# Patent

## Title
Substituted N-heterocyclic compounds and their use as dopamine D3 receptor ligands

## Abstract

The invention relates to substituted N-heterocyclic compounds of general formula (I.A)




and to the tautomers of the compounds the physiologically acceptable salts of the compounds and the physiologically acceptable salts of the tautomers of the compounds. The invention also relates to the use of these compounds and their pharmacologically acceptable salts in the production of a pharmaceutical agent for treating diseases that respond to the influence exerted by dopamine D3 receptor ligands, especially for treating diseases of the central nervous system, especially schizophrenia and/or depression.

## Background
The present invention relates to novel substituted N-heterocyclic compounds. These compounds have valuable therapeutic properties and are suitable in particular for the treatment of disorders which respond to modulation of the dopamine D3 receptor.
Neurons receive their information inter alia via G protein-coupled receptors. There are numerous substances which exert their effect via these receptors. One of these is dopamine. Confirmed findings about the presence of dopamine and its physiological function as neurotransmitter have been published. Disturbances in the dopaminergic transmitter system result in disorders of the central nervous system which include, for example, schizophrenia, depression or Parkinson's disease. These and other disorders are treated with medicaments which interact with the dopamine receptors.
Until 1990, two subtypes of dopamine receptors were clearly defined pharmacologically, namely the D1 and D2 receptors. More recently, a third subtype has been found, namely the D3 receptor, which appears to mediate some effects of antipsychotics and antiparkinsonian drugs (J. C. Schwartz et al., The Dopamine D3 Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging 1998, 12, 495-514, J. N. Joyce, Pharmacology and Therapeutics 2001, 90, pp. 231-259 “The Dopamine D3-Receptor as a Therapeutic Target for Antipsychotic and Antiparkinsonian Drugs”).
Dopamine receptors are now divided into two families. Firstly the D2 group consisting of D2, D3 and D4 receptors, and secondly the D1 group consisting of D1 and D5 receptors. Whereas D1 and D2 receptors are widespread, the expression of D3 receptors by contrast appears to be regioselective. Thus, these receptors are preferentially found in the limbic system, the projecting regions of the mesolimbic dopamine system, especially in the nucleus accumbens, but also in other regions such as amygdala. Because of this comparatively regioselective expression, D3 receptors are regarded as a target with few side effects, and it is assumed that a selective D3 ligand ought to have the properties of known antipsychotics but not their dopamine D2 receptor-mediated neurological side effects (P. Sokoloff et al., Localization and Function of the D3 Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D3) as a Target for Neuroleptics, Nature, 347, 146 (1990)).
Pyrimidine compounds having dopamine D3 receptor affinity are disclosed in WO 03/002543 and WO 96/02519. Some of these compounds exhibit high affinities for the D3 receptor. They are therefore proposed for the treatment of disorders of the central nervous system. However, the selectivity in relation to other receptors is unsatisfactory.
PCT/EP04/002609 relates to pyrimidinones, and the earlier patent application DE 102004027359.6 relates to pyridinones, each of which binds with high selectivity to the dopamine D3 receptor.
There is a need for further compounds which show very high affinity for the D3 receptor and moreover bind with high selectivity to this receptor. The invention is therefore based on the object of providing compounds which act as selective dopamine D3 receptor ligands.
This object is achieved by substituted N-heterocyclic compounds of the general formula (I)




in which

    Ar is phenyl, pyridinone, pyrimidinone or a 5- or 6-membered heteroaromatic radical which has 1 N atom as ring member and 0, 1, 2 or 3 further heteroatoms selected independently of one another from O, S and N as ring members;
    
        where Ar is optionally substituted by 1, 2 or 3 groups Ra which are selected independently of one another from CN, NO2, halogen, OR3, NR4R5, C(O)NR4R5, O—C(O)NR4R5, SR6, SOR6, SO2R6, SO2NR4R5, COOR7, O—C(O)R8, COR8, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl; where C1-C6-alkyl and C2-C6-alkenyl are optionally substituted by 1, 2 or 3 radicals which are selected independently of one another from halogen, OR3, NR4R5, C(O)NR4R5, O—C(O)NR4R5, SR6, SOR6, SO2R6, SO2NR4R5, COOR7, O—C(O)R8, COR8, C3-C6-cycloalkyl, phenyl and 4- to 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N; where phenyl and heterocyclyl in turn may be substituted by one or two radicals which are selected independently of one another from C1-C4-alkyl, C1-C4-alkoxy, NR4R5, OH, CN, C1-C2-fluoroalkyl and halogen; and
        where Ar may carry as substituent Ra1 also a phenyl radical or a 4- to 6-membered heterocyclyl radical which has 1, 2, 3 or 4 heteroatoms selected independently of one another from O, S and N as ring members; where the phenyl radical and the heterocyclyl radical is optionally substituted by 1, 2, 3 or 4 groups Ra selected independently of one another;
    
    
    A1 is a 3- to 6-membered hydrocarbon chain which may have a double bond or a triple bond and/or a C1-C4-alkyl group and/or a group Z which is selected from O, S, C(O), NR3, C(O)NR3, NR3C(O), OC(O) and C(O)O;
    X is CH or N;
    Y is CH2 or CH2CH2; or
    X—Y together are C═CH, C═CH—CH2 or CH—CH═CH; and
    A2 is a 1- to 2-membered hydrocarbon chain which may have 1 or 2 methyl groups as substituents, in which 1 carbon atom may be replaced by a carbonyl group;
    Q is 5- or 6-membered carbocyclyl or heterocyclyl having 1, 2 or 3 heteroatoms selected from O, N and S;
    
        where carbocyclyl and heterocyclyl may each be completely saturated, partly unsaturated or aromatic, and may have 1, 2 or 3 substituents which are selected independently of one another from
        C1-C6-alkyl which is optionally substituted one or more times by OH, C1-C4-alkoxy, halogen or phenyl which may in turn carry 1, 2 or 3 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, NR4R5, OH, CN, C1-C2-fluoroalkyl and halogen;
        C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C4-C10-bicycloalkyl, C6-C10-tricycloalkyl, where the last five groups mentioned may optionally be substituted by halogen or C1-C4-alkyl;
        halogen, CN, OR3, NR4R5, NO2, SR6, SO2R6, SO2NR4R5, COOR7, COR8;
        phenyl, 5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, where phenyl and heterocyclyl optionally carry 1 or 2 substituents which are selected independently of one another from C1-C4-alkyl, C1-C4-alkoxy, NR4R5, OH, CN, C1-C2-fluoroalkyl and halogen; and where 2 substituents bonded to adjacent C atoms of the 5- or 6-membered carbocyclyl or heterocyclyl may together be C3- or C4-alkylene, or together with the C atoms to which they are bonded may be a fused, unsaturated 4-, 5- or 6-membered carbocycle or a 4-, 5- or 6-membered heterocycle having 1 or 2 heteroatoms selected from O, N and S as ring members;
    
    
    R3, R4, R5, R6, R7, R8 are independently of one another H, C1-C6-alkyl which is optionally substituted by OH, C1-C4-alkoxy or phenyl which in turn may have 1, 2 or 3 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, NR4R5, OH, CN, C1-C2-fluoroalkyl or halogen, or COR11, C1-C6-haloalkyl or phenyl which in turn may have 1, 2 or 3 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, NR4R5, OH, CN, C1-C2-fluoroalkyl or halogen; where
    R5 may also be a group COR9; and where
    R4 with R5 also together with the nitrogen atom to which they are bonded may form a 4-, 5- or 6-membered, saturated or unsaturated heterocycle which may have a further heteroatom selected from O, S and NR10 as ring member, where the heterocycle is unsubstituted or carries one or two C1-C4-alkyl groups;
    R9 is hydrogen, C1-C4-alkyl or phenyl which is optionally substituted by 1, 2 or 3 radicals which are selected independently of one another from C1-C4-alkyl, C1-C4-alkoxy, NR4R5, CN, C1-C2-fluoroalkyl or halogen;
    R10 is hydrogen or C1-C4-alkyl, and
    R11 is H, C1-C6-alkyl which is optionally substituted by OH, C1-C4-alkoxy or phenyl which in turn may have 1, 2 or 3 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, NR4R5, OH, CN, C1-C2-fluoroalkyl or halogen, or C1-C6-haloalkyl or phenyl which in turn may have 1, 2 or 3 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, NR4R5, OH, CN, C1-C2-fluoroalkyl or halogen;

and the tautomers of the compounds I, the physiologically acceptable salts of the compounds I and the physiologically acceptable salts of the tautomers of the compounds I.



The present invention therefore relates to the compounds of the general formula I, their tautomers and the physiologically tolerated salts of the compounds I and the physiologically acceptable salts of the tautomers of I.
The present invention additionally relates to a pharmaceutical composition comprising at least one pyri(mi)dinone compound of the formula I, the tautomers thereof, the physiologically acceptable acid addition salts thereof and/or the physiologically acceptable acid addition salts of the tautomers and, where appropriate, one or more physiologically acceptable carriers.
The present invention also relates to the use of a substituted N-heterocyclic compound of the formula I and of the tautomers thereof, and of the salts thereof or the salts of its tautomers for producing a pharmaceutical composition for the treatment of disorders which respond to modulation by dopamine D3 receptor ligands.
The disorders which respond to modulation by dopamine D3 receptor ligands include for example impairments and disorders of the central nervous system, especially schizophrenia and depression, Parkinsonism and epilepsy, also addictive disorders and renal functional impairments.
The aforementioned indications are treated by using according to the invention at least one compound of the general formula I with the meanings mentioned at the outset. If the compounds of the formula I have one or more centers of asymmetry, it is also possible to employ mixtures of enantiomers, especially racemates, mixtures of diastereomers, mixtures of tautomers, but preferably the respective substantially pure enantiomers, diastereomers and tautomers.
It is likewise possible to use physiologically acceptable salts of the compounds of the formula I, especially acid addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid and benzoic acid. Further acids which can be used are described in Fortschritte der Arzneimittelforschung, volume 10, pages 224 et seq., Birkhäuser Verlag, Basle and Stuttgart, 1966.
Halogen here and hereinafter is fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.
Cn-Cm-Alkyl (also in radicals such as alkoxy, alkylthio, alkylamino, etc.) means a straight-chain or branched alkyl group having n to m carbon atoms, e.g. 1 to 6 carbon atoms and in particular 1 to 4 carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, neopentyl, n-hexyl and the like.
The alkyl group may have one or more substituents which are selected independently of one another from halogen, OR3, NR4R5, C(O)NR4R5, O—C(O)NR4R5, SR6, SOR6, SO2R6, SO2NR4R5, COOR7, O—C(O)R8, COR8, C3-C6-cycloalkyl, 4-, 5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, and phenyl, where phenyl and heterocyclyl may be substituted by one or two radicals which are selected independently of one another from C1-C4-alkyl, C1-C4-alkoxy, NR4R5, CN, OH, C1-C2-fluoroalkyl or halogen.
In the case of a halogen substituent, the alkyl group may include in particular 1, 2, 3 or 4 halogen atoms, specifically fluorine or chlorine, which may be located on one or more C atoms, preferably in the α or ω position. Groups of this type are also referred to hereinafter as haloalkyl. Preferred haloalkyl is C1-C2-fluoroalkyl or C1-C2-fluorochloroalkyl, in particular CF3, CHF2, CF2Cl, CH2F, CH2CF3.
In the case of hydroxy-substituted alkyl, the alkyl group has in particular one hydroxy group, such as, for example, hydroxymethyl, 2-hydroxyeth-1-yl, 2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-1-yl, 3-hydroxybut-1-yl, 4-hydroxybut-1-yl, 1-hydroxybut-2-yl, 1-hydroxybut-3-yl, 2-hydroxybut-3-yl, 1-hydroxy-2-methylprop-3-yl, 2-hydroxy-2-methylprop-3-yl or 2-hydroxymethylprop-2-yl, in particular 2-hydroxyethyl.
In the case of alkoxy-substituted alkyl, the alkyl group has in particular one alkoxy substituent. These radicals are referred to, depending on the number of carbon atoms, also as Cn-Cm-alkoxy-Cn-Cm-alkyl and are, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-ethoxyethyl, 1-ethoxyethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, (1-methylpropoxy)methyl, (2-methylpropoxy)methyl, CH2—OC(CH3)3, 2-(methoxy)ethyl, 2-(ethoxy)ethyl, 2-(n-propoxy)ethyl, 2-(1-methylethoxy)ethyl, 2-(n-butoxy)ethyl, 2-(1-methylpropoxy)ethyl, 2-(2-methylpropoxy)ethyl, 2-(1,1-dimethylethoxy)ethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl, 2-(n-propoxy)propyl, 2-(1-methylethoxy)propyl, 2-(n-butoxy)propyl, 2-(1-methylpropoxy)propyl, 2-(2-methylpropoxy)propyl, 2-(1,1-dimethylethoxy)propyl, 3-(methoxy)propyl, 3-(ethoxy)propyl, 3-(n-propoxy)propyl, 3-(1-methylethoxy)propyl, 3-(n-butoxy)propyl, 3-(1-methylpropoxy)propyl, 3-(2-methylpropoxy)propyl, 3-(1,1-dimethylethoxy)propyl, 2-(methoxy)butyl, 2-(ethoxy)butyl, 2-(n-propoxy)butyl, 2-(1-methylethoxy)butyl, 2-(n-butoxy)butyl, 2-(1-methylpropoxy)butyl, 2-(2-methylpropoxy)butyl, 2-(1,1-dimethylethoxy)butyl, 3-(methoxy)butyl, 3-(ethoxy)butyl, 3-(n-propoxy)butyl, 3-(1-methylethoxy)butyl, 3-(n-butoxy)butyl, 3-(1-methylpropoxy)butyl, 3-(2-methylpropoxy)butyl, 3-(1,1-dimethylethoxy)butyl, 4-(methoxy)butyl, 4-(ethoxy)butyl, 4-(n-propoxy)butyl, 4-(1-methylethoxy)butyl, 4-(n-butoxy)butyl, 4-(1-methylpropoxy)butyl, 4-(2-methylpropoxy)butyl or 4-(1,1-dimethylethoxy)butyl, preferably methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl or 3-(methoxy)propyl, 3-(ethoxy)propyl.
Cycloalkyl is in particular C3-C6-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term “alkylene” comprises in principle straight-chain or branched radicals having preferably 3 to 10 and particularly preferably 3 to 8 carbon atoms, such as prop-1,2-ylene, prop-1,3-ylene, but-1,2-ylene, but-1,3-ylene, but-1,4-ylene, 2-methylprop-1,3-ylene, pent-1,2-ylene, pent-1,3-ylene, pent-1,4-ylene, pent-1,5-ylene, pent-2,3-ylene, pent-2,4-ylene, 1-methylbut-1,4-ylene, 2-methylbut-1,4-ylene, hex-1,3-ylene, hex-2,4-ylene, hex-1,4-ylene, hex-1,5-ylene, hex-1,6-ylene and the like. C0-Alkylene is a single bond, C1-alkylene is methylene and C2-alkylene is 1,1-ethylene or 1,2-ethylene.
The term “1- to 2-membered hydrocarbon chain” comprises a chain having 1 or 2 carbon atoms each having a free valency on the terminal atoms of the hydrocarbon chain. If a carbon atom in the 1- to 2-membered hydrocarbon chain is replaced by a carbonyl group, examples thereof are —C(O)—, —CH2C(O)— or —C(O)CH2—. The hydrocarbon chain may additionally carry one or two methyl groups. Examples thereof are —C(CH3)H—, —CH(CH3)CH2—, —CH2C(CH3)H—, —CH(CH3)CH(CH3)2—, —CH(CH3)C(O)—, —C(O)CH(CH3)— and the like.
The term “3- to 6-membered hydrocarbon chain” comprises a chain having 3, 4, 5 or 6 carbon atoms, with the two terminal atoms of the hydrocarbon chain each having a free valency. If the 3- to 6-membered hydrocarbon chain does not comprise a group Z or comprises a non-terminal group Z, the two terminal carbon atoms of the hydrocarbon chain each have a free valency. If the 3- to 6-membered hydrocarbon chain comprises a terminal group Z, one free valency is located on group Z and the second free valency is located on the terminal carbon atom of the chain. In addition, the 3- to 6-membered hydrocarbon chain may have a double bond or triple bond at any position, and/or carry a C1-C4-alkyl group. Examples thereof are —CH2CH(CH3)CH2—, —CH2CH(CH3)CH2CH2—, —CH2CH2CH2—CH(CH3)—, —CH2C(H)═C(H)CH2—, —CH2C(CH3)═C(H)CH2— and the like.
4-, 5- or 6-membered heterocyclyl comprises both aromatic heterocyclyl (hetaryl or heteroaryl) and completely saturated or partly unsaturated heterocyclic radicals. Heterocyclyl has 1, 2 or 3 heteroatoms selected from O, S and N, e.g. 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, or 1 oxygen atom and 1 or 2 nitrogen atoms or 1 sulfur atom and 1 or 2 nitrogen atoms.
Heterocyclyl may be unsubstituted or have 1 or 2 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, OH, CN, NR4R5, C1-C2-fluoroalkyl and halogen. Heterocyclyl may also have a fused 5- or 6-membered carbocycle, e.g. a benzene, cyclopentane or cyclohexene ring or a fused heterocycle, e.g. a fused pyrrolyl, furan, thiophene, thiazole, pyridine, pyrimidine or pyridazine ring.
Examples of saturated heterocyclyl are azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetan-2-yl, oxetan-3-yl, thietan-2-yl, thietan-3-yl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, oxolanyl, 1,3-dioxolanyl, 1,3- and 1,4-dioxanyl, 1,3-oxothiolanyl, oxazolidinyl and the like.
Examples of 5- or 6-membered aromatic heterocyclic radicals (5- or 6-membered aromatic heterocyclyl) having 1, 2 or 3 heteroatoms which are selected from O, S and N are in particular pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, pyrrotyl, pyrazolyl, thienyl, furyl, oxazolyl, thiazolyl, isoxazolyl, tetrazolyl, thiadiazolyl and triazolyl. These may have 1 or 2 of the aforementioned substituents on the nitrogen atoms and on the carbon atoms. If one of the substituents is hydroxy, the radicals may also be in a tautomeric form with carbonyl groups. Examples of 5- or 6-membered heterocyclic radicals having a fused carbocycle comprise benzofuranyl, benzothienyl, indolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzopyrazolyl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, and the corresponding partly hydrogenated groups.
Examples of a fused 5 or 6-membered carbocycle are cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene and benzene. Examples of a fused 5- or 6-membered heterocycle having 1 or 2 nitrogen atoms as ring members are pyridine, 1,2,3,4- and 1,2,5,6-tetrahydropyridine, 1,2- and 1,4-dihydropyridine, pyrimidine, pyrazine and pyridazine.
In the group A1, the carbon atoms of the chain, optionally together with the group Z, form a chain having at least three, and preferably at least four, members, which separates the ring of the group Ar from the nitrogen atom of the central (partly) saturated N-heterocycle of the formula (I) by at least 4 and preferably by at least 5 bonds. If A1 does not have a group Z, then A1 comprises 3 to 6 and preferably 4 or 5 and specifically 4 carbon atoms. If A1 has at least one of said groups Z, then A1 comprises 3 to 6, in particular 3 or 4 carbon atoms and the group Z. Preferred groups Z are O, S and NR3. The heteroatoms of group Z are usually not connected to the nitrogen atom of the N-heterocycle carrying the group A2-Q. The heteroatoms of the group Z are, if Ar is linked via a heteroatom to A1, preferably bonded neither to the atom of the ring of group Ar nor to the nitrogen atom of the central (partly) saturated heterocycle. The hydrocarbon chain may carry a C1-C4-alkyl group. The saturated linkages in the carbon chain (alkylene) may be replaced by unsaturated linkages (alkenylene; alkynylene). Possible results are thus straight-chain or branched unsaturated groups A1 whose number and arrangement of the carbon atoms corresponds to that of the aforementioned alkylene radicals, but where a single bond is replaced by an unsaturated double or triple bond.
Where the group A2 is ethylene, the bonding sites are not located on the same atom, but form a two-membered chain which separates the ring of the group Q from the atom X of the central (partly) saturated N-heterocycle of the formula (I) by 3 bonds.
With a view to the use of the compounds of the invention as dopamine D3 receptor ligands, Ar is preferably a radical of the formulae (a) to (m)







in which

    * marks the position at which Ar is connected to A1;
    n in the formulae a and b is 0 or 1;
    R is H, OH or halogen;
    Ra2 has the meanings previously mentioned for Ra or Ra1;
    Rb, Re, Rf, Ri, Rk are each independently of one another H or a substituent Ra or Ra1 as defined above;
    Rc, Rd, Rg, Rh are each independently of one another H, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxymethyl or C1-C2-fluoroalkyl;
    W is CH or N;
    R1 is hydrogen or a group Ra or Ra1 as defined above; and
    R2 is hydrogen or a group Ra as defined above.


