Non-steroidal IL-5 inhibitors, processes and intermediates for their preparation and pharmaceutical compositions comprising said inhibitors

A compound having the formula:

• 168
• the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
• p represents an integer being 0, 1, 2, 3 or 4;
• X represents O, S. NR5 or a direct bond or —X—R2 taken together may represent cyano;
• Y represents O, S, NR5, or S(O)2;
• each R independently represents C(═O).Z-R14, C1-6alkyl, halo, polyhaloC1-6alkyl, hydroxy, mercapto, C1-6alkyloxy, C1-6alkylthio, C1-6alkylcarbonyloxy, aryl, cyano, nitro, Het3, R6, NR7R8 or C1-4alkyl substituted with C(═O)-Z.R14, Het3, R6 or NR7R8;
• R2 represents Het1, C3-7cycloalkyl optionally substituted with C(═O)-Z-R14, C1-6alkyl or C1-6alkyl substituted with one or two substituents selected from C(═O)-Z-R14, hydroxy, mercapto, cyano, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxy optionally substituted with C(═O)-Z-R14, C1-6alkylthio optionally substituted with C(═O)-Z-R14, C1-6alkylsulfonyloxy, C3-7cycloalkyl optionally substituted with C(═O)-Z-R14, aryl, aryloxy, arylthio, Het1, Het1oxy and Het1thio;
• and if X is O, S or NR5, then R2 may also represent aminothiocarbonyl, C1-4alkylcarbonyl optionally substituted with C(═O)-Z-R14, C1-4alkylthiocarbonyl optionally substituted with C(═O)-Z-R14, arylcarbonyl, arylthiocarbonyl, Het1carbonyl or Het1thiocarbonyl;
• R3 represents hydrogen, C1-6alkyl or C3-7cycloalkyl;
• R4 represents hydrogen, C1-6alkyl or C3-7cycloalkyl;
• or
• R3 and R4 taken together form a C2-6alkanediyl;
• R5 represents hydrogen or C1-4alkyl;
• each R6 independently represents C1-6alkylsulfonyl, aminosulfonyl, piperidinylsulfonyl, mono- or di(C1-4alkyl)aminosulfonyl, mono- or di(benzyl)aminosulfonyl, polyhaloC1-6alkylsulfonyl, C1-6alkylsulfinyl, phenylC1-4alkylsulfonyl, piperazinylsulfonyl, aminopiperidinylsulfonyl, piperidinyl-aminosulfonyl, N—C1-4alkyl-N-piperidinylaminosulfonyl, Y—R14, mono- or di-(C1-4alkyl)aminoC1-4alkylsulfonyl, Het6sulfonyl or C3-7 cycloalkylsulfonyl;
• each R7 and each R8 are independently selected from hydrogen, C1-4alkyl, hydroxyC1-4alkyl, mercapto-C1-4alkyl, dihydroxyC1-4alkyl, aryl, arylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkylcarbonyl, C1-4alkyl-thiocarbonyl, arylcarbonyl, arylthiocarbonyl, Het3thiocarbonyl, Het3carbonyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het3aminocarbonyl, Het3aminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, C1-4alkanediyl-C(═O)-Z-R14, —C(═O)-Z-R14, —Y—C1-4alkanediyl-C(═O)-Z-R14, Het3, Het4 and R6;
• or R7 and R3 taken together with the nitrogen atom to which they are attached form a radical of formula
• 169
• R9 and R10 are each independently selected from hydrogen, C1-4alkyl, hydroxyC1-4alkyl, mercapto-C1-4alkyl, dihydroxyC1-4alkyl, phenyl, phenylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkylcarbonyl, arylcarbonyl, Het3carbonyl, Het3thiocarbonyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, arylaminocarbonyl, arylaminothiocarbonyl, Het3aminocarbonyl, Het3aminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, C1-4alkanediyl-C(═O)-Z-R14, —C(═O)-Z-R14, —Y—C1-4alkanediyl-C(═O)-Z-R14, Het3, Het4 and R6;
• or R9 and R10 taken together with the nitrogen atom to which they are attached form a radical of formula
• 170
