Antibody-drug conjugates and their use

Abstract

In particular, antibody-drug conjugates (ADCs) that bind to the B7-H3 antigen are provided. Furthermore, pharmaceutical compositions and therapeutic methods for treating cancer using the ADCs provided herein are disclosed. This disclosure provides ADCs comprising an anti-B7-H3 antibody conjugated to a camptothecin derivative toxin or a duostatin derivative toxin via a linker moiety. In embodiments, the anti-B7-H3 antibody binds to B7-H3 expressing cancer cells, enabling selective uptake of the ADC into the cancer cells.

Description

Technical Field

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 457,196, filed on April 5, 2023, which is incorporated herein by reference in its entirety for all purposes.

[0002] Throughout this Application, various publications, patents, and / or patent applications are referenced. The disclosures of these publications, patents, and / or patent applications are thus incorporated into this Application by reference in whole to better illustrate the state of the art relating to this Disclosure.

[0003] Technical field This disclosure relates to antibody-drug conjugates (ADCs) containing anti-B7-H3 antibodies, and methods for preparing them. Methods for treating cancer using the ADCs described herein are also provided herein.

Background Art

[0004] Introduction and Overview Antibody-drug conjugates (ADCs) enable targeted delivery of drug portions to tumors where systemic administration of unconjugated drugs would result in unacceptable levels of toxicity to normal cells, and, in some embodiments, intracellular accumulation in tumors (Polakis P. (2005) Current Opinion in Pharmacology 5:382-387). ADCs are targeted chemotherapy molecules that combine the properties of both antibodies and cytotoxic agents by targeting potent cytotoxic drugs to antigen-expressing tumor cells (Teicher, BA (2009) Current Cancer Drug Targets). 9:982-1004) and therefore, it is a targeted chemotherapy molecule that improves the therapeutic index by maximizing efficacy and minimizing off-target toxicity (Carter, PJ and Senter PD (2008) The Cancer Jour. 14(3):154-169; Chari, RV (2008) Acc. Chem. Res. 41:98-107).

Prior Art Documents

Non-Patent Documents

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Summary of the Invention

Means for Solving the Problems

[0006] This disclosure provides ADCs comprising an anti-B7-H3 antibody conjugated to a camptothecin derivative toxin or a duostatin derivative toxin by a linker moiety. In embodiments, the anti-B7-H3 antibody binds to B7-H3 expressing cancer cells, enabling selective uptake of the ADC into the cancer cells. In embodiments, the ADCs provided herein selectively deliver an effective amount of the camptothecin derivative toxin or duostatin derivative toxin to tumor tissue, reducing the nonspecific toxicity associated with the associated ADC. The ADC compounds described herein include those having anticancer activity. The B7 family of checkpoint molecules has become a cutting edge in cancer research, based on the concept that tumor cells exploit them to evade immune surveillance. B7 family molecules can control and suppress the immune response of not only NK cells but also T cells. The ever-growing B7 family now includes 10 members: CD80 (also known as B7.1), CD86 (also known as B7.2), B7-H1 (also known as PD-L1 or CD274), B7-DC (also known as PD-L2 or CD273), B7-H2 (also known as ICOSL), B7-H3 (also known as CD276), B7-H4 (also known as B7S1, B7x or Vtcn1), B7-H5 (also known as VISTA, GI24, Dies1 or PD-1H), B7-H6 (also known as NCR3LG1), and B7-H7 (also known as HHLA2). Strong evidence indicates that the B7 molecule provides not only crucial positive signals for stimulating and supporting T cell activity, but also negative signals for regulating and repressing T cell responses.

[0007] B7 homology 3 protein (B7-H3) (also known as CD276 and B7RP-2, and referred to herein as "B7-H3") is a type I transmembrane glycoprotein of the immunoglobulin superfamily. Human B7-H3 contains a signal peptide at the N terminus, an extracellular immunoglobulin-like variable region (Ig-like type V1) and a constant region (Ig-like type C21), a transmembrane region, and a cytoplasmic tail region with 45 amino acids (Zhou YH et al., 2007, Tissue Antigens. 70 (2): 96-104). B7-H3 has three splice variants, B7-H3α and B7-H3β. The extracellular domain of B7-H3α consists of two immunoglobulin domains (also known as 2IgB7-H3) consisting of Ig-like type V and Ig-like type C, while the extracellular domain of B7-H3β consists of four immunoglobulin domains (also known as 4IgB7-H3) consisting of Ig-like type V, Ig-like type C, Ig-like type V, and Ig-like type C. The major B7-H3 isoform in human tissues and cell lines is the 4IgB7-H3 isoform (Steinberger et al., 2004, J. Immunol. 172(4): 2352-9).

[0008] B7-H3 has been reported to possess both co-stimulatory and co-inhibitory signaling functions (e.g., Chapoval et al., 2001, Nat. Immunol. 2: 269-74; Suh et al., 2003, Nat. Immunol. 4: 899-906; Prasad et al., 2004, J. See Immunol. 173: 2500-6; and Wang et al., 2005, Eur. J. Immunol. 35: 428-38; Yang, S. et al., 2020, Int. J. Biol. Sci. 16(11):1767-1773). For example, in vitro studies have shown that B7-H3 induces proliferation of cytotoxic T lymphocytes (CTLs) in the presence of stimulating anti-CD3 antibodies that mimic T cell receptor signaling and upregulates interferon-gamma (IFN-γ) production, demonstrating the co-stimulatory function of B7-H3 (Chapoval et al., 2001, Nat. Immunol. 2: 269-74). Furthermore, in vivo studies using cardiac allografts in B7-h3 knockout / deficient mice showed reduced production of vital cytokines, chemokines, and chemokine receptor mRNA transcripts (e.g., IL-2, IFN-γ, monocyte chemotactic protein (MCP-1), and IFN-inducible protein (IP)-10) compared to wild-type littermates (Wang et al., 2005, Eur. J. Immunol. 35: 428-38). In contrast, B7-H3 co-inhibitory function has been observed; for example, in mice, the B7-h3 protein inhibited T cell activation and effector cytokine production (Suh et al., 2003, Nat. Immunol. 4: 899-906). Although the ligand for human B7-H3 has not been identified, mouse B7-h3 has been found to bind to induced receptor (TREM)-like transcript 2 (TLT-2), which is expressed on myeloid cells and is a modulator of adaptive and innate immune cell responses. CD8 + The binding of mouse B7-h3 to TLT-2 on T cells induces T cell effector functions, such as proliferation, cytotoxicity, and cytokine production (Hashiguchi et al., 2008, Proc. Nat'l. Acad. Sci. USA). 105(30): 10495-500)。

[0009] Enobrituzumab (MGA271; from Macrogenics), a humanized mAb targeting B7-H3, mediates potent antibody-dependent cell-mediated cytotoxicity (ADCC) by recruiting NK cells against a wide range of tumor types. For example, it has been investigated in the treatment of refractory B7-H3-expressing tumors such as melanoma, as well as B7-H3-expressing neoplasms including osteosarcoma and Ewing's sarcoma. Furthermore, MGA271 showed potent antitumor activity in xenograft models of B7-H3-expressing renal cells and bladder cancer. In addition, no significant safety findings were found in toxicity studies in cynomolgus monkeys (Loo, D. et al.). 2012, Clin. Cancer Res. 18:3834-45).

[0010] The B7-H3 protein is not expressed or is only slightly expressed in normal tissues and cells, but is highly expressed in various tumors (including solid tumors and hematological malignancies) and is closely correlated with tumor progression, patient survival, and disease prognosis. B7-H3 has been clinically reported to be overexpressed in many types of cancer, including prostate cancer, clear cell renal cell carcinoma, glioma, melanoma, lung cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, pancreatic cancer, gastric cancer, acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), ovarian cancer, colorectal cancer, colon cancer, kidney cancer, hepatocellular carcinoma, renal cancer, head and neck cancer, hypopharyngeal squamous cell carcinoma, glioblastoma, neuroblastoma, breast cancer, urothelial carcinoma, and urothelial cell carcinoma. While the role of B7-H3 in cancer cells is unclear, its expression may orchestrate signaling events (and / or mediate cell-to-cell engagement) that can protect cancer cells from innate and adaptive immune responses. For example, B7-H3 is overexpressed in high-grade prostatic intraepithelial neoplasms and prostatic adenocarcinomas, and high levels of B7-H3 expression in these cancerous cells are associated with an increased risk of cancer progression after surgery (Roth et al., 2007, Cancer Res. 67(16): 7893-900). Furthermore, tumor B7-H3 expression in NSCLC was inversely correlated with the number of tumor-infiltrating lymphocytes and significantly correlated with lymph node metastasis (Sun (Yamato et al., 2006, Lung Cancer 53(2): 143-51). Levels of circulating soluble B7-H3 (sB7-H3) polypeptide in NSCLC patients have also been associated with more advanced tumor stages, increased / increasing tumor size, lymph node metastasis, and distant metastasis indicating invasive disease progression (Yamato et al., 2009, Br. J. Cancer 101(10):1709-16).

[0011] B7-H3 has co-inhibitory and co-stimulatory functions on T cells, and its expression on either tumor cells or diffuse tumor angiography is significantly associated with an increased risk of death and fatal outcomes. Targeting B7-H3 not only enhances anti-tumor immunity, but also inhibits tumor angiogenesis, possibly through engagement with B7-H3 expressed by vascular-associated macrophages, which are known to favor tumor angiogenesis through cytokine secretion.

[0012] Camptothecin (CPT) is a species of tree native to China. Camptothecin is a cytotoxic quinoline alkaloid isolated from *Acuminta*. CPT was discovered in the 1960s (Wall ME et al., 1966, J. Am. Chem. Soc. 88:3888-3890). The antitumor activity of camptothecin depends on highly specific inhibition of topoisomerase-I (TOPO 1). The enzyme TOPO 1 cleaves one strand of double-stranded DNA, partially unwinds the DNA, and then re-anneals the strand to relieve tension. Camptothecin and its derivatives can bind to the TOPO 1 / DNA complex, preventing re-annealing and potentially causing cell death due to the accumulation of partially cleaved DNA (Hsiang). YH, et al, 1985, J. Biol. Chem. 260:14873-14878).

[0013] The clinical application of camptothecin is limited not only by its low solubility but also by 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, including topotecan (9-dimethylamino-10-hydroxycamptothecin; TPT) and irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin; CPT-11) (Naumczuk B. et al., 2017, Magn. Reason. Chem. 55:128-136; Hamilton G. et al., 2014, Molecules 19:2077-2088). The U.S. Food and Drug Administration has approved these CPT derivatives for the treatment of ovarian and colon cancer (Vladu et al., 2000, Mol. Pharmacol. 57:243-251; Chazin et al., 2014, Mini Rev. Med. Chem. 14:953-962).

[0014] Another camptothecin derivative is exatecan, a water-soluble derivative of camptothecin (US Patent Nos. 10,195,288 and 8,575,188). Unlike irinotecan, which is currently used in clinical settings, it does not require enzymatic activation. Dxd is another useful camptothecin derivative.

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[0015] Many camptothecin drugs are widely used clinically, with the main indications being bone cancer, prostate cancer, breast cancer, gastric cancer, pancreatic cancer, ovarian cancer, esophageal cancer, and endometrial cancer (Iqbal et al., 2014, Mol. Biol. Int. 2014). Camptothecin drugs are released into the plasma. Due to its short half-life, maintaining drug efficacy in clinical use requires increasing the dose or frequency of administration, which can therefore lead to tolerability issues for patients.

[0016] Dorastatin, such as the natural product dorastatin 10, and its synthetic derivatives monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF), are products that exhibit potent antineoplastic and tubulin inhibitory properties. Due to their high toxicity, direct use of dorastatin as a therapeutic agent has not been effective. Instead, they have been conjugated with antibodies for targeted delivery to kill cancer cells.

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[0017] In one embodiment, an antibody-drug conjugate (ADC) containing an anti-B7-H3 antibody is provided herein. In another embodiment, a method for preparing an ADC containing an anti-B7-H3 antibody is provided herein. In yet another embodiment, a method for treating cancers such as B7-H3 expressing cancer using the ADC disclosed herein is provided herein.

[0018] In embodiments, the Disclosure provides an antibody-drug conjugate (ADC) having an IgG antibody that binds to a B7-H3 target, wherein the ADC is conjugated at one or more cysteine ​​sites of the IgG antibody. In embodiments, the Disclosure provides an antibody-drug conjugate (ADC) having an IgG antibody that binds to a B7-H3 target, wherein the ADC is conjugated at one or more lysine sites of the IgG antibody. In embodiments, the Disclosure provides an antibody-drug conjugate (ADC) having a modified IgG antibody that binds to a B7-H3 target. The Disclosure further provides a method for treating ovarian, colon, prostate, skin, pancreatic, kidney, urothelial or lung cancer, comprising the step of providing an effective amount of B7-H3 ADC. In one embodiment, equation (I):

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[0019] In one embodiment, a method for treating B7-H3 expressing cancer in a subject requiring such treatment is provided herein, comprising the step of administering to the subject an ADC described herein (including embodiments, examples, tables, examples, or claims) or a pharmaceutically acceptable salt thereof. In one embodiment, equation (I)

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[0020] In one embodiment, a pharmaceutical composition comprising an ADC described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive is provided herein. [Brief explanation of the drawing]

[0021] [Figure 1] Figure 1 shows the chemical structures of the linker-payload compounds linked to the anti-B7-H3 antibody to synthesize ADCs used in in vitro and in vivo efficacy studies.

[0022] [Figure 2A] Figure 2A shows the results of B7-H3 receptor quantification experiments in various human cancer cell lines (Hs700T, Calu6, U2OS, A375, FaDu, H1703, PA-1, Paca-2, A549, MDA-MB-468, and NCI-H929). Figure 2B shows the results of anti-B7-H3 antibody binding by human B7-H3 protein as evaluated by ELISA assay. [Figure 2B] Figure 2A shows the results of B7-H3 receptor quantification experiments in various human cancer cell lines (Hs700T, Calu6, U2OS, A375, FaDu, H1703, PA-1, Paca-2, A549, MDA-MB-468, and NCI-H929). Figure 2B shows the results of anti-B7-H3 antibody binding by human B7-H3 protein as evaluated by ELISA assay.

[0023] [Figure 3AB]Figures 3A-E show the results of in vitro efficacy studies of anti-B7-H3 antibody (Sorrento, Daiichi, or Macrogenics)-conjugated duostatin derivatives (ADCs) in Hs700T(B7-H3+) cells (Figure 3A), Calu6(B7-H3+) cells (Figure 3B), U2OS(B7-H3+) cells (Figure 3C), PA-1(B7-H3+) cells (Figure 3D), and H929(B7-H3-) cells (Figure 3E). [Figure 3CD] Figures 3A-E show the results of in vitro efficacy studies of anti-B7-H3 antibody (Sorrento, Daiichi, or Macrogenics)-conjugated duostatin derivatives (ADCs) in Hs700T(B7-H3+) cells (Figure 3A), Calu6(B7-H3+) cells (Figure 3B), U2OS(B7-H3+) cells (Figure 3C), PA-1(B7-H3+) cells (Figure 3D), and H929(B7-H3-) cells (Figure 3E). [Figure 3E] Figures 3A-E show the results of in vitro efficacy studies of anti-B7-H3 antibody (Sorrento, Daiichi, or Macrogenics)-conjugated duostatin derivatives (ADCs) in Hs700T(B7-H3+) cells (Figure 3A), Calu6(B7-H3+) cells (Figure 3B), U2OS(B7-H3+) cells (Figure 3C), PA-1(B7-H3+) cells (Figure 3D), and H929(B7-H3-) cells (Figure 3E).

[0024] [Figure 4A] Figures 4A-E show the results of in vitro efficacy studies of anti-B7-H3 antibody-conjugated camptothecin derivatives (ADCs) in Hs700T(B7-H3+) cells (Figure 4A), Calu6(B7-H3+) cells (Figure 4B), U2OS(B7-H3+) cells (Figure 4C), PA-1(B7-H3+) cells (Figure 4D), and NCI-H929(B7-H3-) cells (Figure 4E). [Figure 4BC]Figures 4A-E show the results of in vitro efficacy studies of anti-B7-H3 antibody-conjugated camptothecin derivatives (ADCs) in Hs700T(B7-H3+) cells (Figure 4A), Calu6(B7-H3+) cells (Figure 4B), U2OS(B7-H3+) cells (Figure 4C), PA-1(B7-H3+) cells (Figure 4D), and NCI-H929(B7-H3-) cells (Figure 4E). [Figure 4DE] Figures 4A-E show the results of in vitro efficacy studies of anti-B7-H3 antibody-conjugated camptothecin derivatives (ADCs) in Hs700T(B7-H3+) cells (Figure 4A), Calu6(B7-H3+) cells (Figure 4B), U2OS(B7-H3+) cells (Figure 4C), PA-1(B7-H3+) cells (Figure 4D), and NCI-H929(B7-H3-) cells (Figure 4E).

[0025] [Figure 5] Figures 5A and 5B show the results of anti-B7-H3 antibody (Sorrento, Daiichi, or Macrogenics)-conjugated duostatin derivatives (ADCs) in PA-1(B7-H3+) cells (Figure 5A) and H929(B7-H3-) cells (Figure 5B).

[0026] [Figure 6] Figures 6A and 6B show the results of in vivo efficacy studies of anti-B7-H3 antibody-conjugated camptothecin derivatives (ADCs) in PA-1 xenografts in Nu / Nu nude mice, where mice were treated intravenously once with 10 mg / kg of ADC. Figure 6A shows tumor volume as a function of time. Figure 6B shows the percentage change in tumor volume as a function of time (same experiment as Figure 3A).

[0027] [Figure 7]Figures 7A and 7B show the results of in vivo efficacy studies of anti-B7-H3 antibody-conjugated duostatin derivatives (ADCs) in PA-1 xenografts in Nu / Nu nude mice, where mice were treated intravenously once with 5 mg / kg of ADC. Figure 7A shows tumor volume as a function of time. Figure 7B shows the percentage change in tumor volume (same experiment as Figure 7A) as a function of time.

[0028] [Figure 8] Figures 8A and 8B show the results of in vivo toxicity studies in Nu / Nu nude mice after the treatment described in Figure 6. Figure 8B shows the body weight of ADC-treated mice. Figure 8B also shows the percentage change in body weight in ADC-treated mice. [Modes for carrying out the invention]

[0029] Detailed description of the invention Definition: Unless otherwise defined, the specialized and scientific terms used herein have the meanings generally understood by those skilled in the art. Generally, the terminology relating to cell and tissue culture, molecular biology, immunology, microbiology, genetics, transgenic cell production, protein chemistry and nucleic acid chemistry, and hybridization techniques described herein are well known and commonly used in the art. The methods and techniques provided herein are generally conventional methods well known in the art unless otherwise indicated. The procedure is carried out as described in the various general and more specific references cited and discussed herein. 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., See Current Protocols in Molecular Biology, Greene Publishing Associates (1992). Numerous basic textbooks describe standard antibody production procedures, including Borrebaeck (ed) Antibody Engineering, 2nd Edition Freeman and Company, NY, 1995;McCafferty et al. Antibody Engineering, A Practical Approach IRL at Oxford Press, Oxford, England, 1996; and Paul (1995) Antibody Engineering Protocols Humana Press, Towata, NJ, 1995; Paul (ed.), Fundamental Immunology, Raven Press, NY, 1993; Coligan (1991) Current Protocols in Immunology Wiley / Greene, NY;Harlow and Lane (1989) Antibodies: A Laboratory Manual Cold Spring Harbor Press, NY;Stites et al. (eds.) Basic and Clinical Immunology (4th ed.) Lange Medical Publications, Los Altos, Calif., and the references cited therein; Coding Monoclonal Antibodies: Principles and Practice (2nd ed.) Academic Press, New York, NY, 1986; and Kohler and Milstein Nature 256: 495-497, 1975. All references cited herein are incorporated herein by reference in their entirety. Enzymatic reactions and concentration / purification techniques are also well known and performed according to the manufacturer's specifications, as is commonly done in the art, or as described herein. The terminology used in relation to analytical chemistry, synthetic organic chemistry, medicinal chemistry, and pharmaceutical chemistry described herein, as well as the testing methods and experimental techniques of said chemistry, are well known and commonly used in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation, and delivery, as well as in patient care.

[0030] The titles provided herein are not intended to limit the various aspects of this disclosure, and the various aspects of this disclosure can be understood by referring to this specification as a whole.

[0031] Unless otherwise intended by context, singular terms include plural terms, and plural terms include singular terms. The singular forms "(a) one," "(an) one," and "(the) that," as well as the singular form of any word, include plural referents unless explicitly and clearly limited to a single referent.

[0032] The use of alternatives (e.g., "or") in this specification is understood to mean either one or both of the alternatives, or any combination thereof.

[0033] As used herein, the term "and / or" should be understood to mean a specific disclosure of each of the specified features or components, whether accompanied or not accompanied by others. For example, when the term "and / or" is used herein in a phrase such as "A and / or B," it is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, when the term "and / or" is used in a phrase such as "A, B and / or C," it is intended to include each of the following embodiments: 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).

[0034] As used herein, the term “about” means a value or composition that is within a tolerance range for a particular value or composition as determined by those skilled in the art, and this tolerance range will depend in part on the method by which the value or composition is measured or determined, i.e., on the limitations of the measurement system. For example, “about” or “approximately” means according to practice in the art. This can mean a standard deviation of 1 or less, or a standard deviation greater than 1. Alternatively, "approximately" or "about" can mean a range of 10% (i.e., ±10%) or more, depending on the limitations of the measurement system. For example, approximately 5 mg may include any number between 4.5 mg and 5.5 mg. Furthermore, particularly with respect to living systems or biological processes, these terms may mean an order of magnitude or less, or five times or less, of the value. Where a particular value or composition is provided in this disclosure, unless otherwise stated, the meaning of "approximately" or "about" should be considered to be within the tolerance range for that particular value or composition. In embodiments, approximately includes the specified value. 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.

[0035] In this disclosure, “comprises,” “comprising,” “contains,” and “have,” etc., may have the meanings attributed to them in U.S. patent law, and may mean “includes,” “including,” etc. Similarly, “consisting essentially of” or “consists essentially” has the meanings defined in U.S. patent law, and this term is non-restrictive and therefore permits the existence of more than those listed, provided that the basic or novel features of those listed are not altered by the existence of more than those listed, but excludes prior art embodiments.

[0036] As used herein, the terms “polypeptide,” “peptide,” and “protein,” as well as other related terms, are used synonymously to refer to polymers of amino acid residues, which, in embodiments, may also be conjugated to portions that are not amino acids. These terms apply not only to naturally occurring and non-naturally occurring amino acid polymers, but also to amino acid polymers in which one or more amino acid residues are artificial chemical mimics of corresponding naturally occurring amino acids. A “fusion protein” refers to a chimeric protein that encodes two or more separate protein sequences that are recombinantly expressed as a single portion. A polypeptide includes a cleaved mature molecule. These terms encompass native and artificial proteins, protein fragments, and polypeptide analogs of protein sequences (e.g., mutant proteins, variants, chimeric proteins, and fusion proteins), as well as proteins that have been post-translationally modified, or otherwise covalently or non-covalently modified. Two or more polypeptides (e.g., three polypeptide chains) may associate with each other by covalent and / or non-covalent association to form a multimeric polypeptide complex (e.g., a multispecific antigen-binding protein complex). The association of polypeptide chains can also include peptide folding. Therefore, polypeptide complexes can be dimers, trimers, tetramers, or higher-order complexes, depending on the number of polypeptide chains forming the complex.

[0037] As used herein, the terms “cancer,” “neoplasm,” and “tumor” are used synonymously, and in both singular and plural forms, refer to cells that have undergone malignant transformation to become pathogenic to a host organism. Primary cancer cells can be readily distinguished from non-cancerous cells by 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 ancestral cells. This includes metastatic cancer cells, as well as in vitro cultures and cell lines derived from cancer cells. When referring to types of cancer that typically manifest as solid tumors, a “clinically detectable” tumor is one that is detectable based on tumor volume by procedures such as computed tomography (CT) scans, magnetic resonance imaging (MRI), X-rays, ultrasound, or palpation during a physical examination, and / or one or more cancers in a sample obtainable from a patient. These can be detected by the expression of specific antigens. Tumors can also be hematopoietic cancers (or hematologic cancers, hematological cancers, or blood-related cancers), such as cancers originating from blood cells or immune cells, which may be called “humoral tumors.” Specific examples of clinical conditions based on hematological tumors include leukemia, e.g., chronic myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and acute lymphoblastic leukemia; plasma cell malignancies, e.g., multiple myeloma, MGUS, and Waldenström macroglobulinemia; and lymphomas, e.g., non-Hodgkin lymphoma, Hodgkin lymphoma.

[0038] The term “cancer” refers to any type of cancer, neoplasm, or malignant tumor found in mammals (e.g., humans), including leukemia, lymphoma, carcinoma, and sarcoma. In embodiments, the ADCs and methods provided herein are useful for treating B7-H3 expressing cancers. In embodiments, B7-H3 expressing cancers are solid tumors. Cancers can be any cancer diagnosed as: breast cancer, including metastatic breast cancer, which has an abnormal number of blast cells or undesirable cell proliferation; esophageal cancer, including squamous cell carcinoma, particularly adenocarcinoma; ovarian cancer, including epithelial ovarian cancer; endometrial cancer, including endometrial cancer such as endometrial serous carcinoma; lung cancer, including non-small cell lung cancer and small cell lung cancer; prostate cancer; colon cancer; liver cancer; bladder cancer; pancreatic cancer; stomach cancer; skin cancer; and kidney cancer.

