Cysteine protease inhibitors for the treatment of parasitic disease

Abstract

Several parasites responsible for mammalian diseases are dependent on cysteine protease for various life-cycle functions. Inhibition or decreasing function of these proteases can be useful in the treatment and/or prevention of these parasitic diseases including; toxoplasmosis, malaria, African trypanosomiasis, Chagas disease, leishmaniasis, schistosomiasis, amebiasis, giardiasis, clonorchiasis, opisthorchiasis, paragonimiasis, fasciolopsiasis, lymphatic filariasis, onchocerciasis, dracunculiasis, ascariasis, trichuriasis, strongyloidiasis, trichostrongyliasis, trichomoniasis or cestodiasis. Compounds of formula I of the invention are capable of treating and/or preventing the above-identified diseases:

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is aryl or heteroaryl optionally substituted with one, two or three substituents independently selected from C 1-6  alkyl, —COOR 5 , halo, haloalkyl, cyano, aryl, heteroaryl or —SO m (C 1-6  alkyl); 
         R 2  is C 1-6  alkyl, C 3-6  cycloalkyl wherein said alkyl group is optionally substituted with C 3-6  cycloalkyl or one to six halo; 
         R 3  is C 1-6  alkyl substituted with one to six halo; 
         R 4  is halo, aryl, heteroaryl, arylalkyl, heteroarylalkyl or heterocyclyl wherein said R 4  aryl, R 4  heteroaryl, R 4  arylalkyl or R 4  heteroarylalkyl groups are optionally substituted with one, two, or three substituents independently selected from halo, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  halo hydroxyalkyl, alkoxy, haloalkoxy, cyano, aryl, aryl-SO 2 CH 3 , heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, —SO m (C 1-6  alkyl), —SO 2 NR 6 R 7 , —COOR 5 , —CONR 6 R 7  and C 3-6  cycloalkyl-R 8 ; 
         R 5  is hydrogen or C 1-6  alkyl; 
         R 6  is hydrogen, C 1-6  alkyl, C 2 -C 6  alkene, (C 1-6  alkyl)aryl, C 1-6  hydroxyalkyl, —O(C 1-6  alkyl), hydroxyl, aryl, heteroaryl, C 3-8  cycloalkyl, heterocyclyl, C 1-6  alkyl-COOR 5 , C 0-6  alkyl-C(O)NH 2 , wherein said alkyl, aryl, heteroalkyl, C 3-8  cycloalkyl and heterocyclyl can be optionally substituted on either the carbon or the heteroatom with one, two or three substituents independently selected from C 1-6  alkyl or halo; 
         R 7  is hydrogen, C 1-6  alkyl, (C 1-6  alkyl)aryl, C 1-6  hydroxyalkyl, —O(C 1-6  alkyl), hydroxyl, aryl, heteroaryl, C 3-8  cycloalkyl, heterocyclyl, wherein said alkyl, aryl, heteroaryl, C 3-8  cycloalkyl and heterocyclyl can be optionally substituted on either the carbon or the heteroatom with one, two, or three substituents independently selected from C 1-6  alkyl or halo; 
         R 6  and R 7  can be taken together with the nitrogen atom to which they are attached to form a C 3-8  heterocyclyl ring wherein said 3-8 membered ring system may be optionally substituted with one or two substituents independently selected from C 1-6  alkyl and halo; 
         R 8  is either H, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, C 1-6  halo hydroxyalkyl, alkoxy, haloalkoxy, cyano, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, —SO 2 CH 3 , —SO 2 NR 6 R 7 , —SO m (C 1-6  alkyl), —COOR 5  or —CONR 6 R 7 ; 
         wherein m is an integer from zero to two; 
         or a pharmaceutically acceptable salt or stereoisomer thereof. 
       