• each R11 independently being selected from hydroxy, mercapto, cyano, nitro, halo, trihalomethyl, C1-4alkyloxy optionally substituted with C(═O)-Z-R14, C1-6alkylthio optionally substituted with C(═O)-Z-R14, formyl, trihaloC1-4alkylsulfonyloxy, R6, NR7R8, C(═O)NR15R16, —C(═O)-Z-R14—Y—C1-4alkanediyl-C(═O)-Z-R14, aryl, aryloxy, arylcarbonyl, arylthiocarbonyl, C3-7cycloalkyl optionally substituted with C(═O)-Z-R14, C3-7cycloalkyloxy optionally substituted with C(═O)-Z-R14, C3-7cycloalkylthio optionally substituted with C(═O)-Z-R14, phthalimide-2-yl, Het3, Het4, C(═O)Het3, C(═O)C1-4alkyl optionally be substituted with one or more substituents independently selected from hydroxy, mercapto, halo and phenyl;
• R12 and R13 are each independently selected from hydrogen, C1-4alkyl, hydroxyC1-4alkyl, mercapto-C1-4alkyl, dihydroxyC1-4alkyl, phenyl, phenylC1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkylcarbonyl, C1-4alkylthiocarbonyl, arylcarbonyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, arylaminocarbonyl, arylaminothiocarbonyl, C3-7cycloalkyl, pyridinylC1-4alkyl, C1-4alkanediyl-C(═O)-Z-R14, —C(═O)-Z-R14, —Y—C1-4alkanediyl-C(═O)-Z-R14 and R6;
• or R12 and R13 taken together with the nitrogen atom to which they are attached form a radical of formula
• 171
• each R14 independently represents hydrogen;
• C1-20acyl or C1-20alkylC1-20acyl (having a straight or branched, saturated or unsaturated hydrocarbon chain having 1 to 20 carbon atoms) optionally substituted with one or more substituents selected from hydroxy, mercapto, hydroxyC1-4alkyl, mercaptoC1-4alkyl, NR17R18, aryl, mono- or di-(C1-4alkyl)amino, cyano and Het5;
• C1-20alkyl optionally substituted with one or more substituents selected from hydroxy, halo, mercapto, C1-4alkyloxyC1-4alkyloxy, mercaptoC1-4alkyl, NR17R18, aryl, mono- or di-(C1-4alkyl)amino, cyano, Het5, C1-4alkyloxycarbonyl, arylC1-4 alkyloxycarbonyl, arylC1-4alkyloxy, arylC1-4alkylthiocarbonyl, arylC1-4alkylthio, Het5C1-4alkyloxy, arylC1-4alkylthio, C3-7 cycloalkyl and Het5C1-4alkylthio;
• C3-20alkenyl optionally substituted with phenyl;
• C3-20alkynyl;
• C3-7 cycloalkyl optionally substituted with one or more substituents selected from hydroxy, mercapto, halo, mercaptoC1-4alkyl and hydroxyC1-4alkyl;
• Het5 or phenyl or R14 represents a radical having any of the following formulae:
• 172
• wherein m is 1 to 4, n is 0 to 5, q is 0 to 2, r is 0 to 2 and s is 0 to 4;
• Rb is selected from hydrogen, C1-6alkyl, phenyl, C3-7cycloalkyl, C1-4 alkyloxyC1-6alkyl and C1-4 alkyl-Y—C1-4alkyl;
• Ra, Rc, Rd, Re and Rf are each independently selected from hydrogen, C1-6alkyl, phenyl and C3-7cycloalkyl, or Re and Rf taken together may form —CH2—CH2—, —CH2—CH2—CH2— or —CH2—CH2—CH2—CH2—;
• Rg, Rh and Rk are each independently hydrogen or C1-4 alkyl;
• Ri is selected from hydroxy, C3-7cycloalkyl and C1-4alkyl, or two Ri taken together may form —CH2—CH2—, —CH2—CH2—CH2— or —CH2—CH2—CH2—CH2— (thus building a spiro radical);
• Rj is selected from —O—Rb;
• C1-6alkyl optionally substituted with phenyl or C3-7cycloalkyl;
• phenyl;
• C3-7cycloalkyl optionally substituted with C1-4 alkyloxy and mono-or di(C1-4alkyl)amino;
• Rm is hydrogen or C1-4 alkyloxy;
• Rn is hydrogen, C1-4alkyl, C3-7cycloalkyl, phenyl or phenylC1-4alkyl;
• and
• W represents O or S;
• each Z independently represents O, S, NH, —CH2—O— or —CH2—S— whereby —CH2— is attached to the carbonyl group;
• or
• -Z-R14 taken together form a radical of formula
• 173
• R15 and R16 are each independently selected from hydrogen;
• C1-4alkyl optionally substituted with one or more substituents independently selected from hydroxy, mercapto, aryl, mono- or di(C1-4alkyl) amino and pyridinyl;
• C1-4alkyloxy;
• aryl;
• —C(═O)-Z-R14;
• arylcarbonyl;
• arylthiocarbonyl;
• arylaminocarbonyl;
• arylaminothiocarbonyl;
• aminocarbonylmethylene;
• mono- or di(C1-4alkyl) aminocarbonylmethylene;
• Het3aminocarbonyl;
• Het3aminothio-carbonyl;
