Antibody-drug conjugate and use thereof

Abstract

The present disclosure relates to an antibody-drug conjugate, and in particular, to an antibody-drug conjugate (ADC) loaded with an Ras mutation inhibitor, a composition comprising the ADC molecule, and therapeutic use thereof.

Description

An antibody-drug conjugate and its uses

[0001] Cross-references

[0002] This application claims priority to Chinese invention patent application 2024119227932 filed on December 24, 2024, Chinese invention patent application 202510421517.6 filed on April 3, 2025, and Chinese invention patent application 202511926685.7 filed on December 19, 2025. Technical Field

[0003] This disclosure relates to antibody-drug conjugates (ADCs) based on Ras mutation inhibitors, pharmaceutical compositions comprising the same, and methods of using them for treating or preventing diseases associated with Ras mutations. Specifically, this disclosure relates to compounds, uses, and methods for treating or preventing related diseases such as tumors or cancers by targeting oncogenic mutants of Ras. Background Technology

[0004] Ras belongs to the GTPase family of proteins. Under normal physiological conditions, Ras is activated by growth factors and various other extracellular signals, and is responsible for regulating cell growth, survival, migration, and differentiation. These regulatory functions of Ras are carried out through a "molecular switch"—the switching between an inactive GDP-bound state and an active GTP-bound state. GDP-bound Ras is inactive; when exposed to proliferative stimuli such as guanine nucleotide exchange factor (GEF), it is activated, releasing GDP and binding to GTP, thus converting to the active GTP-bound state. This active GTP-bound state then recruits and activates various downstream effectors, enabling signal transduction and controlling numerous key cellular processes such as differentiation, survival, and proliferation.

[0005] Ras possesses GTPase activity, capable of cleaving the terminal phosphate of GTP to convert it into GDP, effectively rendering it inactive. However, Ras' endogenous GTPase activity is very low; the conversion of GTP-Ras to GDP-Ras requires the exogenous protein GAP (GTPase activator). GAP interacts with Ras and promotes the conversion of GTP to GDP. Therefore, any Ras gene mutation affecting the interaction between Ras and GAP or the conversion of GTP to GDP will lead to an over-activated state of Ras, continuously transmitting growth and division signals to the cell, stimulating cell proliferation, and ultimately leading to tumor formation and development. In fact, dysregulation of the Ras signaling pathway is almost always associated with disease. Somatic mutations of overactivated Ras are among the most common pathological changes in human cancers.

[0006] Although mutations in any of the three Ras subtypes (K-Ras, N-Ras, or H-Ras) have been shown to lead to oncogenic transformation, K-Ras mutations are by far the most common mutations in human cancers, frequently found in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and bile duct cancer, and also in 25% of non-small cell lung cancer patients. The vast majority of K-Ras mutations occur at codons G12, G13, and Q61, with approximately 80% of K-Ras mutations occurring at the glycine residue of codon 12, such as G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutations, among which G12D mutation is one of the most common.

[0007] In light of this, Ras mutant proteins, such as KRas mutant proteins, have become very attractive targets for anticancer drugs in the pharmaceutical field, and the development of their inhibitors is considered a very promising research direction in anticancer / tumor drug development. However, drug development targeting K-Ras mutations over the past few decades has shown that existing K-Ras mutant small molecule inhibitors have many insurmountable drawbacks, such as ineffective delivery to some lesions such as the colon, breast, and pancreas, severe drug resistance, poor membrane permeability, poor hydrophilicity, unsatisfactory oral pharmacokinetics, and high toxicity when administered intravenously. Therefore, KRas has long been considered an "undrugable" target.

[0008] Therefore, the inventors have been dedicated to developing small molecule inhibitors of Ras, such as KRas mutations, with improved structural patterns. Due to the specifically designed structural fragments, these small molecule inhibitors have shown enhanced Ras, such as KRas mutation inhibitory activity and inhibitory activity against related tumors compared to existing Ras, such as KRas mutation inhibitors. At the same time, they have good oral pharmacokinetic properties, thus exhibiting good drugability, reduced toxic side effects, improved drug resistance and safety, and reduced risk of drug interactions.

[0009] Nevertheless, the field of cancer treatment still urgently needs novel therapies that can more precisely deliver Ras, such as KRas mutation inhibitors, to the tumor environment, can be administered in a more user-friendly manner, and can prolong efficacy while reducing toxicity and drug resistance. This disclosure addresses these needs.

[0010] Targeted drug conjugates (DDCs) represent a highly efficient and low-toxicity drug delivery technology that has demonstrated significant advantages in anticancer drug development. Cytotoxic molecules are linked to target molecules such as antibodies and peptides via suitable linkers. These target molecules can selectively deliver the conjugates to tumor tissues with high expression of target receptors. Through internalization, the anticancer drug is selectively delivered into cancer cells. Then, the differentially functional molecules accumulated in the tumor tissue and cancer cells cleave and release the active anticancer molecules. Because the active anticancer molecules can only be released and accumulated within tumor tissues with high expression of target receptors and specific "cutting edges," this dual-selective drug delivery method significantly reduces the toxicity of anticancer drugs and improves their efficacy.

[0011] The inventors utilized a targeted conjugation strategy to further link a group of developed Ras, such as KRas, mutation inhibitor compounds with antibody, peptide, or other guiding molecules via suitable linkers, thus preparing a set of ADC compounds based on Ras, such as KRas, mutation inhibitors. These developed ADC compounds, by using Ras, such as K-Ras, enzyme inhibitors as ADC loads, exhibit dual selectivity, significantly reducing toxicity. Specific modifications to the linker unit increase conjugation efficiency and product purity, inhibiting ADC macromolecule aggregation and improving efficacy. Furthermore, these ADC macromolecules delay the metabolism of the loaded Ras, such as KRas, mutation inhibitors, thereby further improving the systemic stability and pharmacokinetic properties of the drug, resulting in a longer half-life, sustained target inhibition, and prolonged efficacy in vivo, thus delaying the development of drug resistance.

[0012] Invention Overview

[0013] To meet the aforementioned needs in the field, the present discloses, through in-depth research, a set of specific Ras-targeting, such as KRas mutation inhibitor compounds, are coupled to a target molecule via selected linker units to obtain antibody-drug conjugates as shown in the examples.

[0014] Currently, Ras inhibitors under development, such as KRas inhibitors, have shown many shortcomings in their development and use, including ineffective delivery to certain lesions, severe drug resistance, poor membrane permeability, poor hydrophilicity, poor oral pharmacokinetic properties, and high toxicity after intravenous administration. In contrast, the antibody-drug conjugate disclosed in this paper, through innovative structural modification of the components of the ADC linker unit and the first use of this linker unit to conjugate a Ras small molecule inhibitor and an antibody targeting unit, can be rapidly and effectively internalized by tumor cells. In animal models, it has demonstrated significant tumor growth inhibitory activity and good tolerability compared to antibodies and Ras inhibitors alone, effectively overcoming the above shortcomings. It is expected to be able to be administered via more mature and user-friendly routes (such as oral and parenteral), providing enhanced and prolonged efficacy, good pharmacokinetic properties, reduced toxicity and drug resistance, as well as expanded indications and beneficiary populations.

[0015] Therefore, in a first aspect, this disclosure provides antibody-drug conjugates (ADCs) having the following formula (X) or their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates:

[0016] [PL] q -Ab (X)

[0017] in,

[0018] P represents a Ras inhibitor, such as a Ras inhibitor as defined in the pharmaceutical P unit portion of this disclosure (e.g., compounds of formula (I) and its various sub-formulas as defined in this disclosure);

[0019] L represents the connecting body unit that connects P to Ab;

[0020] q represents the number of [PL] linkers connected to Ab, for example, q = an integer or non-integer from 1 to 20, such as 1-10, 1-8, 2-8, 3-8, 4-8 or 6-8;

[0021] Ab represents an antibody or antigen-binding fragment.

[0022] In this regard, this disclosure also provides compounds comprising the linker unit L structure of formula (II) or various sub-formulas as defined herein, or stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof.

[0023] In this regard, this disclosure also provides Ras inhibitor compound-linker unit L conjugates of formula (III) or any of its sub-formulas as defined herein, or stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, compounds comprising Ras inhibitor compound-linker unit L conjugate structural fragments of formula (III) or any of its sub-formulas thereof, or stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, pharmaceutical compositions comprising said compounds and optionally one or more pharmaceutically acceptable excipients, and the pharmaceutical uses of said compounds as described in this disclosure.

[0024] In a second aspect, this disclosure provides pharmaceutical compositions comprising the ADC of this disclosure or its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, optionally at least one other therapeutic agent, and optionally one or more pharmaceutically acceptable excipients.

[0025] In a third aspect, this disclosure provides the ADC of this disclosure, or its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, or pharmaceutical compositions comprising thereof, for use as therapeutic agents for treating or preventing diseases mediated by Ras mutant proteins (e.g., but not limited to G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutant proteins), more specifically for treating or preventing hyperproliferative diseases, particularly as antitumor therapeutic agents. In some specific embodiments, the Ras mutant protein is a KRas mutant protein.

[0026] In a fourth aspect, this disclosure provides the use of the ADC of this disclosure or its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, or pharmaceutical compositions comprising the thereof in the prevention or treatment of diseases mediated by Ras mutant proteins (e.g., but not limited to G12C mutations, G12D mutations, G12V mutations, G12A mutations, G12R mutations, G12S mutations, and G13D mutant proteins), and more specifically in the treatment or prevention of hyperproliferative diseases, particularly in tumors.

[0027] In a fifth aspect, this disclosure provides methods for treating or preventing diseases mediated by Ras mutant proteins (e.g., but not limited to G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutant proteins) in subjects, the method comprising administering to a human or animal an ADC of the present disclosure or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, or a pharmaceutical composition comprising thereof; specifically, this disclosure provides methods for treating or preventing hyperproliferative diseases, particularly tumors, in subjects, the method comprising administering to a human or animal an ADC of the present disclosure or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate, or a pharmaceutical composition comprising thereof.

[0028] In a sixth aspect, this disclosure provides the use of the ADC of this disclosure or its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, or pharmaceutical compositions comprising thereof in the preparation of medicaments for the prevention or treatment of diseases mediated by Ras mutant proteins (e.g., but not limited to G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, and G13D mutant proteins); specifically, this disclosure provides the use of the ADC of this disclosure or its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, or pharmaceutical compositions comprising thereof in the preparation of medicaments for the treatment or prevention of hyperproliferative diseases, particularly tumors.

[0029] In a seventh aspect, this disclosure provides a pharmaceutical combination comprising the ADC of this disclosure or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, and at least one other therapeutic agent; the combination for the prevention or treatment of diseases mediated by Ras mutant proteins (e.g., but not limited to G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, and G13D mutant proteins), more specifically for the treatment or prevention of hyperproliferative diseases, particularly tumors; and a method of treating or preventing diseases mediated by Ras mutant proteins (e.g., G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, and G13D mutant proteins), more specifically for hyperproliferative diseases, particularly tumors, in a subject, the method comprising administering the pharmaceutical combination of this disclosure to a human or animal.

[0030] In an eighth aspect, this disclosure also provides a method for preparing the ADC of the present disclosure or its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts, or solvates by conjugating a Ras inhibitor as defined herein to an antibody or its antigen-binding fragment via a linker unit. The Ras inhibitor compound as defined herein can be conjugated to an antibody or antigen-binding fragment via a cleavable or non-cleavable linker unit. In a specific embodiment, upon cleavage of the linker unit, the Ras inhibitor is released into tumor cells, cancer-associated immune cells, or the tumor microenvironment.

[0031] In some embodiments of the various aspects of this disclosure above, the Ras mutant protein is a KRas mutant protein, specifically a KRas G12D mutant protein, and the corresponding P inhibitor compound is a KRas inhibitor, specifically a KRas G12D inhibitor; in other embodiments, the Ras mutant protein is not limited to a specific subtype and / or mutation site, i.e., pan-Ras, and the corresponding P inhibitor compound is a pan-Ras inhibitor.

[0032] This disclosure is further illustrated in the following figures and specific embodiments. However, these figures and specific embodiments should not be considered as limiting the scope of this disclosure, and modifications readily apparent to those skilled in the art will be included within the spirit of this disclosure and the scope of protection of the appended claims. Attached Figure Description

[0033] Figure 1 shows the antitumor effects of some representative KRAS G12D inhibitor-loaded ADCs in a BALB / c Nude mouse model of subcutaneous xenograft of KRAS-G12D mutant human colon cancer cells GP2D (dose 10 mg / kg, administered on day D0, day 17).

[0034] Figure 2 shows the antitumor effects of some representative panKRAS inhibitor-loaded ADCs of this disclosure in a subcutaneous xenograft BALB / c Nude mouse model of KRAS-G12D mutant human colon cancer cells GP2D (dose 10 mg / kg, administered on day D0, day 17).

[0035] Figure 3 shows the antitumor effects of some representative KRAS G12D inhibitor loadings and different linker ADCs in the subcutaneous xenograft GP2D human colon cancer cells of the present disclosure in the BALB / c Nude mouse animal model (dose 10 mg / kg, administered on day D0, day 17).

[0036] Invention Details

[0037] definition

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of this disclosure, the following terms are defined below.

[0039] When a trade name is used in this document, unless the context otherwise indicates, the trade name includes the product formulation of the trade name product, the generic name of the drug, and the active pharmaceutical ingredient.

[0040] In this document, the term "substantially" means the vast majority, i.e., >50% of the population, mixture, sample, content, or any other numerical value, preferably greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

[0041] In this document, the term "and / or" should be understood as meaning any one of the options or any combination of two or more of the options.

[0042] In this document, unless otherwise specified, the terms “an” and “a” are used generically and also cover the plural cases described therein.

[0043] In this document, the terms "comprising" or "including" mean to include the stated elements, integers, or steps, but do not exclude any other elements, integers, or steps. Unless otherwise specified, the situation consisting of the stated elements, integers, or steps is also covered.

[0044] In this article, the term "ADC" or "conjugate" refers to antibody-drug conjugates.

[0045] In this article, the term "drug" refers to a substance that produces a beneficial preventive or therapeutic effect on diseases mediated by Ras mutant proteins, such as KRas mutant proteins (e.g., but not limited to G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, and G13D mutant proteins).

[0046] In this document, the term "Ras mutation" or "Ras mutant protein" refers to a protein encoded and expressed by the Ras gene with mutations in one or more of its codons. This typically includes, but is not limited to, Ras proteins with mutations in the glycine residue at codon 12, the glycine residue at codon 13, or the glutamine residue at codon 61, such as mutant HRas, NRas, or KRas. These residues are located at the active site of Ras, and mutations in these residues can impair Ras's inherent or GAP-catalyzed GTPase activity, resulting in the persistence of GTP-bound Ras.

[0047] For the purposes of this disclosure, the terms "Ras mutation" or "Ras mutant protein" and the "Ras" used to describe inhibitory activity are interchangeable, for example referring to mutated KRas, such as, but not limited to, KRas-G12C (glycine to cysteine ​​mutation at codon G12), KRas-G12D (glycine to aspartic acid mutation at codon G12), HRas-G12D, NRas-G12D, KRas-G12V (glycine to valine mutation at codon G12), and KRas-G1 3D (a mutation from glycine to aspartic acid at codon G13); in some embodiments, it refers to a KRas mutant protein, more particularly to KRas-G12C mutant protein, KRas-G12D mutant protein, KRas-G12V mutant protein, G12A mutant protein, G12R mutant protein, G12S mutant protein, KRas-G13D mutant protein, and most particularly to KRas-G12D. In other embodiments, it refers to a pan-RAS mutant protein, i.e., not limited to specific subtypes and mutation sites.

[0048] In this document, the term "Ras mutation-mediated disease" refers to a disease in which Ras mutations promote the occurrence and development of the disease, or in which inhibiting Ras mutations reduces the incidence of the disease, decreases or eliminates the symptoms. For the purposes of this disclosure, "Ras mutation-mediated disease" in some embodiments refers to KRas mutation-mediated disease, most preferably KRas-G12D, and in other embodiments refers to pan-Ras-mediated disease, such as hyperproliferative diseases like cancer or tumors.

[0049] As used herein, the terms "cancer" or "tumor" refer to abnormal cell growth and proliferation, including solid tumors and hematogenous tumors, whether malignant or benign, and all precancerous cells and cancer cells and tissues. For all aspects of this disclosure, the cancers or tumors mentioned include, but are not limited to, lung adenocarcinoma, lung cancer (including squamous cell carcinoma and non-small cell lung cancer, small cell lung cancer (SCLC)), bone cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, skin cancer, head and neck cancer (including squamous cell carcinoma of the head and neck), melanoma (including cutaneous or intraocular melanoma), squamous cell carcinoma, anal region cancer, testicular cancer, urethral cancer, ureteral cancer, penile cancer, prostate cancer (including hormone-resistant prostate cancer), bladder cancer, uterine cancer, Ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, stomach cancer, gastric adenocarcinoma, colon cancer, rectal cancer, colorectal cancer, liver cancer, breast cancer (including metastatic breast cancer and triple-negative breast cancer (TNBC)), esophageal cancer, small intestine cancer, lip cancer, laryngeal cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, peritoneal cancer, gastrointestinal stromal tumor, gastroesophageal junction (GEJ) cancer, mesothelioma, biliary tract cancer, hepatocellular carcinoma, seminoma, soft tissue sarcoma, osteosarcoma, urethral epithelium Cancer, sweat gland cancer, endocrine system cancer, thyroid cancer, medullary thyroid carcinoma, follicular thyroid carcinoma, papillary thyroid carcinoma, parathyroid carcinoma, kidney cancer, renal parenchymal carcinoma, renal cell carcinoma, renal pelvis carcinoma, adrenal cancer, brain cancer such as glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumor, glioblastoma (including glioblastoma multiforme), neuroblastoma; chronic or acute leukemia, Hodgkin's disease, lymphoma (including lymphocytic lymphoma, Hodgkin's lymphoma) Non-Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell lymphoma, diffuse lymphoma (DLBCL), primary CNS lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CLL) and lymphocytic carcinoma, acute myeloid leukemia (AML), myeloid leukemia (chronic myeloid leukemia (CML), central nervous system tumors (CNS), spinal tumors, brainstem gliomas or pituitary adenomas.

[0050] For all aspects of this disclosure, preferably, the cancer or tumor is associated with Ras mutations, such as KRas mutations, including but not limited to the aforementioned tumor types and their preferred range. Particularly preferred tumors of the present invention include lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, pancreatic cancer, endometrial cancer, bile duct cancer, leukemia, and ovarian cancer.

[0051] In this paper, the term "antitumor effect" refers to biological effects that can be characterized in a variety of forms, including but not limited to, for example, reduction in tumor volume, reduction in the number of tumor cells, reduction in tumor cell proliferation, or reduction in tumor cell survival.

[0052] In this document, the terms “inhibition” and “reduction” or any variations thereof refer to the ability of a bioactive agent to reduce the signal transduction activity of a target by interacting directly or indirectly with the target, and to any measurable reduction or complete inhibition of the target activity. For example, this could be a reduction in activity (e.g., Ras activity, such as KRas activity) of about, at most about, or at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more, or any range thereof, compared to normal.

[0053] As used herein, the term "selective inhibition" refers to the ability of a bioactive agent to preferentially reduce the signal transduction activity of a target site, compared to off-target signaling activity, through direct or indirect interaction with the target. With respect to the Ras inhibitors and their ADCs disclosed herein, they possess the ability to selectively inhibit G12 or G13 mutations in the KRas protein, such as G12C, G12D, G12V, G12A, G12R, G12S, and G13D mutations, with a preference for selectively inhibiting G12D mutations in the KRas protein. For example, compared to another specific Ras mutation, the Ras inhibitors and their ADCs disclosed herein exhibit inhibitory activity against a specific mutation such as KRas-G12D that is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range thereof, or compared to activity against another specific Ras mutation, exhibit inhibitory activity against a specific mutation such as KRas-G12D that is at least 0.1-, 0.5-, 1-, 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250- or 500-fold or higher.

[0054] The term "dual-selective inhibition" as used in this article refers to the ability of a drug-drug conjugate to exert a dual-selective inhibitory effect by, on the one hand, targeting and inhibiting a specific Ras mutation through a small molecule targeting inhibitor, and on the other hand, by using a linked guide antibody molecule to highly selectively deliver the loaded Ras targeting inhibitor to tumor tissues with high expression of the guide receptor.

[0055] In this article, the term "antigen" refers to an entity that specifically binds to an antibody.

[0056] In this document, the term "antibody" refers to a polypeptide containing at least a light or heavy chain immunoglobulin variable region that specifically recognizes and binds to an antigen. This term encompasses a wide range of antibody structures, including but not limited to monoclonal antibodies, single-chain or multi-chain antibodies, monospecific or multispecific antibodies (e.g., bispecific antibodies), chimeric or humanized antibodies, full-length antibodies, and antibody fragments, as long as they exhibit the desired antigen-binding activity. Antibodies can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA), type (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subtype.

[0057] In this document, the terms "antibody fragment" and "antigen-binding fragment" are used interchangeably to refer to a molecule that is not a complete antibody but contains the portion of the complete antibody used to bind the antigen bound by that complete antibody. As those skilled in the art will understand, for the purpose of antigen binding, antibody fragments typically contain amino acid residues from the "complementarity-determining region" or "CDR". Antibody fragments can be prepared by recombinant DNA technology or by enzymatic or chemical cleavage of complete antibodies. Antigen-binding fragments include, but are not limited to, Fab, scFab, Fab', F(ab')2, Fab'-SH, Fv, single-chain Fv, diabody, triabody, tetrabody, minibody, single-domain antibody (sdAb); and multispecific antibodies formed from antibody fragments.

[0058] In this document, the term IgG antibody refers to a heterotetrameric protein having the structure of an IgG-like immunoglobulin. In IgG antibodies, typically the VH-CH1 of the heavy chain pairs with the VL-CL of the light chain to form a Fab fragment that specifically binds to the antigen. Therefore, an IgG antibody essentially consists of two Fab molecules linked by an immunoglobulin hinge region and two dimerized Fc regions. In some embodiments, the IgG antibody is, for example, an IgG1, IgG2, IgG3, or IgG4 antibody. In other embodiments, the IgG antibody is an IgGκ or IgGλ antibody, such as an IgG1κ or IgG1λ antibody.

[0059] In this document, the terms "complementarity-determining region" or "CDR region" or "hypervariant region" are used interchangeably to refer to regions within the antibody variable domain that are highly variable in sequence and form structurally defined loops ("hypervariant loops") and / or contain antigen contact residues ("antigen contact sites"). CDRs are primarily responsible for binding to antigen epitopes. In this document, the CDRs of the antibody heavy and light chains are sequentially numbered starting from the N-terminus and are commonly referred to as CDR1, CDR2, and CDR3. CDRs located within the antibody heavy chain variable domain are also referred to as HCDR1, HCDR2, and HCDR3, while CDRs located within the antibody light chain variable domain are referred to as LCDR1, LCDR2, and LCDR3. Within a given amino acid sequence of a light chain variable region or heavy chain variable region, its CDR sequence can be determined using various schemes known in the art, including CDR sequences based on Kabat, AbM, Chothia, Contact, and IMGT definitions. Furthermore, CDRs can also be determined based on having the same Kabat numbering position as a reference CDR sequence.

[0060] In this paper, "variable region" or "variable domain" refers to the domain in the heavy or light chain of an antibody that participates in the binding of the antibody to its antigen. The heavy chain variable region (VH) and light chain variable region (VL) can be further subdivided into hypervariable regions (HVR, also known as complementarity-determining regions (CDRs)), interspersed with more conserved regions (i.e., framework regions (FRs)). Each VH and VL consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some respects, the antibody variable region can be modified by CDR transplantation. Since the CDR sequence is responsible for most antibody-antigen interactions, recombinant antibody variants that mimic the properties of known antibodies can be constructed. In these antibody variants, CDR sequences from known antibodies are transplanted into the framework regions of different antibodies with different properties. The properties of mutated and / or modified antibodies or ADC conjugates containing them can be evaluated in in vitro or in vivo assays, such as target antigen binding properties or other desired functional properties, such as ADC endocytosis, pharmacokinetics, and in vivo tumor-killing activity.

[0061] In this document, the term "isotype" refers to the antibody type determined by the antibody heavy chain constant region. For example, the antibody portion of an ADC according to this disclosure may be an IgA (e.g., IgA1 or IgA2), IgG1, IgG2 (e.g., IgG2a or IgG2b), IgG3, IgG4, IgE, IgM, and IgD antibody, and has a heavy chain constant region of said immunoglobulin type. Furthermore, this disclosure contemplates not only antibodies employing native sequence constant regions but also antibodies containing variant sequence constant regions.

[0062] In this paper, the term "epitope" includes any protein determinant capable of specifically binding to immunoglobulins or otherwise interacting with molecules. Epitope determinants typically consist of chemically active surface groups of a molecule, such as amino acid or carbohydrate or sugar side chains, and may possess specific three-dimensional structural features as well as specific charge characteristics. Epitopes can be "linear" or "conformal." The distinction between conformational and linear epitopes lies in the loss of binding with the former, but not the latter, in the presence of denaturing solvents.

[0063] In this paper, the term "receptor-mediated endocytosis" refers to the process by which a ligand / receptor complex is internalized and delivered into the cytosol or translocated to a suitable intracellular compartment, triggered by the binding of a ligand to the corresponding receptor on the cell surface. The receptor-mediated endocytic activity of an antibody can be characterized by measuring the endocytosis rate.

[0064] In this paper, “sequence identity” refers to the degree of sequence similarity on a nucleotide-by-nucleotide or amino acid-by-amino acid basis within a comparison window. The “sequence identity percentage” can be calculated by comparing two optimally aligned sequences within a comparison window, determining the number of positions in the two sequences containing the same nucleic acid bases (e.g., A, T, C, G, I) or the same amino acid residues (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys, and Met) to obtain the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window (i.e., the window size), and multiplying the result by 100 to produce the sequence identity percentage. Optimal alignments for determining the sequence identity percentage can be performed in various ways known in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine suitable parameters for aligning sequences, including any algorithms required to achieve maximum alignment across the full length of the sequence being compared or within the target sequence region.

[0065] In this document, the term "isolated" antibody refers to an antibody that has been separated from its components in its natural environment. In some embodiments, the antibody is purified to a purity greater than 90%, 95%, or 99%, which can be determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reversed-phase HPLC).

[0066] In this paper, the term "affinity" or "binding affinity" refers to the intrinsic binding affinity that reflects the interaction between members of a binding pair, such as the strength of the interaction between an antibody and an antigen at a single antigenic site; the stronger the interaction, the stronger the affinity. The affinity of a molecule for its partner can generally be determined by the equilibrium dissociation constant (Kp). D The equilibrium dissociation constant represents the dissociation rate constant and the binding rate constant (k, k, k) respectively. dis and k on The ratio of affinity to antigen protein or cell-based assays. Affinity can be measured by common methods known in the art, such as ELISA, flow cytometry, and biofilm layer optical interference (BLI) techniques.

[0067] In this article, the term "K" D "(M) in this paper refers to the dissociation equilibrium constant of a specific antibody-antigen interaction. Affinity is related to K..." D The values ​​are inversely correlated; that is, the higher the affinity, the higher the K value. D The smaller the value, the lower the affinity; conversely, the larger the value, the lower the affinity. D The larger the value, the better. Generally, K... D The value depends on the dissociation rate constant (Kd or Kdis, sec) between the interacting antibody-antigen pairs. -1 ) and binding rate constant (Ka, M -1 ×sec -1 ).

[0068] In this paper, the term "binding" or "specific binding" refers to the ability of a single antibody binding site to react with one antigenic determinant and not with different antigenic determinants. In the context of antibody binding to an associated antigen, it is used to refer to a binding site with approximately 10... -6 M or smaller K D Value affinity combination, for example, K D The value is approximately 10 -7 M or smaller, or about 10 -8 M or smaller. Binding to non-specific antigens (e.g., irrelevant antigens such as BSA) K D Compared to the value, the binding K of the antibody to its associated antigen D The value is preferably at least 100 times lower, or for example, at least 1000 times lower. K D The measurement of values ​​is known in the art, for example based on biofilm layer optical interferometry (BLI) techniques, in ForteBio, etc. The instrument uses antibodies as ligands and antigens as analytes for measurement.

[0069] In this document, the term "effective function" refers to those biological activities attributable to the Fc region of an antibody, which vary depending on the antibody class. It is known that the IgG Fc region can mediate several important effector functions, such as cytokine induction, ADCC, phagocytosis, complement-dependent cytotoxicity (CDC), and the half-life / clearance rate of the antibody and antigen-antibody complex. In some cases, depending on the therapeutic purpose, these effector functions are desirable for therapeutic antibodies, but in others they may be unnecessary. Therefore, in one embodiment, this disclosure provides an antibody having an Fc region that induces effector functions such as ADCC or CDC, thereby inducing tumor cell apoptosis, cell lysis, and / or inhibiting the proliferation, dissemination, and / or metastasis of tumor cells carrying the TF antigen in tumor cells. In other embodiments, this disclosure also provides antibodies with Fc regions having altered effector functions. The effector function can be altered by sequence modification of the Fc region of the antibody. Alternatively, antibodies with altered types of glycosylation in the Fc region can be prepared. The alteration of the glycosylation pattern in the Fc region can be easily achieved by changing the amino acid sequence of the Fc region to create or remove one or more glycosylation sites.

[0070] In this document, the term "linker unit" or "linker" refers to the bifunctional portion in an antibody-drug conjugate that links a drug to an antibody. The linker unit of this disclosure has multiple components, such as a self-disintegrating linker, a cleavable linker, a property-regulating unit, and an antibody linker.

[0071] In this document, the term "self-decomposing linker" refers to a temporary elongator, spacer, or placeholder unit that links two or more molecules together by chemical bonds, which break under defined conditions to release the two molecules. Typically, self-decomposing linkers can be straight-chain or branched and can link two or more identical molecules together, or two or more different molecules together. A self-decomposing unit can be defined as a bifunctional chemical group capable of covalently linking two spaced-apart chemical moieties together to form a generally stable molecule, releasing one of the spaced-apart chemical moieties from the molecule via enzymatic cleavage; and, following the enzymatic cleavage, spontaneously cleaving from the remaining portion of the bifunctional chemical group to release the other of the spaced-apart chemical moieties. In some embodiments, a self-decomposing unit refers to a heterocyclic self-decomposing moiety. Typical self-decomposing linkers include, but are not limited to, His-Ala, p-aminobenzyloxycarbonyl (PABC), p-hydroxybenzyloxycarbonyl, 2,4-bis(hydroxymethyl)aniline, -NH-(CH2)4-C(O)-, and -NH-(CH2)3-C(O)-, etc.

[0072] In this document, the term "cleavable linker" refers to the portion of the linker unit of an ADC that is unstable in vivo. Preferably, the "cleavable linker" allows activation of a marker or therapeutic agent by cleaving the marker or agent from the remainder of the conjugate. Operationally defined, the cleavable linker is preferably cleaved in vivo by the biological environment. Cleavage can originate from any process without limitation, such as enzymatic, reduction, pH, etc. Preferably, the cleavable group is selected so that activation occurs at the desired site of action, which can be a site in or near the target cell (e.g., cancer cell) or tissue, such as the site of therapeutic action or marker activity. This cleavage can be enzymatic, and exemplary cleavable groups comprise native amino acids or peptide sequences ending with native amino acids, and are linked to a linker unit or self-degrading linker at their carboxyl terminus.

[0073] In this article, the term "antibody linker" refers to any chemical group designed to facilitate the attachment of a drug conjugate to an antibody.

[0074] In this document, the term "property regulation unit" refers to a functional portion connected in series or branched manner within the linker unit of an ADC, designed to regulate the properties of the ADC, such as stability in blood circulation and improved hydrophilicity. Commonly used property regulation units for ADCs include, but are not limited to, polyethylene glycol (PEG), hydrophilic peptides, monosaccharides, oligosaccharides, polysaccharides, cyclodextrin units, polyamines, polyamides, dendritic polymers, and bifunctional hydrocarbon chains. In the ADC of this disclosure, the property regulation unit can be a separate component connected in series within the linker unit, or it can exist as a branch of each component within the linker unit. For example, the property regulation unit can be attached to a self-decomposing linker, a cleavable linker, and / or an antibody linker.

[0075] In this document, a specific example of the term "property-regulating unit" includes "PEG unit". The term "PEG unit" refers to an organic portion comprising repeating ethylene-oxygen subunits (PEG or PEG subunits), which can be polydisperse, monodisperse, or discrete (i.e., having a discrete number of ethylene-oxygen subunits). Preferred PEG units have a single polyethylene glycol chain having 2 to 24 tandemly covalently linked -CH2CH2O- subunits.

[0076] In this document, specific examples of the term "property regulation unit" also include "hydrophilic peptide". The term "hydrophilic peptide" can be attached, for example, to a self-decomposing linker of a linker unit, or to an antibody linker head, which can be directly attached to the linker unit, or attached to the linker unit by a suitable structural fragment (such as the fragment of formula (A) or (A1) as defined in this disclosure). Specifically, "hydrophilic peptide" refers to an organic moiety comprising a repeating subunit -CO-CR′R″-NR-, wherein one or more amino acids, identical or different from each other, are linked by amide bonds in a linear, branched, or star configuration, and each hydrophilic peptide generally contains 1-20 amino acids, preferably 4-14 amino acids, more preferably 6-12 amino acids.

[0077] In this paper, the amino acid monomers constituting the hydrophilic peptides can be natural amino acids, such as alanine (Ala), arginine (Arg), aspartic acid (Asp), asparagine (Asn), histidine (His), glycine (Gly), glutamic acid (Glu), glutamine (Gln), phenylalanine (Phe), lysine (Lys), leucine (Leu), serine (Ser), tyrosine (Tyr), threonine (Thr), isoleucine (Ile), proline (Pro), tryptophan (Trp), valine (Val), cysteine ​​(Cys), and methionine (Met). Correspondingly, in the repeating subunit -CO-CR'R”-NR-, R is H and one of R' and R” is H, while the other corresponds to the corresponding group or fragment in each natural amino acid. Polar natural amino acids are preferred, such as arginine, serine, threonine, tyrosine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, histidine, glycine, and tryptophan.

[0078] In this article, the amino acid monomers constituting the hydrophilic peptide can also be amino acids other than the twenty natural amino acids mentioned above, such as ornithine (Orn), β-alanine (β-Ala), citrulline (Cit), sarcosine (Sar), and those amino acids in the repeating subunit -CO-CR'R”-NR- where R, R', and R” are different from the corresponding groups or segments in natural amino acids. For example, R, R', and R” are selected from alkyl, aryl, acyl, amide, ketone, azide, hydroxyl, mercapto, hydrazine, cyano, quaternary ammonium, halogen, acylhydrazine, alkenyl, alkynyl, ether, thiol, selenyl, sulfonic acid, sulfate, borate ester, phosphonyl, phosphate, heterocyclic, enone, imine, aldehyde, ester, thioacid, hydroxylamine, amino, etc., or any combination thereof. The group comprises alkyl, aryl, acyl, amide, ketone, azide, hydroxyl, mercapto, hydrazine, cyano, quaternary ammonium, halogen, acylhydrazine, alkenyl, alkynyl, ether, thiol, selenyl, sulfonic acid, sulfate, borate ester, phosphonoyl, phosphoric acid, heterocyclic, enone, imine, aldehyde, ester, thioacid, hydroxylamine, amino, etc.; preferably, R, R', and / or R" contain hydrophilic amino acids, for example, R, R', and R" are each independently carboxyl, sulfonic acid, sulfate, phosphoric acid, amino, amide, quaternary ammonium, oxygen-containing group, ether, mercapto, or hydroxyl, or are groups containing carboxyl, sulfonic acid, sulfate, phosphoric acid, amino, amide, quaternary ammonium, oxygen-containing group, ether, mercapto, and / or hydroxyl, such as alkyl groups containing said groups, for example, C 1-6 alkyl.

