Haloalkyl heteroaryl benzamide compounds

Abstract

A new class of haloalkyl heteroaryl benzamides is described. These compounds show strong activity against hepatitis viruses.

The invention claimed is: 
     
       1. A pharmaceutical composition comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  through R 5  and R 10  are, independently, hydrogen, CN, NO 2 , F, Cl, Br, I, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkenyloxyalkyl, alkenyloxyalkenyl, alkenyloxyalkynyl, alkynyloxyalkyl, alkenyloxyalkenyl, alkenyloxyalkynyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylalkenyloxy, cycloalkylalkynyloxy, cycloalkenyloxy, cycloalkenylalkoxy, cycloalkenylalkenyloxy, cycloalkenylalkynyloxy, alkoxyalkylamino, hydroxyalkyl, acyl, acyloxy, aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy, heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl, heteroarylalkoxycarbonyl, alkoxycarbonyloxy, carbamoyl, carbamoyloxy, alkylamino, dialkylamino, alkylaminoalkyl, amido, alkylamido, dialkylamido, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, cycloalkylsulfonylalkyl, cycloalkylalkylsulfonylalkyl, arylsulfonyl, arylalkylsulfonyl, arylalkenylsulfonyl, heteroarylsulfonyl, heteroarylalkylsulfonyl, heteroarylalkenylsulfonyl, alkylsulfonamido, N,N′-dialkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, sulfonamidoarylalkyl, sulfonamidoarylalkenyl, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino, arylalkylamino, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino, heteroarylalkylamino, heteroarylthio, heteroarylalkylthio, heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl, heterocycloalkoxy, or heterocycloalkenyloxy, any of which may be optionally substituted 
 wherein R 6  is selected from the group consisting of haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, S(O) m C(R 7 R 8 ) n CF 3 , and C(R 7 R 8 ) n CF 3 ; 
 wherein W, X and Y are, independently, S, O, N, NR 9  or CR 10  where at least two of W, X, and Y are S, O, N, or NR 9 ; 
 wherein R 7 , R 8 , and R 9  are, independently, hydrogen, fluoro, chloro, alkyl, perhaloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, or together with the atoms to which they are attached, may be joined to form an optionally substituted 4-to 8-membered heterocycloalkyl or an optionally substituted 3- to 8-membered cycloalkyl ring, any of which may be optionally substituted; 
 m is an integer between 0 and 2; and 
 n is an integer between 0 and 5; 
 
       or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier, wherein the composition comprises an effective amount of the compound for treating a viral pathogen. 
     
     
       2. The pharmaceutical composition of  claim 1 , wherein the viral pathogen is Hepatitis B or Hepatitis C Virus infection. 
     
     
       3. The pharmaceutical composition of  claim 1 , wherein the viral pathogen is a parainfluenza, an influenza A, or an influenza B infection. 
     
     
       4. A method for treating a viral infection comprising administering the pharmaceutical composition of  claim 1  to a patient in need thereof. 
     
     
       5. A method for treating a viral infection comprising administering the pharmaceutical composition as claimed in  claim 1 , to a patient in need thereof, in combination with another antiviral composition. 
     
     
       6. The method of  claim 4 , wherein the viral infection is selected from the group consisting of respiratory viruses, herpes viruses, and gastrointestinal viruses. 
     
     
       7. The method of  claim 6 , wherein said respiratory viral infection is selected from the group consisting of parainfluenza, influenza A, influenza B, coronavirus, rhinovirus (RHV), and respiratory syncytial virus (RSV). 
     
     
       8. The method of  claim 6 , wherein said gastrointestinal virus is selected from the group consisting of rotavirus and adenovirus. 
     
     
       9. A method for treating rhabdovirus comprising administering the pharmaceutical composition of  claim 1  to a patient in need thereof. 
     
     
       10. The pharmaceutical composition of  claim 1 , wherein:
 R 1  through R 5  and R 10  are, independently, hydrogen, cyano, nitro, halo, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, acyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkoxycarbonyloxy, carbamoyl, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, perhaloalkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino, arylalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino, heteroarylalkylamino, heteroarylthio, heteroarylalkylthio, heterocycloalkyl, and heterocycloalkoxy, all optionally substituted with substituents selected independently from carbonyl (oxo), carboxyl, lower alkyl carboxylate, lower alkyl carbonate, lower alkyl carbamate, halogen, hydroxy, amino, amido, cyano, hydrazinyl, hydrazinylcarbonyl, alkylhydrazinyl, dialkylhydrazinyl, arylhydrazinyl, heteroarylhydrazinyl, nitro, thiol, sulfonic acid, trisubstituted silyl, urea, acyl, acyloxy, acylamino, arylthio, lower alkyl, lower alkylamino, lower dialkylamino, lower alkyloxy, lower alkoxyalkyl, lower alkylthio, lower alkylsulfonyl, lower alkenyl, lower alkenylamino, lower dialkenylamino, lower alkenyloxy, lower alkenylthio, lower alkenyl sulfonyl, lower alkynyl, lower alkynylamino, lower dialkynylamino, lower alkynyloxy, lower alkynylthio, lower alkynylsulfonyl, lower cycioalkyl, lower cycioalkyloxy, lower cycioalkylamino, lower cycloalkylthio, lower cycioalkylsulfonyl, lower cycioalkylalkyl, lower cycioalkylalkyloxy, lower cycioalkylalkylamino, lower cycioalkylalkylthio, lower cycioalkylalkylsulfonyl, aryl, aryloxy, arylamino, arylthio, arylsulfonyl, arylalkyl, arylalkyloxy, arylalkylamino, arylalkylthio, arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylthio, heteroarylsulfonyl, heteroarylalkyl, heteroarylalkyloxy, heteroarylalkylamino, heteroarylalkylthio, heteroarylalkylsulfonyl, heterocycioalkyl, heterocycioalkyloxy, heterocycioalkylamino, heterocycioalkylthio, heterocycloalkylsulfonyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower haloalkoxy, and lower acyloxy;   R 6  is selected from the group consisting of haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, S(O) m C(R 7 R 8 ) n CF 3 , and C(R 7 R 8 ) n CF 3 ;   wherein W, X and Y are independently chosen from the group consisting of S, O, N, NR 9  and CR 10  and at least two of W, X and Y are heteroatoms;   wherein R 7 , R 8 , and R 9  are independently selected from the group consisting of hydrogen, fluoro, chloro, alkyl, perhaloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or together with the atoms to which they are attached, may be joined to form an optionally substituted 4- to 8-membered heterocycioalkyl or an optionally substituted 3- to 8-membered cycioalkyl ring, any of which may be optionally substituted as for R 1  through R 5  and R 10 ;   m is an integer between 0 and 2; and   n is an integer between 0 and 5.   
     