[0039] In the embodiments, cancers include non-small cell lung cancer, small cell lung cancer, renal cancer, urothelial carcinoma, colon cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, and pancreatic cancer (Johnson, KA et al, 2007, Analytical Biochemistry, 360:75 - 83; Winter, G. et al., 1994, Annu. Rev. Immunol., 12:433 - 455; Ashraf, SQ et al., 2009, British Journal Of Cancer 101(10):1758 - 1768; Barbara, BM and Stanley, MS, 1980, "Selected Methods in Cellular Immunology";WH Freeman and company;Yamato, I. et al., 2009, British Journal Of Cancer 101(10):1709 - 1716;Sun, J. et al., 2010, Cancer Immunology, Immunotherapy 59: 1163 - 1171;Roth, TJ et al., 2007, Cancer Research 67: 7893 - 7900; Carmen, S. et al., 2002, Briefings In Functional Genomics and Proteomics 1(2):189 - 203). In prostate cancer, B7-H3 expression intensity has been reported to be positively correlated with clinicopathological malignancy, such as tumor volume, extraprostatic invasion, and Grimson score, as well as cancer progression. (Yamato, I. et al., 2009, British Journal of Cancer 101(10):1709 - 1716). Similarly, B7-H3 expression and recurrence-free survival are negatively correlated in glioblastoma multiforme (Sun, J. et al., 2010, Cancer Immunology, Immunotherapy 59: 1163 - 1171). In pancreatic cancer, B7-H3 expression is correlated with lymph node metastasis and disease progression (Carmen, S. et al., 2002, Briefings in Functional Genomics and Proteomics 1(2):189 - 203). In ovarian cancer, B7-H3 expression is correlated with lymph node metastasis and disease progression.

[0040] In embodiments, cancer includes, but is not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemia or lymphoid malignancies. In embodiments, cancer includes glioblastoma, glioma, neuroblastoma, melanoma, hepatocellular carcinoma, clear cell renal cell carcinoma, acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), colorectal cancer, oral cancer, head and neck cancer, breast cancer (e.g., triple-negative breast cancer), squamous cell tumor, hypopharyngeal squamous cell carcinoma, squamous cell carcinoma (e.g., squamous cell lung cancer) or head and neck squamous cell carcinoma (squamous This includes cell head and neck cancer, urothelial cell carcinoma, gastric cancer, anal cancer, endometrial cancer, and vulvar cancer. In embodiments, the cancer may be metastatic, refractory, or recurrent.

[0041] The B7-H3 protein is overexpressed in various human tumors, and methods commonly used in this art, such as immunohistochemical staining (IHC) to evaluate the overexpression of the B7-H3 protein, or fluorescence in to evaluate the amplification of the B7-H3 gene, have been used. It can be evaluated using situ hybridization (FISH). B7-H3 is overexpressed in high-grade prostatic intraepithelial neoplasms and prostatic adenocarcinomas.

[0042] The term "carcinoma" refers to a new, malignant growth composed of epithelial cells that tends to invade surrounding tissues and metastasize.

[0043] As used herein, the terms “metastasis,” “metastatic,” and “metastatic cancer” may be used synonymously and may refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or part of the body. “Metastatic cancer” is also called “stage IV cancer.” Cancer originates in a site of origin, e.g., the breast, which is also called a primary tumor, e.g., primary breast cancer. Some cancer cells in a primary tumor or site of origin acquire the ability to penetrate and invade the surrounding normal tissue in a local area, and / or to penetrate the walls of the lymphatic or vascular system and circulate through the system to other parts and tissues in the body. A second clinically detectable tumor formed from cancer cells of a primary tumor is called a metastatic or secondary tumor. When cancer cells have metastasized, the metastatic tumor and its cells are presumed to be similar to those of the primary tumor. Therefore, if lung cancer has metastasized to the breast, the secondary tumor in that site of the breast will consist of abnormal lung cells, not abnormal breast cells. This secondary tumor in the breast is called metastatic lung cancer. Therefore, the phrase metastatic cancer refers to a disease in which the subject currently or has previously had a primary tumor and currently has one or more secondary tumors. The phrase non-metastatic cancer, or subject with non-metastatic cancer, refers to a disease in which the subject has a primary tumor but does not have one or more secondary tumors. For example, metastatic lung cancer refers to a disease in a subject who has or has a history of a primary lung tumor and has one or more secondary tumors in a second or more locations, such as the breast.

[0044] Exemplary cancers that can be treated with ADCs or methods provided herein include ovarian, colon, prostate, skin, pancreatic, kidney, urothelial, and lung cancers.

[0045] In embodiments, cancers that can be treated with ADC or methods provided herein include acute myeloid lymphoma (AML), non-Hodgkin lymphoma (NHL), non-small cell lung cancer (NSCLC), small cell lung cancer, urothelial cell carcinoma, esophageal cancer, hepatocellular carcinoma, glioma, neuroblastoma, glioblastoma multiforme, blastoma, sarcoma, leukemia, lymphoid malignancies, pancreatic cancer, head and neck cancer, ovarian cancer, oral cancer, breast cancer, triple-negative breast cancer (TNBC), lymphoma, renal cell carcinoma, clear cell renal cell carcinoma, colon cancer, colorectal cancer, melanoma, gastric cancer, lung cancer, liver cancer, bladder cancer, prostate cancer, anal cancer, endometrial cancer, vulvar cancer, squamous cell tumors, hypopharyngeal squamous cell carcinoma, or squamous cell carcinoma (e.g., lung squamous cell carcinoma or head and neck squamous cell carcinoma).

[0046] In this embodiment, the cancer is metastatic cancer, refractory cancer, or recurrent cancer.

[0047] As used herein, “antibody” and “antibodies” and related terms refer to intact immunoglobulin or its antigen-binding moiety that specifically binds to an antigen. The antigen-binding moiety may be produced by recombinant DNA technology or by enzymatic or chemical cleavage of intact antibodies. Antigen-binding moieties include, among others, Fab, Fab', and F(ab'). 2 A polypeptide comprising, Fv, domain antibody (dAb), and complementarity-determining region (CDR) fragment, single-chain antibody (scFv), chimeric antibody, diabody, triabody, tetrabody, and at least a portion of immunoglobulin, one The polypeptide comprises a portion that is sufficient to bring a specific antigen binding to the polypeptide.

[0048] Antibodies include recombinantly produced antibodies and antigen-binding moieties. Antibodies include non-human, chimeric, humanized, and fully human antibodies. Antibodies include monospecific and multispecific (e.g., bispecific, triplicate, and higher-order specificity) antibodies. Antibodies include tetrameric antibodies, light chain monomers, heavy chain monomers, light chain dimers, and heavy chain dimers. Antibodies include F(ab') 2 The antibodies include fragments, Fab' fragments, and Fab fragments. The antibodies include single-domain antibodies, monovalent antibodies, single-chain antibodies, single-chain variable fragments (scFv), camelized antibodies, aphibodies, disulfide-linked Fv (sdFv), anti-idiotype antibodies (anti-Id), and minibodies. The antibodies include monoclonal and polyclonal populations. Anti-B7-H3 antibodies are described herein.

[0049] The term "monoclonal antibody," as used herein, refers to an antibody obtained from a substantially homogeneous population of antibodies; that is, the individual antibodies constituting the population are identical and / or bind to the same epitope, with the exception of possible variant antibodies, such as those containing spontaneous mutations or arising during the production of monoclonal antibody preparations, which generally exist in small amounts. In contrast to polyclonal antibody preparations, which typically contain different antibodies against different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is an antibody against a single determinant on an antigen. Therefore, the modifier "monoclonal" indicates a characteristic of the antibody that it is obtained from a substantially homogeneous population of antibodies, and this modifier should not be interpreted as requiring the production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with the present invention can be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals having all or part of a human immunoglobulin locus, and such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0050] As used herein, “epitope” and related terms refer to a portion of an antigen that is bound by an antigen-binding protein (e.g., by an antibody or its antigen-binding moiety). An epitope may comprise two or more portions of an antigen that are bound by an antigen-binding protein. An epitope may comprise discontinuous portions of an antigen, or two or more portions of an antigen (e.g., amino acid residues that are not contiguous in the primary sequence of the antigen, but are close enough to each other to be bound by an antigen-binding protein in the context of the tertiary and quaternary structures of the antigen). Generally, the variable region of an antibody, particularly the CDR, interacts with an epitope. Anti-B7-H3 antibodies that bind to epitopes of the B7-H3 polypeptide and their antigen-binding proteins are described herein.

[0051] As used herein, “antibody fragment,” “antibody moiety,” “antigen-binding fragment of an antibody,” or “antigen-binding moiety of an antibody,” and other related terms refer to molecules other than the intact antibody, including a portion of the intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include Fv, Fab, Fab', Fab'-SH, and F(ab'). 2 Examples include, but are not limited to, polypeptides containing at least a portion of an antibody, such as Fd and Fv fragments, as well as dAb; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and polypeptides in which the portion is sufficient to confer specific antigen binding to the polypeptide. The antigen-binding portion of an antibody may be produced by recombinant DNA technology or by enzymatic or chemical cleavage of an intact antibody. Antigen-binding portions include, in particular, Fab, Fab', F(ab')2, Fv, domain antibodies (dAb), and complementarity-determining region (CDR) fragments, chimeric antibodies, diabodies, triabodies, tetrabodies, and polypeptides containing at least a portion of an immunoglobulin sufficient to confer antigen-binding properties to an antibody fragment. It contains lipeptides. Antigen-binding fragments of anti-B7-H3 antibodies are described herein.

[0052] Antigen-binding proteins may have structures such as immunoglobulins. In one embodiment, “immunoglobulin” refers to a tetrameric molecule. Each tetrameric molecule consists of two identical pairs of polypeptide chains, each pair having one “light” chain (approximately 25 kDa) and one “heavy” chain (approximately 50–70 kDa). The N-terminus of each chain defines a variable region of approximately 100–110 amino acids or more, primarily involved in antigen recognition. The carboxyl-terminus of each chain defines a constant region primarily involved in effector function. Human light chains are classified as kappa or lambda light chains. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, defining antibody isotypes as IgM, IgD, IgG, IgA, and IgE, respectively. The variable and constant regions within the light and heavy chains are linked by "J" regions with approximately 12 or more amino acids, and the heavy chain also includes "D" regions with approximately 10 or more amino acids. See, for general reference, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)) (the entire work is incorporated herein by reference for all purposes). The variable regions of each light / heavy chain pair form antibody-binding sites, and thus, intact immunoglobulins have two antigen-binding sites. In one embodiment, the antigen-binding protein may be a synthetic molecule that, while different from the tetrameric immunoglobulin molecule, still has a structure that binds to a target antigen or to two or more target antigens. For example, a synthetic antigen-binding protein may include an antibody fragment, 1 to 6 or more polypeptide chains, an asymmetric assembly of polypeptides, or other synthetic molecules. (Terms: "variable heavy chain", "V") H "VH" refers to the variable region of the immunoglobulin heavy chain, including Fv, scFv, dsFv, or Fab, while the term "variable light chain" refers to the "VH" region. L "VH" or "VL" refers to the variable region of an 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 that is involved in the binding of the antibody to the antigen. The variable domains of the heavy and light chains of native antibodies (VH and VL, respectively) generally have a similar structure, with each domain containing four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, for example, Kindt et al. Kuby Immunology, 6th ed., WH Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen can be isolated using the VH or VL domain from antibodies that bind to that antigen, and libraries of complementary VL or VH domains can be screened, respectively. See, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991). Antigen-binding proteins having immunoglobulin-like properties that specifically bind to B7-H3 are described herein.

[0053] Examples of functional fragments of antibodies include, but are not limited to, complete antibody molecules, antibody fragments such as Fv, single-chain Fv (scFv), complementarity-determining region (CDR), VL (light chain variable region), VH (heavy chain variable region), Fab, F(ab)2', and any combination thereof, or any other functional part of an immunoglobulin peptide that can bind to a target antigen (e.g., Fundamental Immunology (Paul ed., 4th ed.)). See 2001). As will be understood by those skilled in the art, various antibody fragments can be obtained by various methods, e.g., digestion of intact antibodies with enzymes such as pepsin, or by de novo synthesis. Antibody fragments are often de novo synthesized either chemically or by using recombinant DNA methodologies. Thus, as used herein, the term antibody includes any antibody fragment produced by modification of a whole antibody, or one that has been de novo synthesized using recombinant DNA methodologies (e.g., single-stranded Fv), or one that has been identified using a phage display library (e.g., McCafferty et al., (1990) Nature 348:552). The term “antibody” includes a divalent or bispecific molecule, diabode This also includes triabodies and tetrabodies. Divalent and bispecific molecules are, for example, Kostelny et al. (1992) J. Immunol. 148:1547, Pack and Pluckthun (1992). Biochemistry 31:1579, Hollinger et al. (1993), PNAS. USA 90:6444, Gruber et al. (1994) J Immunol. 152:5368, Zhu et al. (1997) Protein Sci. 6:781, Hu et al. (1996) Cancer Res. 56:3055, Adams et al. (1993) Cancer This is described in Res. 53:4026 and McCartney, et al. (1995) Protein Eng. 8:301.

[0054] 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, if necessary, a scaffold or framework portion that causes the antigen-binding portion to adopt a three-dimensional structure 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 grafted CDRs or CDR derivatives. Such scaffolds include, but are not limited to, antibody-derived scaffolds containing introduced mutations to stabilize the three-dimensional structure of the antigen-binding protein, as well as fully synthetic scaffolds containing, for example, biocompatible polymers. See, for example, Korndorfer et al., 2003. See Proteins: Structure, Function, and Bioinformatics, Volume 53, Issue 1:121-129; Roque et al., 2004, Biotechnol. Prog. 20:639-654. In addition, peptide antibody mimes ("PAMs") can be used, and antibody mime-based scaffolds that utilize fibronectin components as a scaffold can also be used. Antigen-binding proteins that bind to B7-H3 are described herein.

[0055] In one embodiment, a BIACORE surface plasmon resonance (SPR) assay is used to determine the dissociation constant (K D Surface plasmon resonance can be measured, for example, in the BIACORE system (Biacore Life Sciences division of This refers to an optical phenomenon that enables real-time interaction analysis by detecting changes in protein concentration within a biosensor matrix using GE Healthcare (Piscataway, NJ).

[0056] Where used throughout this specification in reference to anti-B7-H3 antigen-binding proteins, "specifically binds" means that the antigen-binding protein binds to human B7-H3 (hB7-H3) with little to no binding to other human proteins. However, this term does not exclude the fact that the antigen-binding proteins of the present invention may cross-react with other forms of B7-H3, such as primate B7-H3. In one embodiment, the antibody binds to the antigen, and 10 -5 M or less, or 10 -6 M or less, or 10 -7 M or less, or 10 -8 M or less, or 10 -9 M or less, or 10 -10 M or a dissociation constant less than M, K. D If present, the antibody specifically binds to the target antigen.

[0057] When used herein, the term "B7-H3" refers, unless otherwise indicated, to any native B7-H3 from any vertebrate source, including mammals, e.g., primates (e.g., humans, cynomolgus monkeys (cynos)), and rodents (e.g., mice and rats). This term encompasses not only "full-length" unprocessed B7-H3, but also any form of B7-H3 resulting from cellular processing. This term also encompasses naturally occurring variants of B7-H3, e.g., splice variants, allele variants, and isoforms. The amino acid sequence of an exemplary human B7-H3 protein is shown in SEQ ID NO: 16.

[0058] The term "B7-H3 expressing cancer" refers to cancer that includes cells that express B7-H3 on their surface. In the embodiment, the term "B7-H3 expressing cancer" refers to cancer that includes cells that internalize B7-H3 within the cell.

[0059] The terms “anti-B7-H3 antibody” and “antibody that binds to B7-H3” refer to an antibody that can bind to B7-H3 with sufficient affinity for it to be useful as a therapeutic agent for targeting B7-H3. In one embodiment, the degree of binding of the anti-B7-H3 antibody to unrelated non-B7-H3 proteins is less than about 10% of the binding of the antibody to B7-H3, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the antibody that binds to B7-H3 has a molecular weight of ≤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 -8 M or less, for example, 10 -8 M~10 -13 M, for example, 10 -9 M~10 -13 It has a dissociation constant (Kd) of M). In certain embodiments, the anti-B7-H3 antibody binds to an epitope of B7-H3 that is conserved among B7-H3 from different species.

[0060] As used herein, the term “chimeric antibody” and related terms refer to an antibody containing 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 another embodiment, CDRs from one or more human antibodies are mixed and matched in the chimeric antibody. For example, a chimeric antibody includes CDR1 from the light chain of a first human antibody, CDR2 and CDR3 from the light chain of a second human antibody, and a CDR from the heavy chain of a third antibody. In another example, the CDRs are of different species, e.g., human and mouse, or human and rabbit, or human and goat. It will be understood by those skilled in the art that other combinations are possible.

[0061] Furthermore, the framework region may originate from the same antibody, from one or more different antibodies, such as human antibodies, or from a humanized antibody. In an example of a chimeric antibody, a portion of the heavy chain and / or light chain is identical, homologous, or derived from an antibody from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical, homologous, or derived from an antibody from another species or belonging to another antibody class or subclass. Fragments of such antibodies exhibiting 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-B7-H3 antibodies described herein.

[0062] "Effector function" refers to the biological activity resulting from the Fc region of an antibody, which varies depending on the antibody isotype. Examples of antibody effector functions include C1q binding and complement-dependent cell-mediated 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.

[0063] The term “Fc” or “Fc region,” as used herein, refers to the portion of the constant region of an antibody heavy chain that begins within 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 having half of the Fc region, can dimerize to form an Fc region. The Fc region can bind to Fc cell surface receptors and to proteins of the immune complement system. The Fc region exhibits effector functions, including one or more of two or more activities, or any combination thereof, including complement-dependent cell-mediated cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent phagocytosis (ADP); opsonization and / or cell binding. The Fc region is FcγR It can bind to Fc receptors, including FcγRII (e.g., CD64), FcγRII (e.g., CD32), and / or FcγRIII (e.g., CD16a).

[0064] A "humanized antibody" refers to an antibody having a sequence that differs from that of an antibody derived from a non-human species in terms of one or more amino acid substitutions, deletions, and / or additions, and therefore, when administered to a human subject, a humanized antibody is less likely to induce an immune response and / or induces a less severe immune response compared to a non-human antibody. In one embodiment, certain amino acids in the heavy and / or light chain framework and constant domain of a non-human antibody are mutated to produce a humanized antibody. In another embodiment, a constant domain from a human antibody is fused to a variable domain of 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 possible immunogenicity of the non-human antibody when administered to a human subject, and the altered amino acid residues are not important for the antibody's immune-specific binding to its antigen, or the added amino acid sequence alteration is not a conservative alteration, and therefore, the binding of the humanized antibody to the antigen is not significantly worse than that of the non-human antibody. Examples of methods for producing humanized antibodies can be found in U.S. Patent Nos. 6,054,297, 5,886,152, and 5,877,293.

[0065] 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 methodologies or by immunization with the antigen of interest of a mouse genetically modified to express antibodies derived from human heavy and / or light chain coding genes. Fully human anti-B7-H3 antibodies and their antigen-binding proteins are described herein. This definition of human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0066] The term “isolated” means altered “by human hands” from its natural state, changed or removed from its original environment, or both. When applied to nucleic acids or proteins, “isolated” indicates that the nucleic acid or protein is essentially free from other cellular components with which it naturally associates. It may be, for example, homogeneous, or in either a dry place or an aqueous solution. Purity and homogeneity are usually determined using analytical chemistry techniques, such as polyacrylamide gel electrophoresis, high-performance liquid chromatography, or mass spectrometry. The protein, which is the main species present in the preparation, is substantially purified. For example, a polynucleotide or polypeptide that naturally exists in a living organism is not “isolated,” but the same polynucleotide or polypeptide that has been separated from the material with which it naturally coexists is “isolated,” but such polynucleotide or polypeptide is “isolated,” even if the cell is of the same species or type as the cell from which the polynucleotide or polypeptide was separated, for example, when such polynucleotide or polypeptide has been introduced into a cell and returned.

[0067] "CDR" is defined as the complementarity-determining region amino acid sequence of an antibody, which is the hypervariable domain of the immunoglobulin heavy chain and light chain. The variable region of an immunoglobulin contains three heavy chain and three light chain CDRs (or CDR regions). Therefore, as used herein, "CDR" may refer to all three heavy chain CDRs or all three light chain CDRs (or, as appropriate, both all heavy chain CDRs and all light chain CDRs).

[0068] CDRs provide the majority of contact residues for antibody binding to an antigen or epitope. The CDRs of interest in this invention are derived from donor antibody variable heavy and light chain sequences and include naturally occurring CDR analogs, which are also analogs of donor antibodies from which they are derived. It shares or retains the same antigen-binding specificity and / or neutralizing ability as the body.

[0069] The CDR sequence of the antibody is assigned to the Kabat numbering system (Kabat et al; (Sequences of They can be determined by the proteins of Immunological Interest (NIH, 1987), or by using the Chothia numbering system (Al-Lazikani et al., (1997) 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 for numbering residues in antibodies and determining CDRs that is known to those skilled in the art.

[0070] Other numbering methods for CDR sequences available to those skilled in the art include the "AbM" (University of Bath) and "Contact" (University College London) methods. The minimum overlap region can be determined using at least two of the Kabat, Chothia, AbM, and Contact methods to obtain the "minimum binding unit." The minimum binding unit may be a sub-part of the CDR.

[0071] "Affinity" refers to the total strength 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 intrinsic binding affinity, which represents the 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y can generally be expressed by a dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific, descriptive, and exemplary embodiments for measuring binding affinity are described below.

[0072] An "affinity-matured" antibody refers to an antibody that has one or more modifications in one or more hypervariable regions (HVRs) that result in improved antibody affinity for an antigen compared to a parent antibody that does not have such modifications.

[0073] As used herein, the terms “variant” polypeptide and “variant” polypeptide refer to a polypeptide comprising an amino acid sequence in which one or more amino acid residues are inserted into, deleted from, and / or substituted within an amino acid sequence compared to a reference polypeptide sequence. Polypeptide variants include fusion proteins. Similarly, variant polynucleotides comprise a nucleotide sequence in which one or more nucleotides are inserted into, deleted from, and / or substituted within a nucleotide sequence compared to another polynucleotide sequence. Polynucleotide variants include fusion polynucleotides.

[0074] As used herein, the term “domain” refers to a folded protein structure having a tertiary structure independent of the rest of the protein. Generally, a domain is responsible for a distinct functional property of a protein and can often be added to, removed from, or transferred to other proteins without loss of function of the rest of the protein and / or domain. An “antibody single variable domain” is a folded polypeptide domain containing sequences specific to an antibody variable domain. Thus, it includes a complete antibody variable domain; and modified variable domains, e.g., modified variable domains in which one or more loops are replaced by sequences not specific to the antibody variable domain; or antibody variable domains that are shortened or include N-terminal or C-terminal extensions; and folded fragments of variable domains that retain at least the binding activity and specificity of the full-length domain.

[0075] As used in this text, the term "cytotoxic agent" refers to a substance that inhibits or interferes with the function of a cell 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 Radioisotopes of Pb and Lu; chemotrexate or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other inserts); growth inhibitors; enzymes and their fragments, e.g., nucleases; antibiotics; toxins, e.g., small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof; and various antitumor or anticancer agents disclosed below.

[0076] "Chemotherapy agents" are chemical substances that are useful in treating cancer. Examples of chemotherapeutic agents include: alkylating agents, e.g., thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates, e.g., busulfan, improsulfan and pigosulfan; aziridines, e.g., benzodopa, carbocone, metsuredopa and uredopa; ethyleneimines and methylamelamines (including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine); acetogenins (especially bratacin and bratacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-rapacone; lapacol; colchicine; betulinic acid; camptothecin (synthetic analogues include topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®)); and Cetylcamptothecin, including scopoletin and 9-aminocamptothecin; bryostatin; callistatin; CC-1065 (including its adzeresin, karzeresin and bizeresin synthetic analogs); podophyllotoxin; podophyllic acid; teniposide; cryptophycin (especially cryptophycin 1 and cryptophycin 8); dorastatin; duocalmycin (including its synthetic analogs KW-2189 and CB1-TM1); erytherovin; pancratista Sarcodicin; spongistatin; nitrogen mustards, e.g., chlorambucil, chlornafadin, chlorophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobembitin, fenesterine, prednimustine, trophosphamide, uracil mustard; nitrosoureas, e.g., carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine;Antibiotics, for example, engine antibiotics (e.g., calicheamicin, in particular calicheamicin gamma 1I and calicheamicin omega I1 (see, e.g., Agnew, Chem Intl. Ed. Engl., 33: 183-186 (1994)); dynemycin (including dynemycin A); esperamicin; and neocardinostatin chromophores and related pigment protein engine antibiotic chromophores), acrasinomycin, actinomycin, anthramycin, azaserin, bleomycin, kakutinomycin, carabicin, carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detrubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (morpholino-doxorubicin, cyanomorpholino-doxorubicin) (including 2-pyrrolinodoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, e.g., mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, porphyromycin, puromycin, queramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, solubicin; antimetabolites, e.g., methotrexate and 5-fluorouracil (5-FU); folic acid analogs, e.g., denopterin, methotrexate, pteropteri; Trimethrexate; purine analogs, e.g., fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, phloxuridine; androgens, e.g., carsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; corticosteroid synthesis inhibitors, e.g., aminoglutethimide, mitotane, trilostane; folic acid supplements, e.g., folic acid; acegraton; aldofrosphamide glycoside; aminolevulinic acid; enyluracil; amsacri. N; Bestlovesil; Bisantrene; Edatraxate; Defofamine; Demecolsin; Diadiquan; Eflornithine; Erliptinium acetate; Epotilon; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Maytansinoids, e.g., Maytansine and Anthamitosin; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraerine; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; 2-Ethylhydrazide; Procarbazine; PSK (Registered Trademark) Polysaccharide Complex (JHS Natural Products, Eugene, OR); Lazoxane; Rhizoxin; Schizophyllan; Spirogermanium; Tenuazonic Acid; Triadicone; 2,2',2''-Trichlorotriethylamine; Trichothecene (especially T-2 toxin, verracurin A, loridine A and anguidin); Urethane; Vindesine (ELDISINE®, FILDESIN®); Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacitosine; Arabinoside ("Ara-C"); Thiotepa; Taxoids, e.g., Paclitaxel (TAXOL®); Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® Paclitaxel Cremofoll-Free Albumin-Modified Nanoparticle Formulation (American Pharmaceutical Partners, Schaumberg, Illinois), and Docetaxel (TAXOTERE®; Rhone-Poulenc. Rorer, Antony, France); Chlorambucil; Gemcitabine (GEMZAR®); 6-Thiogunine; Mercaptopurine; Methotrexate; Platinum analogs, e.g., cisplatin and carboplatin; Vinblastine (VELBAN®); Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine (ONCOVIN®); Oxaliplatin; Leucovorin; Vinorelbine (NAVELBINE®); Novantrone; Edatrexate; Daunomycin; Aminopterin; Ibandronate; Topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, e.g., retinoic acid; capecitabine (XELODA®); pharmaceutically acceptable salts, acids or derivatives of any of the above; and combinations of two or more of the above, e.g., 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 using oxaliplatin (ELOXATIN®) in combination with 5-FU and leucovorin).

