Anti-viral compounds, pharmaceutical compositions, and methods of use thereof

Abstract

Disclosed herein are compounds, pharmaceutical compositions, and related methods for the treatment of viral infection, including RNA viral infection in subjects. The compounds, pharmaceutical compositions, and methods can modulate the innate immune antiviral response in vertebrate cells, including activating the RIG-I pathway.

What is claimed is: 
     
         1 . A method for treating or preventing a viral infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, 
         wherein R 4  is R d , SO 2 R d , C(═O)R d , NH C(═O)R d , R e , OR c , or CF 3 , wherein R c  is H or C 1 -C 10  hydrocarbyl, R d  is substituted heterocyclic, unsubstituted heterocyclic, or unsubstituted carbocyclic, and R e  is substituted heteroaryl or substituted phenyl; and 
         n is 1 or 2. 
       
     
     
         2 . The method of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, 
         wherein R 4  is: 
         (i) C(═O)R d  and R d  is a pyrrolidonyl group, 
         (ii) SO 2 R d  and R d  is a piperidinyl group, 
         (iii) NHC(═O)R d  and R d  is a phenyl group or a furanyl group, 
         (iv) an imidazolyl group, or 
         (v) a thiazolyl group. 
       
     
     
         3 . The method of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof 
         wherein X is NH or 0. 
       
     
     
         4 . The method of  claim 1 , wherein R 4  is CF 3 , OR c , or a phenyl group substituted by at least one OCH 3  group. 
     
     
         5 . The method of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . A method for treating or preventing a viral infection in a subject, said method comprising administering to said subject a pharmaceutically effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, 
         wherein L is NR 2 , O, S, C(═O)N, CR 2 R 3 CR 2 R 3 , CR 2 R 3 NR 2 , CR 4 ═CR 4 , CR 2 R 3 O, CR 2 R 3 S, NR 2 CR 2 R 3 , NR 2 C(═O), NS(O) t  , OCR 2 R 3 , SCR 2 R 3 ; 
         V is (CR 2 R 3 ) u , C(═O)CR 2 R 3 , CR 2 R 3 O, CR 2 R 3 OCR 2 R 3 , CR 4 ═CR 4 , C(=NR 2 ), or C(═O); 
         Q is NR 2 , O, S(O) t , or a bond; 
         t=0, 1, 2; u=0-3; 
         wherein a dashed line indicates the presence or absence of a bond; 
         R 1  is R a , OR 2 , or NR 2 R 3 ; 
         each R a  is independently H, optionally substituted hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl; 
         R 2  and R 3  are each independently R a , C(═O)R a , SO 2 R a , or R 2  and R 3  form an optionally substituted carbocyclic, heterocarbocyclic, aryl, or heteroaryl ring; 
         each R 4  is independently R 2 , OR a , C(═O)R a , C(═O)NR 2 R 3 , NR 2 R 3 , NR b (═O)R a , SR a , SOR a , SO 2 R a , SO 2 NHR a , SO 2 NR 2 R 3 , NCOR a , halogen, trihalomethyl, CN, S═O, nitro, or two R 4  groups form an optionally substituted carbocyclic, heterocarbocyclic, aryl, or heteroaryl ring; 
         W and X are each independently N, NR a , NR S , O, S, CR 2 R 4  or CR 4 ; 
         R 5  is R a , C(═O)R a , SO 2 R a , or is not present; and 
         Y 1 , Y 2 , Y 3  and Y 4  are each independently CR 4  or N. 
       
     
     
         7 . The method of  claim 6  wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, 
         wherein in each of Formula 1A and Formula 1C, 
         R 1  is R a , OR 2 , or NR 2 R 3 ; 
         each R a  is independently H, optionally substituted hydrocarbyl, optionally substituted aryl, optionally substituted heteroaryl; 
         R 2  and R 3  are each independently R a , C(═O)R a , or SO 2 R a ; 
         each R 4  is independently R 2 , OR a , NR 2 R 3 , SR a , SOR a , SO 2 R a , SO 2 NHR a , NCOR a , C(═O)R a , CONR 2 R 3 , halogen, trihalomethyl, CN, S═O, or nitro; 
         V is CR 2 R 3 , C(═O), C(═O)CR 2 R 3 , or C(═N)R 2 ; and 
         W is O or S. 
       
     
     
         8 . The method of  claim 7  wherein R 4  is H; and V is C═O. 
     
     
         9 . The method of  claim 7  wherein R 1  is optionally substituted phenyl or optionally substituted naphthyl. 
     
     
         10 . The method of  claim 6 , wherein W is S and X is N. 
     
     
         11 . The method of  claim 6 , wherein W is O and X is N. 
     
     
         12 . The method of  claim 1  wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof 
         wherein R 4  is optionally substituted heteroaryl. 
       
     
     
         13 . The method of  claim 1  wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The method of  claim 1  wherein the viral infection is caused by a virus from one or more of the following families: Arenaviridae, Arterivirus, Astroviridae, Birnaviridae, Bromoviridae, Bunyaviridae, Caliciviridae, Closteroviridae, Comoviridae, Coronaviridae, Cystoviridae, Filoviridae, Flaviviridae, Flexiviridae, Hepadnaviridae, Hepevirus, Herpesviridae, Leviviridae, Luteoviridae, Mesoniviridae, Mononegavirales, Mosaic Viruses, Nidovirales, Nodaviridae, Orthomyxoviridae, Papillomaviridae, Paramyxoviridae, Picobirnaviridae, Picobirnavirus, Picornaviridae, Potyviridae, Reoviridae, Retroviridae, Roniviridae, Sequiviridae, Tenuivirus, Togaviridae, Tombusviridae, Totiviridae, and Tymoviridae. 
     
     
         15 . The method of  claim 6  wherein the viral infection is caused by a virus from one or more of the following families: Arenaviridae, Arterivirus, Astroviridae, Birnaviridae, Bromoviridae, Bunyaviridae, Caliciviridae, Closteroviridae, Comoviridae, Coronaviridae, Cystoviridae, Filoviridae, Flaviviridae, Flexiviridae, Hepadnaviridae, Hepevirus, Herpesviridae, Leviviridae, Luteoviridae, Mesoniviridae, Mononegavirales, Mosaic Viruses, Nidovirales, Nodaviridae, Orthomyxoviridae, Papillomaviridae, Paramyxoviridae, Picobirnaviridae, Picobirnavirus, Picornaviridae, Potyviridae, Reoviridae, Retroviridae, Roniviridae, Sequiviridae, Tenuivirus, Togaviridae, Tombusviridae, Totiviridae, and Tymoviridae. 
     
     
         16 . The method of  claim 1 , wherein the viral infection is caused by Alfuy virus, Banzi virus, bovine diarrhea virus, Chikungunya virus, Dengue virus (DNV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), human cytomegalovirus (hCMV), human immunodeficiency virus (HIV), Ilheus virus, influenza virus (including avian and swine isolates), rhinovirus, norovirus, adenovirus, Japanese encephalitis virus, Kokobera virus, Kunjin virus, Kyasanur forest disease virus, louping-ill virus, measles virus, MERS-coronavirus (MERS), metapneumovirus, any of the Mosaic Viruses, Murray Valley virus, parainfluenza virus, poliovirus, Powassan virus, respiratory syncytial virus (RSV), Rocio virus, SARS-coronavirus (SARS), St. Louis encephalitis virus, tick-borne encephalitis virus, West Nile virus (WNV), Ebola virus, Nipah virus, Lassa virus, Tacaribe virus, Junin virus, or yellow fever virus. 
     
     
         17 . The method of  claim 6 , wherein the viral infection is caused by Alfuy virus, Banzi virus, bovine diarrhea virus, Chikungunya virus, Dengue virus (DNV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), human cytomegalovirus (hCMV), human immunodeficiency virus (HIV), Ilheus virus, influenza virus (including avian and swine isolates), rhinovirus, norovirus, adenovirus, Japanese encephalitis virus, Kokobera virus, Kunjin virus, Kyasanur forest disease virus, louping-ill virus, measles virus, MERS-coronavirus (MERS), metapneumovirus, any of the Mosaic Viruses, Murray Valley virus, parainfluenza virus, poliovirus, Powassan virus, respiratory syncytial virus (RSV), Rocio virus, SARS-coronavirus (SARS), St. Louis encephalitis virus, tick-borne encephalitis virus, West Nile virus (WNV), Ebola virus, Nipah virus, Lassa virus, Tacaribe virus, Junin virus, or yellow fever virus. 
     
     
         18 . The method of  claim 1  wherein the viral infection is an RNA virus. 
     
     
         19 . The method of  claim 6  wherein the viral infection is an RNA virus. 
     
     
         20 . The method of  claim 1  wherein the viral infection is a DNA virus. 
     
     
         21 . The method of  claim 6  wherein the viral infection is a DNA virus. 
     
     
         22 . The method of  claim 1  wherein the viral infection is caused by Coronaviridae virus. 
     
     
         23 . The method of  claim 6  wherein the viral infection is caused by Coronaviridae virus. 
     
     
         24 . The method of  claim 1  wherein the viral infection is caused by MERS-coronavirus (MERS) or by SARS-coronavirus (SARS). 
     
     
         25 . The method of  claim 6  wherein the viral infection is caused by MERS-coronavirus (MERS) or by SARS-coronavirus (SARS).