Drug-conjugates, conjugation methods, and uses thereof

Abstract

In certain aspects, compounds and uses thereof are provided. In certain aspects, compound-conjugates and uses thereof are provided.

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)