DRUG-CONJUGATES, CONJUGATION METHODS, AND USES THEREOF

1 . A compound having the structure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is a tubulin binding moiety;

B is an functional moiety; and

R 1 -R 8 are each independently selected from the group consisting of H (hydrogen), optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or optionally R 1 and R 2 together with the nitrogen to which they are attached are an optionally substituted 5- to 7-membered ring, or optionally R 1 and R 3 together with the atoms to which they are attached are an optionally substituted 5- to 7-membered ring, or optionally R 7 and Re together with the atoms to which they are attached are an optionally substituted 5- to 7-membered ring, or optionally R 1 is R 1A or R 1B ;

R 1A comprises a targeting moiety;

R 1B is -L 1 (CH 2 ) n R C , -L 1 O(CH 2 ) n R C or —(CH 2 ) n R;

R C is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more R D , or optionally R C comprises a targeting moiety;

each R n is independently selected from the group consisting of —OH, —N 3 , halo, cyano, nitro, —(CH 2 ) n NR E R F , —(CH 2 ) n C(═O)NR E R F , —O(CH 2 ) n NR E R F , —O(CH 2 ) n C(═O)NR E R F , —O(CH 2 ) m OC(═O)NR E R F , —NR G C(═O)R H , —NR G S(O)R H , —O(CH 2 ) m O(CH 2 ) m R J , —O(CH 2 ) n C(═O)R J , —O(CH 2 ) n R J , optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted —O(C 1 -C 8 alkyl);

R E and R F are each independently selected from hydrogen, -[(L 1 ) s (C(R 2A ) 2 )(NR 2A ) s (C(R 2A ) 2 ) r ]-[L 1 (C(R 2A ) 2 )(NR 2A ) s (C(R 2A ) 2 ) r ] s -(L 1 ) s -R J , -[(L 1 (C(R A ) 2 )(NR 2A ) s (C(R 2A ) 2 ) r ]-(L 1 )[(C(R 2A ) 2 ) r O(C(R 2A ) 2 ) r (L 2 ) s ] s -(L 1 ) s -R J , optionally substituted C 1-8 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

each R G is independently hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;

each R H is independently hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or —NR E R F ;

each R is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted —O—(C 1 -C 8 alkyl), optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —(CH 2 ) n OR 2B , —O(CH 2 ) n OR 2B , —(CH 2 ) n NR 2B R 2B , —C(R 2A ) 2 NR 2B R 2B , —(CH 2 ) n C(═O)OR 2B , and —C(═O)NHR 2B ;

each R 2A is independently selected, wherein R 2A is selected from the group consisting of hydrogen, halo, —OH, optionally substituted C 1 -C 3 alkyl, optionally substituted —O—(C 1 -C 8 alkyl), optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, —(CH 2 ) n OR 2B , —(CH 2 ) n NR 2C R 2C , —C(═O)OR 2B , and —C(═O)NR 2C R 2C , or optionally two geminal R 2A and the carbon to which they are attached form an optionally substituted three- to six-membered carbocyclic ring;

each R 2B is independently selected from the group consisting of hydrogen, OH, —(CH 2 ) n C(═O)OH, —C(═O)(C(R 2D ) 2 ) n L 3 R 2E , optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted —O—(C 1 -C 8 alkyl), optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

each R 2c is independently selected from the group consisting of hydrogen, —OH, optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted —O—(C 1 -C 8 alkyl), optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, or optionally both R 2c together with the nitrogen to which they are attached are an optionally substituted heterocyclyl;

each R 2D is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 cycloalkyl, optionally substituted —O—(C 1 -C 8 alkyl), optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

each R 2E is independently selected from the group consisting of optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, and —(CH 2 ) n C(═O)OR 2F ;

each R 2F 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 L 1 is independently selected from the group consisting of —C(═O)—, —S(═O)—, —C(═S)—, —S(═O) 2 —, —C(═O)O—, —C(═O)NR 2A —, —S(═O)NR 2A —, —S(═O) 2 NR 2A —, —C(═O)NR 2A C(═O)—, and —C(CF 3 ) 2 NR 2A —;

each L 2 is independently selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;

each L 3 is independently selected from the group consisting of —C(═O)—, —S(═O)—, —C(═S)—, —S(═O) 2 —, —C(═O)O—, —C(═O)NR 2 —, —S(═O)NR 2A —, —S(═O) 2 NR 2A —, —C(═O)NR 2A C(═O)—, and —C(CF 3 ) 2 NR 2A —;

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;

each z independently is 1 or 2;

R 7 is selected from the group consisting of H (hydrogen), optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, and optionally substituted heterocyclyl;

R 8 is selected from the group consisting of H (hydrogen), —(CH 2 ) n R C , optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, and optionally substituted heterocyclyl; and

R is selected from the group consisting of H (hydrogen), optionally substituted C 1 -C 8 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

2 - 60 . (canceled)