[0077] An "antibody-drug conjugate" or "ADC" is an antibody conjugated to one or more heterologous molecules, including but not limited to cytotoxic agents.

[0078] As used herein, the term “conjugated” when referring to two parts means that the two parts are joined together, and the joining (singular) or joining (plural) connecting the two parts may be covalent or non-covalent. In embodiments, the two parts are covalently joined to each other (e.g., directly or via an intermediate covalent joining). In embodiments, the two parts are non-covalently joined (e.g., (By on-bonds, van der Waals bonds / interactions, hydrogen bonds, polar bonds, or combinations or mixtures thereof).

[0079] The “individual” or “subject” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates, e.g., monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human. In certain embodiments, the subject is an adult, adolescent, child, or infant. In some embodiments, the terms “individual” or “patient” are used and intended to be synonymous with “subject.”

[0080] The "amino acid sequence identity percentage (%)" relative to the reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after the sequences have been aligned and gaps have been introduced as necessary to achieve the maximum possible sequence identity percentage. Alignment aimed at determining the percentage of amino acid sequence identity can be achieved in various ways within the scope of the skills in the art, for example, by utilizing the local homology algorithm by Smith and Waterman, 1981, Ads App. Math. 2, 482; by utilizing the local homology algorithm by Needleman and Wunsch, 1970, J. Mol. Biol. 48, 443; by utilizing the similarity search algorithm by Pearson and Lipman, 1988, Proc. Natl Acad. Sci. USA 88, 2444; or by utilizing a computer program that uses such algorithms (e.g., EMBOSS Needle or EMBOSS Water, available at www.ebi.ac.uk / Tools / psa / ). Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm necessary to achieve the greatest possible alignment over the entire length of the sequences being compared. The “percentage of sequence identity” or “[sequence] identity percentage (%)” as used herein is determined by comparing two optimally locally aligned sequences across a comparison window defined by the local alignment length between these two sequences. (This may also be considered a percentage of homology, or “homology percentage (%).”) The amino acid sequences within the comparison window may contain additions or deletions (e.g., gaps or overhangs) compared to the reference sequence for optimal alignment between the two sequences. The local alignment between the two sequences includes only segments of each sequence that appear sufficiently similar according to criteria that depend on the algorithm used to perform the alignment (e.g., EMBOSS Water).The “identical” or “identity” percentage refers to two or more sequences or subsequences that are the same or have a specific percentage of identical amino acid residues or nucleotides (i.e., when compared across a comparison window or designated region and aligned for maximum match, they have approximately 60% identity across a designated region, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity). The identity percentage is calculated by determining the number of positions in which identical nucleic acid bases or amino acid residues exist in both sequences to obtain the number of matched positions, dividing the number of matched 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 performed using the local homology algorithm of Smith and Waterman (Add. APL. Math. 2:482, 1981), the global homology alignment algorithm of Needleman and Wunsch (J. Mol. Biol. 48:443, 1970), the similarity search method of Pearson and Lipman (Proc. Natl. Acad. Sci. USA 85: 2444, 1988), or by inspection. As a further example, GAP and BESTFIT can be used to determine the optimal alignment of two sequences identified for comparison. Typically, a gap weight of 5.00 and a gap weight length of 0.30 are used. The default value will be used.

[0081] The comparison of sequences and the determination of the percentage of identity between two polypeptide sequences or two polynucleotide sequences can be performed 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 the sequences using the GAP computer program (part of the GCG Wisconsin Package, version 10.3 (Accelrys, San Diego, Calif.)) with its default parameters. Expressions such as "contains a sequence having at least X% identity with Y" mean that, when aligned with sequence Y as described above, the test sequence contains residues that are identical to at least X% of the residues of Y.

[0082] In one embodiment, the amino acid sequence of the test antibody may be similar, but not identical, to any of the amino acid sequences of the polypeptides constituting the multispecific antigen-binding protein complexes described herein. The similarity between the test antibody and the polypeptide may be at least 95% identical, at least 96% identical, at least 97% identical, at least 98% identical, or at least 99% identical to any of the polypeptides constituting the multispecific antigen-binding protein complexes described herein. In one embodiment, the similar polypeptides may contain amino acid substitutions in their heavy and / or light chains. In one embodiment, the amino acid substitutions include one or more conserved amino acid substitutions. A “conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). Generally, conservative amino acid substitutions will not substantially alter the functional properties of the protein. If two or more amino acid sequences differ from each other in terms of conservative substitutions, the sequence identity percentage or similarity can be adjusted up to compensate for the conservative nature of the substitutions. Means for making this adjustment are well known to those skilled in the art. For example, see Pearson (1994) Methods Mol. Biol. 24: 307-331, which is incorporated herein by reference in its entirety. Examples of groups of amino acids having side chains with similar chemical properties include: (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; (2) aliphatic-hydroxyl 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: aspartate and glutamate; and (7) sulfur-containing side chains: cysteine ​​and methionine.

[0083] Antibodies can be obtained from sources such as serum or plasma containing immunoglobulins with diverse antigen specificities. Such antibodies can be concentrated for specific antigen specificities by affinity purification. Such concentrated antibody preparations are typically made with less than 10% of the antibody having specific binding activity to a particular antigen. By subjecting these preparations to several rounds of affinity purification, the proportion of antibody with specific binding activity to the antigen can be increased. Antibodies prepared in this way are often called "monospecific." Monospecific antibody preparations may consist of approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 99.9% of antibody having specific binding activity to a particular antigen. Antibodies can be produced using recombinant nucleic acid technologies, as described below.

[0084] The term “vector,” as used herein, refers to a nucleic acid molecule capable of transmitting another nucleic acid to which the nucleic acid molecule is ligated. This term includes vectors as self-replicating nucleic acid structures, and vectors that are incorporated into the genome of a host cell into which such vector is introduced. Certain vectors can instruct the expression of the nucleic acid to which they are operably ligated. Such vectors are referred to herein as “expression vectors.”

[0085] The terms “host cell,” “host cell line,” and “host cell culture” are used synonymously and refer to cells into which exogenous nucleic acids have been introduced, including their offspring. Host cells include “transformed organisms” and “transformed cells,” which include primary transformed cells and their offspring, regardless of passage number. Offspring may not be completely identical to the parent cells in terms of nucleic acid content and may contain mutations. Mutant offspring having the same function or biological activity as those screened or selected in the initially transformed cells are included herein.

[0086] The term “pharmaceutically acceptable salt” is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. If a compound of the disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. If a compound of the disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either neat 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, monocarbonate, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, and methanesulfonic acid. Salts of amino acids such as alginates, as well as salts of organic acids such as glucuronic acid or galacturonic acid, are also included (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds in this disclosure contain both basic and acidic functional groups, which enable the conversion of the compound into either a base addition salt or an acid addition salt.

[0087] Accordingly, the compounds of this disclosure may exist as salts, for example, salts with pharmaceutically acceptable acids. This disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobroms, phosphates, sulfates, methanesulfons, nitrates, maleates, acetates, citrates, fumarates, propions, tartrates (e.g., mixtures of these including (+)-tartrate, (-)-tartrate, and racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts can be prepared by methods known to those skilled in the art.

[0088] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound using conventional methods. The parent form of the compound may differ from various salt forms in terms of certain physical properties, such as solubility in polar solvents.

[0089] In addition to salt forms, this disclosure provides compounds in prodrug forms. The prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of this disclosure. The prodrugs of the compounds described herein are in It can be converted in vivo. In addition, the prodrug can be converted to the compounds of this disclosure by chemical or biochemical methods in an ex vivo environment, such as by contact with a suitable enzyme or chemical reagent.

[0090] Certain compounds in this disclosure may exist in solvated forms, including hydrated forms, as well as in non-solvated forms. Generally, solvated forms are equivalent to non-solvated forms and are included within the scope of this disclosure. Certain compounds in this disclosure may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent in terms of the uses envisioned by this disclosure and are intended to be within the scope of this disclosure.

[0091] "Pharmacologically acceptable additives" and "pharmaceutically acceptable carriers" refer to substances that assist in the administration of active agents to a subject and their absorption by the subject, and can be included in the compositions of the Disclosure without causing significant adverse toxic effects to the patient. Non-limiting examples of pharmacopeial additives include water, NaCl, physiological saline, Ringer's lactate solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates, e.g., lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and colorants. Such preparations can be sterilized and, if desired, can be mixed with adjuvants that do not react adversely with the compounds of the Disclosure, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants and / or fragrances. Those skilled in the art will recognize that other pharmaceutical excipients may be useful in this disclosure.

[0092] The term "pharmaceutical preparation" refers to a preparation in which the biological activity of the active ingredient contained therein is effective, and which does not contain any further ingredients that are unacceptably toxic to the subject to whom the preparation is administered.

[0093] The terms “administer,” “be administered,” and their grammatical variations refer to the physical introduction of a drug into a target 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, for example, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, such as by injection or infusion. The term “parenteral administration,” as used herein, means, but is not limited to, methods of administration other than intestinal and topical administration, typically by injection, including, but not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intralymphatic, intrafocal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions, as well as in vivo electroporation. In some embodiments, the formulations are administered by parenteral routes, e.g., orally. Other parenteral routes include topical, cutaneous, or mucosal administration routes, e.g., intranasal, transvaginal, rectal, sublingual, or topical. The administration may be carried out, for example, once, multiple times, and / or over one or more extended periods.

[0094] The “effective dose” of a drug, such as a pharmaceutical preparation, refers to the amount that is effective in achieving the desired therapeutic or preventive outcome over the required period of time.

[0095] The abbreviations used herein have their conventional meanings in the fields of chemistry and biochemistry. The chemical structures and formulas shown herein are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0096] The description of the compounds in this disclosure is constrained 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 several substituents, such substitutions are selected in accordance with the principles of chemical bonding and in such a way that the resulting compounds are not inherently unstable, and / or are compounds that would be known to those skilled in the art to be likely to be unstable under ambient conditions, e.g., aqueous conditions, neutral conditions and certain known physiological conditions. For example, heterocycloalkyl or heteroaryl groups are bonded to the remainder of the molecule via ring heteroatoms in accordance with the principles of chemical bonding known to those skilled in the art, thereby This avoids compounds that are inherently unstable.

[0097] When substituents are specified by conventional chemical formulas written from left to right, they similarly encompass chemically identical substituents that would result from writing the structure from right to left, for example, -CH 2 O- is -OCH 2 - is equivalent to

[0098] The term sugars refers to carbohydrates (or sugars). In embodiments, sugars are monosaccharides. In embodiments, sugars are polysaccharides. The basic unit of most sugars is a monomer of a carbohydrate. The general formula is C n H 2n O n The term "sugar derivative" refers to a sugar molecule modified with substituents other than a hydroxyl group. Examples include glycosylamines, sugar phosphate esters, and sugar esters. Other sugar derivatives include, for example, beta-D-glucuronyl, D-galactosyl, and D-glucosyl.

[0099] The term "charged group" refers to a chemical group having a positive or negative charge, such as a phosphate group, phosphonic acid group, sulfate group, sulfonic acid group, nitrate group, carboxylic acid group, or carbonate group. In some embodiments, the charged group is at least 50% ionized in aqueous solution at at least one pH in the range of 5 to 9. In some embodiments, the charged group is anionically charged.

[0100] Alkyl, either alone or as part of another substituent, means a linear (i.e., unbranched) or branched carbon chain (or carbons), or a combination thereof, which may be fully saturated, monovalent or polyunsaturated, and may contain monovalent, divalent, and polyvalent radicals, unless otherwise specified. Alkyl can contain a specified number of carbons (e.g., C 1 ~C 10 (where ∫ means 1 to 10 carbon atoms). Alkyl is a non-cyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers such as n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated alkyl groups have one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, clotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkoxy is an alkyl group to which the remainder of the molecule is bonded via an oxygen linker (-O-). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be completely saturated. Alkenyls may contain one or more double bonds, and / or one or more double bonds plus one or more triple bonds. Alkynnyls may contain one or more triple bonds, and / or one or more triple bonds plus one or more double bonds.

[0101] The term "alkylene," either alone or as part of another substituent, is not limited to, unless otherwise stated, -CH 2 CH 2 CH 2 CH 2 - refers to a divalent radical derived from an alkyl group, as exemplified by -. Typically, an alkyl (or alkylene) group has 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms preferred herein. "Lower alkyl" or "lower alkylene" is a shorter-chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," either alone or as part of another substituent, refers to a divalent radical derived from an alkene, unless otherwise stated.

[0102] Either alone or in combination with another term, the term "heteroalkyl" means, unless otherwise stated, at least one carbon atom and at least one heteroatom (e.g., O, N, P, This refers to a stable linear or branched chain, or a combination thereof, containing Si (or S), wherein the nitrogen and sulfur atoms may be oxidized as necessary, and the nitrogen heteroatom may be quaternized as necessary. 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 bonded to the remainder of the molecule. The heteroalkyl group is an acycline chain. An example is -CH 2 -CH 2 -O-CH 3 ,-CH 2 -CH 2 -NH-CH 3 ,-CH 2 -CH 2 -N(CH 3 )-CH 3 ,-CH 2 -S-CH 2 -CH 3 ,-CH 2 -S-CH 2 ,-S(O)-CH 3 ,-CH 2 -CH 2 -S(O) 2 -CH 3 -CH=CH-O-CH 3 -Si(CH 3 ) 3 ,-CH 2 -CH=N-OCH 3 -CH=CH-N(CH 3 )-CH 3 ,-O-CH 3 ,-O-CH 2 -CH 3 Examples include, but are not limited to, -CN, and -CH. 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3 A heteroalkyl moiety may contain two or three or fewer heteroatoms in sequence. A heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain two heteroatoms as needed (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain three heteroatoms as needed (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain four heteroatoms as needed (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain five heteroatoms as needed (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain eight or fewer heteroatoms as needed (e.g., O, N, S, Si, or P). The term "heteroalkenyl" alone or in combination with another term means a heteroalkyl containing at least one double bond, unless otherwise noted. Heteroalkenyls may, as they may, contain one or more double bonds, and / or one or more triple bonds in addition to one or more double bonds. Either alone or in combination with other terms, the term “heteroalkenyl” means a heteroalkyl group containing at least one triple bond, unless otherwise stated. Heteroalkenyls may, as they may, contain one or more triple bonds, and / or one or more double bonds in addition to one or more triple bonds.

[0103] Similarly, the term "heteroalkylene," either alone or as part of another substituent, is not limited to these unless otherwise stated, but also includes -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 - refers to divalent radicals derived from heteroalkyl groups, as exemplified by -. For heteroalkylene groups, heteroatoms may occupy either or both of the chain ends (e.g., alkylene oxy, alkylenedioxy, alkylene amino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, any orientation of the linking group is not implied by the direction in which the formula of the linking group is written. For example, formula -C(O) 2 R'- is -C(O) 2 R'- and -R'C(O) 2 - Represents both. As described above, a heteroalkyl group, when used herein, is a group bonded to the remainder of a molecule by a heteroatom, e.g., -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SO 2 It includes R'. When "heteroalkyl" is mentioned, followed by a specific heteroalkyl group, such as -NR'R'', it will be understood that the terms heteroalkyl and -NR'R'' are neither redundant nor mutually exclusive. More precisely, the specific heteroalkyl group is mentioned for clarity. Therefore, the term "heteroalkyl" in this specification should not be interpreted as excluding specific heteroalkyl groups, such as -NR'R''.

[0104] Whether used alone or in combination with other terms, the terms "cycloalkyl" and "heterocycloalkyl" are, unless otherwise noted, "alkyl" and "heteroalkyl" respectively. This refers to the cyclic version of "cycloalkylene". Cycloalkyl and heterocycloalkyl are not aromatic. In addition, for heterocycloalkyls, the heteroatom may occupy the position where the heterocycle is bonded to the rest of the molecule. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, and cycloheptyl. Examples of heterocycloalkyls 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, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, and 2-piperazinyl. "Cycloalkylene" and "heterocycloalkylene" refer to divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively, either alone or as part of another substituent.

[0105] In embodiments, the term "cycloalkyl" means monocyclic, bicyclic, or polycyclic cycloalkyl ring systems. In embodiments, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms, which may be saturated or unsaturated but is never aromatic. In embodiments, the cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic heteroalkyl ring system is a bridging monocyclic ring or a condensed bicyclic ring. In embodiments, a bridging monocyclic ring is an alkylene bridge (i.e., form (CH)) of two non-adjacent carbon atoms of the monocyclic ring with 1 to 3 additional carbon atoms. 2 ) w The bicyclic ring system contains a monocyclic cycloalkyl ring linked by a crosslinking group (where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, the condensed bicyclic cycloalkyl ring system contains a monocyclic cycloalkyl ring condensed with phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the crosslinked or condensed bicyclic cycloalkyl is bonded to the parent molecule by any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, the cycloalkyl group is optionally substituted with one or two groups that are independently oxo or thia. In the embodiment, the condensed bicyclic cycloalkyl is a 5 or 6-membered monocyclic cycloalkyl ring condensed with one of the following: a phenyl ring, a 5 or 6-membered monocyclic cycloalkyl, a 5 or 6-membered monocyclic cycloalkenyl, a 5 or 6-membered monocyclic heterocyclil, or a 5 or 6-membered monocyclic heteroaryl, wherein the condensed bicyclic cycloalkyl is optionally substituted with one or two groups that are independently oxo or thia. In the embodiment, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (basic ring) condensed with either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclil, 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 heterocyclil. In this embodiment, the polycyclic cycloalkyl group is bonded to the parent molecule by any carbon atom contained within the basic ring.In the embodiment, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (basic ring) fused with either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of alkyl groups include, but are not limited to, tetradecahydrophenantrenyl, perhydrophenothiazine-1-yl, and perhydrophenoxazine-1-yl.

[0106] In embodiments, cycloalkyl is cycloalkenyl. The term “cycloalkenyl” is used according to its obvious and ordinary meaning. In embodiments, cycloalkenyl is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. In embodiments, a monocyclic cycloalkenyl ring system is the aforementioned group which is a cyclic hydrocarbon group containing 3 to 8 carbon atoms and is unsaturated (i.e., contains at least one cyclic carbon-carbon double bond) but not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, a bicyclic cycloalkenyl ring is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring is an alkylene bridge (i.e., form (CH)) of two non-adjacent carbon atoms of the monocyclic ring with 1 to 3 additional carbon atoms. 2 ) w The system contains a monocyclic cycloalkenyl ring linked by a crosslinking group (where w is 1, 2, or 3). Typical examples of bicyclic cycloalkenyls include, but are not limited to, norborneyl and bicyclo[2.2.2]octa2enyl. In embodiments, the condensed bicyclic cycloalkenyl ring system contains a monocyclic cycloalkenyl ring condensed with one of phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclyl, or monocyclic heteroaryl. In embodiments, the crosslinked or condensed bicyclic cycloalkenyl is bonded to the parent molecule by any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, the cycloalkenyl group is optionally substituted with one or two groups that are independently oxo or thia. In the embodiment, the polycyclic cycloalkenyl ring contains a monocyclic cycloalkenyl ring (basic ring) fused with either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, 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 heterocyclyl. In the embodiment, the polycyclic cycloalkenyl is bonded to the parent molecule by any carbon atom contained within the basic ring. In the embodiment, the polycyclic cycloalkenyl ring contains a monocyclic cycloalkenyl ring (basic ring) fused with either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.

[0107] In embodiments, heterocycloalkyl is heterocyclyl. The term “heterocyclyl,” as used herein, means monocyclic, bicyclic, or polycyclic heterocycle. A heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6, or 7-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S, and is saturated or unsaturated, but not aromatic. A 3 or 4-membered ring contains one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring may contain 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 contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A heterocyclyl monocyclic heterocycle is connected to its parent molecule by any carbon or nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Typical examples of heterocyclyl monocyclic heterocycles include azetidinyl, azepanyl, azilidinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoox Examples include, but are not limited to, sazolinil, isoxazolidinil, morpholinil, oxadiazolinil, oxadiazolidinil, oxazolinil, oxazolidinil, piperazinil, piperidinil, pyranil, pyrazolinil, pyrazolidinil, pyrrolidinil, pyrrolidinil, tetrahydrofuranil, tetrahydrothienyl, thiadiazolinil, thiadiazolidinil, thiazolinil, thiazolidinil, thiazolidinil, thiomorpholinil, 1,1-dioxidethiomorpholinil (thiomorpholine sulfone), thiopyranil, and trithianil. A heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused with either a phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. A heterocyclyl bicyclic heterocycle is connected to its parent molecule by any carbon or nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclils include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In embodiments, the heterocyclil group is optionally substituted with one or two groups that are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6-membered monocyclic heterocyclyl ring condensed with a phenyl ring, a 5 or 6-membered monocyclic cycloalkyl, a 5 or 6-membered monocyclic cycloalkenyl, a 5 or 6-membered monocyclic heterocyclyl, or a 5 or 6-membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted with one or two groups that are independently oxo or thia.A polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (basic ring) fused with either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, 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 heterocyclyl. The polycyclic heterocyclyl is bonded to the parent molecule by any carbon or nitrogen atom contained within the basic ring. In the embodiment, the polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (basic ring) fused with either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of polycyclic heterocyclyl groups include, but are not limited to, 10H-phenothiazine-10-yl, 9,10-dihydroacridine-9-yl, 9,10-dihydroacridine-10-yl, 10H-phenoxazine-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinoline-2-yl, 12H-benzo[b]phenoxazine-12-yl, and dodecahydro-1H-carbazole-9-yl.

[0108] The term "halo" or "halogen," either alone or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom unless otherwise specified. In addition, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C) 1 ~C 4 "Alkyl" is not limited to these, but includes fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0109] The term "acyl" means -C(O)R unless otherwise specified, where R represents a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heteroalkyl. It is a kill, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0110] The term "aryl," unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent that may be a single ring, fused to one another (i.e., a fused ring aryl), or multiple rings (preferably 1 to 3 rings) linked by covalent bonds. A fused ring aryl refers to multiple fused rings in which at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, e.g., N, O, or S, in which the nitrogen and sulfur atoms are oxidized as necessary, and the nitrogen atom is quaternized as necessary. Therefore, the term "heteroaryl" includes fused ring heteroaryl groups (i.e., multiple fused rings in which at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two fused rings in which one ring has 5 members and the other ring has 6 members, and at least one of the rings is a heteroaryl ring. Similarly, a 6,6-fused heteroarylene refers to two fused rings, one having 6 members and the other having 6 members, with at least one ring being a heteroaryl ring. A 6,5-fused heteroarylene refers to two fused rings, one having 6 members and the other having 5 members, with at least one ring being a heteroaryl ring. The heteroaryl group may be bonded to the remainder of the molecule by carbon atoms or by heteroatoms.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridadinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, prinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrzolyl, 3-pyrzolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-i Examples include sooxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above-mentioned aryl and heteroaryl ring systems are selected from the group of acceptable substituents listed below. "Arylene" and "heteroarylene," either alone or as part of another substituent, refer to divalent radicals derived from aryl and heteroaryl, respectively. Substituents for heteroaryl groups may be -O- bonded to the nitrogen, which is the ring heteroatom.

[0111] A fused ring heterocycloalkyl-aryl is an aryl compound fused with a heterocycloalkyl compound. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl compound fused with a heterocycloalkyl compound. A fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl compound fused with a cycloalkyl compound. A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl compound fused with another heterocycloalkyl compound. Each of these compounds may independently be unsubstituted or substituted with one or more substituents described herein.

[0112] A spirocyclic ring is a ring in which two or more adjacent rings are bonded together by a single atom. There are many rings. The individual rings within a spirocyclic ring may be identical or different. The individual rings within a spirocyclic ring may be substituted or unsubstituted and may have different substituents than the other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within a spirocyclic ring are possible substituents for the same ring if it is not part of the spirocyclic ring (e.g., substituents for cycloalkyl or heterocycloalkyl rings). A spirocyclic ring can be a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heterocycloalkylene, and the individual rings within the spirocyclic ring group can be any of the immediately preceding lists, including those having all rings of one type (e.g., all rings that are substituted heterocycloalkylenes, where each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is heterocyclic and each ring can be different. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted and each substituent can be different as required.

[0113] symbol

change

[0114] As used herein, the term "oxo" refers to oxygen double-bonded to a carbon atom.

[0115] The term "alkylsulfonyl" as used herein refers to a compound of the formula -S(O 2 )-R' refers to the part containing R', where R' is a substituted or unsubstituted alkyl group as defined above. R' can have the number of carbons specified (e.g., "C 1 ~C 4 (Alkyl sulfonyl).

[0116] The term "alkylarylene" refers to an arylene moiety covalently bonded to an alkylene moiety (also called an alkylene linker in this specification). In embodiments, the alkylarylene group is of the formula

change

[0117] The alkyl arylene moiety is an alkylene moiety or arylene linker (for example, carbon 2, 3, 4, or 6) containing halogens, oxo, -N 3 -CF 3 -CCl 3 -CBr 3 , -CI 3 -CN, -CHO, -OH, -NH 2 -COOH, -CONH 2 , -NO 2 -SH, -SO 2 CH 3 -SO 3 H, ,-OSO 3 H, -SO 2 NH 2 , -NHNH 2 ,-ONH 2 ,-NHC(O)NHNH 2 , substitution or non-substitution C 1 ~C 5 They may be substituted (e.g., by substituents) with alkyl or substituted or unsubstituted 2- to 5-membered heteroalkyl groups. In embodiments, the alkylarylene is unsubstituted.