It is self-evident to the skilled worker that in the case of the substituted N-heterocyclic compounds of the formula I where Ar is a radical of the formula (m), in the case where W═CH one of the substituents R1 or R2 may also be linked to the C atom located at the position of W.
The variables Ar, W, A1, X, Y, A2, R1, R2 and Q have independently of one another preferably the meanings indicated below:

    Ar is a pyridinone or pyrimidinone residue of the formula (m), particularly preferably pyrimidinone (i.e. W═N), where the pyri(mi)dinone ring is optionally substituted by 1, 2 or 3 groups Ra as defined above, and/or one group Ra1 as defined above, where the number of groups Ra and Ra1 does not exceed 3.
    A1 is a 3- to 6-membered, in particular 4- to 6-membered, hydrocarbon chain which includes no group Z, where the hydrocarbon chain may have a double bond and/or a methyl group. In particularly preferred compounds of the formula I, A1 is —(CH2)a1 in which a1 is 4, 5 or 6 and in particular 4, or A1 is trans-CH2—CH═CH—CH2—, trans-CH2—C(CH3)═CH—CH2—, —CH2—CH(CH3)—CH2—CH2— or —CH2—CH2-CH2—CH(CH3)—. A1 is particularly preferably —(CH2)4—;
    X is CH or N, in particular N; and
    Y is CH2; or
    X—Y together are C═CH; in particular, X is N and Y is CH2;
    A2 is CH2, CH2CH2, CO, CH2CO or COCH2, in particular CH2.
    R1 is a group halogen, OR3, NR4R5, SR6, C3-C6-cycloalkyl, C1-C6-alkyl which is optionally substituted by 1, 2, 3 or 4 radicals OH, C1-C4-alkoxy, halogen or phenyl, which are selected independently of one another, is phenyl or 5- or 6-membered aromatic heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and N, where heterocyclyl and phenyl may be substituted by one or two radicals which are selected independently of one another from C1-C4-alkyl, C1-C4-alkoxy, NR4R5, OH, CN, C1-C2-fluoroalkyl or halogen.
    
        R1 is in particular C1-C6-alkyl, specifically C1-C4-alkyl, halogen, optionally substituted phenyl or 2-furyl, C1-C2-fluoroalkyl, in particular trifluoromethyl, C4-C6-cycloalkyl, a group OR3, a group SR6 or a radical NR4R5. In this connection, R3 is in particular hydrogen, C1-C4-alkyl, phenyl or benzyl and specifically hydrogen.
        R4 is preferably hydrogen or alkyl. R5 is preferably hydrogen, C1-C4-alkyl, phenyl or benzyl or forms together with the nitrogen atom and the radical R4 a 4-, 5- or 6-membered saturated heterocycle such as azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl. R6 in this connection is preferably hydrogen, C1-C4-alkyl, phenyl or benzyl and in particular hydrogen. Substituted phenyl means here that the phenyl radical may be substituted by one or two radicals, e.g. by C1-C4-alkyl, C1-C4-alkoxy, NR4R5, OH, CN, C1-C2-fluoroalkyl and/or halogen.
        In a particularly preferred embodiment of the invention, R1 is C1-C6-alkyl, in particular C1-C4-alkyl and specifically methyl, isopropyl or tert-butyl, C1-C2-fluoroalkyl, in particular CF3, C4-C6-cycloalkyl, in particular cyclobutyl or cyclohexyl, 2-furyl, phenyl which may be substituted by one or two radicals which are selected independently of one another from C1-C4-alkyl, C1-C4-alkoxy, NR4R5, OH, CN, C1-C2-fluoroalkyl or halogen, in particular p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl, or is a radical OR3. In this, R3 has the aforementioned meanings and is in particular H, C1-C4-alkyl, phenyl or benzyl and specifically H. In this connection, the phenyl ring in phenyl and in benzyl may be substituted by one or two radicals which are selected independently of one another from C1-C4-alkyl, C1-C4-alkoxy, NR4R5, OH, CN, C1-C2-fluoroalkyl or halogen.
    
    
    R2 is preferably disposed in 5-position of the pyri(mi)din-2-one ring. R2 is preferably selected from H, C1-C4-alkyl, in particular methyl, C1-C2-fluoroalkyl, in particular trifluoromethyl, halogen, in particular fluorine, and CN. In a particularly preferred embodiment, R2 is C1-C4-alkyl, specifically methyl. In another particularly preferred embodiment, R2 is hydrogen.


A very particularly preferred embodiment of the invention relates to compounds of the formula I in which R1 is OR3 and in particular OH, or is methyl, isopropyl, tert-butyl, CF3, cyclobutyl, cyclohexyl, phenyl, p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl or 2-furyl, and R2 is in particular selected from H, halogen, CN, CF3 and C1-C4-alkyl and specifically hydrogen, methyl, fluorine or chlorine.
A further very particularly preferred embodiment of the invention relates to compounds of the formula I in which R1 is OH, phenyl, p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl, in particular OH, and R2 is in particular selected from H, fluorine, chlorine and C1-C4-alkyl and specifically is hydrogen, fluorine or methyl.
Q is preferably phenyl which optionally has 1, 2 or 3 substituents RQ which are selected independently of one another from OH, C1-C6-alkyl which is optionally completely or partly substituted by halogen, or halogen, cyano, C1-C4-alkoxy, C1-C2-haloalkoxy, NR4R5, C3-C6-cycloalkyl, or where 2 substituents bonded to adjacent C atoms of the phenyl are, together with the C atoms to which they are bonded, a fused, unsaturated 4-, 5- or 6-membered carbocycle or are a 4-, 5- or 6-membered heterocycle having 1 or 2 heteroatoms selected from O, N and S as ring members. RQ may also be COOR7.
In a particularly preferred embodiment, Q is phenyl which has 1, 2 or 3 substituents RQ which are selected independently of one another from methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, hydroxyl, chlorine, fluorine, trifluoromethyl, OCF3, OCHF2, CN, dimethylamino, methoxy or ethoxy.
In this embodiment, Q is for example 2-chlorophenyl, 2-fluorophenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chloro-6-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-n-propylphenyl, 3-n-propylphenyl, 4-n-propylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2-cyclopropylphenyl, 3-cyclopropylphenyl, 4-cyclopropylphenyl, 2-cyclobutylphenyl, 3-cyclobutylphenyl, 4-cyclobutylphenyl, 2-tert-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 4-trifluoromethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 2,4,6-trimethylphenyl, 2,3,4-trimethoxyphenyl, 2,4,5-trimethoxyphenyl.
If Q is phenyl, it has in particular two substituents RQ. The two substituents RQ are then particularly preferably located in position 2,3; 2,4 or 3,4 on the phenyl ring. Examples thereof are 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-2-fluorophenyl, 4-chloro-2-fluorophenyl, 4-chloro-3-fluorophenyl, 2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl, 3-chloro-4-methylphenyl, 3-chloro-2-methylphenyl, 4-chloro-2-methylphenyl, 4-chloro-3-methylphenyl, 2-chloro-3-methoxyphenyl, 2-chloro-4-methoxyphenyl, 3-chloro-4-methoxyphenyl, 3-chloro-2-methoxyphenyl, 4-chloro-2-methoxyphenyl, 4-chloro-3-methoxyphenyl, 2-chloro-3-trifluormethoxyphenyl, 2-chloro-4-trifluormethoxyphenyl, 3-chloro-4-trifluormethoxyphenyl, 3-chloro-2-trifluormethoxyphenyl, 4-chloro-2-trifluormethoxyphenyl, 4-chloro-3-trifluormethoxyphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl and 3,4-dimethoxyphenyl.
In a further particularly preferred embodiment, Q is phenyl which has 1 or, in particular, 2 substituents selected from halogen, specifically fluorine and chlorine, where preferably 1 halogen atom is disposed in the para position relative to the binding site to A2. Q is in particular preferably 2,4-dichlorophenyl or 3,4-dichlorophenyl.
In another embodiment, Q is naphthyl or phenyl which carries a fused 5-membered heterocycle having 1 or 2 O atoms as ring members. In this embodiment, Q is for example naphth-1-yl, naphth-2-yl, 2-methyl-α-naphthyl, 1,3-benzodioxol-4-yl or 1,3-benzodioxol-5-yl.
In another embodiment, Q is 5- or 6-membered aromatic heterocyclyl having 1 or 2 heteroatoms selected from O, N and S, which may have 1 or 2 substituents. The substituents are preferably selected from chlorine and methyl. In this embodiment, Q is for example 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 4,6-dimethoxypyrimidin-2-yl, 2-thienyl, 3-thienyl, 4-thienyl, 2-furyl, 3-furyl, 4-furyl, 2-chlorothiazol-5-yl, 6-chloropyridin-2-yl, 1-methylimidazol-2-yl, 2-methylthiazol-5-yl.
In another embodiment, Q is 5- or 6-membered aromatic heterocyclyl having 1 or 2 heteroatoms selected from O, N and S, which carries a fused, unsaturated six-membered carbocycle and in particular a fused benzene ring. In this embodiment, Q is for example benzimidazol-2-yl, benzoxazol-2-yl or benzothiazol-2-yl.
Otherwise, the groups R3, R4, R5, R6, R7 and R8 preferably have the meanings indicated below:
R3 is preferably H, C1-C4-alkyl, phenyl-substituted C1-C4-alkyl or COR11. In this, R11 has the meanings indicated for R8 and is in particular C1-C4-alkyl. R3 in groups NR3 is preferably H, C1-C4-alkyl, phenyl-substituted C1-C4-alkyl or COR11. NR3 is particularly preferably NH, NCH3, NCOCH3 or NCH2-phenyl. R3 in the groups C(O)NR3 and NR3C(O) is preferably H, C1-C4-alkyl, phenyl-substituted C1-C4-alkyl or COR11. C(O)NR3 is particularly preferably CONH, CONCH3 or CONCH2-phenyl. NR3C(O) is particularly preferably NHCO, NCH3CO or N(CH2-phenyl)CO.
R3 is preferably H, C1-C4-alkyl, CF3, CHF2 or phenyl. OR3 is particularly preferably methoxy, trifluoromethoxy or phenoxy.
R4 is preferably hydrogen or C1-C4-alkyl. R5 is preferably hydrogen, C1-C4-alkyl, phenyl, benzyl or a group. COR11. R4 in substituents CONR4R5 is preferably H or C1-C4-alkyl, and R5 is preferably H, C1-C4-alkyl or COR11. CONR4R5 is particularly preferably CONH2, CONHCH3, CON(CH3)2 or C(O)NHC(O)CH3. R4 in substituents NR4R5 is preferably H, C1-C4-alkyl or phenyl-substituted C1-C4-alkyl and R5 is H, C1-C4-alkyl or COR11. NR4R5 is particularly preferably NH2, NHCH3, N(CH3)2, NH-benzyl or NHCOCH3. R4 in substituents SO2NR4R5 is preferably H or C1-C4-alkyl and R5 is preferably H, C1-C4-alkyl or COR11. SO2NR4R5 is particularly preferably sulfamoyl. R4 and R5 in the aforementioned groups may also form together with the nitrogen atom to which they are bonded a saturated or unsaturated 4-, 5- or 6-membered, preferably saturated nitrogen heterocycle which may have a further heteroatom such as N, S or O and which may be substituted by 1, 2, 3 or 4 alkyl groups. Examples of such heterocycles are piperidinyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl and 4-methylpiperidinyl.
R6 is preferably H, C1-C4-alkyl, phenyl or benzyl. R6 in substituents SR6 is preferably H, C1-C4-alkyl, phenyl or benzyl. R6 in substituents SOR6 is preferably phenyl or C1-C4-alkyl. R6 in substituents SO2R6 is preferably H or C1-C4-alkyl. SO2R6 is particularly preferably methylsulfonyl.
R7 in substituents COOR7 is H or C1-C4-alkyl. COOR7 is particularly preferably C1-C4-alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl or t-butoxycarbonyl.
R8 in the substituents COR8 and OC(O)R8 is preferably H, C1-C4-alkyl or phenyl. CORE is particularly preferably formyl, acetyl or benzoyl.
Among the substituted N-heterocyclic compounds of the invention, preference is given to the compounds of the general formula I.A




in which W, R1, R2, A2 and Q have the aforementioned meanings, and n is 4, 5 or 6, in particular 4; and the tautomers of the compounds I.A, the physiologically acceptable salts of the compounds I.A and the physiologically acceptable salts of the tautomers of the compounds I.A.

Compounds of the formula I.A which may in particular be in the form of tautomers are those in which one or both of the radicals R1 or R2 are OH or NHR4 in which R4 has the aforementioned meanings.
Among the compounds of the general formula I.A, particular preference is given to the compounds of the general formula I.A-1




in which R1 and R2 have the aforementioned meanings, in particular the meanings indicated as preferred; and Q is phenyl which is substituted by 1 or 2 groups Ra as defined above, which may in each case be identical or different and also be linked to each other.

Examples of such compounds are the compounds I.A-1.1 to I.A-1.1386 detailed in the following Table 1, where the variables R1, R2 and Q in each case together have the meaning indicated in one line of Table 1, and for R1=OH the tautomers of these compounds.










