Conjugates of cell binding molecules with cytotoxic agents

A conjugate having a structure of Formula (I′):

• or a pharmaceutically acceptable salt or solvate thereof,
• wherein T is a cell-binding ligand, a dendrimer or a liposome;
• 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 is an antibody, or an antibody fragment that binds to a target cell;
• 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 absent, 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, R2, 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;
• 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 H, R14, —R14C(═O)X1R15, or —R14XR15, wherein X1 is O, S, S—S, NH, or NR14, and wherein R14 and R15 are independently C1˜C8 alkyl, heteroalkyl;
• C2˜C8 alkenyl, alkynyl;
• heterocyclic;
• or C3˜C8 aryl, carbocyclic, cycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, alkylcarbonyl;
• wherein R9 is independently H, —OH, —OR14, —OC(═O)R14, —OC(═O)NHR14, —OP(═O)(OR14)2, or —OR14OP(═O)(OR15)2, wherein R14 and R15 are independently C1˜C8 alkyl, heteroalkyl;
• C2˜C8 alkenyl, alkynyl, heterocyclic;
• or C3˜C8 aryl, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl;
• wherein R11 is independently H, —R14, —R14C(═O)R16, —R14X2R16, —R14—, —R14C(═O)R17—, —R14X2R17—, or —R14C(═O)X2—, wherein X2 is —O—, —S—, —NH—, —N(R14)—, —O—R14—, —S—R14—, —S(═O)—R14—, or —NHR14—, and wherein R14 is C1˜C8 alkyl, heteroalkyl;
• C2˜C8 alkenyl, alkynyl, heterocyclic;
• or C3˜C8 aryl, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl;
• R16 is H, OH, R14 or one to four amino acid units;
• R17 is absent, C1˜C8 alkyl, or heteroalkyl;
• C2˜C8 alkenyl, alkynyl, or heterocyclic;
• C3˜C8 arylene, heterocyclic, carbocyclic, heterocycloalkyl;
• or an amino acid, or two amino acid units, provided that when R11 is —R14C(═O)X2— and connects to L, wherein X2 is —O—, R14 is not C1˜C8 alkyl;
• wherein R12 is independently R14, —O—, —S—, —N—, ═N—, ═NNH—, —OH, —SH, —NH2, ═NH, ═NNH2, —NH(R14), —OR14, —N(R14)—, —OR14—, —C(O)O—, —C(O)NHR14—, —SR14—, —S(═O)R14—, —NHR14—, —CH2OP(═O)(OR15)—, —P(═O)(OR15)—, —C(O)OP(═O)(OR15)—, —OP(═O)(OR15)O—, or —SO2R14—, —C(O)OR16—, —COR16, —COOR14—, —C(O)NH—, —C(O)NH2, —C(O)NHR14, —SR14, —S(═O)R14, —P(═O)(OR16)1, —OP(═O)(OR16)2, —CH2OP(═O)(OR16)2, or —SO2R16, wherein R14 and R15 are independently H, C1˜C8 alkyl, heteroalkyl;
• C2˜C8 alkenyl, alkynyl, heterocyclic;
• or C3˜C8 aryl, cycloalkyl, carbocyclic, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, 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, alkylcarbonyl, or C4-C12 glycoside;
• or R12 and R13 form a 3˜7 membered carbocyclic, cycloalkyl, heterocyclic, aromatic or heterocycloalkyl ring system.