Title of Invention

NOVEL PIPERAZINYL-PYRAZINONE DERIVATIVES FOR THE TREATMENT OF 5-HT2A RECEPTOR-RELATED DISORDERS

Abstract Compounds of the general formula (I): (I)wherein m, n, R<1>, R<2>, R<3> and R<4> are as described in the specification. Further included are pharmaceutical compositions comprising the compounds, processes for their preparation, as well as the use of the compounds for the preparation of a medicament for the treatment of 5-HT2A receptor-related disorders or medical conditions.
Full Text RELATED APPLICATIONS This application claims priority to Swedish application number 0202287-9, filed on July 19,2002, and U.S. provisional application 60/426,240, filed on November 14,2002, the contents of which are incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds for the preparation of a medicament.
BACKGROUND ART
Many disorders and conditions of the central nervous system are influenced by the serotonergic neurotransmitter system. For example, serotonin (5-hydroxytryptamine; 5-HT) has been implicated in a number of disorders and conditions that originate in the central nervous system. The serotonin receptors are divided into seven main classes 5-HT1- 5-HT7. Additionally, the 5-HT2 family of serotonin receptors is subdivided into the S-HTJA, 5-HT2B and 5-HT2c receptor subtypes. For reviews dealing with tlie classification and function characteristics of serotonin receptors, see for example; Hoyer, D. et al. Pharmacol. Rev. 1994,46,157-203; Saxena, P.R. Pharmacol. Ther. 1995,66,339-368; Barnes, N.M. et al. Neuropharmacol. 1999,38,1083-1152; Roth, B.L. et al. Pharmacol. Ther. 1998,79, 231-257.
The 5-HT2A receptor subtype is expressed in the human brain, including many cortical, limbic, and forebrain regions and is postulated to be involved in the modulation of higher cognitive and affective functions. The 5-HT2A receptor subtype is also expressed on mature blood platelets where it mediates, in part, platelet aggregation, one of the initial steps in the process of vascular thrombosis. Several lines of evidence strongly implicate the 5-HT2A receptor subtype in the etiology of such medical conditions as hypertension, thrombosis, migraine, vasospasm, ischemia, depression, anxiety, schizophrenia, obsessive-compulsive disorder, sexual

function disorders, sleep disorders, and eating disorders, such as anorexia nervosa. They may further be effective in the lowering of intraocular pressure and may therefore be benefiC1al in treatmg glaucoma (cf. T. Mano et al. and H. Takaneka et al., Invest. Ophthalmol. Vis SC1. 1995,36,719 and 734, respectively). The compound (+)-a-(2,3-dimethoxyphenyl)-l-[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol (also known as M-100907) has been shown to be a potent antagonist of human 5-. HT2A receptors and is described in WO 91/18602.
The 5-HT2A receptor subtype has further been suggested to be involved in
urological disorders such as diabetic nephropathy and urinary incontinence (diabetic nephropathy, see: Ishimura, E. et al. Nephron 1997, 76,227-229; urinary incontinence, including coexisting diabetes, see: Kodama, M. et al. Int. J. Urol 2000, 7,231-235 and Ichiyanagi, N. et al. J. Urol. 2002,168,303-307).
Compounds that have an effect on the 5-HT2A receptor may therefore have a therapeutic potential in the treatment of disorders like those mentioned above.
INFORMATION DISCLOSURE
Various classes of compounds have been disclosed to act as antagonists at the 5-HT2A receptor. For example, 4-aryl- or 4-heteroarylpiperazines such as those described in J. Med. Chem. 1991,34,2477, Chem. Pharm. Bull. 1987, 35,1919-, Bioorg. Med. Chem. Lett. 1997, 7,1635-1638, and Arch. Pharm. 1995, 328,659-666. Other compound classes reported to act as 5-HT2A antagonists are disclosed in WO 0114332, WO 0004017, WO 0043362, WO 0107434, WO 0107435 and WO 0151469. A further class of 5-HT2A antagonists is represented by the iV-aralkyl-piperidine-methanol derivatives disclosed in US Patent no. 5,169,096, encompassing M-100907 mentioned above. The class of 5-HT2A antagonists disclosed in U.S. Patent 5,169,096 are claimed to be useful in the treatment of a variety of disease states such as anorexia nervosa, variant angma, Raynaud"s phenomenon, coronary vasospasms, hypertension, profylactic treatment of migraine, cardiovascular diseases such as hypertension, peripheral vascular disease, thrombotic episodes, cardiopulmonary emergenC1es and arrythmias, and has anesthetic properties. See also U.S. patents no. 4,877,798 (fibromyalgia); U.S. Patent no. 4,908,369 (insomnia); U.S. Patent no. 5,106,855 (glaucoma); U.S. Patent no. 6,004,980 (anxiety, Raynaud"s

phenomenon, cardiac anythmia; extrapyramidal symptoms; drug abuse, anorexia, fibromyalgia); EP 337136 (treatment of extrapyramidal side effects assoC1ated with neuroleptic therapy). Psychotic iltoess such as schizophrenia and mania, among other indications are disclosed uses for M-100907 in U.S. Patent no. 5,134,149. The use of M-100907 for the treatment of various developmental neurological disorders such as autism and attention defiC1t hyperactivity disorder is disclosed in WO 99/56750. The use of M-100907, and prodrugs thereof, for the treatment of symptoms of dementia, such as Alzheimer"s disease, is disclosed in WO 01/89498. The use of M-100907 for the treatment of obsessive-compulsive disorders (OCD) is disclosed in U.S. Patent no. 5,618,824.
Ketanserin (3-[2-[4-(4-fluoroben2oyl)-l -piperidinyl]ethyl]-2,4(li/,3/0-quinazolinedione) is a 5-HT2A antagonist that has been on certain markets for hypertension and is patented by Janssen in EP 13612 B. The use of ketanserin for the treatment of glaucoma is disclosed in EP 522226 (cf Ophthalmologica 2001,215, 419-423).
Sarpogrelate (butanedioic aC1d, mono[2-(dimethylamino)-l-[[2-[2-(3-methoxyphenyl)ethyl]phenoxy]methyl]ethyl] ester, MC1-9042; Anplag""""^, Mitsubishi, Japan, is a 5-HT2A antagonist used for the treatment of thromboemboUsm in Japan and is disclosed in EP 72942 B. The use of sarpogrelate for the treatment of glaucoma is disclosed by Mitsubishi in EP 695545 and by Senju Pharmaceutical in CA 2144810. Sarpogrelate is also reported to have therapeutic potential in the treatment of diabetic compUcations (cf Hotta, N. et al. Clin, Drug Invest. 1999,18, 199-207; Kobori, S. et al. hit. Congr. Ser. 2000,1209,283-286).
The 5-HT2A antagonist amperozide (4-(4,4-bis(4-fluorophenyl)butyl)-A"-ethyl-1-piperazinecarboxamide) has been disclosed to possess antipsychotic properties and was first claimed by PharmaC1a"s subsidiary Ferrosan in the patent DE 02941880. Its use for the treatment of substance abuse is disclosed in the assoC1ated patent WO 09216211.
Ajinomoto is developmg the 5-HT2A antagonist and platelet aggregation inhibitor, AT-1015 (N-[2- {4-(5if-dibenzo[a,rf]cyclohepten-5-ylidene)piperidino} -ethyl]-l-formyI-4-piperidinecarboxamide monohydrochloride monohydrate) for the potential treatment of thrombotic conditions (cf European Journal of Pharmacology 2001,433(2-3), 157-162).

