Antibody-multidrug conjugate precursor and synthetic intermediate thereof

A synthetic intermediate of an antibody-multidrug conjugate precursor of Formula (II-1) or a salt thereof:

• where
• Z1 is a reactive group capable of reacting with a functional group present in an antibody or a bonding group for bonding said reactive group or an antitumor drug residue to a linker, and the bonding group may be a protective body protected by a protecting group,
• G1 is a group of Formula (i), (ii), (iii), or (iv),
• L1-1 is a linker linking G1 to D1-1,
• L2-l is a linker linking G1 to D2-1,
• L3-1 is a linker linking G1 to Z1,
• L1-1, L2-l, and L3-1 may be identical to or different from each other,
• D1-1 and D2-1 are antitumor drug residues wherein a hydrogen atom or one hydroxyl group is removed from any position of an antitumor drug molecule, an analog thereof, or a derivative thereof, bonding groups, or protective bodies thereof,
• D1-1 and D2-1 may be identical to or different from each other,
• when there is at least one group independently selected from the group consisting of a lactonyl group, a phosphoryl group, a phosphorylalkylcarbonyl group (—C(═O)-alkylene-P(═O)(OH)2), dialkylamino group, and a cyclic amino group that forms a ring together with the dialkyl group at any position(s) of the antitumor drug residues or L1-1, L2-l, or L3-1 and there are a plurality of groups in total, the groups may be identical to or different from each other, and
• when Z1 is a reactive group, at least one of D1-1 and D2-1 is a bonding group.

A synthetic intermediate of a conjugate precursor of Formula (II-2) or a salt thereof

• where
• L1-1 and L2-l are each independently an optionally substituted alkylene group, and a methylene group in a chain of the alkylene group are optionally replaced with one or more divalent groups independently selected from the group consisting of —C(R1)(R2)—, —O—;
• —N(R3)—, —N(R3)—N(R3)—, —S—, —Se—, —Si(R4)(R5)—, —S—S—, —Se—Se—, —SOm-, —SeOn-, —C(═C(R6)(R7))—, —C(═O)—, —C(═S)—, —C(═N(R8))—, —C(═N—OR9)—, —C(═N—N(R10)(R11))—, —P(═O)(R12)—, —P(=O)(OR13)—, —O—P(═O)(R12)O—, —O—P(═O)(OR13)—O—, —C(R14)=, ═C(R14)—, —C(R14)═C(R14)—, —N═, =N—, —C≡C—, —(O—C(R1)(R2)—C(R1)(R2))1-30—, —(C(R1)(R2)—C(R1)(R2)-0)1-30—, an optionally substituted alkenylene group, an optionally substituted alkynylene group, an optionally substituted cycloalkylene group, an optionally substituted cycloalkenylene group, an optionally substituted arylene group, an optionally substituted heteroarylene group, and an optionally substituted heterocyclylene group,
• R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are each independently a group selected from the group consisting of a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, and an optionally substituted heterocyclyl group, and
• when R3 is an alkyl group, the alkyl group is optionally combined with an alkyl group on an adjacent methylene group to form a cyclic structure,
• m and n are each independently an integer of 0 to 2,
• D1-1 and D2-1 are an antitumor drug residue independently selected from the group consisting of camptothecin, MMAE, maytansine, PBD (parabenzodiazepine) dimer, eribulin, 5-FU, PD-318088, AS-703026, TAK-733, LY-3023414, calicheamicin, paclitaxel, docetaxel, mitomycin C, bleomycin, cyclocytidine, vincristine, vinblastine, daunomycin, doxorubicin, dolastatin 10, superdox, ciprofloxacin, cadrofloxacin (CS-940), Auristatin E, and seco-DUBA, or a bonding group selected from the group consisting of a hydroxyl group, a nitro group, a cyano group, an amide group, an oxo group, an azide group, an amino group, an optionally substituted monoalkylamino group, an imino group, a carboxy group, a phosphoryl group, an alkynyl group, a cycloalkynyl group, and a sulfhydryl group, and
• D1-1 and D2-1 may be identical to or different from each other,
• when there are one or more groups independently selected from a lactonyl group, a phosphoryl group, a phosphorylalkylcarbonyl group (—C(═O)-alkylene-P(═O)(OH)2), dialkylamino group, and a cyclic amino group that forms a ring together with the dialkyl group as substituents or protecting groups at any position(s) of said L1-1 and L2-l or antitumor drug residues and there are a plurality of said groups in total, the groups may be identical to or different from each other, and
• R17 is a hydrogen atom or a protecting group.

42:

• A compound selected from groups of the following compounds,
• Z-L3-a-N(-L1-a-D1-b)(L2-e-D2-ba),
• Z-L3-a-N(-L1-a-D1-a)(L2-e-D2-ba),
• Z-L3-a-N(-L1-a-D1-b)(L2-e-D2-bd),
• Z-L3-a-N(-L1-a-D1-a)(L2-e-D2-bd),
• Z-L3-a-N(-L1-a-D1-b)(L2-b-D2-bf), and
• Z-L3-a-N(-L1-a-D1-a)(L2-b-D2-bf), wherein
• Z is
• L3-a is
• L1-a is
• D1-a is
• D1-b is
• D2-ba is
• D2-bd is
• D2-bf is
• L2-e is
• and
• L2-b is

46:

• The precursor or a salt thereof according to claim 44,
• wherein the linker is a branched linker, and
• the branched linker has at least one branch, at least a first linker moiety (L1), a second linker moiety (L2) and a third linker moiety L3),
• the third linker is interposed between the antibody and the branch,
• the first linker moiety and the second linker moiety are each linked to the branch at one end via covalent bond, and each linked at the other end to a first antitumor drug molecule or an analog thereof or a derivative;
• a derivative of the analog and a second antitumor drug molecule or an analog thereof or a derivative thereof;
• or a derivative of the analog via a covalent bond,
• wherein the first linker moiety and the second linker moiety are identical to or different from each other, and the first antitumor drug molecule and the second antitumor drug molecule are identical to or different from each other.

47:

• The precursor or a salt thereof according to claim 45,
• wherein the linker is a branched linker, and
• the branched linker has at least one branch, at least a first linker moiety (L1), a second linker moiety (L2) and a third linker moiety L3),
• the third linker is interposed between the antibody and the branch,
• the first linker moiety and the second linker moiety are each linked to the branch at one end via covalent bond, and each linked at the other end to a first antitumor drug molecule or an analog thereof or a derivative;
• a derivative of the analog and a second antitumor drug molecule or an analog thereof or a derivative thereof;
• or a derivative of the analog via a covalent bond,
• wherein the first linker moiety and the second linker moiety are identical to or different from each other, and the first antitumor drug molecule and the second antitumor drug molecule are identical to or different from each other.