Pyridinone and pyridinethione derivatives having HIV inhibiting properties

Compounds of formula (I)

• the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and stereochemically isomeric forms thereof, wherein
• Y is O or S;
• Q is halo;
• X is a bivalent radical of formula
• —(CH2)p— (a-1)
• or
• —(CH2)q-Z-(CH2)r— (a-2);
• wherein p is an integer of value 1 to 5;
• q is an integer of value 0 to 5;
• r is an integer of value 0 to 5;
• Z is O, S, NR7, C(═O), S(═O), S(═O)2, CHOR13, CH═CH, CH(NR7R8) or CF2;
• and wherein each hydrogen atom may be replaced by C1-4alkyl or hydroxyC1-4alkyl;
• R1 is C3-6cycloalkyl, C2-6alkenyl or aryl;
• R2 is selected from hydrogen;
• formyl;
• cyano;
• azido;
• hydroxy;
• oxiranyl;
• amino;
• mono- or di(C1-4alkyl)amino;
• formylamino;
• mercapto(C1-6)alkyl;
• hydrazino;
• R5aR6aN—C(═O—;
• R9—N═C(R10)—;
• C2-6alkenyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, di(C1-6alkyl)carbamoyl, [di(C1-4alkyl)amino(C1-6alkyl)](C1-4alkyl)carbamoyl, [di(C1-4alkyl)amino(C1-6alkyl)](arylC1-4alkyl)carbamoyl, di(C1-4alkyloxy)(C1-4alkyl)carbamoyl, (cyanoC1-6alkyl)(C1-6alkyl)aminoC1-6alkyl, N-hydroxy-imino, aryl, Het2, Het2carboxamido, Het2(C1-6alkyl)carbamoyl;
• C2-6alkynyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino, aryl or Het2;
• C1-6alkyloxy;
• hydroxyC1-6alkyloxy;
• aminoC1-6alkyloxy, mono- or di(C1-4alkyl)aminoC1-6alkyloxy;
• C1-6alkylcarbonyl;
• arylcarbonyl;
• Het2carbonyl;
• C1-6alkyloxycarbonyl;
• C1-6alkylcarbonyloxy;
• aryl;
• aryloxy;
• arylC1-6alkyloxy;
• arylthio;
• arylC1-6alkylthio;
• mono- or di(aryl)amino;
• Het2;
• Het2oxy;
• Het2thio;
• Het2C1-6alkyloxy;
• Het2C1-6alkylthio;
• Het2SO2;
• Het2SO;
• mono- or di(Het2)amino;
• C3-6cycloalkyl;
• C3-6cycloalkyloxy;
• C3-6cycloalkylthio;
• C1-6alkylthio;
• hydroxyC1-6alkylthio;
• aminoC1-6alkylthio;
• mono- or di(C1-4alkyl)aminoC1-6alkylthio;
• C1-6alkyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, carboxyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkylsulfonyl, C1-6alkycarbamoylC1-4alkylthio, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxyC1-6alkylthio C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, aminocarbonyloxy, mono- or di(C1-4alkyl)aminocarbonyloxy, C1-6alkyloxycarbonyl, C1-6alkyloxycarbonylC1-6alkyloxy, C1-6alkyloxycarbonylC1-6alkylthio, aryl, Het2, aryloxy, arylthio, arylC1-6alkyloxy, arylC1-6alkylthio, Het2C1-6alkyloxy, Het2C1-6alkylthio, C1-6alkyl-S(═O)2-oxy, amino, mono- or di(C1-6alkyl)amino, di(C1-6alkyl)aminoC1-6alkylthio, [di(C1-6alkyl)amino(C1-6alkyl)](C1-6alkyl)amino, di(cyanoC1-6alkyl)amino, C1-6alkyloxycarbonylamino, C1-6alkyloxyC1-6alkylcarbonylamino, mono- or di(aryl)amino, mono- or di(arylC1-4alkyl)amino, mono- or di(C1-4alkyloxyC1-4alkyl)amino, mono- or di(C1-4alkylthioC1-4alkyl)amino, mono- or di(Het2C1-4alkyl)amino, (Het2C1-4alkyl)(C1-4alkyl)amino, (cyanoC1-6alkyl)(C1-6alkyl)amino, C3-6cycloalkylthio, R11—(C═O)—NH—, R12—NH—(C═O)—NH—, R14—S(═O)2—NH—, C1-6alkyl-P(O—R15)2=O, C1-6alkyl-P(O—C1-6alkyl-O)═O or a radical of formula
• with A1 being CH or N, and A2 being CH2, NR13, S or O, provided that when A1 is CH then A2 is other than CH2, said radical (c-1), (c-2) and (c-3) being optionally substituted with one or two substituents each independently selected from H, C1-6 alkyl, C1-6 alkyloxy, hydroxy C1-4alkyl, C1-6alkyloxycarbonyl, C1-6alkyloxycarbonylC1-4alkyl, aminoC1-6alkyl, C1-4alkylcarbonyl, arylcarbonyl, aryl, Het1, Het1—(C═O)—, hydroxy, cyano, C1-4alkylcyano, CONR16R17 with R16 and R17 being independently H or alkyl, mono or di(C1-4alkyl)aminoalkyl, 4-hydroxy-4-phenyl or 4-cyano-4-phenyl;
• R3 is selected from hydrogen;
• halo;
• formyl;
• cyano;
• azido;