[0079] For the ADC of this disclosure, when the linker unit carries a hydrophilic peptide, at least 50% to 100% of the amino acids constituting the hydrophilic peptide are hydrophilic amino acids, for example 80%-100%, such as 60%, 70%, 80%, 90%, or 100%, and the amino acids are preferably arginine, serine, threonine, tyrosine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, histidine, glycine, tryptophan, ornithine, citrulline (Cit), and sarcosine (Sar).

[0080] For the ADC disclosed herein, the hydrophilic peptide carried by the linker unit is preferably 4-14 units of polysarcosine, polyarginine, or polyglycine, more preferably 6-12, 4-12, 5-10, or 4-10 units of polysarcosine.

[0081] In this document, the term "drug:antibody ratio" or "DAR" refers to the ratio of the drug portion (D) coupled to the Ab portion as described herein to the Ab portion in an ADC conjugate. In some embodiments described herein, the DAR may be determined by q in Formula I, for example, the DAR may be an integer or non-integer that is at least 1, such as about 1 to 20, such as about 2-18, 4-16, 5-12, 6-10, 1-10, 1-8, 2-8, 3-8, 2-6, 4-6, 4-8, 6-8, 6-10, such as about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. DAR can also be calculated as the average DAR of the molecular population in the product, which is the overall ratio of the small molecule drug fraction (D) coupled to the Ab fraction described herein to the Ab fraction in the product as determined by detection methods (e.g., by conventional methods such as mass spectrometry, ELISA assay, electrophoresis and / or HPLC). This DAR is referred to as the average DAR in this document. In some embodiments, the average DAR value of the conjugates disclosed herein is about 1 to 20, for example about 2-18, 4-16, 5-12, 1-10, 1-8, 6-10, 2-8, 3-8, 2-6, 4-6, 4-8, 6-8, 6-10, for example 1.0-8.0, 2.0-6.0, for example about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 0, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0, a range with two of these values ​​as endpoints.

[0082] In this article, the term "halogen" generally refers to fluorine, chlorine, bromine, and iodine, for example, fluorine and chlorine.

[0083] In this document, the term "alkyl" refers to a straight-chain or branched aliphatic saturated hydrocarbon group having a specified number of carbon atoms. Specifically, alkyl groups may have 1 to 14, 1 to 12, 1 to 10, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. A suitable C 1-14 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, dimethylmethyl, dipropylmethyl, ethylbutylmethyl, diethylmethyl, methylethylmethyl, ethylpropylmethyl, diethylethyl, diethylpropyl, dipropylethyl, etc. A particular alkyl group has 1 to 7 carbon atoms, for example, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.

[0084] In this document, the term "-O-alkyl" or "alkoxy" means an alkyl group as defined herein, which is attached to the remainder of the molecule by an oxygen atom. Specifically, -O-alkyl has 1 to 10, for example, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, as used herein, the term "-OC"... 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group with 1 to 6 carbon atoms that is attached to the rest of the molecule by an oxygen atom. Examples include -O-methyl, -O-ethyl, -O-propyl (including -O-n-propyl and -O-isopropyl), -O-butyl (including -O-n-butyl, -O-isobutyl, -O-sec-butyl or -O-tert-butyl), -O-pentyl (including -O-n-pentyl, -O-isopentyl, -O-neopentyl), -O-n-hexyl, 2-methylpentyl-O-, etc.

[0085] In this article, the term "optionally halogenated C" is used. 1-6 "alkyl" refers to the C mentioned above. 1-6 Alkyl groups, wherein one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are optionally replaced by halogens. Those skilled in the art will understand that when there is more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different C atoms. "Halogen-substituted C..." 1-6 Examples of "alkyl" include -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, -CH2CH2CF3 or -CF(CF3)2, etc.

[0086] In this document, the term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, containing at least one double bond. Specifically, alkenyl groups have 2 to 8, for example, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. For example, as used herein, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, propenyl, allyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexadienyl, etc. The carbon atoms in the alkenyl group that are attached to the rest of the molecule can be saturated or alkene-bonded carbon atoms.

[0087] In this document, the term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group consisting of carbon and hydrogen atoms and containing at least one triple bond. Specifically, an alkynyl group has 2 to 8, for example, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. For example, as used herein, the term "C 2-6 "Alynyl" refers to a straight-chain or branched alkynyl group with 2 to 6 carbon atoms, such as ethynyl, propynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-methyl-1-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-methyl-2-hexynyl, etc. The carbon atom in the alkynyl group that is attached to the rest of the molecule can be saturated or an alkyne bond.

[0088] In this document, the term "alkylene" refers to a divalent group obtained by removing two hydrogen atoms from the same or two different carbon atoms of a straight-chain or branched saturated alkane. Specifically, alkylene groups have 1 to 10 carbon atoms, for example, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, as used herein, the term "C 1-6 "Alkylene" refers to a straight-chain or branched alkylene with 1 to 6 carbon atoms, including but not limited to methylene, ethylene, propylene, butylene, etc.

[0089] In this document, a specific “alkylene” refers to a divalent group obtained by removing two hydrogen atoms from the same carbon atom of a straight-chain or branched saturated alkane, such as the =C(R) group defined in the Pharmaceutical P section of this disclosure. d )2 groups, such as structural fragments As shown.

[0090] In this paper, the structural fragment of drug P in ADC is discussed. In the middle, by R9 and R 10 Replacement - (C) 1-3 - refers to an alkylene group containing 1-3 carbon atoms, i.e., -(CH2).1-3 Where any one or both H are R9 and / or R 10 replace.

[0091] In this document, the term "alkenyl" refers to a divalent group obtained by removing two hydrogen atoms from the same or two different carbon atoms of a straight-chain or branched unsaturated alkene containing at least one double bond. Specifically, alkenyl groups have 2 to 8, for example 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. For example, as used herein, the term "C 2-6 "Alkenyl" refers to a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, such as vinylene, propenylene, allylene, butenylene, pentenylene, and hexenylene.

[0092] In this document, the term "ynynyl" refers to a divalent group obtained by removing two hydrogen atoms from the same or two different carbon atoms of a straight-chain or branched unsaturated alkyne containing at least one triple bond. Specifically, ynynyl groups have 2 to 8, for example, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. For example, as used herein, the term "C2-C6 ynynyl" refers to a straight-chain or branched ynynyl group having 2 to 6 carbon atoms, such as ethynylene, propynylene, propynylene, butynylene, penynylene, and hexynylene.

[0093] In this document, the term "cycloalkyl" refers to a monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic non-aromatic monovalent hydrocarbon ring structure having a specified number of ring atoms. It can be saturated or unsaturated, for example, containing one or more double bonds. The cycloalkyl group may contain three or more carbon atoms in the ring, for example, 3-18, 3-10, or 3-8 carbon atoms, such as C1. 3-10 cycloalkyl, C 3-8 cycloalkyl, C 3-6 cycloalkyl, C 5-6 Cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0094] In this document, the term "heterocycle" or "heterocyclic group" refers to a 5-20 membered (e.g., 5-14, 5-8, 5-6) aromatic or non-aromatic monocyclic, bicyclic, or polycyclic ring system having 1-4 independent heteroatom ring members selected from N, O, or S. One or more N, C, or S atoms in the heterocycle may be oxidized. Preferably, the heterocycle is a 5-10 membered ring system, which is a monocyclic or fused bicyclic ring. Representative examples include, but are not limited to, pyrrolidine, azaheterocyclic butane, piperidine, morpholine, tetrahydrofuran, tetrahydropyran, benzofuran, benzothiophene, indole, benzopyrazole, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, pyrimidine, pyridine, pyrazine, pyridazine, isothiazine, and isoxazole. In some embodiments, the heterocyclic group is a heterocyclic alkyl group; in other embodiments, the heterocyclic group is a heteroaryl group; and in still other embodiments, the heterocyclic group is a heterocyclic alkenyl group.

[0095] In this document, the term "heterocyclic alkyl" means a monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic nonaromatic saturated ring structure comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from O, N, and S, and a specified number of ring atoms, or its N-oxide, or its S-oxide or S-dioxide. Heterocyclic alkyls may have 3 to 12 ring members (which may be referred to as 3-12-membered heterocyclic alkyls), for example, 3 to 10 ring members, 3 to 8 ring members, 3 to 7 ring members, 4 to 7 ring members, 4 to 6 ring members, or 5 to 6 ring members. Heterocyclic alkyls typically contain up to 4 (e.g., 1, 2, 3, or 4) heteroatoms, such as 4-7-membered heterocyclic alkyls containing 1 to 3 heteroatoms selected from N, O, and S, for example, 4-7-membered monocyclic heterocyclic alkyls. Suitable examples of heterocyclic alkyl groups include, but are not limited to, azaheterocyclic butyl, oxacyclobutyl, thioheterocyclic butyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g., 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl, and 3-tetrahydrothiophenyl), and piperidinyl (e.g., 1-piperidinyl). 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), tetrahydrothiaranyl (e.g., 4-tetrahydrothiaranyl), morpholinyl (e.g., morpholino), thiomorpholinyl, dioxane, piperazine, or aziridine heptyl, diazacyclic heptyl such as 1,4-diazacyclic heptyl, 3,6-diaza-bicyclo[3.1.1]heptyl, or 3-aza-bicyclo[3.2.1]octyl. The atom in the heterocyclic alkyl group attached to the rest of the compound can be a carbon atom or a heteroatom, as long as it is chemically feasible.

[0096] In this document, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group having 6-20, for example, 6-12 carbon atoms in the ring moiety. Preferably, the aryl group is (C6-C4) 10Aryl. Non-limiting examples include phenyl, biphenyl, naphthyl, or tetrahydronaphthyl, each of which may optionally be substituted with 1 to 4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxyl, alkoxy, acyl, alkyl-C(O)-O-, aryl-O-, heteroaryl-O-, amino, mercapto, alkyl-S-, aryl-S-, nitro, cyano, carboxyl, alkyl-OC(O)-, carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamide, heterocyclic, etc.

[0097] In this document, the term "heteroaryl" refers to a 5-20 membered (e.g., 5-14, 5-8, 5-6 membered) aromatic monocyclic or polycyclic ring system containing 1-4 heteroatoms selected from N, O, or S, which may be substituted or unsubstituted. Preferably, the heteroaryl is a 5-10 membered ring system, which is a monocyclic or fused bicyclic ring, such as a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Representative heteroaryl groups include 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrroleyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isooxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridinyl, 3- or 4-pyridazinyl, 3-, 4- or 5-pyrazinyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl.

[0098] In this document, the term "heteroalkyl" refers to a stable straight-chain or branched hydrocarbon that is fully saturated or contains 1 to 3 degrees of unsaturation, consisting of the indicated number of carbon atoms and one to ten, preferably one to three, heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, Si, and S may be located at any internal position of the heteroalkyl group or at the position where the heteroalkyl group is attached to the rest of the molecule. Representative examples of heteroalkyl groups include –CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -NH-CH2-CH2-NH-C(O)-CH2-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=NO-CH3, and –CH=CH-N(CH3)-CH3. At most two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3 and –CH2-O-Si(CH3)3. Typically, C1 to C4 heteroalkyl or heteroalkylene groups have 1 to 4 carbon atoms and 1 or 2 heteroatoms, while C1 to C3 heteroalkyl or heteroalkylene groups have 1 to 3 carbon atoms and 1 or 2 heteroatoms. In some respects, heteroalkyl and heteroalkylene compounds are saturated.

[0099] Unless otherwise indicated, the term "substituted" as used in defining various groups herein means that the corresponding group can be substituted, for example, but not limited to, the following groups as defined herein or conventional in the art: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, halogen, cyano, nitro, azide, carboxyl, hydroxyl, mercapto, amino, mono- or dialkylamino, mono- or dicycloalkylamino, mono- or diarylamino, mono- or diheterocyclicamino, mono- or diheteroarylamino, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-oxy, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-thio, Alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-acyl, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-acylamino, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-acyloxy, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-sulfonyl, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-sulfonyloxy, alkyl- or cycloalkyl- or heterocyclic- or heteroaryl- or aryl-sulfonylamino, or the optional substituted amino-formyl group described above, and groups thereof further substituted by other optional substituents, wherein the various groups are as defined herein. Examples of substituents include, but are not limited to, one or more groups independently selected from the following: halogen, OH, SH, CN, NH2, NHCH3, N(CH3)2, NO2, N3, C(O)CH3, COOH, C(O)-amino, OCOCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO2, phenyl, piperidinyl, piperazine, and pyrimidinyl.

[0100] In this document, the term “substitution” or “substituted” means that one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on a specified atom are replaced by a specified group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and forms a stable compound. Combinations of substituents and variables are only permitted if such combinations form a stable compound.

[0101] As used herein, the term "optionally substituted" means, unless otherwise indicated, that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4, or 5 or more, or any range thereof) of the listed substituents, wherein said substituents may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 identical or different substituents. In another embodiment, the optionally substituted group has 3 identical or different substituents. In another embodiment, the optionally substituted group has 4 identical or different substituents. In yet another embodiment, the optionally substituted group has 5 identical or different substituents.

[0102] Many of the groups defined herein are optional substitutions. The list of substituents given in the definition section for a particular group is not intended to limit the substituents defined in other parts of this specification and claims.

[0103] In this document, the term “compound” or “compound of this disclosure” means and covers the compound itself, whether by name or structural representation, as well as its isomers, isotopic variants, solvates or their salt forms such as pharmaceutically acceptable salts, unless defined differently in the context.

[0104] In this document, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effects and properties of the ADC conjugates of this disclosure, and that such salt is not biologically or otherwise undesirable. The ADC conjugates of this disclosure may exist in the form of their pharmaceutically acceptable salts, including acid addition salts and base addition salts. In this disclosure, a pharmaceutically acceptable, non-toxic acid addition salt refers to a salt formed by the ADC conjugate of this disclosure with an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the ADC conjugates of this disclosure with organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and organic base salts, such as ammonium salts formed by reacting with an organic base containing an N group.

[0105] In this document, the term "solvent" refers to an association formed by one or more solvent molecules with the ADC conjugate of this disclosure. Solvents forming solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. It should be understood that such solvates of the compounds of the present invention also include solvates of pharmaceutically acceptable salts of the compounds of the present invention.

[0106] In this document, the terms "stable isotopic variant" and "isotopic variant" or "isotopic-labeled form" are used interchangeably to refer to a compound in which one or more atoms constituting the compound are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into one or more atoms of the compounds disclosed herein include, for example... 2 H, 3 H, 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S and 18 F, thus forming isotopic variations of the compounds disclosed herein, whether or not they are radioactive, are intended to be included within the scope of this disclosure. In some embodiments, the compounds of this disclosure are provided in an unlabeled form, and in other embodiments, the compounds of this disclosure are provided in an isotopically labeled form, such as in a form labeled with the hydrogen isotope D, and in particular, R9, R in the definition of drug P herein. 10 and R 11 One or more H atoms in the group can be substituted with isotopes D, such as R9 and R. 10 Each independently represents H or D, R 11 -C can be replaced by one or more Ds, especially -C can be replaced by one or more Ds. 1-6 alkyl.

[0107] In this document, the term "isomer" means any stereoisomer, enantiomer mixture, including racemic mixtures, diastereomer mixtures, geometric isomers, blocked isomers, and / or tautomers that a compound may exist structurally. Methods for determining and isolating the stereochemistry of such isomers are well known to those skilled in the art (SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994). This disclosure covers all possible isomeric forms of the compounds as defined herein, and their pharmaceutically acceptable salts or solvates, unless otherwise indicated. Furthermore, the compounds of this disclosure may exist as mixtures of two or more different structural forms in rapid equilibrium (commonly referred to as tautomers). It should be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0108] In some embodiments, the term "isomer" for the compounds of this disclosure refers to a stereoisomer. Specifically, certain compounds of this disclosure contain at least one (e.g., 1, 2, 3, or 4) asymmetric centers and can therefore be prepared as (R)- or (S)- stereoisomers, or mixtures thereof.

[0109] The compounds disclosed herein, in their structural formulas or structural fragments, are used in The configuration representing the chiral center, i.e., the chiral center, is indicated by R or S in the nomenclature of the compounds or intermediates provided in this invention; connected to the chiral center This indicates a racemic form in which both configurations coexist at the chiral center, such as... express The mixture. In some of the compound definitions in this disclosure, axial chirality may also be used to describe the compound configuration. These configurations are determined using the Cahn-Ingold-Prelog rule well known to those skilled in the art, as shown in the following two example structures where the absolute configuration of axial chirality is described:

[0110] When the chiral bond of the link axis is marked with "*", it indicates that the compound has a single chiral configuration and was obtained by SFC resolution, but the absolute configuration is uncertain. For example, express or

[0111] It should be understood that when a person skilled in the art can determine, based on the structure of the compound shown herein, that the compound has a chiral isomer and can be easily separated using conventional methods in the art, then the disclosure of the racemic form of the compound herein (whether in terms of structural formula or chemical name) should be regarded as having disclosed each isomer of the compound separately.

[0112] In this document, the number of groups attached to each atom in a compound definition, structural formula, or structural fragment depends on the chemical valence of that atom and need not all be shown. Generally, only non-hydrogen groups are shown in the group definition, structural formula, or structural fragment; groups not shown generally represent H, and those skilled in the art can easily determine whether and how many of the not shown groups exist.

[0113] The structural fragments discussed in this article use The bonds that cross it are the bonds that connect the structural segment to the rest of the molecule.

[0114] The substituents in the cyclic structural segments discussed in this article, indicated by crossing chemical bonds, are, for example... -(R) 12 ) m , refers to the m R 12 Substituents can replace one or more chemically feasible substitution sites in the ring, including X when chemically feasible.

[0115] Unless otherwise specified, C in the definition of compounds in this invention n-n+m Or C n -C m This includes various cases with n to n+m carbons, such as C 1-6 This includes C1, C2, C3, C4, C5, and C6, as well as any range from n to n+m, such as C 0-6 Including C1, C2, C3, C4, C5, C6, C 0-1 C 0-2 C 0-3 C 0-4 C 0-5 C 1-2 C 1-3 C 1-4 C 2-3 C 1-6 Including C 1-2 C 1-3 C 1-4 C 2-6 C 3-6 wait.

[0116] In this document, the term “approximately” used to modify numerical values, ranges, or parameters means that the numerical value or parameter used with it fluctuates by ±10%, such as ±5%, ±2%, or ±1%. For example, the expression “approximately 100” as used herein includes 90 and 110 and all values ​​in between (e.g., 90.5, 95, 101, 105, 109.95, etc.). With respect to ratios, the term “approximately” is used to specify each number in the given ratio; for example, the ratio “approximately 1:1” means a ratio of (0.9–1.1):(0.9–1.1), and the range of “approximately nm” or “approximately n–approximately m” refers to the range from 90%n–110%n to 90%m–110%m.

[0117] Where there is no contradiction in the context, "pharmaceutical acceptable" and "medicinal" are used interchangeably in this article.

[0118] In this document, the term "pharmaceutical composition" refers to a composition which is present in a form that allows the biological activity of the active ingredient contained therein to be effective, and which does not contain any additional ingredients that would have unacceptable toxicity to a subject administering the composition.

[0119] In this document, the terms “pharmaceutical-acceptable excipient,” “pharmaceutical-acceptable carrier,” and “therapeutic-inert excipient” are used interchangeably and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is not therapeutically active and is non-toxic to the subject to administration, such as disintegrants, binders, fillers, solvents, buffers, tensioning agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants used to formulate pharmaceutical products.

[0120] In this document, the term "drug combination" refers to non-fixed combination products or fixed combination products, including but not limited to pillboxes and pharmaceutical compositions. The term "non-fixed combination" means that active ingredients, such as (i) the ADC conjugates of this disclosure, and (ii) other therapeutic agents are administered to a patient simultaneously, without a specific time limit, or at the same or different time intervals, in separate entities, wherein such administration to the patient provides a preventive or therapeutically effective level. In some embodiments, the ADC conjugates of this disclosure and other therapeutic agents used in the drug combination are administered at levels not exceeding those achieved when used alone. The term "fixed combination" means that two or more active agents are administered to a patient simultaneously in the form of a single entity. Preferably, the dosage and / or time interval of the two or more active agents are selected so that the combined use of the components produces an effect greater than that achieved by using any one component alone in treating a disease or condition. The components may each be in a separate formulation, and their formulations may be the same or different.

[0121] In this document, the term "combination therapy" refers to the administration of two or more therapeutic agents or treatment modalities, such as radiation therapy or surgery, to treat the disease described herein. Such administration includes the co-administration of these therapeutic agents in a substantially simultaneous manner, for example, in a single capsule containing active ingredients in a fixed proportion. Alternatively, such administration includes the co-administration of individual active ingredients in multiple or separate containers (e.g., tablets, capsules, powders, and liquids). Powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. Furthermore, such administration includes the sequential administration of each type of therapeutic agent at substantially the same time or at different times. In either case, the treatment regimen will provide the beneficial effect of the combination of drugs in treating the condition or symptom described herein.

[0122] In this document, the terms “individual” or “subject” are used interchangeably and refer to mammals. 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 such as monkeys), rabbits, and rodents (e.g., mice and rats). In particular, a subject is a human.

[0123] In this article, the term "treatment" refers to slowing down, interrupting, blocking, relieving, stopping, reducing, or reversing the progression or severity of existing symptoms, conditions, illnesses, or diseases.

[0124] In this document, the term "prevention" includes the suppression of the occurrence or development of a disease or condition, or symptoms of a particular disease or condition. In some implementations, subjects with a family history of cancer are candidates for preventative programs. Generally, in the context of cancer, the term "prevention" refers to the administration of a drug prior to the onset of signs or symptoms of cancer, particularly in subjects at risk of cancer.

[0125] In this document, the term "effective amount" refers to such an amount or dose of the antibody-drug conjugate or a combination thereof as disclosed herein, which, when administered to a patient in a single or multiple doses, produces the intended effect in a patient requiring treatment or prevention.

[0126] In this document, the term "therapeutic effective amount" refers to the amount that effectively achieves the desired therapeutic outcome at the required dose and for the required duration. A therapeutic effective amount is also a amount in which any toxic or harmful effects of the antibody-drug conjugate or its composition or combination thereof are less than the beneficial therapeutic effect. Relative to untreated individuals, the "therapeutic effective amount" preferably achieves at least about 30%, and more preferably at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 100% inhibition of measurable parameters (e.g., tumor volume).

[0127] In this article, the term "preventive effective dose" refers to the amount that, at the required dose and for the required duration, effectively achieves the desired preventive outcome. Typically, because the prophylactic dose is used in subjects before or at an early stage of the disease, the preventive effective dose will be less than the therapeutic effective dose.

[0128] As used in this specification and the following claims, the term "comprising" and variations thereof such as "including" and "containing" mean "including, but not limited to," and are not intended to exclude, for example, other additives, ingredients, integers, or steps. When an element is described as comprising multiple ingredients, steps, or conditions, it should be understood that the element may also be described as comprising any combination of said multiple ingredients, steps, or conditions, or "consisting of multiple or combined ingredients, steps, or conditions" or "consisting substantially of multiple or combined ingredients, steps, or conditions."

[0129] I: Antibody-drug conjugate

[0130] In one aspect, this disclosure provides antibody-drug conjugates (ADCs) having the following formula (X) or pharmaceutically acceptable salts or solvates thereof:

[0131] [PL] q -Ab (X)

[0132] in,

[0133] P represents a Ras inhibitor, such as a KRas inhibitor;

[0134] L represents the connecting body unit that connects P to Ab;

[0135] q represents the number of [PL] units connected to Ab, and is an integer or non-integer that is at least 1, for example, q = 1 to 20, such as about 1-10, 1-8, 2-8, 3-10, 3-8, 4-10, 4-8, 6-8 or 6-10;

[0136] Ab represents an antibody or antigen-binding fragment.

[0137] In some embodiments of formula X, q represents an integer selected from 1 to 20, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some cases, the range of q is 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, or 1 to 20, or a range consisting of any two values ​​between 1 and 20, such as 2 to 10, 2 to 8, 2 to 6, 2 to 4, 3 to 8, 3 to 10, 4 to 6, 4 to 8, 4 to 10, 6 to 8, or 6 to 10. In other embodiments, Formula X describes the ADC in the ADC mixture, which exhibits a q value ranging from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19 or 1 to 20, or a range consisting of any two values ​​between 1 and 20, such as 2 to 10, 2 to 8, 2 to 6, 2 to 4, 3 to 8, 3 to 10, 4 to 6, 4 to 8, 4 to 10, 6 to 8 or 6 to 10.

[0138] In some embodiments, Formula X describes the ADC in the ADC mixture such that the q value of more than 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the ADC in the mixture is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, Formula X describes the ADC in the ADC mixture such that the q value of more than 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the ADC in the mixture ranges from about 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, or 1 to 20, or is a range of any two values ​​between 1 and 20, such as about 2 to 10, 2 to 8, 2 to 6, 2 to 4, 3 to 8, 3 to 10, 4 to 6, 4 to 8, 4 to 10, 6 to 8, or 6 to 10.

[0139] In other embodiments, formula X describes the ADC mixture, where q is "q 平均 ", " represents the average q value of the mixture, or the average DAR, which is the average number of linker units (L) in the mixture that are linked to a given antibody (Ab). In such an implementation, q 平均Or, the average DAR represents an integer or non-integer value from 1 to 20, such as approximately 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, or 1 to 20, or an integer or decimal within a range of any two values ​​from 1 to 20, such as approximately 2 to 10, 2 to 8, 2 to 6, 2 to 4, 3 to 8, 3 to 10, 4 to 6, 4 to 8, 4 to 10, 6 to 8, or 6 to 10.

[0140] In a preferred embodiment, q in this disclosure (X) is an integer or non-integer from 1 to 10, or a range of any two values ​​between 1 and 10, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, about 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 2 to 10, 2 to 8, 2 to 6, 2 to 4, 4 to 6, 3 to 8, 3 to 10, 4 to 8, 4 to 10, 6 to 8, or 6 to 10.

[0141] In some embodiments, q represents an average DAR of about 3. In some preferred embodiments, q represents an average DAR of about 4. In some preferred embodiments, q represents an average DAR of about 5. In some embodiments, q represents an average DAR of about 6. In some embodiments, q represents an average DAR of about 8.

[0142] In some implementations, q represents an average DAR of about 1-10, 1-8, 2-8, 3-10, 3-8, 4-10, 4-8, 6-8, or 6-10, preferably an average DAR of 4 to 8.

[0143] Those skilled in the art should also understand that the various ADCs described herein may be in the form of salts or solvates, and in some specific embodiments, may be pharmaceutically acceptable salts.

[0144] The following provides a detailed description of each component of the ADC couplings disclosed herein, and the ADC couplings composed therefrom. Those skilled in the art will understand that the ADCs disclosed herein are inherently "modular," as each has the aforementioned modular components Ab, L, and P. Throughout this disclosure, various specific, non-limiting embodiments and examples of these modular components are described, and this disclosure covers specific combinations of all specific implementations of the modules as if each specific combination were described separately and explicitly.

[0145] Ab—Antibody or antigen-binding fragment

[0146] In the ADC of this disclosure, the antibody is an antibody or antigen-binding fragment that specifically binds to a target antigen. Its function is to target and present a KRas mutation inhibitor compound to a specific target cell population. Due to the presence of its targeting component or molecule, the antibody or antigen-binding fragment interacts with the specific target cell population, subsequently releasing the free drug within the target cells (intracellular mode) or releasing the free drug near the target cells (extracellular mode).

[0147] In one set of embodiments, an antibody or antigen-binding fragment is bonded to a linker unit comprising a releasable peptide component. As described above, other linker components may also be present in the conjugates described herein to provide additional space between Ras, such as a KRas mutation inhibitor compound, and the antibody unit, or to provide properties that increase solubility in the composition. In some of these embodiments, the antibody or antigen-binding fragment is bonded to the linker unit via its heteroatoms. Heteratoms that may be present on the antibody or antigen-binding fragment for this bonding include sulfur (in one embodiment, from a thiol group of the targeting ligand), oxygen (in one embodiment, from a carboxyl or hydroxyl group of the targeting ligand), and optionally substituted nitrogen (in one embodiment, from a primary or secondary amine functional group of the targeting ligand, or in another embodiment, from an optionally substituted amide nitrogen). These heteroatoms may be present on the antibody unit in the native state of the ligand, such as in naturally occurring antibodies, or may be introduced into the antibody unit through chemical modification or bioengineering.

[0148] The conjugation sites on antibodies affect the stability, pharmacokinetics, and pharmacodynamic properties of antibody-drug conjugates (ADCs). Excessive drug loading can sometimes lead to rapid plasma clearance, while ADCs with a low drug-to-antibody ratio (DAR) may exhibit weak activity. The drug loading of antibodies can be controlled by selecting conjugation strategies and specific conjugation sites on the antibody, while maintaining the structural integrity and homogeneity of the antibody.

[0149] In some embodiments, the antibody or antigen-binding fragment has a thiol functional group, such that it is bonded to the linker unit via the sulfur atom of the thiol functional group. In other embodiments, the thiol group is generated by reducing the interchain disulfide of the antibody. Therefore, in some embodiments, the linker unit is conjugated to a cysteine ​​residue from the reduced interchain disulfide in the antibody. In other embodiments, the thiol group is chemically introduced into the antibody, for example, by introducing a cysteine ​​residue. Accordingly, in some embodiments, the linker unit is conjugated to the antibody or antigen-binding fragment via a cysteine ​​residue introduced from the antibody or antigen-binding fragment.

[0150] In other embodiments, the antibody or antigen-binding fragment has one or more lysine residues that are capable of reacting with an activated ester (including, but not limited to, N-hydroxysuccinimide, pentafluorophenyl, and p-nitrophenyl ester) in the linker unit, thereby providing an amide bond consisting of a nitrogen atom of the antibody or antigen-binding fragment and a C=O atom of the linker unit.

[0151] In other embodiments, the antibody or antigen-binding fragment has one or more lysine residues that can be chemically modified to introduce one or more thiol groups. In these embodiments, the antibody or antigen-binding fragment is covalently attached to the linker unit via the sulfur atom of the thiol functional group. Reagents that can be used to modify lysine in this manner include, but are not limited to, N-succinimide-S-acetylthioacetate (SATA) and 2-iminothiacyclopentane hydrochloride (Traut reagent).

[0152] In other embodiments, the antibody or antigen-binding fragment has one or more carbohydrate groups that can be modified to provide one or more thiol functional groups. The chemically modified antibody or antigen-binding fragment in the ADC is bonded to the linker unit via the sulfur atom of the thiol functional group.

[0153] In other embodiments, the antibody or antigen-binding fragment has one or more carbohydrate groups that can be oxidized to provide an aldehyde (-CHO) functional group. In these embodiments, the corresponding aldehyde interacts with reactive sites on the linker unit to form a chemical bond between the linker unit and the antibody unit.

[0154] In other implementations, artificial linker sites are introduced into the antibody to achieve more targeted conjugation.

[0155] Other schemes for modifying proteins to link to linker units or related substances can be found in Coligan et al., Current Protocols in Protein Science, Vol. 2, John Wiley & Sons (2002), which are incorporated herein by reference.

[0156] In some embodiments, the antibody or antigen-binding fragment can form a covalent bond between the linker unit and the antibody or antigen-binding fragment corresponding to the antibody unit by interacting with a reactive functional group on the linker unit. The functional group capable of interacting with the antibody unit will depend on the nature of the antibody or antigen-binding fragment. In some embodiments, the reactive group is maleimide. The covalent linking of the antibody or antigen-binding fragment to the linker unit is achieved by the interaction of the thiol functional group of the antibody or antigen-binding fragment with the maleimide functional group of the linker unit, forming a sulfur-substituted succinimide. The thiol functional group can be present in the native state of the antibody or antigen-binding fragment, such as in naturally occurring residues, or can be introduced into the antibody or antigen-binding fragment through chemical modification or bioengineering.

[0157] The antibodies constituting the ADC of this disclosure may be polyclonal, monoclonal, genetically engineered and / or otherwise modified, and are suitable for administration to humans, such as humanized antibodies or fully human antibodies.

[0158] In some embodiments, the Ab unit of the ADC of this disclosure is a monospecific antibody. In some embodiments, the Ab unit of the ADC of this disclosure is a multispecific antibody. In some embodiments, the Ab unit, upon binding to an antigen receptor expressed on the surface of tumor cells, triggers antigen receptor-mediated endocytosis, thereby effectively delivering the antitumor drug of the ADC into the tumor cells.

[0159] In some embodiments, the Ab unit of the ADC disclosed herein can be a bispecific antibody, a bivariate domain antibody, a multi-chain or single-chain antibody, a single domain antibody, a camelified antibody, an scFv-Fc antibody, a substitute antibody, etc. In some embodiments where the Ab unit is a bispecific antibody, one specificity of the antibody can target a tumor-associated antigen to promote the specific binding of the ADC to tumor cells; while the other specificity of the antibody can target a receptor on the surface of tumor cells to further promote the internalization and degradation of the ADC. Examples of such combinations of bispecific targets include, but are not limited to, the combination of HER2 and PRLR dual targets on breast cancer cells. In other embodiments, the two specificities of the antibody can target different tumor-associated antigens respectively to provide a mechanism against drug resistance. Examples of such combinations of bispecific targets include, but are not limited to, the combination of EGFR and MET dual targets on lung cancer cells. In other embodiments, the two specificities of the antibody can also target different epitopes of the same tumor-associated antigen respectively to increase the selectivity of the antibody for cancer cells, and / or enhance internalization and transport to lysosomes by inducing the clustering and cross-linking of antigens on the surface of tumor cells. Examples of such tumor-associated antigens include, but are not limited to, HER2 on breast cancer cells.

[0160] The antibody portion constituting the ADC of this disclosure may be in the form of a full-length antibody, which may have or be derived from any antibody isotype, including, for example, IgA, IgD, IgE, IgG, IgM, or IgY. In some embodiments, the antibody constituting the ADC is IgG (e.g., IgG1, IgG2, IgG3, or IgG4). In some embodiments, the antibody constituting the ADC comprises all or part of the constant region of IgG immunoglobulin.

[0161] The antibody portion constituting the ADC of this disclosure may be a functionally active fragment, derivative, or analog of an antibody that specifically binds to target cells (e.g., cancer cell antigens, viral antigens, or microbial antigens). In this respect, "functionally active" means that the fragment, derivative, or analog is capable of specifically binding to target cells.