TABLE 1






R1
R2
Q


















1
phenyl
H
2-chloro-4-fluorophenyl


2
phenyl
CH3
2-chloro-4-fluorophenyl


3
H
CH3
2-chloro-4-fluorophenyl


4
CH3
H
2-chloro-4-fluorophenyl


5
OH
H
2-chloro-4-fluorophenyl


6
C(CH3)3
H
2-chloro-4-fluorophenyl


7
CF3
H
2-chloro-4-fluorophenyl


8
CH(CH3)2
H
2-chloro-4-fluorophenyl


9
2-furyl
H
2-chloro-4-fluorophenyl


10
cyclohexyl
H
2-chloro-4-fluorophenyl


11
cyclobutyl
H
2-chloro-4-fluorophenyl


12
4-methylphenyl
H
2-chloro-4-fluorophenyl


13
2-methylphenyl
H
2-chloro-4-fluorophenyl


14
2-fluorophenyl
H
2-chloro-4-fluorophenyl


15
3-fluorophenyl
H
2-chloro-4-fluorophenyl


16
4-fluorophenyl
H
2-chloro-4-fluorophenyl


17
OH
CH3
2-chloro-4-fluorophenyl


18
OH
CF3
2-chloro-4-fluorophenyl


19
OH
F
2-chloro-4-fluorophenyl


20
OH
CN
2-chloro-4-fluorophenyl


21
OH
Cl
2-chloro-4-fluorophenyl


22
OH
C2H5
2-chloro-4-fluorophenyl


23
phenyl
H
2-chloro-3-fluorophenyl


24
phenyl
CH3
2-chloro-3-fluorophenyl


25
H
CH3
2-chloro-3-fluorophenyl


26
CH3
H
2-chloro-3-fluorophenyl


27
OH
H
2-chloro-3-fluorophenyl


28
C(CH3)3
H
2-chloro-3-fluorophenyl


29
CF3
H
2-chloro-3-fluorophenyl


30
CH(CH3)2
H
2-chloro-3-fluorophenyl


31
2-furyl
H
2-chloro-3-fluorophenyl


32
cyclohexyl
H
2-chloro-3-fluorophenyl


33
cyclobutyl
H
2-chloro-3-fluorophenyl


34
4-methylphenyl
H
2-chloro-3-fluorophenyl


35
2-methylphenyl
H
2-chloro-3-fluorophenyl


36
2-fluorophenyl
H
2-chloro-3-fluorophenyl


37
3-fluorophenyl
H
2-chloro-3-fluorophenyl


38
4-fluorophenyl
H
2-chloro-3-fluorophenyl


39
OH
CH3
2-chloro-3-fluorophenyl


40
OH
CF3
2-chloro-3-fluorophenyl


41
OH
F
2-chloro-3-fluorophenyl


42
OH
CN
2-chloro-3-fluorophenyl


43
OH
Cl
2-chloro-3-fluorophenyl


44
OH
C2H5
2-chloro-3-fluorophenyl


45
phenyl
H
3-chloro-4-fluorophenyl


46
phenyl
CH3
3-chloro-4-fluorophenyl


47
H
CH3
3-chloro-4-fluorophenyl


48
CH3
H
3-chloro-4-fluorophenyl


49
OH
H
3-chloro-4-fluorophenyl


50
C(CH3)3
H
3-chloro-4-fluorophenyl


51
CF3
H
3-chloro-4-fluorophenyl


52
CH(CH3)2
H
3-chloro-4-fluorophenyl


53
2-furyl
H
3-chloro-4-fluorophenyl


54
cyclohexyl
H
3-chloro-4-fluorophenyl


55
cyclobutyl
H
3-chloro-4-fluorophenyl


56
4-methylphenyl
H
3-chloro-4-fluorophenyl


57
2-methylphenyl
H
3-chloro-4-fluorophenyl


58
2-fluorophenyl
H
3-chloro-4-fluorophenyl


59
3-fluorophenyl
H
3-chloro-4-fluorophenyl


60
4-fluorophenyl
H
3-chloro-4-fluorophenyl


61
OH
CH3
3-chloro-4-fluorophenyl


62
OH
CF3
3-chloro-4-fluorophenyl


63
OH
F
3-chloro-4-fluorophenyl


64
OH
CN
3-chloro-4-fluorophenyl


65
OH
Cl
3-chloro-4-fluorophenyl


66
OH
C2H5
3-chloro-4-fluorophenyl


67
phenyl
H
2,4-dichlorophenyl


68
phenyl
CH3
2,4-dichlorophenyl


69
H
CH3
2,4-dichlorophenyl


70
CH3
H
2,4-dichlorophenyl


71
OH
H
2,4-dichlorophenyl


72
C(CH3)3
H
2,4-dichlorophenyl


73
CF3
H
2,4-dichlorophenyl


74
CH(CH3)2
H
2,4-dichlorophenyl


75
2-furyl
H
2,4-dichlorophenyl


76
cyclohexyl
H
2,4-dichlorophenyl


77
cyclobutyl
H
2,4-dichlorophenyl


78
4-methylphenyl
H
2,4-dichlorophenyl


79
2-methylphenyl
H
2,4-dichlorophenyl


80
2-fluorophenyl
H
2,4-dichlorophenyl


81
3-fluorophenyl
H
2,4-dichlorophenyl


82
4-fluorophenyl
H
2,4-dichlorophenyl


83
OH
CH3
2,4-dichlorophenyl


84
OH
CF3
2,4-dichlorophenyl


85
OH
F
2,4-dichlorophenyl


86
OH
CN
2,4-dichlorophenyl


87
OH
Cl
2,4-dichlorophenyl


88
OH
C2H5
2,4-dichlorophenyl


89
phenyl
H
3,4-dichlorophenyl


90
phenyl
CH3
3,4-dichlorophenyl


91
H
CH3
3,4-dichlorophenyl


92
CH3
H
3,4-dichlorophenyl


93
OH
H
3,4-dichlorophenyl


94
C(CH3)3
H
3,4-dichlorophenyl


95
CF3
H
3,4-dichlorophenyl


96
CH(CH3)2
H
3,4-dichlorophenyl


97
2-furyl
H
3,4-dichlorophenyl


98
cyclohexyl
H
3,4-dichlorophenyl


99
cyclobutyl
H
3,4-dichlorophenyl


100
4-methylphenyl
H
3,4-dichlorophenyl


101
2-methylphenyl
H
3,4-dichlorophenyl


102
2-fluorophenyl
H
3,4-dichlorophenyl


103
3-fluorophenyl
H
3,4-dichlorophenyl


104
4-fluorophenyl
H
3,4-dichlorophenyl


105
OH
CH3
3,4-dichlorophenyl


106
OH
CF3
3,4-dichlorophenyl


107
OH
F
3,4-dichlorophenyl


108
OH
CN
3,4-dichlorophenyl


109
OH
Cl
3,4-dichlorophenyl


110
OH
C2H5
3,4-dichlorophenyl


111
phenyl
H
2,4-dimethoxyphenyl


112
phenyl
CH3
2,4-dimethoxyphenyl


113
H
CH3
2,4-dimethoxyphenyl


114
CH3
H
2,4-dimethoxyphenyl


115
OH
H
2,4-dimethoxyphenyl


116
C(CH3)3
H
2,4-dimethoxyphenyl


117
CF3
H
2,4-dimethoxyphenyl


118
CH(CH3)2
H
2,4-dimethoxyphenyl


119
2-furyl
H
2,4-dimethoxyphenyl


120
cyclohexyl
H
2,4-dimethoxyphenyl


121
cyclobutyl
H
2,4-dimethoxyphenyl


122
4-methylphenyl
H
2,4-dimethoxyphenyl


123
2-methylphenyl
H
2,4-dimethoxyphenyl


124
2-fluorophenyl
H
2,4-dimethoxyphenyl


125
3-fluorophenyl
H
2,4-dimethoxyphenyl


126
4-fluorophenyl
H
2,4-dimethoxyphenyl


127
OH
CH3
2,4-dimethoxyphenyl


128
OH
CF3
2,4-dimethoxyphenyl


129
OH
F
2,4-dimethoxyphenyl


130
OH
CN
2,4-dimethoxyphenyl


131
OH
Cl
2,4-dimethoxyphenyl


132
OH
C2H5
2,4-dimethoxyphenyl


133
phenyl
H
3,4-dimethoxyphenyl


134
phenyl
CH3
3,4-dimethoxyphenyl


135
H
CH3
3,4-dimethoxyphenyl


136
CH3
H
3,4-dimethoxyphenyl


137
OH
H
3,4-dimethoxyphenyl


138
C(CH3)3
H
3,4-dimethoxyphenyl


139
CF3
H
3,4-dimethoxyphenyl


140
CH(CH3)2
H
3,4-dimethoxyphenyl


141
2-furyl
H
3,4-dimethoxyphenyl


142
cyclohexyl
H
3,4-dimethoxyphenyl


143
cyclobutyl
H
3,4-dimethoxyphenyl


144
4-methylphenyl
H
3,4-dimethoxyphenyl


145
2-methylphenyl
H
3,4-dimethoxyphenyl


146
2-fluorophenyl
H
3,4-dimethoxyphenyl


147
3-fluorophenyl
H
3,4-dimethoxyphenyl


148
4-fluorophenyl
H
3,4-dimethoxyphenyl


149
OH
CH3
3,4-dimethoxyphenyl


150
OH
CF3
3,4-dimethoxyphenyl


151
OH
F
3,4-dimethoxyphenyl


152
OH
CN
3,4-dimethoxyphenyl


153
OH
Cl
3,4-dimethoxyphenyl


154
OH
C2H5
3,4-dimethoxyphenyl


155
phenyl
H
2,4-dimethylphenyl


156
phenyl
CH3
2,4-dimethylphenyl


157
H
CH3
2,4-dimethylphenyl


158
CH3
H
2,4-dimethylphenyl


159
OH
H
2,4-dimethylphenyl


160
C(CH3)3
H
2,4-dimethylphenyl


161
CF3
H
2,4-dimethylphenyl


162
CH(CH3)2
H
2,4-dimethylphenyl


163
2-furyl
H
2,4-dimethylphenyl


164
cyclohexyl
H
2,4-dimethylphenyl


165
cyclobutyl
H
2,4-dimethylphenyl


166
4-methylphenyl
H
2,4-dimethylphenyl


167
2-methylphenyl
H
2,4-dimethylphenyl


168
2-fluorophenyl
H
2,4-dimethylphenyl


169
3-fluorophenyl
H
2,4-dimethylphenyl


170
4-fluorophenyl
H
2,4-dimethylphenyl


171
OH
CH3
2,4-dimethylphenyl


172
OH
CF3
2,4-dimethylphenyl


173
OH
F
2,4-dimethylphenyl


174
OH
CN
2,4-dimethylphenyl


175
OH
Cl
2,4-dimethylphenyl


176
OH
C2H5
2,4-dimethylphenyl


177
phenyl
H
3,4-dimethylphenyl


178
phenyl
CH3
3,4-dimethylphenyl


179
H
CH3
3,4-dimethylphenyl


180
CH3
H
3,4-dimethylphenyl


181
OH
H
3,4-dimethylphenyl


182
C(CH3)3
H
3,4-dimethylphenyl


183
CF3
H
3,4-dimethylphenyl


184
CH(CH3)2
H
3,4-dimethylphenyl


185
2-furyl
H
3,4-dimethylphenyl


186
cyclohexyl
H
3,4-dimethylphenyl


187
cyclobutyl
H
3,4-dimethylphenyl


188
4-methylphenyl
H
3,4-dimethylphenyl


189
2-methylphenyl
H
3,4-dimethylphenyl


190
2-fluorophenyl
H
3,4-dimethylphenyl


191
3-fluorophenyl
H
3,4-dimethylphenyl


192
4-fluorophenyl
H
3,4-dimethylphenyl


193
OH
CH3
3,4-dimethylphenyl


194
OH
CF3
3,4-dimethylphenyl


195
OH
F
3,4-dimethylphenyl


196
OH
CN
3,4-dimethylphenyl


197
OH
Cl
3,4-dimethylphenyl


198
OH
C2H5
3,4-dimethylphenyl


199
phenyl
H
2-chloro-4-methylphenyl


200
phenyl
CH3
2-chloro-4-methylphenyl


201
H
CH3
2-chloro-4-methylphenyl


202
CH3
H
2-chloro-4-methylphenyl


203
OH
H
2-chloro-4-methylphenyl


204
C(CH3)3
H
2-chloro-4-methylphenyl


205
CF3
H
2-chloro-4-methylphenyl


206
CH(CH3)2
H
2-chloro-4-methylphenyl


207
2-furyl
H
2-chloro-4-methylphenyl


208
cyclohexyl
H
2-chloro-4-methylphenyl


209
cyclobutyl
H
2-chloro-4-methylphenyl


210
4-methylphenyl
H
2-chloro-4-methylphenyl


211
2-methylphenyl
H
2-chloro-4-methylphenyl


212
2-fluorophenyl
H
2-chloro-4-methylphenyl


213
3-fluorophenyl
H
2-chloro-4-methylphenyl


214
4-fluorophenyl
H
2-chloro-4-methylphenyl


215
OH
CH3
2-chloro-4-methylphenyl


216
OH
CF3
2-chloro-4-methylphenyl


217
OH
F
2-chloro-4-methylphenyl


218
OH
CN
2-chloro-4-methylphenyl


219
OH
Cl
2-chloro-4-methylphenyl


220
OH
C2H5
2-chloro-4-methylphenyl


221
phenyl
H
4-chloro-2-fluorophenyl


222
phenyl
CH3
4-chloro-2-fluorophenyl


223
H
CH3
4-chloro-2-fluorophenyl


224
CH3
H
4-chloro-2-fluorophenyl


225
OH
H
4-chloro-2-fluorophenyl


226
C(CH3)3
H
4-chloro-2-fluorophenyl


227
CF3
H
4-chloro-2-fluorophenyl


228
CH(CH3)2
H
4-chloro-2-fluorophenyl


229
2-furyl
H
4-chloro-2-fluorophenyl


230
cyclohexyl
H
4-chloro-2-fluorophenyl


231
cyclobutyl
H
4-chloro-2-fluorophenyl


232
4-methylphenyl
H
4-chloro-2-fluorophenyl


233
2-methylphenyl
H
4-chloro-2-fluorophenyl


234
2-fluorophenyl
H
4-chloro-2-fluorophenyl


235
3-fluorophenyl
H
4-chloro-2-fluorophenyl


236
4-fluorophenyl
H
4-chloro-2-fluorophenyl


237
OH
CH3
4-chloro-2-fluorophenyl


238
OH
CF3
4-chloro-2-fluorophenyl


239
OH
F
4-chloro-2-fluorophenyl


240
OH
CN
4-chloro-2-fluorophenyl


241
OH
Cl
4-chloro-2-fluorophenyl


242
OH
C2H5
4-chloro-2-fluorophenyl


243
phenyl
H
4-chloro-3-fluorophenyl


244
phenyl
CH3
4-chloro-3-fluorophenyl


245
H
CH3
4-chloro-3-fluorophenyl


246
CH3
H
4-chloro-3-fluorophenyl


247
OH
H
4-chloro-3-fluorophenyl


248
C(CH3)3
H
4-chloro-3-fluorophenyl


249
CF3
H
4-chloro-3-fluorophenyl


250
CH(CH3)2
H
4-chloro-3-fluorophenyl


251
2-furyl
H
4-chloro-3-fluorophenyl


252
cyclohexyl
H
4-chloro-3-fluorophenyl


253
cyclobutyl
H
4-chloro-3-fluorophenyl


254
4-methylphenyl
H
4-chloro-3-fluorophenyl


255
2-methylphenyl
H
4-chloro-3-fluorophenyl


256
2-fluorophenyl
H
4-chloro-3-fluorophenyl


257
3-fluorophenyl
H
4-chloro-3-fluorophenyl


258
4-fluorophenyl
H
4-chloro-3-fluorophenyl


259
OH
CH3
4-chloro-3-fluorophenyl


260
OH
CF3
4-chloro-3-fluorophenyl


261
OH
F
4-chloro-3-fluorophenyl


262
OH
CN
4-chloro-3-fluorophenyl


263
OH
Cl
4-chloro-3-fluorophenyl


264
OH
C2H5
4-chloro-3-fluorophenyl


265
phenyl
H
3-chloro-2-fluorophenyl


266
phenyl
CH3
3-chloro-2-fluorophenyl


267
H
CH3
3-chloro-2-fluorophenyl


268
CH3
H
3-chloro-2-fluorophenyl


269
OH
H
3-chloro-2-fluorophenyl


270
C(CH3)3
H
3-chloro-2-fluorophenyl


271
CF3
H
3-chloro-2-fluorophenyl


272
CH(CH3)2
H
3-chloro-2-fluorophenyl


273
2-furyl
H
3-chloro-2-fluorophenyl


274
cyclohexyl
H
3-chloro-2-fluorophenyl


275
cyclobutyl
H
3-chloro-2-fluorophenyl


276
4-methylphenyl
H
3-chloro-2-fluorophenyl


277
2-methylphenyl
H
3-chloro-2-fluorophenyl


278
2-fluorophenyl
H
3-chloro-2-fluorophenyl


279
3-fluorophenyl
H
3-chloro-2-fluorophenyl


280
4-fluorophenyl
H
3-chloro-2-fluorophenyl


281
OH
CH3
3-chloro-2-fluorophenyl


282
OH
CF3
3-chloro-2-fluorophenyl


283
OH
F
3-chloro-2-fluorophenyl


284
OH
CN
3-chloro-2-fluorophenyl


285
OH
Cl
3-chloro-2-fluorophenyl


286
OH
C2H5
3-chloro-2-fluorophenyl


287
phenyl
H
2-chlorophenyl


288
phenyl
CH3
2-chlorophenyl


289
H
CH3
2-chlorophenyl


290
CH3
H
2-chlorophenyl


291
OH
H
2-chlorophenyl


292
C(CH3)3
H
2-chlorophenyl


293
CF3
H
2-chlorophenyl


294
CH(CH3)2
H
2-chlorophenyl


295
2-furyl
H
2-chlorophenyl


296
cyclohexyl
H
2-chlorophenyl


297
cyclobutyl
H
2-chlorophenyl


298
4-methylphenyl
H
2-chlorophenyl


299
2-methylphenyl
H
2-chlorophenyl


300
2-fluorophenyl
H
2-chlorophenyl


301
3-fluorophenyl
H
2-chlorophenyl


302
4-fluorophenyl
H
2-chlorophenyl


303
OH
CH3
2-chlorophenyl


304
OH
CF3
2-chlorophenyl


305
OH
F
2-chlorophenyl


306
OH
CN
2-chlorophenyl


307
OH
Cl
2-chlorophenyl


308
OH
C2H5
2-chlorophenyl


309
phenyl
H
4-chlorophenyl


310
phenyl
CH3
4-chlorophenyl


311
H
CH3
4-chlorophenyl


312
CH3
H
4-chlorophenyl


313
OH
H
4-chlorophenyl


314
C(CH3)3
H
4-chlorophenyl


315
CF3
H
4-chlorophenyl


316
CH(CH3)2
H
4-chlorophenyl


317
2-furyl
H
4-chlorophenyl


318
cyclohexyl
H
4-chlorophenyl


319
cyclobutyl
H
4-chlorophenyl


320
4-methylphenyl
H
4-chlorophenyl


321
2-methylphenyl
H
4-chlorophenyl


322
2-fluorophenyl
H
4-chlorophenyl


323
3-fluorophenyl
H
4-chlorophenyl


324
4-fluorophenyl
H
4-chlorophenyl


325
OH
CH3
4-chlorophenyl


326
OH
CF3
4-chlorophenyl


327
OH
F
4-chlorophenyl


328
OH
CN
4-chlorophenyl


329
OH
Cl
4-chlorophenyl


330
OH
C2H5
4-chlorophenyl


331
phenyl
H
3-chlorophenyl


332
phenyl
CH3
3-chlorophenyl


333
H
CH3
3-chlorophenyl


334
CH3
H
3-chlorophenyl


335
OH
H
3-chlorophenyl


336
C(CH3)3
H
3-chlorophenyl


337
CF3
H
3-chlorophenyl


338
CH(CH3)2
H
3-chlorophenyl


339
2-furyl
H
3-chlorophenyl


340
cyclohexyl
H
3-chlorophenyl


341
cyclobutyl
H
3-chlorophenyl


342
4-methylphenyl
H
3-chlorophenyl


343
2-methylphenyl
H
3-chlorophenyl


344
2-fluorophenyl
H
3-chlorophenyl


345
3-fluorophenyl
H
3-chlorophenyl


346
4-fluorophenyl
H
3-chlorophenyl


347
OH
CH3
3-chlorophenyl


348
OH
CF3
3-chlorophenyl


349
OH
F
3-chlorophenyl


350
OH
CN
3-chlorophenyl


351
OH
Cl
3-chlorophenyl


352
OH
C2H5
3-chlorophenyl


353
phenyl
H
4-fluorophenyl


354
phenyl
CH3
4-fluorophenyl


355
H
CH3
4-fluorophenyl


356
CH3
H
4-fluorophenyl


357
OH
H
4-fluorophenyl


358
C(CH3)3
H
4-fluorophenyl


359
CF3
H
4-fluorophenyl


360
CH(CH3)2
H
4-fluorophenyl


361
2-furyl
H
4-fluorophenyl


362
cyclohexyl
H
4-fluorophenyl


363
cyclobutyl
H
4-fluorophenyl


364
4-methylphenyl
H
4-fluorophenyl


365
2-methylphenyl
H
4-fluorophenyl


366
2-fluorophenyl
H
4-fluorophenyl


367
3-fluorophenyl
H
4-fluorophenyl


368
4-fluorophenyl
H
4-fluorophenyl


369
OH
CH3
4-fluorophenyl


370
OH
CF3
4-fluorophenyl


371
OH
F
4-fluorophenyl


372
OH
CN
4-fluorophenyl


373
OH
Cl
4-fluorophenyl


374
OH
C2H5
4-fluorophenyl


375
phenyl
H
2-fluorophenyl


376
phenyl
CH3
2-fluorophenyl


377
H
CH3
2-fluorophenyl


378
CH3
H
2-fluorophenyl


379
OH
H
2-fluorophenyl


380
C(CH3)3
H
2-fluorophenyl


381
CF3
H
2-fluorophenyl


382
CH(CH3)2
H
2-fluorophenyl


383
2-furyl
H
2-fluorophenyl


384
cyclohexyl
H
2-fluorophenyl


385
cyclobutyl
H
2-fluorophenyl


386
4-methylphenyl
H
2-fluorophenyl


387
2-methylphenyl
H
2-fluorophenyl


388
2-fluorophenyl
H
2-fluorophenyl


389
3-fluorophenyl
H
2-fluorophenyl


390
4-fluorophenyl
H
2-fluorophenyl


391
OH
CH3
2-fluorophenyl


392
OH
CF3
2-fluorophenyl


393
OH
F
2-fluorophenyl


394
OH
CN
2-fluorophenyl


395
OH
Cl
2-fluorophenyl


396
OH
C2H5
2-fluorophenyl


397
phenyl
H
3-fluorophenyl


398
phenyl
CH3
3-fluorophenyl


399
H
CH3
3-fluorophenyl


400
CH3
H
3-fluorophenyl


401
OH
H
3-fluorophenyl


402
C(CH3)3
H
3-fluorophenyl


403
CF3
H
3-fluorophenyl


404
CH(CH3)2
H
3-fluorophenyl


405
2-furyl
H
3-fluorophenyl


406
cyclohexyl
H
3-fluorophenyl


407
cyclobutyl
H
3-fluorophenyl


408
4-methylphenyl
H
3-fluorophenyl


409
2-methylphenyl
H
3-fluorophenyl


410
2-fluorophenyl
H
3-fluorophenyl


411
3-fluorophenyl
H
3-fluorophenyl


412
4-fluorophenyl
H
3-fluorophenyl


413
OH
CH3
3-fluorophenyl


414
OH
CF3
3-fluorophenyl


415
OH
F
3-fluorophenyl


416
OH
CN
3-fluorophenyl


417
OH
Cl
3-fluorophenyl


418
OH
C2H5
3-fluorophenyl


419
phenyl
H
2-chloro-3-methylphenyl


420
phenyl
CH3
2-chloro-3-methylphenyl


421
H
CH3
2-chloro-3-methylphenyl


422
CH3
H
2-chloro-3-methylphenyl


423
OH
H
2-chloro-3-methylphenyl


424
C(CH3)3
H
2-chloro-3-methylphenyl


425
CF3
H
2-chloro-3-methylphenyl


426
CH(CH3)2
H
2-chloro-3-methylphenyl


427
2-furyl
H
2-chloro-3-methylphenyl


