Bioactive conjugates, methods for preparing them, and uses thereof

Abstract

A compound of formula (Ia) is provided. The conjugator portion is a group capable of binding BA and linking the BA to the rest of the compound, and together the cleavable portion and the linker portion include at least one site for enzymatic cleavage, providing distance between the conjugator portion and the payload portion, the payload being a cytotoxic agent, and the BA being a conjugate selected from a humanized antibody, a monoclonal antibody, a chimeric antibody or a human antibody, or an antigen-binding fragment thereof. Antibody-drug conjugate platforms and antibody-drug conjugates (ADCs) are provided herein.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to International Application No. PCT / CN2023 / 104058, filed on 29 June 2023, the disclosures of which are incorporated herein by reference in their entirety.

[0002] Antibody-drug conjugate platforms, as well as antibody-drug conjugates (ADCs) comprising the platform and an antibody or its antigen-binding fragment, and the use of ADC platforms and ADCs are provided herein.

[0003] Sequence List This application includes a sequence listing submitted electronically in XML format. The XML file is titled "01368-0075-00PCT-ST26.xml", was created on June 20, 2024, and has a size of 8,226 bytes. The sequence listing is incorporated herein by reference in its entirety. [Background technology]

[0004] Antibody-drug conjugates (ADCs) contain antibodies against tumor antigens conjugated to biologically active small molecules such as toxins or payloads (i.e., drugs). ADCs selectively deliver the payload to cells expressing the tumor antigen. The payload monomethyl auristatin E (MMAE) is an antimitotic agent that inhibits cell division. ADCs containing MMAE can become highly hydrophobic, leading to aggregation of ADCs with a high drug-to-antibody ratio (DAR) and nonspecific uptake of the ADC. ADCs containing MMAE may be unstable, potentially leading to deconjugation, premature release of the payload, deterioration of the pharmacokinetic profile, and off-target effects. ADCs employing other payloads may suffer from similar shortcomings.

[0005] The linker component of ADCs (including the portion that directly conjugates with the antibody) is a key feature in developing optimized therapeutic agents that exhibit high activity at well-tolerated doses. Electrophilic maleimide functional groups are used to link the linker to the free thiols of the antibody. In vivo, the conjugate product slowly disappears, reversing the conjugate reaction and leaving the maleimide of the ADC free to transfer to any other available thiols, including those derived from serum albumin in the plasma.

[0006] There is an ongoing need for the development of new linkers for use with MMAEs and other payloads within ADCs that resist deconjugation and premature payload release, enabling increased DAR, improved circulating stability, improved pharmacokinetics, and improved efficacy. This disclosure addresses these needs. [Overview of the initiative]

[0007] Antibody-drug conjugate platforms and antibody-drug conjugates (ADCs) are provided herein. The use of an ADC platform for preparing ADCs is also provided.

[0008] In some embodiments, the ADC compound of formula (Ia): [ka] Or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof is provided herein, [in formula: BA is a binder selected from humanized antibodies, monoclonal antibodies, chimeric antibodies, or human antibodies, or their antigen-binding fragments; The conjugator part is selected from equations (II) and (III): [ka] {In formula: U is a bond, heteroarylene, or arylene; V is a bond or -C≡C-(CH2) -; n is an integer from 0 to 10 (including both ends); W2 is -C(=O)-, -NH- or -O-; RG is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0009] In some embodiments, the ADC compound of formula (Ib): [ka] Or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof is provided herein, [in formula: BA is a binder selected from humanized antibodies, monoclonal antibodies, chimeric antibodies, or human antibodies, or their antigen-binding fragments; The conjugator part is selected from equations (II) and (III): [ka] {In formula: U is a bond, heteroarylene, or arylene; V represents a bond or -C≡C-(CH2). n -and; n is an integer between 0 and 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] -(succinimido-3-yl-N)-, or [ka] and; RS is -NR 1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6 -or- OC(=O)NHS(=O)2NR 6 -and; R 6 is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently 0, 1, or 2; [ka] This indicates a covalent bond site within the compound, and * indicates a connection where the conjugator part connects to BA; The severable portion has the formula (Va), (Vb), or (Vc): [ka] {In formula: R 2 Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. 1-4 Alkyl, -CN, or -NO2, *** indicates a connection where the severable portion connects to the conjugator portion, and **** indicates a connection where the severable portion connects to the linker portion. The linker section has equation (IV'): [ka] {in ceremony HG is a hydrophilic residue, and **! indicates a connection where the linker part connects to the cap.} The caps are CH3C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -NH-C(=O)-, CH3(C(=O)N(CH3)CH2) a C(=O)-, -NH-(CH2CH2O) a -(CH2) b CH3 or -(N(CH3)(CH2) c C(=O)) a It is NH2, and {in the formula: a is an integer from 1 to 18 (including both ends). b and d are independently 0, 1, or 2, and c is an integer between 1 and 4 (including both ends); The payload portion consists of payload residues; and x is between 1 and 15 (including both ends).

[0010] In some embodiments, the ADC compound of formula (Ic): [ka] Or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof is provided herein, [in formula: BA is a binder selected from humanized antibodies, monoclonal antibodies, chimeric antibodies, or human antibodies, or their antigen-binding fragments; The conjugator part is selected from equations (II) and (III): [ka] {in formula; U is a bond, heteroarylene, or arylene; V is a bond or -C≡C-(CH2) n -; n is an integer from 0 to 10 (including both ends); W2 is -C(=O)-, -NH- or -O-; RG is

Chem.

Chem.

Chem.

Chem.

[0011] In some embodiments, the ADC compound of formula (Id): [ka] Or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof is provided herein, [in formula: BA is a binder selected from humanized antibodies, monoclonal antibodies, chimeric antibodies, or human antibodies, or their antigen-binding fragments; The conjugator part is selected from equations (II) and (III): [ka] {In formula: U is a bond, heteroarylene, or arylene; V represents a bond or -C≡C-(CH2). n -and; n is an integer between 0 and 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] -(succinimido-3-yl-N)-, or [ka] and; RS is -NR 1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6 -or- OC(=O)NHS(=O)2NR 6 -and; R 6 is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently 0, 1, or 2; [ka] indicates the covalent bond points within the compound, and * indicates the bond by which the conjugator part is connected to BA}; The linker part has the formula (IV’):

Chemical formula

Chemical formula

[0012] In some embodiments, the platform is a conjugator-linker-payload compound of formula (Ia’): [Chemical formula] Or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof, [wherein: The conjugator part is selected from formula (II’) and (III’): [[ID=5I]][Chemical formula] {Wherein: U is a bond, heteroarylene or arylene; V is a bond or -C≡C-(CH2) n -; n is an integer from 0 to 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] and; RS is -NR 1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6 -or- OC(=O)NHS(=O)2NR 6 -and; R 6 is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently 1 or 2, and [ka] This indicates a covalent bond site within the compound; The linker section has formula (IV): [ka] {In formula: HG is a hydrophilic residue, and **This indicates a connection where the linker section connects to the conjugator section. The severable portion has formula (V): [ka] {In formula: R 2 Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. 1-4Alkyl, -CN or -NO2, and **** indicates a connection where the severable portion connects to the linker portion; and The payload portion consists of payload residues.

[0013] In some embodiments, the platform is a conjugator-linker-payload compound of formula (Ib'): [ka] or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, [in the formula: The conjugator part is selected from equations (II') and (III'): [ka] {In formula: U is a bond, heteroarylene, or arylene; V represents a bond or -C≡C-(CH2). n -and; n is an integer between 0 and 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] and; RS is -NR 1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6 -or- OC(=O)NHS(=O)2NR 6 -and; R 6is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently 1 or 2, and [ka] This indicates a covalent bond site within the compound; The severable portion has the formula (Va), (Vb), or (Vc): [ka] {In formula: R 2 Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. 1-4 Alkyl, -CN, or -NO2, *** indicates a connection where the severable portion connects to the conjugator portion, and **** indicates a connection where the severable portion connects to the linker portion. The linker section has equation (IV'): [ka] {in ceremony HG is a hydrophilic residue, and **! indicates a connection where the linker part connects to the cap.} The caps are CH3C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -NH-C(=O)-, CH3(C(=O)N(CH3)CH2) a C(=O)-, -NH-(CH2CH2O) a -(CH2) b CH3 or -(N(CH3)(CH2) c C(=O)) a It is NH2, and {in the formula: a is an integer from 1 to 18 (including both ends). b and d are independently 0, 1, or 2, and c is an integer from 1 to 4 (including both ends); and The payload portion consists of payload residues.

[0014] In some embodiments, the platform is a conjugator-linker-payload compound of formula (Ib'): [ka] or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, [in the formula: The conjugator part is selected from equations (II') and (III'): [ka] {In formula: U is a bond, heteroarylene, or arylene; V represents a bond or -C≡C-(CH2). n -and; n is an integer between 0 and 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] and; RS is -NR 1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6 -or- OC(=O)NHS(=O)2NR 6 -and; R 6 is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently 1 or 2, and [ka] This indicates a covalent bond site within the compound; The linker section has formula (IV): [ka] {In formula: HG is a hydrophilic residue, and **This indicates a connection where the linker section connects to the conjugator section. The severable portion has the formula (Va'), (Vb'), or (Vc'): [ka] {In formula: R 2 Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. 1-4 Alkyl, -CN, or -NO2, ***! indicates a connection where the severable portion connects to the cap, and **** indicates a connection where the severable portion connects to the linker portion. The caps are CH3C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -NH-C(=O)-, CH3(C(=O)N(CH3)CH2) a C(=O)-, -NH-(CH2CH2O) a -(CH2) b CH3 or -(N(CH3)(CH2) c C(=O))a It is NH2, and {in the formula: a is an integer from 1 to 18 (including both ends). b and d are independently 0, 1, or 2, and c is an integer from 1 to 4 (including both ends); and The payload portion consists of payload residues.

[0015] In some embodiments, the platform is a conjugator-linker-payload compound of formula (Id'): [ka] or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, [in the formula: The conjugator part is selected from equations (II') and (III'): [ka] {In formula: U is a bond, heteroarylene, or arylene; V represents a bond or -C≡C-(CH2). n -and; n is an integer between 0 and 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] and; RS is -NR 1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6-or- OC(=O)NHS(=O)2NR 6 -and; R 6 is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently 1 or 2, and [ka] This indicates a covalent bond site within the compound; The linker section has equation (IV'): [ka] {In formula: HG is a hydrophilic residue, and **! indicates a connection where the linker part connects to the cap.} The severable portion has the formula (Va"), (Vb"), or (Vc): [ka] {In formula: R 2 Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. 1-4 Alkyl, -CN, or -NO2, ***† indicates a connection where the severable portion connects to the launcher, and **** indicates a connection where the severable portion connects to the linker portion. The caps are CH3C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -NH-C(=O)-, CH3(C(=O)N(CH3)CH2) a C(=O)-, -NH-(CH2CH2O) a -(CH2) bCH3 or -(N(CH3)(CH2) c C(=O)) a It is NH2, and {in the formula: a is an integer from 1 to 18 (including both ends). b and d are independently 0, 1, or 2, and c is an integer between 1 and 4 (including both ends); Blancher has formulas (XIIa), (XIIa1), (XIIb), or (XIIb1): [ka] {In formula: Hydrophilic substances are -NH-(CH2CH2O) a1 -(CH2) b1 CH3, -C(=O)NH2, -C(=O)-(CH2CH2O) a1 -(CH2) b1 CH3 or -(N(CH3)(CH2) c1 C(=O)) a1 It is NH2, † indicates a connection where the launcher connects to the conjugator section. †† indicates a connection where the plancher connects to the cuttable section. a1 is an integer from 1 to 18 (including both ends), b1 is 0, 1 or 2, and Each of c1, p, and q is an independent integer between 1 and 1 (including both ends); and The payload portion consists of payload residues.

[0016] Further objectives and advantages are partially described in subsequent embodiments for carrying out the invention, and partially understood or known by embodiments for carrying out the invention. These objectives and advantages are realized and achieved by the elements and combinations detailed in the appended claims.

[0017] Please understand that the above general description and the following embodiments for carrying out the invention are merely illustrative and descriptive, and do not limit the scope of the claims.

[0018] The accompanying drawings incorporated herein, and which constitute part thereof, serve to illustrate embodiments and to illustrate the principles described herein, along with modes for carrying out the invention. [Brief explanation of the drawing]

[0019] [Figure 1] Direct cell killing of U937 cells by ADC3-1, ADC3-2, ADC3-3, and ADC3-4 is demonstrated. [Figure 2] Direct cell killing of HL60 cells by ADC3-1, ADC3-2, ADC3-3, and ADC3-4 is demonstrated. [Figure 3] Direct cell killing of TF1 cells by ADC3-1, ADC3-2, ADC3-3, and ADC3-4 is demonstrated. [Figure 4] This demonstrates direct cell killing of U937 cells by ADC3-5 and ADC3-6. [Figure 5] This demonstrates direct cell killing of HL60 cells by ADC3-5 and ADC3-6. [Figure 6] This demonstrates direct cell killing of TF1 cells by ADC3-5 and ADC3-6. [Figure 7] This demonstrates direct cell killing of U937 cells by ADC3-7, ADC3-8, and ADC3-9. [Figure 8] This demonstrates direct cell killing of HL60 cells by ADC3-7, ADC3-8, and ADC3-9. [Figure 9] This demonstrates direct cell killing of TF1 cells by ADC3-7, ADC3-8, and ADC3-9. [Figure 10] This demonstrates direct cell killing of U937 cells by ADC3-10, ADC3-11, and ADC3-12. [Figure 11] This demonstrates direct cell killing of HL60 cells by ADC3-10, ADC3-11, and ADC3-12. [Figure 12]This demonstrates direct cell killing of TF1 cells by ADC3-10, ADC3-11, and ADC3-12. [Figure 13] This demonstrates direct cell killing of U937 cells by ADC3-15. [Figure 14] This demonstrates direct cell killing of HL60 cells by ADC3-15. [Figure 15] This demonstrates direct cell killing of TF1 cells by ADC3-15. [Figure 16] This demonstrates direct cell killing of NCI-H358 cells by ADC3-B. [Figure 17] This demonstrates direct cell killing of NCI-H1048 cells by ADC3-B. [Figure 18] This demonstrates direct cell killing of MDA-MB-453 cells by ADC3-B. [Figure 19] This demonstrates direct cell killing of NCI-H358 cells by ADC4-1, ADC4-2, and ADC4-3. [Figure 20] This demonstrates direct cell killing of NCI-H1048 cells by ADC4-1, ADC4-2, and ADC4-3. [Figure 21] This demonstrates direct cell killing of MDA-MB-453 cells by ADC4-1, ADC4-2, and ADC4-3. [Figure 22] The ADC, payload, and total antibody ("TAB") PK profiles in mice are shown. [Figure 23] This study demonstrates the antitumor efficacy of ADC in an NCI-H1650 xenograft model. [Modes for carrying out the invention]

[0020] Antibody-drug conjugates (ADCs) and covalent linkers and conjugator-linker-payload (platforms) for producing such ADCs are provided herein. ADCs may be used to treat diseases or disorders (such as cancer), for example, by providing compositions comprising ADCs. The ADCs disclosed herein exhibit superior resistance to deconjugation and premature payload release, enabling increased DAR, improved circulating stability, improved pharmacokinetics, and improved efficacy compared to known ADCs, including those with a payload of MMAE. The conjugate comprises a linker having at least one portion that improves its performance, such as increasing serum stability compared to a conjugate without that portion. The linker comprises a hydrophilic portion (group) that can be cleaved by a glycosidase, such as a lysosome-specific glycosidase.

[0021] definition In this disclosure, the following terms have the meanings set forth below unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art in which this disclosure pertains. If there are multiple definitions of a term used herein, these definitions shall prevail unless otherwise noted.

[0022] Where a trademark is used herein, unless the context otherwise specifies, a reference to the trademark name also refers to the product formulations, generic drugs, and active pharmaceutical ingredients of the trademarked product.

[0023] In this specification, the term “antibody” is used in its broadest sense and specifically encompasses intact monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments exhibiting desired biological activity. Intact antibodies primarily have two regions: a variable region and a constant region. The variable region binds to and interacts with the target antigen. The variable region includes a complementary determining region (CDR) that recognizes and binds to a specific binding site on a particular antigen. The constant region is recognized by the immune system and can interact with it (e.g., Janeway et al., 2001, Immuno. Biology, 5). th (Ed., Garland Publishing, New York). Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. Antibodies can be derived from any suitable species. In some embodiments, the antibodies are derived from humans or mice. Antibodies can be, for example, human antibodies, humanized antibodies, or chimeric antibodies.

[0024] The terms "humanized" or "humanized antibody" refer to a form of antibody that contains sequences derived from non-human (e.g., rodent) antibodies, and even from human antibodies. Such antibodies contain minimal sequences derived from non-human immunoglobulins. Generally, humanized antibodies contain substantially all of at least one, typically two, variable domains, where all or substantially all hypervariable loops in the variable domains correspond to the hypervariable loops of non-human immunoglobulins, and all or substantially all FR regions are FR regions of human immunoglobulin sequences. Humanized antibodies also optionally contain at least a portion of the immunoglobulin constant region (Fc), typically at least a portion of the human immunoglobulin constant region (Fc). When it is necessary to distinguish humanized antibodies from rodent-parent antibodies, the prefix "hum," "hu," "Hu," or "h" is added to the name of the antibody clone. Humanized forms of rodent antibodies generally contain the same CDR sequence as the parent rodent antibody, but may include certain amino acid substitutions to increase affinity, improve the stability of the humanized antibody, remove post-translational modifications, or for other reasons.

[0025] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially identical population of antibodies (i.e., an individual antibody that is identical except for potentially naturally occurring mutations that may exist in trace amounts). Monoclonal antibodies are highly specific and target a single antigenic site. The modifier “monoclonal” should not be interpreted as requiring antibody production by any particular method.

[0026] An "intact antibody" is an antibody that, in addition to an antigen-binding variable region, contains a light chain constant domain (CL) and a heavy chain constant domain (CH1, CH2, CH3, and CH4) (depending on the antibody class). The constant domain may be a native sequence constant domain (e.g., a human native sequence constant domain) or an amino acid sequence variant thereof.

[0027] An "antibody fragment" includes a portion of an intact antibody containing an antigen-binding region or a variable region. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments, diabodies, triabodies, tetrabodies, linear antibodies, single-chain antibody molecules, scFv, scFv-Fc, antibody fragments (multiple), multispecific antibody fragments formed from fragments (multiple) produced by a Fab expression library, or any of the above epitope-binding fragments that bind immunospecifically to a target antigen (e.g., cancer cell antigen, viral antigen, or microbial antigen).

[0028] An "antigen" is the substance to which an antibody specifically binds.

[0029] The terms "specific binding" and "specifically binding" mean that an antibody or antibody derivative binds to its corresponding target antigen in a highly selective manner and does not bind to a large number of other antigens. Typically, an antibody or antibody derivative binds to at least about 1 × 10⁻¹⁶ antigens. -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, or 10 -12 It binds with affinity M, and binds to the given antigen with an affinity at least twice as great as the affinity it has for binding to the given antigen or nonspecific antigens other than the given antigen or closely related antigens (e.g., BSA, casein).

[0030] The terms "inhibit" or "inhibit" mean to reduce a measurable amount or to completely prevent it.

[0031] The term "therapeutic dose" refers to the amount of a drug effective in treating a disease or disorder in a mammal. In the case of cancer, a therapeutic dose of a drug can reduce the number of cancer cells, shrink tumor size, inhibit (i.e., slow or stop to some extent) cancer cells from invading peripheral organs, inhibit (i.e., slow or stop to some extent) tumor metastasis, inhibit tumor growth to some extent, and / or alleviate to some extent one or more symptoms associated with cancer. A drug has cell division inhibitory and / or cytotoxic properties to the extent that it can inhibit growth and / or kill existing cancer cells. In the case of cancer treatment, efficacy can be measured, for example, by evaluating the time to progression (TTP) and / or determining the response rate (RR).

[0032] The terms “substantial” or “substantially” refer to the majority of a mixture or sample population, i.e., >50%, preferably 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or more than 99% of the population.

[0033] The terms "intracellularly cleaved" and "intracellular cleavage" refer to intracellular metabolic processes or reactions to ligand-drug conjugates (e.g., antibody-drug conjugates (ADCs)) where the covalent bond between the drug portion (D) and the ligand unit (e.g., antibody (BA or Ab)), such as the linker, is cleaved, resulting in the release of the drug or another metabolite of the conjugate within the cell. Thus, the cleaved portion of a drug-linker-ligand conjugate is an intracellular metabolite.

[0034] The term "cytotoxic activity" refers to the cytotoxic, inhibitory, or antiproliferative effect of a drug-linker-ligand conjugate compound or its intracellular metabolite. Cytotoxic activity may also be expressed as an IC50 value, which is the concentration (moles or mass) per unit volume at which half of the cells survive.

[0035] As used herein, the term “cytotoxic agent” refers to a substance that inhibits cellular function and / or causes cellular destruction. This term is intended to include radioisotopes (e.g., radioisotopes of 211At, 131I, 125I, 90Y, 186Re, 188Re, 153Sm, 212Bi, 32P, 60C, and Lu), chemotherapeutic agents, and toxins, examples of which include small molecule toxins or enzymatic toxins of bacterial, fungal, plant, or animal origin, including their synthetic analogs and derivatives.

[0036] The terms “cancer” and “malignant” refer to or describe physiological conditions or disorders in mammals that are typically characterized by unregulated cell growth. A “tumor” includes one or more cancerous cells.

[0037] As used herein, “autoimmune disease” refers to a disease or disorder that originates from and directly targets the tissues or proteins of an individual.

[0038] Examples of “patient” or “subject” include, but are not limited to, mammals (such as humans, rats, mice, guinea pigs, monkeys, pigs, goats, cattle, horses, dogs, or cats), and birds or poultry. In one embodiment, the patient is human.

[0039] The terms “to treat” or “treatment” refer to therapeutic treatment and preventive measures to prevent recurrence, unless otherwise indicated by the context, and their purpose is to suppress or slow (mitigate) undesirable physiological changes or impairments (e.g., the development or spread of cancer). For the purposes of this disclosure, beneficial or desirable clinical outcomes include, but are not limited to, symptom relief, reduction of disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or mitigation of the disease state, and remission (partial or overall), whether detectable or undetectable. “Treatment” may also mean extending survival compared to the survival expected without treatment. Those requiring treatment include those who already have a condition or impairment, as well as those who are prone to developing a condition or impairment.

[0040] In the context of cancer, the term “to treat” includes any or all of the following: inhibiting tumor cells, cancer cells, or tumor growth; inhibiting the replication of tumor cells or cancer cells; reducing the overall tumor burden or decreasing the number of cancer cells; and improving one or more symptoms associated with the disease.

[0041] In the context of autoimmune diseases, the term “treat” includes any or all of the following: inhibiting the replication of cells associated with the autoimmune disease (including, but not limited to, cells that produce autoimmune disease antibodies); reducing the autoimmune antibody load; and improving one or more symptoms of the autoimmune disease.

[0042] As used herein and in the appended claims, the indefinite articles "a" and "an," and the definite article "the," include singular as well as plural referents, unless otherwise explicitly indicated by the context.

[0043] As used herein, and unless otherwise specified, the terms “about” and “approximately” mean, when used in relation to the amount or weight percentage of a component of a composition, an amount or weight percentage that would be recognized by those skilled in the art as producing an equivalent pharmacological effect to that obtained from a specified amount or weight percentage. In certain embodiments, when used in this context, the terms “about” and “approximately” mean an amount or weight percentage that is within 30%, 20%, 15%, 10%, or 5% of a specified amount or weight percentage.

[0044] As used herein, unless otherwise specified, the terms “about” and “approximately” mean, when used in relation to a numerical value or range of values ​​provided to characterize a particular solid form, e.g., a specific temperature or temperature range, e.g., one describing melting, dehydration, desolvation, or glass transition temperature; a mass change, e.g., a mass change as a function of temperature or humidity; a solvent or water content (e.g., in terms of mass or percentage); or a peak position, e.g., in analysis by IR, Raman spectroscopy, or XRPD, that the value or range of values ​​may deviate to an extent that is reasonable to those skilled in the art, but still describe a solid form. Techniques for characterizing crystalline morphology and amorphous solids include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy, such as infrared (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. In certain embodiments, the terms “about” and “approximately” used in this context indicate that a numerical value or range may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the given numerical value or range. For example, in some embodiments, the XRPD peak position value may vary by up to ±0.2° 2θ while still describing a specific XRPD peak.

[0045] As used herein, the term “including both ends” means, when used in relation to a range, to include both endpoints of the range. For example, if n is an integer between 0 and 4, then n may be 0, 1, 2, 3, or 4.

[0046] The "alkyl" group is a saturated, partially saturated, or unsaturated linear or branched acyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbon atoms, or in some embodiments 1 to 6, 1 to 4, or 2 to 6 carbon atoms. Representative alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and 2,3-dimethylbutyl. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and CH2C≡C(CH2CH3). Alkyl groups may be substituted or unsubstituted. In certain embodiments, where an alkyl group described herein is expressed as “substituted,” the alkyl group may be substituted with halogens (chloro, iodine, bromo, or fluoro), hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonato, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, B(OH)2, or O(alkyl)aminocarbonyl, in addition to any substituent(s) shown in the compounds and embodiments disclosed herein.

[0047] The "alkenyl" group is a linear or branched acyclic hydrocarbon having 2 to 10 carbon atoms, typically 2 to 8 carbon atoms, and containing at least one carbon-carbon double bond. Representative linear and branched (C2-C8) alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutyrenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, and 3-octenyl. The double bond of the alkenyl group may or may not conjugate with another unsaturated group. The alkenyl group may be unsubstituted or substituted.

[0048] The "cycloalkyl" group is a saturated or partially saturated cyclic alkyl group of 3 to 10 carbon atoms having a single cyclic ring or multiple fused or crosslinked rings, and may optionally be substituted with 1 to 3 alkyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms is in the range of 3 to 5, 3 to 6, or 3 to 7. Examples of such cycloalkyl groups include monocyclic structures (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc.) or polycyclic or crosslinked ring structures (e.g., adamantyl, etc.). Examples of unsaturated cycloalkyl groups include, in particular, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. The cycloalkyl group may be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanone.