• pyridinylC1-4alkyl;
• Het3 and R6;
• or R15 and R16 taken together with the nitrogen atom to which they are attached form a radical of formula
• 174
• R17 and R18 are each independently selected from hydrogen, C1-6alkyl optionally substituted with one or more substituents independently selected from hydroxy, mercapto, aryl, mono- or di(C1-4alkyl) amino, C1-4 alkyloxy and pyridinyl;
• C1-4alkyloxycarbonyl;
• aryl;
• C1-4alkylcarbonyl;
• C1-4alkylthiocarbonyl;
• arylcarbonyl;
• arylthiocarbonyl;
• arylaminocarbonyl;
• arylaminothiocarbonyl;
• C3-7cycloalkyl;
• C1-4alkane-diyl-C(═O)-Z-C1-6alkyl;
• —C(═O)-Z-C1-6alkyl;
• —Y—C1-4alkanediyl-C(═O)-Z-C1-6alkyl and R6;
• aryl represents phenyl optionally substituted with one, two or three substituents each independently selected from nitro, azido, cyano, halo, hydroxy, mercapto, C1-4alkyl, C3-7cycloalkyl, C1-4alkyloxy, C1-4alkylthio, formyl, polyhaloC1-4alkyl, NR9R10, C(═O)NR9R10, C(═O)-Z-R14, R6, —O—R6, phenyl, Het3, C(═O)Het3 and C1-4alkyl substituted with one or more substituents. each independently selected from halo, hydroxy, mercapto, C1-4alkyloxy, C1-4alkylthio, C(═O)-Z-R14, —Y—C1-4alkanediyl-C(═O)-Z-R14, Het3 or NR9R10;
• Het1 represents a three-membered, four-membered, five-membered or six-membered aromatic or non-aromatic, monocyclic or polycyclic heterocycle comprising one or more, preferably one to four, heteroatoms, preferably selected from nitrogen, oxygen, sulfur and phosphorus, or a fused polycyclic ring system including such heterocycle (such as for instance a fused benzoheterocycle);
• non-limiting examples of such heterocycles include for instance pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, benzodioxanyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl;
• wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het2, R11 and C1-4alkyl optionally substituted with one or, where possible, two or three substituents each independently selected from Het2 and R11;
• Het2 represents a three-membered, four-membered, five-membered or six-membered aromatic or non-aromatic, monocyclic or polycyclic heterocycle comprising one or more, preferably one to four, heteroatoms, preferably selected from nitrogen, oxygen, sulfur and phosphorus, or a fused polycyclic ring system including such heterocycle (such as for instance a fused benzoheterocycle);
• non-limiting examples of such heterocycles include for instance pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl;
• wherein said heterocycles each independently may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het4, R11 and C1-4alkyl optionally substituted with one or, where possible, two or three substituents each independently selected from Het4 and R11;
• Het3 represents a three-membered, four-membered, five-membered or six-membered aromatic or non-aromatic monocyclic heterocycle comprising one or more, preferably one to four, heteroatoms, preferably selected from nitrogen, oxygen, sulfur and phosphorus;
• non-limiting examples of such heterocycles include for instance pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolanyl and tetrahydropyranyl;
• wherein said monocyclic heterocycles each independently may optionally be substituted with, where possible, one, two, three or four substituents each independently selected from hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, piperidinyl, NR12R13, C(═O)-Z-R14, R6 and C1-4alkyl substituted with one or two substituents independently selected from hydroxy, carbonyl C1-4alkyloxy, phenyl, C(═O)-Z-R14, —Y—C1-4alkanediyl-C(═O)-Z-R14, R6 and NR12R13;
