Heterocyclic derivatives for the treatment of rsv

Abstract

Disclosed herein are compounds and compositions for treating or inhibiting RSV and related members of the pneumovirus and paramyxovirus families such as human metapneumovirus, mumps virus, human parainfluenzaviruses, and Nipah and hendra virus, and methods of treatment or prevention thereof.

What is claimed is: 
     
         1 . A method of inhibiting RSV, comprising administering to a patient in need thereof, an effective amount of a compound of Formula 1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         X is selected from O, S, or NR 7 ; 
         z is selected from 0, 1, 2, 3, 4, 5, and 6; 
         y is selected from 0, 1, 2, 3, 4, 5, and 6; 
         R 1  and R 2  are independently selected from R a , OR a , N(R a ) 2 , SR a , C(═O)R a , C(═O)OR a , C(═O)N(R a ) 2 , C(═O)SR a ; 
         R 3 , R 4 , R 5 , and R 6  are independently selected from independently selected from —R a , —OR a , —N(R a ) 2 , —SR a , —SO 2 R a , —SO 2 N(R a ) 2 ; —C(O)R a , OC(O)R a , —COOR a , —C(O)N(R a ) 2 , —OC(O)N(R a ) 2 , —N(R a )C(O), —N(R a )C(O)N(R a ) 2 , —F, —Cl, —Br, —I, —CN, —NO 2 ; wherein when multiple R a  groups are present, said R a  groups may together form a ring; 
         R 7 , when present, is R a , C(O)R a , SO 2 R a , COOR a , C(O)N(R a ) 2 , 
         wherein either of R 3  and R 4 , or R 5  and R 6  may together form a double bond 
         wherein either of R 4  and R 6  or R 3  and R 5  may together form a carbonyl, imine or olefin; and 
         wherein any of two or more of R 1 , R 2 , R 3 , R 4 , R 5 , R 6  or R 7 , or R a  groups may together form a ring; and 
         wherein R a  is in each case independently selected from hydrogen, C 1-8  alkyl, C 3-8  cycloalkyl, C 2-8  heterocyclyl, C 6-12  aryl, C 3-12  heteroaryl, C 1-8  alkyl-C 3-8  cycloalkyl, C 1-8  alkyl-C 2-8  heterocyclyl, C 1-8  alkyl-C 6-12  aryl, and C 1-8  alkyl-C 3-12  heteroaryl. 
       
     
     
         2 . The method according to  claim 1 , wherein X is S. 
     
     
         3 . The method according to  claim 1 , wherein R 3  and R 4  together form a ring. 
     
     
         4 . The method according to  claim 1 , wherein R 3  and R 4  together form an aryl or heteroaryl ring. 
     
     
         5 . The method according to  claim 1 , wherein R 3  and R 4  can together form a phenyl ring, to give a compound of Formula 1b or 1b-i: 
       
         
           
           
               
               
           
         
         wherein a is selected from 0, 1, 2, 3 and 4; and 
         R 8  is independently selected from —R a , —OR a , —N(R a ) 2 , —SR a , —SO 2 R a , —SO 2 N(R a ) 2 ; —C(O)R a , OC(O)R a , —COOR a , —C(O)N(R a ) 2 , —OC(O)N(R a ) 2 , —N(R a )C(O), —N(R a )C(O)N(R a ) 2 , —F, —Cl, —Br, —I, —CN, —NO 2 , 
         wherein R a  has the meanings as set forth in  claim 1 . 
       
     
     
         6 . The method according to  claim 1 , wherein z is 0. 
     
     
         7 . The method according to  claim 1 , wherein y is 1. 
     
     
         8 . The method according to  claim 1 , wherein R 1  is N(R a ) 2 . 
     
