# Patent

## Title
Pyridinone and pyridinethione derivatives having HIV inhibiting properties

## Abstract

The present invention is concerned among others with compounds of formula (1), the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and stereochemically isomeric forms thereof, wherein Q is halo, C1-6 alkyl or C2-6 alkenyl; X is (a-2) with q and r being O and Z being O, S or SO; R1 is aryl; R2 is selected from formyl; C1-6alkyloxycarbonylalkyl; Het2; Het2C1-6alkyl, C1-6alkylthio; C1-6alkyl optionally substituted with one or two substituents each independently selected from hydroxy, and halo; R3 is selected from formyl; C1-6alkyl optionally substituted with one or two C1-6alkyloxy; R4 is hydrogen, with HTV inhibiting properties

## Background
The present invention is concerned with pyridinone and pyridinethione derivatives having Human Immunodeficiency Virus (HIV) replication inhibiting properties. It further relates to processes for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of said compounds in the manufacture of a medicament useful for the treatment of subjects suffering from HIV infection.
Compounds structurally related to the present compounds are disclosed in the prior art.

    Naturforsch. B, Anorg. Chem., Org. Chem., 1983, 38 B (3), 398–403 discloses iodine, nitrogen and sulfurylides of 2-pyridones.
    Pol. J. Chem., 1979, 53 (11), 2349–2354 discloses N-(tetrahalo-4-pyridyl) aminobenzoic acid derivatives and their use as herbicides.
    J. Med. Chem., 1983, 26 (9), 1329–1333 discloses the synthesis of aza analogs of lucanthone useful as antitumor and bactericidal agents.
    WO 86/01815 discloses the synthesis of monoazodyes and their use as dyestuffs.
    Can. J. Chem., 1980, 58 (5), 501–526 discloses the chemistry of aurodox and related antibiotics.
    WO 97/05113 discloses 4-aryl-thio-pyridin-2(1H)-ones and their use for treating HIV related diseases.
    WO 99/55676 discloses 3-(amino- or aminoalkyl)pyridinone or pyridinethione derivatives and their use for the treatment of HIV related diseases.


However their activities are still moderate and their use in human therapy also could lead to the emergence of resistant strains. The most active thiopyridinones disclosed in WO 97/05113 have a 50% inhibitory concentration of virus multiplication (IC50) for nevirapine resistant strains of about 260 nM, whereas the free amino or aminoalkyl pyridinone and pyridinone derivatives disclosed in WO 99/55676 have a 50% inhibitory concentration of virus multiplication for nevirapine resistant strains of more than 10 000 nM.
The Inventors have found a new family of pyridinones and pyridinethiones derivatives which show better HIV inhibitory properties.
The present invention is concerned with compounds of formula




the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and stereochemically isomeric forms thereof, wherein

    Y is O or S;
    Q is hydrogen; halo; C1-6alkyl; di(C1-4alkyl)amino; C1-6alkyloxy, C1-6alkyloxyC1-6alkyl; C1-6alkylthio; C1-6alkylthioC1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C1-6alkyl-S(═O)—; C1-6alkyl-S(═O)2—; hydroxyC1-6alkyl; polyhaloC1-6alkyl; C1-6akyloxycarbonylC1-6alkyl; C1-6alkyloxycarbonylC1-6alkylthio; aminocarbonyl6C1-6alkylthio; C1-6alkyloxyC1-6alkyloxycarbonyl, C2-6alkenyl optionally substituted with halo, hydroxy, cyano, formyl, —COOH, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino or aryl; C2-6alkynyl optionally substituted with halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino or aryl; C3-6cycloalkyl optionally substituted with C1-4alkyl; cyano; carboxyl; formyl; R5R6N—C(═O)—; R5R6N—C(═O)—C1-6alkyl; N-hydroxy-imino; N—C1-4alkyloxy-imino; aryl; aryloxy; arylthio; arylC1-6alkyl; arylcarbonyl; arylC1-6alkyloxycarbonyl; C1-6alkyl substituted with hydroxy or aryl; Het1; Het1oxy, Het1thio; Het1C1-6alkyl; Het1carbonyl; Het1C1-6alkyloxycarbonyl; C1-6alkyl-P(OR15)2═O or C1-6alkyl-P(O—C1-6alkyl-O)═O;
    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 C1-6alkyl, C3-6cycloalkyl, C1-6alkenyl, C1-6alkoxy, aryl or a monocyclic or bicyclic heterocycle selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, oxazolyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, or a radical of formula






     with n being an integer of 1 or 2,
    
        said monocyclic or bicyclic heterocycle or said radical of formula (b-1) or (b-2) optionally being substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, polyhaloC1-4alkyl or phenyl;
    
    
    or Q and X—R1 may be taken together with the pyridinone to form a tricyclic heterocycle of formula






     with R16 and R17 being C1-6alkyl or forming together ═O.
    R2 and R3 each independently are 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)](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; arylC1-6allyloxy; 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, 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;
    or R2 and R3 may be taken together to form a bivalent radical of formula

—(CH2)t—CH2-A3-CH2—  (d-1)

or

—CH═CH—CH═CH—  (d-2)

    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) or (d-2) may be substituted with halo, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, haloC1-4alkylcarbonyl or arylcarbonyl;
    R4 is hydrogen, hydroxy, C1-6alkyl, C1-6alkyloxy, C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, C2-6alkenyl, amino, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminoC1-6alkyl or aryl;
    or R4 and R3 may be taken together to form a bivalent radical of formula

—(CH2)t—CH2-A4-CH2—  (e-1)

or

—CH═CH—CH═CH—  (e-2)

    with t being an integer of 0, 1 or 2 and A4 being CH2, O, S, NR7b or N[C(═O)R8b] and wherein each hydrogen in said formula (e-1) or (e-2) may be substituted with halo, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, haloC1-4alkylcarbonyl or arylcarbonyl;
    or X—R1 and R2 may be taken together to form a tricyclic heterocycle of formula






    with R16 and R17 being C1-6alkyl or forming together ═O.
    R5 and R6 each independently are hydrogen, C1-4alkyl or C1-4alkyloxy;
    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, C1-4alkyloxycarbonyl-C1-4alkyloxy, 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 C1-4 alkyl;
    Het1 and Het2 each independently are a heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrmidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrimidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexabydropyridazinyl, 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

    5,6,7,8-tetrahydro-3-iodo-4-phenoxy-1-phenyl-2(1H)quinolinone;
    3-iodo-6-methyl-4-phenoxy-2(1H)-pyridinone;
    2-[(3,5,6-trifluoro-1,2-dihydro-2-oxo-4-pyridinyl)amino]benzoic acid;
    1,2-dihydro-6-hydroxy-2-oxo-4-(2-phenylethyl)-3-pyridinecarbonitrile;
    1,2-dihydro-6-hydroxy-2-oxo-4-(4-pyridinylmethyl)-3-pyridinecarbonitrile;
    4-[(4-bromophenyl)methoxy]-3,5-diodo-1-methyl-2(1H)-pyridinone;
    4-[(4-bromophenyl)methoxy]-1,2-dihydro-1-methyl-2-oxo-3-pyridinecarboxylic acid; 1,2-dihydro-6-methyl-2-oxo-4-(phenylthio)-3-pyridinecarboxylic acid and the alkyl-4-arylthio-1,2-dihydro-5-methyl-6-methyl-2-oxo-3-pyridine carboxylate
    3-bromo-4-[[[2-(3,4-dimethoxyphenyl)ethyl]amino]methyl-2(1H)quinolinone;
    3-iodo-7-methoxy-1-methyl-4-phenoxy-2(1H)quinolinone;
    1-ethyl-3-iodo-7-methoxy-4-phenoxy-2(1H)quinolinone;
    3-iodo-7-methoxy-4-(4-methoxyphenoxy)-1-methyl-2(1H)quinolinone;
    1-ethyl-3-iodo-7-methoxy-4-(4-methoxyphenoxy)-1-methyl-2(1H)quinolinone;
    3-iodo-7-methoxy-4-(3-methoxyphenoxy)-1-methyl-2(1H)quinolinone;
    1-ethyl-3-iodo-7-methoxy-4-(3-methoxyphenoxy)-1-methyl-2(1H)quinolinone;
    3-iodo-7-methoxy-4-phenoxy-2(1H)quinolinone;
    4-(3-chloro-4-methoxyphenoxy)-3-iodo-7-methoxy-2(1H)quinolinone;
    3-iodo-4-phenoxy-2(1H)quinolinone;
    3-iodo-4-phenoxy-1-phenyl-2(1H)quinolinone;
    3-iodo-4-(4-methylphenoxy)-2(1H)quinolinone;
    3-iodo-4-(4-methoxyphenoxy)-2(1H)quinolinone;

are not included.



As used herein C1-4alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl and the like; C1-6alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for C1-4alkyl and pentyl, hexyl, 2-methylpropyl, 2-methylbutyl and the like; C2-4alkenyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 4 carbon atoms and containing a double bond such as ethenyl, propenyl, butenyl and the like; C2-6alkenyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and containing at least one double bond such as the groups defined for C2-4alkenyl and pentenyl, hexenyl, 2,4-hexadienyl, 1,3-butadienyl, 3-methylbutenyl and the like; C2-4alkynyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 4 carbon atoms and containing one triple bond such as ethynyl, propynyl, butynyl and the like; C2-6alkynyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and containing one triple bond such as the groups defined such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, 3-methylbutynyl and the like; C3-6cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used hereinbefore, the term (═O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom, a sulfonyl moiety when two of said terms are attached to a sulfur atom, a phosphonate when attached to a phosphorus atom.
The term halo is generic to fluoro, chloro, bromo and iodo. As used in the foregoing and hereinafter, polyhalomethyl as a group or part of a group is defined as mono- or polyhalosubstituted methyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl; polyhaloC1-6alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C1-6alkyl, for example, the groups defined in halomethyl, 1,1-difluoro-ethyl and the like. In case more than one halogen atom is attached to an alkyl group within the definition of polyhalomethyl or polyhaloC1-6alkyl, they may be the same or different.
The R1 or Het1, Het2, Het3, Het4 or Het5 radical as described above for the compounds of formula (I) may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. For example, when Het1 is pyridyl, it may be 2-pyridyl, 3-pyridyl or 4-pyridyl.
Lines drawn into ring systems indicate that the bond may be attached to any suitable ring atom.
When any variable (e.g. aryl) occurs more than one time in any constituent, each definition is independent.
It will be appreciated that some of the compounds of formula (I) and their N-oxides, addition salts, quaternary amines and stereochemically isomeric forms may contain one or more centers of chirality and exist as stereochemically isomeric forms.
The term “stereochemically isomeric forms” as used herein before defines all the possible stereoisomeric forms which the compounds of formula (I), and their N-oxides, addition salts, quaternary amines or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) and their N-oxides, salts, solvates, quaternary amines substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention.
The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic) malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzensulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, thiehylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Conversely the salt forms can be converted by treatment with acid into the free acid form.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The term “quaternary amine” as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen.
Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term “compounds of formula (I)” or “compounds of formula (I-a)” is meant to include also the N-oxides, the addition salts, the quaternary amines and all stereoisomeric forms.
A special group of compound contains those compounds of formula (I) wherein

    Q is halo; C1-6alkyl; C1-6alkyloxy; C1-6alkyloxyC1-6alkyl; C1-6alkylthio; C1-6alkylthioC1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonylC1-6alkyl-S(═O)—; C1-6alkyl-S(═O)2—; hydroxyC1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxycarbonylC1-6alkyl; C1-6alkyloxyC1-6alkyloxycarbonyl; C2-6alkenyl optionally substituted with halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino or aryl; C2-6alkynyl optionally substituted with halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino or aryl; C3-6cycloalkyl optionally substituted with C1-4alkyl; cyano; carboxyl; formyl; R5R6N—C(═O)—; R5R6N—C(═O)—C1-6alkyl; N-hydroxy-imino; N—C1-4alkyloxy-imino; aryl; aryloxy; arylthio; arylC1-6alkyl; arylcarbonyl; arylC1-6alkyloxycarbonyl; C1-6alkyl substituted with both hydroxy and aryl; Het1; Het1oxy; Het1thio; Het1C1-6alkyl; Het1carbonyl; Het1C1-6alkyloxycarbonyl; C1-6alkyl-P(OR15)2═O or C1-6alkyl-P(O—C1-6alkyl-O)═O
    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, aryl or a monocyclic or bicyclic heterocycle selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, oxazolyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, or a radical of formula






     with n being an integer of 1 or 2,
    
        said monocyclic or bicyclic heterocycle or said radical of formula (b-1) or (b-2) optionally being substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, polyhaloC1-4alkyl or phenyl;
    
    
    R2 and R3 each independently are selected from hydrogen; halo; formyl; cyano; azido; hydroxy; oxiranyl; amino; mono- or di(C1-4alkyl)amino; formylamino; 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, N-hydroxy-imino, aryl or Het2; 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; 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, C1-6alkyloxy, C1-6alkylthio, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, 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, C1-6alkyloxy-carbonylamino, 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, 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) and (c-2) being optionally substituted with one or two substituents each independently selected from H, C1-6alkyl, C1-6alkyloxy, hydroxy C1-4alkyl, C1-6alkyloxycarbonyl, C1-6alkyloxycarbonylC1-4alkyl, aminoC1-6alkyl, carbonyl, hydroxy, cyano, 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)

or

—CH═CH—CH═CH—  (d-2)

    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) or (d-2) may be substituted with halo, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, haloC1-4alkylcarbonyl or arylcarbonyl;
    R4 is hydrogen, hydroxy, C1-6alkyl, C1-6alkyloxy, C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, C2-6alkenyl, amino, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminoC1-4alkyl or aryl;
    or R4 and R3 may be taken together to form a bivalent radical of formula

—(CH2)t—CH2-A4-CH2—  (e-1)

or

—CH═CH—CH═CH—  (e-2)

    with t being an integer of 0, 1 or 2 and A4 being CH2, O, S, NR7b or N[C(═O)R8b] and wherein each hydrogen in said formula (e1) or (e-2) may be substituted with halo, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, haloC1-4alkylcarbonyl or arylcarbonyl;
    R5 and R6 each independently are hydrogen, C1-4alkyl or C1-4alkyloxy,
    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, C1-4alkyloxycarbonyl-C1-4alkyloxy, 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, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexahydropyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl or 2-oxo-1,2-dihydro-quinolinyl, 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;
    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 or oxazolyl;
    aryl is phenyl optionally -substituted with one, two or three substituents each independently selected from halo; hydroxy; carboxyl; cyano; formyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; mono- or di(C1-4alkyl)aminocarbonylamino; C1-4alkyl-S(═O)2—NH—; C1-6alkyloxy; C1-6alkyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxycarbonyl, C1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het5; C2-6alkenyl 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; 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 or phenyloxy;


A special group of compound contains those compounds of formula (I) wherein

    Q is halo, C1-6alkyl or C2-6alkenyl;
    X is (a-2) with q and r being 0 and Z being O, S or SO;
    R1 is aryl;
    R2 is selected from formyl; C1-6alkyloxycarbonylalkyl; Het2; Het2C1-6alkyl; C1-6alkylthio; C1-6alkyl optionally substituted with one or two substituents each independently selected from hydroxy or halo;
    R3 is selected from formyl; C1-6alkyl optionally substituted with one or two C1-6alkyloxy;
    R4 is hydrogen.


Particular compounds are those compounds of formula (I) wherein Q is iodo.
Preferred compounds are those compounds of formula (I) wherein Q is iodo, X—R1 is a 3,5-dimethylphenylthio or a 3,5-dimethylphenyloxy and R2 is a hydroxymethyl or a N-morpholinomethyl or a 3-phenylpropyl or a furan-2-yl-methylthiomethyl. Also preferred compounds are those compounds of formula (I) wherein Q is iodo, X—R1 is a 3-(2-cyano-vinyl)-5-iodophenyloxy or 5-bromo-3-(2-cyano-vinyl) and R2 is ethyl.
Most preferred compounds are compounds n° 242, 255, 43, 264, 124, 249, 298, 326, 133, 241, 253, 306, 328, 46, 105, 234, 254, 256, 272, 284, 296, 319, 83, 88, 108, 109, 115, 277, 286, 299, 45, 85, 86, 231, 244, 297, 250, 257, 307, 324, 81, 92, 140, 143, 217, 221, 230, 232, 245, 309, 321, 322, 31, 218, 222, 314, 8, 99, 121, 219, 233, 280, 551, 470, 375, 483, 547, 606, 618, 662, 694, 700, 709 and 713 of table 1.
The present invention also relates to a method of treating warm-blooded animals suffering from HIV infection. Said method comprises the administration of the therapeutically effective amount of a compound of formula (I) or any sub group thereof, a N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof in admixture with a pharmaceutical carrier.
The compounds of formula (I) can be prepared according to art-known procedures.
In general, compounds of formula (I) wherein X is an oxygen and R1 a 3,5-dimethylphenyl, said compound being represented by formula (I-a) can be prepared by reacting an intermediate of formula (II) with a derivative of formula (III)




In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.
The compounds of formula (I) wherein X is a sulphur, said compound being represented by formula (I-b) can be prepared by reacting an intermediate of formula (IV) with a derivative of formula (V) in an appropriate solvent such as for example methanol, ethanol, propanol, butanol, dioxane, tetrahydrofurane, 2-methoxyethylether or toluene, and the like. This reaction can be performed at a temperature comprised between 20 and 130° C.




The compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.
The compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t.butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Some of the compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization of chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography using a chiral stationary phase.
Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to art-known procedures.
The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized as a mixture of stereoisomeric forms, in particular in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
It will be appreciated by those skilled in the art that in the processes described above the functional groups of intermediate compounds may need to be blocked by protecting groups.
Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C1-6alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after a reaction step.
The use of protecting groups is fully described in ‘Protective Groups in Organic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’ 2nd edition, T W Greene & P G M Wutz, Wiley Interscience (1991).
The compounds of the present invention show antiretroviral properties, in particular against Human Immunodeficiency Virus (HIV), which is the aetiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans. The HIV virus preferentially infects human T-4 cells and destroys them or changes their normal function, particularly the coordination of the immune system. As a result, an infected patient has an everdecreasing number of T-4 cells, which moreover behave abnormally. Hence, the immunological defense system is unable to combat infections and neoplasms and the HIV infected subject usually dies by opportunistic infections such as pneumonia, or by cancers. Other conditions associated with HIV infection include thrombocytopaenia, Kaposi's sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as progressive dysarthria, ataxia and disorientation. HIV infection further has also been associated with peripheral neuropathy progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC).
The present compounds also show activity against HIV-1 strains that have acquired resistance to art-know non-nucleoside reverse transcriptase inhibitors. They also have little or no binding affinity to human α-1 acid glycoprotein.
Due to their antiretroviral properties, particularly their anti-HIV properties, especially their anti-HIV-1-activity, the compounds of the present invention are useful in the treatment of individuals infected by HIV and for the prophylaxis of these individuals. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses whose existence is mediated by, or depends upon, the enzyme reverse transcriptase. Conditions which may be prevented or treated with the compounds of the present invention, especially conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis.
The compounds of the present invention or any subgroup thereof may therefore be used as medicines against above-mentioned conditions. Said use as a medicine or method of treatment comprises the systemic administration to HIV-infected subjects of an amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, especially HIV-1.
The compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid sugars, kaolin, lubricants, binders, disintegrating agent and the like in the case of powders pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the list advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
To aid solubility of the compounds of formula (I), suitable ingredients, e.g. cyclodextrins, may be included in the compositions. Appropriate cyclodextrins are α, β, γ-cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C1-6alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyC1-6alkyl, particularly hydroxyethyl, hydroxy-propyl or hydroxybutyl; carboxyC1-6alkyl, particularly carboxymethyl or carboxy-ethyl; C1-6alkylcarbonyl, particularly acetyl. Especially noteworthy as complexants and/or solubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxypropyl-β-CD and (2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD (2-HP-β-CD).
The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxyethyl.
The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The M.S. and D.S. value can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative. Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10 and the D.S. ranges from 0.125 to 3.
Other suitable compositions for oral or rectal administration comprise particles obtainable by melt-extruding a mixture comprising a compound of formula (I) and an appropriate water-soluble polymer and subsequently milling said melt-extruded mixture. Said particles can then be formulated by conventional techniques into pharmaceutical dosage forms such as tablets and capsules.
Said particles consist of a solid dispersion comprising a compound of formula (I) and one or more pharmaceutically acceptable water-soluble polymers. The preferred technique for preparing solid dispersions is the melt-extrusion process comprising the following steps:

    
    
        a) mixing a compound of formula (I) and an appropriate water-soluble polymer,
        b) optionally blending additives with the thus obtained mixture,
        c) heating the thus obtained blend until one obtains a homogenous melt,
        d) forcing the thus obtained melt through one or more nozzles; and
        e) cooling the melt till it solidifies.
    
    


The solid dispersion product is milled or ground to particles having a particle size of less than 1500 μm, preferably less than 400 μm, more preferably less than 250 μm and most preferably less than 125 μm.
The water-soluble polymers in the particles are polymers that have an apparent viscosity, when dissolved at 20° C. in an aqueous solution at 2% (w/v), of 1 to 5000 mPa.s, more preferably of 1 to 700 mPa.s, and most preferred of 1 to 100 mPa.s. For example, suitable water-soluble polymers include alkylcelluloses, hydroxyalkyl-celluloses, hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectines, chitin derivates, polysaccharides, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts and esters thereof, methacrylate copolymers, polyvinylalcohol, polyalkylene oxides and copolymers of ethylene oxide and propylene oxide. Preferred water-soluble polymers are Eudragit E® (Röhm GmbH, Germany) and hydroxypropyl methylcelluloses.
Also one or more cyclodextrins can be used as water soluble polymer in the preparation of the above-mentioned particles as is disclosed in WO 97/18839. Said cyclodextrins include the pharmaceutically acceptable unsubstituted and substituted cyclodextrins known in the art, more particularly α, β, γ-cyclodextrins or the pharmaceutically acceptable derivatives thereof.
Substituted cyclodextrins which can be used include polyethers described in U.S. Pat. No. 3,459,731. Further substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C1-6alkyl, hydroxyC1-6alkyl, carboxy-C1-6alkyl or C1-6alkyloxycarbonylC1-6alkyl or mixed ethers thereof. In particular such substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C1-3alkyl, hydroxyC2-4alkyl or carboxyC1-2alkyl or more in particular by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy-methyl or carboxyethyl.
Of particular utility are the β-cyclodextrin ethers, e.g. dimethyl-β-cyclodextrin as described by M. Nogradi (Drugs of the Future, (1984) Vol. 9, No. 8, p. 577–578) and polyethers, e.g. hydroxypropyl β-cyclodextrin and hydroxyethyl β-cyclodextrin, being examples. Such an alkyl ether may be a methyl ether with a degree of substitution of about 0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin may for example be formed from the reaction between β-cyclodextrin an propylene oxide and may have a MS value of about 0.125 to 10, e.g. about 0.3 to 3.
A more novel type of substituted cyclodextrins is sulfobutylcyclodextrines.
The ratio of the compound of formula (I) over cyclodextrin may vary widely. For example ratios of 1/100 to 100/1 may be applied. Interesting ratios of the compound of formula (I) over cyclodextrin range from about 1/10 to 10/1. More interesting ratios range from about 1/5 to 5/1.
It may further be convenient to formulate the compounds of formula (I) in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers are believed to include those which physically adhere to the surface of the compound of formula (I) but do not chemically bond to said compound.
Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
Yet another interesting way of formulating the compounds of formula (I) involves a pharmaceutical composition whereby the compounds of formula (I) are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.
Said beads comprise a central, rounded or spherical core, a coating film of a hydrophilic polymer and a compound of formula (I) and a seal-coating polymer layer.
Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
Those of skill in the treatment of HIV-infection could determine the effective daily amount from the test results presented here. In general, it is contemplated that an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose at two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, the weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased of the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines and are not intended to limit the scope or use of the invention to any extent.
Also, the combination of an antiretroviral compound and a compound of the present invention can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of the present invention, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. Said other antiretroviral compounds may be known antiretroviral compounds such as nucleoside reverse transcriptase inhibitors, e.g. zidovudine (3′-azido-3′-deoxythymidine; AZT), didanosine (dideoxy inosine; ddI), zalcitabine (dideoxycytidine; ddC) or lamivudine (3′-thia-2′-3′-dideoxycytidine; 3TC) and the like; non-nucleoside reverse transcriptase inhibitors such as suramine, pentamidine, thymopentin, castanospermine, efavirenz, rescriptor (BHAP derivative), dextran (dextran sulfate), foscarnet-sodium (trisodium phosphono formate), nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6Hdipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one), tacrine (tetrahydroaminoacridine) and the like; compounds of the TIBO (tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and thione)-type e.g. (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione compounds of the α-APA (α-anilino phenyl acetamide) type e.g. α-[(2-nitro-phenyl)amino]-2,6-dichloro-benzene-acetamide and the like; TAT-inhibitors, e.g. RO-5-3335 and the like; protease inhibitors e.g. indinavir, ritanovir, saquinovir, ABT-378 and the like; fusion inhibitors; integrase inhibitors; or immunomodulating agents, e.g. levamisole and the like. The compound of formula (I) can also be combined with another compound of formula (I).
The following examples are intended to illustrate the present invention. The numbers under the formulas correspond to the numbers in the table (I).


EXAMPLE 1
Ethyl 2-azido-4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-6-oxo-3-pyridinecarboxylate (compound 106)




2-chloro-4-hydroxy-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (intermediate 1) was obtained as described by J. A. Elvidge and N. A. Zaidi (J. Chem. Soc., (1968), 17, 2188) and dichloro-3,5-dimethyliodobenzene (intermediate 2) as described by H. J. Lucas, E. R. Kennedy, Org. Synth. (1955) Vol-III, 482–483.
1.1.: Ethyl 2-chloro-4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-6-oxo-3-pyridinecarboxylate (intermediate 3)
Intermediate 2 (0.73 g, 2.2 mmol) was suspended in 10 ml of water containing sodium carbonate (0.24 g, 2.2 mmol) and stirred for 30 min. at room temperature. To this mixture a solution of intermediate 1 (0.44 g, 2 mmol) in 10 ml of water containing also sodium carbonate (0.22 g; 2 mmol) was added. After stirring for one hour at 20° C. the precipitate was filtered off, washed with water, dried in vacuo and suspended in diglyme (5 ml). After heating at 100° C. for 10 min., the solvent was removed in vacuo. Purification by flash chromatography (SiO2, CH2Cl2/ethanol 98:2) gave the titled compound (0.6 g, 67%) as yellow microcrystals, m.p. 180–182° C.
1.2.: Ethyl 2-azido-4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-6-oxo-3-pyridinecarboxylate (compound 106)
Sodium azide (0.20 g, 3.12 mmol) was added to a solution of intermediate 3 (0.50 g, 1.56 mmol) in DMSO (5 ml), and the mixture was heated at 50° C. for 5 hours Reaction mixture was partitioned between water (30 ml) and ethyl acetate (40 ml). The organic layer was dried over magnesium sulfate and concentred. Flash chromatography (SiO2, CH2Cl2/ethanol 95:5) gave the desired product (0.49 g, 70%) as a white solid, m.p.=216–218° C.
EXAMPLE 2
4-[3,5-dimethylphenyl)-sulfinyl]-5-ethyl-3-iodo-6-methyl-2(1H)-pyridinone (compound 108)




4-[3,5-dimethylphenyl)-thio]-5-ethyl-6-methyl-2(1H)-pyridinone (intermediate 4) was obtained as described by Dollé et al. (J. Med. Chem., (1995), 38, 4679–4686).
2.1.: 4-[3,5-dimethylphenyl)-thio]-5-ethyl-3-iodo-6-methyl-2(1H)-pyridinone (intermediate 5)
The intermediate 4 (273 mg, 1 mmol) was dissolved in acetic acid (4 ml) and ethyl acetate (4 ml). At room temperature and in the dark N-iodosuccinimide (225 mg; 1 mmol) was added in one portion. After 4 hours under stirring at room temperature, the mixture was poured into water (15 ml) and the pH of the solution was adjusted to 7 with 28% ammonia. The combined organic layers obtained by extraction with ethyl acetate (3×30 ml) were washed with brine (10 ml), dried over magnesium sulfate and evaporated to give a gum. It was then purified by flash chromatography on silica gel column with CH2Cl2-ethanol (98:2) as the eluent to give the main fraction containing the titled compound which was recristallized from ethanol furnishing the pure intermediate 5 as yellow microcrystals (122 mg; 51%), m.p.=252° C.
2.2.: 4[-3,5-dimethylphenyl)-sulfinyl]-5-ethyl-3-iodo-6-methyl-2(1H)-pyridinone (compound 108)
m-chloroperbenzoic acid and water (70%, 123 mg; 0.5 mmol) in chloroform (15 ml) was dried over magnesium sulfate and filtered. To this solution at 0° C. was added the intermediate 5 (200 mg; 0.5 mmol) and the mixture was kept under stirring for 1 hour. A saturated solution of sodium carbonate (5 ml) was added and the combined organic layers obtained by extraction with CH2Cl2 (3×30 ml) were dried over magnesium sulfate and evaporated. The residue obtained was then chromatographed (SiO2, CH2Cl2/ethanol 98:2) to give the titled compound (113 mg; 50%).
1H NMR. (200 MHz, CDCl3), d: 0.66 (t, 3H, CH3-CH2, J=6.9 Hz); 2.20–2.90 (m, 11H, CH3-6,3′,5′, CH2CH3); 7.08 (s, 1H, H-4′); 7.25 (s, 2H, H-2′,6′); 12.9 (s, 1H, NH).
EXAMPLE 3
4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-2-methyl-6-oxo-3-pyridinecarboxaldehyde (compound 269)




Ethyl 4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarboxylate (intermediate 6) was described by E. Knoevenagel and A. Fries (Ber., (1898), 31, 768).
3.1.: Ethyl 4-hydroxy-5-hydroxymethyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarboxylate (intermediate 7)
The mixture of intermediate 6 (1.8 g; 9.1 mmol), Na2CO3 (970 mg; 9.1 mmol) and water (30 ml) was heated in an oil bath at 90° C. Three portions of 37% formaldehyde solution in water (1.46 ml; 18.2 mmol each) were added every 45 min. The homogeneous mixture obtained was kept at the same temperature for 30 min. further and the oil bath was removed. When the internal temperature reaches 60° C., ethyl acetate (40 ml) and acetic acid (1.8 ml) were added and after extraction with hot ethyl acetate (4×40 ml) the organic layer was evaporated under reduced pressure. The residue was then purified by flash chromatography on a silica gel column with CH2Cl2/ethanol (95:5) as the eluent to give the expected intermediate 7 (830 mg; 40%), m.p.=262–265° C.
3.2.: Ethyl 5-formyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridine-3-carboxylate (intermediate 8)
To a stirred solution of intermediate 7 (500 mg; 2.2 mmol) in CH2Cl2 (80 ml) was added at reflux MnO2 (4 g; 46 mmol) and the reflux was maintained for 50 hours. The hot mixture was filtered off, the solid was washed successively with hot methanol (3×50 ml) and hot ethyl acetate (3×50 ml). The solvents were evaporated and the solid residue obtained was then purified by flash chromatography on a column of silica gel with CH2Cl2/ethanol (98:2) as the eluent to give the intermediate 8 (420 mg; 85%); m.p.=248–250° C.
3.3.: 4-hydroxy-2-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxaldehyde (intermediate 9)
To a solution of intermediate 8 (350 mg; 1.5 mmol) in 1,4-dioxane (15 ml) was added water (7.6 ml) and 1N HCl (2.4 ml) and the mixture was heated under reflux for 24 hours. The hot solution was extracted with ethyl acetate (3×30 ml) and the solvent was removed under reduced pressure furnishing the titled intermediate 9 as yellow microcrystals (110 mg; 47%); m.p.>260° C. This compound was used for the next step without any further purification.
3.4.: 4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-2-methyl-6-oxo-3-pyridinecarboxaldehyde (compound 269)
Intermediate 2 (1.31 g, 4.32 mmol) was suspended in 25 ml of water containing sodium carbonate (0.46 g, 4.32 mmol) and stirred for 30 min. at room temperature. To this mixture a solution of intermediate 9 (0.55 g, 3.6 mmol) in 25 ml of water containing also sodium carbonate (0.38 g; 3.6 mmol) was added. After stirring for 1 hour at 20° C. the precipitate was filtered off, washed with water, dried in vacuo and suspended in dimethylformamide (15 ml). After heating under reflux for 1 h the solvent was removed in vacuo. Purification by flash chromatography (SiO2, CH2Cl2/EtOH 95:5) gave the titled compound (1.01 g, 73%) as yellow microcrystals, m.p.>260° C.
EXAMPLE 4
4-(3,5-dimethylphenoxy)-5-(hydroxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (compound 257)




