It is an unsubstituted imidazole group.

[0237] In the implementation, R * It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted thiazole group. In the embodiments, R * It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) thiazole group. In the embodiment, R * It is an unsubstituted thiazolyl group.

[0238] In the implementation, R 1 It is H. In the implementation method, R 1 It is a C1-C8 alkyl group.

[0239] In the implementation, R 1 It is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl. In the embodiments, R 1 It is a methyl group. In the embodiment, R... 1 It is ethyl. In the embodiments, R 1 It is propyl. In the embodiments, R 1 It is isopropyl. In the embodiment, R... 1 It is butyl. In the implementation, R 1 It is isobutyl. In the implementation, R... 1 It is tert-butyl. In the implementation, R1 It is pentyl. In the implementation, R 1 It is self-foundation.

[0240] In the implementation, R 3 It includes H, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, and -OR. 3A -NR 3A R 3B -(CH2) v OR 6 Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl or C1-C4 alkyl) or substituted or unsubstituted heteroalkyl groups (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl or 2 to 4-membered heteroalkyl).

[0241] In the implementation, R 3 It is H, -OR 3A -(CH2) v OR 6 Alkyl groups that are substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), or heteroalkyl groups that are substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0242] In the implementation, R 3 It is a substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 3 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 3 It is a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R 3 It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl or 2 to 4-membered heteroalkyl).

[0243] In the implementation, R 3It is methyl, ethyl, propyl, butyl, -CH2OH, -CH2CH2OH, -CH2N3, -CH2CH2N3, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3 or In the implementation method, R 3 It is H, methyl, ethyl, propyl, butyl, -CH2OH, -CH2CH2OH, -CH2N3, -CH2CH2N3, -CH2OCH3, -CH2OCH2CH3, or -CH2CH2OCH3. In the embodiments, R 3 It is methyl, -CH2OH or -CH2N3.

[0244] In the implementation, R 3 It is a methyl group. In the embodiment, R... 3 It is ethyl. In the embodiments, R 3 It is propyl. In the embodiments, R 3 It is butyl. In the implementation, R 3 It is -CH2OH. In the embodiments, R 3 It is -CH2CH2OH. In the embodiment, R 3 It is -CH2N3. In the implementation, R 3 It is -CH2CH2N3. In the implementation, R 3 It is -CH2OCH3. In the implementation, R 3 It is -CH2OCH2CH3. In the implementation, R 3 It is -CH2CH2OCH3. In the implementation, R 3 It is -CH2CH2OCH2CH3. In the implementation, R 3 It is -OH. In the implementation, R 3 It is H. In the implementation method, R 3 yes .

[0245] In the implementation, R 3 It is methyl, -CH2OH, Or -CH2N3. In the implementation, R 3 It is -CH2N3.

[0246] In this implementation, v is an integer from 1 to 24. In this implementation, v is 1. In this implementation, v is 2. In this implementation, v is 3. In this implementation, v is 4. In this implementation, v is 5. In this implementation, v is 6. In this implementation, v is 7. In this implementation, v is 8. In this implementation, v is 9. In this implementation, v is 10. In this implementation, v is 11. In this implementation, v is 12. In this implementation, v is 13. In this implementation, v is 14. In this implementation, v is 15. In this implementation, v is 16. In this implementation, v is 17. In this implementation, v is 18. In this implementation, v is 19. In this implementation, v is 20. In this implementation, v is 21. In this implementation, v is 22. In this implementation, v is 23. In this implementation, v is 24.

[0247] In the implementation, R 4 It is H, halogen, -OR 4A -NR 4A R 4B Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl or C1-C4 alkyl) or substituted or unsubstituted heteroalkyl groups (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl or 2 to 4-membered heteroalkyl).

[0248] In the implementation, R 4 It is H, -OR 4A Substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), or substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl).

[0249] In the implementation, R 4 It is H or a substituted or unsubstituted alkyl group. In the embodiments, R 4 It is H or a substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) or an unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0250] In the implementation, R 4 It is a substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 4It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 4 It is a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In embodiments, R 4 It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl or 2 to 4-membered heteroalkyl).

[0251] In the implementation, R 4 It is H, -OH, methyl, ethyl, propyl, or butyl. In the embodiments, R 4 It is H or -OH. In the embodiment, R 4 It is H or methyl. In the embodiments, R 4 It is a methyl group. In the embodiment, R... 4 It is ethyl. In the embodiments, R 4 It is propyl. In the embodiments, R 4 It is butyl. In the implementation, R 4 It is H. In the implementation method, R 4 It is -OH.

[0252] In the implementation, each R 3A R 3B R 4A and R 4B It is independently H or a substituted or unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0253] In the implementation, each R 3A R 3B R 4A and R 4B Independently, it is H or a substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) or an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, each R 3A R 3B R 4A and R 4B H is independent. In the implementation, each R 3A R 3B R 4A and R 4B Independently, it is a substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, each R 3AR 3B R 4A and R 4B It is independently an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0254] In the implementation, each R 3A R 3B R 4A and R 4B Independently, it is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, or pentyl. In embodiments, each R 3A R 3B R 4A and R 4B H is independent. In the implementation, each R 3A R 3B R 4A and R 4B Independently, it is methyl. In the embodiments, each R 3A R 3B R 4A and R 4B Independently, it is ethyl. In the embodiments, each R 3A R 3B R 4A and R 4B Independently, it is propyl. In the implementation, each R... 3A R 3B R 4A and R 4B Independently, it is isopropyl. In the implementation, each R... 3A R 3B R 4A and R 4B Independently, it is butyl. In the implementation, each R 3A R 3B R 4A and R 4B Independently, it is isobutyl. In the implementation, each R... 3A R 3B R 4A and R 4B It is independently tert-butyl. In the implementation, each R 3A R 3B R 4A and R 4B It is pentyl on its own.

[0255] In the implementation, R 6It is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO(CH2CH2O) w CH2CH2M、-CONH(CH2CH2O) w CH2CH2M, , charged groups or sugar derivatives, where w is an integer from 1 to 24; M is -NH2, -OH, -COOH, or -OCH3; R 10 It is -OH, -OCH3, or -COOH.

[0256] In the implementation, R 6 It is H or a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl), a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C4 alkyl). 10 Aryl, C 10 Aryl or phenyl), substituted (e.g., substituted by at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl) or sugar derivatives.

[0257] In the implementation, R 6 It is H or a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) heterocyclic alkyl (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0258] In the implementation, R 6 Is it H or In the implementation method, R 6 It is H.

[0259] In this implementation, w is an integer from 1 to 24. In this implementation, w is 1. In this implementation, w is 2. In this implementation, w is 3. In this implementation, w is 4. In this implementation, w is 5. In this implementation, w is 6. In this implementation, w is 7. In this implementation, w is 8. In this implementation, w is 9. In this implementation, w is 10. In this implementation, w is 11. In this implementation, w is 12. In this implementation, w is 13. In this implementation, w is 14. In this implementation, w is 15. In this implementation, w is 16. In this implementation, w is 17. In this implementation, w is 18. In this implementation, w is 19. In this implementation, w is 20. In this implementation, w is 21. In this implementation, w is 22. In this implementation, w is 23. In this implementation, w is 24.

[0260] In this embodiment, M is -NH2, -OH, -COOH, or -OCH3. In this embodiment, M is -NH2. In this embodiment, M is -OH. In this embodiment, M is -COOH. In this embodiment, M is -OCH3.

[0261] In the implementation, R 6 yes , or In the implementation method, R 6 yes In the implementation method, R 6 yes In the implementation method, R 6 yes .

[0262] In the implementation, R 6 It is a sugar derivative. In the embodiment, R... 6 yes In the implementation method, R 6 yes In the implementation method, R 6 yes .

[0263] In the implementation method, Z 1 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, Z 1 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, Z 1It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, Z 1 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl). In the embodiments, Z 1 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) heterocyclic alkyl group (e.g., a 3- to 8-membered heterocyclic alkyl group, a 3- to 6-membered heterocyclic alkyl group, or a 5- to 6-membered heterocyclic alkyl group). In the embodiments, Z 1 It is an unsubstituted heterocyclic alkyl group (e.g., a 3- to 8-membered heterocyclic alkyl group, a 3- to 6-membered heterocyclic alkyl group, or a 5- to 6-membered heterocyclic alkyl group). In the embodiments, Z 1 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or an unsubstituted aryl group (e.g., C6-C). 10 Aryl, C 10 Aryl or phenyl). In the embodiments, Z 1 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) aryl group (e.g., C6-C). 10 Aryl, C 10 Aryl or phenyl). In the embodiments, Z 1 It is an unsubstituted aryl group (e.g., C6-C). 10 Aryl, C 10 Aryl or phenyl). In the embodiments, Z 1 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiment, Z 1 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) heteroaryl group (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). In an embodiment, Z 1 It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl or 5 to 6-membered heteroaryl).

[0264] In the implementation method, Z 1 yes or Each Q is independently a halogen, methyl, ethyl, or propyl; and q is an integer from 1 to 5.

[0265] In the implementation method, Z 1 yes In the implementation method, Z 1 yes , wherein Q and q are included in the implementation as described herein.

[0266] In the implementation method, Z 2 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene). In the embodiments, Z 2 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkylene (e.g., 3- to 8-membered heterocyclic alkylene, 3- to 6-membered heterocyclic alkylene, or 5- to 6-membered heterocyclic alkylene). In embodiments, Z 2 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or an unsubstituted arylene (e.g., C6-C) group. 10 Alpha-aryl, C 10 (arylene or phenylene). In the embodiments, Z 2 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or an unsubstituted heteroaryl (e.g., 5 to 10 nucleotide heteroaryl, 5 to 9 nucleotide heteroaryl, or 5 to 6 nucleotide heteroaryl).

[0267] In the implementation method, Z 2 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or an unsubstituted arylene (e.g., C6-C) group. 10 Alpha-aryl, C 10 (arylene or phenylene). In the embodiments, Z 2 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) arylene (e.g., C6-C) 10 Alpha-aryl, C 10 (arylene or phenylene). In the embodiments, Z 2 It is an unsubstituted aryl group (e.g., C6-C) 10 Alpha-aryl, C 10 (arylene or phenylene).

[0268] In the implementation method, Z 2 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl group (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiment, Z 2 It is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) heteroaryl group (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiment, Z2 It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0269] In the implementation method, Z 2 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5- to 6-membered heteroaryl group. In the embodiment, Z 2 It is a 5- to 6-membered heteroaryl group that has been substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent). In an embodiment, Z 2 It is an unsubstituted 5- to 6-membered heteroaryl group.

