Compounds comprising a linker for increasing transcyclooctene stability

A compound according to Formula (1):

• wherein t1 is 0 or 1,
• wherein t2 is 0 or 1,
• wherein x is an integer in a range of from 1 to 12,
• wherein y is 0 or 1,
• wherein z is an integer in a range of from 6 to 48,
• wherein L is selected from the group consisting of —CH2—OCH3, —CH2—OH, —CH2-C(O)OH, —C(O)OH,
• wherein when at least one of t1 or t2 is 0, then G is selected from the group consisting of CR′, C5-C6 arenetriyl, C4-C5 heteroarenetriyl, C3-C6 cycloalkanetriyl, and C4-C6 cycloalkenetriyl, wherein when both t1 and t2 are 1, then G is selected from the group consisting of CR′, N, C5-C6 arenetriyl, C4-C5 heteroarenetriyl, C3-C6 cycloalkanetriyl, and C4-C6 cycloalkenetriyl,
• wherein for G, the arenetriyl, heteroarenetriyl, cycloalkanetriyl, and cycloalkenetriyl are optionally further substituted with groups selected from the group consisting of —Cl, —F, —Br, —I, —OR′, —N(R′)2, —SR′, —SO3H, —PO3H, —PO4H2, —NO2, —CF3 and —R1, and optionally contain one or more heteroatoms selected from the group consisting of —O—, —S—, —NR′—, —P—, and —Si—, wherein the N, S, and P atoms are optionally oxidized, wherein the N atoms are optionally quaternized,
• wherein R1 is selected from the group consisting of hydrogen, C1-C6 alkyl groups, C6 aryl groups, C4-C5 heteroaryl groups, C3-C6 cycloalkyl groups, C5-C12 alkyl(hetero)aryl groups, C5-C12 (hetero)arylalkyl groups, C4-C12 alkylcycloalkyl groups, —N(R′)2, —OR′, —SR′, —SO3H, —C(O)OR′, and Si(R′)3,
• wherein for R1 the alkyl groups, (hetero)aryl groups, cycloalkyl groups, alkyl(hetero)aryl groups, (hetero)arylalkyl groups, alkylcycloalkyl groups are optionally substituted with a moiety selected from the group consisting of —Cl, —F, —Br, —I, NO2, SO3H, PO3H, —PO4H2, —OR′, —N(R′)2, —CF3, ═O, ═NR′, —SR′, and optionally contain one or more heteroatoms selected from the group consisting of —O—, —S—, —NR′—, —P—, and —Si—, wherein the N, S, and P atoms are optionally oxidized, wherein the N atoms are optionally quaternized,
• wherein R2 is selected from the group consisting of N-maleimidyl groups, halogenated N-alkyl-amido groups, sulfonyloxy N-alkylamido groups, vinyl sulfone groups, activated carboxylic acids, benzenesulfonyl halides, ester groups, carbonate groups, sulfonyl halide groups, thiol groups, C2-6 alkenyl groups, C2-6 alkynyl groups, C7-18 cycloalkynyl groups, C5-18 heterocycloalkynyl groups, bicyclo[6.1.0]non-4-yn-9-yl] groups, C4-12 cycloalkenyl groups, azido groups, phosphine groups, nitrile oxide groups, nitrone groups, nitrile imine groups, isonitrile groups, diazo groups, ketone groups, (O-alkyl) hydroxylamino groups, hydrazine groups, halogenated N-maleimidyl groups, aryloxymaleimides, dithiophenol-maleimides, bromo- and dibromopyridazinediones, 2,5-dibromohexanediamide groups, alkynone groups, 3-arylpropiolonitrile groups, 1,1-bis(sulfonylmethyl)-methylcarbonyl groups, carbonyl halide groups, allenamide groups, 1,2-quinone groups, isothiocyanate groups, aldehyde groups, triazine groups, squaric acids, 2-imino-2-methoxyethyl groups, (oxa)norbornene groups, (imino)sydnones, methylsulfonyl phenyloxadiazole groups, aminooxy groups, and 2-amino benzamidoxime groups,
• wherein each individual R3 is selected from the group consisting of C1-C12 alkylene groups, C2-C12 alkenylene groups, C2-C12 alkynylene groups, C6 arylene groups, C4-C5 heteroarylene groups, C3-C8 cycloalkylene groups, C5-C8 cycloalkenylene groups, C5-C12 alkyl(hetero)arylene groups, C5-C12 (hetero)arylalkylene groups, C4-C12 alkylcycloalkylene groups, C4-C12 cyclo-alkylalkylene groups,
• wherein each individual R5 is selected from the group consisting of C1-C8 alkylene groups, C2-C8 alkenylene groups, C2-C8 alkynylene groups, C6 arylene groups, C4-C5 heteroarylene groups, C3-C6 cycloalkylene groups, C5-C8 cycloalkenylene groups, C5-C12 alkyl(hetero)arylene groups, C5-C12 (hetero)arylalkylene groups, C4-C12 alkylcycloalkylene groups, C4-C12 cyclo-alkylalkylene groups,
