Stabilized trioxacarcin antibody drug conjugates and uses thereof

A compound of Formula (IV):

• or a pharmaceutically acceptable salt thereof;
• wherein:
• R1 is hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORA1;
• —C(═O)RA2;
• —CO2RA2;
• —CN;
• —SCN;
• —SRA1;
• —SORA1;
• —SO2RA;
• —NO2;
• —N3;
• ═O;
• ═N(RA2);
• ═S;
• —N(RA2)2;
• —NRA2C(═O)RA2;
• —NRA2C(═O)N(RA2)2;
• —OC(═O)ORA1;
• —OC(═O)RA2;
• —OC(═O)N(RA2)2;
• —NRAC(═O)ORA1;
• or —C(RA2)3;
• wherein each occurrence of RA1 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• or substituted or unsubstituted heteroaryl;
• and wherein each occurrence of RA2 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• substituted hydroxyl;
• substituted thiol;
• amino;
• or substituted amino, or two RA2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
• R2 is hydrogen;
• or R1 and R2 are joined to form ═O;
• ═N(RA2);
• or ═S;
• R3 is hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORC1;
• —C(═O)RC2;
• —CO2RC1;
• —CN;
• —SCN;
• —SRC1;
• —SORC1;
• —SO2RC2;
• —NO2;
• —N3;
• ═O;
• ═N(RC2);
• ═S;
• —N(RC2)2;
• —NHC(═O)RC2;
• —NRC2C(═O)N(RC2)2;
• —OC(═O)ORC1;
• —OC(═O)RC2;
• —OC(═O)N(RC2)2;
• —NRC2C(═O)ORC1;
• or —C(RC2)3;
• wherein each occurrence of RC1 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• or substituted or unsubstituted heteroaryl;
• and wherein each occurrence of RC2 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• substituted hydroxyl;
• substituted thiol;
• amino;
• or substituted amino;
• or two RC2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
• R4 is hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORD1;
• —C(═O)RD2;
• —CO2RD2;
• —CN;
• —SCN;
• —SRD1;
• —SORD1;
• —SO2RD2;
• —NO2;
• —N3;
• —N(RD2)2;
• —NRD2C(═O)RD2;
• —NRD2C(═O)N(RD2)2;
• —OC(═O)ORD1;
• —OC(═O)RD2;
• —OC(═O)N(RD2)2;
• —NRD2C(═O)ORD1;
• or C(RD2)3;
• wherein each occurrence of RD1 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• or substituted or unsubstituted heteroaryl;
• and wherein each occurrence of RD2 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• substituted hydroxyl;
• substituted thiol;
• amino;
• or substituted amino;
• or two RD2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
• R5 is hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORE1;
• —C(═O)RE2;
• —CO2RE1;
• —CN;
• —SCN;
• —SRE1;
• —SORE1;
• —SO2RE2;
• —NO2;
• —N3;
• —N(RE2)2;
• —NRE2C(═O)RE2;
• —NRE2C(═O)N(RE2)2;
• —OC(═O)ORE1;
• —OC(═O)RE2;
• —OC(═O)N(RE2)2;
• —NRE2C(═O)ORE1;
• or —C(RE2)3;
• wherein each occurrence of RE1 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• or substituted or unsubstituted heteroaryl;
• and wherein each occurrence of RE2 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• substituted hydroxyl;
• substituted thiol;
• amino;
• or substituted amino;
• or two RE2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
• R6 is hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORF1;
• —C(═O)RF2;
• —CO2RF1;
• —CN;
• —SCN;
• —SRF1;
• —SORF1;
• —SO2RF2;
• —NO2;
• —N3;
• —N(RF2)2;
• —NRF2C(═O)RF2;
• —NRF2C(═O)N(RF2)2;
• —OC(═O)ORF1;
• —OC(═O)RF2;
• —OC(═O)N(RF2)2;
• —NRF2C(═O)ORF1;
• or —C(RF2)3;
• wherein each occurrence of RF1 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• or substituted or unsubstituted heteroaryl;
• and wherein each occurrence of RF2 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• substituted hydroxyl;
• substituted thiol;
• amino;
• or substituted amino;
• or two RF2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
• R7 is -L-T;
• X is a halogen;
• R8 is hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORI1;
• —C(═O) RI2;
• —CO2R11;
• —CN;
• —SCN;
• —SRI1;
• —SORI1;
• —SO2RI2;
• —NO2;
• —N3;
• —N(RI2)2;
• —NRI2C(═O) RI2;
• —NRI2C(═O) N(RI2)2;
• —OC(═O)ORI1;
• —OC(═O)RI2;
• —OC(═O)N(RI2)2;
• —NRI2C(═O)ORI1;
• or —C(RI2)3;
• wherein each occurrence of RI1 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• or substituted or unsubstituted heteroaryl;
• and wherein each occurrence of RI2 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• substituted hydroxyl;