[0162] Useful antibody fragments include, but are not limited to, F(ab')2 fragments, Fab fragments, Fvs, single-chain antibodies, biantibodies, triple-chain antibodies, quadruple-chain antibodies, scFv, scFv-FV, or any other molecule with the same specificity as an antibody. These fragments can be obtained through molecular engineering, chemical or enzymatic treatment of the intact antibody or antibody chain, or recombinant methods.

[0163] Useful modified antibody analogs and derivatives include, but are not limited to, antibody derivatives and analogs obtained through glycosylation, acetylation, polyethylene glycolation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, and linking to cellular antibody units or other proteins. Any of the numerous chemical modifications can be performed using known techniques, including but not limited to specific chemical cleavage, acetylation, formylation, and metabolic synthesis in the presence of tunicamycin.

[0164] The antibody or antigen-binding fragment thereof used as the Ab unit of the ADC disclosed herein is commercially available or can be prepared by techniques known in the art, such as hybridoma technology, recombinant technology, phage display technology, transgenic animals or combinations thereof.

[0165] Target antigens and antibodies

[0166] The antibody portion of the ADC disclosed herein can target any suitable target molecule presented on the surface of target cells, such as peptides, proteins, polysaccharides, or lipid molecules. The binding of the antibody to the target molecule should be highly specific to ensure that the ADC specifically binds to the target cell and reduce off-target toxicity. In some embodiments, the binding affinity of the antibody to the target molecule can be selected at the nanomolar or sub-nanomolar level.

[0167] Suitable target antigens can be selected by searching for cell surface proteins that are highly expressed in tumors but poorly expressed or even barely expressed in non-malignant tissues. In some embodiments, such target molecules are membrane antigens expressed on the surface of target tumor cells, such as tumor-specific antigens or tumor-associated antigens, including hematologic malignancies and solid tumors, including primary and metastatic tumors. In a particularly preferred embodiment, the antibody or antigen-binding fragment in the ADC of this disclosure specifically binds to one or more tumor-specific antigens or tumor-associated antigens, or immune cell-associated antigens.

[0168] In some embodiments, the tumor-specific antigens or tumor-associated antigens targeted by the ADC antibody portion of this disclosure are selected from: HER2, Her3, HER1 (ErbB1), HER4 (ErbB4), TROP2, Nectin-4, tissue factor, PD-L1, PD-1, PD-L1 / PD-L2, MET, CLDN18.2, KIT, CTLA-4, RPR1, adrenaline A2 receptor (EphA2), folate receptor (F... Ra), mesothelin, endothelin receptor, GCPII, IL-13Ra, BCMA, GD2, CLL-1, CA-IX, MUC1, 5T4, AOC3, ALK, AXL, C242, CA-125, CCL11, CCR5, CD2, CD3, CD4, CDS, CD15, CA15-3, CD16, CD18, CD19, CD20, CD21, CD22, CD25, CD30, CD32 CD33, CD37, CD38, CD44, CD52, CD56, CD64, CD66e, CD70, CD72, CD74, CD79a, CD79b, CD123, CD138, CD1 42. CD174, CD276, CDH3, CDH6, CDH17, CCD79b, CLDN9 / CLDN6, CA19-9, DPEP3, AGS-16, IGF1R, IGF2R, VE GFR1, VEGFR2, VEGFR3, PDGFR-α, PDGFR-β, EGFR, EGFRvIII, ENPP3, FcRH5, FRα, KAAG1, LIV-1, Mesothelin, cMet, ROR1, SLTRK6, TF, BMPR1B, E16, TOP1, STEAP1, STEAP2, 0772P, MUC16, Napi2b, Napi3b, Sema 5b. PSCAhIg, ETBR, RNF124, prostate cancer-associated gene 1, TrpM4, teratoma-derived growth factor 1, C3DR, FcRH2, NCA, MDP, IL20R-α, Brevican, EphB2R, ASLG659, prostate stem cell antigen precursor, GEDA, BAFF-R, CXCR5, CCR2, CCR8, HLA-DOB, P2X5, LY64, FcRH1, IRTA2, TENB2, integrin α5β6, integrin α4β7, FGF2, FGFR1, FGFR2, FGFR3, FGFR4, PSMA, somatostatin receptor, RANK, SLAMF7, ITGB6, CEACAM5, CA9, EGFRv IL-11, IL-2RA, AXL receptor tyrosine kinase, TGF-βR, TNFRSF8, cancer / testis-associated antigen, CLEC14A, GRP78, stem cell-specific antigen, ASG-5, PRR4, GUCY2C, SLC39A6, TPBG, tumor-associated antigen CA242, FOLR1, GPNMB, HAVCR1, prostate tumor target Mindin, VTCN1, PTK7 protein tyrosine kinase 7, macrophage stimulation 1 receptor, TACSTD2, CA6, DLL3, DLL4, EpCAM, FAP, Fibronectin-EDB, DKK-1, Endoglin, VCAM1, GPC3, DR5, ASCT2, B7H1, B7H3, B7H4.

[0169] In some embodiments, tumor-associated antigens and immune cell antigens are T-cell co-inhibitory molecules. In some embodiments, the antibody or its antigen-binding fragment specifically binds to a tumor-associated antigen selected from PD-L1, PD-L2, CD47, CD80, CD86, HVEM, UL144, CD155, CD112, CD113, galectin-1, galectin-3, galectin-9, CD48, LIGHT, BTLA, and CD160. In some embodiments, the tumor-associated antigen is a molecule that binds to a T-cell molecule selected from BTLA, Tim-3, PD-1, CTLA-4, TIGIT, CD244, and CD223.

[0170] In some implementations, the antibody is an anti-PD-L1 antibody, such as atezolizumab, durvalumab, avelumab, or an antigen-binding fragment thereof, or an antibody having an equivalent amino sequence thereof, or an antigen-binding fragment thereof.

[0171] In some embodiments, the antibody is an anti-PD-1 antibody, such as nivolumab, pembrolizumab, cemiplimab, anti-mouse PD-1 antibody clone J43, anti-mouse PD-1 antibody clone RMP1-14, mouse anti-PD-1 antibody clone EH12, ANB011, MDX-1106, AMP-514, AMP-224, or pitilizumab. In some embodiments, the anti-PD-1 antibody is either pembrolizumab or nivolumab.

[0172] In some implementations, the antibody is an anti-CTLA-4 antibody, such as ipilimumab, clone 9H10, tremelimumab, or clone BNI3.

[0173] In some implementations, the antibody is an anti-CD47 antibody, such as antibodies to Hu5F9-G4, IBI188, CC-90002, ZL1201, TTI-621, AO-176, SGN-CD47M, the ALX148 antigen-binding domain, or an antigen-binding fragment thereof, or an antibody having an equivalent amino acid sequence thereof or an antigen-binding fragment thereof.

[0174] In other embodiments, the antibody or its antigen-binding fragment specifically binds to a tumor-associated antigen, which is a growth factor receptor (GFR). In some embodiments, the tumor-associated antigen is an EGFR / ErbB / HER family GFR. In some embodiments, the tumor-associated antigen is selected from EGFR / HER1 (ErbB1), HER2 / c-Neu (ErbB2), Her3 (ErbB3), and Her4 (ErbB4) receptors. In some embodiments, the tumor-associated antigen is an IGFR family GFR. In some embodiments, the cancer-associated tumor antigen is an IGF1R or IGF2R receptor. In some embodiments, the tumor-associated antigen is a TGF-βR (TβR) family GFR. In some embodiments, the cancer-associated tumor antigen is a TβR I or TβR II receptor. In some embodiments, the tumor-associated antigen is a VEGFR family GFR. In some embodiments, the cancer-associated tumor antigen is a VEGFR1, VEGFR2, or VEGFR3 receptor. In some embodiments, the tumor-associated antigen is a PDGFR family GFR. In some embodiments, the cancer-associated tumor antigen is a PDGFR-α or PDGFR-β receptor. In some embodiments, the tumor-associated antigen is an FGFR family GFR. In some embodiments, the cancer-associated tumor antigen is an FGFR1, FGFR2, FGFR3, or FGFR4 receptor.

[0175] In some embodiments, the antibody is an anti-EGFR / HER1 (ErbB1) antibody, such as cetuximab, panitumumab, necitumumab, or an antigen-binding fragment thereof, or an antibody having an equivalent amino acid sequence thereof. In some embodiments, the antibody is an anti-HER2 (ErbB2) antibody, such as trastuzumab, pertuzumab, or an antigen-binding fragment thereof, or an antibody having an equivalent amino acid sequence thereof. In some embodiments, the antibody is an anti-VEGFR2 antibody, such as ramucirumab, or an antigen-binding fragment thereof, or an antibody having an equivalent amino acid sequence thereof. In some embodiments, the antibody is an anti-PDGFR-α antibody, such as olaratumab, or an antigen-binding fragment thereof, or an antibody having an equivalent amino acid sequence thereof.

[0176] In other embodiments, the antibody or its antigen-binding fragment specifically binds to a lymphoma-associated antigen. In some embodiments, the lymphoma-associated antigen is CD20, CD30, CD19 / CD3, CD22, or CD33. In some embodiments, the antibody is an anti-CD20 antibody, such as rituximab, ibritumomab, ofatumumab, or obinutuzumab, or its antigen-binding fragment, or an antibody having an equivalent amino acid sequence thereof, or its antigen-binding fragment. In some embodiments, the antibody is an anti-CD30 antibody, such as brentuximab, or its antigen-binding fragment, or an antibody having an equivalent amino acid sequence thereof, or its antigen-binding fragment. In some embodiments, the antibody is an anti-CD19 / CD3 antibody, such as blinatumomab, or its antigen-binding fragment, or an antibody having an equivalent amino acid sequence thereof, or its antigen-binding fragment. In some embodiments, the antibody is an anti-CD22 antibody, such as inotuzumab or its antigen-binding fragment, or an antibody having an equivalent amino sequence or its antigen-binding fragment. In some embodiments, the antibody is an anti-CD33 antibody, such as gemtuzumab or its antigen-binding fragment, or an antibody having an equivalent amino sequence or its antigen-binding fragment.

[0177] In other embodiments, the antibody or its antigen-binding fragment specifically binds to a myeloma-associated antigen. In some embodiments, the myeloma-associated antigen is SLAMF7 or CD38. In some embodiments, the antibody is an anti-SLAMF7 antibody, such as elotuzumab or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an equivalent amino acid sequence. In some embodiments, the antibody is an anti-CD38 antibody, such as daratumumab or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an equivalent amino acid sequence.

[0178] In other embodiments, the antibody or its antigen-binding fragment specifically binds to the germ cell tumor-associated antigen. In some embodiments, the germ cell tumor-associated antigen is GD2. In some embodiments, the antibody is an anti-GD2 antibody, such as dinutuximab or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an equivalent amino sequence.

[0179] In other embodiments, the antibody or its antigen-binding fragment specifically binds to the RANK ligand. In some embodiments, the antibody is an anti-RANK ligand antibody, such as denosumab or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an equivalent amino acid sequence.

[0180] In other embodiments, the antibody or its antigen-binding fragment specifically binds to TROP2. In some embodiments, the antibody is an anti-TROP2 antibody, such as sacituzumab and datopotamab, or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an equivalent amino acid sequence.

[0181] In other embodiments, the antibody or its antigen-binding fragment specifically binds to Claudin18.2. In some embodiments, the antibody is an anti-Claudin18.2 antibody, such as Zolbetuximab, Osemitamab (TST001), CMG901, ASKB589, ZL-1211, or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an equivalent amino acid sequence thereof.

[0182] In other embodiments, the antibody or its antigen-binding fragment specifically binds to Met (also known as c-Met, or hepatocyte growth factor receptor (HGFR)). In some embodiments, the antibody is an anti-Met antibody, such as onartuzumab or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an equivalent amino acid sequence.

[0183] In other embodiments, the antibody or its antigen-binding fragment specifically binds to the adrenergic receptor Eph, particularly the EphA2 receptor. In some embodiments, the antibody is an anti-EphA2 antibody or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an equivalent amino acid sequence.

[0184] In other embodiments, the antibody or its antigen-binding fragment specifically binds to Nectin-4. In some embodiments, the antibody is an anti-Nectin-4 antibody, such as Enfortumab or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an equivalent amino acid sequence.

[0185] In other embodiments, the antibody or its antigen-binding fragment specifically binds to both EGFR and Met (also known as c-Met). In some embodiments, the antibody is a bispecific antibody against EGFR and Met, such as Amivantamab or its antigen-binding fragment, or an antibody or its antigen-binding fragment having an equivalent amino acid sequence.

[0186] In some embodiments, the tumor-associated antigens specifically bound to the antibody or its antigen-binding fragment are selected from AXL, B7H1, B7H3, B7H4, BCMA, CD16, CD19, CD22, CD25, CD30, CD32, CD33, CD44, CD64, CD70, CD74, CD79, CD138, CD142, CD276, CDH3, CEACAM5, Claudin 18.2, CLDN9 / CLDN6, DPEP3, EGFR, ENPP3, EphA, FcRH5, FORR1, FRα, GCPII, HER2, HER3, KAAG1, KIT, LIV-1, Mesothelin, c-Met, MUC1, Nectin-4, PD-L1, PD-L1 / PD-L2, PSMA, ROR1, RPR1, TF, TOP1, TROP2, etc., and the corresponding antibodies are commercially available or can be prepared using techniques known in the art.

[0187] In a preferred embodiment, the antibody is an antibody that binds to antigens preferentially expressed or overexpressed in cancer cells, such as HER2 (ErbB2), PD-1, PD-L1, EGFR, TROP2, Claudin 18.2, EphA-2, Nectin-4, and Met, more preferably HER2 (ErbB2), EGFR, TROP2, Claudin 18.2, Nectin-4, or a combination of EGFR and Met.

[0188] Regarding the tumor-associated antigens mentioned above, the ADC compounds disclosed herein can treat tumors associated with the expression of the aforementioned antigens. The specific list of tumors is known or determined by those skilled in the art based on the prior art.

[0189] Antibodies with immune specificity against tumor-associated antigens can be commercially available or produced by any method known to those skilled in the art, such as recombinant expression techniques. The nucleotide sequences encoding immune-specific antibodies against cancer cell antigens can be obtained, for example, from GenBank or similar databases, literature publications, or through routine cloning and sequencing.

[0190] Antibodies applicable to the ADCs disclosed herein include, but are not limited to: abagovomab, abatacept acasunlimab,abciximab adalimumab adebrelimab,adecatumumab,alacizumab,alemtuzumab altumomab,amivantamab,afelimomab,amostomig,anatumomab,anbenitamab,anetumumab,anvatabart,anrukizumab,apolizumab,arcitumomab,aselizumab,atezolizumab,atlizumab,atorolimumab,avelumab,azerutamig,azirkitug,bapineuzumab,barecetamab,basiliximab bavituximab,becotatug,bectumomab belimumab benmelstobart,bertilimumab,betifisolimab,besilesomab,bevacizumab blinatumomab, biciromab, bintrafusp, brallobarbital, brentuximab, bivatuzumab, cafelkibart, calotatug, camidanlumab, cantuzumab, canakinumab (ACZ885), cantuzumab, capromab catumaxomab caxmotabart,cedelizumab cemavafusp,certolizumab,cetuximab ciletatug,citatuzumab,clenoliximab,clivatuzumab,conatumumab,coprelotamab,cosibelimab,dacetuzumab,dacliximab,daclizumab danburstotug,daratumumab,datopotamab,demupitamab,denikitug,denosumab(AMG162),depatuxizumab,detumomab,disitamab,dorlimomab,dorlixizumab,duligotuzumab,duntumumab,durlimumab,durmulumab,durvalumab,edrecolomab,ecromegab edobacomab,edrecolomab(Mabl7-lA, ), efalizumab efungumab elgemtumab,elotuxumab,elsilimomab,emphyzatamab2,enlimomab,enoblituzumab,enristomig,enzelkitug,envafolimab,epitumomab cituxetan,efalizumab,epitumomab,epratusumab,erfonrilimab,erlizumab,ertumaxomab etanercept etevritamab,etaracizumab(etaratuzumab, ),exbivirumab,fanolesomab faralimomab,farletuzumab,felvizumab,figtumumab,fontolizumab futuximab, galiximab, gantenerumab, gavilimomab Garetatug, Garivulimab, Gevastomig, Gresonitamab, Glembatumab, Golimumab (CNTO148), Gomiliximab, Ibalizumab (TNX-355), Ibritumab, Finatamab, Igovomab, Intetumab, Dixim, Abkit Uglybarizumab, inolimomab, inotuzumab, ipilimumab (MDX-010, MDX-101), istratumab, iratumumab, itanistomig, izalontamab, keliximab, LAPR Tuximab, Labetuzumab, Lanerkitug, Lemalesomab, Lebrilizumab, Lesabelimab, Lerdelimumab, Lexatumumab (HGS-ETR2, ETR2-ST01). , lexitumumab, libivirumab, lintuzumab, lodapolymab, losatuxizumab, lucatumumab, lumiliximab, lumretuzumab, manilimab, MAP atumumab (HGSETRl, TRM-1), marlotamig, margetuximab, marstacimab, matuzumab, maslimomab, matuzumab (EMD72000), mepolizumab metelimumab, milatuzumab, minretumab, mirzotamab, mitumab, modotuximab, morolimumab, motavizwnab nacolomab, nebratamig1, naptumab, natalizumab nebacumab, necitumumab, nerelimomab, nezutatug, nimotuzumab (THERACIM ), nofetumomab,bintunzumab,obrindatamab, ocrelizumab, odulimomab,ofatumumab, olaratumab,omalizumab omburtamab, omectatug, oregovomab osemitamab, opamistomig, opucolimab, oportuzumab, otelixizumab, pacmilimab, pagibaximab, palivizumab Pamvatamig, panitumumab(ABX-EGF, ), panitumumab,pascolizumab, patritumab, pemtumab pertuzumab(2C4, ), petosemtamab, pexelizumab, pimurutamab, pintumomab, priliximab, pritumumab, pumitamig2, ragistomig, ranibizumab raxibacumab, regavirumab, reozalimab, retlirafusp, reslizumab, rilotumab, rituximab robatumumab, rovalpituzumab, rovelizumab, ruplizumab, ruzaltatug, safimestomig, sacituzumab (IMMU-132), satumomab, sevirumab, serclutamab, seribantumab, sibrotuzumab, si mlukafusp, simridarlimab, splizumab (MEDI-507), socazolimab, solabafusp, sonestatug, sontuzumab, spevatamig, stamulumab (MY0-029), sudubrilimab, sugemalimab, sulesomab tacatuzumab,tadocizumab,tagitanlimab,talizumab,taplitumomab,tecotabart,tenatumomab,tefibazumab telimomab,teneliximab,teplizumab,ticilimumab,tigatuzumab,timigutuzumab,tizetatug,tocilizumab tomuzotuximab,toralizumab,tositumomab,trastuzumab tremelimumab,tositumomab,tucotuzumab,tuvirumab,umizortamig2,urtoxazumab,ustekinumab(CNTO1275),vapaliximab,veltuzumab,vepalimomab,vobramitamab,volociximab,vopikitug,votumumab xirestomig, zalutumumab, zanolimumab (HuMAX-CD4), zanidatamab, zenocutuzumab, ziralimumab, zolbetuximab, zolimomab.

[0191] Ab unit targeting HER2

[0192] In a particularly preferred embodiment, the antibody-drug conjugates provided herein comprise an antibody or antigen-binding fragment that specifically binds to human HER2 (anti-HER2 antibody), i.e., the antibody partially and specifically targets the tumor-associated antigen HER2. Therefore, in some aspects, this disclosure provides an antibody-drug conjugate (ADC) comprising an antibody that specifically binds to HER2 or an antigen-binding fragment thereof as the Ab unit of the ADC.

[0193] HER2 is the receptor tyrosine protein kinase ErbB2, and it is overexpressed or amplified in approximately 20-30% of breast cancers. Increased activation of HER2 triggers multiple downstream pathways, leading to abnormal proliferation of cancer cells (Treish I, Schwartz R, Lindley C: Pharmacology and therapeutic use of trastuzumab in breast cancer. Am J Health Syst Pharm. 2000 Nov 15; 57(22):2063-76; quiz 2077-9). HER2 is also overexpressed in many other types of cancer, such as gastric cancer, esophageal cancer, colon cancer, rectal cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, bladder cancer, pancreatic cancer, lung cancer, prostate cancer, osteosarcoma, neuroblastoma, or head and neck cancer.

[0194] In some implementations, the antibody that specifically binds to human HER2 or an antibody fragment thereof (e.g., an antigen-binding fragment) may be selected from trastuzumab, pertuzumab, margetuximab or HT-19 or an antibody fragment thereof or a site-specific mutant thereof, or other anti-human HER2 antibodies that recognize the same epitope or competitively bind to human HER2.

[0195] In some embodiments, exemplary antibodies targeting HER2 that can be used with the ADC of this disclosure may be antibody or antigen-binding fragments comprising all six CDR sequences of antibodies selected from the group consisting of: trastuzumab (Herceptin, Genentech, US6,054,297); ATCC accession numbers PTA-10355, PTA-10356, PTA-10357, PTA 10358 (US20100119511); ATCC accession number CRL-10463 (Genentech); ATCC accession numbers HB-12215, HB-12216, CRL 10463, HB-12697; pertuzumab (Pertuzumab, Genentech, US20110117097); ATCC accession numbers HB-12215, HB-12216, CRL 10463, CRL 10463, HB-12697. 10463, HB-12698 (US20090202546); ATCC Registry Numbers HB-12215, HB-12216 (US20060088523); ATCC Registry Numbers (7C2)HB-12215, (7F3)HB-12216, (4D5)CRL-10463, (2C4)HB-12697 (US20060018899); TrasGEX (Glycotope: http: / / www.glycotope.conn / pipeline).

[0196] In one embodiment, the antibody portion for the ADC of this disclosure comprises all six CDR sequences of trastuzumab. In another embodiment, the antibody portion for the ADC of this disclosure comprises the heavy chain variable region sequence and the light chain variable region sequence of trastuzumab. In yet another embodiment, the antibody portion for the ADC of this disclosure comprises the heavy chain sequence and the light chain sequence of trastuzumab.

[0197] In some embodiments, the Ab unit of the ADC of this disclosure comprises three CDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:10 and three CDRs of the light chain variable region (VL) sequence of SEQ ID NO:9, and preferably, wherein the CDRs are defined according to Kabat or IMGT or a combination thereof.

[0198] In some embodiments, the Ab unit of the ADC of this disclosure includes three heavy chain complementarity determination regions (HCDRs) and three light chain complementarity determination regions (LCDRs), wherein:

[0199] According to Kabat's definition, HCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:6, HCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:7, HCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:8, LCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:3, LCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:4, and LCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:5.

[0200] In one embodiment, the Ab unit of the ADC of this disclosure includes a heavy chain variable region, wherein the heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO:10, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0201] In one embodiment, the Ab unit of the ADC of this disclosure includes a light chain variable region, wherein the light chain variable region comprises: the amino acid sequence shown in SEQ ID NO:9, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0202] In some preferred embodiments, the Ab unit of the ADC of this disclosure includes a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes the amino acid sequence described in SEQ ID NO:10, and wherein the light chain variable region includes the amino acid sequence shown in SEQ ID NO:9.

[0203] In some embodiments, the Ab unit of the ADC of this disclosure preferably further comprises a heavy chain constant region and / or a light chain constant region of the antibody. Preferably, the heavy chain constant region is a heavy chain constant region derived from human immunoglobulins. Preferably, the light chain constant region is a light chain constant region derived from human immunoglobulins. In some aspects, the heavy chain constant region contained in the Ab unit can be any isotype or subtype, such as the heavy chain constant region of IgG1, IgG2, IgG3, or IgG4 isotypes, and preferably the IgG1, IgG2, or IgG4 heavy chain constant region, especially the human IgG1 heavy chain constant region. In still other aspects, the light chain constant region contained in the Ab unit can be a κ light chain constant region or a λ light chain constant region, especially the human κ light chain constant region.

[0204] In some embodiments, the Ab unit of the ADC of this disclosure comprises a human IgG1 heavy chain constant region. Preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:11, or an amino acid sequence comprising at least one, two, or three, but not more than 20, 10, or 5 amino acid changes relative to the amino acid sequence of SEQ ID NO:11, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:11.

[0205] In some embodiments, the Ab unit of the ADC of this disclosure comprises a human κ light chain constant region. Preferably, the light chain constant region comprises the amino acid sequence of SEQ ID NO:12, or an amino acid sequence comprising at least one, two, or three, but not more than 20, 10, or 5 amino acid changes relative to the amino acid sequence of SEQ ID NO:12, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:12.

[0206] In some embodiments, the Ab unit of the ADC of this disclosure is a full-length antibody comprising a heavy chain constant region and a light chain constant region. In some embodiments, the Ab unit is a tetrameric structure having two light chains and two heavy chains. In still other embodiments, the Ab unit is an IgG antibody, particularly an IgG1 antibody.

[0207] In some preferred embodiments, the Ab unit of the ADC of this disclosure comprises a heavy chain and a light chain, wherein: the heavy chain comprises the amino acid sequence shown in SEQ ID NO:2, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it, or is composed of it. In other preferred embodiments, the Ab unit of the ADC of this disclosure comprises a heavy chain and a light chain, wherein: the light chain comprises the amino acid sequence shown in SEQ ID NO:1, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0208] In some more preferred embodiments, the Ab unit of the ADC of this disclosure includes:

[0209] (a) A heavy chain containing the amino acid sequence of SEQ ID NO:2, and

[0210] (b) A light chain containing the amino acid sequence of SEQ ID NO:1.

[0211] Ab unit targeting TROP2

[0212] In a particularly preferred embodiment, the antibody-drug conjugates provided herein comprise an antibody or antigen-binding fragment (anti-TROP2 antibody) that specifically binds to human TROP2, i.e., the antibody partially and specifically targets the tumor-associated antigen TROP2. Therefore, in some aspects, this disclosure provides an antibody-drug conjugate (ADC) comprising an antibody that specifically binds to TROP2 or an antigen-binding fragment thereof as the Ab unit of the ADC.

[0213] Tropoblast cell surface antigen 2 (TROP2), also known as tumor-associated calcium signal transducer 2 (TACSTD2), is a type I transmembrane cell surface glycoprotein. The sequence of human TROP2 is available from UniProtKB accession number P09758. TROP2 has been confirmed to be overexpressed in many solid tumors, including, but not limited to, various human epithelial cancers such as cervical cancer, endometrial cancer, breast cancer, urothelial carcinoma, lung cancer, gastric cancer, prostate cancer, colorectal cancer, and pancreatic cancer.

[0214] In some implementations, the antibody that specifically binds to human TROP2 or an antibody fragment thereof (e.g., an antigen-binding fragment) may be selected from Sacituzumab, Datopotamab, or an antibody fragment thereof, or other anti-human TROP2 antibodies that recognize the same epitope or competitively bind to human TROP2.

[0215] In some embodiments, exemplary antibodies targeting human TROP2 that can be used with the ADC of this disclosure may be antibody or antigen-binding fragments comprising all six CDR sequences of antibodies selected from the group consisting of Sacituzumab and Datopotamab.

[0216] In one embodiment, the antibody portion for the ADC of this disclosure comprises all six CDR sequences of Sacituzumab or Datopotamab. In another embodiment, the antibody portion for the ADC of this disclosure comprises the heavy chain variable region sequence and the light chain variable region sequence of Sacituzumab or Datopotamab. In yet another embodiment, the antibody portion for the ADC of this disclosure comprises the heavy chain sequence and the light chain sequence of Sacituzumab or Datopotamab.

[0217] In some embodiments, the Ab unit of the ADC of this disclosure comprises three CDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:22 and three CDRs of the light chain variable region (VL) sequence of SEQ ID NO:21, and preferably, wherein the CDRs are defined according to Kabat or IMGT or a combination thereof.

[0218] In some embodiments, the Ab unit of the ADC of this disclosure includes three heavy chain complementarity determination regions (HCDRs) and three light chain complementarity determination regions (LCDRs), wherein:

[0219] According to Kabat's definition, HCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:18, HCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:19, HCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:20, LCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:15, LCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:16, and LCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:17.

[0220] In one embodiment, the Ab unit of the ADC of this disclosure includes a heavy chain variable region, wherein the heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO:22, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0221] In one embodiment, the Ab unit of the ADC of this disclosure includes a light chain variable region, wherein the light chain variable region comprises: the amino acid sequence shown in SEQ ID NO:21, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0222] In some preferred embodiments, the Ab unit of the ADC of this disclosure includes a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes the amino acid sequence described in SEQ ID NO:22, and wherein the light chain variable region includes the amino acid sequence shown in SEQ ID NO:21.

[0223] In some embodiments, the Ab unit of the ADC of this disclosure preferably further comprises a heavy chain constant region and / or a light chain constant region of the antibody. Preferably, the heavy chain constant region is a heavy chain constant region derived from human immunoglobulins. Preferably, the light chain constant region is a light chain constant region derived from human immunoglobulins. In some aspects, the heavy chain constant region contained in the Ab unit can be any isotype or subtype, such as the heavy chain constant region of IgG1, IgG2, IgG3, or IgG4 isotypes, and preferably the IgG1, IgG2, or IgG4 heavy chain constant region, especially the human IgG1 heavy chain constant region. In still other aspects, the light chain constant region contained in the Ab unit can be a κ light chain constant region or a λ light chain constant region, especially the human κ light chain constant region.

[0224] In some embodiments, the Ab unit of the ADC of this disclosure comprises a human IgG1 heavy chain constant region. Preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:23, or an amino acid sequence comprising at least one, two, or three, but not more than 20, 10, or 5 amino acid changes relative to the amino acid sequence of SEQ ID NO:23, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:23.

[0225] In some embodiments, the Ab unit of the ADC of this disclosure comprises a human κ light chain constant region. Preferably, the light chain constant region comprises the amino acid sequence of SEQ ID NO:12, or an amino acid sequence comprising at least one, two, or three, but not more than 20, 10, or 5 amino acid changes relative to the amino acid sequence of SEQ ID NO:12, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:12.

[0226] In some embodiments, the Ab unit of the ADC of this disclosure is a full-length antibody comprising a heavy chain constant region and a light chain constant region. In some embodiments, the Ab unit is a tetrameric structure having two light chains and two heavy chains. In still other embodiments, the Ab unit is an IgG antibody, particularly an IgG1 antibody.

[0227] In some preferred embodiments, the Ab unit of the ADC of this disclosure comprises a heavy chain and a light chain, wherein: the heavy chain comprises, or consists of, the amino acid sequence shown in SEQ ID NO:14, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it. In other preferred embodiments, the Ab unit of the ADC of this disclosure comprises a heavy chain and a light chain, wherein: the light chain comprises, or comprises, the amino acid sequence shown in SEQ ID NO:13, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0228] In some more preferred embodiments, the Ab unit of the ADC of this disclosure includes:

[0229] (a) A heavy chain containing the amino acid sequence of SEQ ID NO:14, and

[0230] (b) A light chain containing the amino acid sequence of SEQ ID NO:13.

[0231] Cancers that can be treated with this disclosed ADC targeting TROP2 include, but are not limited to, adenocarcinoma, squamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), colorectal cancer, gastric adenocarcinoma, esophageal cancer, hepatocellular carcinoma, ovarian epithelial cancer, breast cancer, metastatic breast cancer, triple-negative breast cancer (TNBC), prostate cancer, hormone-refractory prostate cancer, pancreatic ductal adenocarcinoma, head and neck cancer, renal cell carcinoma, bladder tumors, cervical cancer, endometrial cancer, uterine cancer, follicular thyroid cancer, and glioblastoma multiforme.

[0232] Ab unit targeting Claudin18.2

[0233] In a particularly preferred embodiment, the antibody-drug conjugates provided herein comprise an antibody or antigen-binding fragment (anti-Claudin18.2 antibody) that specifically binds to human Claudin18.2, i.e., the antibody partially and specifically targets the tumor-associated antigen Claudin18.2. Therefore, in some aspects, this disclosure provides antibody-drug conjugates (ADCs) comprising an antibody or antigen-binding fragment specifically binding to Claudin18.2 as the Ab unit of the ADC.

[0234] Claudin 18.2 (also abbreviated as CLDN18.2) is a tight junction membrane protein belonging to the Claudin family. The Claudin 18.2 sequence in humans and many other mammals can be found in UniProtKB. For example, the human Claudin 18.2 sequence is available in UniProtKB accession number P56856-2. While expression of this protein in healthy tissues is primarily confined to differentiated gastric mucosal epithelial cells, it exhibits aberrant overexpression in a range of malignancies, particularly digestive system malignancies. Therefore, Claudin 18.2 has been proposed as a promising target for the development of antibody-drug conjugate (ADC) cancer therapeutics.

[0235] In some embodiments, the antibody that specifically binds to human Claudin18.2 or an antibody fragment thereof (e.g., an antigen-binding fragment) may be selected from Zolbetuximab, Osemitamab (TST001), CMG901, ASKB589, ZL-1211, or an antibody fragment thereof, or other anti-human Claudin18.2 antibodies that recognize the same epitope or competitively bind to human Claudin18.2.

[0236] In some embodiments, exemplary antibodies that can be used for the ADC of this disclosure targeting human CLDN18.2 may be antibodies or antigen-binding fragments comprising all six CDR sequences of antibodies selected from the group consisting of: Zolbetuximab, Osemitamab (TST001), and CMG901.

[0237] In one embodiment, the antibody portion for the ADC of this disclosure comprises all six CDR sequences of Zolbetuximab. In another embodiment, the antibody portion for the ADC of this disclosure comprises the heavy chain variable region sequence and the light chain variable region sequence of Zolbetuximab. In yet another embodiment, the antibody portion for the ADC of this disclosure comprises the heavy chain sequence and the light chain sequence of Zolbetuximab.

[0238] In some embodiments, the Ab unit of the ADC of this disclosure comprises three CDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:33 and three CDRs of the light chain variable region (VL) sequence of SEQ ID NO:32, and preferably, wherein the CDRs are defined according to Kabat or IMGT or a combination thereof.

[0239] In some embodiments, the Ab unit of the ADC of this disclosure includes three heavy chain complementarity determination regions (HCDRs) and three light chain complementarity determination regions (LCDRs), wherein:

[0240] According to Kabat's definition, HCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:29, HCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:30, HCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:31, LCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:26, LCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:27, and LCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:28.

[0241] In one embodiment, the Ab unit of the ADC of this disclosure includes a heavy chain variable region, wherein the heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO:33, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0242] In one embodiment, the Ab unit of the ADC of this disclosure includes a light chain variable region, wherein the light chain variable region comprises: the amino acid sequence shown in SEQ ID NO:32, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0243] In some preferred embodiments, the Ab unit of the ADC of this disclosure includes a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes the amino acid sequence described in SEQ ID NO:33, and wherein the light chain variable region includes the amino acid sequence shown in SEQ ID NO:32.

[0244] In some embodiments, the Ab unit of the ADC of this disclosure preferably further comprises a heavy chain constant region and / or a light chain constant region of the antibody. Preferably, the heavy chain constant region is a heavy chain constant region derived from human immunoglobulins. Preferably, the light chain constant region is a light chain constant region derived from human immunoglobulins. In some aspects, the heavy chain constant region contained in the Ab unit can be any isotype or subtype, such as the heavy chain constant region of IgG1, IgG2, IgG3, or IgG4 isotypes, and preferably the IgG1, IgG2, or IgG4 heavy chain constant region, especially the human IgG1 heavy chain constant region. In still other aspects, the light chain constant region contained in the Ab unit can be a κ light chain constant region or a λ light chain constant region, especially the human κ light chain constant region.

