Toll-like receptor-7 and -8 modulatory 1h imidazoquinoline derived compounds

Abstract

The present disclosure provides novel imidazoquinoline derived compounds, derivatives thereof, analogues thereof, and pharmaceutically acceptable salts thereof, and methods of making and using such compounds. The present disclosure also provides TLR7 agonists and TLR7/TLR8 dual agonists, probes, tissue-specific molecules, adjuvants, immunogenic compositions, therapeutic compositions, and self-adjuvanting vaccines including the imidazoquinoline derived compounds, derivatives thereof, analogues thereof, and pharmaceutically acceptable salts thereof. Derivatives of the imidazoquinoline derived compounds also include dendrimers and dimers of the imidazoquinoline derived compounds, and methods of making and using the dendrimeic and dimeric imidazoquinoline derived compounds. The present disclosure also provides dual TLR2/TLR7 hybrid agonists that include imidazoquinoline derived compounds of the present disclosure.

1 . An imidazoquinoline derived compound of Formula I, a derivative thereof, or analogue thereof, or pharmaceutically acceptable salt thereof, wherein
 Formula I has the structure:   
       
         
           
           
               
               
           
         
         
           wherein, R is selected from the group consisting of: —NH(R 5 ) and isothiocyanate; 
           R 5  is selected from the group consisting of hydrogen, acetyl, —CO-tert-Bu (-Boc), —CO—(CH 2 ) x —R 6 , C 1 -C 16  alkyl, 
         
         —CO-4-(phenylboronic acid), —C(S)—NH—(CH 2 ) x —NH—(CH 2 ) x —NH—(CH 2 ) x —NH 2 , 
       
       
         
           
           
               
               
           
         
          a reporter moiety, a tissue-specific moiety, a peptide antigen moiety, a protein antigen moiety, a polysaccharide antigen moiety, and a TLR2 agonist moiety;
 R 6  is selected from the group consisting of hydrogen, alkyne, azido, carboxylic acid, and —CONH—(CH 2 ) x —O—(CH 2 ) x —O—(CH 2 ) x —O—(CH 2 ) x —R 7 ; 
 R 7  is selected from the group consisting of amino, isothiocyanate, and —NH—CO—(CH 2 ) x —CO 2 H; 
 R 8  is selected from a peptide antigen moiety or a protein antigen moiety; and 
 x is any integer from 1 to 10. 
 
       
     
     
         2 . The imidazoquinoline derived compound of  claim 1 , wherein the compound is capable of activating Toll-like receptor (TLR) 7. 
     
     
         3 . The imidazoquinoline derived compound of  claim 1 , wherein the compound is capable of activating TLR7 and TLR8. 
     
     
         4 . The imidazoquinoline derived compound of  claim 1 , wherein the compound of Formula 1 is chosen from an isothiocyanate derivative of Formula I and a maleimide derivative of Formula I. 
     
     
         5 . The imidazoquinoline derived compound of  claim 1 , wherein R 5  comprises a reporter moiety comprising a reporter molecule capable of producing a detectable signal. 
     
     
         6 . The imidazoquinoline derived compound of  claim 1 , wherein R 5  comprises an antigen moiety is chosen from a peptide antigen moiety, a protein antigen moiety, or a polysaccharide antigen moiety, and wherein the imidazoquinoline derived compound is capable of activating TLR7. 
     
     
         7 . The imidazoquinoline derived compound of  claim 1 , wherein R 5  comprises a tissue-specific moiety including a tissue-specific agent. 
     
     
         8 . The imidazoquinoline derived compound of  claim 1 , wherein R 5  comprises a TLR2 agonist moiety including a TLR2 agonist, and wherein the imidazoquinoline derived compound is capable of dual activation of TLR2 and TLR7. 
     
     
         9 . An imidazoquinoline derived compound comprising a dimer or a dendrimer of a compound of Formula I, a compound of Formula II, derivatives thereof, analogues thereof, or pharmaceutically acceptable salts thereof, wherein 
       
         
           
           
               
               
           
         
         wherein, R 1  and R 3  are each independently selected from the group consisting of hydrogen, halogen, nitro, —NH 2 , azido, hydroxyl, —CF 3 , carboylic acid and —CO 2 R 2 ; 
         R 2  is a C 2 -C 5  alkyl, and 
         R for Formula I and R 4  for Formula II are each independently selected from the group consisting of: —NH(R 5 ) and isothiocyanate; 
         R 5  is selected from the group consisting of hydrogen, acetyl, —CO-tert-Bu (-Boc), —CO—(CH 2 ) x —R 6 , C 1 -C 16  alkyl, 
         —CO-4-(phenylboronic acid), —C(S)—NH—(CH 2 ) x —NH—(CH 2 ) x —NH—(CH 2 ) x —NH 2 , 
       
       
         
           
           
               
               
           
         
          a reporter moiety, a tissue-specific moiety, a peptide antigen moiety, a protein antigen moiety, a polysaccharide antigen moiety, and a TLR2 agonist moiety; 
         R 6  is selected from the group consisting of hydrogen, alkyne, azido, carboxylic acid, and —CONH—(CH 2 ) x —O—(CH 2 ) x —O—(CH 2 ) x —O—(CH 2 ) x —R 7 ; 
         R 7  is selected from the group consisting of amino, isothiocyanate, and —NH—CO—(CH 2 ) x —CO 2 H; 
         R 8  is selected from a peptide antigen moiety or a protein antigen moiety; and 
         x is any integer from 1 to 10. 
       
     
     
         10 . The imidazoquinoline derived compound of claim  22 , wherein the dimer or dendrimer compound is a Toll-like receptor (TLR) 7 agonist or a dual TLR7/TLR8 agonist. 
     
     
         11 . An imidazoquinoline derived compound of Formula II, a derivative thereof, analogue thereof, or pharmaceutically acceptable salt thereof, wherein
 Formula II has the structure:   
       
         
           
           
               
               
           
         
         
           wherein, R 1  and R 3  are each independently selected from the group consisting of hydrogen, halogen, nitro, —NH 2 , azido, hydroxyl, —CF 3 , carboylic acid, and —CO 2 R 2 ; 
           R 2  is a C 2 -C 5  alkyl, and 
           R 4  selected from the group consisting of: —NH(R 5 ) and 
         
         isothiocyanate;
 R 5  is selected from the group consisting of hydrogen, acetyl, —CO-tert-Bu (-Boc), —CO—(CH 2 ) x —R 6 , C 1 -C 16  alkyl, 
 
         —CO-4-, —C(S)—NH—(CH 2 ) x —NH—(CH 2 ) x —NH—(CH 2 ) x —NH 2 , 
       
       
         
           
           
               
               
           
         
          a reporter moiety, a tissue-specific moiety, a peptide antigen moiety, a protein antigen moiety, a polysaccharide antigen moiety, and a TLR2 agonist moiety;
 R 6  is selected from the group consisting of hydrogen, alkyne, azido, carboxylic acid, and —CONH—(CH 2 ) x —O—(CH 2 ) x —O—(CH 2 ) x —O—(CH 2 ) x —R 7 ; 
 R 7  is selected from the group consisting of amino, isothiocyanate, and —NH—CO—(CH 2 ) x —CO 2 H; 
 R 8  is selected from a peptide antigen moiety or a protein antigen moiety; and 
 x is any integer from 1 to 10. 
 
       
     
     
         12 . The imidazoquinoline derived compound of claim  31 , wherein the compound is capable of activating TLR7 or dual activation of TLR7 and TLR8.