To a stirred solution of compound 269 (500 mg; 1.3 mmol) in methanol (50 ml) was added NaBH4 (350 mg; 9.2 mmol) in small portions for a period of 10 min. After 1 hour on stirring at room temperature, water (20 ml) and a solution 10% potassium carbonate (30 ml) were added. The mixture was extracted with ethyl acetate (3×60 ml) and the organic layer was washed with brine, dried over magnesium sulfate and the solvent was removed under reduced pressure giving colorless microcrystals which correspond to the titled compound (490 mg; 97%) m.p.=248–250° C.
EXAMPLE 5
5-(chloromethyl)-4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-2(1H)-pyridinone (compound 125)




The heterogeneous solution of compound 257 (450 mg; 1.2 mmol) in CH2Cl2 (30 ml) became homogeneous mixture by addition at room temperature of SOCl2 (2.6 ml). After 2 hours on stirring at room temperature, all the volatiles were removed under reduced pressure giving a yellow solid which corresponds to the expected compound 125 in quantitative yield (470 mg); m.p.=256–258° C. This compound was used for the next step without any further purification.
EXAMPLE 6
4-(3,5-dimethylphenoxy)-5-(ethoxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (compound 255)




A solution of compound 125 (60 mg; 0.15 mmol) in absolute ethanol (5 ml) and potassium carbonate (60 mg; 0.44 mmol) was heated under reflux for 16 hours. After evaporation under reduced pressure, water (5 ml) was added and the mixture was extracted with ethyl acetate (3×10 ml). The organic layer was washed with brine (5 ml), dried over magnesium sulfate and the solvent was removed. The colorless solid residue was then purified by flash chromatography on a silica gel column with CH2Cl2/ethanol (98:2) as the eluent to give the titled compound 255 (59 mg; 95%); m.p.=234–236° C.
EXAMPLE 7
4-(3,5-dimethylphenoxy)-5-ethyl-3-iodo-6-methyl-2(1H)-pyridinone (compound 258)




This compound was prepared starting from the 5-ethyl-6-methyl-4-hydroxypyridin-2(1H)-one (intermediate 10) which was obtained as described by Dollé et al. (J. Med. Chem., (1995), 38, 4679–4686).
Intermediate 2 (3.75 g; 12.4 mmol) was suspended in water (50 ml) containing sodium carbonate (1.31 g; 12.4 mmol) and stirred for 30 min at room temperature. To this mixture a solution intermediate 10 (1.9 g; 12.4 mmol) in water (50 ml) containing also sodium carbonate (1.31 g; 12.4 mmol) was added. After stirring for 1 hour at 20° C. the precipitate was filtered off, washed with water, dried under vacuum at room temperature and suspended in dimethylformamide (20 ml). The mixture was refluxed for 1 hour. The solvent was removed in vacuo. Purification by flash chromatography (SiO2, CH2Cl2/Et OH 98:2) gave the titled compound (4.3 g; 90%) as colorless microcrystals; m.p.=240° C.
EXAMPLE 8
4-(3,5-dimethylphenoxy)-3-ethenyl-5-ethyl-6-methyl-2(1H)-pyridinone (compound 234)




Compound 258 (300 mg, 0.1783 mmol) and palladium tetrakistriphenylphosphine (45 mg, 5% mol) were dissolved in toluene (6 ml). Tributyl(vinyl)tin (358 mg, 0.94 mmol) was added at room temperature. The mixture was refluxed for 12 hours. Water (8 ml) was added and the aqueous layer was extracted with dichloromethane and dried over magnesium sulfate. The solvent was removed under vacuum and the residue was purified by flash chromatography (SiO2, CH2Cl2/ethanol 98:2) to give the titled compound 234 as colorless microcrystals (87 mg, 39%); m.p.=200° C.
EXAMPLE 9
4-(3,5-dimethylphenoxy)-3,5-diethyl-6-methyl-2(1H)-pyridinone (compound 231)




Compound 234 (90 mg, 0.318 mmol) was dissolved in absolute ethanol (10 ml). The catalyst palladium on carbon 10% (44 mg) was added. The mixture was stirred under hydrogen atmosphere at room temperature for 12 hours. The catalyst was filtered off and the solvent was evaporated under vacuum. The residue was purified by flash chromatography (SiO2, CH2Cl2/ethanol 98:2) to give the desired compound as colorless microcrystals (60 mg, 66%);, m.p.=180° C.
EXAMPLE 10
4-[3,5-dimethylphenyl)-thio]-5-(ethoxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (compound 86)




10.1. Ethyl 4-hydroxy-2-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (intermediate 12)

This compound was prepared starting from the di-(2,4,6-trichlorophenyl)malonate (intermediate 11) which was obtained as described by Kappe, Th., (Mh. Chem. (1967), 98, 874).
A solution of ethyl 3-aminocrotonate (12.6 g, 97.5 mmol) and of intermediate 11 in diglyme (400 ml) was heated at 100° C. for 3 hours during which the product separated out. After cooling, diethylether (1.5 l) was added and the desired intermediate 12 was filtered (14.2 g, 75%). m.p. 243–245° C.
10.2.: Ethyl 4-chloro-2-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (intermediate 13)
To a solution of intermediate 12 (2 g; 10 mmol) and benzyltriethylammonium chloride (9.1 g; 40 mmol) in acetonitrile (40 ml) was added in one portion phosphorus oxychloride (2.2 ml; 24 mmol). The obtained mixture was stirred at room temperature under nitrogen atmosphere for 5 min. and heated under reflux for 2 hours. After evaporation of the solvent, cool water (40 ml) was added and the mixture was stirred for 0.5 hour. Extraction with CH2Cl2 followed by a silica gel column chromatography using CH2Cl2/ethanol (99:1) as eluent gave i) ethyl 2,4-dichloro-6-methylpyridin-5-ylcarboxylate (1.7 g; 72%) (which can be transformed into the intermediate 13 and ii) intermediate 13 (506 mg; 24%) m.p.=161–163° C.
10.3.: Ethyl 4-[(3,5-dimethylphenyl)-thio]-1,6-dihydro-2-methyl-6-oxo-3-pyridinecarboxylate (intermediate 14)
A mixture of the intermediate 13 (1.2 g; 5.6 mmol) in ethanol (15 ml), triethylamine (1.5 ml) and 3,5-dimethylthiophenol (1.45 ml; 11 mmol) was heated under reflux for 16 hours. After evaporation under reduced pressure, diethylether (50 ml) was added and the precipitate was filtered off. The intermediate 14 was obtained (1.42 g; 80%) as a colorless solid m.p.=233–235° C.
10.4.: 4-[(3,5-dimethylphenyl)-thio]-5-(hydroxymethyl)-6-methyl-2(1H)-pyridinone (intermediate 15)
Under nitrogen atmosphere, the intermediate 14 (500 mg; 1.6 mmol) was suspended in dry tetrahydrofurane (20 ml) and LiAlH4 (120 mg; 3.2 mmol) was added at 0° C. The mixture was stirred at room temperature for 18 hours and poured in ethyl acetate (50 ml) at 0° C. and a solution 10% H2SO4 (100 ml) was added dropwise. The mixture was extracted with ethyl acetate (2×100 ml) and the organic layer was removed under reduced pressure giving the intermediate 15 (310 mg; 71%) m.p.=268–270° C.
10.5.: 4-[(3,5-dimethylphenyl)-thio]-5-(chloromethyl)-6-methyl-2(1H)-pyridinone (intermediate 16)
A suspension of intermediate 15 (275 mg; 1 mmol) in dichloromethane (10 ml) became homogeneous by addition of SOCl2 (2.3 ml) at room temperature. After 2 hours of stirring at room temperature, all the volatiles were removed under reduced pressure giving a yellow solid which corresponds to the expected intermediate 16 in quantitative yield (294 mg).
This compound was used for the next step without further purification.
10.6.: 4-[(3,5-dimethylphenyl)-thio]-5-(ethoxymethyl)-6-methyl-2(1H)-pyridinone (intermediate 17)
A solution of intermediate 16 (250 mg; 0.85 mmol) in absolute ethanol (10 ml) and triethylamine (0.24 ml) was heated at 50° C. for 18 hours. After evaporation under reduced pressure the residue was purified by flash chromatography on a silica gel column with CH2Cl2/ethanol (99:1) as the eluent to give the titled intermediate 17 (243 mg; 94%) m.p.=203–205° C.
10.7.: 4-[3,5-dimethylphenyl)-thio]-5-(ethoxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (compound 86)
The intermediate 17 (100 mg; 0.33 mmol) was dissolved in acetic acid (2 ml) and ethyl acetate (2 ml). At room temperature and in the dark N-iodosuccinimide (75 mg; 0.33 mmol) was added in one portion. After 2.5 h under stirring at room temperature, the mixture was poured into water (5 ml) and the pH of the solution was adjusted to ca.7 with 28% ammonia. The combined organic layers obtained by extraction with CH2Cl2 (3×10 ml) were washed with water (15 ml), dried over magnesium sulfate and evaporated to give a solid residue. It was then chromatographed on silica gel column with CH2Cl2/ethanol (99:1) as the eluent to give the titled compound 86 as colorless microcrystals (96 mg; 68%) m.p.=220–222° C.
EXAMPLE 11
3-bromo-4-[3,5-dimethylphenyl)-thio]-5-(ethoxymethyl)-6-methyl-2(1H)-pyridinone (compound 85)




The intermediate 17 (50 mg; 0.16 mmol) was dissolved in acetic acid (3 ml) and ethyl acetate (3 ml). At room temperature and in the dark N-bromosuccinimide (29 mg; 0.16 mmol) was added in one portion. After 30 min. under stirring at room temperature, the mixture was poured into water (10 ml) and the pH of the solution was adjusted to ca.7 with 28% ammonia. The combined organic layers obtained by extraction with ethyl acetate (3×15 ml) were dried over magnesium sulfate and evaporated to give a solid residue. It was then purified by flash chromatography on silica gel column with CH2Cl2/ethanol (99:1) as the eluent to give the titled compound 85 as colorless microcrystals (48 mg; 76%) m.p.=183–184° C.
EXAMPLE 12
Ethyl 4-[3,5-dimethylphenyl)-thio]-1,6-dihydro-5-iodo-2-methyl-6-oxo-3-pyridinecarboxylate (compound 71)




12.1.: Ethyl 4-[3,5-dimethylphenyl)-thio]-1,6-dihydro-2-methyl-1-6-oxo-3-pyridinecarboxylate (intermediate 18)

3,5-dimethylthiophenol (0.69 ml; 5.1 mmol) was added to a mixture of intermediate 13 (1 g; 4.6 mmol) in triethylamine (1 ml) and ethanol (10 ml). The mixture was stirred and refluxed then brought to room temperature and poured out into water. The precipitate was filtered. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried to yield (1.2 g; 80%) of intermediate 18; m.p.=230° C.
12.2.: Ethyl 4-[3,5-dimethylphenyl)-thio]-1,6-dihydro-5-iodo-2-methyl-6-oxo-3-pyridinecarboxylate (compound 71)
N-iodosuccinimide (0.085 g; 0.4 mmol) was added at room temperature to a solution of intermediate 18 (0.1 g; 0.3 mmol) in ethyl acetate (0.3 ml) and acetic acid (0.3 ml) under nitrogen. The mixture was stirred 48 hours in darkness. The solvent was evaporated. The residue was purified by column chromatography over Kromasil® (CH2Cl2; 100). Two fractions were collected and the solvent was evaporated to give 0.052 g of a compound which was crystallized from diisopropyl ether. The precipitate was filtered off and dried to yield (32 mg; 23%) of compound 71; m.p.=210° C.
EXAMPLE 13
4-[3,5-dimethylphenyl)-thio]-5-(hydroxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (compound 61)




Diisobutylaluminium hydride (20 wt. % solution in toluene) (0.75 ml; 0.9 mmol) was added at −70° C. to a mixture of compound 71 (0.1 g; 0.2 mmol) in toluene (10 ml). The mixture was stirred at 0° C. for 1 hour, poured out into water and extracted with ethyl acetate. The residue was crystallized from diisopropyl ether. The precipitate was filtered off and dried to yield (56 mg; 70%) of compound 61; m.p.=240° C.
EXAMPLE 14
5-(chloromethyl)-4-[-3,5-dimethylphenyl)-thio]-3-iodo-6-methyl-2(1H)-pyridinone (compound 60)




SOCl2 (0.9 ml; 12.3 mmol) was added dropwise at 0° C. to a solution of compound 61 (0.8 g; 1.9 mmol) in CH2Cl2 (90 ml). The mixture was stirred at room temperature overnight and evaporated till dryness. The residue was taken up in CH2Cl2 and evaporated (3 times) to yield 0.7 g (89%) m.p.=218° C. The product was used without further purification in the next reaction step.
EXAMPLE 15
4-[3,5-dimethylphenyl)-thio]-5-[(ethylthio)methyl]-3-iodo-6-methyl-2(1H)-pyridinone (compound 45)




A mixture of compound 60 (0.1 g; 0.2 mmol) and ethanethiol (0.0361 ml; 0.5 mmol) in triethylamine (0.1 ml) and ethanol (2 ml) was stirred and refluxed for 4 hours. The solvent was evaporated. The residue (0.06 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 95/5/0.1). The pure fractions were collected and the solvent was evaporated. The residue (0.02 g) was crystallized from diisopropylether. The precipitate was filtered off and dried to yield 0.018 g (17%); m.p.=210° C.
EXAMPLE 16
4-[(3,5-dimethylphenyl)-thio]-3-iodo-6-methyl-5-morpholinomethyl-1H-pyridin-2-one (compound 43)




A mixture of compound 60 (0.05 g; 0.1 mmol), morpholine (0.02 ml; 0.0002 mol) and K2CO3 (0.082 g; 0.6 mmol) in acetonitrile (2 ml; 0.6 mmol) was stirred at 50° C. in a sealed tube for 2 hours, poured out into water and extracted with ethylacetate. The solvent was evaporated. The residue was crystallized from diisopropyl ether. The precipitate was filtered off and dried. The residue (0.057 g) was crystallized from isopropanol. The precipitate was filtered off and dried to yield 0.041 g (73%), m.p.=230° C.
EXAMPLE 17
6-(diethoxymethyl)-4-(3,5-dimethylphenoxy)-5-ethyl-3-iodo-2(1H)-pyridinone (compound 134)




17.1.: 6-(diethoxymethyl)-5-ethyl-4-hydroxy-2H-pyran-2-one (intermediate 19)

A solution of sodium hydride (60% dispersion in mineral oil) in tetrahydrofurane (500 ml) was cooled at 0° C. under nitrogen. 3-oxo-hexanoic-acid ethyl ester (25 g; 158 mmol) was added dropwise and the mixture was stirred at 0° C. for 15 minutes. Butyllithium 1.6 M (99 ml; 158 mmol) was added dropwise and the mixture was stirred at 0° C. for 1 hour. Diethoxy-acetic acid ethyl ester (27.8 g; 0.178 mol) was added drop wise and the mixture was stirred at 0° C. for 1 hour. Hydrochloric acid 12 N (50 ml) was added and the mixture was stirred at room temperature for 1 hour and extracted with diethyl ether to yield 20 g (53%) of intermediate 19. The product was used without further purification in the next reaction step.
17.2.: 6-(diethoxymethyl)-5-ethyl-4-hydroxy-2(1H)-pyridinone (intermediate 20)
A mixture of intermediate 19 (20 g; 82 mmol) in CH3OH/NH3 (150 ml) was stirred at 60° C. for 4 hours, evaporated till dryness and taken up in diisopropyl ether. The precipitate was filtered to yield 1.5 g of intermediate 20 (7.5%). The product was used without further purification in the next reaction step.
17.3.: [6-diethoxymethyl-5-ethyl-4-hydroxy-2-oxo-3-pyridinyl]-3,5-dimethylphenyl)-iodonium, hydroxide, inner salt (intermediate 21)
A mixture of intermediate 20 (3.4 g; 14 mmol) and Na2CO3 (3 g; 28 mmol) in water (50 ml) was stirred at room temperature for 15 min to give residue 1. A mixture of intermediate 2 (4.66 g; 15.4 mmol) and Na2CO3 (3 g; 28 mmol) in water (50 ml) was stirred at room temperature for 15 min to give residue 2. Residue 1 and residue 2 were combined and then stirred at room temperature for 2 hours. The precipitate was filtered off, washed with water and dried. Yield 8 g of intermediate 21; m.p.=125° C.).
17.4.: 6-(diethoxymethyl)-4-(3,5-dimethylphenoxy)-5-ethyl-3-iodo-2(1H)-pyridinone (compound 134)
A mixture of intermediate 21 (6 g; 12.7 mmol) in DMF (20 ml) was stirred at 120° C. for 1 hour. The solvent was evaporated till dryness to yield 5 g of compound 134 (83%). The residue was used immediately without further purification.
EXAMPLE 18
4-(3,5-dimethylphenoxy)-3-ethyl-1,6-dihydro-5-iodo-6-oxo-2-pyridinecarboxaldehyde (compound 159)