• substituted thiol;
• amino;
• or substituted amino;
• or two RI2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
• R9 is hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORG1;
• —C(═O)RG2;
• —CO2RG1;
• —CN;
• —SCN;
• —SRG1;
• —SORG1;
• —SO2RG2;
• —NO2;
• —N3;
• —N(RG)2;
• —NRG2C(═O)RG2;
• —NRG2C(═O)N(RG2)2;
• —OC(═O)ORG1;
• —OC(═O)RG2;
• —OC(═O)N(RG2)2;
• —NRG2C(═O)ORG1;
• or —C(RG2)3;
• wherein each occurrence of RG1 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• or substituted or unsubstituted heteroaryl;
• and wherein each occurrence of RG2 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• substituted hydroxyl;
• substituted thiol;
• amino;
• or substituted amino;
• or two RG2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
• R10 is hydrogen;
• halogen;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• —ORB1;
• —C(═O)RB2;
• —CO2RB2;
• —CN;
• —SCN;
• —SRB1;
• —SORB1;
• —SO2RB2;
• —NO2;
• —N3;
• ═O;
• ═N(RB2);
• ═S;
• —N(RB2)2;
• —NRB2C(═O)RB2;
• —NRB2C(═O)N(RB2)2;
• —OC(═O)ORB1;
• —OC(═O)RB2;
• —OC(═O)N(RB2)2;
• —NRB2C(═O)ORB1;
• or —C(RB2)3;
• wherein each occurrence of RB1 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• or substituted or unsubstituted heteroaryl;
• and wherein each occurrence of RB2 is independently hydrogen;
• carbohydrate;
• a protecting group;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic;
• cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic;
• acyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• substituted hydroxyl;
• substituted thiol;
• amino;
• or substituted amino;
• or two RB2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;
• R11 is hydrogen;
• an oxygen protecting group;
• substituted or unsubstituted alkyl;
• substituted or unsubstituted alkenyl;
• substituted or unsubstituted alkynyl;
• substituted or unsubstituted carbocyclyl;
• substituted or unsubstituted heterocyclyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• or —C(═O)RH1;
• wherein RH1 is hydrogen, substituted or unsubstituted alkyl;
• —ORH9;
• —OC(═O)RH9;
• —N(RH9)2;
• or —NHC(═O)RH9;
• wherein each occurrence of RH9 is independently hydrogen;
• substituted or unsubstituted alkyl;
• an oxygen protecting group when attached to an oxygen atom;
• or a nitrogen protecting group when attached to a nitrogen atom;
• or two RH9 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
• or R1 and R10 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety;
• or R10 and R3 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety;
• or R1 and R4 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety;
• or R4 and R9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety;
• or R6 and R9 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety;
• L is a bond, or of the formula:
• R20 is substituted or unsubstituted alkylene;
• or substituted or unsubstituted heteroalkylene;
• X1 is
• heterocyclylene;
• or heteroarylene;
• R21 is independently substituted or unsubstituted alkyl;
• or substituted or unsubstituted carbocyclyl;
• or two R21 groups are joined to form an optionally substituted heterocyclyl ring;
• R22 is hydrogen;
• substituted or unsubstituted alkyl;
• substituted or unsubstituted carbocyclyl;
• or
• Ar is substituted or unsubstituted arylene;
• each occurrence of Z is independently an amino acid;
• each occurrence of Y is independently an amino acid;
• E is a bond or an amino acid;
• m is independently 1, 2, or 3;
• k is 0 or 1;
• Ar1 is a bond or substituted or unsubstituted heteroarylene;
• R40 is substituted or unsubstituted alkylene;
• or substituted or unsubstituted heteroalkylene;
• and combinations thereof;
• T is hydrogen, —N═C═S,
• Q is —S— or —O—;
• RX1 is a leaving group;
• RX2 is hydrogen;
• substituted or unsubstituted alkyl;
• substituted or unsubstituted heterocyclyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• or an oxygen protecting group;
• and
• RW1 is independently hydrogen;
• substituted or unsubstituted alkyl;
• or a nitrogen protecting group.