[0270] In the implementation method, Z 2 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted phenylene. In the embodiments, Z 2 It is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) phenylene. In the embodiment, Z 2 It is an unsubstituted phenylene.

[0271] In the implementation method, Z 2 It is an unsubstituted aryl group. In the implementation, Z 2 yes .

[0272] In this implementation, V is N. In this implementation, V is O. In this implementation, V is C.

[0273] In the implementation, -Z 2 -V- is or Each G is independently Cl, Br, I, F, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OH or -NH2; and p is an integer from 0 to 4.

[0274] In the implementation, -Z 2 -V- is , or In the implementation method, -Z 2 -V- is In the implementation method, -Z 2 -V- is In the implementation method, -Z 2 -V- is .

[0275] In an implementation, this document provides an ADC of formula (IA) or formula (IIA): Or its pharmaceutically acceptable salt, wherein: Ring A is formed by the interaction of heteroatom Y and L. 2 Connected substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; Ring A' is a substituted or unsubstituted heterocyclic alkyl or substituted or unsubstituted heteroaryl group connected to D' by heteroatom Y; Each Y is independently N, P, or S; and L 1 L 2 Ab, m, D and D' are each as defined herein (including implementations).

[0276] In embodiments, ring A is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl) or a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, ring A is substituted by one or more substituents. In embodiments, ring A is substituted by one or more size-restricted substituents. In embodiments, ring A is substituted by one or more lower substituents. Ring A is connected to L via heteroatom Y. 2 connect.

[0277] In embodiments, ring A' is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl) or a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, ring A' is substituted by one or more substituents. In embodiments, ring A' is substituted by one or more size-restricted substituents. In embodiments, ring A' is substituted by one or more lower substituents. Ring A' is connected to D' via a heteroatom Y. In embodiments, each Y is N.

[0278] In embodiments, ring A is substituted with one or more 3- to 8-membered heterocyclic alkyl groups (e.g., substituted with substituents, size-restricted substituents, or lower substituents), wherein ring A is substituted with L via heteroatom Y. 2Connection. In an embodiment, ring A' is substituted with one or more 3- to 8-membered heterocyclic alkyl groups (e.g., substituted with substituents, size-restricted substituents, or lower substituents), wherein ring A' is connected to D' via heteroatom Y. In an embodiment, each Y is N.

[0279] In embodiments, ring A is substituted with one or more 5- to 6-membered heterocyclic alkyl groups (e.g., substituted with substituents, size-restricted substituents, or lower substituents), wherein ring A is substituted with L via heteroatom Y. 2 Connection. In an embodiment, ring A' is substituted with one or more 5- to 6-membered heterocyclic alkyl groups (e.g., substituted with substituents, size-restricted substituents, or lower substituents), wherein ring A' is connected to D' via heteroatom Y. In an embodiment, each Y is N.

[0280] In its implementation, this document provides an ADC of formula (IB) or formula (IIB): Or its pharmaceutically acceptable salt, wherein: Each R 7 Independently, it is H, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 7A -NR 7A R 7B -COOR 7A -CONR 7A R 7B -NO2, -SR 7A -SO n7 R 7A -SO v7 NR 7A R 7B -PO(OH)2, -PO m7 R 7A PO r7 NR 7A R 7B Substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted cycloalkyl groups, or substituted or unsubstituted heterocycloalkyl groups; Any two R atoms located on adjacent carbon atoms 7 Substituents may optionally be linked to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 7A and R7B Independently, it is H, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 7A and R 7B Substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; X is -Cl, -Br, -I, or -F; Each n7 is an independent integer from 0 to 4; Each v7 is independently 1 or 2; Each m7 is an independent integer from 0 to 3; Each r7 is independently 1 or 2; and Y, m, D, D', L 1 L 2 Ab and Ab are each as defined herein (including implementations).

[0281] In its implementation, this document provides an ADC of formula (IC) or formula (IIC): Or a pharmaceutically acceptable salt thereof; wherein R 7 D, D', m, Y, L 1 L 2 Ab and Ab are each as defined herein (including implementations).

[0282] In its implementation, this document provides an ADC of formula (ID) or formula (IID): Or a pharmaceutically acceptable salt thereof; wherein R 7 D, D', m, Y, L 1 L 2 Ab and Ab are each as defined herein (including implementations).

[0283] In this implementation, an ADC of formula (ID1) or formula (IID1) is provided: Or a pharmaceutically acceptable salt thereof; wherein R 7 D, D', m, Y, L 1 L 2 Ab and Ab are each as defined herein (including implementations).

[0284] In its implementation, this document provides an ADC of formula (IE) or formula (IIE): Or a pharmaceutically acceptable salt thereof; wherein R 7 D, D', m, Y, L 1 L 2 Ab and Ab are each as defined herein (including implementations).

[0285] In its implementation, this document provides an ADC of formula (IF) or formula (IIF): Or a pharmaceutically acceptable salt thereof; wherein R 7 D, D', m, Y, L 1 L 2 Ab and Ab are each as defined herein (including implementations).

[0286] In its implementation, this document provides an ADC of formula (IG) or formula (IH): Or its pharmaceutically acceptable salt, wherein: Ring W is a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted arylene; ring C is a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, or a substituted or unsubstituted heteroarylene; and wherein D, m, L 1 L 2 Ab and Ab are each as defined herein (including implementations).

[0287] In one embodiment, -NH- and -D are attached to different carbon atoms on ring W. In another embodiment, -NH- and -D are attached to the same carbon atom on ring W.

[0288] In embodiments, ring W is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C3-C8 cycloalkylene, C3-C6 cycloalkylene, or C5-C6 cycloalkylene) or a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted arylene (e.g., C5-C6 cycloalkylene). 10(Arylene, C5-C8 arylene, or C5-C6 arylene). In embodiments, ring W is substituted with one or more substituents. In embodiments, ring W is substituted with one or more size-restricted substituents. In embodiments, ring W is substituted with one or more lower substituents.

[0289] In embodiments, ring W is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted C3-C8 cycloalkylene group. In embodiments, ring W is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) C3-C8 cycloalkylene group. In embodiments, ring W is an unsubstituted C3-C8 cycloalkylene group.

[0290] In the embodiments, ring W is substituted with one or more C3-C8 cycloalkyl substituents (e.g., substituted with substituents, size-restricted substituents, or lower substituents).

[0291] In one embodiment, ring W is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cyclobutylene. In another embodiment, ring W is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cyclopentylene. In yet another embodiment, ring W is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cyclohexylene.

[0292] In one embodiment, ring W is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted C5-C6 arylene. In another embodiment, ring W is an unsubstituted C5-C6 arylene. In yet another embodiment, ring W is substituted by one or more C5-C6 arylenes (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent).

[0293] In embodiments, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl) or a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, ring C is substituted with one or more substituents. In embodiments, ring C is substituted with one or more size-restricted substituents. In embodiments, ring C is substituted with one or more lower substituents.

[0294] In embodiments, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclic alkyl (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl) or a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In embodiments, ring C is substituted with one or more substituents. In embodiments, ring C is substituted with one or more size-restricted substituents. In embodiments, ring C is substituted with one or more lower substituents.

[0295] In one embodiment, ring C is substituted with one or more 5- to 9-membered heteroaryl groups (e.g., substituted with substituents, size-restricted substituents, or lower substituents). In another embodiment, ring C is an unsubstituted 5- to 9-membered heteroaryl group.

[0296] In one embodiment, ring C is substituted with one or more 5- to 6-membered heteroaryl groups (e.g., substituted with substituents, size-restricted substituents, or lower substituents). In another embodiment, ring C is an unsubstituted 5- to 6-membered heteroaryl group.

[0297] In one embodiment, ring C is substituted with one or more 3- to 8-membered heterocyclic alkyl groups (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent). In another embodiment, ring C is substituted with one or more 5- to 6-membered heterocyclic alkyl groups (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent).

[0298] In embodiments, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted furanyl, pyrroloyl, pyridyl, pyranyl, imidazoleyl, thiophenyl, oxazolyl, or thiazolyl group. In embodiments, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) furanyl, pyrroloyl, pyridyl, pyranyl, imidazoleyl, thiophenyl, oxazolyl, or thiazolyl group. In embodiments, ring C is an unsubstituted furanyl, pyrroloyl, pyridyl, pyranyl, imidazoleyl, thiophenyl, oxazolyl, or thiazolyl group.

[0299] In one embodiment, ring C is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted furanyl group. In another embodiment, ring C is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) furanyl group. In yet another embodiment, ring C is an unsubstituted furanyl group.

[0300] In one embodiment, ring C is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyrrole group. In another embodiment, ring C is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) pyrrole group. In yet another embodiment, ring C is an unsubstituted pyrrole group.

[0301] In one embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyridinyl group. In another embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) pyridinyl group. In yet another embodiment, ring C is an unsubstituted pyridinyl group.

[0302] In one embodiment, ring C is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyranyl group. In another embodiment, ring C is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) pyranyl group. In yet another embodiment, ring C is an unsubstituted pyranyl group.

[0303] In one embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted imidazole group. In another embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) imidazole group. In yet another embodiment, ring C is an unsubstituted imidazole group.

[0304] In one embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted thiazolyl group. In another embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) thiazolyl group. In yet another embodiment, ring C is an unsubstituted thiazolyl group.

[0305] In one embodiment, ring C is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted thiophene group. In another embodiment, ring C is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) thiophene group. In yet another embodiment, ring C is an unsubstituted thiophene group.

[0306] In one embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted oxazolyl group. In another embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) oxazolyl group. In yet another embodiment, ring C is an unsubstituted oxazolyl group.

[0307] In embodiments, the cyclic C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl) or a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl (e.g., C5-C) group. 10 Aryl, C5-C8 aryl, or C5-C6 aryl). In embodiments, ring C is substituted with one or more substituents. In embodiments, ring C is substituted with one or more size-restricted substituents. In embodiments, ring C is substituted with one or more lower substituents.

[0308] In some embodiments, the ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted C3-C8 cycloalkyl group. In some embodiments, the ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) C3-C8 cycloalkyl group. In some embodiments, the ring C is unsubstituted C3-C8 cycloalkyl. In some embodiments, the ring C is substituted by one or more C3-C8 cycloalkyl groups (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent).

