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EP-4740967-A1 - LINKER-DRUG MOLECULE AND ANTIBODY DRUG CONJUGATE, PREPARATION METHOD THEREFOR AND USE THEREOF

EP4740967A1EP 4740967 A1EP4740967 A1EP 4740967A1EP-4740967-A1

Abstract

A compound represented by formula (1), or a tautomer, mesomer, racemate, enantiomer, and diastereomer thereof, or mixture form thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the structure of formula (1) is as shown below: formula (1). According to the compound, a strong hydrophilic sulfonate inner salt and/or phosphate inner salt side chain are introduced at the position of polypeptide (VC, VA, AAA, etc.)-PAB (self-immolative group) of a linker, greatly enhancing the druggability (comprising hydrophilicity and stability) of an antibody drug conjugate corresponding to the compound, reducing the in-vivo drug clearance effect, and improving the tumor treatment effect.

Inventors

  • ZENG, Di
  • ZHOU, QING
  • XU, Chuanying
  • NIAN, Weihong
  • YAN, HONGBIN
  • HE, Zhuzi
  • Wei, Hongli
  • ZHENG, Xintong
  • ZHANG, XINMIN
  • HE, FENG

Assignees

  • Shanghai Escugen Biotechnology Co., Ltd.

Dates

Publication Date
20260513
Application Date
20240704

Claims (20)

  1. A compound represented by Formula (1), or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein Formula (1) has the following structural formula: M is a spacer; Sp is -L a -Q a -; A is selected from absent, hydrogen or alkyl; T represents a straight or branched (C 1 -C 8 ) trivalent alkyl group; Y, Y' and Y" are each independently -L b -Q b -; L a and L b are each independently selected from absent, alkylene, alkenylene, alkynylene, alicyclylene, heteroalicyclylene, arylene, heteroarylene or polyethylene glycol group, wherein the alkylene, alkenylene, alkynylene, alicyclylene, heteroalicyclylene, arylene, heteroarylene or polyethylene glycol group is optionally substituted by a substituent; Q a , and Q b are each independently selected from absent, -C(=O)NR-, -C(=O)O-, -OC(=O)NR-, -S(=O) 2 NR-, -NRC(=O)-, -OC(=O)-, -NRC(=O)O-, -NRS(=O) 2 -, -NRC(=O)NR-, -NHC-(=NH)NH-, -C(=O)-, -OC(=O)O-, -O-, -NR-, -S-, S(=O) 2 -, S(=O)-, or -Se-, wherein R is selected from hydrogen or optionally substituted alkyl; Z is selected from absent, hydrogen, optionally substituted alkyl or a sulfonate inner salt; Z', and Z" are each independently selected from absent, hydrogen, optionally substituted alkyl, a sulfonate inner salt or a phosphate inner salt; at least one of Z, Z' and Z" is a sulfonate inner salt or a phosphate inner salt; X comprises a self-immolative unit or is absent; D comprises a drug molecule; i is an integer equal to or greater than 1; h is an integer from 1 to 6; and o, p and q are each independently an integer from 0 to 5.
  2. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to claim 1, wherein Formula (1) is Formula (1-1): wherein M, Sp, A, T, Y, h, o, i, X, D, and Z are defined as in claim 1; and at least one of the i Zs is a sulfonate inner salt.
  3. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to claim 2, wherein the Formula (1-1) is Formula (1-1-1): wherein AA is an amino acid residue, and W is an integer equal to or greater than 1.
  4. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to claim 1, wherein Formula (1) is Formula (1-2): wherein M, Sp, A, T, Y, Z, o, p, i, h, X, Y', and D are defined as in claim 1; and Z' is a sulfonate inner salt or a phosphate inner salt.
  5. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to claim 4, wherein Formula (1) is Formula (1-2-1): wherein AA is an amino acid residue, and W is an integer equal to or greater than 1.
  6. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to claim 1, wherein Formula (1) is Formula (1-3): wherein M, Sp, A, Y, T, Z, o, i, h, q, X, Y", and D are defined as in claim 1; and Z" is a sulfonate inner salt or a phosphate inner salt.
  7. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to claim 6, wherein Formula (1) is Formula (1-3-1): wherein AA is an amino acid residue, and W is an integer equal to or greater than 1.
  8. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 1-7, wherein when A and Z are absent, N, Y and T form a ring to have a structural formula of: preferably
  9. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 3, 5 and 7, wherein the amino acid(s) is one or more selected from the group consisting of: alanine, arginine, asparagine, aspartic acid, γ-carboxyglutamic acid, citrulline, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, norleucine, norvaline, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
  10. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 3, 5 and 7, wherein the amino acid(s) is one or more selected from the group consisting of: valine, glutamic acid, citrulline, lysine, alanine, phenylalanine, arginine, glutamine, asparagine, and glycine.
  11. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 3, 5 and 7, wherein the amino acid(s) is one or more selected from the group consisting of: valine, citrulline, alanine, phenylalanine, glutamine, and glycine.
  12. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 1-11, wherein M is selected from N 3 , SH, ONH 2 , NH 2 , CO 2 H, (alkyl)-CO-, HCO-, BrCH 2 -, ICH 2 -, or
  13. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 1-12, wherein M is
  14. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 1-13, wherein M is
  15. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 1-14, wherein A is hydrogen, methyl, ethyl or propyl.
  16. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 1-15, wherein A is hydrogen.
  17. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 1-16, wherein the T is any one selected from the group consisting of:
  18. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 1-17, wherein the T is
  19. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 1-18, wherein L a is one, two, three or more selected from the group consisting of: alkylene, alkenylene, alkynylene, saturated or unsaturated alicyclylene with 3-10 ring carbon atoms, saturated or unsaturated heteroalicyclylene with 3-10 ring carbon atoms and 1-4 heteroatoms, arylene with 6-18 carbon atoms in one or more rings, heteroarylene with 6-18 carbon atoms and 1-4 heteroatoms in one or more rings, and polyethylene glycol group; and wherein the alkylene, alkenylene, alkynylene, alicyclylene, heteroalicyclylene, arylene, or heteroarylene is optionally substituted by a substituent; and the heteroatom is selected from nitrogen, oxygen, or sulfur.
  20. The compound, or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof according to any one of claims 1-19, wherein L a is one, two, three or more selected from the group consisting of: C 1 -C 10 linear or branched alkylene, C 2 -C 12 linear or branched alkenylene, C 2 -C 12 linear or branched alkynylene, saturated or unsaturated alicyclylene with 3-6 ring carbon atoms, saturated or unsaturated heteroalicyclylene with 3-6 ring carbon atoms and 1-4 heteroatoms, or arylene with 6-10 carbon atoms in one or more rings, heteroarylene with 6-10 carbon atoms and 1-4 heteroatoms in one or more rings, and polyethylene glycol group; and wherein the alkylene, alkenylene, alkynylene, alicyclylene, heteroalicyclylene, arylene, or heteroarylene is optionally substituted by a substituent; and the heteroatom is selected from nitrogen, oxygen, or sulfur.

