C-16 modified trioxacarcins, antibody drug conjugates, and uses thereof

A compound of Formula (II):

• or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug 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;
• —SO2RA1;
• —NO2;
• —N3;
• —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;
• or two RA1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring;
• 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;
• or substituted or unsubstituted heteroaryl;
• —ORA1;
• —SRA1;
• or —N(RA1)2;
• or two RA2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring;
• with the proviso that if R1 is —ORA1, RA1 is not 4-methoxybenzyl or carbohydrate.
• 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;
• —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;
• or two RC1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring;
• 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;
• or substituted or unsubstituted heteroaryl;
• —ORC1;
• —SRC1;
• or —N(RC1)2;
• or two RC2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted 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;
• or two RD1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring;
• 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;
• or substituted or unsubstituted heteroaryl;
• —ORD1;
• —SRD1;
• or —N(RD1)2;
• or two RD2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted 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;
• or two RE1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring;
• 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;
• or substituted or unsubstituted heteroaryl;
• —ORE1;
• —SRE1;
• or —N(RE1)2;
• or two RE2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted 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;
• or two RF1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring;
• 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;
• or substituted or unsubstituted heteroaryl;
• —ORF1;
• —SRF1;
• or —N(RF1)2;
• or two RF2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring;
• R7 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;
• or two RG1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring;
• 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;
• or substituted or unsubstituted heteroaryl;
• —ORG1;
• —SRG1;
• or —N(RG1)2;
• or two RG2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring;
• R8 is hydrogen;
• an oxygen protecting group;
• a carbohydrate;
• 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;
• substituted or unsubstituted heteroaliphatic;
• acyl;
• —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;
• R9 is hydrogen or —C(RI1)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;
• —ORI2;
• —SRI2;
• —N(RI2)2;
• azido;
• or halogen;
• with the proviso that not more than one occurrence of RI1 is —ORI2;
• wherein each occurrence of RI2 is independently hydrogen;
• carbohydrate;
• 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 or unsubstituted heteroarylalkyl;
• substituted or unsubstituted phosphono;
• -L-A-B;
• or -L-T;
• or two RI2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted 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;
• —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;
• or two RB1 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring;
• 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;
• or substituted or unsubstituted heteroaryl;
• —ORB1;
• —SRB1;
• or —N(RB1)2;
• or two RB2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring;
• RI1 is hydrogen;
• substituted or unsubstituted aliphatic;
• acyl;
• -L-A-B;
• or -L-T;
• X is a halogen;
• 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 R7 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety;
• or R6 and R7 are optionally taken together with the intervening carbon atoms to form an optionally substituted cyclic moiety;
• L is a linker;
• A is a bond or a group of formula:
• Q is —S— or —O—;
• RW1 is independently hydrogen, substituted or unsubstituted alkyl;
• or a nitrogen protecting group;
• B is a targeting moiety;
• and
• T is hydrogen, —N═C═S,
• RX1 is a leaving group;
• and
• RX2 is hydrogen;
• substituted or unsubstituted alkyl;
• substituted or unsubstituted heterocyclyl;
• substituted or unsubstituted aryl;
• substituted or unsubstituted heteroaryl;
• or an oxygen protecting group.

A method of preparing a compound of Formula (C):

• or salt thereof, the method comprising deprotecting and oxidizing a compound of formula (D):
• or salt thereof, wherein:
• PG is a protecting group;
• and
• R9 is hydrogen or —C(RI1)3;
• wherein each occurrence of RI1 is independently hydrogen;
• carbohydrate;
• 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;
• —ORI2;
• —SRI2;
• azido;
• halogen;
• or —N(RI2)2;
• with the proviso that not more than one occurrence of RI1 is —ORI2;
• wherein each occurrence of RI2 is independently hydrogen;
• carbohydrate;
• 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 or unsubstituted heteroarylalkyl;
• C(═O)RI1;
• -L-A-B;
• or -L-T;
• or two RI2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring.

A compound of Formula:

• or a salt thereof;
• wherein:
• R9 is hydrogen or —C(RI1)3;
• wherein each occurrence of RI1 is independently hydrogen;
• carbohydrate;
• 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;
• —ORI2;
• —SRI2;
• azido;
• halogen;
• or —N(RI2)2;
• with the proviso that not more than one occurrence of RI1 is —ORI2;
• wherein each occurrence of RI2 is independently hydrogen;
• carbohydrate;
• 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 or unsubstituted heteroarylalkyl;
• C(═O)RI1;
• -L-A-B;
• or -L-T;
• or two RI2 groups are optionally joined to form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl ring.