[0309] In one embodiment, ring C is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cyclobutyl. In another embodiment, ring C is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cyclopentyl. In yet another embodiment, ring C is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cyclohexyl.

[0310] In some embodiments, ring C is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted C5-C6 aryl group. In some embodiments, ring C is a substituted (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent) C5-C6 aryl group. In some embodiments, ring C is an unsubstituted C5-C6 aryl group. In some embodiments, ring C is substituted by one or more C5-C6 aryl groups (e.g., substituted by a substituent, a size-restricted substituent, or a lower substituent).

[0311] In this implementation, an ADC of formula (IK) is provided: Or its pharmaceutically acceptable salt, wherein: Z is S, N, or O; and R is... 7 D, m, L 1 L 2Ab and Ab are each as defined herein (including implementations).

[0312] In this implementation, Z is N. In this implementation, Z is O. In this implementation, Z is S.

[0313] In implementation, this document provides an ADC of formula (IL) or formula (IM): Or a pharmaceutically acceptable salt thereof; wherein R 7 D, Z, m, L 1 L 2 Ab and Ab are each as defined herein (including implementations).

[0314] In implementation, this document provides an ADC of formula (IN) or formula (IO): Or a pharmaceutically acceptable salt thereof; wherein R 7 D, Z, m, L 1 L 2 Ab and Ab are each as defined herein (including implementations).

[0315] In its implementation, this document provides an ADC of formula (IP) or formula (IQ): Or a pharmaceutically acceptable salt thereof; wherein R 7 D, Z, m, L 1 L 2 Ab and Ab are each as defined herein (including implementations).

[0316] In this implementation, an ADC with the following structure is provided: , , , , , , or Or its pharmaceutically acceptable salt.

[0317] In this implementation, an ADC with the following structure is provided: Or its pharmaceutically acceptable salt.

[0318] In this implementation, an ADC with the following structure is provided: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or Its pharmaceutically acceptable salt.

[0319] Drug loading The drug loading is represented by m, which is the average number of drug portions (i.e., D, D', or D'') of each monoclonal antibody in the antibody-drug conjugate (ADC) of formula (I), (II), or (III) and its variants. The drug loading can range from 1 to 20 drug portions per antibody. The ADC of formula (I), (II), or (III) and any embodiments, variants, or aspects thereof comprise an array of antibodies conjugated to a range of 1 to 20 drug portions. In the preparation of ADCs from conjugation reactions, the average number of drug portions per antibody can be characterized by conventional methods such as mass spectrometry, ELISA assays, and HPLC. The quantitative distribution of the ADC with respect to m can also be determined. In some cases, homogeneous ADCs with other drug loadings, where m is a specific value, can be separated, purified, and characterized by methods such as HIC or reversed-phase HPLC or electrophoresis. In embodiments, the average number of drug portions (i.e., D, D', or D'') of each monoclonal antibody can range from 1 to 20 drug portions per antibody. In embodiments, the average number of drug portions (i.e., D, D', or D'') of each monoclonal antibody can range from 1 to 8 drug portions per antibody. In embodiments, the monoclonal antibody is an anti-CD25 antibody, an anti-B7-H3 antibody, an anti-ROR1 antibody, an anti-Trop-2 antibody, or an anti-BCMA antibody. In embodiments, the average number of drug portions (i.e., D, D', or D'') of each anti-CD25 antibody can range from 1 to 8 drug portions per antibody. In embodiments, the average number of drug portions (i.e., D, D', or D'') of each anti-B7-H3 antibody can range from 1 to 8 drug portions per antibody. In embodiments, the average number of drug portions (i.e., D, D', or D'') of each anti-ROR1 antibody can range from 1 to 8 drug portions per antibody. In embodiments, the average number of drug portions (i.e., D, D', or D'') of each anti-Trop-2 antibody can range from 1 to 8 drug portions per antibody. In implementation, the average number of drug fractions per anti-BCMA antibody (i.e., D, D', or D'') can range from 1 to 8 drug fractions per antibody.

[0320] For some ADCs, m may be limited by the number of linker sites on the antibody. For example, in some exemplary embodiments as described herein, when the linker is a cysteine ​​thiol, the antibody may have only one or a few cysteine ​​thiol groups, or may have only one or a few sufficiently reactive thiol groups that can be linked by its linker. In embodiments, the average drug loading of the ADC is in the range of 1 to about 8 or about 3 to about 8. In embodiments, L 1 It can form a covalent bond with the thiol group of free cysteine ​​in IgG antibodies.

[0321] In embodiments, a coupling method for derivatizing peptides with a payload can be achieved by forming an amide bond with the lysine side chain. Due to the presence of numerous lysine side chain amines with similar reactivity, this coupling strategy can produce very complex heterogeneous mixtures. The compositions and methods provided herein provide coupling via lysine, wherein, in some embodiments, enhanced lysine selectivity can produce mixtures with lower heterogeneity. In embodiments, the average drug loading of the ADC is in the range of 1 to about 20, 1 to about 8, or about 3 to about 8. In embodiments, L... 1 It can form a covalent bond with the amine group of lysine in IgG antibodies.

[0322] In this embodiment, during the coupling reaction, the amount of drug moiety conjugated to the antibody is less than the theoretical maximum. Antibodies typically do not include many free and reactive cysteine ​​thiols that can be linked to the drug moiety; in fact, most cysteine ​​thiols in antibodies exist as disulfide bridges. In this embodiment, the antibody can be reduced under partial or complete reducing conditions with reducing agents such as dithiothreitol (DTT) or tricarboxyethylphosphine (TCEP) to generate reactive cysteine ​​thiols. In this embodiment, the antibody is subjected to degrading conditions to reveal reactive nucleophilic groups such as lysine or cysteine.

[0323] The loading of an ADC (drug / antibody ratio or "DAR") can be controlled in various ways, for example, by: (i) limiting the molar excess of the drug-linker intermediate or linker reagent relative to the antibody; (ii) limiting the coupling reaction time or temperature; and (iii) using partial or limiting reduction conditions for cysteine ​​thiol modification. DAR can also be controlled by the reactivity of the groups reacting with the antibody or the reactivity of the antibody's groups.

[0324] It should be understood that when more than one nucleophilic group reacts with a drug-linker intermediate or linker reagent, the resulting product is a mixture of ADC compounds containing one or more drug moieties linked to the antibody. The average number of drugs per antibody can be calculated using HIC, RP, UV, or LC-MS. Individual ADC molecules can be identified in mixtures by mass spectrometry and separated by HPLC, such as hydrophobic interaction chromatography (see, for example, McDonald et al. (2006), *Protein Engineering Design & Selection*, 19(7):299-307; Hamblett et al. (2004), *Clin. Cancer Res.*, 10:7063-7070; Hamblett, KJ et al., “Effect of drug loading on the pharmacology, pharmacokinetics, and toxicity of an anti-CD30 antibody-drug conjugate”, Abstract No. 624, *American Association for Cancer Research*, 2004 Annual Meeting, March 27-31, 2004, *Proceedings of the American Association for Cancer Research*). American Association for Cancer Research (AACR), Vol. 45, March 2004; Alley, SC et al., “Controlling the location of drug attachment in antibody-drug conjugates”, Abstract No. 627, AACR Annual Meeting, March 27-31, 2004, AACR Proceedings, Vol. 45, March 2004. In embodiments, homogeneous ADCs with a single loading value can be separated from the conjugation mixture by electrophoresis or chromatography.

[0325] i. Exemplary antibodies and antibody sequences Anti-CD25 antibody In embodiments, the ADC comprises an antibody that binds to CD25. It has been reported, for example, in leukemia and lymphoma, that CD25 is upregulated independently of baseline levels of CD25 expression. In embodiments, the ADC compounds described herein comprise an anti-CD25 antibody. In embodiments, the ADC compounds described herein comprise an anti-CD25 antibody comprising one or more mutations in the Fc region, wherein the mutation may comprise mutations L234A and / or L235A (a substitution of a residue at position 234 in the EU index shown in Kabat and / or a substitution of a residue at position 235 in the EU index shown in Kabat). In embodiments, the ADC compounds described herein comprise an anti-CD25 antibody comprising a mutation in the Fc region, wherein the mutation is L234A (LA mutation). In embodiments, the ADC compounds described herein comprise an anti-CD25 antibody comprising a mutation in the Fc region, wherein the mutation is L235A (LA mutation). In embodiments, the ADC compounds described herein comprise an anti-CD25 antibody comprising a double mutation in the Fc region, wherein the mutations are L234A and L235A (LALA mutation). In this implementation, the anti-CD25 antibody (MAA-V clone) includes mutants L234A and L235A (MAA-V LALA) in the Fc region.

[0326] In some embodiments, the anti-CD25 antibody provided herein includes a cysteine ​​residue. In some embodiments, the anti-CD25 antibody binds to the drug via a linker through the sulfur of the cysteine ​​residue. In some embodiments, the anti-CD25 antibody binds to the drug via a linker through the sulfur of two cysteine ​​residues.

[0327] In some embodiments, the anti-CD25 antibody provided herein comprises lysine. In some embodiments, the anti-CD25 antibody binds to the drug via a linker through an amine of one or two lysine residues.

[0328] In an embodiment, the ADC provided herein comprises an anti-CD25 antibody, the antibody comprising a light chain variable region and a heavy chain variable region, wherein the light chain variable region comprises a light chain complementarity-determining region 1 (CDR1), a light chain CDR2, and a light chain CDR3, and the heavy chain variable region comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3.