[0049] An "aryl" group is an aromatic carbocyclic group with 6 to 14 carbon atoms, having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl). In some embodiments, the aryl group contains 6 to 14 carbon atoms in the ring portion of the group, and in others, 6 to 12, and possibly 6 to 10 carbon atoms. Specific examples of aryls include phenyl, biphenyl, and naphthyl. The aryl group may be substituted or unsubstituted. The term "aryl group" also includes groups containing fused rings, such as aromatic-aliphatic fused ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0050] The "arylene" group is a divalent aryl group as defined herein.

[0051] A "heteroaryl" group is an aryl ring system having 1 to 4 heteroatoms as ring atoms in a heteroaromatic ring system, with the remaining atoms being carbon atoms. In some embodiments, the heteroaryl group contains 5 to 6 ring atoms in the ring portion of the group, and in other cases, 6 to 9 or 6 to 10 atoms. Preferred heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl (e.g., isobenzofuran-1,3-diimine), indolyl, azaindolyl (e.g., pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo Examples of groups include [d]imidazolyl), imidazopyridyl (e.g., azabenzimidazolyl, 3H-imidazo[4,5-b]pyridyl, or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0052] A "heteroarylene" group is a divalent heteroaryl group as defined herein.

[0053] A "heterocyclyl" is an aromatic (also called heteroaryl) or non-aromatic cycloalkyl group in which 1 to 4 of the ring carbon atoms are independently replaced by heteroatoms from the group consisting of O, S, and N. In some embodiments, the heterocyclyl group has 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. Furthermore, the heterocyclyl may be bonded to other groups by any ring atom (i.e., any carbon or heteroatom of the heterocyclic ring). The heteroaryl group may be substituted or unsubstituted. Heterocyclyl groups include unsaturated, partially saturated, and saturated ring systems (e.g., imidazolyl, imidazolinyl, and imidazolidinyl groups). The term "heterocyclyl" includes fused ring species (including ring species containing fused aromatic and non-aromatic groups), such as benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxynyl, and benzo[1,3]dioxolyl. The term also includes bridged polycyclic ring systems containing heteroatoms, such as quinuclidyl, but is not limited to these.Typical examples of heterocyclyl groups include azilidinyl, azetidinyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, dioxolyl, furanil, thiophenyl, pyrrolyl, pyrrolidyl, imidazolyl, imidazolinil, pyrazolyl, pyrazolinil, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinil, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinil, thiomorpholinil, and tetra Hydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxatian, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolidinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, Nzooxadiazolyl, benzoxazinyl, benzodithinyl, benzoxathinyl, benzothiadinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzoimidazolyl; e.g., 1H-imidazo[4,5-b]pyridyl, or 1H-imidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolidinyl, quinoxal This includes, but is not limited to, the groups yl, quinazolinyl, synnolinyl, phthalazinyl, naphthilidinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiadinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxynyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl.Typical substituted heterocyclyl groups may be monosubstituted or multiple times, and examples include, but are not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents (such as those listed below).

[0054] The "cycloalkylalkyl" group is a radical of the formula :-alkyl-cycloalkyl (wherein alkyl and cycloalkyl are defined above). A substituted cycloalkylalkyl group may be substituted with the alkyl moiety, the cycloalkyl moiety, or both the alkyl and cycloalkyl moieties of this group. Representative cycloalkylalkyl groups, but not limited to, include cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl. Representative substituted cycloalkylalkyl groups may be monosubstituted or polysubstituted.

[0055] An "aralkyl" group is a radical of the formula :-alkyl-aryl (wherein alkyl and aryl are defined above). A substituted aralkyl group can be substituted with the alkyl moiety, the aryl moiety, or both the alkyl and aryl moieties of the group. Representative aralkyl groups, but not limited to, include benzyl and phenethyl groups, as well as condensed (cycloalkylaryl)alkyl groups (e.g., 4-ethyl-indanyl).

[0056] The "heterocyclylalkyl" group is a radical of the formula :-alkyl-heterocyclyl (wherein alkyl and aryl are defined above). Substituted heterocyclylalkyl groups can be substituted with the alkyl moiety, the heterocyclyl moiety, or both the alkyl and heterocyclyl moieties of the group. Representative heterocyclylalkyl groups include, but are not limited to, 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-ylmethyl, furan-3-ylmethyl, pyrzin-3-ylmethyl, (tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-4-yl)ethyl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0057] "Halogen" refers to chloro, iodine, bromo, or fluoro compounds.

[0058] A "hydroxyalkyl" group is one in which the aforementioned alkyl group is replaced with one or more hydroxyl groups.

[0059] The "alkoxy" group is O(alkyl) (wherein alkyl is defined above).

[0060] The "alkoxyalkyl" group is -(alkyl)-O-(alkyl) (where alkyl is defined above).

[0061] As used herein, “alkynyl” refers to a monovalent hydrocarbon radical moiety comprising at least two carbon atoms and one or more carbon-carbon triple bonds. Alkynnyls can be optionally substituted and may be linear, branched, or cyclic. Alkynnyls are radicals having 2 to 20 carbon atoms, i.e., C 2-20 Alkynyl radicals are radicals having 2 to 12 carbon atoms, i.e., C 2-12 Alkynyl radicals are radicals having 2 to 8 carbon atoms, i.e., C 2-8 Alkynyl radicals are radicals having 2 to 6 carbon atoms, i.e., C 2-6Alkynyl radicals, and radicals having 2 to 4 carbon atoms, i.e., C 2-4 This includes, but is not limited to, alkynyl radicals. Examples of alkynyl moieties include, but are not limited to, ethynyl, propynyl, and butynyl.

[0062] As used herein, “haloalkyl” refers to the alkyl group as defined above, where the alkyl group comprises at least one substituent selected from halogens, such as fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Examples of haloalkyl groups, but not limited to, include -CF3, -CH2CF3, -CCl2F, and -CCl3.

[0063] As used herein, “haloalkoxy” means the alkoxy as defined above, where the alkoxy comprises at least one substituent selected from a halogen, e.g., F, Cl, Br, or I.

[0064] As used herein, “arylalkyl” refers to the monovalent radical portion of an alkyl compound, and the alkyl compound is substituted with an aromatic substituent. That is, the aromatic compound contains a single bond to the alkyl group, and the radical is localized to the alkyl group. The arylalkyl group is bonded to the shown chemical structure via the alkyl group. The arylalkyl group can be represented by the structure, for example, B-CH2-, B-CH2-CH2-, B-CH2-CH2-CH2-, B-CH2-CH2-CH2-CH2-, B-CH(CH3)-CH2-CH2-, B-CH2-CH(CH3)-CH2-, where B is an aromatic moiety, for example, phenyl. The arylalkyl group is optionally substituted; that is, the aryl group and / or alkyl group can be substituted as disclosed herein. Examples of arylalkyl groups, but not limited to, benzyl.

[0065] As used herein, “alkylaryl” refers to the monovalent radical portion of an aryl compound, where the aryl compound is substituted with an alkyl substituent. That is, the aryl compound contains a single bond to the alkyl group, and the radical is localized to the aryl group. The alkylaryl group is bonded to the shown chemical structure via the aryl group. Alkylaryls can be represented by structures such as -B-CH3, -B-CH2-CH3, -B-CH2-CH2-CH3, -B-CH2-CH2-CH2-CH3, -B-CH(CH3)-CH2-CH3, and -B-CH2-CH(CH3)-CH3, where B is an aromatic moiety, such as phenyl. Alkylaryls are optionally substituted; that is, the aryl group and / or alkyl group can be substituted as disclosed herein. Examples of alkylaryls include, but are not limited to, toluyl.

[0066] As used herein, "aryloxy" refers to the monovalent radical portion of an aromatic compound, where the ring atom is a carbon atom and the ring is substituted with an oxygen radical; that is, the aromatic compound contains a single bond to the oxygen atom and the radical is localized to the oxygen atom (e.g., in the case of phenoxy, C6H5-O-). The aryloxy substituent bonds to the compound it substitutes through this oxygen atom. The aryloxy is optionally substituted. The aryloxy can be any radical having 6 to 20 ring carbon atoms, i.e., C6H5-O-. 6~20 Aryloxy radicals are radicals having 6 to 15 ring carbon atoms, i.e., C 6~15 Aryloxy radicals, and radicals having 6-10 ring carbon atoms, i.e., C 6~10 Examples include aryloxy radicals. Examples of aryloxy parts include, but are not limited to, phenoxy, naphthoxy, and anthroxy.

[0067] The "amino" group is a radical with the formula:NH2.

[0068] The "hydroxylamine" group is represented by formula: N(R #) is a radical of OH or NHOH (where R is the radical in the formula). # (wherein this specification is a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group).

[0069] The "alkoxyamine" group is represented by the formula: -N(R # ) an O-alkyl or -NHO-alkyl radical (wherein R is the radical in the formula) # (This is as defined above).

[0070] The "aralcoxyamine" group is represented by formula: N(R # ) an O-aryl or NHOaryl radical (wherein R is the radical in the formula) # (This is as defined above).

[0071] The "alkylamine" group is a radical of the formula:NH alkyl or N(alkyl)2 (wherein each alkyl is independently as defined above).

[0072] The "aminocarbonyl" group is represented by the formula: -C(=O)N(R # )2, -C(=O)NH(R # ), or a radical of C(=O)NH2 (wherein each R # (This is as defined above).

[0073] The "acylamino" group is represented by the formula: NHC(=O)(R # ) or N(alkyl)C(=O)(R # ) is a radical (wherein each alkyl and R # (These are independent, as defined above.)

[0074] The "O(alkyl)aminocarbonyl" group has the formula: -O(alkyl)C(=O)N(R # )2,-O(alkyl)C(=O)NH(R # ), or a radical of -O(alkyl)C(=O)NH2 (wherein each R, #(These are independent, as defined above.)

[0075] The "N-oxide" group is represented by the formula: -N + -O - It is radical.

[0076] The "carboxyl" group is a radical with the formula: -C(O)OH.

[0077] The "ketone" group is represented by the formula: C(=O)(R # ) is a radical (where R is in the formula) # (This is as defined above).

[0078] The "aldehyde" group is a radical with the formula -CH(=O).

[0079] The "ester" group is represented by the formula: C(=O)O(R # ) or OC (=O) (R # ) is a radical (where R is in the formula) # (This is as defined above).

[0080] The "urea" group has the formula: -N(alkyl)C(=O)N(R # )2,-N(alkyl)C(=O)NH(R # ), -N(alkyl)C(=O)NH2, -NHC(=O)N(R # )2, -NHC(=O)NH(R # ), or NHC(=O)NH2 # It is a radical of (wherein each alkyl and R # (These are independent, as defined above.)

[0081] The "imine" group is given by the formula: -N=C(R # )2 or -C(R # )=N(R # ) is a radical (where each R # (These are independent, as defined above.)

[0082] The "imide" group is represented by the formula: -C(=O)N(R#)C(=O)(R# ) or N((C=O)(R # ))2 radicals (where each R # (These are independent, as defined above.)

[0083] The "urethane" group is represented by the formula: -OC(=O)N(R # )2, -OC(=O)NH(R # ), -N(R # )C(=O)O(R # ), or -NHC(=O)O(R # ) is a radical (where each R # (These are independent, as defined above.)

[0084] The "amidine" group is represented by the formula: -C(=N(R # ))N(R # )2, -C(=N(R # ))NH(R # ), -C(=N(R # ))NH2, -C(=NH)N(R # )2, -C(=NH)NH(R # ), -C(=NH)NH2, -N=C(R # )N(R # )2, -N=C(R # )NH(R # ), -N=C(R # )NH2, -N(R # )C(R # )=N(R # ), -NHC(R # )=N(R # ), -N(R # )C(R # )=NH, or -NHC(R # ) = NH radical (where R # (These are independent, as defined above.)

[0085] The "guanidine" group is represented by the formula: -N(R # )C(=N(R # ))N(R # )2, -NHC(=N(R # ))N(R # )2, -N(R# )C(=NH)N(R # )2, -N(R # )C(=N(R # ))NH(R # ), -N(R # )C(=N(R # ))NH2, -NHC(=NH)N(R # )2, -NHC(=N(R # ))NH(R # ), -NHC(=N(R # ))NH2, -NHC(=NH)NH(R # ), -NHC(=NH)NH2, -N=C(N(R # )2)2, -N=C(NH(R # ))2, or the radical of -N=C(NH2)2 (where R is the radical in the formula). # (These are independent, as defined above.)

[0086] The "enamine" group is represented by the formula: -N(R # )C(R # )=C(R # )2, -NHC(R # )=C(R # )2, -C(N(R # )2)=C(R # )2, -C(NH(R # ))=C(R # )2, -C(NH2)=C(R # )2, -C(R # )=C(R # )(N(R # )2), C(R # )=C(R # )(NH(R # )) or -C(R # )=C(R # The radical of )(NH2) (where R is in the formula) # (These are independent, as defined above.)

[0087] The "oxime" group is represented by the formula: -C(=NO(R # ))(R # ), -C(=NOH)(R # ), -CH(=NO(R #)), or a radical of -CH(=NOH) (where each R # (These are independent, as defined above.)

[0088] The "hydrazide" group is represented by the formula: -C(=O)N(R # )N(R # )2, -C(=O)NHN(R # )2, -C(=O)N(R # )NH(R # ), -C(=O)N(R # )NH2, -C(=O)NHNH(R # )2, or the radical of -C(=O)NHNH2 (where R is the radical in the formula) # (These are independent, as defined above.)

[0089] The "hydrazine" group is represented by the formula: -N(R # )N(R # )2, -NHN(R # )2, -N(R # )NH(R # ), -N(R # )NH2, -NHNH(R # )2, or the radical of -NHNH2 (wherein R, R # (These are independent, as defined above.)

[0090] The "hydrazone" group is represented by the formula: -C(=NN(R # )2)(R # )2, -C(=NNH(R # ))(R # )2, -C(=N-NH2)(R # )2, -N(R # )(N=C(R # )2), or -NH(N=C(R # )2) is a radical (where R is # (These are independent, as defined above.)

[0091] The "azide" group is a radical of formula -N3.

[0092] The "isocyanate" group is a radical with the formula N=C=O.

[0093] The "isothiocyanate" group is a radical with the formula N=C=S.

[0094] The "cyanate" group is the radical of formula OCN.

[0095] The "thiocyanate" group is a radical of formula SCN.

[0096] The "thioether" group is represented by the formula: -S(R # ) is a radical (where R is in the formula) # (This is as defined above).

[0097] The "thiocarbonyl" group is represented by the formula: -C(=S)(R # ) is a radical (where R is in the formula) # (These are independent, as defined above.)

[0098] The "sulfinyl" group is represented by the formula: -S(=O)(R # ) is a radical (where R is in the formula) # (These are independent, as defined above.)

[0099] The "sulfone" group is represented by the formula: -S(=O)2(R # ) is a radical (where R is in the formula) # (These are independent, as defined above.)

[0100] The "sulfonylamino" group is represented by the formula -NHSO2(R # ) or -N(alkyl)SO2(R # ) is a radical, where each alkyl and R # This is defined above.

[0101] The "sulfonamide" group is represented by the formula -S(=O)2N(R # )2, or -S(=O)2NH(R # ), or -S(=O)2NH2 radical, and each R # These are defined independently as described above.

[0102] The "phosphonate" group is represented by the formula -P(=O)(O(R # ))2, -P(=O)(OH)2, -OP(=O)(O(R # ))(R # ), or -OP(=O)(OH)(R # ) is a radical, in the formula, each R # These are defined independently as described above.

[0103] The "phosphine" group is represented by the formula: -P(R # )2 radicals (where each R # (These are independent, as defined above.)

[0104] Where a group described herein (with the exception of alkyl groups) is expressed as "substituted," that group may be substituted with any suitable substituent(s) (one or more). Exemplary examples of substituents include those found in the compounds and embodiments disclosed herein, as well as halogens (chloro, iodo, bromo, or fluoro), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonate, phosphine, thiocarbonyl, sulfinyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, oxygen (=O), B(OH)2, O(alkyl)aminocarbonyl, monocyclic, condensed or These include cycloalkyl compounds that may be non-condensed polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclil compounds that may be monocyclic, condensed, or non-condensed polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiadinyl), monocyclic, condensed, or non-condensed polycyclic aryl or heteroaryl compounds (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanil, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridadinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranil), aryloxys, aralkyloxys, heterocyclyloxys, and heterocyclylalkoxys.

[0105] As used herein, “pharmaceutically acceptable salts” means salts prepared from pharmaceutically acceptable, non-toxic acids or bases, including inorganic acids or bases and organic acids or bases.

[0106] As used herein, unless otherwise indicated, the term “solvate” means a compound or a salt thereof that further contains a stoichiometric or nonstoichiometric amount of solvent bonded by non-covalent intermolecular forces. In one embodiment, the solvate is a hydrate.

[0107] As used herein, unless otherwise indicated, the term “hydrate” means a compound or salt thereof that further contains stoichiometric or nonstoichiometric amounts of water bound by non-covalent intermolecular forces.

[0108] As used herein, unless otherwise indicated, the term “prodrug” means a compound derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide an active compound. Examples of prodrugs, but not limited to, are derivatives and metabolites of compounds containing biohydrolyzable sites, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureids, and biohydrolyzable phosphate analogs. In certain embodiments, a prodrug of a compound having a carboxyl functional group is a lower alkyl ester of a carboxylic acid. Carboxylic acid esters can be formed by esterifying any of the carboxylic acid moieties present on the molecule. Typically, prodrugs are formed by well-known methods (e.g., Burger's Medicinal Chemistry and Drug Discovery 6). th It can be prepared using the methods described in (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).

[0109] As used herein, and unless otherwise indicated, the terms “stereoisomer” or “stereoisomerically pure” mean a single stereoisomer of a compound that is substantially free of other stereoisomers. For example, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of that compound. Typical stereoisomerically pure compounds contain about 80% by weight of one stereoisomer and less than about 20% by weight of other stereoisomers of that compound, about 90% by weight of one stereoisomer and less than about 10% by weight of other stereoisomers of that compound, about 95% by weight of one stereoisomer and less than about 5% by weight of other stereoisomers of that compound, or about 97% by weight of one stereoisomer and less than about 3% by weight of other stereoisomers of that compound. Compounds may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments disclosed herein. The use of stereoisomerically pure forms of such compounds, as well as mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equimolar or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers may be synthesized asymmetrically or resolved using standard techniques such as chiral columns or chiral resolving agents.For example, see Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p.268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0110] It should also be noted that the compound may include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In certain embodiments, the compound is isolated as either a cis or trans isomer. In other embodiments, the compound is a mixture of cis and trans isomers.

[0111] A "tautomer" refers to an isomer of a compound that is in equilibrium with itself. The concentrations of these isomers vary depending on the environment in which the compound is found; for example, they may differ depending on whether the compound is in a solid state or in an organic solution or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomers, which are referred to as tautomers of each other: [ka]

[0112] As will be readily apparent to those skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of a compound are within the scope of this disclosure.

[0113] It should also be noted that compounds may contain unnatural proportions of atomic isotopes in one or more atoms. For example, a compound may contain tritium ( 3 H), Iodine-125( 125 I), Sulfur-35( 35 S), or carbon-14 ( 14 It may be radioactively labeled with radioactive isotopes such as C, or deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15( 15 The compounds may be isotope-enriched, such as N). As used herein, “isotope-substituted compound” refers to an isotope-enriched compound. The term “isotope-enriched” refers to an atom having an isotope composition other than the atom’s natural isotope composition. “Isotope-enriched” may also refer to a compound containing at least one atom having an isotope composition other than the atom’s natural isotope composition. The term “isotope composition” refers to the amount of each isotope present in a given atom. Radiolabeled and isotope-enriched compounds are useful as therapeutic agents, e.g., cancer and inflammation treatments; research reagents, e.g., binding assay reagents; and diagnostic agents, e.g., in vivo contrast agents. All isotope variations of the compounds described herein, whether radioactive or not, are intended to be included within the scope of the embodiments provided herein. In some embodiments, isotopologs of the compounds are provided, for example, isotopologs are deuterium, carbon-13, or nitrogen-15 enriched compounds.

[0114] Please note that if there is a discrepancy between the illustrated structure and its name, the illustrated structure will be given more weight.

[0115] In this specification, the term “residue” refers to a chemical portion of a compound that remains after a chemical reaction. For example, the terms “amino acid residue” or “N-alkyl amino acid residue” refer to the product of an amide coupling or peptide coupling of an amino acid or N-alkyl amino acid with a suitable coupling partner, for example, a water molecule being expelled after the amide or peptide coupling of an amino acid or N-alkyl amino acid, resulting in the incorporation of an amino acid residue or N-alkyl amino acid residue into the product.

[0116] As used herein, “sugar,” “sugar group,” or “sugar residue” refers to a carbohydrate portion that may include 3-carbon (triose) units, 4-carbon (tetrose) units, 5-carbon (pentose) units, 6-carbon (hexose) units, 7-carbon (heptose) units, or combinations thereof, and may be a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, pentasaccharide, oligosaccharide, or any other polysaccharide. In some cases, “sugar,” “sugar group,” or “sugar residue” may include furanoses (e.g., ribofuranose, fructofuranose) or pyranoses (e.g., glucopyranose, galactopyranose), or combinations thereof. In some cases, “sugar,” “sugar group,” or “sugar residue” may include aldoses or ketoses, or combinations thereof. Non-limiting examples of monosaccharides include ribose, deoxyribose, xylose, arabinose, glucose, mannose, galactose, and fructose. Non-exclusive examples of disaccharides include sucrose, maltose, lactose, lactulose, and trehalose. Other “sugars,” “sugar groups,” or “sugar residues” include, but are not limited to, polysaccharides and / or oligosaccharides, including amylose, amylopectin, glycogen, inulin, and cellulose. In some cases, the “sugar,” “sugar group,” or “sugar residue” is an amino sugar. In some cases, the “sugar,” “sugar group,” or “sugar residue” is a glucamine residue (1-amino-1-deoxy-D-glucitol), which is linked to the rest of the molecule via its amino group to form an amide linkage with the rest of the molecule (i.e., a glucamide).

[0117] As used herein, “binding agent” refers to any molecule (e.g., an antibody) that is capable of binding with specificity to a given binding partner (e.g., an antigen).

[0118] As used herein, the term “amino acid” refers to an organic compound that contains an amino group (-NH2) and a carboxyl group (-COOH) along with a side chain (R group) specific to each amino acid. Amino acids can be either proteinogenic or non-proteinogenic. “Protogenic” means that an amino acid is one of the 20 naturally occurring amino acids found in proteins. Examples of proteinogenic amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. “Non-proteinogenic” means that the amino acid is not naturally present in proteins or is not directly produced by cellular mechanisms (e.g., it is a product of post-translational modification). Non-proteinogenic amino acids include, but are not limited to, gamma-aminobutyric acid (GABA), taurine (2-aminoethanesulfonic acid), theanine (L-γ-glutamylethylamide), hydroxyproline, beta-alanine, ornithine, and citrulline.

[0119] As used herein, “peptide” is defined in its broadest sense, in its various grammatical forms, to a compound of two or more subunits of amino acids, amino acid analogs, or other peptide mimetic compounds. Subunits may be linked by peptide bonds or other bonds (e.g., esters, ethers, etc.). As used herein, the term “amino acid” refers to natural and / or unnatural or synthetic amino acids (including glycine and both D and L optical isomers), as well as amino acid analogs and peptide mimetic compounds. When the peptide chain is short (e.g., two, three, or more amino acids), it is generally called an oligopeptide. When the peptide chain is longer, the peptide is usually called a polypeptide or protein. Full-length proteins, analogs, variants, and fragments of these are included in this definition. The term also includes post-expression modifications of polypeptides, such as glycosylation, acetylation, and phosphorylation. Furthermore, because ionizable amino and carboxyl groups are present in the molecule, certain peptides can be obtained as acidic or basic salts or in neutral forms. Peptides can be obtained directly from source organisms, or they can be produced through recombinant DNA or synthesis.

[0120] The amino acid sequences of antibodies can be numbered using any known numbering scheme, including those described in Kabat et al., ("Kabat" numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 ("Chothia" numbering scheme); MacCallum et al., 1996, J. Mol. Biol. 262:732-745 ("Contact" numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 ("IMGT" numbering scheme); and Honegge and Pluckthun, J. Mol. Biol., 2001, 309:657-70 ("Aho" numbering scheme). Unless otherwise specified, the numbering scheme used herein is the Kabat numbering scheme. However, the choice of numbering scheme is not intended to imply sequence differences where they do not exist, and those skilled in the art can easily determine the sequence locations by examining the amino acid sequences of one or more antibodies. Unless otherwise stated, the “EU numbering scheme” is generally used when referring to residues within the constant region of the antibody heavy chain (as reported, e.g., by Kabat et al. (see above)).

[0121] As used herein, the term “anti-HER2 antibody” refers to an antibody that selectively binds to the HER2 receptor, such as trastuzumab. In one embodiment, trastuzumab may be prepared and used as described in US6407213 and US5821337. The entire disclosures of these documents are incorporated herein by reference.

[0122] As used herein, the term “anti-HER3 antibody” refers to an antibody that selectively binds to the HER3 receptor (e.g., patritumab). In one embodiment, patritumab may be prepared and used as described in US7705130. The entire disclosure of that document is incorporated herein by reference.

[0123] As used herein, the term “anti-PTK7 antibody” refers to an antibody that selectively binds to the PTK7 receptor (e.g., cofetuzumab). In one embodiment, cofetuzumab may be prepared and used as described in US9777070. The entire disclosure of that document is incorporated herein by reference.

[0124] As used herein, the term "ifinatamab" refers to an antibody that selectively binds to the B7H3 receptor, i.e., an anti-human B7H3 antibody. In one embodiment, ifinatamab may be prepared and used as described in US10117952 or WO2022102695. The entire disclosures of these documents are incorporated herein by reference.

[0125] As used herein, the term "6E7" refers to the CLL1 monoclonal antibody.

[0126] As used herein, the term “cytotoxic activity” refers to activity that reduces or diminishes the cell viability of the cell line being tested.

[0127] In the subsequent claims and prior descriptions, unless the context requires other meanings by explicit language or necessary implied language, the word “comprise” or variations such as “comprises” or “comprising” are used in a comprehensive sense, that is, to specify the presence of the described features, but not to exclude the presence or addition of further features in various embodiments.

[0128] Conjugate In various embodiments, the conjugate, or a pharmaceutically acceptable salt thereof, tautomer, solvate, or stereoisomer thereof, comprises a protein bound to at least one payload or payload residue (also referred herein as a drug unit) and to at least one hydrophilic moiety via a covalent linker. The covalent linker is directly or indirectly bound to each of the protein, payload residue, and hydrophilic moiety. In some embodiments, the protein is a binder such as an antibody or its antigen-binding fragment.