Senju Pharmaceuticals has disclosed a series of 1,5-heiizoxa-thiepine derivatives (e.g., methyl 7-methoxy-3-oxo-3,4-dihydro-2H-l,5-benzoxathiepiii-4-carboxylate) in US 5538974 and which are stated to be serotonin S2 receptor antagonists and being useful for the treatment of glaucoma.
WO 00/64441 discloses, inter alia, a series of known 5-HT2A antagonists (e.g., M-100907) for therapeutic or prophylactic treatment of disorders involving bronchoconstriction.
Some structurally related compounds to those of formula (I) in the present invention are disclosed in J. Med. Chem. 1981,24,93-101 and in GB 1,440,722. Particular compounds are 3-piperazin-l-yl-l^-quinoxalin-2-one, l-methyl-3-piperazin-1 -yl-liy-quinoxalin-2-one, 3-(4-methyl-piperazin-1 -yl)-l^-quinoxaIin-2-one, and 3-(l-piperazinyl)-l-[2-(dimethylamino)-ethyI]-2(lH-quinoxalinone. l-Benzyl-3-(4-methyl-piperazin-l-yl)-l//-quuioxalin-2-one is disclosed in Chem. Phaim. Bull. 1993,41,1832-1841. WO 00/76984 discloses pyrazinyl ether compounds that bind to the S-HTzc receptor.
SUMMARY OF THE INVENTION The present invention provides a new class of antagonists of the human 5-HT2A receptor of general formula (I):

wherein
m represents 1 or 2;
n represents 0,1,2,3, or 4;

R" is H or C1-6-alkyl, aryl-C1-C3-alkyl, heteroaryl-C1-Cs-alkyl, 2-hydroxyetfayl, methoxy-C2-C4-alkyI, C1-C4-alkoxycarbonyl, aryloxy-C2-C3-alkyl, or heteroaryloxy-C2-C3-alkyl; wherein
any aryl or heteroaryl residue may be substituted with C1-4-alkyl, CM-alkoxy, Cu-alkylthio, halogen, trifluoromethyl, trifluoromethoxy or cyano; R2 and R3 each, independently, represent H or CH3; R4" and R5 each, independently, represent H, halogen, methyl, or together with the ring, to which carbon atoms they are attached, form a lH-qmnoxalin-2-one nucleus; and
R6 represents aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-NH, heteroaryl-NH, aryl, arylcarbonyl, heteroaryl, or heteroarylcarbonyl; wherein
any aryl or heteroaryl residue, alone or as part of another group, may be unsubstituted or substituted. Where substituted, one, two, three, four or five substituents may be present, preferably one or two for non-halogen substituents, and are independently selected from aryl, aryl-C1-2-alkyl, arylcarbonyl, heteroaryl, heteroaryl-C1-2-alkyl, heteroarylcarbonyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylamino, heteroarylamino, C3.6-cycloalkyl, C3-6-cycloalkyloxy, C3-6-cycloalkylcarbonyl, C1-6-alkyl, C2.6-alkanoyl, C2.6-alkynyl, C2-6-alkaiyl, or fluoro-C2-4alkyloxy, halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, trifluoromethylthio, C1-6 alkoxy, C1-g-alkylthio, C1-6-alkylamino, CM-dialkylamino, hydroxy or 0x0; wherein
any aryl or heteroaryl residue as substituents on aryl or heteroaryl, alone or as part of another group, in turn may be substituted in one, two, three, four or five positions, preferably one, independently of each other by C1-4-alkyl, C1-4-alkoxy, C1-4-alkyltihio, halogen, trifluoromethyl, trifluoromethoxy, or cyano; and pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, iV-oxides and prodrug forms thereof, with the provisos that:
R2 and R3 are not both CH3;
when R1, R2 R4 and R5 are H and R3 is H or CH3, then R^ is not 3-pyridyloxy, 6-methyl-2-nitro-3-pyridyloxy, or 2-chloro-3-pyridyloxy;

when n = 0, then R6 is not aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-NH or heteroaryl-NH; and
the compound of fonnula (I) is not l-ben2yl-3-(4-methyl-piperazin-l-yl)-lH-quinoxalin-2-one.
The compounds of the present invention may be regarded as structural isomers of compounds represented by formula (lb), wherein Xi is 0, disclosed in WO 00/76984.
In case the compoimds of formula (I) can be in the form of optical isomers, the invention comprises the racemic mixture as well as the individual enantiomers as such.
In case the compounds of formula (J) contain groups, which may exist in tautomeric forms, the invention comprises the tautomeric forms of the compounds as well as mixtures thereof
In case the compounds of formula (I) can be in the form of geometrical isomers, the invention comprises the geometrical isomers as well as mixtures thereof According to another aspect, the invention provides the compounds according to formula (I) above for use in therapy in a number of disease states.
Still another aspect of the invention provides a pharmaceutical composition comprising a compoimd according to formula (I) above as the active ingredient, preferably together with a pharmaceutically acceptable carrier and, if desired, bther pharmacologically active agents.
In yet another aspect, the invention provides a method for the treatment of a human or animal subject suffering from a serotonin-related disorder or medical condition, particularly 5-HT2A receptor-related, such as angina, Raynaud"s phenomenon, intermittent claudication, coronary or peripheral vasospasms, hypertension, fibromyalgia, thrombotic illness (including stroke), memory disorders, such as Alzheuner"s disease; schizophrenia; obsessive-compulsive disorder; mood disorders; autism; anxiety disorders; depression disorders (including depression with coexisting diabetes), sexual function disorders, sleep disorders such as insomnia and sleep apnea, pain; substance abuse; extrapyramidal symptoms (e.g., assoC1ated with neuroleptic drug therapy using drugs such as, for example, haloperidol and chlorpromazine); Parkinson"s disease; glaucoma including normal tension glaucoma; urinary incontinence including urinary incontinence with co-existing diabetes;