Description

TECHNICAL FIELD The present invention relates to biomedical field, in particular to a method for preparing an linker-drug molecule and an antibody-drug conjugate and use thereof. CROSS REFERENCE This application claims the priority of PCT/CN2023/106385 filed on July 7, 2023, the content of which is incorporated herein by reference in its entirety. SIMULTANEOUSLY SUBMITTED SEQUENCE LISTING DOCUMENT The content of the attached XML file is incorporated herein by reference in its entirety: sequence listing of computer readable format (CRF) (file name: TFH01015PCT-sequence listing.xml, date: May 29, 2024, size: 6KB) BACKGROUND By conjugation of a biologically active drug compound to a tumor targeting antibody, protein, or polypeptide, the cancer treatment window of drug compounds can be increased. This is mainly achieved through two aspects: firstly, the drug conjugate cannot produce toxic side effects before reaching the cancer target lesion due to the inability of the active drug to detach smoothly; secondly, the active drug can increase the concentration of the drug compound at the cancer target lesion through the conjugation of the targeted antibody, protein, or polypeptide to the active drug, because a specially designed linker can be triggered by the special environment of the cancer target lesion to break and thereby release the active drug compound The specially designed amino acid peptide segments sensitive to tissue proteases in the linker can be efficiently cleaved by tissue proteases in the lysosomes of cancer cells. A drug compound is connected to the amino acid peptide segment of the linker through a chemical self-immolative group, after the polypeptide is cleaved by tissue protease, the chemical self-immolative group releases free drug compounds through the "self-immolative effect", resulting in a tumor killing effect. Among them, the clinical validation data and the approved corresponding drugs obtained from the antibody- or polypeptide-drug conjugates in the form of peptide (VC, VA, AAA, etc.)-PAB (self-immolative group) linkers are the most. However, due to the strong lipophilic characteristics of drug compounds, especially those with important bystander killing effect on tumors, the antibody, protein, or polypeptide drug conjugates, especially when the drug to antibody ratio (DAR) is high, exhibit poor drug properties and low hydrophilicity, thereby forming polymers and accelerating in vivo clearance. By adding hydrophilic group such as polyethylene glycol (PEG) (Mol Cancer Ther, 2017, 16(1): 116-123; Nat. Biotech. 2015, 33:733-735, Toxicol. App. Pharmacol., 2020, 392: 114932; WO2023280227), polylysine (PSAR) (Chem. Sci, 2019, 10(14): 4048-4053; WO 2022228493), sugar alcohol (Cancer Res (2018) 78 (13_Supplement): 755; US 9907854) on the linker to mask drug compounds, the drug formation of antibodies, proteins, or peptide drug conjugates will be improved to some extent. However, the use of PEG polymers to modify proteins has exposed many drawbacks in clinical practice, such as a high proportion of patients exhibiting anti-PEG immunogenicity and related toxic side effects, and excessive modification leading to decreased protein function. SUMMARY Based on this, this application introduces a strong hydrophilic sulfonate inner salt and/or phosphate inner salt side chain (sometimes referred to as the linker or the inner salt linkers of this application, i.e., a compound represented by Formula (1) as described below) at the position of the polypeptide (VC, VA, AAA, etc.)-PAB (self-immolative group) of the linker. As both the sulfonate group and the phosphate group have hydrogen bond donor and acceptor, they belong to a strong hydrophilic group, and the sulfonate inner salt or phosphate inner salt has both positive and negative charges, thereby further enhancing the hydrophilicity. At the same time, the water-soluble functional groups in the form of inner salts also have the potential to enhance the tumor targeting and reduce non-specific binding of the antibody-drug conjugate, thus greatly enhancing the drug formation (including hydrophilicity and stability) of the tested antibody-drug conjugate, reducing in vivo drug clearance, and improving tumor treatment efficacy. The technical solutions of this application are as follows: 1. A compound represented by Formula (1), or a tautomer, mesomer, raceme, enantiomer or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein Formula (1) has the following structural formula: M is a spacer; Sp is -La-Qa-; A is selected from absent, hydrogen or alkyl; T represents a straight or branched (C1-C8) trivalent alkyl group; Y, Y' and Y" are each independently -Lb-Qb-; La and Lb are each independently selected from absent, alkylene, alkenylene, alkynylene, alicyclylene, heteroalicyclylene, arylene, heteroarylene or polyethylene glycol group, wherein the alkylene, alkenylene, alkynylene, alicyclylene, hetero