[0129] In some embodiments, the protein is directly bound to a covalent linker (e.g., a linker) as described herein. In such cases, the binder is one binding site away from the covalent linker. Alternatively, the covalent linker may be directly bound to a payload residue so that it is one binding site away from the payload residue. The payload may be any payload as described herein (e.g., MMAE). In some embodiments, the covalent linker may be directly or indirectly bound to a hydrophilic moiety so that it is one or more binding sites away from the hydrophilic moiety. The hydrophilic moiety may be any hydrophilic moiety as described herein.

[0130] In some embodiments, the binder is indirectly bonded to the covalent linker so that it is located at more than one bond position away from the covalent linker. In such cases, the binder is bonded to the covalent linker via another portion. For example, the binder may be bonded to a maleimide group bonded to a polyethylene glycol group bonded to the covalent linker.

[0131] In some embodiments, the covalent linker is also indirectly attached to the payload residue, so that it is located more than one bond site away from the payload residue. The covalent linker is attached to the payload via another part. For example, the covalent linker may be attached to a dipeptide (examples include, but are not limited to, Val-Ala or Val-Cit), which may be attached to a unit derived from p-aminobenzyl alcohol (PAB), which may be attached to the payload residue. An example of a PAB-derived unit is -NH-(C6H4)-CH2-OC(=O)-, and the phenylene portion of the PAB unit may be substituted with -C1-C8 alkyl, -O-(C1-C8 alkyl), -halogen, -nitro, or -cyano.

[0132] The compounds disclosed herein comprise at least a conjugator portion, a linker portion, a cleavable portion, and a payload portion. In some embodiments, the compound comprises a cap. In some embodiments, the compound comprises a launcher. In some embodiments, such as in the case of a conjugate, the compound comprises a binder (BA). The conjugator portion is a group that can bind the BA and link the BA to the rest of the compound. Together, the cleavable portion and the linker portion comprise at least one site for enzymatic cleavage and provide distance between the conjugator portion and the payload portion. The linker portion may comprise a hydrophilic portion. The linker portion may link the conjugator portion to the cleavable portion, or the cleavable portion to the cap (if present). The launcher is a group that extends the linker framework and comprises a hydrophilic substance. The linker portion, cleavable portion, cap, and launcher may form the linker portion of the conjugate. The payload portion (also referred to herein as the drug unit) is a cytotoxic agent or a residue thereof.

[0133] Appearance 1

[0134] Compound of formula (Ia): [ka] Or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof is provided herein, [in formula: BA is a binder selected from humanized antibodies, monoclonal antibodies, chimeric antibodies, or human antibodies, or their antigen-binding fragments; The conjugator part is selected from equations (II) and (III): [ka] {In formula: U is a bond, heteroarylene, or arylene; V represents a bond or -C≡C-(CH2). n -and; n is an integer between 0 and 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] -(succinimido-3-yl-N)-, or [ka] and; RS is -NR 1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6 -or- OC(=O)NHS(=O)2NR 6 -and; R 6 is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently either 1 or 2; [ka] This indicates a covalent bond site within the compound, and * indicates a connection where the conjugator part connects to BA; The linker section has formula (IV): [ka] {In formula: HG is a hydrophilic residue, and **This indicates a connection where the linker section connects to the conjugator section. The severable portion has formula (V): [ka] {In formula: R 2 Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. 1-4 Alkyl, -CN or -NO2, and **** indicates a connection where the severable portion connects to the linker portion. The payload portion consists of payload residues; and x is between 1 and 15 (including both ends).

[0135] In some embodiments of Embodiment 1, the severable portion has the following formula: [ka]

[0136] Appearance 2

[0137] Compound of formula (Ib): [ka] Or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof is provided herein, [in formula: BA is a binder selected from humanized antibodies, monoclonal antibodies, chimeric antibodies, or human antibodies, or their antigen-binding fragments; The conjugator part is selected from equations (II) and (III): [ka] {In formula: U is a bond, heteroarylene, or arylene; V represents a bond or -C≡C-(CH2). n -and; n is an integer between 0 and 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] -(succinimido-3-yl-N)-, or [ka] and; RS is -NR 1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6 -or- OC(=O)NHS(=O)2NR 6 -and; R 6 is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently 0, 1, or 2; [ka] This indicates a covalent bond site within the compound, and * indicates a connection where the conjugator part connects to BA; The severable portion has the formula (Va), (Vb), or (Vc): [ka] {In formula: R 2 Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. 1-4 Alkyl, -CN, or -NO2, *** indicates a connection where the severable portion connects to the conjugator portion, and **** indicates a connection where the severable portion connects to the linker portion. The linker section has equation (IV'): [ka] {in ceremony HG is a hydrophilic residue, and **! indicates a connection where the linker part connects to the cap.} The caps are CH3C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -NH-C(=O)-, CH3(C(=O)N(CH3)CH2) a C(=O)-, -NH-(CH2CH2O) a -(CH2) b CH3 or -(N(CH3)(CH2) c C(=O)) a It is NH2, and {in the formula: a is an integer from 1 to 18 (including both ends). b and d are independently 0, 1, or 2, and c is an integer between 1 and 4 (including both ends); The payload portion consists of payload residues; and x is between 1 and 15 (including both ends).

[0138] In some embodiments of the second embodiment, the severable portion has one of the following formulas: [ka]

[0139] In some embodiments of the second aspect, the cap is CH3C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -C(=O)- or CH3(C(=O)N(CH3)CH2) a C(=O)-

[0140] In some embodiments of the second aspect, the cap is CH3C(=O)- CH3-O-(CH2CH2O) 11 -(CH2CH2)-C(=O)- or -CH3(C(=O)N(CH3)CH2) 12 C(=O)-

[0141] Appearance 3

[0142] Compounds of formula (Ic): [ka] Or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof is provided herein, [in formula: BA is a binder selected from humanized antibodies, monoclonal antibodies, chimeric antibodies, or human antibodies, or their antigen-binding fragments; The conjugator part is selected from equations (II) and (III): [ka] {in formula; U is a bond, heteroarylene, or arylene; V represents a bond or -C≡C-(CH2). n -and; n is an integer between 0 and 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] -(succinimido-3-yl-N)-, or [ka] and; RS is -NR 1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6 -or- OC(=O)NHS(=O)2NR 6 -and; R 6 is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently 0, 1, or 2; [ka] This indicates a covalent bond site within the compound, and * indicates a connection where the conjugator part connects to BA; The linker section has formula (IV): [ka] {In formula: HG is a hydrophilic residue, and; **This indicates a connection where the linker section connects to the conjugator section. The severable portion has the formula (Va'), (Vb'), or (Vc'): [ka] {In formula: R 2 Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. 1-4 Alkyl, -CN, or -NO2, ***! indicates a connection where the severable portion connects to the cap, and **** indicates a connection where the severable portion connects to the linker portion. The caps are CH3C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -C(=O)-, -C(=O)-(CH2CH2O) a -(CH2) b CH3, CH3(C(=O)N(CH3)CH2) a C(=O)-, -NH-(CH2CH2O) a -(CH2) b CH3 or -(N(CH3)(CH2) c C(=O)) a It is NH2; a is an integer between 1 and 18 (including both ends); b and d are independently 0, 1, or 2. c is an integer between 1 and 4 (including both ends); The payload portion consists of payload residues; and x is between 1 and 15 (including both ends).

[0143] In some embodiments of the third aspect, the severable portion has one of the following formulas: [ka]

[0144] In some embodiments of the third aspect, the cap is -NH-(CH2CH2O) a -(CH2) b CH3 or -(N(CH3)(CH2) c C(=O)) a It is NH2.

[0145] In some embodiments of the third aspect, the cap is -NH-(CH2CH2O) 12 -CH3 or -(N(CH3)CH2C(=O)) 12 It is NH2.

[0146] Pattern 4

[0147] ADC compound of formula (Id): [ka] Or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof is provided herein, [in formula: BA is a binder selected from humanized antibodies, monoclonal antibodies, chimeric antibodies, or human antibodies, or their antigen-binding fragments; The conjugator part is selected from equations (II) and (III): [ka] {In formula: U is a bond, heteroarylene, or arylene; V represents a bond or -C≡C-(CH2). n -and; n is an integer between 0 and 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] -(succinimido-3-yl-N)-, or [ka] and; RS is -NR 1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6 -or- OC(=O)NHS(=O)2NR 6 -and; R 6 is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently 0, 1, or 2; [ka] This indicates a covalent bond site within the compound, and * indicates a connection where the conjugator part connects to BA; The linker section has equation (IV'): [ka] {In formula: HG is a hydrophilic residue, and **! indicates a connection where the linker part connects to the cap.} The severable portion has the formula (Va"), (Vb"), or (Vc): [ka] {In formula: R 2 Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. 1-4 Alkyl, -CN, or -NO2, ***† indicates a connection where the severable portion connects to the launcher, and **** indicates a connection where the severable portion connects to the linker portion. The caps are CH3C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -C(=O)-, -C(=O)-(CH2CH2O) a -(CH2) b CH3, CH3(C(=O)N(CH3)CH2) a C(=O)-, -NH-(CH2CH2O) a -(CH2) b CH3 or -(N(CH3)(CH2) c C(=O)) a It is NH2, and {in the formula} a is an integer between 1 and 18 (including both ends); b and d are independently 0, 1, or 2, and c is an integer between 1 and 4 (including both ends); Blancher has formulas (XIIa), (XIIa1), (XIIb), or (XIIb1): [ka] {In formula: Hydrophilic substances are -NH-(CH2CH2O) a1 -(CH2) b1 CH3, -C(=O)NH2, -C(=O)-(CH2CH2O) a1 -(CH2) b1 CH3 or -(N(CH3)(CH2) c1 C(=O)) a1 It is NH2, † indicates a connection where the launcher connects to the conjugator section. †† indicates a connection where the plancher connects to the cuttable section. a1 is an integer from 1 to 18 (including both ends), b1 is 0, 1 or 2, and Each of c1, p, and q is an independent integer between 1 and 4 (including both ends). The payload portion consists of payload residues; and x is between 1 and 15.

[0148] In some embodiments of the 4th aspect, the severable portion has one of the following formulas: [ka]

[0149] In some embodiments of the 4th embodiment, a1 is 12, b1 is 0, c1 is 1, p is 2, and q is 2 or 4.

[0150] In some embodiments of the 4th aspect, the blancher has one of the following formulas: [ka]

[0151] In some embodiments of the 4th embodiment, the hydrophilic substance is -C(=O)-(CH2CH2O) a1 -CH3 or -(N(CH3)-CH2-C(=O)) a1 It is NH2, and a1 is an integer between 10 and 16 (including both ends).

[0152] In some embodiments of the 4th embodiment, a1 is 12.

[0153] In some embodiments of the 4th embodiment, the cap is CH3C(=O)-.

[0154] Appearances 1, 2, 3 and 4

[0155] The ADC compounds of the aforementioned formulas (Ia), (Ib), (Ic), and / or (Id) have a drug-antibody ratio (DAR)(x) and each comprises a conjugator, a linker, a payload, and a BA (binding agent) as described below.

[0156] In embodiments 1 to 4, x is 1 to 15 (including both ends). In one embodiment, x is 1 to 12. In another embodiment, x is 1 to 10. In another embodiment, x is 2 to 10. In yet another embodiment, x is 3.5 to 10. In yet another embodiment, x is 3.5 to 8. In yet another embodiment, x is 3.5 to 6. In yet another embodiment, x is 3.5 to 4.5.

[0157] Binder

[0158] For example, binders (BA or Ab) for use in the ADC described herein are provided herein.

[0159] The compound of formula (I) may contain any of the BAs described herein.

[0160] In some embodiments, BA is an antibody or its antigen-binding fragment, examples of which include a humanized antibody, a chimeric antibody or a human antibody, or its antigen-binding fragment.

[0161] In some embodiments, the antibody or its antigen-binding fragment is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human-modified antibody, a single-chain antibody (scFv), a Fab fragment, a Fab' fragment, or an F(ab')2 fragment.

[0162] In some embodiments, BA is B7H3, cytokeratin 15, PTK7, HER3, HER2, CD7, CD19, CD20, CD22, CD25, CD27, CD30, CD33, CD37, CD38, CD46, CD70, CD71, CD74, CD79b, CD123, CD138, CD142, CD166, CD205, CD228, CCR2, CA6, p-cadherin, CEA, CEACAM5, C4.4a, DLL3, EGFR, EGFRVIII, ENPP3, EphA2, Ephrin A, FLOR1, FGFR2, GCC, cK An antibody or its antigen-binding fragment that binds to one or more of the following: IT, LIV1, LY6E, MSLN, MUC16, NaPi2b, Nectin 4, gpNMB, PSMA, SLITRK6, STEAP1, TROP2, 5T4, SSEA4, GloboH, Gb5, STn, Tn, B7H3, BCMA, MUC1, cMet, ROR1MSLn, FRa, CLDN18.2, CLDN6, PTK7, Axl, FGFR2b, CLL1, CCR7, GPC1, GPC3, ISAC, CDCP1, ITGB6, ADAM9, or CD45-iADC.

[0163] In some embodiments, BA is an anti-human B7H3 antibody, an anti-CLL1 antibody, an anti-PTK7 antibody, an anti-HER3 antibody, an anti-HER2 antibody, or one of the aforementioned antigen-binding fragments. In some embodiments, the anti-human B7H3 antibody is ifinatamab. In some embodiments, the anti-CLL1 antibody is 6E7. In some embodiments, the anti-PTK7 antibody is cofetuzumab. In some embodiments, the anti-HER3 antibody is patrizumab. In some embodiments, the anti-HER2 antibody is trastuzumab.

[0164] In some embodiments, the antibody or its antigen-binding fragment specifically binds to human B7H3. In some embodiments, the antibody or its antigen-binding fragment is ifinatamab.

[0165] In some embodiments, the antibody or its antigen-binding fragment specifically binds to CLL1. In some embodiments, the antibody or its antigen-binding fragment is 6E7.

[0166] In some embodiments, the antibody or its antigen-binding fragment specifically binds to PTK7. In some embodiments, the antibody or its antigen-binding fragment is cofetuzumab.

[0167] In some embodiments of any of the 1 to 4 embodiments, the conjugator portion includes formula (II).

[0168] In some embodiments of any of the embodiments 1 to 4, U is arylene.

[0169] In some embodiments of any of the embodiments 1 to 4, U is phenylene.

[0170] In some embodiments of any of embodiments 1 to 4, U is [ka] That is the case.

[0171] In some embodiments of any of embodiments 1 to 4, U is a heteroarylene.

[0172] In some embodiments of any of embodiments 1 to 4, U is a divalent pyrimidine ring.

[0173] In some embodiments of any of embodiments 1 to 4, U is [ka] That is the case.

[0174] In some embodiments of any of the embodiments 1 to 4, U is a coupling.

[0175] In some embodiments of any of the embodiments 1 to 4, V is a bond.

[0176] In some embodiments of any of embodiments 1 to 4, V is -C≡C-(CH2) n - is

[0177] In some embodiments of any of the 1 to 4 embodiments, V is -C≡C-(CH2)3-.

[0178] In some embodiments of any of the embodiments 1 to 4, W2 is -C(=O)-.

[0179] In some embodiments of any of embodiments 1 to 4, the conjugator portion has formula (III).

[0180] In some embodiments of any of the embodiments 1 to 4, RS is -N(CH3)2.

[0181] In some embodiments of any of embodiments 1 to 4, RS is -NH2.

[0182] In some embodiments of any of embodiments 1 to 4, RE is -OC(=O)NH-.

[0183] In some embodiments of any of embodiments 1 to 4, RG is [ka] That is the case.

[0184] Certain RGs described herein (for example, [ka] ) can be induced to undergo a ring-opening process when conjugated with BA. During such a process, the maleimide structure formed when RG conjugates with BA (e.g., [ka] ) undergoes ring opening. It will be understood that two possible positional isomers may arise from the ring opening of such a maleimide structure. For example, [ka] The ring is opened [ka] They may be formed, or [ka] The ring is opened [ka] They may form. For simplicity, unless otherwise indicated, both possible ring-opening positional isomers are included in the description of a single ring-opening positional isomer. Therefore, unless otherwise indicated, the ring-opening positional isomer [ka] The description is [ka] It includes, and similarly, ring-opening positional isomers. [ka] The description is [ka] This includes. In some embodiments, a mixture of ring-opening positional isomers exists. In some embodiments, a single ring-opening positional isomer exists.

[0185] In some embodiments of any of embodiments 1 to 4, s and t are each 2.

[0186] In some embodiments of any of embodiments 1 to 4, the conjugator portion has formula (IIa1), (IIa2), (IIa3), or (IIIa): [ka]

[0187] In some embodiments of any of embodiments 1 to 4, the linker portion has the following formula: [ka]

[0188] In some embodiments of any of embodiments 1 to 4, HG is [ka] In the formula, e is either 0, 1, or 2, or HG is -(CH2CH2) z -NR a C(O)NR b R c And in the formula, z is 1, 2, 3 or 4, R a , R b and R c Each of these independently represents H, or a substituted or unsubstituted C. 1-4 It is alkyl.

[0189] In some embodiments of any of embodiments 1 to 4, the linker section has one of the following formulas: [ka]

[0190] In some embodiments of any of embodiments 1 to 4, the payload portion is one residue from the following formula: [ka]

[0191] In some embodiments of any of the 1 to 4 embodiments, the payload section is [ka] That is the case.

[0192] In some embodiments of Embodiment 1, the compound is [ka] (wherein Ab is 6E7 or its antigen-binding fragment); or [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment.) Alternatively, it may be any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers mentioned above.

[0193] In some embodiments of Embodiment 1, the compound is [ka] (wherein Ab is 6E7 or its antigen-binding fragment); or [ka] (wherein Ab is 6E7 or its antigen-binding fragment), or any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers described above.

[0194] In some embodiments of the second embodiment, the compound is [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is ifinatamab or its antigen-binding fragment); [ka] (In the formula, Ab is ifinatamab or its antigen-binding fragment); [ka] (wherein Ab is 6E7 or its antigen-binding fragment); or [ka] (In the formula, Ab is cofetuzumab or its antigen-binding fragment.) Alternatively, it may be any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers mentioned above.

[0195] In some embodiments of the second embodiment, the compound is [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is ifinatamab or its antigen-binding fragment); [ka] (In the formula, Ab is ifinatamab or its antigen-binding fragment); [ka] (wherein Ab is 6E7 or its antigen-binding fragment); or [ka] (wherein Ab is cofetuzumab or its antigen-binding fragment), or any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers described above.

[0196] In some embodiments of the third embodiment, the compound is [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is ifinatamab or its antigen-binding fragment); [ka] (wherein Ab is ifinatamab or its antigen-binding fragment); or [ka] (wherein Ab is cofetuzumab or its antigen-binding fragment), or any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers described above.

[0197] In some embodiments of the third embodiment, the compound is [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (In the formula, Ab is ifinatamab or its antigen-binding fragment); [ka] (wherein Ab is ifinatamab or its antigen-binding fragment); or [ka] (In the formula, Ab is cofetuzumab or its antigen-binding fragment.) Alternatively, it may be any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers mentioned above.

[0198] In some embodiments of the 4th embodiment, the compound is [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (wherein Ab is 6E7 or its antigen-binding fragment); or [ka] (In the formula, Ab is ifinatamab or its antigen-binding fragment.) Alternatively, it may be any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers mentioned above.

[0199] In some embodiments of the 4th embodiment, the compound is [ka] (In the formula, Ab is 6E7 or its antigen-binding fragment); [ka] (wherein Ab is 6E7 or its antigen-binding fragment); or [ka] (In the formula, Ab is ifinatamab or its antigen-binding fragment.) Alternatively, it may be any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers mentioned above.

[0200] Appearance 5

[0201] Compound of formula (Ia'): [ka] Or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof is provided herein, [in formula: The conjugator part is selected from equations (II') and (III'): [ka] {In formula: U is a bond, heteroarylene, or arylene; V represents a bond or -C≡C-(CH2). n -and; n is an integer between 0 and 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] and; RS is -NR 1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6 -or -OC(=O)NHS(=O)2NR 6 -and; R 6 is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently 1 or 2, and [ka] This indicates a covalent bond site within the compound; The linker section has formula (IV): [ka] {In formula: HG is a hydrophilic residue, and **This indicates a connection where the linker section connects to the conjugator section. The severable portion has formula (V): [ka] {In formula: R 2 Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. 1-4 Alkyl, -CN or -NO2, and **** indicates a connection where the severable portion connects to the linker portion; and The payload portion consists of payload residues.

[0202] In some embodiments of the 5th model, the severable portion has the following formula: [ka]

[0203] Appearance 6

[0204] Compound of formula (Ib'): [ka] Or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof is provided herein, [in formula: The conjugator part is selected from equations (II') and (III'): [ka] {In formula: U is a bond, heteroarylene, or arylene; V represents a bond or -C≡C-(CH2). n -and; n is an integer between 0 and 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] and; RS is -NR 1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6 -or -OC(=O)NHS(=O)2NR 6 -and; R 6 is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently 1 or 2, and [ka] This indicates a covalent bond site within the compound; The severable portion has the formula (Va), (Vb), or (Vc): [ka] {In formula: R 2 Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. 1-4 Alkyl, -CN, or -NO2, *** indicates a connection where the severable portion connects to the conjugator portion, and **** indicates a connection where the severable portion connects to the linker portion. The linker section has equation (IV'): [ka] {in ceremony HG is a hydrophilic residue, and **! indicates a connection where the linker part connects to the cap.} The caps are CH3C(=O)-, CH3-(CH2) b-O-(CH2CH2O) a -(CH2CH2) d -C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -NH-C(=O)-, CH3(C(=O)N(CH3)CH2) a C(=O)-, -NH-(CH2CH2O) a -(CH2) b CH3 or -(N(CH3)(CH2) c C(=O)) a It is NH2, and {in the formula: a is an integer from 1 to 18 (including both ends). b and d are independently 0, 1, or 2, and c is an integer from 1 to 4 (including both ends); and The payload portion consists of payload residues.

[0205] In some embodiments of the 6th model, the severable portion has one of the following formulas: [ka]

[0206] In some embodiments of the 6th model, the cap is CH3C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -C(=O)- or CH3(C(=O)N(CH3)CH2) a C(=O)-

[0207] In some embodiments of Embodiment 6, the cap is CH3C(=O)- CH3-O-(CH2CH2O) 11 -(CH2CH2)-C(=O)- or -CH3(C(=O)N(CH3)CH2) 12 C(=O)-

[0208] Appearance 7

[0209] Compounds of formula (Ic'): [ka] Or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof is provided herein, [in formula: The conjugator part is selected from equations (II') and (III'): [ka] {In formula: U is a bond, heteroarylene, or arylene; V represents a bond or -C≡C-(CH2). n -and; n is an integer between 0 and 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] and; RS is -NR 1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6 -or -OC(=O)NHS(=O)2NR 6 -and; R 6 is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently 1 or 2, and [ka] This indicates a covalent bond site within the compound; The linker section has formula (IV): [ka] {In formula: HG is a hydrophilic residue, and **This indicates a connection where the linker section connects to the conjugator section. The severable portion has the formula (Va'), (Vb'), or (Vc'): [ka] {In formula: R 2 Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. 1-4 Alkyl, -CN, or -NO2, ***! indicates a connection where the severable portion connects to the cap, and **** indicates a connection where the severable portion connects to the linker portion. The caps are CH3C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -NH-C(=O)-, CH3(C(=O)N(CH3)CH2) a C(=O)-, -NH-(CH2CH2O) a -(CH2) b CH3 or -(N(CH3)(CH2) c C(=O)) a It is NH2, and {in the formula: a is an integer from 1 to 18 (including both ends). b and d are independently 0, 1, or 2, and c is an integer from 1 to 4 (including both ends); and The payload portion consists of payload residues.

[0210] In some embodiments of the 7th model, the severable portion has one of the following formulas: [ka]

[0211] In some embodiments of Embodiment 7, the cap is -NH-(CH2CH2O) a -(CH2) b CH3 or -(N(CH3)(CH2) c C(=O)) a It is NH2.

[0212] In some embodiments of Embodiment 7, the cap is -NH-(CH2CH2O) 12 -CH3 or -(N(CH3)CH2C(=O)) 12 It is NH2.

[0213] Appearance 8

[0214] Compound of formula (Id'): [ka] Or a pharmaceutically acceptable salt, tautomer, solvate or stereoisomer thereof is provided herein, [in formula: The conjugator part is selected from equations (II') and (III'): [ka] {In formula: U is a bond, heteroarylene, or arylene; V represents a bond or -C≡C-(CH2). n -and; n is an integer between 0 and 10 (including both ends); W2 is -C(=O)-, -NH-, or -O-; RG is [ka] and; RS is -NR1a R 1b and; R 1a and R 1b Each of these is independently H, or a substituted or unsubstituted C. 1-4 It is alkyl; RE stands for bond, -O-, -OC(=O)-, -OC(=O)NR 6 -, -NHC(=O)NR 6 -, -OS(=O)2NR 6 -, -NHS(=O)2NR 6 -or -OC(=O)NHS(=O)2NR 6 -and; R 6 is H, or substituted or unsubstituted C 1-4 It is alkyl; W3 is -C(=O)-, -NH-, or -O-; s and t are independently 1 or 2, and [ka] This indicates a covalent bond site within the compound; The linker section has equation (IV'): [ka] {In formula: HG is a hydrophilic residue, and **! indicates a connection where the linker part connects to the cap.} The severable portion has the formula (Va"), (Vb"), or (Vc): [ka] {In formula: R 2 Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. 1-4 Alkyl, -CN, or -NO2, ***† indicates a connection where the severable portion connects to the launcher, and **** indicates a connection where the severable portion connects to the linker portion. The caps are CH3C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -C(=O)-, CH3-(CH2) b -O-(CH2CH2O) a -(CH2CH2) d -NH-C(=O)-, CH3(C(=O)N(CH3)CH2) a C(=O)-, -NH-(CH2CH2O) a -(CH2) b CH3 or -(N(CH3)(CH2) c C(=O)) a It is NH2, and {in the formula: a is an integer from 1 to 18 (including both ends). b and d are independently 0, 1, or 2, and c is an integer between 1 and 4 (including both ends); Blancher has formulas (XIIa), (XIIa1), (XIIb), or (XIIb1): [ka] {In formula: Hydrophilic substances are -NH-(CH2CH2O) a1 -(CH2) b1 CH3, -C(=O)NH2, -C(=O)-(CH2CH2O) a1 -(CH2) b1 CH3 or -(N(CH3)(CH2) c1 C(=O)) a1 It is NH2, † indicates a connection where the launcher connects to the conjugator section. †† indicates a connection where the plancher connects to the cuttable section. a1 is an integer from 1 to 18 (including both ends), b1 is 0, 1 or 2, and Each of c1, p, and q is an independent integer between 1 and 1 (including both ends); and The payload portion consists of payload residues.