     
     
         2 . The compound of  claim 1  wherein R 1  is pyridine, pyridine N-oxide or phenyl wherein the said phenyl may be substituted in ortho and/or para position with substituents independently selected from bromo, fluoro, chloro, cyano, trifluoromethyl, methyl sulfone, pyridine or pyridine-N-oxide; or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         3 . The compound of  claim 1  wherein R 2  is dichloroethyl, 2,2-fluoromethyl propyl, methylenecyclopropyl, cyclopropyl, 2-methyl propyl or isopropyl; or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         4 . The compound of  claim 1  wherein R 3  is trifluoromethyl; or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         5 . The compound of  claim 1  wherein R 4  is methyl pyrazole, N-methylpyrrole, pyridine, pyridine N-oxide or phenyl wherein the said phenyl maybe optionally disubstituted with chloro in ortho position and —SO 2 Me in para position or monosubstituted in para position with —SO 2 Me, —SO 2 NH 2 , piperazine, 2,2-difluoroethanol, —SMe, —SOMe, pyridine, pyridine N-oxide, 2-methylpropane-1-ol, methyl-pyrazole, 4-SO 2 Me-phenyl or cyclopropyl wherein the said cyclopropyl may be substituted with —CONR 6 R 7 , —COOR 5  or cyano; R 5  is hydrogen; R 6  and R 7  are independently hydrogen, ethanol, allyl, cyclopropyl, —CH2CONH2, 1,1,1-trifluroethane, methylacetate or R 6  and R 7  are forming a morpholine ring; or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         6 . The compound of  claim 1  selected from
 (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-cyano-(1-oxy-pyridin-2-ylmethyl)-methyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid ((S)-cyano-pyridin-3-ylmethyl-methyl)-amide   (S)—N—((S)-Benzyl-cyano-methyl)-3-cyclopropyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-propionamide   (S)—N—[(S)-Cyano-(2-fluoro-4-trifluoromethyl-benzyl)-methyl]-3-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-butyramide   (S)—N—[(S)-Cyano-(2-fluoro-4-trifluoromethyl-benzyl)-methyl]-2-{(S)-1-[4′-((R)-2,2-difluoro-1-hydroxy-ethyl)-biphenyl-4-yl]-2,2,2-trifluoro-ethylamino}-3-methyl-butyramide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid ((S)-cyano-pyridin-4-ylmethyl-methyl)-amide   1-{4′-[(S)-1-((S)-1-{[(S)-Cyano-(4-cyano-2-fluoro-benzyl)-methyl]-carbamoyl}-2-methyl-propylamino)-2,2,2-trifluoro-ethyl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (2-hydroxy-ethyl)-amide   1-{4′-[(S)-1-((S)-1-{[(S)-Cyano-(4-cyano-2-fluoro-benzyl)-methyl]-carbamoyl}-2-methyl-propylamino)-2,2,2-trifluoro-ethyl]-biphenyl-4-yl}-cyclopropanecarboxylic acid amide   1-{4′-[(S)-1-((S)-1-{[(S)-Cyano-(4-cyano-2-fluoro-benzyl)-methyl]-carbamoyl}-2-methyl-propylamino)-2,2,2-trifluoro-ethyl]-biphenyl-4-yl}-cyclopropanecarboxylic acid   (S)—N—[(S)-Cyano-(4-cyano-2-fluoro-benzyl)-methyl]-2-{(S)-1-[4′-((R)-2,2-difluoro-1-hydroxy-ethyl)-biphenyl-4-yl]-2,2,2-trifluoro-ethylamino}-3-methyl-butyramide   1-[4′-((S)-1-{(S)-1-[((S)-Benzyl-cyano-methyl)-carbamoyl]-3-fluoro-3-methyl-butylamino}-2,2,2-trifluoro-ethyl)-biphenyl-4-yl]-cyclopropanecarboxylic acid allylamide   1-[4′-((S)-1-{(S)-1-[((S)-Benzyl-cyano-methyl)-carbamoyl]-3-fluoro-3-methyl-butylamino}-2,2,2-trifluoro-ethyl)-biphenyl-4-yl]-cyclopropanecarboxylic acid cyclopropylamide   1-[4′-((S)-1-{(S)-1-[((S)-Benzyl-cyano-methyl)-carbamoyl]-3-fluoro-3-methyl-butylamino}-2,2,2-trifluoro-ethyl)-biphenyl-4-yl]-cyclopropanecarboxylic acid carbamoylmethyl-amide   1-[4′-((S)-1-{(S)-1-[((S)-Benzyl-cyano-methyl)-carbamoyl]-3-fluoro-3-methyl-butylamino}-2,2,2-trifluoro-ethyl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (2,2,2-trifluoro-ethyl)-amide   ({1-[4′-((S)-1-{(S)-1-[((S)-Benzyl-cyano-methyl)-carbamoyl]-3-fluoro-3-methyl-butylamino}-2,2,2-trifluoro-ethyl)-biphenyl-4-yl]-cyclopropanecarbonyl}-amino)-acetic acid methyl ester   1-[4′-((S)-1-{(S)-1-[((S)-Benzyl-cyano-methyl)-carbamoyl]-3-fluoro-3-methyl-butylamino}-2,2,2-trifluoro-ethyl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (2-hydroxy-ethyl)-amide   (S)—N—[(S)-Cyano-(4-cyano-2-fluoro-benzyl)-methyl]-3-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-butyramide   (S)—N—[(S)-Cyano-(4-cyano-2-fluoro-benzyl)-methyl]-3-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-butyramide   (S)—N—((S)-Benzyl-cyano-methyl)-2-{(S)-1-[4′-((R)-2,2-difluoro-1-hydroxy-ethyl)-biphenyl-4-yl]-2,2,2-trifluoro-ethylamino}-3-methyl-butyramide   (S)—N—((S)-Benzyl-cyano-methyl)-3-methyl-2-[(S)-2,2,2-trifluoro-1-(4-pyridin-4-yl-phenyl)-ethylamino]-butyramide   1-[4′-((S)-1-{(S)-1-[((S)-Benzyl-cyano-methyl)-carbamoyl]-2-methyl-propylamino}-2,2,2-trifluoro-ethyl)-biphenyl-4-yl]-cyclopropanecarboxylic acid amide   4-[4′-((S)-1-{(S)-1-[((S)-Benzyl-cyano-methyl)-carbamoyl]-2-methyl-propylamino}-2,2,2-trifluoro-ethyl)-biphenyl-4-yl]-piperazin-1-ium; chloride   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-cyano-(2-fluoro-4-trifluoromethyl-benzyl)-methyl]-amide   (S)-4-Fluoro-4-methyl-2-{(S)-2,2,2-trifluoro-1-[4′-(1-oxy-pyridin-4-yl)-biphenyl-4-yl]-ethylamino}-pentanoic acid ((S)-1-cyano-2-phenyl-ethyl)-amide   (S)-2-[(S)-1-(4-Bromo-phenyl)-2,2,2-trifluoro-ethylamino]-4-fluoro-4-methyl-pentanoic acid [(S)-1-cyano-2-(4-cyano-2-fluoro-phenyl)-ethyl]-amide   (S)-4-Fluoro-4-methyl-2-((S)-2,2,2-trifluoro-1-{4′-[1-(morpholine-4-carbonyl)-cyclopropyl]-biphenyl-4-yl}-ethylamino)-pentanoic acid [(S)-1-cyano-2-(4-cyano-2-fluoro-phenyl)-ethyl]-amide   (S)-4-Fluoro-4-methyl-2-{(S)-2,2,2-trifluoro-1-[4′-(2-hydroxy-2-methyl-propyl)-biphenyl-4-yl]-ethylamino}-pentanoic acid [(S)-1-cyano-2-(4-cyano-2-fluoro-phenyl)-ethyl]-amide   (S)—N—((S)-1-Cyano-2-phenyl-ethyl)-3-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-butyramide   (S)-2-[(S)-1-(4-Bromo-phenyl)-2,2,2-trifluoro-ethylamino]-N—((S)-1-cyano-2-phenyl-ethyl)-3-methyl-butyramide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-pyridin-4-yl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-1-cyano-2-(4-cyano-2-fluoro-phenyl)-ethyl]-amide   1-[4′-((S)-1-{(S)-1-[(S)-1-Cyano-2-(4-cyano-2-fluoro-phenyl)-ethylcarbamoyl]-3-fluoro-3-methyl-butylamino}-2,2,2-trifluoro-ethyl)-biphenyl-4-yl]-cyclopropanecarboxylic acid amide   (S)-2-{(S)-1-[4′-((R)-2,2-Difluoro-1-hydroxy-ethyl)-biphenyl-4-yl]-2,2,2-trifluoro-ethylamino}-4-fluoro-4-methyl-pentanoic acid [cyano-(2-fluoro-4-trifluoromethyl-benzyl)-methyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-pyridin-4-yl-biphenyl-4-yl)-ethylamino]-pentanoic acid ((S)-1-cyano-2-phenyl-ethyl)-amide   (S)-4-Fluoro-4-methyl-2-{(S)-2,2,2-trifluoro-1-[4-(1-methyl-1H-pyrrol-2-yl)-phenyl]-ethylamino}-pentanoic acid ((S)-1-cyano-2-phenyl-ethyl)-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [cyano-(2,4-difluoro-benzyl)-methyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [cyano-(2-fluoro-4-trifluoromethyl-benzyl)-methyl]-amide   (S)-2-{(S)-1-[4′-((R)-2,2-Difluoro-1-hydroxy-ethyl)-biphenyl-4-yl]-2,2,2-trifluoro-ethylamino}-4-fluoro-4-methyl-pentanoic acid [(S)-cyano-(4-cyano-2-fluoro-benzyl)-methyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-sulfamoyl-biphenyl-4-yl)-ethylamino]-pentanoic acid ((S)-1-cyano-2-phenyl-ethyl)-amide   1-(4′-{(S)-1-[(S)-1-((S)-1-Cyano-2-phenyl-ethylcarbamoyl)-3-fluoro-3-methyl-butylamino]-2,2,2-trifluoro-ethyl}-biphenyl-4-yl)-cyclopropanecarboxylic acid amide   (S)-4-Fluoro-4-methyl-2-{(S)-2,2,2-trifluoro-1-[4′-(1-[1,2,4]oxadiazol-3-yl-cyclopropyl)-biphenyl-4-yl]-ethylamino}-pentanoic acid ((S)-1-cyano-2-phenyl-ethyl)-amide   (S)-4-Fluoro-4-methyl-2-((S)-2,2,2-trifluoro-1-{4′-[1-(morpholine-4-carbonyl)-cyclopropyl]-biphenyl-4-yl}-ethylamino)-pentanoic acid ((S)-1-cyano-2-phenyl-ethyl)-amide   (S)-2-{(S)-1-[4′-(1-Cyano-cyclopropyl)-biphenyl-4-yl]-2,2,2-trifluoro-ethylamino}-4-fluoro-4-methyl-pentanoic acid ((S)-1-cyano-2-phenyl-ethyl)-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methylsulfanyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-1-cyano-2-(4-cyano-2-fluoro-phenyl)-ethyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfinyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-1-cyano-2-(4-cyano-2-fluoro-phenyl)-ethyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4-methanesulfonyl-[1,1′;4′,1″]terphenyl-4″-yl)-ethylamino]-pentanoic