428
cyclohexyl
H
2-chloro-3-methylphenyl


429
cyclobutyl
H
2-chloro-3-methylphenyl


430
4-methylphenyl
H
2-chloro-3-methylphenyl


431
2-methylphenyl
H
2-chloro-3-methylphenyl


432
2-fluorophenyl
H
2-chloro-3-methylphenyl


433
3-fluorophenyl
H
2-chloro-3-methylphenyl


434
4-fluorophenyl
H
2-chloro-3-methylphenyl


435
OH
CH3
2-chloro-3-methylphenyl


436
OH
CF3
2-chloro-3-methylphenyl


437
OH
F
2-chloro-3-methylphenyl


438
OH
CN
2-chloro-3-methylphenyl


439
OH
Cl
2-chloro-3-methylphenyl


440
OH
C2H5
2-chloro-3-methylphenyl


441
phenyl
H
3-chloro-4-methylphenyl


442
phenyl
CH3
3-chloro-4-methylphenyl


443
H
CH3
3-chloro-4-methylphenyl


444
CH3
H
3-chloro-4-methylphenyl


445
OH
H
3-chloro-4-methylphenyl


446
C(CH3)3
H
3-chloro-4-methylphenyl


447
CF3
H
3-chloro-4-methylphenyl


448
CH(CH3)2
H
3-chloro-4-methylphenyl


449
2-furyl
H
3-chloro-4-methylphenyl


450
cyclohexyl
H
3-chloro-4-methylphenyl


451
cyclobutyl
H
3-chloro-4-methylphenyl


452
4-methylphenyl
H
3-chloro-4-methylphenyl


453
2-methylphenyl
H
3-chloro-4-methylphenyl


454
2-fluorophenyl
H
3-chloro-4-methylphenyl


455
3-fluorophenyl
H
3-chloro-4-methylphenyl


456
4-fluorophenyl
H
3-chloro-4-methylphenyl


457
OH
CH3
3-chloro-4-methylphenyl


458
OH
CF3
3-chloro-4-methylphenyl


459
OH
F
3-chloro-4-methylphenyl


460
OH
CN
3-chloro-4-methylphenyl


461
OH
Cl
3-chloro-4-methylphenyl


462
OH
C2H5
3-chloro-4-methylphenyl


463
phenyl
CH3
3-chloro-2-methylphenyl


464
phenyl
CH3
3-chloro-2-methylphenyl


465
H
CH3
3-chloro-2-methylphenyl


466
CH3
H
3-chloro-2-methylphenyl


467
OH
H
3-chloro-2-methylphenyl


468
C(CH3)3
H
3-chloro-2-methylphenyl


469
CF3
H
3-chloro-2-methylphenyl


470
CH(CH3)2
H
3-chloro-2-methylphenyl


471
2-furyl
H
3-chloro-2-methylphenyl


472
cyclohexyl
H
3-chloro-2-methylphenyl


473
cyclobutyl
H
3-chloro-2-methylphenyl


474
4-methylphenyl
H
3-chloro-2-methylphenyl


475
2-methylphenyl
H
3-chloro-2-methylphenyl


476
2-fluorophenyl
H
3-chloro-2-methylphenyl


477
3-fluorophenyl
H
3-chloro-2-methylphenyl


478
4-fluorophenyl
H
3-chloro-2-methylphenyl


479
OH
CH3
3-chloro-2-methylphenyl


480
OH
CF3
3-chloro-2-methylphenyl


481
OH
F
3-chloro-2-methylphenyl


482
OH
CN
3-chloro-2-methylphenyl


483
OH
Cl
3-chloro-2-methylphenyl


484
OH
C2H5
3-chloro-2-methylphenyl


485
phenyl
H
4-chloro-2-methylphenyl


486
phenyl
CH3
4-chloro-2-methylphenyl


487
H
CH3
4-chloro-2-methylphenyl


488
CH3
H
4-chloro-2-methylphenyl


489
OH
H
4-chloro-2-methylphenyl


490
C(CH3)3
H
4-chloro-2-methylphenyl


491
CF3
H
4-chloro-2-methylphenyl


492
CH(CH3)2
H
4-chloro-2-methylphenyl


493
2-furyl
H
4-chloro-2-methylphenyl


494
cyclohexyl
H
4-chloro-2-methylphenyl


495
cyclobutyl
H
4-chloro-2-methylphenyl


496
4-methylphenyl
H
4-chloro-2-methylphenyl


497
2-methylphenyl
H
4-chloro-2-methylphenyl


498
2-fluorophenyl
H
4-chloro-2-methylphenyl


499
3-fluorophenyl
H
4-chloro-2-methylphenyl


500
4-fluorophenyl
H
4-chloro-2-methylphenyl


501
OH
CH3
4-chloro-2-methylphenyl


502
OH
CF3
4-chloro-2-methylphenyl


503
OH
F
4-chloro-2-methylphenyl


504
OH
CN
4-chloro-2-methylphenyl


505
OH
Cl
4-chloro-2-methylphenyl


506
OH
C2H5
4-chloro-2-methylphenyl


507
phenyl
H
4-chloro-3-methylphenyl


508
phenyl
CH3
4-chloro-3-methylphenyl


509
H
CH3
4-chloro-3-methylphenyl


510
CH3
H
4-chloro-3-methylphenyl


511
OH
H
4-chloro-3-methylphenyl


512
C(CH3)3
H
4-chloro-3-methylphenyl


513
CF3
H
4-chloro-3-methylphenyl


514
CH(CH3)2
H
4-chloro-3-methylphenyl


515
2-furyl
H
4-chloro-3-methylphenyl


516
cyclohexyl
H
4-chloro-3-methylphenyl


517
cyclobutyl
H
4-chloro-3-methylphenyl


518
4-methylphenyl
H
4-chloro-3-methylphenyl


519
2-methylphenyl
H
4-chloro-3-methylphenyl


520
2-fluorophenyl
H
4-chloro-3-methylphenyl


521
3-fluorophenyl
H
4-chloro-3-methylphenyl


522
4-fluorophenyl
H
4-chloro-3-methylphenyl


523
OH
CH3
4-chloro-3-methylphenyl


524
OH
CF3
4-chloro-3-methylphenyl


525
OH
F
4-chloro-3-methylphenyl


526
OH
CN
4-chloro-3-methylphenyl


527
OH
Cl
4-chloro-3-methylphenyl


528
OH
C2H5
4-chloro-3-methylphenyl


529
phenyl
H
2-chloro-4-methoxyphenyl


530
phenyl
CH3
2-chloro-4-methoxyphenyl


531
H
CH3
2-chloro-4-methoxyphenyl


532
CH3
H
2-chloro-4-methoxyphenyl


533
OH
H
2-chloro-4-methoxyphenyl


534
C(CH3)3
H
2-chloro-4-methoxyphenyl


535
CF3
H
2-chloro-4-methoxyphenyl


536
CH(CH3)2
H
2-chloro-4-methoxyphenyl


537
2-furyl
H
2-chloro-4-methoxyphenyl


538
cyclohexyl
H
2-chloro-4-methoxyphenyl


539
cyclobutyl
H
2-chloro-4-methoxyphenyl


540
4-methylphenyl
H
2-chloro-4-methoxyphenyl


541
2-methylphenyl
H
2-chloro-4-methoxyphenyl


542
2-fluorophenyl
H
2-chloro-4-methoxyphenyl


543
3-fluorophenyl
H
2-chloro-4-methoxyphenyl


544
4-fluorophenyl
H
2-chloro-4-methoxyphenyl


545
OH
CH3
2-chloro-4-methoxyphenyl


546
OH
CF3
2-chloro-4-methoxyphenyl


547
OH
F
2-chloro-4-methoxyphenyl


548
OH
CN
2-chloro-4-methoxyphenyl


549
OH
Cl
2-chloro-4-methoxyphenyl


550
OH
C2H5
2-chloro-4-methoxyphenyl


551
phenyl
H
2-chloro-3-methoxyphenyl


552
phenyl
CH3
2-chloro-3-methoxyphenyl


553
H
CH3
2-chloro-3-methoxyphenyl


554
CH3
H
2-chloro-3-methoxyphenyl


555
OH
H
2-chloro-3-methoxyphenyl


556
C(CH3)3
H
2-chloro-3-methoxyphenyl


557
CF3
H
2-chloro-3-methoxyphenyl


558
CH(CH3)2
H
2-chloro-3-methoxyphenyl


559
2-furyl
H
2-chloro-3-methoxyphenyl


560
cyclohexyl
H
2-chloro-3-methoxyphenyl


561
cyclobutyl
H
2-chloro-3-methoxyphenyl


562
4-methylphenyl
H
2-chloro-3-methoxyphenyl


563
2-methylphenyl
H
2-chloro-3-methoxyphenyl


564
2-fluorophenyl
H
2-chloro-3-methoxyphenyl


565
3-fluorophenyl
H
2-chloro-3-methoxyphenyl


566
4-fluorophenyl
H
2-chloro-3-methoxyphenyl


567
OH
CH3
2-chloro-3-methoxyphenyl


568
OH
CF3
2-chloro-3-methoxyphenyl


569
OH
F
2-chloro-3-methoxyphenyl


570
OH
CN
2-chloro-3-methoxyphenyl


571
OH
Cl
2-chloro-3-methoxyphenyl


572
OH
C2H5
2-chloro-3-methoxyphenyl


573
phenyl
H
3-chloro-4-methoxyphenyl


574
phenyl
CH3
3-chloro-4-methoxyphenyl


575
H
CH3
3-chloro-4-methoxyphenyl


576
CH3
H
3-chloro-4-methoxyphenyl


577
OH
H
3-chloro-4-methoxyphenyl


578
C(CH3)3
H
3-chloro-4-methoxyphenyl


579
CF3
H
3-chloro-4-methoxyphenyl


580
CH(CH3)2
H
3-chloro-4-methoxyphenyl


581
2-furyl
H
3-chloro-4-methoxyphenyl


582
cyclohexyl
H
3-chloro-4-methoxyphenyl


583
cyclobutyl
H
3-chloro-4-methoxyphenyl


584
4-methylphenyl
H
3-chloro-4-methoxyphenyl


585
2-methylphenyl
H
3-chloro-4-methoxyphenyl


586
2-fluorophenyl
H
3-chloro-4-methoxyphenyl


587
3-fluorophenyl
H
3-chloro-4-methoxyphenyl


588
4-fluorophenyl
H
3-chloro-4-methoxyphenyl


589
OH
CH3
3-chloro-4-methoxyphenyl


590
OH
CF3
3-chloro-4-methoxyphenyl


591
OH
F
3-chloro-4-methoxyphenyl


592
OH
CN
3-chloro-4-methoxyphenyl


593
OH
Cl
3-chloro-4-methoxyphenyl


594
OH
C2H5
3-chloro-4-methoxyphenyl


595
phenyl
H
4-chloro-3-methoxyphenyl


596
phenyl
CH3
4-chloro-3-methoxyphenyl


597
H
CH3
4-chloro-3-methoxyphenyl


598
CH3
H
4-chloro-3-methoxyphenyl


599
OH
H
4-chloro-3-methoxyphenyl


600
C(CH3)3
H
4-chloro-3-methoxyphenyl


601
CF3
H
4-chloro-3-methoxyphenyl


602
CH(CH3)2
H
4-chloro-3-methoxyphenyl


603
2-furyl
H
4-chloro-3-methoxyphenyl


604
cyclohexyl
H
4-chloro-3-methoxyphenyl


605
cyclobutyl
H
4-chloro-3-methoxyphenyl


606
4-methylphenyl
H
4-chloro-3-methoxyphenyl


607
2-methylphenyl
H
4-chloro-3-methoxyphenyl


608
2-fluorophenyl
H
4-chloro-3-methoxyphenyl


609
3-fluorophenyl
H
4-chloro-3-methoxyphenyl


610
4-fluorophenyl
H
4-chloro-3-methoxyphenyl


611
OH
CH3
4-chloro-3-methoxyphenyl


612
OH
CF3
4-chloro-3-methoxyphenyl


613
OH
F
4-chloro-3-methoxyphenyl


614
OH
CN
4-chloro-3-methoxyphenyl


615
OH
Cl
4-chloro-3-methoxyphenyl


616
OH
C2H5
4-chloro-3-methoxyphenyl


617
phenyl
H
4-chloro-2-methoxyphenyl


618
phenyl
CH3
4-chloro-2-methoxyphenyl


619
H
CH3
4-chloro-2-methoxyphenyl


620
CH3
H
4-chloro-2-methoxyphenyl


621
OH
H
4-chloro-2-methoxyphenyl


622
C(CH3)3
H
4-chloro-2-methoxyphenyl


623
CF3
H
4-chloro-2-methoxyphenyl


624
CH(CH3)2
H
4-chloro-2-methoxyphenyl


625
2-furyl
H
4-chloro-2-methoxyphenyl


626
cyclohexyl
H
4-chloro-2-methoxyphenyl


627
cyclobutyl
H
4-chloro-2-methoxyphenyl


628
4-methylphenyl
H
4-chloro-2-methoxyphenyl


629
2-methylphenyl
H
4-chloro-2-methoxyphenyl


630
2-fluorophenyl
H
4-chloro-2-methoxyphenyl


631
3-fluorophenyl
H
4-chloro-2-methoxyphenyl


632
4-fluorophenyl
H
4-chloro-2-methoxyphenyl


633
OH
CH3
4-chloro-2-methoxyphenyl


634
OH
CF3
4-chloro-2-methoxyphenyl


635
OH
F
4-chloro-2-methoxyphenyl


636
OH
CN
4-chloro-2-methoxyphenyl


637
OH
Cl
4-chloro-2-methoxyphenyl


638
OH
C2H5
4-chloro-2-methoxyphenyl


639
phenyl
H
2,4,5-trimethoxyphenyl


640
phenyl
CH3
2,4,5-trimethoxyphenyl


641
H
CH3
2,4,5-trimethoxyphenyl


642
CH3
H
2,4,5-trimethoxyphenyl


643
OH
H
2,4,5-trimethoxyphenyl


644
C(CH3)3
H
2,4,5-trimethoxyphenyl


645
CF3
H
2,4,5-trimethoxyphenyl


646
CH(CH3)2
H
2,4,5-trimethoxyphenyl


647
2-furyl
H
2,4,5-trimethoxyphenyl


648
cyclohexyl
H
2,4,5-trimethoxyphenyl


649
cyclobutyl
H
2,4,5-trimethoxyphenyl


650
4-methylphenyl
H
2,4,5-trimethoxyphenyl


651
2-methylphenyl
H
2,4,5-trimethoxyphenyl


652
2-fluorophenyl
H
2,4,5-trimethoxyphenyl


653
3-fluorophenyl
H
2,4,5-trimethoxyphenyl


654
4-fluorophenyl
H
2,4,5-trimethoxyphenyl


655
OH
CH3
2,4,5-trimethoxyphenyl


656
OH
CF3
2,4,5-trimethoxyphenyl


657
OH
F
2,4,5-trimethoxyphenyl


658
OH
CN
2,4,5-trimethoxyphenyl


659
OH
Cl
2,4,5-trimethoxyphenyl


660
OH
C2H5
2,4,5-trimethoxyphenyl


661
phenyl
H
2,3,4-trimethoxyphenyl


662
phenyl
CH3
2,3,4-trimethoxyphenyl


663
H
CH3
2,3,4-trimethoxyphenyl


664
CH3
H
2,3,4-trimethoxyphenyl


665
OH
H
2,3,4-trimethoxyphenyl


666
C(CH3)3
H
2,3,4-trimethoxyphenyl


667
CF3
H
2,3,4-trimethoxyphenyl


668
CH(CH3)2
H
2,3,4-trimethoxyphenyl


669
2-furyl
H
2,3,4-trimethoxyphenyl


670
cyclohexyl
H
2,3,4-trimethoxyphenyl


671
cyclobutyl
H
2,3,4-trimethoxyphenyl


672
4-methylphenyl
H
2,3,4-trimethoxyphenyl


673
2-methylphenyl
H
2,3,4-trimethoxyphenyl


674
2-fluorophenyl
H
2,3,4-trimethoxyphenyl


675
3-fluorophenyl
H
2,3,4-trimethoxyphenyl


676
4-fluorophenyl
H
2,3,4-trimethoxyphenyl


677
OH
CH3
2,3,4-trimethoxyphenyl


678
OH
CF3
2,3,4-trimethoxyphenyl


679
OH
F
2,3,4-trimethoxyphenyl


680
OH
CN
2,3,4-trimethoxyphenyl


681
OH
Cl
2,3,4-trimethoxyphenyl


682
OH
C2H5
2,3,4-trimethoxyphenyl


683
phenyl
H
4-tert-butylphenyl


684
phenyl
CH3
4-tert-butylphenyl


685
H
CH3
4-tert-butylphenyl


686
CH3
H
4-tert-butylphenyl


687
OH
H
4-tert-butylphenyl


688
C(CH3)3
H
4-tert-butylphenyl


689
CF3
H
4-tert-butylphenyl


690
CH(CH3)2
H
4-tert-butylphenyl


691
2-furyl
H
4-tert-butylphenyl


692
cyclohexyl
H
4-tert-butylphenyl


693
cyclobutyl
H
4-tert-butylphenyl


694
4-methylphenyl
H
4-tert-butylphenyl


695
2-methylphenyl
H
4-tert-butylphenyl


696
2-fluorophenyl
H
4-tert-butylphenyl


697
3-fluorophenyl
H
4-tert-butylphenyl


698
4-fluorophenyl
H
4-tert-butylphenyl


699
OH
CH3
4-tert-butylphenyl


700
OH
CF3
4-tert-butylphenyl


701
OH
F
4-tert-butylphenyl


702
OH
CN
4-tert-butylphenyl


703
OH
Cl
4-tert-butylphenyl


704
OH
C2H5
4-tert-butylphenyl


705
phenyl
H
4-methylphenyl


706
phenyl
CH3
4-methylphenyl


707
H
CH3
4-methylphenyl


708
CH3
H
4-methylphenyl


709
OH
H
4-methylphenyl


710
C(CH3)3
H
4-methylphenyl


711
CF3
H
4-methylphenyl


712
CH(CH3)2
H
4-methylphenyl


713
2-furyl
H
4-methylphenyl


714
cyclohexyl
H
4-methylphenyl


715
cyclobutyl
H
4-methylphenyl


716
4-methylphenyl
H
4-methylphenyl


717
2-methylphenyl
H
4-methylphenyl


718
2-fluorophenyl
H
4-methylphenyl


719
3-fluorophenyl
H
4-methylphenyl


720
4-fluorophenyl
H
4-methylphenyl


721
OH
CH3
4-methylphenyl


722
OH
CF3
4-methylphenyl


723
OH
F
4-methylphenyl


724
OH
CN
4-methylphenyl


725
OH
Cl
4-methylphenyl


726
OH
C2H5
4-methylphenyl


727
phenyl
H
3-methoxyphenyl


728
phenyl
CH3
3-methoxyphenyl


729
H
CH3
3-methoxyphenyl


730
CH3
H
3-methoxyphenyl


731
OH
H
3-methoxyphenyl


732
C(CH3)3
H
3-methoxyphenyl


733
CF3
H
3-methoxyphenyl


734
CH(CH3)2
H
3-methoxyphenyl


735
2-furyl
H
3-methoxyphenyl


736
cyclohexyl
H
3-methoxyphenyl


737
cyclobutyl
H
3-methoxyphenyl


738
4-methylphenyl
H
3-methoxyphenyl


739
2-methylphenyl
H
3-methoxyphenyl


740
2-fluorophenyl
H
3-methoxyphenyl


741
3-fluorophenyl
H
3-methoxyphenyl


742
4-fluorophenyl
H
3-methoxyphenyl


743
OH
CH3
3-methoxyphenyl


744
OH
CF3
3-methoxyphenyl


745
OH
F
3-methoxyphenyl


746
OH
CN
3-methoxyphenyl


747
OH
Cl
3-methoxyphenyl


748
OH
C2H5
3-methoxyphenyl


749
phenyl
H
4-methoxyphenyl


750
phenyl
CH3
4-methoxyphenyl


751
H
CH3
4-methoxyphenyl


752
CH3
H
4-methoxyphenyl


753
OH
H
4-methoxyphenyl


754
C(CH3)3
H
4-methoxyphenyl


755
CF3
H
4-methoxyphenyl


756
CH(CH3)2
H
4-methoxyphenyl


757
2-furyl
H
4-methoxyphenyl


758
cyclohexyl
H
4-methoxyphenyl


759
cyclobutyl
H
4-methoxyphenyl


760
4-methylphenyl
H
4-methoxyphenyl


761
2-methylphenyl
H
4-methoxyphenyl


762
2-fluorophenyl
H
4-methoxyphenyl


763
3-fluorophenyl
H
4-methoxyphenyl


764
4-fluorophenyl
H
4-methoxyphenyl


765
OH
CH3
4-methoxyphenyl


766
OH
CF3
4-methoxyphenyl


767
OH
F
4-methoxyphenyl


768
OH
CN
4-methoxyphenyl


769
OH
Cl
4-methoxyphenyl


770
OH
C2H5
4-methoxyphenyl


771
phenyl
H
4-trifluoromethylphenyl


772
phenyl
CH3
4-trifluoromethylphenyl


773
H
CH3
4-trifluoromethylphenyl


774
CH3
H
4-trifluoromethylphenyl


775
OH
H
4-trifluoromethylphenyl


776
C(CH3)3
H
4-trifluoromethylphenyl


777
CF3
H
4-trifluoromethylphenyl


778
CH(CH3)2
H
4-trifluoromethylphenyl


779
2-furyl
H
4-trifluoromethylphenyl


780
cyclohexyl
H
4-trifluoromethylphenyl


781
cyclobutyl
H
4-trifluoromethylphenyl


782
4-methylphenyl
H
4-trifluoromethylphenyl


783
2-methylphenyl
H
4-trifluoromethylphenyl


784
2-fluorophenyl
H
4-trifluoromethylphenyl


785
3-fluorophenyl
H
4-trifluoromethylphenyl


786
4-fluorophenyl
H
4-trifluoromethylphenyl


787
OH
CH3
4-trifluoromethylphenyl


788
OH
CF3
4-trifluoromethylphenyl


789
OH
F
4-trifluoromethylphenyl


790
OH
CN
4-trifluoromethylphenyl


791
OH
Cl
4-trifluoromethylphenyl


792
OH
C2H5
4-trifluoromethylphenyl


793
phenyl
H
2-chloro-4-trifluoromethylphenyl


794
phenyl
CH3
2-chloro-4-trifluoromethylphenyl


795
H
CH3
2-chloro-4-trifluoromethylphenyl


796
CH3
H
2-chloro-4-trifluoromethylphenyl


797
OH
H
2-chloro-4-trifluoromethylphenyl


798
C(CH3)3
H
2-chloro-4-trifluoromethylphenyl


799
CF3
H
2-chloro-4-trifluoromethylphenyl


800
CH(CH3)2
H
2-chloro-4-trifluoromethylphenyl


801
2-furyl
H
2-chloro-4-trifluoromethylphenyl


802
cyclohexyl
H
2-chloro-4-trifluoromethylphenyl


803
cyclobutyl
H
2-chloro-4-trifluoromethylphenyl


804
4-methylphenyl
H
2-chloro-4-trifluoromethylphenyl


805
2-methylphenyl
H
2-chloro-4-trifluoromethylphenyl


806
2-fluorophenyl
H
2-chloro-4-trifluoromethylphenyl


807
3-fluorophenyl
H
2-chloro-4-trifluoromethylphenyl


808
4-fluorophenyl
H
2-chloro-4-trifluoromethylphenyl


809
OH
CH3
2-chloro-4-trifluoromethylphenyl


810
OH
CF3
2-chloro-4-trifluoromethylphenyl


811
OH
F
2-chloro-4-trifluoromethylphenyl


812
OH
CN
2-chloro-4-trifluoromethylphenyl


813
OH
Cl
2-chloro-4-trifluoromethylphenyl


814
OH
C2H5
2-chloro-4-trifluoromethylphenyl


815
phenyl
H
3-chloro-4-trifluoromethylphenyl


816
phenyl
CH3