[0215] In some embodiments of the 8th model, the severable portion has one of the following formulas: [ka]

[0216] In some embodiments of the 8th aspect, a1 is 12, b1 is 0, c1 is 1, p is 2, and q is 2 or 4.

[0217] In some embodiments of the 8th model, the blancher has one of the following formulas: [ka]

[0218] In some embodiments of the 8th model, the hydrophilic substance is -C(=O)-(CH2CH2O) a1 -CH3 or -(N(CH3)-CH2-C(=O)) a1 It is NH2, and a1 is an integer between 10 and 16 (including both ends).

[0219] In some embodiments of the 8th model, a1 is 12.

[0220] In some embodiments of the 8th model, the cap is CH3C(=O)-.

[0221] Appearances 5, 6, 7 and 8

[0222] The platform compounds of the aforementioned formulas (Ia'), (Ib'), (Ic'), and / or (Id') each include a conjugator portion, a linker portion, and a payload portion, as described below.

[0223] In some embodiments of any of embodiments 5 to 8, the conjugator portion has formula (II').

[0224] In some embodiments of any of embodiments 5 to 8, U is arylene.

[0225] In some embodiments of any of embodiments 5 to 8, U is phenylene.

[0226] In some embodiments of any of embodiments 5 to 8, U is [ka] That is the case.

[0227] In some embodiments of any of embodiments 5 to 8, U is a heteroarylene.

[0228] In some embodiments of any of embodiments 5 to 8, U is a divalent pyrimidine ring.

[0229] In some embodiments of any of embodiments 5 to 8, U is [ka] That is the case.

[0230] In some embodiments of any of aspects 5 to 8, U is a coupling.

[0231] In some embodiments of any of aspects 5 to 8, V is a bond.

[0232] In some embodiments of any of aspects 5 to 8, V is -C≡C-(CH2) n - is

[0233] In some embodiments of any of aspects 5 to 8, V is -C≡C-(CH2)3-.

[0234] In some embodiments of any of aspects 5 to 8, W2 is -C(=O)-.

[0235] In some embodiments of any of embodiments 5 to 8, the conjugator portion has formula (III').

[0236] In some embodiments of any of aspects 5 to 8, RS is -N(CH3)2.

[0237] In some embodiments of any of embodiments 5 to 8, RS is -NH2.

[0238] In some embodiments of any of aspects 5 to 8, RE is -OC(=O)NH-.

[0239] In some embodiments of any of embodiments 5 to 8, RG is [ka] That is the case.

[0240] In some embodiments of any of embodiments 5 to 8, s and t are each 2.

[0241] In some embodiments of any of aspects 5 to 8, the conjugator portion has formula (Iia1) or (IIIa1): [ka]

[0242] In some embodiments of aspects 5 to 8, the linker section has the following formula: [ka]

[0243] In some embodiments of any of embodiments 5 to 8, [ka] In the formula, e is either 0, 1, or 2. Alternatively, HG is -(CH2CH2) z -NR a C(O)NR b R c And in the formula, z is 1, 2, 3 or 4, R a , R band R c Each of these independently represents H, or a substituted or unsubstituted C. 1-4 It is alkyl.

[0244] In some embodiments of any of aspects 5 to 8, the linker section has one of the following formulas: [ka]

[0245] In some embodiments of any of aspects 5 to 8, the payload portion is one residue from the following formula: [ka]

[0246] In some embodiments of any of embodiments 5 to 8, the payload section is [ka] That is the case.

[0247] In some embodiments of Embodiment 5, the compound [ka] Alternatively, it may be any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers mentioned above.

[0248] In some embodiments of the 6th embodiment, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] Alternatively, it may be any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers mentioned above.

[0249] In some embodiments of the 7th embodiment, the compound is [ka] [ka] [ka] [ka] Alternatively, it may be any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers mentioned above.

[0250] In some embodiments of the 8th model, the compound is [ka] [ka] [ka] Alternatively, it may be any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers mentioned above.

[0251] Method or process for producing a conjugate A method for preparing a conjugate is provided herein by contacting a conjugator (BA) with a conjugator-linker-payload compound under conditions suitable for forming a bond between the conjugator and the conjugator-linker-payload compound. The reaction conditions may be any suitable reaction conditions known in the art. The conjugator may be an antibody, and the bond may form an antibody-drug conjugate.

[0252] Examples of such reactions are shown in the following examples.

[0253] In some embodiments, the method for preparing the conjugate includes treating or contacting a compound with a binder under coupling conditions. The compound may include a reactive linker bound to at least one payload. This compound may be any linker compound or platform compound disclosed herein.

[0254] Pharmaceutical composition This specification also provides compositions (including pharmaceutical compositions) comprising the ADC described herein. In some embodiments, the composition (e.g., a pharmaceutical composition) further comprises pharmaceutically acceptable excipients.

[0255] An antibody-drug conjugate having the desired purity is placed on one or more optionally selected pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 1) 6tBy mixing with (h edition, Osol, A. Ed. (1980)), pharmaceutical compositions according to this disclosure can be prepared in the form of lyophilized formulations or aqueous solutions. Generally, pharmaceutically acceptable carriers are non-toxic to the recipient at the dosage and concentration used, and such carriers include, but are not limited to, buffers, e.g., phosphates, citrates, and other organic acids; antioxidants (including ascorbic acid and methionine); preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens, e.g., methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); and low molecular weight (about 1 Polypeptides (less than 0 residues); proteins, e.g., serum albumin, gelatin, or immunoglobulin; hydrophilic polymers, e.g., polyvinylpyrrolidone; amino acids, e.g., glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates (including glucose, mannose, or dextrin); chelating agents, e.g., EDTA; sugars (e.g., sucrose, mannitol, trehalose, or sorbitol); salt-forming counterions, e.g., sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants, e.g., polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers as used herein include interstitial drug dispersants such as soluble neutral active hyaluronidase glycoproteins (sHASEGP), e.g., human soluble PH-20 hyaluronidase glycoproteins such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in U.S. Patents US7,871,607 and US2006 / 0104968. In one embodiment, sHASEGP is combined with one or more additional glycosaminoglycanases, such as chondroitinase.

[0256] How to use conjugates In some embodiments, methods for treating a disease or disorder (e.g., cancer) in an object requiring treatment (e.g., a patient) are described herein, the methods comprising administering a therapeutically effective dose of the conjugate disclosed herein to the patient.

[0257] The conjugates disclosed herein may be administered by any preferred means, including parenteral, intrapulmonary, intranasal, and, if desired for local treatment, intrafocal administration. Parenteral administration may include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. Administration may be carried out by any preferred route, for example, by injection (e.g., intravenous or subcutaneous injection), depending in part whether the administration is short-term or chronic. Various administration schedules, including but not limited to single or multiple doses, bolus administration, and pulse infusion, are contemplated herein.

[0258] The conjugates of this disclosure may be formulated, administered, and given in a manner consistent with good medical practice. Factors to be considered in this regard include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration plan, and other factors known to the healthcare professional. [Examples]

[0259] The following examples are illustrative and should not be considered limiting in any way. Unless otherwise specified, the experimental methods in the following examples are conventional. Unless otherwise specified, reagents and materials are commercially available. All solvents and chemicals used are analytical grade or of chemical purity. Solvents were redistilled before use. Anhydrous solvents were prepared according to standard or reference methods. Silica gel for column chromatography (100-200 mesh) and silica gel for thin-layer chromatography (TLC) (GF254) are commercially available from Tsingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd. in China, and both were eluted with petroleum ether (60-90°C) / ethyl acetate (v / v) and visualized with iodine or molybd phosphoric acid solution in ethanol unless otherwise specified. All extraction solvents were dried with anhydrous Na2SO4 unless otherwise specified. 1 ¹H NMR spectra were recorded using a Bruck-400, Varian 400MR nuclear magnetic resonance spectrometer (using TMS (tetramethylsilane) as an internal standard). Coupling constants are shown in Hertz. Peaks are reported as singlelines (s), doublelines (d), triplelines (t), quadruplines (q), quintuplines (p), hexatlines (h), heptuplines (hept), multilines (m), or combinations thereof. br stands for broad. LC / MS data were recorded using an Agilent 1100, 1200 high-performance liquid chromatography-ion trap mass spectrometer (LC-MSD trap) equipped with a diode array detector (DAD) detecting at 214 nm and 254 nm and an ion trap (ESI source). All compound names except for reagents were generated using ChemDraw® 18.0.

[0260] For the sake of brevity, this specification uses certain abbreviations. One example is the one-letter abbreviations for amino acids. The amino acids and their corresponding three-letter and one-letter abbreviations are as follows: [Table 1]

[0261] In the following examples, the following abbreviations will be used. [Table 2-1] [Table 2-2]

[0262] UPLC analysis method Method A: Mobile phase A: 0.1% FA in water, B: MeCN, Gradient: 10% B maintained for 0.2 minutes, 10%~95% B for 5.8 minutes, 95% B maintained for 0.5 minutes, Flow rate: 0.6 mL / min, Column: ACQUITY UPLC(registered trademark) BEH C18 1.7 μm.

[0263] Method B: Mobile phase A: 0.1% FA in water, B: MeCN, Gradient: 10% B maintained for 0.5 minutes, 10%~90% B for 2.5 minutes, 90% B maintained for 0.2 minutes, Flow rate: 0.6 mL / min, Column: ACQUITY UPLC(registered trademark) BEH C18 1.7 μm.

[0264] Method C: Mobile phase A: 0.1% FA in water, B: MeCN, Gradient: 10% B maintained for 0.2 minutes, 10% to 90% B for 1.3 minutes, 90% B maintained for 0.3 minutes, Flow rate: 0.6 mL / min, Column: ACQUITY UPLC(registered trademark) BEH C18 1.7 μm.

[0265] Example 1: Synthesis of conjugator-linker-payload Example 1-1 [ka]

[0266] Step 1: Mcanyl (R)-3-(((benzyloxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)butanoate (1-1b)

[0267] 1-1a (2.00g, 5.68 mmol) and K 2.00 CO3 (863 mg, 6.24 mmol) was added to DMF (10 mL), followed by the dropwise addition of CH3I (1.61 g, 11.35 mmol) at 0°C. The resulting mixture was stirred at 0°C for 20 minutes, then heated to 25°C and stirred further at 25°C for 60 minutes. The reaction was monitored by TLC (PE / EA) and LC-MS. After the reaction was complete, the reaction mixture was diluted with EA (80 mL) and washed with brine (30 mL x 3) and H2O (30 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl ester 1-1b (2.08 g, quantified) as a pale yellow solid. MS (ESI) m / z: 267.2 [M-Boc+H] +

[0268] Step 2: Benzyl tert-butyl (4-hydroxybutan-1,2-diyl)(R)-dicarbamate(1-1c)

[0269] 1-1b (1.00 g, 2.73 mmol) was dissolved in MeOH (15 mL), followed by the addition of LiBH4 (2 M stock solution in THF, 6.80 mL) at 0°C. The resulting mixture was stirred at 25°C for 2 hours. The reaction was monitored by LC-MS and TLC. After the reaction was complete, saturated NH4Cl aqueous solution (10 mL) was added to quench the reaction product. The reaction mixture was diluted with H2O (80 mL) and extracted with EA (50 mL x 3). The mixed organic layers were washed with brine (40 mL x 2) and water (40 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and further purified by flash column chromatography (PE / EA) to obtain 1-1c (760 mg, yield 82.3%) as a white solid. MS (ESI) m / z: 239.2 [M-Boc+H] +

[0270] Step 3: Benzyl tert-butyl (4-(((4-nitrophenoxy)carbonyl)oxy)butane-1,2-diyl)(R)-dicarbamate(1-1e)

[0271] 1-1c (300 mg, 0.89 mmol) and 1-1d (405 mg, 1.33 mmol) were dissolved in DMF (5 mL), followed by ad6868uccn of DIEA (229 mg, 1.77 mmol). The resulting mixture was stirred at 25°C for 1.5 hours. After the reaction was complete, the reaction mixture was diluted with EA (100 mL) and washed with brine (35 mL x 2) and water (35 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-1e as a white solid (371 mg, yield 83.1%). MS (ESI) m / z: 404.4 [M-Boc+H] +

[0272] Step 4: (9H-fluoren-9-yl)methyl tert-butyl (4-(((3-(dimethylamino)-3-oxopropyl)carbamoyl)oxy)butan-1,3-diyl)(S)-dicarbamate (1-1g).

[0273] 1-1e (420 mg, 0.83 mmol) and 1-1f (149 mg, 1.67 mmol) were dissolved in DMF (5 mL), followed by the addition of NaHCO3 aqueous solution (1 M, 5 mL). The resulting mixture was stirred at 25°C for 2.5 hours. After complete reaction, the reaction mixture was concentrated and purified by flash column chromatography (DCM / MeOH) to obtain 1-1 g as a pale yellow solid (365 mg, 96.5% yield). MS (ESI) m / z: 354.4 [M-Boc+H] +

[0274] Step 5: (R)-7-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-2,2-dimethyl-4,11-dioxo-3,10-dioxa-5,12-diazapentadecane-15-acid(1-h)

[0275] 1-1 g (360 mg, 0.79 mmol) was dissolved in MeOH (18 mL), followed by the addition of Pd / C (wet base, 108 mg). The resulting mixture was stirred at room temperature under H2 (15 psi) for 2 hours. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure to obtain 1-1 h as a clear syrup (252 mg, 99.4% yield). The crude product was used directly in the next step without purification. MS (ESI) m / z: 320.3 [M+H] +

[0276] Step 6: (R)-7-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-2,2-dimethyl-4,11-dioxo-3,10-dioxa-5,12-diazapentadecane-15-acid(1-j)

[0277] 1-1h (250 mg, 0.78 mmol) and 1-1i (243 mg, 1.57 mmol) were dissolved in a mixed scatter of ACN (8 mL) and NaHCO3 aqueous solution (1 M, 16 mL). The resulting mixture was stirred at 0°C for 1 hour, and then stirred further at 25°C until the reaction was complete. The reaction mixture was then acidified with aqueous solution. It was acidified with KHSO4 (20 mL) aqueous solution and extracted with EA (35 mL x 3). The mixed organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude yellow oil, which was purified by flash column chromatography to obtain 1-1j (280 mg, yield 89.6%) as a white solid. MS (ESI) m / z: 422.3 [M+Na] +

[0278] 1 H NMR (400 MHz, d6-DMSO) δ 12.48 (s, 1H), 7.03-7.01 (m, 2H), 6.99 (s, 2H), 4.08-4.03 (m, 3H), 3.86-3.83 (m, 2H), 3.14-3.11 (m, 2H), 2.35 (t, J=7.2 Hz, 2H), 2.16-2.09 (m, 1H), 1.91-1.84 (m, 1H), 1.32 (s, 9H).

[0279] Step 7: 4-((S)-2-((S)-2-amino-3-methylbutanamide)-5-ureidopentanamide)benzyl((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidine-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate(1-1l)

[0280] 1-1k (126 mg, 0.10 mmol, purchased from ChemExpress) was added to DCM (6 mL), followed by TFA (1.5 mL). The resulting mixture was stirred at 25°C until all of the 1-1k was consumed. The mixture was then concentrated under reduced pressure to obtain 1-1l (116 mg, quantitative) as a white solid. The crude product was used directly in the next step without purification. MS (ESI) m / z: 1123.9 [M+can can Step 8: (R)-4-((tert-butoxycarbonyl)amino)-3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)butyl(3-(((S)-1-(((S)-1-((4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-1-methoxy C-2-met69ucc69uccinimideyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-oxopropyl)carbamate(1-1m)

[0281] 1-1j (20 mg, 0.050 mmol), 1-1l (51 mg, 0.045 mmol), and HATU (22 mg, 0.058 mmol) were dissolved in DMF (3 mL), followed by 69ucuccination with DIEA (13 mg, 0.10 mmol). The resulting mixture was stirred at room temperature until 1-1l was completely consumed. After complete reaction, the reaction mixture was purified by preparative HPLC (Method: Column: XBridge Prep C18 OBD 5um 19*250 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min). After lyophilization, 1-1m (35 mg, yield 51.6%) was obtained as a white solid. MS (ESI) m / z: 1504.9 [M+H] +

[0282] Step 9: 4-((2S,5S,15R)-16-amino-15-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-5-isopropyl-4,7,11-trioxo-2-(3-ureidopropyl)-12-oxa-3,6,10-triazahexadecanamide)benzyl((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(( (1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-1-methoxy-2-met70ucc70uccinimideyl)pyrrolidine-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate(1-1)

[0283] 1-1 m (32 mg, 0.021 mmol) was added to DCM (2 mL), followed by TFA (0.5 mL) at 0°C. The resulting mixture was stirred at 25°C until the reaction was complete. The reaction mixture was then concentrated and purified by preparative HPLC (Method: Column: XBridge Prep C18 OBD 5 μm 19*250 mm; Mobile phase: A-Water (0.1% trifluoroacetic acid): B-Acetonitrile; Flow rate: 20 mL / min). After lyophilization, 1-1 (23 mg, yield 72.0%) was obtained as a white solid. MS (ESI) m / z: 1406.0 [M+H] +

[0284] Examples 1-2 [ka]

[0285] Step 1: Methyl 4-(5-(methylthio)-1,2,4-thiadiazole-3-yl)benzoate (1-2c)

[0286] Compound 1-2b (110 mg, 0.57 mmol), K2CO3 (168 mg, 0.95 mmol), and Pd(dppf)Cl2 (35 mg, 0.047 mmol) were added to a solution of compound 1-2a (100 mg, 0.47 mmol) in toluene (4 mL) and H2O (1 mL). The mixture was heated under an N2 atmosphere at 110°C. o The mixture was stirred in 1C for 3 hours. The mixture was then filtered through a Celite pad, diluted with EA (100 mL), and washed with brine (50 mL x 4). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (elution at PE:EA = 100 / 0 to 60 / 40). Compound 1-2c (56 mg, yield 44.4%) was obtained as an off-white solid. MS (ESI) m / z: 267.1 [M+H] +

[0287] Step 2: 4-(5-(methylthio)-1,2,4-thiadiazole-3-yl)benzoic acid (1-2d)

[0288] To a solution of compound 1-2c (54 mg, 0.20 mmol) in MeOH (3 mL) and H2O (1 mL), LiOH (17 mg, 0.41 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 7 and purified by preparative HPLC (method: column: XBridge Prep C18 OBD 5 μm 19*250 mm, mobile phase: A-water (0.1% formic acid): B-acetonitrile, flow rate: 20 mL / min) to obtain compound 1-2d (36 mg, yield 70.3%) as a white solid. MS (ESI) m / z: 253.1 [M+H]+

[0289] Step 3: 4-(5-(methylsulfonyl)-1,2,4-thiadiazole-3-yl)benzoic acid (1-2e)

[0290] A solution of compound 1-2d (35 mg, 0.14 mmol) in DCM (3 mL) and THF (3 mL) was mixed with m-CPBA (96 mg, 0.55 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified by preparative HPLC (Method: Column: XBridge Prep C18 OBD 5 μm 19*250 mm; Mobile phase: A-Water (0.1% TFA): B-Acetonitrile; Flow rate: 20 mL / min). Compound 1-2e (12 mg, 99% purity) was obtained as a white solid. MS (ESI) m / z: 284.8 [M+H] +

[0291] Step 4: 4-((S)-2-((S)-3-methyl-2-(4-(5-(methylsulfonyl)-1,2,4-thiadiazole-3-yl)benzamide)butanamide)-5-ureidopentanamide)benzyl((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1- Phenylpropan-2-yl)amino)-1-methoxy-2-met71ucc71uccinimideyl)pyrrolidine-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate(1-2)

[0292] 1-2 (13 mg, 31.8% yield) was synthesized according to step 8 of Example 1-1. MS (ESI) m / z: 1389.8 [M+H] +

[0293] Examples 1-3 [ka] [ka]

[0294] Step 1: (2R,3R,4S,5S,6S)-2-((S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(Benzyloxy)-3-oxopropoxy)-6-(Methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-3c)

[0295] To a solution of compound 1-3a (1.00 g, 2.41 mmol) in DCM (30 mL), compounds 1-3b (1.14 g, 2.87 mmol) and 4A molecular sieve (4.00 g) were added. The mixture was stirred at room temperature for 30 minutes. The mixture was cooled to -20°C. Then, AgOTf (0.74 g, 2.87 mmol) was added to the mixture in fractions at -20°C. The mixture was stirred at -20°C for 4 hours. The mixture was filtered, the filtrate was diluted with EA (150 mL), and washed with saturated NaHCO3 (100 mL x 3) and brine (100 mL x 3), respectively. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residues were purified by flash column chromatography (eluting petroleum ether: siRNA = 0%~40%) to obtain the crude product. The crude product was further purified with isopropanol to obtain compound 1-3c (340 mg, 19.3% yield) as a white solid. MS (ESI) m / z: 734.4 [M+H] +

[0296] Step 2: (2R,3R,4S,5S,6S)-2-((S)-2-amino-3-(benzyloxy)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-3d)

[0297] To a solution of compound 1-3c (250 mg, 0.34 mmol) in DMF (1 mL), Et2NH (125 mg, 1.70 mmol) was added. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under high vacuum and evaporated with toluene (3 mL * 3) to obtain compound 1-3d (174 mg, crude product) as brown oil. This was used directly without further purification. MS (ESI) m / z: 512.3 [M+H] +

[0298] Step 3: (2R,3R,4S,5S,6S)-2-((S)-3-(benzyloxy)-2-((S)-2-(((benzyloxy)carbonyl)amino)-3-methylbutanamide)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-3f)

[0299] Compounds 1-3e (103 mg, 0.41 mmol), HATU (168 mg, 73uc / 73uccmol), and DIEA (88 mg, 0.68 mmol) were added to a solution of compound 1-3d (174 mg, 0.34 mmol) in DMF (4 mL). The mixture was stirred at room temperature for 4 hours. The reaction product was diluted with EA (50 mL) and washed with saturated NaHCO3 solution (30 mL * 3) and brine (30 mL * 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain residues. The residues were purified by flash column chromatography (elution at CH2Cl2:Â=100 / 0~70 / 30). Compound 1-3f (230 mg, 91% yield) was obtained as a white solid. MS (ESI) m / z: 745.4 [M+H] +

[0300] Step 4: N-(L-valyl)-O-((2R,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-L-serine (1-3g)

[0301] A solution of compound 1-3f (230 mg, 0.31 mmol) in MeOH (3 mL) was mixed with Pd / C (10%, 23 mg). The mixture was stirred at room temperature for 1 hour under H2 (15 psi). H2O (3 mL) was added to the mixture, filtered, and concentrated to obtain 1-3 g (161 mg, crude) of crude organism as a white solid. This was used directly without further purification. MS (ESI) m / z: 521.3 [M+H] +

[0302] Step 5: N-(acetyl-L-valyl)-O-((2R,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-L-serine(1-3h)

[0303] To a solution of 1-3 g (161 mg, 0.31 mmol) of the compound in CH3COOH (3 mL), Ac2O (316 mg, 3.09 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and purified by preparative HPLC (Method: Column: XBridge Prep C18 OBD 5 μm 19*250 mm; Mobile phase: A-Water (0.1% TFA): B-Acetonitrile; Flow rate: 20 mL / min). Compound 1-3 h (145 mg, yield 83.3%) was obtained as a white solid. MS (ESI) m / z: 563.4 [M+H] +

[0304] Step 6: Sodium 2-(hydroxymethyl)-5-nitrobenzoate (1-3j)

[0305] A solution of compound 1-3i (5.00 g, 27.9 mmol) in NaOH (1N, 27.9 mL, 27.9 mmol) was refluxed for 2 hours. The mixture was cooled to room temperature and lyophilized to obtain compound 1-3j (6.12 g, crude product) directly for the next step without further purification. MS (ESI) m / z: 195.9 [MH] -

[0306] Step 7: 2-(acetoxymethyl)-5-nitrobenzoic acid (1-3k)

[0307] To a solution of compound 1-3j (5.00 g, 22.8 mmol) in DMF (100 mL), Ac2O (11.60 g, 114 mmol) and Et3N (11.5 g, 114 mmol) were added at 0°C. The mixture was stirred at 25°C for 16 hours. The mixture was diluted with siRNA (500 mL) and washed with brine (200 mL * 4). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain residues. The crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH = 100 / 0~10 / 90) to obtain compound 1-3k (2.30 g, yield 42.1%) as a pale yellow solid. MS (ESI) m / z: 239.2 [M+H] +

[0308] Step 8: 2-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-nitrobenzyl acetate (1-3m)

[0309] To a solution of compound 1-3k (1.60 g, 6.69 mmol) in DMF (10 mL), compound 1-3l (1.29 g, 8.03 mmol), HATU (3.82 g, 74uc / 74uccmol), and DIEA (1.73 g, 13.38 mmol) were added. The mixture was stirred at room temperature for 30 minutes. The reaction product was diluted with EA (150 mL) and washed with saturated NaHCO3 solution (50 mL * 3) and food brine (50 mL * 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain residues. The residues were purified by silica gel column chromatography (eluting with petroleum ether: siRNA = 100 / 0 to 70 / 30). Compound 1-3m (1.20 g, yield 47.1%) was obtained as a white solid. MS (ESI) m / z: 404.3 [M+Na] +

[0310] Step 9: 4-amino-2-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)benzylacetate (1-3n)

[0311] To a solution of compound 1-3m (1.20 g, 3.15 mmol) in RINKAN (15 mL), PtO2 (120 mg) was added. The mixture was stirred under H2 at room temperature for 2 hours. The mixture was filtered and concentrated to obtain crude product 1-3n (1110 mg, crude) as an off-white solid. This was used directly without further purification. MS (ESI) m / z: 374.3 [M+Na] +

[0312] Step 10: tert-butyl(2-(5-amino-2-(hydroxymethyl)benzamide)ethyl)carbamate(1-3o)

[0313] A solution of compound 1-3n (1.10 g, 3.13 mmol) in MeOH (10 mL) was mixed with K2CO3 (216 mg). The mixture was stirred at room temperature for 1 hour. The mixture was filtered and concentrated to obtain the crude product. The residues were purified by silica gel column chromatography (elution at CH2Cl2 / MeOH = 100 / 0 to 90 / 10) to obtain compound 1-3o (783 mg, yield 80.8%). MS (ESI) m / z: 292.3 [M-H2O+H] +

