Modulators of peroxisome proliferator activated receptors

Abstract

Disclosed is a compound represented by Structural Formula (I): Ar is a substituted or unsubstituted aromatic group. Q is a covalent bond, —CH 2 — or —CH 2 CH 2 —; W is a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene linking group from two to ten atoms in length, preferably from two to seven atoms in length. Phenyl Ring A is optionally substituted with up to four substituents in addition to R 1 and W. R 1 is —(CH 2 ) n —CH(OR 2 )—(CH 2 ) m E, —(CH)═C(OR 2 )—(CH 2 ) m E, —(CH 2 ) n —CH(Y)—(CH 2 ) m E or —(CH)═C(Y)—(CH 2 ) m E; wherein E is COOR 3 , C 1 -C 3 -alkylnitrile, carboxamide, sulfonamide, acylsulfonamide or tetrazole and wherein sulfonamide, acylsulfonamide and tetrazole are optionally substituted with one or more substituents independently selected from: C 1 -C 6 alkyl, haloalkyl and aryl-C 0-4 -alkyl; R 2 is —H, an aliphatic group, a substituted aliphatic group, haloalkyl, an aromatic group, a substituted aromatic group, —COR 4 , —COOR 4 , —CONR 5 R 6 , —C(S)R 4 , —C(S)OR 4 or —C(S)NR 5 R 6 . R 3 is —H, an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group. Y is —O—, —CH 2 —, —CH 2 CH 2 — or —CH═CH— and is bonded to a carbon atom in Phenyl Ring A that is ortho to R 1 . R 4 -R 6 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group. n and m are independently 0, 1 or 2.

1 . A compound represented by the following structural formula:  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts, hydrates, stereoisomers and solvates thereof, wherein: 
 Ar is represented by a structural formula selected from:  
                     wherein: 
 Rings B-Z are independently substituted or unsubstituted:  
 X is —O—, —S—, —CH 2 — or —C(O)—;  
 Z is a covalent bond, —O—, (—CH 2 ) q —, —CH(CH 3 )(CH 2 ) q —, —C(CH 3 ) 2 (CH 2 ) q —; —(CH 2 ) q CH(CH 3 )—, —(CH 2 )C(CH 3 ) 2 —, —O(CH 2 ) q —, —(CH 2 ) q O—, —(CH 2 ) q NH—, —(CH 2 ) q NH—, —(CH 2 ) q CHR 20 —, —CHR 20 (CH 2 ) q —, —(CH 2 ) q CR 20 R 20 —, —(CH 2 ) q CR 20 R 20 —, —(CH 2 ) q NR 20 —, —NR 20 (CH 2 ) q —, —(CH 2 ) q C(═NOH)—, —C(═NOH)(CH 2 ) q —, —CH(OH)—(CH 2 ) q —, —(CH 2 ) q —CH(OH)—, —CO—(CH 2 ) q —, —(CH 2 ) q —CO—, —COO—(CH 2 ) q —, —OCO—(CH 2 ) q —, —(CH 2 ) q —OCO—, —(CH 2 ) q —COO—, —(CH 2 ) q CO—NH—, —(CH 2 ) q NH—CO—, —(CH 2 ) q CONR 20 —, —CONR 20 (CH 2 ) q —, —(CH 2 ) q NR 20 CO— or —NR 20 CO(CH 2 ) q —;  
 q is 0, 1, 2 or 3; and  
 each R 20  is independently a C1-C5 alkyl group or a halogenated C1-C5 alkyl group;  
   Q is a covalent bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;    W is a substituted or unsubstituted heteroalkylene group wherein the heteroalkylene group is an alkylene group from two to ten atoms in length in which one or more methylene groups have been replaced with a functional group selected from —CH═CH—, —C≡C—, —O—, —CO—, and C(═NOH)—, wherein W is optionally substituted with ═O, ═CH 2 , C1-C6 alkyl or C2-C4 alkylene, the C 2 -C 4  alkylene group together with the carbon atoms of W to which the two ends of the C2-C4 alkylene group are bonded and any intervening carbon atoms forming a cycloalkyl ring;    phenyl Ring A is optionally substituted with up to four substituents in addition to R 1 ;    R 1  is —(CH 2 ) n —CH(OR 2 )—(CH 2 ) m COOR 3  or —(CH)═C(OR 2 )—(CH 2 ) m COOR 3 ;    R 2  is H, C1-C 10  alkyl, phenyl, naphthyl, benzyl or benzoyl;    R 3 -R 6  are independently —H, an optionally substituted C1-C10 aliphatic group, an optionally substituted aromatic group; and 
 n and m are independently 0, 1 or 2,  
   wherein: 
 the aromatic groups in R 3 -R 6  are carbocyclic aromatic C5-C14 rings, optionally fused with a 5- or 6-membered cycloalkyl group; 5 to 14 membered heteroaromatic monocyclic, bicyclic or tricyclic rings having one to four heteroatoms selected from O, N, or S; or carbocyclic aromatic or heteroaromatic rings fused with one or more other heteroaromatic or 5 to 14 membered nonaromatic heterocyclic rings; the aromatic groups being selected from phenyl, 1-naphthyl, 2-naphyl, 1-anthracenyl, 2-anthracenyl, phenanthrenyl, fluorene, 9-fluorenone, indan, N-imidazolyl, 2-imidazole, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 4-pyrazolyl, 5-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazoyl, 4-oxazoyl, 5-oxazoyl, 2-imidazolyl, isoxazoyl, pyrrolyl, pyrazinyl, purinyl, 2,3-dihydrobenzofuran, dibenzothiophene, dibenzofuran, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl, 2-benzooxazolyl, 2-benzoimidazolyl, 2-qinolinyl, 3-quinolinyl, 1-isoqinolinyl, 3-quinolinyl, 1-isoinoldyl, 3-isoindolyl, and benzotriazolyl; and  
 for substituted Rings B-Z, substituted W, substituted phenyl Ring A, and the substituted aliphatic and aromatic groups in R 3 -R 6 , one or more substituents are independently selected from —Br, —Cl, —I, —F, —R, —OR, —CN, —NO 2 , —N(R) 2 , —COR, —COOR, —CON(R) 2 , —SO k R (k is 0, 1 or 2) —NH—C(═NH)—NH 2 , sulfonamide, acylsulfonamide, —NR—CO—R, —OS(O)R, —OS(O 2 )R, C3-C8 cycloalkyl groups, an allyl group, substituted or unsubstituted non-aromatic heterocyclic groups, —O(CH 2 ) r COOH, —O—O(CH 2 ) r —N(R) 2 , —O(CH 2 ) r -(cycloalkyl), —O(CH 2 ) r OH, —O(CH 2 ) r —OSi(R) 3 , and —(CH 2 ) a CH(OR 30 )(CH 2 ) b COOR 31 ; and each R is independently —H, an optionally substituted C1-C10 aliphatic group, a halogenated C1-C10 aliphatic group, an optionally substituted benzyl group, an optionally substituted aromatic group, a C1-C10 alkyl group, a C1-C10 halogenated alkyl group, an optionally substituted phenyl group; R 30  is a C1-C6 alkyl group or C1-C6 halogenated alkyl group, R 31  is —H, a C1-C6 alkyl group or C1-C6 halogenated alkyl group; r is an integer from 1 to 6; and a and b are independently 0, 1 or 2.  
   
 
     
     
         2 . The compound of  claim 1 , wherein the compound is represented by the following structural formula:  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts, hydrates and solvates thereof.  
     
     
         3 . (canceled)  
     
     
         4 . The compound of  claim 1  wherein the compound is represented by the following structural formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 p is an integer from one to nine;  
 W 1  is —O—, —C(O)—, or —C(═NOH)—.  
 
     
     
         5 . The compound of  claim 1  wherein the compound is represented by the following structural formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 p is an integer from one to four;  
 W 1  is —O—, —C(O)—, or —C(═NOH)—.  
 
     
     
         6 . The compound of  claim 5  wherein R 1  is para to W 1  and is represented by the following structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 5  wherein R 1  is meta to W 1  and is represented by the following structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 6  wherein the compound is represented by a structural formula selected from:  
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 4  wherein the compound is represented by a structural formula selected from:  
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 8  wherein R 2  is a C1-C6 alkyl group, phenyl, benzyl or benzoyl; and R 3  is —H or a C1-C6 alkyl group.  
     
     
         11 . The compound of  claim 10  wherein the compound is represented by the following structural formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 Phenyl Rings A′ and A″ are independently substituted with one or more substituents selected from the group of substituents for Phenyl Ring A or unsubstituted;  
 Z is —O— or —CO—; and  
 p is 3 or 4.  
 
     
     
         12 . The compound of  claim 11  wherein: 
 Phenyl Rings A′ and A″ are independently substituted with one or more groups selected from halogen, —R 9 , —OR 9 , —COR 9 , —COOR 9 , —CN, a non-aromatic heterocyclic group, an allyl group, —(CH 2 ) a CH(OR 30 )(CH 2 ) b COOR 31 , and —NR 9 C(O)R 9 ;    R 9  is —H, a C1-C10 alkyl group, a C1-C 10  halogenated alkyl group, or a phenyl;    R 30  is a C1-C6 alkyl group or a halogenated C1-C6 alkyl group;    R 31  is —H, a C1-C6 alkyl group or a halogenated C1-C6 alkyl group; and    a and b are independently 0, 1 or 2.    
     
     
         13 . The compound of  claim 12  wherein Phenyl Rings A′ and A″ are independently substituted with one or more groups selected from halogen, C1-C8 straight chained or branched alkyl, C3-C8 cycloalkyl, C1-C8 straight chained or branched alkoxy, —Br, —F, N-morpholino, —CN, —COOH, —OH, —CF 3  and —OCF 3 .  
     
     
         14 . The compound of  claim 12  wherein: 
 Phenyl Ring A is substituted with one or more groups selected from halogen, —OR 10 , —R 10 , or optionally substituted allyl, 2-phenylethenyl, 2-phenylethyl, phenyl, o-biphenyl, m-biphenyl p-biphenyl, -o-C 6 H 4 OCH 3 , -m-C 6 H 4 OCH 3 , -p-C 6 H 4 OCH 3 , -o-C 6 H 4 F, -m-C 6 H 4 F and -p-C 6 H 4 F;    R 10  is a C1-C10 alkyl group or a C1-C10 halogenated alkyl group.    
     
     
         15 . The compound of  claim 12  wherein Phenyl Ring A is substituted with one or more groups selected from —F, —Cl, —OCH 3 , —OCF 3 , —CH 3 , ethyl, n-propyl, iso-propyl, allyl, 2-phenylethenyl, 2-phenylethyl, phenyl, -o-biphenyl, -m-biphenyl, -p-biphenyl, -o-C 6 H 4 OCH 3 , -m-C 6 H 4 OCH 3 , -p-C 6 H 4 OCH 3 , -o-C 6 H 4 F, -m-C 6 H 4 F and -p-C 6 H 4 F.  
     
     
         16 . The compound of  claim 11  wherein R 2  is methyl and R 3  is hydrogen.  
     
     
         17 - 83 . (canceled)