Modulators of toll-like receptors

Abstract

Provided are modulators of TLRs of Formula II: pharmaceutically acceptable salts thereof, compositions containing such compounds, and therapeutic methods that include the administration of such compounds.

We claim: 
     
         1 . A method for treating a hepatitis B viral infection comprising administering to a human subject infected with hepatitis B virus a therapeutically effective amount of a compound of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester thereof, wherein: 
         Y—Z is —CR 4 R 5 —, —CR 4 R 5 —CR 4 R 5 —, —C(O)CR 4 R 5 —, —CR 4 R 5 C(O)—, —NR 8 C(O)—, —C(O)NR 8 —, —CR 4 R 5 S(O) 2 —, or —CR 5 ═CR 5 —; 
         L 1  is —NR 8 —, —O—, —S—, —N(R 8 )C(O)—, —S(O) 2 —, —S(O)—, —C(O)N(R 8 )—, —N(R 8 )S(O) 2 —, —S(O) 2 N(R 8 )— or a covalent bond; 
         R 1  is alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl, heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, or substituted heteroarylheteroalkyl; 
         X 1  is alkylene, substituted alkylene, heteroalkylene, substituted heteroalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, carbocyclylene, substituted carbocyclylene, heterocyclylene, substituted heterocyclylene, —NR 8 —, —O—, —C(O)—, —S(O)—, S(O) 2 —, or a bond; 
         D is carbocyclyl, substituted carbocyclyl, heterocyclyl or substituted heterocyclyl wherein said carbocyclyl, substituted carbocyclyl, heterocyclyl or substituted heterocyclyl is substituted with one or two -L 2 -NR 6 R 7 ; or 
         D is a heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl wherein said heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl comprises one to four nitrogen atoms; 
         each L 2  is independently alkylene, substituted alkylene, heteroalkylene, substituted heteroalkylene, or a covalent bond; 
         each R 3  is independently halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl, substituted heteroalkyl, alkoxy, haloalkyl, haloalkoxy, —CHO, —C(O)OR 8 , —S(O)R 8 , —S(O) 2 R 8 ; —C(O)NR 9 R 10 , —N(R 9 )C(O)R 8 , carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —S(O) 2 NR 9 R 10 , —N(R 9 )S(O) 2 R 8 , —N(R 9 )S(O) 2 OR 10 , —OS(O) 2 NR 9 R 10 ; 
         n is 0, 1, 2, 3, 4 or 5; 
         R 4  and R 5  are each independently H, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl, heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, or substituted heteroarylheteroalkyl, cyano, azido, OR B , —C(O)H, —C(O)R 8 , —S(O)R 8 , —S(O) 2 R 8 , —C(O)OR 8 , or —C(O)NR 9 R 10 ; or 
         R 4  and R 5 , taken together with the carbon to which they are both attached, form a carbocycle, substituted carbocycle, heterocycle or substituted heterocycle; or 
         R 4  and R 5 , when on the same carbon atom, taken together with the carbon to which they are attached are —C(O)— or —C(NR 8 )—; or 
         two R 4  or two R 5  on adjacent carbon atoms when taken together with the carbons to which they are attached form a 3 to 6 membered carbocycle, substituted carbocycle, heterocycle or substituted heterocycle; 
         R 6  and R 7  are each independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, haloalkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl, heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, or substituted heteroarylheteroalkyl, —C(O)H, —C(O)R 8 , —S(O)R 8 , —S(O) 2 R 8 , —C(O)OR 8 , or —C(O)NR 9 R 10 , S(O) 2 NR 9 R 10 ; or 
         R 6  and R 7 , taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle, which may contain one or more additional heteroatoms selected from N, O, P, or S; or 
         R 7  taken together with L 2 , and the N to which they are both attached, forms a substituted or unsubstituted 3 to 8 membered heterocycle which may contain one or more additional heteroatoms selected from N, O, S, or P; 
         R 8  is H, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl, heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, or substituted heteroarylheteroalkyl; and 
         R 9  and R 10  are each independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, haloalkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl, heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, or substituted heteroarylheteroalkyl; or 
         R 9  and R 10 , taken together with the nitrogen to which they are both bonded, form a substituted or unsubstituted heterocycle; 
         wherein each substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heteroalkyl, substituted carbocyclyl, substituted carbocyclylalkyl, substituted heterocyclyl, substituted heterocyclylalkyl, substituted arylalkyl, substituted heteroarylalkyl, substituted carbocyclylheteroalkyl, substituted heterocyclylheteroalkyl, substituted arylheteroalkyl, substituted heteroarylheteroalkyl, substituted alkylene, substituted heteroalkylene, substituted alkenylene, substituted alkynylene, substituted carbocyclylene, or substituted heterocyclylene is independently substituted with one to four substituents selected from the group consisting of -halogen, —R, —O − , ═O, —OR, —SR, —S − , —NR 2 , —N(+)R 3 , ═NR, —C(halogen) 3 , —CR(halogen) 2 , —CR 2 (halogen), —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO 2 , ═N 2 , —N 3 , —NRC(═O)R, —NRC(═O)OR, —NRC(═O)NRR, —C(═O)NRR, —C(═O)OR, —OC(═O)NRR, —OC(═O)OR, —C(═O)R, —S(═O) 2 OR, —S(═O) 2 R, —OS(═O) 2 OR, —S(═O) 2 NR, —S(═O)R, —NRS(═O) 2 R, —NRS(═O) 2 NRR, —NRS(═O) 2 OR, —OP(═O)(OR) 2 , —P(═O)(OR) 2 , —P(O)(OR)(0)R, —C(═O)R, —C(═S)R, —C(═O)OR, —C(═S)OR, —C(═O)SR, —C(═S)SR, —C(═O)NRR, —C(═S)NRR, —C(═NR)NRR, and —NRC(═NR)NRR; wherein each R is independently H, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl. 
       