[0314] Step 11

[0315] (2R,3R,4S,5S,6S)-2-((S)-2-((S)-2-acetamido-3-methylbutanamide)-3-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-(hydroxymethyl)phenyl)amino)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-3p)

[0316] To a solution of compound 1-3o (780 mg, 1.39 mmol) in CH2Cl2 (6 mL), compound 1-3h (515 mg, 1.66 mmol) and EEDQ (446 mg, 1.80 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction product was diluted with  (150 mL) and washed with saturated NaHCO3 solution (50 mL x 3) and brine (50 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain residues. The residues were purified by silica gel column chromatography (eluted with petroleum ether = 100 / 0 to 70 / 30). Compound 1-3p (650 mg, yield 55.1%) was obtained as a white solid. MS (ESI) m / z: 876.5 [M+Na] +

[0317] Step 12

[0318] (2R,3R,4S,5S,6S)-2-((S)-2-((S)-2-acetamido-3-methylbutanamide)-3-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-3q)

[0319] To a solution of compound 1-3p (600 mg, 0.70 mmol) in DMF (10 mL), bis(4-nitrophenyl) carbonate (641 mg, 75uc75uccmol) and DIEA (272 mg, 2.11 mmol) were added. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under high vacuum. The crude product was purified by silica gel column chromatography (elution at CH2Cl2:MeOH = 100 / 0 to 10 / 90) to obtain compound 1-3q (476 mg, yield 66.5%) as a pale yellow oil. MS (ESI) m / z: 1041.6 [M+Na] +

[0320] Step 13

[0321] (2R,3R,4S,5S,6S)-2-((S)-2-((S)-2-acetamido-3-methylbutanamide)-3-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amide (1-1-Methoxy-2-met75ucc75uccinimideyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-3s)

[0322] To a solution of compound 1-3q (353 mg, 0.35 mmol) in DMF (6 mL), 1-3r (261 mg, 0.36 mmol), HOBt (47 mg, 75uc / 75uccmol), and DIEA (90 mg, 0.69 mmol) were added. The mixture was stirred at room temperature for 16 hours. The solvent was evaporated under high vacuum. The crude product was purified by silica gel column chromatography (elution at CH2Cl2:MeOH = 100 / 0 to 90 / 10) to obtain compound 1-3s (455 mg, yield 82.3%) as a pale yellow oil. MS (ESI) m / z: 1598.3 [M+H] +

[0323] Step 14

[0324] (2S,3S,4S,5R,6R)-6-((S)-2-((S)-2-acetamido-3-methylbutanamide)-3-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2- (1-3t)

[0325] To a solution of compound 1-3s (100 mg, 0.063 mmol) in MeOH (15 mL), NaOMe (1.25 mL, 2 N, 0.13 mmol) was added at 0°C. The mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0°C, and then NaOH (63 μL, 2 N, 0.13 mmol) was added dropwise. The mixture was stirred at 0°C for 1 hour. The reaction product was quenched with CH3COOH (1 mL) and concentrated. The crude product was purified using preparative HPLC (Method: Column: XBridge Prep C18 OBD 5 μm 19*150 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min) to obtain compound 1-3t (71 mg, yield 77.8%) as a white solid. MS (ESI) m / z: 1458.2 [M+H] +

[0326] Step 15

[0327] (2S,3S,4S,5R,6R)-6-((S)-2-((S)-2-acetamido-3-methylbutanamide)-3-((3-((2-aminoethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-met76u cc76uccinimideyl)pyrroridine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-3-oxopropoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-α-oxylic acid-2,2,2-trifluoroacetaldehyde (1 / 1)(1-3u)

[0328] A solution of compound 1-3t (71 mg, 0.049 mmol) in CH2Cl2 (2 mL) was mixed with TFA (1 mL, 20% in DCM). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to obtain compound 1-3u (70.9 mg, crude) as an off-white solid. This was used in the next step without further purification. MS (ESI) m / z: 1358.8 [M+H] +

[0329] Process 16

[0330] (2S,3S,4S,5R,6R)-6-((S)-2-((S)-2-acetamido-3-methylbutanamide)-3-((4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-1-methoxy-2-met76ucc76uccinimideyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-di Sopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazacancanesyl)-3-(((R)-8-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-13,13-dimethyl-4,11-dioxo-5,12-dioxa-3,10-diazatetradecyl)carbamoyl)phenyl)amino)-3-oxopropoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-3w)

[0331] To a solution of compound 1-3u (35 mg, 0.024 mmol) in DMF (2 mL), compound 1-3v (21 m76uc76ucc8 mmol) and DIEA (6.2 mg, 0.048 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction product was purified using preparative HPLC (Method: Column: XBridge Prep C18 OBD 5 μm 19*150 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min) to obtain compound 1-3w (19 mg, yield 47.5%) as a white solid. MS (ESI) m / z: 1668.9 [M+H]+

[0332] Process 17

[0333] (2S,3S,4S,5R,6R)-6-((S)-2-((S)-2-acetamido-3-methylbutanacancan 3-((3-((2-(((((R)-4-amino-3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)butoxy)carbonyl)amino)ethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydro Xy-1-phenylpropane-2-yl)amino)-1-methoxy76ucc76uccinimidexopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-3-oxopropoxy)-3,4,5-trihydroxytetrahydro-2H-pa-2-carboxylic acid--formic acid (1 / 1)(1-3)

[0334] To a solution of compound 1-3w (19 mg, 0.011 mmol) in CH2Cl2 (2 mL), TFA (1 mL, 20% in CH2Cl2) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and purified using preparative HPLC (Method: Column: XBridge Prep C18 OBD 5 μm 19*150 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min) to obtain compound 1-3 (12 mg, yield 65.8%) as a white solid. MS (ESI) m / z: 1568.5 [M+H] +

[0335] Examples 1-4 [ka] [ka] [ka]

[0336] Compounds 1-4 (8.5 mg, 77.4% yield) were synthesized according to the procedure of Examples 1-3.

[0337] Examples 1-5 [ka] [ka] [ka]

[0338] Steps 1-5: 5-amino-N-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl)-2-(hydroxymethyl)benzamide (1-5g)

[0339] 1-5 g (281 mg, 98.7% yield) was synthesized according to the synthesis procedure of 1-3o in Examples 1-3. MS (ESI) m / z: 709.8 [M+H] +

[0340] Step 6: (2R,3R,4S,5S,6S)-2-((S)-3-((3-((2,5,8,11,14,17,20,23,26,29,32,35-Dodecaoxaheptatricontan-37-yl)carbamoyl)-4-(hydroxymethyl)phenyl)amino)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamide)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-5i)

[0341] A mixture of 1-5 g (281 mg, 0.40 mmol) and 1-5 h (295 mg, 0.40 mmol) in THF (5 mL) was mixed with EEDQ (108 mg, 0.44 mmol). The mixture was stirred at room temperature for 9 hours. TLC showed that the reactants were consumed. The mixture was concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography ((MeOH:DCM=1:5) / DCM) = 0 / 100~30 / 70. The fraction was concentrated under vacuum to obtain 1-5i (377 mg, yield 66.3%) as a white solid. MS (ESI) m / z: 1435.2 [M+H] +

[0342] Step 7: (2R,3R,4S,5S,6S)-2-((S)-3-((3-((2,5,8,11,14,17,20,23,26,29,32,35-Dodecaoxaheptatricontan-37-yl)carbamoyl)-4-((((4-Nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-2-((S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-Methylbutanamide)-3-Oxopropoxy)-6-(Methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-5j)

[0343] A mixture of 1-5i (375 mg, 0.26 mmol) and NPC (88 mg, 0.29 mmol) in D79uc79ucc mL was mixed with DIEA (100 μL, 74 mg, 0.575 mmol). The resulting pale yellow mixture was stirred at room temperature for 12 hours. The mixture was quenched with saturated KHSO4 (5 mL) / H2O (20 mL) and extracted with EA (20 mL * 2). After separation, the mixed organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain 1-5j (206 mg, yield 49.2%) as a pale yellow solid. MS (ESI) m / z: 1600.2 [M+H] +

[0344] Step 8: (2R,3R,4S,5S,6S)-2-((S)-3-((3-((2,5,8,11,14,17,20,23,26,29,32,35-Dodecaoxaheptatricontan-37-yl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-Hydroxy-1-phenylpropane-2-yl)amino)-1-methoxy79ucc79uccinim idexopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamide)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (1-5l)

[0345] Pyridine (19 μL, 19 mg, 0.24 mmol) was added to a mixture of 1-5j (190 mg, 0.12 mmol), 1-5k (128 mg, 0.19 mmol), and HOBt (1.6 mg, 0.012 mmol) in DMF (1 mL). The mixture was stirred overnight at room temperature. The mixture was purified by preparative HPLC (Method: Column: XBridge Prep C18 OBD 5 μm 19*150 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min) to obtain 1-5 L (130 mg, yield 50.2%) as a white solid. MS (ESI) m / z: 2178.0 [M+H] +

[0346] Step 9: (2S,3S,4S,5R,6R)-6-((S)-3-((3-((2,5,8,11,14,17,20,23,26,29,32,35-Dodecaoxaheptatricontan-37-yl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-Hydroxy-1-phenylpropane-2-yl)amino)-1-m ethoxy80ucc80uccinimidexopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-2-((S)-2-amino-3-methylbutanamide)-3-oxopropoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-5m)

[0347] To a solution of 1-5 L (130 mg, 0.06 mmol) in THF (8 mL), 1 N LiOH (2.6 mL) was added. The mixture was stirred at 0°C for 30 minutes. The mixture was then acidified to pH=5 with AcOH. The mixture was concentrated under vacuum to obtain the crude product. This was dissolved in DMF (2 mL). Diethylamine (309 μL, 2.99 mmol) was added, and the mixture was reacted at room temperature for 1 hour. Finally, the mixture was purified by preparative HPLC (Method: Column: XBridge Prep C18 OBD 5 μm 19*150 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min). The fraction was concentrated under vacuum to obtain 1-5 m (60 mg, yield 55.4%) as a white solid. MS (ESI) m / z: 1816.1 [M+H] +

[0348] Step 10: (2S,3S,4S,5R,6R)-6-(((7R,17S,20S)-20-((3-((2,5,8,11,14,17,20,23,26,29,32,35-Dodecaoxaheptatricontan-37-yl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-Hydroxy-1-phenylpropane-2-yl)amino)-1-methoxy80ucc80uccinimidexopropyl)pyllo Zin-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)carbamoyl)-7-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-17-isopropyl-2,2-dimethyl-4,11,15,18-tetraoxo-3,10-dioxa-5,12,16,19-tetraazahenicosan-21-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-5o)

[0349] A mixture of 1-5n (9.7 mg, 0.024 mmol) and HATU (9.2 mg, 0.024 mmol) in DMF (2 mL) was mixed with DIPEA (8 μL, 5.70 mg, 0.044 mmol). The mixture was stirred at room temperature for 10 minutes. 1-5m (40 mg, 0.022 mmol) was added. The mixture was stirred at room temperature for 1 hour. This was purified by preparative HPLC (Method: Column: XBridge Prep C18 OBD 5 μm 19*150 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min), and the fraction was lyophilized to obtain 1-5o (24 mg, yield 48.5%) as a white solid. MS (ESI) m / z: 2196.8 [M+H] +

[0350] Step 11

[0351] (2S,3S,4S,5R,6R)-6-(((2S,5S,15R)-2-((3-((2,5,8,11,14,17,20,23,26,29,32,35-Dodecaoxaheptatricontan-37-yl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-Hydroxy-1-phenylpropane-2-yl)amino)-1-methoxy80ucc80uccinimidexopro pyl)pyrroridine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)carbamoyl)-16-amino-15-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-5-isopropyl-4,7,11-trioxo-12-oxa-3,6,10-triazahexadecyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-5)

[0352] A mixture of 1-5o (24 mg, 0.011 mmol) in TFA / DCM (v / v=1:4, 2 mL) was stirred at 0°C for 1 hour. DCM was removed by bubbling under a nitrogen atmosphere, then diluted with acetonitrile (2 mL), and purified by preparative HPLC (Method: Column: XBridge Prep C18 OBD 5 μm 19*150 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min) to obtain 1-5o (16 mg, yield 71.8%) as a white solid. MS (ESI) m / z: 2096.8 [M+H] +

[0353] Examples 1-6 [ka]

[0354] (2S,3S,4S,5R,6R)-6-((S)-3-((3-((2,5,8,11,14,17,20,23,26,29,32,35-Dodecaoxaheptatricontan-37-yl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-Hydroxy-1-phenylpropane-2-yl)amino)-1-methoxy81ucc81uccinimid exopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-2-((S)-3-methyl-2-(4-(5-(methylsulfonyl)-1,2,4-thiadiazole-3-yl)benzamide)butanamide)-3-oxopropoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-6)

[0355] Compounds 1-6 (8.9 mg, 38.9% yield) were synthesized according to the synthesis procedure of step 10 in Examples 1-5. MS (ESI) m / z: 2082.1 [M+H] +

[0356] Examples 1-7 [ka] [ka] [ka]

[0357] Step 1: N-((2,5,8,11,14,17,20,23,26,29,32,35-Dodecaoxaoctatricontan-38-oil)-L-valyl)-O-((2R,3R,4S,5S,6S)-3,4,5-Triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-a-yl)-L-serine(1-7a)

[0358] Compound 1-7a (380 mg, 51.8% yield) was synthesized according to the synthesis procedure of step 5 in Examples 1-3. MS (ESI) m / z: 1091.7 [M+H] +

[0359] Step 2: (2R,3R,4S,5S,6S)-2-(((40S,43S)-43-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-(hydroxymethyl)phenyl)carbamoyl)-40-isopropyl-38,41-dioxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39,42-diazatetratetracontan-44-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-7b)

[0360] Compound 1-7b (294 mg, 51.7% yield) was synthesized according to the synthesis procedure of step 11 in Examples 1-3. MS (ESI) m / z: 1383.2 [M+H] +

[0361] Step 3: (2R,3R,4S,5S,6S)-2-(((40S,43S)-43-((3-((2-((tert-butoxycarbonylamino)ethyl)carbamoyl)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)carbamoyl)-40-isopropyl-38,41-dioxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39,42-diazatetratetracontan-44-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-7c)

[0362] Compound 1-7c (289 mg, 87.8% yield) was synthesized according to the synthesis procedure of step 12 in Examples 1-3. MS (ESI) m / z: 1548.4 [M+H] +

[0363] Step 4: (2R,3R,4S,5S,6S)-2-(((40S,43S)-43-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-1-methoxy83ucc83uccinimidexopropyl)pyrrolidine-1-yl)-2 -Oxoethyl l)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)carbamoyl)-40-isopropyl-38,41-dioxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39,42-diazatetratetracontan-44-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-7d)

[0364] Compound 1-7d (290 mg, 73.0% yield) was synthesized according to the synthesis procedure in step 13 of Examples 1-3. MS (ESI) m / z: 2126.8 [M+H] +

[0365] Step 5: (2S,3S,4S,5R,6R)-6-(((40S,43S)-43-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-1-methoxy83ucc83uccinimidexopropyl)pyrrolidine-1- (Iyl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)carbamoyl)-40-isopropyl-38,41-dioxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39,42-diazatetratetracontan-44-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-7e)

[0366] Compound 1-7e (243 mg, crude product) was synthesized according to the synthesis procedure of step 14 in Examples 1-3. MS (ESI) m / z: 1987.2 [M+H] +

[0367] Step 6: (2S,3S,4S,5R,6R)-6-(((40S,43S)-43-((3-((2-aminoethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-1-methoxy84ucc84uccinimidexopropyl)pyrrolidine-1-yl)-2-oxoethyl )-5,8-diisopropyl-o-propyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)carbamoyl)-40-isopropyl-38,41-dioxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39,42-diazatetratetracontan-44-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-7f)

[0368] Compound 1-7f (63 mg, 27.3% in two steps) was synthesized according to the synthesis procedure of step 15 in Examples 1-3. MS (ESI) m / z: 1887.1 [M+H] +

[0369] Step 7: (2S,3S,4S,5R,6R)-6-(((40S,43S)-43-((4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-1-methoxy84ucc84uccinimidexopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-Cantharyl (1,4,5-Dioxo-2,5-Dihydro-1H-Pyrrole-1-yl)-13,13-Dimethyl-4,11-Dioxo-5,12-Dioxa-3,10-Diazatetradecyl)Carbamoyl)Phenyl)Carbamoyl)-40-Isopropyl-38,41-Dioxo-2,5,8,11,14,17,20,23,26,29,32,35-Dodecaoxa-39,42-Diazatetratetracontan-44-yl)Oxy)-3,4,5-Trihydroxytetrahydro-2H-Pyran-2-carboxylic acid (1-7g)

[0370] Compound 1-7 g (28 mg, yield 80.0%) was synthesized according to the synthesis procedure of step 16 in Examples 1-3. MS (ESI) m / z: 2197.2 [M+H] +

[0371] Step 8: (2S,3S,4S,5R,6R)-6-(((4can43S)-43-((3-((2-((((R)-4-amino-3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)butoxy)carbonyl)amino)ethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-1-meth8484uccinimideyl -3-Oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)carbamoyl)-40-isopropyl-38,41-dioxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39,42-diazatetratetracontan-44-yl)oxy)-3,4,-trihydroxytetrahydro-2-pyran-2-carboxylic acid--formic acid (1-7)

[0372] Compounds 1-7 (8.2 mg, 30.8% yield) were synthesized according to the synthesis procedure of step 17 in Examples 1-3. MS (ESI) m / z: 2097.1 [M+H] +

[0373] Examples 1-8 [ka]

[0374] Step 1: (2S,3S,4S,5R,6R)-6-(((40S,43S)-43-((4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-1-meth8484uccinimideyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2, 13-Dioxa-4,7,10-Triazatetradecyl)-3-((2-(4-(5-(methylsulfonyl)-1,2,4-thiadiazole-3-yl)benzamide)ethyl)carbamoyl)phenyl)carbamoyl)-40-isopropyl-38,41-dioxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39,42-diazatetratetracontan-44-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid(1-8)

[0375] To a solution of compound 1-2e (6.6 mg, 0.023 mmol) in DMF (1 mL), HATU (85 ucc mg, 0.020 mmol) and DIEA (4.0 mg, 0.031 mmol) were added. The mixture was stirred at room temperature for 10 minutes. Compound 1-7f (30 mg, 0.016 mmol) was added to the mixture and stirred at room temperature for 1 hour. The mixture was purified using preparative HPLC (Method: Column: XBridge Prep C18 OBD 5 μm 19*150 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min) to obtain compound 1-8 (19 mg, yield 56.9%) as a white solid. MS (ESI) m / z: 2152.7 [M+H] +

[0376] Examples 1-9 [ka] [ka]

[0377] Step 1: tert-butyl(S)-44-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39-azapentatetracontane-45-oate(1-9c)

[0378] To a solution of 1-9a (580 mg, 0.99 mmol) in DMF (6 mL), HATU86ucc (5 mg, 0.99 mmol) and DIEA (343 μL, 255 mg, 1.97 mmol) were added. The mixture was stirred at room temperature for 10 minutes. Next, 1-9b (454 mg, 0.99 mmol) was added to the brown mixture and stirred at room temperature for 15 minutes. The mixture was quenched with water (20 mL) and extracted with  (30 mL * 2). After separation, the mixed organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and purified by silica gel column chromatography (MeOH:DCM=0 / 100~10 / 90) to obtain 1-9c (1.08 g, quantitative yield) as a brown oil. MS (ESI) m / z: 995.7 [M+H] +

[0379] Step 2: (S)-44-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39-azapentatetracontan-45-acid(1-9d)

[0380] A mixture of 1-9c (1.08 g, 0.99 mmol) in DCM / TFA (v / v=5 mL / 5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated three times under vacuum and evaporated with Tol (10 mL) to obtain the crude product (1.20 g) as a brown oil. This was then purified by silica gel column chromatography (MeOH / DCM=0 / 100~10 / 90) to obtain 1-9d (874 mg, yield 94.5%) as a yellow oil. MS (ESI) m / z: 939.7 [M+H] +

[0381] Step 3: (S)-44-amino-38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39-azapentatetracontan-45-acid(1-9e)

[0382] To a solution of 1-9d (874 mg, 0.88 mmol) in DMF (13 mL), Et2N (909 μL, 642 mg, 8.78 mmol) was added. The mixture was stirred at room temperature for 40 minutes, then concentrated three times under vacuum and evaporated with Tol (10 mL) to obtain the crude product. Purification by preparative HPLC yielded 1-9e (179 mg, yield 28.4%) as a white solid. MS (ESI) m / z: 717.5 [M+H] +

[0383] Step 4: (S)-44-((R)-7-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-2,2-dimethyl-4,11-dioxo-3,10-dioxa-5,12-diazapentadecane-15-amide)-38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39-azapentatetracontane-45-acid(1-9f)

[0384] A mixture of 1-1j (105 mg, 0.26 mmol) and HATU (100.0 mg, 0.26 mmol) in 86uccDMF (6 mL) was mixed with DIEA (87 μL, 65 mg, 0.50 mmol). The mixture was stirred at room temperature for 10 minutes. 1-9e (179 mg, 0.25 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was purified by preparative HPLC (Method: Column: XBridge Prep C18 OBD 5 μm 19*150 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min) to obtain 1-9f (153 mg, yield 55.7%) as a clear glass solid. MS (ESI) m / z: 1098.8 [M+H] +

[0385] Step 5: (2S,3S,4S,5R,6R)-6-((S)-2-((S)-2-acetamido-3-methylbutanamide)-3-((4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-1-meth8686uccinimideyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,1 0-Triazocantradecyl)-3-(((S)-44-((R)-7-(2,5-Dioxo-2,5-Dihydro-1H-Pyrrole-1-yl)-2,2-Dimethyl-4,11-Dioxo-3,10-Dioxa-5,12-Diazapentadecane-15-amide)-38,45-Dioxo-2,5,8,11,14,17,20,23,26,29,32,35-Dodecaoxa-39,46-Diazaoctatetracontan-48-yl)Carbamoyl)Phenyl)amino)-3-Oxopropoxy)-3,4,5-Trihydroxytetrahydro-2H-Pyran-2-carboxylic acid (1-9g)

[0386] Compound 1-9 g (19 mg, yield 35.2%) was synthesized according to the synthesis procedure of Step 1 in Examples 1-8. MS (ESI) m / z: 2438.2 [M+H] +

[0387] Step 6: (2S,3S,4S,5R,6R)-6-((S)-2-((S)-2-Acetamido-3-methylbutanecan-3-((3-(((S)-44-(3-((((R)-4-amino-3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)butoxy)carbonyl)amino)propanamide)-38,45-dioxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39,46-diazaoctatetracontan-48-yl)carbamoyl)-4-((5S,8S,11S,12R)-11-( (S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-87ucc87uccinimideethyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-3-oxopropoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-9)

[0388] Compounds 1-9 (8.4 mg, 31.2% yield) were synthesized according to the synthesis procedure of step 17 in Examples 1-3. MS (ESI) m / z: 2338.0 [M+H] +

[0389] Examples 1-10 [ka]

[0390] Compounds 1-10 (2.6 mg, 88.0% yield) were synthesized according to the synthesis procedures of Examples 1-9.

[0391] Examples 1-11 [ka]

[0392] Step 1: Allyl 2-(hydroxymethyl)-5-nitrobenzoate (1-11b)

[0393] NaOH (670 mg, 16.75 mmol) was added to a solution of reactant 1 (3.0 g, 16.75 mmol) in H2O (100 mL). The reaction mixture was stirred under reflux for 1 hour. The reaction mixture was concentrated in vacuum and used directly for allylation. The residues were dissolved in anhydrous DMF (50 mL) and allyl bromide (2027 mg, 16.75 mmol) was added. The reaction mixture was stirred for 16 hours and then concentrated in vacuum. Silica gel flash column chromatography (30 g, siRNA / petroleum ether = 0 / 100~30 / 70) was used to obtain 1-11b (3.0 g, yield 75.8%) as a white solid.

[0394] 1 H NMR (400 MHz, CDCl3) δ 8.87 (d, J = 2.4 Hz, 1H), 8.39 (dd, J = 8.4, 2.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 6.15 - 5.98 (m, 1H), 5.52 - 5.43 (m, 1H), 5.38 (dd, J = 10.4, 1.2 Hz, 1H), 4.97 (s, 3H), 4.89 (dt, J = 5.9, 1.2 Hz, 2H).

[0395] Step 2: Allyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitrobenzoate(1-11c)

[0396] To a solution of 1-11b (1000 mg, 4.22 mmol) in DCM (10 mL), TBS-Cl (763 mg, 5.06 mmol) and imidazole (431 mg, 6.32 mmol) were added. The mixture was stirred at room temperature for 2 hours. Quenched with 1N NaHCO3 (30 mL) and extracted with DCM (30 mL * 2). After separation, the mixed organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, concentrated under vacuum, and then purified by silica gel column chromatography (Â / petroleum ether = 0%~10%) to obtain P1 (1.01 g, yield 68.2%) as a colorless oil. MS (ESI) m / z: 352.5 [M+H] +

[0397] 1 H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 2.4 Hz, 1H), 8.41 (dd, J = 8.8, 2.4 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 6.06 (ddt, J = 16.4, 10.4, 5.9 Hz, 1H), 5.45 (dq, J = 17.2, 1.4 Hz, 1H), 5.40 - 5.29 (m, 1H), 5.20 (s, 3H), 4.85 (dt, J = 5.8, 1.2 Hz, 2H), 1.01 - 0.95 (m, 9H), 0.17 - 0.13 (m, 6H).

[0398] Step 3: Allyl 5-amino-2-(((tert-butyldimethylsilyl)oxy)methyl)benzoate (1-11d)

[0399] A mixture of 1-11c (1.0 g, 2.87 mmol) in MeOH (10 mL) and H2O (3 mL) was mixed with Fe (802 mg, 14.4 mmol) and NH4Cl (1537 mg, 28.73 mmol). The mixture was heated at 75°C for 4 hours. The mixture was then filtered through a Celite pad, washed with siRNA (30 mL), and the resulting organic layer was washed with brine (20 mL). It was dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. This was purified by silica gel column chromatography (siRNA / petroleum ether = 0 / 100~70 / 30) to obtain 1-11d (868 mg, 94% yield) as a colorless oil. MS (ESI) m / z: 322.5 [M+H] +

[0400] 1 H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 6.93 (dd, J = 8.4, 2.1 Hz, 1H), 6.02 (ddd, J = 16.0, 10.8, 5.7 Hz, 1H), 5.40 (dd, J = 17.2, 1.4 Hz, 1H), 5.31 - 5.25 (m, 1H), 5.01 (s, 2H), 4.77 (dt, J = 5.7, 1.4 Hz, 2H), 4.31 (s, 2H), 1.04 - 0.86 (m, 10H), 0.21 - 0.01 (m, 6H).

