WO-2026092685-A1 - ANTIBODY-DRUG CONJUGATE HAVING LINKING SYSTEM

Abstract

An antibody-drug conjugate (ADC) having a linking system, a preparation method therefor, and the use thereof. The linking system has high linking stability and enhanced solubility, allows efficient coupling of hydrophobic drugs, and effectively achieves intracellular delivery of drugs.

Inventors

• ZHAI, Wenqiang
• HE, WEIMING
• YANG, FANGLONG
• WANG, SIQIN
• JIN, LEI

Assignees

• 长春金赛药业有限责任公司

Dates

Publication Date

20260507

Application Date

20251031

Priority Date

20241101

Claims (10)

1. Compounds of formula (I), their racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds: M-Z-Tr-L-D (I) Where M is the linker site that binds to the antibody or its antigen-binding fragment, selected from... Lg is a leaving group; R21 and R22 may be the same or different, and are independently selected from H, CN, C1-6 alkyl- OC1-6 alkylene-, C1-10 alkoxy, -( OCH2CH2 ) m1 - OCH3 ; t is selected from 1, 2, 3 , 4, 5 or 6; m1 is selected from integers from 1 to 36; Z is selected from single bond, -N(R_z )-(CH₂)n₁-C(=O)-,-N(R₁)-(CH ₂CH₂O)z ₁-(CH ₂ )n ₂-C(=O)-, Among them, ring A is selected from cyclohexane ring or six-membered heterocycle; R1 and Rz may be the same or different, and are independently selected from H, -( CH2CH2O ) z3 - CH3 , z1 , z2 , z3 , z4 , z5 , and z6 are either the same or different, and are independently selected from integers from 1 to 36; n1 , n2 , n3 , n4 , n5 , n6 , n7 , and n8 may be the same or different, and are independently selected from 0, 1, 2, 3, 4, 5, and 6; Tr is a divalent trigger group, selected from divalent dipeptide or polypeptide residues; L represents the linker between Tr and the bioactive molecular structural fragment D, selected from single bonds, -NH- C1-10 alkyl-, -N( CH3 ) -C1-10 alkylene-, etc. D is a bioactive molecular structural fragment; preferably, D is selected from...
2. The compound of formula (I) as claimed in claim 1, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, is characterized in that the leaving group Lg is selected from halogen, sulfone, trifluoromethanesulfonyl, methanesulfonyl. Preferably, the leaving group Lg is selected from methanesulfonyl; Preferably, R 22 is selected from H; Preferably, R21 is selected from CN, CH3OCH2- , C1-3 alkoxy , or -(OCH2CH2 ) m1 - OCH3 ; Preferably, R21 is selected from methoxy , -( OCH2CH2 ) 6 - OCH3 or -( OCH2CH2 ) 8 -OCH3 ; Preferably, t is selected from 2, 3, or 4; Preferably, m1 is selected from integers from 1 to 12; Preferably, m1 is selected from 6, 7, 8, 9 or 10; Preferably, M is selected from Preferably, ring A is selected from Preferably, R1 is selected from H; Preferably, R _z is selected from the following groups: -(CH ₂CH ₂O)_z 3 -CH₃, Preferably, R_z is selected from the following groups: -(CH ₂CH ₂O)₉-CH ₃ , -(CH ₂ CH ₂ O) ₁₃-CH₃, Preferably, z1 , z2 , z3 , z4 , z5 , and z6 are the same or different, and are independently selected from integers between 6 and 15; Preferably, z1 , z2 , z3 , z4 , z5 , and z6 are the same or different, and are independently selected from integers of 8-14; Preferably, n1 , n2 , n3 , n4 , n5 , n6 , n7 , and n8 are the same or different, and are independently selected from 0, 1, 2, and 3; Preferably, Z is selected from single bonds, -N( Rz )-( CH2 ) n1 -C(=O)-, -NH-( CH2CH2O ) z1- ( CH2 ) n2 -C(=O)-, Wherein, X1 and X2 may be the same or different, and are independently selected from CH or N; preferably, at least one of X1 and X2 is an N atom; Rz, z1 , z2 , n1 , n2 , n3 , and n4 have the definitions described above; Preferably, when X2 is CH, n4 is selected from 0; Preferably, Z is selected from single bonds, -NH-( CH₂CH₂O ) ₈ - CH₂CH₂ -C(=O)-, -NH- ( CH₂CH₂O ) ₁₀ - CH₂CH₂-C(= O )-, -N( Rz ) -CH₂ - C(=O)-, -N(Rz)-( CH₂ ) ₂ -C(=O)-, -N ( Rz )-( CH₂ ) ₃- C(=O)-, -N( Rz )-( CH₂ ) ₄ -C(=O)-, Wherein, R z has the definition as described above; Preferably, Z is selected from single bonds, Preferably, the Tr is selected from dipeptide or polypeptide residues, wherein the dipeptide or polypeptide is selected from glycine-glycine-phenylalanine-glycine (GGFG), glutamic acid-valine-citrulline (EVC), valine-citrulline (VC), valine-alanine (VA), aspartic acid-valine-citrulline (DVC), glutamic acid-glycine-glycine-phenylalanine-glycine (EGGFG), aspartic acid-glycine-glycine-phenylalanine-glycine (DGGFG), and lysine-glycine-glycine-phenylalanine-glycine (KGGFG). Preferably, Tr is selected from glycine-glycine-phenylalanine-glycine (GGFG) residues, i.e. Preferably, Tr is selected from valine-alanine (VA) residues, that is: Preferably, L is selected from single bonds; Preferably, L is selected from