3-chloro-4-trifluoromethylphenyl


817
H
CH3
3-chloro-4-trifluoromethylphenyl


818
CH3
H
3-chloro-4-trifluoromethylphenyl


819
OH
H
3-chloro-4-trifluoromethylphenyl


820
C(CH3)3
H
3-chloro-4-trifluoromethylphenyl


821
CF3
H
3-chloro-4-trifluoromethylphenyl


822
CH(CH3)2
H
3-chloro-4-trifluoromethylphenyl


823
2-furyl
H
3-chloro-4-trifluoromethylphenyl


824
cyclohexyl
H
3-chloro-4-trifluoromethylphenyl


825
cyclobutyl
H
3-chloro-4-trifluoromethylphenyl


826
4-methylphenyl
H
3-chloro-4-trifluoromethylphenyl


827
2-methylphenyl
H
3-chloro-4-trifluoromethylphenyl


828
2-fluorophenyl
H
3-chloro-4-trifluoromethylphenyl


829
3-fluorophenyl
H
3-chloro-4-trifluoromethylphenyl


830
4-fluorophenyl
H
3-chloro-4-trifluoromethylphenyl


831
OH
CH3
3-chloro-4-trifluoromethylphenyl


832
OH
CF3
3-chloro-4-trifluoromethylphenyl


833
OH
F
3-chloro-4-trifluoromethylphenyl


834
OH
CN
3-chloro-4-trifluoromethylphenyl


835
OH
Cl
3-chloro-4-trifluoromethylphenyl


836
OH
C2H5
3-chloro-4-trifluoromethylphenyl


837
phenyl
H
2-trifluoromethylphenyl


838
phenyl
CH3
2-trifluoromethylphenyl


839
H
CH3
2-trifluoromethylphenyl


840
CH3
H
2-trifluoromethylphenyl


841
OH
H
2-trifluoromethylphenyl


842
C(CH3)3
H
2-trifluoromethylphenyl


843
CF3
H
2-trifluoromethylphenyl


844
CH(CH3)2
H
2-trifluoromethylphenyl


845
2-furyl
H
2-trifluoromethylphenyl


846
cyclohexyl
H
2-trifluoromethylphenyl


847
cyclobutyl
H
2-trifluoromethylphenyl


848
4-methylphenyl
H
2-trifluoromethylphenyl


849
2-methylphenyl
H
2-trifluoromethylphenyl


850
2-fluorophenyl
H
2-trifluoromethylphenyl


851
3-fluorophenyl
H
2-trifluoromethylphenyl


852
4-fluorophenyl
H
2-trifluoromethylphenyl


853
OH
CH3
2-trifluoromethylphenyl


854
OH
CF3
2-trifluoromethylphenyl


855
OH
F
2-trifluoromethylphenyl


856
OH
CN
2-trifluoromethylphenyl


857
OH
Cl
2-trifluoromethylphenyl


858
OH
C2H5
2-trifluoromethylphenyl


859
phenyl
H
4-trifluoromethoxyphenyl


860
phenyl
CH3
4-trifluoromethoxyphenyl


861
H
CH3
4-trifluoromethoxyphenyl


862
CH3
H
4-trifluoromethoxyphenyl


863
OH
H
4-trifluoromethoxyphenyl


864
C(CH3)3
H
4-trifluoromethoxyphenyl


865
CF3
H
4-trifluoromethoxyphenyl


866
CH(CH3)2
H
4-trifluoromethoxyphenyl


867
2-furyl
H
4-trifluoromethoxyphenyl


868
cyclohexyl
H
4-trifluoromethoxyphenyl


869
cyclobutyl
H
4-trifluoromethoxyphenyl


870
4-methylphenyl
H
4-trifluoromethoxyphenyl


871
2-methylphenyl
H
4-trifluoromethoxyphenyl


872
2-fluorophenyl
H
4-trifluoromethoxyphenyl


873
3-fluorophenyl
H
4-trifluoromethoxyphenyl


874
4-fluorophenyl
H
4-trifluoromethoxyphenyl


875
OH
CH3
4-trifluoromethoxyphenyl


876
OH
CF3
4-trifluoromethoxyphenyl


877
OH
F
4-trifluoromethoxyphenyl


878
OH
CN
4-trifluoromethoxyphenyl


879
OH
Cl
4-trifluoromethoxyphenyl


880
OH
C2H5
4-trifluoromethoxyphenyl


881
phenyl
H
4-isopropylphenyl


882
phenyl
CH3
4-isopropylphenyl


883
H
CH3
4-isopropylphenyl


884
CH3
H
4-isopropylphenyl


885
OH
H
4-isopropylphenyl


886
C(CH3)3
H
4-isopropylphenyl


887
CF3
H
4-isopropylphenyl


888
CH(CH3)2
H
4-isopropylphenyl


889
2-furyl
H
4-isopropylphenyl


890
cyclohexyl
H
4-isopropylphenyl


891
cyclobutyl
H
4-isopropylphenyl


892
4-methylphenyl
H
4-isopropylphenyl


893
2-methylphenyl
H
4-isopropylphenyl


894
2-fluorophenyl
H
4-isopropylphenyl


895
3-fluorophenyl
H
4-isopropylphenyl


896
4-fluorophenyl
H
4-isopropylphenyl


897
OH
CH3
4-isopropylphenyl


898
OH
CF3
4-isopropylphenyl


899
OH
F
4-isopropylphenyl


900
OH
CN
4-isopropylphenyl


901
OH
Cl
4-isopropylphenyl


902
OH
C2H5
4-isopropylphenyl


903
phenyl
H
4-cyclopropylphenyl


904
phenyl
CH3
4-cyclopropylphenyl


905
H
CH3
4-cyclopropylphenyl


906
CH3
H
4-cyclopropylphenyl


907
OH
H
4-cyclopropylphenyl


908
C(CH3)3
H
4-cyclopropylphenyl


909
CF3
H
4-cyclopropylphenyl


910
CH(CH3)2
H
4-cyclopropylphenyl


911
2-furyl
H
4-cyclopropylphenyl


912
cyclohexyl
H
4-cyclopropylphenyl


913
cyclobutyl
H
4-cyclopropylphenyl


914
4-methylphenyl
H
4-cyclopropylphenyl


915
2-methylphenyl
H
4-cyclopropylphenyl


916
2-fluorophenyl
H
4-cyclopropylphenyl


917
3-fluorophenyl
H
4-cyclopropylphenyl


918
4-fluorophenyl
H
4-cyclopropylphenyl


919
OH
CH3
4-cyclopropylphenyl


920
OH
CF3
4-cyclopropylphenyl


921
OH
F
4-cyclopropylphenyl


922
OH
CN
4-cyclopropylphenyl


923
OH
Cl
4-cyclopropylphenyl


924
OH
C2H5
4-cyclopropylphenyl


925
phenyl
H
4-dimethylaminophenyl


926
phenyl
CH3
4-dimethylaminophenyl


927
H
CH3
4-dimethylaminophenyl


928
CH3
H
4-dimethylaminophenyl


929
OH
H
4-dimethylaminophenyl


930
C(CH3)3
H
4-dimethylaminophenyl


931
CF3
H
4-dimethylaminophenyl


932
CH(CH3)2
H
4-dimethylaminophenyl


933
2-furyl
H
4-dimethylaminophenyl


934
cyclohexyl
H
4-dimethylaminophenyl


935
cyclobutyl
H
4-dimethylaminophenyl


936
4-methylphenyl
H
4-dimethylaminophenyl


937
2-methylphenyl
H
4-dimethylaminophenyl


938
2-fluorophenyl
H
4-dimethylaminophenyl


939
3-fluorophenyl
H
4-dimethylaminophenyl


940
4-fluorophenyl
H
4-dimethylaminophenyl


941
OH
CH3
4-dimethylaminophenyl


942
OH
CF3
4-dimethylaminophenyl


943
OH
F
4-dimethylaminophenyl


944
OH
CN
4-dimethylaminophenyl


945
OH
Cl
4-dimethylaminophenyl


946
OH
C2H5
4-dimethylaminophenyl


947
phenyl
H
2-pyridinyl


948
phenyl
CH3
2-pyridinyl


949
H
CH3
2-pyridinyl


950
CH3
H
2-pyridinyl


951
OH
H
2-pyridinyl


952
C(CH3)3
H
2-pyridinyl


953
CF3
H
2-pyridinyl


954
CH(CH3)2
H
2-pyridinyl


955
2-furyl
H
2-pyridinyl


956
cyclohexyl
H
2-pyridinyl


957
cyclobutyl
H
2-pyridinyl


958
4-methylphenyl
H
2-pyridinyl


959
2-methylphenyl
H
2-pyridinyl


960
2-fluorophenyl
H
2-pyridinyl


961
3-fluorophenyl
H
2-pyridinyl


962
4-fluorophenyl
H
2-pyridinyl


963
OH
CH3
2-pyridinyl


964
OH
CF3
2-pyridinyl


965
OH
F
2-pyridinyl


966
OH
CN
2-pyridinyl


967
OH
Cl
2-pyridinyl


968
OH
C2H5
2-pyridinyl


969
phenyl
H
3-pyridinyl


970
phenyl
CH3
3-pyridinyl


971
H
CH3
3-pyridinyl


972
CH3
H
3-pyridinyl


973
OH
H
3-pyridinyl


974
C(CH3)3
H
3-pyridinyl


975
CF3
H
3-pyridinyl


976
CH(CH3)2
H
3-pyridinyl


977
2-furyl
H
3-pyridinyl


978
cyclohexyl
H
3-pyridinyl


979
cyclobutyl
H
3-pyridinyl


980
4-methylphenyl
H
3-pyridinyl


981
2-methylphenyl
H
3-pyridinyl


982
2-fluorophenyl
H
3-pyridinyl


983
3-fluorophenyl
H
3-pyridinyl


984
4-fluorophenyl
H
3-pyridinyl


985
OH
CH3
3-pyridinyl


986
OH
CF3
3-pyridinyl


987
OH
F
3-pyridinyl


988
OH
CN
3-pyridinyl


989
OH
Cl
3-pyridinyl


990
OH
C2H5
3-pyridinyl


991
phenyl
H
4-pyridinyl


992
phenyl
CH3
4-pyridinyl


993
H
CH3
4-pyridinyl


994
CH3
H
4-pyridinyl


995
OH
H
4-pyridinyl


996
C(CH3)3
H
4-pyridinyl


997
CF3
H
4-pyridinyl


998
CH(CH3)2
H
4-pyridinyl


999
2-furyl
H
4-pyridinyl


1000
cyclohexyl
H
4-pyridinyl


1001
cyclobutyl
H
4-pyridinyl


1002
4-methylphenyl
H
4-pyridinyl


1003
2-methylphenyl
H
4-pyridinyl


1004
2-fluorophenyl
H
4-pyridinyl


1005
3-fluorophenyl
H
4-pyridinyl


1006
4-fluorophenyl
H
4-pyridinyl


1007
OH
CH3
4-pyridinyl


1008
OH
CF3
4-pyridinyl


1009
OH
F
4-pyridinyl


1010
OH
CN
4-pyridinyl


1011
OH
Cl
4-pyridinyl


1012
OH
C2H5
4-pyridinyl


1013
phenyl
H
4,6-dimethoxypyrimidin-2-yl


1014
phenyl
CH3
4,6-dimethoxypyrimidin-2-yl


1015
H
CH3
4,6-dimethoxypyrimidin-2-yl


1016
CH3
H
4,6-dimethoxypyrimidin-2-yl


1017
OH
H
4,6-dimethoxypyrimidin-2-yl


1018
C(CH3)3
H
4,6-dimethoxypyrimidin-2-yl


1019
CF3
H
4,6-dimethoxypyrimidin-2-yl


1020
CH(CH3)2
H
4,6-dimethoxypyrimidin-2-yl


1021
2-furyl
H
4,6-dimethoxypyrimidin-2-yl


1022
cyclohexyl
H
4,6-dimethoxypyrimidin-2-yl


1023
cyclobutyl
H
4,6-dimethoxypyrimidin-2-yl


1024
4-methylphenyl
H
4,6-dimethoxypyrimidin-2-yl


1025
2-methylphenyl
H
4,6-dimethoxypyrimidin-2-yl


1026
2-fluorophenyl
H
4,6-dimethoxypyrimidin-2-yl


1027
3-fluorophenyl
H
4,6-dimethoxypyrimidin-2-yl


1028
4-fluorophenyl
H
4,6-dimethoxypyrimidin-2-yl


1029
OH
CH3
4,6-dimethoxypyrimidin-2-yl


1030
OH
CF3
4,6-dimethoxypyrimidin-2-yl


1031
OH
F
4,6-dimethoxypyrimidin-2-yl


1032
OH
CN
4,6-dimethoxypyrimidin-2-yl


1033
OH
Cl
4,6-dimethoxypyrimidin-2-yl


1034
OH
C2H5
4,6-dimethoxypyrimidin-2-yl


1035
phenyl
H
2-thienyl


1036
phenyl
CH3
2-thienyl


1037
H
CH3
2-thienyl


1038
CH3
H
2-thienyl


1039
OH
H
2-thienyl


1040
C(CH3)3
H
2-thienyl


1041
CF3
H
2-thienyl


1042
CH(CH3)2
H
2-thienyl


1043
2-furyl
H
2-thienyl


1044
cyclohexyl
H
2-thienyl


1045
cyclobutyl
H
2-thienyl


1046
4-methylphenyl
H
2-thienyl


1047
2-methylphenyl
H
2-thienyl


1048
2-fluorophenyl
H
2-thienyl


1049
3-fluorophenyl
H
2-thienyl


1050
4-fluorophenyl
H
2-thienyl


1051
OH
CH3
2-thienyl


1052
OH
CF3
2-thienyl


1053
OH
F
2-thienyl


1054
OH
CN
2-thienyl


1055
OH
Cl
2-thienyl


1056
OH
C2H5
2-thienyl


1057
phenyl
H
2-furyl


1058
phenyl
CH3
2-furyl


1059
H
CH3
2-furyl


1060
CH3
H
2-furyl


1061
OH
H
2-furyl


1062
C(CH3)3
H
2-furyl


1063
CF3
H
2-furyl


1064
CH(CH3)2
H
2-furyl


1065
2-furyl
H
2-furyl


1066
cyclohexyl
H
2-furyl


1067
cyclobutyl
H
2-furyl


1068
4-methylphenyl
H
2-furyl


1069
2-methylphenyl
H
2-furyl


1070
2-fluorophenyl
H
2-furyl


1071
3-fluorophenyl
H
2-furyl


1072
4-fluorophenyl
H
2-furyl


1073
OH
CH3
2-furyl


1074
OH
CF3
2-furyl


1075
OH
F
2-furyl


1076
OH
CN
2-furyl


1077
OH
Cl
2-furyl


1078
OH
C2H5
2-furyl


1079
phenyl
H
benzimidazol-2-yl


1080
phenyl
CH3
benzimidazol-2-yl


1081
H
CH3
benzimidazol-2-yl


1082
CH3
H
benzimidazol-2-yl


1083
OH
H
benzimidazol-2-yl


1084
C(CH3)3
H
benzimidazol-2-yl


1085
CF3
H
benzimidazol-2-yl


1086
CH(CH3)2
H
benzimidazol-2-yl


1087
2-furyl
H
benzimidazol-2-yl


1088
cyclohexyl
H
benzimidazol-2-yl


1089
cyclobutyl
H
benzimidazol-2-yl


1090
4-methylphenyl
H
benzimidazol-2-yl


1091
2-methylphenyl
H
benzimidazol-2-yl


1092
2-fluorophenyl
H
benzimidazol-2-yl


1093
3-fluorophenyl
H
benzimidazol-2-yl


1094
4-fluorophenyl
H
benzimidazol-2-yl


1095
OH
CH3
benzimidazol-2-yl


1096
OH
CF3
benzimidazol-2-yl


1097
OH
F
benzimidazol-2-yl


1098
OH
CN
benzimidazol-2-yl


1099
OH
Cl
benzimidazol-2-yl


1100
OH
C2H5
benzimidazol-2-yl


1101
phenyl
H
benzoxazol-2-yl


1102
phenyl
CH3
benzoxazol-2-yl


1103
H
CH3
benzoxazol-2-yl


1104
CH3
H
benzoxazol-2-yl


1105
OH
H
benzoxazol-2-yl


1106
C(CH3)3
H
benzoxazol-2-yl


1107
CF3
H
benzoxazol-2-yl


1108
CH(CH3)2
H
benzoxazol-2-yl


1109
2-furyl
H
benzoxazol-2-yl


1110
cyclohexyl
H
benzoxazol-2-yl


1111
cyclobutyl
H
benzoxazol-2-yl


1112
4-methylphenyl
H
benzoxazol-2-yl


1113
2-methylphenyl
H
benzoxazol-2-yl


1114
2-fluorophenyl
H
benzoxazol-2-yl


1115
3-fluorophenyl
H
benzoxazol-2-yl


1116
4-fluorophenyl
H
benzoxazol-2-yl


1117
OH
CH3
benzoxazol-2-yl


1118
OH
CF3
benzoxazol-2-yl


1119
OH
F
benzoxazol-2-yl


1120
OH
CN
benzoxazol-2-yl


1121
OH
Cl
benzoxazol-2-yl


1122
OH
C2H5
benzoxazol-2-yl


1123
phenyl
H
benzothiazol-2-yl


1124
phenyl
CH3
benzothiazol-2-yl


1125
H
CH3
benzothiazol-2-yl


1126
CH3
H
benzothiazol-2-yl


1127
OH
H
benzothiazol-2-yl


1128
C(CH3)3
H
benzothiazol-2-yl


1129
CF3
H
benzothiazol-2-yl


1130
CH(CH3)2
H
benzothiazol-2-yl


1131
2-furyl
H
benzothiazol-2-yl


1132
cyclohexyl
H
benzothiazol-2-yl


1133
cyclobutyl
H
benzothiazol-2-yl


1134
4-methylphenyl
H
benzothiazol-2-yl


1135
2-methylphenyl
H
benzothiazol-2-yl


1136
2-fluorophenyl
H
benzothiazol-2-yl


1137
3-fluorophenyl
H
benzothiazol-2-yl


1138
4-fluorophenyl
H
benzothiazol-2-yl


1139
OH
CH3
benzothiazol-2-yl


1140
OH
CF3
benzothiazol-2-yl


1141
OH
F
benzothiazol-2-yl


1142
OH
CN
benzothiazol-2-yl


1143
OH
Cl
benzothiazol-2-yl


1144
OH
C2H5
benzothiazol-2-yl


1145
phenyl
H
2-chlorothiazol-5-yl


1146
phenyl
CH3
2-chlorothiazol-5-yl


1147
H
CH3
2-chlorothiazol-5-yl


1148
CH3
H
2-chlorothiazol-5-yl


1149
OH
H
2-chlorothiazol-5-yl


1150
C(CH3)3
H
2-chlorothiazol-5-yl


1151
CF3
H
2-chlorothiazol-5-yl


1152
CH(CH3)2
H
2-chlorothiazol-5-yl


1153
2-furyl
H
2-chlorothiazol-5-yl


1154
cyclohexyl
H
2-chlorothiazol-5-yl


1155
cyclobutyl
H
2-chlorothiazol-5-yl


1156
4-methylphenyl
H
2-chlorothiazol-5-yl


1157
2-methylphenyl
H
2-chlorothiazol-5-yl


1158
2-fluorophenyl
H
2-chlorothiazol-5-yl


1159
3-fluorophenyl
H
2-chlorothiazol-5-yl


1160
4-fluorophenyl
H
2-chlorothiazol-5-yl


1161
OH
CH3
2-chlorothiazol-5-yl


1162
OH
CF3
2-chlorothiazol-5-yl


1163
OH
F
2-chlorothiazol-5-yl


1164
OH
CN
2-chlorothiazol-5-yl


1165
OH
Cl
2-chlorothiazol-5-yl


1166
OH
C2H5
2-chlorothiazol-5-yl


1167
phenyl
H
6-chloropyridin-2-yl


1168
phenyl
CH3
6-chloropyridin-2-yl


1169
H
CH3
6-chloropyridin-2-yl


1170
CH3
H
6-chloropyridin-2-yl


1171
OH
H
6-chloropyridin-2-yl


1172
C(CH3)3
H
6-chloropyridin-2-yl


1173
CF3
H
6-chloropyridin-2-yl


1174
CH(CH3)2
H
6-chloropyridin-2-yl


1175
2-furyl
H
6-chloropyridin-2-yl


1176
cyclohexyl
H
6-chloropyridin-2-yl


1177
cyclobutyl
H
6-chloropyridin-2-yl


1178
4-methylphenyl
H
6-chloropyridin-2-yl


1179
2-methylphenyl
H
6-chloropyridin-2-yl


1180
2-fluorophenyl
H
6-chloropyridin-2-yl


1181
3-fluorophenyl
H
6-chloropyridin-2-yl


1182
4-fluorophenyl
H
6-chloropyridin-2-yl


1183
OH
CH3
6-chloropyridin-2-yl


1184
OH
CF3
6-chloropyridin-2-yl


1185
OH
F
6-chloropyridin-2-yl


1186
OH
CN
6-chloropyridin-2-yl


1187
OH
Cl
6-chloropyridin-2-yl


1188
OH
C2H5
6-chloropyridin-2-yl


1189
phenyl
H
1-methylimidazol-2-yl


1190
phenyl
CH3
1-methylimidazol-2-yl


1191
H
CH3
1-methylimidazol-2-yl


1192
CH3
H
1-methylimidazol-2-yl


1193
OH
H
1-methylimidazol-2-yl


1194
C(CH3)3
H
1-methylimidazol-2-yl


1195
CF3
H
1-methylimidazol-2-yl


1196
CH(CH3)2
H
1-methylimidazol-2-yl


1197
2-furyl
H
1-methylimidazol-2-yl


1198
cyclohexyl
H
1-methylimidazol-2-yl


1199
cyclobutyl
H
1-methylimidazol-2-yl


1200
4-methylphenyl
H
1-methylimidazol-2-yl


1201
2-methylphenyl
H
1-methylimidazol-2-yl


1202
2-fluorophenyl
H
1-methylimidazol-2-yl


1203
3-fluorophenyl
H
1-methylimidazol-2-yl


1204
4-fluorophenyl
H
1-methylimidazol-2-yl


1205
OH
CH3
1-methylimidazol-2-yl


1206
OH
CF3
1-methylimidazol-2-yl


1207
OH
F
1-methylimidazol-2-yl


1208
OH
CN
1-methylimidazol-2-yl


1209
OH
Cl
1-methylimidazol-2-yl


1210
OH
C2H5
1-methylimidazol-2-yl


1211
phenyl
H
2-methylthiazol-5-yl


1212
phenyl
CH3
2-methylthiazol-5-yl


1213
H
CH3
2-methylthiazol-5-yl


1214
CH3
H
2-methylthiazol-5-yl


1215
OH
H
2-methylthiazol-5-yl


1216
C(CH3)3
H
2-methylthiazol-5-yl


1217
CF3
H
2-methylthiazol-5-yl


1218
CH(CH3)2
H
2-methylthiazol-5-yl


1219
2-furyl
H
2-methylthiazol-5-yl


1220
cyclohexyl
H
2-methylthiazol-5-yl


1221
cyclobutyl
H
2-methylthiazol-5-yl


1222
4-methylphenyl
H
2-methylthiazol-5-yl


1223
2-methylphenyl
H
2-methylthiazol-5-yl


1224
2-fluorophenyl
H
2-methylthiazol-5-yl


1225
3-fluorophenyl
H
2-methylthiazol-5-yl


1226
4-fluorophenyl
H
2-methylthiazol-5-yl


1227
OH
CH3
2-methylthiazol-5-yl


1228
OH
CF3
2-methylthiazol-5-yl


1229
OH
F
2-methylthiazol-5-yl


1230
OH
CN
2-methylthiazol-5-yl


1231
OH
Cl
2-methylthiazol-5-yl


1232
OH
C2H5
2-methylthiazol-5-yl


1233
phenyl
H
2-methyl-α-naphthyl


1234
phenyl
CH3
2-methyl-α-naphthyl


1235
H
CH3
2-methyl-α-naphthyl


1236
CH3
H
2-methyl-α-naphthyl


1237
OH
H
2-methyl-α-naphthyl


1238
C(CH3)3
H
2-methyl-α-naphthyl


1239
CF3
H
2-methyl-α-naphthyl


1240
CH(CH3)2
H
2-methyl-α-naphthyl


1241
2-furyl
H
2-methyl-α-naphthyl


1242
cyclohexyl
H
2-methyl-α-naphthyl


1243
cyclobutyl
H
2-methyl-α-naphthyl