[0401] Step 4: (2R,3R,4S,5S,6S)-2-((S)-2-((S)-2-(((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamide)-3-((3-((allyloxy)carbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-11e)

[0402] To a solution of 1-5h (400 mg, 0.54 mmol) and 1-11d (173 mg, 0.54 mmol) in DCM (5 mL), EEDQ (133 mg, 0.539 mmol) was added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum to obtain residues, and then purified by silica gel column chromatography (Â100~70 / 30) to obtain 1-11e (392 mg, yield 69.6%) as a white solid. MS (ESI) m / z: 914.8 [M-OTBS] +

[0403] Step 5: (2R,3R,4S,5S,6S)-2-((S)-2-((S)-2-(((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamide)-3-((3-((allyloxy)carbonyl)-4-(hydroxymethyl)phenyl)amino)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-11f)

[0404] A mixture of 1-11e (375 mg, 0.36 mmol) in AcOH / THF / H2O (1 mL / 1 mL / 0.5 mL) was stirred overnight at room temperature. The mixture was concentrated under vacuum to obtain residues, and then purified by silica gel column chromatography (Âxy / petroleum ether = 0 / 100~100 / 0) to obtain 1-11f (326 mg, 97.6%) as a white solid. MS (ESI) m / z: 915.3 [M-OH] +

[0405] Step 6: (2R,3R,4S,5S,6S)-2-((S)-2-((S)-2-(((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamide)-3-((3-((allyloxy)carbonyl)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (1-11g)

[0406] A mixture of 1-11f (326 mg, 0.35 mmol) and NPC (160 mg, 0.53 mmol) in DMF (5 mL) was mixed with DIPEA (79 μL, 0.46 mmol). The resulting golden mixture was stirred at room temperature for 2 hours. The mixture was diluted with siRNA (20 mL), washed with brine (20 mL * 3), dried over Na2SO4, filtered, and f90uc90uccinas was concentrated under vacuum to obtain residues. This was then purified by silica gel column chromatography (siRNA / petroleum ether = 0 / 100~100 / 0), and the fraction was concentrated under vacuum to obtain 1-11 g (266 mg, yield 69.3%) as a white solid. MS (ESI) m / z: 1097.8 [M+H] +

[0407] Step 7: (2R,3R,4S,5S,6S)-2-((S)-2-((S)-2-(((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamide)-3-((3-((allyloxy)carbonyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-I (L)amino)-90ucc90uccinimideethyl-3-oxopropyl)pyrroridine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-11h) [ka]

[0408] A mixture of 1-11 g (266 mg, 0.24 mmol) and 1-5 k (183 mg, 0.26 mmol) in DMF (5 mL) was mixed with HOBt (9.8 mg, 0.073 mmol) and pyridine (39 μL, 0.49 mmol). The mixture was stirred overnight at room temperature. The mixture was diluted with  (20 mL), washed with brine (10 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum to obtain the residue. This was purified by silica gel column chromatography (methanol / DCM = 0 / 100~10 / 90) to obtain 1-11 h (369 mg, yield 90.8%) as a white solid. MS (ESI) m / z: 1676.9 [M+H] +

[0409] Step 8: 5-((S)-2-((S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamide)-3-(((2R,3R,4S,5S,6S)-3,4,5-triacetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)oxy)propanamide)-2-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-( 2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-90ucc90uccinimideethyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)benzoic acid (1-11i) [ka]

[0410] Pd(PPh3)4 (22 mg, 0.019 mmol) was added to a mixture of 1-11h (107 mg, 0.064 mmol) and 5,5-dimethylcyclohexane-1,3-dione (18 mg, 0.13 mmol) in DCM (1 ml). The resulting yellow mixture was degassed three times with a nitrogen balloon and then stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was concentrated under vacuum, dissolved in MeCN (2 mL), filtered, and purified by preparative HPLC (0.1% FA) (Method: Column: XBridge Prep C18 OBD 5um 19*250 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min). The fraction was concentrated under vacuum to obtain 1-11i (76 mg, yield 72.8%) as a white solid. MS (ESI) m / z: 1637.3 [M+H] +

[0411] Step 9: (2R,3R,4S,5S,6S)-2-((S)-2-((S)-2-(((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamide)-3-((3-((35-amino-3,6,9,12,15,18,21,24,27,30,33-undecamethyl-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxo-3,6,9,12,15,18,21,24,27,30,33-undecazapentatricontyl)(methyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)- sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-91ucc91uccinimideethyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-11k) [ka]

[0412] A mixture of 1-11i (76 mg, 0.046 mmol) and HATU (5.3 mg, 0.014 mmol) in DMF (2 mL) was mixed with DIPEA (16 μL, 0.093 mmol), then stirred at room temperature for 10 minutes, and 1-11j (40 mg, 0.046 mmol, purchased from WuXi AppTec) was added. Finally, the mixture was stirred at room temperature for 1 hour, filtered, and purified by preparative HPLC (0.1% FA) (Method: Column: XBridge Prep C18 OBD 5 μm 19*250 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min). The fraction was concentrated under vacuum to obtain 1-11k (100 mg, yield 86.5%) as a white solid. MS (ESI) m / z: 2487.2 [M+H] +

[0413] Step 10: (2S,3S,4S,5R,6R)-6-((S)-3-((3-((35-amino-3,6,9,12,15,18,21,24,27,30,33-undecamethyl-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxo-3,6,9,12,15,18,21,24,27,30,33-undecazapentatricontyl)(methyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-( ((1S,2R)-1-hydroxy-1-phenylpropane-2-yl)amino)-92ucc92uccinimideethyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-2-((S)-2-amino-3-methylbutanamide)-3-oxopropoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-11l) [ka]

[0414] A mixture of 1-11k (100 mg, 0.04 mmol) in THF (6 mL) was mixed with 1N LiOH (2 mL) at 0°C, stirred for 60 minutes at 0°C, then acidified to pH=6 with AcOH, and concentrated under vacuum to obtain the crude product. This was dissolved in DMF (2 mL), DEA (83 μL, 0.804 mmol) was added, and the mixture was reacted at room temperature for 1 hour. Finally, the mixture was purified by preparative HPLC (0.1% FA) (Method: Column: XBridge Prep C18 OBD 5 μm 19*250 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min), and the fraction was lyophilized to obtain 1-11 L (38 mg, yield 44.5%) as a white solid. MS (ESI) m / z: 2126.2 [M+H] +

[0415] Process 11: (2S,3S,4S,5R,6R)-6-(((2S,5S,15S)-16-amino-butylcarbamate-2-((3-((35-amino-3,6,9,12,15,18,21,24,27,30,33-undecamethyl-2,5,8,11,14,17,20,23,26,29,32,35- Dodecaoxo-3,6,9,12,15,18,21,24,27,30,33-Undecazapentatricontyl)(methyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydro Xy-1-phenylpropane-2-yl)amino)-92ucc92uccinimideethyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)carbamoyl)-15-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-5-isopropyl-4,7,11-trioxo-12-oxa-3,6,10-triazahexadecyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-11m) [ka]

[0416] A mixture of 1-5n (3.9 mg, 0.010 mmol) and HATU (3.7 mg, 0.01 mmol) in DMF (2 mL) was mixed with DIPEA (3 μL, 2.3 mg, 0.018 mmol). The mixture was stirred at room temperature for 5 minutes. 1-11m (19 mg, 0.009 mmol) was added. The mixture was stirred at room temperature for 1 hour. This was purified by preparative HPLC (0.1% FA) (Method: Column: XBridge Prep C18 OBD 5 μm 19*250 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min). The fraction was lyophilized to obtain 1-11m (10.6 mg, yield 47.3%) as a white solid. MS (ESI) m / z: 2506.3 [M+H] +

[0417] Process 12: (2S,3S,4S,5R,6R)-6-(((2S,5S,15S)-16-amino-2-((3-((35-amino-3,6,9,12,15,18,21,24,27,30,33-undecamethyl-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxo- 3,6,9,12,15,18,21,24,27,30,33-Undecazapentatricontyl)(methyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1 -phenylpropane-2-yl)amino)-93ucc93uccinimideethyl-3-oxopropyl)pyrroridine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)carbamoyl)-15-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-5-isopropyl-4,7,11-trioxo-12-oxa-3,6,10-triazahexadecyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid(1-11) [ka]

[0418] A mixture of 1-11m (10.6 mg, 0.011 mmol) in TFA / DCM (1:4, 2 mL) was stirred at 0°C for 1 hour. DCM was removed by bubbling under a nitrogen atmosphere, then diluted with ACN (2 mL), and purified by preparative HPLC (0.1% FA) (Method: Column: XBridge Prep C18 OBD 5 μm 19*250 mm; Mobile phase: A-Water (0.1% formic acid): B-Acetonitrile; Flow rate: 20 mL / min). The fraction was lyophilized to obtain 1-11 (9 mg, yield 84.4%) in the form of trifluoroacetate salt. MS (ESI) m / z: 2406.9 [M+H] +

[0419] Examples 1-12 [ka] Step 1: (2S,3S,4S,5R,6R)-6-((S)-3-((3-((35-amino-3,6,9,12,15,18,21,24,27,30,33-undecamethyl-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxo-3,6,9,12,15,18,21,24,27,30,33-undecazapentatricontyl)(methyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1- Phenylpropan-2-yl)amin94ucc94uccinimide 2-methyl-3-oxopropyl)pyrroridine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-2-((S)-3-methyl-2-(4-(5-(methylsulfonyl)-1,2,4-thiadiazole-3-yl)benzamide)butanamide)-3-oxopropoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-12)

[0420] A mixture of 1-6m (5.6mg, 0.020 mmol) and HATU (7.5mg, 0.020 mmol) in DMF (2 mL) was mixed with DIPEA (6 μL, 4.6 mg, 0.036 mmol). The mixture was stirred at room temperature for 5 minutes. 1-11l (19 mg, 0.011 mmol) was added. The mixture was stirred at room temperature for 1 hour. This was purified by preparative HPLC (FA), and the fraction was lyophilized to obtain 1-12 (9.2 mg, yield 43.0%) as a white solid. MS (ESI) m / z: 2391.8 [M+H] +

[0421] Examples 1-13 [ka]

[0422] Compounds 1-13 (9.9 mg, 51.2% yield) were synthesized according to the synthesis procedure of Examples 1-9. MS (ESI) m / z: 2618.6 [M+H] +

[0423] Examples 1-14 [ka]

[0424] Step 1: (2R,3R,4S,5S,6S)-2-((S)-2-((S)-2-acetamido-3-methylbutanamide)-3-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-(((((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,1 3,15-'Exo'hydro-1H'12'-benzo[de]95ucc95uccinimi':6,7]indolidino[1,2-b]quinoline-1-yl)carbamoyl)oxy)methyl)phenyl)amino)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-14b)

[0425] Compound 1-14b (135 mg, 72.2% yield) was synthesized according to the synthesis procedure in step 13 of Examples 1-4. MS (ESI) m / z: 1316.0 [M+H] +

[0426] Step 2: (2S,3S,4S,5R,6R)-6-((S)-2-((S)-2-acetamido-3-methylbutanamide)-3-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-(((((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-'exo'hydro-1H'12'-benzo[de]95ucc95uccinimi':6,7]indolidino[1,2-b]quinoline-1-yl)carbamoyl)oxy)methyl)phenyl)amino)-3-oxopropoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid(1-14c)

[0427] Compound 1-14c (121 mg, crude) was synthesized according to the synthesis procedure of step 14 in Examples 1-4. MS (ESI) m / z: 1176.0 [M+H] +

[0428] Step 3: (2S,3S,4S,5R,6R)-6-((S)-2-((S)-2-acetamido-3-methylbutanamide)-3-((3-((2-aminoethyl)carbamoyl)-4-(((((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-'exo'hydro-1H'12'-benzo[de]95ucc95uccinimi':6,7]indolidino[1,2-b]quinoline-1-yl)carbamoyl)oxy)methyl)phenyl)amino)-3,4,5-trihydroxytetra-h-ro-2H-pyran-2-carboxylic acid--2,2,2-trifluoroacetic acid (1 / 1)(1-14d)

[0429] Compound 1-14d (78 mg, 57.4% yield) was synthesized according to the synthesis procedure of step 15 in Examples 1-4. MS (ESI) m / z: 1075.8 [M+H] +

[0430] Step 4: (2S,3S,4S,5R,6R)-6-((S)-2-((S)-2-Acetocancan3-methylbutanamide)-3-((3-(((R)-8-(2,5-Dioxo-2,5-Dihydro-1H-Pyrrole-1-yl)-13,13-Dimethyl-4,11-Dioxo-5,12-Dioxa-3,10-Diazatetradecyl)Carbamoyl)-4-(((((1S,9S)-9-Ethyl-5-Fluoro-9 -Hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,'5-'exahydro'1H'12H-benzo[96ucc96uccinimi',4':6,7]indolidino[1,2-b]quinoline-1-yl)carbamoyl)oxy)methyl)phenyl)amino)-3-oxopropoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid(1-14e)

[0431] Compound 1-14e (21 mg, 60.0% yield) was synthesized according to the synthesis procedure of step 16 in Examples 1-4. MS (ESI) m / z: 1386.3 [M+H] +

[0432] Step 5: (2S,3S,4S,5R,6R)-6-((S)-2-((S)-2-acetamcan-3-methylbutanamide)-3-((3-((2-(((((R)-4-amino-3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)butoxy)carbonyl)amino)ethyl)carbamoyl)-4-(((((1S,9S)-9-ethyl-5-fluoro-9-hydroxy -4-methyl-10,13-dioxo-2,3,9,10,'3,'5-hexahydro'1H'12H-ben96uccini96uccinimi',4':6,7]indolidino[1,2-b]quinoline-1-yl)carbamoyl)oxy)methyl)phenyl)amino)-3-oxopropoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid(1-14)

[0433] Compounds 1-14 (13.6 mg, 64.5% yield) were synthesized according to the synthesis procedure of step 17 in Examples 1-4. MS (ESI) m / z: 1286.1 [M+H] +

[0434] Examples 1-15 [ka]

[0435] (2S,3S,4S,5R,6R)-6-((S)-2-((S)-2-acetamido-3-methylbutanamide)-3-((4-(((((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,'3,'5-hexahydro'1H'12H-ben96uccini96uccinimi',4':6, 7]Indolidino[1,2-b]quinoline-1-yl)carbamoyl)oxy)methyl)-3-((2-(4-(5-(methylsulfonyl)-1,2,4-thiadiazole-3-yl)benzamide)ethyl)carbamoyl)phenyl)amino)-3-oxopropoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid hydrate (1-15)

[0436] Compound 1-15 (7.3 mg, 49.7% yield) was synthesized according to the synthesis procedure of Step 1 in Examples 1-8. MS (ESI) m / z: 1341.9 [M+H] +

[0437] Examples 1-16 [ka]

[0438] Step 1: (2R,3R,4S,5S,6S)-2-((S)-2-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamide)-3-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-(hydroxymethyl)phenyl)amino)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (1-16a)

[0439] A mixture of 1-3o (416 mg, 1.34 mmol) and 1-5h (1000 mg, 1.34 mmol) in DCM (10 mL) was mixed with EEDQ (397 mg, 1.60 mmol). The mixture was stirred at room temperature for 5 hours. TLC showed that the reactants were consumed. The mixture was concentrated under vacuum to obtain the crude product, which was purified by silica gel column chromatography (EA:DCM = 0-10%) to obtain 1-16a (900 mg, yield 51.4%) as a white solid. MS (ESI) m / z: 1035.1 [M+H] +

[0440] Step 2: (2R,3R,4S,5S,6S)-2-((S)-2-((S)-2-(((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamide)-3-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (1-16b)

[0441] A mixture of 1-16a (300 mg, 0.29 mmol) and 4-nitrophenyl chloroformate (11697 ucc 097 uccmol) in DCM (3 mL) was mixed with DIEA (202 μL, 1.16 mmol). The resulting pale yellow mixture was stirred at room temperature for 12 hours. The mixture was concentrated and purified by silica gel column chromatography (EA:DCM = 0-10%) to obtain 1-16b (250 mg, yield 71.8%) as a pale yellow solid. MS (ESI) m / z: 1200.2 [M+H] +

[0442] Step 3: (2R,3R,4S,5S,6S)-2-((S)-2-((S)-2-(((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamide)-3-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-butyl) Phenylpropane-2-y98uccini98uccinimidexy-2-methyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-16c)

[0443] To a solution of compound 1-16b (250 mg, 0.208 mmol) and MMAE (164 mg, 0.229 mmol) in DMF (3.0 mL), DIPEA (90 mL, 0.52 mmol) and HOBt (7 mg, 0.052 mmol) were added at 0°C. The mixture was stirred at room temperature for 24 hours. The reaction product was concentrated and purified by flash column chromatography (MeOH / DCM = 0-5%). Compound 1-16c (100 mg, yield 27.0%) was obtained as a white solid. MS (ESI) m / z: 1779.2 [M+H] + .

[0444] Step 4: (2R,3R,4S,5S,6S)-2-((S)-2-((S)-2-amino-3-methylbutanamide)-3-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-y98uc cini98uccinimidexy-2-methyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)amino)-3-oxopropoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-16d) [ka]

[0445] A solution of compound 1-16c (100 mg, 0.0562 mmol) in DMF (2.0 mL) was mixed with DEA ​​(58 mL, 0.562 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction product was concentrated to obtain crude product 1-16d. MS (ESI) m / z: 1156.3 [M+H] + .

[0446] Step 5: (2R,3R,4S,5S,6S)-2-(((2S,5S)-2-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-y98uccini98uccininndexy-2-methyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-to Lioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)carbamoyl)-5-isopropyl-9,12,15,18,21,24,27,30,33,36,39,42-dodecamethyl-4,7,10,13,16,19,22,25,28,31,34,37,40,43-tetradekaoxo-3,6,9,12,15,18,21,24,27,30,33,36,39,42-tetradekazatetratetracontyl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-16e) [ka]

[0447] To a solution of crude compound 1-16d (0.0562 mmol) and 3,6,9,12,15,18,21,24,27,30,33,36-dodecamethyl-4,7,10,13,16,19,22,25,28,31,34,37-dodecaoxo-3,6,9,12,15,18,21,24,27,30,33,36-dodecazaoctatricontanoic acid (51 mg, 0.0562 mmol) in DMF (2.0 mL), HATU (25 mg, 0.067 mmol) and DIPEA (19 mL, 0.11 mmol) were added at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction product was purified by preparative HPLC (Method: Column XBridge Prep C18 OBD 5um 19*150mm; Mobile phase: A-Water (0.1% TFA): B-Acetonitrile; Flow rate: 20 mL / min), and the fraction was lyophilized to obtain 1-16e (trifluoroacetate) (40 mg, yield 29.0%, 2 steps) as a white solid. MS (ESI) m / z: 2451.3 [M+H] + .

[0448] Step 6: (2R,3R,4S,5S,6S)-2-(((2S,5S)-2-((3-((2-aminoethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-y99uccmi99uccinimidexy-2-methyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13- Dioxa-4,7,10-triazatetradecyl)phenyl)carbamoyl)-5-isopropyl-9,12,15,18,21,24,27,30,33,36,39,42-dodecamethyl-4,7,10,13,16,19,22,25,28,31,34,37,40,43-tetradekaoxo-3,6,9,12,15,18,21,24,27,30,33,36,39,42-tetradekazatetratetracontyl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate(1-16f) [ka]

[0449] To a solution of compound 1-16e (30 mg, 0.0122 mmol) in DCM (1.0 mL), TFA (0.2 mL) was added at 0°C. The mixture was stirred at 0°C for 10 minutes. The reaction product was purified by preparative HPLC (Method: Column XBridge Prep C18 OBD 5um 19*150 mm; Mobile phase: A-Water (0.1% TFA): B-Acetonitrile; Flow rate: 20 mL / min), and the fraction was lyophilized to obtain 1-16f (trifluoroacetate) (20 mg, yield 69.7%) as a white solid. MS (ESI) m / z: 2351.2 [M+H] + .

[0450] Step 7: (2S,3S,4S,5R,6R)-6-(((2S,5S)-2-((3-((2-aminoethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-y99uccini99uccinimidexy-2-methyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo -2,13-Dioxa-4,7,10-Triazatetradecyl)phenyl)carbamoyl)-5-Isopropyl-9,12,15,18,21,24,27,30,33,36,39,42-Dodecamethyl-4,7,10,13,16,19,22,25,28,31,34,37,40,43-Tetradecaoxo-3,6,9,12,15,18,21,24,27,30,33,36,39,42-Tetradecazatetratetracontyl)oxy)-3,4,5-Trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-16g) [ka]

[0451] To a solution of compound 1-16f (20 mg, 0.0085 mmol) in saturated LiBr(MeCn / water 10 / 1) (1.0 mL), NEt3 (7 mL, 0.0510 mmol) was added at 0°C. The mixture was stirred at room temperature for 4 hours. The reaction product was purified by preparative HPLC (Method: Column XBridge Prep C18 OBD 5 μm 19*150 mm; Mobile phase: A-Water (0.1% TFA): B-Acetonitrile; Flow rate: 20 mL / min), and the fraction was lyophilized to obtain 1-16 g (trifluoroacetate) (10 mg, yield 53.2%) as a white solid. MS (ESI) m / z: 2211.27 [M+H] + .

[0452] Step 8: (2S,3S,4S,5R,6R)-6-(((2S,5S)-2-((4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-2-y100uccini100uccinimidexy-2-methyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8-diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-decan-4,7,10-triazatetradecyl)-3-(((R)-8-(2,5-dioxo-2,5-dihydro- 1H-pyrrole-1-yl)-13,13-dimethyl-4,11-dioxo-5,12-dioxa-3,10-diazatetradecyl)carbamoyl)phenyl)carbamoyl)-5-isopropyl-9,12,15,18,21,24,27,30,33,36,39,42-dodecamethyl-4,7,10,13,16,19,22,25,28,31,34,37,40,43-tetradekaoxo-3,6,9,12,15,18,21,24,27,30,33,36,39,42-tetradekazatetratetracontyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-16h) [ka]

[0453] To a solution of 1-16 g (10 mg, 0.0045 mmol) and 1-3 v (2.4 mg, 0.0054 mmol) of the compound in DMF (1.0 mL), DIPEA (2.3 mL, 0.0135 mmol) was added at 0°C. The mixture was stirred at room temperature for 5 hours. The reaction product was purified by preparative HPLC (Method: Column XBridge Prep C18 OBD 5um 19*150 mm; Mobile phase: A-Water (0.1% TFA): B-Acetonitrile; Flow rate: 20 mL / min), and the fraction was lyophilized to obtain 1-16h (trifluoroacetate) (7 mg, yield 61.7%) as a white solid. MS (ESI) m / z: 2522.1 [M+H] + .

[0454] Step 9: (2cancanS,5R,6R)-6-(((2S,5S)-2-((3-((2-((((R)-4-amino-3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)butoxy)carbonyl)amino)ethyl)carbamoyl)-4-((5S,8S,11S,12R)-11-((S)-sec-butyl)-12-(2-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropane-101ucc101uccinimide-methoxy-2-methyl-3-oxopropyl)pyrrolidine-1-yl)-2-oxoethyl)-5,8- Diisopropyl-4,10-dimethyl-3,6,9-trioxo-2,13-dioxa-4,7,10-triazatetradecyl)phenyl)carbamoyl)-5-isopropyl-9,12,15,18,21,24,27,30,33,36,39,42-dodecamethyl-4,7,10,13,16,19,22,25,28,31,34,37,40,43-tetradekaoxo-3,6,9,12,15,18,21,24,27,30,33,36,39,42-tetradekazatetratetracontyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (1-16) [ka] To a solution of crude compound 1-16h (7 mg, 0.00277 mmol) in DCM (1.0 mL), TFA (0.2 mL) was added at 0°C. The mixture was stirred at 0°C for 10 minutes. The reaction product was purified by preparative HPLC (Method: Column XBridge Prep C18 OBD 5um 19*150 mm; Mobile phase: A-Water (0.1% TFA): B-Acetonitrile; Flow rate: 20 mL / min), and the fraction was lyophilized to obtain 1-16 (trifluoroacetate) (3 mg, yield 44.7%) as a white solid. MS (ESI) m / z: 2421.94 [M+H] + .

[0455] The conjugator-linker-payload structures prepared in this specification are summarized in Table 1 below. [Table 3-1] [Table 3-2] [Table 3-3]

[0456] Example 2: Preparation and Characterization of Antibody-Drug Conjugates Preparation of DAR 3-5 antibody-drug conjugates. Antibody (concentration 0.5–25 mg / mL, PBS buffer pH 6.0–8.5) in conjugate buffer was incubated at reducing temperature (0–40°C) for 10 minutes. 2–10 equivalents. TECP solution (5 mM stock in PBS buffer) was added to the reaction mixture, and the reduction reaction product was allowed to stand at reducing temperature for 1–8 hours. After cooling the reduction mixture to 0–25°C, organic solvents (e.g., DMSO, DMF, DMA, PG, acetonitrile, 0–25% v / v) and the conjugator-linker-payload stock prepared herein (6–25 equivalents, 10 mM stock in organic solvent) (see Tables 2A–2D) were added stepwise. The conjugate solution was allowed to stand at 0–25°C for 1–3 hours, and the reaction product could be quenched with N-acetylcysteine ​​(1 mM stock). The solution was transferred to a storage buffer (e.g., histidine acetate buffer with a pH of 5.5–6.5, with optional additives such as sucrose, trehalose, and tween® 20, 60, and 80) via buffer exchange (spin desalting column, ultrafiltration, and dialysis).

[0457] After the conjugation step, the ADC was subjected to buffer exchange with a ring-opening buffer (pH 6.5–9.0, PBS, boric acid, or Tris buffer), and the solution was left to stand at 22°C or 37°C for 1–48 hours. The maleimide ring-opening process was monitored by reducing LC-MS. Once the hydrolysis of the conjugated maleimide was complete, the resulting ADC was buffer-exchanged by dialysis with basic Tris pH 8.0–8.5 buffer or acidic histidine-acetic acid pH 5.0–6.5 buffer.

