1H-PYRAZOLO[4,3-d]PYRIMIDINE COMPOUNDS AS TOLL-LIKE RECEPTOR 7 (TLR7) AGONISTS AND METHODS AND USES THEREFOR

Abstract

Compounds according to formula I are useful as agonists of Toll-like receptor 7 (TLR7). Such compounds can be used in cancer treatment, especially in combination with an anti-cancer immunotherapy agent, or as a vaccine adjuvant.

What is claimed is: 
     
         1 . A method of treating a cancer, comprising administering to a patient suffering from such cancer a therapeutically effective combination of an anti-cancer immunotherapy agent and a compound having a structure according to formula I 
       
         
           
           
               
               
           
         
         wherein 
         each X 1  is independently N or CR 2 ; 
         X 2  is O, CH 2 , NH, S, or N(C 1 -C 3  alkyl); 
         R 1  is H, CH 3 (CH 2 ) 1-3 , CH 3 (CH 2 ) 0-1 O(CH 2 ) 2-3 , CH 3 (CH 2 ) 0-3 C(═O), CH 3 (CH 2 ) 0-1 O(CH 2 ) 2-3 C(═O), 
       
       
         
           
           
               
               
           
         
         R 2  is H, O(C 1 -C 3  alkyl), C 1 -C 3  alkyl, Cl, F, or CN; 
         R 3  is H, halo, OH, CN, NH 2 , NH(C 1 -C 5  alkyl), N(C 1 -C 5  alkyl) 2 , NH(CH 2 ) 0-1 (C 3 -C 6  cycloalkyl), NH(C 4 -C 8  bicycloalkyl), NH(C 6 -C 10  spirocycloalkyl), N(C 3 -C 6  cycloalkyl) 2 , NH(CH 2 ) 1-3 (aryl), N((CH 2 ) 1-3 (aryl)) 2 , a cyclic amine moiety having the structure 
       
       
         
           
           
               
               
           
         
         
            (CH 2 ) 0-4 , a 6-membered aromatic or heteroaromatic moiety or a 5-membered heteroaromatic moiety; wherein the 5-membered heteroaromatic and the 6-membered heteroaromatic moiety comprises from 1 to 4 heteroatoms independently selected from N, O, or S; 
           wherein 
           the alkyl, cycloalkyl, bicycloalkyl, spirocycloalkyl, cyclic amine, 6-membered aromatic or heteroaromatic, or 5-membered heteroaromatic moiety is optionally substituted with one or more substituents selected from OH, halo, CN, (C 1 -C 3  alkyl), O(C 1 -C 3  alkyl), C(═O)(Me), SO 2 (C 1 -C 3  alkyl), C(═O)(Et), NH 2 , NH(Me), N(Me) 2 , NH(Et), N(Et) 2 , and N(C 1 -C 3  alkyl), (CH 2 ) 1-2 OH, (CH 2 ) 1-2 OMe; and 
           wherein a CH 2  group in the cycloalkyl, bicycloalkyl, spirocycloalkyl, or cyclic amine 
           moiety is optionally replaced by O, S, NH, N(C 1 -C 3  alkyl), or N(Boc); 
         
         m is 0 or 1; 
         and 
         n is 1, 2, or 3; 
         or a pharmaceutically acceptable salt or tautomer thereof. 
       
     
     
         2 . The method according to  claim 1 , wherein the group R 1  of the compound or a pharmaceutically acceptable salt or tautomer thereof, is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method according to  claim 1 , wherein the group R 1  of the compound or a pharmaceutically acceptable salt or tautomer thereof, is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method according to  claim 1 , wherein the moiety of the compound or a pharmaceutically acceptable salt or tautomer thereof, 
       
         
           
           
               
               
           
         
         is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
     
     
         5 . The method according to  claim 1 , wherein the moiety of the compound or a pharmaceutically acceptable salt or tautomer thereof, 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method according to  claim 1 , wherein the group R 3  of the compound or a pharmaceutically acceptable salt or tautomer thereof, is selected from the group consisting of Cl, H, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The method according to  claim 1 , wherein R 3  of the compound or a pharmaceutically acceptable salt or tautomer thereof, is a moiety 
       
         
           
           
               
               
           
         
       
       selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method according to  claim 1 , wherein the compound or a pharmaceutically acceptable salt or tautomer thereof, has a structure according to formula (I′) 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method according to  claim 1 , wherein the compound or a pharmaceutically acceptable salt or tautomer thereof, has a structure according to formula Ia 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method according to  claim 9 , wherein R 1  of the compound or a pharmaceutically acceptable salt or tautomer thereof, is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method according to  claim 1 , wherein the compound or a pharmaceutically acceptable salt or tautomer thereof, has a structure according to formula Ib 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method according to  claim 11 , wherein 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method according to  claim 1 , wherein the compound is covalently bonded to a poly(ethylene glycol) moiety between 2 kDa and 40 kDa in size. 
     
     
         14 . The method according to  claim 1 , wherein the anti-cancer immunotherapy agent is an antagonistic anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibody. 
     
     
         15 . The method according to  claim 1 , wherein the cancer is lung cancer (including non-small cell lung cancer), pancreatic cancer, kidney cancer, head and neck cancer, lymphoma (including Hodgkin's lymphoma), skin cancer (including melanoma and Merkel skin cancer), urothelial cancer (including bladder cancer), gastric cancer, hepatocellular cancer, or colorectal cancer. 
     
     
         16 . The method according to  claim 14 , wherein the anti-cancer immunotherapy agent is ipilimumab, nivolumab, or pembrolizumab.