[0118] Each of the above terms (for example, "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") is shown This includes both substituted and unsubstituted forms of the radical. Preferred substituents for each type of radical are provided below.

[0119] Substituents for alkyl and heteroalkyl radicals (including groups often called alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) range from zero to (2m'+1) and include -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', and -CO 2 R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O) 2 R', -NR-C(NR'R''R''')=NR''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R'', -NRSO 2 R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R''', -CN, -NO 2 , -NR'SO 2 R'', R''C(O)R'', R''C(O)-OR'', R''OR'' may be one or more of a variety of groups, selected from but not limited to these, where m' is the total number of carbon atoms in such radicals. R, R', R'', R'''', and R'''' each preferably independently refer to hydrogen, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group (e.g., an aryl group substituted with 1 to 3 halogens), a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkyl group, an alkoxy or thioalkoxy group, or an arylalkyl group. If the compounds described herein contain more than one R group, for example, each R group is independently selected, and each R', R'', R''', and R'''' group is also independently selected if more than one of these groups are present. If R' and R'' are bonded to the same nitrogen atom, they may combine with the nitrogen atom to form a 4-membered, 5-membered, 6-membered, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, the term "alkyl" is used for haloalkyls (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 ,-C(O)CH 2 OCH 3 Those skilled in the art will understand that it is intended to include groups containing carbon atoms bonded to groups other than hydrogen groups, such as (etc.).

[0120] Similar to the substituents described for alkyl radicals, substituents for aryl and heteroaryl groups are diverse, for example, -OR', -NR'R'', -SR', -halogens, -SiR'R''R''', -OC(O)R', -C(O)R', -CO 2 R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O) 2 R', -NR-C(NR'R''R''')=NR''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R'', -NRSO 2 R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R''', -CN, -NO 2 -R', -N 3 -CH(Ph) 2 , fluoro(C 1 ~C 4 )alkoxy and fluoro(C 1 ~C 4 ) alkyl, -NR'SO 2 R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR'' are selected from 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. If the compounds described herein contain more than one R group, for example, each R group is independently selected, and each R', R'', R''', and R'''' group is also independently selected if more than one of these groups are present.

[0121] Substituents on a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be described as substituents on the ring rather than on specific atoms of the ring (generally called floating substituents). In such cases, the substituent may be bonded to any of the ring atoms (according to the rules of chemical valency), and a substituent described as associated with one of the members of a fused or spirocyclic ring (a floating substituent on a single ring) may also be a substituent on either the fused or spirocyclic ring (a floating substituent on multiple rings). If the substituent is bonded to a ring rather than a specific atom (a floating substituent), and the subscript of the substituent is an integer greater than 1, then multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent may be different as needed. If the bond point of the ring to the rest of the molecule is not limited to a single atom (in the case of a floating substituent), the bond point may be any atom of the ring, but according to the rules of chemical valence, and in the case of a fused or spirocyclic ring, it may be any atom of the fused or spirocyclic ring. If the ring, fused or spirocyclic ring contains one or more ring heteroatoms, and the ring, fused or spirocyclic ring is shown together with another floating substituent (including, but not limited to, a bond point to the rest of the molecule), the floating substituent may be bonded to the heteroatom. If the ring heteroatom is shown bonded to one or more hydrogens in a structure or formula having a floating substituent (e.g., a ring nitrogen with two bonds to a ring atom and a third bond to a hydrogen), it will be understood that when the heteroatom is bonded to the floating substituent, the substituent replaces the hydrogen, but according to the rules of chemical valence.

[0122] Two or more substituents may be attached as needed to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are usually found attached to a cyclic base structure, though not always. In one embodiment, the ring-forming substituent is attached to an adjacent member of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituent is attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituent is attached to a non-adjacent member of the base structure.

[0123] Two of the substituents on adjacent atoms of an aryl or heteroaryl ring are, if necessary, of the formula -TC(O)-(CRR') p A -U- ring may be formed, where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and p is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be added as needed to the formula -A-(CH 2) r -B- can be substituted with the substituent -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'-, or a single bond, where r is an integer from 1 to 4. One of the single bonds in the new ring thus formed can be replaced with a double bond as needed. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can be replaced with a double bond as needed. s -X'-(C''R''R''') d - can be replaced by substituents, where s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 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.

[0124] As used herein, the terms “heteroatom” or “ring heteroatom” are intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0125] When used herein, “substituent” means a group selected from the following parts: (A) Oxo, halogen, -CCl 3 -CBr 3 -CF 3 , -CI 3 ,-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I,-CHCl 2 -CHBr 2 , -CHF 2 ,-CHI 2 -CN, -OH, -NH 2 -COOH, -CONH 2 , -NO 2 -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 ,-ONH 2 ,-NHC(O)NHNH 2 ,-NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 -OCBr 3 , -OCI 3 ,-OCHCl 2 ,-OCHBr 2 ,-OCHI 2 -OCHF 2 、-N 3 , unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl), unsubstituted heteroalkyl (e.g., 2-8 member heteroalkyl, 2-6 member heteroalkyl, or 2-4 member heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 Cycloalkyls), unsubstituted heterocycloalkyls (e.g., 3-8 member heterocycloalkyls, 3-6 member heterocycloalkyls, or 5-6 member heterocycloalkyls), unsubstituted aryls (e.g., C 6 ~C 10 Ariel, C 10 (A) Aryl (or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (B) alkyl (e.g., C 1 ~C 8 Alkyl, C 1~C 6 Alkyl, or C 1 ~C 4 Alkyl), heteroalkyl (e.g., 2-8 member heteroalkyl, 2-6 member heteroalkyl, or 2-4 member heteroalkyl), cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 Cycloalkyls), heterocycloalkyls (e.g., 3-8 member heterocycloalkyls, 3-6 member heterocycloalkyls, or 5-6 member heterocycloalkyls), aryls (e.g., C 6 ~C 10 Ariel, C 10 An aryl (or phenyl), heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl) substituted with at least one substituent selected from (i) and (ii) below: (i) Oxo, halogen, -CCl 3 -CBr 3 -CF 3 , -CI 3 ,-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I,-CHCl 2 -CHBr 2 , -CHF 2 ,-CHI 2 -CN, -OH, -NH 2 -COOH, -CONH 2 , -NO 2 -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 ,-ONH 2 ,-NHC(O)NHNH 2 ,-NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 -OCBr 3 , -OCI 3 ,-OCHCl 2 ,-OCHBr 2 ,-OCHI 2 -OCHF 2 、-N 3 , unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl), unsubstituted heteroalkyl (e.g., 2-8 member heteroalkyl, 2-6 member heteroalkyl, or 2-4 member heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 Cycloalkyls), unsubstituted heterocycloalkyls (e.g., 3-8 member heterocycloalkyls, 3-6 member heterocycloalkyls, or 5-6 member heterocycloalkyls), unsubstituted aryls (e.g., C 6 ~C 10 Ariel, C 10 Aryl (or phenyl), or unsubstituted heteroaryls (e.g., 5-10 membered heteroaryls, 5-9 membered heteroaryls, or 5-6 membered heteroaryls), and (ii) alkyl (for example, C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl), heteroalkyl (e.g., 2-8 member heteroalkyl, 2-6 member heteroalkyl, or 2-4 member heteroalkyl), cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 Cycloalkyl, heterocycloalkyl (e.g., 3-8 member heterocycloalkyl, 3-6 member heterocycloalkyl, Or 5-6 member heterocycloalkyl, aryl (e.g., C 6 ~C 10 Ariel, C 10 An aryl (or phenyl), heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl) substituted with at least one substituent selected from (a) and (b) below: (a) Oxo, halogen, -CCl 3 -CBr 3 -CF 3 , -CI 3 ,-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I,-CHCl 2 -CHBr 2 , -CHF 2 ,-CHI 2 -CN, -OH, -NH 2 -COOH, -CONH 2 , -NO 2 -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 ,-ONH 2 ,-NHC(O)NHNH 2 ,-NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 -OCBr 3 , -OCI 3 -OCHCl 2 ,-OCHBr 2 ,-OCHI 2 -OCHF 2 、-N 3 , unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl), unsubstituted heteroalkyl (e.g., 2-8 member heteroalkyl, 2-6 member heteroalkyl, or 2-4 member heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 Cycloalkyls), unsubstituted heterocycloalkyls (e.g., 3-8 member heterocycloalkyls, 3-6 member heterocycloalkyls, or 5-6 member heterocycloalkyls), unsubstituted aryls (e.g., C 6 ~C 10 Ariel, C 10 (b) Aryl (or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (b) alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1~C 4 Alkyl), heteroalkyl (e.g., 2-8 member heteroalkyl, 2-6 member heteroalkyl, or 2-4 member heteroalkyl), cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 Cycloalkyls), heterocycloalkyls (e.g., 3-8 member heterocycloalkyls, 3-6 member heterocycloalkyls, or 5-6 member heterocycloalkyls), aryls (e.g., C 6 ~C 10 Ariel, C 10 A heteroaryl (e.g., aryl or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl) substituted with at least one substituent selected from: oxo, halogen, -CCl 3 -CBr 3 -CF 3 , -CI 3 ,-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I,-CHCl 2 -CHBr 2 , -CHF 2 ,-CHI 2 -CN, -OH, -NH 2 -COOH, -CONH 2 , -NO 2 -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 ,-ONH 2 ,-NHC(O)NHNH 2 ,-NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCF 3 -OCBr 3 , -OCI 3 ,-OCHCl 2 ,-OCHBr 2 ,-OCHI 2 -OCHF 2 、-N 3 , unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl), unsubstituted heteroalkyl (e.g., 2-8 member heteroalkyl, 2-6 member heteroalkyl, or 2-4 member heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 Cycloalkyls), unsubstituted heterocycloalkyls (e.g., 3-8 member heterocycloalkyls, 3-6 member heterocycloalkyls, or 5-6 member heterocycloalkyls), unsubstituted aryls (e.g., C 6 ~C 10 Ariel, C 10 Aryl or phenyl, or unsubstituted heteroaryls (e.g., 5-10 membered heteroaryls, 5-9 membered heteroaryls, or 5-6 membered heteroaryls).

[0126] When used herein, "size-restricted substituent" or "size-restricted substituent group" means that each substituted or unsubstituted alkyl group is substituted or unsubstituted C 1 ~C 20 It is an alkyl group, where each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2-20 member heteroalkyl group, and each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C 3 ~C 8 It is a cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-8 member heterocycloalkyl, and each substituted or unsubstituted A Reel is replaced or not replaced C 6 ~C 10 The term "substituent" refers to a group selected from all of the substituents listed above, where each substituted or unsubstituted heteroaryl is an aryl group, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0127] When used herein, "substituent" or "substituent group" refers to each substituted or unsubstituted alkyl group. 1 ~C 8 It is an alkyl group, where each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, and each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C 3 ~C 7 The term "substituent" refers to a group selected from all of the substituents listed above, wherein the cycloalkyl 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.

[0128] In some embodiments, each substituted group described herein with respect to the compounds 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 herein with respect to the compounds 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-limited substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0129] In other embodiments of the compounds described herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 ~C 20 Each alkyl group is a substituted or unsubstituted heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C group. 3 ~C 8 Each cycloalkyl group is a substituted or unsubstituted heterocycloalkyl group, each substituted or unsubstituted aryl group is a substituted or unsubstituted C group. 6 ~C 10 The aryl and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments of the compounds described herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 ~C 20 Each alkylene is a substituted or unsubstituted heteroalkylene, each substituted or unsubstituted 2-20 member heteroalkylene, and each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 ~C 8 Each cycloalkylene is a substituted or unsubstituted heterocycloalkylene, each substituted or unsubstituted 3- to 8-membered heterocycloalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 ~C 10 It is an arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0130] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 ~C 8 Each alkyl group is a substituted or unsubstituted heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C group. 3 ~C 7 Each cycloalkyl group is a substituted or unsubstituted heterocycloalkyl group, each substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C group. 6 ~C 10 The heteroaryl is and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 ~C 8 Each alkylene is a substituted or unsubstituted heteroalkylene, each substituted or unsubstituted 2- to 8-membered heteroalkylene, and each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 ~C 7 It is a cycloalkylene, and each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 7-membered heterocycloalkylene. Each arylen is a substituted or unsubstituted C 6 ~C 10 The compound is an arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is the chemical species shown in the Examples section, figures, or tables below.

[0131] In the embodiment, the substituted or unsubstituted portion (for example, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkylene, a substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (for example, 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 heteroarylene). In the embodiment, the substituted or unsubstituted portions (for example, 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 heteroarylene) are substituted (for example, 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, respectively).

[0132] In the 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, and if the substituted portion is substituted with multiple substituents, each substituent may be different as required. In the embodiments, if the substituted portion is substituted with multiple substituents, each substituent is different.

[0133] In the embodiment, the substituted moieties (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) are substituted with at least one size-restricted substituent, and if the substituted moieties are substituted with multiple size-restricted substituents, each size-restricted substituent may be different as required. In the embodiment, if the substituted moieties are substituted with multiple size-restricted substituents, each size-restricted substituent is different.

[0134] In the embodiment, 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, and if the substituted portion is substituted with multiple lower substituents, each lower substituent may be different as required. In the embodiment, if the substituted portion is substituted with multiple lower substituents, each lower substituent is different.

[0135] In the embodiments, the substituted moieties (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) are substituted with at least one substituent, a size-restricted substituent, or a lower substituent; if the substituted moieties are substituted with multiple groups selected from substituents, size-restricted substituents, and lower substituents, each substituent, size-restricted substituent, and / or lower substituent may be different as needed.

[0136] Certain compounds in this disclosure have a chiral carbon atom (optical or chiral center) or a double bond; enantiomers, racemic compounds, diastereomers, tautomers, geometric isomers, stereoisomeric forms (which may be defined as (R)- or (S)- from the standpoint of absolute stereochemistry, or (D)- or (L) for amino acids), and individual isomers are included within the scope of this disclosure. The compounds in this disclosure do not include those known in the art to be too unstable to be synthesized and / or isolated. This disclosure is intended to include racemic and optically pure forms of compounds. Optically active (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or can be separated using prior art. Where the compounds described herein contain an olefin bond or other geometric chiral center, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0137] As used herein, the term "isomer" refers to compounds having the same number and types of atoms, and therefore having the same molecular weight, but differing in the structural arrangement or stereochemistry of their atoms.

[0138] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another.

[0139] It will be apparent to those skilled in the art that certain compounds in this disclosure may exist in the form of tautomers, and that all such tautomers of the compounds are within the scope of this disclosure.

[0140] Unless otherwise stated, the structures described herein are also intended to include all stereochemical forms of those structures, i.e., the R and S configurations for each chiral center. Thus, not only single stereochemical isomers of the compound, but also enantiomers and diastereomer mixtures are within the scope of this disclosure.

[0141] Throughout this application, it should be noted that alternatives, for example, each amino acid position containing one or more possible amino acids, are described in the Markush group. Each member of the Markush group should be considered separately and therefore, it is particularly intended that they constitute different embodiments and that the Markush group should not be read as a single constituent unit.

[0142] A "linker" refers to a chemical portion containing a covalent bond or an atomic chain that covalently bonds the antibody to the drug moiety. In various embodiments, the linker contains a divalent radical. In various embodiments, the linker may contain one or more amino acid residues. In embodiments, the linker is a non-cleaving linker. In embodiments, the linker is an enzymatically cleaving linker (for example) (For example, the Val-Cit or Val-Cit-PAB linker.)

[0143] The "amino acid unit" is expressed in the formula

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[0144] As used herein, the terms “bioponjugate” and “bioponjugate linker” refer to the resulting association between atoms or molecules of a “bioponjugate reactive group” or “bioponjugate reactive moiety.” The association may be direct or indirect. For example, the first bioconjugate reactive group provided herein (e.g., -NH) 2 Conjugation between a hydroxysuccinimide (-C(O)OH, -N-hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., thiols, sulfur-containing amino acids, amines, amine-side-chain-containing amino acids, or carboxylates) can be direct, for example, by covalent bonds or linkers (e.g., a first or second linker), or indirect, for example, by 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 (PI effect), hydrophobic interactions, etc.). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., association of two bioconjugate reactive groups), including, but not limited to, nucleophilic substitution (e.g., reaction of an amine with an alcohol having an acyl halide as an active ester), electrophilic substitution (e.g., enamine reaction), and addition to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed, for example, in March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, DC, 1982. In the embodiment, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently bonded to the second bioconjugate reactive group (e.g., thiol). In the embodiment, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently bonded to the second bioconjugate reactive group (e.g., thiol). In the embodiment, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently bonded to the second bioconjugate reactive group (e.g., thiol). In the embodiment, the first bioconjugate reactive group (e.g., -N-hydroxysuccinimide moiety) is covalently bonded to the second bioconjugate reactive group (e.g., amine). In the embodiment, the first bioconjugate reactive group (e.g., fluorophenyl ester moiety) reacts with the second bioconjugate reactive group (e.g., amine) to form a covalent bond. In the embodiment, the first bioconjugate reactive group (e.g., -sulfo-N-hydroxysuccinimide moiety) reacts with the second bioconjugate reactive group (e.g., amine) to form a covalent bond.

[0145] Examples of useful bioconjugate reactive moieties used in bioconjugate chemistry as described herein include the following: (a) Carboxyl groups and various derivatives thereof (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 that can be converted to esters, ethers, aldehydes, etc. (c) Haloalkyl groups, which can later be substituted with nucleophilic groups such as amines, carboxylate anions, thiol anions, carbanions, or alkoxide ions, thereby resulting in the formation of a new covalent bond of the group at the position of the halogen atom; (d) Dienophile groups that can be involved in the Diels-Alder reaction, such as maleimido or maleimide groups; (e) Aldehyde or ketone groups that can be subsequently derivatized by the formation of carbonyl derivatives, such as imines, hydrazones, semicarbazones, or oximes, or by mechanisms such as Grignard addition or alkyllithium addition; (f) For example, a sulfonyl halogen group for a subsequent reaction with an amine to form a sulfonamide; (g) Thiol groups that can be converted to disulfides, react with acyl halides, bond to metals such as gold, or react with maleimides; (h) an amine or thiol group that can be acylated, alkylated, or oxidized (for example, present in cysteine); (i) Alkenes that can undergo processes such as cycloaddition, acylation, and Michael addition; (j) Epoxides that can react with amines and hydroxyl compounds, for example; (k) Phosphoamidites and other standard functional groups useful in nucleic acid synthesis; (l) Metallic silicon oxide bond; and (m) For example, the bonding of a metal to a reactive phosphite group (e.g., phosphine) to form a phosphate diester bond. (n) Azide coupled with an alkyne using copper-catalyzed cycloaddition click chemistry. (o) A biotin conjugate that can react with avidin or streptavidin to form an avidin-biotin complex or a streptavidin-biotin complex.

[0146] The reactive groups in the bioconjugate may be selected such that they do not participate in or interfere with the chemical stability of the conjugate described herein. Alternatively, the reactive functional groups may be protected from participation in the crosslinking reaction by the presence of protecting groups. In embodiments, the bioconjugate comprises a molecular entity derived from the reaction of unsaturated bonds, such as maleimide and thiol groups.

[0147] The terms "analog" or "analogous" are used according to their obvious and ordinary meaning in chemistry and biology to refer to a chemical substance that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in terms of composition, for example, in terms of the substitution of one atom with an atom of a different element, or in terms of the presence of a particular functional group, or in terms of the substitution of one functional group with another, or in terms of the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent to a reference compound in terms of function and appearance, but not in terms of structure or origin.

[0148] As used herein, common organic and cell type abbreviations are defined as follows: Acetyl ACN Acetonitrile Ala Alanine Asn asparagine aq. Water-based β-Ala (Beta-alanine) BOC or Boc tert-butoxycarbonyl Temperature in degrees Celsius (℃) CBZ Benzoxycarbonyl Cit Citrulline DBU 1,8-Diazabicyclo[5.4.0]Undeca-7-Ene DCM Dichloromethane DIEA (Diisopropylethylamine) DMAP 4-(dimethylamino)pyridine DMF (N,N'-dimethylformamide) DMSO (Dimethyl Sulfoxide) EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EEDQ N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline Et ethyl HCl ethyl acetate Eq equivalent Fmoc 9-Fluorenylmethoxycarbonyl g grams Gly (glycine) hr (hours) (hours) HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HOBt N-hydroxybenzotriazole HPLC (High-Performance Liquid Chromatography) LC / MS Liquid Chromatography-Mass Spectrometry Lysine Me methyl mg milligrams MeOH methanol mL (milliliter) μL / μL microliter mole mmol millimol μmol / umol micromoles MS mass spectrometry NHS N-hydroxysuccinimide PAB or PABC p-aminobenzyloxycarbonyl Phe phenylalanine Pip piperidine PyAOP (7-Azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate RP-HPLC Reverse-phase HPLC rt room temperature Serine t-Butyl Tert, t Tertiary TFA (Trifluoroacetic Acid) Threonine Val Valin composition Antibody-drug conjugates

[0149] In one embodiment, an antibody-drug conjugate (ADC) is provided herein, comprising a monoclonal antibody (Ab), a drug portion (D), and a linker portion that covalently binds the monoclonal antibody to the drug portion.

[0150] In another embodiment, the ADC of equation (I), equation (II), or equation (III):

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[0151] In this embodiment, D'' is

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[0152] In this embodiment, D'' is

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[0153] In this embodiment, D'' is

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[0154] In the embodiment, m is an integer from 1 to 8. In the embodiment, m is 1. In the embodiment, m is 2. In the embodiment, m is 3. In the embodiment, m is 4. In the embodiment, m is 5. In the embodiment, m is 6. In the embodiment, m is 7. In the embodiment, m is 8.

[0155] In the embodiment, n is an integer from 1 to 24. In the embodiment, n is an integer from 1 to 4. In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3. In the embodiment, n is 4. In the embodiment, n is 5. In the embodiment, n is 6. In the embodiment, n is 7. In the embodiment, n is 8. In the embodiment, n is 9. In the embodiment, n is 10. In the embodiment, n is 11. In the embodiment, n is 12. In the embodiment, n is 13. In the embodiment, n is 14. In the embodiment, n is 15. In the embodiment, n is 16. In the embodiment, n is 17. In the embodiment, n is 18. In the embodiment, n is 19. In the embodiment, n is 20. In the embodiment, n is 21. In the embodiment, n is 22. In the embodiment, n is 23. In the embodiment, n is 24.

[0156] In the embodiment, the anti-B7-H3 antibody is a modified antibody. In the embodiment, the modified antibody binds to a transmembrane protein, for example, to the extracellular domain of the transmembrane protein. In the embodiment, the transmembrane protein is a transmembrane receptor, for example, a transmembrane receptor kinase. In the embodiment, the transmembrane receptor kinase is a transmembrane receptor tyrosine kinase. In the embodiment, the modified antibody binds to the tyrosine kinase.

[0157] In this embodiment, L 1 This is a linker bound to the anti-B7-H3 antibody. In this embodiment, L 1 This is a linker bound to one or two sulfur or nitrogen atoms on the anti-B7-H3 antibody. In the embodiment, L 1 This is a linker bonded to one sulfur atom on the anti-B7-H3 antibody. In the embodiment, L 1 This is a linker bonded to two sulfur atoms on the anti-B7-H3 antibody. In the embodiment, L 1 This is a linker bonded to one nitrogen atom on the anti-B7-H3 antibody. In the embodiment, L 1 This is a linker that is bound to two nitrogen atoms on the anti-B7-H3 antibody.

[0158] In this embodiment, L 1 This is a linker bound to the modified anti-B7-H3 antibody.

[0159] In this embodiment, L 1 This is a linker bound to one cysteine ​​molecule on the anti-B7-H3 antibody. In the embodiment, L 1 This is a linker bound to two cysteine ​​molecules on the anti-B7-H3 antibody. In the embodiment, L 1 This is a linker bound to one lysine molecule on the anti-B7-H3 antibody. In the embodiment, L 1 This is a linker that is bound to two lysine molecules on the anti-B7-H3 antibody.

[0160] In this embodiment, L 1 This is a linker bound to a modified anti-B7-H3 antibody.

[0161] In this embodiment, L 1 teeth,

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[0162] In this embodiment, L 1 teeth,

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change

change

change

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[0163] L 1 but,

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[0164] In this embodiment, L 2 The bonds are -C(O)-, -NH-, -Val-, -Phe-, -Lys-, -Gly-, -O-, -(4-aminobenzyloxycarbonyl)-, -(C(O)N(R 2 )CH 2 CH 2 N(R 5 ))-, -Ser-, -Thr-, -Ala-, -β-Ala-, -Citrulline-(Cit), -(CH 2 ) n -,-(CH 2 CH 2 O) n -, or any combination thereof.

[0165] Control mechanism, each R 2 and R 5 These are independently H, or substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl) is. In this embodiment, each R 2 and R 5 H is independent of each other. In this embodiment, each R 2 and R 5 R is independently a substituted or unsubstituted alkyl. In this embodiment, each R 2 and R 5 These are independently substituted or unsubstituted alkyl groups (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl) is. In this embodiment, each R 2 and R5 These are independently unsubstituted alkyl groups (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl) is. In this embodiment, each R 2 and R 5 These are independently substituted alkyl groups (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 It is alkyl.

[0166] Control mechanism, each R 2 and R 5 Independently, H, or substituted (e.g., substituted with at least one substituent, a size-limited substituent group, or a lower substituent) or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl) is. In this embodiment, each R 2 and R 5 R is independently a substituted (e.g., substituted with at least one substituent, a size-limited substituent, or a lower substituent) or an unsubstituted alkyl. In the embodiment, each R 2 and R 5 These are independently substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl) is. In this embodiment, each R 2 and R 5 These are independently unsubstituted alkyl groups (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl) is. In this embodiment, each R 2 and R 5 These are independently substituted alkyls (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 It is alkyl.

[0167] Control mechanism, each R 2 and R 5 R is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, or hexyl. In the embodiment, each R2 and R 5 is independently methyl. In this embodiment, each R 2 and R 5 is independently ethyl. In the embodiment, each R 2 and R 5 In this embodiment, each R is independently propyl. 2 and R 5 It is independently butyl.