[0458] LC-MS method for monitoring and determining maleimide hydrolysis. LC-MS analysis was performed under the following measurement conditions. LC-MS system: Vanquish Flex UHPLC and Orbitrap exploris 240 mass spectrometer Column: MAbPac(TM) RP, 2.1*50mm, 4μm, 1,500Å, Thermo Scientific(TM) Column temperature: 80℃ Mobile phase A: 0.1% formic acid (FA) aqueous solution Mobile phase B: Acetonitrile solution containing 0.1% formic acid (FA) Gradient Program 1: 25%B~25%B (0 min~2 min), 25%B~50%B (2 min~18 min), 50%B~90%B (18 min~18.1 min), 90%B~90%B (18.1 min~20 min), 90%B~25%B (20 min~20.1 min), 25%B~25%B (20.1 min~25 min) Gradient Program 2 Injection sample volume: 2 μg MS parameters: Intact and denatured MS data were acquired in HMR mode with R=15k and deconvolved using the ReSpect algorithm and sliding window integration with Thermo Scientific® BioPharma Finder® 4.0 software.

[0459] Characterization of ADCs. The ADCs were characterized using the following analytical methods. The drug-antibody ratio (DAR) of the ADCs was determined by LC-MS or HIC. The SEC purity of all prepared ADCs was over 95%.

[0460] LC-MS method: LC-MS analysis was performed under the following measurement conditions. LC-MS system: Vanquish Flex UHPLC and Orbitrap exploris 240 mass spectrometer Column: MAbPac(TM) RP, 2.1*50mm, 4μm, 1,500Å, Thermo Scientific(TM) Column temperature: 80℃ Mobile phase A: 0.1% formic acid (FA) aqueous solution Mobile phase B: Acetonitrile solution containing 0.1% formic acid (FA) Gradient Programs: 25%B~25%B (0 min~2 min), 25%B~50%B (2 min~18 min), 50%B~90%B (18 min~18.1 min), 90%B~90%B (18.1 min~20 min), 90%B~25%B (20 min~20.1 min), 25%B~25%B (20.1 min~25 min) Injection sample volume: 1 μg MS parameters: Intact and denatured MS data were acquired in HMR mode with R=15k and deconvolved using the ReSpect algorithm and sliding window integration with Thermo Scientific® BioPharma Finder® 4.0 software.

[0461] HIC method: HPLC analysis was performed under the following measurement conditions. HPLC System: Waters ACQUITY ARC HPLC System Detector: Measurement wavelength: 280nm Column: Tosoh Bioscience 4.6μm ID×3.5cm, 2.5μm butyl nonporous resin column Column temperature: 25℃ Mobile phase A: 1.5M ammonium sulfate, 50mM phosphate buffer, pH 7.0 Mobile phase B: 50 mM phosphate buffer, 25% (V / V) isopropanol, pH 7.0 Gradient Programs: 0%B~0%B (0 min~2 min), 0%B~100%B (2 min~15 min), 100%B~100%B (15 min~16 min), 100%B~0%B (16 min~17 min), 0%B~0%B (17 min~20 min) Injection sample volume: 20 μg

[0462] SEC method: HPLC analysis was performed under the following measurement conditions to determine the purity of ADC. HPLC System: Waters H-Class UPLC System Detector: Measurement wavelength: 280nm Column: ACQUITY UPLC BEH200 SEC 1.7um 4.6x150mm, Waters Column temperature: Room temperature Mobile phase A: 200 mM phosphate buffer, 250 mM potassium chloride, 15% isopropyl alcohol, pH 7.0 Gradient program: Isocratic elution for 10 minutes (flow rate 0.3 mL / min) Injection sample volume: 20 μg

[0463] ADC Hydrophobicity Evaluation: ADCs with higher hydrophobic properties are expected to be identified by their slower retention time ("RT") from HIC (Hydrophobic Interaction Column) chromatography. The results are shown in Tables 2A-2D, using the DAR8 peak as the reference. [Table 4] [Table 5-1] [Table 5-2] [Table 5-3] [Table 6-1] [Table 6-2] [Table 7]

[0464] Antibody information Ifinatamab (anti-B7H3 antibody)

[0465] Light chain sequence (Sequence ID: 1)

[0466] EIVLTQSPATLSLSPGERATLSCRASSRLIYMHWYQQKPGQAPRPLIYATSNLASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWNSNPPTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0467] Heavy chain sequence (SEQ ID NO: 2)

[0468] QVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYVMHWVRQAPGQGLEWMGYINPYNDDVKYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARWGYYGSPLYYFDYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0469] 6E7 (anti-CLL1 antibody)

[0470] Light chain sequence (Sequence ID: 3)

[0471] DIQMTQSPSSLSASVGDRVTITCRASQSVSTSSYNYMHWYQQKPGKPPKLLIKYASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHSWEIPLTFGQGTKVE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0472] Heavy chain sequence (SEQ ID NO: 4)

[0473] EVQLVQSGAEVKKPGASVKVSCKASGYSFTDYYMHWVRQAPGQGLEWIGRINPYAGAAFYSQNFKDRVTLTVDTSTSTAYLELSSLRSEDTAVYYCAIERGADLEGYAMDYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0474] Cofetuzumab (anti-PTK7 antibody)

[0475] Light chain sequence (Sequence ID: 5)

[0476] DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFGQGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0477] Heavy chain sequence (SEQ ID NO: 6)

[0478] QVQLVQSGPEVKKPGASVKVSCKASGYTFTDYAVHWVRQAPGKRLEWIGVISTYNDYTYNNQDFKGRVTMTRDTSASTAYMELSRLRSEDTAVYYCARGNSYFYALDYWGQG TSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0479] Example 3: Direct ADC killing in U937, HL60, TF-1, NCI-H358, NCI-H1048 and MDA-MB-453 cancer cell lines

[0480] cell line U937 (ATCC, CRL-1593.2). U-937 is a cell line exhibiting monocyte morphology, derived from malignant cells obtained from the pleural effusion of a 37-year-old Caucasian male with histiocytic lymphoma in 1974. U937 was purchased from ATCC. The basic medium for U937 was ATCC-formulated RPMI-1640 medium (ATCC 30-2001). To prepare a full-growth medium, 10% final concentration fetal bovine serum (Gibco, 10099-141C) was added to the basic medium. The cell line was grown at 37°C in a humidified 5% CO2 atmosphere and periodically tested for the presence of mycoplasma using the MycoAlert® PLUS Mycoplasma Detection Kit (Lonza, LT07-710).

[0481] HL60 (ATCC, CCL-240). HL-60 cells are promyeloblasts isolated by leukophagesis from the peripheral blood of a 36-year-old Caucasian woman with acute promyelocytic leukemia. HL60 cells were purchased from ATCC. The basic medium for HL60 was ATCC-formulated Iscob modified Dulbecco's medium (catalog no. 30-2005). To prepare a full growth medium, 20% final concentration fetal bovine serum (Gibco, 10099-141C) was added to the basic medium. The cell line was grown at 37°C in a humidified 5% CO2 atmosphere and periodically tested for the presence of mycoplasma using the MycoAlert® PLUS Mycoplasma Detection Kit (Lonza, LT07-710).

[0482] TF1 (ATCC, CRL-2003). TF-1 erythroblasts were isolated in 1987 from the bone marrow of a 35-year-old Asian male with severe pancytopenia. TF-1 was purchased from ATCC. The basic medium for TF-1 was ATCC-formulated RPMI-1640 medium (catalog no. 30-2001). To prepare a full-growth medium, 10% final concentration fetal bovine serum (Gibco, 10099-141C) was added to the basic medium. The cell line was grown at 37°C in a humidified 5% CO2 atmosphere and periodically tested for the presence of mycoplasma using the MycoAlert® PLUS Mycoplasma Detection Kit (Lonza, LT07-710).

[0483] NCI-H358 (ATCC, CRL-5807). NCI-H358 cells are epithelial-like cells isolated from the bronchi of a male patient with bronchoalveolar carcinoma. NCI-H358 was purchased from ATCC. The basic medium for NCI-H358 was ATCC-formulated RPMI-1640 medium (ATCC 30-2001). To prepare a full growth medium, 10% final concentration fetal bovine serum (Gibco, 10099-141C) was added to the basic medium. The cell line was grown at 37°C in a humidified 5% CO2 atmosphere and periodically tested for the presence of mycoplasma using the MycoAlert® PLUS Mycoplasma Detection Kit (Lonza, LT07-710).

[0484] NCI-H1048 (ATCC, CRL-5853). NCI-H1048 is a cell line exhibiting epithelial morphology. NCI-H1048 was purchased from ATCC. The basic medium for NCI-H1048 was ATCC-formulated DMEM:F12 (catalog number 30-2006). To prepare a complete growth medium, 10% final concentration fetal bovine serum (Gibco, 10099-141C) was added to the basic medium. The cell line was grown at 37°C in a humidified 5% CO2 atmosphere and periodically tested for the presence of mycoplasma using the MycoAlert® PLUS Mycoplasma Detection Kit (Lonza, LT07-710).

[0485] MDA-MB-453 (SIBS). MDA-MB-453 was derived from the exudate of a 48-year-old female patient with metastatic breast cancer involving the nodules, brain, and both pleural and pericardial cavities, and was purchased from SIBS. The basic medium for MDA-MB-453 was RPMI 1640 medium HEPES (Gibco; 22400105). To prepare a full growth medium, 10% final concentration fetal bovine serum (Gibco, 10099-141C) was added to the basic medium. The cell line was grown in a humidified 5% CO2 atmosphere at 37°C and periodically tested for the presence of mycoplasma using the MycoAlert® PLUS Mycoplasma Detection Kit (Lonza, LT07-710). [Table 8] [Table 9]

[0486] Direct ADC killing was evaluated in U937, HL60, and TF1 cancer strains. Cells were seeded in 2D 96-well plates (Greiner: 655090) at 100 μl / well (containing 150 μg / ml of Fc blocker) (U937 or HL60 (3E3 / well) or TF1 (6E3 / well)) and incubated at 37°C and 5% CO2 for 1 hour. Fresh growth medium containing various concentrations of ADC was added at 50 μl / well and incubated at 37°C and 5% CO2 for 6 days. Cell viability was detected using Cell Titer-Glo (Promega, G7573), 70 μl / well. The 2D plates were incubated at room temperature for 10 minutes to stabilize the luminescence signal. The plates were analyzed using a microplate reader.

[0487] Direct ADC killing was evaluated in NCI-H358, NCI-H1048, and MDA-MB-453 cancer strains. Cells were seeded at 80 μl / well (2E3 / well) in 3D 96-well plates (Corning: 4520) and incubated overnight at 37°C and 5% CO2. Fresh growth medium containing various concentrations of ADC was added at 40 μl / well and incubated at 37°C and 5% CO2 for 6 days. Cell viability was detected using 3D reagent (Promega; G9683), 100 μl / well. The 3D plates were incubated at room temperature for 30 minutes to stabilize the luminescence signal. The plates were analyzed using a microplate reader.

[0488] Direct ADC cell elimination data for U937, HL60, and TF1 cells are shown in Figures 1 to 15 and Tables 5 to 9. Direct ADC cell elimination data for NCI-H358, NCI-H1048, and MDA-MB-453 cells are shown in Figures 16 to 21, Tables 10 and 11. [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16]

[0489] Example 4: PK study of ADCs in mice Female BALB / c nude mice (n=3 per group) were treated with freshly prepared ADC (5 or 10 mg / kg) by intravenous administration. After administration, the mice were anesthetized with isoflurane at the specified time. Whole blood samples were collected from the orbital venous sinus into coagulation tubes (Kangjian, numbers 041-0121) at 0.5, 2, 6, 8, 24, 48, 72, and 168 hours after administration. Blood samples were left at room temperature for approximately 30 minutes and then processed by centrifugation (4°C, 3000 × g, 7 min) to separate the plasma. Serum samples were transferred to new 1.5 mL tubes and stored in a -80°C freezer before analysis.

[0490] Serum payload concentration. To determine the serum payload concentration, 150 μL of IS (verapamil, 10 ng / mL) in ACN / MeOH (1:1) was added to a 15 μL sample aliquot. The mixture was vortexed for 1 minute and centrifuged at 4000 rpm for 10 minutes at 4°C. An 80 μL supernatant aliquot was diluted with 80 μL of water, and the mixed sample was injected into an LC-MS / MS.

[0491] LC-MS / MS method for determining the biological analysis of the payload. LC-MS / MS analysis was performed under the following measurement conditions. Equipment: LC-MS / MS (Triple Quad 6500 plus) Monitor: MRM Column: Advanced Materials Technology, HALO AQ-C18 2.7μm 90Å, 50*2.1mm Column temperature: 40℃ Mobile phase A: H2O-0.1%FA Mobile phase B: ACN-0.1%FA MMAE gradient programs: 15%B~15%B (0 min~0.4 min), 15%B~30%B (0.4 min~0.8 min), 30%B~30%B (0.8 min~1.8 min), 30%B~90%B (1.8 min~1.9 min), 90%B~90%B (1.9 min~2.4 min), 90%B~15%B (2.4 min~2.5 min), 15%B~15%B (2.5 min~3.0 min) Injection sample volume: 10 μL (MMAE)

[0492] Plasma ADC and total Ab (Tab) concentrations. Plasma ADC and Tab concentrations were determined using an ELISA assay with CLL1 or PTK7 (where applicable) ECD (extracellular domain) as the capture reagent. The detection reagent was anti-payload Ab for ADC concentration and anti-human IgG polyclonal Ab for Tab concentration.

[0493] For ADC concentration, microplates were coated with CLL1 or PTK7 (if applicable), 1 μg / mL ECD, 100 μL per well, and incubated overnight at 4°C. The microplates were washed three times with 0.05% PBST, and then 200 μL of 2% BSA solution was added per well. The plates were incubated at 37°C for 1 hour, and then washed three times with 0.05% PBST. Then 100 μL (for ADC sample or standard curve) was added to each well. The plates were incubated at 37°C for 1 hour, and then washed three times with 0.05% PBST. 100 μL of 1 μg / mL biotin anti-MMAE antibody was added per well. The plates were incubated again at 37°C for 1 hour, and then washed three times with 0.05% PBST. Next, 100 μL of SA-HRP at a 1:10000 ratio was added to each well, incubated at 37°C for 0.5 hours, and then washed three times with 0.05% PBST. Finally, 100 μL of TMB was added to each well, the plate was incubated at room temperature for 15 minutes, and then 100 μL of stop solution was added to each well. The plate was read at OD 450 using an ELISA microplate reader.

[0494] For tab enrichment of anti-CLL1 antibody, the aforementioned ADC method was used, with the following modification: 100 μL of anti-human IgG Fc HRP (1:10000) was added per well.

[0495] For tab enrichment of the anti-PTK1 antibody, the aforementioned ADC method was used, with the following modification: 100 μL of 1 μg / ml anti-human IgG Fc HRP (1:10000) was added per well.

[0496] Changes in ADC DAR in mouse serum PK samples. The stability of ADC, as reflected in the decrease in DAR over time, was studied using the plasma samples described above. The time points after administration of the tested samples are shown in Tables 16 and 17 below.

[0497] Human CLL1 or PTK7 (where applicable), ECDs were biotinylated and immobilized on Dynabeads M-280 streptavidin. ADCs were captured from plasma samples by incubation at 37°C for 2 hours using an ECD bead system. The captured ADCs were then washed with HBS-EP buffer (10 mM Hepes [pH 7.4], 150 mM NaCl, 3.4 mM ethylenediaminetetraacetic acid [EDTA], 0.005% surfactant P20) and digested at 37°C for 1 hour using IdeS enzyme. After thoroughly washing the beads with HBS-EP, water, and 10% acetonitrile, the ADC analytes were eluted using 30% acetonitrile containing 1% formic acid. The samples were then reduced with 100 mM TCEP for 45 minutes. Liquid chromatography-tandem mass spectrometry (LC-MS / MS) was used for ADC DAR analysis.

[0498] The mouse PK parameters of several anti-CLL1 ADCs (ADC3-A, ADC3-3, ADC3-5, ADC3-6, and ADC3-7) are shown in Table 12 below. The results indicate that ADC3-3, ADC3-5, ADC3-6, and ADC3-7 showed lower payload exposure and lower DAR changes than ADC3-A. [Table 17]

[0499] The mouse PK parameters of anti-PTK7 ADCs (ADC5-A, ADC5-1, and ADC5-2) are shown in Table 13 and Figure 22. The results indicate that ADC5-1 and ADC5-2 showed lower payload exposure and lower DAR changes than ADC5-A. [Table 18]

[0500] Example 5: Tumor growth inhibition in an NCI-H1650 xenograft model NCI-H1650 (ATCC) is an epithelial cell line isolated in 1987 from the lung tissue of a 27-year-old male smoker with stage 3 bronchoalveolar carcinoma. NCI-H1650 cells were cultured in RPMI-1640 medium supplemented with 10% (v / v) fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin. Cultured cells were collected on the day of transplantation and resuspended in a cold (4°C) mixture of PBS and Matrigel (1:1). Cell density was set to 2.5 × 10⁶. 7 The solution was adjusted to the desired cell / mL concentration, and the cells were placed on ice before inoculation.

[0501] A 5x10 cm specimen was found on the right flank of a female BALB / c nude mouse. 6 NCI-H1650 cells (mixed with Matrigel in a 1:1 ratio) were subcutaneously injected. After inoculation, the length (a) and width (b) of the tumor were measured with calipers, and the formula V = 0.5(a × b) was used. 2 The tumor volume was calculated using ). The tumor volume was approximately 200 mm 3Upon reaching a certain size, the mice were randomly divided on day 0 into four groups: Vehicle, ADC5-A, ADC5-1, and ADC5-2 (each containing 6 animals). On day 1 of treatment, the animals were intravenously administered either Vehicle, ADC5-A (3 mg / kg), ADC5-1 (3 mg / kg), or ADC5-2 (3 mg / kg). Whole blood samples were collected at 2, 6, 48, and 168 hours post-treatment from 3 mice per group (samples at 2 and 48 hours were collected from one group (3 mice), and samples at 6 and 168 hours were collected from another group (3 mice)). The blood was centrifuged at 5000 xg for 10 minutes at 4°C to obtain serum for PK assay. Animal body weight and tumor volume were measured twice weekly. Tumor growth inhibition (TGI) was calculated using the following formula: %TGI = [1 - (TreatedT t - Treated T0) / (Vehicle T t - Vehicle T0) × 100% Treated T t = Mean tumor volume of the group taking the medication on day t Mean tumor volume of the group receiving treatment on day T0=0 after treatment Vehicle T t = Mean tumor volume of the vehicle group on day t Mean tumor volume of the vehicle group on day T0 = 0

[0502] The results of evaluating the antitumor effects of ADC5-A, ADC5-1, and ADC5-2 in a subcutaneous NCI-H1650 xenograft model are shown in Table 14 and Figure 23. Data are presented as mean tumor volume ± standard error of mean (SEM). Treatment with a single dose containing 3 mg / kg of ADC5-A, ADC5-1, and ADC5-2 showed antitumor activity of 65% (adjusted p=0.0008), 78% (adjusted p=0.0007), and 94% (adjusted p=0.0012), respectively, on day 18 of treatment. At 3 mg / kg, ADC5-1 and ADC5-2 showed superior efficacy compared to ADC5-A. All ADCs in the treatment groups were well-tolerated, and no animals in any treatment group showed significant weight loss or abnormal clinical observations. [Table 19]

[0503] While the foregoing disclosures are presented in some detail through descriptions and examples for the purpose of clarification, it will be apparent to those skilled in the art that certain minor changes and modifications will be made. Therefore, the descriptions and examples should not be construed as limiting.

[0504] Where any prior art publication is referenced herein, it should be understood that such reference does not constitute an endorsement that such publication forms part of the common general knowledge in the art in any country.

[0505] All non-patent literature, patents, patent applications, and published patent application disclosures referenced herein by identifying citation are incorporated herein by reference in their entirety.

Claims

1. Compound of formula (Ia): 【Chemistry 239】 or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, [wherein: BA is a binder selected from humanized antibodies, monoclonal antibodies, chimeric antibodies, or human antibodies, or their antigen-binding fragments; The conjugator part has formula (II) or (III): 【Chemistry 240】 {In the formula: U is a bond, heteroarylene, or arylene; V is a bond or -C≡C-(CH ２ ) ｎ - and; n is an integer between 0 and 10 (including both ends); W ２ is -C(=O)-, -NH-, or -O-; RG is 【Chemistry 241】 -(succinimido-3-yl-N)-, or 【Chemistry 242】 And; RS is -NR １ａ R １ｂ And; R １ａ and R １ｂ Each of these is independently H, or a substituted or unsubstituted C. １－４ It is alkyl; RE is a bond, -O-, -OC(=O)-, -OC(=O)NR ６ -, -NHC(=O)NR ６ -, -OS(=O) ２ NR ６ -, -NHS(=O) ２ NR ６ - or - OC(=O)NHS(=O) ２ NR ６ -; R ６ is H, or substituted or unsubstituted C １－４ It is alkyl; W ３ is -C(=O)-, -NH-, or -O-; s and t are independently either 1 or 2; 【Chemistry 243】 This indicates a covalent bond site within the compound, and * indicates a connection where the conjugator part connects to BA. The linker section has formula (IV): 【Chemistry 244】 {In the formula: HG is a hydrophilic residue, and ** indicates a connection where the linker section connects to the conjugator section. The severable portion has formula (V): 【Chemistry 245】 {In the formula: R ２ Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. １－４ Alkyl, -CN, or -NO ２ and **** indicates a connection where the severable portion connects to the linker portion; The payload portion consists of payload residues; and x is 1 to 15 (including both ends), the compound, or a pharmaceutically acceptable salt thereof, tautomer, solvate, or stereoisomer.

2. The cuttable portion has the following formula: 【Chemistry 246】 The compound according to claim 1.

3. Compound of formula (Ib): 【Chemistry 247】 or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, [wherein: BA is a binder selected from humanized antibodies, monoclonal antibodies, chimeric antibodies, or human antibodies, or their antigen-binding fragments; The conjugator part has formula (II) or (III): 【Chemistry 248】 {In the formula: U is a bond, heteroarylene, or arylene; V is a bond or -C≡C-(CH ２ ) ｎ - and; n is an integer between 0 and 10 (including both ends); W ２ is -C(=O)-, -NH-, or -O-; RG is 【Chemistry 249】 -(succinimido-3-yl-N)-, or [Chemical 250] And; RS is -NR １ａ R １ｂ And; R １ａ and R １ｂ Each of these is independently H, or a substituted or unsubstituted C. １－４ It is alkyl; RE represents bond, -O-, -OC(=O)-, -OC(=O)NR ６ -, -NHC(=O)NR ６ -, -OS (=O) ２ NR ６ -, -NHS (=O) ２ NR ６ - or - OC (=O) NHS (=O) ２ NR ６ - and; R ６ is H, or substituted or unsubstituted C １－４ It is alkyl; W ３ is -C(=O)-, -NH-, or -O-; s and t are independently 0, 1, or 2; 【Chemistry 251】 This indicates a covalent bond site within the compound, and * indicates a connection where the conjugator part connects to BA. The severable portion has the formula (Va), (Vb), or (Vc): 【Chemistry 252】 {In the formula: R ２ Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. １－４ Alkyl, -CN, or -NO ２ And, *** indicates a connection where the severable part connects to the conjugator part, and **** indicates a connection where the severable portion connects to the linker portion; The linker section has formula (IV'): 【Chemistry 253】 {during the ceremony HG is a hydrophilic residue, and **! indicates the connection where the linker part connects to the cap. The cap is CH ３ C(=O)-, CH ３ - (CH ２ ) ｂ -O-(CH ２ CH ２ O) ａ - (CH ２ CH ２ ) ｄ -C(=O)-, CH ３ - (CH ２ ) ｂ -O-(CH ２ CH ２ O) ａ - (CH ２ CH ２ ) ｄ -NH-C(=O)-, CH ３ (C(=O)N(CH ３ )CH ２ ) ａ C(=O)-, -NH-(CH ２ CH ２ O) ａ - (CH ２ ) ｂ CH ３ or -(N(CH ３ ) (CH ２ ) ｃ C (=O) ａ NH ２ And {in the formula: a is an integer from 1 to 18 (including both ends), b and d are independently 0, 1, or 2, and c is an integer between 1 and 4 (including both ends); The payload portion consists of payload residues; and x is 1 to 15 (including both ends), the compound, or a pharmaceutically acceptable salt thereof, tautomer, solvate, or stereoisomer.

4. The severable portion has one of the following equations: 【Chemistry 254】 The compound according to claim 3.

5. The cap is CH ３ C(=O)-, CH ３ -(CH ２ ) ｂ -O-(CH ２ CH ２ O) ａ -(CH ２ CH ２ ) ｄ -C(=O)- or CH ３ (C(=O)N(CH ３ )CH ２ ) ａ C(=O)-, a compound according to claim 3 or 4.

6. The cap is CH ３ C(=O)-CH ３ -O-(CH ２ CH ２ O) １１ -(CH ２ CH ２ )-C(=O)- or -CH ３ (C(=O)N(CH ３ )CH ２ ) １２ C(=O)-, the compound according to claim 5

7. Compound of formula (Ic): 【Chemistry 255】 or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, [wherein: BA is a binder selected from humanized antibodies, monoclonal antibodies, chimeric antibodies, or human antibodies, or their antigen-binding fragments; The conjugator part has formula (II) or (III): 【Chemistry 256】 {in the formula; U is a bond, heteroarylene, or arylene; V is a bond or -C≡C-(CH ２ ) ｎ - and; n is an integer between 0 and 10 (including both ends); W ２ is -C(=O)-, -NH-, or -O-; RG is 【Chemistry 257】 -(succinimido-3-yl-N)-, or 【Chemistry 258】 And; RS stands for amino group or -NR １ａ R １ｂ And; R １ａ and R １ｂ Each of these is independently H, or a substituted or unsubstituted C. １－４ It is alkyl; RE represents bond, -O-, -OC(=O)-, -OC(=O)NR ６ -, -NHC(=O)NR ６ -, -OS (=O) ２ NR ６ -, -NHS (=O) ２ NR ６ - or - OC (=O) NHS (=O) ２ NR ６ - and; R ６ is H, or substituted or unsubstituted C １－４ It is alkyl; W ３ is -C(=O)-, -NH-, or -O-; s and t are independently 0, 1, or 2; 【Chemistry 259】 This indicates a covalent bond site within the compound, and * indicates a connection where the conjugator part connects to BA. The linker section has formula (IV): 【Chemistry 260】 {In the formula: HG is a hydrophilic residue, and; ** indicates a connection where the linker section connects to the conjugator section. The severable portion has the formula (Va'), (Vb'), or (Vc'): 【Chemistry 261】 {In the formula: R ２ Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. １－４ Alkyl, -CN, or -NO ２ And, ***! indicates a connection where the severable part connects to the cap, and **** indicates a connection where the severable portion connects to the linker portion; キャップは、CH ３ C(=O)-、CH ３ -(CH ２ ) ｂ -O-(CH ２ CH ２ O) ａ -(CH ２ CH ２ ) ｄ -C(=O)-、-C(=O)-(CH ２ CH ２ O) ａ -(CH ２ ) ｂ CH ３ 、CH ３ (C(=O)N(CH ３ )CH ２ ) ａ C(=O)-、-NH-(CH ２ CH ２ O) ａ -(CH ２ ) ｂ CH ３ または-(N(CH ３ )(CH ２ ) ｃ C(=O)) ａ NH ２ であり; a is an integer between 1 and 18 (including both ends); b and d are independently 0, 1, or 2. c is an integer between 1 and 4 (including both ends); The payload portion consists of payload residues; and x is 1 to 15 (including both ends), the compound, or a pharmaceutically acceptable salt thereof, tautomer, solvate, or stereoisomer.

