US2020289659A1PendingUtilityA1

Conjugates for treating diseases

Assignee: ENDOCYTE INCPriority: Mar 13, 2015Filed: Mar 20, 2020Published: Sep 17, 2020

Est. expiryMar 13, 2035(~8.6 yrs left)· nominal 20-yr term from priority

Inventors:Iontcho Radoslavov Vlahov Christopher Paul Leamon Longwu Qi Yingcai Wang Kevin Yu Wang Ning Zou Albert E. Felten

A61K 47/65A61P 35/00A61P 43/00A61P 35/02A61K 47/551

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References

Claims

Abstract

The present disclosure relates to pyrrolobenzodiazepine (PBD) prodrugs and conjugates thereof. The present disclosure also relates to pharmaceutical compositions of the conjugates described herein, methods of making and methods of using the same.

Claims

exact text as granted — not AI-modified

1 .- 50 . (canceled) 
     
     
         51 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 2c , R 3c , R 4c , R 5c  are H; and
 L 5  is selected from the group consisting of C 1 -C 10  alkyl, —(CR 49 ═CR 49′ ) u —, —(CR 49 R 49′ ) u C(O)—, —CH 2 CH 2 (OCR 49 R 49′ CR 49 R 49′ ) u —, —CH 2 CH 2 CH 2 (OCR 49 R 49′ CR 49 R 49′ CR 49 R 49′ ) u —, —CH 2 CH 2 (OCR 49 R 49′ CR 49 R 49′ ) u C(O)— and —CH 2 CH 2 (OCR 49 R 49′ CR 49 R 49′ CR 49 R 49′ ) u C(O)—, wherein 
 each R 49  and R 49′  is independently selected from the group consisting of H, D, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl and C 3 -C 6  cycloalkyl, wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl and C 3 -C 6  cycloalkyl is independently optionally substituted by halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, 5- to 7-membered heteroaryl, —OR 50 , —OC(O)R 50 , —OC(O)NR 50 R 50′ , —OS(O)R 50 , —OS(O) 2 R 50 , —SR 50 , —S(O)R 50 , —S(O) 2 R 50 , —S(O)NR 50 R 50′ , —S(O) 2 NR 50 R 50′ , —OS(O)NR 50 R 50′ , —OS(O) 2 NR 50 R 50′ , —NR 50 R 50′ , —NR 50 C(O)R 51 , —NR 50 C(O)OR 51 , —NR 50 C(O)NR 51 R 51′ , —NR 50 S(O)R 51 , —NR 50 S(O) 2 R 51 , —NR 50 S(O)NR 51 R 51′ , —NR 50 S(O) 2 NR 51 R 51′ , —C(O)R 50 , —C(O)OR 50  or —C(O)NR 50 R 50′ ; 
 R 50 , R 50′ , R 51  and R 51′  are each independently selected from the group consisting of H, D, C 1 -C 7  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl and 5- to 7-membered heteroaryl; 
 u is in each instance 0, 1, 2, 3, 4 or 5, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         52 . The compound of  claim 51 , or a pharmaceutically acceptable salt thereof, wherein L 5  is C 1 -C 10  alkyl or —(CR 49 R 49′ ) u C(O)—, each R 49  and R 49′  is H, and u is 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. 
     
     
         53 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein, R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a  and R 10a  are H; and
 L 5  is selected from the group consisting of C 1 -C 10  alkyl, —(CR 49 ═CR 49′ ) u —, —(CR 49 R 49′ ) u C(O)—, —CH 2 CH 2 (OCR 49 R 49′ CR 49 R 49′ ) u —, —CH 2 CH 2 CH 2 (OCR 49 R 49′ CR 49 R 49′ CR 49 R 49′ ) u —, —CH 2 CH 2 (OCR 49 R 49′ CR 49 R 49′ ) u C(O)— and —CH 2 CH 2 (OCR 49 R 49′ CR 49 R 49′ CR 49′ ) u C(O)—, wherein 
 each R 49  and R 49′  is independently selected from the group consisting of H, D, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl and C 3 -C 6  cycloalkyl, wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl and C 3 -C 6  cycloalkyl is independently optionally substituted by halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl, 5- to 7-membered heteroaryl, —OR 50 , —OC(O)R 50 , —OC(O)NR 50 R 50′ , —OS(O)R 50 , —OS(O) 2 R 50 , —SR 50 , —S(O)R 50 , —S(O) 2 R 50 , —S(O)NR 50 R 50′ , —S(O) 2 NR 50 R 50′ , —OS(O)NR 50 R 50′ , —OS(O) 2 NR 50 R 50′ , —NR 50 R 50′ , —NR 50 C(O)R 51 , —NR 50 C(O)OR 51 , —NR 50 C(O)NR 51 R 51′ , —NR 50 S(O)R 51 , —NR 50 S(O) 2 R 51 , —NR 50 S(O)NR 51 R 51′ , —NR 50 S(O) 2 NR 51 R 51′ , —C(O)R 50 , —C(O)OR 50  or —C(O)NR 50 R 50′ ; 
 R 50 , R 50′ , R 51  and R 51′  are each independently selected from the group consisting of H, D, C 1 -C 7  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 6  cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10  aryl and 5- to 7-membered heteroaryl; 
 u is in each instance 0, 1, 2, 3, 4 or 5, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         54 . The compound of  claim 53 , wherein, L 5  is C 1 -C 10  alkyl or —(CR 49 R 49′ ) u C(O)—, wherein each R 49  and R 49′  is H, and u is 1, 2, 3, 4 or 5; or a pharmaceutically acceptable salt thereof. 
     
     
         55 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein, R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a  and R 1e  are H; or a pharmaceutically acceptable salt thereof. 
     
     
         56 . The compound of  claim 55 , or a pharmaceutically acceptable salt thereof, wherein L 5  is C 1 -C 10  alkyl or —(CR 49 R 49′ ) u C(O)—, each R 49  and R 49′  is H, and u is 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. 
     
     
         57 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a , R 10a , R 1d  are H; or a pharmaceutically acceptable salt thereof. 
     
     
         58 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein L 5  is C 1 -C 10  alkyl or —(CR 49 R 49′ ) u C(O)—, each R 49  and R 49′  is H, and u is 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. 
     
     
         59 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a  and R 10a  are H; or a pharmaceutically acceptable salt thereof. 
     
     
         60 . The compound of  claim 59 , or a pharmaceutically acceptable salt thereof, wherein L 5  is C 1 -C 10  alkyl or —(CR 49 R 49′ ) u C(O)—, each R 49  and R 49′  is H, and u is 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. 
     
     
         61 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8a , R 9a  and R 10a  are H; or a pharmaceutically acceptable salt thereof. 
     
     
         62 . The compound of  claim 61 , or a pharmaceutically acceptable salt thereof, wherein L 5  is C 1 -C 10  alkyl or —(CR 49 R 49′ ) u C(O)—, each R 49  and R 49′  is H, and u is 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

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