Aryl dicarboxamides

A method of treating or preventing at least one disease selected from the group consisting of diabetes, inadequate glucose tolerance, hyperlipidemia, hypertriglyceridemia hypercholesterolemia, and polycystic ovary syndrome, in a subject in need thereof, comprising, administering at least one aryl dicarboxamide of formula (I):

• as well as its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherein
• A is an aminocarbonyl moiety of the formula —CO—NHR6, wherein R6 is C6-C15 alkyl, C2-C15-alkenyl, C2-C15-alkynyl, a 3-8 membered cycloalkyl, C1-C6 alkyl-(3-8 membered) cycloalkyl, phenyl, C1-C12 alkyl phenyl, C2-C6-alkenyl phenyl, or C2-C6-alkynyl phenyl;
• Cy is an aryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, aryl-aryl, cycloalkyl or heterocycle group;
• n is either 0 or 1;
• R1 and R2 are independently from each other selected from the group consisting of hydrogen and C1-C6-alkyl;
• R3 is selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C1-C6-alkyl amine, C1-C6-alkyl alkoxy, aryl, heteroaryl, saturated 3-8-membered cycloalkyl, unsaturated 3-8-membered cycloalkyl, 3-8-membered heterocycloalkyl, C1-C6-alkyl aryl, C1-C6-alkyl heteroaryl, C2-C6-alkenyl aryl, C2-C6-alkenyl heteroaryl, C2-C6-alkynyl aryl, C2-C6-alkynyl heteroaryl, C1-C6-alkyl cycloalkyl, C1-C6-alkyl heterocycloalkyl, C2-C6-alkenyl cycloalkyl, C2-C6-alkenyl heterocycloalkyl, C2-C6-alkynyl cycloalkyl, and C2-C6-alkynyl heterocycloalkyl;
• R4 and R5 are each independently from each other selected from the group consisting of H, hydroxy, C1-C6 alkyl, carboxy, C1-C6 alkoxy, C1-C3 alkyl carboxy, C2-C3 alkenyl carboxy, C2-C3 alkynyl carboxy, and amino, or R4 and R5 may form an unsaturated or saturated heterocyclic ring, whereby at least one of R4 or R5 is not a hydrogen or C1-C6 alkyl, to the subject in an amount sufficient to treat or prevent the at least one disease.

A method of treating or preventing at least one metabolic disorder mediated by insulin resistance or hyperglycemia, in a subject in need thereof, comprising, administering at least one aryl dicarboxamide of formula (I):

• as well as its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherein
• A is an aminocarbonyl moiety of the formula —CO—NHR6, wherein R6 is C6-C15 alkyl, C2-C15-alkenyl, C2-C15-alkynyl, a 3-8 membered cycloalkyl, C1-C6 alkyl-(3-8 membered) cycloalkyl, phenyl, C1-C12 alkyl phenyl, C2-C6-alkenyl phenyl, or C2-C6-alkynyl phenyl;
• Cy is an aryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, aryl-aryl, cycloalkyl or heterocycle group;
• n is either 0 or 1;
• R1 and R2 are independently from each other selected from the group consisting of hydrogen and C1-C6-alkyl;
• R3 is selected from the group consisting of C1-C6 alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C1-C6-alkyl amine, C1-C6-alkyl alkoxy, aryl, heteroaryl, saturated 3-8-membered cycloalkyl, unsaturated 3-8-membered cycloalkyl, 3-8-membered heterocycloalkyl, C1-C6-alkyl aryl, C1-C6-alkyl heteroaryl, C2-C6-alkenyl aryl, C2-C6-alkenyl heteroaryl, C2-C6-alkynyl aryl, C2-C6-alkynyl heteroaryl, C1-C6-alkyl cycloalkyl, C1-C6-alkyl heterocycloalkyl, C2-C6-alkenyl cycloalkyl, C2-C6-alkenyl heterocycloalkyl, C2-C6-alkynyl cycloalkyl, and C2-C6-alkynyl heterocycloalkyl;
• R4 and R5 are each independently from each other selected from the group consisting of H, hydroxy, C1-C6 alkyl, carboxy, C1-C6 alkoxy, C1-C3 alkyl carboxy, C2-C3 alkenyl carboxy, C2-C3 alkynyl carboxy, and amino, or R4 and R5 may form an unsaturated or saturated heterocyclic ring, whereby at least one of R4 or R5 is not a hydrogen or C1-C6 alkyl,
• to the subject in an amount sufficient to treat or prevent the at least one disorder.

