Malonyl-CoA Decarboxylase Inhibitors Useful as Metabolic Modulators

Abstract

The present invention relates to novel compounds (I), their prodrugs, and the pharmaceutically acceptable salts as well as pharmaceutical compositions containing such compounds useful in treating certain metabolic diseases and diseases modulated by the inhibition of the enzyme malonyl-coenzyme A decarboxylase (malonyl-CoA decarboxylase, MCD). In particular, the invention relates to compounds and compositions and the methods for the prophylaxis, management and treatment of cardiovascular diseases, diabetes, acidosis, cancers, and obesity through the inhibition of malonyl-coenzyme A decarboxylase.

1 .- 14 . (canceled)  
     
     
         15 . A method of modulating malonyl-CoA decarboxylase activity or malonyl-CoA concentration in a subject in need of such modulation, comprising administering a therapeutically effective amount of a compound represented by the following structural formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is independently chosen from halo, haloalkyl, hydroxy, thiol, substituted thiol, sulfonyl, sulfinyl, nitro, cyano, amino, substituted amino, C 1 -C 6  alkyl and C 1 -C 6  alkoxy, and when R 1  is hydroxy, C 1 -C 6  alkoxy, thiol, substituted thiol, amino, substituted amino, or C 1 -C 6  alkyl, such radical may be combined with R 2  to form a ring of 5-7 members when R 1  is ortho to R 2 ;  
 R 2  is selected from NR 3 C(S)NR 4 R 5 , NR 3 C(═NR 3 )NR 4 R 5 , NR 3 C(═NCN)NR 4 R 5 , NR 3 C(═CHNO 2 )NR 4 R 5 , NR 3 P(O)R 4 R 5 , NR 3 P(O)(OR 4 )(OR 5 ), NR 3 P(O)(OR 4 )(N5), NR 3 P(O)(NR)(NR 5 ), NR 3 C(═NR 3 )R 6 , CO 6 , R 6 C(OH)R 7 , CR 8 ═NOR 4 , CR 8 ═NR 3 , CR 8 ═NR 5 , SOR 7 , SO 2 R 7 , P(O)(OR 4 )(OR 5 ), P(O)(R 4 )(R 5 ), P(O)(OR 4 )(OR 5 ), P(O)(N3)(OR 4 ), P(O)(NR)(NR 5 ), a 3-7 membered ring containing from zero to three heteroatoms selected from O, N, or S, which may be substituted by R 9 , R 10 , R 11 , R 12  or R 13 , with the exception of the following groups:  
                     
 or may be combined with R 1  to form a ring of 5-7 members when R 1  is ortho to R 2 ;  
 R 3  is hydrogen, alkyl, aryl, heterocyclyl, acyl, or may form a ring of 5-7 members with R 4  or R 5 ;  
 R 4  is hydrogen, alkyl, aryl, heterocyclyl, acyl, or may form a ring of 5-7 members with R 5  or R 3 ;  
 R 5  is hydrogen, alkyl, aryl, or heterocyclyl, acyl or may form a ring of 5-7 members with R 3  or R 4 ;  
 R 6  and R 7  may be equal or different and are selected from hydrogen, alkyl, aryl, or heterocyclyl;  
 R 8  is hydrogen, alkyl, aryl, heterocyclyl, amino or substituted amino;  
 R 9 , R 10 , R 11  and R 12  may be equal or different and are selected from hydrogen, alkyl, aryl, heterocyclyl, nitro, cyano, carboxylic acid, ester, amide, halo, hydroxyl, amino, substituted amino, alkoxy, acyl, ureido, sulfonamido, sulfamido, sulfonyl, sulfinyl, or guanadinyl;  
 R 13  is hydrogen, alkyl, aryl, heterocyclyl, acyl, ester, sulfonyl, ureido, or guanadinyl;  
 A is O, S, or NR 3 ;  
 m is from zero to four;  
 X is H, CF 2 Z, or CF 3 , or together with Y forms a double bond when A is O;  
 Y is hydrogen, or together with X forms a double bond when A is O;  
 Z is F, Br, Cl, I or CF 3 ;  
 its corresponding enantiomers, diastereoisomers or tautomers; or a pharmaceutically acceptable salt, or a prodrug thereof.  
 
     
     
         16 . The method of claim  1 , wherein the malonyl-CoA decarboxylase activity is inhibited in the subject or the malonyl-CoA concentration is increased in the subject.  
     