[0245] In some embodiments, the Ab unit of the ADC of this disclosure comprises a human IgG1 heavy chain constant region. Preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:34, or an amino acid sequence comprising at least one, two, or three, but not more than 20, 10, or 5 amino acid changes relative to the amino acid sequence of SEQ ID NO:34, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:34.

[0246] In some embodiments, the Ab unit of the ADC of this disclosure comprises a human κ light chain constant region. Preferably, the light chain constant region comprises the amino acid sequence of SEQ ID NO:12, or an amino acid sequence comprising at least one, two, or three, but not more than 20, 10, or 5 amino acid changes relative to the amino acid sequence of SEQ ID NO:12, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:12.

[0247] In some embodiments, the Ab unit of the ADC of this disclosure is a full-length antibody comprising a heavy chain constant region and a light chain constant region. In some embodiments, the Ab unit is a tetrameric structure having two light chains and two heavy chains. In still other embodiments, the Ab unit is an IgG antibody, particularly an IgG1 antibody.

[0248] In some preferred embodiments, the Ab unit of the ADC of this disclosure comprises a heavy chain and a light chain, wherein: the heavy chain comprises, or consists of, the amino acid sequence shown in SEQ ID NO:25, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it. In other preferred embodiments, the Ab unit of the ADC of this disclosure comprises a heavy chain and a light chain, wherein: the light chain comprises, or consists of the amino acid sequence shown in SEQ ID NO:24, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0249] In some more preferred embodiments, the Ab unit of the ADC of this disclosure includes:

[0250] (a) A heavy chain containing the amino acid sequence of SEQ ID NO:25, and

[0251] (b) A light chain containing the amino acid sequence of SEQ ID NO:24.

[0252] Cancers that can be treated with the presently disclosed ADC targeting Claudin18.2 include, but are not limited to, various gastrointestinal cancers such as gastric cancer (GC), gastroesophageal junction (GEJ) cancer, esophageal cancer, and pancreatic cancer.

[0253] Ab units targeting EGFR

[0254] In a particularly preferred embodiment, the antibody-drug conjugates provided herein comprise an antibody or antigen-binding fragment (anti-EGFR antibody) that specifically binds to human EGFR, i.e., the antibody partially and specifically targets the tumor-associated antigen EGFR. Therefore, in some aspects, the present invention provides an antibody-drug conjugate (ADC) comprising an antibody that specifically binds to EGFR or an antigen-binding fragment thereof as the Ab unit of the ADC.

[0255] Epidermal growth factor receptor, abbreviated as EGFR in this article, is a member of the epidermal growth factor receptor (HER) family and is encoded by the c-erbB proto-oncogene (also known as HER-1 or Erb-B1). EGFR sequences in humans and many other mammals can be found in UniProtKB. For example, the human EGFR sequence is available in UniProtKB accession number P00533. EGFR is overexpressed in many solid tumors, including lung cancer, head and neck cancer, breast cancer, kidney cancer, gastric cancer, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer, and bladder cancer; and EGFR can induce tumor proliferation through homodimerization.

[0256] Various anti-EGFR monoclonal antibodies have been developed to bind to the extracellular domain of the receptor, thereby blocking receptor-ligand interaction or dimerization. These antibodies are all applicable to this invention. Furthermore, antibodies targeting human EGFR that can be used in the ADC of this invention can also be prepared using antibody preparation processes known in the art.

[0257] In some embodiments, the antibody targeting human EGFR used in the ADC of the present invention may be a monospecific antibody that binds to EGFR. In some embodiments, the antibody targeting human EGFR used in the ADC of the present invention may also be a multispecific antibody, especially a bispecific antibody, such as a bispecific antibody targeting EGFR and MET; or a bispecific antibody targeting MUC1 and EGFR.

[0258] In some embodiments, the anti-human EGFR antibody or its antibody fragment (e.g., antigen-binding fragment) used in the ADC of the present invention may be selected from cetuximab. ), panitumumab ), nimotuzumab, ), necitumuma depatuxizumab (ABT-806), NECITUMUMAB, IZALONTAMAB, BAFISONTAMAB, Petosemtamab, PIMURUTAMAB, FUTUXIMAB, MODOTUXIMAB (Zatuximab) or antibody fragments thereof, or other anti-human EGFR antibodies that recognize the same epitope or competitively bind to human EGFR.

[0259] In some embodiments, exemplary antibodies targeting human EGFR that can be used in the ADC of the present invention may be antibodies or antigen-binding fragments comprising all six CDR sequences of antibodies selected from the group consisting of: cetuximab, panitumumab, nimotuzumab, necitumuma, depatuxizumab, NECITUMUMAB, IZALONTAMAB, BAFISONTAMAB, Petosemtamab, PIMURUTAMAB, FUTUXIMAB, and MODOTUXIMAB.

[0260] In one embodiment, the antibody portion of the ADC of the present invention comprises all six CDR sequences of Cetuximab. In another embodiment, the antibody portion of the ADC of the present invention comprises the heavy chain variable region sequence and the light chain variable region sequence of Cetuximab. In yet another embodiment, the antibody portion of the ADC of the present invention comprises the heavy chain sequence and the light chain sequence of Cetuximab.

[0261] In some embodiments, the Ab unit of the ADC of the present invention comprises three CDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:44 and three CDRs of the light chain variable region (VL) sequence of SEQ ID NO:43, and preferably, wherein the CDRs are defined according to Kabat or IMGT or a combination thereof.

[0262] In some embodiments, the Ab unit of the ADC of the present invention includes three heavy chain complementarity determination regions (HCDRs) and three light chain complementarity determination regions (LCDRs), wherein:

[0263] According to Kabat's definition, HCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:40, HCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:41, HCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:42, LCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:37, LCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:38, and LCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:39.

[0264] In one embodiment, the Ab unit of the ADC of the present invention includes a heavy chain variable region, wherein the heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO:44, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0265] In one embodiment, the Ab unit of the ADC of the present invention includes a light chain variable region, wherein the light chain variable region comprises: the amino acid sequence shown in SEQ ID NO:43, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0266] In some preferred embodiments, the Ab unit of the ADC of the present invention includes a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes the amino acid sequence described in SEQ ID NO:44, and wherein the light chain variable region includes the amino acid sequence shown in SEQ ID NO:43.

[0267] In some embodiments, the Ab unit of the ADC of the present invention preferably further comprises a heavy chain constant region and / or a light chain constant region of an antibody. Preferably, the heavy chain constant region is a heavy chain constant region derived from human immunoglobulins. Preferably, the light chain constant region is a light chain constant region derived from human immunoglobulins. In some aspects, the heavy chain constant region contained in the Ab unit can be any isotype or subtype, such as the heavy chain constant region of IgG1, IgG2, IgG3, or IgG4 isotypes, and preferably the IgG1, IgG2, or IgG4 heavy chain constant region, especially the human IgG1 heavy chain constant region. In still other aspects, the light chain constant region contained in the Ab unit can be a κ light chain constant region or a λ light chain constant region, especially the human κ light chain constant region.

[0268] In some embodiments, the Ab unit of the ADC of the present invention comprises a human IgG1 heavy chain constant region. Preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:34, or an amino acid sequence comprising at least one, two, or three, but not more than 20, 10, or 5 amino acid changes relative to the amino acid sequence of SEQ ID NO:34, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:34.

[0269] In some embodiments, the Ab unit of the ADC of the present invention comprises a human κ light chain constant region. Preferably, the light chain constant region comprises the amino acid sequence of SEQ ID NO:12, or an amino acid sequence comprising at least one, two, or three, but not more than 20, 10, or 5 amino acid changes relative to the amino acid sequence of SEQ ID NO:12, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:12.

[0270] In some embodiments, the Ab unit of the ADC of the present invention is a full-length antibody comprising a heavy chain constant region and a light chain constant region. In some embodiments, the Ab unit has a tetrameric structure having two light chains and two heavy chains. In still other embodiments, the Ab unit is an IgG antibody, particularly an IgG1 antibody.

[0271] In some preferred embodiments, the Ab unit of the ADC of the present invention comprises a heavy chain and a light chain, wherein: the heavy chain comprises the amino acid sequence shown in SEQ ID NO:36, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it, or is composed of it. In other preferred embodiments, the Ab unit of the ADC of the present invention comprises a heavy chain and a light chain, wherein: the light chain comprises the amino acid sequence shown in SEQ ID NO:35, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0272] In some more preferred embodiments, the Ab unit of the ADC of the present invention comprises:

[0273] (a) A heavy chain containing the amino acid sequence of SEQ ID NO:36, and

[0274] (b) A light chain containing the amino acid sequence of SEQ ID NO:35.

[0275] Cancers that can be treated with the EGFR-targeting ADCs of this disclosure include, but are not limited to, various primary and metastatic solid tumors, such as lung cancer (e.g., lung adenocarcinoma, lung squamous cell carcinoma and non-small cell lung cancer), head and neck cancer (e.g., head and neck squamous cell carcinoma), nasopharyngeal carcinoma, esophageal cancer, biliary tract cancer, colon cancer, colorectal cancer, pancreatic cancer, gastric cancer, and glioblastoma.

[0276] Ab units targeting EGFR and MET

[0277] In a particularly preferred embodiment, the antibody-drug conjugates provided herein comprise antibodies or antigen-binding fragments (anti-EGFR / MET antibodies) that specifically bind to human EGFR and MET (also known as c-Met), i.e., the antibody partially and specifically targets tumor-associated antigens EGFR and MET. Therefore, in some aspects, this disclosure provides antibody-drug conjugates (ADCs) comprising antibodies or antigen-binding fragments thereof that specifically bind to EGFR and MET as the Ab unit of the ADC.

[0278] MET amplification or protein overexpression has been identified as a key mechanism of clinical resistance to EGFR inhibitors. Similarly, emerging evidence suggests that activation of the EGFR pathway may contribute to resistance to c-MET-targeting inhibitors. Furthermore, co-expression of cMet and EGFR has been observed in various cancers, including non-small cell lung cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell carcinoma, breast cancer, and esophageal-gastric cancer. Therefore, drug molecules based on multispecific antibodies (such as bispecific antibodies) targeting both EGFR and c-MET have been proposed as a promising therapeutic approach for EGFR / cMET single-positive and double-positive tumors.

[0279] In some implementations, antibodies or antibody fragments thereof (e.g., antigen-binding fragments) that specifically bind to human EGFR and MET are selected from: Amivantamab, AZD9592, Pamvatamig (MCLA-129), Bafisontamab (EMB01), and LY-3164530, or antibody fragments thereof or site-specific mutants thereof, or other anti-human EGFR and MET antibodies that recognize the same epitopes or competitively bind to human EGFR and MET. These antibodies can all promote endocytosis at the relevant targets and enter tumor cells for degradation, thus making them suitable drug delivery vehicles.

[0280] In some embodiments, exemplary antibodies targeting EGFR and MET that can be used in the ADC of this disclosure may be antibodies or antigen-binding fragments comprising all six CDR sequences specifically binding to EGFR and all six CDR sequences specifically binding to MET (preferably comprising anti-EGFR heavy / light chain variable region sequences and anti-MET heavy / light chain variable region sequences of antibodies selected from the group consisting of: Amivantamab, AZD9592, Pamvatamig (MCLA-129), Bafisontamab (EMB01), and LY-3164530.

[0281] In one embodiment, the antibody portion for the ADC of the present invention comprises all six CDR sequences of the anti-EGFR arm and all six CDR sequences of the anti-MET arm of etanercept. In another embodiment, the antibody portion for the ADC of the present invention comprises the heavy chain variable region sequence and the light chain variable region sequence of the anti-EGFR arm of etanercept, and the heavy chain variable region sequence and the light chain variable region sequence of the anti-MET arm of etanercept. In yet another embodiment, the antibody portion for the ADC of the present invention comprises the anti-EGFR heavy chain sequence and the light chain sequence of etanercept, and the anti-MET heavy chain sequence and the light chain sequence of etanercept.

[0282] In some embodiments, the Ab unit of the ADC of the present invention includes a first set of complementary determinant regions (CDRs) binding to EGFR and a second set of complementary determinant regions (CDRs) binding to MET, wherein the first set of CDRs includes three CDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:61 and three CDRs of the light chain variable region (VL) sequence of SEQ ID NO:62, and the second set of CDRs includes three CDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:63 and three CDRs of the light chain variable region (VL) sequence of SEQ ID NO:64. Preferably, the CDRs are defined according to Kabat or IMGT or a combination thereof.

[0283] In some embodiments, the Ab unit of the ADC of the present invention includes a first set of complementary determination regions that bind to EGFR and a second set of complementary determination regions that bind to MET, wherein:

[0284] The first set of complementarity-determining regions includes three heavy chain complementarity-determining regions (HCDRs) and three light chain complementarity-determining regions (LCDRs), wherein:

[0285] According to Kabat's definition, HCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:49, HCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:50, HCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:51, LCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:52, LCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:53, and LCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:54.

[0286] The second set of complementarity-determining regions includes three heavy chain complementarity-determining regions (HCDRs) and three light chain complementarity-determining regions (LCDRs), wherein:

[0287] According to Kabat's definition, HCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:55, HCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:56, HCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:57, LCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:58, LCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:59, and LCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:60.

[0288] In one embodiment, the Ab unit of the ADC of the present invention comprises a first heavy chain variable region and a first light chain variable region for binding EGFR, and a second heavy chain variable region and a second light chain variable region for binding MET. In some embodiments, the first heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO:61, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity therewith. In some embodiments, the first light chain variable region comprises: the amino acid sequence shown in SEQ ID NO:62, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity therewith. In some embodiments, the second heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO:63, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity therewith. In some embodiments, the second light chain variable region comprises: the amino acid sequence shown in SEQ ID NO:64, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0289] In some embodiments, the Ab unit of the ADC of the present invention includes a first heavy chain variable region and a first light chain variable region that bind EGFR, and a second heavy chain variable region and a second light chain variable region that bind MET, wherein:

[0290] The first heavy chain variable region comprises the amino acid sequence described in SEQ ID NO:61, and the first light chain variable region comprises the amino acid sequence shown in SEQ ID NO:62; and

[0291] The second heavy chain variable region contains the amino acid sequence described in SEQ ID NO:63, and the second light chain variable region contains the amino acid sequence shown in SEQ ID NO:64.

[0292] In some embodiments, the Ab unit of the ADC of this disclosure preferably further comprises a heavy chain constant region and / or a light chain constant region of the antibody. Preferably, the heavy chain constant region is a heavy chain constant region derived from human immunoglobulins. Preferably, the light chain constant region is a light chain constant region derived from human immunoglobulins. In some aspects, the heavy chain constant region contained in the Ab unit can be any isotype or subtype, such as the heavy chain constant region of IgG1, IgG2, IgG3, or IgG4 isotypes, and preferably the IgG1, IgG2, or IgG4 heavy chain constant region, especially the human IgG1 heavy chain constant region. In still other aspects, the light chain constant region contained in the Ab unit can be a κ light chain constant region or a λ light chain constant region, especially the human κ light chain constant region.

[0293] In some embodiments, the Ab unit of the ADC of this disclosure comprises a human IgG1 heavy chain constant region. Preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:65 or 66, or an amino acid sequence comprising at least one, two, or three, but not more than 20, 10, or 5 amino acid changes relative to the amino acid sequence of SEQ ID NO:65 or 66, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:65 or 66.

[0294] In some embodiments, the Ab unit of the ADC of this disclosure comprises a human κ light chain constant region. Preferably, the light chain constant region comprises the amino acid sequence of SEQ ID NO:12, or an amino acid sequence comprising at least one, two, or three, but not more than 20, 10, or 5 amino acid changes relative to the amino acid sequence of SEQ ID NO:12, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:12.

[0295] In some embodiments, the Ab unit of the ADC of this disclosure comprises or is composed of a first heavy chain, a first light chain, a second heavy chain, and a second light chain, wherein from the N-terminus to the C-terminus,

[0296] -The first heavy chain includes an anti-EGFR heavy chain variable region and a first heavy chain constant region;

[0297] -The first light chain includes an anti-EGFR light chain variable region and a first light chain constant region;

[0298] - The second heavy chain includes the MET-resistant heavy chain variable region and the second heavy chain constant region;

[0299] The second light chain comprises a variable region of the anti-MET light chain and a constant region of the second light chain.

[0300] In some embodiments, the first and second heavy chain constant regions are heavy chain constant regions as defined above, preferably human IgG1 constant regions; the first and second light chain constant regions are light chain constant regions as defined above, preferably human κ light chain constant regions. In some embodiments, the first heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:65, and the second heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:66. In some embodiments, the first and second light chain constant regions each comprise or consist of the amino acid sequence of SEQ ID NO:12.

[0301] In some embodiments, the Ab unit of the ADC of this disclosure is a full-length antibody comprising a heavy chain constant region and a light chain constant region. In some embodiments, the Ab unit is a tetrameric structure having two light chains and two heavy chains. In still other embodiments, the Ab unit is an IgG antibody, particularly an IgG1 antibody.

[0302] In some preferred embodiments, the Ab unit of the ADC of this disclosure comprises a first heavy chain, a first light chain, a second heavy chain, and a second light chain, wherein:

[0303] The first heavy chain comprises the amino acid sequence shown in SEQ ID NO:45, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it, or is composed of it; and the first light chain comprises the amino acid sequence shown in SEQ ID NO:46, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it;

[0304] The second heavy chain comprises the amino acid sequence shown in SEQ ID NO:47, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it, or is composed of it; and the second light chain comprises the amino acid sequence shown in SEQ ID NO:48, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0305] In some more preferred embodiments, the Ab unit of the ADC of this disclosure includes:

[0306] (a) An anti-EGFR heavy chain containing the amino acid sequence of SEQ ID NO:45 and an anti-EGFR light chain containing the amino acid sequence of SEQ ID NO:46, and

[0307] (b) The anti-MET heavy chain containing the amino acid sequence of SEQ ID NO:47 and the anti-MET light chain containing the amino acid sequence of SEQ ID NO:48.

[0308] Cancers that can be treated with the EGFR and MET-targeting ADCs of this disclosure are EGFR and / or MET-positive cancers, such as solid tumors and hematologic malignancies, including but not limited to: non-small cell lung cancer, breast cancer, lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, gastric cancer, prostate cancer, head and neck tumors, liver cancer, bladder cancer, melanoma, esophageal cancer, kidney tumors, thyroid cancer, cervical cancer, lymphoma, uterine cancer, skin tumors, colon cancer, sarcoma, leukemia, glioblastoma, etc.

[0309] Ab unit targeting Nectin4

[0310] In a particularly preferred embodiment, the antibody-drug conjugates provided herein comprise an antibody or antigen-binding fragment (anti-Nectin-4 antibody) that specifically binds to human Nectin-4, i.e., the antibody partially and specifically targets the tumor-associated antigen Nectin-4. Therefore, in some aspects, this disclosure provides an antibody-drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof that specifically binds to Nectin-4 as the Ab unit of the ADC.

[0311] Nectin-4 (Nectin cell adhesion molecule 4), also known as poliovirus receptor-associated (PRR) protein, is a type I transmembrane cell adhesion molecule belonging to the Nectin family. Nectin-4 forms physical connections between adjacent cells and is essential for intercellular communication, migration, and other important cellular processes. Nectin-4 protein is expressed at low levels in only a few normal adult tissues (including skin), but is abnormally highly expressed in tumor tissues. Cancers that overexpress Nectin4 include, for example, breast cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer, head and neck cancer, lung cancer, non-small cell lung cancer, melanoma, bladder cancer, thyroid cancer, as well as hepatocellular carcinoma and urothelial carcinoma.

[0312] In some implementations, the antibody that specifically binds to human Nectin-4 or its antibody fragment (e.g., antigen-binding fragment) may be selected from Enfortumab, LY4052031, 9MW2821, BAT8007, SBT6290 or its antibody fragment, or other anti-human Nectin4 antibodies that recognize the same epitope or competitively bind to human Nectin4.

[0313] In some embodiments, exemplary antibodies targeting human Nectin4 that can be used with the ADC of this disclosure may be antibodies or antigen-binding fragments comprising all six CDR sequences of antibodies selected from the group consisting of: Enfortumab, LY4052031, 9MW2821, BAT8007, and SBT6290.

[0314] In one embodiment, the antibody portion for the ADC of this disclosure comprises all six CDR sequences of Enfortumab. In another embodiment, the antibody portion for the ADC of this disclosure comprises the heavy chain variable region sequence and the light chain variable region sequence of Enfortumab. In yet another embodiment, the antibody portion for the ADC of this disclosure comprises the heavy chain sequence and the light chain sequence of Enfortumab.

[0315] In some embodiments, the Ab unit of the ADC of this disclosure comprises three CDRs of the heavy chain variable region (VH) sequence of SEQ ID NO:76 and three CDRs of the light chain variable region (VL) sequence of SEQ ID NO:75, and preferably, wherein the CDRs are defined according to Kabat or IMGT or a combination thereof.

[0316] In some embodiments, the Ab unit of the ADC of this disclosure includes three heavy chain complementarity determination regions (HCDRs) and three light chain complementarity determination regions (LCDRs), wherein:

[0317] According to Kabat's definition, HCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:72, HCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:73, HCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:74, LCDR1 contains or is composed of the amino acid sequence of SEQ ID NO:69, LCDR2 contains or is composed of the amino acid sequence of SEQ ID NO:70, and LCDR3 contains or is composed of the amino acid sequence of SEQ ID NO:71.

[0318] In one embodiment, the Ab unit of the ADC of this disclosure includes a heavy chain variable region, wherein the heavy chain variable region comprises: the amino acid sequence shown in SEQ ID NO:76, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0319] In one embodiment, the Ab unit of the ADC of this disclosure includes a light chain variable region, wherein the light chain variable region comprises: the amino acid sequence shown in SEQ ID NO:75, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0320] In some preferred embodiments, the Ab unit of the ADC of this disclosure includes a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes the amino acid sequence described in SEQ ID NO:76, and wherein the light chain variable region includes the amino acid sequence shown in SEQ ID NO:75.

[0321] In some embodiments, the Ab unit of the ADC of this disclosure preferably further comprises a heavy chain constant region and / or a light chain constant region of the antibody. Preferably, the heavy chain constant region is a heavy chain constant region derived from human immunoglobulins. Preferably, the light chain constant region is a light chain constant region derived from human immunoglobulins. In some aspects, the heavy chain constant region contained in the Ab unit can be any isotype or subtype, such as the heavy chain constant region of IgG1, IgG2, IgG3, or IgG4 isotypes, and preferably the IgG1, IgG2, or IgG4 heavy chain constant region, especially the human IgG1 heavy chain constant region. In still other aspects, the light chain constant region contained in the Ab unit can be a κ light chain constant region or a λ light chain constant region, especially the human κ light chain constant region.

[0322] In some embodiments, the Ab unit of the ADC of this disclosure comprises a human IgG1 heavy chain constant region. Preferably, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO:23, or an amino acid sequence comprising at least one, two, or three, but not more than 20, 10, or 5 amino acid changes relative to the amino acid sequence of SEQ ID NO:23, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:23.

[0323] In some embodiments, the Ab unit of the ADC of this disclosure comprises a human κ light chain constant region. Preferably, the light chain constant region comprises the amino acid sequence of SEQ ID NO:12, or an amino acid sequence comprising at least one, two, or three, but not more than 20, 10, or 5 amino acid changes relative to the amino acid sequence of SEQ ID NO:12, or a sequence having at least 95-99% identity with the amino acid sequence of SEQ ID NO:12.

[0324] In some embodiments, the Ab unit of the ADC of this disclosure is a full-length antibody comprising a heavy chain constant region and a light chain constant region. In some embodiments, the Ab unit is a tetrameric structure having two light chains and two heavy chains. In still other embodiments, the Ab unit is an IgG antibody, particularly an IgG1 antibody.

[0325] In some preferred embodiments, the Ab unit of the ADC of this disclosure comprises a heavy chain and a light chain, wherein: the heavy chain comprises, or consists of, the amino acid sequence shown in SEQ ID NO:68, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it. In other preferred embodiments, the Ab unit of the ADC of this disclosure comprises a heavy chain and a light chain, wherein: the light chain comprises, or consists of the amino acid sequence shown in SEQ ID NO:67, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0326] In some more preferred embodiments, the Ab unit of the ADC of this disclosure includes:

[0327] (a) A heavy chain containing the amino acid sequence of SEQ ID NO:68, and

[0328] (b) A light chain containing the amino acid sequence of SEQ ID NO:67.

[0329] Cancers that can be treated with the Nectin-4-targeting ADC of this disclosure are Nectin4-positive cancers, including but not limited to breast cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer, head and neck cancer, lung cancer, non-small cell lung cancer, melanoma, bladder cancer, thyroid cancer, as well as hepatocellular carcinoma and urothelial carcinoma.

[0330] Drug P unit

[0331] The drug P unit of antibody-drug conjugates is also referred to as the payload of ADC drugs in this paper.

[0332] In some embodiments, the drug P unit that can be used in the ADC of this disclosure is a KRas mutation inhibitor, including but not limited to G12C mutation, G12D mutation, G12V mutation, G12A mutation, G12R mutation, G12S mutation, and G13D mutation inhibitors. In some embodiments, the drug P unit that can be used in the ADC of this disclosure is one of the KRas mutation inhibitors described in the applicant's previously completed and filed PCT application PCT / CN2023 / 122129, and more specifically, a KRas mutation inhibitor as defined herein.

[0333] In other embodiments, the drug P unit that can be used in the ADC of this disclosure is a pan-Ras inhibitor that can inhibit almost all Ras subtypes, regardless of mutation status, such as some drug P units implemented or exemplified below in this disclosure, including but not limited to P8, P9, P12, P13, P16-23, P25-46, etc.

[0334] Implementation Scheme 1: The drug P unit that can be used in the ADC of this disclosure is specifically a compound of formula (I), its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates.

[0335] in:

[0336] M is selected from N or C-R1;

[0337] M' is selected from N or C-R1';

[0338] R1 and R1' are each independently selected from H, halogens, CN, or -C arbitrarily substituted with halogens. 1-6 Alkyl groups and optionally halogenated -OC 1-6 alkyl;

[0339] R a Selected from H, halogens, CN, and -C optionally substituted with halogens. 1-6 Alkyl groups, optionally halogenated -C 2-6 Alkyne groups and -OC groups optionally substituted with halogens or deuterium1-6 alkyl;

[0340] R b and R c Together with the N connected to them, they form Where X is selected from CH2, N, and O;

[0341] Alternatively, the bond fusion between X and adjacent ring carbon atoms forms a 5-6 membered heteroaromatic ring comprising one to two heteroatoms selected from N, O, and S, which is bounded by -C 1-6 Alkylene-OC 1-6 Alkyl substitution, and additionally selected from -C(O)NH2, -C(O)NHC 1-6 Alkyl groups and -C(O)N(C) 1-6 Substitution of alkyl groups;

[0342] R2 and R2' are each independently selected from H, OH, or optionally halogenated -C. 1-6 Alkyl groups; or R2 and R2' attached to non-adjacent ring carbon atoms together to form an intracyclic bridge -(CH2). 1-2 - or -CH=CH-; or R2 and R2' attached to the same ring carbon atom together with the ring carbon atom to which they are attached to form a 4-6 membered spirocycloalkyl group or a 4-6 membered spiroheterocycloalkyl group containing one or two heteroatoms selected from N and O;

[0343] Ar selected

[0344] R3 is selected from H, -NH2, and -NHC. 1-6 Alkyl, -N(C) 1-6 alkyl)2 and -OC 1-6 alkyl;

[0345] R4 is selected from -CN, halogen, -NO2, or -C optionally substituted with a halogen. 2-6 Alkyne group and -C optionally substituted with halogen 1-6 alkyl;

[0346] R5 is selected from H, -CN, halogens, -NO2, and halogen-substituted -C. 1-6 alkyl;

[0347] R6 is selected from H, halogens, CN, and -C. 1-6 Alkyl and -C 2-6 The alkynyl group, in which -C 1-6 Alkyl and -C 2-6 Each alkynyl group can be independently and optionally substituted with a halogen;

[0348] R7, R7', R8, and R8' are each independently selected from H, halogens, CN, -NO2, and -C optionally substituted with a halogen. 1-6 alkyl;

[0349] V and W are each independently selected from H, halogens, and -C. 1-6 Alkyl groups, OH, and NH₂;

[0350] Z is selected from O, N, and CH2;

[0351] R is Preferred

[0352] R9 and R 10 Each is independently selected from H, deuterium, and -C. 1-6 Alkyl groups and -(CH2) n -C 3-6 cycloalkyl, wherein -C 1-6 Alkyl and -C 3- Each of the six cycloalkyl groups is independently optionally coated with deuterium, halogen, or -OC. 1-6 Alkyl substitution, or R9 and R attached to the same carbon atom 10 Together with the carbon atoms they are attached to, they form C 3-4 cycloalkyl;

[0353] R 11 Selected from H, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 Alkyne group and -(CH2) n -C 3-6 cycloalkyl, wherein C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3-6 Each cycloalkyl group is independently and optionally coated with deuterium, halogen, CN, or -OC. 1-6 Alkyl substitution;

[0354] R 12 Selected from H, halogens, -CN, -OH, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -OC 1-6 Alkyl, -OC 3-6 cycloalkyl, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 Alkyne group, -(CH2) n -C 3-6 Cycloalkyl and =C(R) d )2, where R d Each is independently selected from H, halogens, and -C that is optionally halogenated. 1-6 Alkyl groups, wherein each C10 ... 1-6 Alkyl, -C 2-6alkenyl, -C 2-6 alkynyl or C 3-6 Each cycloalkyl group is independently and optionally halogenated, CN- or -OC-. 1-6 Alkyl substitution;

[0355] R 13 Selected from H, -C 1-6 Alkyl groups and -(CH2) n -C 3-6 cycloalkyl, wherein -C 1-6 Alkyl and -C 3-6 Each cycloalkyl group is independently and optionally halogenated or -OC. 1-6 Alkyl substitution;

[0356] k is an integer selected from 0 or 1.

[0357] m is selected from integers between 0 and 6; and

[0358] n is an integer selected from 0 to 2;

[0359] Therefore, equation (I) can be specifically expressed as:

[0360] In one specific implementation, R in equation (I) b and R c Together with the N connected to them, they form X is selected from CH2, N, and O.

[0361] Implementation scheme 1.1: The compound of formula (I) of implementation scheme 1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein M is C-R1.

[0362] Implementation scheme 1.1.1: The compound of formula (I) of implementation scheme 1.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R1 is H.

[0363] Implementation scheme 1.1.2: The compound of formula (I) of implementation scheme 1.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R1 is a halogen, such as F or Cl.

[0364] Implementation scheme 1.1.3: Compound of formula (I) of implementation scheme 1.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R1 is CN.

[0365] Implementation Scheme 1.1.4: Compound of Formula (I) of Implementation Scheme 1.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R1 is optionally a -C substituted with a halogen. 1-6 Alkyl groups, preferably -C substituted with halogens. 1-3 Alkyl groups, more preferably -C substituted with 1-3 halogens. 1-3 Alkyl groups, preferably -C substituted with 1-3 F atoms. 1- 3 alkyl groups, such as -CF3; Examples of R1 include, but are not limited to, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5.

[0366] Implementation Scheme 1.1.5: Compound of Formula (I) of Implementation Scheme 1.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R1 is optionally halogenated -OC 1-6 Alkyl groups, preferably -OC groups optionally substituted with halogens. 1-3 Alkyl groups, such as -OC 1-3 Alkyl groups, such as -OCH3 and -OCH2CH3.

[0367] Implementation Scheme 1.1.6: Compound of Formula (I) of Implementation Scheme 1.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R1 is selected from halogens and optionally halogen-substituted -C. 1-6 Alkyl groups, preferably halogenated and halogenated -C groups. 1-3 Alkyl groups, such as F, Cl, and -CF3.

[0368] Implementation Scheme 1.1.7: Compound of formula (I) of any one of Implementation Schemes 1.1 to 1.1.6, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R a For H.

[0369] Implementation Scheme 1.1.8: Compound of formula (I) of any one of Implementation Schemes 1.1 to 1.1.6, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R a It can be CN or a halogen, such as F or Cl.

[0370] Implementation Scheme 1.1.9: Compound of formula (I) of any one of Implementation Schemes 1.1 to 1.1.6, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R a -C can be arbitrarily substituted with halogens 1-6 Alkyl groups, as generally or specifically defined in embodiment 1.1.4.

[0371] Implementation Scheme 1.1.10: Compound of formula (I) of any one of Implementation Schemes 1.1 to 1.1.6, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R a -C can be arbitrarily substituted with halogens 2-6 Alkyne group, preferably -C substituted with halogen. 2-4 alkynyl group, more preferably -C 2-4 alkynyl groups, such as but not limited to

[0372] Implementation Scheme 1.1.11: Compound of formula (I) of any one of Implementation Schemes 1.1 to 1.1.6, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R a -OC can be optionally replaced by halogen or deuterium. 1-6 Alkyl groups, preferably -OC groups optionally substituted with halogen or deuterium. 1-3 Alkyl groups, more preferably -OC groups optionally substituted with deuterium. 1-3 Alkyl groups, such as -OCH3, -OCD3, -OCH2CH3, with -OCH3 being the most preferred.

[0373] Implementation scheme 1.1.12: Compound of formula (I) of any one of implementation schemes 1.1 to 1.1.11, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein M' is N.

[0374] Implementation scheme 1.1.13: Compound of formula (I) of any one of implementation schemes 1.1 to 1.1.11, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein M' is C-R1'.

[0375] Implementation Scheme 1.1.14: The compound of formula (I) of Implementation Scheme 1.1.13, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R1' is selected from halogens, such as F, Cl, preferably F.

[0376] Implementation scheme 1.1.15: Compound of formula (I) of implementation scheme 1.1.13, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R1' is CN.

[0377] Implementation Scheme 1.1.16: Compound of Formula (I) of Implementation Scheme 1.1.13, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R1' is selected from -C optionally substituted with halogen. 1-6 Alkyl groups and optionally halogenated -OC 1-6 Alkyl groups, each as generally or specifically defined in embodiments 1.1.4 and 1.1.5.

[0378] Implementation scheme 1.2: Compound of formula (I) of implementation scheme 1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein M is N.

[0379] Implementation Scheme 1.2.1: Compound of formula (I) of Implementation Scheme 1.2, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R a For H.

[0380] Implementation Scheme 1.2.2: Compound of formula (I) of Implementation Scheme 1.2, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R a For CN, or R a Halogens, such as F and Cl.

[0381] Implementation Scheme 1.2.3: Compound of formula (I) of Implementation Scheme 1.2, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R a -C can be arbitrarily substituted with halogens 1-6 Alkyl groups, as generally or specifically defined in embodiment 1.1.4.

