TRIOXACARCINS, TRIOXACARCIN-ANTIBODY CONJUGATES, AND USES THEREOF

摘要

Provided herein are trioxacarcin-antibody drug conjugates of Formula (A): and pharmaceutically acceptable salts thereof, comprising at least one instance of the group -L1-(A-L2)a-B attached thereto, wherein a is an integer between 1 and 10, inclusive, L1 is absent or is a linking group, A is a moiety formed from the reaction of two complimentary groups (X and Y), L2 is absent or is another linking group, and B is an antibody or antibody fragment. Also provided are methods of preparing these antibody-drug conjugates, pharmaceutically acceptable compositions thereof, and methods of their use and treatment. Further provided are precursors to the trioxacarcin-antibody drug conjugates, novel trioxacarcins without an antibody conjugated thereto, pharmaceutical compositions thereof, and methods of their use and treatment.;

主权项

1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; comprising at least one instance of the group -L1-(A-L2)a-B attached thereto; wherein:
a is an integer between 1 and 10, inclusive;L1 is absent or is a linking group selected from the group consisting of substituted or unsubstituted alkylene; substituted or unsubstituted alkenylene; substituted or unsubstituted alkynylene; substituted or unsubstituted heteroalkylene; substituted or unsubstituted heteroalkenylene; substituted or unsubstituted heteroalkynylene; substituted or unsubstituted heterocyclylene; substituted or unsubstituted carbocyclylene; substituted or unsubstituted arylene; substituted or unsubstituted heteroarylene; peptidyl groups; dipeptidyl groups; and polypeptidyl groups; and combinations thereof;L2 is absent or is a linking group selected from the group consisting of substituted or unsubstituted alkylene; substituted or unsubstituted alkenylene; substituted or unsubstituted alkynylene; substituted or unsubstituted heteroalkylene; substituted or unsubstituted heteroalkenylene; substituted or unsubstituted heteroalkynylene; substituted or unsubstituted heterocyclylene; substituted or unsubstituted carbocyclylene; substituted or unsubstituted arylene; substituted or unsubstituted heteroarylene; peptidyl groups; dipeptidyl groups; and polypeptidyl groups; and combinations thereof;A is a group of the formula —NH—, —NH—NH—, —NH—O—, —O—NH—, —S—, —O—, Q is —NH—, —NH—NH—, —O—NH—, —NH—O—, —S—, or —O—;W is —O—, —S—, or —NRW1—, wherein RW1 is hydrogen, 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 a nitrogen protecting group;RW2 is hydrogen, 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 two RW2 groups are joined to form a 5-6 membered ring;B is an antibody or antibody fragment;R1 is hydrogen; halogen; 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; —ORA1; —C(═O)RA2; —CO2RA2; —CN; —SCN; —SRA1; —SORA1; —SO2RA2; —NO2; —N3; —N(RA2)2; —NRA2C(═O)RA2; —NRA2C(═O)N(RA2)2; —OC(═O)ORA1; —OC(═O)RA2; —OC(═O)N(RA2)2; —NRA2C(═O)ORA1; —C(RA2)3; or a group -L1-(A-L2)a-B; and R2 is hydrogen; or R1 and R2 are joined to form ═O; ═N(RA2); or ═S;each occurrence of RA1 is independently hydrogen; an oxygen protecting group if attached to oxygen; a sulfur protecting group if attached to sulfur; 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; acyl; or a group -L1-(A-L2)a-B;each occurrence of RA2 is independently hydrogen; a nitrogen protecting group if attached to nitrogen; 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; acyl; hydroxyl; substituted hydroxyl; thiol; substituted thiol; amino; or substituted amino; or a group -L1-(A-L2)a-B; or two RA2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;or RA1 or RA2 represent a group of Formula (i): each occurrence of RA3, RA4, RA5, RA6, and RA7 is independently hydrogen, substituted or unsubstituted alkyl; —ORA9; —OC(═O)RA9; —N(RA9)2; —NHC(═O)RA9; or a group -L1-(A-L2)a-B; wherein each occurrence of RA9 is independently hydrogen; substituted or unsubstituted alkyl; an oxygen protecting group when attached to an oxygen atom; a nitrogen protecting group when attached to a nitrogen atom; or a group -L1-(A-L2)a-B; or two RA9 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;M1 is —O—, —NRA8—, or —CHRA8—, wherein RA8 is hydrogen; substituted or unsubstituted alkyl; a nitrogen protecting group if attached to nitrogen; —ORA9; or a group -L1-(A-L2)a-B; wherein RA9 is independently hydrogen; substituted or unsubstituted alkyl; acyl; an oxygen protecting group; or a group -L1-(A-L2)a-B;R3 is hydrogen or —ORC1, wherein RC1 is hydrogen; an oxygen protecting group; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; acyl; or