A mixture of compound 134 (5 g; 10 mmol) in HCl 3N (30 ml) and tetrahydrofurane (5 ml) was stirred at 100° C. for 30 min. and then extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (5 g) was crystallized from diisopropyl ether. The precipitate was filtered off and dried to yield 3.5 g of titled compound 159 (83%), m.p.=158° C.
The residue was used without further purification.
EXAMPLE 19
4-(3,5-dimethylphenoxy)-5-ethyl-6-(hydroxymethyl)-3-iodo-2(1H)-pyridinone (compound 133)




NaBH4 (0.047 g; 1.3 mmol) was added to a mixture of compound 159 (0.5 g; 0.013 mol) in methanol (3 ml). The mixture was stirred at room temperature for 1 hour. Water was added. The precipitate was filtered off, taken up in diisopropyl ether and dried to yield 0.26 g (52%), m.p.=70° C.).
EXAMPLE 20
[3-(5-ethyl-3-iodo-6-methyl-2-oxo-1,2-dihydro-pyridin-4-yloxy)-5-iodo-phenyl]-acetonitrile (compound n° 426)




A mixture of compound 81 (0.1 g; 0.001 mol) and potassium cyanide (0.024 g; 0.0003 mol) in ethanol (2 ml) was stirred at 80° C. in a celled tube overnight. H2O was added. The mixture was extracted with CH2Cl2. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.03 g) was crystallized from DIPE. The precipitate was filtered off and dried to yield 0.21 g (21%), m.p.=220° C.
EXAMPLE 21
4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-5-[2-methylthiazol-4-ylmethylsulfanylmethyl)-1H-pyridin-2-one (compound n° 483)
21.1: 4-(3,5-dimethylphenoxy)-3-iodo-5-mercaptomethyl-6-methyl-1H-pyridin-2-one (compound n° 451)




A mixture of compound 125 (1.5 g; 0.0037 mol) and thiourea (0.31 g; 0.00408 mol) in DMSO (30 ml) was stirred at room temperature for 1 hour. NaOH 3N was added. The mixture was stirred for 15 minutes, acidified with HCl 3N and extracted with ethylacetate (EtOAc). The organic layer was separated, dried on magnesium sulfate (MgSO4), filtered and the solvent was evaporated. The residue was taken up in DIPE and filtered. The precipitate (1.2 g) was purified by column chromatography over silica gel (eluent: EtOAc 100%; 35–70 μm) and dried to yield 0.3 g (20%).
21.2: 4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-5-[2-methylthiazol-4-ylmethyl-sulfanylmethyl)-1H-pyridin-2-one (compound n° 483)




A mixture of compound 451 (0.07 g; 0.0001 mol) and 4-chloromethyl-2-methylthiazole (0.16 g, 0.0008 mol) in ethanol (3 ml) and triethylamine (0.2 ml) was stirred at 80° C. for 1 hour. H2O was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (0.04 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2; 15–40 μm). The pure fractions were collected and the solvent was evaporated and dried to yield 0.018 g.
EXAMPLE 22
4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-5-(3-phenyl-propyl)-1H-pyridin-2-one (compound 547)
22.1: 2-(1-amino-ethylidene)-5-phenyl-pentanoic acid ethyl ester (intermediate 23)
Ammonium nitrate (3.1 g; 0.039 mol) was added to a solution of intermediate 22 (2-acethyl-5-phenyl-pentanoic acid ethyl ester) (8.8 0.0354 mol) in tetrahydrofuran (90 ml). Ammoniac was bubbled. The mixture was stirred and refluxed for 6 hours, then stirred at room temperature for 12 hours, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, dried on magnesium sulfate (MgSO4), filtered and the solvent was evaporated and dried to yield 8.3 g.
22.2: ethyl 4-hydroxy-6-methyl-2-oxo-5-(3-phenyl-propyl)-1,2dihydro-pyridine-3-carboxylic acid ethyl ester (intermediate 24)




Sodium ethoxide in ethanol (27.5 ml; 0.0738 mol) was stirred and refluxed. Malonic acid diethyl ester (11.8 ml; 0.0738 mol) was added dropwise. A solution of intermediate 23 (8.3 g; 0.0335 mol) in ethanol (30 ml) was added dropwise. The mixture was stirred and refluxed for 15 hours. Three-quarters of EtOH were evaporated. The mixture was poured out in ice, acidified with HCl 3N and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated The residue (19.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/NH4OH 96/4/0.1; 15–35 μm). Two fractions were collected and the solvent was evaporated and dried to yield 0.43 g (4%).
22.3: 4-hydroxy-6-methyl-5-(3-phenyl-propyl)-1H-pyridin-2-one (intermediate 25)
A mixture of intermediate 24 (0.1 g; 0.003 mol) and sodium hydroxide (0.038 g; 0.0009 mol) in H2O (1.5 ml) was stirred and refluxed for 15 hours, then cooled to 5° C. with HCl 3N. The precipitate was filtered, washed with H2O, then with isopropanol and dried to yield 0.07 g (91%).
22.4: 4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-5-(3-phenyl-propyl)-1H-pyridin-2-one (compound 547)




A mixture of dichloro-3,5-dimethyliodobenzene (0.096 g; 0.0003 mol) and sodium carbonate (0.12 g; 0.0005 mol) in dimethylformamide (1 ml; 0.5 ml) was stirred at room temperature for 30 minutes. A solution of intermediate 25 (0.07 g; 0.0002 mol) and sodium carbonate (0.6 g; 0.0005 mol) in H2O (0.5 ml) was added. The mixture was stirred at room temperature for 1 hour. The precipitate was filtered, washed with H2O, then with DIPE and dried. The residue (0.12 g) was taken up in DMF and stirred at 100° C. for 30 minutes. The solvent was evaporated till dryness. The residue (0.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98/2/0 to 95/5/0.1; 35–70 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.07 g) was taken up in iPrOH. The precipitate was filtered off and dried to yield 0.06 g (44%), m.p.=220° C.
EXAMPLE 23
6-methyl-5-ethyl-3-iodo-4-[(3-bromo,5-acrylonitrilephenoxy]pyridin-2(1H)-one (compound 470)




23.1. 3-Bromo-5-iodobenzaldehyde dichloride (intermediate 26)

3-Bromo-5-iodobenzaldehyde dichloride (intermediate 26) was obtained as described by H. J. Lucas and E. R. Kennedy, Org. Synth. (1955), III, 482–483.
23.2. 6-methyl-5-ethyl-3-iodo-4-[(3-bromo,5-formylphenoxy]pyridin-2(1H)-one (compound 469)
Intermediate 26 (311 mg, 1 mmol) was suspended in 10 ml of water containing sodium carbonate (106 mg, 1 mmol) and stirred for 30 min. at room temperature. To this mixture a solution of 5-ethyl-6-methyl-4-hydroxypyridin-2(1H)-one (153 mg, 1 mmol) in 10 ml of water containing also Na2CO3 (106 mg, 1 mmol) was added. After stirring for 1 h at 20° C. the precipitate was filtered off, washed with water, dried in vacuo and suspended in dimethylformamide (5 mL). After heating at 120° C. for 10 min., the solvent was removed. Purification by flash chromatography (SiO2, CH2Cl2/EtOH 98:2) gave the titled compound (205 mg, 44%) as yellow microcrystals, m.p.>260° C.
23.3. 6-methyl-5-ethyl-3-iodo-4-[(3-bromo,5-acrylonitrilephenoxy]pyridin-2(1H)-one (compound 470)
To a 0° C. magnetically stirred solution of diethyl(cyanomethyl)-phosphonate (113 μL, 0.68 mmol) in anhydrous THF (3 mL), NaH (28 mg; 0.68 mmol) was added (60% in mineral water). After stirring at room temperature for 1 h, compound 469 (80 mg; 0.17 mmol) was added and the reaction mixture was stirred 18 h at room temperature and poured into water (5 ml). The resulting solution was extracted with AcOEt, dried over MgSO4 and evaporated. The oily residue obtained was then crystallized from Et2O to give the pure titled compound (65 mg; 77%), m.p.>260° C.
Table 1 lists intermediates and compounds of formula (I) which were made analogous to one of the above examples.
















 














N° =
Y
Q
X—R1
R2
R3
R4
mp. ° C./[MH+]

















1
O
I








Me
H
245





Chemistry 5
Chemistry 6


 


2
O
I








Me
H
>250 





Chemistry 11
Chemistry 12


 


3
O
I








Me
H
>250 





Chemistry 17
Chemistry 18


 


4
O
I




Et




H
210





Chemistry 23

Chem 25


 


5
O
I








Me
H
>250 





Chemistry 29
Chemistry 30


 


6
O
I








Me
H
[520]





Chemistry 35
Chemistry 36


 


7
O
I—Pr




Et
Me
H
260–262





Chemistry 41


 


8
O
I








Me
H
230





Chemistry 47
Chemistry 48


 


9
O
I












H
125





Chemistry 53
Et
Chem 55


 


10
O
I








Me
H
[639]





Chemistry 59
Chemistry 60


 


11
O
I








Me
H
[569]





Chemistry 65
Chemistry 66


 


12
O
I








Me
H
[593]





Chemistry 71
Chemistry 72


 


13
O
I








Me
H
[539]





Chemistry 77
Chemistry 78


 


14
O
I








Me
H
[543]





Chemistry 83
Chemistry 84


 


15
O
I








Me
H
[551]





Chemistry 89
Chemistry 90


 


16
O
I








Me
H
[539]





Chemistry 95
Chemistry 96


 


17
O
I








Me
H
[531]





Chemistry 101
Chemistry 102


 


18
O
I








Me
H
[477]





Chemistry 107
Chemistry 108


 


19
O
I








Me
H
[463]





Chemistry 113
Chemistry 114


 


20
O
I








Me
H
[531]





Chemistry 119
Chemistry 120


 


21
O








I
Me
H
240–244




Chem 124
Chemistry 125


 


22
O








H
Me
H
192–194




Chem 130
Chemistry 131


 


23
O
I




Et
Me
H
102–104





Chemistry 137


 


24
O
I




Et
Me
H
170–172





Chemistry 143


 


25
O
I




Et
Me
H
225–226





Chemistry 149


 


26
O
I




Et
Me
H
236–238





Chemistry 155


 


27
O
I




Et
Me
H
260–262





Chemistry 161


 


28
O
I




Et




H
118





Chemistry 167

Chem 169


 


29
O
I




Et




H
184





Chemistry 173

Chem 175


 


30
O
I








Me
H
160





Chemistry 179
Chemistry 180


 


31
O
I








Me
H
165





Chemistry 185
Chemistry 186


 


32
O
I








Me
H
>250 





Chemistry 191
C═NOH


 


33
O
I








Me
H
150





Chemistry 197
Chemistry 198


 


34
O
I








Me
H
>250 





Chemistry 203
Chemistry 204


 


35
O
I








Me
H
>250 





Chemistry 209
Chemistry 210


 


36
O
I








Me
H
200





Chemistry 215
Chemistry 216


 


37
O
I




Et




H
[519]





Chemistry 221

Chem 223


 


38
O
I




Et




H
—





Chemistry 227

Chem 229


 


39
O
I








Me
H
210





Chemistry 233
Chemistry 234


 


40
O
I




Et




H
210





Chemistry 239

Chem 241


 


41
O
I




Et




H
>250





Chemistry 245

C═NOH


 


42
O
I








Me
H
>250





Chemistry 251
Chemistry 252


 


43
O
I








Me
H
230





Chemistry 257
Chemistry 258


 


44
O
I








Me
H
120





Chemistry 263
Chemistry 264


 


45
O
I








Me
H
210





Chemistry 269
Chemistry 270


 


46
O
I








Me
H
250





Chemistry 275
Chemistry 276


 


47
O
I








Me
H
>250 





Chemistry 281
Chemistry 282


 


48
O
I




Et




H
218





Chemistry 287

Chem 289


 


49
O
I








Me
H
>250 





Chemistry 293
Chemistry 294


 


50
O
I




Et




H
226





Chemistry 299

Chem 301


 


51
O
I








Me
H
236





Chemistry 305
Chemistry 306


 


52
O
I








Me
H
>250 





Chemistry 311
Chemistry 312


 


53
O
I








Me
H
>250 





Chemistry 317
Chemistry 318


 


54
O
I








Me
H
150





Chemistry 323
Chemistry 324


 


55
O
I








Me
H
>250 





Chemistry 329
CN


 


56
O
H








Me
H
>250 





Chemistry 335
CN


 


57
O
I








Me
H
>250 





Chemistry 341
Formyl


 


58
O
I




Et




H
182





Chemistry 347

Chem 349


 


59
O
I








Me
H
245





Chemistry 353
CH2NMe2


 


60
O
I








Me
H
218





Chemistry 359
CH2Cl


 


61
O
I








Me
H
240





Chemistry 365
CH2OH


 


62
O
I




Et




H
165





Chemistry 371

Chem 373


 


63
O
I




Et




H
235





Chemistry 377

Chem 379


 


64
O
I








Me
H
>250 





Chemistry 383
Chemistry 384


 


65
O
I








Me
H
>250 





Chemistry 389
CO2H


66
O
I




Et




H
240





Chemistry 395

CH2CN


 


67
O
I




Et




H
[502]





Chemistry 401

Chem 403


 


68
O
Me




Et
Me
H
207–209





Chemistry 407


 


69
O
H




Et
Me
H
—





Chemistry 413


 


70
O
I




Et




H
224





Chemistry 419

Chem 421


 


71
O
I








Me
H
210





Chemistry 425
CO2Et


 


72
O
H








Me
H
230





Chemistry 431
CO2Et


 


73
O
I




Et




H
181





Chemistry 437

Chem 439


 


74
O
I




Et




H
170





Chemistry 443

Chem 445


 


75
O
I




Et




H
 95





Chemistry 449

Chem 451


 


76
O
I








Me
H
112





Chemistry 455
Chemistry 456


 


77
O
H




CO2Et




H
216–218





Chemistry 461

Azido


 


78
O
I




Ph
H
H
230–232





Chemistry 467


 


79
O
I




Et
Me
H
138–139





Chemistry 473


 


80
O
I




Et
Me
H
178–149





Chemistry 479


 


81
O
I




Et
Me
H
248–250





Chemistry 485


 


82
O
I




Et
Me
H
202–204





Chemistry 491


 


83
O
I




Et
Me
H
258–260





Chemistry 497


 


84
O
H








Me
H
205–207





Chemistry 503
Chemistry 504


 


85
O
Br








Me
H
183–184





Chemistry 509
Chemistry 510


 


86
O
I








Me
H
220–222





Chemistry 515
Chemistry 516


 


87
O
CO2Et




Et
Me
H
189–191





Chemistry 521


 


88
O
I




Et
Me
H
—





Chemistry 527


 


89
O
H




Et
Me
H
229–231





Chemistry 533


 


90
O
I




Et
Me
H
288–290





Chemistry 539


 


91
O
I








Me
H
238





Chemistry 545
CH2NMe2


 


92
O
I








Me
H
220





Chemistry 551
Chemistry 552


 


93
O
I




Et




H
160





Chemistry 557

Chem 559


 


94
O
I








Me
H
218





Chemistry 563
Chemistry 564


 


95
O
I




Et




H
214





Chemistry 569

Chem 571


 


96
O
I




Et




H
190





Chemistry 575

Chem 577


 


97
O
I








Me
H
>250  





Chemistry 581
Chemistry 582


 


98
O
I




Et




H
240





Chemistry 587

Chem 589


 