[0168] In this embodiment, L 2 The bonds are -C(O)-, -NH-, -Val-, -Phe-, -Lys-, -Gly-, -(4-aminobenzyloxycarbonyl)-, -(C(O)N(CH 3 )CH 2 CH 2 N(CH 3 ))-, -Ser-, -Thr-, -Ala-, -β-Ala-, -O-, -Citrulline-(Cit), -(CH 2 ) n -,-(CH 2 CH 2 O) n -, or any combination thereof.

[0169] In this embodiment, L 2 -C(O)-, -NH-, -Val-, -Gly-, -Cit-, -Ala-, -O-, -(4-aminobenzyloxycarbonyl)-, -(CH 2 ) n -,-(CH 2 CH 2 O) n -,-(C(O)N(CH 3 )CH 2 CH 2 N(CH 3 ))-, or any combination of these.

[0170] In this embodiment, L 2 -C(O)-, -NH-, -Gly-, -(CH 2 ) n -,-(CH 2 CH 2 O) n -, or any combination thereof.

[0171] In this embodiment, L 2 -C(O)-, -NH-, -Val-, -Cit-, -(CH 2 CH 2 O) n -,-(4-aminobenzyloxycarbonyl)-,-(CH 2 ) n -,-(C(O)N(CH 3 )CH 2 CH 2 N(CH 3 ))-, or any combination of these.

[0172] In this embodiment, L 2 -C(O)-, -NH-, -Val-, -(4-aminobenzyloxycarbonyl)-, -Gly-, -citrulline-(-Cit-), -(CH 2 ) n -,-(CH 2 CH 2 O) n -, or any combination thereof.

[0173] In this embodiment, L 2 teeth,

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[0174] In this embodiment, L 2 teeth,

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[0175] In this embodiment, L 2 teeth,

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[0176] In this embodiment, L 2 This is a bond. In this embodiment, L 2 is -C(O)-. In the embodiment, L 2 is -NH-. In the embodiment, L 2 is -Val-. In the embodiment, L 2 is -Phe-. In this embodiment, L 2 is -Lys-. In this embodiment, L 2 is -(4-aminobenzyloxycarbonyl)-. In the embodiment, L 2 is, -(CH 2 ) n - is. In this embodiment, L 2 is, -(CH 2 CH 2 O) n - is. In this embodiment, L 2 It is -Gly-. In the embodiment, L 2 is -Ser-. In the embodiment, L 2 is -Thr-. In the embodiment, L 2 is -Ala-. In the embodiment, L 2 is -β-Ala-. In this embodiment, L 2 is -Cit-. In the embodiment, L 2 It is -O-.

[0177] In this embodiment, -L 1 -L 2 -teeth,

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[0178] In this embodiment, -L 1 -L 2 -teeth,

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[0179] In this embodiment, L 3 This includes substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heterocycloalkylenes (e.g., 3-8 member heterocycloalkylenes, 3-6 member heterocycloalkylenes, or 5-6 member heterocycloalkylenes), substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heteroarylenes (e.g., 5-10 member heteroarylenes, 5-9 member heteroarylenes, or 5-6 member heteroarylenes), substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(heterocycloalkylene (e.g., 3-8 member heterocycloalkylene, 3-6 member heterocycloalkylene, or 5-6 member heterocycloalkylene)), substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(heteroarylenes (e.g., 5-10 member heteroarylenes, 5-9 member heteroarylenes, or 5-6 member heteroarylenes)), substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted-CH 2 NCH 2 -(heterocycloalkyl (for example, 3-8 member heterocycloalkyl, 3-6 member heterocycloalkyl, or 5-6 member heterocycloalkyl) )), or substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted-CH 2 NCH 2 -(heteroaryl (e.g., 5-10 member heteroaryl, 5-9 member heteroaryl, or 5-6 member heteroaryl)). In the embodiment, L 3 L is substituted with one or more substituents. In the embodiment, L 3 L is substituted with one or more size-restricted substituents. In the embodiment, L 3 It is substituted with one or more lower substituents.

[0180] In this embodiment, L 3 CH4 is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted (e.g., 3- to 8-membered heterocycloalkylene, 3- to 6-membered heterocycloalkylene, or 5- to 6-membered heterocycloalkylene), or substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(heterocycloalkyl (e.g., 3-8 member heterocycloalkyl, 3-6 member heterocycloalkyl, or 5-6 member heterocycloalkyl)). In the embodiment, L 3 L is substituted with one or more substituents. In the embodiment, L 3 L is substituted with one or more size-restricted substituents. In the embodiment, L 3 It is substituted with one or more lower substituents.

[0181] In this embodiment, L 3 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heterocycloalkylene (e.g., a 3- to 8-membered heterocycloalkylene, a 3- to 6-membered heterocycloalkylene, or a 5- to 6-membered heterocycloalkylene). In the embodiment, L 3 L is substituted with one or more substituents. In the embodiment, L 3 L is substituted with one or more size-restricted substituents. In the embodiment, L 3 It is substituted with one or more lower substituents.

[0182] In this embodiment, L 3 is a substituted heterocycloalkylene (e.g., substituted with substituents, size-restricted substituents, or lower substituents) (e.g., a 3- to 8-membered heterocycloalkylene, a 3- to 6-membered heterocycloalkylene, or a 5- to 6-membered heterocycloalkylene). In the embodiment, L 3 is an unsubstituted heterocycloalkylene (e.g., a 3-8 member heterocycloalkylene, a 3-6 member heterocycloalkylene, or a 5-6 member heterocycloalkylene). In the embodiment, L 3 is a substituted heteroarylene (e.g., substituted with substituents, size-restricted substituents, or lower substituents) (e.g., 5-10 membered heteroarylene, 5-9 membered heteroarylene, or 5-6 membered heteroarylene). In embodiments, L 3 is an unsubstituted heteroarylene (e.g., a 5-10 member heteroarylene, a 5-9 member heteroarylene, or a 5-6 member heteroarylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(heterocycloalkyl (e.g., 3-8 member heterocycloalkyl, 3-6 member heterocycloalkyl, or 5-6 member heterocycloalkyl)). In the embodiment, L 3 is unsubstituted-OCH 2 -(heterocycloalkylene (e.g., 3-8 member heterocycloalkylene, 3-6 member heterocycloalkylene, or 5-6 member heterocycloalkylene)). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(heteroarylene (e.g., 5-10 member heteroarylene, 5-9 member heteroarylene, or 5-6 member heteroarylene)). In the embodiment, L3 is unsubstituted-OCH 2 -(heteroarylene (e.g., 5-10 member heteroarylene, 5-9 member heteroarylene, or 5-6 member heteroarylene)). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(heterocycloalkyl (e.g., 3-8 member heterocycloalkyl, 3-6 member heterocycloalkyl, or 5-6 member heterocycloalkyl)). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(heterocycloalkyl (e.g., 3-8 member heterocycloalkyl) (, 3-6 member heterocycloalkyl, or 5-6 member heterocycloalkyl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(heteroaryl (e.g., 5-10 member heteroaryl, 5-9 member heteroaryl, or 5-6 member heteroaryl)). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(heteroaryl (e.g., 5-10 member heteroaryl, 5-9 member heteroaryl, or 5-6 member heteroaryl)).

[0183] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 3- to 8-membered heterocycloalkylene. In the embodiment, L 3 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) 3- to 8-membered heterocycloalkylene. In embodiments, L 3 This is an unsubstituted 3- to 8-membered heterocycloalkylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(3-8 member heterocycloalkyl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(3-8 member heterocycloalkyl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(3-8 member heterocycloalkyl). In the embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(3-8 member heterocycloalkylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(3-8 member heterocycloalkylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(3-8 member heterocycloalkylene)

[0184] In this embodiment, L 3 These are substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted 3- to 8-membered heterocycloalkylenes.

[0185] In this embodiment, L 3 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted 3- to 6-membered heterocycloalkylene. In embodiments, L 3 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) 3- to 6-membered heterocycloalkylene. In embodiments, L 3 This is an unsubstituted 3-6 member heterocycloalkylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(3-6 member heterocycloalkyl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(3-6 member heterocycloalkyl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(3-6 member heterocycloalkyl). In the embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(3-6 member heterocycloalkylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(3-6 member heterocycloalkylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(3-6 member heterocycloalkylene)

[0186] In this embodiment, L 3 These are substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted 3- to 6-membered heterocycloalkylenes.

[0187] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclobutylene, heterocyclopentylene, or heterocyclohexylene. In embodiments, L 3 is a substitution (for example, substitution) The heterocyclobutylene, heterocyclopentylene, or heterocyclohexylene (substituted with a group, a size-limited substituent, or a lower substituent). In embodiments, L 3 is unsubstituted heterocyclobutylene, heterocyclopentylene, or heterocyclohexylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(heterocyclobutyl, heterocyclopentyl, or heterocyclohexyl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(heterocyclobutyl, heterocyclopentyl, or heterocyclohexyl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(heterocyclobutyl, heterocyclopentyl, or heterocyclohexyl). In the embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(heterocyclobutylene, heterocyclopentylene, or heterocyclohexylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(heterocyclobutylene, heterocyclopentylene, or heterocyclohexylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(heterocyclobutylene, heterocyclopentylene, or heterocyclohexylene)

[0188] In this embodiment, L 3 These are substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heterocyclobutylene, heterocyclopentylene, or heterocyclohexylene.

[0189] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclobutylene. In embodiments, L 3 is a substituted heterocyclobutylene (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, L 3 is an unsubstituted heterocyclobutylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(heterocyclobutyl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH2 -(heterocyclobutyl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(heterocyclobutyl). In the embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(heterocyclobutylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(heterocyclobutylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(heterocyclobutylene)

[0190] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclopentylene. In the embodiment, L 3 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) heterocyclopentylene. In the embodiment, L 3 L is an unsubstituted heterocyclopentylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(heterocyclopentyl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(heterocyclopentyl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(heterocyclopentyl). In the embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(heterocyclopentylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(heterocyclopene) It is ethylene. In this embodiment, L 3 is unsubstituted-OCH 2 -(heterocyclopentylene)

[0191] In this embodiment, L 3 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heterocyclohexylene. In the embodiment, L 3 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) heterocyclohexylene. In the embodiment, L 3 L is an unsubstituted heterocyclohexylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(heterocyclohexyl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(heterocyclohexyl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(heterocyclohexyl). In the embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(heterocyclohexylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(heterocyclohexylene). In the embodiment, L3 is unsubstituted-OCH 2 -(heterocyclohexylene)

[0192] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5- to 10-membered heteroarylene. In embodiments, L 3 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) 5-10 member heteroarylene. In embodiments, L 3 This is an unsubstituted 5-10 member heteroarylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(5-10 member heteroaryl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(5-10 member heteroaryl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(5-10 member heteroaryl). In the embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(5-10 member heteroarylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(5-10 member heteroarylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(5-10 members are heteroarrine)

[0193] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5- to 9-membered heteroarylene. In embodiments, L 3 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) 5- to 9-membered heteroarylene. In embodiments, L 3 is an unsubstituted 5-9 member heteroarylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(5-9 member heteroaryl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(5-9 member heteroaryl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(5-9 member heteroaryl). In the embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(5-9 member heteroarylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(5-9 member heteroarylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(5-9 members are heteroarrine)

[0194] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5-6 member heteroarylene. In embodiments, L 3 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) 5-6 member heteroarylene. In embodiments, L 3 is an unsubstituted 5-6 member heteroarylene. In the embodiment, L3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(5-6 member heteroaryl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(5-6 member heteroaryl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(5-6 member heteroaryl). In the embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(5-6 member heteroarylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(5-6 member heteroarylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(5-6 members are heteroarrene)

[0195] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted furanylene, pyrrolylene, pyridylene, pyranylene, imidazoylene, thienylene, oxazolylene, or thiazoylene. In embodiments, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) furanylene, pyrrolylene, pyridylene, pyranylene, imidazoylene, thienylene, oxazolylene, or thiazoylene. In embodiments, L 3 is unsubstituted furanylene, pyrrolylene, pyridylene, pyraniylene, imidazoylene, thienylene, oxazolylene, or thiazoylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(furanyl, pyrrolyl, pyridyl, pyranyl, imidazolyl, thienyl, oxazolyl, or thiazolyl). In embodiments, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(furanyl, pyrrolyl, pyridyl, pyranyl, imidazolyl, thienyl, oxazolyl, or thiazolyl). In embodiments, L 3 is unsubstituted-CH 2 NCH 2 -(furanyl, pyrrolyl, pyridyl, pyranyl, imidazolyl, thienyl, oxazolyl, or thiazolyl). In embodiments, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(furanylene, pyrrolylene, pyridylene, pyraniylene, imidazoylene, thienylene, oxazolylene, or thiazoylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(furanylene, pyrrolylene, pyridylene, pyraniylene, imidazoylene, thienylene, oxazolylene, or thiazoylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(Furanilen, pyrrolylene, pyridylene, pyranilen, imidazolene, thienylene, oxazolylene, or thiazolene)

[0196] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted furanylene. In the embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) furanylene. In the embodiment, L 3 is an unsubstituted furanylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(furanyl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(furanyl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(furanyl). In the embodiment, L3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(furanylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(furanylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(furanylene)

[0197] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyrrolylene. In the embodiment, L 3 is a substituted pyrrolylene (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, L 3 is an unsubstituted pyrrolylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(pyrrolyl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(pyrrolyl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(pyrrolyl). In the embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(pyrrolylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(pyrrolylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(pyrolylene)

[0198] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyridylene. In the embodiment, L 3 is a substituted pyridylene (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, L 3 is an unsubstituted pyridylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(pyridyl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(pyridyl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(pyridyl). In the embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(pyridylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(pyridylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(pyridylene)

[0199] In this embodiment, L3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyranylene. In the embodiment, L 3 is a substituted pyranylene (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, L 3 is an unsubstituted pyranilene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(pyranil). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(pyranil). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(pyranil). In the embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(pyranylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(pyranylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(pyranirene)

[0200] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted imidazoylene. In the embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) imidazoylene. In the embodiment, L 3 L is an unsubstituted imidazoylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(imidazolyl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(imidazolyl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(imidazolyl). In the embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(imidazoylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(imidazoylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(imidazoline)

[0201] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted thiazolyylene. In the embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) thiazolyene. In the embodiment, L 3 L is an unsubstituted thiazolyene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(thiazolyl). In this embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(thiazolyl). In this embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(thiazolyl). In this embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(thiazoylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(thiazoylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(thiazoylene)

[0202] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted thienylene. In the embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) thienylene. In the embodiment, L 3 is an unsubstituted thienylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(thienyl). In this embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(thienyl). In this embodiment, L 3 is unsubstituted-CH 2 NCH 2 -(thienyl). In this embodiment, L 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(thienylene). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(thienylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(Chieniren) is

[0203] In this embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted oxazolylene. In the embodiment, L 3 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) oxazolylene. In the embodiment, L 3 L is an unsubstituted oxazolylene. In the embodiment, L 3 L is an unsubstituted oxazolylene. In the embodiment, L 3 CH is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted. 2 NCH 2 -(oxazolyl). In the embodiment, L 3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents)-CH 2 NCH 2 -(oxazolyl). In the embodiment, L 3 is unsubstituted-CH 2 NCH 2 - (Oxazolyl) is used in the embodiment. 3 This is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted -OCH 2 -(oxazolylene). In the embodiment, L3 is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) - OCH 2 -(oxazolylene). In the embodiment, L 3 is unsubstituted-OCH 2 -(oxazolylene)

[0204] In this embodiment, R * is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heterocycloalkyl (e.g., 3-8 member heterocycloalkyl, 3-6 member heterocycloalkyl, or 5-6 member heterocycloalkyl), or a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heteroaryl (e.g., 5-10 member heteroaryl, 5-9 member heteroaryl, or 5-6 member heteroaryl). In embodiments, R * is substituted with one or more substituents. In the embodiment, R * is substituted with one or more size-restricted substituents. In the embodiment, R * It is substituted with one or more lower substituents.

[0205] In this embodiment, R * is a substituted heterocycloalkyl (e.g., substituted with substituents, size-restricted substituents, or lower substituents) (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In embodiments, R * is an unsubstituted heterocycloalkyl (e.g., a 3-8 member heterocycloalkyl, a 3-6 member heterocycloalkyl, or a 5-6 member heterocycloalkyl). In the embodiment, R * is a substituted heteroaryl (e.g., substituted with substituents, size-restricted substituents, or lower substituents) (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl). In embodiments, R * These are unsubstituted heteroaryls (e.g., 5-10 membered heteroaryls, 5-9 membered heteroaryls, or 5-6 membered heteroaryls).

[0206] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 3- to 8-membered heterocycloalkyl. In embodiments, R * is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) 3- to 8-membered heterocycloalkyl. In embodiments, R * These are unsubstituted 3- to 8-membered heterocycloalkyl groups.

[0207] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 3- to 6-membered heterocycloalkyl. In embodiments, R * is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) 3- to 6-membered heterocycloalkyl. In embodiments, R * These are unsubstituted 3- to 6-membered heterocycloalkyl groups.

[0208] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclobutyl, heterocyclopentyl, or heterocyclohexyl. In embodiments, R * is a substituted heterocyclobutyl, heterocyclopentyl, or heterocyclohexyl (e.g., substituted with substituents, size-restricted substituents, or lower substituents). In embodiments, R * These are unsubstituted heterocyclobutyl, heterocyclopentyl, or heterocyclohexyl.

[0209] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclobutyl. In the embodiment, R * is a substituted heterocyclobutyl (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, R * is unsubstituted heterocyclobutyric It is.

[0210] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclopentyl. In embodiments, R * is a substituted heterocyclopentyl (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent). In embodiments, R * This is an unsubstituted heterocyclopentyl.

[0211] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocyclohexyl. In embodiments, R * is a substituted heterocyclohexyl (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent). In embodiments, R * It is an unsubstituted heterocyclohexyl.

[0212] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5- to 10-membered heteroaryl. In embodiments, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) 5- to 10-membered heteroaryl. In embodiments, R * This is a non-substitutable 5-10 member heterogeneous aryl.

[0213] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5- to 9-membered heteroaryl. In embodiments, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) 5- to 9-membered heteroaryl. In embodiments, R * This is a non-substitutable 5-9 member heterogeneous aryl.

[0214] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5-6 member heteroaryl. In embodiments, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) 5-6 member heteroaryl. In embodiments, R * This is a non-substitutable 5-6 member heterogeneous aryl.

[0215] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted furanyl, pyrrolyl, pyridyl, pyranyl, imidazolyl, or thiazolyl. In embodiments, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) furanyl, pyrrolyl, pyridyl, pyranyl, imidazolyl, or thiazolyl. In embodiments, R * These are unsubstituted furanyl, pyrrolyl, pyridyl, pyranyl, imidazolyl, or thiazolyl.

[0216] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted furanyl. In embodiments, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) furanyl. In the embodiment, R * It is an unsubstituted furanyl.

[0217] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyrrolyl. In embodiments, R * is a substituted pyrrolyl (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent). In embodiments, R * It is an unsubstituted pyrrolyl compound.

[0218] In this embodiment, R * This refers to substitutions (e.g., substituents, size-restricted substituents, or It is either substituted with a lower substituent or unsubstituted pyridyl. In the embodiment, R * is a substituted pyridyl (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent). In the embodiment, R * It is an unsubstituted pyridyl.

[0219] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyranyl. In embodiments, R * is a substituted pyranyl (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent). In embodiments, R * This is unsubstituted pyranyl.

[0220] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted imidazolyl. In embodiments, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) imidazolyl. In embodiments, R * It is an unsubstituted imidazolyl.

[0221] In this embodiment, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted thiazolyl. In embodiments, R * is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) thiazolyl. In embodiments, R * This is an unsubstituted thiazolyl.

[0222] In this embodiment, R 1 H is H. In this embodiment, R 1 is -C 1 ~C 8 It is alkyl.

[0223] In this embodiment, R 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl. In embodiments, R 1 is methyl. In this embodiment, R 1 is ethyl. In the embodiment, R 1 R is propyl. In the embodiment, R 1 is isopropyl. In an embodiment, R 1 is butyl. In the embodiment, R 1 is isobutyl. In the embodiment, R 1 is tert-butyl. In the embodiment, R 1 is pentyl. In the embodiment, R 1 It is hexyl.

[0224] In this embodiment, R 3 H, halogen, -CCl 3 -CBr 3 -CF 3 , -CI 3 -CHCl 2 -CHBr 2 , -CHF 2 ,-CHI 2 ,-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OR 3A , -NR 3A R 3B ,-(CH 2 ) v Ure 6 , substituted or unsubstituted alkyl (for example, C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 It is an alkyl group, or a substituted or unsubstituted heteroalkyl group (e.g., a 2-8 member heteroalkyl group, a 2-6 member heteroalkyl group, or a 2-4 member heteroalkyl group).

[0225] In this embodiment, R 3 H, -OR 3A ,-(CH 2 ) v Ure 6 , substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 It is an alkyl group, or a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or an unsubstituted heteroalkyl group (e.g., a 2- to 8-membered heteroalkyl group, a 2- to 6-membered heteroalkyl group, or a 2- to 4-membered heteroalkyl group).

[0226] In this embodiment, R 3 substituted alkyl (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 It is alkyl. In this embodiment, R 3 This is an unsubstituted alkyl (for example, C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Al Kill) is. In this embodiment, R 3is a substituted heteroalkyl (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). In embodiments, R 3 These are unsubstituted heteroalkyls (e.g., 2-8 member heteroalkyls, 2-6 member heteroalkyls, or 2-4 member heteroalkyls).

[0227] In this embodiment, R 3 These are methyl, ethyl, propyl, butyl, and -CH 2 OH, -CH 2 CH 2 OH, -CH 2 N 3 ,-CH 2 CH 2 N 3 ,-CH 2 OCH 3 ,-CH 2 OCH 2 CH 3 ,-CH 2 CH 2 OCH 3 ,-CH 2 CH 2 OCH 2 CH 3 ,or

change

[0228] In this embodiment, R 3 is methyl. In this embodiment, R 3 is ethyl. In the embodiment, R 3 R is propyl. In the embodiment, R 3 is butyl. In the embodiment, R 3 is, -CH 2 It is OH. In the embodiment, R 3 is, -CH 2 CH 2 It is OH. In the embodiment, R 3 is, -CH 2 N 3 In this embodiment, R 3 is, -CH 2 CH 2 N 3 In this embodiment, R 3 is, -CH 2 OCH 3 In this embodiment, R 3 is, -CH 2 OCH 2 CH 3 In this embodiment, R 3 is, -CH 2 CH 2 OCH 3 In this embodiment, R 3 is, -CH 2 CH 2 OCH 2 CH 3 In this embodiment, R 3 is -OH. In the embodiment, R 3 H is H. In this embodiment, R 3 teeth,

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[0229] In this embodiment, R 3 methyl, -CH 2 OH,

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[0230] In the embodiment, v is an integer from 1 to 24. In the embodiment, v is 1. In the embodiment, v is 2. In the embodiment, v is 3. In the embodiment, v is 4. In the embodiment, v is 5. In the embodiment, v is 6. In the embodiment, v is 7. In the embodiment, v is 8. In the embodiment, v is 9. In the embodiment, v is 10. In the embodiment, v is 11. In the embodiment, v is 1 In the embodiment, v is 2. In the embodiment, v is 13. In the embodiment, v is 14. In the embodiment, v is 15. In the embodiment, v is 16. In the embodiment, v is 17. In the embodiment, v is 18. In the embodiment, v is 19. In the embodiment, v is 20. In the embodiment, v is 21. In the embodiment, v is 22. In the embodiment, v is 23. In the embodiment, v is 24.

[0231] In this embodiment, R 4 H, halogen, -OR 4A , -NR 4A R 4B , substituted or unsubstituted alkyl (for example, C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 It is an alkyl group, or a substituted or unsubstituted heteroalkyl group (e.g., a 2-8 member heteroalkyl group, a 2-6 member heteroalkyl group, or a 2-4 member heteroalkyl group).

[0232] In this embodiment, R 4 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., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 It is an alkyl group, or a substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or an unsubstituted heteroalkyl group (e.g., a 2- to 8-membered heteroalkyl group, a 2- to 6-membered heteroalkyl group, or a 2- to 4-membered heteroalkyl group).

[0233] In this embodiment, R 4 is H, or a substituted or unsubstituted alkyl group. In this embodiment, R 4 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., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 It is alkyl.

[0234] In this embodiment, R 4 substituted alkyl (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 It is alkyl. In this embodiment, R 4 This is an unsubstituted alkyl (for example, C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 It is alkyl. In this embodiment, R 4 is a substituted heteroalkyl (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl). In embodiments, R 4 These are unsubstituted heteroalkyls (e.g., 2-8 member heteroalkyls, 2-6 member heteroalkyls, or 2-4 member heteroalkyls).

[0235] In this embodiment, R 4 is H, -OH, methyl, ethyl, propyl, or butyl. In the embodiment, R 4 is H or -OH. In the embodiment, R 4 is H or methyl. In the embodiment, R4 is methyl. In this embodiment, R 4 is ethyl. In the embodiment, R 4 R is propyl. In the embodiment, R 4 is butyl. In the embodiment, R 4 H is H. In this embodiment, R 4 It is -OH.

[0236] Control mechanism, each R 3A 、R 3B 、R 4A , and R 4B These are independently H, or substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 It is alkyl.

[0237] Control mechanism, each R 3A 、R 3B 、R 4A , and R 4B Independently, H, or substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl) is. In this embodiment, each R 3A 、R 3B 、R 4A , and R 4B H is independent of each other. In this embodiment, each R 3A 、R 3B 、R 4A , and R 4B These are independently substituted alkyls (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) (e.g., C 1 ~C 8 Alki Ru, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl) is. In this embodiment, each R 3A 、R 3B、R 4A , and R 4B These are independently unsubstituted alkyl groups (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 It is alkyl.