     
       11. The pharmaceutical composition of  claim 1 , wherein
 R 1  through R 5  are, independently, hydrogen, CN, F, Cl, Br, hydroxy, alkyl, alkoxy, hydroxyalkyl, acyloxy, aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy, heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy, carbamoyloxy, alkylamino, haloalkyl, perhaloalkyl, perhaloalkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, cycloalkylsulfonyl, or cycloalkylalkylsulfonyl, any of which may be optionally substituted with halogen, alkoxy, perhalo-C 1 -C 3 -alkyl, or C 1 -C 3  alkyl;   R 6  is selected from the group consisting of perhaloalkyl, S(O) m C(R 7 R 8 ) n CF 3 , and C(R 7 R 8 ) n CF 3 ,   R 7 , R 8 , and R 9  are independently selected from the group consisting of hydrogen, fluoro, chloro, alkyl, and perhaloalkyl, any of which may be optionally substituted;   R 10  is selected from the group consisting of hydrogen, CN, NO 2 , F, Cl, Br, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, heteroaryloxycarbonyl, heteroarylalkoxycarbonyl, carbamoyl, alkylamino, amido, alkylamido, dialkylamido, perhaloalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, alkylsulfonamido, aryl, arylalkyl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylamino, arylalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, heteroarylamino, heteroarylalkylamino, heteroarylthio, heteroarylalkylthio, heteroarylalkylamino, heterocycloalkyl, heterocycloalkenyl, heterocycloalkoxy, and heterocycloalkenyloxy; and   n is an integer between 0 and 2.   
     
     
       12. The pharmaceutical composition of  claim 11 , wherein:
 R 1 , R 2 , and R 3  are, independently, hydroxy, acyloxy, aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy, heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy, or carbamoyloxy, any of which may be optionally substituted;   R 6  is selected from the group consisting of perhaloalkyl and C(R 7 R 8 )—CF 3 ;   R 7  and R 8  are independently selected from the group consisting of hydrogen, fluoro, and chloro; and   R 10  is selected from the group consisting of hydrogen, CN, NO 2 , F, Cl, Br, alkyl, cycloalkyl, cycloalkoxy, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, dialkylamido, perhaloalkyl, alkylthio, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylthio, heteroarylalkylthio, heterocycloalkyl, and heterocycloalkenyl.   
     
     
       13. The pharmaceutical composition of  claim 12  comprising a compound of Formula II or III or V or VI or VII or VIII or IX or X or XI or XII or XIII or XVI or XVII or XVIII or XIX 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 R 10  is selected from the group consisting of hydrogen, CN, NO 2 , F, Cl, Br, alkyl, cycloalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkenyl. 
 
       
     
     
       14. The pharmaceutical composition of  claim 1 , wherein the compound is of Formula IV 
       
         
           
           
               
               
           
         
       
       wherein:
 R 10  is selected from the group consisting of hydrogen, CN, NO 2 , F, Cl, alkyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoyl, amido, dialkylamido, perhaloalkyl, alkylsulfonyl, alkylsulfonylalkyl, cycloalkylsulfonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkenyl; and 
 with the proviso that when R 4  is Br, R 10  may not be unsubstituted phenyl. 
 
     
     
       15. The pharmaceutical composition of  claim 1 , wherein the salt is selected from the group consisting of acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate, undecanoate, lithium, sodium, calcium, potassium, aluminum, ammonium, tetraethylammonium, methylammonium, dimethylammonium, N-methylmorpholinium, and ethanolammonium. 
     
     
       16. The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is a solid. 
     
     
       17. A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is hydroxy, acyloxy, aroyloxy, arylalkanoyloxy, arylalkenoyloxy, heteroaroyloxy, heteroarylalkanoyloxy, heteroarylalkenoyloxy, alkoxycarbonyloxy, or carbamoyloxy and R 2  and R 3  and R 4  and R 5  are H;
 wherein R 6  is CF 3 ; 
 wherein X is N, W is S, and Y is CR 10 ; and 
 R 10  is hydrogen 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       18. The compound according to claim 17, wherein R 1  is hydroxy or C 1 -C 3  acyloxy. 
     
     
       19. The compound according to claim 18, wherein R 1  is hydroxy. 
     
     
       20. The compound according to claim 17, wherein the salt is selected from the group consisting of acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane-sulfonate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate, undecanoate, lithium, sodium, calcium, potassium, aluminum, ammonium, tetraethylammonium, methylammonium, dimethylammonium, N-methylmorpholinium and ethanolammonium. 
     
     
       21. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to claim 17.