[0329] In embodiments, the ADC provided herein comprises an anti-CD25 antibody (e.g., MAA-V or MAA-V LALA), said antibody comprising at least one, two, three, four, five or six CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VL CDR2 comprising the sequence of SEQ ID NO: 2; (c) VLCDR3 comprising the sequence of SEQ ID NO: 3; (d) VH CDR1 comprising the sequence of SEQ ID NO: 4; (e) VH CDR2 comprising the sequence of SEQ ID NO: 5; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 6. In an embodiment, the ADC comprises an anti-CD25 antibody, the antibody comprising at least one CDR selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VL CDR2 comprising the sequence of SEQ ID NO: 2; (c) VL CDR3 comprising the sequence of SEQ ID NO: 3; (d) VHCDR1 comprising the sequence of SEQ ID NO: 4; (e) VH CDR2 comprising the sequence of SEQ ID NO: 5; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 6. In an embodiment, the ADC comprises an anti-CD25 antibody, the antibody comprising at least two CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VL CDR2 comprising the sequence of SEQ ID NO: 2; (c) VL CDR3 comprising the sequence of SEQ ID NO: 3; (d) VH CDR1 comprising the sequence of SEQ ID NO: 4; (e) VHCDR2 comprising the sequence of SEQ ID NO: 5; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 6. In an embodiment, the ADC comprises an anti-CD25 antibody, the antibody comprising at least three CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VL CDR2 comprising the sequence of SEQ ID NO: 2; (c) VL CDR3 comprising the sequence of SEQ ID NO: 3; (d) VH CDR1 comprising the sequence of SEQ ID NO: 4; (e) VH CDR2 comprising the sequence of SEQ ID NO: 5; and (f) VHCDR3 comprising the sequence of SEQ ID NO: 6.In an embodiment, the ADC comprises an anti-CD25 antibody, the antibody comprising at least four CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VL CDR2 comprising the sequence of SEQ ID NO: 2; (c) VL CDR3 comprising the sequence of SEQ ID NO: 3; (d) VH CDR1 comprising the sequence of SEQ ID NO: 4; (e) VH CDR2 comprising the sequence of SEQ ID NO: 5; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 6. In an embodiment, the ADC comprises an anti-CD25 antibody, the antibody comprising at least five CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VL CDR2 comprising the sequence of SEQ ID NO: 2; (c) VL CDR3 comprising the sequence of SEQ ID NO: 3; (d) VH CDR1 comprising the sequence of SEQ ID NO: 4; (e) VH CDR2 comprising the sequence of SEQ ID NO: 5; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 6. In an embodiment, the ADC comprises an anti-CD25 antibody, the antibody comprising at least six CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VL CDR2 comprising the sequence of SEQ ID NO: 2; (c) VL CDR3 comprising the sequence of SEQ ID NO: 3; (d) VH CDR1 comprising the sequence of SEQ ID NO: 4; (e) VH CDR2 comprising the sequence of SEQ ID NO: 5; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 6.

[0330] In an embodiment, the ADC comprises an anti-CD25 antibody (e.g., MAA-V or MAA-V LALA), the antibody comprising a CDR selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VL CDR2 comprising the sequence of SEQ ID NO: 2; (c) VL CDR3 comprising the sequence of SEQ ID NO: 3; (d) VH CDR1 comprising the sequence of SEQ ID NO: 4; (e) VH CDR2 comprising the sequence of SEQ ID NO: 5; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 6. In an embodiment, the ADC comprises an anti-CD25 antibody, the antibody comprising two CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VL CDR2 comprising the sequence of SEQ ID NO: 2; (c) VLCDR3 comprising the sequence of SEQ ID NO: 3; (d) VH CDR1 comprising the sequence of SEQ ID NO: 4; (e) VH CDR2 comprising the sequence of SEQ ID NO: 5; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 6. In an embodiment, the ADC comprises an anti-CD25 antibody, the antibody comprising three CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VL CDR2 comprising the sequence of SEQ ID NO: 2; (c) VL CDR3 comprising the sequence of SEQ ID NO: 3; (d) VHCDR1 comprising the sequence of SEQ ID NO: 4; (e) VH CDR2 comprising the sequence of SEQ ID NO: 5; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 6. In an embodiment, the ADC comprises an anti-CD25 antibody, the antibody comprising four CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VL CDR2 comprising the sequence of SEQ ID NO: 2; (c) VL CDR3 comprising the sequence of SEQ ID NO: 3; (d) VH CDR1 comprising the sequence of SEQ ID NO: 4; (e) VH CDR2 comprising the sequence of SEQ ID NO: 5; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 6.In an embodiment, the ADC comprises an anti-CD25 antibody, the antibody comprising five CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VL CDR2 comprising the sequence of SEQ ID NO: 2; (c) VL CDR3 comprising the sequence of SEQ ID NO: 3; (d) VHCDR1 comprising the sequence of SEQ ID NO: 4; (e) VH CDR2 comprising the sequence of SEQ ID NO: 5; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 6. In an embodiment, the ADC comprises an anti-CD25 antibody, the antibody comprising a CDR selected from the following six: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VL CDR2 comprising the sequence of SEQ ID NO: 2; (c) VL CDR3 comprising the sequence of SEQ ID NO: 3; (d) VH CDR1 comprising the sequence of SEQ ID NO: 4; (e) VH CDR2 comprising the sequence of SEQ ID NO: 5; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 6.

[0331] In one embodiment, the anti-CD25 antibody (e.g., MAA-V or MAA-V LALA) includes VL CDR1 containing the sequence of SEQ ID NO:1, VL CDR2 containing the sequence of SEQ ID NO:2, VL CDR3 containing the sequence of SEQ ID NO:3, VH CDR1 containing the sequence of SEQ ID NO:4, VH CDR2 containing the sequence of SEQ ID NO:5, and VH CDR3 containing the sequence of SEQ ID NO:6. In another embodiment, the anti-CD25 antibody includes VL CDR1 containing the sequence of SEQ ID NO:1. In yet another embodiment, the anti-CD25 antibody includes VL CDR2 containing the sequence of SEQ ID NO:2. In yet another embodiment, the anti-CD25 antibody includes VL CDR3 containing the sequence of SEQ ID NO:3. In yet another embodiment, the anti-CD25 antibody includes VH CDR1 containing the sequence of SEQ ID NO:4. In yet another embodiment, the anti-CD25 antibody includes VH CDR2 containing the sequence of SEQ ID NO:5. In one embodiment, the anti-CD25 antibody includes VH CDR3 containing the sequence SEQ ID NO: 6.

[0332] In an embodiment, the ADC comprises an anti-CD25 antibody (e.g., MAA-V or MAA-V LALA), said antibody comprising a light chain CDR1 having the amino acid sequence of SEQ ID NO: 1, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 2, a light chain CDR3 having the amino acid sequence of SEQ ID NO: 3, a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 5, and a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 6.

[0333] In one embodiment, the anti-CD25 antibody (e.g., MAA-V or MAA-V LALA) comprises a VL having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 10. In another embodiment, the anti-CD25 antibody (e.g., MAA-V or MAA-V LALA) comprises a VL having the sequence of SEQ ID NO: 10. In another embodiment, although the VL sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 10 includes substitutions (e.g., conserved substitutions), insertions, or deletions relative to the reference sequence, the anti-CD25 antibody including said sequence retains the ability to bind to CD25. In another embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 10. In another embodiment, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 10. In another embodiment, the substitution, insertion, or deletion occurs in regions outside the CDR (i.e., in the FR). In one embodiment, the anti-CD25 antibody comprises the VL sequence of SEQ ID NO: 10 and includes post-translational modifications of the sequence.

[0334] In one embodiment, the anti-CD25 antibody (e.g., MAA-V or MAA-V LALA) comprises a VH having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 11. In another embodiment, the anti-CD25 antibody (e.g., MAA-V or MAA-V LALA) comprises a VH having the sequence of SEQ ID NO: 11. In another embodiment, although the VH sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 11 includes substitutions (e.g., conserved substitutions), insertions, or deletions relative to the reference sequence, the anti-CD25 antibody including said sequence retains its ability to bind to CD25. In another embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 11. In another embodiment, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 11. In another embodiment, the substitution, insertion, or deletion occurs in regions outside the CDR (i.e., in the FR). In one embodiment, the anti-CD25 antibody includes the VH sequence of SEQ ID NO: 11 and includes post-translational modifications of the sequence.

[0335] In this embodiment, the anti-CD25 antibody is an IgG antibody. In this embodiment, the anti-CD25 antibody is an IgG1, IgG2, IgG3, or IgG4 antibody. In this embodiment, the anti-CD25 antibody is an IgG1 or IgG4 antibody. In this embodiment, the anti-CD25 antibody is an IgG1 antibody.

[0336] In one embodiment, the anti-CD25 antibody binds to human CD25. In another embodiment, human CD25 has the amino acid sequence of SEQ ID NO:70.

[0337] In any of the embodiments described above, the anti-CD25 antibody is humanized. In embodiments, the anti-CD25 antibody includes a CDR as described in any of the embodiments described above, and further includes a human receptor framework, such as a human immunoglobulin framework or a human common framework. In embodiments, the humanized anti-CD25 antibody (e.g., MAA-V or MAA-V LALA) includes: (a) VL CDR1 comprising the sequence of SEQ ID NO: 1; (b) VLCDR2 comprising the sequence of SEQ ID NO: 2; (c) VL CDR3 comprising the sequence of SEQ ID NO: 3; (d) VH CDR1 comprising the sequence of SEQ ID NO: 4; (e) VH CDR2 comprising the sequence of SEQ ID NO: 5; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 6.

[0338] In one embodiment, the anti-CD25 antibody is a monoclonal antibody, including chimeric antibodies, humanized antibodies, or human antibodies. In one embodiment, the anti-CD25 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, a bifunctional antibody, or an F(ab')2 fragment. In another embodiment, the antibody is a substantially full-length antibody, such as an IgG1 antibody, or other antibody classes or isotypes as defined herein.

[0339] Anti-B7-H3 antibody In embodiments, the ADC comprises an antibody that binds to B7-H3. It has been reported, for example, in lung cancer, that B7-H3 is upregulated independently of baseline levels of B7-H3 expression. In embodiments, the ADC compounds described herein comprise an anti-B7-H3 antibody. In embodiments, the B7-H3 compounds described herein comprise an anti-B7-H3 antibody containing one or more mutations in the Fc region, wherein the mutation may include mutations L234A and / or L235A (a substitution of a residue at position 234 in the EU index shown in Kabat and / or a substitution of a residue at position 235 in the EU index shown in Kabat). In embodiments, the ADC compounds described herein comprise an anti-B7-H3 antibody containing a mutation in the Fc region, wherein the mutation is L234A (LA mutation). In embodiments, the ADC compounds described herein comprise an anti-B7-H3 antibody containing a mutation in the Fc region, wherein the mutation is L235A (LA mutation). In embodiments, the ADC compounds described herein comprise anti-B7-H3 antibodies containing a double mutation in the Fc region, wherein the mutations are L234A and L235A (LALA mutation). In embodiments, the anti-B7-H3 antibody (VA clone) comprises the mutants L234A and L235A (VA LALA) in the Fc region.