[0238] Control mechanism, each R 3A 、R 3B 、R 4A , and R 4B R is independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, or pentyl. In the embodiment, each R 3A 、R 3B 、R 4A , and R 4B H is independent of each other. In this embodiment, each R 3A 、R 3B 、R 4A , and R 4B is independently methyl. In this embodiment, each R 3A 、R 3B 、R 4A , and R 4B is independently ethyl. In the embodiment, each R 3A 、R 3B 、R 4A , and R 4B In this embodiment, each R is independently propyl. 3A 、R 3B 、R 4A , and R 4B is independently isopropyl. In the embodiment, each R 3A 、R 3B 、R 4A , and R 4B Independently, R is butyl. In the embodiment, each R 3A 、R 3B 、R 4A , and R 4B is independently isobutyl. In this embodiment, each R 3A 、R 3B 、R 4A , and R 4B is independently tert-butyl. In the embodiment, each R 3A 、R 3B 、R 4A , and R 4B It is independently a pentill.

[0239] In this embodiment, R 6 H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO(CH 2 CH 2 O) w CH 2 CH 2 M, -CONH(CH 2 CH 2 O) w CH 2 CH 2 M、

change

[0240] In this embodiment, R 6 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., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl, or C 1 ~C 4 Alkyl), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent), or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 Cycloalkyl), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl (e.g., C 6 ~C 10 Ariel, C 10 The heteroaryls are aryl or phenyl, substituted (e.g., substituted with at least one substituent, a size-restricted substituent, or a lower substituent), unsubstituted heteroaryls (e.g., 5-10 membered heteroaryls, 5-9 membered heteroaryls, or 5-6 membered heteroaryls), or sugar derivatives.

[0241] In this embodiment, R6 is H, or a substituted heterocycloalkyl (e.g., substituted with substituents, size-restricted substituents, or lower substituents) (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl).

[0242] In this embodiment, R 6 H or

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[0243] In the embodiment, w is an integer from 1 to 24. In the embodiment, w is 1. In the embodiment, w is 2. In the embodiment, w is 3. In the embodiment, w is 4. In the embodiment, w is 5. In the embodiment, w is 6. In the embodiment, w is 7. In the embodiment, w is 8. In the embodiment, w is 9. In the embodiment, w is 10. In the embodiment, w is 11. In the embodiment, w is 12. In the embodiment, w is 13. In the embodiment, w is 14. In the embodiment, w is 15. In the embodiment, w is 16. In the embodiment, w is 17. In the embodiment, w is 18. In the embodiment, w is 19. In the embodiment, w is 20. In the embodiment, w is 21. In the embodiment, w is 22. In the embodiment, w is 23. In the embodiment, w is 24.

[0244] In this embodiment, M is -NH 2 -OH, -COOH, or -OCH 3 In this embodiment, M is -NH 2 In the embodiment, M is -OH. In the embodiment, M is -COOH. In the embodiment, M is -OCH 3 That is the case.

[0245] In this embodiment, R 6 teeth,

change

change

change

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[0246] In this embodiment, R 6 is a sugar derivative. In this embodiment, R 6 teeth,

change

change

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[0247] In the embodiment, Z 1 This refers to substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted cycloalkyls (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 It is a cycloalkyl compound. In this embodiment, Z 1 This refers to substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) cycloalkyls (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 It is a cycloalkyl compound. In this embodiment, Z 1 This is an unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 It is a cycloalkyl compound. In this embodiment, Z 1 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl). In embodiments, Z 1 is a substituted heterocycloalkyl (e.g., substituted with substituents, size-restricted substituents, or lower substituents) (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl). In the embodiment, Z 1 is an unsubstituted heterocycloalkyl (e.g., a 3-8 member heterocycloalkyl, a 3-6 member heterocycloalkyl, or a 5-6 member heterocycloalkyl). In the embodiment, Z 1 This refers to substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted aryls (e.g., C 6 ~C 10 Ariel, C 10 It is an aryl or phenyl compound. In this embodiment, Z 1 aryl (e.g., C) is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents). 6 ~C 10 Ariel, C 10 It is an aryl or phenyl compound. In this embodiment, Z 1 This is an unsubstituted aryl (e.g., C 6 ~C 10 Ariel, C 10 It is an aryl or phenyl compound. In this embodiment, Z 1 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heteroaryl (e.g., a 5-10 member heteroaryl, a 5-9 member heteroaryl, or a 5-6 member heteroaryl). In embodiments, Z 1 is a substituted heteroaryl (e.g., substituted with substituents, size-restricted substituents, or lower substituents) (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl). In embodiments, Z 1 is an unsubstituted heteroaryl (for example, These are 5-10 member heteroaryls, 5-9 member heteroaryls, or 5-6 member heteroaryls.

[0248] In the embodiment, Z 1 teeth,

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[0249] In the embodiment, Z 1 teeth,

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[0250] In the embodiment, Z 2 This refers to substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted cycloalkylenes (e.g., C 3 ~C 8 Cycloalkylene, C 3 ~C 6 Cycloalkylene, or C 5 ~C 6 It is a cycloalkylene. In the embodiment, Z 2 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heterocycloalkylene (e.g., a 3- to 8-membered heterocycloalkylene, a 3- to 6-membered heterocycloalkylene, or a 5- to 6-membered heterocycloalkylene). In embodiments, Z 2 This refers to substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted arylenes (e.g., C 6 ~C 10 Alliren, C 10 (Arylene or phenylene). In the embodiment, Z 2 These are substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heteroarylenes (e.g., 5-10 membered heteroarylenes, 5-9 membered heteroarylenes, or 5-6 membered heteroarylenes).

[0251] In the embodiment, Z 2 This refers to substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted arylenes (e.g., C 6 ~C 10 Alliren, C 10 (Arylene or phenylene). In the embodiment, Z 2 arylenes are substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) (e.g., C 6~C 10 Alliren, C 10 (Arylene or phenylene). In the embodiment, Z 2 is an unsubstituted arylene (e.g., C 6 ~C 10 Alliren, C 10 It is arylene (or phenylene).

[0252] In the embodiment, Z 2 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heteroarylene (e.g., 5-10 membered heteroarylene, 5-9 membered heteroarylene, or 5-6 membered heteroarylene). In embodiments, Z 2 is a substituted heteroarylene (e.g., substituted with substituents, size-restricted substituents, or lower substituents) (e.g., 5-10 membered heteroarylene, 5-9 membered heteroarylene, or 5-6 membered heteroarylene). In embodiments, Z 2 These are unsubstituted heteroarylenes (e.g., 5-10 member heteroarylenes, 5-9 member heteroarylenes, or 5-6 member heteroarylenes).

[0253] In the embodiment, Z 2 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted 5- to 6-membered heteroarylene. In embodiments, Z 2 is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) 5-6 member heteroarylene. In embodiments, Z 2 This is an unsubstituted 5-6 member heteroarylene.

[0254] In the embodiment, Z 2 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted phenylene. In embodiments, Z 2 is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) phenylene. In the embodiment, Z 2 This is unsubstituted phenylene.

[0255] In the embodiment, Z 2 is an unsubstituted arylene. In the embodiment, Z 2 teeth,

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[0256] In the embodiment, V is N. In the embodiment, V is O. In the embodiment, V is C.

[0257] In the embodiment, -Z 2 -V- is,

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[0258] In the embodiment, -Z 2 -V- is,

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[0259] In the embodiment, the ADC of formula (IA) or formula (IIA):

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[0260] In this embodiment, ring A is substituted (for example, a substituent, a size-restricted substituent, or The heterocycloalkylenes are either substituted with lower substituents or unsubstituted (e.g., 3-8 membered heterocycloalkylenes, 3-6 membered heterocycloalkylenes, or 5-6 membered heterocycloalkylenes), or substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted (e.g., 5-10 membered heteroarylenes, 5-9 membered heteroarylenes, or 5-6 membered heteroarylenes). In the embodiment, ring A is substituted with one or more substituents. In the embodiment, ring A is substituted with one or more size-restricted substituents. In the embodiment, ring A is substituted with one or more lower substituents. Ring A is L by heteroatom Y 2 Connected.

[0261] In the embodiments, ring A' is a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl), or a substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). In the embodiments, ring A' is substituted with one or more substituents. In the embodiments, ring A' is substituted with one or more size-restricted substituents. In the embodiments, ring A' is substituted with one or more lower substituents. Ring A' is connected to D' by heteroatoms Y. In the embodiments, each Y is N.

[0262] In the embodiment, ring A is a substituted (one or more, e.g., substituted with substituents, size-restricted substituents, or lower substituents) 3- to 8-membered heterocycloalkylene, and ring A is L by heteroatom Y 2 It is connected to D'. In the embodiment, ring A' is a substituted (one or more, e.g., substituted with substituents, size-restricted substituents, or lower substituents) 3- to 8-membered heterocycloalkyl, and ring A' is connected to D' by heteroatoms Y. In the embodiment, each Y is N.

[0263] In the embodiment, ring A is a substituted (one or more, e.g., substituted with substituents, size-restricted substituents, or lower substituents) 5-6 membered heterocycloalkylene, and ring A is L by heteroatom Y 2 It is connected to D'. In the embodiment, ring A' is a substituted (one or more, e.g., substituted with substituents, size-restricted substituents, or lower substituents) 5-6 member heterocycloalkyl, and ring A' is connected to D' by heteroatoms Y. In the embodiment, each Y is N.

[0264] In this embodiment, the ADC of formula (IB) or formula (IIB):

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[0265] In this embodiment, the ADC of formula (IC) or formula (IIC):

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[0266] In this embodiment, the ADC of formula (ID) or formula (IID):

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[0267] In this embodiment, the ADC of formula (ID1) or formula (IID1):

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[0268] In the embodiment, the ADC of formula (IE) or formula (IIE):

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[0269] In this embodiment, the ADC of formula (IF) or formula (IIF):

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[0270] In the embodiment, the ADC of formula (IG) or formula (IH):

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[0271] In the embodiment, -NH- and -D are connected to different carbon atoms on ring W. In the embodiment, -NH- and -D are connected to the same carbon atom on ring W.

[0272] In the embodiment, ring W is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cycloalkylene (e.g., C 3 ~C 8 Cycloalkylene, C 3 ~C 6 Cycloalkylene, or C 5 ~C 6 Cycloalkylenes), or substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted arylenes (e.g., C 5 ~C 10 Alliren, C 5 ~C 8 Arirene, or C 5 ~C 6 (Arylene). In the embodiment, ring W is substituted with one or more substituents. In the embodiment, ring W is substituted with one or more size-restricted substituents. In the embodiment, ring W is substituted with one or more lower substituents.

[0273] In the embodiment, ring W is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted C 3 ~C 8 It is a cycloalkylene. In the embodiment, ring W is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) C 3 ~C 8 It is a cycloalkylene. In the embodiment, the ring W is an unsubstituted C 3 ~C 8 It is a cycloalkylene.

[0274] In this embodiment, ring W is substituted (one or more of which are substituents, size-restricted substituents, or lower substituents) C 3 ~C 8 It is a cycloalkylene.

[0275] In the embodiment, ring W is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cyclobutylene. In the embodiment, ring W is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cyclopentylene. In the embodiment, ring W is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cyclohexylene.

[0276] In the embodiment, ring W is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted C 5 ~C 6 It is an arylene. In the embodiment, the ring W is substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) C 5 ~C 6 It is an arylene. In this embodiment, the ring W is an unsubstituted C 5 ~C 6 a It is reylene. In the embodiment, ring W is substituted (one or more of which are substituted, for example, substituents, size-restricted substituents, or lower substituents) C 5 ~C 6 It is arrine.

[0277] In the embodiment, ring C is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heterocycloalkyl (e.g., 3-8 member heterocycloalkyl, 3-6 member heterocycloalkyl, or 5-6 member heterocycloalkyl), or substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heteroaryl (e.g., 5-10 member heteroaryl, 5-9 member heteroaryl, or 5-6 member heteroaryl). In the embodiment, ring C is substituted with one or more substituents. In the embodiment, ring C is substituted with one or more size-restricted substituents. In the embodiment, ring C is substituted with one or more lower substituents.

[0278] In the embodiment, ring C is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), or substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiment, ring C is substituted with one or more substituents. In the embodiment, ring C is substituted with one or more size-restricted substituents. In the embodiment, ring C is substituted with one or more lower substituents.

[0279] In the embodiment, ring C is a substituted (one or more, e.g., substituted with substituents, size-restricted substituents, or lower substituents) 5- to 9-membered heteroaryl. In the embodiment, ring C is an unsubstituted 5- to 9-membered heteroaryl.

[0280] In the embodiment, ring C is a substituted (one or more, e.g., substituted with substituents, size-restricted substituents, or lower substituents) 5-6 member heteroaryl. In the embodiment, ring C is an unsubstituted 5-6 member heteroaryl.

[0281] In the embodiment, ring C is a substituted (one or more, e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) 3- to 8-membered heterocycloalkyl. In the embodiment, ring C is a substituted (one or more, e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) 5- to 6-membered heterocycloalkyl.

[0282] In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted furanyl, pyrrolyl, pyridyl, pyranyl, imidazolyl, thienyl, oxazolyl, or thiazolyl. In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) furanyl, pyrrolyl, pyridyl, pyranyl, imidazolyl, thienyl, oxazolyl, or thiazolyl. In the embodiment, ring C is an unsubstituted furanyl, pyrrolyl, pyridyl, pyranyl, imidazolyl, thienyl, oxazolyl, or thiazolyl.

[0283] In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted furanyl. In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) furanyl. In the embodiment, ring C is an unsubstituted furanyl.

[0284] In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyrrolyl. In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) pyrrolyl. In the embodiment, ring C is an unsubstituted pyrrolyl.

[0285] In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyridyl. In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) pyridyl. In the embodiment, ring C is an unsubstituted pyridyl.

[0286] In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted pyranyl. In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) pyranyl. In the embodiment, ring C is an unsubstituted pyranyl.

[0287] In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted imidazolyl. In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) imidazolyl. In the embodiment, ring C is an unsubstituted imidazolyl.

[0288] In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or an unsubstituted thiazolyl. In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) thiazolyl. In the embodiment, ring C is an unsubstituted thiazolyl.

[0289] In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or an unsubstituted thienyl. In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) thienyl. In the embodiment, ring C is an unsubstituted thienyl.

[0290] In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted oxazolyl. In the embodiment, ring C is a substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) oxazolyl. In the embodiment, ring C is an unsubstituted oxazolyl.

[0291] In the embodiment, ring C is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 Cycloalkyl), or substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted aryl (e.g., C 5 ~C 10 Ariel, C 5 ~C 8 Aryl, or C 5 ~C 6 In the embodiment, ring C is substituted with one or more substituents. In the embodiment, ring C is substituted with one or more size-restricted substituents. In the embodiment, ring C is substituted with one or more lower substituents.

[0292] In the embodiment, ring C is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted C 3 ~C 8 It is a cycloalkyl group. In the embodiment, ring C is substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) C 3 ~C 8 It is a cycloalkyl group. In the embodiment, the ring C is an unsubstituted C. 3 ~C 8 It is a cycloalkyl group. In the embodiment, ring C is substituted (one or more of which are substituted, for example, substituents, size-restricted substituents, or lower substituents) C 3 ~C 8 It is a cycloalkyl group.

[0293] In the embodiment, ring C is substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cyclobutyl. In the embodiment, ring C is substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cyclopentyl. In the embodiment, ring C is substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cyclohexyl.

[0294] In the embodiment, ring C is either substituted (e.g., substituted with substituents, size-restricted substituents, or lower substituents) or unsubstituted C 5 ~C 6 It is an aryl ring. In the embodiment, the ring C is substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) C 5 ~C 6 It is an aryl compound. In this embodiment, the ring C is an unsubstituted C 5 ~C 6 It is an aryl compound. In the embodiment, the ring C is substituted (one or more of which are substituted, for example, substituents, size-restricted substituents, or lower substituents) C 5 ~C 6 It is Ariel.

[0295] In this embodiment, the ADC of formula (IK):

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[0296] In the embodiment, Z is N. In the embodiment, Z is O. In the embodiment, Z is S.

[0297] In this embodiment, the ADC of formula (IL) or formula (IM):

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[0298] In this embodiment, the ADC of expression (IN) or expression (IO):

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[0299] In this embodiment, the ADC of formula (IP) or formula (IQ):

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[0300] In this embodiment, the ADC has the following structure:

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[0301] In this embodiment, the ADC has the following structure:

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[0302] In this embodiment, the ADC has the following structure:

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[0303] In this embodiment, the ADC has the following structure:

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[0304] The drug load is represented by m, which is the average number of drug moieties (i.e., D, D', or D'') per anti-B7-H3 antibody in an antibody-drug conjugate (ADC) of formula (I), formula (II), or formula (III) or its variant. The drug load may range from 1 to 20 drug moieties per antibody. An ADC of formula (I), formula (II), or formula (III), and any embodiment, variant, or aspect thereof, comprises a collection of antibodies conjugated with drug moieties ranging from 1 to 20. The average number of drug moieties per antibody in a preparation of ADCs from a conjugation reaction can be characterized by conventional means such as mass spectrometry, ELISA assay, and HPLC. The quantitative distribution in the ADC in units of m can also be determined. In some cases, separation, purification, and characterization of a homogeneous ADC, where m is a specific value, from ADCs with other drug loads can be achieved by means such as HIC, reverse-phase HPLC, or electrophoresis. In the embodiment, the average number of drug moieties per anti-B7-H3 antibody (i.e., D, D', or D'') may range from 1 to 20 drug moieties per antibody. In the embodiment, the average number of drug moieties per anti-B7-H3 antibody (i.e., D, D', or D'') may range from 1 to 8 drug moieties per antibody.

[0305] For some ADCs, m may be limited by the number of binding sites on the antibody. For example, if the binding is cysteinethiol, as in some exemplary embodiments described herein, the antibody may have one or more cysteinethiol groups. or it may have one or more sufficiently reactive thiol groups to which a linker can be attached. In embodiments, the average drug load 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.

[0306] In embodiments, the conjugation method for derivatizing polypeptides in a payload can be carried out by forming amide bonds with lysine side chains. Due to the presence of numerous lysine side-chain amines with similar reactivity, this conjugation strategy can produce highly complex heterogeneous mixtures. The compositions and methods provided herein provide lysine conjugations in which, in some embodiments, enhanced lysine selectivity may result in a less heterogeneous mixture. In embodiments, the mean drug load 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.

[0307] In embodiments, a drug moiety less than the theoretical maximum amount is conjugated to the antibody during the conjugation reaction. Generally, antibodies do not contain many free and reactive cysteinethiol groups that can be linked to the drug moiety; in fact, most cysteinethiol residues in antibodies exist as disulfide crosslinks. In embodiments, the antibody is reduced with a reducing agent, such as dithiothreitol (DTT) or tricarbonoxyethylphosphine (TCEP), under partial or complete reducing conditions to generate reactive cysteinethiol groups. In embodiments, the antibody is subjected to reducing conditions to expose reactive nucleophiles such as lysine or cysteine.

[0308] The ADC load (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 conjugation reaction time or temperature, and (iii) by partial or restrictive reduction conditions for cysteinethiol modification. The DAR can also be controlled by the reactivity of the group reacting with the antibody or the reactivity of the groups in the antibody.

[0309] It should be understood that if more than one nucleophile reacts with the drug-linker intermediate or linker reagent, the resulting product is a mixture of ADC compounds with a distribution of one or more drug moieties bound to the antibody. The average number of drugs per antibody is g The ADC can be calculated from the mixture using HIC, RP, UV, or LC-MS. Individual ADC molecules in the mixture can be identified by mass spectrometry and separated by HPLC, for example, hydrophobic interaction chromatography (e.g., McDonagh et al (2006) Prot. Engr. Design & Selection 19(7):299-307; Hamblet et al (2004) Clin. Cancer Res. 10:7063-7070;Hamblett, KJ, et al. See "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 AACR, Volume 45, March 2004; Alley, SC, et al. "Controlling the location of drug attachment in antibody-drug conjugates," Abstract No. 627, American Association for Cancer Research, 2004 Annual Meeting, March 27-31, 2004, Proceedings of the AACR, Volume 45, March 2004). In embodiments, a homogeneous ADC having a single loading value can be isolated from the conjugation mixture by electrophoresis or chromatography. Anti-B7-H3 antibody i. Exemplary antibodies and antibody sequences

[0310] In the embodiments, the ADC comprises an antibody that binds to B7-H3. B7-H3 has been reported to be upregulated, for example, in lung cancer, regardless of baseline levels of B7-H3 expression. In the embodiments, the ADC compounds described herein comprise an anti-B7-H3 antibody.

[0311] In embodiments, the anti-B7-H3 antibody provided herein contains cysteine. In embodiments, the anti-B7-H3 antibody is conjugated to the drug via a linker by the sulfur of a cysteine ​​residue. In embodiments, the anti-B7-H3 antibody is conjugated to the drug via a linker by the sulfur of two cysteine ​​residues.

[0312] In embodiments, the anti-B7-H3 antibody provided herein contains lysine. In embodiments, the anti-B7-H3 antibody is conjugated to the drug via a linker by an amine of a lysine residue. In embodiments, the anti-B7-H3 antibody is conjugated to the drug via a linker by an amine of one or two lysine residues.

[0313] In embodiments, the ADC provided herein comprises an anti-B7-H3 antibody comprising a light chain variable region and a heavy chain variable region, wherein the light chain variable region comprises light chain complementarity determining region 1 (CDR1), light chain CDR2, and light chain CDR3, and the heavy chain variable region comprises heavy chain CDR1, heavy chain CDR2, and heavy chain CDR3.

[0314] In embodiments, the ADC provided herein comprises an anti-B7-H3 antibody comprising at least one CDR selected from (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 embodiments, the ADC comprises an anti-B7-H3 antibody comprising at least one CDR selected from (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 one embodiment, the ADC comprises an anti-B7-H3 antibody comprising at least two CDRs selected from (a) VL CDR1 containing the sequence of SEQ ID NO: 1; (b) VL CDR2 containing the sequence of SEQ ID NO: 2; (c) VL CDR3 containing the sequence of SEQ ID NO: 3; (d) VH CDR1 containing the sequence of SEQ ID NO: 4; (e) VH CDR2 containing the sequence of SEQ ID NO: 5; and (f) VH CDR3 containing the sequence of SEQ ID NO: 6. In another embodiment, the ADC comprises an anti-B7-H3 antibody comprising at least three CDRs selected from (a) VL CDR1 containing the sequence of SEQ ID NO: 1; (b) VL CDR2 containing the sequence of SEQ ID NO: 2; (c) VL CDR3 containing the sequence of SEQ ID NO: 3; (d) VH CDR1 containing the sequence of SEQ ID NO: 4; (e) VH CDR2 containing the sequence of SEQ ID NO: 5; and (f) VH CDR3 containing the sequence of SEQ ID NO: 6. In this embodiment, the ADC comprises an anti-B7-H3 antibody comprising at least four CDRs selected from (a) VL CDR1 containing the sequence of SEQ ID NO: 1; (b) VL CDR2 containing the sequence of SEQ ID NO: 2; (c) VL CDR3 containing the sequence of SEQ ID NO: 3; (d) VH CDR1 containing the sequence of SEQ ID NO: 4; (e) VH CDR2 containing the sequence of SEQ ID NO: 5; and (f) VH CDR3 containing the sequence of SEQ ID NO: 6.In this embodiment, the ADC includes (a) VL CDR1 containing the sequence of sequence number 1; (b) VL CDR2 containing the sequence of sequence number 2; (c) VL CDR3 containing the sequence of sequence number 3; (d) VH CDR1 containing the sequence of sequence number 4; and (e) VH containing the sequence of sequence number 5. The ADC comprises an anti-B7-H3 antibody comprising at least five CDRs selected from (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 CDR3 comprising the sequence of SEQ ID NO: 4. The antibody comprises an anti-B7-H3 antibody containing at least six CDRs selected from DR1; (e) VH CDR2 containing the sequence of SEQ ID NO: 5; and (f) VH CDR3 containing the sequence of SEQ ID NO: 6.

[0315] In one embodiment, the ADC comprises an anti-B7-H3 antibody comprising one CDR selected from (a) VL CDR1 containing the sequence of SEQ ID NO: 1; (b) VL CDR2 containing the sequence of SEQ ID NO: 2; (c) VL CDR3 containing the sequence of SEQ ID NO: 3; (d) VH CDR1 containing the sequence of SEQ ID NO: 4; (e) VH CDR2 containing the sequence of SEQ ID NO: 5; and (f) VH CDR3 containing the sequence of SEQ ID NO: 6. In another embodiment, the ADC comprises an anti-B7-H3 antibody comprising two CDRs selected from (a) VL CDR1 containing the sequence of SEQ ID NO: 1; (b) VL CDR2 containing the sequence of SEQ ID NO: 2; (c) VL CDR3 containing the sequence of SEQ ID NO: 3; (d) VH CDR1 containing the sequence of SEQ ID NO: 4; (e) VH CDR2 containing the sequence of SEQ ID NO: 5; and (f) VH CDR3 containing the sequence of SEQ ID NO: 6. In one embodiment, the ADC comprises an anti-B7-H3 antibody comprising three CDRs selected from (a) VL CDR1 containing the sequence of SEQ ID NO: 1; (b) VL CDR2 containing the sequence of SEQ ID NO: 2; (c) VL CDR3 containing the sequence of SEQ ID NO: 3; (d) VH CDR1 containing the sequence of SEQ ID NO: 4; (e) VH CDR2 containing the sequence of SEQ ID NO: 5; and (f) VH CDR3 containing the sequence of SEQ ID NO: 6. In another embodiment, the ADC comprises an anti-B7-H3 antibody comprising four CDRs selected from (a) VL CDR1 containing the sequence of SEQ ID NO: 1; (b) VL CDR2 containing the sequence of SEQ ID NO: 2; (c) VL CDR3 containing the sequence of SEQ ID NO: 3; (d) VH CDR1 containing the sequence of SEQ ID NO: 4; (e) VH CDR2 containing the sequence of SEQ ID NO: 5; and (f) VH CDR3 containing the sequence of SEQ ID NO: 6. In this embodiment, the ADC comprises an anti-B7-H3 antibody comprising five CDRs selected from (a) VL CDR1 containing the sequence of SEQ ID NO: 1; (b) VL CDR2 containing the sequence of SEQ ID NO: 2; (c) VL CDR3 containing the sequence of SEQ ID NO: 3; (d) VH CDR1 containing the sequence of SEQ ID NO: 4; (e) VH CDR2 containing the sequence of SEQ ID NO: 5; and (f) VH CDR3 containing the sequence of SEQ ID NO: 6.In this embodiment, the ADC comprises an anti-B7-H3 antibody comprising six CDRs selected from (a) VL CDR1 containing the sequence of SEQ ID NO: 1; (b) VL CDR2 containing the sequence of SEQ ID NO: 2; (c) VL CDR3 containing the sequence of SEQ ID NO: 3; (d) VH CDR1 containing the sequence of SEQ ID NO: 4; (e) VH CDR2 containing the sequence of SEQ ID NO: 5; and (f) VH CDR3 containing the sequence of SEQ ID NO: 6.

