Conjugates of Cell Binding Molecules with Cytotoxic Agents

A conjugate of a cell binding molecule with cytotoxic agents having a structure of Formula (I):

• and pharmaceutical acceptable salts and solvates thereof,
• Wherein T is a targeting or binding ligand;
• L is a releasable linker;
• ----- is a linkage bond that L connects to an atom inside the bracket independently;
• n is 1˜20 and m is 1˜10.
• Inside the bracket is a potent antimitotic agent wherein R1, R2, R3, and R4 are independently C1˜C8 of alkyl, heteroalkyl;
• C2˜C8 of heterocyclic, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl;
• C3˜C8 of aryl, Ar-alkyl, heteroalkylcycloalkyl, alkylcarbonyl;
• or two R's, such as R1R2, R1R3, R2 R3, R3 R4, R5 R6, and R12 R13 can be 3˜7 members of a carbocyclic, cycloalkyl, or heterocyclic, heterocycloalkyl ring system;
• Y is N or CH;
• In addition, R1, R3, and R4 can be H, and R2 can be absent.
• Wherein R5, R6, R8 and R10 are independently selected from H and C1˜C4 of alkyl or heteroalkyl.
• Wherein R7 is independently selected from H, R14, or —R14C(═O)X1R15;
• —R14X1R15, wherein R14 and R15 are independently selected from C1˜C8 of alkyl, heteroalkyl;
• C2˜C8 of alkenyl, alkynyl, heterocyclic, carbocyclic, cycloalkyl;
• C3˜C8 of aryl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl;
• X1 is selected from O, S, S—S, NH, or NR14.
• Wherein R9 is independently H, —O—, —OR14, —OC(═O)R14—, —OC(═O)NHR14—, —OC(═O) R14SSR15—, OP(═O)(OR14)—, or OR14OP(═O)(OR15), wherein R14 and R15 are independently C1˜C8 of alkyl, heteroalkyl;
• C2˜C8 of alkenyl, alkynyl, heterocyclic, carbocyclic;
• C3˜C8 of aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl.
• Wherein R11 is independently H, R14, —R14C(═O)R16, —R14X2R16, —R14C(═O)X2, wherein X2 is —O—, —S—, —NH—, —N(R14)—, —O—R14—, —S—R14—, —S(═O)—R14—, or —NHR14—;
• R14 is C1˜C8 of alkyl, heteroalkyl;
• C2˜C8 of alkenyl, alkynyl, heterocyclic, carbocyclic;
• C3˜C8 of aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl;
• R16 is H, OH, R14, or one to four amino acid units;
• Wherein R12 is independently R14, —O—, —S—, —N—, ═N—, ═NNH—, —OH, —SH, —NH2, ═NH, ═NNH2, —NH(R14), —OR14, —C(O)O—, —C(O)OR16—, —COR16, —COOR14—, C(O)NH—, C(O)NH2, C(O)NHR14, —SR14, —S(═O)R14, —P(═O)(OR16)2, —OP(═O)(OR16)2, —CH2OP(═O)(OR16)2, —SO2R16. R14 is independently C1˜C8 of alkyl, heteroalkyl;
• C2˜C8 of alkenyl, alkynyl, hetero-cyclic, carbocyclic;
• C3˜C8 of aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, alkylcarbonyl. R16 is H, OH, R14 or one to four amino acid units;
• Wherein R13 is C1˜C10 of alkyl, heteroalkyl, alkyl acid, alkyl amide, alkyl amine, or Ar;
• Ar refers to an aromatic or hetero aromatic group, composed of one or several rings, comprising four to ten carbon atoms, preferentially four to six carbon atoms. The term of hetero aromatic group refers to an aromatic group that has one or several carbon atoms replaced by hetero atoms, preferentially one, two or three carbon atoms replaced by O, N, Si, Se, P or S, more preferentially O, S, N. The term aryl or Ar also refers to an aromatic group, wherein one or several H atoms can be replaced independently by R17, F, Cl, Br, I, OR16, SR16, NR16R17, N═NR16, N═R16, NR16 R17, NO2, SOR16R17, SO2 R16, SO3 R16, OSO3 R16, PR16R17, POR16R17, PO2R16R17, P(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, R17 are independently H, C1˜C8 of alkyl, heteroalkyl;
• C2˜C8 of alkenyl, alkynyl, heterocyclic, carbocyclic;
• C3˜C8 of aryl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, heteroaralkyl, alkylcarbonyl or C4˜C12 of glycosides, or pharmaceutical salts.
• In addition, R12 can be H when R10 is not H, or 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 glycosides, or C1˜C8 of alkyl, carboxyalkyl, heterocyclic;
• R18 is H, C1˜C8 of alkyl, carboxyalkyl, heteroalkyl;
• C2˜C8 of alkenyl, alkynyl, heterocyclic;
• C3˜C8 of aryl, alkylcarbonyl;
• R19 is H, OH, NH2, OSO2(OR18), XCH2OP(O)(OR18)2, XPO(OR18)2, XC(O)OP(O)(OR18)2, XC(O) R18, XC(O)NHR18, C1˜C8 of alkyl, carboxyalkyl, carboxylic acid derivative;
• C2˜C8 of alkenyl, alkynyl, heterocyclic;
• C3˜C8 of aryl, alkylcarbonyl;
• or pharmaceutical salts;
• X is O, S, NH;
• Y1 and Y2 are N or CH respectively.
• Or R12 can be H when R11 is:
• wherein X2 is O, S, N—R8;
• R6 and R8 are H, C1˜C6 of alkyl or heteroalkyl.
• Wherein the said conjugate of the invention specifically excludes the following structures:
• Wherein R24 is H or CH3;
• R25 is alkyl or C(O)alkyl or C(O)aryl;
• R26 is H, C1˜C5 alkyl, C2˜C5 alkenyl, C(═O)C1˜C5 alkyl, or C(═O)C2˜C5 alkenyl;
• R28 is H or C1˜C5 alkyl;
• R27 is H, 1 to 3 substituents selected from halo, nitro, carboxylate or a derivative thereof, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, phenol protecting groups, prodrug moieties, or OR29, where R29 is substituted aryl, C(O)R30, P(O)(OR30)2, or SO3R30, where R30 is selected from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl or a metal cation;
• T is a targeting or binding ligand;
• L is a releasable linker.