     
         9 . The method according to  claim 1 , wherein R 1  is selected from 
       
         
           
           
               
               
           
         
         b is selected from 0, 1, 2, 3 and 4. 
         R 9  is independently selected from —R a , —OR a , —N(R a ) 2 , —SR a , —SO 2 R a , —SO 2 N(R a ) 2 ; —C(O)R a , OC(O)R a , —COOR a , —C(O)N(R a ) 2 , —OC(O)N(R a ) 2 , —N(R a )C(O), —N(R a )C(O)N(R a ) 2 , —F, —Cl, —Br, —I, —CN, —NO 2 , wherein R a  has the meanings given above, and any two or more R 9  groups may together form a ring; 
         wherein R 10  when present, is independently selected from R a , C(O)R a , SO 2 R a , COOR a , C(O)N(R a ) 2 , wherein R 10  may, with any one or more of R 1 , R 2 , R 3 , R 4 , R 5 , R 6  or R 7 , R 8 , or R a  groups, together form a ring. 
       
     
     
         10 . The method according to  claim 1 , wherein R 1  is a group of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method according to  claim 1 , wherein R 2  is C(═O)NHR a1 , wherein said R a1  is selected from C 3-8  cycloalkyl, C 2-8  heterocyclyl, C 6-12  aryl, and C 3-12  heteroaryl. 
     
     
         12 . The method according to  claim 1 , wherein R 2  is C(═O)NH—C 3-8  cycloalkyl. 
     
     
         13 . The method according to  claim 1 , wherein R 2  is C(═O)NHcyclohexyl. 
     
     
         14 . The method according to  claim 1  wherein the compound of formula 1 is: 
       
         
           
           
               
               
           
         
       
     
     
         15 . A method of treating or preventing an RSV infection, comprising administering to a patient in need thereof, an effective amount of a compound of Formula 1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         X is selected from O, S, or NR 7 ; 
         z is selected from 0, 1, 2, 3, 4, 5, and 6; 
         y is selected from 0, 1, 2, 3, 4, 5, and 6; 
         R 1  and R 2  are independently selected from R a , OR a , N(R a ) 2 , SR a , C(═O)R a , —C(═O)OR a , C(═O)N(R a ) 2 , C(═O)SR a ; 
         R 3 , R 4 , R 5 , and R 6  are independently selected from independently selected from —R a , —OR a , —N(R a ) 2 , —SR a , —SO 2 R a , —SO 2 N(R a ) 2 ; —C(O)R a , OC(O)R a , —COOR a , —C(O)N(R a ) 2 , —OC(O)N(R a ) 2 , —N(R a )C(O), —N(R a )C(O)N(R a ) 2 , —F, —Cl, —Br, —I, —CN, —NO 2 ; wherein when multiple R a  groups are present, said R a  groups may together form a ring; 
         R 7 , when present, is R a , C(O)R a , SO 2 R a , COOR a , C(O)N(R a ) 2 , 
         wherein either of R 3  and R 4 , or R 5  and R 6  may together form a double bond 
         wherein either of R 4  and R 6  or R 3  and R 5  may together form a carbonyl, imine or olefin; and 
         wherein any of two or more of R 1 , R 2 , R 3 , R 4 , R 5 , R 6  or R 7 , or R a  groups may together form a ring; and 
         wherein R a  is in each case independently selected from hydrogen, C 1-8  alkyl, C 3-8  cycloalkyl, C 2-8  heterocyclyl, C 6-12  aryl, C 3-12  heteroaryl, C 1-8  alkyl-C 3-8  cycloalkyl, C 1-8  alkyl-C 2-8  heterocyclyl, C 1-8  alkyl-C 6-12  aryl, and C 1-8  alkyl-C 3-12  heteroaryl. 
       
     
     
         16 . The method of treating or preventing an RSV infection according to  claim 15  wherein the compound is administered via a route of administration selected from the group consisting of buccal, oral, intravenous, inhalation, intradermal, intramuscular, topical, subcutaneous, rectal, vaginal, parenteral, pulmonary, intranasal, and ophthalmic. 
     
