Small molecule-drug-conjugates cleavable in a tumor microenvironment

A compound or a pharmaceutically acceptable salt thereof, having the structure of Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VII):

• wherein:
• each T is a prostate-specific membrane antigen binder, carbonic anhydrase 9 binder, fibroblast activation protein binder, folate receptor binder, heat-shock protein 90 binder, or an αvβ6 integrin binder, preferably
• each L1, L2, and L3, is independently a bivalent linker,
• A1 is a trivalent linker,
• A2 is a tetravalent linker;
• each EL is a cleavable peptide linker, preferably cleaved by cathepsin B, legumain, or neutrophil elastase, more preferably neutrophil elastase, and
• each P is a payload,
• MOD is a pharmacokinetic modulating group
• preferably having the structure of Formula (II) or Formula (III):
• preferably having the structure:
• wherein:
• R1 is hydrogen, —CH3, —CH2CH3, —CH2CH2CH3, —CH2C(O)NH2, or —CH2C(O)OH;
• and
• R2 is —CH3, —CH(CH3)2, —CH2CH(CH3)2, or —CH(CH3)CH2CH3.
• preferably having the structure:

A compound having a structure of Formula (II), Formula (III), Formula (IV) Formula (V), or Formula (VII):

• wherein:
• each P is a tubulin polymerization inhibitor, a kinesin spindle protein inhibitor, a cyclin-dependent kinase inhibitor, an immunomodulator, an epidermal growth factor receptor inhibitor, or a microtubule inhibitor;
• preferably an auristatin, more preferably auristatin E, monomethyl auristatin E, or a derivative thereof, a kinesin spindle protein inhibitor, a cyclin-dependent kinase 9 inhibitor, a toll-like receptor 7 and/or 8 agonist, an epidermal growth factor receptor inhibitor, or a taxane, more preferably paclitaxel, or a derivative thereof;
• each EL is a cleavable peptide linker, preferably cleaved by cathepsin B, legumain, or neutrophil elastase, more preferably by neutrophil elastase.
• each L1, L2, and L3, is independently a bivalent linker,
• A1 is a trivalent linker,
• A2 is a tetravalent linker;
• each T is a target protein binder, preferably a prostate-specific membrane antigen binder, carbonic anhydrase 9 binder, fibroblast activation protein binder, folate receptor binder, heat-shock protein 90 binder, an αvβ6 integrin binder, or an αvβ3 integrin binder or
• or a pharmaceutically acceptable salt thereof;
• and
• MOD is a pharmacokinetic modulating group,
• preferably having the structure of Formula (II) or Formula (III):
• preferably having the structure:
• wherein:
• P is an auristatin, a kinesin spindle protein inhibitor, a toll-like receptor 7 and/or 8 agonist, an epidermal growth factor receptor inhibitor, or a taxane;
• Ra is hydrogen or —CH3;
• R1 is hydrogen, —CH3, —CH2CH3, —CH2CH2CH3, —CH2C(O)NH2, or —CH2C(O)OH;
• R2 is —CH3, —CH(CH3)2, —CH2CH(CH3)2, or —CH(CH3)CH2CH3;
• and
• T is a target protein binder.
• preferably having the structure:
• wherein:
• P is an auristatin, a kinesin spindle protein inhibitor, a toll-like receptor 7 and/or 8 agonist, an epidermal growth factor receptor inhibitor, or a taxane;
• R1 is hydrogen, —CH3, —CH2CH3, —CH2CH2CH3, —CH2C(O)NH2, or —CH2C(O)OH;
• and
• R2 is —CH3, —CH(CH3)2, —CH2CH(CH3)2, or —CH(CH3)CH2CH3.

A compound, or a pharmaceutically acceptable salt thereof, having a structure Formula (IV), Formula (V), or Formula (VII):

• wherein:
• each P is a payload;
• preferably a tubulin polymerization inhibitor, topoisomerase inhibitor, oxidative phosphorylation inhibitor, kinase inhibitor, dihydrofolate reductase inhibitor, histone deacetylase inhibitor, microtubule inhibitor, or an immuonomodulator, or a camptothecin or camptothecin derivative, an auristatin or auristatin derivative, a kinesin spindle protein inhibitor, a cyclin-dependent kinase 9 inhibitor, a toll-like receptor agonist, an epidermal growth factor receptor inhibitor, or a taxane;
• each EL is a cleavable peptide linker, preferably cleaved by cathepsin B, legumain, or neutrophil elastase, more preferably by neutrophil elastase;
• each L2 and L3 is independently a bivalent linker,
• A1 is a trivalent linker,
• A2 is a tetravalent linker;
• each T is a target protein binder, preferably a prostate-specific membrane antigen binder, carbonic anhydrase 9 binder, fibroblast activation protein binder, folate receptor binder, heat-shock protein 90 binder, an αvβ6 integrin binder, or an αvβ3 integrin binder, and
• MOD is a pharmacokinetic modulating group.
• having preferably the structure:
• wherein:
• A* represents A1 or A2
• Ra is hydrogen or —CH3;
• R1 is hydrogen, —CH3, —CH2CH3, —CH2CH2CH3, —CH2C(O)NH2, or —CH2C(O)OH;
• R2 is —CH3, —CH(CH3)2, —CH2CH(CH3)2, or —CH(CH3)CH2CH3;
• R21 is hydrogen or —CH3;
• and
• P is a camptothecin or camptothecin derivative, an auristatin or auristatin derivative, a kinesin spindle protein inhibitor, a cyclin-dependent kinase 9 inhibitor, a toll-like receptor agonist, an epidermal growth factor receptor inhibitor, or a taxane.