Drug-conjugates, conjugation methods, and uses thereof

A compound having the structure of Formula II:

• or a pharmaceutically acceptable salt thereof, wherein:
• Y is CH2;
• R9 is selected from the group consisting of H (hydrogen), optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• optionally R1 and R2, R1 and R3, R7 and R8, R8 and R9, or R7 and R9 together with the atoms to which they are attached form an optionally substituted cyclic 5- to 7-membered ring;
• X is selected from the group consisting of —OR10 and —SO2—R10;
• R10 is RC;
• R1 is H (hydrogen), optionally substituted C1-C6 alkyl, R1A, or R1B;
• R1A is a monoclonal antibody or an antibody fragment;
• R1B is -L1(CH2)nRC, -L1O(CH2)nRCor —(CH2)nRC;
• R2-R7 are each independently selected from the group consisting of H (hydrogen), optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R8 is selected from the group consisting of H (hydrogen), —(CH2)nRC, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally, substituted aryl, and optionally substituted heterocyclyl;
• RC is C1-C8 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl, and heterocyclyl, each optionally substituted with one or more RD, or RC is a monoclonal antibody or an antibody fragment;
• each RD is independently selected from the group consisting of —OH, —N3, halo, cyano, nitro, —(CH2)nNRERF, —(CH2)nC(═O)NRERF, —O(CH2)nNRERF, —O(CH2)nC(═O)NRERF, —O(CH2)mOC(═O)NRERF, —NRGC(═O)RH, —NRGS(O)zRH, —O(CH2)mO(CH2)mRJ, —O(CH2)nC(═O)RJ, —O(CH2)nRJ, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted —O—(C1-C8 alkyl);
• RE and RF are each independently selected from hydrogen, -[(L1)s(C(R2A)2)r(NR2A)s(C(R2A)2)r]-[L1(C(R2A)2)r(NR2A)s(C(R2A)2)r]s- (L1)s-RJ, -[(L1)s(C(R2A)2)r(NR2A)s(C(R2A)2)r]-(L1)s[(C(R2A)2)rO(C(R2A)2)r(L2)s]s-(L1)s-RJ, optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
• each RG is independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
• each RH is independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or —NRERF;
• each RJ is independently selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted —O—(C1-C8 alkyl), optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —(CH2)nOR2B, —O(CH2)nOR2B, —(CH2)nNR2BR2B, —C(R2A)2NR2BR2B, —(CH2)nC(═O)OR2B, and —C(═O)NHR2B;
• each R2A is independently selected, wherein R2A is selected from the group consisting of hydrogen, halo, —OH, optionally substituted C1-C8 alkyl, optionally substituted —O—(C1-C8 alkyl), optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —(CH2)nOR2B, —(CH2)nNR2CR2C, —C(═O)OR2B, and —C(═O)NR2CR2C, or optionally two geminal R2A and the carbon to which they are attached form an optionally substituted three- to six-membered carbocyclic ring;
• each R2B is independently selected from the group consisting of hydrogen, —OH, —(CH2)nC(═O)OH, —C(═O)(C(R2D)2)nL3R2E, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted —O—(C1-C8 alkyl), optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
• each R2C is independently selected from the group consisting of hydrogen, —OH, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted —O—(C1-C8 alkyl), optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, or optionally both R2C together with the nitrogen to which they are attached form a optionally substituted heterocyclyl;
• each R2D is independently selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted —O—(C1-C8 alkyl), optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
• each R2E is independently selected from the group consisting of optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, and —(CH2)nC(═O)OR2F;
• each R2F is independently selected from the group consisting hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
• each L1 is independently selected from the group consisting of —C(═O)—, —S(═O)—, —C(═S)—, —S(═O)2—, —C(═O)O—, —C(═O)NR2A—, —S(═O)NR2A—, —S(═O)2NR2A—, —C(═O)NR2AC(═O)—, and —C(CF3)2NR2A—;
• each L2 is independently selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
• each L3 is independently selected from the group consisting of —C(═O)—, —S(═O)—, —C(═S)—, —S(═O)2—, —C(═O)O—, —C(═O)NR2A—, —S(═O)NR2A—, —S(═O)2NR2A—, —C(═O)NR2AC(═O)—, and —C(CF3)2NR2A—;
• each m independently is 1 or 2;
• each n independently is 0, 1, 2, 3, 4, 5, or 6;
• each r independently is 0, 1, 2, 3, 4, 5, or 6;
• each s independently is 0 or 1;
• and
• each z independently is 1 or 2.