Agents for cleaving labels from biomolecules in vivo

A method comprising administering a compound of Formula (1) to a subject and subsequently administering to said subject a diene;

• wherein said compound of Formula (1) is:
• and pharmaceutically acceptable salts thereof, wherein
• the compound of Formula (1) comprises at least one Label and at least one Administration Agent;
• the Label is a moiety comprising a radionuclide;
• the Administration Agent is an antibody, an antibody fragment which is at least a portion of the variable region of the immunoglobulin that binds to its target, or an antibody mimetic;
• each X1, X2, X3, X4 is independently selected from the group consisting of
• —C(R47)2—, —NR37—, —C(O)—, —O—, such that at most two of X1, X2, X3, X4 are not
• —C(R47)2—, and with the proviso that no sets consisting of adjacent atoms are present selected from the group consisting of —O—O—, —O—N—, —C(O)—O—, N—N—, and —C(O)—C(O)—;
• X5 is —C(R47)2— or —CHR48;
• each R48 is independently selected from the group consisting of -LB, and -LA;
• R48 is bound to the remainder of the compound of Formula (1) via a part of R48 that is —O—, —S—, —OC(O)—, —OC(S)—, —SC(O)—, or —SC(S)—;
• LB is a moiety satisfying Formula (2):
• Formula (2);
• wherein
• the dashed line denotes a bond to the remainder of the compound of Formula (1);
• SL is a linker, which optionally is a self-immolative linker LC;
• each R98 individually is the Label or a clearance-directing group, wherein a clearance-directing group is a moiety that directs a compound to an excretory organ;
• each d independently is 0 or 1;
• e is an integer in a range of from 0 to 4;
• LA is a moiety satisfying Formula (3):
• Formula (3);
• wherein
• the dashed line denotes a bond to the remainder of the compound of Formula (1);
• each s is independently 0 or 1;
• i is an integer in a range of from 0 to 4;
• each SP independently is a spacer, which optionally is a self-immolative linker LC;
• AA denotes the Administration Agent;
• CC denotes a Construct-C, wherein each Construct-C is independently selected from the group consisting of the Label and the Administration Agent;
• provided that LA only comprises both the Label and the Administration Agent when LA is R48;
• provided that if LA being R48 comprises both the Label and the Administration Agent, then the SP linked to said Label and said Administration Agent is a self-immolative linker, wherein said Label and said Administration Agent will be uncoupled after reaction of the compound of Formula (1) with a Cleaving Agent due to the self-immolative character of the linker, wherein the Cleaving Agent is a diene;
• each R47 is independently selected from the group consisting of
• hydrogen, -LB, -LA, —(SP)i—CC, —F, —Cl, —Br, —I, —OR37, —N(R37)2, —SO3, —PO3—, —NO2, —CF3, —SR37, S(═O)2N(R37)2, OC(═O)R37, SC(═O) R37, OC(═S)R37, SC(═S)R37, NR37C(═O)—R37, NR37C(═S)—R37, NR37C(═O)O—R37, NR37C(═S)O—R37, NR37C(═O)S—R37, NR37C(═S)S—R37, OC(═O)N(R37)2, SC(═O)N(R37)2, OC(═S)N(R37)2, SC(═S)N(R37)2, NR37C(═O)N(R37)2, NR37C(═S)N(R37)2, C(═O)R37, C(═S)R37, C(═O)N(R37)2, C(═S)N(R37)2, C(═O)O—R37, C(═O)S—R37, C(═S)O—R37, C(═S)S—R37, S(O)R37, —S(O)2R37, NR37S(O)2R37, —ON(R37)2, —NR37OR37, C1-C24 alkyl groups, C2-C24 alkenyl groups, C2-C24 alkynyl groups, C6-C24 aryl groups, C2-C24 heteroaryl groups, C3-C24 cycloalkyl groups, C5-C24 cycloalkenyl groups, C12-C24 cycloalkynyl groups, C3-C24 (cyclo)alkyl(hetero)aryl groups, C3-C24 (hetero)aryl(cyclo)alkyl, C4-C24 (cyclo)alkenyl(hetero)aryl groups, C4-C24 (hetero)aryl(cyclo)alkenyl groups, C4-C24 (cyclo)alkynyl(hetero)aryl groups, C4-C24 (hetero)aryl(cyclo)alkynyl groups, C4-C24 alkylcycloalkyl groups, and C4-C24 cycloalkylalkyl groups;
• wherein i is an integer in a range of from 0 to 4,
• wherein the alkyl groups, alkenyl groups, alkynyl groups, aryl, heteroaryl, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, (cyclo)alkyl(hetero)aryl groups, (hetero)aryl(cyclo)alkyl groups, (cyclo)alkenyl(hetero)aryl groups, (hetero)aryl(cyclo)alkenyl groups, (cyclo)alkynyl(hetero)aryl groups, (hetero)aryl(cyclo)alkynyl groups, alkylcycloalkyl groups, cycloalkylalkyl groups are optionally substituted with a moiety selected from the group consisting of —Cl, —F, —Br, —I, —OR37, —N(R37)2, —SO3R37, —PO3(R37)2, —PO4(R37)2, —NO2, —CF3, ═O, ═NR37, and —SR37, and optionally contain one or more heteroatoms selected from the group consisting of O, S, NR37, P, and Si, wherein the N, S, and P atoms are optionally oxidized, wherein the N atoms are optionally quaternized;
• two R47 and/or R37 are optionally comprised in a ring,
• two R47 and/or R37 are optionally comprised in a ring so as to form a ring fused to the eight membered trans-ring of Formula (1);
• each R37 is independently selected from the group consisting of hydrogen, -LB, -LA, —(SP)i—CC, C1-C24 alkyl groups, C2-C24 alkenyl groups, C2-C24 alkynyl groups, C6-C24 aryl groups, C2-C24 heteroaryl groups, C3-C24 cycloalkyl groups, C5-C24 cycloalkenyl groups, C12-C24 cycloalkynyl groups, C3-C24 (cyclo)alkyl(hetero)aryl groups, C3-C24 (hetero)aryl(cyclo)alkyl, C4-C24 (cyclo)alkenyl(hetero)aryl groups, C4-C24 (hetero)aryl(cyclo)alkenyl groups, C4-C24 (cyclo)alkynyl(hetero)aryl groups, C4-C24 (hetero)aryl(cyclo)alkynyl groups, C4-C24 alkylcycloalkyl groups, and C4-C24 cycloalkylalkyl groups;
• wherein i is an integer in a range of from 0 to 4;
• the R37 groups not being hydrogen are optionally substituted with a moiety selected from the group consisting of —Cl, —F, —Br, —I, —OH, —NH2, —SO3H, —PO3H, —PO4H2, —NO2, —CF3, ═O, ═NH, and —SH, and optionally contain one or more heteroatoms selected from the group consisting of O, S, NH, P, and Si, wherein the N, S, and P atoms are optionally oxidized, wherein the N atoms are optionally quaternized.