Camptothecin derivative for treating or preventing cancer and antibody-drug conjugate thereof

The antibody-drug conjugate according to any one of the preceding claims, or a pharmaceutically acceptable salt or ester, solvate, tautomer, stereoisomer, prodrug, or isotopically labeled form thereof, wherein R3 is C1-6 alkyl, C1-6 alkoxy, halogen, cyano, —NH2, —NH—CO—(C1-6 hydroxyalkyl), or NO2;

• preferably, R3 is C1-6 alkyl, halogen, —NH2, —NH—CO—(C1-6 hydroxyalkyl), or NO2;
• or, R3 is halogen, cyano, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6hydroxyalkyl, C1-6 alkoxy, or NRaRb, wherein Ra and Rb are each independently H, C1-6 alkyl, —SO—(C1-6 alkyl), —SO2—(C1-6 alkyl), or —(CH2)q(C3-8 cycloalkyl), wherein the alkyl and the cycloalkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, OH, SH and amino;
• preferably, R3 is C1-6 alkyl, C1-6 alkoxy, halogen, cyano, —NH2 or NO2;
• more preferably, R3 is C1-6 alkyl, halogen, —NH2 or NO2;
• or, R3 is C1-6 alkyl or NRaRb, wherein Ra and Rb are each independently H or —CO—(C1-6 alkyl), wherein the alkyl is optionally substituted with one or more OH groups;
• or, R3 is C1-6 alkyl, —NH2 or —NH—CO—(CH2OH), preferably R3 is C1-6 alkyl or —NH—CO—(CH2OH);
• or R3 is C1-6 alkyl.

The antibody-drug conjugate according to any one of the preceding claims, or a pharmaceutically acceptable salt or ester, solvate, tautomer, stereoisomer, prodrug, or isotopically labeled form thereof, wherein D is a moiety selected from the following:

• No.
• Structure
• 1′
• 2′
• STI-A-6′
• 3′
• 4′
• STI-A2′
• 5′
• 6′
• STI-E-05′
• 7′
• 8′
• STI-F-8′
• 9′
• STI-F2′
• 10′
• STI-F-03c-1′
• 11′
• STI-G1′
• 12′
• STI-G03′
• 13′
• STI-G2-06c′
• 14′
• STI-G2′
• 15′
• STI-D′
• 16′
• STI-F′
• 17′
• STI-F6′
• 18′
• STI-F7′
• 19′
• STI-F13′
• 20′
• STI-G4′
• 21′
• SIT-F12R′
• 22′
• STI-F10′
• P1′
• STI-F5′
• P2′
• STI-F8′
• P3′
• STI-F14′
• P4′
• STI-F15′
• P5′
• STI-F17′
• P6′
• STI-F18′
• P7′
• STI-G5′

The antibody-drug conjugate according to any one of the preceding claims, or a pharmaceutically acceptable salt or ester, solvate, tautomer, stereoisomer, prodrug, or isotopically labeled form thereof, wherein L2 is each independently a linking unit selected from the group consisting of:

• —(CH2)t—(CH2CH2O)s—(CH2)t—CO—,
• —(CH2)t—CO—NH—(CH2CH2O)s—(CH2)t—CO—, —(CH2)t—NH—CO—(CH2CH2O)s—(CH2)t—CO—,
• —(CH2)t—CO—NH—(CH2)t-(3- to 8-membered heteroarylene)-(CH2)t—(OCH2CH2)m—NH—CO—(CH2O)—(CH2)t—CO—,
• —(CH2)t—CO—NH—(CH2)t—NH—CO—(CH2CH2O)m—(CH2)t—NH—CO—(CH2O)—(CH2)t—CO—,
• —(CH2)t—CO—NH—(CH2)t—NH—CO—(CH2)t—(OCH2CH2)m—NH—CO—(CH2O)—(CH2)t—CO—,
• —(CH2)t—NH—CO—(CH2)t—N(Rp)—(CH2)t—N(Rp)—(CH2)t—CO—,
• —(CH2)t—CO—NH—(CH2)t—N(Rp)—(CH2)t—N(Rp)—(CH2)t—CO—, or
• —(CH2)t—CO—NH—CH(Rp)—CO— or —(CH2)t—NH—CO—CH(Rp)—CO—,
• wherein the —CO— terminus of L2 is connected to L3, and the other terminus of L2 is connected to L1.

The antibody-drug conjugate according to any one of the preceding claims, or a pharmaceutically acceptable salt or ester, solvate, tautomer, stereoisomer, prodrug, or isotopically labeled form thereof, wherein:

• L1 is each independently:
• preferably
• more preferably
• wherein position 1 is connected to Ab, and position 2 is connected to L2;
• L2 is each independently a linking unit of the formula —(CH2CH2O)x—(CH2)y—CO—, wherein the —CO— terminus is connected to L3 and the other terminus is connected to L1, and wherein x is an integer from 0 to 5, y is an integer from 1 to 5, and x+y≤6;
• preferably, L2 is —(CH2)—CO—, —(CH2)2—CO—, —(CH2)3—CO—, —(CH2)4—CO—, —(CH2)5—CO—, —(CH2)6—CO—, —(CH2CH2O)—(CH2)—CO—, —(CH2CH2O)—(CH2)2—CO—, —(CH2CH2O)—(CH2)3—CO—, —(CH2CH2O)—(CH2)4—CO—, —(CH2CH2O)—(CH2)5—CO—, —(CH2CH2O)2—(CH2)—CO—, —(CH2CH2O)2—(CH2)2—CO—, —(CH2CH2O)2—(CH2)3—CO—, —(CH2CH2O)2—(CH2)4—CO—, —(CH2CH2O)3—(CH2)—CO—, —(CH2CH2O)3—(CH2)2—CO—, —(CH2CH2O)3—(CH2)3—CO—;
• more preferably, L2 is each independently —(CH2)5—CO— or —(CH2CH2O)3—(CH2)2—CO—;
• L3 is each independently an amino acid residue, a short peptide chain consisting of 2-6 amino acid residues, or —NH—(CH2)p—CO—, wherein p is 0, 1, 2, 3, 4, 5, or 6;
• preferably, the amino acid is selected from the group consisting of glycine (Gly), alanine (Ala), valine (Val), phenylalanine (Phe), citrulline (Cit), lysine (Lys) and asparagine (Asn);
• for example, L3 is Gly-Gly-Phe-Gly, Val-Cit, Val-Ala, Phe-Lys, Val-Lys, Ala-Ala-Ala, Ala-Ala-Asn, or —NH—(CH2)2—CO—;
• and
• L4 is each independently a bond,
• wherein position 1 is connected to L3 and position 2 is connected to D.

The antibody-drug conjugate according to any one of the preceding claims, or a pharmaceutically acceptable salt or ester, solvate, tautomer, stereoisomer, prodrug, or isotopically labeled form thereof, wherein the -L1-L2-L3-L4-D moiety is each independently selected from:

• No.
• Structure
• 23′
• STI-A3′
• 24′
• STI-F3′
• 25′
• STI-F4′
• 26′
• STI-G′
• 27′
• STI-G3′
• 28′
• STI-F1002′
• 29′
• STI-F1001′
• 30′
• STI-F1003′
• 31′
• STI-F1004′
• 32′
• STI-F1006
• 33′
• STI-F1010
• 34′
• STI-F1011
• 35′
• STI-F1012
• 36′
• STI-F1013
• 37′
• STI-F1014
• 38′
• STI-F1015
• 39′
• STI-F1018
• 40′
• STI-F1019
• 41′
• STI-G1001
• 42′
• STI-F1031
• 43′
• STI-F1034
• 44′
• STI-F1035
• 45′
• STI-F1043
• wherein position 1 represents the point of attachment to Ab.

The antibody-drug conjugate according to any one of the preceding claims, or a pharmaceutically acceptable salt or ester, solvate, tautomer, stereoisomer, prodrug, or isotopically labeled form thereof, wherein the antibody-drug conjugate is selected from the group consisting of:

• Name
• Structure
• Fa-ADC1
• Fa-ADC2
• Fa-ADC3
• Fa-ADC4
• Fa-ADC5
• Fa-ADC6
• Tra-ADC7
• Tra-ADC8
• Tra-ADC9
• Tra-ADC10
• Tra-ADC11
• Tra-ADC12
• Tra-ADC13
• Tra-ADC14
• Tra-ADC15
• Tra-ADC16
• Tra-ADC17
• Tra-ADC18
• Tra-ADC19
• Tra-ADC20
• wherein, in Fa-ADCs, mAb represents farletuzumab;
• in Tra-ADCs, mAb represents trastuzumab, and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

A compound of formula (II):

• or a pharmaceutically acceptable salt or ester, solvate, tautomer, stereoisomer, prodrug, or isotopically labeled form thereof,
• wherein,
• R1 is:
• H;
• halogen;
• CN;
• OH;
• SH;
• C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, OH, SH and amino;
• —(CH2)p—(C3-8 cycloalkyl) or —(CH2)p—(C3-8 heterocycloalkyl), wherein the cycloalkyl and heterocycloalkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, OH, SH, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl and C1-6 aminoalkyl;
• —(CH2)p—(C1-6 alkoxy);
• —(CH2)p—(C1-6 alkylthio);
• —(CH2)p—NRaRb;
• —(CH2)p—CH═NRa;
• —NH—CO—Ra;
• —NH—CO—(CH2)p—CH(OH)—Ra;
• —NH—(CH2)p—(CH═CH)—Ra;
• or —COOH;
• R2 and R3 are each independently halogen, cyano, NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, —NH—CO—(C1-6 hydroxyalkyl), or NRaRb;
• or R2 and R3, together with the atoms to which they are attached, form a 4- to 8-membered heterocyclic group;
• R4 is H or C3-8 cycloalkyl, preferably H;
• Ra and Rb are each independently H, C1-6 alkyl, —CO—(C1-6 alkyl), —SO—(C1-6 alkyl), —SO2—(C1-6 alkyl), or —(CH2)q—(C3-8 cycloalkyl), wherein the alkyl and the cycloalkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, OH, SH and amino, and wherein the cycloalkyl is further optionally substituted with one or more substituents independently selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl and C1-6 aminoalkyl;
• and
• p and q are each independently 0, 1, 2, 3, 4, 5, or 6.