1244
4-methylphenyl
H
2-methyl-α-naphthyl


1245
2-methylphenyl
H
2-methyl-α-naphthyl


1246
2-fluorophenyl
H
2-methyl-α-naphthyl


1247
3-fluorophenyl
H
2-methyl-α-naphthyl


1248
4-fluorophenyl
H
2-methyl-α-naphthyl


1249
OH
CH3
2-methyl-α-naphthyl


1250
OH
CF3
2-methyl-α-naphthyl


1251
OH
F
2-methyl-α-naphthyl


1252
OH
CN
2-methyl-α-naphthyl


1253
OH
Cl
2-methyl-α-naphthyl


1254
OH
C2H5
2-methyl-α-naphthyl


1255
phenyl
H
α-naphthyl


1256
phenyl
CH3
α-naphthyl


1257
H
CH3
α-naphthyl


1258
CH3
H
α-naphthyl


1259
OH
H
α-naphthyl


1260
C(CH3)3
H
α-naphthyl


1261
CF3
H
α-naphthyl


1262
CH(CH3)2
H
α-naphthyl


1263
2-furyl
H
α-naphthyl


1264
cyclohexyl
H
α-naphthyl


1265
cyclobutyl
H
α-naphthyl


1266
4-methylphenyl
H
α-naphthyl


1267
2-methylphenyl
H
α-naphthyl


1268
2-fluorophenyl
H
α-naphthyl


1269
3-fluorophenyl
H
α-naphthyl


1270
4-fluorophenyl
H
α-naphthyl


1271
OH
CH3
α-naphthyl


1272
OH
CF3
α-naphthyl


1273
OH
F
α-naphthyl


1274
OH
CN
α-naphthyl


1275
OH
Cl
α-naphthyl


1276
OH
C2H5
α-naphthyl


1277
phenyl
H
benzo-1,3-dioxol-5-yl


1278
phenyl
CH3
benzo-1,3-dioxol-5-yl


1279
H
CH3
benzo-1,3-dioxol-5-yl


1280
CH3
H
benzo-1,3-dioxol-5-yl


1281
OH
H
benzo-1,3-dioxol-5-yl


1282
C(CH3)3
H
benzo-1,3-dioxol-5-yl


1283
CF3
H
benzo-1,3-dioxol-5-yl


1284
CH(CH3)2
H
benzo-1,3-dioxol-5-yl


1285
2-furyl
H
benzo-1,3-dioxol-5-yl


1286
cyclohexyl
H
benzo-1,3-dioxol-5-yl


1287
cyclobutyl
H
benzo-1,3-dioxol-5-yl


1288
4-methylphenyl
H
benzo-1,3-dioxol-5-yl


1289
2-methylphenyl
H
benzo-1,3-dioxol-5-yl


1290
2-fluorophenyl
H
benzo-1,3-dioxol-5-yl


1291
3-fluorophenyl
H
benzo-1,3-dioxol-5-yl


1292
4-fluorophenyl
H
benzo-1,3-dioxol-5-yl


1293
OH
CH3
benzo-1,3-dioxol-5-yl


1294
OH
CF3
benzo-1,3-dioxol-5-yl


1295
OH
F
benzo-1,3-dioxol-5-yl


1296
OH
CN
benzo-1,3-dioxol-5-yl


1297
OH
Cl
benzo-1,3-dioxol-5-yl


1298
OH
C2H5
benzo-1,3-dioxol-5-yl


1299
phenyl
H
2-cyanophenyl


1300
phenyl
CH3
2-cyanophenyl


1301
H
CH3
2-cyanophenyl


1302
CH3
H
2-cyanophenyl


1303
OH
H
2-cyanophenyl


1304
C(CH3)3
H
2-cyanophenyl


1305
CF3
H
2-cyanophenyl


1306
CH(CH3)2
H
2-cyanophenyl


1307
2-furyl
H
2-cyanophenyl


1308
cyclohexyl
H
2-cyanophenyl


1309
cyclobutyl
H
2-cyanophenyl


1310
4-methylphenyl
H
2-cyanophenyl


1311
2-methylphenyl
H
2-cyanophenyl


1312
2-fluorophenyl
H
2-cyanophenyl


1313
3-fluorophenyl
H
2-cyanophenyl


1314
4-fluorophenyl
H
2-cyanophenyl


1315
OH
CH3
2-cyanophenyl


1316
OH
CF3
2-cyanophenyl


1317
OH
F
2-cyanophenyl


1318
OH
CN
2-cyanophenyl


1319
OH
Cl
2-cyanophenyl


1320
OH
C2H5
2-cyanophenyl


1321
phenyl
H
4-cyanophenyl


1322
phenyl
CH3
4-cyanophenyl


1323
H
CH3
4-cyanophenyl


1324
CH3
H
4-cyanophenyl


1325
OH
H
4-cyanophenyl


1326
C(CH3)3
H
4-cyanophenyl


1327
CF3
H
4-cyanophenyl


1328
CH(CH3)2
H
4-cyanophenyl


1329
2-furyl
H
4-cyanophenyl


1330
cyclohexyl
H
4-cyanophenyl


1331
cyclobutyl
H
4-cyanophenyl


1332
4-methylphenyl
H
4-cyanophenyl


1333
2-methylphenyl
H
4-cyanophenyl


1334
2-fluorophenyl
H
4-cyanophenyl


1335
3-fluorophenyl
H
4-cyanophenyl


1336
4-fluorophenyl
H
4-cyanophenyl


1337
OH
CH3
4-cyanophenyl


1338
OH
CF3
4-cyanophenyl


1339
OH
F
4-cyanophenyl


1340
OH
CN
4-cyanophenyl


1341
OH
Cl
4-cyanophenyl


1342
OH
C2H5
4-cyanophenyl


1343
phenyl
H
3-trifluoromethylphenyl


1344
phenyl
CH3
3-trifluoromethylphenyl


1345
H
CH3
3-trifluoromethylphenyl


1346
CH3
H
3-trifluoromethylphenyl


1347
OH
H
3-trifluoromethylphenyl


1348
C(CH3)3
H
3-trifluoromethylphenyl


1349
CF3
H
3-trifluoromethylphenyl


1350
CH(CH3)2
H
3-trifluoromethylphenyl


1351
2-furyl
H
3-trifluoromethylphenyl


1352
cyclohexyl
H
3-trifluoromethylphenyl


1353
cyclobutyl
H
3-trifluoromethylphenyl


1354
4-methylphenyl
H
3-trifluoromethylphenyl


1355
2-methylphenyl
H
3-trifluoromethylphenyl


1356
2-fluorophenyl
H
3-trifluoromethylphenyl


1357
3-fluorophenyl
H
3-trifluoromethylphenyl


1358
4-fluorophenyl
H
3-trifluoromethylphenyl


1359
OH
CH3
3-trifluoromethylphenyl


1360
OH
CF3
3-trifluoromethylphenyl


1361
OH
F
3-trifluoromethylphenyl


1362
OH
CN
3-trifluoromethylphenyl


1363
OH
Cl
3-trifluoromethylphenyl


1364
OH
C2H5
3-trifluoromethylphenyl


1365
phenyl
H
4-methoxycarbonylphenyl


1366
phenyl
CH3
4-methoxycarbonylphenyl


1367
H
CH3
4-methoxycarbonylphenyl


1368
CH3
H
4-methoxycarbonylphenyl


1369
OH
H
4-methoxycarbonylphenyl


1370
C(CH3)3
H
4-methoxycarbonylphenyl


1371
CF3
H
4-methoxycarbonylphenyl


1372
CH(CH3)2
H
4-methoxycarbonylphenyl


1373
2-furyl
H
4-methoxycarbonylphenyl


1374
cyclohexyl
H
4-methoxycarbonylphenyl


1375
cyclobutyl
H
4-methoxycarbonylphenyl


1376
4-methylphenyl
H
4-methoxycarbonylphenyl


1377
2-methylphenyl
H
4-methoxycarbonylphenyl


1378
2-fluorophenyl
H
4-methoxycarbonylphenyl


1379
3-fluorophenyl
H
4-methoxycarbonylphenyl


1380
4-fluorophenyl
H
4-methoxycarbonylphenyl


1381
OH
CH3
4-methoxycarbonylphenyl


1382
OH
CF3
4-methoxycarbonylphenyl


1383
OH
F
4-methoxycarbonylphenyl


1384
OH
CN
4-methoxycarbonylphenyl


1385
OH
Cl
4-methoxycarbonylphenyl


1386
OH
C2H5
4-methoxycarbonylphenyl









Examples of further compounds of the general formula I.A are the compounds of the general formulae I.A-1a, I.A-2, I.A-2a, I.A-3, I.A-3a, I.A-4, I.A-4-a, I.A-5 and I.A-5a:







in which R1, R2 and Q have the aforementioned meanings, in particular the meanings indicated as preferred. Examples of such compounds are the compounds I.A-1a.1 to I.A-1a.1386, I.A-2.1 to I.A-2.1386, I.A-2a.1 to I.A-2a.1386, .A-3.1 to I.A-3.1386, I.A-3a. to I.A-3a.1386, A-4.1 to I.A-4.1386, I.A-4-a1. to I.A-4-a.1386, A-5.1 to I.A-5.1386, I.A-5a.1 to I.A-5a.1386, where the variables R1, R2 and Q in each case together have the meaning indicated in one line of Table 1, and for R1═OH the tautomers of these compounds. In the formulae I.A-3, I.A-3a, I.A-4 and I.A-4-a, * indicates a center of asymmetry. In this case, these formulae include both the R and the S enantiomer, and mixtures thereof, e.g. the racemates.

Further examples of compounds of the general formula I.A are the compounds of the general formula I.A-6




in which R1 and Ra have the meanings indicated above, in particular the meanings indicated as preferred, and p is 1, 2 or 3. The groups RQ may in each case be identical or different and also be connected together. Examples of such compounds are the compounds I.A-6.1 to I.A-6.225, where the variables R1 and Ra in each case together have the meanings indicated in one line of Table 2.











TABLE 2







R1
RQ


















1.
methyl
2,3-dichloro


2.
methyl
2,4-dichloro


3.
methyl
3,4-dichloro


4.
methyl
2-chloro-3-fluoro


5.
methyl
2-chloro-4-fluoro


6.
methyl
3-chloro-4-luoro


7.
methyl
2-fluoro-3-chloro


8.
methyl
2-fluoro-4-chloro


9.
methyl
3-fluoro-4-chloro


10.
methyl
2-chloro-3-methyl


11.
methyl
2-chloro-4-methyl


12.
methyl
3-chloro-4-methyl


13.
methyl
2-methyl-3-chloro


14.
methyl
2-methyl-4-chloro


15.
methyl
3-methyl-4-chloro


16.
methyl
2-chloro-3-methoxy


17.
methyl
2-chloro-4-methoxy


18.
methyl
3-chloro-4-methoxy


19.
methyl
2-methoxy-3-chloro


20.
methyl
2-methoxy-4-chloro


21.
methyl
3-methoxy-4-chloro


22.
methyl
2-chloro-3-trifluoromethyl


23.
methyl
2-chloro-4-trifluoromethyl


24.
methyl
3-chloro-4-trifluoromethyl


25.
methyl
2-trifluoromethyl-3-chloro


26.
methyl
2-trifluoromethyl-4-chloro


27.
methyl
3-trifluoromethyl-4-chloro


28.
methyl
2-chloro-3-trifluoromethoxy


29.
methyl
2-chloro-4-trifluoromethoxy


30.
methyl
3-chloro-4-trifluoromethoxy


31.
methyl
2-trifluoromethoxy-3-chloro


32.
methyl
2-trifluoromethoxy-4-chloro


33.
methyl
3-trifluoromethoxy-4-chloro


34.
methyl
2-chloro-3-hydroxy


35.
methyl
2-chloro-4-hydroxy


36.
methyl
3-chloro-4-hydroxy


37.
methyl
2-hydroxy-3-chloro


38.
methyl
2-hydroxy-4-chloro


39.
methyl
3-hydroxy-4-chloro


40.
methyl
2-chloro-3-cyano


41.
methyl
2-chloro-4-cyano


42.
methyl
3-chloro-4-cyano


43.
methyl
2-cyano-3-chloro


44.
methyl
2-cyano-4-chloro


45.
methyl
3-cyano-4-chloro


46.
methyl
2-chloro-3-dimethylamino


47.
methyl
2-chloro-4-dimethylamino


48.
methyl
3-chloro-4-dimethylamino


49.
methyl
2-dimethylamino-3-chloro


50.
methyl
2-dimethylamino-4-chloro


51.
methyl
3-dimethylamino-4-chloro


52.
methyl
2-chloro-3-cyclopropyl


53.
methyl
2-chloro-4-cyclopropyl


54.
methyl
3-chloro-4-cyclopropyl


55.
methyl
2-cyclopropyl-3-chloro


56.
methyl
2-cyclopropyl-4-chloro


57.
methyl
3-cyclopropyl-4-chloro


58.
methyl
2,3-dimethyl


59.
methyl
2,4-dimethyl


60.
methyl
3,4-dimethyl


61.
methyl
2,3-dimethoxy


62.
methyl
2,4-dimethoxy


63.
methyl
3,4-dimethoxy


64.
methyl
2-methyl-3-methoxy


65.
methyl
2-methyl-4-methoxy


66.
methyl
3-methyl-4-methoxy


67.
methyl
2-methoxy-3-methyl


68.
methyl
2-methoxy-4-methyl


69.
methyl
3-methoxy-4-methyl


70.
methyl
2-trifluoromethoxy-3-methoxy


71.
methyl
2-trifluoromethoxy-4-methoxy


72.
methyl
3-trifluoromethoxy-4-methoxy


73.
methyl
2-methoxy-3-trifluoromethoxy


74.
methyl
2-methoxy-4-trifluoromethoxy


75.
methyl
3-methoxy-4-trifluoromethoxy


76.
methoxy
2,3-dichloro


77.
methoxy
2,4-dichloro


78.
methoxy
3,4-dichloro


79.
methoxy
2-chloro-3-fluoro


80.
methoxy
2-chloro-4-fluoro


81.
methoxy
3-chloro-4-fluoro


82.
methoxy
2-fluoro-3-chloro


83.
methoxy
2-fluoro-4-chloro


84.
methoxy
3-fluoro-4-chloro


85.
methoxy
2-chloro-3-methyl


86.
methoxy
2-chloro-4-methyl


87.
methoxy
3-chloro-4-methyl


88.
methoxy
2-methyl-3-chloro


89.
methoxy
2-methyl-4-chloro


90.
methoxy
3-methyl-4-chloro


91.
methoxy
2-chloro-3-methoxy


92.
methoxy
2-chloro-4-methoxy


93.
methoxy
3-chloro-4-methoxy


94.
methoxy
2-methoxy-3-chloro


95.
methoxy
2-methoxy-4-chloro


96.
methoxy
3-methoxy-4-chloro


97.
methoxy
2-chloro-3-trifluoromethyl


98.
methoxy
2-chloro-4-trifluoromethyl


99.
methoxy
3-chloro-4-trifluoromethyl


100.
methoxy
2-trifluoromethyl-3-chloro


101.
methoxy
2-trifluoromethyl-4-chloro


102.
methoxy
3-trifluoromethyl-4-chloro


103.
methoxy
2-chloro-3-trifluoromethoxy


104.
methoxy
2-chloro-4-trifluoromethoxy


105.
methoxy
3-chloro-4-trifluoromethoxy


106.
methoxy
2-trifluoromethoxy-3-chloro


107.
methoxy
2-trifluoromethoxy-4-chloro


108.
methoxy
3-trifluoromethoxy-4-chloro


109.
methoxy
2-chloro-3-hydroxy


110.
methoxy
2-chloro-4-hydroxy


111.
methoxy
3-chloro-4-hydroxy


112.
methoxy
2-hydroxy-3-chloro


113.
methoxy
2-hydroxy-4-chloro


114.
methoxy
3-hydroxy-4-chloro


115.
methoxy
2-chloro-3-cyano


116.
methoxy
2-chloro-4-cyano


117.
methoxy
3-chloro-4-cyano


118.
methoxy
2-cyano-3-chloro


119.
methoxy
2-cyano-4-chloro


120.
methoxy
3-cyano-4-chloro


121.
methoxy
2-chloro-3-dimethylamino


122.
methoxy
2-chloro-4-dimethylamino


123.
methoxy
3-chloro-4-dimethylamino


124.
methoxy
2-dimethylamino-3-chloro


125.
methoxy
2-dimethylamino-4-chloro


126.
methoxy
3-dimethylamino-4-chloro


127.
methoxy
2-chloro-3-cyclopropyl


128.
methoxy
2-chloro-4-cyclopropyl


129.
methoxy
3-chloro-4-cyclopropyl


130.
methoxy
2-cyclopropyl-3-chloro


131.
methoxy
2-cyclopropyl-4-chloro


132.
methoxy
3-cyclopropyl-4-chloro


133.
methoxy
2,3-dimethyl


134.
methoxy
2,4-dimethyl


135.
methoxy
3,4-dimethyl


136.
methoxy
2,3-dimethoxy


137.
methoxy
2,4-dimethoxy


138.
methoxy
3,4-dimethoxy


139.
methoxy
2-methyl-3-methoxy


140.
methoxy
2-methyl-4-methoxy


141.
methoxy
3-methyl-4-methoxy


142.
methoxy
2-methoxy-3-methyl


143.
methoxy
2-methoxy-4-methyl


144.
methoxy
3-methoxy-4-methyl


145.
methoxy
2-trifluoromethoxy-3-methoxy


146.
methoxy
2-trifluoromethoxy-4-methoxy


147.
methoxy
3-trifluoromethoxy-4-methoxy


148.
methoxy
2-methoxy-3-trifluoromethoxy


149.
methoxy
2-methoxy-4-trifluoromethoxy


150.
methoxy
3-methoxy-4-trifluoromethoxy


151.
trifluoromethyl
2,3-dichloro


152.
trifluoromethyl
2,4-dichloro


153.
trifluoromethyl
3,4-dichloro


154.
trifluoromethyl
2-chloro-3-fluoro


155.
trifluoromethyl
2-chloro-4-fluoro


156.
trifluoromethyl
3-chloro-4-fluoro


157.
trifluoromethyl
2-fluoro-3-chloro


158.
trifluoromethyl
2-fluoro-4-chloro


159.
trifluoromethyl
3-fluoro-4-chloro


160.
trifluoromethyl
2-chloro-3-methyl


161.
trifluoromethyl
2-chloro-4-methyl


162.
trifluoromethyl
3-chloro-4-methyl


163.
trifluoromethyl
2-methyl-3-chloro


164.
trifluoromethyl
2-methyl-4-chloro


165.
trifluoromethyl
3-methyl-4-chloro


166.
trifluoromethyl
2-chloro-3-methoxy


167.
trifluoromethyl
2-chloro-4-methoxy


168.
trifluoromethyl
3-chloro-4-methoxy


169.
trifluoromethyl
2-methoxy-3-chloro


170.
trifluoromethyl
2-methoxy-4-chloro


171.
trifluoromethyl
3-methoxy-4-chloro


172.
trifluoromethyl
2-chloro-3-trifluoromethyl


173.
trifluoromethyl
2-chloro-4-trifluoromethyl


174.
trifluoromethyl
3-chloro-4-trifluoromethyl


175.
trifluoromethyl
2-trifluoromethyl-3-chloro


176.
trifluoromethyl
2-trifluoromethyl-4-chloro


177.
trifluoromethyl
3-trifluoromethyl-4-chloro


178.
trifluoromethyl
2-chloro-3-trifluoromethoxy


179.
trifluoromethyl
2-chloro-4-trifluoromethoxy


180.
trifluoromethyl
3-chloro-4-trifluoromethoxy


181.
trifluoromethyl
2-trifluoromethoxy-3-chloro


182.
trifluoromethyl
2-trifluoromethoxy-4-chloro


183.
trifluoromethyl
3-trifluoromethoxy-4-chloro


184.
trifluoromethyl
2-chloro-3-hydroxy


185.
trifluoromethyl
2-chloro-4-hydroxy


186.
trifluoromethyl
3-chloro-4-hydroxy


187.
trifluoromethyl
2-hydroxy-3-chloro


188.
trifluoromethyl
2-hydroxy-4-chloro


189.
trifluoromethyl
3-hydroxy-4-chloro


190.
trifluoromethyl
2-chloro-3-cyano


191.
trifluoromethyl
2-chloro-4-cyano


192.
trifluoromethyl
3-chloro-4-cyano


193.
trifluoromethyl
2-cyano-3-chloro


194.
trifluoromethyl
2-cyano-4-chloro


195.
trifluoromethyl
3-cyano-4-chloro


196.
trifluoromethyl
2-chloro-3-dimethylamino


197.
trifluoromethyl
2-chloro-4-dimethylamino


198.
trifluoromethyl
3-chloro-4-dimethylamino


199.
trifluoromethyl
2-dimethylamino-3-chloro


200.
trifluoromethyl
2-dimethylamino-4-chloro


201.
trifluoromethyl
3-dimethylamino-4-chloro


202.
trifluoromethyl
2-chloro-3-cyclopropyl


203.
trifluoromethyl
2-chloro-4-cyclopropyl


204.
trifluoromethyl
3-chloro-4-cyclopropyl


205.
trifluoromethyl
2-cyclopropyl-3-chloro


206.
trifluoromethyl
2-cyclopropyl-4-chloro


207.
trifluoromethyl
3-cyclopropyl-4-chloro


208.
trifluoromethyl
2,3-dimethyl


209.
trifluoromethyl
2,4-dimethyl


210.
trifluoromethyl
3,4-dimethyl


211.
trifluoromethyl
2,3-dimethoxy


212.
trifluoromethyl
2,4-dimethoxy


213.
trifluoromethyl
3,4-dimethoxy


214.
trifluoromethyl
2-methyl-3-methoxy


215.
trifluoromethyl
2-methyl-4-methoxy


216.
trifluoromethyl
3-methyl-4-methoxy


217.
trifluoromethyl
2-methoxy-3-methyl


218.
trifluoromethyl
2-methoxy-4-methyl


219.
trifluoromethyl
3-methoxy-4-methyl


220.
trifluoromethyl
2-trifluoromethoxy-3-methoxy


221.
trifluoromethyl
2-trifluoromethoxy-4-methoxy


222.
trifluoromethyl
3-trifluoromethoxy-4-methoxy


223.
trifluoromethyl
2-methoxy-3-trifluoromethoxy


224.
trifluoromethyl
2-methoxy-4-trifluoromethoxy


225.
trifluoromethyl
3-methoxy-4-trifluoromethoxy









The substituted N-heterocyclic compounds I of the invention are prepared in analogy to methods disclosed in the literature. One important route to the compounds I.A of the invention is shown in Scheme 1.