• wherein for R3 and R5 the alkylene groups, alkenylene groups, alkynylene groups, (hetero)arylene groups, cycloalkylene groups, cycloalkenylene groups, alkyl(hetero)arylene groups, (hetero)arylalkylene groups, alkylcycloalkylene groups, cycloalkylalkylene groups, are optionally substituted with a moiety selected from the group consisting of —Cl, —F, —Br, —I, —OR′, —N(R′)2, —O, ═NR′, —SR′, —SO3H, —PO3H, —PO4H2, —NO2 and —Si(R′)3, and optionally contain one or more heteroatoms selected from the group consisting of —O—, —S—, —NR′—, —P—, and —Si—, wherein the N, S, and P atoms are optionally oxidized, wherein the N atoms are optionally quaternized,
• wherein each R′ is independently selected from the group consisting of hydrogen, C1-C6 alkylene groups, C2-C6 alkenylene groups, C2-C6 alkynylene groups, C6 arylene, C4-C5 heteroarylene, C3-C6 cycloalkylene groups, C5-C8 cycloalkenylene groups, C5-C12 alkyl(hetero)arylene groups, C5-C12 (hetero)arylalkylene groups, C4-C12 alkylcycloalkylene groups, and C4-C12 cycloalkyl-alkylene groups,
• wherein for R′ the alkylene groups, alkenylene groups, alkynylene groups, (hetero)arylene groups, cycloalkylene groups, cycloalkenylene groups, alkyl(hetero)arylene groups, (hetero)arylalkylene groups, alkylcycloalkylene groups, cycloalkylalkylene groups are optionally substituted with a moiety selected from the group consisting of —Cl, —F, —Br, —I, —OH, —NH2, ═O, —SH, —SO3H, —PO3H, —PO4H2, —NO2, 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 each R″ is independently selected from the group consisting of
• wherein the wiggly line depicts a bond to an ethylene glycol group or optionally to the R3 adjacent to R2 when y is 0, and the dashed line depicts a bond to R3 or G,
• wherein R4 is selected from the group consisting of —OH, —OC(O)Cl, —OC(O)O—N-succinimidyl, —OC(O)O-4-nitrophenyl, —OC(O)O-tetrafluorophenyl, —OC(O)O-pentafluorophenyl, —OC(O)—CA, —OC(S)—CA, —O-(LC(CA)s(CA)s)q—CA, and —CA,
• wherein q is an integer in range of from 0 to 2,
• wherein each s is independently 0 or 1,
• wherein LC is a self-immolative linker,
• wherein CA denotes a Construct A, wherein said Construct A is a drug,
• wherein, when R4 is —OC(O)—CA or —OC(S)—CA, CA is bound to the —OC(O)— or —OC(S)— of R4 via an atom selected from the group consisting of O, S, N, a secondary N and a tertiary N, wherein this atom is part of CA,
• wherein, when R4 is —O-(LC(CA)s(CA)s)q—CA and q is 0, CA is bound to the —O— moiety of R4 on the allylic position of the trans-cyclooctene ring of Formula (1) via a group selected from the group consisting of —C(O)—, and —C(S)—, wherein this group is part of CA,
• wherein, when R4 is —O-(LC(CA)s(CA)s)q—CA and q is 1, LC is bound to the —O— moiety on the allylic position of the trans-cyclooctene ring of Formula (1) via a group selected from the group consisting of —C(YC2)YC1—, and a carbon atom, which is optionally an aromatic carbon, wherein this group is part of Lc,
• wherein YC1 is selected from the group consisting of —O—, —S—, and —NR6—,
• wherein YC2 is selected from the group consisting of O and S,
• wherein, when R4 is —O-(LC(CA)s(CA)s)q—CA, and q is 1, then CA is bound to LC via a moiety selected from the group consisting of —O—, —S—, —N—, a secondary N and a tertiary N, wherein said moiety is part of CA,
• wherein, when R4 is —CA, then CA is bound to the allylic position of the trans-cyclooctene of Formula (1) via an-O-atom, wherein this atom is part of CA,
• wherein R6 is selected from the group consisting of hydrogen, C1-C4 alkyl groups, C2-C4 alkenyl groups, and C4-6 (hetero)aryl groups,
• wherein for R6 the alkyl groups, alkenyl groups, and (hetero)aryl groups are optionally substituted with a moiety selected from the group consisting of —Cl, —F, —Br, —I, —OH, —NH2, ═O, —SH, —SO3H, —PO3H, —PO4H2 and —NO2 and optionally contain at most two heteroatoms selected from the group consisting of —O—, —S—, —NH—, —P—, and —Si—, wherein the N, S, and P atoms are optionally oxidized,
• and pharmaceutically accepted salts thereof.