acid ((S)-benzyl-cyano-methyl)-amide   (S)-4,4-Dichloro-N—[(S)-cyano-(4-cyano-2-fluoro-benzyl)-methyl]-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-butyramide   (S)—N-(Benzyl-cyano-methyl)-4,4-dichloro-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-butyramide   (2S)—N-[(1S)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-4-fluoro-4-methyl-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}amino)pentanamide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [2-(2-chloro-4-cyano-phenyl)-1-cyano-ethyl]-amide   (S)-2-[(S)-1-(2′-Chloro-4′-methanesulfonyl-biphenyl-4-yl)-2,2,2-trifluoro-ethylamino]-4-fluoro-4-methyl-pentanoic acid [2-(2-chloro-4-cyano-phenyl)-1-cyano-ethyl]-amide   (S)-2-[(S)-1-(2′-Chloro-4′-methanesulfonyl-biphenyl-4-yl)-2,2,2-trifluoro-ethylamino]-4-fluoro-4-methyl-pentanoic acid [1-cyano-2-(4-cyano-2-fluoro-phenyl)-ethyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [1-cyano-2-(4-cyano-2-fluoro-phenyl)-ethyl]-amide   (S)-2-[(S)-1-(4-Bromo-phenyl)-2,2,2-trifluoro-ethylamino]-4-methyl-pentanoic acid [(S)-1-cyano-2-(4-cyano-phenyl)-ethyl]-amide   (S)-4-Methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [1-cyano-2-(4-cyano-phenyl)-ethyl]-amide   (S)-2-[(S)-1-(4-Bromo-phenyl)-2,2,2-trifluoro-ethylamino]-4-methyl-pentanoic acid [(S)-1-cyano-2-(4-methanesulfonyl-phenyl)-ethyl]-amide   (S)-2-{(S)-1-[4′-((R)-2,2-Difluoro-1-hydroxy-ethyl)-biphenyl-4-yl]-2,2,2-trifluoro-ethylamino}-4-fluoro-4-methyl-pentanoic acid [(S)-1-cyano-2-(4-methanesulfonyl-phenyl)-ethyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-1-cyano-2-(4-cyano-phenyl)-ethyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-1-cyano-2-(4-trifluoromethyl-phenyl)-ethyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-1-cyano-2-(2,4-dichloro-phenyl)-ethyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-1-cyano-2-(2-fluoro-phenyl)-ethyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-cyano-(4-fluoro-benzyl)-methyl]-amide   4-((S)-2-Cyano-2-{(S)-4-fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoylamino}-ethyl)-benzoic acid ethyl ester   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-1-cyano-2-(4-pyridin-3-yl-phenyl)-ethyl]-amide   (S)-2-{(S)-1-[4′-((R)-2,2-Difluoro-1-hydroxy-ethyl)-biphenyl-4-yl]-2,2,2-trifluoro-ethylamino}-4-fluoro-4-methyl-pentanoic acid ((S)-benzyl-cyano-methyl)-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid ((S)-benzyl-cyano-methyl)-amide   (2S)—N-[(1R)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-4-fluoro-4-methyl-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}amino)pentanamide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-(4-bromo-2,6-difluoro-benzyl)-cyano-methyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-cyano-(4-cyano-2,6-difluoro-benzyl)-methyl]-amide   (S)—N—[(S)-Cyano-(4-cyano-2-fluoro-benzyl)-methyl]-2-cyclopropyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-acetamide   (S)—N—[(S)-Cyano-(4-cyano-2-fluoro-benzyl)-methyl]-2-cyclopropyl-2-{(S)-1-[4′-((R)-2,2-difluoro-1-hydroxy-ethyl)-biphenyl-4-yl]-2,2,2-trifluoro-ethylamino}-acetamide   (S)—N—[(S)-(4-Bromo-2,6-difluoro-benzyl)-cyano-methyl]-3-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-butyramide   (S)—N—[(S)-(4-Bromo-2,6-difluoro-benzyl)-cyano-methyl]-2-{(S)-1-[4′-((R)-2,2-difluoro-1-hydroxy-ethyl)-biphenyl-4-yl]-2,2,2-trifluoro-ethylamino}-3-methyl-butyramide   (S)—N—[(S)-Cyano-(4-cyano-2,6-difluoro-benzyl)-methyl]-3-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-butyramide   (S)—N—[(S)-Cyano-(4-cyano-2,6-difluoro-benzyl)-methyl]-2-{(S)-1-[4′-((R)-2,2-difluoro-1-hydroxy-ethyl)-biphenyl-4-yl]-2,2,2-trifluoro-ethylamino}-3-methyl-butyramide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-cyano-(1-oxy-pyridin-3-ylmethyl)-methyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-cyano-(1-oxy-pyridin-4-ylmethyl)-methyl]-amide   (S)-4-Fluoro-4-methyl-2-[(S)-2,2,2-trifluoro-1-(4′-methanesulfonyl-biphenyl-4-yl)-ethylamino]-pentanoic acid [(S)-cyano-(2,6-difluoro-benzyl)-methyl]-amide   or a pharmaceutically acceptable salt or stereoisomer thereof.   
     
