Compounds useful as anti-inflammatory agents

A compound of the formula (I):

• wherein:
• E is —NH—;
• G is:
• phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl;
• pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzooxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofiiranyl, dibenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2-onyl, benzofuran-3-onyl, tetrahydrobenzopyranyl, indolyl, 2,3-dihydro-1H-indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl, chromonyl;
• oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholino, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl;
• wherein G is substituted by one R3 and further substituted by one or more R1 or R2;
• Ar is:
• phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofiiranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionally substituted by one or more R4 or R5;
• X is:
• a C5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C1-4 alkyl, C1-4 alkoxy or C1-4 alkylamino chains each being branched or unbranched;
• aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl;
• each being optionally independently substituted with one to three C1-4 alkyl, C1-4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen;
• Y is:
• a bond or a C1-10 saturated or unsaturated branched or unbranched carbon chain, wherein one or more C atoms are optionally replaced by O, N, or S(O)m;
• and wherein Y is optionally partially or fully halogenated and optionally independently substituted with one to two oxo groups, nitrile, amino, imino, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms;
• Z is:
• aryl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocycle selected from tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholino, thiomorpholino, thiomorpholino sulfoxidyl, thiomorpholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, C1-3 alkoxy-C1-3 alkyl, C1-6 alkoxycarbonyl, aroyl, C1-3 acyl, oxo, hydroxy, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-6 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1-3 alkyl)amino;
• or Z is optionally substituted with one to three amino or amino-C1-3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC1-6 alkyl, C1-3 alkyl, arylC0-3 alkyl, C1-5 alkoxyC1-3 alkyl, C1-5 alkoxy, aroyl, C1-3 acyl, C1-3 alkyl-S(O)m, or arylC0-3 alkyl-S(O)m each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy;
• or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C1-6 alkyl or C1-6 alkoxy;
• or Z is hydroxy, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C1-3 acyl, C1-6 alkyl or C1-3 alkoxyC1-3 alkyl, C1-6 alkyl branched or unbranched, C1-6 alkoxy, C1-3 acylamino, nitrileC1-4 alkyl, C1-6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino;
• each R1 is independently:
• C1-10 alkyl branched or unbranched optionally partially or fully halogenated, wherein one or more C atoms are optionally independently replaced by O, N or S(O)m, and wherein said C1-10 alkyl is optionally substituted with one to three C3-10 cycloalkyl, hydroxy, oxo, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl, dioxolanyl, isoxazolyl or isothiazolyl;
• each of the aforementioned being optionally substituted with one to five groups selected from halogen, C1-6 alkyl which is optionally partially or fully halogenated, C3-8 cycloalkanyl, C5-8 cycloalkenyl, hydroxy, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated or NH2C(O), mono- or di(C1-3alkyl)amino, and mono- or di(C1-3alkyl)aminocarbonyl;
• or R1 is
• cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C1-3alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC1-3 alkyl or aryl;
• phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or aryl;
• cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or aryl;
• C3-10 branched or unbranced alkenyl each being optionally partially or fully halogenated, and optionally substituted with one to three C1-5 branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned being substituted with one to five halogen, C1-6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O), mono- or di(C1-3alkyl)aminocarbonyl;
• the C3-10 branched or unbranced alkenyl being optionally interrupted by one or more heteroatoms chosen from O, N and S(O)m;
• cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups;
• oxo, nitrile, halogen;
• silyl containing three C1-4 alkyl groups optionally partially or fully halogenated;
• or
• C3-6 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, hydroxy, pyrroldinyl, pyrrolyl, tetrahydropyranyl, one or more C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di(C1-3alkyl)amino optionally substituted by one or more halogen atoms;
• each R2, R4 and R5 is
• a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-6 acyl, aroyl, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, methoxycarbonyl, C1-3 alkyl-S(O)m optionally partially or fully halogenated, or phenyl-S(O)m;
• C1-6 alkoxy, hydroxy, carboxy, oxo, nitrile, nitro, halogen;
• or amino-S(O)m— wherein the N atom is optionally independently mono- or di-substituted by C1-6alkyl or arylC0-3alkyl, or amino wherein the N atom is optionally independently mono- or di-substituted by C1-3 alkyl, arylC0-3 alkyl, C1-6 acyl, C1-6alkyl-S(O)m— or arylC0-3 alkyl-S(O)m—, each of the aforementioned alkyl and aryl in this subparagraph are optionally partially or fully halogenated and optionally substituted with one to two C1-6 alkyl or C1-6 alkoxy;
• each R3 is independently:
• (J)p—L—S(O)m—N(L)—, [(J)p—L]2N—S(O)m—, [(J)p—L]2N—,
• wherein for R3:
• J is:
• cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl;
• cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl;
• phenyl, naphthyl, morpholino, thiomorpholino, pyridinyl, piperadinyl, piperazinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, thienyl, furyl, dioxolanyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, a fused aryl selected from benzocyclobutaflyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptaflyl and benzocycloheptenyl,
• or J is a fused heteroaryl selected from cyclopentenopyridiflyl, cyclohexanopyridiflyl, cyclopentanopyrimidinyl, cyclohexanopyrimidiflyl, cyclopentanopyraziflyl, cyclohexanopyraziflyl, cyclopentanopyridazinyl, cyclohexanopyridaziflyl, cyclopentanoquiflOliflyl, cyclohexanoquinoliflyl, cyclopentanoisoquiflOliflYl, cyclohexanoisoquiflOliflYl, cyclopentanoindolyl, cyclohexanoindolyl, cyclopentanobenzimidazOlYl, cyclohexanobeflzimidaZOlYl, cyclopentanobenzoxazolYl, cyclohexanobenzoxaZOlYl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothieflyl and cyclohexanothieflyl
• wherein each of the above J is optionally substituted by one to three R6;
• each R6 is independently
• C1-6 alkyl, C1-6 alkoxy, arylC0-6 alkyl, heterocycleC0-6 alkyl, heteroarylC0-6 alkyl each optionally substituted by halogen, hydroxy, carboxy, oxo, nitro, nitrile or amino optionally mono- or di-substituted by C1-3 alkyl, or R6 is amino optionally mono- or di-substituted by C1-6 alkyl, C1-6 acyl, C0-6 alkylaryl, C0-6 alkylheterocycle or C0-6 alkylheteroaryl, halogen, hydroxy, carboxy, oxo, nitro or nitrile;
• wherein each of the above heterocycle and heteroaryl in this paragraph are independently chosen from those hereinabove described for J;
• L is
• a bond, hydrogen, oxy, a C1-6 saturated or unsaturated branched or unbranched carbon chain, wherein one or more C atoms are optionally replaced by O, N, or S(O)m;
• and wherein each L is optionally partially or fully halogenated and optionally independently substituted with one to two oxo groups, nitrile, amino, imino, guanidino, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms;
• with the proviso that when R3 is [(J)p—L]2N—, the combination of L and N cannot form:
• m and p are each independently 0, 1 or 2;
• W is O or S and
• pharmaceutically acceptable derivatives thereof.