99
O
I








Me
H
180





Chemistry 593
Chemistry 594


 


100
O
I








Me
H
>250 





Chemistry 599
Ac


 













101
O
I




Et




210





Chemistry 605

(CH2)3


 














102
O
I




Et




H
170





Chemistry 611

Chem 613


 


103
O
I




Et




H
170





Chemistry 617

Chem 619


 


104
O
I




Et




H
200





Chemistry 623

Chem 625


 


105
O
I




Et




H
>250 





Chemistry 629

Chemistry 631


 


106
O
I




CO2Et




H
216–218





Chemistry 635

Azido


 


107
O
I




Et
Me
H
263–265





Chemistry 641


 


108
O
I




Et
Me
H
—





Chemistry 647


 


109
O
Br




Et
Me
H
187–189





Chemistry 653


 


110
O
I








Me
H
240





Chemistry 659
Chemistry 660


 


111
O
CO2Et




Et
Me
H
202–204





Chemistry 665


 


112
O
H




CN
NH2
H
282–283





Chemistry 671


 


113
O
I




CN
NH2
H
283–285





Chemistry 677


 


114
O
H




Et
Me
H
166–168





3-Methylbenzyl


 


115
O
I




Et
Me
H
229–231





Chemistry 695


 


116
O
Br




Et
CH2Br
H
[430]





Chemistry 701


 


117
O
H




Et
Me
H
—





Chemistry 707


 


118
O
I




Et
Me
H
—





Chemistry 713


 


119
O
I




Et
Me
H
266–267





Chemistry 719


 


120
O
I




Et
Me
H
186–187





Chemistry 725


 


121
O
I




Et
Me
H
225–226





Chemistry 731


 


122
O
I




CN




H
225–227





Chemistry 737

Azido


 


123
O
I








Me
H
[539]





Chemistry 743
Chemistry 744


 


124
O
I








Me
H
140





Chemistry 749
Chemistry 750


 


125
O
I




CH2Cl
Me
H
256–258





Chemistry 755


 


126
O
I








Me
H
>250 





Chemistry 761
Chemistry 762


 


127
O
I








Me
H
—





Chemistry 767
C═C(CN)2


 


128
O
I








Me
H
>240 





Chemistry 773
Chemistry 774


 


129
O
I








Me
H
230





Chemistry 779
Chemistry 780


 


130
O
I




Et




H
180





Chemistry 785

Chem 787


 


131
O
I




Et




H
130





Chemistry 791

CH2NMe2


 


132
O
I




Et
CH2Cl
H
>240 





Chemistry 797


 


133
O
I




Et
CH2OH
H
 97





Chemistry 803


 


134
O
I




Et




H
—





Chemistry 809

Chem 811


 


135
O
I








Me
H
>250 





Chemistry 815
Chemistry 816


 


136
O
I








Me
H
>250 





Chemistry 821
Chemistry 822


 


137
O
I








Me
H
>250 





Chemistry 827
Chemistry 828


 


138
O
I








Me
H
250





Chemistry 833
Chemistry 834


 


139
O
I




Et




H
[442]





Chemistry 839

Chem 841


 


140
O
I








Me
H
>250





Chemistry 845
CH═CHCN


 


141
O
I








Me
H
[508]





Chemistry 851
Chemistry 852


 


142
O
I








Me
H
[491]





Chemistry 857
Chemistry 858


 


143
O
I








Me
H
[529]





Chemistry 863
Chemistry 864


 


144
O
I








Me
H
[540]





Chemistry 869
Chemistry 870


 


145
O
I








Me
H
[545]





Chemistry 875
Chemistry 876


 


146
O
I








Me
H
[543]





Chemistry 881
Chemistry 882


 


147
O
I








Me
H
[593]





Chemistry 887
Chemistry 888


 


148
O
I








Me
H
[544]





Chemistry 893
Chemistry 894


 


149
O
I








Me
H
[570]





Chemistry 899
Chemistry 900


 


150
O
I








Me
H
[516]





Chemistry 905
Chemistry 906


 


151
O
I








Me
H
[519]





Chemistry 911
Chemistry 912


 


152
O
I








Me
H
[569]





Chemistry 917
Chemistry 918


 


153
O
I








Me
H
[535]





Chemistry 923
Chemistry 924


 


154
O
I








Me
H
[572]





Chemistry 929
Chemistry 930


 


155
O
I








Me
H
[586]





Chemistry 935
Chemistry 936


 


156
O
I








Me
H
[518]





Chemistry 941
Chemistry 942


 


157
O
I




Et




H
195





Chemistry 947

Chem 949


 


158
O
I




Et




H
200





Chemistry 953

Chem 955


 


159
O
I




Et




H
158





Chemistry 959

Formyl


 


160
O
I








Me
H
>250 





Chemistry 965
Chemistry 966


 


161
O
I








Me
H
195





Chemistry 971
Chemistry 972


 


162
O
I








Me
H
220





Chemistry 977
Chemistry 978


 


163
O
I








Me
H
>240 





Chemistry 983
C═CHAc


 


164
O
I








Me
H
>240 





Chemistry 989
Chemistry 990


 


165
O
I








Me
H
>240 





Chemistry 995
Chemistry 996


 


166
O
I








Me
H
>250 





Chemistry 1001
Chemistry 1002


 


167
O
I








Me
H
242





Chemistry 1007
Chemistry 1008


 


168
O
I








Me
H
262





Chemistry 1013
Chemistry 1014


 


169
O
I








Me
H
>250 





Chemistry 1019
Chemistry 1020


 


170
O
I








Me
H
230





Chemistry 1025
Chemistry 1026


 


171
O
I








Me
H
[573]





Chemistry 1031
Chemistry 1032


 


172
O
I








Me
H
[561]





Chemistry 1037
Chemistry 1038


 


173
O
I








Me
H
[593]





Chemistry 1043
Chemistry 1044


 


174
O
I








Me
H
[526]





Chemistry 1049
Chemistry 1050


 


175
O
I








Me
H
[441]





Chemistry 1055
Chemistry 1056


 


176
O
I








Me
H
>250 





Chemistry 1061
C═NOH


 


177
O
H




Et
Me
H
—





Chemistry 1067


 


178
O
CO2Et




Et
Me
H
—





Chemistry 1073


 


179
O
CO2Et




Et
Me
H
—





Chemistry 1079


 


180
O
n-Pr




Et
Me
H
158–160





Chemistry 1085


 


181
O
I




Me
H
H
>260 





Chemistry 1091


 


182
O








Et
Me
H
158–160




Chem 1096
Chemistry 1097


 


183
O








Et
Me
H
159–161




Chem 1102
Chemistry 1103


 


184
O
I




CN




H
261–262





Chemistry 1109

Chem 1111


 


185
O
I




CN




H
263–264





Chemistry 1115

Chem 1117


 


186
O
I




CN




H
265–267





Chemistry 1121

SPh


 


187
O
I




CN




H
224–225





Chemistry 1127

Chem 1129


 


188
O
I




CN




H
218–220





Chemistry 1133

Chem 1135


 


189
O
I




CN




H
235–237





Chemistry 1139

Chem 1141


 


190
O
I




CN




H
242–244





Chemistry 1145

Chem 1147


 


191
O
I




Et
CH2CH2Ph
H
240





Chemistry 1151




























192
O
I








Me
H
[514]





Chemistry 1157
Chemistry 1158


 


193
O
I








Me
H
[529]





Chemistry 1163
Chemistry 1164


 


194
O
I








Me
H
[580]





Chemistry 1169
Chemistry 1170


 


195
O
I












H
[504]





Chemistry 1175
Chemistry 1176
Me


 


196
O
I








Me
H
[562]





Chemistry 1181
Chemistry 1182


 


197
O
I








Me
H
[518]





Chemistry 1187
Chemistry 1188


 


198
O
I








Me
H
[456]





Chemistry 1193
Chemistry 1194


 


199
O
I








Me
H
[503]





Chemistry 1199
Chemistry 1200


 


200
O
I








Me
H
[545]





Chemistry 1205
Chemistry 1206


 


201
O
I








Me
H
[469]





Chemistry 1211
Chemistry 1212


 


202
O
I








Me
H
[513]





Chemistry 1217
Chemistry 1218


 


203
O
I








Me
H
[538]





Chemistry 1223
Chemistry 1224


 


204
O
I








Me
H
[481]





Chemistry 1229
Chemistry 1230


 


205
O
I








Me
H
[490]





Chemistry 1235
Chemistry 1236


 


206
O
I








Me
H
[492]





Chemistry 1241
Chemistry 1242


 


207
O
I








Me
H
[542]





Chemistry 1247
Chemistry 1248


 


208
O
I








Me
H
[505]





Chemistry 1253
Chemistry 1254


 


209
O
I








Me
H
[487]





Chemistry 1259
Chemistry 1260


 


210
O
I








Me
H
[452]





Chemistry 1265
Chemistry 1266


 


211
O
I








Me
H
[516]





Chemistry 1271
Chemistry 1272


 


212
O
I








Me
H
[514]





Chemistry 1277
Chemistry 1278


 


213
O
I








Me
H
[427]





Chemistry 1283
Chemistry 1284


 


214
O
I








Me
H
>250





Chemistry 1289
Chemistry 1290


 


215
O
I








Me
H
>250





Chemistry 1295
CH═CHCO2Et


 


216
O
I




Et




H
160





Chemistry 1301

Chem 1303


 


217
O
I




Et




H
230





Chemistry 1307

Chem 1309


 


218
O
I








Me
H
>250





Chemistry 1313
Chemistry 1314


 


219
O
I








Me
H
>250





Chemistry 1319
Chemistry 1320


 


220
O
I




CH2NH2
Me
H
240





Chemistry 1325


 













221
O
I








H
264–266





Chemistry 1331
Chemistry 1332


 


222
O
I








H
252–253





Chemistry 1337
(CH2)4


 


223
O
I








H
243–244





Chemistry 1343
(CH2)3


 


224
O
H








H
260–262





Chemistry 1349
Chemistry 1350


 














225
O
I




CO2Et
Me
H
190





Chemistry 1355


 


226
O
I




Et
Cl
NH2
146–147





Chemistry 1361


 


227
O
I




CN




H
282–284





Chemistry 1367

Chem 1369


 


228
O
I




CO2Et
Cl
H
180–182





Chemistry 1373


 


229
O
H




CN
Cl
H
240–242





Chemistry 1379


 


230
O








Et
Me
H
188–190




Chem 1384
Chemistry 1385


 


231
O
Et




Et
Me
H
179–181





Chemistry 1391


 


232
O
I








Me
H
>240





Chemistry 1397
Chemistry 1398


 


233
O
I








Me
H
[539]





Chemistry 1403
Chemistry 1404


 


234
O
Vinyl




Et
Me
H
198–200





Chemistry 1409


 













235
O
H








H
—





Chemistry 1415
(CH2)3


 














236
O
I




CN
Cl
H
276–277





Chemistry 1421


 


237
O
I




Et
Me
H
280–282





Chemistry 1427


 


238
O
I




CN
Me
H
>240





Chemistry 1433


 


239
O
I








Me
H
>240





Chemistry 1439
Chemistry 1440


 


240
O
I








Me
H
—





Chemistry 1445
Chemistry 1446


 


241
O
I








Me
H
>240





Chemistry 1451
Chemistry 1452


 


242
O
I








Me
H
220





Chemistry 1457
Chemistry 1458


 


243
O
I








Me
H
216–217





Chemistry 1463
Chemistry 1464


 


244
O
I








Me
H
216–218





Chemistry 1469
Chemistry 1470


 


245
O
I








Me
H
212–214





Chemistry 1475
Chemistry 1476


 


246
O








Et
Me
H
—




Chem 1480
3-Methylbenzyl


 


247
S
H




Et
Me
H
>240





Chemistry 1487


 


248
S
I




Et
Me
H
210





Chemistry 1493


 


249
O
I




2-Methoxybenzyl
Me
H
156





Chemistry 1505


 


250
O
I








Me
H
141





Chemistry 1511
Chemistry 1512


 


251
O








Et
Me
H
—




Chem 1516
3-Methylbenzyl


 


252
O








Et
Me
H
—




Chem 1522
3-Methylbenzyl


 


253
O
I








Me
H
184–186





Chemistry 1529
Chemistry 1530


 


254
O
I








Me
H
224–226





Chemistry 1535
Chemistry 1536


 


255
O
I








Me
H
234–236





Chemistry 1541
Chemistry 1542


 


256
O
I








H
H
160–162





Chemistry 1547
Chemistry 1548


 


257
O
I




CH2OH
Me
H
248–250





Chemistry 1553


 


258
O
I




Et
Me
Me
240





Chemistry 1559


 


259
O
I




Et
Me




179





Chemistry 1565


Chem 1562


 


260
O
SOMe




Et
Me
H
196–197





Chemistry 1571


 


261
O
I




Et
Cl
H
186–187





Chemistry 1577


 


262
O
H




Me
Cl
H
210–242





Chemistry 1583


 


263
O
I




Me
Cl
H
240–242





Chemistry 1589


 


264
O
I




2-Methoxyethyl
Me
H
212





Chemistry 1595


 


265
O
H




Me




H
176





3-Methylbenzoyl

Chem 1603


 


266
O
I




Me




H
>260





3-Methylbenzoyl

Chem 1609


 


267
O
H




Et
Cl
H
210–211





Chemistry 1613


 


268
O
CH2OH




H
Me
H
212–214





Chemistry 1619


 


269
O
I








Me
H
282–284





Chemistry 1625
Formyl


 


270
O








Et
Me
H
192




Chem 1630
Chemistry 1631


 


271
O








Et
Me
H
182




Chem 1636
Chemistry 1637


 


272
O
SMe




Et
Me
H
186–188





Chemistry 1643


 


273
O








Et
Me
H
[336]




Chem 1648
3-Methylbenzyl


 


274
S








Et
Me
H
[313]




Chem 1654
3-Methylbenzyl


 


275
O
CO2Me




Et
Me
H
[300]





3-Methylbenzyl


 


276
O
C═NOH




Et
Me
H
262





Chemistry 1667


 


277
O
OMe




Et
Me
H
178





Chemistry 1673


 


278
O








Et
Me
H
225




Chem 1678
Chemistry 1679


 


279
O








Et
Me
H
166




Chem 1684
Chemistry 1685


 


280
O
SPh




Et
Me
H
211





Chemistry 1691


 


281
O
CH(OH)Ph




Et
Me
H
198





Chemistry 1697


 


282
O
CO2Et




Et
Me
H
—





3-Methylbenzyl


 


283
O
CO2H




Et
Me
H
—





3-Methylbenzyl


 


284
O
Br




Et
Me
H
240–241





Chemistry 1715


 


285
O
CN




Et
Me
H
282–284





Chemistry 1721


 


286
O
I




Et
Me
H
204–206





3-Methylbenzyl


 


287
O
I




H
Me
H
274–275





Chemistry 1733


 


288
O
CCPh




Et
Me
H
260





Chemistry 1739


 


289
O
CH═CHCO2Et




Et
Me
H
256





Chemistry 1745 


 


290
O
Formyl




Et
Me
H
228





Chemistry 1751


 


291
O
3-Thiophenyl




Et
Me
H
222





Chemistry 1757




























292
O
3-Cl-phenyl




Et
Me
H
223





Chemistry 1763


 


293
O
2-Furyl




Et
Me
H
228





Chemistry 1769


 


294
O
CH2OH




Et
Me
H
200





Chemistry 1775


 


295
O
CO2H




Et
Me
H
221





Chemistry 1781


 


296
O
I




Et
Me
H
232–234





Chemistry 1787


 


297
O
I




Et
Me
H
248–250





Chemistry 1793


 


298
O
I




Et
Me
H
250





Chemistry 1799


 


299
O
I




Et
Me
H
265–266





Chemistry 1805


 


300
O
I




Et
Me
H
275–276





Chemistry 1811


 


301
O
CO2H




H
H
H
[290]





2,5-Dimethoxybenzyl


 


302
O
H




H
Me
H
[283]





Chemistry 1823


 


303
O
CO2Et




H
Me
H
[355]





Chemistry 1829


 


304
O
CO2H




H
Me
H
[299]





Chemistry 1835


 


305
O
CO2Et




H
Me
H
[303]





Chemistry 1841


 


306
O
I




Et
Me
H
200–202





Chemistry 1859


 


307
O
I




Et
Me
H
238–240





Chemistry 1865


 


308
O
H




Et
Me
H
212–214





3,5-Dimethylbenzyl


 


