Podophyllotoxin derivatives and their use

Abstract

Provided herein are compounds, compositions, and methods for treating cancer in a subject in need thereof; wherein the compound has formula (I): or an N-oxide thereof, or a pharmaceutically acceptable salt of each thereof, or a pharmaceutically acceptable solvate of each of the foregoing, wherein R 1 is H or has a structure of: R 3 is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted 3-10 membered cycloalkyl, an optionally substituted 3-10 membered heterocyclyl, an optionally substituted 6-10 membered aryl, or an optionally substituted 5-10 membered heteroaryl; R 5 is H or has a structure of: and R 11 and R 12 independently is an optionally substituted C 1 -C 8 alkyl.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or an N-oxide thereof, or a pharmaceutically acceptable salt of each thereof, or a pharmaceutically acceptable solvate of each of the foregoing, wherein
 R 1  is H or has a structure of: 
 
       
         
           
           
               
               
           
         
         R 3  is H, an optionally substituted C1-C 8  alkyl, an optionally substituted 3-10 membered cycloalkyl, an optionally substituted 3-10 membered heterocyclyl, an optionally substituted 6-10 membered aryl, or an optionally substituted 5-10 membered heteroaryl; 
         R 5  is H or has a structure of: 
       
       
         
           
           
               
               
           
         
       
       and
 R 11  and R 12  independently is an optionally substituted C1-C 8  alkyl. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is H. 
     
     
         3 . The compound of  claim 1 , wherein R 1  has the structure of: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein R 3  is H. 
     
     
         5 . The compound of  claim 1 , wherein R 5  is: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein R 11  and R 12  independently is C1-C 8  alkyl. 
     
     
         7 . The compound of  claim 6 , wherein R 11  is methyl and R 12  is methyl. 
     
     
         8 . The compound of  claim 1 , wherein R 5  is H. 
     
     
         9 . The compound of  claim 1 , wherein R 3  is C 1 -C 8  alkyl. 
     
     
         10 . The compound of  claim 1 , wherein R 3  is an ethyl. 
     
     
         11 . The compound of  claim 1  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or an N-oxide thereof, or a pharmaceutically acceptable salt of each thereof, or a pharmaceutically acceptable solvate of each of the foregoing. 
     
     
         12 . A pharmaceutical composition comprising a compound  claim 1  and at least one pharmaceutically acceptable excipient. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the pharmaceutical composition is a solid form, liquid form, injectable form, or a liposomal formulation. 
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 11  and at least one pharmaceutically acceptable excipient. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the pharmaceutical composition is a solid form, liquid form, injectable form, or a liposomal formulation 
     
     
         16 . A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the therapeutically effective amount of a compound of  claim 1  is about 15 mg/m 2  to about 1500 mg/m 2 . 
     
     
         18 . The method of  claim 16 , wherein the cancer is colon cancer, non-small lung cancer, chronic myeloid leukemia, acute myeloid leukemia, small cell lung cancer, cervical cancer, stomach cancer, breast cancer, prostate cancer, skin cancer, melanoma, lymphoma, brain tumor, sarcoma, testicle cancer, ovarian cancer, renal cancer, head and neck cancer, liver cancer, leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, hairy cell leukemia, T-cell prolymphocytic leukemia, large granular lymphocytic leukemia, adult T-cell leukemia, and a blood cancer. 
     
     
         19 . The method of  claim 16 , wherein the cancer comprises a solid tumor. 
     
     
         20 . A method of delaying or regressing tumor growth in a subject or treating cancer in a subject wherein the subject is in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of  claim 1 . 
     
     
         21 .- 35 . (canceled)