[0340] In some embodiments, the anti-B7-H3 antibody provided herein includes a cysteine ​​residue. In some embodiments, the anti-B7-H3 antibody binds to the drug via a linker through the sulfur content of the cysteine ​​residue. In some embodiments, the anti-B7-H3 antibody binds to the drug via a linker through the sulfur content of two cysteine ​​residues.

[0341] In some embodiments, the anti-B7-H3 antibody provided herein comprises lysine. In some embodiments, the anti-B7-H3 antibody binds to the drug via a linker through an amine of one or two lysine residues.

[0342] In an embodiment, the ADC provided herein comprises an anti-B7-H3 antibody, the antibody comprising a light chain variable region and a heavy chain variable region, wherein the light chain variable region comprises a light chain complementarity-determining region 1 (CDR1), a light chain CDR2, and a light chain CDR3, and the heavy chain variable region comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3.

[0343] In embodiments, the ADC provided herein comprises an anti-B7-H3 antibody (e.g., VA or VA LALA), said antibody comprising at least one, two, three, four, five or six CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 12; (b) VL CDR2 comprising the sequence of SEQ ID NO: 13; (c) VLCDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VH CDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17. In an embodiment, the ADC comprises an anti-B7-H3 antibody, the antibody comprising at least one CDR selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 12; (b) VL CDR2 comprising the sequence of SEQ ID NO: 13; (c) VL CDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VH CDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17. In an embodiment, the ADC comprises an anti-B7-H3 antibody, the antibody comprising at least two CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 12; (b) VL CDR2 comprising the sequence of SEQ ID NO: 13; (c) VL CDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VH CDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17. In an embodiment, the ADC comprises an anti-B7-H3 antibody, the antibody comprising at least three CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 12; (b) VL CDR2 comprising the sequence of SEQ ID NO: 13; (c) VLCDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VH CDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17.In an embodiment, the ADC comprises an anti-B7-H3 antibody, the antibody comprising at least four CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 12; (b) VL CDR2 comprising the sequence of SEQ ID NO: 13; (c) VL CDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VH CDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17. In an embodiment, the ADC comprises an anti-B7-H3 antibody, the antibody comprising at least five CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 12; (b) VL CDR2 comprising the sequence of SEQ ID NO: 13; (c) VL CDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VH CDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17. In an embodiment, the ADC comprises an anti-B7-H3 antibody, the antibody comprising at least six CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 12; (b) VL CDR2 comprising the sequence of SEQ ID NO: 13; (c) VLCDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VH CDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17.

[0344] In an embodiment, the ADC comprises an anti-B7-H3 antibody (e.g., VA or VA LALA), the antibody comprising a CDR selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 12; (b) VL CDR2 comprising the sequence of SEQ ID NO: 13; (c) VL CDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VH CDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17. In an embodiment, the ADC comprises an anti-B7-H3 antibody, the antibody comprising two CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 12; (b) VL CDR2 comprising the sequence of SEQ ID NO: 13; (c) VL CDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VHCDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17. In an embodiment, the ADC comprises an anti-B7-H3 antibody, the antibody comprising three CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 12; (b) VL CDR2 comprising the sequence of SEQ ID NO: 13; (c) VL CDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VH CDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17. In an embodiment, the ADC comprises an anti-B7-H3 antibody, the antibody comprising four CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 12; (b) VL CDR2 comprising the sequence of SEQ ID NO: 13; (c) VL CDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VH CDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17.In an embodiment, the ADC comprises an anti-B7-H3 antibody, the antibody comprising five CDRs selected from the following: (a) VLCDR1 comprising the sequence of SEQ ID NO: 12; (b) VL CDR2 comprising the sequence of SEQ ID NO: 13; (c) VL CDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VH CDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17. In an embodiment, the ADC comprises an anti-B7-H3 antibody, the antibody comprising a CDR selected from the following six: (a) VL CDR1 comprising the sequence of SEQ ID NO: 12; (b) VL CDR2 comprising the sequence of SEQ ID NO: 13; (c) VL CDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VH CDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17.

[0345] In one embodiment, the anti-B7-H3 antibody (e.g., VA or VA LALA) comprises VL CDR1 containing the sequence of SEQ ID NO: 12, VL CDR2 containing the sequence of SEQ ID NO: 13, VL CDR3 containing the sequence of SEQ ID NO: 14, VH CDR1 containing the sequence of SEQ ID NO: 15, VH CDR2 containing the sequence of SEQ ID NO: 16, and VH CDR3 containing the sequence of SEQ ID NO: 17. In another embodiment, the anti-B7-H3 antibody comprises VL CDR1 containing the sequence of SEQ ID NO: 12. In yet another embodiment, the anti-B7-H3 antibody comprises VL CDR2 containing the sequence of SEQ ID NO: 13. In yet another embodiment, the anti-B7-H3 antibody comprises VL CDR3 containing the sequence of SEQ ID NO: 14. In yet another embodiment, the anti-B7-H3 antibody comprises VH CDR1 containing the sequence of SEQ ID NO: 15. In one embodiment, the anti-B7-H3 antibody comprises VHCDR2 containing the sequence of SEQ ID NO: 16. In another embodiment, the anti-B7-H3 antibody comprises VHCDR3 containing the sequence of SEQ ID NO: 17.

[0346] In an embodiment, the ADC comprises an anti-B7-H3 antibody (e.g., VA or VA LALA), said antibody comprising a light chain CDR1 having the amino acid sequence of SEQ ID NO: 12, a light chain CDR2 having the amino acid sequence of SEQ ID NO: 13, a light chain CDR3 having the amino acid sequence of SEQ ID NO: 14, a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 15, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 16, and a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 17.

[0347] In one embodiment, the anti-B7-H3 antibody (e.g., VA or VA LALA) comprises a VL having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 20. In another embodiment, the anti-B7-H3 antibody (e.g., VA or VA LALA) comprises a VL having the sequence of SEQ ID NO: 20. In another embodiment, although the VL sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 20 includes substitutions (e.g., conserved substitutions), insertions, or deletions relative to the reference sequence, the anti-B7-H3 antibody including said sequence retains the ability to bind to B7-H3. In another embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 20. In another embodiment, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 20. In another embodiment, the substitution, insertion, or deletion occurs in regions outside the CDR (i.e., in the FR). In one embodiment, the anti-B7-H3 antibody comprises the VL sequence of SEQ ID NO: 20 and includes post-translational modifications of the sequence.

[0348] In one embodiment, the anti-B7-H3 antibody (e.g., VA or VA LALA) comprises a VH having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 21. In another embodiment, the anti-B7-H3 antibody (e.g., VA or VA LALA) comprises a VH having the sequence of SEQ ID NO: 21. In another embodiment, although the VH sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO: 21 includes substitutions (e.g., conserved substitutions), insertions, or deletions relative to the reference sequence, the anti-B7-H3 antibody including said sequence retains the ability to bind to B7-H3. In another embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 21. In another embodiment, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 21. In another embodiment, the substitution, insertion, or deletion occurs in regions outside the CDR (i.e., in the FR). In an embodiment, the anti-B7-H3 antibody includes the VH sequence of SEQ ID NO: 21 and includes post-translational modifications of said sequence.

[0349] In this embodiment, the anti-B7-H3 antibody is an IgG antibody. In this embodiment, the anti-B7-H3 antibody is an IgG1, IgG2, IgG3, or IgG4 antibody. In this embodiment, the anti-B7-H3 antibody is an IgG1 or IgG4 antibody. In this embodiment, the anti-B7-H3 antibody is an IgG1 antibody.

[0350] In one embodiment, the anti-B7-H3 antibody binds to human B7-H3. In another embodiment, the human B7-H3 has the amino acid sequence SEQ ID NO: 71.

[0351] In any of the embodiments described above, the anti-B7-H3 antibody is humanized. In the embodiments, the anti-B7-H3 antibody includes a CDR as described in any of the embodiments described above, and further includes a human receptor framework, such as a human immunoglobulin framework or a human common framework. In the embodiments, the humanized anti-B7-H3 antibody (e.g., VA or VA LALA) includes: (a) VL CDR1 comprising the sequence of SEQ ID NO: 12; (b) VLCDR2 comprising the sequence of SEQ ID NO: 13; (c) VL CDR3 comprising the sequence of SEQ ID NO: 14; (d) VH CDR1 comprising the sequence of SEQ ID NO: 15; (e) VH CDR2 comprising the sequence of SEQ ID NO: 16; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 17.

[0352] In one embodiment, the anti-B7-H3 antibody is a monoclonal antibody, including chimeric antibodies, humanized antibodies, or human antibodies. In one embodiment, the anti-B7-H3 antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, a bifunctional antibody, or an F(ab')2 fragment. In another embodiment, the antibody is a substantially full-length antibody, such as an IgG1 antibody, or other antibody classes or isotypes as defined herein.

[0353] Anti-ROR1 antibody In embodiments, the ADC comprises an antibody that binds to ROR1. ROR1 has been reported to be upregulated independently of baseline levels of ROR1 expression, for example, in lung and breast cancer. In embodiments, the ADC compounds described herein comprise anti-ROR1 antibodies. In embodiments, the ROR1 compounds described herein comprise anti-ROR1 antibodies containing one or more mutations in the Fc region, wherein the mutations may include mutations L234A and / or L235A (a substitution of a residue at position 234 in the EU index shown in Kabat and / or a substitution of a residue at position 235 in the EU index shown in Kabat). In embodiments, the ADC compounds described herein comprise anti-ROR1 antibodies containing mutations in the Fc region, wherein the mutation is L234A (LA mutation). In embodiments, the ADC compounds described herein comprise anti-ROR1 antibodies containing mutations in the Fc region, wherein the mutation is L235A (LA mutation). In embodiments, the ADC compounds described herein comprise anti-ROR1 antibodies containing double mutations in the Fc region, wherein the mutations are L234A and L235A (LALA mutation). In one embodiment, the anti-ROR1 antibody (RO6D8-s10) comprises mutants L234A and L235A (RO6D8-s10 LALA) in the Fc region. In another embodiment, the anti-ROR1 antibody (RO6A-a7gm) comprises mutants L234A and L235A (RO6A-a7gm LALA) in the Fc region.

[0354] In some embodiments, the anti-ROR1 antibody provided herein comprises cysteine. In some embodiments, the anti-ROR1 antibody binds to the drug via a linker through the sulfur of the cysteine ​​residue. In some embodiments, the anti-ROR1 antibody binds to the drug via a linker through the sulfur of two cysteine ​​residues.

