Thiazolidinedione analogs for the treatment of nafld and metabolic diseases

A method of treating non-alcoholic fatty liver disease (NAFLD) and/or at least one metabolic inflammation-mediated disease or disorder, comprising administering to a subject in need thereof:

• (i) a therapeutically effective amount of a compound of structural Formula (I):
• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR1A;
• R2 is halogen, hydroxyl, or optionally substituted aliphatic;
• R2′ is hydrogen, or R2 and R2′ may optionally be joined to form oxo;
• R3 is hydrogen or deuterium;
• R4 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR4A;
• A is phenyl;
• and
• R1A and R4A are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CHF2, —CHCl2, —CHBr2, —CHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• and
• (ii) at least one additional therapeutic agent selected from a phosphodiesterase (PDE) inhibitor, a thyroid hormone beta receptor agonist, or a GLP1 agonist.

A method of treating non-alcoholic fatty liver disease (NAFLD) and/or metabolic syndrome, comprising administering to a subject in need thereof:

• (i) a therapeutically effective amount of a pharmaceutical composition, comprising a compound of structural Formula (I):
• or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein:
• R1 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR1A;
• R2 is halogen, hydroxyl, or optionally substituted aliphatic;
• R2′ is hydrogen, or R2 and R2′ may optionally be joined to form oxo;
• R3 is hydrogen or deuterium;
• R4 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR4A;
• A is phenyl;
• and
• R1A and R4A are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CHF2, —CHCl2, —CHBr2, —CHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• and
• (ii) at least one additional therapeutic agent selected from a GLP1 agonist, a phosphodiesterase (PDE) inhibitor, or a thyroid hormone beta receptor agonist.

A method of treating non-alcoholic fatty liver disease (NAFLD) and/or at least one metabolic inflammation-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising:

• i) a compound of structural Formula (I), or a pharmaceutically acceptable salt thereof:
• wherein:
• R1 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR1A;
• R2 is halogen, hydroxyl, or optionally substituted aliphatic;
• R2′ is hydrogen, or R2 and R2′ may optionally be joined to form oxo;
• R3 is hydrogen or deuterium;
• R4 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR4A;
• A is phenyl;
• and
• R1A and R4A are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CHF2, —CHCl2, —CHBr2, —CHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• (ii) at least one additional therapeutic agent selected from a GLP1 agonist, a phosphodiesterase (PDE) inhibitor, or a thyroid hormone beta receptor agonist;
• and
• (iii) and a pharmaceutically acceptable excipient, wherein the compound of Formula (I) and the at least one additional therapeutic agent selected from a GLP1 agonist, a phosphodiesterase (PDE) inhibitor, or a thyroid hormone beta receptor agonist are co-formulated.

A method of treating at least one metabolic inflammation-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structural Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR1A;
• R2 is halogen, hydroxyl, or optionally substituted aliphatic;
• R2′ is hydrogen, or R2 and R2′ may optionally be joined to form oxo;
• R3 is deuterium;
• R4 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR4A;
• A is phenyl;
• and
• R1A and R4A are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CHF2, —CHCl2, —CHBr2, —CHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

A method of inhibiting hepatic mitochondrial pyruvate carrier (MPC) in a cell, comprising contacting the MPU with a compound of structural Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR1A;
• R2 is halogen, hydroxyl, or optionally substituted aliphatic;
• R2′ is hydrogen, or R2 and R2′ may optionally be joined to form oxo;
• R3 is hydrogen or deuterium;
• R4 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR4A;
• A is phenyl;
• and
• R1A and R4A are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CHF2, —CHCl2, —CHBr2, —CHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

A method of improving or increasing glucose tolerance and/or insulin sensitivity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structural Formula (I)

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR1A;
• R2 is halogen, hydroxyl, or optionally substituted aliphatic;
• R2′ is hydrogen, or R2 and R2′ may optionally be joined to form oxo;
• R3 is hydrogen or deuterium;
• R4 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR4A;
• A is phenyl;
• and
• R1A and R4A are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, CI3, —CHF2, —CHCl2, —CHBr2, —CHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

A method of treating or preventing a hepatic disease, disorder, or injury, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structural Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR1A;
• R2 is halogen, hydroxyl, or optionally substituted aliphatic;
• R2′ is hydrogen, or R2 and R2′ may optionally be joined to form oxo;
• R3 is hydrogen or deuterium;
• R4 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR4A;
• A is phenyl;
• and
• R1A and R4A are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CHF2, —CHCl2, —CHBr2, —CHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

A method of treating or preventing hepatocyte fibrogenesis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structural Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR1A;
• R2 is halogen, hydroxyl, or optionally substituted aliphatic;
• R2′ is hydrogen, or R2 and R2′ may optionally be joined to form oxo;
• R3 is hydrogen or deuterium;
• R4 is hydrogen, halogen, substituted or unsubstituted alkyl, or —OR4A;
• A is phenyl;
• and
• R1A and R4A are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —CHF2, —CHCl2, —CHBr2, —CHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.