• Het4 represents a three-membered, four-membered, five-membered or six-membered aromatic or non-aromatic monocyclic heterocycle comprising one or more, preferably one to four, heteroatoms, preferably selected from nitrogen, oxygen, sulfur and phosphorus;
• non-limiting examples of such heterocycles include for instance pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl and triazinyl;
• Het5 represents a three-membered, four-membered, five-membered or six-membered aromatic or non-aromatic, monocyclic or polycyclic heterocycle comprising one or more, preferably one to four, heteroatoms, preferably selected from nitrogen, oxygen, sulfur and phosphorus, or a fused polycyclic ring system including such heterocycle (such as for instance a fused benzoheterocycle);
• non-limiting examples of such heterocycles include for instance pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dioxanyl, dithianyl, trithianyl, triazinyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoxazolyl, benzodioxanyl, indolyl, isoindolyl, indolinyl, purinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, thiazolopyridinyl, oxazolopyridinyl and imidazo[2,1-b]thiazolyl;
• wherein said heterocycles each independently may be substituted with, where possible, one, two, three or four substituents each independently selected from hydroxy, mercapto, carbonyl, C1-4alkyl, C1-4alkyloxy, C1-4alkylthio, C1-4alkylcarbonyl, piperidinyl, NR17R18, C(═O)-Z-C1-6alkyl, R6, sulfonamido and C1-4alkyl substituted with one or two substituents independently selected from hydroxy, C1-4alkyloxy, mercapto, C1-4alkylthio, phenyl, C(═O)-Z-C1-6alkyl, —Y—C1-4alkanediyl-C(═O)-Z-C1-6alkyl, R6 and NR17R18;
• Het6 represents a three-membered, four-membered, five-membered or six-membered aromatic or non-aromatic monocyclic heterocycle comprising one or more, preferably one to four, heteroatoms, preferably selected from nitrogen, oxygen, sulfur and phosphorus;
• non-limiting examples of such heterocycles include for instance pyrrolidinyl, piperidinyl, azaridinyl, pyrazolinyl and pyrolinyl, wherein said heterocycle may optionally be substituted with one, or where possible, two or three substituents each independently selected from Het2, R11 and C1-4alkyl optionally substituted with one or more substituents independently selected from Het2 and R11. provided however that
• R2 is other than C1-6 alkyloxycarbonylC1-6alkyl or aminocarbonyl;
• and
• R7, R8, R9 and R10 are other than aminocarbonyl, C1-4alkylcarbonyloxy-C1-4alkylcarbonyl, hydroxyC1-4alkylcarbonyl, C1-4alkyloxycarbonylcarbonyl, C(═O)—O—R19, C1-4alkanediylC(═O)—O—R19 or —Y—C1-4alkanediylC(═O)—O—R19;
• and
• R12 and R13 are other than C1-4alkylcarbonyloxy-C1-4alkylcarbonyl, hydroxyC1-4alkylcarbonyl or C1-4alkylcarbonylcarbonyl;
• and
• R11 is other than C(═O)—O—R19, Y—C1-4alkanediyl —C(═O)—OR19, C(═O)NH2, C(═O)NHC1-4alkyl or C(═O)NHC3-7cycloalkyl;
• and
• R15 and R16 are other than aminocarbonyl, C1-4alkylcarbonyloxy-C1-4alkylcarbonyl, hydroxy C1-4alkylcarbonyl or C1-4alkyloxycarbonylcarbonyl;
• and
• aryl is other than phenyl substituted with C(═O)—O—R19, C(═O)NH2, C(═O)NHC1-4alkyl, C(═O)NHC3-7cycloalkyl and/or with C1-4alkyl substituted with C(═O)—O—R19 or Y—C1-4alkanediyl —C(═O)—O—R14;
• and
• Het3 is other than a monocyclic heterocycle substituted with C(═O).O—R19 and/or with C1-4alkyl substituted with C(═O)—O—R19 and/or Y—C1-4alkanediyl C(═O)—O—R19;
• and
• in each of the above proviso's R19 is defined as hydrogen, C1-4alkyl, C3-7cycloalkyl, aminocarbonylmethylene or mono- or di(C1-4alkyl)aminocarbonylmethylene;
• and
• wherein the said compound having the formula (1) contains at least one —C(═O)-Z-R14 moiety.