[0355] In some embodiments, the anti-ROR1 antibody provided herein comprises lysine. In some embodiments, the anti-ROR1 antibody binds to the drug via a linker through an amine of one or two lysine residues.

[0356] In an embodiment, the ADC provided herein comprises an anti-ROR1 antibody, the antibody comprising a light chain variable region and a heavy chain variable region, wherein the light chain variable region comprises a light chain complementarity-determining region 1 (CDR1), a light chain CDR2, and a light chain CDR3, and the heavy chain variable region comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3.

[0357] In embodiments, the ADC provided herein comprises an anti-ROR1 antibody (e.g., RO6D8-s10 or RO6D8-s10LALA), said antibody comprising at least one, two, three, four, five or six CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 22; (b) VL CDR2 comprising the sequence of SEQ ID NO: 23; (c) VL CDR3 comprising the sequence of SEQ ID NO: 24; (d) VH CDR1 comprising the sequence of SEQ ID NO: 25; (e) VHCDR2 comprising the sequence of SEQ ID NO: 26; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 27. In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising at least one CDR selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 22; (b) VL CDR2 comprising the sequence of SEQ ID NO: 23; (c) VL CDR3 comprising the sequence of SEQ ID NO: 24; (d) VH CDR1 comprising the sequence of SEQ ID NO: 25; (e) VH CDR2 comprising the sequence of SEQ ID NO: 26; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 27. In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising at least two CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 22; (b) VL CDR2 comprising the sequence of SEQ ID NO: 23; (c) VL CDR3 comprising the sequence of SEQ ID NO: 24; (d) VH CDR1 comprising the sequence of SEQ ID NO: 25; (e) VH CDR2 comprising the sequence of SEQ ID NO: 26; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 27. In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising at least three CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 22; (b) VL CDR2 comprising the sequence of SEQ ID NO: 23; (c) VL CDR3 comprising the sequence of SEQ ID NO: 24; (d) VH CDR1 comprising the sequence of SEQ ID NO: 25; (e) VH CDR2 comprising the sequence of SEQ ID NO: 26; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 27.In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising at least four CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 22; (b) VL CDR2 comprising the sequence of SEQ ID NO: 23; (c) VL CDR3 comprising the sequence of SEQ ID NO: 24; (d) VH CDR1 comprising the sequence of SEQ ID NO: 25; (e) VH CDR2 comprising the sequence of SEQ ID NO: 26; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 27. In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising at least five CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 22; (b) VL CDR2 comprising the sequence of SEQ ID NO: 23; (c) VL CDR3 comprising the sequence of SEQ ID NO: 24; (d) VH CDR1 comprising the sequence of SEQ ID NO: 25; (e) VH CDR2 comprising the sequence of SEQ ID NO: 26; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 27. In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising at least six CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 22; (b) VL CDR2 comprising the sequence of SEQ ID NO: 23; (c) VLCDR3 comprising the sequence of SEQ ID NO: 24; (d) VH CDR1 comprising the sequence of SEQ ID NO: 25; (e) VH CDR2 comprising the sequence of SEQ ID NO: 26; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 27.

[0358] In embodiments, the ADC provided herein comprises an anti-ROR1 antibody (e.g., RO6A-a7gm or RO6A-a7gmLALA), said antibody comprising at least one, two, three, four, five or six CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 32; (b) VL CDR2 comprising the sequence of SEQ ID NO: 33; (c) VL CDR3 comprising the sequence of SEQ ID NO: 34; (d) VH CDR1 comprising the sequence of SEQ ID NO: 35; (e) VHCDR2 comprising the sequence of SEQ ID NO: 36; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 37. In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising at least one CDR selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 32; (b) VL CDR2 comprising the sequence of SEQ ID NO: 33; (c) VL CDR3 comprising the sequence of SEQ ID NO: 34; (d) VH CDR1 comprising the sequence of SEQ ID NO: 35; (e) VH CDR2 comprising the sequence of SEQ ID NO: 36; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 37. In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising at least two CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 32; (b) VL CDR2 comprising the sequence of SEQ ID NO: 33; (c) VL CDR3 comprising the sequence of SEQ ID NO: 34; (d) VH CDR1 comprising the sequence of SEQ ID NO: 35; (e) VH CDR2 comprising the sequence of SEQ ID NO: 36; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 37. In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising at least three CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 32; (b) VL CDR2 comprising the sequence of SEQ ID NO: 33; (c) VL CDR3 comprising the sequence of SEQ ID NO: 34; (d) VH CDR1 comprising the sequence of SEQ ID NO: 35; (e) VH CDR2 comprising the sequence of SEQ ID NO: 36; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 37.In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising at least four CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 32; (b) VL CDR2 comprising the sequence of SEQ ID NO: 33; (c) VL CDR3 comprising the sequence of SEQ ID NO: 34; (d) VH CDR1 comprising the sequence of SEQ ID NO: 35; (e) VH CDR2 comprising the sequence of SEQ ID NO: 36; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 37. In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising at least five CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 32; (b) VL CDR2 comprising the sequence of SEQ ID NO: 33; (c) VL CDR3 comprising the sequence of SEQ ID NO: 34; (d) VH CDR1 comprising the sequence of SEQ ID NO: 35; (e) VH CDR2 comprising the sequence of SEQ ID NO: 36; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 37. In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising at least six CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 32; (b) VL CDR2 comprising the sequence of SEQ ID NO: 33; (c) VLCDR3 comprising the sequence of SEQ ID NO: 34; (d) VH CDR1 comprising the sequence of SEQ ID NO: 35; (e) VH CDR2 comprising the sequence of SEQ ID NO: 36; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 37.

[0359] In an embodiment, the ADC comprises an anti-ROR1 antibody (e.g., RO6D8-s10 or RO6D8-s10 LALA), the antibody comprising a CDR selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 22; (b) VL CDR2 comprising the sequence of SEQ ID NO: 23; (c) VL CDR3 comprising the sequence of SEQ ID NO: 24; (d) VH CDR1 comprising the sequence of SEQ ID NO: 25; (e) VH CDR2 comprising the sequence of SEQ ID NO: 26; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 27. In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising two CDRs selected from the following: (a) VL CDR1 comprising the sequence of SEQ ID NO: 22; (b) VL CDR2 comprising the sequence of SEQ ID NO: 23; (c) VL CDR3 comprising the sequence of SEQ ID NO: 24; (d) VH CDR1 comprising the sequence of SEQ ID NO: 25; (e) VH CDR2 comprising the sequence of SEQ ID NO: 26; and (f) VH CDR3 comprising the sequence of SEQ ID NO: 27. In an embodiment, the ADC comprises an anti-ROR1 antibody, the antibody comprising three CDRs selected from the...

Claims

1. An antibody-drug conjugate (ADC) of formula (I), formula (II) or formula (III): Or its pharmaceutically acceptable salt, wherein: Ab is a monoclonal antibody, which includes an Fc variant comprising two amino acid substitutions for L234A and L235A; m is an integer from 1 to 8; L 1 It is a linker that binds to the monoclonal antibody; L 2 It is a bond, -C(O)-, -NH-, amino acid unit, -(CH2CH2O) n -、-(CH2) n -、-O-、-(4-aminobenzyloxycarbonyl)-、-(C(O)CH2CH2NH)-、-(C(O)N(R 2 )CH2CH2N(R 5 ))- or any combination thereof; where n is an integer from 1 to 24; Each R 2 and R 5 It is independently H or a substituted or unsubstituted alkyl group; L 3 It is a substituted or unsubstituted heterocyclic alkyl group, a substituted or unsubstituted heteroaryl group; or L 3 It is a substituted or unsubstituted -OCH2- (heterocyclic alkyl) or a substituted or unsubstituted -OCH2- (heteroaryl), wherein L 3 Through oxygen-D linkage; or L 3 It is a substituted or unsubstituted -CH2NCH2- (heteroaryl) or a substituted or unsubstituted -CH2NCH2- (heterocyclic alkyl), wherein L 3 It is connected to D via -CH2- and to L via nitrogen. 2 connect; R * It is a substituted or unsubstituted heterocyclic alkyl or a substituted or unsubstituted heteroaryl; D is ; D' is D' interacts with R through its amide group. * Connect and via oxygen and L 2 Connect; and D'' is or in: R 1 It is an H or -C1-C8 alkyl group; R 3 It includes H, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, and -OR. 3A -NR 3A R 3B -(CH2) v OR 6 Substituted or unsubstituted alkyl groups or substituted or unsubstituted heteroalkyl groups; R 4 It is H, halogen, -OR 4A -NR 4A R 4B Substituted or unsubstituted alkyl groups or substituted or unsubstituted heteroalkyl groups; V is N, O, or C; Z 1 It is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group; Z 2 It is a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, a substituted or unsubstituted cycloalkylene, or a substituted or unsubstituted heteroalkylene; R 6 It is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO(CH2CH2O) w CH2CH2M、-CONH(CH2CH2O) w CH2CH2M, Charged groups or sugar derivatives; v is an integer from 1 to 24; w is an integer from 1 to 24; M is -NH2, -OH, -COOH, or -OCH3; R 10 It is -OH, -OCH3, or -COOH; and Each R 3A R 3B R 4A and R 4B It is independently H or a substituted or unsubstituted alkyl group.

2. The ADC of claim 1 or a pharmaceutically acceptable salt thereof, wherein the monoclonal antibody is an anti-CD25 antibody, an anti-B7-H3 antibody, an anti-ROR1 antibody, an anti-Trop-2 antibody, or an anti-BCMA antibody.

3. The ADC or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein L 1 It is a linker that binds to one or two sulfur or nitrogen atoms of the monoclonal antibody.

4. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein L 1 yes: , , , , , , , , , , , or .

5. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein L 1 yes: or .

6. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein m is 1, 2, 3, 4, 5, 6, 7 or 8.

7. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein n is an integer from 1 to 4.

8. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein L 2 It is a bond, -C(O)-, -NH-, -Val-, -Phe-, -Lys-, -(4-aminobenzyloxycarbonyl)-, -Gly-, -Ser-, -Thr-, -Ala-, β-Ala-, -citrulline-(-Cit-), -(CH2) n -、-(CH2CH2O) n -, -O-, -(C(O)N(CH3)CH2CH2N(CH3))-, N-dimethyllysine or any combination thereof.

9. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein L 2 The following are possible combinations: -C(O)-, -NH-, -Val-, -(4-aminobenzyloxycarbonyl)-, -Gly-, -citrulline-(-Cit-), -(CH2). n -、-(CH2CH2O) n -, N-dimethyllysine or any combination thereof.

10. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein L 2 yes: , , or .

11. The ADC of claim 10 or a pharmaceutically acceptable salt thereof, wherein L 2 yes 。 12. The ADC of claim 10 or a pharmaceutically acceptable salt thereof, wherein L 2 yes 。 13. The ADC of claim 10 or a pharmaceutically acceptable salt thereof, wherein L 2 yes 。 14. The ADC of claim 10 or a pharmaceutically acceptable salt thereof, wherein L 2 yes 。 15. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein D'' is in: R 1 It is an H or -C1-C8 alkyl group; R 3 It is H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 4 It is H, halogen, or substituted or unsubstituted alkyl; V is N; and Z 2 It is a substituted or unsubstituted aryl group.

16. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R 1 It is H.

17. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R 3 It is H, methyl, ethyl, propyl, butyl, -CH2OH, -CH2CH2OH, -CH2N3, -CH2CH2N3, -CH2OCH3, -CH2OCH2CH3 or -CH2CH2OCH3.

18. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein R 3 It is methyl, -CH2OH or -CH2N3.

19. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein R 4 It is H or a substituted or unsubstituted alkyl group.

20. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein R 4 It is H or methyl.

21. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein R 4 It is H.

22. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein Z 2 It is an unsubstituted aryl ester.

23. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein Z 2 yes .

24. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein D'' is .

25. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein the ADC is: 。 26. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein L 3 It is a substituted or unsubstituted heterocyclic alkyl group; or L 3 It is a substituted or unsubstituted -CH2NCH2- (heterocyclic alkyl), wherein L 3 It is connected to D via -CH2- and to L via nitrogen. 2 connect.

27. The ADC of claim 26 or a pharmaceutically acceptable salt thereof, wherein L 3 It is a substituted or unsubstituted heterocyclic alkyl group.

28. The ADC of claim 27 or a pharmaceutically acceptable salt thereof, wherein L 3 It is a substituted or unsubstituted 3 to 8-membered heterocyclic alkyl group.

29. The ADC of claim 27 or a pharmaceutically acceptable salt thereof, wherein L 3 It is a substituted or unsubstituted 3 to 6-membered heterocyclic alkyl group.

30. The ADC of claim 29 or a pharmaceutically acceptable salt thereof, wherein L 3 It is a substituted or unsubstituted heterocyclic butyl, heterocyclic pentyl, or heterocyclic hexyl group.

31. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 or 26 to 30, having a structure of formula (IA) or formula (IIA): in: Ring A is formed by the interaction of heteroatom Y and L. 2 Connected substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; Ring A' is a substituted or unsubstituted heterocyclic alkyl group or a substituted or unsubstituted heteroaryl group linked to D' by heteroatom Y; and Y is N, P, or S.

32. The ADC of claim 31 or a pharmaceutically acceptable salt thereof, having a structure of formula (IB) or formula (IIB): in Each R 7 Independently, it is H, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 7A -NR 7A R 7B -COOR 7A -CONR 7A R 7B -NO2, -SR 7A -SO n7 R 7A -SO v7 NR 7A R 7B -PO(OH)2, -PO m7 R 7A PO r7 NR 7A R 7B Substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted cycloalkyl groups, or substituted or unsubstituted heterocycloalkyl groups; Any two R atoms located on adjacent carbon atoms 7 Substituents may optionally be linked to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 7A and R 7B Independently, it is H, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 7A and R 7B Substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; X is -Cl, -Br, -I, or -F; Each n7 is an integer from 0 to 4 independently; Each v7 is independently 1 or 2; Each m7 is an independent integer from 0 to 3; and Each r7 is independently 1 or 2.

33. The ADC of claim 31 or a pharmaceutically acceptable salt thereof, having a structure of formula (IC) or formula (IIC): 。 34. The ADC of claim 31 or a pharmaceutically acceptable salt thereof, having a structure of formula (ID) or formula (IID): 。 35. The ADC of claim 31 or a pharmaceutically acceptable salt thereof, having a structure of formula (ID1) or formula (IID1): 。 36. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 or 26 to 30, having the structure of formula IG: Or its pharmaceutically acceptable salt, wherein: The ring W is a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted arylene.

37. The ADC of claim 36 or a pharmaceutically acceptable salt thereof, having the structure of formula IM: Where Z is S, N, or O.

38. The ADC of claim 36 or a pharmaceutically acceptable salt thereof, having the structure of formula 10: 。 39. The ADC of claim 36 or a pharmaceutically acceptable salt thereof, having the structure of formula IQ: 。 40. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 or 26 to 39, wherein the ADC is: , , , , , , or Or its pharmaceutically acceptable salt.

41. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, wherein (a) The anti-CD25 antibody comprises VL CDR1 containing the sequence of SEQ ID NO: 1, VL CDR2 containing the sequence of SEQ ID NO: 2, VL CDR3 containing the sequence of SEQ ID NO: 3, VH CDR1 containing the sequence of SEQ ID NO: 4, VH CDR2 containing the sequence of SEQ ID NO: 5, and VH CDR3 containing the sequence of SEQ ID NO:

6. (b) The anti-B7-H3 antibody comprises VL CDR1 containing the sequence of SEQ ID NO: 12, VL CDR2 containing the sequence of SEQ ID NO: 13, VL CDR3 containing the sequence of SEQ ID NO: 14, VH CDR1 containing the sequence of SEQ ID NO: 15, VH CDR2 containing the sequence of SEQ ID NO: 16, and VH CDR3 containing the sequence of SEQ ID NO:

17. (c) The anti-ROR1 antibody comprises VL CDR1 containing the sequence of SEQ ID NO: 22, VL CDR2 containing the sequence of SEQ ID NO: 23, VL CDR3 containing the sequence of SEQ ID NO: 24, VH CDR1 containing the sequence of SEQ ID NO: 25, VH CDR2 containing the sequence of SEQ ID NO: 26, and VH CDR3 containing the sequence of SEQ ID NO:

27. (d) The anti-ROR1 antibody comprises VL CDR1 containing the sequence of SEQ ID NO: 32, VL CDR2 containing the sequence of SEQ ID NO: 33, VL CDR3 containing the sequence of SEQ ID NO: 34, VH CDR1 containing the sequence of SEQ ID NO: 35, VH CDR2 containing the sequence of SEQ ID NO: 36, and VH CDR3 containing the sequence of SEQ ID NO:

37. (e) The anti-Trop-2 antibody comprises VL CDR1 containing the sequence of SEQ ID NO: 42, VL CDR2 containing the sequence of SEQ ID NO: 43, VL CDR3 containing the sequence of SEQ ID NO: 44, VH CDR1 containing the sequence of SEQ ID NO: 45, VH CDR2 containing the sequence of SEQ ID NO: 46, and VH CDR3 containing the sequence of SEQ ID NO:

47. (f) The anti-BCMA antibody includes VL CDR1 containing the sequence of SEQ ID NO: 52, VL CDR2 containing the sequence of SEQ ID NO: 53, VL CDR3 containing the sequence of SEQ ID NO: 54, VH CDR1 containing the sequence of SEQ ID NO: 55, VH CDR2 containing the sequence of SEQ ID NO: 56, and VH CDR3 containing the sequence of SEQ ID NO:

57.

42. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 41, wherein (a) The anti-CD25 antibody comprises a VL having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:

10. (b) The anti-B7-H3 antibody comprises a VL having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:

20. (c) The anti-ROR1 antibody comprises a VL having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:

30. (d) The anti-ROR1 antibody comprises a VL having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:

40. (e) The anti-Trop-2 antibody comprises a VL having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:

50. (f) The anti-BCMA antibody comprises a VL having a sequence having at least 95%, 96%, 97%, 98% or 99% identity with SEQ ID NO:

60.

43. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 42, wherein... (a) The anti-CD25 antibody comprises a VH having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:

11. (b) The anti-B7-H3 antibody comprises a VH having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:

21. (c) The anti-ROR1 antibody comprises a VH having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:

31. (d) The anti-ROR1 antibody comprises a VH having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:

41. (e) The anti-Trop-2 antibody comprises a VH having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQ ID NO:

51. (f) The anti-BCMA antibody includes VH having a sequence having at least 95%, 96%, 97%, 98% or 99% identity with SEQ ID NO:

61.

44. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 43, wherein (a) The anti-CD25 antibody comprises VL having the sequence of SEQ ID NO:

10. (b) The anti-B7-H3 antibody comprises VL having the sequence SEQ ID NO:

20. (c) The anti-ROR1 antibody comprises VL having the sequence SEQ ID NO:

30. (d) The anti-ROR1 antibody comprises VL having the sequence SEQ ID NO:

40. (e) The anti-Trop-2 antibody comprises VL having the sequence SEQ ID NO:

50. (f) The anti-BCMA antibody includes VL having the sequence SEQ ID NO:

60.

45. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 44, wherein (a) The anti-CD25 antibody comprises VH having the sequence SEQ ID NO:

11. (b) The anti-B7-H3 antibody comprises VH having the sequence SEQ ID NO:

21. (c) The anti-ROR1 antibody includes VH having the sequence SEQ ID NO:

31. (d) The anti-ROR1 antibody comprises VH having the sequence SEQ ID NO:

41. (e) The anti-Trop-2 antibody comprises VH having the sequence SEQ ID NO:

51. (f) The anti-BCMA antibody includes VH having the sequence SEQ ID NO:

61.

46. ​​The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 45, wherein the anti-CD25 antibody, the anti-B7-H3 antibody, the anti-ROR1 antibody, the anti-Trop-2 antibody, or the anti-BCMA antibody is an IgG antibody, optionally wherein the anti-CD25 antibody, the anti-B7-H3 antibody, the anti-ROR1 antibody, the anti-Trop-2 antibody, or the anti-BCMA antibody is an IgG1 antibody.

47. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 46, wherein (a) The anti-CD25 antibody binds to human CD25, optionally wherein the human CD25 has the amino acid sequence of SEQ ID NO:

70. (b) The anti-B7-H3 antibody binds to human B7-H3, optionally wherein the human B7-H3 has the amino acid sequence of SEQ ID NO:

71. (c) The anti-ROR1 antibody binds to human ROR1, optionally wherein the human ROR1 has the amino acid sequence of SEQ ID NO:

72. (d) The anti-Trop-2 antibody binds to human Trop-2, optionally wherein the human Trop-2 has the amino acid sequence of SEQ ID NO:

73. (e) The anti-BCMA antibody binds to human BCMA, optionally wherein the human BCMA has the amino acid sequence of SEQ ID NO:

74.