309
O
I




Et
Me
H
258–260





Chemistry 1877


 


310
O
I




Et
Me
H
—





Chemistry 1883


 


311
O
I




Et
Me
H
198–199





Chemistry 1889


 


312
O
I




Et
Me
H
182–183





Chemistry 1895


 


313
O
I




Et
Me
H
265–266





Chemistry 1901


 


314
O
I




Et
H
H
210–212





Chemistry 1907


 


315
O
I




Me
Me
H
261–262





Chemistry 1913


 













316
O
I








H
218–219





Chemistry 1919
Chemistry 1920


 


317
O
I








H
230–232





Chemistry 1925
(CH2)4


 


318
O
I








H
206–208





Chemistry 1931
(CH2)3


 














319
O
I




Et
Me
H
242–243





Chemistry 1937


 


320
O
H




Et
Me
H
241–242





Chemistry 1943


 


321
O
I




Et
Me
H
198–200





Chemistry 1949


 


322
O
I




Et
Me
H
—





Chemistry 1955


 


323
O
CO2Et




Et
Me
H
198





Chemistry 1961


 


324
O
CO2Et




Et
Me
H
184–185





3,5-Dimethylbenzyl


 


325
O
H




Et
Me
H
232–233





Chemistry 1973


 


326
O
I




Et
Me
H
240





Chemistry 1979


 


327
O
H
OPh
Et
Me
H
228–229


328
O
I
OPh
Et
Me
H
180–182


329
O
I
OPh
H
Me
H
265–266


 


330
O
CO2Et




Et
Me
H
228–229





Chemistry 2003


 


331
O








Et
Me
H
192–193




Chem 2008
3,5-Dimethylbenzyl


 


332
O
CO2H




Et
Me
H
—





3,5-Dimethylbenzyl


 


333
O
CN




H
n-Pr
H
132





Benzyl


 


334
O








Et
Me
H
207




Chem 2026
3-Methylbenzoyl


 


335
O








Et
Me
H
216




Chem 2032
3-Methylbenzyl


 













336
O
CH2NMe2








H
185





3-Methylbenzyl
(CH2)4


 


337
O
CH2NH2








H
—





3-Methylbenzyl
(CH2)4
















 













No =
Q
X-R1
R2
R3
R4
mp. ° C./(MH+)





338
















H
245



I
Chemistry 3
Chemistry 4
Me


 


339
















H
175



I
Chemistry 8
Chemistry 9
Me


 


340
















H
[460]



I
Chemistry 13
Chemistry 14
Me


 


341
















H
[324, 326]



H
Chemistry 18
Et
Me


 


342
















H
[292, 294]



Cl
Chemistry 23
Et
Me


 


343
















H
[288]



Chemistry 27
Chemistry 28


 


344
















H
[462]



I
Chemistry 33
Et
Me


 


345
















H
[588]



I
Chemistry 38
Et
Me


 


346
















H
[506



I
Chemistry 43
Chemistry 44
Me


 


347
















H
[304]



CH2OH
Chemistry 48
Et
Me


 


348
















H
[627]



I
Chemistry 53
Et
Me


 


349
















H
[610]



I
Chemistry 58
Et
Me


 


350
















H
[616]



I
Chemistry 63
Et
Me


 


351
















H
[604]



I
Chemistry 68
Et
Me


 


352
















H
[615]



I
Chemistry 73
Et
Me


 


353
















H
[579



I
Chemistry 78
Et
Me


 


354
















H
[596]



I
Chemistry 83
Et
Me


 


355
















H
[640]



I
Chemistry 88
Et
Me


 


358
















H
[614]



I
Chemistry 93
Et
Me


 


357
















H
205



I
Chemistry 98
Chemistry 99
Me


 


358
















H
210



I
Chemistry 103
Chemistry 104
Me


 


359
















H
>250



I
Chemistry 108
Chemistry 109
Me


 


360
















H
[487]



I
Chemistry 113
Chemistry 114
Me


 


381
















H
[570]



I
Chemistry 118
Chemistry 119
Me


 


362
















H
[455]



I
Chemistry 123
Chemistry 124
Me


 


363
















H
215



I
Chemistry 128
Chemistry 129
Me


 


364
















H
205



I
Chemistry 133
Chemistry 134
Me


 


365
















H
>250



I
Chemistry 138
Chemistry 139
Me


 


366
















H
240



I
Chemistry 143
Chemistry 144
Me


 


367
















H
135



I
Chemistry 148
Chemistry 149
Me


 


368
















H
>250



I
Chemistry 153
Chemistry 154
Me


 


369
















H
>250



I
Chemistry 158
Chemistry 159
Me


 


370
















H
>250



I
Chemistry 163
Chemistry 164
Me


 


371
















H
>250



I
Chemistry 168
Chemistry 169
Me


 


372
















H
>250



I
Chemistry 173
Chemistry 174
Me


 


373
















H
>250



I
Chemistry 178
Chemistry 179
Me


 


374
















H
170



I
Chemistry 183
Chemistry 184
Me


 


375
















H
220



I
Chemistry 188
Chemistry 189
Me


 


376
















H
>250



I
Chemistry 193
Chemistry 194
Me


 


377
















H
>250



I
Chemistry 198
Et
Chemistry 200


 


378
















H
>250



I
Chemistry 203
Chemistry 204
Me


 


379
















H
[395]



I
Chemistry 208
Et
CN


 


380
















H
[399]



I
Chemistry 213
Et
CH2NH2


 


381
















H
230



I
Chemistry 218
Chemistry 219
Me


 


382
















H
226



I
Chemistry 223
Chemistry 224
Me


 


383
















H
[532]



Chemistry 227
Chemistry 228


 


384
















H
[540]



I
Chemistry 233
Chemistry 234
Me


 


385
















H
[512]



I
Chemistry 238
Chemistry 239
Me


 


386
















H
[256]



Vinyl
Chemistry 243
H
Me


 


387
















H
[258]



Et
Chemistry 248
H
Me


 


388
















H
[384]



Et
Chemistry 253
I
Me


 


389
















H
>250



I
Chemistry 258
Chemistry 259
Me


 


390
















H
>250



I
Chemistry 263
Chemistry 264
Me


 


391
















H
>250



I
Chemistry 268
CH2NH2
Me


 


392
















H
239



I
Chemistry 273
Chemistry 274
Me


 


393
















H
220



I
Chemistry 278
Chemistry 279
Me


 


394
















H
[458]



I
Chemistry 283
Chemistry 284
Me


 


395
















H
240



I
Chemistry 288
Chemistry 289
Me


 


396
















H
190



I
Chemistry 293
Chemistry 294
Me


 


397
















H
>240



I
Chemistry 298
Chemistry 299
Me


 


398
















H
>250



I
Chemistry 303
Chemistry 304
Me


 


399
















H
>250



I
Chemistry 308
Chemistry 309
Me


 


400
















H
>250



I
Chemistry 313
Chemistry 314
Me


 


401
















H
212



I
Chemistry 318
Chemistry 319
Me


 


402
















H
238



I
Chemistry 323
Chemistry 324
Me


 


403
















H
188



I
Chemistry 328
Chemistry 329
Me



























404
















H
104



I
Chemistry 333
Chemistry 334
Me


 


405
















H
240



I
Chemistry 338
Chemistry 339
Me


 


406
















H
148



I
Chemistry 343
Chemistry 344
Me


 


407
















H
214



I
Chemistry 348
Et
Chemistry 350


 


408
















H
[308, 310]



Cl
Chemistry 353
Et
Me


 


409
















H
[326]



CF3
Chemistry 358
Et
Me


 


410
















H
[541]



I
Chemistry 363
Chemistry 364
Me


 


411
















H
[429]



I
Chemistry 368
Chemistry 369
Me


 


412
















H
220



I
Chemistry 373
Chemistry 374
Me


 


413
















H
>250



I
Chemistry 378
Chemistry 379
Me


 


414
















H
[557]



I
Chemistry 383
Chemistry 384
Me


 


416
















H
162



I
Chemistry 388
Chemistry 389
Me


 


416
















H
><240



I
Chemistry 393
Chemistry 394
Me


 


417
















H
[328]



Chemistry 397
Chemistry 398
Et
Me


 


418
















H
[362, 364]



Chemistry 402
Chemistry 403
Et
Me


 


419
















H
248



I
Chemistry 408
Chemistry 409
Me


 


420
















H
226



I
Chemistry 413
Chemistry 414
Me


 


421
















H
174



I
Chemistry 418
Chemistry 419
Me


 


422
















H
[350]



H
Chemistry 423
Et
CH(OH)Ph


 


423
















H
[476]



I
Chemistry 428
Et
CH(OH)Ph


 


424
















H
158



I
Chemistry 433
Chemistry 434
Me


 


425
















H
236



I
Chemistry 438
Chemistry 439
Me


 


426
















H
[521]



I
Chemistry 443
Et
Me


 


427
















H
234



I
Chemistry 448
Chemistry 449
Me


 


428
















H
204



I
Chemistry 463
Chemistry 464
Me


 


429
















H
[556]



I
Chemistry 458
CO2Et
Me


 


430
















H
[574]



I
Chemistry 463
Et
Me


 


431
















H
[410]



Chemistry 467
Chemistry 468
Et
Me


 


432
















H
[432]



Chemistry 472
Chemistry 473
Et
Me


 


433
















H
236



I
Chemistry 478
Chemistry 479
Me


 


434
















H
>250



I
Chemistry 483
Chemistry 484
Me


 


435
















H
200



I
Chemistry 488
Chemistry 489
Me


 


436
















H
>250



I
Chemistry 493
Chemistry 494
Me


 


437
















H
[442]



I
Chemistry 488
Et
Chemistry 500


 


438
















H
186



I
Chemistry 503
Et
Chemistry 505


 


439
















H
[370]



I
Chemistry 508
Me
Me


 


440
















H
[514]



I
Chemistry 513
CH2OH
Me


 


441
















H
[372]



I
Chemistry 518
Me
Me


 


442
















H
[390, 392]



I
Chemistry 523
Me
Me


 


443
















H
[380]



I
Chemistry 528
Me
Me


 


444
















H
[430]



I
Chemistry 533
Me
Me


 


445
















H
[314]



Chemistry 537
Chemistry 538
Et
Me


 


446
















H
[356]



Chemistry 542
Chemistry 543
Et
Me


 


447
















H
[525]



I
Chemistry 548
Et
Me


 


448
















H
[535]



I
Chemistry 553
Et
Me


 


449
















H
>240



I
Chemistry 558
Chemistry 559
Me


 


450
















H
230



I
Chemistry 563
Chemistry 564
Me


 


451
















H
230



I
Chemistry 566
Chemistry 569
Me


 


452
















H
140



I
Chemistry 573
Chemistry 574
Me


 


453
















H
210



I
Chemistry 578
CO2Me
CH2OMe


 


454
















H
230



I
Chemistry 583
CH2OH
CH2OMe


 


455
















H
[434, 436]



I
Chemistry 588
CH2Cl
CH2OMe


 


456
















H
232



I
Chemistry 593
Chemistry 594
CH2OMe


 


457
















H
230



I
Chemistry 598
Chemistry 599
CH2OH


 


458
















H
188



I
Chemistry 603
Chemistry 604
Me


 


459
















H
190



I
Chemistry 608
Chemistry 609
Me


 


460
















H
240



I
Chemistry 613
Chemistry 614
Me


 


461
















H
204



I
Chemistry 618
Chemistry 619
Me


 


462
















H
248



I
Chemistry 623
Chemistry 624
Me


 


463
















H
220



I
Chemistry 628
Chemistry 629
Me


 


464
















H
[583]



I
Chemistry 633
Chemistry 634
Me


 


465
















H
[576, 578]



I
Chemistry 638
Chemistry 639
Me


 


466
















H
[560, 562]



I
Chemistry 643
Chemistry 644
Me


 


467
















H
[542]



I
Chemistry 648
Chemistry 649
Me


 


468
















H
[558]



I
Chemistry 653
Chemistry 654
Me


 


469
















H
[462, 464]



I
CHemistry 658
Et
Me


 


470
















H
[485, 487]



I
Chemistry 663
Et
Me


 


471
















H
[380]



Chemistry 567
Chemistry 668
Et
Me


 


472
















H
[506]



I
Chemistry 673
Et
Me


 


473
















H
[507]



I
Chemistry 678
Et
Me


 


474
















H
165



H
Chemistry 683
CO2Me
CH2OMe


 


475
















H
[306]



H
Chemistry 688
CH2OH
CH2OMe


 


476
















H
142



I
Chemistry 683
CO2Me
CH2OMe


 


477
















H
198



I
Chemistry 698
CH2OH
CH2OMe


 


478
















H



I
Chemistry 703
CH2Cl
CH2OMe


 


479
















H
115



I
Chemistry 708
Chemistry 709
CH2OMe


 


480
















H
[487]



I
Chemistry 713
Chemistry 714
CH2OH


 


481
















H
230



I
Chemistry 718
Chemistry 719
Me


 


482
















H
168



I
Chemistry 723
Chemistry 724
Me


 


483
















H
[513]



I
Chemistry 728
Chemistry 729
Me


 


484
















H
200



I
Chemistry 733
Chemistry 734
Me


 


485
















H
[486]



I
Chemistry 738
Chemistry 739
Me


 


486
















H
220



I
Chemistry 743
Chemistry 744
Me


 


487
















H
174



I
Chemistry 748
Chemistry 749
Me


 


488
















H
204



I
Chemistry 753
Chemistry 754
Me


 


489
















H
>250



I
Chemistry 758
Chemistry 759
Me


 


490
















H
162



I
Chemistry 763
Chemistry 764
Me


 


491
















H
[600]



I
Chemistry 768
Chemistry 769
Me


 


492
















H
[500]



I
Chemistry 773
Chemistry 774
Me


 


493
















H
164



I
Chemistry 778
Chemistry 779
Me


 


494
















H
[513]



I
Chemistry 783
Chemistry 784
Me


 


495
















H
206



I
Chemistry 788
Chemistry 789
Me


 


496
















H
185



I
Chemistry 793
Chemistry 794
Me


 


497
















H
[460]



I
Chemitsyr 798
Chemistry 799
CH2OMe


 


498
















H
[498]



I
Chemistry 803
Chemistry 804
Me


 


499
















H
[495]



I
Chemistry 808
Chemistry 809
Me


 


500
















H
203



I
Chemistry 813
Chemistry 814
Me


 


501
















H
204



I
Chemistry 818
Chemistry 819
Me


 


502
















H
168



I
Chemistry 823
Chemistry 824
Me


 


503
















H
217



I
Chemistry 828
Chemistry 829
Me


 


504
















H
200



I
Chemistry 833
Chemistry 834
Me


 


505
















H



Me
Chemistry 838
CH2Cl
Me


 


506
















H
206



Me
Chemistry 843
Chemistry 844
Me


 


507
















H
170



Me
Chemistry 848
CO2Et
Me


 


508
















H
218



Me
Chemistry 853
CH2OH
Me


 


509
















H
200



Me
Chemistry 858
Chemistry 859
Me


 


510
















H
166



I
Chemistry 863
Chemistry 864
Me


 


511
















H
213



I
Chemistry 868
Chemistry 869


 


512
















H
[610]



I
Chemistry 873
Chemistry 874
Me


 


513
















H
[751]



I
Chemistry 878
CO2Et
Me


 


514
















H
[567]



I
Chemistry 883
Chemistry 884
Me


 


515
















H
[418, 420]



I
Chemistry 888
Et
Me


 


516
















H
[472]



I
Chemistry 893
Et
Me


 


517
















H
[621]



I
Chemistry 898
Chemistry 899
Me


 


518
















H
[416]



I
Chemistry 903
Et
Me


 


519
















H
[556]



I
Chemistry 908
Chemistry 909
Me


 


520
















H
[452, 454, 456]



I
Chemistry 913
Et
Me


 


521
















H
[434, 436]



I
Chemistry 918
Et
Me


 


522
















H
[476]



I
Chemistry 923
Et
Me


 


523
















H
[517]



I
Chemistry 928
Chemistry 929
Me


 


524
















H
[362]



Chemistry 932
Chemistry 933
Et
Me


 


525
















H
[361]



Chemistry 937
Chemistry 938
Et
Me


 


526
















H
[450]



I
Chemistry 943
Chemistry 944
Me


 


527
















H
[399]



I
Chemistry 948
Et
Me


 


528
















H
[381]