8. The severable portion has one of the following equations: 【Chemistry 262】 The compound according to claim 7.

9. The cap is -NH-(CH ２ CH ２ O) ａ - (CH ２ ) ｂ CH ３ or -(N(CH ３ ) (CH ２ ) ｃ C (=O) ａ NH ２ The compound according to claim 7 or 8.

10. The cap is -NH-(CH ２ CH ２ O) １２ -CH ３ or -(N(CH ３ )CH ２ C (=O) １２ NH ２ The compound according to claim 9.

11. Compound of formula (Id): 【Chemical 263】 or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, [wherein: BA is a binder selected from humanized antibodies, monoclonal antibodies, chimeric antibodies, or human antibodies, or their antigen-binding fragments; The conjugator part has formula (II) or (III): 【Chemistry 264】 {In the formula: U is a bond, heteroarylene, or arylene; V is a bond or -C≡C-(CH ２ ) ｎ - and; n is an integer between 0 and 10 (including both ends); W ２ is -C(=O)-, -NH-, or -O-; RG is 【Chemical 265】 -(succinimido-3-yl-N)-, or 【Chemical 266】 And; RS is -NR １ａ R １ｂ And; R １ａ and R １ｂ Each of these is independently H, or a substituted or unsubstituted C. １－４ It is alkyl; RE represents bond, -O-, -OC(=O)-, -OC(=O)NR ６ -, -NHC(=O)NR ６ -, -OS (=O) ２ NR ６ -, -NHS (=O) ２ NR ６ - or - OC (=O) NHS (=O) ２ NR ６ - and; R ６ is H, or substituted or unsubstituted C １－４ It is alkyl; W ３ is -C(=O)-, -NH-, or -O-; s and t are independently 0, 1, or 2; 【Chemistry 267】 This indicates a covalent bond site within the compound, and * indicates a connection where the conjugator part connects to BA. The linker section has formula (IV'): 【Chemical 268】 {In the formula: HG is a hydrophilic residue, and **! indicates the connection where the linker part connects to the cap. The severable portion has the formula (Va''), (Vb''), or (Vc''): 【Chemistry 269】 {In the formula: R ２ Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. １－４ Alkyl, -CN, or -NO ２ And, ***† indicates a connection where the severable portion connects to the launcher, and **** indicates a connection where the severable portion connects to the linker portion; The cap is CH ３ C(=O)-, CH ３ - (CH ２ ) ｂ -O-(CH ２ CH ２ O) ａ - (CH ２ CH ２ ) ｄ -C(=O)-, -C(=O)-(CH ２ CH ２ O) ａ - (CH ２ ) ｂ CH ３ ,CH ３ (C(=O)N(-H ３ )CH ２ ) ａ C(=O)-, -NH-(CH ２ CH ２ O) ａ - (CH ２ ) ｂ CH ３ or -(N(CH ３ ) (CH ２ ) ｃ C (=O) ａ NH ２ And {in the formula} a is an integer between 1 and 18 (including both ends); b and d are independently 0, 1, or 2, and c is an integer between 1 and 4 (including both ends); Blancher has formulas (XIIa), (XIIa1), (XIIb), or (XIIb1): 【Chemistry 270】 {In the formula: The hydrophilic substance is -NH-(CH ２ CH ２ O) ａ１ - (CH ２ ) ｂ１ CH ３ ,--C(=O)NH ２ , -C(=O)-(CH ２ CH ２ O) ａ１ - (CH ２ ) ｂ１ CH ３ or -(N(CH ３ ) (CH ２ ) ｃ１ C (=O) ａ１ NH ２ And, † indicates a connection where the launcher connects to the conjugator section. †† indicates a connection where the plancher connects to the cuttable section. a1 is an integer from 1 to 18 (including both ends), b1 is 0, 1 or 2, and Each of c1, p, and q is an independent integer between 1 and 4 (including both ends). The payload portion consists of payload residues; and x is 1 to 15], the compound, or a pharmaceutically acceptable salt thereof, tautomer, solvate, or stereoisomer.

12. The severable portion has one of the following equations: 【Chemistry 271】 The compound according to claim 11.

13. The compound according to claim 11 or 12, wherein a1 is 12, b1 is 0, c1 is 1, p is 2, and q is 2 or 4.

14. Blancher has one of the following equations: 【Chemistry 272】 The compound according to any one of claims 11 to 13.

15. The hydrophilic substance is -C(=O)-(CH ２ CH ２ O) ａ１ -CH ３ or -(N(CH ３ ) - CH ２ -C (=O)) ａ１ NH ２ The compound according to any one of claims 11 to 14, wherein a1 is an integer from 10 to 16 (including both ends).

16. The compound according to claim 15, wherein a1 is 12.

17. The cap is CH ３ The compound according to any one of claims 11 to 16, wherein it is C(=O)-.

18. The compound according to any one of claims 1 to 17, wherein the conjugator portion has formula (II).

19. The compound according to claim 18, wherein U is arylene.

20. The compound according to claim 19, wherein U is phenylene.

21. U is 【Chemistry 273】 The compound according to claim 20.

22. The compound according to claim 18, wherein U is a heteroarylene.

23. The compound according to claim 22, wherein U is a divalent pyrimidine ring.

24. U is 【Chemistry 274】 The compound according to claim 23.

25. The compound according to claim 18, wherein U is a bond.

26. The compound according to any one of claims 18 to 25, wherein V is a bond.

27. V is -C≡C-(CH ２ ) ｎ - The compound according to any one of claims 18 to 25.

28. V is -C≡C-(CH ２ ) ３ - The compound according to claim 27.

29. W ２ The compound according to any one of claims 18 to 28, wherein is -C(=O)-.

30. The compound according to any one of claims 1 to 17, wherein the conjugator portion has formula (III).

31. RS is -NH ２ or -N(CH ３ ) ２ The compound according to claim 30.

32. RS is -NH ２ The compound according to claim 31.

33. The compound according to any one of claims 30 to 32, wherein RE is -OC(=O)NH-.

34. RG is, 【Chemistry 275】 The compound according to any one of claims 30 to 33.

35. The compound according to any one of claims 30 to 34, wherein s and t are each 2.

36. W ３ The compound according to any one of claims 30 to 35, wherein is -C(=O)-.

37. The conjugator portion has formula (IIa1), (IIa2), (IIa3), or (IIIa): 【Chemistry 276】 The compound according to any one of claims 1 to 17.

38. The linker section has the following formula: 【Chemistry 277】 The compound according to any one of claims 1 to 37.

39. HG is, 【Chemistry 278】 And in the formula, e is 0, 1 or 2; or HG is -(CH ２ CH ２ ) ｚ -NR ａ C(O)NR ｂ R ｃ And in the formula, z is 1, 2, 3 or 4, R ａ , R ｂ and R ｃ Each of these independently represents H, or a substituted or unsubstituted C. １－４ A compound according to any one of the prior claims, wherein it is alkyl.

40. The linker section has one of the following equations: 【Chemistry 279】 The compound according to claim 39.

41. The payload is one of the residues in the following formula: 【Chemistry 280】 The compound according to any one of claims 1 to 40.

42. The payload section is 【Chemistry 281】 The compound according to any one of claims 1 to 41.

43. The compound according to any one of claims 1 to 42, wherein BA binds to one or more receptors selected from B7H3, PTK7, or CLL1.

44. The compound according to any one of claims 1 to 43, wherein BA is ifinatamab, 6E7, or cofetuzumab, or an antigen-binding fragment of ifinatamab, 6E7, or cofetuzumab.

45. The aforementioned compound, 【Chemistry 282】 (wherein Ab is 6E7 or its antigen-binding fragment); or 【Chemistry 283】 (In the formula, Ab is 6E7 or its antigen-binding fragment.) The compound according to claim 1, or any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers described above.

46. The compound according to any one of claims 1 to 45, wherein x is approximately 3.5 to approximately 4.

5.

47. The aforementioned compound, 【Chemistry 284】 (wherein Ab is 6E7 or its antigen-binding fragment); or 【Chemical 285】 The compound according to claim 46, wherein Ab is 6E7 or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.

48. The aforementioned compound, 【Chemistry 286】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemistry 287】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemical 288】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemistry 289】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemistry 290】 (In the formula, Ab is ifinatamab or its antigen-binding fragment); 【Chemistry 291】 (In the formula, Ab is ifinatamab or its antigen-binding fragment); 【Chemistry 292】 (wherein Ab is 6E7 or its antigen-binding fragment); or 【Chemistry 293】 The compound according to claim 3, wherein Ab is cofetuzumab or its antigen-binding fragment, or any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers described above.

49. The compound according to any one of claims 1 to 45 and 48, wherein x is approximately 3.5 to approximately 8.

50. The aforementioned compound, 【Chemistry 294】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemistry 295】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemistry 296】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemistry 297】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemistry 298】 (In the formula, Ab is ifinatamab or its antigen-binding fragment); 【Chemistry 299】 (In the formula, Ab is ifinatamab or its antigen-binding fragment); 【Chemical 300】 (wherein Ab is 6E7 or its antigen-binding fragment); or 【Chemical 301】 The compound according to claim 49, wherein Ab is cofetuzumab or its antigen-binding fragment, or any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers described above.

51. The aforementioned compound, 【Chemical 302】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemical 303】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemical 304】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemical 305】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemical 306】 (In the formula, Ab is ifinatamab or its antigen-binding fragment); 【Chemical 307】 (wherein Ab is ifinatamab or its antigen-binding fragment); or 【Chemical 308】 The compound according to claim 7, wherein Ab is cofetuzumab or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.

52. The compound according to claim 51, wherein x is approximately 3.5 to approximately 4.

5.

53. The aforementioned compound, 【Chemical 309】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemical 310】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemical 311】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemical 312】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemistry 313】 (In the formula, Ab is ifinatamab or its antigen-binding fragment); 【Chemical 314】 (wherein Ab is ifinatamab or its antigen-binding fragment); or 【Chemical Industry 315】 The compound according to claim 52, wherein Ab is cofetuzumab or an antigen-binding fragment thereof, or any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers described above.

54. The aforementioned compound, 【Chemical 316】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chemical 317】 (wherein Ab is 6E7 or its antigen-binding fragment); or 【Chemical 318】 The compound according to claim 11, wherein Ab is ifinatamab or an antigen-binding fragment thereof, or any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers described above.

55. The compound according to claim 54, wherein x is approximately 3.5 to approximately 4.

5.

56. The aforementioned compound, 【Chemical 319】 (In the formula, Ab is 6E7 or its antigen-binding fragment); 【Chem.320】 (wherein Ab is 6E7 or its antigen-binding fragment); or 【Chemistry 321】 The compound according to claim 55, wherein Ab is ifinatamab or an antigen-binding fragment thereof, or any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers described above.

57. Compound of formula (Ia'): 【Chemistry 322】 or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, [wherein: The conjugator part has formula (II') or (III'): 【Chemical 323】 {In the formula: U is a bond, heteroarylene, or arylene; V is a bond or -C≡C-(CH ２ ) ｎ - and; n is an integer between 0 and 10 (including both ends); W ２ is -C(=O)-, -NH-, or -O-; RG is 【Chemical 324】 And; RS is -NR １ａ R １ｂ And; R １ａ and R １ｂ Each of these is independently H, or a substituted or unsubstituted C. １－４ It is alkyl; RE represents bond, -O-, -OC(=O)-, -OC(=O)NR ６ -, -NHC(=O)NR ６ -, -OS (=O) ２ NR ６ -, -NHS (=O) ２ NR ６ - or - OC (=O) NHS (=O) ２ NR ６ - and; R ６ is H, or substituted or unsubstituted C １－４ It is alkyl; W ３ is -C(=O)-, -NH-, or -O-; s and t are independently 1 or 2, and 【Chemical 325】 This indicates a covalent bond site within the compound; The linker section has formula (IV): 【Chemistry 326】 {In the formula: HG is a hydrophilic residue, and ** indicates a connection where the linker section connects to the conjugator section. The severable portion has formula (V): 【Chemistry 327】 {In the formula: R ２ Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. １－４ Alkyl, -CN, or -NO ２ and **** indicates a connection where the severable portion connects to the linker portion; and The payload portion is a payload residue, the compound, or a pharmaceutically acceptable salt thereof, tautomer, solvate, or stereoisomer.

58. The cuttable portion has the following formula: 【Chemical 328】 The compound according to claim 57.

59. Compound of formula (Ib'): 【Chemistry 329】 or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, [wherein: The conjugator part has formula (II') or (III'): 【Chemistry 330】 {In the formula: U is a bond, heteroarylene, or arylene; V is a bond or -C≡C-(CH ２ ) ｎ - and; n is an integer between 0 and 10 (including both ends); W ２ is -C(=O)-, -NH-, or -O-; RG is 【Chemistry 331】 And; RS is -NR １ａ R １ｂ And; R １ａ and R １ｂ Each of these is independently H, or a substituted or unsubstituted C. １－４ It is alkyl; RE represents bond, -O-, -OC(=O)-, -OC(=O)NR ６ -, -NHC(=O)NR ６ -, -OS (=O) ２ NR ６ -, -NHS (=O) ２ NR ６ - or - OC (=O) NHS (=O) ２ NR ６ - and; R ６ is H, or substituted or unsubstituted C １－４ It is alkyl; W ３ is -C(=O)-, -NH-, or -O-; s and t are independently 1 or 2, and 【Chemistry 332】 This indicates a covalent bond site within the compound; The severable portion has the formula (Va), (Vb), or (Vc): 【Chemical 333】 {In the formula: R ２ Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. １－４ Alkyl, -CN, or -NO ２ And, *** indicates a connection where the severable part connects to the conjugator part, and **** indicates a connection where the severable portion connects to the linker portion; The linker section has formula (IV'): 【Chemistry 334】 {during the ceremony HG is a hydrophilic residue, and **! indicates the connection where the linker part connects to the cap. The cap is CH ３ C(=O)-, CH ３ - (CH ２ ) ｂ -O-(CH ２ CH ２ O) ａ - (CH ２ CH ２ ) ｄ -C(=O)-, CH ３ - (CH ２ ) ｂ -O-(CH ２ CH ２ O) ａ - (CH ２ CH ２ ) ｄ -NH-C(=O)-, CH ３ (C(=O)N(CH ３ )CH ２ ) ａ C(=O)-, -NH-(CH ２ CH ２ O) ａ - (CH ２ ) ｂ CH ３ or -(N(CH ３ ) (CH ２ ) ｃ C (=O) ａ NH ２ And {in the formula: a is an integer from 1 to 18 (including both ends), b and d are independently 0, 1, or 2, and c is an integer from 1 to 4 (including both ends); and The payload portion is a payload residue, the compound, or a pharmaceutically acceptable salt thereof, tautomer, solvate, or stereoisomer.

60. The severable portion has one of the following equations: 【Chemistry 335】 The compound according to claim 59.

61. The cap is CH ３ C(=O)-, CH ３ - (CH ２ ) ｂ -O-(CH ２ CH ２ O) ａ - (CH ２ CH ２ ) ｄ -C (=O)- or CH ３ (C(=O)N(CH ３ )CH ２ ) ａ The compound according to claim 59 or 60, wherein it is C(=O)-.

62. The cap is CH ３ C(=O)- CH ３ -O-(CH ２ CH ２ O) １１ - (CH ２ CH ２ )-C(=O)- or -CH ３ (C(=O)N(CH ３ )CH ２ ) １２ The compound according to claim 61, wherein it is C(=O)-.

63. Compound of formula (Ic'): 【Chemistry 336】 or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, [wherein: The conjugator part has formula (II') or (III'): 【Chemistry 337】 {In the formula: U is a bond, heteroarylene, or arylene; V is a bond or -C≡C-(CH ２ ) ｎ - and; n is an integer between 0 and 10 (including both ends); W ２ is -C(=O)-, -NH-, or -O-; RG is 【Chemical 338】 And; RS is -NR １ａ R １ｂ And; R １ａ and R １ｂ Each of these is independently H, or a substituted or unsubstituted C. １－４ It is alkyl; RE represents bond, -O-, -OC(=O)-, -OC(=O)NR ６ -, -NHC(=O)NR ６ -, -OS (=O) ２ NR ６ -, -NHS (=O) ２ NR ６ - or - OC (=O) NHS (=O) ２ NR ６ - and; R ６ is H, or substituted or unsubstituted C １－４ It is alkyl; W ３ is -C(=O)-, -NH-, or -O-; s and t are independently 1 or 2, and 【Chemistry 339】 This indicates a covalent bond site within the compound; The linker section has formula (IV): 【Chemistry 340】 {In the formula: HG is a hydrophilic residue, and ** indicates a connection where the linker section connects to the conjugator section. The severable portion has the formula (Va'), (Vb'), or (Vc'): 【Chemistry 341】 {In the formula: R ２ Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. １－４ Alkyl, -CN, or -NO ２ And, ***! indicates a connection where the severable part connects to the cap, and **** indicates a connection where the severable portion connects to the linker portion; The cap is CH ３ C(=O)-, CH ３ - (CH ２ ) ｂ -O-(CH ２ CH ２ O) ａ - (CH ２ CH ２ ) ｄ -C(=O)-, CH ３ - (CH ２ ) ｂ -O-(CH ２ CH ２ O) ａ - (CH ２ CH ２ ) ｄ -NH-C(=O)-, CH ３ (C(=O)N(CH ３ )CH ２ ) ａ C(=O)-, -NH-(CH ２ CH ２ O) ａ - (CH ２ ) ｂ CH ３ or -(N(CH ３ ) (CH ２ ) ｃ C (=O) ａ NH ２ And {in the formula: a is an integer from 1 to 18 (including both ends), b and d are independently 0, 1, or 2, and c is an integer from 1 to 4 (including both ends); and The payload portion is a payload residue, the compound, or a pharmaceutically acceptable salt thereof, tautomer, solvate, or stereoisomer.

64. The severable portion has one of the following equations: 【Chemistry 342】 The compound according to claim 63.

65. The cap is -NH-(CH ２ CH ２ O) ａ - (CH ２ ) ｂ CH ３ or -(N(CH ３ ) (CH ２ ) ｃ C (=O) ａ NH ２ The compound according to claim 63 or 64.

66. The cap is -NH-(CH ２ CH ２ O) １２ -CH ３ or -(N(CH ３ )CH ２ C (=O) １２ NH ２ The compound according to claim 65.

67. Compound of formula (Id'): 【Transformation 343】 or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, [wherein: The conjugator part has formula (II') or (III'): 【Transformation 344】 {In the formula: U is a bond, heteroarylene, or arylene; V is a bond or -C≡C-(CH ２ ) ｎ - and; n is an integer between 0 and 10 (including both ends); W ２ is -C(=O)-, -NH-, or -O-; RG is 【Chemistry 345】 And; RS is -NR １ａ R １ｂ And; R １ａ and R １ｂ Each of these is independently H, or a substituted or unsubstituted C. １－４ It is alkyl; RE represents bond, -O-, -OC(=O)-, -OC(=O)NR ６ -, -NHC(=O)NR ６ -, -OS (=O) ２ NR ６ -, -NHS (=O) ２ NR ６ - or - OC (=O) NHS (=O) ２ NR ６ - and; R ６ is H, or substituted or unsubstituted C １－４ It is alkyl; W ３ is -C(=O)-, -NH-, or -O-; s and t are independently 1 or 2, and 【Transformation 346】 This indicates a covalent bond site within the compound; The linker section has formula (IV'): 【Transformation 347】 {In the formula: HG is a hydrophilic residue, and **! indicates the connection where the linker part connects to the cap. The severable portion has the formula (Va''), (Vb''), or (Vc''): 【Transformation 348】 {In the formula: R ２ Each of these is independently hydrogen, halogen, and substituted or unsubstituted C. １－４ Alkyl, -CN, or -NO ２ And, ***† indicates a connection where the severable portion connects to the launcher, and **** indicates a connection where the severable portion connects to the linker portion; The cap is CH ３ C(=O)-, CH ３ - (CH ２ ) ｂ -O-(CH ２ CH ２ O) ａ - (CH ２ CH ２ ) ｄ -C(=O)-, CH ３ - (CH ２ ) ｂ -O-(CH ２ CH ２ O) ａ - (CH ２ CH ２ ) ｄ -NH-C(=O)-, CH ３ (C(=O)N(CH ３ )CH ２ ) ａ C(=O)-, -NH-(CH ２ CH ２ O) ａ - (CH ２ ) ｂ CH ３ or -(N(CH ３ ) (CH ２ ) ｃ C (=O) ａ NH ２ And {in the formula: a is an integer from 1 to 18 (including both ends), b and d are independently 0, 1, or 2, and c is an integer between 1 and 4 (including both ends); Blancher has formulas (XIIa), (XIIa1), (XIIb), or (XIIb1): 【Chemistry 349】 {In the formula: The hydrophilic substance is -NH-(CH ２ CH ２ O) ａ１ - (CH ２ ) ｂ１ CH ３ , -C(=O)NH ２ , -C(=O)-(CH ２ CH ２ O) ａ１ - (CH ２ ) ｂ１ CH ３ or -(N(CH ３ ) (CH ２ ) ｃ１ C (=O) ａ１ NH ２ And, † indicates a connection where the launcher connects to the conjugator section. †† indicates a connection where the plancher connects to the cuttable section. a1 is an integer from 1 to 18 (including both ends), b1 is 0, 1 or 2, and Each of c1, p, and q is an independent integer between 1 and 4 (including both ends); and The payload portion is a payload residue, the compound, or a pharmaceutically acceptable salt thereof, tautomer, solvate, or stereoisomer.

68. The severable portion has one of the following equations: [Chemical 350] The compound according to claim 67.

69. The compound according to claim 67 or 68, wherein a1 is 12, b1 is 0, c1 is 1, p is 2, and q is 2 or 4.

70. Blancher has one of the following equations: 【Chemistry 351】 The compound according to any one of claims 67 to 69.

71. The hydrophilic substance is -C(=O)-(CH ２ CH ２ O) ａ１ -CH ３ or -(N(CH ３ ) - CH ２ -C (=O)) ａ１ NH ２ The compound according to any one of claims 67 to 70, wherein a1 is an integer from 10 to 16 (including both ends).

72. The compound according to claim 71, wherein A1 is 12.

73. The cap is CH ３ The compound according to any one of claims 67 to 72, wherein it is C(=O)-.

74. The compound according to any one of claims 57 to 73, wherein the conjugator portion has formula (II').

75. The compound according to claim 74, wherein U is arylene.

76. The compound according to claim 75, wherein U is phenylene.

77. U is 【Chemistry 352】 The compound according to claim 76.

78. The compound according to claim 74, wherein U is a heteroarylene.

79. The compound according to claim 78, wherein U is a divalent pyrimidine ring.

80. U is 【Chemistry 353】 The compound according to claim 79.

81. The compound according to claim 74, wherein U is a bond.

82. The compound according to any one of claims 74 to 81, wherein V is a bond.

83. V is -C≡C-(CH ２ ) ｎ - The compound according to any one of claims 74 to 81.

84. V is -C≡C-(CH ２ ) ３ - The compound according to claim 83.

85. W ２ The compound according to any one of claims 74 to 84, wherein is -C(=O)-.

86. The compound according to any one of claims 57 to 73, wherein the conjugator portion has formula (III').

87. RS is -NH ２ or -N(CH ３ ) ２ The compound according to claim 86.

88. RS is -NH ２ The compound according to claim 87.

89. The compound according to any one of claims 86 to 88, wherein RE is -OC(=O)NH-.

90. RG is, 【Chemistry 354】 The compound according to any one of claims 86 to 89.

91. The compound according to any one of claims 86 to 90, wherein S and t are each 2.

92. W ３ The compound according to any one of claims 86 to 91, wherein is -C(=O)-.

93. The conjugator part has formula (IIa1) or (IIIa1): 【Chemical 355】 The compound according to any one of claims 57 to 73.

94. The linker section has the following formula: 【Transformation 356】 The compound according to any one of claims 57 to 93.

95. HG is, 【Chemistry 357】 And in the formula, e is 0, 1 or 2; or HG is -(CH ２ CH ２ ) ｚ -NR ａ C(O)NR ｂ R ｃ And in the formula, z is 1, 2, 3 or 4, R ａ , R ｂ and R ｃ Each of these independently represents H, or a substituted or unsubstituted C. １－４ The compound according to any one of claims 57 to 94, wherein it is alkyl.

96. The linker section has one of the following equations: 【Chemical 358】 The compound according to claim 95.

97. The payload is one of the residues in the following formula: 【Chemistry 359】 【Chemical 360】 The compound according to any one of claims 57 to 96.

98. The payload section is 【Chemical 361】 The compound according to any one of claims 57 to 97.

99. The aforementioned compound, 【Chemical 362】 【Chemical 363】 The compound according to claim 57, or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.

100. The aforementioned compound, 【Chemical 364】 【Chemical 365】 【Chemical 366】 【Chemical 367】 【Chemical 368】 【Chemical 369】 【Chemistry 370】 The compound according to claim 59, or any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers described above.

101. The aforementioned compound, 【Chemistry 371】 【Chemistry 372】 【Chemistry 373】 【Chemistry 374】 The compound according to claim 63, or any of the pharmaceutically acceptable salts, tautomers, solvates, or stereoisomers described above.

102. The aforementioned compound, 【Chemistry 375】 【Transformation 376】 【Chemical 377】 The compound according to claim 67, or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof.

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