menopausal and post-menopausal hot flushes; bronchoconstriction disorders, such as asthma and chronic obstructive pulmonary disease; eating disorders, such as binge eating disorders, anorexia nervosa and bulimia; diabetic complications such as nephropathy, neuropathy and retinopathy.
The method includes adrimustering to a subject (e.g., a mammal, a human, a horse, a dog, or a cat) in need thereof (e.g., identified as in need thereof) an effective amount of one or more compounds of formula (I),

wherein
m represents 1 or 2;
n represents 0,1,2,3, or 4;
R" is H or C1-6-alkyl, aryl-C1-Ca-alkyl, heteroaryl-C1-Ca-alkyI, 2-hydroxyethyl, methoxy-C2-C4-alkyl, C1-C4-alkoxycarbonyl, aryloxy-C2-C3-alkyl, or heteroaryloxy-C2-C3-alkyl; wherem
any aryl or heteroaryl residue may be substituted with CM-alkyl, CM-
alkoxy, C1.4-alkylthio, halogen, trifluoromethyl, trifluoromethoxy or cyano;
R2 and R3 each, independently, represent H or CH3;
R4 and R5 each, independently, represent H, halogen, methyl, or together with the ring, to which carbon atoms they are attached, form a l/f-quinoxalin-2-one nucleus; and
R^ represents aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-NH, heteroaryl-NH, aryl, arylcarbonyl, heteroaryl, or heteroarylcarbonyl; wherein

any aryl or heteroaryl residue, alone or as part of another group, may be unsubstituted or substituted. Where substituted, one, two, three, four or five substituents may be present, preferably one or two for non-halogen substituents, and are independently selected from aryl, aryl-C1.2-alkyl, arylcarbonyl, heteroaryl, heteroaryl-C1.2-alkyl, heteroarylcarbonyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylamino, heteroarylamino, C3-6-cycloalkyl, C3-6-cycloalkyloxy, C3.6-cycloalkylcarbonyl, C1-6-alkyl, C3-6-alkanoyl, C2-6-alkynyl, C2-6-alkenyl, or fluoro-C3-6-alkyloxy, halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, trifluoromethylthio, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylamino, C1-4-dialkylamino, hydroxy or oxo; wherein
any aryl or heteroaryl residue as substituents on aryl or heteroaryl, alone or as part of another group, in turn may be substituted in one, two, three, four or five positions, preferably one, independently of each other by C1-4-alkyl, C1-4-alkoxy, C1=4-alkylthio, halogen, trifluoromethyl, trifluoromethoxy, or cyano; and pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, A"^oxides and prodrug forms thereof, with the provisos that:
R2 and R3 are not both CH3;
when R1 R2 R4 and R5 are H and R3 is H or CH3, then R6 is not 3-pyridyloxy, 6-methyl-2-mtro-3-pyridyloxy, or 2-chloro-3-pyridyloxy;
when n = 0, then R6 is not aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-NH or heteroaryl-NH.
Another aspect of the invention relates to the use of the compounds of formula (I) for the manufacture of a medicament for the treatment of a serotonin-related disorder or medical condition, particularly 5-HT2A recq)tor-related, such as angina, Raynaud"s phenomenon, intermittent claudication, coronary or peripheral vasospasms, hypertension, fibromyalgia, thrombotic ilhiess (including stroke), memory disorders, such as Alzheuner"s disease; schizophrenia; obsessive-compulsive disorder; mood disorders; autism; anxiety disorders; d^ression disorders (includmg depression with coexisting diabetes), sexual function disorders, sleep

disorder, such as insomnia and sleep apnea, pain; substance abuse; extrapyramidal symptoms (e.g., assoC1ated with neuroleptic drug therapy using drugs such as, for example, haloperidol and chlorpromazine); Parkinson"s disease; glaucoma including normal tension glaucoma; urinary incontinence including urinary incontinence with co-existing diabetes; menopausal and post-menopausal hot flushes; bronchoconstriction disorders, such as asthma and chronic obstructive pulmonary disease; eating disorders, such as binge eating disorders, anorexia nervosa and bulimia; diabetic complications such as nephropathy, neuropathy and retinopathy.
The methods delineated herein can also include the step of identifying that the subject is in need of treatment of the aforementioned diseases.
Finally a method for modulating 5-HT2A receptor function is an aspect of the invention.
This invention features a method of making a compound of formula (I), wherein R6 is selected from aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-NH, or heteroaryl-NH,
by reacting a compound of the following formula (IT):

wherein
m is 1 or 2;
n is 1 or 2;
X is OH;
R1 is H or C1-6-alkyl, aryl-C1-C3-alkyl, heteroaryl-C1-C3-alkyl, 2-hydroxyethyl, methoxy-C2-C4-alkyl, C1-C4-alkoxycarbonyl, aryloxy-C2-C3-alkyl, or heteroaryloxy-C2-C3-alkyl; wherein
any aryl or heteroaryl residue may be substituted with C1-4-alkyl, C1-4-
alkoxy, CM-alkylthio, halogen, trifluoromethyl, trifluoromethoxy or cyano;
R2 and R3 each, independently, represent H or CH3;

R4 and R5 each, independently, represent H, halogen, methyl, or together with the ring, to which carbon atoms they are attached, form a lH-quinoxalin-2-one nucleus;
with an optionally substituted phenol or ihiophenol; in a solvent.
This invention further features a method of preparing a compound of formula (I), wherein R6 is selected from aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-NH, heteroaryl-NH, aryl, arylcarbonyl, heteroaryl, or heteroarylcarbonyl, by reacting a compound of the following formula (IV),

wherein
m is 1 or 2;
Hal is halogen;
R1 is H or C1-6-allcyl, aryl-C1-C3-alkyi, heteroaryl-C1-C3-alkyI, 2-hydroxyethyl, methoxy-C2-C4-alkyl, C1-C4-alkoxycarbonyl, aryloxy-C2-C3-alkyl, or heteroaryloxy-C2-C3-alkyl; wherein
any aryl or heteroaryl residue may be substituted with C1-4-alkyl, C1-4-
alkoxy, C1-4-alkylthio, halogen, trifluoromethyl, trifluoromethoxy or cyano;
R2 and R3 each, independently, represent H or CH3;
R4 and R5 each, independently, represent H, halogen, methyl, or together with the ring, to which carbon atoms they are attached, form a lH-quinoxalin-2-one nucleus;
with an alkali metal or alkaline earth metal basic salt to produce a compound of formula (V),


