Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors

Abstract

The present invention provides a compound of formula (1) wherein R 1 -R 5 , R 25 , R 26 , Y and X 2 are defined as in claim 1. The compounds activate human peroxisome proliferator activated receptors (hPPARs) and arc useful for the treatment of associated disorders such as cardiovascular disease and hypercholesteremia.

1 . A compound of formula (I) or a pharmaceutically acceptable salt, solvate, or hydrolyzable ester thereof wherein:  
       
         
           
           
               
               
           
         
         R 1  and R 2  are independently hydrogen or C 1-3  alkyl;  
         X 2  is O, S, or CH 2 ;  
         R 3 , R 4 , and R 5  are independently H, C 1-3 alkyl, OCH 3 , CF 3 , OCF 3 , CN, allyl, or halogen;  
         Y is S or O;  
         each R 25  is independently CH 3 , OCH 3 , CF 3 , or halogen;  
         y is 0, 1, 2, 3, 4 or 5; and  
         R 26  is selected from the group consisting of the moieties A through K depicted below:  
         
           
             
             
                 
                 
             
           
         
         wherein R 12  is selected from the group consisting of C 1-6 alkyl, C 1-6 alkylenearyl, and the moieties depicted below in Group II,  
         
           
             
             
                 
                 
             
           
         
         wherein R 17  and R 18  are independently hydrogen, halogen, hydroxy, —CN, C 1-6 alkyl, C 1-6  perfluoroalkyl, C 1-6 acyl, —OC 1-6 alkyl, perfluoroOC 1-6 alkyl, or C 1-6 hydroxyalkyl;  
         R 19  is hydrogen or C 1-6 alkyl;  
         R 21  is C 1-6 alkyl, —C 1-6 alkylenearyl, aryl, or -aryl-heteroaryl;  
         R 22  is C 1-6 alkyl, aryl, or —C 1-6 alkylenearyl;  
         R 23  is C 1-6 alkyl, C 3-6 cycloalkyl, or aryl;  
         R 24  is C 1-6 alkyl, —C 1-6 alkylenearyl, C 3-6 cycloalkyl, or aryl;  
         
           
             
             
                 
                 
             
           
         
         wherein Z is O, N or S (note that when Z is N, the depicted bond can be attached to the nitrogen in the ring as well as any of the carbons in the ring);  
         
           
             
             
                 
                 
             
           
         
         wherein R 20  is C 1-6 alkyl, aryl, —OC 1-6 alkyl, hydroxy, C 1-6 hydroxyalkyl, or 1-alkoxyC 1-6 alkyl;  
         
           
             
             
                 
                 
             
           
         
         wherein R 13  and R 14  are independently hydrogen, halogen, CN, perfluroC 1-6 alkyl, perflurOC 1-6 alkyl, C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyleneOC 1-6 alkyl, —SC 1-6 alkyl, or aryl;  
         
           
             
             
                 
                 
             
           
         
         wherein R 21  is independently as defined above;  
         
           
             
             
                 
                 
             
           
         
         wherein R 15  and R 16  are independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl optionally substituted with 1 or 2 C 1-3 alkyl groups, or R 12  as defined above;  
         
           
             
             
                 
                 
             
           
         
         I  
         —(CH 2 ) n Ph  
         wherein n is 1-3  
         J  
         —O—R 21    
         wherein R 21  is independently as defined above; and  
         K  
         —S—R 21    
         wherein R 21  is independently as defined above.  
       
     
     
         2 . A compound according to  claim 1  wherein R 1  and R 2  are independently H or CH 3 .  
     
     
         3 . A compound according to  claim 2  wherein R 1  and R 2  are either both H or both CH 3 .  
     
     
         4 . A compound according to any of claims  1 - 3  wherein X 2  is O or S.  
     
     
         5 . A compound according to any of claims  14  wherein R 3  is CH 3  or H.  
     
     
         6 . A compound according to any of claims  1 - 5  wherein R 4  and R 5  are H.  
     
     
         7 . A compound according to any preceding claim wherein Y is S.  
     
     
         8 . A compound according to any of claims  1 - 8  wherein y is 1 or 2.  
     
     
         9 . A compound according to  claim 8  wherein each R 5  is independently halogen or CF 3 .  
     
     
         10 . A compound according to any preceding claim wherein R 26  is selected from the group consisting of  
       
         
           
           
               
               
           
         
         where in R 12 , Z, R 13 , and R 14  are as defined in  claim 1 .  
       
     
     
         11 . A compound according to any preceeding claim wherein R 13  and R 14  are independently fluorine, bronime, phenyl, thienyl, CF 3 , OCF 3 , OCH 3 , SCH 3 , or t-butyl, R 17  and R 18  are independently hydrogen, OH, CN, OC 1-3 alkyl, halogen, CF 3 , COCH 3 , CH(OH)CH 3 , or OCF 3 , R 21  is phenyl optionally substituted by methyl or CN, —C 1-3 alkylenephenyl, or phenyl-5-methyl-1,2,4-oxadiazol-3-yl, R 22  is C 1-6  alkyl, phenyl, or benzyl, R 23  is C 1-6 alkyl, furanyl, thienyl, phenyl optionally substituted by a halogen a methoxy or a dimethylamino group, methoxymethylcyclopropyl, or C 3-6 cyclalkyl, and R 24  is H, C 1-6 alkyl, cyclohexyl, m-methoxyphenyl, p-fluorophenyl, or —CH 2 CH 2 -phenyl.  
     
     
         12 . A compound according to  claim 11  wherein R 26  is  
       
         
           
           
               
               
           
         
         and R 12  is selected from the moieties shown in Group IV.  
         
           
             
             
                 
                 
             
           
         
       
     
     
         13 . A compound according to  claim 12  wherein R 17  is fluorine, chlorine, OC 1-3 alkyl or COCH 3  and R 18  is OCH 3  or hydrogen, and R 19  is hydrogen.  
     
     
         14 . A compound according to  claim 10  wherein R 26  is  
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound according to  claim 14  wherein R 14  is thienyl, OCH 3 , OCF 3 , CF 3 , or fluorine, and R 13  is hydrogen or fluorine.  
     
     
         16 . A compound of formula (I) selected from: 
 2-[4-({[4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-(4-fluorophenyl)1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]-2-methylpropanoic acid,    2-methyl-2-{2-methyl-4-[({4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,    {2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,    {4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2,5-dimethylphenoxy}acetic acid,    2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy)propanoic acid,    2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-ethylphenoxy}propanoic acid,    2-{2-methyl-4-[({4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,    2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,    2-{4-[({4-{[4-(4-ethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,    2-methyl-2-{2-methyl-4-[({4-{[4-(phenoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,    2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoic acid,    {2-methyl-4-[({4-[4-(3-thienyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,    2-(4-{[(2-(4-fluorophenyl)-4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-1,3-thiazol-5-yl)methyl]sulfanyl}-2-methylphenoxy)-2-methylpropanoic acid,    2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid,    2-{4-[({4-{[4-(2,4-dimethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,    {2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,    2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoic acid,    2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,    2-{2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,    2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,    2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid,    {4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acetic acid,    {4-[({4-([1,1′-biphenyl]-4-ylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid,    2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,    {4[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid,    2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,    {4-[({4-{[4-(2-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid,    2-{2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,    2-{4-[({4-(4-tert-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid,    2-{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,    2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2,3-dimethylphenoxy}propanoic acid,    2-{4-[({4-{[4-(4-chlorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,    2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-fluorophenoxy}propanoic acid,    2-{4-[({4-{[4-(2,4-difluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,    {4-[({4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid,    2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid,    2-methyl-2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]phenoxy}propanoic acid,    2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,    {2-ethyl-4-[({4-{4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,    2-{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid,    2-methyl-2-{4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,    2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid,    2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid,    2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,    2-{4-[({4-{[4-(4-isopropoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,    2-{2-methyl-4-[({4-{[4-(2-pyrimidinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid.    {2-methyl-4-[({4-(3-phenylpropyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,    [4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-(trifluoromethyl)phenoxy]acetic acid,    {2-methyl-4-[({4-{[(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,    {4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-5-chloro-2-methylphenoxy}acetic acid,    {4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid,    {4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid,    {2,5-dimethyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,    {2-methyl-4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,    {4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2,3-dimethylphenoxy}acetic acid,    [4-({[2-(4-chlorophenyl)-4-methyl-1,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid,    {2-methyl-4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,    {4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-bromophenoxy}acetic acid,    {2-methyl-4-[({4-[(2-phenylethoxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl)methyl)sulfanyl]phenoxy}acetic acid,    {2-methyl-4-[({4-(2-phenylethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid, and    pharmaceutically acceptable salts, solvates, and hydrolyzable esters thereof.    
     
     
         17 . A compound of formula (I) selected from: 
 2-methyl-2-{2-methyl-4-[({4-(3-thienylmethyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,    2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,    {2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,    2-{4-[({4-(4-methoxybenzyl)2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid,    2-methyl-2-{4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl-1,3-thiazol-5-ylmethyl)sulfanyl]phenoxy}propanoic acid,    2-{4-[({[4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid,    2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid,    2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy)propanoic acid,    2-{4-[({4-{[4-(4-isopropoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,    2-{2-methyl-4-[({4-{[4-(2-pyrimidinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid, and    pharmaceutically acceptable salts, solvates, or hydrolyzable esters thereof    
     
     
         18 . A compound according to any preceding claim which is a hPPARδ agonist.  
     
     
         19  A compound according to  claim 18  which is also a hPPARα or hPPARgamma agonist.  
     
     
         20 . A compound according to any preceding claim which is a hPPAR pan agonist.  
     
     
         21 . A compound according to any of claims  1 - 20  for use in therapy.  
     
     
         22 . A pharmaceutical composition comprising a compound according to any of claims  120 .  
     
     
         23 . A pharmaceutical composition according to  claim 22  further comprising a pharmaceutically acceptable diluent or carrier.  
     
     
         24 . Use of a compound according to any of claims  1 - 20  for the manufacture of a medicament for the treatment of a hPPAR disease or condition.  
     
     
         25 . Use according to  claim 24  wherein the hPPAR mediated disease or condition is dyslipidemia, syndrome X, heart failure, hypercholesteremia, cardiovascular disease, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, obesity, anorexia bulimia and anorexia nervosa  
     
     
         26 . A method of treating a hPPAR mediated disease or condition in a patient comprising the administration of a therapeutically effective amount of a compound according to any of claims  1 - 20 .  
     
     
         27 . A method according to  claim 26  wherein the hPPAR mediated disease or condition is dyslipidemia, syndrome X, heart failure, hypercholesteremia, cardiovascular disease, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, obesity, anorexia bulimia and anorexia nervosa.