• hydroxy;
• oxiranyl;
• amino;
• mono- or di(C1-4alkyl)amino;
• formylamino;
• mercapto(C1-6)alkyl;
• hydrazino;
• R5aR6aN—C(═O)—;
• R9—N═C(R10)—;
• C2-6alkenyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, di(C1-4alkyl)carbamoyl, [di(C1-4alkyl)amino(C1-6alkyl)](CC1-4alkyl)carbamoyl, [di(C1-4alkyl)amino(C1-6alkyl)](arylC1-4alkyl)carbamoyl, di(C1-4alkyloxy)(C1-4alkyl)carbamoyl, (cyanoC1-6alkyl)(CC1-6alkyl)aminoC1-6alkyl, N-hydroxy-imino, aryl, Het2, Het2carboxamido, Het2(C1-6alkyl)carbamoyl;
• C2-6alkynyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino, aryl or Het2;
• C1-6alkyloxy;
• hydroxyC1-6alkyloxy;
• aminoC1-6alkyloxy;
• mono- or di(C1-4alkyl)aminoC1-6alkyloxy;
• C1-6alkylcarbonyl;
• arylcarbonyl;
• Het2carbonyl;
• C1-6alkyloxycarbonyl;
• C1-6alkylcarbonyloxy;
• aryl;
• aryloxy;
• arylC1-6alkyloxy;
• arylthio;
• arylC1-6alkylthio;
• mono- or di(aryl)amino;
• Het2;
• Het2oxy;
• Het2thio;
• Het2C1-6alkyloxy;
• Het2C1-6alkylthio;
• Het2SO2;
• Het2SO;
• mono- or di(Het2)amino;
• C3-6cycloalkyl;
• C3-6cycloalkyloxy;
• C3-6cycloalkylthio;
• C1-6alkylthio;
• hydroxyC1-6alkylthio;
• aminoC1-6alkylthio;
• mono- or di(C1-4alkyl)aminoC1-6alkylthio;
• C1-6alkyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, carboxyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkylsulfonyl, C1-6alkycarbamoylC1-4alkylthio, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxyC1-6alkylthio, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, aminocarbonyloxy, mono- or di(C1-4alkyl)aminocarbonyloxy, C1-6alkyloxycarbonyl, C1-6alkyloxycarbonylC1-6alkyloxy, C1-6alkyloxycarbonylC1-6alkylthio, aryl, Het2, aryloxy, arylthio, arylC1-6alkyloxy, arylC1-6alkylthio, Het2C1-6alkyloxy, Het2C1-6alkylthio, C1-6alkyl-S(═O)2-oxy, amino, mono- or di(C1-6alkyl)amino, di(C1-6alkyl)aminoC1-6alkylthio, [di(C1-6alkyl)amino(C1-6alkyl)](C1-6alkyl)amino, di(cyanoC1-6alkyl)amino, C1-6alkyloxycarbonylamino, C1-6alkyloxyC1-6alkylcarbonylamino, mono- or di(aryl)amino, mono- or di(arylC1-4alkyl)amino, mono- or di(C1-4alkyloxyC1-4alkyl)amino, mono- or di(C1-4alkylthioC1-4alkyl)amino, mono- or di(Het2C1-4alkyl)amino, (Het2C1-4alkyl)(C1-4alkyl)amino, (cyanoC1-6alkyl)(C1-6alkyl)amino, C3-6cycloalkylthio, R11—(C═O)—NH—, R12—NH—(C═O)—NH—, R14—S(═O)2—NH—, C1-6alkyl-P(O—R15)2=O, C1-6alkyl-P(O—C1-6alkyl-O)═O or a radical of formula
• with A1 being CH or N, and A2 being CH2, NR13, S or O, provided that when A1 is CH then A2 is other than CH2, said radical (c-1), (c-2) and (c-3) being optionally substituted with one or two substituents each independently selected from H, C1-6alkyl, C1-6alkyloxy, hydroxyC1-4alkyl, C1-6alkyloxycarbonyl, C1-6alkyloxycarbonylC1-4alkyl, aminoC1-6alkyl, C1-4alkylcarbonyl, arylcarbonyl, aryl, Het1, Het1-(C═O)—, hydroxy, cyano, C1-4alkylcyano, CONR16R17 with R16 and R17 being independently H or alkyl, mono or di(C1-4alkyl)aminoalkyl, 4-hydroxy-4-phenyl or 4-cyano-4-phenyl;
• or R2 and R3 may be taken together to form a bivalent radical of formula
• —(CH2)t—CH2-A3-CH2— (d-1)
• with t being an integer of 0, 1 or 2 and A3 being CH2, O, S, NR7a or N[C(═O)R8a] and wherein each hydrogen in said formula (d-1) may be substituted with halo, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, haloC1-4alkylcarbonyl or arylcarbonyl;
• R4 is hydrogen;
• R5a and R6a each independently are hydrogen;
• C1-4alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkylthio, amino, mono- or di(C1-4alkyl)amino or a radical of formula
• with A5 and A6 each independently being CH2, NR13 or O;
• R7, R7a and R7b each independently are hydrogen, formyl or C1-4alkyl;
• R8, R8a and R8b each independently are hydrogen or C1-4alkyl;
