Sulfonyl-substituted bicyclic compounds as ppar modulators for the treatment of non-alcoholic steatohepatitis

A method for the treatment of NASH comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I:

• or a salt, ester, or prodrug thereof, wherein:
• A is a saturated or unsaturated hydrocarbon chain or a heteroatom-comprising hydrocarbon chain having from 3 to 5 atoms, forming a five- to seven-membered ring;
• T is selected from the group consisting of —C(O)OH, —C(O)NH2, and tetrazole;
• G1 is selected from the group consisting of —(CR1R2)n—, -Z(CR1R2)n—, —(CR1R2)nZ-, —(CR1R2)rZ(CR1R2)s—;
• Z is O, S or NR;
• n is 0, 1, or 2;
• r and s are independently 0 or 1;
• R1 and R2 are independently selected from the group consisting of hydrogen, halo, optionally substituted lower alkyl, optionally substituted lower heteroalkyl, optionally substituted lower alkoxy, and lower perhaloalkyl or together may form an optionally substituted cycloalkyl;
• X1, X2, and X3 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, halogen, perhaloalkyl, hydroxy, optionally substituted lower alkoxy, nitro, cyano, and NH2;
• G2 is selected from the group consisting of a saturated or unsaturated cycloalkyl or heterocycloalkyl linker, optionally substituted with X4 and X5;
• X4 and X5 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, halogen, lower perhaloalkyl, hydroxy, optionally substituted lower alkoxy, nitro, cyano, NH2, and CO2R, or X4 and X5 together may form a cycloalkyl;
• R is selected from the group consisting of optionally substituted lower alkyl and hydrogen;
• G3 is selected from the group consisting of a bond, a double bond, —(CR3R4)m—, carbonyl, and —(CR3R4)mCR3═CR4—;
• m is 0, 1, or 2;
• R3 and R4 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted aryl, lower perhaloalkyl, cyano, and nitro;
• G4 is selected from the group consisting of hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted cycloheteroaryl, optionally substituted cycloalkenyl, and —N═(CR5R6);
• and
• R5 and R6 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, and optionally substituted cycloheteroalkyl.