Modulators of protease activated receptors

A method of treating a disease or disorder selected from metabolic syndrome, obesity, type II diabetes, fibrosis and cardiovascular diseases comprising administering to a subject in need thereof an effective amount of a PAR2 antagonist represented by formula (I):

• wherein
• R1 is hydrogen, C1-C6alkyl, aminoalkyl, hydroxyalkyl, or —C(O)R8;
• R8 is a 5- or 6-membered saturated or unsaturated heterocyclic ring comprising 1 to 3 heteroatoms selected from N and O, optionally substituted with one or more substituents selected from alkyl, alkoxy, amine, aminoalkyl, amidoalkyl, halo, hydroxy, trihaloalkyl, trihaloalkoxy or phenyl, wherein the phenyl group is optionally substituted with 1 to 3 substituents selected from alkyl, alkoxy, hydroxy, halo, nitro, trihaloalkyl, or trihaloalkoxy;
• or
• R1, together with the nitrogen atom to which it is attached, forms a mono- or bicyclic-nitrogen containing heterocycle, optionally substituted with alkyl;
• R2 is an aromatic or aliphatic C3-C8cyclic group or C3-C8heterocyclic group comprising 1 to 3 heteroatoms selected from N and O, wherein the C3-C8cyclic group or C3-C8heterocyclic group may be further substituted with one or more substituents selected from alkyl, amine, hydroxy, or the cyclic group or heterocyclic group is fused with an optionally substituted aromatic or aliphatic C3-C8cyclic group or C3-C8heterocyclic group;
• R3 is hydrogen or C1-C6alkyl;
• R4 is hydrogen, C1-C6alkyl, aminoalkyl or amidoalkyl;
• R5 is a benzyl group optionally substituted with alkyl, aminoalkyl, alkoxy, C4-C7heterocycle, hydroxy, halo, nitro, dioxalane, trihaloalkyl, trihaloalkoxy or —C(O)NHCHR9R10;
• R9 is —C(O)NH2 and
• R10 is a C2-C5aminoalkyl;
• or
• R4 and R5 combined, together with the nitrogen to which they are attached, form piperidine, optionally substituted with phenyl, benzyl, aminoalkyl, aminoaryl, amidoalkyl or a heterocycle;
• or
• R4 and R5 combined, together with the nitrogen to which they are attached, form piperidine fused with an aromatic or aliphatic C3-C8cyclic group or C3-C8heterocyclic group;
• wherein the phenyl, benzyl, aminoaryl, heterocycle or the aromatic or aliphatic C3-C8cyclic group or C3-C8heterocyclic group fused with piperidine may be further substituted with 1 to 3 substituents selected from alkyl, alkylamine, alkylamide, alkylsulfonyl, alkoxy, aminoalkyl, aminoaryl, amidoalkyl, arylamine, hydroxy, halo, nitro, oxo, optionally substituted phenyl, optionally substituted piperidine, dioxalane, trihaloalkyl, or trihaloalkoxy;
• or the aromatic or aliphatic C3-C8cyclic group or C3-C8heterocyclic group fused with the piperidine is further fused with an additional C6-C10cyclic or C6-C10heterocyclic group;
• R6 is hydrogen or C1-C6alkyl;
• R7 is C1-C6alkyl, amino, hydroxy, alkoxy, aminoalkyl, amidoalkyl, saturated or unsaturated cycloalkyl, or heterocycle;
• or
• R6 and R7 combined, together with the carbon to which they are attached, form C5-C8 aromatic or aliphatic cyclic group or heterocyclic group, optionally substituted with a group selected from alkyl, aminoalkyl, alkoxy, hydroxy, halo, nitro, trihaloalkyl or trihaloalkoxy;
• and
• R12 is hydrogen or C1-C6alkyl;
• and
• salts thereof;
• provided that the compound is not 5-isoxazoyl-Cha-Ile-spiro[indene-1,4′-piperidine], 5-isoxazoyl-Cha-Ile-spiro[indane-1,4′-piperidine], 5-isoxazoyl-Cha-Ile-spiro[octahydro-1H-indene-1,4′-piperidine] or 5-isoxazoyl-Cha-Ile-1,2,3,4-tetrahydroisoquinoline.