| CPC C07D 207/40 (2013.01) [A61K 45/06 (2013.01); A61K 47/64 (2017.08); A61K 47/6803 (2017.08); A61K 47/6811 (2017.08); A61K 47/6849 (2017.08); A61K 47/6851 (2017.08); A61K 47/6855 (2017.08); A61K 47/6863 (2017.08); A61K 47/6867 (2017.08); Y02A 50/30 (2018.01)] | 14 Claims |
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1. A conjugate having a structure of Formula (I):
 or a pharmaceutically acceptable salt or solvate thereof,
wherein T is a cell-binding ligand; L is a releasable linker;
 is a linkage bond that L connects to an atom in a moiety inside the bracket independently; n is 1-20 and m is 1-10;wherein the cell-binding ligand T is selected from the group consisting of an antibody, a single chain antibody, an antibody fragment that binds to a target cell, a monoclonal antibody, a single chain monoclonal antibody, a monoclonal antibody fragment that binds to the target cell, a chimeric antibody, a chimeric antibody fragment that binds to the target cell, a domain antibody, a domain antibody fragment that binds to the target cell, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, a nutrient-transport molecule, and a cell-binding peptide, protein, or small molecule attached on albumin, a polymer, a dendrimer, a liposome, a nanoparticle, a vesicle, or a viral capsid;
wherein the releasable linker L has a formula of: —Ww-(Aa)r-Vv—, wherein: —W— is a stretcher unit, which links the moiety inside the bracket to an amino acid unit (Aa) when present, or V when an Aa is not present, and W is independently a self-immolative spacer, a peptidyl unit, a hydrazone, a disulfide, a thioether, an ester, or an amide bond; w is 0 or 1; wherein Aa is independently a natural or unnatural amino acid unit; r is independently an integer ranging from 0 to 12; (Aa)r represents a natural or unnatural amino acid, dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit; wherein V is a spacer unit and is independently H, O, NH, S, C1-C8 alkyl, C2-C8 heteroalkyl, alkenyl, or alkynyl, C3-C8 aryl, heterocyclic, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, or alkylcarbonyl, or one to four amino acid units, or (CH2CH2O)r, r is an integer ranging from 0 to 12; and v is 0, 1 or 2;
wherein R1, R3, and R4 are independently H, C1˜C8 alkyl; C2˜C8 heteroalkyl, or heterocyclic; C3˜C8 aryl, Ar-alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, carbocyclic, or alkylcarbonyl; R2 is independently absent, H, C1˜C8 alkyl; C2˜C8 heteroalkyl, or heterocyclic; or C3˜C8 aryl, Ar-alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, carbocyclic, or alkylcarbonyl; or R1 and R2, R1 and R3, R2 and R3, or R3 and R4 form a 3 ˜7 membered carbocyclic, cycloalkyl, heterocyclic, or heterocycloalkyl ring system;
wherein Y is N or CH;
wherein R5, R6, R8 and R10 are independently H, or C1˜C4 alkyl or heteroalkyl, or R5 and R6 form a 3 ˜7 membered carbocyclic, cycloalkyl, heterocyclic, or heterocycloalkyl ring system;
wherein R7 is independently absent, H, R14, —R14C(═O)X1R15, —R14X1R15, —R14C(═O)X1R15—, or —R14X1R15—; wherein X1 is O, S, S—S, NH, or NR14, and wherein R14 and R15 are independently C1˜C8 alkyl, or heteroalkyl; C2˜C8 alkenyl, alkynyl, or heterocyclic; or C3˜C8 aryl, carbocyclic, cycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, or alkylcarbonyl;
wherein R9 is independently absent, H, —O—, —OH, —OR14, —OR14—, —OC(═O)R14, —OC(═O)R14—, —OC(═O)NHR14, —OC(═O)NHR14—, —OC(═O)R14SSR15—, OP(═O)(OR14)—, OP(═O)(OR14)O—, OP(═O)(OR14)2, or OR14OP(═O)(OR15)2, wherein R14 and R15 are independently C1˜C8 alkyl, or heteroalkyl; C2˜C8 alkenyl, alkynyl, or heterocyclic; or C3˜C8 aryl, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, or alkylcarbonyl;
wherein R11 is independently H, R14, —R14C(═O)R16, —R14X2R16, or —R14C(═O)NHR14, wherein X2 is —O—, —S—, —NH—, —N(R14)—, —O—R14—, —S—R14—, or —S(═O)—R14—, and wherein R14 is C1˜C8 alkyl, or heteroalkyl; C2˜C8 alkenyl, alkynyl, or heterocyclic; or C3˜C8 aryl, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, or alkylcarbonyl; R16 is H, OH, R14 or one to four amino acid units;
wherein R12 is independently R14, —OH, —SH, —NH2, ═NH, ═NNH2, —NH(R14), —OR14, —COR16, —C(O)NH2, —C(O)NHR14, —SR14, —S(═O)R14, —P(═O)(OR16)2, —OP(═O)(OR16)2, —CH2OP(═O)(OR16)2, or —SO2R16, wherein R14 is H, C1˜C8 alkyl, heteroalkyl; C2˜C8 alkenyl, alkynyl, or heterocyclic; or C3˜C8 aryl, cycloalkyl, carbocyclic, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, or alkylcarbonyl; R16 is H, OH, R14 or one to four amino acid units;
wherein R13 is C1˜C10 alkyl, heteroalkyl, alkyl acid, alkyl amide, alkyl amine, or Ar; Ar is an aromatic or hetero aromatic group, composed of one or several rings, and comprising four to ten carbon atoms; the hetero aromatic group is an aromatic group that has one or several carbon atoms replaced by hetero atoms; wherein in the aromatic group, one or several H atoms are optionally replaced independently by R17, F, Cl, Br, I, OR16, SR16, NR16R17, N═NR16, N═R16, NR16R17, NO2, SOR16R17, SO2R16, SO3R16, OSO3R16, PR16R17, POR16R17, PO2R16R17, OP(O)(OR17)2, OCH2OP(O)(OR17)2, OC(O)OP(O)(OR17)2, PO(OR16)(OR17), OP(O)(OR17)OP(O)(OR17)2, OC(O)R17 or OC(O)NHR17, wherein R16 and R17 are independently H, OH, C1˜C8 alkyl, or heteroalkyl; C2˜C8 alkenyl, alkynyl, or heterocyclic; C3˜C8 aryl, cycloalkyl, alkylcycloalkyl, carbocyclic, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, or alkylcarbonyl, or C4˜C12 glycoside;
or R12 and R13 form a 3 ˜7 membered carbocyclic, cycloalkyl, heterocyclic, or heterocycloalkyl ring system.
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