Modulators of PPAR and methods of their preparation

A compound having the formula:

• Z—K—Ar1—L—Ar2—R1 (I)
• wherein
• Ar1 is selected from the group consisting of benzene, imidazole, indole and indazole, each of which is optionally substituted with a R2 substituent, a R3 substituent or a combination thereof;
• Ar2 is benzene, which is optionally substituted with from one to two R4 substituents;
• K is absent or is a linking group selected from the group consisting of —CH2—, —CH2CH2, —CH2O—, —CH(CH3)O—, —C(CH3)2O—, —CH(CH3)—, —CH(OCH3)— and —C(CH3)2— wherein K can be attached to any available ring member of Ar1;
• L is a linking group joining Ar1 and Ar2 and is selected from the group consisting of —O(CH2)3O—, —O(CH2)2O—, —S(CH2)3O—, and —S(CH2)2O— wherein L can be attached to any available ring member of Ar1 and to any available ring member of Ar2;
• Z is CO2R8;
• R1 is a member independently selected from the group consisting of:
• each R2 or R3 is independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, —OR7, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, aryl, aryl(C1-C4)alkyl, aryl(C2-C8)alkenyl, aryl(C2-C8)alkynyl, heterocyclyl, heterocyclyl(C1-C4)alkyl, —COR7, —CO2R7, —NR7R24, —NO2, —CN, —S(O)r1R7, −X1OR7, —X1COR7, —X1CO2R7, —X1NR7R24, —X1NO2, —X1CN and —X1S(O)r1R7;
• each R4 is independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, —OR7, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, aryl(C1-C4)alkyl, aryl(C2-C8)alkenyl, aryl(C2-C8)alkynyl, heterocyclyl, heterocyclyl(C1-C4)alkyl, —COR7, —CO2R7, —NR7R24, —NO2, —CN, —S(O)r1R7, —X2OR7, —X2COR7, —X2CO2R7, —X2NR7R24, —X2NO2, —X2CN, —X2S(O)r1R7,
• each ring of which is optionally substituted with from one to two substituents independently selected from the group consisting of halo and (C1-C8)alkyl;
• each R7 and R24 is a member independently selected from the group consisting of H, (C1-C8)alkyl, halo(C1-C8)alkyl, —X3OR25, —CO, aryl, aryl(C1-C4)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 R8 is a member independently selected from the group consisting of H, (C1-C8)alkyl, halo(C1-C8)alkyl, —X4OR7, —X4NR7R24, (C2-C8)alkenyl, (C3-C7)cycloalkyl, heterocyclyl, heteroaryl, aryl, aryl(C1-C4)alkyl and aryl(C2-C8)alkenyl
• each R9 or R10 is independently selected from the group consisting of H, (C1-C8)alkyl, halo and (C1-C8)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 —OR7, —CO2R7, —NR7R24, —CN, S(O)r1R7, halo, (C1-C8)alkyl and (C1-C8)haloalkyl;
• each R11 or R12 is independently selected from the group consisting of H, (C1-C8)alkyl, halo and (C1-C8)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 —OR7, —CO2R7, —NR7R24, —CN, —S(O)r1R7, halo, (C1-C8)alkyl and (C1-C8)haloalkyl;
• each R13 or R14 is independently selected from the group consisting of H, (C1-C8)alkyl, halo and (C1-C8)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 —OR7, —CO2R7, —NR7R24, —CN, —S(O)r1R7, halo, (C1-C8)alkyl and (C1-C8)haloalkyl;
• each R15 or R16 is independently selected from the group consisting of H, (C1-C8)alkyl, halo and (C1-C8)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 —OR7, —CO2R7, —NR7R24, —CN, —S(O)r1R7, halo, (C1-C8)alkyl and (C1-C8)haloalkyl;
• each R17 or R18 is independently selected from the group consisting of H, (C1-C8)alkyl, halo and (C1-C8)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 —OR7, —CO2R7, —NR7R24, —CN, —S(O)r1R7, halo, (C1-C8)alkyl and (C1-C8)haloalkyl;
• each R19 or R20 is independently selected from the group consisting of H, (C1-C8)alkyl, halo and (C1-C8)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 —OR7, —CO2R7, —NR7R24, —CN, —S(O)r1R7, halo, (C1-C8)alkyl and (C1-C8)haloalkyl;
• R21 is CH3, 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 —OR7, halo, (C1-C8)alkyl and (C1-C8)haloalkyl;
• each of R22 or R23 is independently selected from the group consisting of H, (C1-C8)alkyl, —OR7, halo and (C1-C9)haloalkyl;
• R25 is a member selected from the group consisting of H, (C1-C8)alkyl, halo(C1-C8)alkyl, aryl, aryl(C1-C4)alkyl and heteroaryl;
• each W1 or W2 is independently N or CR22;
• each X1, X2, X3 and X4 is a member independently selected from the group consisting of (C1-C4)alkylene, (C2-C4)alkenylene and (C2-C4)alkynylene;
• the subscript r1 is an integer of from 0 to 2;
• and
• pharmaceutically acceptable salts thereof.