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;
• 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, an adnectin that mimics antibody, DARPins, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, a nutrient-transport molecule, and a binding peptide, protein, 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, 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 absent, H, R14, —R14C(═O)X1R15, —R14X1R15, —R14C(═O)X1R15—, or —R14X1R15—;
• X1 is O, S, S—S, NH, or NR14;
• wherein R9 is independently absent, H, —O—, —OH, —OR14, —OR14—, —OC(═O)R14—, —OC(═O)NHR14—, —OC(═O) R14SSR15—, OP(═O)(OR14)—, OP(═O)(OR14)O—, OP(═O)(OR14)2, or OR14OP(═O)(OR15)2;
• wherein R11 is independently H, R14, —R14C(═O)R16, —R14X2R16, —R14C(═O)NHR14, wherein X2 is —O—, —S—, —NH—, —N(R14)—, —O—R14—, —S—R14—, or —S(═O)—R14—;
• 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 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;
• Ar is an aromatic group, wherein 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, SO2 R16, 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 R14 and R15 are independently H, C1˜C8 alkyl, or heteroalkyl;
• C2˜C8 alkenyl, alkynyl, or heterocyclic;
• C3˜C8 aryl, heterocycloalkyl, heteroalkylcycloalkyl, carbocyclic, cycloalkyl, heteroaralkyl, or alkylcarbonyl, or one to four amino acid units;
• 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 a pharmaceutical salt;
• or R12 and R13 form a 3˜7 membered carbocyclic, cycloalkyl, heterocyclic, or heterocycloalkyl ring system;
• provided that:
• (i) R12 is H when R10 is not H,
• or (ii) R12 is H when R13 is:
• wherein Z1 is H, CH2OP(O)(OR18)2, C(O)OP(O)(OR18)2, PO(OR18)2, P(O)(OR18)OP(O)(OR18)2, C(O)R18, C(O)NHR18, SO2(OR18), C4-C12 glycoside, C1-C8 alkyl, or C3-C8 carboxyalkyl, or heterocyclic;
• wherein R18 is H, C1˜C8 alkyl, or heteroalkyl;
• C2˜C8 carboxyalkyl, alkenyl, alkynyl, or heterocyclic;
• C3˜C8 aryl, or alkylcarbonyl;
• wherein R19 is H, OH, NH2, OSO2(OR18), XCH2OP(O)OR18)2, XPO(OR18), XC(O)OP(O)(OR18)2, XC(O)R18, XC(O)NHR18, C1˜C8 alkyl, carboxylic acid derivative;
• C2˜C8 alkenyl, alkynyl, heterocyclic, or carboxyalkyl;
• C3˜C8 aryl, or alkylcarbonyl;
• or a pharmaceutical salt;
• X is O, S, or NH;
• Y1 and Y2 are N or CH independently;
• or (iii) R12 is H when R11 is:
• wherein X2 is O, S, or N—R8;
• R8 is H, C1˜C6 alkyl or heteroalkyl;
• R8, is R8,