a group -L1-(A-L2)a-B;R4 is hydrogen or —ORD1, wherein RD1 is hydrogen; an oxygen protecting group; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; acyl; or a group -L1-(A-L2)a-B;R5 is hydrogen or —ORE1, wherein RE1 is hydrogen; an oxygen protecting group; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; acyl; or a group -L1-(A-L2)a-B;R6 is hydrogen; halogen; 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; —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; —C(RF2)3, or a group -L1-(A-L2)a-B;each occurrence of RF1 is independently hydrogen; an oxygen protecting group if attached to oxygen; a sulfur protecting group if attached to sulfur; 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; acyl; or a group -L1-(A-L2)a-B;each occurrence of RF2 is independently hydrogen; a nitrogen protecting group if attached to nitrogen; 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; acyl; hydroxyl; substituted hydroxyl; thiol; substituted thiol; amino; substituted amino, or a group -L1-(A-L2)a-B; or two RF2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;R7 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; —C(═O)RH1; a group -L1-(A-L2)a-B; or a group of Formula (ii): wherein:
each occurrence of RH1, RH3, and RH5 is independently hydrogen, substituted or unsubstituted alkyl; —ORH9; —OC(═O)RH9; —N(RH9)2; —NHC(═O)RH9; a group -L1-(A-L2)a-B; wherein each occurrence of RH9 is independently hydrogen; substituted or unsubstituted alkyl; an oxygen protecting group when attached to an oxygen atom; a nitrogen protecting group when attached to a nitrogen atom; or a group -L1-(A-L2)a-B; or two RH9 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;each instance of RH2 and RH4 is independently, hydrogen; —ORH7; —N(RH7)2; —OC(═O)RH7; —NHC(═O)RH8; —C(═O)RH7; —C(═NRH7)RH8; —C(═N—ORH7)RH8; —C(═N—NHRH7)RH8; C(RH8)2NHRH7; —C(RH8)2ORH7; or a group -L1-(A-L2)a-B; wherein RH7 is independently hydrogen; substituted or unsubstituted alkyl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; a group -L1-(A-L2)a-B; and RH8 is hydrogen or substituted or unsubstituted alkyl; or RH7 and RH8 or two RH7 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;R8 is hydrogen; halogen; 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; —ORI1; —C(═O)RI2; —CO2RI1; —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; —CH2(ORI1), —CH(ORI1)2, —CH2OC(═O)RI2, or a group -L1-(A-L2)a-B;each occurrence of RI1 is independently hydrogen; an oxygen protecting group if attached to oxygen; a sulfur protecting group if attached to sulfur; 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; acyl; a group of Formula (iii) or (iv), or a group -L1-(A-L2)a-B; andeach occurrence of RI2 is independently hydrogen; a nitrogen protecting group if attached to nitrogen; 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; acyl; hydroxyl; substituted hydroxyl; thiol; substituted thiol; amino; substituted amino, a group of Formula (iii) or (iv); or a group -L1-(A-L2)a-B; or two RI2 groups are optionally joined to form a heterocyclyl or heteroaryl ring;wherein Formula (iii) and (iv) is: wherein:
each occurrence of RI3, RI5, RI6, RI7, RI8, RI10, RI11, and RI12, is independently hydrogen, substituted or unsubstituted alkyl; —ORI13; —OC(═O)RI13; —N(RI13)2; —NHC(═O)RI13; or a group -L1-(A-L2)a-B; wherein each occurrence of RI13 is independently hydrogen; substituted or unsubstituted alkyl; an oxygen protecting group when attached to an oxygen atom; a nitrogen protecting group when attached to a nitrogen atom; or a group -L1-(A-L2)a-B; or two RI13 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;each occurrence of RI4 and RI9 is independently, hydrogen; substituted or unsubstituted alkyl; —ORI14; —N(RI14)2; —OC(═O)RI14; —NHC(═O)RI15; —OC(═O)RI14; —C(═O)RI14; —C(═NRI14)RI15; —C(═N—ORI14)RI15; —C(═N—NHRI14)RI15; —C(RI15)2NHRI14; —C(RI15)2ORI14; or a group -L1-A-L2-B; wherein RI14 is independently hydrogen; substituted or unsubstituted alkyl; an oxygen protecting group if attached to an oxygen atom; a nitrogen protecting group if attached to a nitrogen atom; a group -L1-(A-L2)a-B; and RI15 is hydrogen, or substituted or unsubstituted alkyl; andeach occurrence of M4 and M5 is independently —O—, —NR16—, or —CHRI16—, wherein RI16 is hydrogen; substituted or unsubstituted alkyl; a nitrogen protecting group if attached to nitrogen; —ORI13; or a group -L1-(A-L2)a-B; wherein each occurrence of RI13 is independently hydrogen; an oxygen protecting group; substituted or unsubstituted alkyl; acyl; or a group -L1-(A-L2)a-B.