Camptothecin Derivative, Conjugate Thereof, Preparation Method Therefor and Medical Use Thereof

A compound represented by general formula (A):

• or a pharmaceutically acceptable salt thereof, wherein:
• Dr has the structure:
• R2;
• wherein R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and —(CH2)m—OH;
• and L1 is selected from —NRa—* and —NRbC(═O)O—(CH2)4-6—O—*,
• wherein * is a connection site with L2;
• or
• Dr has the structure:
• R2;
• wherein L1 is selected from —(CH2)m—O—*, —(CH2)m—NRa*, —NRb—(CH2)m—O—*, —NRf—(CH2)m—NRa—*, —O—(CH2)m—O—*, and —O—(CH2)m—NRa—*, wherein * is a connection site with L2;
• Ra is selected from hydrogen and C1-C6 alkyl;
• Rb is selected from hydrogen and C1-C6 alkyl;
• m is an integer from 1 to 6;
• optionally an integer from 1 to 4;
• R2 is selected from hydrogen, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, alkenyl, and alkynyl, wherein the alkyl, alkoxy, alkenyl, and alkynyl are optionally further substituted by one or more halogen groups;
• L2 is selected from a bond,
• wherein * is a connection site with L1;
• L is
• L3 is formed by two or more amino acids, wherein L3 optionally comprises one or more of the following structures, and L6 is selected from one or more of the following structures:
• wherein R, Raa, and Rbb are each independently selected from hydrogen and alkyl;
• L4 is
• Z1 is selected from a bond, —(CH2)p—, —(C2H4O)q-, —(CH2)p—C(O)NH—, —(CH2)p—O—(CH2)p C(O)NH—, —(CH2)p—C(O)-L6-NH—, —(CH2)p—O—(CH2)p—C(O)-L6-NH—, —C(O)NH—, —C(O)O—, —C(O)—, —OC(O)—, —NH—, —O—, and —OC(O)NH—;
• s is an integer from 1 to 6;
• t is an integer from 0 to 10;
• s1, s2, s3, and s4 are each independently an integer from 0 to 10;
• s5 and s6 are each independently an integer from 1 to 6;
• t1 is an integer from 1 to 6;
• t2 is an integer from 0 to 6;
• t3 is an integer from 1 to 6;
• t4 is an integer from 0 to 10;
• t5 is an integer from 0 to 10;
• p is an integer from 1 to 10;
• q is an integer from 1 to 10;
• and
• Q is a linker unit, optionally selected from the group consisting of:
• further optionally selected from

A compound represented by general formula (I):

• or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, mixture, or pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from hydrogen, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, alkenyl, and alkynyl, wherein the alkyl, alkoxy, alkenyl, and alkynyl are optionally further substituted by one or more halogen groups;
• R9 is selected from hydrogen, C1-C6 alkyl, and C1-C6 alkoxy and R10 is —NRfC(═O)O—(CH2)4-6—OH, or
• R9 is selected from —(CH2)m—OH, —(CH2)m—NRdRe, —O—(CH2)m—NRdRe, —O—(CH2)m—OH, —NRf—(CH2)m—OH, and —NRf—(CH2)m—NRdRe and R10 is selected from hydrogen, hydroxyl, C1-C6 alkyl, —NRdRe, —NRf—(CH2)m—OH, —NRf—(CH2)m—NRdRe, —NRf—C(═O)Rd, —NRf—C(═O)—(CH2)m—Rd, —NRfC(═O)O—(CH2)m—Rd, —NRfC(═O)O—(CH2)m—OH, —NRfC(═O)NRd—(CH2)m—OH, —NRfC(═O)NRd—(CH2)m—O—(CH2)n—OH, —NRfC(═O)O—(CH2)m—O—(CH2)n—OH, —NRfC(═O)NRd—(CH2)m—O—(CH2)n—NRdRe, —NRfC(═O)O—(CH2)m—O—(CH2)n—NRdRe, —NRfC(═O)NRd—(CH2)m NRdRe, and —NRfC(═O)O—(CH2)m—NRdRe;
• Rd and Re are each independently selected from hydrogen and C1-C6 alkyl;
• Rf is selected from hydrogen and C1-C6 alkyl;
• m is an integer from 1 to 6;
• and
• n is an integer from 1 to 6.

A ligand-drug conjugate represented by general formula (B):

• or a pharmaceutically acceptable salt thereof, wherein:
• Dr has the structure:
• wherein R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and —(CH2)m—OH;
• L1 is selected from —NRa—* and —NRbC(═O)O—(CH2)4-6—O—*, wherein * is a connection site with L2;
• or
• Dr has the structure:
• wherein L1 is selected from —(CH2)m—O—*, —(CH2)m—NRa—*, —NRf—(CH2)m—O—* —NRb—(CH2)m—NRa—*, —O—(CH2)m—O—*, —O—(CH2)m—NRa—*, wherein * is a connection site with L2;
• Ra is selected from hydrogen and C1-C6 alkyl;
• Rb is selected from hydrogen and C1-C6 alkyl;
• m is an integer from 1 to 6;
• R2 is selected from hydrogen, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, alkenyl, and alkynyl, wherein the alkyl, alkoxy, alkenyl, and alkynyl are optionally further substituted by one or more halogen groups;
• L2 is selected from a bond,
• wherein * is a connection site with L1;
• L′ is
• Q′ is selected from
• wherein, * is a connection site with L4, and is a connection site with Pc;
• L3 is formed by two or more amino acids, L3 optionally comprises one or more of the following structures, and L6 is selected from one or more of the following structures:
• wherein R, Raa, and Rbb are each independently selected from hydrogen and alkyl;
• L4 is
• Z1 is selected from a bond, —(CH2)p—, —(C2H4O)q-, —(CH2)p—C(O)NH—, —(CH2)p—O—(CH2)p C(O)NH—, —(CH2)p—C(O)-L6-NH—, —(CH2)p—O—(CH2)p—C(O)-L6-NH—, —C(O)NH—, —C(O)O—, —C(O)—, —OC(O)—, —NH—, —O—, and —OC(O)NH—;
• s is an integer from 1 to 6;
• t is an integer from 0 to 10;
• s1, s2, s3, and s4 are each independently an integer from 0 to 10;
• s5 and s6 are each independently an integer from 1 to 6;
• t1 is an integer from 1 to 6;
• t2 is an integer from 0 to 6;
• t3 is an integer from 1 to 6;
• t4 is an integer from 0 to 10;
• t5 is an integer from 0 to 10;
• p is an integer from 1 to 10;
• q is an integer from 1 to 10;
• v is from 1 to 10, and v is a decimal or an integer;
• Pc is an antibody or an antigen-binding fragment thereof, or a modified antibody;
• the modified antibody has Pc′-((L5)w-F)x structure, wherein:
• Pc′ is an antibody;
• L5 is a linker;
• w is 0 or 1;
• F is a clickable probe or sulfhydryl or a precursor thereof that can be connected to Q′ after a reaction such as a metal-free click reaction, optionally wherein F is an azido group;
• and
• x is an integer from 1 to 8.