I
Chemistry 953
Et
Me


 


529
















H
[282]



I
Chemistry 958
Chemistry 959
Me


 


530
















H
210



I
Chemistry 963
Chemistry 964
Me


 


531
















H
144



I
Chemistry 968
Chemistry 969
Me


 


532
















H
[512]



I
Chemistry 973
CH2OH
Me


 


533
















H
[579



I
Chemistry 978
Chemistry 979
Me


 


534
















H
[469]



I
Chemistry 983
Chemistry 984
Me


 


535
















H
[485]



I
Chemistry 988
Chemistry 989
Me


 


536
















H
[380]



I
Chemistry 993
Et
Me


 


537
















H
[424]



I
Chemistry 998
Et
Me


 


538
















H
[494]



I
Chemistry 1003
Chemistry 1004
Me


 


539
















H
203



I
Chemistry 1008
Chemistry 1009
Me


 


540
















H
230



I
Chemistry 1013
Chemistry 1014
Me


 


541
















H
[510]



I
Chemistry 1018
Chemistry 1019
Me


 


542
















H
206



Me
Chemistry 1023
Chemistry 1024
Me


 


543
















H
>250



Me
Chemistry 1028
Chemistry 1029
Me


 


544
















H
[560, 562, 564]



I
Chemistry 1033
Chemistry 1034
Me


 


545
















H
248



I
Chemistry 1038
Chemistry 1039
Me


 


546
















H
100



I
Chemistry 1043
Chemistry 1044
Me


 


547
















H
220



I
Chemistry 1048
Chemistry 1049
Me


 


548
















H
[459]



I
Chemistry 1053
Et
Me


 


549
















H
[431]



I
Chemistry 1058
Et
Me


 


550
















H
[398]



I
Chemistry 1063
Et
Me


 


551
















H
[421]



I
Chemistry 1068
Et
Me


 


552
















H
[370]



I
Chemistry 1073
Et
Me


 


553
















H
[298]



H
Chemistry 1078
Et
Me


 


554
















H
[424]



I
Chemistry 1083
Et
Me


 


555
















H
[376, 378]



Br
Chemistry 1088
Et
Me


 


556
















H
[600]



I
Chemistry 1093
Et
Me


 


557
















H
[435]



I
Chemistry 1098
Et
Me


 


558
















H
194



I
Chemistry 1103
Chemistry 1104
Me


 


559
















H
146



I
Chemistry 1108
Chemistry 1109
Me


 


560
















H
168



I
Chemistry 1113
Chemistry 1114
Me


 


561
















H
>250



I
Chemistry 1118
Chemistry 1119
Me


 


562
















H



I
Chemistry 1123
Chemistry 1124
Me


 


563
















H
232



I
Chemistry 1128
Chemistry 1129
Me


 


564
















H
>250



I
Chemistry 1133
Chemistry 1134
Me


 


565
















H
235



H
Chemistry 1138
CO2Et
Chemistry 1140


 


566
















H
210



I
Chemistry 1143
Chemistry 1144
Me


 


567
















H
202



Vinyl
Chemistry 1148
Chemistry 1149
Me


 


568
















H
[330]



H
Chemistry 1153
Chemistry 1154
Me


 


569
















H
[302]



H
Chemistry 1158
CH2CH2CO2H
Me


 


570
















H
[371]



H
Chemistry 1163
Chemistry 1164
Me


 


571
















H
>250



I
Chemistry 1168
Chemistry 1169
Me


 


572
















H
230



I
Chemistry 1173
Chemistry 1174
Me


 


573
















H
249



I
Chemistry 1178
Chemistry 1179
Me


 


574
















H
>250



I
Chemistry 1183
Chemistry 1184
Me


 


575
















H
216



I
Chemistry 1188
Chemistry 1189
Me


 


576
















H
>250



I
Chemistry 1193
Chemistry 1194
Me


 


577
















H
[472]



I
Chemistry 1198
Et
Me


 


578
I








Me
H
[427]




Chemistry 3
Et


 


579
I








Me
H
[468]




Chemistry 8
Et


 


580
I








Me
H
[467]




Chemistry 13
Et


 


581
I








Me
H
[469]




Chemistry 18
Et


 


582
I








Me
H
[502]




Chemistry 23
Et


 


583
I








Me
H
[515]




Chemistry 28
Et


 


584
I








Me
H
[498]




Chemistry 33
Et


 


585
I








Me
H
180




Chemistry 38
Chemistry 39


 


586
I








Me
H
168




Chemistry 43
Chemistry 44


 


587
I








Me
H
236




Chemistry 48
Chemistry 49


 


588
I








Me
H
228




Chemistry 53
Chemistry 54


 


589
I








Me
H
>250




Chemistry 58
Chemistry 59


 


590
H








Me
H
[399]




Chemistry 63
Chemistry 64


 


591
I








Me
H
144




Chemistry 68
Chemistry 69


 


592
I








Me
H
>250




Chemistry 73
Chemistry 74


 


593
I








Me
H
192




Chemistry 78
Chemistry 79


 


594
I








Me
H
212




Chemistry 83
Chemistry 84


 


595
I








Me
H
>250




Chemistry 88
Chemistry 89


 


596
I








Me
H
[466]




Chemistry 93
Chemistry 94


 


597
I








Me
H
>250




Chemistry 98
Chemistry 99


 


598
Chemistry 102








Me
H
[227]




Chemistry 103
H


 


599
Chemistry 107








Me
H
[255]




Chemistry 108
H


 


600
Chemistry 112








Me
H
[244]




Chemistry 113
H


 


601
Chemistry 117








Me
H
[291]]




Chemistry 118
H


 


602
I








Me
H
[508]




Chemistry 123
Et


 


603
I








Me
H
[427]




Chemistry 128
Et


 


604
I








Me
H
[429]




Chemistry 133
Et


 


605
I








Me
H
178




Chemistry 138
Chemistry 139


 


606
I








Me
H
120




Chemistry 143
Chemistry 144


 


607
I








Me
H
>250




Chemistry 148
Chemistry 149


 


608
I








Me
H
[437]




Chemistry 153
Chemistry 154


 


609
I








Me
H
[439]




Chemistry 158
Chemistry 159


 


610
I








Me
H
[426]




Chemistry 163
Chemistry 164


 


611
I








Me
H
>250




Chemistry 168
Chemistry 169



























612
H








Me
H
[302]




Chemistry 173
CO2Et


 


613
Br








Me
H
[381]




Chemistry 178
CO2Et


 


614
Br








Me
H
[338, 340]




Chemistry 183
CH2OH


 


615
Br








Me
H




Chemistry 188
CH2Cl


 


616
Br








Me
H
>250




Chemistry 193
Chemistry 194


 


617
I








Me
H
>250




Chemistry 198
Chemistry 199


 


618
I








Me
H
[451]




Chemistry 203
Chemistry 204


 


619
I








Me
H
[513]




Chemistry 508
Chemistry 209


 


620
I








Me
H
[639]




Chemistry 213
Chemistry 214


 


621
I








Me
H
[456]




Chemistry 218
Chemistry 219


 


622
I








Me
H
[582]




Chemistry 223
Chemistry 224


 


623
I








Me
H
[428]




Chemistry 228
CH2CH2CO2H


 


624
I








Me
H
[554]




Chemistry 233
CH2CH2CO2H


 


626
I








Me
H
[529]




Chemistry 238
Chemistry 239


 


626
I








Me
H
[453]




Chemistry 243
Chemistry 244


 


627
I








Me
H
[481]




Chemistry 248
Chemistry 249


 


628
I








Me
H
[541]




Chemistry 253
Chemistry 254


 


629
I








Me
H
[510]




CHemistry 258
Chemistry 259


 


630
I








Me
H
[483]




Chemistry 263
Chemistry 264


 


631
I








Me
H
[478]




Chemistry 268
Chemistry 269


 


632
I








Me
H
[492]




Chemistry 273
Chemistry 274


 


633
I








Me
H
[586]




Chemistry 278
Chemistry 279


 


634
I








Me
H
[493]




Chemistry 283
Chemistry 284


 


635
I








Me
H
[536]




Chemistry 288
Chemistry 289


 


636
I








Me
H
[511]




Chemistry 293
Chemistry 294


 


637
I








Me
H
[523]




Chemistry 298
Chemistry 299


 


638
I








Me
H
[508]




Chemistry 303
Chemistry 304


 


639
I








Me
H
[584]




Chemistry 308
Chemistry 309


 


640
I








Me
H
[571]




Chemistry 313
Chemistry 314


 


641
I








Me
H
[484]




Chemistry 318
Et


 


642
I








Me
H
[498]




Chemistry 323
Et


 


643
I








Me
H
[510]




Chemistry 328
Et


 


644
I








Me
H
[545]




Chemistry 333
Et


 


645
I








Me
H
[514]




Chemistry 338
Et


 


646
I








Me
H
[546]




Chemistry 343
Et


 


647
I








Me
H
[497]




Chemistry 348
Et


 


648
I








Me
H
>250




Chemistry 353
Chemistry 354


 


649
I








Me
H
165




Chemistry 358
Chemistry 359


 


650
I








Me
H
181




Chemistry 363
Chemistry 364


 


651
I








Me
H
[497]




Chemistry 368
Et


 


652
I








Me
H
[515]




Chemistry 373
Et


 


653
I








Me
H
[443]




Chemistry 378
NHCO2Et


 


654
I








Me
H
[371]




Chemistry 383
Et


 


655
H








Me
H
[245]




Chemistry 388
Et


 


656
I








Me
H
[386]




Chemistry 393
Et


 


657
I








Me
H
[401]




Chemistry 398
Et


 


658
I








Me
H
[386]




Chemistry 403
Et


 


659
I








Me
H
[506]




Chemistry 408
Et


 


660
Br








Me
H
>250




Chemistry 413
Chemistry 414


 


661
Br








Me
H
>250




Chemistry 418
Chemistry 419


 


662
I








Me
H
>250




Chemistry 423
Chemistry 424


 


663
I








Me
H
[552]




Chemistry 428
Chemistry 429


 


664
I








Me
H
[483]




Chemistry 433
Chemistry 434


 


665
I








Me
H
[533]




Chemistry 438
Chemistry 439


 


666
I








Me
H
[559]




Chemistry 443
Chemistry 444


 


667
I








Me
H
[516]




Chemistry 448
Chemistry 449


 


668
I








Me
H
[516]




Chemistry 453
Chemistry 454


 


669
I








Me
H
[505]




Chemistry 458
Chemistry 459


 


670
I








Me
H
[497]




Chemistry 463
Chemistry 464


 


671
I








Me
H
[513]




Chemistry 468
Chemistry 469


 


672
I








Me
H
[588]




Chemistry 473
Chemistry 474


 


673
I








Me
H
[558]




Chemistry 478
Chemistry 479


 


674
I








Me
H
[465]




CHemistry 483
Chemistry 484


 


675
I








Me
H
[559]




Chemistry 488
Chemistry 489


 


676
I








Me
H
[521]




Chemistry 493
Chemistry 494


 


677
I








Me
H
[525]




Chemistry 498
Chemistry 499


 


678
I








Me
H
>250




CHemistry 503
Chemistry 504


 


679
I








Me
H
>250




Chemistry 508
Chemistry 509


 


680
I








Me
H
>250




Chemistry 513
Chemistry 514


 


681
H








Me
H
[392]




Chemistry 518
CO2Et


 


682
I








Me
H
[440]




Chemistry 523
Et


 


683
I








Me
H
[492]




Chemistry 528
Et


 


684
I








Me
H
[486]




Chemistry 533
Et


 


685
I








Me
H
[412]




Chemistry 538
Et


 


686
I








Me
H
[414]




Chemistry 543
Et


 


687
I








Me
H
[398]




Chemistry 548
Et


 


688
H








Me
H
[272]




Chemistry 553
Et


 


689
CO2Et








Me
H
[344]




Chemistry 558
Et


 


690
H








Me
H
[272]




Chemistry 563
Et


 


691
I








Me
H
[471]




Chemistry 568
Chemistry 569


 


692
I








Me
H
[531]




Chemistry 573
Et


 


693
I








Me
H
[468]




Chemistry 578
Chemistry 579


 


694
I








Me
H
[572]




Chemistry 583
Chemistry 584


 


695
I








Me
H
[544]




Chemistry 588
Chemistry 589


 


696
I








Me
H
[531]




Chemistry 593
Chemistry 594


 


697
I








Me
H
[482]




Chemistry 598
Chemistry 599


 


698
I








Me
H
[557]




Chemistry 603
Chemistry 604


 


699
I








Me
H
[598, 600, 602]




Chemistry 608
Chemistry 609


 


700
I








Me
H
[548]




Chemistry 613
Chemistry 614


 


701
I








Me
H
[496]




Chemistry 618
Chemistry 619


 


702
I








Me
H
[532]




Chemistry 623
Chemistry 624


 


703
I








Me
H
[544]




Chemistry 628
Chemistry 629


 


704
I








Me
H
>250




Chemistry 633
Chemistry 634


 


705
I








Me
H
[530]




Chemistry 638
Chemistry 639


 


706
I








Me
H
[450]




Chemistry 643
Chemistry 644


 


707
I








Me
H
[542, 544]




Chemistry 648
Chemistry 649


 


708
I








Me
H
[514, 516]




Chemistry 653
Chemistry 654


 


709
I








Me
H
[528, 530]




Chemistry 658
Chemistry 659


 


710
I








Me
H
[513]




Chemistry 663
Chemistry 664


 


711
I








Me
H
[438]




Chemistry 668
Chemistry 669


 


712
I








Me
H
[451]




Chemistry 673
Chemistry 674


 


713
I








Me
H
[437]




Chemistry 678
Chemistry 679


 


714
I








Me
H
[465]




Chemistry 683
Chemistry 684


 


715
I








Me
H
[513]




Chemistry 688
Chemistry 689


 


716
I








Me
H
[530]




Chemistry 693
Chemistry 694


 


717
I








Me
H
[512]




Chemistry 698
Chemistry 699


 


718
I








Me
H
[450]




Chemistry 703
Chemistry 704


 


719
I








Me
H
[466]




Chemistry 708
Chemistry 709


 


720
I








Me
H
[512]




Chemistry 713
Chemistry 714


 


721
I








Me
H
[464]




Chemistry 718
Chemistry 719


 


722
I








Me
H
[478]




Chemistry 723
Chemistry 724


 


723
I








Me
H
[450]




Chemistry 728
Chemistry 729


 


724
I








Me
H
[526]




Chemistry 733
Chemistry 734


 


725
I








Me
H
[537]




Chemistry 738
Chemistry 739


 


726
I








Me
H
[537]




Chemistry 743
Chemistry 744


 


727
I








Me
H
>250




Chemistry 748
Chemistry 749


 


728
I








Me
H
164




Chemistry 753
Chemistry 754


 


729
H








Me
H
[254]




Chemistry 758
Et


 


730
I








Me
H
[464, 466]




Chemistry 763
Et


 


731
H








Me
H
[338, 340]




Chemistry 768
Et


 


732
H








Me
H
[285]




Chemistry 773
Et


 


733
I








Me
H
[450, 451]




Chemistry 778
Et


 


734
I








Me
H
[371]




Chemistry 783
NH2


735
I








Me
H
[475]




Chemistry 788
Chemistry 789


 


736
I








Me
H
[491]




Chemistry 793
Chemistry 794


 


737
I








Me
H
[399]




Chemistry 798
NMe2


 


738
CO2Et








Me
H
[428]




Chemistry 803
Et


 


739
I








Me
H
[461]




Chemistry 808
Chemistry 809


 


740
I








Me
H
248




Chemistry 813
Chemistry 814


 


741
I








Me
H
>250




Chemistry 818
Chemistry 819


 


742
I








Me
H
[486]




Chemistry 823
Chemistry 824


 


743
I








Me
H
[504, 506, 508]




Chemistry 828
Chemistry 829


 


744
I








Me
H
[513]




Chemistry 833
Chemistry 834


 


745
I








Me
H
[562]




Chemistry 838
Chemistry 839


 


746
I








Me
H
[563]




Chemistry 843
Chemistry 844


 


747
I








Me
H
[527]




Chemistry 848
Chemistry 849


 


748
I








Me
H
[563, 565]




Chemistry 853
Chemistry 854


 


749
I








Me
H
[486]




Chemistry 858
Chemistry 859


 


750
I








Me
H
[515]




Chemistry 863
Chemistry 864


 


751
I








Me
H
[500]




