Modulators of protease activated receptors

A method for the therapeutic treatment of a disease or disorder associated with undesirable PAR2 activity selected from arthritis, colitis and inflammatory bowel disease, pancreatitis, stroke, gastric ulcer, asthma, epilepsy, Alzheimer's disease, diabetes, irritable bowel syndrome and cancers of the stomach, colon, bowel, breast, liver or pancreas, comprising administering to a subject in need thereof a compound of the formula (I):

• wherein
• R1 is —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;
• 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-C5heterocyclic 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 a group selected from phenyl, benzyl, aminoalkyl, aminoaryl, amidoalkyl or a heterocycle, or piperidine is fused with an aromatic or aliphatic C3-C8cyclic group or C3-C8heterocyclic group;
• wherein
• the phenyl, benzyl, aminoaryl, heterocycle or fused aromatic or aliphatic C3-C8cyclic group or C3-C8heterocyclic group may be further substituted with 1 to 3 substituents selected from alkyl, alkylamine, alkylsulfonyl, alkoxy, aminoalkyl, aminoaryl, amidoalkyl, arylamine, hydroxy, halo, nitro, oxo, optionally substituted phenyl, optionally substituted piperidine, dioxalane, trihaloalkyl, or trihaloalkoxy;
• or
• the fused aromatic or aliphatic C3-C8cyclic group or C3-C8heterocyclic group is 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
• a salt 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] or 5-isoxazoyl-Cha-Ile-spiro[octahydro-1H-indene-1,4′-piperidine].