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US 2026/0199535 A1Published application
PCTA derivatives, conjugates thereof and uses thereof
AssigneeNovartis AG
InventorsEmmanuelle BRIARD, Claus EHRHARDT, Philipp HOLZER, Pascal RIGOLLIER
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Abstract
The present disclosure relates to compounds comprising a macrocyclic chelator, and their conjugates with a target binding moiety. In particular, the present disclosure pertains to PCTA derivatives and conjugates thereof.
Claims61
A compound of formula (I)
- or a pharmaceutically acceptable salt thereof,
- wherein
- is a single bond or a double bond,
- when is a single bond, X is —O— or
- when is a double bond, X is ═N— and Z5 and Z7 form, together with the N atom, a heteroaryl having 5 or 6 ring atoms, otherwise, Z5 and Z7 are each independently selected from the group consisting of H, an albumin-binder and —X1-L1-X2-L2-A;
- each R is independently selected from the group consisting of H and C1-C6 alkyl;
- each R1 is independently selected from the group consisting of H, C(═O)OR2, (C1-C6 alkyl)-C(═O)OR2, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C6-C1 aryl, heteroaryl having 5 to 10 ring atoms, and any combination thereof, wherein said alkyl, heteroalkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from:
- —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(═O)R′, —C(═O)R′, —C(═O)OR′, —C(═O)NR′R″, —OC(═O)NR′R″, —NR″C(═O)R′, —NR′—C(═O)NR″R′″, —NR″C(═O)OR′, —NR′—C(NR″R′″)═NR″″, —S(═O)R′, —S(═O)2R′, —S(═O)2NR′R″, —NRS(═O)2R′, —CN and —NO2;
- each R2 is independently selected from the group consisting of H and C1-C6 alkyl;
- R3 is selected from the group consisting of H, C1-C6 alkyl and C(═O)OR;
- R4 is selected from the group consisting of H, C(═O)OR, (C1-C6 alkyl)-C(═O)OR, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C8 heterocycle, C6-C10 aryl, and heteroaryl having 5 to 10 ring atoms, or any combination thereof;
- Z1, Z2, Z3, Z4, and Z6 are each independently selected from the group consisting of H, an albumin-binder and —X1-L1-X2-L2-A, provided that at least one of Z1, Z2, Z3, Z4, Z5, Z6, and Z7 is the group —X1-L1-X2-L2-A;
- X1 is present or absent wherein when present:
- X1 is selected from the group consisting of —O—, —NR′—, —C(═O)NR′—, —NR′C(═O)—, —OC(═O)—, —C(═O)O—, —OC(═O)NR′—, —NR′C(═O)O—, —CH2—O—, and —NR′C(═O)NR′—, with the proviso that when X1 is NR′, R4 is not H;
- L1 is a linker selected from the group consisting of C1-C5 alkylene, (—CH2CH2O)n, C1-C6 heteroalkylene, C3-C6 cycloalkylene, —C3-C8 heterocycloalkylene, heteroarylene having 5 to 10 ring atoms, one or more natural or non-natural amino acids, and any combination thereof, said alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, heteroarylene, and amino acid are optionally substituted with one or more substituents selected from:
- an albumin-binder, C1-C6 alkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(═O)R′, (C1-C6 alkyl)-C(═O)OR′, —C(═O)R′, —C(═O)OR′, (C1-C6 alkyl)-C(═O)OR′, —C(═O)NR′R″, —OC(═O)NR′R″, —NR″C(═O)R′, —NR′—C(═O)NR″R′″, —NR″C(═O)OR′, —NR′—C(NR″R′″)═NR″″, —S(═O)R′, —S(═O)2R′, —S(═O)2NR′R″, —NRS(═O)2R′, —CN and —NO2;
- R′, R″, R′″ and R″″ are each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C8 heterocycle, C6-C10 aryl, and heteroaryl having 5 to 10 ring atoms;
- X2 is selected from the group consisting of:
- L2 is a bond or a linker comprising one or more amino acids, one or more N-substituted amino acids, optionally substituted polyether, optionally substituted C1-C12 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted arylene having 6 to 10 ring atoms, optionally substituted C3-C6 cycloalkylene, optionally substituted heterocycloalkylene having 5 to 10 ring atoms, optionally substituted heteroarylene having 5 to 10 ring atoms, or any combination thereof, wherein the alkylene and alkenylene optionally comprise one or more heteroatom or chemical groups selected from —O—, —S—, —C(═O)—, —NR″—, —C(═O)NR″—, —NR″—C(═O)—, —NR″—C(═O)—NR′″—, —NR″—C(═O)—O—, —O—C(═O)NR″—;
- and
- each m is independently 0 or 1;
- n is 1, 2, 3, 4, 5, or 6;
- p is 1, 2, 3, 4, 5, or 6;
- q is 1, 2, 3, 4, 5, or 5;
- and
- A is a target binding moiety.
