A NOVEL HYDROPHILIC LINKER, ANTIBODY-DRUG CONJUGATE, AND THEIR USE

Claims

This application provides a linker, an antibody-drug conjugate, a method for its preparation, and its use in the prevention and / or treatment of diseases associated with abnormal cellular activity, including, but not limited to, the prevention and / or treatment of neoplastic diseases.

1. A drug conjugate represented by formula (1), or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof; wherein Ab is a targeting molecular group, such as an antibody or an antigen-binding fragment thereof; p is an integer selected from 1-20, for example, an integer selected from 2-18, 2-16, 2-10, 2-8, 4-10, 6-8, 3-7, 4-8, or 2-6, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 16, 17, 18, 19, or 20; D is an active drug molecule; L is a linker; G is a hydrophilic group, comprising at least one G0 group represented by formula (1a) and a PEG unit; R1 is selected from CH or N; R2 and R3 are each independently selected from H and C1-6 alkyl; R4 is selected from -C(O)-, -NH- or absent; X1 is selected from CH, N or absent, and when X1 is absent, R3 is also correspondingly absent;when X1 is selected from CH or N atom, X1 together with the N atom in -NR2 and the atoms to which they are attached to form a 5- to 10-membered heterocycle; specifically, R2 is replaced with X1 to form a 5- to 10-membered heterocycle, or R2 is replaced with R3 to form a 5- to 10-membered heterocycle; n is an integer selected from 0-4, such as 0, 1, 2, 3, or 4; m is an integer selected from 0-3, such as 0, 1, 2, or 3; and m + n does not equal 0; t is an integer selected from 1-6, such as 1, 2, 3, 4, 5, or 6; M1 and M2 are sugar residues; the structures of M1 and M2 may be the same or different; wavy line represents the site where G0 is bound; Preferably, the structure of G0 is shown in formula (1a-1) or (1a-2) as follows, wherein R3' is -C1-6-alkylene, such as methylene, ethylene, or propylene; other symbols (such as R1, R4, X1, m, n, M1, M2) are as defined above.

84. A pharmaceutical composition comprising the drug conjugate or pharmaceutically acceptable salt thereof, or the solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof according to any one of claims 1 to 61 and claim 83; or the compound or pharmaceutically acceptable salt thereof, or the solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof according to any one of claims 64 to 71; and optionally a pharmaceutically acceptable carrier.