     
         7 . The compound of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
         wherein X 1  is hydrogen or halo; 
         X 2  is hydrogen, cyano, chloro or C 1-6  haloalkyl; 
         R 2  is C 1-6  haloalkyl; 
         R 3  is C 1-6  haloalkyl; 
         X 3  is hydrogen, —SO m (C 1-6  alkyl) or heterocyclyl; 
         X 4  is hydrogen or halo; 
         m is an integer from zero to two; 
         or a pharmaceutically acceptable salt or stereoisomer thereof. 
       
     
     
         8 . The compound of  claim 7  wherein X 1  is fluoro or chloro; R 2  is cyano or trifluoromethyl; or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         9 . The compound of  claim 7  wherein R 2  is dichloroethyl or 2,2-fluoromethyl propyl; R 4  is trifluoromethyl; or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         10 . The compound of  claim 7  wherein X 3  is methylsulfone or piperazine; or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         11 . The compound of  claim 7  selected from
 (2S)-4,4-dichloro-N-[(1S)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}amino)butanamide;   N-[(1S)-1-cyano-2-(4-cyanophenyl)ethyl]-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide;   N-[(1S)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide;   N-[(1R)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide;   N-[2-(2-chloro-4-cyanophenyl)-1-cyanoethyl]-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide;   N-[2-(2-chloro-4-cyanophenyl)-1-cyanoethyl]-N 2 -{(1S)-1-[2′-chloro-4′-(methylsulfonyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-4-fluoro-L-leucinamide;   N˜2˜-{(1S)-1-[2′-chloro-4′-(methylsulfonyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-N-[1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-4-fluoro-L-leucinamide;   N-[1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide;   N-[1-cyano-2-(4-cyanophenyl)ethyl]-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide;   N-{(1S)-1-cyano-2-[4-(trifluoromethyl)phenyl]ethyl}-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide;   or a pharmaceutically acceptable salt or stereoisomer thereof.   
     