Chemistry 868
Chemistry 869


 


752
I








Me
H
[499]




Chemistry 873
Chemistry 874


 


753
I








Me
H
[514]




Chemistry 878
Chemistry 879


 


754
I








Me
H
>250




Chemistry 883
Chemistry 884


 


755
I








Me
H
[466]




Chemistry 888
Et


 


756
I








Me
H
[478]




Chemistry 893
Chemistry 894


 


757
I








Me
H
>250




Chemistry 898
Chemistry 899


 


758
I








Me
H
>250




Chemistry 903
Chemistry 904


 


759
I








Me
H
213




Chemistry 908
Chemistry 909


 


760
I








Me
H
207




Chemistry 913
Chemistry 914


 


761
I








Me
H
>250




Chemistry 918
Chemistry 919


 


762
I








Me
H
[437]




Chemistry 923
Et


 


763
I








Me
H
[458]




Chemistry 928
Et


 


764
Vinyl








Me
H
[321]




Chemistry 933
Et


 


765
H








Me
H
[286]




Chemistry 938
Et


 


766
I








Me
H
[429]




Chemistry 943
Et


 


767
H








Me
H
[284]




Chemistry 948
Et


 


768
CO2Et








Me
H
[388]




Chemistry 953
Et


 


769
H








Me
H
[316]




Chemistry 958
Et


 


770
I








Me
H
[442]




Chemistry 963
Et


 


771
CO2Et








Me
H
[380, 382]




Chemistry 968
Et


 


772
H








Me
H
[308, 310]




Chemistry 973
Et


 


773
I








Me
H
>250




Chemistry 978
Chemistry 979


 


774
I





Me
H
[481]




Chemistry 983
Chemistry 984


 


775
I








Me
H
[545]




Chemistry 988
Chemistry 989


 


776
I








Me
H
[476]




Chemistry 993
Chemistry 994


 


777
I








Me
H
[484]




Chemistry 998
Chemistry 999


 


778
I








Me
H
[588]




Chemistry 1003
Chemistry 1004


 


779
I








Me
H
[560]




Chemistry 1008
Chemistry 1009


 


780
I








Me
H
[547]




Chemistry 1013
Chemistry 1014


 


781
I








Me
H
[591]




Chemistry 1018
Chemistry 1019


 


782
I








Me
H
[580]




Chemistry 1023
Chemistry 1024


 


783
I








Me
H
[546]




Chemistry 1028
Chemistry 1029


 


784
I








Me
H
[574]




Chemistry 1033
Chemistry 1034


 


785
I








Me
H
[614, 616, 618]




Chemistry 1038
Chemistry 1039


 


786
I








Me
H
[564]




Chemistry 1043
Chemistry 1044


 


787
I








Me
H
[548]




Chemistry 1048
Chemistry 1049


 


788
I








Me
H
[552]




Chemistry 1053
Chemistry 1054


 


789
I








Me
H
[560]




Chemistry 1058
Chemistry 1059


 


790
I








Me
H
[586]




Chemistry 1063
Chemistry 1064


 


791
I








Me
H
[530, 532]




Chemistry 1068
Chemistry 1069


 


792
I








Me
H
[604]




Chemistry 1073
Chemistry 1074


 


793
I








Me
H
[580]




Chemistry 1078
Chemistry 1079


 


794
I








Me
H
[493]




Chemistry 1083
Chemistry 1084


 


795
H








Me
H
[260]




Chemistry 1088
CH2OH


 


796
H








Me
H




Chemistry 1093
CH2Cl


 


797
H








Me
H
>250




Chemistry 1098
Chemistry 1099


 


798
I








Me
H
245




Chemistry 1103
Chemistry 1104


 


799
I








Me
H
>250




Chemistry 1108
Chemistry 1109


 


800
I








Me
H
232




Chemistry 1113
Chemistry 1114


 


801
I








Me
H
224




Chemistry 1118
Chemistry 1119


 


802
I








Me
H
184




Chemistry 1123
Chemistry 1124


 


803
I








me
H
>250




Chemistry 1128
Chemistry 1129


 


804
I








Me
H
>250




Chemistry 1133
Chemistry 1134


 


805
I








Me
H
>250




Chemistry 1138
Chemistry 1139


 


806
I








Me
H
>250




Chemistry 1143
Chemistry 1144


 


807
I








Me
H
250




Chemistry 1148
Chemistry 1149


 


808
I








Me
H
198




Chemistry 1153
Chemistry 1154


 


809
NO2








Me
H
[363]




Chemistry 1158
CO2Et


 


810
NH2








Me
H
[317]




Chemistry 1163
CO2Et


 


811
NMe2








Me
H
[361]




Chemistry 1168
CO2Et


 


812
NMe2








Me
H
146




Chemistry 1173
CH2OH


 


813
NMe2








Me
H
[337]




Chemistry 1178
CH2Cl


 


814
NMe2








Me
H
178




Chemistry 1183
Chemistry 1184


 


815
NMe2








Me
H
168




Chemistry 1188
Chemistry 1189


 


816
I








Me
H
[493]




Chemistry 1193
Chemistry 1194


 


817
I








Me
H
[493]




Chemistry 1198
Chemistry 1199


 


818
I








Me
H
>250




Chemistry 1203
Chemistry 1204


 


819
I








Me
H
>250




Chemistry 1208
Chemistry 1209


 


820
I








Me
H
[509]




Chemistry 1213
Chemistry 1214


 


821
I








Me
H
>250




Chemistry 1218
Chemistry 1219


 


822
I








Me
H
>250




Chemistry 1223
Chemistry 1224


 


823
I








Me
H
>250




Chemistry 1228
Chemistry 1229


 


824
I








Me
H
>250




Chemistry 1233
Chemistry 1234


 


825
I








Me
H
>250




Chemistry 1238
Chemistry 1239









A rapid, sensitive and automated assay procedure was used for the in vitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cell line, MT-4, which was previously shown (Koyanagi et al., Int. J. Cancer, (1985), 36, 445–451) to be highly susceptible to and permissive for HIV infection, served as the target cell line. Inhibition of the HIV-induced cytopathic effect was used as the end point. The viability of both HIV- and mock-infected cells was assessed spectrophotometrically via the in situ reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The 50% cytotoxic concentration (CC50 in μM) was defined as the concentration of compound that reduced the absorbance of the mock-infected control sample by 50%. The percent protection achieved by the compound in HIV-infected cells was calculated by the following formula:




  
    
      
        (
        
          OD
          T
        
        )
      
      HIV
    
    -
    
      
        (
        
          OD
          C
        
        )
      
      HIV
    
  
  
    
      
        (
        
          OD
          C
        
        )
      
      MOCK
    
    -
    
      
        (
        
          OD
          C
        
        )
      
      HIV
    
  




expressed in %,

whereby (ODT)HIV is the optical density measured with a given concentration of the test compound in HIV-infected cells; (ODC)HIV is the optical density measured for the control untreated HIV-infected cells; (ODC)MOCK is the optical density measured for the control untreated mock-infected cells; all optical density values were determined at 540 nm. The dose achieving 50% protection according to the above formula was defined as the 50% inhibitory concentration (IC50 in μM). The ratio of CC50 to IC50 was defined as the selectivity index (SI). The compounds of formula (I) were shown to inhibit HIV-1 effectively. Particular IC50, CC50 and SI values are listed in Table 2 hereinbelow.















TABLE 2







N°
IC50(μm)
c
SI
c
CC50(μm)























242
0,0006
>
158489
>
100



255
0,0006
>
15849
>
10



684
0,0008
>
125893
>
100



43
0,0010

10000

10



264
0,0010
>
10000
>
10



470
0,0010

12589

13



483
0,0010
>
100000
>
100



551
0,0010

12589

13



124
0,0013
>
7943
>
10



249
0,0013
>
25119
>
32



298
0,0013
>
7943
>
10



326
0,0013

7943

10



375
0,0013
>
79433
>
100



589
0,0013
>
7943
>
10



606
0,0013

15849

20



133
0,0016
>
6310
>
10



241
0,0016
>
63096
>
100



253
0,0016
>
6310
>
10



306
0,0016
>
19953
>
32



328
0,0016
>
63096
>
100



370
0,0016
>
63096
>
100



662
0,0016
>
63096
>
100



426
0,0016

39811

63



46
0,0020
>
50119
>
100



105
0,0020
>
5012
>
10



234
0,0020

5012

10



254
0,0020
>
15849
>
32



256
0,0020
>
5012
>
10



272
0,0020

12589

25



284
0,0020
>
5012
>
10



296
0,0020

12589

25



319
0,0020
>
50119
>
100



574
0,0020
>
50119
>
100



618
0,0020

25119

50



650
0,0020
>
50119
>
100



83
0,0025

3162

8



88
0,0025
>
39811
>
100



108
0,0025

19953

50



109
0,0025

12589

32



115
0,0025

3162

8



277
0,0025
>
39811
>
100



286
0,0025
>
12589
>
32



299
0,0025

32

0



713
0,0025
>
39811
>
100



45
0,0032
>
31623
>
100



85
0,0032
>
31623
>
100



86
0,0032
>
31623
>
100



231
0,0032

3162

10



409
0,0032

12589

40



244
0,0040
>
25119
>
100



297
0,0040
>
7943
>
32



250
0,0050

5012

25



257
0,0050
>
6310
>
32



307
0,0050
>
6310
>
32



324
0,0050

6310

32



81
0,0063

1995

13



92
0,0063
>
5012
>
32



140
0,0063
>
1585
>
10



143
0,0063
>
1585
>
10



217
0,0063
>
1585
>
10



221
0,0063
>
3162
>
20



230
0,0063

1259

8



232
0,0063
>
5012
>
32



245
0,0063
>
15849
>
100



309
0,0063

1585

10



321
0,0063
>
15849
>
100



322
0,0063
>
15849
>
100



547
0,0063
>
15849
>
100



31
0,0079
>
12589
>
100



218
0,0079
>
1259
>
10



222
0,0079

251

2



700
0,0079
>
1000
>
8



314
0,0079
>
3981
>
32



701
0,0100

6310

63



8
0,0100
>
10000
>
100



99
0,0100
>
10000
>
100



121
0,0100
>
10000
>
100



219
0,0100
>
3162
>
32



233
0,0100
>
1000
>
10



694
0,0100

39811

63



280
0,0100

2512

25



696
0,0158
>
2512
>
40

## Claims

1. 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.

2. A compound according to claim 1 wherein
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; or aryl;
R2 is selected from hydrogen; formyl; cyano; azido; hydroxy; oxiranyl; amino; mono- or di(C1-4alkyl)amino; formylamino; 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, N-hydroxy-imino, aryl or Het2; 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; 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, C1-6alkyloxy, C1-6alkylthio, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, 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, C1-6alkyloxy-carbonylamino, 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, 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 CH2 or N, and A2 being CH2, NR13, S or O, provided that when A1 is CH2 then A2 is other than CH2, said radical (c-1) and (c-2) being optionally substituted with one or two substituents each independently selected from H, C1-6alkyl, C1-6alkyloxy, hydroxy C1-4alkyl, C1-6alkyloxycarbonyl, C1-6alkyloxycarbonylC1-4alkyl, aminoC1-6alkyl, carbonyl, hydroxy, cyano, 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)](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, C1-6alkyloxyC1-6alkylthioC1-6alkylcarbonyl, 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(C1-6amino, 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(CC1-4alkylthioC1-4alkyl)amino, mono- or di(Het2CC1-4alkyl)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 C1-4 alkyl;
Het1 and Het2 each independently are a heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexahydropyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl or 2-oxo-1,2-dihydro-quinolinyl, 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;
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 or oxazolyl;
aryl is phenyl optionally substituted with one, two or three substituents each independently selected from halo; hydroxy; carboxyl; cyano; formyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; mono- or di(C1-4alkyl)aminocarbonylamino; C1-4alkyl-S(═O)2—NH—; C1-6alkyloxy; C1-6alkyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxycarbonyl, C1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het5; C2-6alkenyl 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; 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 or phenyloxy.

3. A compound according to claim 1 wherein
Q is halo;
X is (a-2) with q and r being 0 and Z being O, S or SO; R1 is phenyl optionally substituted with one, two or three substituents each independently selected from halo; hydroxy; carboxyl; cyano; formyl; nitro; amino; mono- or di(C1-6alkyl)amino; C1-4alkylcarbonylamino; mono- or di(C1-4alkyl)aminocarbonylamino; C1-4alkyl-S(O)2—NH—; C1-6alkyloxy; C1-6alkyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxycarbonyl, C1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het5; C2-6alkenyl 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; C1-6alkynyl 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 or phenyloxy;
R2 is selected from formyl; C1-6alkyloxycarbonylalkyl; Het2; Het2C1-6alkyl; C1-6alkylthio; C1-6alkyl optionally substituted with one or two substituents each independently selected from hydroxy or halo;
R3 is selected from formyl or C1-6alkyl optionally substituted with one or two C1-6alkyloxy; and
R4 is hydrogen.

4. A compound as according to claim 1 wherein Q is iodo.

5. A compound according to claim 1 wherein Q is iodo, X—R1 is a 3,5-dimethylphenylthio or a 3,5-dimethylphenyloxy and R2 is a hydroxymethyl or a N-morpholinomethyl, or a 3-phenylpropyl or a furan-2-yl-methylthiomethyl.

6. A compound according to claim 1 wherein Q is iodo, X—R1 is a 3-(2-cyano-vinyl)-5-iodophenyloxy or 5-bromo-3-(2-cyano-vinyl) and R2 is ethyl.

7. A compound according to claim 1 wherein the compounds are listed in the following table;
















No
Y
Q
X–R1
R2
R3
R4





















8
O
I








Me
H


 


31
O
I








Me
H


 


43
O
I








Me
H


 


45
O
I








Me
H


 


46
O
I








Me
H


 


81
O
I




Et
Me
H


 


83
O
I




Et
Me
H


 


85
O
Br








Me
H


 


86
O
I








Me
H


 


88
O
I




Et
Me
H


 


92
O
I








Me
H


 


99
O
I








Me
H


 


105
O
I




Et




H


 


108
O
I




Et
Me
H


 


109
O
I




Et
Me
H


 


115
O
I




Et
Me
H


 


121
O
I




Et
Me
H


 


124
O
I








Me
H


 


133
O
I




Et
CH2OH
H


 


140
O
I




CH═CHCN
Me
H


 


143
O
I








Me
H


 


217
O
I




Et




H


 


218
O
I








Me
H


 


219
O
I








Me
H


 












221
O
I








H


 


222
O
I








H


 













232
O
I








Me
H


 


233
O
I








Me
H


 


241
O
I








Me
H


 


242
O
I








Me
H


 


244
O
I








Me
H


 


245
O
I








Me
H


 


249
O
I




2-methoxyethyl
Me
H


 


250
O
I








Me
H


 


253
O
I








Me
H


 


254
O
I








Me
H


 


255
O
I








Me
H


 


256
O
I








H
H


 


257
O
I




CH2OH
Me
H


 


264
O
I




2-methoxyethyl
Me
H


 


284
O
Br




Et
Me
H


 


286
O
I




Et
Me
H


 


296
O
I




Et
Me
H


 


297
O
I




Et
Me
H


 


298
O
I




Et
Me
H


 


299
O
I




Et
Me
H


 


306
O
I




Et
Me
H


 


307
O
I




Et
Me
H


 


309
O
I




Et
Me
H


 


314
O
I




Et
H
H


 


319
O
I




Et
Me
H


 


321
O
I




Et
Me
H


 


322
O
I




Et
Me
H


 


326
O
I




Et
Me
H


 


328
O
I
OPh
Et
Me
H


 


370
O
I








Me
H


 


375
O
I








Me
H


 


426
O
I




Et
Me
H


 


470
O
I




Et
Me
H


 


483
O
I








Me
H


 


547
O
I








Me
H


 


551
O
I




Et
Me
H


 


574
O
I








Me
H


 


589
O
I








Me
H


 


606
O
I








Me
H


 


618
O
I








Me
H


 


650
O
I








Me
H


 


662
O
I








Me
H


 


684
O
I




Et
Me
H


 


694
O
I








Me
H


 


696
O
I








Me
H


 


700
O
I








Me
H


 


701
O
I








Me
H


 


709
O
I








Me
H


 


713
O
I








Me
H

8. A method for treating subjects suffering from Human Immuno Deficiency Virus infection by administering a therapeutically effective amount of a compound according to claim 1.

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to claim 1.