[0316] In the embodiment, the anti-B7-H3 antibody 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 the embodiment, the anti-B7-H3 antibody includes VL CDR1 containing the sequence of SEQ ID NO: 1. In the embodiment, the anti-B7-H3 antibody includes VL CDR2 containing the sequence of SEQ ID NO: 2. In the embodiment, the anti-B7-H3 antibody includes VL CDR3 containing the sequence of SEQ ID NO: 3. In the embodiment, the anti-B7-H3 antibody includes VH CDR1 containing the sequence of SEQ ID NO: 4. In the embodiment, the anti-B7-H3 antibody includes VH CDR2 containing the sequence of SEQ ID NO: 5. In the embodiment, the anti-B7-H3 antibody includes VH CDR3 containing the sequence of SEQ ID NO: 6.

[0317] In this embodiment, the ADC includes an anti-B7-H3 antibody in which the light chain CDR1 has the amino acid sequence of SEQ ID NO: 1, the light chain CDR2 has the amino acid sequence of SEQ ID NO: 2, the light chain CDR3 has the amino acid sequence of SEQ ID NO: 3, the heavy chain CDR1 has the amino acid sequence of SEQ ID NO: 4, the heavy chain CDR2 has the amino acid sequence of SEQ ID NO: 5, and the heavy chain CDR3 has the amino acid sequence of SEQ ID NO: 6.

[0318] In the embodiment, the anti-B7-H3 antibody is present in an amount of at least 95%, 96%, relative to SEQ ID NO: 7. The VL contains a sequence having 97%, 98%, or 99% identity. In the embodiment, the anti-B7-H3 antibody contains a VL having the sequence of SEQ ID NO: 7. In the embodiment, the VL sequence having at least 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 7 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-B7-H3 antibody containing that sequence retains the ability to bind to B7-H3. In the embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 7. In the embodiment, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 7. In the embodiment, the substitution, insertion, or deletion occurs in a region outside the CDR (i.e., in the FR). In the embodiment, the anti-B7-H3 antibody contains the VL sequence of SEQ ID NO: 7 and includes post-translational modifications of that sequence.

[0319] In the embodiment, the anti-B7-H3 antibody includes a VH having a sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In the embodiment, the anti-B7-H3 antibody includes a VH having the sequence of SEQ ID NO: 8. In the embodiment, the VH sequence having at least 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8 contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to the reference sequence, but the anti-B7-H3 antibody containing that sequence retains the ability to bind to B7-H3. In the embodiment, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 8. In the embodiment, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 8. In the embodiment, the substitutions, insertions, or deletions occur in a region outside the CDR (i.e., in the FR). In the embodiment, the anti-B7-H3 antibody includes the VH sequence of SEQ ID NO: 8 and includes post-translational modifications of that sequence.

[0320] In the embodiment, the anti-B7-H3 antibody is an IgG antibody. In the embodiment, the anti-B7-H3 antibody is an IgG1, IgG2, IgG3, or IgG4 antibody. In the embodiment, the anti-B7-H3 antibody is an IgG1 or IgG4 antibody. In the embodiment, the anti-B7-H3 antibody is an IgG1 antibody.

[0321] In this embodiment, the anti-B7-H3 antibody binds to human B7-H3. In this embodiment, human B7-H3 has the amino acid sequence of SEQ ID NO: 16.

[0322] In any of the above embodiments, the anti-B7-H3 antibody is humanized. In the embodiment, the anti-B7-H3 antibody comprises a CDR, similar to any of the above embodiments, and further comprises a human acceptor framework, such as a human immunoglobulin framework or a human consensus framework. In the embodiment, the humanized anti-B7-H3 antibody comprises (a) VL CDR1 containing the sequence of SEQ ID NO: 1; (b) VL CDR2 containing the sequence of SEQ ID NO: 2; (c) VL CDR3 containing the sequence of SEQ ID NO: 3; (d) VH CDR1 containing the sequence of SEQ ID NO: 4; (e) VH CDR2 containing the sequence of SEQ ID NO: 5; and (f) VH CDR3 containing the sequence of SEQ ID NO: 6.

[0323] In one embodiment, the anti-B7-H3 antibody is a monoclonal antibody containing a chimeric, humanized, or human antibody. In one embodiment, the anti-B7-H3 antibody is an antibody fragment, e.g., Fv, Fab, Fab', scFv, diabody, or F(ab') 2 It is a fragment. In another embodiment, the antibody is a substantially full-length antibody, for example, an IgG1 antibody or another antibody class or isotype as defined herein. ii. Antibody affinity

[0324] In embodiments, the anti-B7-H3 antibody provided herein binds to human B7-H3 with an affinity of ≤10 nM, or ≤5 nM, or ≤4 nM, or ≤3 nM, or ≤2 nM. In embodiments, the anti-B7-H3 antibody binds with an affinity of ≥0.0001 nM, or ≥0.001 n The antibody binds to human B7-H3 with an affinity of M, or ≥0.01 nM. Binding affinity can be determined using standard assays known to those skilled in the art. For example, whether an anti-B7-H3 antibody "binds with an affinity of ≤10 nM, or ≤5 nM, or ≤4 nM, or ≤3 nM, or ≤2 nM" can be determined using standard scatchard analysis with a nonlinear curve fitting program (see, e.g., Munson et al., Anal Biochem, 107: 220-239, 1980).

[0325] In embodiments, the anti-B7-H3 antibodies provided herein have a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM, and optionally ≥10 -13 It is M. (For example, 10 -8 M or less, for example, 10 -8 M~10 -13 M, for example, 10 -9 M~10 -13 M)。 iii.Antibody fragment

[0326] In embodiments, the antibodies provided herein (e.g., anti-B7-H3 antibodies) are antibody fragments. Antibody fragments are not limited to these, but include Fab, Fab', Fab'-SH, F(ab'), etc. 2 This includes Fab and F(ab') fragments, as well as other fragments described below. For an overview of a specific antibody fragment, see Hudson et al. Nat. Med. 9:129-134 (2003). For an overview of the scFv fragment, see, for example, Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994), and also see WO93 / 16185 and U.S. Patent Nos. 5,571,894 and 5,587,458. Fab and F(ab') fragments, containing salvage receptor-binding epitope residues, have increased in vivo half-lives. 2 For a discussion of the fragments, see U.S. Patent No. 5,869,046.

[0327] Diabodies are antibody fragments having two antigen-binding sites, which may be bivalent or bispecific. See, for example, EP404,097;WO1993 / 01161;Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

[0328] A single-domain antibody is an antibody fragment that contains all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In embodiments, the single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see also, e.g., U.S. Patent No. 6,248,516B1).

[0329] Antibody fragments can be prepared by a variety of techniques, including, but not limited to, proteolysis of intact antibodies and production by recombinant host cells (e.g., E. coli or phages), as described herein. iv. Chimeric and humanized antibodies

[0330] In embodiments, the anti-B7-H3 antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and in Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In one example, a chimeric antibody includes a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, e.g., a monkey) and a human constant region. In further examples, a chimeric antibody is a “class-switched” antibody in which the class or subclass has been changed from that of the parent antibody. A chimeric antibody includes its antigen-binding fragment.

[0331] In embodiments, the chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized such that its immunogenicity against humans is reduced while retaining the specificity and affinity of the parent non-human antibody. Generally, a humanized antibody contains one or more variable domains in which the HVR, e.g., CDR (or a portion thereof), is derived from the non-human antibody and the FR (or a portion thereof) is derived from the human antibody sequence. The humanized antibody may also optionally contain at least a portion of the human constant region. In embodiments, some FR residues in the humanized antibody are replaced with corresponding residues from the non-human antibody (e.g., the antibody from which the HVR residues are derived) to restore or improve the specificity or affinity of the antibody, for example.

[0332] Humanized antibodies and methods for producing them are outlined, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further, for example, Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Patents No. 5,821,337, No. 7,527,791, No. 6,982,321, and No. 7,087,409; Kashmiri This is described in et al., Methods 36:25-34 (2005) (SDR(a-CDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) ("Resurfacing" is described); Dall'Acqua et al., Methods 36:43-60 (2005) ("FR shuffling" is described); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) ("Induction Selection" approach for FR shuffling is described).

[0333] Human framework domains that can be used for humanization include, but are not limited to, framework domains selected using the "best fit" method (e.g., Sims et al. J. See Immunol. 151:2296 (1993); Framework regions derived from the consensus sequence of human antibodies of a specific subgroup of light chain or heavy chain variable regions (e.g., Carter See et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993); human mature (somatically mutant) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening of FR libraries (see, e.g., Baca et al., This includes J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996). v. Human antibodies

[0334] In embodiments, the anti-B7-H3 antibody provided herein is a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20: 450-459 (2008).

[0335] Human antibodies can be prepared by administering an immunogen to transgenic animals modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigen administration. Such animals typically possess all or part of the human immunoglobulin loci, which are either replaced by endogenous immunoglobulin loci, located extrachromosomally, or randomly incorporated into the animal's chromosomes. Endogenous immunoglobulin loci in such transgenic mice are generally inactivated. For an overview of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). For example, U.S. Patents 6,075,181 and 6,150,584 describing the XENOMOUSE® technology; U.S. Patent 5,770,429 describing the HUMAB® technology; and U.S. Patent 7,041,8 describing the KM MOUSE® technology. See also Patent No. 70, and U.S. Patent Application Publication No. 2007 / 0061900, which describes the VELOCIMOUSE® technology. The human variable region from intact antibodies produced by such animals can be further modified, for example, by combining it with a different human constant region.

[0336] Human antibodies can also be produced using hybridoma-based methods. Human myeloma and mouse-human xenomyeloma cell lines for the production of human monoclonal antibodies have been described. (See, for example, Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991).) Human antibodies produced by human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Further methods include those described in, for example, U.S. Patent No. 7,189,826 (which describes the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (which describes human-human hybridomas). Human hybridoma technology (trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

[0337] Human antibodies can also be generated by isolating selected Fv clone variable domain sequences from a human-derived phage display library. Such variable domain sequences can then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below. vi. Multispecific antibodies

[0338] In embodiments, the anti-B7-H3 antibody provided herein is a multispecific antibody, for example, a bispecific antibody. A multispecific antibody is a monoclonal antibody having binding specificity to at least two different sites. In embodiments, one binding specificity is to B7-H3, and the other is to any other antigen. In embodiments, a bispecific antibody can bind to two different epitopes of B7-H3. Bispecific antibodies can also be used to localize cytotoxic agents to cells expressing B7-H3. Bispecific antibodies can be prepared as full-length antibodies or antibody fragments.

[0339] Techniques for producing multispecific antibodies include, but are not limited to, the recombinant co-expression of two immunoglobulin heavy-light chain pairs with different specificities (see Milstein and Cuello, Nature 305: 537 (1983)), WO93 / 08829, and Traunecker et al., EMBO J. 10: 3655 (1991)), and the "knob-in-hole" operation (see, for example, U.S. Patent No. 5,731,168). Manipulating the electrostatic steering effect to produce antibody Fc-heterodimer molecules (WO2009 / 089004A1); crosslinking two or more antibodies or fragments (see, e.g., U.S. Patent No. 4,676,980 and Brennan et al., Science, 229: 81 (1985)); using leucine zippers to produce bispecific antibodies (see, e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)); using "diabody" techniques to produce bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and using single-stranded Fv(sFv) dimers (see, e.g., Gruber et al., J. Immunol., See 152:5368 (1994); and multispecific antibodies can also be prepared by preparing tripspecific antibodies, for example, as described in Tutt et al. J. Immunol. 147: 60 (1991).

[0340] Modified antibodies having three or more functional antigen-binding sites, including "octopus antibodies," are also included herein (see, for example, U.S. Patent Application Publication 2006 / 0025576A1).

[0341] The antibodies or fragments described herein also include "dual-acting FAbs" or "DAFs" that contain antigen-binding sites that bind not only to B7-H3 but also to other different antigens. vii. Antibody variant

[0342] In embodiments, amino acid sequence variants of antibodies provided herein are intended. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of antibodies can be prepared by introducing appropriate modifications to the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from and / or insertions into residues and / or substitutions of residues in the amino acid sequence of the antibody. Deletions, insertions, and substitutions may be combined in any way to reach the final construct, provided that the final construct has the desired properties, such as antigen binding. a) Substitution, insertion, and deletion variants

[0343] In embodiments, the anti-B7-H3 antibodies provided herein have one or more amino acid substitutions. The target sites for substitutional mutagenesis include HVR and FR. Conservative substitutions are shown under the “Preferred Substitutions” section of Table 1. Larger variations are provided under the “Exemplary Substitutions” section of Table 1, as further described below with respect to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest, and the product can be screened for desired activity, e.g., retention / improvement of antigen binding, decreased immunogenicity, or improvement of ADCC or CDC. Table 1 Amino acids can be classified according to the properties of their common side chains: (1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) Basicity: His, Lys, Arg; (5) Residues that affect chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe. Non-conservative substitutions inevitably involve swapping members of one of these classes with those of another class.

[0344] One type of substitution variant involves the substitution of one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant, selected for further study, will have altered (e.g., improved) biological properties compared to the parent antibody (e.g., increased affinity, decreased immunogenicity) and / or will substantially retain certain biological properties of the parent antibody. An exemplary substitution variant is an affinity-matured antibody, which can be conveniently generated using phage display-based affinity maturation techniques, such as those described herein. Briefly, this involves mutating one or more HVR residues and causing the variant antibody to be displayed on a phage, and specifically Screening is performed for specific biological activities (e.g., binding affinity).

[0345] For example, changes (e.g., substitutions) can be made to HVR to improve antibody affinity. HVR "hot spots" are residues encoded by codons that frequently mutate during the somatic cell maturation process (e.g., Chowdhury, Methods Mol. Biol.). See 207:179-196 (2008), and / or SDR(a-CDR), such modifications can be made, and the resulting variant VH or VL can be tested for binding affinity. Affinity maturation by construction and reselection from a secondary library is described, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In embodiments of affinity maturation, diversity is introduced into the variable gene selected for maturation by one of various methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-specific mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variant with the desired affinity. Another method for introducing diversity involves an HVR-specific approach in which several HVR residues (e.g., 4-6 residues at a time) are randomly assigned. HVR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are often targeted.

[0346] In embodiments, substitutions, insertions, or deletions can be made within one or more HVRs, provided that such modifications do not substantially reduce the antibody's ability to bind to the antigen. For example, conservative modifications that do not substantially reduce binding affinity (e.g., conservative substitutions as provided herein) can be made in an HVR. Such modifications may also be located outside of the HVR "hotspot" or SDR. In embodiments of the variant VH and VL sequences provided above, each HVR is either unmodified or contains at most one, two, or three amino acid substitutions.

[0347] A useful method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis," as described by Cunningham and Wells (1989) Science, 244:1081-1085. This method identifies a residue or target group of residues (e.g., charged residues such as arg, asp, his, lys, and glu) and substituted them with neutral or charged amino acids (e.g., alanine or polyalanine) to determine whether the antibody-antigen interaction is affected. Further substitutions can be introduced at amino acid positions that clearly show functional sensitivity to the initial substitution. Alternatively, or in addition, the crystal structure of the antigen-antibody complex can be used to identify contact points between the antibody and antigen. Such contact residues and adjacent residues can be targeted or excluded as candidate substitutions. Variants can be screened to determine whether they possess the desired properties.

[0348] Amino acid insertions include amino-terminal and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of terminal insertion is an antibody with an N-terminal methionyl residue. Other insertion variants of antibody molecules include fusion of the N-terminal or C-terminal side of an antibody to an enzyme (e.g., for ADEPT) or polypeptide that increases the serum half-life of the antibody. b) Glycosylated variants

[0349] In embodiments, the anti-B7-H3 antibodies provided herein are modified to increase or decrease the degree to which the antibody is glycosylated. Addition of glycosylation sites to the antibody or deletion of glycosylation sites results in the creation or removal of one or more glycosylation sites. This can be easily achieved by modifying the amino acid sequence.

[0350] If an antibody contains an Fc region, the carbohydrate bound to it can be modified. Native antibodies produced by mammalian cells typically contain branched oligosaccharides that are commonly bound to Asn297 of the CH2 domain of the Fc region by N-linking. See, for example, Wright et al. TIBTECH 15:26-32 (1997). Oligosaccharides may include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose bound to GlcNAc in the "stem" of the branched oligosaccharide structure. In embodiments, modifications to the oligosaccharide in the antibody can be made to create antibody variants with certain improved properties.

[0351] In one embodiment, an antibody variant is provided having a carbohydrate structure lacking fucose (directly or indirectly) bound to the Fc region. For example, the amount of fucose in such an antibody may be 1%–80%, 1%–65%, 5%–65%, or 20%–40%. The amount of fucose is determined by calculating the average amount of fucose at Asn297 in the glycan relative to the total of all sugar structures (e.g., complex, hybrid, and high-mannose structures) bound to Asn297, measured by MALDI-TOF mass spectrometry, as described in WO2008 / 077546, for example. Asn297 refers to the asparagine residue located at approximately position 297 (Eu numbering of Fc region residues) within the Fc region, although Asn297 may also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to small sequence changes within the antibody. Such fucosylated variants may have improved ADCC function. For example, see U.S. Patent Application Publication No. 2003 / 0157108 (Presta, L.); U.S. Patent Application Publication No. 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd.). Examples of publications relating to "defucosylated" or "fucose-deficient" antibody variants include U.S. Patent Application Publication No. 2003 / 0157108; WO2000 / 61739; WO2001 / 29246; U.S. Patent Application Publication No. 2003 / 0115614; U.S. Patent Application Publication No. 2002 / 0164328; U.S. Patent Application Publication No. 2004 / 0093621; U.S. Patent Application Publication No. 200 Examples include 4 / 0132140; U.S. Patent Application Publication No. 2004 / 0110704; U.S. Patent Application Publication No. 2004 / 0110282; U.S. Patent Application Publication No. 2004 / 0109865; WO2003 / 085119; WO2003 / 084570; WO2005 / 035586; WO2005 / 035778; WO2005 / 053742; WO2002 / 031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004).Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells lacking protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Patent Application Publication No. 2003 / 0157108A1, Presta, L; and WO2004 / 056312A1, Adams et al., particularly Example 11), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene, FUT8, and knockout CHO cells (see, for example, Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO2003 / 085107).

[0352] For example, antibody variants having a bifid oligosaccharide are provided, in which a branched oligosaccharide bound to the Fc region of the antibody is bifid by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, for example, in WO2003 / 011878 (Jean-Mairet et al.), U.S. Patent No. 6,602,684 (Umana et al.), and U.S. Patent Application Publication No. 2005 / 0123546 (Umana et al.). Antibody variants having at least one galactose residue in the combined oligosaccharide are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO1997 / 30087 (Patel et al.); WO1998 / 58964 (Raju, S.); and WO1999 / 22764 (Raju, S.). c) Fc region variant

[0353] In embodiments, an Fc region variant can be generated by introducing one or more amino acid modifications into the Fc region of an anti-B7-H3 antibody provided herein. The Fc region variant may include a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing amino acid modifications (e.g., substitutions) at one or more amino acid positions.

[0354] In embodiments, antibody variants are intended that possess some, but not all, effector functions, and which, due to their effector functions, are desirable candidates for applications where the in vivo half-life of the antibody is important, and certain effector functions (e.g., complement and ADCC) are unnecessary or detrimental. In vitro and / or in vivo cytotoxicity assays can be performed to confirm reduced / deficient CDC and / or ADCC activity. For example, an Fc receptor (FcR) binding assay can be performed to ensure that the antibody lacks FcγR binding (and therefore is likely to lack ADCC activity) but retains FcRn binding ability. NK cells, the major cells mediating ADCC, express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays for evaluating the ADCC activity of a target molecule are described in U.S. Patent No. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986) and Hellstrom, I et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985)); and Patent No. 5,821,337 (see, Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assay methods can be used (see, for example, the ACTI® non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc., Mountain View, CA); and the CytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, WI)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells.Alternatively, or in addition, the ADCC activity of the molecule of interest can be evaluated in vivo in animal models, such as those disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). A C1q binding assay can also be performed to confirm that the antibody cannot bind to C1q and therefore lacks CDC activity. See, for example, the C1q and C3c binding ELISAs in WO2006 / 029879 and WO2005 / 100402. A CDC assay can also be performed to evaluate complement activation (e.g., Gazzano-Santoro et al.). See J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004). Methods known in the art (e.g., Petkova, SB et al.) FcRn binding and in vivo clearance / half-life determination can also be performed using (see al., Int'l. Immunol. 18(12):1759-1769 (2006)).

[0355] Antibodies exhibiting reduced effector function include those having one or more substitutions among Fc region residues 238, 265, 269, 270, 297, 327, and 329 (US). (National Patent No. 6,737,056). Such Fc variants include the so-called "DANA" Fc variant (US Patent No. 7,332,581) which has substitutions to alanine at residues 265 and 297, as well as Fc variants having substitutions at two or more positions among amino acids 265, 269, 270, 297, and 327.

[0356] Certain antibody variants exhibiting improved or reduced binding to FcR have been described. (See, for example, U.S. Patent No. 6,737,056; WO2004 / 056312, and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001).)

[0357] Increased half-life and improved binding to neonatal Fc receptor (FcRn), which is involved in the transmission of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976), and Kim Antibodies having the description in (et al., J. Immunol. 24:249 (1994)) are described in U.S. Patent Application Publication No. 2005 / 0014934A1 (Hinton et al.). These antibodies contain an Fc region having one or more substitutions therein that improve the binding of the Fc region to FcRn. Such Fc variants include those having substitutions in one or more of the Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434, for example, a substitution of Fc region residue 434 (U.S. Patent No. 7,371,826).

[0358] See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO94 / 29351 for other examples of Fc region variants. viii.Antibody derivatives

[0359] In embodiments, the monoclonal antibodies provided herein, such as anti-B7-H3 antibodies, can be further modified to include one or more additional non-proteinoid moieties known and readily available in the Art (e.g., derivatization). Suitable moieties for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (either homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may be advantageous in manufacturing due to its stability in water. The polymer may have any molecular weight and may be branched or unbranched. The number of polymers bound to the antibody may vary, and if more than one polymer is bound, they may be the same molecule or different molecules. In general, the number and / or type of polymers used in derivatization may be determined based on considerations including, but not limited to, the specific properties or functions of the antibody to be improved, and whether the antibody derivative will be used therapeutically under defined conditions. ix. Recombination methods and compositions

[0360] Antibodies can be produced using recombinant methods and compositions, such as those described in U.S. Patent No. 4,816,567. Those skilled in the art will know how to select host cells suitable for antibody expression. You are probably familiar with this. Exemplary host cells include eukaryotic cells, such as Chinese hamster ovary (CHO) cells, or lymphoid cells (e.g., Y0, NS0, Sp20 cells).

[0361] For recombinant production of anti-B7-H3 antibodies, nucleic acids encoding the antibody, e.g., the antibody described above, are isolated and inserted into one or more vectors for further cloning and / or expression in host cells. Such nucleic acids can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that can specifically bind to the genes encoding the heavy and light chains of the antibody).

[0362] Method for preparing antibody-drug conjugates In equation (I), ADC is formed by (1) covalent bonding of Ab-L 1 The nucleophile of the antibody and the divalent linker reagent (L) for forming the linker 1 ) followed by a reaction with the drug-linker molecule DL 3 or DL 3 -L 2 (2) Reaction with DL by covalent bonding 3 -L 1 or DL 3 -L 2 -L 1 To form the drug portion D and the divalent linker reagent (L 3 -L 2 -L 1 or L 3 -L 1 ADCs of formula (II) can be prepared by several routes using organic chemical reactions, conditions, and reagents known to those skilled in the art, including a reaction with an antibody, followed by a reaction with the nucleophile of the antibody or a reduced antibody. (1) ADCs of formula (II) are covalently bonded Ab-L 1 The nucleophile of the antibody and the divalent linker reagent (L) for forming the linker 1 ) followed by a reaction with the drug-linker molecule R * -D' or R * -D'-L 2 (2) Reaction with R by covalent bond * -D'-L 1 or R * -D'-L 2 -L 1 Drug-linker molecule R for forming * -D' nucleophile and divalent linker reagent (L 2 -L 1 or L 1 ADCs of formula (III) can be prepared by several routes using organic chemical reactions, conditions, and reagents known to those skilled in the art, including the reaction with an antibody followed by the reaction with a nucleophile of an antibody or a reduced antibody. Several such methods are described by Agarwal et al., (2015), Bioconjugate Chem., 26:176-192. ADCs of formula (III) are (1) covalently bonded Ab-L 1 The nucleophile of the antibody and the divalent linker reagent (L) for forming the linker 1 ) reaction with, followed by drug portion D'' or drug-linker molecule D''-L 2 Reaction with; and (2) by covalent bonding of D''-L 2 or D”-L 2 -L 1 The nucleophile of the drug portion D'' and the divalent linker reagent (L) are used to form the drug portion D''. 2 and / or L 1 It can be prepared by several routes using organic chemical reactions, conditions, and reagents known to those skilled in the art, including a reaction with ) followed by a reaction with the nucleophile of the antibody or reduced antibody. Several such methods are described in Agarwal et al., (2015), Bioconjugate Chem., As described in 26: 176-192.

