Triterpene saponin analogues

Abstract

The present application relates to triterpene glycoside saponin-derived adjuvants, syntheses thereof, and intermediates thereto. The application also provides pharmaceutical compositions comprising compounds of the present invention and methods of using said compounds or compositions in the treatment of and immunization for infectious diseases and cancers.

1 . A pharmaceutical combination comprising a TLR agonist and a compound a Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
            is a single or double bond; 
         W is —CHO; 
         V is —OH; 
         Y is —O—; 
         wherein Z is a carbohydrate domain having the structure: 
       
       
         
           
           
               
               
           
         
         wherein:
 R 1  is independently H or 
 
       
       
         
           
           
               
               
           
         
         
           R 2  is NHR 4 ; 
           R 3  is CH 2 OH; and 
           R 4  is -T-R z , —C(O)-T-R z , —NH-T-R z , —O-T-R z , —S-T-R z , —C(O)NH-T-R z , C(O)O-T-R z , C(O)S-T-R z , C(O)NH-T-O-T-R z , —O-T-R z , -T-O-T-R z , -T-S-T-R z , or 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein: 
             X is —O—, —NR—, or T-R z ; 
             T is a covalent bond or a bivalent C 1-26  saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and 
             R z  is hydrogen, halogen, —OR, —OR x , —OR 1 , —SR, NR 2 , —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C 1-6  aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. 
           
         
       
     
     
         2 . The pharmaceutical combination of  claim 1 , wherein the compound of Formula I is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The pharmaceutical combination of  claim 1 , wherein the compound of Formula I is 
       
         
           
           
               
               
           
         
       
     
     
         4 . A vaccine comprising the pharmaceutical combination of  claim 1 . 
     
     
         5 . The vaccine of  claim 4 , wherein the compound of Formula I is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . The vaccine of  claim 4 , wherein the compound of Formula I 
       
         
           
           
               
               
           
         
       
     
     
         7 . A method of stimulating the immune system of a mammal, the method comprising administering the pharmaceutical combination of  claim 1 . 
     
     
         8 . The method of  claim 7 , wherein the compound of Formula I is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 7 , wherein the compound of Formula I is 
       
         
           
           
               
               
           
         
       
     
     
         10 . A method of stimulating a CD4 or CD8 immune response comprising administering the pharmaceutical combination of  claim 1 . 
     
     
         11 . The method of  claim 10 , wherein the compound of Formula I is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 10 , wherein the compound of Formula I is 
       
         
           
           
               
               
           
         
       
     
     
         13 . A method of stimulating a CD4 or CD8 immune response comprising administering a compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
            s a single or double bond; 
         W is —CHO; 
         V is —OH; 
         Y is —O—; 
         wherein Z is a carbohydrate domain having the structure: 
       
       
         
           
           
               
               
           
         
         wherein:
 R 1  is independently H or 
 
       
       
         
           
           
               
               
           
         
         
           R 2  is NHR 4 ; 
           R 3  is CH 2 OH; and 
           R 4  is -T-R z , —C(O)-T-R z , —NH-T-R z , —O-T-R z , —S-T-R z , —C(O)NH-T-R z , C(O)O-T-R z , C(O)S-T-R z , C(O)NH-T-O-T-R z , —O-T-R z , -T-O-T-R z , -T-S-T-R z , or 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein: 
             X is —O—, —NR—, or T-R z ; 
             T is a covalent bond or a bivalent C 1-26  saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and 
             R z  is hydrogen, halogen, —OR, —OR x , —OR 1 , —SR, NR 2 , —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C 1-6  aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. 
           
         
       
     
     
         14 . The method of  claim 13 , wherein the compound of Formula I is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 13 , wherein the compound of Formula I is