التفاصيل البيبلوغرافية
| العنوان: |
CYSTEINE PROTEASE INHIBITORS FOR THE TREATMENT OF PARASITIC DISEASE |
| Document Number: |
20100305056 |
| تاريخ النشر: |
December 2, 2010 |
| Appl. No: |
12/745070 |
| Application Filed: |
November 26, 2008 |
| مستخلص: |
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: [chemical expression included] |
| Inventors: |
Isabel, Elise (Point-Claire, CA); Mellon, Christophe (L'lle Bizard, CA); Beaulieu, Christian (Laval, CA) |
| Assignees: |
Merck Frosst Canada Ltd. (Kirkland, Quebec, CA) |
| Claim: |
1. A compound of the formula: [chemical expression included] wherein R1 is aryl or heteroaryl optionally substituted with one, two or three substituents independently selected from C1-6 alkyl, —COOR5, halo, haloalkyl, cyano, aryl, heteroaryl or —SOm(C1-6 alkyl); R2 is C1-6 alkyl, C3-6 cycloalkyl wherein said alkyl group is optionally substituted with C3-6 cycloalkyl or one to six halo; R3 is C1-6 alkyl substituted with one to six halo; R4 is halo, aryl, heteroaryl, arylalkyl, heteroarylalkyl or heterocyclyl wherein said R4 aryl, R4 heteroaryl, R4 arylalkyl or R4 heteroarylalkyl groups are optionally substituted with one, two, or three substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 halo hydroxyalkyl, alkoxy, haloalkoxy, cyano, aryl, aryl-SO2CH3, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, —SOm(C1-6 alkyl), —SO2NR6R7, —COOR5, —CONR6R7 and C3-6 cycloalkyl-R8; R5 is hydrogen or C1-6 alkyl; R6 is hydrogen, C1-6 alkyl, C2-C6 alkene, (C1-6 alkyl)aryl, C1-6 hydroxyalkyl, —O(C1-6 alkyl), hydroxyl, aryl, heteroaryl, C3-8 cycloalkyl, heterocyclyl, C1-6 alkyl-COOR5, C0-6 alkyl-C(O)NH2, wherein said alkyl, aryl, heteroalkyl, C3-8 cycloalkyl and heterocyclyl can be optionally substituted on either the carbon or the heteroatom with one, two or three substituents independently selected from C1-6 alkyl or halo; R7 is hydrogen, C1-6 alkyl, (C1-6 alkyl)aryl, C1-6 hydroxyalkyl, —O(C1-6 alkyl), hydroxyl, aryl, heteroaryl, C3-8 cycloalkyl, heterocyclyl, wherein said alkyl, aryl, heteroaryl, C3-8 cycloalkyl and heterocyclyl can be optionally substituted on either the carbon or the heteroatom with one, two, or three substituents independently selected from C1-6 alkyl or halo; R6 and R7 can be taken together with the nitrogen atom to which they are attached to form a C3-8 heterocyclyl ring wherein said 3-8 membered ring system may be optionally substituted with one or two substituents independently selected from C1-6 alkyl and halo; R8 is either H, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 halo hydroxyalkyl, alkoxy, haloalkoxy, cyano, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, —SO2CH3, —SO2NR6R7, —SOm(C1-6 alkyl), —COOR5 or —CONR6R7; wherein m is an integer from zero to two; or a pharmaceutically acceptable salt or stereoisomer thereof. |
| Claim: |
2. The compound of claim 1 wherein R1 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. |
| Claim: |
3. The compound of claim 1 wherein R2 is dichloroethyl, 2,2-fluoromethyl propyl, methylenecyclopropyl, cyclopropyl, 2-methyl propyl or isopropyl; or a pharmaceutically acceptable salt or stereoisomer thereof. |
| Claim: |
4. The compound of claim 1 wherein R3 is trifluoromethyl; or a pharmaceutically acceptable salt or stereoisomer thereof. |
| Claim: |
5. The compound of claim 1 wherein R4 is methyl pyrazole, N-methylpyrrole, pyridine, pyridine N-oxide or phenyl wherein the said phenyl maybe optionally disubstituted with chloro in ortho position and —SO2Me in para position or monosubstituted in para position with —SO2Me, —SO2NH2, piperazine, 2,2-difluoroethanol, —SMe, —SOMe, pyridine, pyridine N-oxide, 2-methylpropane-1-ol, methyl-pyrazole, 4-SO2Me-phenyl or cyclopropyl wherein the said cyclopropyl may be substituted with —CONR6R7, —COOR5 or cyano; R5 is hydrogen; R6 and R7 are independently hydrogen, ethanol, allyl, cyclopropyl, —CH2CONH2, 1,1,1-trifluroethane, methylacetate or R6 and R7 are forming a morpholine ring; or a pharmaceutically acceptable salt or stereoisomer thereof. |
| Claim: |
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. |
| Claim: |
7. The compound of claim 1, wherein the compound has the formula: [chemical expression included] wherein X1 is hydrogen or halo; X2 is hydrogen, cyano, chloro or C1-6 haloalkyl; R2 is C1-6 haloalkyl; R3 is C1-6 haloalkyl; X3 is hydrogen, —SOm(C1-6 alkyl) or heterocyclyl; X4 is hydrogen or halo; m is an integer from zero to two; or a pharmaceutically acceptable salt or stereoisomer thereof. |
| Claim: |
8. The compound of claim 7 wherein X1 is fluoro or chloro; R2 is cyano or trifluoromethyl; or a pharmaceutically acceptable salt or stereoisomer thereof. |
| Claim: |
9. The compound of claim 7 wherein R2 is dichloroethyl or 2,2-fluoromethyl propyl; R4 is trifluoromethyl; or a pharmaceutically acceptable salt or stereoisomer thereof. |
| Claim: |
10. The compound of claim 7 wherein X3 is methylsulfone or piperazine; or a pharmaceutically acceptable salt or stereoisomer thereof. |
| Claim: |
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-N2-{(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-N2-{(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-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide; N-[2-(2-chloro-4-cyanophenyl)-1-cyanoethyl]-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide; N-[2-(2-chloro-4-cyanophenyl)-1-cyanoethyl]-N2-{(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-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide; N-[1-cyano-2-(4-cyanophenyl)ethyl]-N2-{(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-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide; or a pharmaceutically acceptable salt or stereoisomer thereof. |
| Claim: |
12. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. |
| Claim: |
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. |
| Claim: |
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. |
| Claim: |
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. |
| Claim: |
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. |
| Claim: |
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. |
| Current U.S. Class: |
514/31 |
| Current International Class: |
61; 07; 07; 07; 07; 07; 07; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61 |
| رقم الانضمام: |
edspap.20100305056 |
| قاعدة البيانات: |
USPTO Patent Applications |