In Scheme 1, W, R1, R2, A1, X, Y and Q have the aforementioned meanings. L1 and L2 are nucleophilically displaceable leaving groups. Examples of suitable nucleophilically displaceable leaving groups are halogen, especially chlorine, bromine or iodine, alkyl- and arylsulfonate such as mesylate, tosylate. L1 and L2 are preferably different from one another and show different reactivity. For example, L1 is bromine or iodine and L2 is chlorine. The reaction conditions necessary for the reaction correspond to the reaction conditions usual for nucleophilic substitutions.
Compounds of the general formula IV are in some cases commercially available and/or disclosed in the literature, e.g. in Chem. Pharm. Bull. 1987, 35 (7), 2782-91; Bioorganical and Medicinal Chemistry Letters (BOMCL) 2002, 12 (8), 1149-52; J. Med. Chem. 1998, 33 (5), 339-47; J. Med. Chem. 1989, 32 (3), 593-7; JCS. Perkin Trans 1: Org. and Bioorg. Chem. 1998, 15, 2239-42; Chem. Pharm. Bull. 1988, 36 (12), 4825-33.
The pyrimidinone compounds of the formulae II (with W═N) are known and in some cases commercially available or can be prepared by known methods of pyrimidinone synthesis as described for example in Austr. J. Chem. 1968, 221, pp. 243-255; J. Med. Chem. 1978, 21, pp. 623-628; Tetrahedron Lett. 1986, 27, pp. 2611-2612; Chemiker Ztg. 1977, 6, p. 305.
The pyridinone compounds of the formulae II (with W═CH or CR1) are known and in some cases commercially available or can be prepared by known methods of pyridinone synthesis as described for example in J. Med. Chem. 16(5), 1973, pp. 524-528, J. Org. Chem., 67, 2002, pp. 4304-4308, Bioorg. Med. Chem. Lett, 12, 2002, pp. 3537-3541.
The compounds II can also be prepared by methods indicated in Schemes 2, 3 and 4.
Thus, the compounds of the formula II if R1 is optionally substituted alkenyl, optionally substituted phenyl or optionally substituted C-linked heteroaryl can be prepared by the route shown in Scheme 2 by Suzuki coupling.




In Scheme 2, W has the meanings indicated above. R1′ is optionally substituted alkenyl, optionally substituted phenyl or optionally substituted, C-linked heteroaryl. X′ is a group B(OH)2, B(OR)2 or is the residue (BO)3/3 derived from the corresponding boronic anhydride. “Pd” stands for a palladium(0) complex which preferably has 4 trialkylphosphine or triarylphosphine ligands. R2 has the meanings indicated above and is in particular hydrogen or C1-C4-alkyl.
The coupling of V with the compound R′-X′ takes place under the conditions of a Suzuki coupling (for review, see A. Suzuki et al. in Chem. Rev. 1995, 95, pp. 2457-2483). The reaction conditions necessary for the Suzuki coupling of 2,4-dichloropyrimidines V with R1—X′ are disclosed in the literature, e.g. in J. Org. Chem. 66(21) (2001), pp. 7124-7128. The 2-chloropyrimidine VI obtained in this way can be converted in a manner known per se, e.g. under the conditions indicated in Acta Chem. Scand. B, 1984, 38, pp. 505-508, into the corresponding 2-pyrimidinone II.
A further possibility is for the compounds of the formula II in which W═N and R1 is optionally substituted C1-C6-alkyl or C3-C6-cycloalkyl, in particular is ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, and R2 is H, to be prepared for example by the method shown in Scheme 3.




In Scheme 3, R′ is for example C1-C4-alkyl. In Scheme 3, firstly a ketone VII is converted into the ketal IX using a formic ester VIII, e.g. methyl formate, in a manner known per se (see Helv. Chim. Acta 2002, 85, 2926-2929, Ex. 6). The reaction is normally carried out in the presence of a base such as an alcoholate in an inert solvent such as an ether. The reaction of the resulting ketal IX with urea X to form the corresponding 2-pyrimidinone II takes place under conditions disclosed in the literature, e.g. as in Aust. J. Chem. 1968, 21, 243-55 (especially p. 252).
The 2-pyri(mi)dinones II in which R1 is hydrogen, and R2 is optionally substituted phenyl, can be prepared for example by the method shown in Scheme 4.




In Scheme 4, W has the meanings indicated above. Hal is halogen, especially bromine or chlorine. The coupling of the halopyrimidinone XI with the borate XII takes place under Suzuki conditions (see Tetrahedron 1997, 53, 14437-50). The modified Suzuki cross-coupling between the pyridinone XI and the borate XII normally takes place in aqueous solvents in the presence of a phosphine-free Pd catalyst such as palladium(II) chloride and in the presence of a base. Examples of suitable bases are alkali metal hydroxides such as sodium hydroxide. The pyridinones XI and the borates XII are disclosed in the literature and commercially available.
The pyri(mi)dinone compounds I.A of the invention, in which R1 is NR4R5, can be prepared for example by the method shown in Scheme 5.




In Scheme 5, W, A1, B, A2 and Q have the meanings indicated above. As shown in Scheme 5, firstly the compound I.A in which R1 is OH is converted into the corresponding thiol I with R1═SH. Examples of suitable sulfurizing agents are organophosphorus sulfides such as Lawesson's reagent, organotin sulfides or phosphorus(V) sulfide. A preferred sulfurizing agent is phosphorus pentasulfide (P4S10). The conditions necessary for the thionation are known to the skilled worker, e.g. from J. Med. Chem. 1984, 27, 1470-80 (especially p. 1478, Example 8b). The thiol I with R1═SH which is obtained in this case can be converted into other compounds I.A with R1═NR4R5 by reaction with a compound of the formula HNR4R5 in which R4 and R5 have the abovementioned meanings. The reaction normally takes place in an inert solvent. The energy of activation necessary for the reaction can be introduced into the reaction mixture by means of microwaves (for reaction employing microwaves, see Tetrahedron 2001, 57, pp. 9199 et seq., pp. 9225 et seq. and generally “Microwaves in Organic Synthesis”, André Loupy (ed.), Wiley-VCH 2002).
The thiol group in the compounds I.A with R1═SH can be converted into other radicals R1 by standard methods of organic chemistry. Scheme 6 gives an overview.




Methods for this are known to the skilled worker and include the conversion of SH into SR6 by alkylation, the oxidation of SR6 to give the corresponding SOR6 and SO2R6 groups, the oxidative degradation of SH to OH with, where appropriate, subsequent alkylation or esterification to give the groups OR3a, OC(O)NR4R5 or OC(O)R8.
Pyrimidinone compounds II in which W═N and R1 is NR4R5 can be prepared for example in analogy to Scheme 5 above. The preparation is outlined in Scheme 7.




Tautomers of the formula I.A can be prepared in a manner analogous to the preparation described herein of the compound I.A. For example, the tautomeric derivatives I.A-a




in which R′ is H or C1-C4-alkyl, can be prepared in analogy to the synthetic route shown in Scheme 1.

In addition, tautomers of the formula I.A-a with R′=methyl can also be obtained by treating the H-analogous compound with an excess of, for example, 5 molar equivalents of MeI/KOH in DMSO at room temperature for several hours, as shown in Scheme 8.




In addition, the compound I.A can be converted into its tautomers I.A-b




in which Hal is halogen by treating it with a suitable halogenating agent such as PCl3 or POCl3.

Unless indicated otherwise, the reactions described above generally take place in a solvent at temperatures between room temperature and the boiling point of the solvent used. Examples of solvents which can be used are ethers such as diethyl ether, diisopropyl ether, methyl-tert-butyl ether or tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, acetonitrile, ketones such as acetone or methyl ethyl ketone, or alcohols such as methanol, ethanol or butanol.
The energy of activation necessary for the reaction can be introduced into the reaction mixture by means of microwaves (for reaction employing microwaves, see Tetrahedron 2001, 57, pp. 9199 et seq., pp. 9225 et seq., and generally “Microwaves in Organic Synthesis”, André Loupy (ed.), Wiley-VCH 2002).
If desired, a base is present to neutralize protons liberated during the reactions. Suitable bases include inorganic bases such as sodium or potassium carbonate, sodium or potassium bicarbonate, in addition alcoholates such as sodium methoxide, sodium ethoxide, alkali metal hydrides such as sodium hydride, organometallic compounds such as butyllithium or alkylmagnesium compounds, or organic nitrogen bases such as triethylamine or pyridine. The latter may serve simultaneously as solvents.
The crude product is isolated in a conventional way, for example by filtration, removal of the solvent by distillation or extraction from the reaction mixture etc. The resulting compounds can be purified in a conventional way, for example by recrystallization from a solvent, chromatography or by conversion into an acid addition salt.
The acid addition salts are prepared in a conventional way by mixing the free base with the appropriate acid, where appropriate in solution in an organic solvent, for example a low molecular weight alcohol such as methanol, ethanol or propanol, an ether such as methyl t-butyl ether or diisopropyl ether, a ketone such as acetone or methyl ethyl ketone or an ester such as ethyl acetate.
The compounds of the invention of the formula I are highly selective dopamine D3 receptor ligands which, because of their low affinity for other receptors, in particular for dopamine D2 receptors, have fewer side effects than classical neuroleptics which comprise D2 receptor antagonists.
The high affinity of the compounds of the invention for D3 receptors is reflected in very low in vitro Ki values of ordinarily less than 100 nM (nmol/l) and especially of less than 50 nM. Binding affinities for D3 receptors can for example be determined via the displacement of [125I]-iodosulpride in receptor-binding studies.
Particularly important according to the invention are compounds whose selectivity Ki(D2)/Ki(D3) is preferably at least 10, even better at least 30 and particularly advantageously at least 50. Receptor-binding studies on D1, D2 and D4 receptors can be carried out for example via the displacement of [3H]SCH23390, [125I]iodosulpride and [125I]spiperone.
The compounds can, because of their binding profile, be used for the treatment of conditions which respond to dopamine D3 ligands, i.e. they are effective for the treatment of those disorders or conditions where an influencing (modulation) of dopamine D3 receptors leads to an improvement in the clinical condition or to cure of the disease. Examples of such conditions are disorders or conditions of the central nervous system.
Disorders or conditions of the central nervous system mean disorders affecting the spinal cord and, in particular, the brain. The term “disorder” in the sense according to the invention refers to abnormalities which are usually regarded as pathological states or functions and may reveal themselves in the form of particular signs, symptoms and/or dysfunctions. The inventive treatment may be directed at individual disorders, i.e. abnormalities or pathological states, but it is also possible for a plurality of abnormalities, which are causally connected together where appropriate, to be combined into patterns, i.e. syndromes, which can be treated according to the invention.
The disorders which can be treated according to the invention include in particular psychiatric and neurological disorders. These comprise in particular organic disorders, symptomatic disorders included, such as psychoses of the acute exogenous type or associated psychoses with an organic or exogenous cause, e.g. associated with metabolic disorders, infections and endocrinopathies; endogenous psychoses such as schizophrenia and schizotypal and delusional disorders; affective disorders such as depressions, mania and manic/depressive states; and combined forms of the disorders described above; neurotic and somatoform disorders, and disorders associated with stress; dissociative disorders, e.g. deficits, clouding and splitting of consciousness and personality disorders; disorders of attention and waking/sleeping behavior, such as behavioral disorders and emotional disorders starting in childhood and adolescence, e.g. hyperactivity in children, intellectual deficits, especially attention deficit disorders, disorders of memory and cognition, e.g. learning and memory impairment (impaired cognitive function), dementia, narcolepsy and sleeping disorders, e.g. restless legs syndrome; developmental disorders; anxiety states; delirium; disorders of the sex life, e.g. male impotence; eating disorders, e.g. anorexia or bulimia; addiction; and other undefined psychiatric disorders.
The disorders which can be treated according to the invention also include parkinsonism and epilepsy and, in particular, the affective disorders associated therewith. Addictive disorders include the psychological disorders and behavioral disorders caused by the abuse of psychotropic substances such as pharmaceuticals or drugs, and other addictive disorders such as, for example, compulsive gambling (impulse control disorders not elsewhere classified). Examples of addictive substances are: opioids (e.g. morphine, heroin, codeine); cocaine; nicotine; alcohol; substances which interact with the GABA chloride channel complex, sedatives, hypnotics or tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants such as 3,4-methylenedioxy-N-methylamphetamine (Ecstasy); amphetamine and amphetamine-like substances such as methylphenidate or other stimulants, including caffeine. Addictive substances requiring particular attention are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol. With a view to the treatment of addictive disorders, the compounds of the invention of the formula I which are particularly preferred are those which themselves have no psychotropic effect. This can also be observed in a test on rats which reduce the selfadministration of psychotropic substances, for example cocaine, after administration of compounds which can be used according to the invention.
According to a further aspect of the present invention, the compounds of the invention are suitable for the treatment of disorders, the causes of which can at least in part be attributed to an abnormal activity of dopamine D3 receptors.
According to another aspect of the present invention, the treatment is directed in particular at those disorders which can be influenced by a binding of, preferably exogenously added, binding partners (ligands) to dopamine D3 receptors in the sense of an expedient medical treatment.
The conditions which can be treated with the compounds of the invention are frequently characterized by a progressive development, i.e. the states described above change over the course of time, the severity usually increasing and, where appropriate, states possibly interchanging or other states being added to previously existing states.
The compounds of the invention can be used to treat a large number of signs, symptoms and/or dysfunctions associated with the disorders of the central nervous system and in particular the aforementioned states. These include for example a distorted relation to reality, lack of insight and the ability to comply with the usual social norms and demands of life, changes in behavior, changes in individual urges such as hunger, sleep, thirst etc. and in mood, disorders of memory and association, personality changes, especially emotional liability, hallucinations, ego disturbances, incoherence of thought, ambivalence, autism, depersonalization or hallucinations, delusional ideas, staccato speech, absence of associated movement, small-step gait, bent posture of trunk and limbs, tremor, mask-like face, monotonous speech, depression, apathy, deficient spontaneity and irresolution, reduced association ability, anxiety, nervous agitation, stammering, social phobia, panic disorders, withdrawal syndromes associated with dependence, expansive syndromes, states of agitation and confusion, dysphoria, dyskinetic syndromes and tic disorders, e.g. Huntington's chorea, Gilles de la Tourette syndrome, vertigo syndromes, e.g. peripheral postural, rotational and vestibular vertigo, melancholia, hysteria, hypochondria and the like. A treatment in the sense according to the invention includes not only the treatment of acute or chronic signs, symptoms and/or dysfunctions but also a preventive treatment (prophylaxis), in particular as recurrence or episode prophylaxis. The treatment may be symptomatic, for example directed at suppression of symptom. It may take place short-term, be directed at the medium term or may also be a long-term treatment, for example as part of maintenance therapy.
The compounds of the invention are preferably suitable for the treatment of disorders of the central nervous system, especially for the treatment of affective disorders; neurotic disorders, stress disorders and somatoform disorders and psychoses and specifically for the treatment of schizophrenia and depression. Owing to their high selectivity in relation to the D3 receptor, the compounds I of the invention are also for the treatment of renal function disorders, especially of renal function disorders caused by diabetes mellitus (see WO 00/67847).
The inventive use of the described compounds comprises a method within the scope of the treatment. This entails the individual to be treated, preferably a mammal, in particular a human or agricultural or domestic animal, being given an effective amount of one or more compounds, usually formulated in accordance with pharmaceutical and veterinary practice. Whether such a treatment is indicated, and the form it is to take, depends on the individual case and is subject to a medical assessment (diagnosis) which takes account of the signs, symptoms and/or dysfunctions present, the risks of developing certain signs, symptoms and/or dysfunctions, and other factors. The treatment usually takes place by administration once or more than once a day, where appropriate together or alternately with other active ingredients or active ingredient containing products, so that an individual to be treated is given a daily dose preferably of about 0.1 to 1000 mg/kg of body weight on oral administration or of about 0.1 to 100 mg/kg of body weight on parenteral administration. The invention also relates to the production of pharmaceutical compositions for the treatment of an individual, preferably a mammal, in particular a human or agricultural or domestic animal. Thus, the ligands are usually administered in the form of pharmaceutical compositions which comprise a pharmaceutically acceptable excipient with at least one ligand of the invention and, where appropriate, further active ingredients. These compositions can be administered for example by the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal route.
Examples of suitable pharmaceutical formulations are solid pharmaceutical forms such as oral powders, dusting powders, granules, tablets, especially film-coated tablets, pastilles, sachets, cachets, sugar-coated tablets, capsules such as hard and soft gelatin capsules, suppositories or vaginal pharmaceutical forms, semisolid pharmaceutical forms such as ointments, creams, hydrogels, pastes or patches, and liquid pharmaceutical forms such as solutions, emulsions, especially oil-in-water emulsions, suspensions, for example lotions, preparations for injection and infusion, eye drops and ear drops. Implanted delivery devices can also be used to administer compounds of the invention. A further possibility is also to use liposomes or microspheres. The compositions are produced by mixing or diluting inhibitors of the invention usually with an excipient. Excipients may be solid, semisolid or liquid materials which serve as vehicle, carrier or medium for the active ingredient.
Suitable excipients are listed in the relevant pharmaceutical monographs. The formulations may additionally comprise pharmaceutically acceptable carriers or conventional excipients such as lubricants; wetting agents; emulsifying and suspending agents; preservatives; antioxidants; antiirritants; chelating agents; tablet-coating aids; emulsion stabilizers; film formers; gel formers; odor-masking agents; masking flavors; resins; hydrocolloids; solvents; solubilizers; neutralizers; permeation promoters; pigments; quaternary ammonium compounds; refatting and superfatting agents; ointment, cream or oil bases; silicone derivatives; spreading aids; stabilizers; sterilants; suppository bases; tablet excipients, such as binders, fillers, lubricants, disintegrants or coatings; propellants; desiccants; opacifiers; thickeners; waxes; plasticizers; white oils. An arrangement concerning this is based on expert knowledge as set forth for example in Fiedler, H. P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, 4th edition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.
The following examples serve to illustrate the invention without limiting it.
The nuclear magnetic resonance spectral properties (NMR) relate to chemical shifts (δ) expressed in parts per million (ppm). The relative area for the shifts in the 1H NMR spectrum corresponds to the number of hydrogen atoms for a particular functional type in the molecule. The nature of the shift in terms of multiplicity is indicated as singlet (s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t), broad triplet (t br.), quartet (q), quintet (quint.), multiplet (m).