48. The ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 47, used in a therapeutic manner.

49. The ADC of claim 48 or a pharmaceutically acceptable salt thereof, for the treatment of cancers expressing CD25, cancers expressing B7-H3, cancers expressing ROR1, cancers expressing Trop-2-2, or cancers expressing BCMA.

50. A method of treating a subject with cancer expressing CD25, cancer expressing B7-H3, cancer expressing ROR1, cancer expressing Trop-2, or cancer expressing BCMA, the method comprising administering an ADC according to any one of claims 1 to 47 to a subject in need.

51. Use of the ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 47, for the preparation of a medicament.

52. Use of the ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 47, for the preparation of a medicament for treating cancers expressing CD25, cancers expressing B7-H3, cancers expressing ROR1, cancers expressing Trop-2, or cancers expressing BCMA.

53. A method for preparing an ADC according to any one of claims 1 to 40, the method comprising reacting a monoclonal antibody with a molecule of formula (PI), formula (P-II), or formula (P-III): Or its pharmaceutically acceptable salt, wherein: B is the reactive portion capable of forming a bond with the monoclonal antibody; L 2 It is a bond, -C(O)-, -NH-, amino acid unit, -(CH2CH2O) n -、-(CH2) n -、-O-、-(4-aminobenzyloxycarbonyl)-、-(C(O)CH2CH2NH)-、-(C(O)N(R 2 )CH2CH2N(R 5 ))- or any combination thereof; where n is an integer from 1 to 24; Each R 2 and R 5 It is independently H or a substituted or unsubstituted alkyl group; L 3 It is a substituted or unsubstituted heterocyclic alkyl group, a substituted or unsubstituted heteroaryl group; or L 3 It is a substituted or unsubstituted -OCH2- (heterocyclic alkyl) or a substituted or unsubstituted -OCH2- (heteroaryl), wherein L 3 Through oxygen-D linkage; or L 3 It is a substituted or unsubstituted -CH2NCH2- (heteroaryl) or a substituted or unsubstituted -CH2NCH2- (heterocyclic alkyl), wherein L 3 It is connected to D via -CH2- and to L via nitrogen. 2 connect; R * It is a substituted or unsubstituted heterocyclic alkyl or a substituted or unsubstituted heteroaryl; D is ; D' is D' interacts with R through its amide group. * Connect and via oxygen and L 2 Connect; and D'' is or in: R 1 It is an H or -C1-C8 alkyl group; R 3 It includes H, halogens, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, and -OR. 3A -NR 3A R 3B -(CH2) v OR 6 Substituted or unsubstituted alkyl groups or substituted or unsubstituted heteroalkyl groups; R 4 It is H, halogen, -OR 4A -NR 4A R 4B Substituted or unsubstituted alkyl groups or substituted or unsubstituted heteroalkyl groups; V is N, O, or C; Z 1 It is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group; Z 2 It is a substituted or unsubstituted arylene, a substituted or unsubstituted heteroarylene, a substituted or unsubstituted cycloalkylene, or a substituted or unsubstituted heteroalkylene; R 6 It is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO(CH2CH2O) w CH2CH2M、-CONH(CH2CH2O) w CH2CH2M, Charged groups or sugar derivatives; v is an integer from 1 to 24; w is an integer from 1 to 24; M is -NH2, -OH, -COOH, or -OCH3; R 10 It is -OH, -OCH3, or -COOH; and Each R 3A R 3B R 4A and R 4B It is independently H or a substituted or unsubstituted alkyl group.

54. The method of claim 53, wherein the monoclonal antibody is an anti-CD25 antibody, an anti-B7-H3 antibody, an anti-ROR1 antibody, an anti-Trop-2 antibody, or an anti-BCMA antibody.

55. The method according to claim 53 or 54, wherein the monoclonal antibody is modified with an aldehyde, azide, alkyne, tetrazine, hydrazine, alkoxyamine, trans-cyclooctene, or cyclopropene.

56. The method according to any one of claims 53 to 55, wherein B is a reactive portion capable of forming a bond with one or both thiol or amino groups of the monoclonal antibody or the modified monoclonal antibody.

57. The method according to any one of claims 53 to 56, wherein B is: , , , , , , , , , , , , .

58. The method of claim 57, wherein B is: or .

59. The method according to any one of claims 53 to 58, wherein L 2 It is a bond, -C(O)-, -NH-, -Val-, -Phe-, -Lys-, -(4-aminobenzyloxycarbonyl)-, -Gly-, -Ser-, -Thr-, -Ala-, -β-Ala-, -citrulline-(-Cit-), -(CH2) n -、-(CH2CH2O) n -, -(C(O)N(CH3)CH2CH2N(CH3))-, N-dimethyllysine or any combination thereof.

60. The method according to any one of claims 53 to 59, wherein L 2 The following are possible combinations: -C(O)-, -NH-, -Val-, -(4-aminobenzyloxycarbonyl)-, -Gly-, -citrulline-(-Cit-), -(CH2). n -、-(CH2CH2O) n -, N-dimethyllysine or any combination thereof.

61. The method according to any one of claims 53 to 60, wherein L 2 yes: , , or .

62. The method of claim 61, wherein L 2 yes 。 63. The method of claim 61, wherein L 2 yes 。 64. The method of claim 61, wherein L 2 yes 。 65. The method of claim 61, wherein L 2 yes 。 66. The method according to any one of claims 53 to 65, wherein D'' is in: R 1 It is an H or -C1-C8 alkyl group; R 3 It is H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 4 It is H, halogen, or substituted or unsubstituted alkyl; V is N; and Z 2 It is a substituted or unsubstituted aryl group.

67. The method according to any one of claims 53 to 66, wherein R 1 It is H.

68. The method according to any one of claims 53 to 67, wherein R 3 It is H, methyl, ethyl, propyl, butyl, -CH2OH, -CH2CH2OH, -CH2N3, -CH2CH2N3, -CH2OCH3, -CH2OCH2CH3 or -CH2CH2OCH3.

69. The method according to any one of claims 53 to 68, wherein R 3 It is methyl, -CH2OH or -CH2N3.

70. The method according to any one of claims 53 to 69, wherein R 4 It is H or a substituted or unsubstituted alkyl group.

71. The method according to any one of claims 53 to 70, wherein R 4 It is H or methyl.

72. The method according to any one of claims 53 to 71, wherein R 4 It is H.

73. The method according to any one of claims 53 to 72, wherein Z 2 It is a substituted or unsubstituted aryl group.

74. The method according to any one of claims 53 to 73, wherein Z 2 yes .

75. The method according to any one of claims 53 to 74, wherein D'' is 。 76. The method according to any one of claims 53 to 75, wherein... yes: 。 77. The method according to any one of claims 53 to 65, wherein L 3 It is a substituted or unsubstituted heterocyclic alkylene or a substituted or unsubstituted heterocyclic alkylene; or L 3 It is a substituted or unsubstituted -CH2NCH2- (heterocyclic alkyl), wherein L 3 It is connected to D via -CH2- and to L via nitrogen. 2 connect.

78. The method of claim 77, wherein L 3 It is a substituted or unsubstituted heterocyclic alkyl group.

79. The method of claim 78, wherein L 3 It is a substituted or unsubstituted 3 to 8-membered heterocyclic alkyl group.

80. The method of claim 78, wherein L 3 It is a substituted or unsubstituted 3 to 6-membered heterocyclic alkyl group.

81. The method of claim 80, wherein L 3 It is a substituted or unsubstituted heterocyclic butyl, heterocyclic pentyl, or heterocyclic hexyl group.

82. The method according to any one of claims 53 to 65 or 77 to 81, wherein the molecule of formula (PI) or formula (P-II) respectively has the structure of formula (P-IA) or formula (P-IIA): in: Ring A is formed by the interaction of heteroatom Y and L. 2 Connected substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; Ring A' is a substituted or unsubstituted heterocyclic alkyl group or a substituted or unsubstituted heteroaryl group linked to D' by heteroatom Y; and Y is N, P, or S.

83. The method according to claim 82, wherein the molecule of formula (PI) or formula (P-II) has the structure of formula (P-IB) or formula (P-IIB): ， in Each R 7 Independently, it is H, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 7A -NR 7A R 7B -COOR 7A -CONR 7A R 7B -NO2, -SR 7A -SO n7 R 7A -SO v7 NR 7A R 7B -PO(OH)2, -PO m7 R 7A PO r7 NR 7A R 7B Substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted cycloalkyl groups, or substituted or unsubstituted heterocycloalkyl groups; Any two R atoms located on adjacent carbon atoms 7 Substituents may optionally be linked to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 7A and R 7B Independently, it is H, -CX3, -CHX2, -CH2X, -C(O)OH, -C(O)NH2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX3, -OCHX2, -OCH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 7A and R 7B Substituents may optionally be linked to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; X is -Cl, -Br, -I, or -F; Each n7 is an integer from 0 to 4 independently; Each v7 is independently 1 or 2; Each m7 is an independent integer from 0 to 3; and Each r7 is independently 1 or 2.

84. The method according to claim 82, wherein the molecule of formula (PI) or formula (P-II) has a structure of formula (P-IC) or formula (P-IIC): 。 85. The method according to claim 82, wherein the molecule of formula (PI) or formula (P-II) has a structure of formula (P-ID) or formula (P-IID): 。 86. The method according to claim 82, wherein the molecule of formula (PI) or formula (P-II) has the structure of formula (P-ID1) or formula (P-IID1): 。 87. The method according to any one of claims 53 to 75 or 77 to 81, wherein the molecule of formula (PI) has the structure of formula P-IG: Or its pharmaceutically acceptable salt, wherein: The ring W is a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted arylene.

88. The method according to claim 87, wherein the molecule of formula (PI) has the structure of formula P-IM: Where Z is S, N, or O.

89. The method according to claim 87, wherein the molecule of formula (PI) has the structure of formula P-IO: 。 90. The method according to claim 87, wherein the molecule of formula (PI) has the structure of formula P-IQ: 。 91. The method according to any one of claims 53 to 65 or 77 to 90, wherein... yes: , , , , , , or Or its pharmaceutically acceptable salt.

92. A pharmaceutical composition comprising an ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 46 and a pharmaceutically acceptable excipient.

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