Modulators of ppar and methods of their preparation

Abstract

The present invention is directed to certain novel compounds represented by Formula (I) and pharmaceutically acceptable salts, solvates, hydrates and prodrugs thereof. The present invention is also directed to methods of making and using such compounds and pharmaceutical compositions containing such compounds to treat or control a number of diseases mediated by PPAR such as glucose metabolism, lipid metabolism and insulin secretion, specifically Type 2 diabetes, hyperinsulinemia, hyperlipidemia, hyperuricemia, hypercholesteremia, atherosclerosis, one or more risk factors for cardiovascular disease, Syndrome X, hypertriglyceridemia, hyperglycemia, obesity and eating disorders.

1 . A method of modulating insulin resistance or leptin levels in a subject, said method comprising the step of administering to said subject a therapeutically effective amount with at least one compound having the formula:
   Z—K—Ar 1 -L-Ar 2 —R 1   (I)   wherein   Ar 1  is selected from the group consisting of benzene, imidazole, indole, and indazole, each of which is optionally substituted with a R 2  substituent, a R 3  substituent or a combination thereof;   Ar 2  is benzene, which is optionally substituted with from one to two R 4  substituents;   K is absent or is a linking group selected from the group consisting of —CH 2 —, —CH 2 CH 2 , —CH 2 O—, —CH(CH 3 )O—, —C(CH 3 ) 2 O—, —CH(CH 3 )—, —CH(OCH 3 )— and —C(CH 3 ) 2 — wherein K can be attached to any available ring member of Ar 1 ;   L is a linking group joining Ar 1  and Ar 2  and is selected from the group consisting of —O(CH 2 ) 3 O—, —O(CH 2 ) 2 O—, —S(CH 2 ) 3 O—, and —S(CH 2 ) 2 O—, wherein L can be attached to any available ring member of Ar 1  and to any available ring member of Ar 2 ;   Z is CO 2 R 8 ;   R 1  is a member independently selected from the group consisting of:   
     
       
         
         
             
             
         
       
       each R 2  or R 3  is independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —OR 7 , (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, aryl(C 2 -C 8 )alkenyl, aryl(C 2 -C 8 )alkynyl, heterocyclyl, heterocyclyl(C 1 -C 4 )alkyl, —COR 7 , —CO 2 R 7 , —NR 7 R 24 , —NO 2 , —CN, —S(O) r1 R 7 , —X 1 OR 7 , —X 1 COR 7 , —X 1 CO 2 R 7 , —X 1 NR 7 R 24 , —X 1 NO 2 , —X 1 CN and —X 1 S(O) r1 R 7 ; 
       each R 4  is independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —OR 7 , (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl, aryl(C 2 -C 8 )alkenyl, aryl(C 2 -C 8 )alkynyl, heterocyclyl, heterocyclyl(C 1 -C 4 )alkyl, —COR 7 , —CO 2 R 7 , —NR 7 R 24 , —NO 2 , —CN, —S(O) r1 R 7 , —X 2 OR 7 , —X 2 COR 7 , —X 2 CO 2 R 7 , —X 2 NR 7 R 24 , —X 2 NO 2 , —X 2 CN, —X 2 s(O) r1 R 7 , 
     
     
       
         
         
             
             
         
       