wherein
m is 1 or 2;
R1 is H or C1-6-alkyl, aryl-C1 -C3-alkyl, heteroaiyl-C1 -C3-alkyl, 2-hydroxyethyl, methoxy-C2-C4-alkyl, C1-C4-alkoxycarbonyl, aryloxy-C2-C3-alkyl, or heteroaryIoxy-C2-C3-aIk;yI; wherein
any aryl or heteroaryl residue may be substituted with CM-a!kyl, CM-
alkoxy, CM-alkylthio, halogen, trifluoromethyl, trifluoromethoxy or cyano;
R2 and R3 each, independently, represent H or CH3; and
R4 and R5 each, independently, represent H, halogen, methyl, or together with the ring, to which carbon atoms they are attached, form a lH-quinoxalin-2-one nucleus;
followed by N-alkylation of the compound of formula (V) by reaction with a compound of formula (VI),
R6-CH2-(CH2)n-Y (VI) wherein
nisO, 1,2, 3or4;
Y is a leaving group; and
R6 represents aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-NH, heteroaryl-NH, aryl, arylcarbonyl, heteroaryl, or heteroarylcarbonyl; and
wherein any aryl or heteroaryl residue, alone or as part of another group is unsubstituted or substituted. Where substituted, one, two, three, four or five substitutents may be present, preferably on or two for non-halogen substituents, and are independently selected from aryl, aryl-C].2-alkyl, arylcarbonyl, heteroaryl, heteroaryl-C1-2-alkyl, heteroarylcarbonyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylamino, heteroarylamino, C3-6-cycloalkyl, C3-6-cycloalkyloxy, C3-6-cycloalkylcarbonyl, C1-3-alkyl, C2.6-alkanoyl, C2.6-alkynyl, C2-6-aIkenyl, or fluoro-

C2.4-alkyloxy, halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, trifluoromethylthio, C1-6-aIkoxy, C1-6-alkylthio, C1-6-alkylamino, CM-dialkylamino, hydroxy or oxo;
wherein any aryl or heteroaryl residue as substituents on aryl or heteroaryl, alone or as part of another group, in turn is optionally substituted in one or more positions, preferably one, independently of each other by C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, halogen, trifluoromethyl, trifluoromethoxy, or cyano; in the presence of a base in a suitable solvent at an elevated temperature.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, a class of novel compounds that bind to the human 5-HT2A receptor has been developed. The compounds act as receptor antagonists at the human S-HT2A receptor and may therefore be used for the treatment of serotonin-related disorders or medical conditions, particularly 5-HT2A receptor-related.
First, the various terms used, separately and in combinations, in the above definition of the compounds havmg the general formula (I) will be explained.
The expression "C1-6 alkyl" refers to straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Particular C1-6 alkyl groups are methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl.
Derived expressions such as" C1-6 alkoxy" and " C1-6 alkylthio" are to be constructed accordingly. An exemplary CM-alkoxycarbonyl is tert-butoxycarbonyl.
The expression "C2.6 alkenyl" as used herein refers to straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl, allyl (2-propenyl), dimethylallyl and butenyl groups.
The expression "C2-6 alkynyl" as used herein refers to straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.
The expression "C2-6 alkanoyl" as used herem refers to straight-chained and branched alkanoyl groups containing from 2 to 6 carbon atoms. Typical examples include acetyl, propionyl, n-butanoyl.

The expression "C3-6a^-cycloalkyl" refers to cyclic alkyl groups containing from 3 to 6 carbon atoms. Particular Ca-e-cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
By "heteroatom" is meant nitrogen, oxygen, sulphur, and in heterocyclic rings (including heteroaromatic as well as saturated and partially saturated heterocyclic rings), also selenium.
By "oxo" is meant that a group, espeC1ally an aryl or heteroaryl residue, substituted by oxo is connected to an exocyclic oxygen atom through a double bond.
By "MPLC" is meant medium pressure liquid chromatography.
The term "base," as used herein, represents a reagent capable of accepting protons during the course of a reaction. Examples of bases include carbonate salts such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, and cesium carbonate; halides such as cesium fluoride; phosphates such as potassium phosphate, potassium dihydrogen phosphate, and potassium hydrogen phosphate; hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; aUcoxides such as sodium tert-butoxide, potassium tert-butoxide, and lithium tert-butoxide; alkylamines such as triethylamine, diisopropylamine, and diisopropylethylamine; heterocyclic amines such as 4-dimethylaminopyridine, 2,6-lutidine, 1-methylimidazole, pyridine; bicyclic ammes such as 1,8-diazabicyclo(4.3.0)undec-7-ene; and hydrides such as lithium hydride, sodium hydride, and potassium hydride. The base chosen for a particular conversion depends on the nature of the starting materials, the solvent or solvents in which the reaction is conducted, and the temperature at which the reaction is conducted.
The term "aryl" is intended to mclude aromatic rings (monocyclic or bicycUc) having from 6 to 10 ring carbon atoms, such as phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl. The aryl group can be linked to the remainder of the molecule via a carbon atom in any ring.
The term "heteroaryl" means a mono- or bicyclic aromatic ring system, only one ring need be aromatic, and the said heteroaryl moiety can be linked to the remainder of the molecule via a carbon or nitrogen atom in any ring, and having from 5 to 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur, oxygen and selenium. Examples of

such heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, coumarin, quinoline, quinoxaline, isoquinoline, phthalazine, C1nnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, benzoxazole, 2H-chromene, benzisoxazol, 1,3-benzooxathiole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, 2,3-dihydro-l,4-benzodioxine, 1,3-benzodioxole, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2iy-l,4-benzoxazine, 1,5-naphthyridine, 1,8-naphthyridine, 3,4-dihydro-2H-pyrido[3,2-6]-1,4-oxazine, 2,3-dihydro-1,4-benzoxathiine, and l,2,4-triazolofl,5-α]pyrimidine. If abicyclic aryl or heteroaryl ring is substituted, it may be substituted in any ring.
Halogen includes fluorine, chlorine, bromine or iodine, preferably fluorine,
chlorine or bromine. Fluorine is a preferred halogen when it is part of R6 as
substituent.
Where it is stated above that aryl and heteroaryl residues may be substituted (in one or more positions), this applies to aryl and heteroaryl per se as well as to any combined groups containing aryl or heteroaryl residues, such as heteroaryl-C1-3-alkyl and arylcarbonyl, etc.
The term "W-oxides" means that one or more nitrogen atoms, when present in a compound, are in N-oxide fonn (N->0).
The term "prodrug forms" means a pharmacologically acceptable derivative, such as a carbamate or an amide, which derivative is biotransformed in the body to form the active drug. Reference is made to Goodman and Gihnan"s, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs, p. 13-15, and "The Organic Chemistry of Drug Design and Drug Action" by Richard B. Silverman. Chapter 8, p 352 (Academic Press, Inc. 1992. ISBN 0-12-643730-0).
"Pharmaceutically acceptable" means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.