• R9 is hydrogen, hydroxy, C1-4alkyloxy, carboxylC1-4alkyloxy, C1-4alkyloxycarbonylC1-4alkyloxy, C2-4alkenyloxy, C2-4alkynyloxy or arylC1-4alkyloxy;
• R10 is hydrogen, carboxyl or C1-4alkyl;
• R11 is hydrogen;
• C1-4alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-S(═O)2—, aryl or Het3;
• C1-4alkyloxy;
• C2-4alkenyl;
• arylC2-4alkenyl;
• Het3C2-4alkenyl;
• C2-4alkynyl;
• Het3C2-4alkynyl, arylC2-4alkynyl;
• C3-6cycloalkyl;
• aryl;
• naphthyl or Het3;
• R12 is C1-4alkyl, arylC1-4alkyl, aryl, arylcarbonyl, C1-4alkylcarbonyl, C1-4alkyloxycarbonyl or C1-4alkyloxycarbonylC1-4alkyl;
• R13 is hydrogen, C1-4alkyl or C1-4alkylcarbonyl;
• R14 is C1-4alkyl optionally substituted with aryl or Het4;
• polyhaloC1-4alkyl or C2-4alkenyl optionally substituted with aryl or Het4;
• R15 is C1-4alkyl;
• Het1 and Het2 each independently are a heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrimidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexahydropyridazinyl, morpholinyl, thiomorpholinyl triazolyl, tetrazolyl, pyrrolyl, pyrazolyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, benzodioxanyl, quinolinyl, 2-oxo-1,2-dihydro-quinolinyl, imidazopyridinyl, dihydropyrrolyl or dihydroisoxazolyl, said heterocycle optionally being substituted with one, two or three substituents each independently selected from O, S, halo, formyl, amino, hydroxy, cyano, C1-4alkyl, hydroxyC1-4alkyl, carboxyC1-4alkyl, carbamoylC1-4alkyl, carbamoylC1-4alkoxy, C1-4alkyloxy, C1-4alkylcarbonyl, C1-4alkyloxyC1-4alkyl, cyanoC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl, —OCONH2, C1-4alkoxyC1-4alkyl, aryl, Het2C1-4alkyl, polyhaloC1-4alkyl, C3-6cycloalkyl or arylC2-6alkenyl;
• Het3 is a monocyclic or bicyclic heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, 2-oxo-1,2-dihydro-quinolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexahydropyridazinyl or a radical of formula
• with A7 or A8 each independently being selected from CH2 or O;
• each of said monocyclic or bicyclic heterocycles may optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl or polyhaloC1-4alkyl;
• Het4 is a monocyclic heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, said heterocycle optionally being substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl or polyhaloC1-4alkyl;
• Het5 is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, piperidinyl, morpholinyl or pyrrolidinyl;
• aryl is phenyl optionally substituted with one, two or three substituents each independently selected from halo;
• hydroxy;
• carboxyl;
• cyano;
• formyl;
• acetyl;
• nitro;
• amino;
• mono- or di(C1-4alkyl)amino;
• C1-4alkylcarbonylamino;
• mono- or di(C1-4alkyl)aminocarbonylamino;
• C1-4alkyl-S(═O)2—NH—;
• Het5(═S)—S—C1-4alkyl;
• C1-6alkyloxy;
• sulfamoyl;
• C1-4alkyl)sulfamoyl;
• arylsulfamoyl;
• Het2sulfamoyl;
• O—P═OR15;
• C1-6alkyl optionally substituted with halo, hydroxy, cyano, nitro, formyl, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxycarbonyl, C1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C2-6alkenyloxy, C1-6alkylcarbonyloxy, C1-6alkyloxycarbonylthio, N-hydroxyimino, phenyl or Het5;
• C2-6alkenyl optionally substituted with halo, hydroxy, cyano, nitro, formyl, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxycarbonyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het5;
• C2-6alkynyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxycarbonyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het5;
• phenyl;
• phenyloxy;
• phenyl(C1-4alkyl)thioC1-4alkyl;
• (C3-6)cyclohexylthioC1-4alkyl or isoxazolinyl optionally substituted by C1-4alkyloxycarbonyl or morpholinylC1-4alkyl
• provided that
• 3-iodo-6-methyl-4-phenoxy-2(1H)-pyridinone
• is not included.