Compounds useful as anti-inflammatory agents

A compound of the formula (III):

• wherein:
• E is —NH—;
• G is:
• phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl;
• wherein G is optionally substituted by one or more R1, R2 or R3;
• Ar is:
• phenyl, naphthyl, tetrahydronaphthyl, indanyl or indenyl each being optionally substituted by one or more R4 or R5;
• X is:
• pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl;
• each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, 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 C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms;
• Z is:
• hydroxy, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C1-3acyl, C1-6alkyl or C1-3alkoxyC1-3alkyl, C1-6alkyl branched or unbranched, C1-6alkoxy, C1-3acylamino, nitrileC1-4alkyl, 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, 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 C1-3 alkyl groups optionally partially or fully halogenated, nitrile, hydroxyC1-3alkyl or aryl;
• or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C═O, >C═S or NH;
• 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;
• or an analog of such cycloaryl group wherein one to two ring methyne groups are independently replaced by N;
• 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;
• or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C═O, >C═S or NH;
• 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, C1-6acyl, 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;
• OR6, C1-6 alkoxy, hydroxy, nitrile, nitro, halogen;
• 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 C1-3alkyl, arylC0-3alkyl, C1-6acyl, C1-6alkyl-S(O)m— or arylC0-3alkyl-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:
• phenyl, naphthyl, morpholino, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alky)lamino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl) aminocarbonyl, C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-5alkyl)amino, mono- or di-(C1-3alkyl)amino-C1-5 alkyl, amino-S(O)2, di-(C1-3alkyl)amino-S(O)2, R7—C1-5 alkyl, R8—C1-5 alkoxy, R9—C(O)—C1-5 alkyl, R10—C1-5 alkyl(R11)N or carboxy-mono- or di-(C1-5alkyl)-amino;
• a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from cyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl, cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl;
• wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C1-6 alkyl which is optionally partially or fully halogenated, halogen, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), mono- or di-(C1-3alkyl)aminocarbonyl, C1-4 alkyl-OC(O), C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, R12—C1-5 alkyl, R13—C1-5 alkoxy, R14—C(O)—C1-5 alkyl or R15—C1-5 alkyl(R16)N;
• cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C═O, >C═S or NH;
• cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
• C1-4 alkyl-phenyl-C(O)—C1-4 alkyl-, C1-4 alkyl-C(O)—C1-4 alkyl- or C1-4 alkyl-phenyl-S(O)m—C1-4 alkyl-;
• C1-6 alkyl or C1-6 branched or unbranched alkoxy each of which is optionally partially or fully halogenated or optionally substituted with R17;
• OR18 or C1-6 alkyl optionally substituted with OR18;
• amino or mono- or di-(C1-5alkyl)amino optionally substituted with R19;
• R20C(O)N(R21)—, R22O— or R23R24NC(O)—;
• R26(CH2)mC(O)N(R21)—, R23R24NC(O)—C1-3alkoxy or R26C(O)(CH2)mN(R21)—;
• C2-6alkenyl substituted by R23R24NC(O)—;
• C2-6 alkynyl branched or unbranched carbon chain, optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O NH, S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl 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(C1-4 alkyl)amino optionally substituted by one or more halogen atoms;
• C1-6acyl or aroyl;
• R6 is a:
• C1-4 alkyl optionally partially or fully halogenated and optionally substituted with R26;
• each R7, R8, R9, R10, R12, R13, R14, R15, R17, R19, R25 and R26 is independently:
• nitrile, phenyl, morpholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetrazolyl, amino or mono- or di-(C1-4alkyl)amino optionally partially or fully halogenated;
• each R11 and R16 is independently:
• hydrogen or C1-4 alkyl optionally partially or fully halogenated;
• R18 is independently:
• hydrogen or a C1-4 alkyl optionally independently substituted with oxo or R25;
• R20 is independently:
• C1-10 alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;
• R21 is independently:
• hydrogen or C1-3 alkyl optionally partially or fully halogenated;
• each R22, R23 and R24 is independently:
• hydrogen, C1-6 alkyl optionally partially or fully halogenated, said C1-6 alkyl is optionally interrupted by one or more O, N or S, said C1-6 alkyl also being independently optionally substituted by mono- or di-(C1-3alkyl)aminocarbonyl, phenyl, pyridinyl, amino or mono- or di-(C1-4alkyl)amino each of which is optionally partially or fully halogenated and optionally substituted with mono- or di-(C1-3alkyl)amino;
• or R23 and R24 taken together optionally form a heterocyclic or heteroaryl ring;
• m=0, 1 or 2;
• W is O or S and
• the pharmaceutically acceptable derivatives thereof.

A compound selected from:

• 1-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-naphthalen-1-yl)-urea;
• 1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
• 1-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalen-1-yl]-urea;
• 1-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
• N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureido]-naphthalen-1-yl}-pyrazin-2-yl)-methanesulfonamide;
• 1-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-1-yl]-3-(5-tert-butyl-2-methoxy-phenyl)-urea;
• and
• N-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-1-yl}-pyridin-2-yl)-acetamide
• or the pharmaceutically acceptable derivatives thereof.