     
         17 . The method of claim  1 , wherein the modulating reduces fatty acid metabolism in the subject or increases carbohydrate metabolism in the subject.  
     
     
         18 . The method of claim  1 , wherein modulating the malonyl-CoA decarboxylase activity or the malonyl-CoA concentration in the subject treats a disease or condition that is associated with fatty acid metabolism or glucose metabolism.  
     
     
         19 . The method of  claim 18 , wherein the disease is a cardiovascular disease, diabetes, obesity, acidosis, or cancer.  
     
     
         20 . The method of  claim 19 , wherein the disease is congestive heart failure, an ischemic cardiovascular disease, or angina pectoris.  
     
     
         21 . The method of  claim 15 , wherein the compound is represented by one of the following structural formulae:  
       
         
           
           
               
               
           
         
       
     
     
         22 . The method of claim  1 , wherein the compound is represented by one of the following structural formulae:  
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen, halo, hydroxyl or cyano.  
       
     
     
         23 . The method of  claim 22 , wherein R 2  is represented by one of the following structural formulae:  
       
         
           
           
               
               
           
         
       
     
     
         24 . The method of  claim 22 , wherein R 2  is represented by one of the following structural formulae:  
       
         
           
           
               
               
           
         
       
     
     
         25 . The method of  claim 15 , wherein the compound is selected from the group consisting of: 
 Ethyl(1Z)-{ethyl[2-(methyloxy)ethyl]amino}({4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)methylidenecarbamate;    3-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-4,5-dihydroisoxazole-5-carboxylic acid;    5-amino-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazole-4-carbonitrile;    Ethyl 5-pyridin-3-yl-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazole-4-carboxylate;    Methyl 5-[(methyloxy)methyl]-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazole-4-carboxylate;    Methyl 3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-4,5-dihydroisoxazole-5-carboxylate;    Diethyl 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl amidophosphate;    Diethyl ethyl{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amidophosphate;    Diethyl 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl phosphonate; and    Phenyl{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}phosphinic acid.    
     
     
         26 . The method of  claim 15 , wherein the compound is represented by the following structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         27 . The method of  claim 26 , wherein R 2  is NR 3 C(S)NR 4 R 5  or NR 3 C(═NR 3 )NR 4 R 5 .  
     
     
         28 . The method of  claim 27 , wherein R 4  and R 5 , and the N atom to which they are attached form a 5-7 membered ring.  
     
     
         29 . The method of  claim 28 , wherein R 4  and R 5 , and the N atom to which they are attached form a morpholine ring.  
     
     
         30 . The method of  claim 29 , wherein X is CF 3 , A is O, Y is H, and Z is F.  
     
     
         31 . The method of  claim 15 , wherein R 2  is NR 3 C(S)NR 4 R 5  or NR 3 C(═NR 3 )NR 4 R 5 .  
     
     
         32 . The method of  claim 15 , wherein X is CF 3 , A is O, Y is H, and Z is F.  
     
     
         33 . The method of  claim 23 , wherein the compound is selected from the group consisting of: 
 N-(4-Cyanobutyl)-N-{4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl]phenyl}morpholine-4-carbothioamide;    Methyl 5-((morpholin-4-ylcarbonothioyl) {4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)pentanoate;    [Bis(1-methylethyl)amino](butyl {4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)methaniminium chloride;    (Butyl{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)(pyrrolidin-1-yl)methaniminium chloride;    (Butyl{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)(diethylamino)methaniminium chloride;    N-[4-(3-Methyl-1,2,4-oxadiazol-5-yl)butyl]-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carbothioamide;    (Butyl{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)(piperidin-1-yl)methaniminium chloride;    N-[(4-Cyanophenyl)methyl]-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carbothioamide;    N-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-N-{[4-(trifluoromethyl)phenyl]methyl}morpholine-4-carbothioamide;    N-[3-(1H-pyrrol-1-yl)propyl]-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carbothioamide;    N-Butyl-N′,N′-diethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}thiourea;    (Dimethylamino)(propyl {4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)methaniminium chloride;    (Butyl{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)(morpholin-4-yl)methaniminium chloride;    (Butyl{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)(dibutylamino)methaniminium chloride;    [Bis(1-methylethyl)amino]({4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}amino)methaniminium chloride;    N-Ethyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}morpholine-4-carbothioamide;    N,N,1-Trimethyl-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-4,5-dihydro-1H-pyrazole-5-carboxamide;    1,1-Dimethylethyl 3-{[(3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-4,5-dihydroisoxazol-5-yl)carbonyl]amino}propanoate;    (1Z)-1-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}butan-1-one O-(2-morpholin-4-yl-2-oxoethyl)oxime;    (Z)-Phenyl {4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}methanone O-methyloxime;    (1Z)-1-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}pentan-1-one O-methyloxime;    3-Methyl-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}butan-1-one;    1-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}pentan-1-one;    2-Methyl-1-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}propan-1-one;    1-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}butan-1-one;    (1E)-1-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}butan-1-one O-methyloxime;    (1Z)-1-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}butan-1-one O-ethyloxime;    (1Z)-1-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}butan-1-one oxime;    (1Z)-1-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}butan-1-one O-(1-methylethyl)oxime; 
 Phenyl{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}methanone;  
   (1Z)-1-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}butan-1-one 0-[2-(phenyloxy)ethyl]oxime;    (1Z)-1-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}butan-1-one O-(phenylmethyl)oxime; and    (1Z)-1-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}butan-1-one O-(2-methylpropyl)oxime.    
     
     
         34 . The method of  claim 24 , wherein the compound is selected from the group consisting of: 
 1-Methyl-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-pyrazole-4-carbonitrile;    1-(1-Phenyl-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-pyrazol-4-yl)ethanone;    Methyl 5-amino-1-phenyl-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-pyrazole-4-carboxylate;    1,1,1,3,3,3-Hexafluoro-2-[4-(4-phenyl-1-propyl-1H-imidazol-2-yl)phenyl]propan-2-ol;    1,1,1,3,3,3-Hexafluoro-2-{4-[4-(hydroxymethyl)-1H-imidazol-2-yl]phenyl}propan-2-ol;    1,1,1,3,3,3-Hexafluoro-2[4-(4-methyl-1H-imidazol-2-yl)phenyl]propan-2-ol; 
 (2-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-4-yl)methyl 2-methylpropanoate;  
   1,1,1,3,3,3-Hexafluoro-2-[4-(1-propyl-4,5-dipyridin-3-yl-1H-imidazol-2-yl)phenyl]propan-2-ol;    1,1,1,3,3,3-Hexafluoro-2-[4-(4-pyridin-3-yl-1H-imidazol-2-yl)phenyl]propan-2-ol;    N-Butyl-4-phenyl-1-propyl-2-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carboxamide;    N-Butyl-4-phenyl-1-(pyridin-3-ylmethyl)-2-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carboxamide;    N-Butyl-1-(2-morpholin-4-ylethyl)-4-phenyl-2-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carboxamide;    N-Butyl-1-(2-cyanoethyl)-4-phenyl-2-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carboxamide;    N-Butyl-1-(3-hydroxypropyl)-4-phenyl-2-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carboxamide;    2-[4-(4,5-Diphenyl-1-propyl-1H-imidazol-2-yl)phenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol;    N-Butyl-1-(1-methylethyl)-4-phenyl-2-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carboxamide;    Methyl{[(4-phenyl-1-propyl-2-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)carbonyl]amino}acetate;    {[(4-Phenyl-1-propyl-2-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazol-5-yl)carbonyl]amino}acetic acid;    N-Butyl-1-(2-methylpropyl)-4-phenyl-2-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carboxamide;    N-Butyl-1-propyl-4-pyridin-3-yl-2-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carboxamide;    N-[(2-{4-[2,2,2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl)}-1H-imidazol-4-yl)methyl]methanesulfonamide;    N-Butyl-4-(4-cyanophenyl)-1-propyl-2-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-imidazole-5-carboxamide;    2-[4-(5-Amino-3-phenyl-1H-pyrazol-4-yl)phenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol;    2-{4-[5-Amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]phenyl}-1,1,1,3,3,3-hexafluoropropan-2-ol;    4-(5-Amino-3-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl)}-1H-pyrazol-1-yl)benzonitrile;    Ethyl(5-amino-3-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-1H-pyrazol-1-yl)acetate;    N-(3-(1-Methylethyl)-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-5-yl)pent-4-enamide;    2-[4-(5-Amino-3-pyridin-4-ylisoxazol-4-yl)phenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol;    2-Methyl-N-(3-pyridin-4-yl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-5-yl)propanamide;    (2E)-3-(5-Methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)prop-2-enenitrile;    N-(3-(1-Methylethyl)-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-5-yl)pyridine-4-carboxamide;    N-(5-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)pyridine-4-carboxamide;    4-Cyano-N-(3-(1-methylethyl)-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-5-yl)benzamide;    2-[4-(3,5-Dimethylisoxazol-4-yl)phenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol;    N-(3-(1-Methylethyl)-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-5-yl)-2-phenylbutanamide;    2-{4-[5-Amino-3-(1-methylethyl)isoxazol-4-yl]phenyl}-1,1,1,3,3,3-hexafluoropropan-2-ol;    N-(3,5-Dimethylisoxazol-4-yl)-N′-(5-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)urea;    2-(4-{5-Amino-3-[(ethyloxy)methyl]isoxazol-4-yl}phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;    3-(5-Amino-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)propan-1-ol;    2-[4-(5-Amino-3-butylisoxazol-4-yl)phenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol;    2-[4-(5-Amino-3-ethylisoxazol-4-yl)phenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol;    N,5-Dimethyl-N-(methyloxy)-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazole-3-carboxamide;    2-Methyl-N-(3-phenyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-5-yl)propanamide;    1-(5-Methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl} isoxazol-3-yl)butan-1-one;    Ethyl 5-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazole-3-carboxylate;    2-Methyl-N-(5-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)propanamide;    N,N,5-Trimethyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazole-3-carboxamide;    4-[(3-(1-Methylethyl)-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-5-yl)amino]-4-oxo-2-phenylbutanoic acid;    1,1,1,3,3,3-Hexafluoro-2-{4-[3-(hydroxymethyl)-5-methylisoxazol-4-yl]phenyl}propan-2-ol;    1,1-Dimethylethyl 5-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-ylcarbamate;    2-(4-{5-Amino-3-[(2E)-but-2-enyl]isoxazol-4-yl}phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;    3-(5-Amino-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)propanoic acid;    4-(5-Amino-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)phenol;    Ethyl 4-(methylthio)-2-({[(5-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)amino]carbonyl}amino)butanoate;    N-(5-Methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)hexanamide;    Ethyl 4-methyl-2-({[(5-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)amino]carbonyl}amino)pentanoate;    ({[(5-Methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)amino]carbonyl}amino)acetic acid;    N-(5-Methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)-N′-phenylurea;    2-[4-(5-Amino-3-furan-3-ylisoxazol-4-yl)phenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol;    5-Methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazole-3-carboxylic acid;    N-(5-Methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)acetamide;    4-(Methylthio)-2-({[(5-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)amino]carbonyl}amino)butanoic acid;    2-{4-[5-Amino-3-(1H-indol-3-ylmethyl)isoxazol-4-yl]phenyl}-1,1,1,3,3,3-hexafluoropropan-2-ol;    2-[4-(5-Amino-3-phenylisoxazol-4-yl)phenyl]-1,1,1,3,3,3-hexafluoropropan-2-ol;    N-(5-Methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)-3-phenylpropanamide;    2-(4-{5-Amino-3-[4-(methyloxy)phenyl]isoxazol-4-yl}phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;    N-(5-Methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)-N′-(2-phenylethyl)urea;    Ethyl(2E)-3-(5-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)prop-2-enoate;    2-{4-[5-Amino-3-(trifluoromethyl)isoxazol-4-yl]phenyl}-1,1,1,3,3,3-hexafluoropropan-2-ol;    4-Methyl-2-({[(5-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)amino]carbonyl}amino)pentanoic acid;    Ethyl({[(5-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)amino]carbonyl}amino)acetate;    N-(1-Methylethyl)-N′-(3-phenyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-5-yl)urea; 
 Bis(1,1-dimethylethyl)5-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl} isoxazol-3-ylimidodicarbonate;  
   N-Cyclohexyl-N′-(5-methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-yl)urea;    2-{4-[5-Amino-3-(phenylmethyl)isoxazol-4-yl]phenyl}-1,1,1,3,3,3-hexafluoropropan-2-ol; and    5-Methyl-4-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}isoxazol-3-aminium trifluoroacetate.