Human helicase ddx3 inhibitors as therapeutic agents

Abstract

The present invention refers to compounds endowed with RNA helicase DDX3 inhibitory activity of formula I and II and their therapeutic use, in particular for the treatment of viral diseases.

1 . A compound of formula: 
       
         
           
           
               
               
           
         
         wherein 
         X and Y are each independently C or N; 
         A is unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, wherein the one or more substituents on the aryl or heteroaryl are independently selected from unsubstituted or substituted C 1 -C 6  alkyl, unsubstituted or substituted C 2 -C 6  alkenyl, unsubstituted or substituted C 2 -C 6  alkynyl, haloalkyl, halogen, OR A , SR A , S(═O)(═O)—R A , SO 2 NHR A , COOR B , OC(O)R B , C(O)R A , NR A R B , OP(O)(OR A ) 2 , NHC(O)R A , COONR A R B , or 
       
       
         
           
           
               
               
           
         
         wherein the one or more substituents on the C 1 -C 6  alkyl or on the C 2 -C 6  alkenyl or on the C 2 -C 6  alkynyl are independently selected from OR A , COOR B , OC(O)R B , C(O)R B  NR A R B , OP(O)(OR A ) 2 , NHC(O)R A , NHC(O)OR A , COONR A R B , SR A , S(═O)(═O)—R A , SO 2 NHR A ; 
         R 1 , R 2 , R 3 , R 4 , R 6 , R 7  and R 10  are each independently selected from H, halogen, alkoxy, C 1 -C 6  alkyl, haloalkyl, OR A , SR A , S(═O)(═O)—R A , SO 2 NHR A , COOR B , OC(O)R B , NR A R B , OP(O)(OR A ) 2 , NHC(O)R A , COONR A R B , NO 2 , CN, 
         R 2 , R 4 , R 7  and R 10  are absent when X and/or Y is N; 
         Z is a heteroaryl group selected from: 
       
       
         
           
           
               
               
           
         
         wherein 
         R 5  is H, unsubstituted or substituted C 1 -C 10  alkyl or C 1 -C 8  haloalkyl, unsubstituted or substituted phenyl, 
         wherein the one or more substituents on the C 1 -C 10  alkyl are independently selected from halogen, OR A , COOR B , OC(O)R B , C(O)R B , NR A R B , OP(O)(OR A ) 2 , OC(O)NR A R B , NHC(O)OR A , NHC(O)R A , COONR A R B , OC(O)CHCHR C , 
       
       
         
           
           
               
               
           
         
         wherein the one or more substituents on the haloalkyl are independently selected from alkoxy, phenyl, OH, COOR B , OC(O)R B , C(O)R B , NR A R B , OP(O)(OR A ) 2 , OC(O)NR A R B , NHC(O)OR A , NHC(O)R A , COONR A R B , OC(O)CHCHR C    
         wherein the one or more substituents on the phenyl are independently selected from halogen, haloalkyl, alkoxy, C 1 -C 3  alkyl, OH; 
         R A  and R B  are each independently selected from H, C 1 -C 6  alkyl, unsubstituted or substituted aralkyl, haloalkyl, 
         or R A  and R B  together with the nitrogen to which they are attached, form a 4-7 membered saturated or partially unsaturated ring optionally containing one or more additional heteroatoms independently selected from N, S and O the ring being optionally substituted by one, two or more groups independently selected from halogen, C 1 -C 6  alkyl, haloalkyl, OH, alkoxy; 
         R C  is substituted or unsubstituted phenyl, 1,3 benzodioxolyl, wherein the one or more substituent(s) on the phenyl are independently selected from halogen, haloalkyl, alkoxy, C 1 -C 3  alkyl, or OH; 
         wherein the one or more substituents on the phenyl are independently selected from halogen, haloalkyl, alkoxy, C 1 -C 3  alkyl, OH; 
         R 8  and R 9  are each independently selected from H, halogen, alkoxy, COOH, nitro and at least one of R 8  and R 9  is a heteroaryl group selected from: 
       
       
         
           
           
               
               
           
         
         or salt, solvate, stereoisomer thereof, 
         provided that compounds: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         are excluded. 
       