3. The compound of formula (I) as claimed in claim 1 or 2, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, is characterized in that the compound of formula (I) is selected from the following structures: Wherein, Z, R21 , Rz , X1 , X2 , Tr, L, D, z1 , z3 , n1 , n3 , and n4 have the definitions as described in claim 1 or 2; Preferably, the compound represented by formula (I) is selected from:
4. Antibody-drug conjugates, their racemates, stereoisomers, tautomers, solvates, polymorphs, and pharmaceutically acceptable salts represented by formula (II) Ab-[M'-Z-Tr-LD] β (II) Wherein, Ab is an antibody or its antigen-binding fragment, M' is a fragment formed by conjugation of M and Ab, β is selected from an integer or decimal between 1 and 10; Z, Tr, L , and D independently have the definitions described in any one of claims 1-3; Preferably, Ab is an antibody or antigen-binding fragment, wherein the antigen-binding fragment is selected from Fab, Fab', (Fab')2, Fd, Fv, disulfide-linked Fv, scFv, di-scFv, (scFv) 2 , diabody, and sdAb; and/or, the antibody is a murine antibody, a humanized antibody, a chimeric antibody, a bispecific antibody, or a multispecific antibody; Preferably, Ab is an antibody against HER2 or its antigen-binding fragment; Preferably, Ab is pertuzumab or its antigen-binding fragment; Preferably, β is selected from an integer or decimal between 1 and 10; more preferably, it is selected from an integer or decimal between 2 and 8; more preferably, it is selected from an integer or decimal between 2 and 5; for example, β is selected from 2, 3, 4, 5, 6, 7, 8, 3.2, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.1, 4.2; Preferably, M'-Z-Tr-LD has the following structure: Wherein, Z, R21 , Rz , X1 , X2 , Tr, L, D, z1 , z3 , n1 , n3 , and n4 have the definitions as described in any one of claims 1-3, and the wavy line is the connection point with Ab; Preferably, the M'-Z-Tr-L in the antibody-drug conjugate has the following structure:
5. According to claim 4, the antibody-drug conjugate of formula (II), its racemic, stereoisomer, tautomer, solvate, polymorph, or pharmaceutically acceptable salt, wherein the antibody-drug conjugate of formula (II) is selected from the following structures: Wherein, Ab, R21 , RZ , z1 , z3 , X1 , X2 , n1 , n3 , n4 , Tr, L, and β independently have the definitions described in any one of claims 1-4; Preferably, the antibody-drug conjugate shown in formula (II) has the following structure: Wherein, Ab and β independently have the definitions described in any one of claims 1-4; Preferably, the antibody-drug conjugate shown in formula (II) has the following structure: Wherein, β has the definition as described in any one of claims 1-4; More preferably, the antibody-drug conjugate is selected from the antibody-drug conjugates in the examples: ADC-001, ADC-002, ADC-003, ADC-004, ADC-005, ADC-007, ADC-009, ADC-010, ADC-014, ADC-019, ADC-020, ADC-021, ADC-022, ADC-023, and ADC-024.
6. Connector shown in equation (III): M-Z-Tr-L’ (III) Wherein, M, Z, and Tr have the definitions described in any one of claims 1-5, and L’ is the reaction form of L; Preferably, when L is a single bond, L’ is the reaction form of Tr, for example, Tr-L’ is a peptide segment with a carboxyl group or active ester at the carbon terminus; Preferably, when L is L' is the carbonate active ester form of p-aminobenzyl alcohol, for example The wavy lines represent the connection sites with peptide residues.
7. The connector shown below, Wherein, Z, R21 , Rz , X1 , X2 , Tr, L, z1 , n1 , n3 , and n4 have the definitions as described in any one of claims 1-7, with 1 bit connected to Ab and 2 bits connected to D; Preferably, the connector is selected from the following structures:
8. The intermediate shown below: Wherein, Lg, R21 , Rz , X1 , X2 , z3 , n3 , and n4 have the definitions as described in any one of claims 1-7, and Y1 is selected from hydroxyl, methoxy, ethoxy, isopropoxy, tert-butoxy, or Osu; Preferably, the intermediate is selected from the following structures:
9. A pharmaceutical composition comprising a therapeutically effective amount of an antibody-drug conjugate of formula (II) as claimed in claim 4 or 5, its racemic, stereoisomer, tautomer, solvate, polymorph, or pharmaceutically acceptable salt.
10. Use of at least one of the antibody-drug conjugate of formula (II) as claimed in claim 4 or 5, its racemic, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or the pharmaceutical composition of claim 9 in the preparation of a topoisomerase I inhibitor and/or in the preparation of a medicament for the prevention or treatment of diseases or conditions related to topoisomerase I. Preferably, the disease or symptom is a tumor, including breast cancer, stomach cancer, lung cancer, colorectal cancer, colon cancer, ovarian cancer, liver cancer, kidney cancer, esophageal cancer, cervical cancer, bladder cancer, pancreatic cancer, prostate cancer, nasopharyngeal carcinoma, melanoma, or leukemia.