"Phannaceutically acceptable salts" mean salts which are phaimaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include aC1d addition salts formed with organic and inorganic aC1ds, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric aC1d, phosphoric aC1d, acetic aC1d, glycolic aC1d, maleic aC1d, malonic aC1d, malic aC1d, oxalic aC1d, toluenesulphonic aC1d, methanesulphonic aC1d, fiunaric aC1d, sucC1nic aC1d, tartaric aC1d, C1tric aC1d, benzoic aC1d, ascorbic aC1d, trifluoroacetic aC1d, isethionic aC1d (i.e. 2-hydroxyethylsulphonic aC1d), and the like.
The expression "comprising" means "including but not limited to." Thus, other non-mentioned substances, additives or carriers may be present.
"Extrapyramidal symptoms" are symptoms that may manifest upon administration of neuroleptic drugs. The symptoms include a parkinsonian-like syndrome wherein the patient experiences muscular rigidity and tremors. Some experience akathesia and acute dystonic reactions.
The expressions "A""-r-BOC derivative" or "N-t-BOC intermediate" as mentioned in the Exemplary Section, refers to a compound of formula (I) where R1 is t-butoxycarbonyl (f-BOC).
Preferred embodiments of the invention are compounds of formula (I) wherein
n=l;
R1, R2 R3 R4 and R5 each are H; and
R6 is phenoxy, where the phenyl ring of the said phenoxy group may be unsubstituted or substituted. Where substituted, one, two, three, four or five substituents may be present, which may be the same or different, preferably one or two for non-halogen substituents. Examples of preferred substituents on the said R6 phenoxy group are independently selected from halogen, 2-propenyl, C1-C6-alkyl, C1-C6-alkoxy, trifluoromethyl, phenyl, phenoxy, benzoyl, and Cs-e-cycloalkyl; wherein any of the phenyl, phenoxy or benzoyl in turn may be substituted in one, two or three positions, preferably by halogen. R6 may also be substituted with 2,4,5-trifluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2,4-difluorophenoxy, 2,3,4-trifluorophenoxy, 2-fluoro-4-chlorophenoxy, 4-bromophenoxy, and 2,3-dichlorophenoxy.

In another preferred embodiment of the invention is a compound of formula (I) in which n=l;
R1 is methoxy-C2-C4-alkyl or straight-chained C1-C4-aIkyl; R2 R3 R4 and R5 each are H; and R6 is 2,4,5-trifluorophenoxy.
In still another preferred embodiment of the mvention is a compound of formula (I) in which n=l;
R1 R2 R3 R4 and R5 each are H; and R6 is 2-0X0-1,3-benzoxathioI-5-yloxy.
In yet another preferred embodiment of the invention is a compound of formula (I) in which
n = 0;
R1, R2 R3 R4 and R5 each are H; and
R6 is phenyl, where the said phenyl may be substituted with halogen, preferably fluorine, in one, two, three, four or five positions. Even more preferably, R6 represents 2,4,5-trifluorophenyl.
Preferred compounds of the general formula (I) above are:
• l-[2-(2-fluoro-4-nitrophenoxy)ethyl]-3-(l-piperazinyl)-2(lH)-pyrazinone,
• l-{2-[(2-oxo-2 H-chromen-7-yl)oxy]ethyl}-3-(l-piperazinyl)-2(lH)-pyrazinone,
• 3-(l-piperazinyl)-l-[2-(2,4,5-trifluorophenoxy)ethyl]-2(IH-pyrazinone,
• 3-(l -piperazinyl)-1 -[2-(2,3,5,6-tetrafluorophenoxy)ethyl]-2(lH-pyrazinone,
• l-[2-(2,3,4,5,6-pentafluorophenoxy)ethyl]-3-(l-piperazinyI)-2(l//)-pyrazinone,
• l-[2-(4-chloro-2-fluorophenoxy)ethyl]-3-(I-piperazinyl)-2(l//)-pyrazinone.

• l-[2-(3-cyanophenoxy)ethyl]-3-(l-piperazinyl)-2(l/r)-pyrazmone,
• l-[2-(4-cyclopentylphenoxy)ethyl]-3-(l-piperazinyl)-2(lii)-pyrazinone,
• l-[2-(l,2-benzisoxazol-3-yloxy)ethyl]-3-(l-piperazmyl)-2(lH)-
pyrazinone,
• l-[2-(3-methoxyphenoxy)ethyl]-3-(l-piperazinyl)-2(lH)-pyrazinone,
• l-i2-(3-«-butyloxyphenoxy)ethyl]-3-(l-piperazinyl)-2(lH-pyrazinone,
• l-[2-([l,l"-biphenyl]-3-yloxy)ethyl]-3-(l-piperazinyl)-2(lH-pyrazinone,
• 3-(l-piperazinyl)-l-[2-(2,3,4-trifluorophenoxy)ethyl]-2(lH)-pyrazmone,
• l-[2-(2,3-dichlorophenoxy)ethyl]-3-(l-piperazmyl)-2(lH)-p,yrazinone,
• l-[2-(l,3-benzodioxol-5-yloxy)ethyI]-3-(l-piperazinyl)-2(lH-pyrazinone,
• 1 -[2-(2,4-difluorophenoxy)ethyl]-3-(l -piperazmyl)-2( IH-pyrazinone,
• 1 - {2-[(2-oxo-l ,3-benzoxathiol-5-yl)oxy]ethyl} -3-(l -piperazinyl)-2(lF)-pyrazinone,
• 1 -[2-(3-hydroxyphenoxy)ethyl]-3-(l -piperazinyl)-2(l H)-pyrazinone,
• 3-(l-piperazinyl)-l-[2-(6-quinoxalinyloxy)ethyl]-2(lH)-pyrazinone,
• 1 - {2-[3-(N,N-dimethylamino)phenoxy]ethyI} -3-( 1 -piperazinyl)-pyrazm-2(lH)-one,
• 3-(l-piperazmyI>l-{2-[3-(trifluoromethyl)phenoxy]ethyI}-2(liiO-pyrazinone,
• l-[2-(3-fluorophenoxy)ethyl]-3-(l-piperazinyl)-2(l//)-pyrazinone,
• l-[2-(3-mtrophenoxy)ethyl]-3-(l-piperazinyI)-2(l/r)-pyrazinone,
• 1 -[2-(3-benzoylphenoxy)ethyI]-3-(l -piperazinyI)-2(lii/)-pyrazinone,
• l-[2-(3,5-difIuorophenoxy)ethyl]-3-(l-piperazinyl)-2(l/0-pyrazinone,
• l-[2-(phenoxy)ethyl]-3-(l-piperazmyl)-2(lH-pyrazmone,
• 1 -[2-(2,6-difluorophenoxy)ethyl]-3-(l -piperazinyl)-2(lH)-pyrazinone,
• 1 -[2-(2-cyanophenoxy)ethyl]-3-(l -pipeTazmyl)-2(lH)-pyTdzmone,
• l-[2-(4-trifluoromethylphenoxy)ethyl]-3-(l -pipera2inyl)-2(l/0-pyrazinone,
• 1 -[2-(4-bromophenoxy)ethyl]-3-(l-piperazmyl)-2(lH-pyazmone,
• l-[2-{4-phenoxy-(phenoxy)}ethyl]-3-(l-piperazinyl)-2(l/0-pyrazinone,
• l-[2-(4-fluorophenoxy)ethyl]-3-(l-piperazinyl)-2(lH)-pyrazinone,
• l-[2-(4-isopropylphenoxy)ethyl]-3-(l-piperazinyI)-2(liy)-pyrazmone,