       each ring of which is optionally substituted with from one to two substituents independently selected from the group consisting of halo and (C 1 -C 8 )alkyl; 
       each R 7  and R 24  is a member independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —X 3 OR 25 , —CO, aryl, aryl(C 1 -C 4 )alkyl and heteroaryl or optionally, if both are present on the same substituent, may be joined together to form a three- to eight-membered ring; 
       each R 8  is a member independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —X 4 OR 7 , —X 4 NR 7 R 24 , (C 2 -C 8 )alkenyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, heteroaryl, aryl, aryl(C 1 -C 4 )alkyl and aryl(C 2 -C 8 )alkenyl 
       each R 9  or R 10  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the triazole ring to form a triazolopyridine, benzotriazole or tetrahydrobenzotriazole ring optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 11  or R 12  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the imidazole ring to form a benzimidazolyl ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 13  or R 14  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the oxazole ring to form a benzoxazolyl ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 15  or R 16  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the thiazole ring to form a benzothiazoyl ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 17  or R 18  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the pyrazole ring to form a indazoyl ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 19  or R 20  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the pyrrolidine ring to form a dihydroisoindole ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       R 21  is CH 3 , phenyl or pyridyl, wherein the phenyl and pyridyl substituents are optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each of R 22  or R 23  is independently selected from the group consisting of (C 1 -C 8 )alkyl, —OR 7 , halo and (C 1 -C 8 )haloalkyl; 
       R 25  is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 4 )alkyl and heteroaryl; 
       each W 1  or W 2  is independently N or CR 22 ; 
       each X 1 , X 2 , X 3  and X 4  is a member independently selected from the group consisting of (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene and (C 2 -C 4 )alkynylene; 
       the subscript r1 is an integer of from 0 to 2; and 
       pharmaceutically acceptable salts thereof. 
     
   
   
       2 . The method of  claim 1 , wherein the method is modulating insulin resistance. 
   
   
       3 . The method of  claim 1 , wherein the method is modulating leptin levels. 
   
   
       4 . A method of modulating a peroxisome proliferator activated receptor, comprising the step of contacting the receptor with at least one compound having the formula:
   Z—K—Ar 1 -L-Ar 2 —R 1   (I)   wherein   Ar 1  is selected from the group consisting of benzene, imidazole, indole, and indazole, each of which is optionally substituted with a R 2  substituent, a R 3  substituent or a combination thereof;   Ar 2  is benzene, which is optionally substituted with from one to two R 4  substituents;   K is absent or is a linking group selected from the group consisting of —CH 2 —, —CH 2 CH 2 , —CH 2 O—, —CH(CH 3 )O—, —C(CH 3 ) 2 O—, —CH(CH 3 )—, —CH(OCH 3 )— and —C(CH 3 ) 2 — wherein K can be attached to any available ring member of Ar 1 ;   L is a linking group joining Ar 1  and Ar 2  and is selected from the group consisting of —O(CH 2 ) 3 O—, —O(CH 2 ) 2 O—, —S(CH 2 ) 3 O—, and —S(CH 2 ) 2 O—, wherein L can be attached to any available ring member of Ar 1  and to any available ring member of Ar 2 ;   Z is CO 2 R 8 ;   R 1  is a member independently selected from the group consisting of:   
     
       
         
         
             
             
         
       
       each R 2  or R 3  is independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —OR 7 , (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, aryl(C 2 -C 8 )alkenyl, aryl(C 2 -C 8 )alkynyl, heterocyclyl, heterocyclyl(C 1 -C 4 )alkyl, —COR 7 , —CO 2 R 7 , —NR 7 R 24 , —NO 2 , —CN, —S(O) r1 R 7 , —X 1 OR 7 , —X 1 COR 7 , —X 1 CO 2 R 7 , —X 1 NR 7 R 24 , —X 1 NO 2 , —X 1 CN and —X 1 S(O) r1 R 7 ; 
       each R 4  is independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —OR 7 , (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl, aryl(C 2 -C 8 )alkenyl, aryl(C 2 -C 8 )alkynyl, heterocyclyl, heterocyclyl(C 1 -C 4 )alkyl, —COR 7 , —CO 2 R 7 , —NR 7 R 24 , —NO 2 , —CN, —S(O) r1 R 7 , —X 2 OR 7 , —X 2 COR 7 , —X 2 CO 2 R 7 , —X 2 NR 7 R 24 , —X 2 NO 2 , —X 2 CN, —X 2 S(O) r1 R 7 , 
     
     
       
         
         
             
             
         
       
       each ring of which is optionally substituted with from one to two substituents independently selected from the group consisting of halo and (C 1 -C 8 )alkyl; 
       each R 7  and R 24  is a member independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —X 3 OR 25 , —CO, aryl, aryl(C 1 -C 4 )alkyl and heteroaryl or optionally, if both are present on the same substituent, may be joined together to form a three- to eight-membered ring; 
       each R 8  is a member independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —X 4 OR 7 , —X 4 NR 7 R 24 , (C 2 -C 8 )alkenyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, heteroaryl, aryl, aryl(C 1 -C 4 )alkyl and aryl(C 2 -C 8 )alkenyl 
       each R 9  or R 10  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the triazole ring to form a triazolopyridine, benzotriazole or tetrahydrobenzotriazole ring optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 11  or R 12  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the imidazole ring to form a benzimidazolyl ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 13  or R 14  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the oxazole ring to form a benzoxazolyl ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 15  or R 16  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the thiazole ring to form a benzothiazoyl ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 17  or R 18  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the pyrazole ring to form a indazoyl ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 19  or R 20  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the pyrrolidine ring to form a dihydroisoindole ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       R 21  is CH 3 , phenyl or pyridyl, wherein the phenyl and pyridyl substituents are optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each of R 22  or R 23  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, —OR 7 , halo and (C 1 -C 8 )haloalkyl; 
       R 25  is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 4 )alkyl and heteroaryl; 
       each W 1  or W 2  is independently N or CR 22 ; 
       each X 1 , X 2 , X 3  and X 4  is a member independently selected from the group consisting of (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene and (C 2 -C 4 )alkynylene; 
       the subscript r1 is an integer of from 0 to 2; and 
       pharmaceutically acceptable salts thereof. 
     
   
   
       5 . A method of treating a disease in a subject, wherein the disease is selected from the group consisting of Type 2 diabetes, hyperinsulinemia, hyperlipidemia, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, atherosclerosis, Syndrome X , one or more risk factors for cardiovascular disease, obesity, and eating disorders, wherein said method comprises administering to said subject a therapeutically effective amount of a compound having the formula:
   Z—K—Ar 1 -L-Ar 2 —R 1   (I)   wherein   Ar 1  is selected from the group consisting of benzene, imidazole, indole, and indazole, each of which is optionally substituted with a R 2  substituent, a R 3  substituent or a combination thereof;   Ar 2  is benzene, which is optionally substituted with from one to two R 4  substituents;   K is absent or is a linking group selected from the group consisting of —CH 2 —, —CH 2 CH 2 , —CH 2 O—, —CH(CH 3 )O—, —C(CH 3 ) 2 O—, —CH(CH 3 )—, —CH(OCH 3 )— and —C(CH 3 ) 2 — wherein K can be attached to any available ring member of Ar 1 ;   L is a linking group joining Ar 1  and Ar 2  and is selected from the group consisting of —O(CH 2 ) 3 O—, —O(CH 2 ) 2 O—, —S(CH 2 ) 3 O—, and —S(CH 2 ) 2 O—, wherein L can be attached to any available ring member of Ar 1  and to any available ring member of Ar 2 ;   Z is CO 2 R 8 ;   R 1  is a member independently selected from the group consisting of:   
     
       
         
         
             
             
         
       
       each R 2  or R 3  is independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —OR 7 , (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, aryl(C 2 -C 8 )alkenyl, aryl(C 2 -C 8 )alkynyl, heterocyclyl, heterocyclyl(C 1 -C 4 )alkyl, —COR 7 , —CO 2 R 7 , —NR 7 R 24 , —NO 2 , —CN, —S(O) r1 R 7 , —X 1 OR 7 , —X 1 COR 7 , —X 1 CO 2 R 7 , —X 1 NR 7 R 24 , —X 1 NO 2 , —X 1 CN and —X 1 S(O) r1 R 7 ; 
       each R 4  is independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —OR 7 , (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl, aryl(C 2 -C 8 )alkenyl, aryl(C 2 -C 8 )alkynyl, heterocyclyl, heterocyclyl(C 1 -C 4 )alkyl, —COR 7 , —CO 2 R 7 , —NR 7 R 24 , —NO 2 , —CN, —S(O) r1 R 7 , —X 2 OR 7 , —X 2 COR 7 , —X 2 CO 2 R 7 , —X 2 NR 7 R 24 , —X 2 NO 2 , —X 2 CN, —X 2 S(O) r1 R 7 , 
     
     
       
         
         
             
             
         
       
       each ring of which is optionally substituted with from one to two substituents independently selected from the group consisting of halo and (C 1 -C 8 )alkyl; 
       each R 7  and R 24  is a member independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —X 3 OR 25 , —CO, aryl, aryl(C 1 -C 4 )alkyl and heteroaryl or optionally, if both are present on the same substituent, may be joined together to form a three- to eight-membered ring; 
       each R 8  is a member independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —X 4 OR 7 , —X 4 NR 7 R 24 , (C 2 -C 8 )alkenyl, (C 3 -C 7 )cycloalkyl, heterocyclyl, heteroaryl, aryl, aryl(C 1 -C 4 )alkyl and aryl(C 2 -C 8 )alkenyl 
       each R 9  or R 10  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the triazole ring to form a triazolopyridine, benzotriazole or tetrahydrobenzotriazole ring optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 11  or R 12  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the imidazole ring to form a benzimidazolyl ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 13  or R 14  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the oxazole ring to form a benzoxazolyl ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 15  or R 16  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the thiazole ring to form a benzothiazoyl ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 17  or R 18  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the pyrazole ring to form a indazoyl ring optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each R 19  or R 20  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, halo and (C 1 -C 8 )haloalkyl or is joined together with the pyrrolidine ring to form a dihydroisoindole ring , optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , —CO 2 R 7 , —NR 7 R 24 , —CN, —S(O) r1 R 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       R 21  is CH 3 , phenyl or pyridyl, wherein the phenyl and pyridyl substituents are optionally substituted with from one to two substituents independently selected from the group consisting of —OR 7 , halo, (C 1 -C 8 )alkyl and (C 1 -C 8 )haloalkyl; 
       each of R 22  or R 23  is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, —OR 7 , halo and (C 1 -C 8 )haloalkyl; 
       R 25  is a member selected from the group consisting of H, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 4 )alkyl and heteroaryl; 
       each W 1  or W 2  is independently N or CR 22 ; 
       each X 1 , X 2 , X 3  and X 4  is a member independently selected from the group consisting of (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene and (C 2 -C 4 )alkynylene; 
       the subscript r1 is an integer of from 0 to 2; and 
       pharmaceutically acceptable salts thereof. 
     
   
   
       6 . The method of  claim 5 , wherein the disease is Type 2 diabetes. 
   
   
       7 . The method of  claim 5 , wherein the disease is hyperinsulinemia. 
   
   
       8 . The method of  claim 5 , wherein the disease is hyperlipidemia. 
   
   
       9 . The method of  claim 5 , wherein the disease is hyperuricemia. 
   
   
       10 . The method of  claim 5 , wherein the disease is hypercholesterolemia. 
   
   
       11 . The method of  claim 5 , wherein the disease is hypertriglyceridemia. 
   
   
       12 . The method of  claim 5 , wherein the disease is hyperglycemia. 
   
   
       13 . The method of  claim 5 , wherein the disease is atherosclerosis. 
   
   
       14 . The method of  claim 5 , wherein the disease is Syndrome X. 
   
   
       15 . The method of  claim 5 , wherein the disease is one or more risk factors for cardiovascular disease. 
   
   
       16 . The method of  claim 5 , wherein the disease is obesity. 
   
   
       17 . The method of  claim 5 , wherein the disease is an eating disorder. 
   
   
       18 .- 29 . (canceled)