An aryl dicarboxamide according to any of the formulae (Ia), (Ib) or (Ic):

• wherein
• A is an aminocarbonyl moiety of the formula —CO—NHR6 wherein R6 is C6-C15 alkyl, C2-C15-alkenyl, C2-C15-alkynyl, a 3-8 membered cycloalkyl, C1-C6 alkyl-(3-8 membered) cycloalkyl, phenyl, C1-C12 alkyl phenyl, C2-C6-alkenyl phenyl, or C2-C6-alkynyl phenyl;
• Cy is an aryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, aryl-aryl, cycloalkyl or heterocycle group;
• n is either 0 or 1;
• R1 and R2 are independently from each other selected from the group consisting of hydrogen and C1-C6-alkyl;
• R3 is selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C1-C6-alkyl amine, C1-C6-alkyl alkoxy, aryl, heteroaryl, saturated 3-8-membered cycloalkyl, unsaturated 3-8 membered cycloalkyl, 3-8-membered heterocycloalkyl, an acyl moiety, C1-C6-alkyl aryl, C1-C6-alkyl heteroaryl, C2-C6-alkenyl aryl, C2-C6-alkenyl heteroaryl, C2-C6-alkynyl aryl, C2-C6-alkynyl heteroaryl, C1-C6-alkyl cycloalkyl, C1-C6-alkyl heterocycloalkyl, C2-C6-alkenyl cycloalkyl, C2-C6-alkenyl heterocycloalkyl, C2-C6-alkynyl cycloalkyl, and C2-C6-alkynyl heterocycloalkyl.

An aryl dicarboxamide according to formula (Ib) or (Ic):

• wherein
• A is an aminocarbonyl moiety of the formula —CO—NHR6 wherein R6 is C6-C15 alkyl, C2-C15-alkenyl, C2-C15-alkynyl, a 3-8 membered cycloalkyl, C1-C6 alkyl-(3-8 membered) cycloalkyl, phenyl, C1-C12 alkyl phenyl, C2-C6-alkenyl phenyl, or a C2-C6-alkynyl phenyl;
• Cy is an aryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, aryl-aryl, cycloalkyl or heterocycle group;
• n is either 0 or 1;
• R1 and R2 are independently from each other is selected from the group consisting of hydrogen and C1-C6-alkyl;
• R3 is selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C1-C6-alkyl amine, C1-C6-alkyl alkoxy, aryl, heteroaryl, saturated 3-8-membered cycloalkyl, unsaturated 3-8-membered cycloalkyl, 3-8-membered heterocycloalkyl, an acyl moiety, C1-C6-alkyl aryl, C1-C6-alkyl heteroaryl, C2-C6-alkenyl aryl, C2-C6-alkenyl heteroaryl, C2-C6-alkynyl aryl, C2-C6-alkynyl heteroaryl, C1-C6-alkyl cycloalkyl, C1-C6-alkyl heterocycloalkyl, C2-C6-alkenyl cycloalkyl, C2-C6-alkenyl heterocycloalkyl, C2-C6-alkynyl cycloalkyl, and C2-C6-alkynyl heterocycloalkyl.

An aryl dicarboxamide selected from the group consisting of:

• 5-[(3-cyclopentylpropanoyl)(4-{[(4-phenoxybenzyl)amino]carbonyl}benzyl)amino]-2-hydroxybenzoic acid
• 5-[(3-cyclopentylpropanoyl)(4-{[(4-phenoxybenzyl)amino]carbonyl}benzyl)amino]-2-hydroxybenzoic acid
• [4-({{[2-(4-{[(4-pentylbenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}-[(2E)-3-phenylprop-2-enoyl]amino}methyl)phenoxy]acetic acid
• 5-[(3-cyclopentylpropanoyl)(4-{[(4-pentylbenzyl)amino]carbonyl}benzyl)amino]-2-hydroxybenzoic acid
• 2-hydroxy-5-{(4-{[(4-pentylbenzyl)amino]carbonyl}benzyl)[4-(trifluoromethyl)benzoyl]amino}benzoic acid
• 2-hydroxy-5-[[(4-{[(4-phenoxybenzyl)amino]carbonyl}-1,3-thiazol-2-yl)methyl](3-phenylpropanoyl)amino]benzoic acid
• 5-{benzoyl[(4-{[(4-phenoxybenzyl)amino]carbonyl}-1,3-thiazol-2-yl)methyl]-amino}-2-hydroxybenzoic acid
• 2-hydroxy-5-{[(4-{[(4-phenoxybenzyl)amino]carbonyl}-1,3-thiazol-2-yl)methyl][4-(trifluoromethyl)benzoyl]amino}benzoic acid
• 5-[(cyclohexylcarbonyl)(4-{[(4-phenoxybenzyl)amino]carbonyl}benzyl)amino]-2-hydroxybenzoic acid
• 2-hydroxy-5-[(4-{[(4-phenoxybenzyl)amino]carbonyl}benzyl)(3-phenylpropanoyl)amino]benzoic acid
• 5-[benzoyl(4-{[(4-phenoxybenzyl)amino]carbonyl}benzyl)amino]-2-hydroxybenzoic acid
• 5-[acetyl(4-{[(4-phenoxybenzyl)amino]carbonyl}benzyl)amino]-2-hydroxybenzoic acid
• 5-[(4-cyanobenzoyl)(4-{[(4-phenoxybenzyl)amino]carbonyl}benzyl)amino]-2-hydroxybenzoic acid
• 2-hydroxy-5-[(phenoxyacetyl)(4-{[(4-phenoxybenzyl)amino]carbonyl}benzyl)amino]-benzoic acid
• 2-hydroxy-5-{(4-{[(4-phenoxybenzyl)amino]carbonyl}benzyl)[4-(trifluoromethyl)benzoyl]amino}benzoic acid
• 2-hydroxy-5-{(4-{[(4-phenoxybenzyl)amino]carbonyl}benzyl)[(2E)-3-phenylprop-2-enoyl]amino}benzoic acid
• 5-[(N,N-dimethylglycyl)(4-{[(4-phenoxybenzyl)amino]carbonyl}benzyl)amino]-2-hydroxybenzoic acid
• 2-hydroxy-5-[(3-methylbut-2-enoyl)(4-{[(4-phenoxybenzyl)amino]carbonyl}benzyl)amino]benzoic acid
• 2-hydroxy-5-{[{4-[(octylamino)carbonyl]benzyl}(phenoxyacetyl)amino]methyl}-benzoic acid
• 2-hydroxy-5-({{4-[(octylamino)carbonyl]benzyl}[4-(trifluoromethyl)benzoyl]-amino}methyl)benzoic acid
• 2-hydroxy-5-({{4-[(octylamino)carbonyl]benzyl}[(2E)-3-phenylprop-2-enoyl]-amino}methyl)benzoic acid
• 5-{[(3-cyclopentylpropanoyl)(4-{[(4-pentylbenzyl)amino]carbonyl}benzyl)amino]methyl}-2-hydroxybenzoic acid
• 2-hydroxy-5-{[(4-{[(4-pentylbenzyl)amino]carbonyl}benzyl)(phenoxyacetyl)amino]methyl}benzoic acid
• 2-hydroxy-5-({(4-{[(4-pentylbenzyl)amino]carbonyl}benzyl)[4-(trifluoromethyl)benzoyl]amino}methyl)benzoic acid
• 2-hydroxy-5-{[(3-methylbut-2-enoyl)(4-{[(4-pentylbenzyl)amino]carbonyl}-benzyl)amino]methyl}benzoic acid
• 5-{[(3-cyclopentylpropanoyl)(4-{[(4-phenylbutyl)amino]carbonyl}benzyl)amino]methyl}-2-hydroxybenzoic acid
• 2-hydroxy-5-({[(4-{[(4-pentylbenzyl)amino]carbonyl}-1,3-thiazol-2-yl)methyl][(2E)-3-phenylprop-2-enoyl]amino}methyl)benzoic acid
• [4-({(4-{[(4-phenoxybenzyl)amino]carbonyl}benzyl)[4-(trifluoromethyl)benzoyl]-amino}methyl)phenoxy]acetic acid
• 2-hydroxy-5-[(4-{[(4-pentylbenzyl)amino]carbonyl}benzyl)(3-phenylpropanoyl)amino]benzoic acid
• 4-[(3-cyclopentylpropanoyl)(4-{[(4-pentylbenzyl)amino]carbonyl}benzyl)amino]-2-hydroxybenzoic acid
• 2-hydroxy-4-{(4-{[(4-pentylbenzyl)amino]carbonyl}benzyl)[4-(trifluoromethyl)benzoyl]amino}benzoic acid
• 2-hydroxy-5-[{[2-(4-{[(4-pentylbenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}(phenoxyacetyl)amino]benzoic acid
• 2-hydroxy-5-{{[2-(4-{[(4-pentylbenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}[4-(trifluoromethyl)benzoyl]amino}benzoic acid
• 5-([(6-chloropyridin-3-yl)carbonyl]{[2-(4-{[(4-pentylbenzyl)amino]carbonyl}-phenyl)-1,3-thiazol-4-yl]methyl}amino)-2-hydroxybenzoic acid
• 5-((4-cyanobenzoyl){[2-(4-{[(4-pentylbenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}amino)-2-hydroxybenzoic acid
• 2-hydroxy-5-((3-methylbut-2-enoyl){[2-(4-{[(4-pentylbenzyl)amino]carbonyl}-phenyl)-1,3-thiazol-4-yl]methyl}amino)benzoic acid
• 5-((3-cyclopentylpropanoyl){[2-(4-{[(4-phenoxybenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}amino)-2-hydroxybenzoic acid
• 2-hydroxy-5-{{[2-(4-{[(4-phenoxybenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}[4-(trifluoromethyl)benzoyl]amino}benzoic acid
• 2-hydroxy-5-[{[2-(4-{[(4-phenoxybenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}(3-phenylpropanoyl)amino]benzoic acid
• 5-(benzoyl {[2-(4-{[(4-phenoxybenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}amino)-2-hydroxybenzoic acid
• [4-({{[2-(4-{[(4-pentylbenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}[4-(trifluoromethyl)benzoyl]amino}methyl)phenoxy]acetic acid
• (4-{[{[2-(4-{[(4-pentylbenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}(3-phenylpropanoyl)amino]methyl}phenoxy)acetic acid
• [4-({{[2-(4-{[(4-phenylbutyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}[4-(trifluoromethyl)benzoyl]amino}methyl)phenoxy]acetic acid
• (4-{[{[2-(4-{[(4-phenylbutyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}(3-phenylpropanoyl)amino]methyl}phenoxy)acetic acid
• [4-({{[2-(4-{[(4-phenylbutyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}[(2E)-3-phenylprop-2-enoyl]amino}methyl)phenoxy]acetic acid
• {4-[((N,N-dimethylglycyl){[2-(4-{[(4-phenylbutyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}amino)methyl]phenoxy}acetic acid
• {4-[((cyclohexylcarbonyl){[2-(4-{[(4-phenylbutyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}amino)methyl]phenoxy}acetic acid
• {4-[((phenoxyacetyl){[2-(4-{[(4-phenoxybenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}amino)methyl]phenoxy}acetic acid
• [4-({{[2-(4-{[(4-phenoxybenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}[4-(trifluoromethyl)benzoyl]amino}methyl)phenoxy]acetic acid
• (4-{[{[2-(4-{[(4-phenoxybenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}(3-phenylpropanoyl)amino]methyl}phenoxy)acetic acid
• {4-[((cyclohexylcarbonyl){[2-(4-{[(4-phenoxybenzyl)amino]carbonyl}phenyl)-1,3-thiazol-4-yl]methyl}amino)methyl]phenoxy}acetic acid
• [4-({[(2-{4-[(octylamino)carbonyl]phenyl}-1,3-thiazol-4-yl)methyl][4-(trifluoromethyl)benzoyl]amino}methyl)phenoxy]acetic acid;
• and
• (4-{[[(2-{4-[(octylamino)carbonyl]phenyl}-1,3-thiazol-4-yl)methyl](3-phenylpropanoyl)amino]methyl}phenoxy)acetic acid.