• 1 -[2-(2,4,5-tncmoroptienoxy)ethylJ-:i-(. i -piperazmyl)-2(lH)-pyrazinone,
• l-[2-(2-methylthiophenoxy)ethyl]-3-(l-piperazinyl)-2(lH)0-pyrazinone,
• l-[2-(3-niethoxyphenylthio)ethyl]-3-(l-piperazinyl)-2(l/0-pyrazinone,
• l-[2-{(4-aUyl-2-methoxy)pheiioxy}ethyl]-3-(l-piperazinyl)-2(l/iO-pyrazinone,
• l-[2-(5,6,7,8-tetrahydro-naphtha]en-2-yloxy)ethylJ-3-(l-piperazinyl)-2(li/)-pyrazmone,
• 1 -[2-(2,6-difluorophenoxy)ethyl]-3-(3 -methyl-1 -piperazinyl)-2(lif)-pyrazinone,
• l-[2-(4-trifluoromethylphenoxy)ethyI]-3-(3-methyI-l-piperazinyl)-2(li;/)-pyrazinone,
• l-[2-(4-bromophenoxy)ethyl]-3-(3-methyI-l-piperazmyl)-2(lH-pyrazinone,
• l-[2-(phenoxy)ethyl]-3-(3-meth.yl-l-piperazinyl)-2(lH)-pyrazmone,
• 1 -[2-(2,4,5-trifluorophenoxy)ethyl]-3-(3-methyl-1 -piperazinyl)-2(l//)-pyrazinone,
• l-[2-(2,4,5-trifluorophenoxy)ethyl]-3-(l,4-diazepan-l-yl)-2(l/0-pyrazinone,
• l-[2-(4-fluorophenoxy)ethyl]-3-(l ,4-diazepan-l -yl)-2(l/0-pyrazinone,
• 1 -[2-(4-isopropylpheiioxy)ethyl]-3-(l ,4-diazepan-1 -yl)-2(l//)-pyrazinone,
• l-[2-(2-methylihiophenoxy)ethyl]-3-(l,4-diazepan-l-yl)-2(l/0-pyrazinone,
• l-(2,4,5-trifluorobenzyl)-3-(l-piperazinyl)-2(lH)-pyrazinone,
• l-[3-(2,4,5-trifluorophenyl)propyl]-3-(l-piperazinyl)-2(l/0-pFazinone,
• l-(2,3-dihydro-benzo[l,4]dioxin-2-ylmethyl)-3-(I-piperazinyl)-2(lii0-pyrazinone,
• 3-piperazin-l-yl-l[2-(2,4,5-trifluoro-phenoxy)-ethyl]-lH-qumoxalin-2-one,
• l-[2-(2,4,5-trifluorophenoxy)ethyl]-3-(4-n-butyl-l-piperazinyl)-2(lH)-pyrazinone,
• l-[2-(2,4,5-trifluorophenoxy)ethyl]-3-[4-(2-methoxyethyl)-l-piperazmyl]-2(lH)-pyrazinone,

• l-[2-(2,4,5-trifluorophenoxy)ethyl3-3-(4-methyl-l-piperazinyl)-2(l/f)-pyrazinone,
• l-[2-(2,4,5-trifluorophenoxy)ethyl]-3-(4-isopropyl-l-pipera2inyl)-2(lH)-pyrazinone,
• l-{2-[(5-methyl[l,2,4]Mazolo[l,5-fl]pyrimi(lin-7-yl)oxy]ethyl}-3-(l-piperazinyI)-2(lH)-pyrazmone,
• l-[2-(4-Cyanophenoxy)ethyl]-3-(l-piperazinyI)-2(lH)-pyrazmone,
• l-[4-(2,4,5-trifluorophenoxy)butyl]-3-(l-piperazinyl)-2(lH)-pyrazmone,
• l-[3-(2,4,5-trifluorophenoxy)propyl]-3-(l-piperazinyl)-2(lH)-pyrazinone,
• 3-[4-(l-phenylethyl)piperazin-l-yl]-l-[2-(2,4,5-trifluorophenoxy)ethyl]-pyrazin-2( lH-one,
• 3-[4-(2-phenoxyethyI)piperazin-I-yI]-l-[2-(2,4,5-trifIuorophenoxy)ethyl]-pyrazin-2( 1 J^-one,
• 3-[4-(2-Phenylethyl)piperazin-l -yl3-l-[2-(2,4,5-trifluorophenoxy)ethyl]pyrazm-2(l/0-one, hydrochloride,
• 3-(4-Benzylpiperazm-1 -yl)-1 -[2-(2,4,5-trifluorophenoxy)ethyl]pyrazin-2(lH)-one hydrochloride,
• 3-[(2R)-2-methylpiperazin-l-yl]-l-[2-(2,4,5-trifluorophenoxy)ethyl]-pyrazin-2( 1H)-on&,
• 3-piperazin-l-yl-l-[2-(3-thienyl)ethyl]pyrazin-2(l/0-one,
• 3-piperazin-l-yM-[2-(2-thienyl)ethyl]pyrazin-2(l//)-one,
• l-[2-(lH-indoI-3-yl)ethyl]-3-piperazin-l-ylpyrazin-2(l/iO-one,
• l-[2-(2,3-dihydro-l,4-benzodioxin-5-yloxy)ethyl]-3-pipera2in-l-ylpyrazin-2(l//)-oiie,
• l-[2-(phenylthio)ethyI]-3-piperazin-l-ylpyrazin-2(l//)-one,
• l-(3-oxo-3-phenylpropyl)-3-piperazin-l-ylpyrazin-2(l/f)-one, and
• l-[3-(4-fluorophenyl)-3-oxopropyl]-3-piperazin-l-ylpyrazin-2(l//)-one, and their pharmacologically acceptable salts and solvates.
As mentioned above, the compounds of tiie present invention are useful for the treatment, including prophylactic treatment, of serotonin-related, espeC1ally 5-HT2A receptor-related, disorders and medical conditions, in a human being or in an animal, including e.g. pets, such as angina; Raynaud"s phenomenon; intermittent