[0363] In embodiments, the antibody can be reduced under partial or complete reduction conditions with a reducing agent, such as dithiothreitol (DTT) or tricarboxyethylphosphine (TCEP), to generate a reactive cysteinethiol group. The interchain cysteine ​​residue can then be alkylated, for example, using maleimide. Alternatively, the interchain cysteine ​​residue can be subjected to cross-linked alkylation, followed by Cu-click ligation, for example, using a bissulfone linker or propargyl dibromomaleimide. In embodiments, the antibody can be conjugated with lysine amino acids. Such conjugations may be one-step or two-step conjugations. In embodiments, the one-step conjugation involves a drug-linker molecule (DL) containing the ε-amino group of the lysine residue and an amine-reactive group. 3 -L 2 -L 1 or DL 3 -L 1 This inevitably involves conjugation via an amide bond with the lysine residue. In embodiments, the one-step conjugation involves a drug-linker molecule (R) containing an amine-reactive group and the ε-amino group of the lysine residue. * -D'-L 2 -L 1 or R * -D'-L 1 This inevitably involves conjugation via an amide bond with the lysine residue. In embodiments, the one-step conjugation involves a drug-linker component containing the ε-amino group and amine-reactive group of the lysine residue. Child(D”-L 2 -L 1 or D”-L 1 This inevitably involves conjugation via an amide bond with the amine-reactive group. In embodiments, the amine-reactive group is an activated ester. In embodiments, the antibody can be conjugated by a two-step conjugation. The two-step conjugation inevitably involves a first step in which a bifunctional reagent containing both an amine-reactive functional group and a thiol-reactive functional group is reacted with a lysine ε-amino group. In the second step, the drug-linker molecule (DL) is conjugated. 3 -L 2 -L 1 DL 3 -L 1 、R * -D'-L 2 -L 1 、R * -D'-L 1 , D''-L 2 -L 1 or D''-L 1 ) is conjugated with the thiol-reactive group of a bifunctional reagent. Several examples are provided by Jain et al., (2015), Pharm. Res., 32:3526-3540. In embodiments, the first step is functionalization of the antibody with azide, followed by alkyne-modified linker or drug-linker molecule (DL 3 -L 2 -L 1 DL 3 -L 1 、R * -D'-L2 -L 1 、R * -D'-L 1 , D''-L 2 -L 1 or D''-L 1 This may include a click chemistry reaction with an alkyne. In embodiments, the first step is functionalization of the antibody with an alkyne, followed by an azide-modified linker or a drug-linker molecule (DL 3 -L 2 -L 1 DL 3 -L 1 、R * -D'-L 2 -L 1 、R * -D'-L 1 , D''-L 2 -L 1 or D''-L 1 This may include a click chemistry reaction with an aldehyde. In embodiments, the first step is functionalization of the antibody with an aldehyde, followed by a click chemistry reaction with an alkoxyamine or hydrazine modified linker or drug-linker molecule (DL). 3 -L 2 -L 1 DL 3 -L 1 、R * -D'-L 2 -L 1 、R * -D'-L 1 , D''-L 2 -L 1 or D''-L 1 This may include a click chemistry reaction with ). In embodiments, the first step is functionalization of the antibody with tetrazine, followed by a trans-cyclooctene or cyclopropene modified linker or drug-linker molecule (DL 3 -L 2 -L 1 DL 3 -L 1 、R * -D'-L 2 -L 1 、R * -D'-L 1 , D''-L 2 -L 1 or D''-L 1 This may include a click chemistry reaction with a tetrazine-modified linker or a drug-linker molecule (DL). In embodiments, the first step is functionalization of the antibody with trans-cyclooctene or cyclopropene, followed by a click chemistry reaction with a tetrazine-modified linker or a drug-linker molecule (DL). 3 -L 2 -L 1 DL 3 -L 1 、R * -D'-L 2 -L 1 、R * -D'-L 1 , D''-L 2 -L 1 or D''-L 1 This may include click chemistry reactions with ). Several examples are described by Pickens et al., (2018), Bioconjug. Chem., 29:686-701; Li et al., (2018), Mabs, 10:712-719; and Chio et al., (2020), Methods Mol. Biol., 2078:83-97.

[0364] In one embodiment, the ADC of formula (I), formula (II), or formula (III) contains an anti-B7-H3 antibody (Ab) and a molecule of formula (PI), formula (P-II), or formula (P-III):

change

change

change

change

change

[0365] In the embodiments, the anti-B7-H3 antibody is modified with a reactive moiety, such as an aldehyde, azide, alkyne, tetrazine, hydrazine, alkoxyamine, trans-cyclooctene, or cyclopropene. In the embodiments, the anti-B7-H3 antibody is modified with an aldehyde. In the embodiments, the anti-B7-H3 antibody is modified with an azide. In the embodiments, the anti-B7-H3 antibody is modified with a tetrazine. In the embodiments, the anti-B7-H3 antibody is modified with an alkoxyamine. In the embodiments, the anti-B7-H3 antibody is modified with a hydrazine. In the embodiments, the anti-B7-H3 antibody is modified with trans-cyclooctene. In the embodiments, the anti-B7-H3 antibody is modified with cyclopropene.

[0366] In this embodiment, B is a reactive moiety capable of forming a binding with an anti-B7-H3 antibody. In this embodiment, Ab is a modified anti-B7-H3 antibody.

[0367] In the embodiments, Ab is modified with an aldehyde, azide, alkyne, tetrazine, hydrazine, alkoxyamine, trans-cyclooctene, or cyclopropene. In the embodiments, Ab is modified with an aldehyde. In the embodiments, Ab is modified with an azide. In the embodiments, Ab is modified with a tetrazine. In the embodiments, Ab is modified with an alkoxyamine. In the embodiments, Ab is modified with a hydrazine. In the embodiments, Ab is modified with trans-cyclooctene. In the embodiments, Ab is modified with cyclopropene. In the embodiments, the modified Ab is a modified anti-B7-H3 antibody.

[0368] In the embodiment, n is an integer from 1 to 24. In the embodiment, n is 1. In the embodiment, n is 2. In the embodiment, n is 3. In the embodiment, n ...

Claims

1. 1. Antibody-drug conjugates (ADCs) of formula (I), formula (II), or formula (III): 、 ,or (I) (II) (III) or a pharmaceutically acceptable salt thereof, wherein Ab is an anti-B7-H3 antibody; m is an integer from 1 to 8; L １ is 、 a linker conjugated to the anti-B7-H3 antibody; L ２ is selected from a bond, -C(O)-, -NH-, an amino acid unit, -(CH ２ CH ２ O) ｎ -, -(CH ２ｎ -,-O-,-(4-aminobenzyloxycarbonyl)-,-(C(O)CH ２ CH ２ NH)-,-(C(O)N(R ２ )CH ２ CH ２ N(R ５ ))-, or any combination thereof; where n is an integer from 1 to 24; Each R ２ and R ５ teeth 、 Independently, it is H, or an alkyl group that may or may not have a substituent; L ３ is a substituted or unsubstituted heterocyclic alkylene, a substituted or unsubstituted heterocyclic aliene; or L ３ teeth 、 Substitutive or non-substitutive -OCH ２ - (heterocyclic alkylene) or substituted or unsubstituted -OCH ２ - (heteroalylene), and L ３ It is bonded to D via oxygen. Or L ３ is a substitution or non-substitution of -CH ２ NCH ２ - (heteroaryl) or substituted or unsubstituted -CH ２ NCH ２ - (heterocycloalkyl), where L ３ ha-CH ２ - is bonded to D via nitrogen, and L via nitrogen. ２ Join; R ＊ is a substituted or unsubstituted heterocyclic alkyl, or a substituted or unsubstituted heteroaryl; D is It is; D' is And D' is R via its amide group. ＊ It binds to L via oxygen. ２ Join; and D'' is is, or Here: R １ is H or -C １ -C ８ Alkyl; R ３ teeth 、 H, halogen, -CCl ３ , - CBr ３ , -CF ３ , -CI ３ -CHCl ２ , -CHBr ２ ,-CHF ２ , -CHI ２ ien-CH ２ Cl, -CH ２ Br, -CH ２ F, -CH ２ I, -CN, -OR ３Ａ , -NR ３Ａ R ３Ｂ ,-(CH ２ ) ｖ OR ６ , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R ４ H, halogen, -OR ４Ａ , -NR ４Ａ R ４Ｂ , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; V is N, O, or C; Z １ 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 is a substituted or unsubstituted allylene, a substituted or unsubstituted heteroalylene, a substituted or unsubstituted cycloalkylene, or a substituted or unsubstituted heterocycloalkylene; R ６ H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -CO(CH ２ CH ２ O) ｗ CH ２ CH ２ M, -CONH(CH ２ CH ２ O) ｗ CH ２ CH ２ M, , charged group, or sugar derivative; v is an integer between 1 and 24; w is an integer between 1 and 24; M is -NH ２ -OH, -COOH, or -OCH ３ is; R １０ -OH, -OCH ３ , or -COOH; Each R ３Ａ , R ３Ｂ , R ４Ａ , and R ４Ｂ Each of these is independently either H or an alkyl group with or without a substituent.

2. 2. ADC according to claim 1 or a pharmaceutically acceptable salt thereof, L １ This is a linker to which one or two sulfur atoms or nitrogen atoms of the anti-B7-H3 antibody are bound.

3. 3. ADC according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, L １ but: 、 、 、 、 、 、 、 、 、 、 ， , or ．

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

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

6. 6. An ADC according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein L ２ is bonded, -C(O)-, -NH-, -Val-, -Phe-, -Lys-, -(4-aminobenzyloxycarbonyl)-, -Gly-, -Ser-, -Thr-, -Ala-, - -Ala-, -citrulline- (-Cit-), -(CH ２ ) ｎ -, -(CH ２ CH ２ O) ｎ -, -O-, -(C(O)N(CH ３ )CH ２ CH ２ N(CH ３ ))-, or any combination thereof.

7. 7. An ADC according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein L ２ is -C(O)-, -NH-, -Val-, -(4-aminobenzyloxycarbonyl)-, -Gly-, -citrulline- (-Cit-), -(CH ２ ), ｎ -(CH ２ CH ２ O) ｎ -, or any combination thereof.

8. 8. ADC according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, L ２ but: 、 ,or That which is.

9. 9. ADC according to claim 8 or a pharmaceutically acceptable salt thereof, L ２ but 。

10. 10. ADC according to claim 8 or a pharmaceutically acceptable salt thereof, L ２ but 。

11. 11. ADC according to claim 8 or a pharmaceutically acceptable salt thereof, L ２ but 。

12. 12. An ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein D'' is Here: R １ is H or -C １ -C ８ It is alkyl; R ３ is H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R ４ is H, a halogen, or a substituted or unsubstituted alkyl; V is N; and Z ２ These are substituted or unsubstituted alienes.

13. 13. An ADC according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, R １ Those that are H.

14. 14. An ADC according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, R ３ H, methyl, ethyl, propyl, butyl, -CH ２ OH, -CH ２ CH ２ OH, -CH ２ N ３ ien -CH ２ CH ２ N ３ ien-CH ２ OCH ３ ien-CH ２ OCH ２ CH ３ , or -CH ２ CH ２ OCH ３ That is the case.

15. 15. An ADC according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, R ３ is methyl, -CH ２ OH, or -CH ２ N ３ That is the case.

16. 16. An ADC according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, R ４ Those in which H is or a substituted or unsubstituted alkyl group.

17. 17. An ADC according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, R ４ Those in which the atom is H or methyl.

18. 18. ADC according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, R ４ Those that are H.

19. 19. ADC according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, Z ２ Those that are aliene without substitution.

20. 20. ADC according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, Z ２ but That which is.

21. 21. An ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein D'' is That which is.

22. 22. An ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein the ADC is: ．

23. 23. ADC according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, L ３ is a substituted or unsubstituted heterocyclic alkylene group; or L ３ is substituted or unsubstituted -CH ２ NCH ２ - (heterocyclic alkyl) group, L ３ ha -CH ２ - is bonded to D via nitrogen, and L via nitrogen. ２ Combine.

24. 24. ADC according to claim 23 or a pharmaceutically acceptable salt thereof, L ３ is a substituted or unsubstituted complex cyclic alkylene.

25. 25. ADC according to claim 24 or a pharmaceutically acceptable salt thereof, L ３ These are substituted or unsubstituted 3- to 8-membered heterocyclic alkylene rings.

26. 26. ADC according to claim 24 or a pharmaceutically acceptable salt thereof, L ３ These are substituted or unsubstituted 3- to 6-membered heterocyclic alkylene rings.

27. 27. ADC according to claim 26 or a pharmaceutically acceptable salt thereof, L ３ is a substituted or unsubstituted heterocyclic butylene, heterocyclic pentylene, or heterocyclic hexylene.

28. 28. An ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 or 23 to 27, having the structure of formula (IA) or formula (IIA): or (IA) (IIA) Here: Ring A is a substituted or unsubstituted heterocyclic alkylene, or a substituted or unsubstituted heterocyclic aliene, with L through a complex atom Y. ２ Join; Ring A' is a substituted or unsubstituted heterocyclic alkyl group, or a substituted or unsubstituted heteroaryl group, bonded to D' via a heteroatom Y; and Y is N, P, or S.

29. 29. ADC according to claim 28 or a pharmaceutically acceptable salt thereof having the structure of formula (IB) or formula (IIB): or (IB) (IIB).

30. 30. ADC according to claim 28 or a pharmaceutically acceptable salt thereof having the structure of formula (IC) or formula (IIC): or (IC) (IIC).

31. 31. ADC according to claim 28 or a pharmaceutically acceptable salt thereof having the structure of formula (ID) or formula (IID): or (ID) (IID).

32. 32. ADC according to claim 28 or a pharmaceutically acceptable salt thereof having the structure of formula (ID1) or formula (IID1): or (ID1) (IID1).

33. 33. An ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 or 23 to 27, having the structure of formula IG: or a pharmaceutically acceptable salt thereof, wherein ring W is a substituted or unsubstituted cycloalkylene, or a substituted or unsubstituted allylene.

34. 34. ADC according to claim 33 or a pharmaceutically acceptable salt thereof having the structure of formula IM: Here, Z is S, N, or O.

35. 35. ADC according to claim 33 or a pharmaceutically acceptable salt thereof having the structure of formula IO: 。

36. 36. ADC according to claim 33 or a pharmaceutically acceptable salt thereof having the structure of formula IQ: ．

37. 37. An ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 or 23 to 36, wherein the ADC is: ， ， ， ,or ， or a pharmaceutically acceptable salt thereof.

38. 38. An ADC or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 37, wherein the anti-B7-H3 antibody comprises VLCDR1 containing the sequence of SEQIDNO:1, VLCDR2 containing the sequence of SEQIDNO:2, VLCDR3 containing the sequence of SEQIDNO:3, VHCDR1 containing the sequence of SEQIDNO:4, VHCDR2 containing the sequence of SEQIDNO:5, VHCDR3 containing the sequence of SEQIDNO:6, and VHCDR4 containing the sequence of SEQIDNO:

7. VHCDR1 containing the sequence of 4, VHCDR2 containing the sequence of SEQIDNO:5, and VHCDR3 containing the sequence of SEQIDNO:

6.

39. 39. An ADC according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, wherein the anti-B7-H3 antibody comprises a VL having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQIDNO:

7.

40. 40. An ADC according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, wherein the anti-B7-H3 antibody comprises a VH having a sequence having at least 95%, 96%, 97%, 98%, or 99% identity with SEQIDNO:

8.

41. 41. An ADC according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof, wherein the anti-B7-H3 antibody comprises a VL having the sequence SEQIDNO:

7.

42. 42. An ADC according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, wherein the anti-B7-H3 antibody comprises a VH having the sequence SEQIDNO:

8.

43. 43. An ADC according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, wherein the anti-B7-H3 antibody is an IGG antibody, and optionally the anti-B7-H3 antibody is an IGG1 antibody.

44. 44. An ADC according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, wherein the anti-B7-H3 antibody binds to human B7-H3, and optionally, the human B7-H3 has the amino acid sequence SEQIDNO:

16.

45. 45. An ADC according to any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof, for use in therapeutic purposes.

46. 46. ​​An ADC according to claim 45 or a pharmaceutically acceptable salt thereof, used for the treatment of cancer expressing B7-H3.

47. 47. A method for treating B7-H3 expressing cancer in a subject, comprising administering an ADC according to any one of claims 1 to 44 to a subject as needed.

48. 48. Using an ADC or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 44 in the manufacture of a pharmaceutical product.

49. 49. Using an ADC or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 44 in the manufacture of a pharmaceutical product for treating cancer expressing B7-H3.

50. 50. A use, method, or application of an ADC or a pharmaceutically acceptable salt thereof according to any one of claims 46, 47, or 49, wherein the cancer expressing B7-H3 is ovarian cancer or pancreatic cancer.

51. 51. A method for preparing an ADC according to any one of claims 1 to 37, wherein the anti-B7-H3 antibody is of formula (P-I), formula (P-II), or formula (P-III): 、 ,or (P-I) (P-II) (P-III) or a pharmaceutically acceptable salt thereof, where: B is a reactive moiety capable of forming a binding with anti-B7-H3 antibody; L ２ The bond is -C(O)-, -NH-, and the amino acid unit is -(CH ２ CH ２ O) ｎ -, - (CH ２ｎ -, -O-, -(4-aminobenzyloxycarbonyl)-, -(C(O)CH ２ CH ２ NH)-,-(C(O)N(R ２ )CH ２ CH ２ N(R) ５ )) - or any combination thereof; where n is an integer from 1 to 24; Each R ２ and R ５ is independently H, or a substituted or unsubstituted alkyl group; L ３ is a substituted or unsubstituted heterocyclic alkylene, a substituted or unsubstituted heteroalylene; or L ３ is a substitution or non-substitution -OCH ２ - (heterocyclic alkylene) or substituted or unsubstituted -OCH ２ - (heteroalylene), where L ３ It binds to D via oxygen; or L ３ is a substitution or non-substitution of -CH ２ NCH ２ - (heteroaryl) or substituted or unsubstituted -CH ２ NCH ２ - (heterocycloalkyl), where L ３ ha-CH ２ - is bonded to D via nitrogen, and L via nitrogen. ２ Join; R ＊ is a substituted or unsubstituted heterocyclic alkyl group, or a substituted or unsubstituted heterocyclic aryl group; D is It is; D' is And here D' is R via its amide group. ＊ It binds to L via oxygen. ２ Join; and D'' is or Here: R １ is H or -C １ -C ８ Alkyl; R ３ H, halogen, -CCl ３ , - CBr ３、 -CF ３ , -CI ３ -CHCl ２ , -CHBr ２ ,-CHF ２ , -CHI ２ ien-CH ２ Cl, -CH ２ Br, -CH ２ F, -CH ２ I, -CN, -OR ３Ａ , -NR ３Ａ R ３Ｂ ,-(CH ２ ) vOR ６ , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R ４ H, halogen, -OR ４Ａ , -NR ４Ａ R ４Ｂ , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; V is N, O, or C; Z １ 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 is a substituted or unsubstituted allylene, a substituted or unsubstituted heteroalylene, a substituted or unsubstituted cycloalkylene, or a substituted or unsubstituted heterocycloalkylene; R ６ H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, -CO(CH₂CH₂O) ｗ CH CH M, -CONH(CH ２ CH ２ O) ｗ CH ２ CH ２ M, , charged groups, or sugar derivatives: v is an integer between 1 and 24; w is an integer between 1 and 24; M is -NH ２ -OH, -COOH, or -OCH ３ is; R １０ -OH, -OCH ３ , or -COOH; and Each R ３Ａ , R ３Ｂ , R ４Ａ , and R ４Ｂ teeth 、 Each is independently either H or an alkyl group with or without a substituent.

52. 52. In the method of claim 51, the anti-B7-H3 antibody is modified with an aldehyde, azide, alkyne, tetrazine, hydrazine, alkoxyamine, trans-cyclooctene, or cyclopropene.

53. 53. The method according to claim 51 or 52, wherein B is a reactive moiety capable of forming a bond with one or two thiol groups or amine groups of the anti-B7-H3 antibody, or with the modified anti-B7-H3 antibody.

54. 54. In the method according to any one of claims 51 to 53, B is: ， ， ， ， ， ， ， ， ，， ， ， ．

55. 55. In the method according to any one of claims 51 to 54, L ２ The bonds are -C(O)-, -NH-, -VAL-, -PHE-, -LYS-, -(4-aminobenzyloxycarbonyl)-, -Gly-, -Ser-, -Thr-, -Ala-, -Ala-, -citrulline- (-Cit-), -(CH ２ｎ )-,-(CH ２ CH ２ O) ｎ -, -O-, -(C(O)N(CH ３ )CH ２ CH ２ N(CH ３ )) -, or any combination thereof.

56. 56. In the method according to any one of claims 51 to 55, L ２ is -C(O)-, -NH-, -VAL-, -(4-aminobenzyloxycarbonyl)-, -GLY-, -citrulline-(-CIT-), -(CH ２ ) ｎ -, - (CH ２ CH ２ O) ｎ -, or any combination thereof.

57. 57. In the method according to any one of claims 51 to 56, L ２ teeth, 、 ,or That is the case.

58. 58. In the method according to claim 57, L ２ teeth 。

59. 59. In the method according to claim 57, L ２ teeth 。

60. 60. In the method according to claim 57, L ２ teeth 。

61. 61. In the method according to any one of claims 51 to 60, D'' is Here: R １ is H or -C １ -C ８ It is alkyl; R ３ is H, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R ４ is H, a halogen, or a substituted or unsubstituted alkyl; V is N; and Z ２ These are substituted or unsubstituted alienes.

62. 62. In the method according to any one of claims 51 to 61, R １ H is H.

63. 63. In the method according to any one of claims 51 to 62, R ３ H, methyl, ethyl, propyl, butyl, -CH ２ OH, -CH ２ CH ２ OH, -CH ２ N ３ ien-CH ２ CH ２ N ３ ien-CH ２ OCH ３ ien-CH ２ OCH ２ CH ３ , or -CH ２ CH ２ OCH ３

64. 64. In the method according to any one of claims 51 to 63, R ３ is methyl, -CH ２ OH, or -CH ２ N ３ That is the case.

65. 65. In the method according to any one of claims 51 to 64, R ４ A method in which is H, or a substituted or unsubstituted alkyl group.

66. 66. In the method according to any one of claims 51 to 65, R ４ A method in which is H or methyl.

67. 67. In the method according to any one of claims 51 to 66, R ４ How to be H.

68. 68. In the method according to any one of claims 51 to 67, Z ２ A method in which alilen is substituted or unsubstituted.

69. 69. In the method according to any one of claims 51 to 68, Z ２ but The way of doing so.

70. 70. The method according to any one of claims 51 to 69, wherein D'' The way of doing so.

71. 71. The method according to any one of claims 51 to 70, teeth: ．

72. 72. In the method according to any one of claims 51 to 60, L ３ is a substituted or unsubstituted heterocyclic alkylene, or a substituted or unsubstituted heterocyclic alkyl; or L ３ -CH is either substituted or unsubstituted. ２ NCH ２ - (heterocyclic alkyl), where L ３ ha-CH ２ - is bonded to D via nitrogen, and L via nitrogen. ２ Combined する .

73. 73. L ３ The method of claim 72, wherein is a substituted or unsubstituted complex cyclic alkylene.

74. 74. In the method of claim 73, L （３）は These are substituted or unsubstituted 3- to 8-membered heterocyclic alkylene rings.

75. 75. In the method of claim 73, L ３ These are substituted or unsubstituted 3- to 6-membered heterocyclic alkylene rings.

76. 76. In the method of claim 75, L ３ is substituted or unsubstituted heterocyclobutylene, heterocyclopentylene, or heterocyclohexylene.

77. 77. In the method according to any one of claims 51 to 60 or any one of claims 72 to 76, the molecule of formula (P-I) or formula (P-II) has the structure of formula (P-IA) or formula (P-IIA), respectively: or (P-IA) (P-IIA) Here: Ring A is a heterocyclic alkylene with or without substituents, or a heteroalylene with or without substituents, and L is connected via the heteroatom Y. ２ Join; Ring A' is a heterocyclic alkyl group with or without substituents, or a heteroaryl group with or without substituents, and is bonded to D' via a heteroatom Y. Y is N, P, or S.

78. 78. In the method according to claim 77, the molecule of formula (P-I) or formula (P-II) has the structure of formula (P-IB) or formula (P-IIB): or (P-IB) (P-IIB).

79. 79. A method according to claim 77, characterized in that a molecule of formula (P-I) or formula (P-II) has the structure of formula (P-IC) or formula (P-IIC): or (P-IC) (P-IIC).

80. 80. A method according to claim 77, characterized in that a molecule of formula (P-I) or formula (P-II) has the structure of formula (P-ID) or formula (P-IID): or (P-ID) (P-IID).

81. 81. A method according to claim 77, characterized in that a molecule of formula (P-I) or formula (P-II) has the structure of formula (P-ID1) or formula (P-IID1): or (P-ID1) (P-IID1).

82. 82. A method according to any one of claims 51 to 70 or any one of claims 72 to 76, characterized in that the molecule of formula (P-I) has the structure of formula P-IG: or a pharmaceutically acceptable salt thereof, wherein ring W is a substituted or unsubstituted cycloalkylene, or a substituted or unsubstituted allylene.

83. 83. In the method according to claim 82, if the molecule of formula (P-I) has the structure of formula P-IM: Here, Z is S, N, or O.

84. 84. The method of claim 82, characterized in that the molecule of formula (P-I) has the structure of formula P-IO. 。

85. 85. The method of claim 82, characterized in that the molecule of formula (P-I) has the structure of formula P-IQ. ．

86. 86. The method according to any one of claims 51 to 60 or any one of claims 72 to 85, teeth: ， ， ， ,or ， or a pharmaceutically acceptable salt thereof.

87. 87. A pharmaceutical composition comprising an ADC according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

88. 88. A method for inhibiting the proliferation of cells expressing B7-H3, comprising inhibiting the proliferation of the cells by exposing them to ADC or a pharmaceutically acceptable salt thereof (as described in any one of claims 1 to 44) under conditions in which an anti-B7-H3 antibody of ADC can bind to the cell surface, wherein the method is optionally in vitro or in vivo.

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