     
     
         2 . The compound according to  claim 1  wherein X and Y are C. 
     
     
         3 . The compound according to  claim 1  or  2  wherein A is substituted aryl. 
     
     
         4 . The compound according to  claim 3  wherein the substituted aryl is phenyl. 
     
     
         5 . The compound according to  claim 4  wherein the phenyl is substituted by one, two or more groups independently selected from methyl, isopropyl, CF 3 , F, Cl, OH, OMe. 
     
     
         6 . The compound according to  claim 1  or  2  wherein A is unsubstituted or substituted heteroaryl. 
     
     
         7 . The compound according to  claim 6  wherein the substituted heteroaryl is pyridinyl or isoquinolinyl. 
     
     
         8 . The compound according to any one of previous claim being selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or salt, solvate, stereoisomer thereof. 
       
     
     
         9 . The compound according to any one of previous claim being selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or pharmaceutical acceptable salt, solvate, stereoisomer thereof. 
       
     
     
         10 . The compound or pharmaceutical acceptable salt, solvate, stereoisomer thereof according to any one of previous claim being an inhibitor of DDX3. 
     
     
         11 . The compound or pharmaceutical acceptable salt, solvate, stereoisomer thereof according to any one of previous claim for medical use. 
     
     
         12 . The compound or pharmaceutical acceptable salt, solvate, stereoisomer thereof according to  claim 11  for use in the treatment of a viral disease. 
     
     
         13 . The compound for use according to  claim 12  wherein the viral disease is modulated by DDX3. 
     
     
         14 . The compound for use according to  claim 12  or  13  wherein the viral disease is caused by a virus that is resistant to at least one compound selected from the group consisting of: protease inhibitor; nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor or integrase inhibitor. 
     
     
         15 . The compound according to  claims 12  to  14  for use in the treatment of a viral disease is caused by a virus selected from the group consisting of: Human Immunodeficiency Virus 1 (HIV-1), Hepatitis C Virus, Hepatitis B Virus, Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus, Venezuelan Equine Encephalitis Virus, Japanese Encephalitis Virus, Tick Borne Encephalitis Virus, Yellow Fever Virus, St. Louis Encephalitis Virus, Murray Valley Encephalitis Virus, Powassan Virus, Dengue Virus, Zika Virus, West Nile Virus, Rubella Virus, Cytomegalovirus, O'nyong'nyong Virus, Mayaro Virus, Ross River Virus, Sindbis Virus, Vaccinia Virus, Influenza Virus, Norovirus, SARS Coronavirus, Chikunguya Virus, Lassa Virus, Ebola Virus, Lujo Virus, Pneumovirus, Severe Fever With Thrombocytopenia Syndrome Virus, Porcine Reproductive And Respiratory Syndrome Virus, Poxvirus, Bovine Viral Diarrhea Virus (BVDV), Border Disease Virus (BDV) of sheep, and Classical Swine Fever Virus (CSFV). 
     
     
         16 . The compound according to  claim 15  for use in the treatment of a viral disease is caused by a virus selected from the group consisting of: Human Immunodeficiency Virus 1 (HIV-1), Hepatitis C Virus, West Nile Virus, Dengue Virus, Japanese Encephalitis Virus, Porcine Reproductive And Respiratory Syndrome Virus, Ebola Virus, Zika Virus. 
     
     
         17 . The compound according to  claim 16  for use in the treatment of a viral disease is caused by a virus selected from the group consisting of: Ebola Virus and Zika Virus. 
     
     
         18 . The compound for use according to any one of  claims 11  to  17  being selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         19 . A pharmaceutical composition comprising the compound according to any one of  claims 1  to  10  and pharmaceutically acceptable excipient. 
     
     
         20 . The pharmaceutical composition according to  claim 19  further comprising at least one antiviral agent. 
     
     
         21 . The pharmaceutical composition according to  claim 20  wherein the antiviral agent is selected from the group consisting of: a nucleoside or a non-nucleoside analogue reverse-transcriptase inhibitor, a nucleotide analogue reverse-transcriptase inhibitor, a NS3/4A serine protease inhibitor, a NS5B polymerase inhibitor or interferon alpha.