claudication; coronary or peripheral vasospasms; hypertension; fibromyalgia; thrombotic illness, including stroke; memory disorders, such as Alzheimer"s disease; schizophrenia; obsessive-compulsive disorder mood disorders; autism; anxiety disorders; depression disorders, including depression with coexisting diabetes; sexual function disorders; sleep disorders, such as insomnia and sleep apnea; pain; substance abuse; extrapyramidal symptoms (e.g., assoC1ated with neuroleptic drug therapy using drugs such as, for example, haloperidol and chlorpromazine); Parkinson"s disease; glaucoma including normal tension glaucoma; urinary incontinence including urinary incontinfflice with co-existing diabetes; menopausal and post-menopausal hot flushes; bronchoconstriction disorders, such as asthma and chronic obstructive pulmonary disease; eating disorders, such as binge eating disorders, anorexia nervosa and bulimia; diabetic complications such as nephropathy, neuropathy and retinopathy.
The compounds of the present invention in radiolabelled form may be used as a diagnostic agent.
PROCESSES FOR PREPARATION
This invention also relates to methods of making compounds of any formulae delineated herein comprising reacting any one or more of the compounds or formulae delineated herein including any processes delineated herein.
hi one aspect, the invention is a method of making a compoxmd of formula (I) delineated herein. The compounds of general formula (I) above may be prepared by, or in analogy with, conventional methods, and espeC1ally accordmg to or in analogy with the following methods:
Compounds of formula (I) are prepared by reacting a compound of the stmctural formula (II):


wherein
m represents 1 or 2;
n represents 1 or 2;
X is OH; and
R1, R2, R3 R4 and R5 are as defined for formula (I); with 1 to 10 molar equivalents of an optionally substituted phenol or thiophenol under Mitsunobu conditions (cf Org. Reactions 1992,42,335-656 and Tetrahedron Lett. 1995,36,3789-3792) to produce a compound of formula (I);

wherein
m represents 1 or 2;
n represents 1 or 2;
R1 R2 R3 R4 R5 and n are as defined for formula (I);
R6 is selected from aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-NH,
or heteroaryl-NH, aryl, arylcarbonyl, heteroaryl, or heteroarylcaibonyl; wherein
any aryl or heteroaryl residue, alone or as part of another group, may be imsubstituted or substituted. Where substituted, one, two, three, four or five substituents may be present, preferably one or two for non-halogen substituents, and are independently selected from aryl, aryl-C1-2-alkyl, arylcarbonyl, heteroaryl, heteroaryl-C1-2-alkyl, heteroarylcarbonyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylamino, heteroarylaraino, C3-6-cycloalkyl, C3-6-cycloalkyloxy, C3-6-cycloalkylcarbonyl, C1-6-alkyl, C2-6-alkanoyl, C2-6-alkynyl, C2-6-alkenyl, or fluoro-C2-4-aIkyloxy, halogen,

trifluoromethyl, nitro, cyano, trifluoromethoxy, trifluoromethylthio, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylamino, CM-dialkylamino, hydroxy or oxo; wherein
any aryl or heteroaryl residue as substituents on aryl or heteroaryl, alone or as part of another group, in turn may be substituted in one or more positions, preferably one, independently of each other by CM-alkyl, C1-.4-aIkoxy, C1-4-alkylthio, halogen, trifluoromethyl, trifluoromethoxy, or cyano. Typically, the said Mitsunobu reaction is carried out in the presence of diethyl azodicarboxylate (DEAD) or 1,1 "-azobis(AVV-dmiethylfoimamide (TMAD), preferably TMAD, and triphenylphosphine or tri-n-butylphosphine, preferably triphenylphosphine, in a solvent such asN,N -dimethylformamide (DMF), dichloromethane or tetrahydrofuran (THF), espeC1ally DMF, or in a suitable mixture of solvents, such as THF:DMF, at -25 to 50 °C, typically at room temperature, for 1-48 hours.
For compounds of formula (I) where R" is H, R" in the corresponding intermediate of formula (II) is a suitable protecting group, preferably tert-butoxycarbonyl (t-BOC) or trityl.
The intermediates of formula (11) may be prepared according to the methodology described in WO 00/76984 and as described in Examples 73-75.
The method described above for produC1ng a compound of formula (I) from a compound of formula (II) may produce a mixture of structural isomers containing the desired compound of formula (I) according to the current invention and the corresponding structural isomer of formula (lb) disclosed in WO 00/76984. The ratio of the two structural isomers may vary depending on the experimental conditions used. These compounds maybe conveniently separated by conventional techniques including chromatography, such as column chromatography on silica gel or preparative HPLC. The identity of the individual structural isomers may be estabUshed by spectroscopic techniques such as nuclear magnetic resonance (MMR) spectroscopy, including proton and carbon NMR (1H NMR and 13C NMR) spectroscopy, and infrared spectroscopy (IR).
Alternatively, the compounds of formula (I) can also be prepared by reacting a compound of formula (TV),