PREPARATION EXAMPLES
Precursors
a. 1-(4-Chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione
10.1 g (80.0 mmol) of 4-hydroxy-5-methylpyrimidin-2(1H)-one (thymine) in 300 ml of dimethyl sulfoxide (DMSO) and 11.1 g (80.0 mmol) of K2CO3 were stirred at room temperature for 1 hour. Then 13.7 g (80.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to the mixture, and the reaction mixture was then stirred at room temperature for 5 hours. Water was added to the reaction mixture, and it was then extracted with ethyl acetate. The aqueous phase was then neutralized and extracted with methylene chloride. Drying of the organic phase, removal of the desiccant by filtration and evaporation of the solvent to dryness in vacuo resulted in 7.1 g of the title compound
ESI-MS: 219.1, [M+H+]=217.1;
1H NMR (500 MHz, CDCl3) δ(ppm): 9.97 (1H, s.), 7.02 (1H, s.), 3.74 (2H, t), 3.55 (2H, t), 1.93 (3H, s), 2.02-1.75 (4H, m).
b. 1-(4-Chlorobutyl)-1H-pyrimidine-2,4-dione
The title compound was prepared in analogy to the procedure described in J. Am. Chem. Soc. 1993, 115, 7636 for preparing 1-(4-bromobutyl)pyrimidine-2,4(1H,3H)dione.
c. 1-(4-Chlorobutyl)-4-phenyl-1H-pyrimidin-2-one
c.1 2-Chloro-4-phenylpyrimidin
2.78 g (20.14 mmol) of K2CO3, 0.21 g (0.18 mmol) of tetrakis(triphenylphosphine)Pd(0) were added to 1.00 g (6.71 mmol) of 2,4-dichloropyrimidine and 0.82 g (6.71 mmol) of benzeneboronic acid in 29 ml of toluene and 7 ml of methanol, and the reaction mixture was stirred at room temperature for 3 hours. The residue after concentration of the reaction mixture was taken up in water/methyl tert-butyl ether. The aqueous phase was then extracted twice with methyl tert-butyl ether. The combined organic phase was then washed with water and with a saturated aqueous NaCl solution, and the organic phase was dried, filtered to remove the desiccant and concentrated. The solid brown residue was purified by flash chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane: 10:90); yield: 0.90 g.
1H NMR (400 MHz, CDCl3) δ (ppm): 8.64 (1H, d), 8.10 (2H, d), 7.650 (1H, d), 7.58-7.48 (3H, m).
c.2 4-Phenylpyrimidin-2-ol
0.80 g (4.20 mmol) of 2-chloro-4-phenylpyrimidine from c.1 was heated in 3.20 ml of conc. HCl at 10° C. for 1 hour. The mixture was then concentrated, suspended in methylene chloride and again concentrated. Yield: 0.83 g.
ESI-MS: 174.3, [M+H+]=173.2.
c.3 1-(4-Chlorobutyl)-4-phenylpyrimidin-2(1H)-one
0.84 g (4.20 mmol) of 4-phenylpyrimidin-2-ol from Example c.2 was stirred in 8.4 ml of N,N-dimethylformamide (DMF) and 0.58 g (4.20 mmol) of K2CO3 at room temperature for 1 hour. Then, 0.72 g (4.20 mmol) of 1-bromo-4-chlorobutane was added dropwise, the reaction mixture was stirred at room temperature for 12 hours, and the reaction mixture was filtered and concentrated. The residue was then taken up in toluene and concentrated, and the residue was again taken up in toluene and concentrated. The resulting residue was stirred with pentane and filtered. Yield: 0.74 g.
1H NMR (400 MHz, CDCl3) δ (ppm): 8.10 (2H, d), 7.71 (1H, d), 7.63-7.40 (3H, m), 6.82 (1H, d), 3.98 (2H, t), 3.58 (2H, t), 2.00 (2H, quint.), 1.90 (2H, quint.).
d. 1-(4-Chlorobutyl)-4-methyl-1H-pyrimidin-2-one
d.1 4-Methylpyrimidin-2(1H)-one (in analogy to Aust. J. Chem. 1968, 21, 243-55)
20.0 ml of conc. HCl were added dropwise to 26.4 g (0.2 mol) of 4,4-dimethoxybutan-2-one in 40 ml of ethanol and 12.0 g (0.2 mol) of urea. A clear brown solution resulted after a short time, and after a further 10 minutes, a yellow precipitate separated out. The reaction mixture was heated to reflux for 1.5 hours and then allowed to cool (ice-water bath). The crystals which had separated out were then filtered off with suction and washed with ethanol, and the crystals were dried in vacuo at 40° C.; yield: 22.0 g.
d.2 1-(4-Chlorobutyl)-4-methyl-1H-pyrimidin-2-one
0.1 mol of 4-methylpyrimidin-2(1H)-one from d.1, 0.1 mol of 1-bromo-4-chlorobutane and 0.3 mol of K2CO3 were stirred in 200 ml of dimethyl sulfoxide at room temperature for 12 hours. The reaction mixture was added to ice-water, and the aqueous mixture was extracted twice with diethyl ether. The aqueous phase was extracted twice with methylene chloride. The methylene chloride phase was dried over Na2SO4, the desiccant was removed by filtration, and the solvent was evaporated to dryness in vacuo. The resulting solid residue was stirred with diethyl ether, and the precipitate was filtered off with suction, washed with diethyl ether and dried.
1H NMR (400 MHz, CDCl3) δ (ppm): 8.46 (1H, d), 7.46 (1H, d), 3.90 (2H, t), 3.57 (2H, t), 2.11 (3H, s.), 1.95 (2H, quint.), 1.88-1.78 (2H, quint.).
e. 1-(4-Chlorobutyl)-5-fluoro-1H-pyrimidine-2,4-dione
2.6 g (15.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to a solution of 1.95 g (15.0 mmol) of 2,4-dihydroxy-5-fluoropyrimidine in 50 ml of dimethyl sulfoxide and 20.0 ml of N,N-dimethylformamide (DMF) at 0° C. 2.07 g (15.0 mmol) of K2CO3 were added in portions over the course of 1 hour, and the mixture was stirred at 20° C. for 1 hour (dialkylated product already identifiable). Water was then added to the reaction mixture, and the aqueous mixture was extracted twice with diethyl ether and twice with methylene chloride. The aqueous phase was adjusted to pH 3-4 with hydrochloric acid and then the aqueous phase was extracted with methylene chloride. The organic phase was then dried, the desiccant was removed by filtration, and the solvent was evaporated to dryness in vacuo; yield: 0.6 g.
Example 1
1-{4-[4-(2,4-Dichlorobenzyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione
1-(4-Chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione (0.69 mmol, 0.15 g), 1-(2,4-dichlorobenzyl)piperazine (0.62 mmol, 0.15 g), sodium bromide (3.46 mmol, 0.36 g) and diisopropylethylamine (6.92 mmol, 0.89 g) were heated in N-methylpyrrolidinone (0.6 ml) at 120° C. for 5 hours. The reaction mixture was then allowed to cool, the suspension was filtered with suction, and the filtrate was concentrated. The residue was then then taken up in ethyl acetate and washed with saturated brine. The organic layer was dried, filtered to remove the desiccant and evaporated in vacuo. The resulting residue was purified by chromatography on silica gel (eluent: methyl tert-butyl ether/methanol (0-100%), resulting in 88.0 mg of the title compound.
ESI-MS: [M+H+]=425.0;
1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.19 (1H, s br.), 7.60-7.36 (4H, m), 3.59 (2H, t), 3.52 (2H, s), 2.41 (8H, s br.), 2.33 (2H, t), 1.74 (3H, s), 1.55 (2H, quint.), 1.38 (2H, quint.).
The free base was then converted into its fumaric acid salt.
Example 2
1-{4-[4-(2,4-Dichlorobenzyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione
0.17 g of the title compound was obtained in analogy to Example 1 from 1-(4-chlorobutyl)-1H-pyrimidine-2,4-dione (0.49 mmol, 0.10 g) and 1-(2,4-dichlorobenzyl)piperazine (0.44 mmol, 0.119).
ESI-MS: 413.05, 411.15;
1H NMR (500 MHz, DMSO-d6) δ (ppm): 11.18 (1H, s br.), 7.63 (1H, d), 7.57 (1 H, s), 7.48 (1H, m), 7.41 (1H, m), 5.52 (1H, d), 3.64 (2H, t), 3.55 (2H, s), 2.46 (8H, s br.), 2.38 (2H, t), 1.55 (2H, quint.), 1.41 (2H, quint.).
The free base was then converted into its fumaric acid salt.
Example 3
1-{4-[4-(2,4-Dichlorobenzyl)piperazin-1-yl]butyl}-4-phenyl-1H-pyrimidin-2-one
0.20 g of the title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-4-phenyl-1H-pyrimidin-2-one (0.76 mmol, 0.20 g) with 1-(2,4-dichlorobenzyl)piperazine (0.69 mmol, 0.17 g).
ESI-MS: [M+Na+]=493.1, 473.15, 471.15, 236.1.
The free base was then converted into its fumaric acid salt.
Example 4
1-{4-[4-(2,4-Dichlorobenzyl)piperazin-1-yl]butyl}-4-methyl-1H-pyrimidin-2-one
21.0 mg of the title compound were obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-4-methyl-1H-pyrimidin-2-one (0.37 mmol, 75.0 mg) with 1-(2,4-dichlorobenzyl)piperazine (0.36 mmol, 87.0 mg).
ESI-MS: 411.15, 409.15, 205.1.
Example 5
1-{4-[4-(2,4-Dichlorobenzyl)piperazin-1-yl]butyl}-5-fluoro-1H-pyrimidine-2,4-dione
22.0 mg of the title compound were obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-fluoro-1H-pyrimidine-2,4-dione (0.45 mmol, 0.10 g) with 1-(2,4-dichlorobenzyl)piperazine (0.41 mmol, 0.10 mg).
ESI-MS: 431.15, 429.15, 243.1.
The free base was then converted into its fumaric acid salt.
Example 6
1-{4-[4-(2-Fluorobenzyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(2-fluorobenzyl)piperazine.
ESI-MS: [M+H+]=375.0.
Example 7
1-{4-[4-(2-Methoxybenzyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(2-methoxybenzyl)piperazine.
ESI-MS: [M+Na+]=409.0, [M+H+]=387.2, 264.9, 120.9.
Example 8
1-{4-[4-(2-Chlorobenzyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(2-chlorobenzyl)piperazine.
ESI-MS: [M+H+]=390.9.
Example 9
5-Methyl-1-{4-[4-(2-methylbenzyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(2-methylbenzyl)piperazine.
ESI-MS: 371.6, [M+H+]=371.0.
Example 10
1-{4-[4-(3,4-Dichlorobenzyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(3,4-dichlorobenzyl)piperazine.
ESI-MS: [M+H+]=425.0.
Example 11
1-{4-[4-(2-Chloro-4-fluorobenzyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(2-chloro-4-fluorobenzyl)piperazine.
ESI-MS: [M+H+]=409.0.
Example 12
1-[4-(4-Benzylpiperazin-1-yl)butyl]-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with N-benzylpiperazine.
ESI-MS: [M+H+]=357.2.
Example 13
5-Methyl-1-{4-[4-(4-methylbenzyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(4-methylbenzyl)piperazine.
ESI-MS: [M+H+]=371.2.
Example 14
5-Methyl-1-{4-[4-(3-methylbenzyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(3-methylbenzyl)piperazine,
ESI-MS: 551.2, [M+H+]=371.1.
Example 15
1-{4-[4-(4-Fluorobenzyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(4-fluorobenzyl)piperazine.
ESI-MS: [M+H+]=375.1.
Example 16
1-{4-[4-(3,4-Dimethylbenzyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(3,4-dimethylbenzyl)piperazine.
ESI-MS: [M+H+]=385.3.
Example 17
1-{4-[4-(4-Methoxybenzyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(4-methoxybenzyl)piperazine.
ESI-MS: [M+H+]=387.1, 120.9.
Example 18
5-Methyl-1-{4-[4-(2,4,6-trimethylbenzyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(2,4,6-trimethylbenzyl)piperazine.
ESI-MS: [M+H+]=399.3, 133.0.
Example 19
1-[4-(4-Benzo[1,3]dioxol-5-ylmethylpiperazin-1-yl)butyl]-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(benzo[1,3]dioxol-5-ylmethyl)piperazine.
ESI-MS: [M+H+]=401.1, 134.9.
Example 20
5-Methyl-1-[4-(4-naphthalen-2-ylmethylpiperazin-1-yl)butyl]-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(naphthalen-2-ylmethyl)piperazine.
ESI-MS: [2M+H+]=813.4, 587.3, [M+H+]=407.1, 140.9.
Example 21
1-{4-[4-(2-Chloro-6-fluorobenzyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(2-chloro-6-fluorobenzyl)piperazine.
ESI-MS: [M+H+]=409.0.
Example 22
1-{4-[4-(4-tert-Butylbenzyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(4-tertbutylbenzyl)piperazine.
ESI-MS: 593.2, [M+H+]=413.1.
Example 23
5-Methyl-1-[4-(4-pyridin-4-ylmethylpiperazin-1-yl)butyl]-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(pyridin-4-ylmethyl)piperazine.
ESI-MS: [M+H+]=357.7, 130.0.
Example 24
5-Methyl-1-[4-(4-pyridin-2-ylmethylpiperazin-1-yl)butyl]-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(pyridin-2-ylmethyl)piperazine.
ESI-MS: [2M+H+]=715.3, [M+H+]=358.1, 130.0.
Example 25
5-Methyl-1-[4-(4-pyridin-3-ylmethylpiperazin-1-yl)butyl]-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(pyridin-3-ylmethyl)piperazine.
ESI-MS: [2M+H+]=715.2, [M+H+]=358.0, 264.8, 130.0.
Example 26
1-[4-(4-Benzylpiperidin-1-yl)butyl]-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 4-benzylpiperidine.
ESI-MS: 536.5, [M+H+]=356.1.
Example 27
5-Methyl-1-{4-[4-(tetrahydrofuran-2-ylmethyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(tetrahydrofuran-2-ylmethyl)piperazine.
ESI-MS: [M+H+]=351.1, 130.0.
Example 28
5-Methyl-1-{4-[4-(2-pyrrol-1-yl-ethyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(2-pyrrol-1-ylethyl)piperazine.
ESI-MS: [M+H+]=360.2.
Example 29
1-{4-[4-(Furan-2-carbonyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with furan-2-ylpiperazin-1-ylmethanone.
Example 30
1-{4-[4-(2-Imidazol-1-ylethyl)piperazin-1-yl]butyl-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(2-imidazol-1-ylethyl)piperazine.
ESI-MS: [2M+H+]=721.3, [M+H+]=361.3, 293.0, 130.0.
Example 31
1-[4-(4-Cyclohexylmethylpiperazin-1-yl)butyl]-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(cyclohexylmethyl)piperazine.
ESI-MS: [M+H+]=363.3.
Example 32
5-Methyl-1-{4-[4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with piperazin-1-yltetrahydrofuran-2-ylmethanone.
ESI-MS: [2M+H+]=729.3, [M+H+]=365.4, 267.0, 130.0.
Example 33
5-Methyl-1-{4-[4-(2-thiophen-2-ylethyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(2-thiophen-2-ylethyl)piperazine.
ESI-MS: [M+H+]=377.0.
Example 34
1-{4-[4-(2-Cyclohexylethyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 1-(2-cyclohexyl)piperazine.
ESI-MS: 557.5, [M+H+]=377.1.
Example 35
5-Methyl-1-{4-[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 2-piperazin-1-yl-1-pyrrolidin-1-ylethanone.
ESI-MS: [2M+H+]=755.3, [M+H+]=378.5, 130.0.
Example 36
5-Methyl-1-{4-[4-(2-oxo-2-piperidin-1-ylethyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione
The title compound was obtained in analogy to Example 1 by reacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione with 2-piperazin-1-yl-1-piperidin-1-ylethanone.
ESI-MS: [M+H+]=392.2.
Examples of Pharmaceutical Administration Forms


    A) Tablets
    
        Tablets of the following composition are compressed in a tablet press in a conventional way:
    
    















  40 mg
of substance of Example 1


 120 mg
of corn starch


13.5 mg
of gelatin


  45 mg
of lactose


2.25 mg
of Aerosil ® (chemically pure silica in submicroscopically fine



distribution)


6.75 mg
of potato starch (as 6% strength paste)









    B) Sugar-Coated Tablets
    
        20 mg of substance of Example 1
        60 mg of core composition
        70 mg of sugar-coating composition
    
    


The core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone/vinyl acetate 60:40 copolymer. The sugar-coating composition consists of 5 parts of sucrose, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated tablets produced in this way are subsequently provided with an enteric coating.
Biological Investigations—Receptor Binding Studies:
The substance to be tested was dissolved either in methanol/Chremophor® (BASFAG) or in dimethyl sulfoxide and then diluted with water to the desired concentration.
Dopamine D3 Receptor:
The mixture (0.250 ml) was composed of membranes from  ̃106 HEK-293 cells with stably expressed human dopamine D3 receptors, 0.1 nM [125I]-iodosulpride and incubation buffer (total binding) or with additional test substance (inhibition plot) or 1 μM spiperone (nonspecific binding). Triplicate mixtures were carried out.
The incubation buffer contained 50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 2 mM MgCl2 and 0.1% bovine serum albumin, 10 μM quinolone, 0.1% ascorbic acid (prepared fresh each day). The buffer was adjusted to pH 7.4 with HCl.
Dopamine D2L Receptor
The mixture (1 ml) was composed of membranes from  ̃106 HEK-293 cells with stably expressed human dopamine D2L receptors (long isoform) and 0.01 nM [1251]-iodospiperone and incubation buffer (total binding) or with additional test substance (inhibition plot) or 1 μM haloperidol (nonspecific binding). Triplicate mixtures were carried out.
The incubation buffer contained 50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 2 mM MgCl2 and 0.1% bovine serum albumin. The buffer was adjusted to pH 7.4 with HCl.
Measurement and Evaluation:
After incubation at 25° C. for 60 minutes, the mixtures were filtered under vacuum through Whatman GF/B glass fiber filters using a cell harvester. The filters were transferred by a filter transfer system into scintillation vials. After addition of 4 ml of Ultima Gold® (Packard), the samples were shaken for one hour and then the radioactivity was counted in a beta counter (Packard, Tricarb 2000 or 2200CA). The cp values were converted into dpm by means of a standard quench series with the aid of the instrument's own program.
Evaluation of the inhibition plots took place by iterative nonlinear regression analysis using the Statistical Analysis System (SAS) similar to the “LIGAND” program described by Munson and Rodbard.
In these assays, the compounds of the invention show very good affinities for the D3 receptor (<100 nM, frequently <50 nM) and bind selectively to the D3 receptor. The results of the binding assays are indicated in table 3.









TABLE 3







Selectivity


Example
Ki (D3) [nM]
D3 vs. D2L*

















1
8.9
98


2
4.6
94


3
3.16
204


4
17.0
31


5
10.6
99


10
18.1
51


11
22.3
48





*Ki(D3)/Ki(D2L)

## Claims

1. A substituted N-heterocyclic compound of the formula (I.A)




in which
W is N;
R1 is OH, methyl, isopropyl, tertbutyl, CF3, cyclobutyl, cyclohexyl, phenyl, p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl or 2-furyl;
R2 is H, C1-C4-alkyl, CF3, halogen or cyano;
N is 4;
A2 is a 1- to 2-membered hydrocarbon chain which may have 1 or 2 methyl groups as substituents, in which 1 carbon atom may be replaced by a carbonyl group;
Q is phenyl which optionally has 1, 2, or 3 substituents RQ which are selected independently of one another from methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, fluorine, chlorine, cyano, and dimethylamino;
and the tautomers of the compound I.A., the physiologically acceptable salts of the compound I.A and the physiologically acceptable salts of the tautomers of the compound I.A.

2. The compound as claimed in claim 1, in which A2 is CH2, CH2CH2, CO, CH2CO, or COCH2.

3. The compound as claimed in claim 2, in which A2 is CH2.

4. The compound as claimed in claim 1, in which Q is phenyl which has two substituents RQ.

5. The compound as claimed in claim 4, in which the two substituents RQ are located in position 2,3 on the phenyl ring.

6. The compound as claimed in claim 4, in which the two substituents RQ are located in position 2,4 on the phenyl ring.

7. The compound as claimed in claim 4, in which the two substituents RQ are located in position 3,4 on the phenyl ring.

8. A pharmaceutical composition comprising the compound of claim 1 and/or salt thereof, together with physiologically acceptable carriers and/or excipients.

9. A method for treating schizophrenia, or parkinsonism, the method comprising administering the compound of claim 1 or a pharmacologically acceptable salt thereof or a tautomer of the at least one compound as defined in claim 1.