Conjugate of cell-penetrating peptide and melphalan, and preparation containing conjugate

A compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, which represents a covalent conjugate of cell-penetrating peptide derivative and melphalan,

• wherein, X1, X2 and X3 represent hydrophobic amino acid, each of which is independently selected from alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M) and non-naturally occurring amino acids α-aminobutyric acid, α-aminopentanoic acid, α-aminohexanoic acid and α-aminoheptanoic acid;
• Z1 and Z2 represent naturally or non-naturally occurring amino acids, which is independently selected from 1, 2, 3, 4 or 5 of glycine (G), alanine (A), lysine (K), arginine (R), serine (S), histidine (H), aspartic acid (D), glutamic acid (E), threonine (T), proline (P), cysteine (C), tyrosine (Y), valine (V), methionine (M), isoleucine (I), leucine (L), phenylalanine (F), tryptophan (W), Glutamine (Q), Asparagin (N), and non-naturally occurring hydroxyproline, α-aminobutyric acid, α-aminopentanoic acid, α-aminohexanoic acid and α-aminoheptanoic acid, and the numbers of Z1 and Z2 are independent of each other;
• n is an integer ranging from 0 to 10, preferably from 0 to 5, for example 0, 1, 2, 3, 4 or 5;
• Mel is the melphalan moiety, and
• linker represents a covalent bond or a linking group formed between melphalan and the adjacent amino acid, such as amide bond, ester bond, ether bond, disulfide bond, hydrazone, urea, oxime, guanidine, amidine, acetal, imine, alkylene or other linking forms;
• for example, linker can be selected from the following forms:
• —O—, —S—, —S—S—, —CH═N—O—, —C1-6 alkylene-, —NH—, —N(R1)—, —CO—NH—, —CO—N(R1)—, —C1-6 alkylene-(CO—NH)—, —C1-6 alkylene-(CO—N(R1))—, —C1-6 alkylene-N(R1)—, —NH—CO—, —N(R1)—CO—, —C1-6 alkylene-NH—CO—, —C1-6 alkylene-N(R1)—CO—, —NH—CO—NH—, —N(R1)—CO—NH, —NH—CO—N(R1)—, —N(R1)—CO—N(R1), —C(═O)O—, —C1-6 alkylene-C(═O)O—, —C(═O)O—C1-6 alkylene-, —S(—O)NH—, —S(═O)N(R1)—, —NH—S(═O)—, —N(R1)S(═O)—, —C1-6 alkylene-S(═O)NH—, —C1-6 alkylene-S(═O)N(R1)—, —C1-6 alkylene-NH—S(═O)—, —C1-6 alkylene-N(R1)S(═O)—, —S(═O)2—NH—, —S(═O)2—N(R1)—, —NH—S(═O)2—, —N(R1)S(═O)2—, —C1-6 alkylene-S(═O)2—NH—, —C1-6 alkylene-S(═O)2—N(R1)—, —C1-6 alkylene-NH—S(═O)2—, —C1-6 alkylene-N(R1)S(═O)2—, or C1-6 alkylene substituted with one or more R1;
• wherein R1 is selected from C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocycloalkyl, each of which is optionally substituted with one or more groups independently selected from halogen, amino, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen-substituted C1-6 alkyl, halogen-substituted C1-6 alkoxy, halogen-substituted C2-6 alkenyl or halogen-substituted C2-6 alkynyl.