[0382] Implementation Scheme 1.2.4: Compound of formula (I) of Implementation Scheme 1.2, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R a -C can be arbitrarily substituted with halogens 2-6 Alkyne group, preferably -C substituted with halogen. 2-4 alkynyl group, more preferably -C 2-4 alkynyl groups, such as but not limited to

[0383] Implementation Scheme 1.2.5: Compound of Formula (I) of Implementation Scheme 1.2, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R a -OC can be optionally replaced by halogen or deuterium. 1-6 Alkyl groups, preferably -OC groups optionally substituted with halogen or deuterium. 1-3 Alkyl groups, more preferably -OC groups optionally substituted with deuterium. 1-3 Alkyl groups, such as -OCH3, -OCD3, -OCH2CH3, with -OCH3 being the most preferred.

[0384] Implementation scheme 1.2.6: Compound of formula (I) of any one of implementation schemes 1.2 to 1.2.5, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein M' is N.

[0385] Implementation scheme 1.2.7: Compound of formula (I) of any one of implementation schemes 1.2 to 1.2.5, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein M' is C-R1'.

[0386] Implementation Scheme 1.2.8: The compound of formula (I) of Implementation Scheme 1.2.7, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R1' is selected from halogens, such as F, Cl, preferably F.

[0387] Implementation scheme 1.2.9: Compound of formula (I) of implementation scheme 1.2.7, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R1' is CN.

[0388] Implementation Scheme 1.2.10: Compound of formula (I) of Implementation Scheme 1.2.7, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R1' is selected from -C optionally substituted with halogen. 1-6 Alkyl groups and optionally halogenated -OC 1-6 Alkyl groups, each as generally or specifically defined in embodiments 1.1.4 and 1.1.5.

[0389] Implementation Scheme 1.3: Compound of Formula (I) of Implementation Scheme 1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein the structural fragments are included. For example, Specifically, M is C-R1, where R1 is selected from halogens (preferably F or Cl) or optionally -C substituted with halogens. 1-6 Alkyl groups (preferably halogen-substituted -C) 1-3Alkyl group, more preferably -CF3), R a The halogen is H, and M' is C-R1' and R1' is a halogen, preferably F; or M is N, R a Selected from H, -C 2-6 alkynyl group (preferably -C) 2-4 Alkyne groups, more preferably -C≡CH) and -OC 1-6 Alkyl groups (preferably optionally deuterated -OC) 1-3 Alkyl group, more preferably -OCH3, -OCD3, -OCH2CH3), and M' is C-R1' and R1' is a halogen, preferably F; specific examples include, but are not limited to:

[0390] Implementation Scheme 2.1: A compound of formula (I) of any one of Implementation Schemes 1 to 1.3, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein Ar is

[0391] Implementation Scheme 2.1.1: Compound of formula (I) of Implementation Scheme 2.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R3 is H; or R3 is selected from -NH2, -NHC 1-6 Alkyl and N(C) 1- 6-alkyl)2, preferably selected from -NH2, -NHC 1-3 Alkyl and N(C) 1-3 Alkyl)2, with -NH2 being the most preferred.

[0392] Implementation Scheme 2.1.2: Compound of Formula (I) of Implementation Scheme 2.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R3 is -OC 1-6 Alkyl group, preferably -OC 1-3 Alkyl groups, such as -OCH3 and -OCH2CH3.

[0393] Implementation scheme 2.1.3: Compound of formula (I) of any one of implementation schemes 2.1 to 2.1.2, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R4 is CN.

[0394] Implementation Scheme 2.1.4: Compound of formula (I) of any one of Implementation Schemes 2.1 to 2.1.2, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R4 is a halogen selected from F, Cl, Br, I; or R4 is NO2.

[0395] Implementation Scheme 2.1.5: A compound of formula (I) of any one of Implementation Schemes 2.1 to 2.1.2, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R4 is optionally a -C substituted with a halogen. 2-6 Alkyne group, preferably -C substituted with halogen. 2-4 alkynyl groups, such as but not limited to

[0396] Implementation Scheme 2.1.6: A compound of formula (I) of any one of Implementation Schemes 2.1 to 2.1.2, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R4 is optionally a -C substituted with a halogen. 1-6 Alkyl groups, preferably -C substituted with halogens. 1-3 Alkyl groups, such as but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5.

[0397] Implementation Scheme 2.1.7: The compound of formula (I) of any one of Implementation Schemes 2.1 to 2.1.6, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R7 and R7' are each H; or R7 and R7' are each halogens, preferably F.

[0398] Implementation Scheme 2.1.8: The compound of formula (I) of any one of Implementation Schemes 2.1 to 2.1.6, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein one of R7 and R7' is H, and the other is selected from halogens, CN and NO2, wherein the halogen is preferably F; for example, R7 is H and R7' is halogen, preferably F, or R7' is H and R7 is halogen, preferably F.

[0399] Implementation Scheme 2.1.9: A compound of formula (I) of any one of Implementation Schemes 2.1 to 2.1.6, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein one of R7 and R7' is H, and the other is selected from -C optionally substituted with a halogen. 1-6 Alkyl groups, preferably -C substituted with halogens. 1-3Alkyl groups, such as but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5.

[0400] Implementation Scheme 2.1.10: A compound of formula (I) of any one of Implementation Schemes 2.1 to 2.1.6, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein one of R7 and R7' is selected from halogens, -NO2, CN and optionally halogen-substituted -C. 1-6 Alkyl group, another selected from -C substituted with halogen. 1-6 Alkyl group, wherein the -C is optionally substituted with a halogen. 1-6 The alkyl group is preferably -C that has been optionally substituted with a halogen. 1-3 Alkyl groups, as specifically exemplified in embodiment 2.1.9.

[0401] Implementation scheme 2.1.11: Compound of formula (I) of any one of implementation schemes 2.1 to 2.1.10, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein V is H.

[0402] Implementation Scheme 2.1.12: Compound of formula (I) of any one of Implementation Schemes 2.1 to 2.1.10, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein V is -OH or V is -NH2.

[0403] Implementation Scheme 2.1.13: A compound of formula (I) of any one of Implementation Schemes 2.1 to 2.1.10, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein V is a halogen; or V is -C 1-6 Alkyl group, preferably -C 1-3 alkyl.

[0404] Implementation Scheme 2.1.14: Compound of Formula (I) of Implementation Scheme 2.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein Ar is Where R3 is H or a halogen, and R4 is selected from halogens and -C. 2-6 alkynyl group (preferably -C) 2-4 ynyl group and -C 1-6 Alkyl (preferably -C) 1-3Alkyl groups, for example but not limited to

[0405] Implementation Scheme 2.1.15: Compound of Formula (I) of Implementation Scheme 2.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein Ar is R3 is selected from -NH2, -NHC 1-6 Alkyl and N(C) 1-6 Alkyl group 2, preferably selected from -NH2, -NHC 1-3 Alkyl and N(C) 1-3 alkyl group)2, most preferably -NH2; R4 is selected from -CN, halogen, -NO2 and -C substituted with halogen. 2-6 Alkyne group; V is selected from H, -C 1-6 Alkyl (preferably -C) 1-3 Alkyl groups and halogens, R7 and R7' each being H, or each being halogen, or one being H and the other being halogenated or halogen-substituted C. 1-6 Alkyl groups (preferably halogen-substituted -C) 1-3 Alkyl group, or one of which is halogen and the other is optionally halogenated C. 1-6 Alkyl groups (preferably halogen-substituted -C) 1-3 Alkyl group), wherein the halogen is preferably F;

[0406] Preferably, Ar is V is H, R7 and R7' are each H, or one of them is H and the other is a halogen, wherein the halogen is preferably F;

[0407] For example, but not limited to:

[0408] Implementation Scheme 2.1.16: Compound of formula (I) of any one of Implementation Schemes 2.1 to 2.1.15, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein... The areas marked with an asterisk may, at discretion (e.g., depending on the values ​​of R1 and R1'), exhibit axial chirality, including... or

[0409] Implementation Scheme 2.2: Compound of formula (I) of any one of Implementation Schemes 1 to 1.3, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein Ar is

[0410] Implementation Scheme 2.2.1: Compound of formula (I) of Implementation Scheme 2.2, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R5 is H; or R5 is a halogen selected from F, Cl, Br, I; preferably R5 is a halogen, most preferably F; or R5 is NO2; or R5 is a halogen-substituted -C 1-3 alkyl.

[0411] Implementation scheme 2.2.2: The compound of formula (I) of implementation scheme 2.2 or 2.2.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R6 is H; or R6 is a halogen selected from F, Cl, Br, I.

[0412] Implementation Scheme 2.2.3: Compound of formula (I) of Implementation Scheme 2.2 or 2.2.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R6 is optionally a -C substituted with a halogen. 1-6 Alkyl groups, preferably -C substituted with halogens. 1-3 Alkyl, more preferably -C 1-3 Alkyl groups, such as but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2Cl, -CH2F, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5.

[0413] Implementation Scheme 2.2.4: Compound of formula (I) of Implementation Scheme 2.2 or 2.2.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R6 is optionally a -C substituted with a halogen. 2-6 Alkyne group, preferably -C substituted with halogen. 2-4 alkynyl group, more preferably -C 2-4 alkynyl groups, such as but not limited to Preferred

[0414] Implementation Scheme 2.2.5: The compound of formula (I) of any one of Implementation Schemes 2.2 to 2.2.4, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R8 and R8' are each H; or R8 and R8' are each halogens, preferably F.

[0415] Implementation Scheme 2.2.6: The compound of formula (I) of any one of Implementation Schemes 2.2 to 2.2.4, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein one of R8 and R8' is H, and the other is selected from halogens, CN and NO2, wherein the halogen is preferably F.

[0416] Implementation Scheme 2.2.7: A compound of formula (I) of any one of Implementation Schemes 2.2 to 2.2.4, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein one of R8 and R8' is H, and the other is selected from -C optionally substituted with a halogen. 1-6 Alkyl groups, preferably -C substituted with halogens. 1-3 Alkyl groups, as generally or specifically defined in embodiment 2.1.9.

[0417] Implementation Scheme 2.2.8: A compound of formula (I) of any one of Implementation Schemes 2.2 to 2.2.4, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein one of R8 and R8' is selected from H, halogens, -NO2, CN and optionally -C substituted with a halogen. 1-6 Alkyl group, another selected from -C substituted with halogen. 1-6 Alkyl groups, wherein the -C is optionally substituted with a halogen 1-6 The alkyl group is preferably -C that has been optionally substituted with a halogen. 1-3 Alkyl groups, as generally or specifically defined in embodiment 2.1.9.

[0418] Implementation scheme 2.2.9: Compound of formula (I) of any one of implementation schemes 2.2 to 2.2.8, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein W is -OH.

[0419] Implementation Scheme 2.2.10: Compound of formula (I) of any one of Implementation Schemes 2.2 to 2.2.8, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein W is -NH2.

[0420] Implementation Scheme 2.2.11: Compound of formula (I) of Implementation Scheme 2.2, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein Ar is Where R5 is H or a halogen, and R6 is selected from halogens and -C. 2-6 alkynyl and -C 1-6Alkyl; R8 and R8' are each H; or R8 and R8' are each halogen; or one of R8 and R8' is H and the other is selected from halogen, CN, and NO2; or one of R8 and R8' is H and the other is selected from -C which is optionally halogenated. 1-6 Alkyl group, or one of R8 and R8', is selected from H, halogen, -NO2, CN, and -C optionally substituted with a halogen. 1- 6-alkyl, another selected from -C substituted with halogen. 1-6 alkyl;

[0421] Preferably, Ar is R5 is a halogen, preferably F, and R6 is selected from -C. 2-6 alkynyl group (preferably -C) 2-4 alkynyl group), for example but not limited to

[0422] Implementation Scheme 2.2.12: Compound of formula (I) of any one of Implementation Schemes 2.2 to 2.2.11, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein... The asterisk (*) may have axial chirality as appropriate, as exemplified in the definition section above.

[0423] Implementation Scheme 3.1: Compounds of formula (I) of any one of Implementation Schemes 1 to 2.2.12, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R b and R c Together with the N connected to them, they form In this context, k is 0 and X is selected from CH2, N, and O, i.e., R b and R c Together with the N connected to them, they form or

[0424] k is 1 and X is selected from CH2, N and O, i.e. R b and R c Together with the N connected to them, they form or

[0425] Structural fragments for Preferred

[0426] Implementation Scheme 3.1.1: Compound of Formula (I) of Implementation Scheme 3.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R b and R c Together with the N connected to them, they form R2 and R2' are each independently selected from H, OH, and -C, which are optionally substituted with halogens. 1-6 Alkyl groups, preferably OH, and -C groups optionally substituted with halogens. 1-6 Alkyl groups, more preferably selected from OH and -C 1-3 Alkyl; or R2 and R2' attached to the same ring carbon atom together with the ring carbon atom to which they are attached to form a 4-6 membered spirocycloalkyl or a 4-6 membered spiroheterocycloalkyl containing one or two heteroatoms selected from N and O.

[0427] Implementation Scheme 3.1.1.1: The compound of formula (I) of Implementation Scheme 3.1.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R2 and R2' can each independently be attached to any ring carbon atom, preferably More For example Furthermore, one of R2 and R2' is -OH and the other is -C. 1-6 Alkyl group, preferably -C 1-3 Alkyl, more preferably methyl; or R2 and R2' together with the cyclic carbon atoms to which they are attached form a 4-6 membered spirocycloalkyl or a 4-6 membered spiroheterocycloalkyl containing one or two heteroatoms selected from N and O;

[0428] Furthermore, where chemically feasible, the substituents R2 and R2' can each be stereoisomers, such as the R or S configuration;

[0429] Specific examples include, but are not limited to:

[0430] Implementation Scheme 3.1.2: Compound of Formula (I) of Implementation Scheme 3.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R b and R c Together with the N connected to them, they form R2 and R2', which are attached to non-adjacent ring carbon atoms, together form intra-ring bridges -CH2-, -CH2CH2-, or -CH=CH-.

[0431] Specific examples include Preferred

[0432] Implementation Scheme 4.1: The compound of formula (I) of any one of Implementation Schemes 1 to 3.1.2, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein Z is O; or Z is N; or Z is CH2; preferably Z is O.

[0433] Implementation Scheme 5.1: A compound of formula (I) of any one of Implementation Schemes 1 to 4.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R is More preferably

[0434] Implementation Scheme 5.1.1: Compound of formula (I) of any one of Implementation Schemes 1 to 5.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R9 and R 10 All are H; or one or both of them are deuterium.

[0435] Implementation Scheme 5.1.1.1: Compound of formula (I) of any one of Implementation Schemes 1 to 5.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R9 and R 10 Each is independently selected from H and -C. 1-6 Alkyl group, preferably -C 1-3 Alkyl groups, optionally coated with deuterium, halogen, or -OC 1-6 Alkyl substitution, for example, one of which is H and the other is a defined alkyl group, or both are defined alkyl groups; wherein the alkyl group is, for example, but not limited to, -CH3, -CD3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3.

[0436] Implementation Scheme 5.1.1.2: Compound of formula (I) of any one of Implementation Schemes 1 to 5.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R9 and R 10 Each is independently selected from H and -(CH2). n -C 3-6 cycloalkyl (preferably -C) 3-6 cycloalkyl), wherein C 3-6 cycloalkyl groups may be halogenated or C 1-6 Alkoxy substitution, for example, one of which is H and the other is a defined cycloalkyl group; for example, but not limited to

[0437] Implementation Scheme 5.1.1.3: Compound of formula (I) of any one of Implementation Schemes 1 to 5.1, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R9 and R are attached to the same carbon atom. 10 Together with the carbon atoms they are attached to, they form C 3-4 Cycloalkyl groups, such as cyclopropyl and cyclobutyl.

[0438] Implementation Scheme 5.1.2: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.1.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 11 For H.

[0439] Implementation Scheme 5.1.2.1: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.1.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 11 -C 1-6 Alkyl group, preferably -C 1-3 Alkyl groups, optionally substituted with deuterium, halogen, CN, or -C 1-6 Alkyl substitution, preferably optionally with deuterium, halogen or -C 1-3 Alkyl substitution; for example, but not limited to -CH3, -CD3, -CH2CH3, -CH2CD3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH(CH3)CH2-OC H3, -CH2CH(CH3)-OCH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH(CH3)F, -CH(CH3)CH2F, -CH2CH(CH3)F, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -CH2CN, -CH2CH2CN; more preferably, R 11 -C 1-3 Alkyl groups, wherein the hydrogen atoms are optionally replaced by one or more isotopes of deuterium, such as -CH3 or -CD3.

[0440] Implementation Scheme 5.1.2.2: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.1.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 11 -C 2-6alkenyl or -C 2-6 Alkyne group, preferably -C 2-4 alkenyl or -C 2-4 Alkyne group, optionally halogenated, CN or -C 1-6 Alkoxy substitution; for example, but not limited to vinyl, propenyl, ethynyl, each optionally halogenated or -C 1-6 Alkyl-substituted.

[0441] Implementation Scheme 5.1.2.3: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.1.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 11 -(CH2) n -C 3-6 Cycloalkyl, preferably -C 3-6 cycloalkyl, the -C 3-6 The cycloalkyl group may be optionally coated with deuterium, halogen, CN, or -C. 1-6 Alkyl substitution; for example, but not limited to

[0442] Implementation Scheme 5.1.3: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.2.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 12 For H.

[0443] Implementation Scheme 5.1.3.1: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.2.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 12 It is a halogen, such as F, Cl, Br, I, with F being preferred; or R 12 For CN.

[0444] Implementation Scheme 5.1.3.2: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.2.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 12 -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 alkyl)2, wherein -C 1-6 Alkyl group preferred -C 1-3 Alkyl groups, optionally halogenated, CN or -OC 1-6 Alkyl substitution.

[0445] Implementation Scheme 5.1.3.3: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.2.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R12 -OH; or R 12 -OC 1-6 Alkyl group, preferably -OC 1-3 Alkyl groups, wherein the alkyl group is optionally coated with halogen, CN or -OC 1-6 Alkyl substitution; for example, but not limited to -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)(CH3), -O-CH2CH2CH2CH3, -O-CH2CH(CH3)CH3, -OC(CH3)3, -O-CH2Cl, -O-CH2CN, -O-CH2F, -O-CHF2, -O-CF3, -O-CCl3, -O-CH2CH2F , -O-CH2CH2CN, -O-CH2CHF2, -O-CH2CF3, -O-CH2CH2CH2F, -O-CH2CH2CHF2, -O-CH2CH2CF3, -OC( CH3)2CF3, -O-C2F5, -O-CH2-OCH3, -O-CH2-O-CH2CH3, -O-CH2CH2-O-CH3, -O-CH2CH2-O-CH2CH3.

[0446] Implementation Scheme 5.1.3.4: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.2.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 12 -C 1-6 Alkyl group, preferably -C 1-3 Alkyl groups, optionally halogenated, CN or -OC 1-6 Alkyl substitution, preferably halogen substitution, such as but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH(CH3)CH2-OCH3, -CH2CH(CH3)-OCH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -CH2CN, -CH2CH2CN.

[0447] Implementation Scheme 5.1.3.5: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.2.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R12 -OC 3-6 cycloalkyl, wherein C 3- The 6-cycloalkyl group may be halogenated, CN- or -OC-treated. 1-6 Alkyl substitution; for example, but not limited to

[0448] Implementation Scheme 5.1.3.6: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.2.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 12 -(CH2) n -C 3-6 Cycloalkyl, preferably -C 3-6 cycloalkyl, the -C 3-6 The cycloalkyl group may be halogenated, CN- or -C-. 1-6 Alkoxy substitution; as exemplified in embodiment 5.1.2.3.

[0449] Implementation Scheme 5.1.3.7: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.2.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 12 -C 2-6 alkenyl or -C 2-6 Alkyne group, preferably -C 2-4 alkenyl or -C 2-4 Alkyne group, optionally halogenated, CN or -C 1-6 Alkoxy substitution; for example, but not limited to vinyl, propenyl, ethynyl, each optionally halogenated or -C 1-6 Alkyl-substituted.

[0450] Implementation Scheme 5.1.3.8: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.2.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 12 =C(R) d )2, where R d Each is independently selected from H, F, Cl, Br, I, or -C that is optionally substituted with a halogen. 1-6 Alkyl (preferably -C) 1-3 Alkyl groups; for example, but not limited to =CH2, =CF2, =CHF, =CCl2, =C(CH3)2, =C(CF3)2.

[0451] Implementation Scheme 5.1.3.9: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.2.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R12 Selected from -C that is arbitrarily substituted with halogen 1- 6-alkyl (preferably -C) 1-3 alkyl) and =C(R) d )2, where R d Each is independently selected from H and halogens (preferably F).

[0452] Implementation scheme 5.1.3.10: Compound of formula (I) of any one of implementation schemes 1 to 5.1.2.3, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein m is 0, 1 or 2, preferably 1.

[0453] Implementation Scheme 5.1.3.11: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.2.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 12 The attached ring carbon atoms may be chiral, having either an R or S configuration, depending on the circumstances.

[0454] Implementation Scheme 5.1.3.12: Compound of formula (I) of any one of Implementation Schemes 5.1.3.8 to 5.1.3.9, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 12 =C(R) d The double bond at 2 can have cis-trans isomers, including E-type and Z-type, with the E-type isomer being preferred.

[0455] Implementation Scheme 5.1.4: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.3.12, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 13 For H.

[0456] Implementation Scheme 5.1.4.1: Compound of formula (I) of any one of Implementation Schemes 1 to 5.1.3.12, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 13 For halogens, F is preferred.

[0457] Implementation Scheme 5.1.4.2: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.3.12, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 13 -C 1-6 Alkyl group, preferably -C 1-3 Alkyl groups, optionally halogenated or -OC 1-6Alkyl substitutions, such as but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH(CH3)CH2-OCH3, -CH2CH(CH3)-OCH3, -CH2F, -CH2Cl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5.

[0458] Implementation Scheme 5.1.4.3: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.3.12, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 13 -(CH2) n -C 3-6 cycloalkyl, wherein C 3-6 cycloalkyl groups may be halogenated or -OC 1-6 Alkyl substitution; for example, but not limited to

[0459] Implementation Scheme 5.1.4.4.: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.3.12, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R 13 -C 1-6 Alkyl group, preferably -C 1-3 Alkyl group, more preferably -CH3.

[0460] Implementation Scheme 5.2: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.4.4, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R is More preferably Among them, R9 and R 10 All are H, or one or both of them are deuterium; R 11 -C 1-3 Alkyl group, wherein the hydrogen atoms are optionally replaced by one or more isotopes of deuterium; R 12 Selected from -C that is arbitrarily substituted with halogen 1-6 Alkyl (preferably -C) 1-3 alkyl) and =C(R) d )2, where R dEach is independently selected from H and halogens (preferably F); R 13 -C 1-6 Alkyl (preferably -C) 1-3 Alkyl); m is 1 or 2, preferably 1;

[0461] Specifically, R is Where R 11 R 12 And m has the defined meaning, R 11 Examples include, but are not limited to, methyl, ethyl, isopropyl, -CD3, -CH2CD3; and / or R 12 Examples include, but are not limited to, fluoromethyl, difluoromethyl, methyl, fluoromethylene, difluoromethylene, and methylene.

[0462] Implementation Scheme 5.3: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1.4.4, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein R is Preferred Among them, R9 and R 10 All are H, or one or both of them are deuterium; R 11 -C 1-3 Alkyl group, wherein the hydrogen atoms are optionally replaced by one or more isotopes of deuterium; R 12 Selected from -C that is arbitrarily substituted with halogen 1-6 Alkyl (preferably -C) 1-3 alkyl) and =C(R) d )2, where R d Each is independently selected from H and halogens (preferably F); R 13 -C 1-6 Alkyl (preferably -C) 1-3 Alkyl); m is 1 or 2, preferably 1;

[0463] Specifically, R is Where R 11 R 12 And m has the defined meaning, R 11 Examples include, but are not limited to, methyl, ethyl, isopropyl, -CD3, -CH2CD3; and / or R 12 Examples include, but are not limited to, fluoromethyl, difluoromethyl, methyl, fluoromethylene, difluoromethylene, and methylene.

[0464] Implementation Scheme 5.4: Compounds of formula (I) of any one of Implementation Schemes 1 to 5.1, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein examples of R include, but are not limited to, those of the following:

[0465] Preferred

[0466] Implementation Scheme 6.1: Compounds of formula (I) of Implementation Scheme 1, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, having the sub-general formulas shown in Table 1 below:

[0467] Each substituent has the meaning as generally or specifically defined in the respective embodiments above, and also covers any combination of the meanings as generally or specifically defined in the embodiments of each substituent;

[0468] Preferably, wherein

[0469] When M is C-R1, R1 is selected from halogens (preferably F or Cl) or optionally from -C substituted with halogens. 1-6 Alkyl groups (preferably halogen-substituted -C) 1- 3 alkyl groups, more preferably -CF3), R a H is H, and M' is C-R1' and R1' is a halogen (preferably F);

[0470] When M is N, R a Selected from H, -C 2-6 alkynyl group (preferably -C) 2-4 Alkyne groups, more preferably -C≡CH) and -OC 1-6 Alkyl groups (preferably optionally deuterated -OC) 1-3 Alkyl group, more preferably -OCH3, -OCD3, -OCH2CH3), and M' is C-R1' and R1' is a halogen (preferably F);

[0471] R2 and R2 attached to non-adjacent ring carbon atoms ’ Together they form an inner ring bridge - (CH2) 1-2 -or -CH = CH-;

[0472] R3 is selected from -NH2, -NHC 1-6 Alkyl and N(C) 1-6 Alkyl group 2 (preferably selected from -NH2, -NHC) 1-3 Alkyl and N(C) 1-3 R4 is selected from -CN, halogens, -NO2, and halogen-substituted -C. 2-6 Alkyne group; V is selected from H, -C 1-6 Alkyl (preferably -C) 1-3Alkyl groups and halogens; R7 and R7' are each H, or each is a halogen, or one is H and the other is a halogen or a halogen-substituted C. 1-6 Alkyl groups (preferably halogen-substituted -C) 1-3 Alkyl), or one of which is halogen and the other is halogen-substituted C 1- 6-alkyl (preferably halogen-substituted -C) 1-3 Alkyl group), wherein the halogen is preferably F;

[0473] Preferably, R3 is -NH2, R4 is -CN, V is H, and R7 and R7' are each H, or one of them is H and the other is a halogen.

[0474] Element (preferably F);

[0475] R5 is H or a halogen (preferably F); R6 is selected from halogens and -C. 2-6 alkynyl group (preferably -C) 2-4 ynyl group and -C 1-6 Alkyl (preferably -C) 1-3 alkyl);

[0476] R8 and R8' are each H, or R8 and R8' are each halogens, or one of R8 and R8' is H and the other is selected from halogens, CN, and NO2, or one of R8 and R8' is H and the other is selected from -C substituted by an optional halogen. 1-6 Alkyl group, or one of R8 and R8', is selected from H, halogen, -NO2, CN, and -C optionally substituted with a halogen. 1-6 Alkyl group, another selected from -C substituted with halogen. 1-6 Alkyl group; W is OH;

[0477] R5 is preferably a halogen (preferably F), and R6 is selected from -C. 2-6 alkynyl group (preferably -C) 2-4 (alkynyl group), R8 and R8' are each H, W is

[0478] OH;

[0479] Z is selected from O, N, and CH2, with O being preferred;

[0480] R9 and R 10 All are H; or one or both of them are deuterium;

[0481] R 11 -C 1-6 Alkyl (preferably -C) 1-3 Alkyl group, wherein the hydrogen atoms are optionally replaced by one or more isotopes of deuterium;

[0482] R 12 Selected from -C that is arbitrarily substituted with halogen 1-6 Alkyl (preferably -C)1-3 alkyl) and =C(R) d )2, where R d Each is independently selected from H and halogens (preferably F);

[0483] m is 0, 1 or 2 (preferably 1 or 2, more preferably 1);

[0484] R 13 -C 1-6 Alkyl (preferably -C) 1-3 Alkyl group, more preferably -CH3).

[0485] Implementation Scheme 6.2: Compounds of formula (I) of Implementation Scheme 1, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, having the sub-formulas shown in Table 2 below:

[0486] Each substituent has the meaning as generally or specifically defined in the respective embodiments above, and also covers any combination of the meanings as generally or specifically defined in the embodiments of each substituent;

[0487] Preferably, wherein

[0488] When M is C-R1, R1 is selected from halogens (preferably F or Cl) or optionally from -C substituted with halogens. 1-6 Alkyl groups (preferably halogen-substituted -C) 1- 3 alkyl groups, more preferably -CF3), R a H is H, and M' is C-R1' and R1' is a halogen (preferably F);

[0489] When M is N, R a Selected from H, -C 2-6 alkynyl group (preferably -C) 2-4 Alkyne groups, more preferably -C≡CH) and -OC 1-6 Alkyl groups (preferably optionally deuterated -OC) 1-3 Alkyl group, more preferably -OCH3, -OCD3, -OCH2CH3), and M' is C-R1' and R1' is a halogen (preferably F);

[0490] Structural fragments Selected from Where X is selected from C, N, and O; one of R2 and R2' is -OH and the other is -C. 1-6 Alkyl groups, or R2 and R2' together with the cyclic carbon atoms to which they are attached, form 4-6 membered spirocycloalkyl groups or 4-6 membered spiroheterocycloalkyl groups containing one or two heteroatoms selected from N and O;

[0491] Preferred Selected from One of R2 and R2' is -OH and the other is -C. 1- 3 alkyl groups, preferably methyl, more preferably

[0492] R3 is selected from -NH2, -NHC 1-6 Alkyl and N(C) 1-6 Alkyl group 2 (preferably selected from -NH2, -NHC) 1-3 Alkyl and N(C) 1-3 R4 is selected from -CN, halogens, -NO2, and halogen-substituted -C. 2-6 Alkyne group; V is selected from H, -C 1-6 Alkyl (preferably -C) 1-3 Alkyl groups and halogens; R7 and R7' are each H, or each is a halogen, or one is H and the other is a halogen or a halogen-substituted C. 1-6 Alkyl groups (preferably halogen-substituted -C) 1-3 Alkyl), or one of which is halogen and the other is halogen-substituted C 1- 6-alkyl (preferably halogen-substituted -C) 1-3 Alkyl group), wherein the halogen is preferably F;

[0493] Preferably, R3 is -NH2, R4 is -CN, V is H, and R7 and R7' are each H, or one of them is H and the other is a halogen.

[0494] Element (preferably F);

[0495] R5 is H or a halogen (preferably F); R6 is selected from halogens and -C. 2-6 alkynyl group (preferably -C) 2-4 ynyl group and -C 1-6 Alkyl (preferably -C) 1-3 alkyl);

[0496] R8 and R8' are each H, or R8 and R8' are each halogens, or one of R8 and R8' is H and the other is selected from halogens, CN, and NO2, or one of R8 and R8' is H and the other is selected from -C substituted by an optional halogen. 1-6 Alkyl group, or one of R8 and R8', is selected from H, halogen, -NO2, CN, and -C optionally substituted with a halogen. 1-6 Alkyl group, another selected from -C substituted with halogen. 1-6 Alkyl group; W is OH;

[0497] R5 is preferably a halogen (preferably F), and R6 is selected from -C. 2-6 alkynyl group (preferably -C) 2-4 (alkynyl group), R8 and R8' are each H, and W is OH;

[0498] Z is selected from O, N, and CH2, with O being preferred;

[0499] R9 and R 10 All are H; or one or both of them are deuterium;

[0500] R 11 -C 1-6 Alkyl (preferably -C) 1-3 Alkyl group, wherein the hydrogen atoms are optionally replaced by one or more isotopes of deuterium;

[0501] R 12 Selected from -C that is arbitrarily substituted with halogen 1-6 Alkyl (preferably -C) 1-3 alkyl) and =C(R) d )2, where R d Each is independently selected from H and halogens (preferably F);

[0502] m is 0, 1 or 2 (preferably 1 or 2, more preferably 1);

[0503] R 13 -C 1-6 Alkyl (preferably -C) 1-3 Alkyl group, more preferably -CH3).

[0504] Implementation Scheme 6.3: Compounds of formula (I'), their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, having the sub-formulas shown in Table 2-1 below:

[0505] in

[0506] Among them, M, M', X, Z, V, W, R1, R1', R3, R4, R5, R6, R7, R7', R8, R8', R9, R 10 R 11 R 12 R 13 k, m, and n are defined as described above for the corresponding implementation schemes of the respective segments of compound (I); structural segments As defined above in any of embodiments 2.1 to 2.1.16 of formula (I) compounds;

[0507] Structural fragments As defined above in any of embodiments 2.2 to 2.2.12 of the compound of formula (I);

[0508] Structural fragments As defined above in any of embodiments 5.1 to 5.4 of the compound of formula (I);

[0509] Y is selected from -CH2-, -CH2CH2-, -CH2OCH2-, or does not exist;

[0510] R 14 and R 15 Each is independently selected from H and -C. 1-6 alkyl.

[0511] Implementation Scheme 6.3.1: The compound of formula (I') of Implementation Scheme 6.3, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein,

[0512] exist In the fragment, when M is C-R1, R1 is selected from halogens (preferably F or Cl) or optionally from -C substituted with halogens. 1-6 Alkyl groups (preferably halogen-substituted -C) 1-3 Alkyl group, more preferably -CF3), and M' is C-R1' and R1' is a halogen (preferably F); or when M is N, M' is C-R1' and R1' is a halogen (preferably F);

[0513] exist In the fragment, both M are C-R1, or one M is N and the other M is C-R1, and R1 is independently selected from H, halogen (preferably F), and halogen-substituted -C. 1-6 Alkyl groups (preferably one or more F-substituted -C) 1-3 Alkyl group, more preferably -CF3), preferably M at the ortho position of R3 is selected from N and C-R1 (preferably C-halogen, more preferably CF), and M at the ortho position of R6 is C-R1 (preferably C-halogen substituted -C). 1-3 Alkyl group, more preferably -C-CF3); R3 is selected from -NH2, -NHC 1-6 Alkyl and N(C) 1-6 Alkyl group 2 (preferably selected from -NH2, -NHC) 1-3 Alkyl and N(C) 1-3 R5 is alkyl group 2, more preferably -NH2; R6 is H or halogen (preferably F); R7 is selected from halogen (preferably Cl) and -C. 1-6 Alkyl (preferably -C) 1-3 alkyl);

[0514] exist In the fragment, R3 is selected from -NH2 and -NHC. 1-6 Alkyl and N(C) 1-6 Alkyl group 2 (preferably selected from -NH2, -NHC) 1-3 Alkyl and N(C) 1-3 R4 is selected from -CN, halogens, -NO2, and halogen-substituted -C. 2-6 Alkyne group (preferably CN); V is selected from H, -C1-6 Alkyl (preferably -C) 1-3 Alkyl groups and halogens; R7 and R7' are each H, or each is a halogen, or one is H and the other is a halogen or a halogen-substituted C. 1-6 Alkyl groups (preferably halogen-substituted -C) 1-3 Alkyl), or one of which is halogen and the other is halogen-substituted C 1-6 Alkyl groups (preferably halogen-substituted -C) 1-3 Alkyl group), wherein the halogen is preferably F;

[0515] Preferably, R3 is -NH2, R4 is -CN, V is H, and R7 and R7' are each H, or one of them is H and the other is a halogen (preferably F);

[0516] exist In the fragment, R5 is H or a halogen (preferably F); R6 is selected from halogens and -C. 2-6 alkynyl group (preferably -C) 2-4 ynyl group and -C 1- 6-alkyl (preferably -C) 1-3 Alkyl); R8 and R8' are each H, or R8 and R8' are each halogen, or one of R8 and R8' is H and the other is selected from halogen, CN, and NO2, or one of R8 and R8' is H and the other is selected from -C which is optionally halogenated. 1-6 Alkyl group, or one of R8 and R8', is selected from H, halogen, -NO2, CN, and -C optionally substituted with a halogen. 1-6 Alkyl group, another selected from -C substituted with halogen. 1-6 Alkyl group; W is OH;

[0517] R5 is preferably a halogen (preferably F), and R6 is selected from -C. 2-6 alkynyl group (preferably -C) 2-4 (alkynyl group), R8 and R8' are each H, W is

[0518] OH;

[0519] X is selected from O and NH, with O being preferred;

[0520] Y is selected from -CH2CH2- and does not exist;

[0521] Z is selected from O;

[0522] R9 and R 10 All are H; or one or both of them are deuterium;

[0523] R 11 -C 1-6 Alkyl (preferably -C) 1-3 Alkyl group, wherein the hydrogen atoms are optionally replaced by one or more isotopes of deuterium;

[0524] R 12 Selected from -C that is arbitrarily substituted with halogen 1-6 Alkyl (preferably -C) 1-3 alkyl) and =C(R) d )2, where R d Each is independently selected from H and halogens (preferably F);

[0525] m is 0, 1 or 2 (preferably 1 or 2, more preferably 1);

[0526] n and k are 0 or 1;

[0527] R 13 -C 1-6 Alkyl (preferably -C) 1-3 Alkyl groups, more preferably -CH3);

[0528] R 14 and R 15 H or -C 1-3 Alkyl, more preferably -CH3.