A method of preparing the aryl dicarboxamide of formula (I), comprising deprotecting, transforming, or deprotecting and transforming (I′) to form the aryl dicarboxamide (Ia):

• wherein FG is A or a leaving group,
• wherein
• A is an aminocarbonyl moiety of the formula —CO—NHR6, wherein R6 is C6-C15 alkyl, C2-C15-alkenyl, C2-C15-alkynyl, a 3-8 membered cycloalkyl, C1-C6 alkyl-(3-8 membered) cycloalkyl, phenyl, C1-C12 alkyl phenyl, C2-C6-alkenyl phenyl, or C2-C6-alkynyl phenyl;
• Cy is an aryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, aryl-aryl, cycloalkyl or heterocycle group;
• n is either 0 or 1;
• R1 and R2 are independently from each other is selected from the group consisting of hydrogen and C1-C6-alkyl;
• R3 is selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C1-C6-alkyl amine, C1-C6-alkyl alkoxy, aryl, heteroaryl, saturated 3-8-membered cycloalkyl, unsaturated 3-8-membered cycloalkyl, 3-8-membered heterocycloalkyl, C1-C6-alkyl aryl, C1-C6-alkyl heteroaryl, C2-C6-alkenyl aryl, C2-C6-alkenyl heteroaryl, C2-C6-alkynyl aryl, C2-C6-alkynyl heteroaryl, C1-C6-alkyl cycloalkyl, C1-C6-alkyl heterocycloalkyl, C2-C6-alkenyl cycloalkyl, C2-C6-alkenyl heterocycloalkyl, C2-C6-alkynyl cycloalkyl, and C2-C6-alkynyl heterocycloalkyl;
• and wherein
• R4 and R5 are each independently from each other selected from the group consisting of H, hydroxy, C1-C6 alkyl, carboxy, C1-C6 alkoxy, C1-C3 alkyl carboxy, C2-C3 alkenyl carboxy, C2-C3 alkynyl carboxy, and amino, or R4 and R5 may form an unsaturated or saturated heterocyclic ring, whereby at least one of R4 or R5 is not a hydrogen or C1-C6 alkyl.