     
     
         2 . The method of  claim 1  wherein L 1  is —NH— or —O—. 
     
     
         3 . The method of  claim 2 , wherein R 1  is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, carbocyclylalkyl or substituted carbocyclylalkyl. 
     
     
         4 . The method of  claim 3  wherein X 1  is C 1 -C 6  alkylene, C 1 -C 6  heteroalkylene or C 1 -C 6  substituted heteroalkylene. 
     
     
         5 . The method of  claim 4  wherein L 1  is —O—. 
     
     
         6 . The method of  claim 5  wherein D is a 3- to 12-membered carbocyclyl or 3- to 12-membered heterocyclyl wherein said carbocyclyl or heterocyclyl is substituted with -L 2 -NR 6 R 7 . 
     
     
         7 . The method of  claim 6  wherein D is phenyl, biphenyl or pyridinyl. 
     
     
         8 . The method of  claim 7  wherein L 2  is C 1 -C 6  alkylene or a covalent bond. 
     
     
         9 . The method of  claim 8  wherein X 1  is —CH 2 —. 
     
     
         10 . The method of  claim 9  wherein R 6  and R 7  independently are H, alkyl, heteroalkyl, or, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclyl. 
     
     
         11 . The method of  claim 10  wherein R 6  and R 7  taken together with the nitrogen to which they are attached form a 4- to 10-membered mono- or bicyclic, saturated, partially saturated, or unsaturated ring containing from 0 to 3 additional heteroatoms selected from N, O, or S. 
     
     
         12 . The method of  claim 11  wherein L 2  is —CH 2 —. 
     
     
         13 . The method of  claim 12  wherein Y—Z is —CR 4 R 5 — or —CR 4 R 5 —CR 4 R 5 —. 
     
     
         14 . The method of  claim 13  wherein Y—Z is —CH 2 —. 
     
     
         15 . The method of  claim 13  wherein Y—Z is —C(O)—. 
     
     
         16 . The method of  claim 5  wherein D is a heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl wherein said heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl comprises one to four nitrogen atoms. 
     
     
         17 . The method of  claim 16  wherein D is optionally substituted pyridinyl, optionally substituted piperidinyl, optionally substituted piperazinyl or optionally substituted 1,2,3,4-tetrahydroisoquinolinyl. 
     
     
         18 . The method of  claim 17  wherein Y—Z is —CR 4 R 5 — or —CR 4 R 5 —CR 4 R 5 —. 
     
     
         19 . A method for treating a hepatitis B viral infection comprising administering to a human subject infected with hepatitis B virus a therapeutically effective amount of a compound of Formula Ia: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         L 1  is —NH— or —O—; 
         R 1  is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, carbocyclylalkyl or substituted carbocyclylalkyl; 
         each of R 4  and R 5  independently is H or C 1 -C 6  alkyl or R 4  and R 5  taken together with the carbon to which they are attached is —C(O)—; 
         X 1  is C 1 -C 6  alkylene, C 1 -C 6  heteroalkylene or C 1 -C 6  substituted heteroalkylene; 
         D is phenyl, biphenyl or pyridinyl, wherein said phenyl, biphenyl or pyridinyl is substituted with -L 2 -NR 6 R 7 ; or 
         D is pyridinyl, piperidinyl, piperazinyl or 1,2,3,4-tetrahydroisoquinolinyl; 
         n is 0 or 1; 
         R 3  is halogen, cyano, alkyl, carbocyclyl, carbocyclylalkyl, haloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10  or —CHO; 
         L 2  is C 1 -C 6  alkylene or a covalent bond; 
         each of R 6  and R 7  independently is H, alkyl, or heteroaryl; or 
         R 6  and R 7  taken together with the nitrogen to which they are attached form a substituted or unsubstituted 4-6 membered heterocycle comprising 0 to 2 heteroatoms selected from N, O or S. 
       
     
     
         20 . The method of  claim 19  wherein each R 4  or R 5  is independently H or CH 3 . 
     
     
         21 . The method of  claim 19  wherein R 4  and R 5  taken together with the carbon to which they are attached is —C(O)—. 
     
     
         22 . The method of  claim 19  wherein L 1  is —O—. 
     
     
         23 . A method for treating a hepatitis B viral infection comprising administering to a human subject infected with hepatitis B virus a therapeutically effective amount of a compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester thereof. 
       
     
     
         24 . The method of  claim 1  further comprising administering an additional therapeutic agent selected from the group consisting of lamivudine, adefovir, tenofovir, telbivudine, entecavir, interferon alpha-2b, pegylated interferon alpha-2a, interferon alpha 2a, interferon alpha N1, prednisone, predinisolone, Thymalfasin®, retinoic acid receptor agonists, 4-methylumbelliferone, Alamifovir®, Metacavir®, Albuferon®, cytokines and agonists of TLRs.