Heterocyclic self-immolative linkers and conjugates
View Patent ↗The present invention provides heterocyclic linker compounds useful for linking drug moieties to ligands. The compounds also include drug-ligand conjugates comprising a ligand capable of targeting a selected cell population, and a drug connected to the ligand by a heterocyclic linker moiety. The linker moiety comprises a peptide sequence that is a substrate for an intracellular enzyme, for example a cathepsin, that cleaves the peptide at an amide bond. The peptide further contains a self-immolating moiety which connects the drug and the protein peptide sequence. Upon cleavage of the peptide sequence by an intracellular enzyme the self-immolating moiety cleaves itself from the drug moiety such that the drug moiety is in an underivatized and active form.
1. A heterocyclic linker compound selected from Formula Ia:
wherein
U is O, S or NR 6 ;
Q is CR 4 or N;
R 1 , R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, —N(R 5 ) 2 , —N(R 5 ) 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, —SO 2 R 5 , —S(═O)R 5 , SR 5 , —SO 2 N(R 5 ) 2 , —C(═O)R 5 , —CO 2 R 5 , —C(═O)N(R 5 ) 2 , —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 halosubstituted alkyl, polyethyleneoxy, phosphonate, phosphate, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 2 -C 8 alkenyl, C 2 -C 8 substituted alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 1 -C 20 heterocycle, and C 1 -C 20 substituted heterocycle; or when taken together, R 2 and R 3 form a carbonyl (═O), or spiro carbocyclic ring of 3 to 7 carbon atoms; and
R 5 and R 6 are independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 2 -C 8 alkenyl, C 2 -C 8 substituted alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 1 -C 20 heterocycle, and C 1 -C 20 substituted heterocycle;
where C 1 -C 8 substituted alkyl, C 2 -C 8 substituted alkenyl, C 2 -C 8 substituted alkynyl, C 6 -C 20 substituted aryl, and C 2 -C 20 substituted heterocycle are independently substituted with one or more substituents selected from F, Cl, Br, I, OH, —N(R 5 ) 2 , —N(R 5 ) 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R 5 , —S(═O)R 5 , —SR 5 , —SO 2 N(R 5 ) 2 , —C(═O)R 5 , —CO 2 R 5 , —C(═O)N(R 5 ) 2 , —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 3 -C 12 carbocycle, C 6 -C 20 aryl, C 2 -C 20 heterocycle, polyethyleneoxy, phosphonate, and phosphate;
R 7 is the side chain of an amino acid and is optionally protected with a protecting group;
X and Y independently: are H; a protecting group selected from Fmoc, Boc, carbobenzoxy (CBz), benzyhydryl, allyloxyl group, and triphenylmethyl, or; a reactive functional group selected from N-hydroxysuccinimide, para-nitrophenyl carbonate, para-nitrophenyl carbamate, pentafluorophenyl, haloacetamide, and maleimide; and
m is 1, 2, 3, 4, 5, or 6.
2. The heterocyclic linker compound of claim 1 having the structure:
3. The heterocyclic linker compound of claim 1 having the structure: