US2015342932A1PendingUtilityA1

Anti-viral compounds

Assignee: KINETA INCPriority: Jan 15, 2013Filed: Jun 8, 2015Published: Dec 3, 2015
Est. expiryJan 15, 2033(~6.5 yrs left)· nominal 20-yr term from priority
A61K 31/47C07D 513/04A61K 31/5377A61K 31/429A61P 31/12A61P 31/14Y02A50/30
48
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Claims

Abstract

Disclosed herein are compounds and related compositions for the treatment of viral infection, including RNA viral infection, and compounds that can modulate the RIG-I pathway in vertebrate cells, including compounds that can activate the RIG-I pathway.

Claims

exact text as granted — not AI-modified
1 - 26 . (canceled) 
     
     
         27 . A method of treating or preventing a viral infection in a vertebrate comprising administering to the vertebrate a pharmaceutical composition comprising a compound represented by a formula: 
       
         
           
           
               
               
           
         
       
       wherein a dashed line indicates the presence or absence of a pi bond;
 A and B are each independently single or double covalent bonds;
   L is A-C(═R x )—NR 5 —B,
 
   A-SO 2 —NR 5 —B,
 
   A-N R 5 —SO 2 —B,
 
   A-CH(CF 3 )—NR 5 —B,
 
   A-NR 5 —CH(CF 3 )—B,
 
 
 
       
         
           
           
               
               
           
         
           A-N R 5 —C(═R y )—NR 5 —B,
 
           A-CR 2 R 3 —R x —B,
 
           A-O—CR 2 R 3 —B,
 
           A-S—CR 2 R 3 —B,
 
           A-C(R 2 )═C(R 3 )—B,
 
       
       
         
           
           
               
               
           
         
         where m and n are independently an integer from 0-5 such that m+n≧1, 
         R 1  is R a , OR 2  or NR 2 R 3 ; 
         each R a  is independently H, hydrocarbyl optionally substituted by OR b , OCF 3 , OCOR b , COOR b , CON b R c , SR b , NR b R c , NR b COR c , SO 2 NR b R c , NO 2 , F, Cl, Br, CN, heterocycloalkyl; aryl optionally substituted by OR b , OCF 3 , OCOR b , COOR b , CON b R c , SR b NR b R c , NR b COR c , SO 2 NR b R c , NO 2 , F, Cl, Br, CN, heterocycloalkyl; or heteroaryl optionally substituted by OR b , OCF 3 , OCOR b , COOR b , CON b R c , SR b , NR b R c , NR b COR c , SO 2 NR b R c , NO 2 , F, Cl, Br, CN, heterocycloalkyl; 
         R 2  and R 3  are each independently R a , COR a , C(═O)OR a , or SO 2 R a ; 
         Y 5 , Y 6 , Y 7  and Y 8  are each independently CR 4 , N, or O; 
         R 4  is R 2 , OR a , NR 2 R 3 , SR a , SOR a , SO 2 R a , SO 2 NHR a , N(R 5 )COR a , halogen, trihalomethyl, CN, S═O, or nitro; 
         each R 5  is independently R a , COR a , SO 2 R a , or is not present; 
         W 1  and W 2  are each independently, O, S, NH, or CH 2 ; 
         each R x  is independently O, S, CR 2 R 3 , or NR 5 ; 
         R y  is S, N—CN, or CHR 4 ; 
         R z  is R b , OR b , SR b , COR b , CO 2 R b , OCOR b , NR b R c , CON b R c , NR b COR c , SO 2 NR b R c , CF 3 , CN, NO 2 , F, Cl, Br, I, or C 2-5  heterocyclyl; 
         each R b  is independently H or C 1-3  hydrocarbyl, and each R c  is independently H or C 1-3  alkyl; and 
         Z 1  and Z 2  are each independently C or N. 
       
     
     
         28 . The method of  claim 27  wherein the compound is represented by a formula 
       
         
           
           
               
               
           
         
         wherein 
         R 10 , R 13 , R 14 , R 19 , R 20 , R 21 , and R 22  are independently R b , OR b , SR b , COR b , CO 2 R b , OCOR b , NR b R c , CON b R c , NR b COR c , SO 2 NR b R c , CF 3 , CN, NO 2 , F, Cl, Br, I, or C 2-5  heterocyclyl; each R b  is independently H or C 1-3  hydrocarbyl, and each R c  is independently H or C 1-3  alkyl. 
       
     
     
         29 . The method of  claim 27 , wherein R 1  is optionally substituted naphthyl or optionally substituted phenyl. 
     
     
         30 . The method of  claim 27 , wherein the compound is further represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         31 . The method of claim of  claim 27 , wherein in the compound, R 5  is H or C 1-3  alkyl. 
     
     
         32 . The method of  claim 27 , wherein the compound is further represented by a formula 
       
         
           
           
               
               
           
         
       
       wherein
 R 10 , R 11 , R 12 , R 13 , and R 14  are independently R b , OR b , COR b , CO 2 R b , OCOR b , NR b R c , CF 3 , CN, NO 2 , F, Cl, Br, or I, wherein R b  and R c  are independently H or C 1-3  alkyl; and, R 5  is H or C 1-3  alkyl. 
 
     
     
         33 . The method of  claim 27 , wherein in the compound, R z  is CH 3 . 
     
     
         34 . The method of  claim 27 , wherein in the compound, R 13  is Br. 
     
     
         35 . The method of  claim 27 , wherein the compound is further represented by a formula 
       
         
           
           
               
               
           
         
       
     
     
         36 . The method of  claim 27  wherein the viral infection is caused by a virus from one or more of the following families: Arenaviridae, Astroviridae, Birnaviridae, Bromoviridae, Bunyaviridae, Caliciviridae, Closteroviridae, Comoviridae, Cystoviridae, Flaviviridae, Flexiviridae, Hepevirus, Leviviridae, Luteoviridae, Mononegavirales, Mosaic Viruses, Nidovirales, Nodaviridae, Orthomyxoviridae, Picobirnavirus, Picornaviridae, Potyviridae, Reoviridae, Retroviridae, Sequiviridae, Tenuivirus, Togaviridae, Tombusviridae, Totiviridae, Tymoviridae, Hepadnaviridae, Herpesviridae, Paramyxoviridae or Papillomaviridae 
     
     
         37 . The method of  claim 27  wherein the viral infection is influenza virus, Hepatitis C virus, West Nile virus, SARS-coronavirus, poliovirus, measles virus, Dengue virus, yellow fever virus, tick-borne encephalitis virus, Japanese encephalitis virus, St. Louis encephalitis virus, Murray Valley virus, Powassan virus, Rocio virus, louping-ill virus, Banzi virus, Ilheus virus, Kokobera virus, Kunjin virus, Alfuy virus, bovine diarrhea virus, Kyasanur forest disease virus, respiratory syncytial virus or human immunodeficiency virus (HIV). 
     
     
         38 . The method of  claim 27 , wherein the pharmaceutical composition is administered as an adjuvant for a prophylactic or therapeutic vaccine. 
     
     
         39 . The method of  claim 37  wherein the method comprises vaccinating a vertebrate by additionally administering a vaccine against influenza virus, Hepatitis C virus, West Nile virus, SARS-coronavirus, poliovirus, measles virus, Dengue virus, yellow fever virus, tick-borne encephalitis virus, Japanese encephalitis virus, St. Louis encephalitis virus, Murray Valley virus, Powassan virus, Rocio virus, louping-ill virus, Banzi virus, Ilheus virus, Kokobera virus, Kunjin virus, Alfuy virus, bovine diarrhea virus, Kyasanur forest disease virus, respiratory syncytial virus or human immunodeficiency virus (HIV). 
     
     
         40 . A method of modulating the innate immune response in a eukaryotic cell, comprising administering to the eukaryotic cell a compound represented by a formula: 
       
         
           
           
               
               
           
         
       
       wherein a dashed line indicates the presence or absence of a pi bond;
 A and B are each independently single or double covalent bonds;
   L is A-C(═R x )—NR 5 —B,
 
 
 A-SO 2 —NR 5 —B,
   A-NR 5 —SO 2 —B,
 
   A-CH(CF 3 )—NR 5 —B,
 
   A-NR 5 —CH(CF 3 )—B.
 
 
 
       
         
           
           
               
               
           
         
           A-NR 5 —C(═R y )—NR 5 —B,
 
           A-CR 2 R 3 —R x —B,
 
           A-O—CR 2 R 3 —B,
 
           A-S—CR 2 R 3 —B,
 
           A-C(R 2 )═C(R 3 )—B,
 
       
       
         
           
           
               
               
           
         
         where m and n are independently an integer from 0-5 such that m+n≧1, 
         R 1  is R a , OR 2  or NR 2 R 3 ; 
         each R a  is independently H, hydrocarbyl optionally substituted by OR b , OCF 3 , OCOR b , COOR b , CON b R c , SR b , NR b R c , NR b COR c , SO 2 NR b R c , NO 2 , F, Cl, Br, CN, heterocycloalkyl; aryl optionally substituted by OR b , OCF 3 , OCOR b , COOR b , CON b R c , SR b , NR b R c , NR b COR c , SO 2 NR b R c , NO 2 , F, Cl, Br, CN, heterocycloalkyl; or heteroaryl optionally substituted by OR b , OCOR b , COOR b , CON b R c , SR b , NR b R c , NR b COR c , SO 2 NR b R c , NO 2 , F, Cl, Br, CN, heterocycloalkyl; 
         R 2  and R 3  are each independently R a , COR a , C(═O)OR a , or SO 2 R a ; 
         Y 5 , Y 6 , Y 7 , and Y 8  are each independently CR 4 , N, or O; 
         R 4  is R 2 , OR a , NR 2 R 3 , SR a , SOR a , SO 2 R a , SO 2 NHR a , N(R 5 )COR a , halogen, trihalomethyl, CN, S═O, or nitro; 
         each R 5  is independently R a , COR a , SO 2 R a , or is not present; 
         W 1  and W 2  are each independently, O, S, NH, or CH 2 ; 
         each R x  is independently O, S, CR 2 R 3 , or NR 5 ; 
         R y  is S, N—CN, or CHR 4 ; 
         R z  is R b , OR b , SR b , COR b , CO 2 R b , OCOR b , NR b R c , CON b R c , NR b COR c , SO 2 NR b R c , CF 3 , CN, NO 2 , F, Cl, Br, I, or C 2-5  heterocyclyl; 
         each R b  is independently H or C 1-3  hydrocarbyl, and each R c  is independently H or C 1-3  alkyl; and 
         Z 1  and Z 2  are each independently C or N. 
       
     
     
         41 . The method of  claim 40 , wherein the eukaryotic cell is in viva 
     
     
         42 . The method of  claim 40 , wherein the eukaryotic cell is in vitro.

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