     
         12 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         13 . The use of a compound of  claim 1  in the preparation of a medicament useful for the treatment of a parasitic disease selected from the group consisting of toxoplasmosis, malaria, African trypanosomiasis, Chagas disease, leishmaniasis, schistosomiasis, amebiasis, giardiasis, clonorchiasis, opisthorchiasis, paragonimiasis, fasciolopsiasis, lymphatic filariasis, onchocerciasis, dracunculiasis, ascariasis, trichuriasis, stronglyoidiasis, trichostrongyliasis, trichomoniasis and cestodiasis. 
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 1  and another agent selected from the group consisting of: nifurtimox, benznidazole, allopurinol, terbinafine, lovastatin, ketoconazole, itraconazole, posaconazole, miltefosine, ilmofosine, pamidronate, alendronate, risedronate, chloroquine, proguanil, mefloquine, quinine, pyrimethamine-sulphadoxine, doxocycline, berberine, halofantrine, primaquine, atovaquone, pyrimethamine-dapsone, artemisinin, quinhaosu. meglumine antimonite, sodium stibogluconate, amphotericin B, praziquantel, oxamniquine, pentamidine, melarsoprol, suramin and eflornithine. and the pharmaceutically acceptable salts and mixtures thereof. 
     
     
         15 . The use of a compound of  claim 1  and a second agent in the preparation of a medicament useful for the treatment of a parasitic disease wherein the second agent selected from the group consisting of: nifurtimox, benznidazole, allopurinol, terbinafine, lovastatin, ketoconazole, itraconazole, posaconazole, miltefosine, ilmofosine, pamidronate, alendronate, risedronate, chloroquine, proguanil, mefloquine, quinine, pyrimethamine-sulphadoxine, doxocycline, berberine, halofantrine, primaquine, atovaquone, pyrimethamine-dapsone, artemisinin, quinhaosu. meglumine antimonite, sodium stibogluconate, amphotericin B, praziquantel, oxamniquine, pentamidine, melarsoprol, suramin and eflornithine and the pharmaceutically acceptable salts and mixtures thereof, and wherein the parasitic disease is selected from the group consisting of toxoplasmosis, malaria, African trypanosomiasis, Chagas disease, leishmaniasis, schistosomiasis, amebiasis, giardiasis, clonorchiasis, opisthorchiasis, paragonimiasis, fasciolopsiasis, lymphatic filariasis, onchocerciasis, dracunculiasis, ascariasis, trichuriasis, stronglyoidiasis, trichostrongyliasis, trichomoniasis and cestodiasis. 
     
     
         16 . A method of treating a patient having a parasitic disease comprising administering to the patent in need thereof a composition comprising a compound of  claim 1 , wherein the parasitic disease is selected from the group consisting of toxoplasmosis, malaria, African trypanosomiasis, Chagas disease, leishmaniasis, schistosomiasis, amebiasis, giardiasis, clonorchiasis, opisthorchiasis, paragonimiasis, fasciolopsiasis, lymphatic filariasis, onchocerciasis, dracunculiasis, ascariasis, trichuriasis, stronglyoidiasis, trichostrongyliasis, trichomoniasis and cestodiasis. 
     
     
         17 . The method of  claim 16 , wherein the composition further comprises a second agent selected from the group consisting of: nifurtimox, benznidazole, allopurinol, terbinafine, lovastatin, ketoconazole, itraconazole, posaconazole, miltefosine, ilmofosine, pamidronate, alendronate, risedronate, chloroquine, proguanil, mefloquine, quinine, pyrimethamine-sulphadoxine, doxocycline, berberine, halofantrine, primaquine, atovaquone, pyrimethamine-dapsone, artemisinin, quinhaosu, meglumine antimonite, sodium stibogluconate, amphotericin B, praziquantel, oxamniquine, pentamidine, melarsoprol, suramin and eflornithine and the pharmaceutically acceptable salts and mixtures thereof.