Description

Antibody-drug conjugates with linker systems This application claims priority to an earlier application filed on November 1, 2024, with patent application number 202411553898.5 and entitled "Antibody-Drug Conjugate with Linkage System"; the entire contents of the earlier application are incorporated herein by reference. Technical Field This invention belongs to the field of medicinal chemistry, and specifically relates to antibody-drug conjugates with a linker system. Background Technology Antibody-drug conjugates (ADCs) link monoclonal antibodies or antibody fragments to biologically active drugs via stable chemical linker compounds. This fully leverages the specificity of antibodies in binding to antigens on the surface of normal and tumor cells, as well as the high efficacy of drugs, while avoiding the drawbacks of lower efficacy with antibodies and excessive toxicity with drugs. This means that, compared to traditional chemotherapy drugs, antibody-drug conjugates can precisely bind to tumor cells and reduce the impact on normal cells. Microtubules are powerful, filamentous cytoskeletal proteins involved in a wide range of cellular functions, including intracellular migration and transport, cell signaling, and maintaining cell shape. Microtubules also play a crucial role in mitotic cell division by forming the mitotic spindle, necessary for chromosomes to divide into two daughter cells. The biological function of microtubules in all cells is largely regulated by their polymerization kinetics, which occur through the reversible, non-covalent addition of α- and β-tubulin dimers to the ends of the microtubules. This kinetic behavior and the resulting control over microtubule length are essential for the proper functioning of the mitotic spindle. Even minor alterations in microtubule kinetics can involve axon checkpoints, inhibiting cell cycle progression during mitosis and subsequently leading to cell death. Because cancer cells divide rapidly, they are generally more sensitive than normal cells to compounds that bind to tubulin and disrupt its normal function. Tubulin inhibitors, such as MMAE and eribulin, hold promise as potential drugs for cancer treatment. Eribulin is a spongin-like microtubule dynamics inhibitor with unique binding properties. Besides its mechanism of action of inhibiting microtubule dynamic growth, non-clinical studies have shown that eribulin has unique effects on the tumor microenvironment, such as increasing vascular perfusion and permeability of the tumor core, promoting epithelial status, and reducing the migration ability of breast cancer cells. Currently, eribulin has been approved in more than 70 countries and regions, including Europe, the Americas, and Asia, for the treatment of breast cancer. The most common grade 3-4 adverse reactions in eribulin mesylate treatment are, in descending order, neutropenia (64%). Antibody-drug conjugates (ADCs) are conjugates of antibodies and small molecule drugs, combining the tumor-targeting activity of antibodies with the activity of bioactive molecules, becoming a kind of biological missile with very promising efficacy and safety advantages. Antibodies guide ADCs to bind to target cells, which are then internalized. The small molecule drug is then released intracellularly through enzymatic decomposition under the action of specific enzymes, treating the disease. Therefore, it is expected that the ADC composed of eribulin and tumor-targeting antibodies can maintain the therapeutic effect of eribulin while eliminating or reducing the toxic side effects caused by eribulin acting on non-disease tissues, thereby improving the therapeutic effect. Summary of the Invention This invention provides compounds of formula (I), their racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof: MZ-Tr-LD (I) Where M is the linker site that binds to the antibody or its antigen-binding fragment, selected from... Lg is a leaving group; R21 and R22 may be the same or different, and are independently selected from H, CN, C1-6 alkyl- OC1-6 alkylene-, C1-10 alkoxy, -( OCH2CH2 ) m1 - OCH3 ; t is selected from 1, 2, 3 , 4, 5 or 6; m1 is selected from integers from 1 to 36; Z is selected from single bond, -N(R_z )-(CH₂)n₁-C(=O)-,-N(R₁)-(CH ₂CH₂O)z ₁-(CH ₂ )n ₂-C(=O)-, Among them, ring A is selected from cyclohexane ring or six-membered heterocycle; R1 and Rz may be the same or different, and are independently selected from H, -( CH2CH2O ) z3 - CH3 , z1 , z2 , z3 , z4 , z5 , and z6 may be the same or different, and are independently selected from integers from 1 to 36; n1 , n2 , n3 , n4 , n5 , n6 , n7 , and n8 may be the same or different, and are independently selected from 0, 1, 2, 3, 4, 5, and 6; Tr is a divalent trigger group, selected from divalent dipeptide or polypeptide residues; L repres