[0529] Implementation Scheme 6.3.2: Compounds of Implementation Schemes 6.3 to 6.3.1, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein structural fragments Specifically for For example Or specifically For example

[0530] Structural fragments Specifically for For example

[0531] Implementation Scheme 6.3.3: The compounds of Implementation Schemes 6.3 to 6.3.2, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein the compounds are linked to the linker unit L of the ADC molecule by means of -NH2, -NH- or -OH carried in their structure.

[0532] Implementation Scheme 6.4: Compounds of Implementation Schemes 6.1 to 6.3.3, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein the R fragment Selected from

[0533] Implementation Scheme 6.5: The compound of any one of Implementation Schemes 6.1 to 6.4, its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein the Ar moiety, i.e., the left-hand fragment, is chiral as appropriate, as shown below:

[0534] For example

[0535] For example

[0536] For example

[0537] Implementation Plan 7: A KRas mutation inhibitor compound selected from the following compounds, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates.

[0538] Or its pharmaceutically acceptable salts or solvates.

[0539] It should be noted that the KRas mutation inhibitor compounds defined above as applicable to the ADCs of this disclosure are obtained through their... The cyclic NH present in the fragment, and / or the OH present on the side chain naphthalene ring or benzothiophene ring, are bonded to the linker unit L of the ADC.

[0540] Implementation Plan 8: A Ras mutation inhibitor compound selected from the following compounds, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates.

[0541] In these compounds, each Ras mutation inhibitor compound is linked to the ADC linker unit L via -NH2, -NH-, N, or -OH in its structure; or is selected from the Ras inhibitor compounds disclosed in the following patents, with representative compounds as follows:

[0542] Ras protein degradation agent

[0543] Ras molecular glue

[0544] Tri- / Tetracyclic Ras inhibitors

[0545] Small molecule Ras inhibitors

[0546] Other types of small molecule Ras inhibitors

[0547] Each compound is connected to the ADC linker unit L through -NH2, -NH-, N or -OH in its structure.

[0548] It should be noted that the Ras mutation inhibitor compounds disclosed herein cover each of the above independent embodiments or specific embodiments, as well as embodiments consisting of any combination or sub-combination of the above embodiments or specific embodiments, and embodiments consisting of any combination of any of the above preferred or exemplary embodiments.

[0549] It should be noted that this disclosure covers ADC compounds formed by any of the above general, specific or preferred Ras mutation inhibitor compounds with the linker unit and antibody drug defined herein.

[0550] Connector unit L

[0551] In the ADCs described herein, Ras inhibitors, such as KRas mutant inhibitors, are linked to antibodies or antigen-binding fragments via linker units. The linker units link the Ras inhibitor, such as the KRas mutant inhibitor, to the antibody or antigen-binding fragment by forming a covalent bond with the Ras inhibitor, such as the KRas mutant inhibitor, at one location and a covalent bond with the antibody or antigen-binding fragment at another location. The linker units can be monovalent with respect to the Ras inhibitor, such as the KRas mutant inhibitor, such that they covalently link a single Ras inhibitor, such as the KRas mutant inhibitor, to a single site on the antibody or a fragment thereof, or they can be polyvalent with respect to the Ras inhibitor, such as the KRas mutant inhibitor, such that they covalently link more than one Ras inhibitor, such as the KRas mutant inhibitor, to a single site on the antibody or a fragment thereof. As used herein, the term "linker unit" is intended to include unconjugated, partially conjugated (i.e., conjugated only with a Ras inhibitor, such as the KRas mutant inhibitor, or only with an Ab), and fully conjugated (i.e., conjugated with both a Ras inhibitor, such as the KRas mutant inhibitor, and an Ab).

[0552] The number of Ras inhibitors, such as KRas mutation inhibitors, attached to an antibody or its antigen-binding fragment to an ADC can vary (referred to as the “drug-antibody ratio” or “DAR”) and will be limited by the number of available linker sites on the antibody or its antigen-binding fragment and the number of Ras inhibitors, such as KRas mutation inhibitors, attached to a single linker. In an ADC containing multiple Ras inhibitors, such as KRas mutation inhibitors, each Ras inhibitor, such as KRas mutation inhibitor, may be the same or different. An ADC with a DAR of 10 or even higher can be considered, provided that the ADC does not exhibit unacceptable levels of polymerization under the conditions of use and / or storage. In some embodiments, the ADC described herein may have a DAR in the range of about 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, or 1 to 4. In some embodiments, the ADC described herein may have a DAR in the range of about 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, or 2 to 4. In some specific embodiments, the DAR of the ADC may be about 1, 2, 3, or 4. In other specific embodiments, the DAR of the ADC can be about 5, 6, 7, or 8. In some specific embodiments, the DAR of the ADC can be about 1.

[0553] The linker unit L suitable for the ADC of this disclosure can be any linker capable of conjugating the drug of this disclosure to an antibody. Suitably, the inclusion of the linker should ensure adequate stability of the ADC of this disclosure in the circulatory system, prevent premature lysis in circulation that could trigger off-target toxicity, and provide rapid and efficient release of KRas mutation inhibitors at the target site (e.g., tumor cells or the tumor environment). For example, the linker unit can be stable to the extracellular environment and serum chemistry, or may include intentionally unstable linker units that can release Ras inhibitors, such as KRas mutation inhibitors, in the extracellular environment or tumor microenvironment.

[0554] In some embodiments, the linker unit includes bonds designed to release Ras inhibitors, such as KRas mutation inhibitors, after intracellular ADC internalization. In some specific embodiments, the linker unit includes bonds designed to be cleaved and / or dissolved or otherwise specifically or nonspecifically degraded intracellularly.

[0555] In some embodiments, the linker unit in the ADC of this disclosure (X) is a non-degradable linker. Examples of non-degradable linker units include, but are not limited to, thioether linkers, N-succinimide-4-(N-maleimidemethyl)cyclohexane-1-carboxylate (SMCC), and maleimide hexanoyl (MC). Typically, such linkers are more stable, and ADCs containing such linkers must be internalized by cells, where the antibody portion of the ADC is degraded by intracellular lysosomal proteases to release the active drug molecule.

[0556] In some further embodiments, the linker unit in the ADC of this disclosure (X) is a degradable linker unit containing one or more chemically or enzymatically degradable chemical bonds. Drug release from an ADC containing such a linker is triggered by the nature of the cleavage site in the linker. Therefore, the cleavage site of such a linker can be designed according to the characteristics of the target therapeutic site (e.g., tumor cell lysosomes and / or the tumor environment).

[0557] In some embodiments, the degradable linker unit contains a chemically unstable group that takes advantage of the differential properties between plasma and some cytoplasmic compartments, such as the acidic environment of endosomes or lysosomes or the high concentration of thiol groups (e.g., glutathione) in the cytosol; in some cases, the plasma stability of the linker containing the chemically unstable group can be increased or decreased by using substituents to change the steric hindrance near the group.

[0558] In some embodiments, the chemically unstable groups of the degradable linker units are acid-labile groups that can remain intact during the neutral pH cycle of the blood and hydrolyze to release Ras inhibitors, such as KRas mutation inhibitors, under acidic conditions, such as in acidic tumor environments or when internalized into endosomes (pH 5.0–6.5) and lysosomes (pH 4.5–5.0) cellular compartments. This pH-dependent release mechanism can be optimized by chemical modification to finely regulate the release of Ras inhibitors, such as KRas mutation inhibitors, for specific pH values. Examples of such acid-labile groups include hydrazones, hydrazides, acetals, orthoesters, or imine groups.

[0559] In some embodiments, the degradable linker unit contains a reducible group, such as a disulfide group. This group is reduced when the ADC is internalized into the cell, as the cytosol provides a more reducing environment (such as reduced glutathione), thereby releasing the drug. Tumor cells can be induced by hypoxia due to irregular blood flow, leading to increased reductase activity and elevated glutathione concentrations, which facilitates the selective release of the drug from the disulfide-containing linker within the tumor cells.

[0560] In some embodiments, the degradable linker unit is an enzyme-degradable linker unit and is more stable than chemically unstable linkers in plasma and extracellular environments. Such linkers can be peptide-based or include peptide regions, or are non-peptide linkers such as peptide mimics, or sugars, esters, and amides. Such linkers can be cleaved by tumor-specific enzymes, such as tumor-specific proteases that have increased abundance in tumors and / or tumor environments, including but not limited to lysosomal proteases such as cathepsins (e.g., cathepsin B), legumain, MMP-2 / 9, plasmin, esterases, amidases, glutathione, etc.

[0561] Typically, an enzyme-degradable linker unit can consist of a self-degrading linker, a cleavable linker, optionally a property-modifying unit, optionally a linker unit, and an antibody linker portion. The self-degrading linker connects the drug P to the cleavable linker, promoting the release of the active drug molecule from the rest of the ADC, such as p-aminobenzyl, p-hydroxybenzyl, p-aminobenzyloxyacyl, p-hydroxybenzyloxyacyl, etc.; the cleavable linker, under an enzyme-based release mechanism, will contain enzyme-recognizable peptides or peptide analogs, esters (e.g., carbamates, sulfates), amides, disulfide-containing moieties, sugars, etc.; the addition of the property-modifying unit may benefit the improvement of the ADC's properties, such as stability in blood circulation, ADC efficacy at the target site, and optimization of the ADC's hydrophilicity. For example, when the drug is highly hydrophobic, the addition of a PEG unit can be considered (but is not necessary) to optimize the ADC's hydrophilicity, such as reducing precipitation and aggregation; the antibody linker links the antibody or antigen-binding fragment targeting the antigen to the rest of the conjugate, and has functional groups that can form bonds with functional groups on the antibody.

[0562] On the one hand, the connector unit L in the ADC of this disclosure (X) has the structure of the following formula (II):

[0563] -JB(D 1 )-DE(D 1 )-G- (II),

[0564] in

[0565] J is a self-decomposing connector;

[0566] B is a cleavable linker, which is absent or selected from peptide residues of 2-8 amino acids, preferably dipeptides, tripeptides or tetrapeptides; amide bond fragments; carbamate fragments; thioether bond fragments;

[0567] D and D 1 Each is an independently selected property-regulating unit, which, when present, is selected from polyethylene glycol (PEG), hydrophilic peptides, cyclodextrin units, polyamines, polyamides, polysaccharides, dendritic polymers, and bifunctional hydrocarbon chains;

[0568] E is an optional connector unit;

[0569] G is the antibody linker that is linked to Ab.

[0570] Accordingly, the composition of the ADC disclosed herein can be represented as: [PJB(D 1 )-DE(D 1 )-G] q -Ab.

[0571] The following provides general, specific, or preferred embodiments for each possible component of the connector unit L. It should be noted that this disclosure covers connector units L obtained by any combination of the general, specific, or preferred embodiments of each component with the general, specific, or preferred embodiments of any other component.

[0572] Accordingly, this disclosure covers compounds, stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, which contain the linker unit L of this disclosure as a structural segment.

[0573] Accordingly, the present invention also covers compounds formed by conjugating the linker unit L of this disclosure with a Ras inhibitor as defined under the "Drug P Unit" of this disclosure, or stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof, as well as compounds comprising the structure of the linker unit L and the Ras inhibitor conjugated fragment as defined under the "Drug P Unit" of this disclosure, or stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates thereof.

[0574] Accordingly, this disclosure also covers ADC compounds obtained by any combination of the linker units obtained by the aforementioned combinations with general, specific, or preferred embodiments of the antibody and drug portions defined in this disclosure.

[0575] G-antibody linker

[0576] The function of an antibody linker is to link an antibody or antigen-binding fragment targeting an antigen to the rest of the conjugate. It has functional groups that can form bonds with functional groups on the antibody.

[0577] The G in the connector unit L of formula (II) of the ADC disclosed herein has the following structure:

[0578] -G1-G2-G3-,

[0579] in:

[0580] G1 represents a bonded atom from Ab, such as an S, N, or C atom;

[0581] G2 is selected from:

[0582] • 5-10 membered heterocyclic group, containing one or two heteroatoms selected from N, S and O, wherein the ring carbon atom is optionally oxidized;

[0583] ·

[0584] The left * indicates the connection point with G1, and the right * indicates the connection point with G1. Indicates the connection point with G3;

[0585] G3 is selected from -C 1-10 Alkylene -C(=O)-, -C 3-10 Ethyne-C(=O)-, -C 3-10 alkenyl-C(=O)-, -C 1-10 Heteroalkyl-C(=O)-, -C 1-10 Alkylene-C 6-10 aryl-C(=O)-, -C 6-10 Aspartic-C 1-10 Alkylene -C(=O)-, -C 1-10 Alkylene-C 3-8 Cycloalkylene-C(=O)-, -C 3-8 Cycloalkyl-C 1-10 Alkylene -C(=O)-, -C 1-10 Alkylene-C 3-8 heterocyclic groups -C(=O)-, -C 3-8 Heterocyclic-C 1-10 Alkylene-C(=O)-, wherein each group in G3 connected to -C(=O)- is optionally replaced by Bu, and G3 is connected to a linker unit E (if present) or a property-regulating unit D (if present, and E is absent) or a cleavable linker B (if neither E nor D is present) via its -C(=O)-, and the other end group is connected to G2.

[0586] In some embodiments, the groups in G3 attached to -C(=O)- are optionally replaced by the following Bu groups: H, deuterium, halogen, NO2, CN, -OR h -OR h -N(R) h )2、-COR h -CO2R h -C-(O)C(O)R h -C(O)CH2C(O)R h -S(O)R h -SO2R h C(O)N(R) h )2、-SO2N(Rh )2、-OC(O)R h -N(R) h SO2R h and -C optionally substituted with prostate groups 1-6 Alkyl, wherein R h H or -C optionally substituted with halogen 1-6 Alkyl groups, or two R atoms attached to the same N atom. h The groups and the nitrogen atoms they are attached to form 4-7 membered heterocyclic groups. Preferably, the substituents of G3 are aminoalkyl moieties, such as -(CH2). 1-6 NH2、-(CH2) 1-6 NHR h Or -(CH2) 1-6 N(R h )2, or two R atoms connected to the same N atom h The groups and the nitrogen atoms they are attached to form nitrogen heterocyclic butyl, pyrrolidinyl, or piperidinyl groups.

[0587] In other embodiments, the groups in G3 connected to -C(=O)- are optionally replaced by the Bu groups of formula (A): in,

[0588] T0 is -C 1-6 alkylene-;

[0589] T is selected from -C(R) a )2-、-O-、-NR a -or does not exist;

[0590] Q is selected from -CO-, -O-, -NR a -or does not exist;

[0591] U is included Hydrophilic peptides;

[0592] R a Selected from H or -C 1-6 Alkyl groups, preferably H or -CH3;

[0593] Subunit Selected from natural and non-natural amino acid residues;

[0594] p is an integer from 0 to 4, for example, 0-2, 1-2, 2-4;

[0595] t is an integer from 0 to 20, for example 0-8, 0-6, 0-4, 0-2, 1-20, 1-10, 2-10, 2-8, 2-6, 2-4, 4-14, 6-10, 6-12, 8-10, 8-14.

[0596] In some embodiments, the amino acid units of the hydrophilic peptide comprise repeating units of natural amino acids as defined herein, preferably selected from arginine, serine, threonine, tyrosine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, histidine, glycine, and tryptophan; in other embodiments, the hydrophilic peptide comprises repeating units of amino acids other than the 20 natural amino acids listed above as defined herein, such as ornithine (Orn), citrulline (Cit), and sarcosine (Sar); in still other embodiments, the hydrophilic peptide is a mixed hydrophilic peptide comprising the natural amino acids and the unconventional amino acids.

[0597] In some implementations, in subunits Preferably, R, R', and R'" are each independently H, -C1-6 alkyl, carboxyl, sulfonic acid, phosphate, amino, amide, quaternary ammonium, mercapto, or hydroxyl groups, or are groups containing hydrophilic groups such as carboxyl, sulfonic acid, phosphate, amino, amide, quaternary ammonium, mercapto, and / or hydroxyl groups, such as aryl or C 1-6 alkyl.

[0598] It should be noted that the context of this disclosure involves hydrophilic peptides in the definition of multiple structural fragments, and their definitions are all applicable to the definition given herein for fragment (A).

[0599] The various structural fragments of the ADC disclosed herein carry hydrophilic peptides, for example, but not limited to those linked via a carboxyl terminus. Or linked via an amino terminus Preferably linked via a carboxyl terminus Where R' and R” are residues carried by various amino acids listed in this article for hydrophilic peptides, R can be R a ;R a Selected from H or -C 1-6 Alkyl group, preferably H or -CH3, more preferably -CH3; preferably the segment shown in square brackets is polysarcosine, polyarginine, or polyglycine containing 4-14 units or 5-10 units, more preferably polysarcosine containing 4-12, 6-12, 4-10, or 5-10 units, for example...

[0600] In each structural segment of the ADC disclosed herein, the included Hydrophilic peptides can be Where R' and R” are residues carried by various amino acids listed in this article for hydrophilic peptides, R can be R a ;R a Selected from H or -C 1-6Alkyl group, preferably H or -CH3, more preferably -CH3; preferably, the fragment in square brackets is polysarcosine, polyarginine, or polyglycine containing 4-14 units or 5-10 units, more preferably polysarcosine containing 4-12, 6-12, 4-10, or 5-10 units, for example...

[0601] In each structural segment of the ADC disclosed herein, the included Hydrophilic peptides can be Where R' and R” are residues carried by various amino acids listed in this article for hydrophilic peptides, R can be R a ;R a Selected from H or -C 1-6 Alkyl group, preferably H or -CH3, more preferably -CH3; preferably, the segment in square brackets is polysarcosine, polyarginine, or polyglycine containing 4-14 units or 5-10 units, more preferably polysarcosine containing 4-12, 6-12, 4-10, or 5-10 units, for example...

[0602] In each structural segment of the ADC disclosed herein, the included Hydrophilic peptides can be Where R' and R” are residues carried by various amino acids listed in this article for hydrophilic peptides, R can be R a ;R a Selected from H or -C 1-6 Alkyl group, preferably H or -CH3, more preferably -CH3; preferably, the fragment in square brackets is polysarcosine, polyarginine, or polyglycine containing 4-14 units or 5-10 units, more preferably polysarcosine containing 4-12, 6-12, 4-10, or 5-10 units, for example...

[0603] In each structural segment of the ADC disclosed herein, the included Hydrophilic peptides can be composed of t subunits linked end-to-end by the amino group of glutamic acid and the terminal carboxyl group. Right now (U5), where R' and R” are residues carried by various amino acids listed in this article for hydrophilic peptides, and R can be R a Preferred -C 1-6 Alkyl, more preferably -CH3; R”' may be R a ;R a Selected from H or -C 1-6Alkyl group, preferably H or -CH3, more preferably -CH3; for example, preferably, the fragment in square brackets is polysarcosine, polyarginine, or polyglycine containing 4-14 units or 5-10 units, more preferably polysarcosine containing 4-12, 6-12, 4-10, or 5-10 units, for example

[0604] In some implementations, U is selected from (U1), (U2), (U3), (U4), and (U5), for example... Where R a Selected from H or -C 1- 6-alkyl, preferably -CH3, t as defined above, for example 4-12, 6-12, 4-10 or 5-10.

[0605] In some implementations, T0 is -C 1-4 Alkylene-, preferably -C 1-2 Alkylene, more preferably methylene.

[0606] In some implementation schemes, In the fragment, T is -O-, for example ), or T is -C(R) a )2-, for example ), or T is -NR a -,For example ), or T does not exist, for example

[0607] In some implementation schemes, In the fragment, T does not exist, p is 0-4, for example 0-2, and Q is -CO-, i.e. For example, but not limited to Furthermore, in such implementations, U is a hydrophilic peptide, such as... For example Specifically, for example

[0608] In some implementations, T0 is -C 1-4 Alkylene-, preferably -C 1-2 alkylene-, more preferably methylene, in In the fragment, T does not exist, p is 0-4, for example 0-2, and Q is selected from -O- or -NR. a -,Right now For example, but not limited to In some implementation schemes, In the fragment, T is either -O- or -NR. a -, p is 0-4, e.g. 1-2, e.g. 2, Q is -O- or -NR a -,For example Furthermore, in such embodiments, U is selected from hydrophilic peptides such as (U1), (U2), (U3), (U4) and (U5) and examples (U1'), (U2'), (U3'), (U4') and (U5').

[0609] In some implementations, t is an integer from 1 to 20, such as 2-10, 2-8, 2-6, 2-4, 4-10, 5-10, 4-14, 4-12, 6-10, 6-12, 8-10, 8-14.

[0610] In some embodiments, G1 is an S atom; in other embodiments, G1 is an N atom; and in still other embodiments, G1 is a C atom. In the ADC of this disclosure, G1 is preferably a sulfur atom of Ab.

[0611] In some embodiments, G2 is a 5-10 membered heterocyclic group, preferably a 5-6 membered heterocyclic group containing one or two heteroatoms selected from N, O, and S, wherein the ring carbon atom is optionally oxidized, for example, but not limited to Preferred The asterisk (*) on the left indicates the connection point with G1, and the wavy line on the right indicates the connection point with G3.

[0612] In some implementations, G2 is selected from The preferred form is the acid-amide moiety formed after partial hydrolysis of maleimide.

[0613] In some implementations, G2 is selected from

[0614] In some implementations, G3 is -C 1-10 Alkylene-C(=O)-, preferably -C 1-5 Alkylene-C(=O)-, wherein the alkylene moiety is optionally replaced by the Bu moiety described above.

[0615] In some implementations, -G2-G3- is Where G3' is -C 1-10 Alkylene-, preferably -C 1-5 Alkylene-, Bu either does not exist or is a structural segment of formula (A) as generally or specifically defined above, where the left * indicates the connection point with G1, and the right... This indicates the connection point with E (when it exists), or property adjustment unit D (when it exists and E does not exist), or cuttable connector B (when neither E nor D exists).

[0616] In specific implementation schemes, -G2-G3- can be... For example Or -G2-G3- can be For example Where T0, T, Q, U, p, and the fragment of equation (A) are defined as in general or specific terms as described above for equation (A), for example, where T0 is -C 1-4 alkylene-(e.g., -C) 1-2 Alkylene (e.g., methylene), T is absent and p is 0-4 (e.g., 0-2) and Q is selected from -O- or -NR. a - U is selected from the hydrophilic peptides (U1), (U2), (U3), (U4) and (U5) of formula (A) defined above for U, such as (U1'), (U2'), (U3'), (U4') and (U5').

[0617] In some implementations, -G1-G2-G3- is... Where G3' is -C 1-10 Alkylene-, preferably -C 1-5 Alkylene-, Bu is absent or is a structural fragment of formula (A), the left * indicates the connection point with the rest of the antibody, the right... This indicates the connection point with connector unit E (when it exists), property adjustment unit D (when it exists and E does not exist), or cuttable connector B (when neither E nor D exists).

[0618] In specific implementation schemes, -G2-G3- in -G1-G2-G3- is defined and exemplified above.

[0619] In the various embodiments described above for G3, -G2-G3-, or -G1-G2-G3-, Bu is the formula... Preferred Where U is a hydrophilic peptide as generally or specifically defined above.

[0620] In an exemplary embodiment, G(-G1-G2-G3-) in this disclosure (II) has the following structure:

[0621] It should be noted that in the linker unit, G1 is the linker atom from the antibody. Therefore, when describing the linker unit or Ras mutation inhibitor-linker unit conjugate in the context, G1 does not need to be shown. In this case, G can also be represented as a -G2-G3- fragment.

[0622] E-Connector Unit

[0623] The linker unit E in the linker unit L of formula (II) of the ADC of this disclosure connects the antibody linker G to the property regulation unit D, or connects the antibody linker G to the cleavable linker B when D is absent, to increase the additional distance between the antibody linker and the cleavable linker B, which may facilitate the activation of B.

[0624] In some implementations, the connector unit E is selected from directly connected keys, -C 1-5 Alkylene-, -NH-, -NH-C 1-5 Alkylene-heteroaryl groups (such as 5- or 6-membered nitrogen-containing heteroaryl groups, for example, triazolyl groups), and the following groups:

[0625] When present, E is connected to property adjustment unit D (when present) or cuttable connector B via its -C(=O)- or -NH- end, and the other end is connected to G3 via its -C(=O)- or -NH- end, as appropriate;

[0626] R g Each is independently selected from H and -C. 1-6 Alkyl group, preferably H or -C 1-3 alkyl;

[0627] R f Selected from -C 1-6 alkylene-, arylene-, -C 1-10 Heteroalkyl-, -C 3-8 heterocyclic group -, -C 1-10 Alkylene-C 6-10 Alpha- and -C 6-10 Aspartic-C 1-10 alkylene-, -C 1-10 Alkylene-C 3-8 Cycloalkylene-, -C 3-8 Cycloalkyl-C 1-10 alkylene-, -C 1-10 Alkylene-C 3-8 Heterocyclic -, -C 3-8 Heterocyclic-C 1-10 alkylene-;

[0628] It should be noted that, when present, each of the specific definitions of E above can be repeated continuously 1-10 times, preferably 1-4 times, in different directions, such as once, twice, three times, and four times.

[0629] In one specific implementation scheme, the connector unit E is... Where R f Each is independently selected from -C 1-6 Alkylene-, preferably -C 2-4 Alkylene, R g For H or C 1-3 Alkyl, for example The wavy line on the left is connected to the cuttable connector B, and the wavy line on the right is connected to the antibody connector G.

[0630] In another specific embodiment, connector unit E is a directly connected key; in another specific embodiment, connector unit E is -C 1-4 Alkylene-; in another specific embodiment, the connector unit E is -NH-.

[0631] D and D 1 —Property Adjustment Unit

[0632] The property adjustment unit D or D in the connecting unit L of formula (II) of the ADC disclosed herein is a property adjustment unit D or D. 1 The addition of [agent name] may improve the properties of ADCs, such as stability in the bloodstream and improved hydrophilicity, leading to decreased clearance and increased exposure. However, [agent name] or [agent name]... 1 The increased quantity of D2 also leads to an increase in the molecular weight and hydrodynamic radius of the ADC, resulting in reduced diffusion. This reduced diffusion rate may decrease the ADC's ability to penetrate tumors. Due to these two competing pharmacokinetic effects, moderate amounts of D2 or D2 are required. 1 To reduce the clearance rate of ADCs, thereby increasing plasma exposure, but not so much as to reduce their diffusivity, thereby interfering with the ability of ADCs to reach the intended target cell population.

[0633] The property adjustment unit D exists in series within the connecting body unit. 1 It exists in a branched form. D can be directly linked to B and E, or it can be linked to B and E through other linking groups, such as amino, carbonyl, alkyl carbonyl, amide, ester, urea, disulfide bridge, carbamate, hydrazone, imine, oxime, triazolyl, maleimide, alkenyl, alkynyl, or alkylene groups. For example, D can be linked through -NH-, -C(=O)-, -C 1-4 Alkylene, -C 1-4 Alkylene -C(=O)-, -NH-C(=O)-(CH2OCH2)-C(=O)-, -C 1-4The alkylene group -NH-C(=O)-(CH2OCH2)-C(=O)- is attached to the cleavable linker B.

[0634] In some implementations, D or D 1 It does not exist.

[0635] In some implementations, D or D 1 Selected from polyamines, such as, but not limited to, polyethyleneimine, polylysine, spermine, dimer polyamines, arginine, amidine, protamine, cationic lipids, cationic porphyrins, quaternary ammonium salts of polyamines, and α-helical peptides.

[0636] In some implementations, D or D 1 Selected from peptides, with hydrophilic peptides being preferred.

[0637] In some implementations, D or D 1 It is a cyclodextrin unit.

[0638] In some implementations, D or D 1 It is a polyamide.

[0639] In some implementations, D or D 1 It can be a polysaccharide, a dendritic polymer, or a bifunctional hydrocarbon chain.

[0640] In some implementations, D or D 1 It is PEG.

[0641] Exemplary embodiments of the PEG fragment D connected to the cuttable connector B and the connector unit E include, but are not limited to, the following:

[0642] Exemplary implementations of linear PEG units (i.e., one end connected to a connector unit and the other end a cap) include:

[0643] The wavy line on the left indicates a connection site with E or G3 (or, as appropriate, a connection site with E or B in branched PEG), and the wavy line on the right indicates a connection site with B. Each subscript c is independently selected from an integer between 2 and 12. In some embodiments, c is 2, 4, 8, or 12. In some embodiments, c is 2. In some embodiments, c is 4. In some embodiments, c is 8. In some embodiments, c is 12.

[0644] B—Cutable connector

[0645] On the one hand, the cleavable linker B in the linker unit L of formula (II) of the ADC disclosed herein is an enzyme-cleavable unit, that is, a substrate that can be cleaved or broken by an enzyme. In order to limit or minimize the off-target toxicity of the ADC while ensuring the release of toxin molecules at the target tumor site, the cleavable linker is designed to be a substrate that is specifically cleaved by an enzyme present near or inside the target cell. Preferably, the level or activity of the enzyme near or inside the target cell is higher than the level or activity in other parts of the body, thereby ensuring that the ADC is specifically recognized, cleaved and released by the enzyme in the target cell / tissue to exert its biological function.

[0646] Therefore, the ADCs of this disclosure are stable in biological fluids until they reach their target, such as tumor cells / tissue. Due to the specific release of the ADCs, administration of the ADCs of this disclosure will result in less toxicity compared to administration of a Ras mutation inhibitor alone, and the activity of the Ras mutation inhibitor will be maximized.

[0647] In some embodiments, the B in the linker unit L of formula (II) of the ADC of this disclosure is a dipeptide, tripeptide, or oligopeptide composed of an amino acid sequence that is specifically recognized and cleaved by a protease, preferably specifically recognized and cleaved by a non-mammalian protease or endogenous mammalian protease present in or near the target cell, such enzymes as, but not limited to: β-APP-cleaving enzyme 1 (BACE1), cathepsin D (CTSD), calpain-1 (CAPN1), aspartate endonuclease (Lugemain), caspase 1 (Casp1), caspase 2 (Casp2), caspase 3 (Casp3) Caspase 5 (CASPS), Caspase 6 (Casp6), Caspase 7 (Casp7), Caspase 8 (Casp8), Caspase 9 (Casp9), cathepsin B (CTSB), cathepsin K (CTSK), cathepsin L (CTSL), cathepsin S (CTSS), esterases (e.g., cholinesterase, alkaline phosphatase, phosphodiesterase, sulfatase), amidases, angiotensin I converting enzyme (ACE), angiotensin I converting enzyme 2 (ACE2), ADAM metallopeptidase domain 10 (ADAM10), dipeptidyl peptidase 3 (DPP3). Insulin-degrading enzyme (IDE), matrix metalloproteinase 1 (MMP1), matrix metalloproteinase 12 (MMP12), matrix metalloproteinase 13 (MMP13), matrix metalloproteinase 14 (membrane insertion) (MMP14), matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 3 (MMP3), matrix metalloproteinase 7 (MMP7), matrix metalloproteinase 8 (MMP8), matrix metalloproteinase 9 (MMP9), membrane metalloendopeptidase (NEPRILYSIN) (MME), ADAM metallopeptidase domain 17 (TACE) (ADAM17), dipeptidyl peptidase 4 (DPP) 4) Dipeptidyl peptidase 8 (DPP8), Dipeptidyl peptidase 9 (DPP9), Coagulation factor Xa (Factor Xa), Coagulation factor VILA (Factor VII), Fibroblast activation protein α (FAP), Furin protease (paired basic amino acid cleaving enzyme), Granulase A (Granula 1, cytotoxic T lymphocyte-associated (GZMA), serine esterase 3), Granulase B (Granula 2, cytotoxic T lymphocyte-associated (GZMB), serine esterase 1), Granulase K (Granula 3, trypsin II) (GZMK), Kallikrein-1 (KLK1), Kallikrein-2 (KLK2), Plasma kallikrein (PSA),KLK3), kallikrein-11 (KLK11), kallikrein-13 (KLK13), kallikrein-15 (KLK15), matrix enzyme (ST14), spinesin (TMPRSSS), plasmin (PLG), prolyl oligopeptidase (PREP), thrombin (F2), tPA, plasminogen activator tissue type (PLAT), UPA, plasminogen activator urokinase (PLAU), HtrA serine peptidase 2 (hTRA2), casein hydrolysate mitochondrial matrix peptidase proteolytic subunit (CIPP / X), constitutive proteasome chymotrypsin-like form (PSMBS, β5), constitutive proteasome trypsin-like form (PSMB7, β7), constitutive proteasome caspase-like form (PSMB6, β6), immunoproteasome chymotrypsin-like form (PSMB8, LMP7), immunoproteasome trypsin-like form (PSMB, β5). 10 MECL1), immunoproteasome caspase-like forms (PSMB9, LMP2).

[0648] In some implementations, B or the cleavable peptide contained in B has the following structure from the C-terminus to the N-terminus:

[0649] -(AA) d - (B)

[0650] Wherein AA is an amino acid selected from alanine (Ala), arginine (Arg), aspartic acid (Asp), asparagine (Asn), histidine (His), glycine (Gly), glutamic acid (Glu), glutamine (Gln), phenylalanine (Glu), lysine (Lys), substituted lysine, leucine (Leu), serine (Ser), tyrosine (Tyr), threonine (Thr), isoleucine (Ile), proline (Pro), tryptophan (Trp), valine (Val), cysteine ​​(Cys), methionine (Met), selenocysteine, ornithine (Asn), β-alanine (β-Ala), citrulline (Cit), and their derivatives; preferably selected from alanine, glycine, asparagine, isoleucine, leucine, valine, phenylalanine, citrulline, and glutamic acid; more preferably selected from alanine, glycine, asparagine, valine, phenylalanine, citrulline, and glutamic acid;

[0651] d is an integer from 2 to 12; preferably an integer from 2 to 8, more preferably an integer from 2 to 4;

[0652] The individual amino acids (AAs) are linked together by peptide bonds.