     
         17 . The method of treating or preventing an RSV infection according to  claim 15  wherein the compound of Formula 1 is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of treating or preventing an RSV infection according to  claim 15  wherein the compound of Formula 1 is: 
       
         
           
           
               
               
           
         
       
     
     
         19 . A compound of Formula 1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         X is selected from O, S, or NR 7 ; 
         z is selected from 0, 1, 2, 3, 4, 5, and 6; 
         y is selected from 0, 1, 2, 3, 4, 5, and 6; 
         R 1  and R 2  are independently selected from R a , OR a , N(R a ) 2 , SR a , C(═O)R a , C(═O)OR a , C(═O)N(R a ) 2 , C(═O)SR a ; 
         R 3 , R 4 , R 5 , and R 6  are independently selected from independently selected from —R a , —OR a , —N(R a ) 2 , —SR a , —SO 2 R a , —SO 2 N(R a ) 2 ; —C(O)R a , OC(O)R a , —COOR a , —C(O)N(R a ) 2 , —OC(O)N(R a ) 2 , —N(R a )C(O), —N(R a )C(O)N(R a ) 2 , —F, —Cl, —Br, —I, —CN, —NO 2 ; wherein when multiple R a  groups are present, said R a  groups may together form a ring; 
         R 7 , when present, is R a , C(O)R a , SO 2 R a , COOR a , C(O)N(R a ) 2 , 
         wherein either of R 3  and R 4 , or R 5  and R 6  may together form a double bond 
         wherein either of R 4  and R 6  or R 3  and R 5  may together form a carbonyl, imine or olefin; and 
         wherein any of two or more of R 1 , R 2 , R 3 , R 4 , R 5 , R 6  or R 7 , or R a  groups may together form a ring; and 
         wherein R a  is in each case independently selected from hydrogen, C 1-8  alkyl, C 3-8  cycloalkyl, C 2-8  heterocyclyl, C 6-12  aryl, C 3-12  heteroaryl, C 1-8  alkyl-C 3-8  cycloalkyl, C 1-8  alkyl-C 2-8  heterocyclyl, C 1-8  alkyl-C 6-12  aryl, and C 1-8  alkyl-C 3-12  heteroaryl. 
       
     
     
         20 . The compound according to  claim 19  wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         21 . A pharmaceutical composition comprising the compound of  claim 19  and a pharmaceutically acceptable carrier, vehicle, or excipient. 
     
     
         22 . A pharmaceutical composition comprising a compound of Formula 1: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         X is selected from O, S, or NR 7 ; 
         z is selected from 0, 1, 2, 3, 4, 5, and 6; 
         y is selected from 0, 1, 2, 3, 4, 5, and 6; 
         R 1  and R 2  are independently selected from R a , OR a , N(R a ) 2 , SR a , C(═O)R a , C(═O)OR a , C(═O)N(R a ) 2 , C(═O)SR a ; 
         R 3 , R 4 , R 5 , and R 6  are independently selected from independently selected from —R a , —OR a , —N(R a ) 2 , —SR a , —SO 2 R a , —SO 2 N(R a ) 2 ; —C(O)R a , OC(O)R a , —COOR a , —C(O)N(R a ) 2 , —OC(O)N(R a ) 2 , —N(R a )C(O), —N(R a )C(O)N(R a ) 2 , —F, —Cl, —Br, —I, —CN, —NO 2 ; wherein when multiple R a  groups are present, said R a  groups may together form a ring; 
         R 7 , when present, is R a , C(O)R a , SO 2 R a , COOR a , C(O)N(R a ) 2 , 
         wherein either of R 3  and R 4 , or R 5  and R 6  may together form a double bond 
         wherein either of R 4  and R 6  or R 3  and R 5  may together form a carbonyl, imine or olefin; and 
         wherein any of two or more of R 1 , R 2 , R 3 , R 4 , R 5 , R 6  or R 7 , or R a  groups may together form a ring; and 
         wherein R a  is in each case independently selected from hydrogen, C 1-8  alkyl, C 3-8  cycloalkyl, C 2-8  heterocyclyl, C 6-12  aryl, C 3-12  heteroaryl, C 1-8  alkyl-C 3-8  cycloalkyl, C 1-8  alkyl-C 2-8  heterocyclyl, C 1-8  alkyl-C 6-12  aryl, and C 1-8  alkyl-C 3-12  heteroaryl; 
         and a pharmaceutically acceptable carrier, vehicle, or excipient. 
       
     
     
         23 . The pharmaceutical composition according to  claim 22  wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The pharmaceutical composition according to  claim 22  wherein the compound is: