Methods and compounds for treating paramyxoviridae virus infections

Abstract

Provided are methods for treating Paramyxoviridae virus infections by administering ribosides, riboside phosphates and prodrugs thereof, of Formula I: wherein the 1′ position of the nucleoside sugar is substituted. The compounds, compositions, and methods provided are particularly useful for the treatment of Human parainfluenza and Human respiratory syncytial virus infections.

1 . A method of treating a Paramyxoviridae infection in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester, thereof; 
       
       wherein:
 each R 1  is H or halogen; 
 each R 2 , R 3  or R 5  is independently H, OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R a , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl or (C 2 -C 8 )substituted alkynyl; 
 or any two R 2 , R 3  or R 5  on adjacent carbon atoms when taken together are —O(CO)O— or when taken together with the ring carbon atoms to which they are attached form a double bond; 
 R 6  is OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R a , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, (C 2 -C 8 )substituted alkynyl, or aryl(C 1 -C 8 )alkyl; 
 each n is independently 0, 1, or 2; 
 each R a  is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), or —SO 2 NR 11 R 12 ; 
 R 7  is H, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , or 
 
       
         
           
           
               
               
           
         
         each Y or Y 1  is, independently, O, S, NR,  + N(O)(R), N(OR),  + N(O)(OR), or N—NR 2 ; 
         W 1  and W 2 , when taken together, are —Y 3 (C(R y ) 2 ) 3 Y 3 —; or one of W 1  or W 2  together with either R 3  or R 4  is —Y 3 — and the other of W 1  or W 2  is Formula Ia; or W 1  and W 2  are each, independently, a group of the Formula Ia: 
       
       
         
           
           
               
               
           
         
         wherein: 
         each Y 2  is independently a bond, O, CR 2 , NR,  + N(O)(R), N(OR),  + N(O)(OR), N—NR 2 , S, S—S, S(O), or S(O) 2 ; 
         each Y 3  is independently O, S, or NR; 
         M2 is 0, 1 or 2; 
         each R x  is independently R y  or the formula: 
       
       
         
           
           
               
               
           
         
         wherein: 
         each M1a, M1c, and M1d is independently 0 or 1; 
         M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 
         each R y  is independently H, F, Cl, Br, I, OH, R, —C(═Y 1 )R, —C(═Y 1 )OR, —C(═Y 1 )N(R) 2 , —N(R) 2 , — + N(R) 3 , —SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), —OC(═Y 1 )R, —OC(═Y 1 )OR, —OC(═Y 1 )(N(R) 2 ), —SC(═Y 1 )R, —SC(═Y 1 )OR, —SC(═Y 1 )(N(R) 2 ), —N(R)C(═Y 1 )R, —N(R)C(═Y 1 )OR, —N(R)C(═Y 1 )N(R) 2 , —SO 2 NR 2 , —CN, —N 3 , —NO 2 , —OR, or W 3 ; or when taken together, two R y  on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms; 
         each R is independently H, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, C 6 -C 20  aryl, C 6 -C 20  substituted aryl, C 2 -C 20  heterocyclyl, C 2 -C 20  substituted heterocyclyl, arylalkyl or substituted arylalkyl; 
         W 3  is W 4  or W 5 ; W 4  is R, —C(Y 1 )R y , —C(Y 1 )W 5 , —SO 2 R y , or —SO 2 W 5 ; and W 5  is a carbocycle or a heterocycle wherein W 5  is independently substituted with 0 to 3 R y  groups; 
         each R 8  is halogen, NR 11 R 12 , N(R 11 )OR 11 NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH(═NR 11 ), —CH═NNHR 11 , —CH═N(OR 11 ), —CH(OR 11 ) 2 , —C(═O)NR 11 R 12 , —C(═S)NR 11 R 12 , —C(═O)OR 11 , (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl, aryl(C 1 -C 8 )alkyl, OR 11  or SR 11 ; 
         each R 9  or R 10  is independently H, halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH(═NR 11 ), —CH═NHNR 11 , —CH═N(OR 11 ), —CH(OR 11 ) 2 , —C(═O)NR 11 R 12 , —C(═S)NR 11 R 12 , —C(═O)OR 11 , R 11 , OR 11  or SR 11 ; and 
         each R 11  or R 12  is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O) (C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 ) alkyl or aryl(C 1 -C 8 )alkyl; or R 11  and R 12  taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NR a —; and 
         wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(C 1 -C 8 )alkyl of each R 2 , R 3 , R 5 , R 6 , R 11  or R 12  is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2  or OR a ; and wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NR a —. 
       
     
     
         2 . The method of  claim 1  wherein the compound of Formula I is represented by Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester, thereof; 
       
       wherein:
 each R 1  is H or halogen; 
 each R 2  is OR a  or halogen; 
 each R 3  or R 5  is independently H, OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R a , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl or (C 2 -C 8 )substituted alkynyl; 
 or any two R 2 , R 3  or R 5  on adjacent carbon atoms when taken together are —O(CO)O— or when taken together with the ring carbon atoms to which they are attached form a double bond; and 
 R 6  is OR a , N(R a ) 2 , N 3 , CN, S(O) n R a , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, or (C 2 -C 8 )substituted alkynyl. 
 
     
     
         3 . The method of  claim 1  wherein the compound of Formula I is represented by Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester, thereof; 
       
       wherein:
 each R 2  is OR a  or F; 
 each R 3  is OR a ; and 
 R 6  is OR a , N(R a ) 2 , N 3 , CN, S(O) n R a , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, or (C 2 -C 8 )substituted alkynyl. 
 
     
     
         4 . The method of  claim 1  wherein R 6  is CN, methyl, ethenyl, or ethynyl. 
     
     
         5 . The method of  claim 1  wherein R 2  is OR a . 
     
     
         6 . The method of  claim 1  wherein R 3  is OH, —OC(═O)R 11 , or —OC(═O)OR 11 . 
     
     
         7 . The method of  claim 1  wherein R 8  is NR 11 R 12  or OR 11 . 
     
     
         8 . The method of  claim 7  wherein R 8  is NH 2 . 
     
     
         9 . The method of  claim 7  wherein R 8  is OH. 
     
     
         10 . The method of  claim 1  wherein R 9  is H. 
     
     
         11 . The method of  claim 1  wherein R 9  is NH 2 . 
     
     
         12 . The method of  claim 1  wherein R 7  is H. 
     
     
         13 . The method of  claim 1  wherein the compound of Formula I is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         14 . The method of  claim 1  further comprising a pharmaceutically acceptable carrier or excipient. 
     
     
         15 . The method of  claim 1  further comprising administering a therapeutically effective amount of at least one other thereapeutic agent or composition thereof selected from the group consisting of a corticosteroid, an anti-inflammatory signal transduction modulator, a β2-adrenoreceptor agonist bronchodilator, an anticholinergic, a mucolytic agent, hypertonic saline and other drugs for treating Paramyxoviridae virus infections; or mixtures thereof. 
     
     
         16 . The method of  claim 15  wherein the at least one other thereapeutic agent is ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637 or BMS-433771 or mixtures thereof. 
     
     
         17 . The method of  claim 15  wherein at least one therapeutic agent or mixtures thereof is administered by inhalation. 
     
     
         18 . The method of  claim 17  wherein at least one therapeutic agent or mixtures thereof is administered by nebulization. 
     
     
         19 . The method of  claim 1  wherein the Paramyxoviridae infection is caused by a Paramyxovirina virus. 
     
     
         20 . The method of  claim 1  wherein the Paramyxoviridae infection is caused by a Respirovirus virus. 
     
     
         21 . The method of  claim 1  wherein the Paramyxoviridae infection is caused by a type 1 or 3 Human parainfluenza virus. 
     
     
         22 . The method of  claim 1  wherein the Paramyxoviridae infection is caused by a Pneumovirinae virus. 
     
     
         23 . The method of  claim 1  wherein the Paramyxoviridae infection is caused by a Human respiratory syncytial virus. 
     
     
         24 . The method of  claim 1  wherein a Paramyxoviridae polymerase is inhibited. 
     
     
         25 . A compound of Formula I that is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         26 . A compound of Formula I represented by Formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or ester, thereof; 
       
       wherein:
 each R 1  is H or halogen; 
 each R 3  or R 5  is independently H, OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R a , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl or (C 2 -C 8 )substituted alkynyl; 
 R 6  is OR a , N(R a ) 2 , N 3 , CN, S(O) n R a , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, or (C 2 -C 8 )substituted alkynyl; 
 each n is independently 0, 1, or 2; 
 each R a  is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), or —SO 2 NR 11 R 12 ; 
 R 7  is H, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , or 
 
       
         
           
           
               
               
           
         
       
       each Y or Y 1  is, independently, O, S, NR,  + N(O)(R), N(OR),  + N(O)(OR), or N—NR 2 ;
 W 1  and W 2 , when taken together, are —Y 3 (C(R y ) 2 ) 3 Y 3 —; or one of W 1  or W 2  together with either R 3  or R 4  is —Y 3 — and the other of W 1  or W 2  is Formula Ia; or W 1  and W 2  are each, independently, a group of the Formula Ia: 
 
       
         
           
           
               
               
           
         
         wherein: 
         each Y 2  is independently a bond, O, CR 2 , NR,  + N(O)(R), N(OR),  + N(O)(OR), N—NR 2 , S, S—S, S(O), or S(O) 2 ; 
         each Y 3  is independently O, S, or NR; 
         M2 is 0, 1 or 2; 
         each R x  is independently R y  or the formula: 
       
       
         
           
           
               
               
           
         
         wherein: 
         each M1a, M1c, and M1d is independently 0 or 1; 
         M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 
         each R y  is independently H, F, Cl, Br, I, OH, R, —C(═Y 1 )R, —C(═Y 1 )OR, —C(═Y 1 )N(R) 2 , —N(R) 2 , — + N(R) 3 , —SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), —OC(═Y 1 )R, —OC(═Y 1 )OR, —OC(═Y 1 )(N(R) 2 ), —SC(═Y 1 )R, —SC(═Y 1 )OR, —SC(═Y 1 )(N(R) 2 ), —N(R)C(═Y 1 )R, —N(R)C(═Y 1 )OR, —N(R)C(═Y 1 )N(R) 2 , —SO 2 NR 2 , —CN, —N 3 , —NO 2 , —OR, or W 3 ; or when taken together, two R y  on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms; 
         each R is independently H, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, C 6 -C 20  aryl, C 6 -C 20  substituted aryl, C 2 -C 20  heterocyclyl, C 2 -C 20  substituted heterocyclyl, arylalkyl or substituted arylalkyl; 
         W 3  is W 4  or W 5 ; W 4  is R, —C(Y 1 )R y , —C(Y 1 )W 5 , —SO 2 R y , or —SO 2 W 5 ; and W 5  is a carbocycle or a heterocycle wherein W 5  is independently substituted with 0 to 3 R y  groups; 
         each R 8  is halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH(═NR 11 ), —CH═NNHR 11 , —CH═N(OR 11 ), —CH(OR 11 ) 2 , —C(═O)NR 11 R 12 , —C(═S)NR 11 R 12 , —C(═O)OR 11 , (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl, aryl(C 1 -C 8 )alkyl, OR 11  or SR 11 ; 
         each R 9  is independently H, halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH(═NR 11 ), —CH═NHNR 11 , —CH═N(OR 11 ), —CH(OR 11 ) 2 , —C(═O)NR 11 R 12 , —C(═S)NR 11 R 12 , —C(═O)OR 11 , R 11 , OR 11  or SR 11 ; 
         each R 11  or R 12  is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or aryl(C 1 -C 8 )alkyl; or R 11  and R 12  taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NR a —; and 
         wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(C 1 -C 8 )alkyl of each R 3 , R 5 , R 6 , R 11  or R 12  is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2  or OR a ; and wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NR a —. 
       
     
     
         27 . The compound of  claim 26  wherein each R 1 , R 5 , and R 7  is H and R 3  is OR a . 
     
     
         28 . The compound of  claim 26  wherein R 6  is CN, methyl, ethenyl, or ethynyl. 
     
     
         29 . The compound of  claim 26  wherein R 8  is NH 2  and R 9  is H. 
     
     
         30 . The compound of  claim 26  that is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         31 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 26  and a pharmaceutically acceptable carrier. 
     
     
         32 . The composition of  claim 31  further comprising administering a therapeutically effective amount of at least one other thereapeutic agent or composition thereof selected from the group consisting of a corticosteroid, an anti-inflammatory signal transduction modulator, a β2-adrenoreceptor agonist bronchodilator, an anticholinergic, a mucolytic agent, hypertonic saline and other drugs for treating Paramyxoviridae virus infections; or mixtures thereof. 
     
     
         33 . The composition of  claim 32  wherein the at least one other thereapeutic agent is ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637 or BMS-433771 or mixtures thereof.