[0653] The N-terminus of the peptide is connected to the D (in the presence), E (in the presence), or G portion of the linker unit, and the C-terminus of the peptide is connected to the J portion of the linker unit or directly connected to the drug P.

[0654] In some embodiments, each amino acid constituting B is independently selected from the L-amino acids of the amino acids described above. In another embodiment, each amino acid constituting B is independently selected from the D-isomers of the amino acids described above.

[0655] In some implementations, d is an integer from 2 to 8, such as 2 to 6, 2 to 4, or 2 to 3, such as 2, 3, 4, 6, 8.

[0656] In some embodiments, d in formula (B) is 2, and B comprises a dipeptide, for example selected from the following dipeptides: Ala-Ala, Ala-(D)Asp, Ala-Cit, Ala-Lys, Ala-Val, Asn-Cit, Asp-Cit, Asn-Lys, Asn-(D)Lys, Asp-Val, Cit-Ala, Cit-Asn, Cit-Asp, Cit-Cit, Cit-Lys, Cit-Ser, Cit-Val, Glu-Val, Glu-Gly, Phenylene Gly -(D)Lys, His-Val, Ile-Cit, Ile-Pro, Ile-Val, Leu-Cit, Lys-Cit, Me3Lys-Pro, Met-Lys, Met-(D)Lys, Phe-Arg, Phe-Cit, Phe-Lys, Pro-(D)Lys, Ser-Cit, Trp-Cit, Ala-Val, Val-(D)Asp, NorVal-(D)Asp, Cit-Val, Val-Glu, Val-Lys, and their salts. In one specific embodiment, the dipeptide is Ala-Ala. In one specific embodiment, the dipeptide is Cit-Val. In another specific embodiment, the dipeptide is Ala-Val. In yet another specific embodiment, the dipeptide is Glu-Gly.

[0657] In some embodiments, d in formula (B) is 3, and B comprises a tripeptide, such as Gly-Gly-Gly, Gly-Gly-Arg, Phe-Lys-Gly, Leu-Lys-Gly, Leu-Leu-Gly, Glu-Val-Cit, Cit-Ala-Glu, Val-Lys-Gly, Val-Lys-Ala, Val-Gly-Gly, Val-Cit-Gly, Val-Gln-Gly, Val-Glu-Gly, Val-Lys-Gly, Val-Lys-Leu, Ala-Ala-Ala, Asn-Ala-Ala. In one specific embodiment, the tripeptide is Asn-Ala-Ala. In one specific embodiment, the tripeptide is Glu-Val-Cit. In one specific embodiment, the tripeptide is Cit-Ala-Glu.

[0658] In some embodiments, d in formula (B) is 4, and B comprises a tetrapeptide, such as Gly-Gly-Gly-Gly, Gly-Gly-Leu-Gly, Gly-Phe-Leu-Gly, Gly-Val-Lys-Gly, A1a-Leu-A1a-Leu, Gly-Phe-Leu-Gly, Ala-Leu-Ala-Leu, Gly-Phe-Gly-Gly, and Val-Lys-Gly-Gly. In one specific embodiment, the tetrapeptide is Gly-Gly-Leu-Gly. In another specific embodiment, the tetrapeptide is Gly-Phe-Gly-Gly.

[0659] In some implementations, d in formula (B) is 6 or 8, and B contains a hexapeptide or an octapeptide, such as Pro-Leu-Gly-Leu-Ala-Gly (PLGLAG), Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln (GPLGIAGQ), and Gly-Pro-Val-Gly-Leu-Ile-Gly-Lys (GPVGLIGK).

[0660] Preferably, the peptides exemplified above are linked to a self-decomposing linker J or a drug P via the carbonyl group of the left-hand amino acid, and to the D (if present), E (if present), or G portion of the linker unit via the N-terminus of the right-hand amino acid.

[0661] In some embodiments, B is a peptide containing a substituted lysine, such as a dipeptide, tripeptide, tetrapeptide, hexapeptide, or octapeptide. In one embodiment, the substituted lysine is:

[0662] Among them, R 15 and R 15'Selected independently from: H, C 1-6 Alkyl, -CO-NH2, -CONH(C 1-6 alkyl) and -CONH(C 1-6 Alkyl)2, wherein the alkyl group is optionally substituted with a group selected from the group consisting of halogen, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 3-6 Cycloalkyl.

[0663] In a preferred embodiment, B is selected from the following peptides: Ala-Ala, Cit-Val, Ala-Val, Glu-Gly, Asn-Ala-Ala, Cit-Ala-Glu, Gly-Phe-Gly-Gly, for example as follows:

[0664] Preferred The left-end carbonyl group is connected to the self-decomposing linker J or to the drug P, and the right-end N is connected to the D (when present), E (when present) or G portion of the linker unit.

[0665] As described above, by designing antibody-drug conjugates (ADCs) that target tumor distribution, linker units containing peptide B units will facilitate the release of Ras, such as KRas mutation inhibitors, into tumor cells and the environment. Therefore, in some embodiments, after the ADC is internalized into tumor cells, the amide bond in the peptide of the B unit will be recognized and degraded by enzymes in the tumor cells, releasing the drug fraction P. In other embodiments, the amide bond in the peptide of the B unit will be recognized and degraded by enzymes in the tumor environment, releasing the drug fraction P.

[0666] In other embodiments, B in the linker unit L of the ADC of this disclosure may be absent; for example, the self-disintegrating linker J is directly connected to the antibody linker G.

[0667] J-Self-decomposing connector

[0668] In some embodiments, the self-decomposing linker J in the linker unit L of formula (II) of the ADC of this disclosure is covalently bonded, that is, the cleavable linker B in the linker unit is directly connected to the drug P, for example, through an amide bond.

[0669] In other embodiments, the self-decomposing linker J in the linker unit L of formula (II) of the ADC of this disclosure is a functional group that facilitates the connection of the cleavable linker B or antibody linker G to the drug P, or a functional group that provides additional structural components to further facilitate the release of the drug P from the remainder of the ADC.

[0670] Specifically, the J connected to drug P is selected from -J1-, -J2-, -J1-J2-, and -J2-J1-, where -J1- is selected from... The asterisk (*) indicates the connection point with drug P or -J2-, and the wavy line indicates the connection point with cuttable connector B or J2.

[0671] -J2- Selected from The asterisk (*) indicates the connection point with drug P or with -J1-, and the wavy line indicates the connection point with cuttable connector B or -J1-.

[0672] Each occurrence of X' is independently selected from CH or N;

[0673] Each occurrence of Y1' is independently selected from -NH- and -NC. 1-6 Alkyl- or -O-;

[0674] Each occurrence of R 16 Each is independently selected from H and -C 1-6 Alkyl groups, preferably H or C 1-3 Alkyl, more preferably H;

[0675] Each occurrence of R 17 Each segment is independently selected from H, -NO2, -NH2, -CF3, or formula (A1):

[0676] Each occurrence of R 18 Each independently is -C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably methyl;

[0677] T is selected from -C(R) a )2-、-O-、-NR a -or does not exist;

[0678] T1 is selected from -C(R) a )2-、-O-、-NR a -;

[0679] T2 is selected from -CR a - and -N-;

[0680] T3 is a peptide composed of 2 to 6 amino acids linked to a carboxyl terminus with N;

[0681] Q is selected from -CO-, -O-, -NR a -or does not exist;

[0682] U is included Hydrophilic peptides;

[0683] Ra Each is independently selected from H or -C. 1-6 Alkyl groups, preferably H or -CH3;

[0684] Subunit Selected from natural and non-natural amino acid residues;

[0685] p is an integer from 0 to 4, for example 0-2, 1-4, 1-2, 2~4;

[0686] t is an integer from 0 to 20, for example 0-8, 0-6, 0-4, 0-2, 1-20, 1-10, 2-10, 2-8, 2-6, 2-4, 4-14, 4-12, 5-10, 6-10, 6-12, 8-10, 8-14.

[0687] It should be noted that when J is directly connected to G, J1, J2, or J1 in the form of J1-J2- or J2-J1-, which are connected one after the other, are connected to G through the wavy line.

[0688] It should be noted that U in the self-decomposing linker J is a hydrophilic peptide, which, as defined accordingly in this article, and more specifically as defined above for Bu in the antibody linker portion, includes... Hydrophilic peptides, preferably hydrophilic peptides of which Polysarcosine, polyarginine, or polyglycine having 4-14 units, such as 5-10 units, more preferably polysarcosine having 4-12, 6-12, 4-10, or 5-10 units.

[0689] Specifically, U appearing in the self-decomposing connector J is a container. The hydrophilic peptides may be selected from (U1), (U2), (U3), (U4), and (U5) as defined above, and specific examples (U1'), (U2'), (U3'), (U4'), and (U5'), for example... Where R can be R a ;R a Selected from H or -C 1-6 Alkyl group, preferably H or -CH3, more preferably -CH3; t is an integer from 1 to 20, for example 2-10, 2-8, 2-6, 2-4, 4-10, 4-12, 4-14, 5-10, 6-10, 6-12, 8-10, 8-14; preferably, the segment in square brackets is polysarcosine, polyarginine, or polyglycine containing 4-14 units, for example 5-10 units, more preferably polysarcosine containing 6-12 units or 5-10 units, more preferably 5 or 10 units.

[0690] In some implementations, the self-decomposing connector J is -J1-, specifically... For example, but not limited to: Preferably, Y1' is selected from -O- and -NH-, R 16 'For H, R 17 'Selected from H or formula (A1)' For example, but not limited to:

[0691] In some implementations, the self-decomposing connector J is -J1-, specifically... For example: Preferred Preferably, Y1' is selected from -O- and -NH-, R 16 'For H, R 17 'Selected from H or formula (A1)' For example, but not limited to:

[0692]

[0693] Preferred

[0694] In some implementations, -J2 is selected from

[0695] In some implementations, the self-decomposing connector J is -J2-, specifically... For example: Where R 18 -C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably methyl, R a H or -C 1-6 Alkyl (preferably C) 1-3 Alkyl groups (more preferably -CH3), for example, but not limited to:

[0696] In some implementations, the self-decomposing connector J is -J2-, specifically... Preferred R 18 -C 1-3 Alkyl, more preferably methyl, T2 is -N-, i.e. p is 0-4, preferably 0-2; Q is absent or -NR. a- or -O-, preferably not present; U is (U1), (U2), (U3), (U4), and (U5) as defined above for the hydrophilic peptides in J, and specific examples (U1'), (U2'), (U3'), (U4'), and (U5'), wherein t is preferably 2-14, for example 4-14, 5-10, 6-12, more preferably 5 or 10; for example, but not limited to

[0697] In some implementations, the self-decomposing connector J is -J2-, specifically... Preferred R 18 -C 1-3 Alkyl, more preferably methyl, T3 is a dipeptide, tripeptide or tetrapeptide with N linked by -CO- (preferably a dipeptide, tripeptide or tetrapeptide as defined in this disclosure for cleavable linker B), p is 0-4, preferably 0-2; Q is absent or is -NR. a - or -O-, preferably not present; U is (U1), (U2), (U3), (U4), and (U5) as defined above for the hydrophilic peptides in J, and specific examples (U1'), (U2'), (U3'), (U4'), and (U5'); for example, but not limited to

[0698] In some embodiments, the self-decomposing linker J is -J1-J2-, selected from structural segments formed by linking each specific embodiment of J1 with each specific embodiment of J2, wherein J is linked to P through J1 and to the remainder of the compound through J2, specifically selected from:

[0699] In other embodiments, the self-decomposing linker J is -J2-J1-, selected from each embodiment of J2 connected to each embodiment of J1 to form a structural segment, wherein J is connected to P through J2 and to the rest of the compound through J1.

[0700] The asterisk (*) indicates the connection point with drug P, and the wavy line indicates the connection point with the rest of the linker unit; each of the J1 and J2 components and each of the substituents therein are defined as generally or specifically for J1 and J2 above.

[0701] In the above sub-formulas, Y1', which is connected to the six-membered aromatic ring containing X', is connected to the opposite position of another connection point of the ring in some embodiments, and to the adjacent position of another connection point of the ring in other embodiments.

[0702] In a preferred embodiment, J is selected from -J1- and -J1-J2-, specifically selected from:

[0703] More preferably (J-1), (J-2), (J-8), (J-9), and (J-10),

[0704] The variables are defined as generally or specifically as described above;

[0705] More specifically, the segments selected from Y1' connected to the aromatic ring are connected to another connection point on the ring at the opposite or adjacent (preferably opposite) position.

[0706] Of the above technical solutions, preferably,

[0707] Each occurrence of X' is independently selected from -N- or -C-;

[0708] Each occurrence of Y1' is independently selected from -NH- or -O-;

[0709] Each occurrence of R 16 Each is independently selected from H or C 1-3 Alkyl group, preferably H;

[0710] Each occurrence of R 17 Each segment is independently selected from H or formula (A1)

[0711] Each occurrence of R 18 Each is independently selected from -C 1-3 Alkyl groups, preferably methyl groups;

[0712] Each occurrence of T is selected from -O- or -NR. a -or does not exist;

[0713] Each occurrence of T1 is selected from -CH2-, -O-, and -NCH3-;

[0714] Each occurrence of T2 is selected as -N-;

[0715] Each occurrence of T3 is a 2-4 peptide linked to N at the carboxyl terminus, preferably selected from Ala-Ala, Cit-Val, Ala-Val, Glu-Gly, Asn-Ala-Ala, Cit-Ala-Glu, Gly-Phe-Gly-Gly;

[0716] Each occurrence of Q is either nonexistent or -NR a -or -O-;

[0717] Each occurrence of U is defined and exemplified above for the hydrophilic peptide in J;

[0718] Each occurrence of p is between 0 and 4, preferably 0 or 2.

[0719] In the above general, specific, or preferred implementation scheme J, Preferred More

[0720] In the above general, specific, or preferred implementation scheme J, Preferred More

[0721] It should be understood that in the self-decomposing connector J, as R 17 'of' (A1) fragment The meaning of the corresponding fragment in formula (A) for the substituents of antibody linker assembly G3 as described above is exactly the same, including various general, preferred or specific embodiments.

[0722] In one specific implementation, the self-decomposing connector J is used as R 17 'of' (A1) fragment In this case, at least one of T and Q exists, or p is not 0.

[0723] In other specific implementations, the self-decomposing connector J is used as R 17 'of' (A1) fragment In this context, T represents -O- or -NR. a -, preferably -O-; p is 1-4, preferably 2-4, more preferably 2; Q is -O- or -NR. a -, Preferred -NR a -; U is selected from (U1), (U2), (U3), (U4), and (U5) as defined above for the hydrophilic peptides in J, and specific examples (U1'), (U2'), (U3'), (U4'), and (U5'), wherein t is preferably 2-14, for example 4-14, 5-10, 6-12, more preferably 5 or 10, in which case the fragment of formula (A1) is, for example, but not limited to: Self-decomposing connectors J include, but are not limited to, examples of, but not limited to, […]. For example

[0724] For the self-decomposing connector J In a specific implementation, T2 is -N-, p is 0, Q is absent, and U is as defined above for the hydrophilic peptides in J (U1), (U2), (U3), (U4), and (U5) and specific examples (U1'), (U2'), (U3'), (U4'), and (U5'), wherein t is preferably 2-14, for example 4-14, 5-10, 6-12, more preferably 5 or 10.

[0725] In the above general, specific, or preferred implementation scheme J, the self-decomposing connector J is (J-7), for example... Where Y1' is selected from -O- and -NH-; X' is selected from CH or N, preferably CH; R 16 'For H; R 17 'Selected from H or formula (A1)' H;R preferred 18 Preferred -C 1-3 Alkyl, more preferably methyl; T2 is preferably N; p is 0-4, preferably 0-2; Q is absent or is -NR. a - or -O-, preferably not present; U is (U1), (U2), (U3), (U4), and (U5) as defined above for the hydrophilic peptides in J, and specific examples (U1'), (U2'), (U3'), (U4'), and (U5'), wherein t is preferably 2-14, for example 4-14, 5-10, 6-12, more preferably 5 or 10; for example, but not limited to

[0726] In the above general, specific, or preferred implementation scheme J, the self-decomposing connector J is (J-8), for example... Where Y1' is selected from -O- and -NH-; X' is selected from CH or N; R 16 'For H; R 17 'Selected from H or formula (A1)' H;R preferred 18 Preferred -C 1-3 Alkyl, more preferably methyl; T1 is selected from O, NR a C(R) a )2; for example, but not limited to

[0727] In the above general, specific, or preferred embodiments, the self-decomposing connector J is (J-9), for example... Where Y1' is selected from -O- and -NH-; X' is selected from CH or N; R 16 'For H; R 17 'Selected from H or formula (A1)' H;R preferred 18 Preferred -C 1-3 Alkyl, more preferably methyl; T2 is preferably N; p is 0-4, preferably 0-2; Q is absent or is -NR. a- or -O-, preferably not present; U is (U1), (U2), (U3), (U4), and (U5) as defined above for the hydrophilic peptides in J, and specific examples (U1'), (U2'), (U3'), (U4'), and (U5'), wherein t is preferably 2-14, for example 4-14, 5-10, 6-12, more preferably 5 or 10; for example, but not limited to

[0728] In the above general, specific, or preferred implementation scheme, the self-decomposing connector J is... Preferred (J-10-1), where Y1' is selected from -O- and -NH-; X' is selected from CH or N; R 16 'For H; R 17 'Selected from H or formula (A1)' H;R preferred 18 Preferred -C 1-3 Alkyl, more preferably methyl; T3 is a dipeptide, tripeptide or tetrapeptide with N linked by -CO- (preferably a dipeptide, tripeptide or tetrapeptide as defined in this disclosure for cleavable linker B, more preferably selected from Ala-Ala, Cit-Val, Ala-Val, Glu-Gly, Asn-Ala-Ala, Cit-Ala-Glu, Gly-Phe-Gly-Gly), p is 0-4, preferably 0-2; Q is absent or is -NR. a - or -O-, preferably not present; U is (U1), (U2), (U3), (U4), and (U5) as defined above for the hydrophilic peptides in J, and specific examples (U1'), (U2'), (U3'), (U4'), and (U5'), wherein t is preferably 2-14, for example 4-14, 5-10, 6-12, more preferably 5 or 10; for example, but not limited to

[0729] It should be understood that the ADC of this disclosure covers ADC technical solutions formed by combining each of the above-described self-decomposing connectors J with any other component of the ADC defined herein, according to the general, specific, or preferred definitions.

[0730] Specific technical solution for connector unit L

[0731] It should be noted that the connector unit L of the ADC disclosed herein includes any combination of the general or specific definition of any one of the components of the connector unit and the general or specific definition of the other one or more components.

[0732] In some embodiments, the connector unit L of formula (II) in the ADC of this disclosure (X) has the general formula shown in Table 3 below:

[0733] Preferred options are (II-3) or (II-4).

[0734] J, B, D, E, and G are defined as generally, specifically, or preferably as described above for each part.

[0735] In some embodiments, the connector units of the ADC of this disclosure are in formulas (II), (II-1), (II-2), (II-3), and (II-4).

[0736] J, as defined in the “J-Self-Decomposing Connector” section above, is selected from -J1-, -J2-, -J1-J2-, and -J2-J1-, specifically from the formulas (J-1), (J-2), (J-5), (J-6), (J-7), (J-8), (J-9), (J-10) and their respective sub-formulas or specific embodiments as generally or specifically defined above, preferably from (J-1), (J-2), (J-6), (J-7), (J-8), (J-9), and (J-10), more preferably from (J-1), (J-2), (J-8), (J-9), and (J-10), and their respective sub-formulas or specific embodiments;

[0737] B represents the formula (B): -(AA) d -, where d is an integer from 2 to 12, preferably an integer from 2 to 4;

[0738] AA is preferably selected from the following amino acids: alanine, glycine, asparagine, valine, phenylalanine, citrulline, and glutamic acid; preferably -(AA). d - The following peptides from C-terminus to N-terminus: Ala-Ala, Cit-Val, Ala-Val, Glu-Gly, Asn-Ala-Ala, Cit-Ala-Glu, Gly-Phe-Gly-Gly, preferably Ala-Ala or Asn-Ala-Ala; wherein the N-terminus of the peptide is linked to the D (present), E (present and D absent) or G (both D and E absent) portion of the linker unit, and the C-terminus of the peptide is linked to J;

[0739] D is selected from The amino terminus is attached to E (if present) or G, the carbonyl terminus is attached to B, and the subscript c is independently selected from integers from 2 to 12.

[0740] E is The carbonyl terminus is connected to B or D, the amino terminus is connected to G, and R... f Each is independently selected from -C 1-6 Alkylene-, preferably -C2-4 Alkylene, R g For H or C 1-3 Alkyl group, most preferred

[0741] G is Where G1 is the atom in Ab responsible for bonding with L, and G3' is -C 1-10 Alkylene-, preferably -C 1-5 Alkylene-, Bu is absent or is a structural segment of formula (A); preferably, G is Where T0, T, Q, U, and p are defined as in section G above for equation (A), preferably, where T0 is -C 1-4 alkylene-(e.g., -C) 1-2 alkylene (e.g., methylene), T is absent or is -C(R) a )2-, p is 0-4 (e.g. 0-2) and Q is selected from -O- or -NR- a -(For example, T does not exist, p is 0 and Q is -NR) a -), and U is selected from (U1), (U2), (U3), (U4) and (U5) as defined above for the hydrophilic peptides in G, and their specific examples (U1'), (U2'), (U3'), (U4') and (U5'); where t is an integer from 1 to 20, such as 2-10, 2-8, 2-6, 2-4, 4-10, 5-10, 4-12, 4-14, 6-10, 6-12, 8-10, 8-14.

[0742] In some embodiments, at least one of the linker unit L in the ADC of this disclosure, such as in formulas (II-1) to (II-4) above, the self-decomposing linker J and the antibody linker G, carries a hydrophilic peptide.

[0743] It should be noted that when U appears in the linker unit as a hydrophilic peptide, it is a hydrophilic peptide as generally or specifically defined in this article for the antibody linker portion, wherein t is preferably 4-14, 4-12 or 5-10 units of polysarcosine, polyarginine or polyglycine, more preferably 6-12 or 5-10 units of polysarcosine.

[0744] It should be noted that in the linker unit, G1 represents the linking atom from the antibody. Therefore, when describing the linker unit or Ras mutation inhibitor-linker unit conjugate fragment or conjugate in context, G can also be represented as -G2-G3- fragment, as shown in the various sub-formulas in the table above.

[0745] In a specific implementation, the connector unit L of the ADC of this disclosure has the general formula (II-3'):

[0746] Specifically:

[0747] Or it may have the general formula (II-4'):

[0748] Specifically

[0749] Where -(AA) d -、Bu、G3'、T0、T、Q、U、p are as defined above, either generally or specifically;

[0750] J is preferably selected from (J-1), (J-2), (J-6), (J-7), (J-8), (J-9), (J-10) as defined above, more preferably (J-1), (J-2), (J-8), (J-9), (J-10), or their respective sub-formulas;

[0751] And the maleimide portion thereof is The corresponding segment.

[0752] The connecting body unit L of formula (II-3') or (II-4') is shown, for example but not limited to, in Table 4 below:

[0753] The variables and segments are defined as generally or specifically as described in the corresponding sections above;

[0754] In the various sub-formulas of the connecting body unit L shown above, and -(AA) d - The connected Y1' can be connected to the opposite position of another connection point of the six-membered aromatic ring, or connected to the adjacent position of another connection point of the six-membered aromatic ring, preferably connected to the opposite position;

[0755] In some implementations of the various sub-formulas of the connecting body unit L shown above, G3' carries In some other implementations, G3' does not carry the fragment. Fragment;

[0756] Specifically,

[0757] Y1' is selected from -O- and -NH-;

[0758] X' is selected from CH or N;

[0759] G3' is -C 1-10 Alkylene-, preferably -C 1-5 alkylene-;

[0760] R 16 'For H;

[0761] R 17 'Selected from H or formula (A1)'

[0762] R 18 -C 1-3 Alkyl groups, preferably methyl groups;

[0763] T1 is selected from -C(R) a )2-、-O-、-NR a -;

[0764] exist In this context, T is selected from -O- or -NR. a -, preferably -O-, p is 2-4, preferably 2, Q is absent or is -O- or -NR. a -, U is selected from (U1), (U2), (U3), (U4) and (U5) as defined above for hydrophilic peptides in G, and their specific examples (U1'), (U2'), (U3'), (U4') and (U5');

[0765] In this context, T2 is -N-, p is 0, Q does not exist, and U is selected from (U1), (U2), (U3), (U4), and (U5) defined above for hydrophilic peptides in G, and their specific examples (U1'), (U2'), (U3'), (U4'), and (U5').

[0766] exist In the middle, T0 is -C 1-4 Alkylene-, preferably -C 1-2 alkylene-, more preferably methylene; T is absent, p is 0, Q is -NR a - or -CO-, U is selected from (U1), (U2), (U3), (U4) and (U5) as defined above for hydrophilic peptides in G, and specific examples (U1'), (U2'), (U3'), (U4') and (U5');

[0767] exist In this context, T3 is a dipeptide, tripeptide, or tetrapeptide linked to N with -CO- (preferably a dipeptide, tripeptide, or tetrapeptide as defined in this disclosure for cleavable linker B, more preferably selected from Ala-Ala, Cit-Val, Ala-Val, Glu-Gly, Asn-Ala-Ala, Cit-Ala-Glu, Gly-Phe-Gly-Gly), p is 0-4, preferably 0-2; Q is absent or is -NR. a- or -O-, preferably not present; U is selected from (U1), (U2), (U3), (U4) and (U5) as defined above for the hydrophilic peptides in G, and specific examples (U1'), (U2'), (U3'), (U4') and (U5');

[0768] R a Selected from H or -C 1-3 Alkyl groups, preferably H or -CH3;

[0769] The value of t is preferably 2-14, for example 4-14, 6-12, 4-10, 5-10, more preferably 5 or 10.

[0770] It should be noted that the general formulas or sub-formulas exemplified above for formulas (II-3') and (II-4') also include the maleimide portion thereof. The corresponding general formula.

[0771] In the various sub-formulas of the linker unit L shown above, the preferred G(-G1-G2-G3-) is as exemplified by the preferred G segment (preferably the -G2-G3- segment) in the G section above; and the maleimide portion therein is The corresponding segment.

[0772] In the various sub-formulas of the connecting body unit L shown above, -(AA) d - The polypeptide is selected from the B fragment exemplified in Part B above, preferably. The left-end carbonyl group is connected to the self-decomposing linker J or the drug P, and the right-end N is connected to the D (when present), E (when present) or G portion of the linker unit.

[0773] In specific implementations, the linker unit L of the ADC disclosed herein is selected from those shown in the synthetic examples, and the maleimide portion therein is... The above segments.

[0774] It should be noted that the linker units of the various general formulas in Table 3 and their specific embodiments (Table 4) defined above for the linker unit L of formula (II) in the ADC of this disclosure (X) are not limited to the drug P unit and / or antibody or antigen-binding fragment Ab that binds to the target antigen described in this disclosure. They can also be used as appropriate for other drugs and / or antibodies or antigen-binding fragments not mentioned in this disclosure. In other words, the linker units of the various general formulas in Table 3 and their specific embodiments (Table 4) independently constitute a part of the technical solution of this invention.

[0775] Therefore, this disclosure also covers compounds comprising the linker unit L structure described herein, or stereoisomers, isotopic variants, pharmaceutically acceptable salts, or solvates thereof, preferably those comprising the linker unit L structure of the hydrophilic peptide described herein, or stereoisomers, isotopic variants, pharmaceutically acceptable salts, or solvates thereof.

[0776] This disclosure discloses a Ras mutation inhibitor-linker unit conjugated fragment.

[0777] Based on the above, the [PL]- in the ADC of this disclosure (X) can be expressed as:

[0778] Among them, P, B, D, D 1 E, G, and J are defined as generally or specifically as described above.

[0779] In some embodiments, in formula (III) [PL]-, P is a compound or its stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate as generally or specifically defined in the various embodiments of the drug P unit portion.

[0780] In formula (III), the drug P unit is connected to the linker unit via an N or O atom in a substituent carried on its parent ring or side chain. For example, the drug P unit is connected via formula (I). The ring N atom in the fragment (e.g. The N atom of the fragment, or the OH or primary, secondary, or tertiary amino groups carried by the drug side chain, are connected to the linker unit.

[0781] In formula (III), the drug unit P can be any of the following formulas: (I), (IA), (IA-1), (IA-1'), (IA-1”), (IA-2), (IA-2'), (IA-2”), (IB), (IB-1), (IB-1'), (IB-1”), (IB-2), (IB-2'), (IB-2”), (IC), (IC-1), (IC-1'), (IC-1”), (IC-2), (IC-2'), (IC-2”), (ID), (ID-1), (ID-1'). (ID-1”), (ID-2), (ID-2'), (ID-2”), (I'-A-1), (I'-B-1), (I'-C-1), (I'-A-2), (I'-B-2) or (I'-C-2) compounds or pharmaceutical units of the P unit as listed in Embodiment 8; preferably (I), (IA), (IA-1), (IA-1'), (IA-1”), (IA-2), (IA-2'), (IA-2”), (IB), (IB-1), (IB-1'), (IB-1”), (IB-2), (I'-C-2) Compounds of formula (IA-1'), (IA-1"), (IA-2"), (IA-2"), (IA-2"), (IA-1"), (IA-1"), (IA-C"), (IA-2"), (IA-2"), or (IA-C"))")")")")")")")"")", (IA-2"), (IA-2"), (IA-2"), (IB-1'), (IB-1"), (IB-2'), (IB-2"), (IA-1"), (IA-2"), (IA-1"), (IA-C"))")")")","I'-A-1"), (I'-B-1"), (I'-C"))")"")")","I'-C")","I'-C")")"")","I'-A-1")", (IA-2")", (IA-2"), (IA-1"), (I'-C"))"")"")","I'-C")","I'-C")")"")","I'-A-1")", (IA-2")", (IA-2")", (IB-1"), (IA-2"), (IA-C"))"")","I'-C")","I'-C")"")"")","I'-C")", (IA-2")","I'-C")","I'-C")")"")","I'-C")", (IA-2")","I'-C")","I'-C")")"")", (IA-2")", (IA-1")", (IA-C"))"")"")", (IA-2")", (IA-1")", (IA-C"))"")"")", (IA-2")", (IA-1")", (IA-C")"")"")","I'-C")", (IA-2")","I'-C")")"")", (IA-2")", (IA-1")", (IA-C")"")"")","I'-C")", (IA-2")"," The compounds listed; more preferably compounds of formula (IA-1”), (IA-2”), (IB-1”) or (IB-2”) or compounds listed in embodiment 8 of the pharmaceutical P unit; most preferably any P1 to P7 compounds as defined in embodiment 7 of the pharmaceutical P unit above or any P8 to P46 compounds listed in embodiment 8 of the pharmaceutical P unit; or their respective stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates, wherein each substituent has the meaning generally or specifically defined above for each general formula in the pharmaceutical P unit.

[0782] In equation (III), the connecting body unit -JB(D 1 )-DE(D 1)-G- can be a structural segment having the above formulas (II), (II-1), (II-2), (II-3), (II-3), (II-4), preferably a structural segment having the formulas (II-3), (II-3'), (II-4), (II-4'), more preferably a structural segment having the formulas (II-3'-1) to (II-3'-5) and (II-4'-1), wherein each component or variable has the meaning of the general or specific definition of each general formula in the connecting body unit L above.

[0783] It should be noted that this disclosure covers Ras mutation inhibitor-linker unit conjugate fragments obtained by any combination of any embodiment of the drug unit P as generally or specifically defined in this disclosure and any embodiment of the linker unit L as generally or specifically defined in this disclosure.

[0784] In some embodiments of formula (III), the pharmaceutical P unit is a compound having the above formulas (I), (IA), (IA-1), (IA-1'), (IA-1”), (IA-2), (IA-2'), (IA-2”), (IB), (IB-1), (IB-1'), (IB-1”), (IB-2), (IB-2'), (IB-2”), (I'-A-1), (I'-B-1), (I'-C-1), or a compound listed in embodiments 7 or 8 (preferably P8 to P46) of the pharmaceutical P unit, or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt, or solvate thereof, wherein each substituent has the meaning generally or specifically defined above for each general formula in the pharmaceutical P unit; and the linker unit -JB(D 1 )-DE(D 1 )-G- is a structural segment with the above formula (II-3) or (II-3') or (II-4) or (II-4'), wherein each component or variable has the meaning of the general or specific definition of each general formula in the connecting body unit L above.

[0785] In some embodiments of formula (III), the pharmaceutical P unit is a compound having formula (IA-1”), (IA-2”), (IB-1”) or (IB-2”) as defined in embodiment 6.1 above, or formula (I'-A-1), (I'-B-1), (I'-C-1) as defined in embodiment 6.3 above, or a compound listed in embodiment 7 or 8 (preferably P8 to P46) of the pharmaceutical P unit, or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof, wherein each substituent has the meaning generally or specifically defined above for each general formula in the pharmaceutical P unit; and the linker unit -JB(D1 )-DE(D 1 )-G- is a structural segment with the above formula (II-3') or (II-4'), in which each component or variable has the meaning of the general or specific definition of each general formula in the connecting body unit L above.

[0786] In some embodiments of formula (III), the drug P unit is a compound having P1, P2, P3, P4, P5, P6 or P7 as defined in embodiment 7 above, or any P8 to P46 compound listed in embodiment 8, or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt or solvate thereof; and the linker unit -JB(D 1 )-DE(D 1 )-G- is a structural segment with the above formula (II-3'-1) to (II-3'-5) or (II-4'-1), in which each component or variable has the meaning of the general or specific definition of each general formula in the connecting body unit L above.

[0787] In some implementations, the specific formula (III) conjugate fragments include, but are not limited to:

[0788] Specifically, it has the structure shown in Table 5.

[0789] Wherein, the drug P unit is selected from Ras inhibitors as defined in any one of embodiments 1-8, such as KRas inhibitor compounds, preferably P1-P46 compounds as defined in embodiments 7-8 or their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates; and

[0790] The variables and segments in the connecting body unit are defined as generally or specifically as described in the corresponding sections above, and the connecting body unit has the structure generally or specifically exemplified in the corresponding sections above. That is, the general or specific or preferred definitions of each variable or segment given in the corresponding sections above apply to equation (III) and its various sub-formulas, such as the definitions given above for equations (II-3'-1), (II-3'-2), (II-3'-3), (II-3'-4), (II-3'-5), and (II-4'-1).

[0791] The Ras mutation inhibitor-linker unit conjugation fragment disclosed herein includes technical solutions formed by the general, preferred or specific definitions of each group in the above general formulas, as well as technical solutions formed by any combination of the general, preferred or specific definitions of each group.

[0792] Specific examples of Ras mutation inhibitor-linker unit conjugate fragments disclosed herein include, but are not limited to, those fragments of compounds C47, C54, C59, C62-74, C84-85, C87-99, C102-109, and C111-114 in the synthesis examples below, or their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates.

[0793] It should be noted that the Ras mutation inhibitor-linker unit conjugation fragments of formula (III) and its various sub-formulas in the ADC of this disclosure, as well as their specific embodiments, are not limited to the antibodies or antigen-binding fragments Ab that bind target antigens as described in this disclosure. They can also be used as appropriate for other antibodies or antigen-binding fragments not mentioned in this disclosure. In other words, formula (III) and its various sub-formulas conjugation fragments and their specific embodiments constitute an independent part of this invention.

[0794] Therefore, this disclosure also provides compounds comprising Ras mutation inhibitor-linker unit conjugate fragment structures of formula (III) of this disclosure, or stereoisomers, tautomers, isotopic variants, pharmaceutically acceptable salts or solvates thereof, preferably those comprising compounds comprising the linker unit L structure of a hydrophilic peptide as described in this disclosure, or stereoisomers, isotopic variants, pharmaceutically acceptable salts or solvates thereof.

[0795] Therefore, this disclosure also provides compounds of formula (PL): PJB(D1)-DE(D1)-G(((PL), such as PJBG(((PL-1) or PJG(((PL-2)).

[0796] Or its stereoisomers, isotopic variants, pharmaceutically acceptable salts or solvates.

[0797] Each variable has the general, specific, or preferred meaning given in the corresponding section above. Specifically, equations (PL), (PL-1), and (PL-2) have the general, specific, or preferred definitions given for equation (III) above, equation (PL-1) has the definition given for equation (III-1) and its various sub-general formulas above, and equation (PL-2) has the definition given for equation (III-2) and its various sub-general formulas above. The difference is that G is the -G2-G3- defined in the general, specific, or preferred G section above, and... quilt Replacement.

[0798] Specifically, the compounds of formula (PL) disclosed herein have the general formulas shown in Table 6 below:

[0799] Wherein, the drug P unit is selected from Ras inhibitors as defined in any one of embodiments 1-8, such as KRas inhibitor compounds, preferably P1-P46 compounds as defined in embodiments 7-8 or their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates; and

[0800] The variables and segments in the connecting body unit are defined as generally or specifically as described in the corresponding sections above, and the connecting body unit has the structure generally or specifically exemplified in the corresponding sections above. That is, the general or specific or preferred definitions of each variable or segment given in the corresponding sections above apply to equation (III) and its various sub-formulas, such as the definitions given above for equations (II-3'-1), (II-3'-2), (II-3'-3), (II-3'-4), (II-3'-5), and (II-4'-1).

[0801] Specific examples of Ras mutation inhibitor-linker unit conjugates disclosed herein include, but are not limited to, the C-series compounds in the synthesis examples below, particularly including C47, C54, C59, C62-74, C84-85, C87-99, C102-109, C111-144, or their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates.

[0802] This disclosed ADC

[0803] Based on the above, the ADC of this disclosure (X) is: [PL] q -Ab, wherein P, L, q and Ab are defined as generally or specifically as in the various sections above; wherein the PL fragment is defined as generally or specifically as in the section "Ras mutation inhibitor-linker unit conjugation fragment of this disclosure", preferably the fragment shown in Table 5, and more preferably the fragment in the C compound series shown in the examples.

[0804] Specifically, the ADC of this disclosure (X) can be:

[0805] Specifically Or its stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates.

[0806] Wherein P is a Ras inhibitor compound as defined in any one of embodiments 1-8 of the above-described drug P unit, preferably compounds P1 to P46 as defined in embodiments 7-8 or their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates; in some embodiments, drug P is a compound of formula (I...

Claims

1. An antibody-drug conjugate of formula (X) or a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof: [P-L] q -Ab (X) wherein, Ab represents an antibody or antigen binding fragment that binds to a target antigen; q represents the number of [P-L] units attached to Ab, which is an integer or a non-integer of at least 1 ; L represents a linker unit that links P to Ab; P represents a Ras mutation inhibitor compound selected from (1) a compound of formula (I), and (2) the following compound of formula (I') or a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, a prodrug, or a solvate thereof, wherein: M is selected from N or C-R1; M’ is selected from N or C-R1’; R1and R1' are each independently selected from H, halogen, CN, -C 1-6 alkyl and -OC 1-6 alkyl; R a selected from H, halogen, CN, -C 1-6 alkyl, -C 2-6 alkynyl and -OC 1-6 alkyl; X is selected from CH2, N and O; or the bond between X in formula (I) and the adjacent ring carbon atom is fused to a 5-6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, which ring is substituted with -C(O)NH2 1-6 alkylene-O-C 1-6 alkyl, and additionally substituted with a group selected from -C(O)NH2, -C(O)NHC 1-6 alkyl and -C(O)N(C 1-6 alkyl)2; Y is selected from -CH2-, -CH2CH2-, -CH2OCH2- or absent; R2and R2 ’ each independently selected from H, OH, or -C 1-6 alkyl; or R2and R2attached to non-adjacent ring carbon atoms together form a cycloalkyi group ’ together form a bridging -(CH2)2- group 1-2 -CH=CH-; or R2and R2 ’ with the ring carbon atom to which they are attached form a 4-6 membered spiro cycloalkyl or a 4-6 membered spiro heterocycloalkyl comprising 1 or 2 heteroatoms selected from N and O; R3is selected from H, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2and -OC 1-6 alkyl; R4 is selected from -CN, halogen, -NO2, or -C optionally substituted with a halogen. 2-6 Alkyne group and -C group optionally substituted with halogen 1-6 alkyl; R5is selected from H, -CN, halogen, -NO2, and halogen-substituted-C 1-6 alkyl; R6 is selected from H, halogens, CN, and -C. 1-6 Alkyl and -C 2-6 The alkynyl group, in which -C 1-6 Alkyl and -C 2-6 Each alkynyl group can be independently and optionally substituted with a halogen; R7, R7, R8, and R8are each independently selected from the group consisting of H, halogen, CN, -NO2, and -C(O)R7a; 1-6 alkyl; V and W are each independently selected from H, halogen, -C 1-6 alkyl, OH, and NH2; Z is selected from O, N and CH2; R9and R 10 each independently is selected from H, deuterium, -C 1-6 alkyl and -(CH2) n -C 3-6 cycloalkyl, wherein the -C 1-6 alkyl and -C 3- 6cycloalkyl is each independently optionally substituted with deuterium, halogen or -O-C 1-6 alkyl, or R9and R 10 with the carbon atom to which they are attached form a C 3-4 cycloalkyl; R 11 H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl and -(CH2) n -C 3-6 cycloalkyl, wherein the C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3-6 cycloalkyl are each independently optionally substituted with deuterium, halogen, CN or -O-C 1-6 alkyl; R 12 H, halogen, -CN, -OH, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -O-C 1-6 alkyl, -O-C 3-6 cycloalkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -(CH2) n -C 3-6 cycloalkyl and =C(R d )2, wherein R d each independently is selected from H, halogen and -C 1-6 alkyl optionally substituted with halogen, wherein each occurrence of C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or C 3-6 cycloalkyl is independently optionally substituted with halogen, CN or -OC 1-6 alkyl; R 13 selected from H, -C 1-6 alkyl and -(CH2) n -C 3-6 cycloalkyl, wherein the -C 1-6 alkyl and -C 3-6 cycloalkyl are each independently optionally substituted with halo or -O-C 1-6 alkyl; R 14 and R 15 each independently is selected from the group consisting of H and -C 1-6 alkyl k is selected from an integer of 0 or 1 ; m is selected from an integer of 0 to 6; n is selected from an integer of 0 to 2; wherein the compound of formula (I) is identified by its ring NH present in the fragment, and / or the bond to the linker unit L via OH present on the side chain naphthalene or benzothiophene ring; wherein the compound of formula (I’) is bonded to the linker unit L via -NH2, -NH- or -OH present in its structure.

2. The antibody-drug conjugate of claim 1, wherein the structural fragment in Formula (I) ###0001### Formula (I) is ###0002### is Preferably, M is C-R1and M' is C-R1', wherein R1is selected from halogen or -C 1-6 alkyl, R a is H, and R1' is halogen, or M is N and M' is C-R1', wherein R a is selected from H, -C 2-6 alkynyl and -OC 1-6 alkyl, and R1' is halogen, More preferably, M is C-R1and M' is C-R1', wherein R1is selected from F or Cl, or -C 1-3 alkyl, R a is H, and R1' is F, or M is N and M' is C-R1', wherein R a is selected from H, -C 2-4 alkynyl, and -OC 1-3 alkyl, and R1' is F; and / or wherein the structural fragment in formula (I) In particular, R3is selected from -NH2, -NHC 1-6 alkyl and N(C 1-6 alkyl)2; R4is selected from -CN, halogen, -NO2, and -C 2-6 alkynyl; V is selected from H, -C 1-6 alkyl and halogen, R7and R7' are each H, or are each halogen, or one is H and the other is halogen or halogen-substituted C 1-6 alkyl, or one is halogen and the other is halogen-substituted C 1-6 alkyl, Preferably, the structural fragment For V is H, R7 and R7’ are each H, or one is H and the other is halogen, or wherein the structural fragment of formula (I) In particular embodiments, W is OH; R5is H or halo, and R6is selected from halo, -C 2-6 alkyl; R8and R8' are each H; or R8and R8' are each halo, or one of R8and R8' is H and the other is selected from halo, CN, and NO2, or one of R8and R8' is H and the other is selected from -C 1-6 alkyl; R8and R8' are each H; or R8and R8' are each halo, or one of R8and R8' is H and the other is selected from halo, CN, and NO2, or one of R8and R8' is H and the other is selected from -C 1-6 alkyl; R8and R8' are each H; or R8and R8' are each halo, or one of R8and R8' is H and the other is selected from halo, CN, and NO2, or one of R8and R8' is H and the other is selected from -C 1-6 alkyl; R8and R8' are each H; or R8and R8' are each halo, or one of R8and R8' is H and the other is selected from halo, CN, and NO2, or one of R8and R8' is H and the other is selected from -C 1-6 alkyl; R8and R8' are each H; or R8and R8' are each halo, or one of R8and R8' is H and the other is selected from halo, CN, and NO2, or one of R8and R8' is H and the other is selected from - Preferably, the structural fragment For wherein R5is halogen, R6is selected from -C 2-6 alkynyl; and / or wherein the structural fragment of formula (I) For wherein R2and R2' attached to non-adjacent ring carbon atoms together form an intra-annular bridge -CH2-, -CH2CH2- or -CH=CH-, preferably or Structure fragment in formula (I) For preferably and / or wherein Z is O and the structural fragment attached to Z is preferably more preferably 3. The antibody-drug conjugate of claim 1 or 2, wherein R9and R 10 are both H, or one or both are deuterium; and / or wherein R 11 is -C 1-6 alkyl, wherein the hydrogen atoms are optionally replaced by one or more isotopes deuterium; and / or wherein R 12 selected from -C 1-6 alkyl and =C(R d )2, wherein R d each independently is selected from H and halo, and m is 1 or 2; and / or wherein R 13 is -C 1-6 alkyl, preferably -C 1-3 alkyl, more preferably -CH3.

4. The antibody-drug conjugate of any one of claims 1 to 3, wherein the structural fragment is selected from 5. The antibody-drug conjugate of any one of claims 1 to 4, wherein the compound of Formula (I) has any of the following sub-formulae: wherein R1, R1', R a , R3, R4, R5, R6, R7, R7', W, V, R 10 , R 11 , R 12 , R 13 , m are each as defined in claims 1 to 4, respectively; preferably R1is selected from F or Cl, or -C 1-3 alkyl, R a is H, and R1is F, or M is N and M is C-R1, wherein R a is selected from H, -C 2-4 alkynyl, and -OC 1-3 alkyl, and R1is F; R3 is -NH2, R4 is -CN, V is H, R7 and R7’ are each H, or one is H and the R5is halogen, R6is selected from -C 2-6 alkynyl, R8and R8' are each H, W is OH; R9and R 10 are both H, or one or both are deuterium; R 11 -C 1-3 alkyl, wherein the hydrogen atoms are optionally replaced by one or more isotopes deuterium; R 12 selected from -C 1-3 alkyl and =C(R d )2, wherein R d are each independently selected from H and halo; m is 1 or 2; R 13 -C 1-3 alkyl.

6. The antibody-drug conjugate of any one of claims 1, 3-4, wherein in the compound of formula (I’), In In fragments where M is C-R1, R1is selected from halo (preferably F or Cl) or -C 1-6 alkyl (preferably -CF3) optionally substituted with halo, and M' is C-R1' and R1' is halo (preferably F); or M is N, M' is C-R1' and R1' is halo (preferably F); or M is N, M' is C-R1' and R1' is -CF3. 1-3 alkyl (preferably -CF3) optionally substituted with halo, and M' is C-R1' and R1' is halo (preferably F); or M is N, M' is C-R1' and R1' is halo (preferably F); or M is N, M' is C-R1' and R1' is -CF3. and / or In In fragments, both M are C-R1, or one M is N and the other M is C-R1, each R1 is independently selected from H, halogen (preferably F) and halogen-substituted -C 1-6 alkyl (preferably one or more F-substituted -C 1-3 alkyl, more preferably -CF3), preferably the M in ortho position to R3 is selected from N and C-R1 (preferably C-halogen, more preferably C-F), and the M in ortho position to R6 is C-R1 (preferably C-halogen-substituted -C 1-3 alkyl, more preferably -C-CF3); R3 is selected from -NH2, -NHC 1-6 alkyl and N(C 1-6 alkyl)2, preferably selected from -NH2, -NHC 1-3 alkyl and N(C 1-3 alkyl)2, more preferably -NH2); R5 is H or halogen (preferably F); R6 is selected from halogen (preferably Cl) and -C 1-6 alkyl (preferably -C 1-3 alkyl); In R3is selected from -NH2, -NHC 1-6 alkyl and N(C 1-6 alkyl)2(preferably from -NH2, -NHC 1-3 alkyl and N(C 1-3 alkyl)2, more preferably -NH2); R4is selected from -CN, halogen, -NO2and -C 2-6 alkynyl; V is selected from H, -C 1-6 alkyl (preferably -C 1-3 alkyl) and halogen; R7and R7' are each H, or are each halogen, or one is H and the other is halogen or halogen-substituted C 1-6 alkyl (preferably halogen-substituted -C 1-3 alkyl), or one is halogen and the other is halogen-substituted C 1-6 alkyl (preferably halogen-substituted -C 1-3 alkyl), wherein the halogen is preferably F; Preferably R3 is -NH2, R4 is -CN, V is H, R7 and In In the fragment, R5 is H or a halogen (preferably F); R6 is selected from halogens and -C. 2-6 alkynyl group (preferably -C) 2-4 ynyl group and -C 1- 6-alkyl (preferably -C) 1-3 Alkyl); R8 and R8' are each H, or R8 and R8' are each halogen, or one of R8 and R8' is H and the other is selected from halogen, CN, and NO2, or one of R8 and R8' is H and the other is selected from -C which is optionally halogenated. 1-6 Alkyl group, or one of R8 and R8', is selected from H, halogen, -NO2, CN, and -C optionally substituted with a halogen. 1-6 Alkyl group, another selected from -C substituted with halogen. 1-6 Alkyl group; W is OH; R5is halogen (preferably F), R6is selected from -C 2-6 alkynyl (preferably -C 2-4 alkynyl), R8and R8' are each H, W is OH; and / or X is selected from O and NH; Y is selected from -CH2CH2- and absent; Z is selected from O; R9and R 10 are both H; or one or both are deuterium; R 11 -C 1-6 alkyl (preferably -C 1-3 alkyl), wherein the hydrogen atoms are optionally replaced by one or more deuterium; R 12 selected from -C 1-6 alkyl (preferably -C 1-3 alkyl) and =C(R d )2, wherein R d each independently is selected from H and halogen (preferably F); m is 0, 1 or 2 (preferably 1 or 2); n, k are each independently 0 or 1 ; R 13 -C 1-6 alkyl (preferably -C 1-3 alkyl, more preferably -CH3); R 14 and R 15 is H or -C 1-3 alkyl (preferably -CH3).

7. The antibody-drug conjugate of claim 1, wherein the Ras inhibitor compound is selected from the group consisting of: or a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceu- tically acceptable salt, or a solvate thereof.

8. The antibody-drug conjugate of any one of claims 1 to 7, wherein the linker unit L has the following formula: -J-B-G- (II-3) or -J-G- (II-4) wherein: J is selected from -J1-, -J2-, -J1-J2-, -J2-J1-, wherein - J1is selected from wherein the asterisk indicates the point of attachment to the drug P or to -J2-, and the wavy line indicates the point of attachment to the cleavable linker B or J2; - J2- is selected from wherein the asterisk indicates the point of attachment to the drug P or to -J1-, and the wavy line indicates the point of attachment to the cleavable linker B or -J1-; B is a peptide of formula (B): -(AA) d - wherein the N-terminus of the peptide is connected to the G moiety of the linker unit and the C-terminus of the peptide is connected to J, wherein d is an integer from 2 to 12, preferably an integer from 2 to 4, AA is preferably an amino acid selected from the group consisting of alanine, glycine, asparagine, valine, phenylalanine, citrulline, glutamic acid, preferably -(AA) d - from C-terminus to N-terminus selected from the group consisting of: Ala-Ala, Cit-Val, Ala-Val, Glu-Gly, Asn-Ala-Ala, Cit-Ala-Glu, Gly-Phe-Gly-Gly, most preferably Ala-Ala or Asn-Ala-Ala; G is wherein G1is the atom in Ab responsible for attachment to L, G3' is -C 1-10 alkylene-, preferably -C 1-5 alkylene-, Bu is absent or is of formula (A) the structural fragment of Preferably G is selected from each occurrence of X’ is independently selected from CH or N; each occurrence of Y1' is independently selected from -NH-, -NC 1-6 alkyl- or -O-; R is, at each occurrence, independently selected from H and -C(O)R 16 R is, at each occurrence, independently selected from H and -C(O)R 1-6 R is, at each occurrence, independently selected from H and -C(O)R 1-3 R is, at each occurrence, independently selected from H and -C(O)R each occurrence of R is independently selected from H, -NO2, -NH2, -CF3, or a fragment of Formula (A1): 17 each R is independently selected from H, -NO2, -NH2, -CF3, or a fragment of Formula (A1): each occurrence of R is independently -C 18 each independently -C 1-6 alkyl, preferably C 1-3 alkyl, more preferably methyl; G1 is a bonding atom from Ab, preferably a S atom; T0is -C 1-6 alkylene-; T is selected from -C(R a )2- -O- -NR a - or is absent; T1 is selected from -C(R) a )2-、-O-、-NR a -; T2is selected from -CR a - and -N-; T3 is a peptide consisting of 2 to 6 amino acids attached to N at the carboxy terminus; Q is selected from -CO-, -0-, -NR a - or is absent; U is a moiety comprising a hydrophilic peptide; R a each independently selected from H or -C 1-6 alkyl, preferably H or -CH3; subunit is selected from natural and unnatural amino acid residues; p is an integer from 0 to 4, such as 0-2, 1-4, 1-2, 2-4; t is an integer from 1 to 20, such as 1-10, 2-10, 2-8, 2-6, 2-4, 4-14, 4-12, 4-10, 5-10, 6-10, 6-12, 8-10, 8-14.

9. The antibody-drug conjugate of claim 8, wherein J in linker unit L is selected from: - -J1-J2- and -J1-J1-J2-, preferably selected from the group consisting of: More preferably (J-1), (J-2), (J-8), (J-9) and (J-10), wherein Y1' attached to the aromatic ring is attached in para- or ortho-position to the other point of attachment on the ring, preferably in para-position; each occurrence of X' is independently selected from -N- or -CH-; each occurrence of Y1' is independently selected from -NH- or -O-; Each occurrence of R 16 Each is independently selected from H or C 1-3 Alkyl group, preferably H; each occurrence of R is independently selected from H or a moiety of formula (A1) 17 each R is independently selected from H or a moiety of formula (A1) Each occurrence of R 18 Each is independently selected from -C 1-3 Alkyl groups, preferably methyl groups; each occurrence of T is selected from -O-, -NR a - or is absent; each occurrence of T1 is selected from -CH2-, -O-, -NCH3-; each occurrence of T2 is selected from -N-; each occurrence of T3 is a 2-4 peptide attached with N in carboxy-terminus, preferably selected from Ala-Ala, Cit-Val, Ala-Val, Glu-Gly, Asn-Ala-Ala, Cit-Ala-Glu, Gly-Phe-Gly-Gly; Q is absent or -NR a - or -O-; each occurrence of p is 0-4, preferably 0 or 2; each occurrence of U is a bond to a hydrophilic peptide.

10. The antibody-drug conjugate of claim 8 or 9, wherein U in linker unit L is selected from: wherein R' and R" are residues carried by natural or unnatural amino acids, R is -C 1-6 alkyl, more preferably -CH3, R'" is H or -C 1-6 alkyl, preferably H or -CH3, R a selected from H or -C 1-6 alkyl, preferably H or -CH3, more preferably -CH3; preferably the moiety in square brackets is a polyornithine, polyarginine, polyglycine comprising 4-14 units or 5-10 units; U is preferably selected from the group consisting of: wherein R a is selected from H or -C 1-6 alkyl, preferably -CH3, and t is 4-12, 6-12, 4-10 or 5-10.

11. The antibody-drug conjugate of any one of claims 8-10, wherein at least one of J and G in linker unit L carries a hydrophilic peptide as defined in any one of claims 8-10.

12. The antibody-drug conjugate of any one of claims 1-11, wherein the linker unit L has the following formula: or the maleimide moiety in each of the above formulae is of the corresponding general formula.

13. A compound comprising the structure of linker unit L of any one of claims 8-12, or a stereoisomer, stable isotopic variant, pharmaceutically acceptable salt, or solvate thereof.

14. A conjugate of the formula, P-J-B-G (PL-1) or P-J-G (PL-2) or a stereoisomer, stable isotopic variant, pharmaceutically acceptable salt, or solvates thereof, wherein P is as defined in any one of claims 1 to 7; J is as defined in any one of claims 8 to 12; B is as defined in claim 8; G is as defined in any one of claims 8, 10-12, except that, in the definition of G, the following proviso is added: wherein in place of; Preferably, the compound of formula (PL) has the following general formula: wherein the variables are as defined in any one of claims 8 to 11.

15. The compound of claim 14, selected from the group consisting of compounds C47, C54, C59, C62-74, C84-85, C87-99, C102-109, C111-114 in the synthesis examples of the specification, or a stereoisomer, isotopic variant, stable isotopic variant, pharmaceutically acceptable salt, or solvate thereof.

16. The antibody-drug conjugate of any one of claims 1 to 12, wherein formula (X) has the following formula: wherein P is as defined in any one of claims 1 to 7; J is defined in any one of claims 8 to 11; B is as defined in claim 8; G is as defined in claim 8, 10 or 11, or a stereoisomer, tautomer, stable isotopic variant, pharmaceutically acceptable salt, or solvate thereof.

17. The antibody-drug conjugate according to any one of claims 1 to 12 and 16, wherein q is 1 to 10, or an average DAR value in the range between any two of the numbers 1 to 10, such as about 1-10, 1-8, 2-8, 3-10, 3-8, 4-10, 4-8, 6-8 or 6-10.

18. The drug-antibody conjugate of any one of claims 1 to 12 and 16 to 17, wherein Ab is an antibody or antigen-binding fragment thereof that binds to a tumor-specific antigen or a tumor-associated antigen, wherein the tumor-specific antigen or tumor-associated antigen is selected from the group consisting of: HER2, Her3, HER1 (ErbB1), HER4 (ErbB4), TROP2, Nectin-4, Tissue Factor, PD-L1, PD-1, PD-L1 / PD-L2, MET, CLDN18.2, KIT, CTLA-4, RPR1, Ephrin A2 receptor (EphA2), Folate receptor (FRa), Mesothelin, Endothelin receptor, GCPII, IL-13Ra, BCMA, GD2, CLL-1, CA-IX, MUC1, 5T4, AOC3, ALK, AXL, C242, CA-125, CCL11, CCR5, CD2, CD3, CD4, CDS, CD15, CA15-3, CD16, CD18, CD19, CD20, CD21, CD22, CD25, CD30, CD32, CD33, CD37, CD38, CD44, CD52, CD56, CD64, CD66e, CD70, CD72, CD74, CD79a, CD79b, CD123, CD138, CD142, CD174, CD276, CDH3, CDH6, CDH17, CCD79b, CLDN9 / CLDN6, CA19-9, DPEP3, AGS-16, IGF1R, IGF2R, VEGFR1, VEGFR2, VEGFR3, PDGFR-a, PDGFR-b, EGFR, EGFRvIII, ENPP3, FcRH5, FRa, KAAG1, LIV-1, Mesothelin, cMet, ROR1, SLTRK6, TF, BMPR1B, E16, TOP1, STEAP1, STEAP2, 0772P, MUC16, Napi2b, Napi3b, Sema 5b, PSCAhlg, ETBR, RNF124, prostate cancer associated gene 1, TrpM4, teratocarcinoma-derived growth factor 1, C3DR, FcRH2, NCA, MDP, IL20R-alpha, Brevican, EphB2R, ASLG659, prostate stem cell antigen precursor, GEDA, BAFF-R, CXCR5, CCR2, CCR8, HLA-DOB, P2X5, LY64, FcRH1, IRTA2, TENB2, integrin alpha 5 beta 6, integrin alpha 4 beta 7, FGF2, FGFR1, FGFR2, FGFR3, FGFR4, PSMA, Somatostatin receptor, RANK, SLAMF7, ITGB6, CEACAM5, CA9, EGFRvlll, IL2RA, AXL receptor tyrosine kinase, TGF-beta R, TNFRSF8, cancer / testis associated antigen, CLEC14A, GRP78, stem cell specific antigen, ASG-5, PRR4, GUCY2C, SLC39A6, TPBG, midkine-related tumor-associated antigen CA242, FOLR1, GPNMB, HAVCR1, prostate tumor target Mindin, VTCN1, PTK7 protein tyrosine kinase 7, macrophage stimulating 1 receptor, TACSTD2, CA6, DLL3, DLL4, EpCAM, FAP, Fibronectin-EDB, DKK-1, Endoglin, VCAM1, GPC3, DR5, ASCT2, B7H1, B7H3, B7H4, or any combination thereof; Preferably, the tumor-specific antigen or tumor-associated antigen is selected from the group consisting of AXL, B7H1, B7H3, B7H4, BCMA, CD16, CD19, CD22, CD25, CD30, CD32, CD33, CD44, CD64, CD70, CD74, CD79, CD138, CD142, CD276, CDH3, CEACAM5, Claudin 18.2, CLDN9 / CLDN6, DPEP3, EGFR, ENPP3, EphA, FcRH5, FOLR1, FRa, GCPII, HER2, HER3, KAAG1, KIT, LIV-1, Mesothelin, cMet, MUC1, Nectin-4, PD-L1, PD-L1 / PD-L2, PSMA, ROR1, RPR1, TF, TOP1, TROP2, or any combination thereof. More preferably, the tumor-specific antigen or tumor-associated antigen is selected from the group consisting of HER2, Claudin 18.2, EGFR, TROP2, Nectin-4, or a combination of EGFR and Met.

19. The drug-antibody conjugate of any one of claims 1 to 12 and 16 to 18, wherein: the Ab comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs) that specifically bind to HER2, wherein: HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 6, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 7, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 8, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 3, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 4, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 5; or the Ab comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs) that specifically bind to Trop2, wherein: HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 18, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 19, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 20, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 15, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 16, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 17; or the Ab comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs) that specifically bind to Claudin 18.2, wherein: HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 29, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 30, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 31, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 26, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 27, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 28; or the Ab comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs) that specifically bind EGFR, wherein: according to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 40, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 41, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 42, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 37, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 38, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 39; or the Ab comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs) that specifically bind Nectin4, wherein: according to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 72, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 73, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 74, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 69, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 70, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 71, or the Ab comprises a first set of complementarity determining regions that specifically bind EGFR and a second set of complementarity determining regions that specifically bind MET, wherein: the first set of complementarity determining regions comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs), wherein: according to the Kabat definition, HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 49, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 50, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 51, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 52, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 53, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:54, The second set of complementarity determining regions comprises 3 heavy chain complementarity determining regions (HCDRs) and 3 light chain complementarity determining regions (LCDRs), wherein: HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 55, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 56, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO: 57, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO: 58, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO: 59, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO:

60.

20. The drug-antibody conjugate of any one of claims 1 to 12 and 16 to 19, wherein the Ab comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 10, and wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 9; or wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 22, and wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 21 ; or wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 33, and wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 32; or wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 44, and wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 43; or wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 76, and wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 75; or wherein the Ab comprises a first heavy chain variable region and a first light chain variable region and a second heavy chain variable region and a second light chain variable region, wherein the first heavy chain variable region and the first light chain variable region comprise the amino acid sequences set forth in SEQ ID NO: 61 and SEQ ID NO: 62, respectively, and wherein the second heavy chain variable region and the second light chain variable region comprise the amino acid sequences set forth in SEQ ID NO: 63 and SEQ ID NO: 64, respectively.

21. The drug-antibody conjugate of any one of claims 1 to 12 and 16 to 20, wherein the Ab comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 1 ; or (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 14, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 13; or (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 25, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 24; or (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 37, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:

36. (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 36, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 35; or (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 76, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 75, or (a) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 45, (b) a first light chain comprising the amino acid sequence of SEQ ID NO: 46, (c) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 47, and (d) a second light chain comprising the amino acid sequence of SEQ ID NO:

48.

22. The drug-antibody conjugate of any one of claims 1 to 12 and 16 to 21, wherein the Ab is selected from Trastuzumab or an antibody fragment thereof, or other anti-human HER2 antibody which recognizes the same epitope or binds to human HER2 in competition therewith, preferably Trastuzumab; or wherein the Ab is selected from Satumomab or an antibody fragment thereof, or other anti-human TROP2 antibody which recognizes the same epitope or binds to human TROP2 in competition therewith, preferably Satumomab; or wherein the Ab is selected from Sotorixumab or an antibody fragment thereof, or other anti-human Claudin 18.2 antibody which recognizes the same epitope or binds to human Claudin 18.2 in competition therewith, preferably Sotorixumab; or wherein the Ab is selected from Cetuximab or an antibody fragment thereof, or other anti-human EGFR antibody which recognizes the same epitope or binds to human EGFR in competition therewith, preferably Cetuximab; or wherein the Ab is selected from Enfortumab or an antibody fragment thereof, or other anti-human Nectin 4 antibody which recognizes the same epitope or binds to human Nectin 4 in competition therewith, preferably Enfortumab; or wherein the Ab is selected from Evinacumab or an antibody fragment thereof, or other anti-human EGFR and MET antibody which recognizes the same epitope or binds to human EGFR and MET in competition therewith, preferably Evinacumab.

23. A drug-antibody conjugate selected from the group consisting of: or a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt, or a solvate thereof.

24. A pharmaceutical composition comprising the drug-antibody conjugate of any one of claims 1-12 and 16-23 or the compound of claim 14 or 15, or a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceuticall acceptable salt, or a solvate thereof, and one or more pharmaceutically acceptable excipients.

25. The pharmaceutical composition of claim 24, which is for intravenous, intratumoral, subcutaneous, intramuscular, oral, intranasal, intrathecal, transdermal or topical administration, preferably for intravenous, intraperitoneal, subcutaneous or intramuscular administration.

26. The drug-antibody conjugate of any one of claims 1-12 and 16-23, the compound of claim 14 or 15, or the pharmaceutical composition of claim 24 or 25 for use in the treatment or prevention of a disease mediated by a Ras mutant protein, such as a KRas mutant protein, in particular a KRas G12D mutant protein, preferably for use in the treatment or prevention of a hyperproliferative disease, more preferably for use in the treatment or prevention of a tumor.

27. Use of the drug-antibody conjugate of any one of claims 1-12 and 16-23, the compound of claim 14 or 15, or the pharmaceutical composition of claim 24 or 25 for the manufacture of a medicament for the treatment or prevention of a disease mediated by a Ras mutant protein, such as a KRas mutant protein, in particular a KRas G12D mutant protein, preferably a hyperproliferative disease, more preferably a tumor.

28. A method of treatment or prevention of a disease mediated by a Ras mutant protein, such as a KRas mutant protein, in particular a KRas G12D mutant protein, preferably a hyperproliferative disease, more preferably a tumor, comprising administering to a human or animal a drug-antibody conjugate of any one of claims 1-12 and 16-23, a compound of claim 14 or 15, or a pharmaceutical composition of claim 24 or 25.

29. The antibody-drug conjugate, compound or pharmaceutical composition of claim 26, the use of claim 27, or the method of claim 28, wherein the hyperproliferative disease or tumor comprises solid tumors and blood-borne tumors, and all precancerous cells and cancer cells and tissues selected from the group consisting of lung adenocarcinoma, lung cancer (including lung squamous cell carcinoma and non-small cell lung cancer, small cell lung cancer), bone cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, skin cancer, head and neck cancer (including head and neck squamous cell carcinoma), melanoma (including cutaneous or intraocular), squamous cell carcinoma, cancer of the anal region, testicular cancer, urethral cancer, ureter cancer, penile cancer, prostate cancer (including hormone refractory prostate cancer), bladder cancer, uterine cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, stomach cancer, gastric adenocarcinoma, colon cancer, rectal cancer, colorectal cancer, liver cancer, breast cancer (including metastatic breast cancer, triple negative breast cancer (TNBC)), esophageal cancer, small bowel cancer, lip cancer, laryngeal cancer, nasopharyngeal cancer, oral cancer, salivary gland cancer, peritoneal cancer, gastrointestinal stromal tumor, gastroesophageal junction (GEJ) cancer, mesothelioma, biliary tract cancer, hepatocellular cancer, seminoma, soft tissue sarcoma, osteosarcoma, urothelial cancer, sweat gland cancer, endocrine system cancer, thyroid cancer, medullary thyroid cancer, follicular thyroid cancer, papillary thyroid cancer, parathyroid cancer, kidney cancer, renal parenchymal cancer, renal cell cancer, renal pelvis cancer, adrenal gland cancer, brain cancers such as glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumor, glioblastoma (including glioblastoma multiforme), neuroblastoma; chronic or acute leukemia, Hodgkin's disease, lymphoma (including lymphocytic lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell lymphoma, diffuse lymphoma (DLBCL), primary CNS lymphoma), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CLL), and lymphocytic cancer, acute myeloid leukemia (AML), myelogenous leukemia (chronic myelogenous leukemia (CML), central nervous system tumor (CNS), spinal cord tumor, brain stem neuroglioma, or pituitary adenoma.

30. The antibody-drug conjugate, compound or pharmaceutical composition, use, or method of claim 29, wherein the tumor is selected from the group consisting of lung cancer, lung adenocarcinoma, colon cancer, rectal cancer, pancreatic cancer, endometrial cancer, cholangiocarcinoma, leukemia, and ovarian cancer.

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