23 more elements
A compound of formula (II)
- or a pharmaceutically acceptable salt thereof,
- wherein
- is a single bond or a double bond, wherein
- when is a single bond, X is —O— or
- when is a double bond, X is ═N— and Z5, and Z7′ form, together with the N atom, a heteroaryl having 5 or 6 ring atoms, otherwise, Z5′ and Z7′ are each independently selected from the group consisting of H, an albumin-binder and —X1-L1-X2′;
- each R is independently selected from the group consisting of H and C1-C6 alkyl;
- each R1 is independently selected from the group consisting of H, C(═O)OR2, (C1-C6 alkyl)-C(═O)OR2, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C6-C10 aryl, heteroaryl having 5 to 10 ring atoms, and any combination thereof, wherein said, alkyl, heteroalkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from:
- —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(═O)R′, —C(═O)R′, —C(═O)OR′, —C(═O)NR′R″, —OC(═O)NR′R″, —NR″C(═O)R′, —NR′—C(═O)NR″R′″, —NR″C(═O)OR′, —NR′—C(NR″R′″)═NR″″, —S(═O)R′, —S(═O)2R′, —S(═O)2NR′R″, —NRS(═O)2R′, —CN and —NO2;
- each R2 is independently selected from the group consisting of H and C1-C6 alkyl;
- R3 is selected from the group consisting of H, C1-C6 alkyl, and C(═O)OR;
- R4 is selected from the group consisting of H, C(═O)OR, (C1-C6 alkyl)-C(═O)OR, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C8 heterocycle, C6-C10 aryl and heteroaryl having 5 to 10 ring atoms, or any combination thereof;
- Z1′, Z2′, Z3′, Z4′, and Z6′ are each independently from the group consisting of H, an albumin-binder H or a group —X1-L1-X2′, provided that at least one of Z1′, Z2′, Z3′, Z4, Z5′, Zr, of Z7′ is a group —X1-L1-X2′;
- X1 present or absent wherein when present:
- X1 is selected from the group consisting of —O—, —NR′—, —C(═O)NR′, —NR′C(═O)—, —OC(═O)—, —C(═O)O—, —OC(═O)NR′—, —NR′C(═O)O—;
- —CH2—O—;
- and —NR′C(═O)NR′, with the proviso that when X1 is NR′, R4 is not H;
- L1 is a linker selected from the group consisting of C1-C5 alkylene, (—CH2CH2O)n, C1-C6 heteroalkylene, C3-C6 cycloalkylene, —C3-C8 heterocycloalkylene-, heteroarylene having 5 to 10 ring atoms, one or more natural or non-natural amino acids, and any combination thereof, said alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, heteroarylene, and amino acid are optionally substituted with one or more substituents preferably selected from:
- albumin-binder, C1-C6 alkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(═O)R′, (C1-C6 alkyl)-C(═O)OR′, —C(═O)R′, —C(═O)OR′, (C1-C6 alkyl)-C(═O)OR′—C(═O)NR′R″, —OC(═O)NR′R″, —NR″C(═O)R′, —NR′—C(═O)NR″R′″, —NR″C(═O)OR′, —NR′—C(NR″R′″)═NR″″, —S(═O)R′, —S(═O)2R′, —S(═O)2NR′R″, —NRS(═O)2R′, —CN and —NO2;
- R′, R″, R′″ and R″″ are each independently selected from a group consisting of H, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C8 heterocycle, 3 to 10 membered heterocycloalkyl, C6-C10 aryl and heteroaryl having 5 to 10 ring atoms;
- X2′ is a group selected from the group consisting of:
- each m is independently 0 or 1;
- n is 1, 2, 3, 4, 5, or 6;
- p is 1, 2, 3, 4, 5, or 6;
- and
- q is 1, 2, 3, 4, 5, or 5.
22 more elements
A compound capable of complexing 68Ga and/or 177Lu at a temperature of ≤60° C., to achieve 85% complexation of the compound in a composition, said compound comprising formula (C)
- or a pharmaceutically acceptable salt thereof
- wherein
- is a single bond or a double bond,
- when is a single bond, X is —O— or
- when is a double bond, X is ═N—
- each m is 0 to 5;
- each R is independently selected from the group consisting of H and C1-C6 alkyl;
- each R1 is independently selected from the group consisting of H, C(═O)OR2, (C1-C6 alkyl)-C(═O)OR2, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C6-C1 aryl, heteroaryl having 5 to 10 ring atoms, and any combination thereof, wherein said, alkyl, heteroalkyl, cycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from:
- —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(═O)R′, —C(═O)R′, —C(═O)OR′, —C(═O)NR′R″, —OC(═O)NR′R″, —NR″C(═O)R′, —NR′—C(═O)NR″R′″, —NR″C(═O)OR′, —NR′—C(NR″R′″)═NR″″, —S(═O)R′, —S(═O)2R′, —S(═O)2NR′R″, —NRS(═O)2R′, —CN and —NO2;
- each R2 is selected from the group consisting of H and C1-C6 alkyl;
- R3 is selected from the group consisting of H, C1-C6 alkyl, and C(═O)OR;
- R4 is selected from the group consisting of H, C(═O)OR, (C1-C6 alkyl)-C(═O)OR, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C8 heterocycle, C6-C10 aryl, heteroaryl having 5 to 10 ring atoms, or any combination thereof, and
- the compound of formula (C) being optionally substituted.
10 more elements
Dependencies are inferred from the claim text.