Benzazepine compounds, conjugates, and uses thereof

Abstract

Benzazepine compounds, conjugates, and pharmaceutical compositions for use in the treatment of disease, such as cancer, are disclosed herein. The disclosed benzazepine compounds are useful, among other things, in the treating of cancer and modulating TLR8. Additionally, benzazepine compounds incorporated into a conjugate with an antibody construct are described herein.

1 .- 222 . (canceled) 
     
     
         223 . A conjugate or salt thereof represented by the formula: 
       
         
           
           
               
               
           
         
         wherein Antibody is an antibody construct comprising a HER2 antigen binding domain, and L 3 -D is a linker-payload selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of the antibody construct, wherein 
       
       
         
           
           
               
               
           
         
       
       on RX* represents the point of attachment to a cysteine residue of the antibody construct. 
     
     
         224 . The conjugate or salt thereof of  claim 223 , wherein RX* is a succinamide moiety. 
     
     
         225 . The conjugate or salt thereof of  claim 223 , wherein RX* is a hydrolyzed succinamide moiety. 
     
     
         226 . The conjugate or salt thereof of  claim 223 , wherein the antibody construct is an antibody comprising light chain CDR1, CDR2 and CDR3 set forth in the light chain variable region amino acid sequence of SEQ ID NO:2, and heavy chain CDR1, CDR2 and CDR3 set forth in the heavy chain variable region amino acid sequence of SEQ ID NO: 1, as determined by the Kabat index. 
     
     
         227 . The conjugate or salt thereof of  claim 223 , wherein the antibody construct is an antibody comprising light chain CDR1, CDR2 and CDR3 set forth in the light chain variable region amino acid sequence of SEQ ID NO:8, and heavy chain CDR1, CDR2 and CDR3 set forth in the heavy chain variable region amino acid sequence of SEQ ID NO:7, as determined by the Kabat index. 
     
     
         228 . The conjugate or salt thereof of  claim 223 , wherein the antibody comprises an antigen binding domain from pertuzumab. 
     
     
         229 . The conjugate or salt thereof of  claim 223 , wherein the antibody comprises an antigen binding domain from trastuzumab. 
     
     
         230 . The conjugate or salt thereof of  claim 226 , wherein the L 3 -D is: 
       
         
           
           
               
               
           
         
       
     
     
         231 . The conjugate or salt thereof of  claim 226 , wherein the L 3 -D is: 
       
         
           
           
               
               
           
         
       
     
     
         232 . The conjugate or salt thereof of  claim 226 , wherein the L 3 -D is: 
       
         
           
           
               
               
           
         
       
     
     
         233 . The conjugate or salt thereof of  claim 226 , wherein the L 3 -D is: 
       
         
           
           
               
               
           
         
       
     
     
         234 . A pharmaceutical composition, comprising the conjugate or salt thereof of  claim 230 , and at least one pharmaceutically acceptable excipient. 
     
     
         235 . The pharmaceutical composition of  claim 234 , wherein the average drug-to-antibody ratio of the conjugate ranges from about 2 to about 8, about 3 to about 8, about 3 to about 7, or about 3 to about 5. 
     
     
         236 . A pharmaceutical composition, comprising the conjugate or salt thereof of  claim 231 , and at least one pharmaceutically acceptable excipient. 
     
     
         237 . The pharmaceutical composition of  claim 236 , wherein the average drug-to-antibody ratio of the conjugate ranges from about 2 to about 8, about 3 to about 8, about 3 to about 7, or about 3 to about 5. 
     
     
         238 . A pharmaceutical composition, comprising the conjugate or salt thereof of  claim 232 , and at least one pharmaceutically acceptable excipient. 
     
     
         239 . The pharmaceutical composition of  claim 238 , wherein the average drug-to-antibody ratio of the conjugate ranges from about 2 to about 8, about 3 to about 8, about 3 to about 7, or about 3 to about 5. 
     
     
         240 . A pharmaceutical composition, comprising the conjugate or salt thereof of  claim 233 , and at least one pharmaceutically acceptable excipient. 
     
     
         241 . The pharmaceutical composition of  claim 240 , wherein the average drug-to-antibody ratio of the conjugate ranges from about 2 to about 8, about 3 to about 8, about 3 to about 7, or about 3 to about 5. 
     
     
         242 . A method for treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition of  claim 234 , wherein the cancer is selected from breast cancer, lung cancer, stomach cancer, and colon cancer. 
     
     
         243 . A method for treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition of  claim 236 , wherein the cancer is selected from breast cancer, lung cancer, stomach cancer, and colon cancer. 
     
     
         244 . A method for treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition of  claim 238 , wherein the cancer is selected from breast cancer, lung cancer, stomach cancer, and colon cancer. 
     
     
         245 . A method for treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition of  claim 240 , wherein the cancer is selected from breast cancer, lung cancer, stomach cancer, and colon cancer.