wherein
m is 1 or 2;
Hal is halogen, typically chlorine; and
R", R^ R^ R", and R^ are as defined for fonnula (I); with an alkali metal or alkaline earth metal basic salt, eg., a hydroxide or carbonate such as NaOH or K2CO3, in aqueous media, such as water.dimetyl sulfoxide (DMSO), at 25 to 150 °C, to produce a compound of formula (V),

wherein m, R", R^, R^, R"*, and R^ are as defined for formula (I), followed by A^-alkylation of the compoimd of formula (V) by reaction with a compoimd of formula (VI),
R6-CH2-(CH2)-Y
wherem
nisO, 1,2, 3 or 4;
Y is a smtable leaving group such as mesylate, tosylate, chlorine, bromine or iodine; and
R6 represents aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-NH, heteroaryl-NH, aryl, arylcarbonyl, heteroaryl, or heteroarylcarbonyl; wherein
any aryl or heteroaryl residue, alone or as part of another group, may
be unsubstituted or substituted. Where substituted, one, two, three, four or
five substituents may be present, preferably one or two for non-halogen

substituents, and are independently selected from aryl, aryl-C1-a-alkyl, arylcarbonyl, heteroaryl, heteroaryl-C1-2-alkyl, heteroaylcarbonyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylamino, heteroarylamino, C3.6-cycloalkyl, C3-6-cycloalkyloxy, Cs-e-cycloalkylcarbonyl, C1-6-alkyl, C2.-6-alkanoyl, C2.6-alkynyl, C2-6-alkenyl, or fluoro-C2-4-alkyloxy, halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, trifluoromethylthio, C1-6-alkoxy, C1-.6-alkylthio, C1-6-alkylamino, C1-4-dialkylamino, hydroxy or 0x0; wherein
any aryl or heteroaryl residue as substituents on aryl or heteroaryl, alone or as part of another group, in turn may be substituted in one or more postions, preferably one, independently of each other by C1-4-alkyl, d^-alkoxy, C1-4-alkylthio, halogen, trifluoromethyl, trifluoromethoxy, or cyano; typically in the presence of a base such as an alkali metal hydride, such as sodium hydride, or sodium or potassium tertbutoxide (t-BuONa or NBuOK), or potassium carbonate or caesium carbonate or the like in a suitable solvent such as THF, dioxane, diglyme, 1,2-dmiethoxyethane, DMF, DMSO, or acetonitrile, suitably at an elevated temperature, typically the reflux temperature of the solvent employed. The said A"-alkylation reaction may be carried out in the presence of sodium iodide or potassium iodide in cases where Y in formula (VI) is other than iodine.
For compoimds of formula (I) where R1 is H, R1 in the intermediate of formula (V) is a suitable protecting group, preferably fert-butoxycarbonyl (t-BOC) or trityl.
The intermediates of formula (IV) may be prepared according to the methodology described in WO 00/76984 and as described in Example 54, Step 1, and Example 55, Step 1.
Whan R1 is a nitrogen protecting group, such as tert-butoxycarbonyl (^BOC) or trityl, the subsequent iV-deprotection is carried out by conventional methods such as those described in Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
An obtained compound of formula (I) above may be converted to another compound of formula (I) by methods well known in the art. Different groups may be

introduced, such as C1-6-alkyl groups for R1 in the fonnula (I). The conditions may be those described in Example 52, Step 2; Example 53, Step 2; and Examples 60-63.
The chemicals used in the above-described synthetic routes may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group agents. The methods described above may also additionally include steps, either before or after the steps described speC1fically herein, to add or remove suitable protecting groups m order to ulttinately allow synthesis of the compounds of any of the formulae described above, their salt forms, or compositions that include the compounds or their salt forms. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds of the fonnula (I) are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3 Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser"s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed,. Encyclopedia ofReagmtsfor Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof
The process that is described above may be carried out to give a compound of the invention in the form of a free base or as an aC1d addition salt. A pharmaceutically acceptable aC1d addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an aC1d, in accordance with conventional procedures for preparing aC1d addition salts from base compounds. Examples of addition salt forming aC1ds are maleic aC1d, malic aC1d, fumaric aC1d, sucC1nic aC1d, methanesulfonic aC1d, acetic aC1d, oxalic aC1d, benzoic aC1d, hydrochloric aC1d, sulphuric aC1d, phosphoric aC1d, and the like.
The compounds of formula (I) may possess one or more chiral carbon atoms, and they may therefore be obtamed in the form of optical isomers, e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers. The separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional

crystallization of salts with optically active (chiral) aC1ds or by chromatographic separation on chiral colunms.
The necessary starting materials for preparing the compounds of formula (I) are either known or may be prepared in analogy with the preparation of known compounds.
In accordance with the present invention, the compounds of formula (I), in the form of free bases or salts with physiologically acceptable aC1ds, can be brought into suitable galenic forms, such as compositions for oral use, for injection, for nasal spray administration or the like, in accordance with accepted pharmaceutical procedures. Such pharmaceutical compositions according to the invention comprise an effective amount of the compounds of formula (I) in assoC1ation with compatible pharmaceutically acceptable carrier materials, or diluents, as are well known in the art. The carriers may be any inert material, organic or inorganic, suitable for enteral, percutaneous, subcutaneous or parenteral administration, such as: water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calC1um hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and &e like. Such compositions may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, and the like.
The compositions according to the invention can e.g. be made up in solid or liquid form for oral administration, such as tablets, pills, capsules, powders, syrups, elixirs, dispersable granules, cachets, suppositories and the like, in the form of sterile solutions, suspensions or emulsions for parenteral administration, sprays, e.g. a nasal spray, transdermal preparations, e.g. patches, and the like.
As mentioned above, the compounds of the invention may be used for the treatment of serotonin-related, espeC1ally S-HT2A receptor-related, disorders and
medical conditions in a human being or an animal, such as angina, Raynaud"s phenomenon, intermittent claudication, coronary or paripheral vasospasms, hypertension, fibromyalgia, thrombotic illness (including stroke), memory disorders, such as Alzheimer"s disease; schizophrenia; obsessive-compulsive disorder; mood disorders; autism; anxiety disorders; depression disorders (including depression with coexisting diabetes), sexual function disorders, sleep disorders, such as insomnia and sleep apnea, pain; substance abuse; extrapyramidal symptoms (e.g., assoC1ated with

neuroleptic drug therapy using drugs such as, for example, haloperidol and chlorpromazine); Parkinson"s disease; glaucoma including normal tension glaucoma; urinary incontinence including urinary incontinence with co-existing diabetes; menopausal and post-menopausal hot flushes; bronchoconstriction disorders, such as asthma and chronic obstructive puhnonary disease; eating disorders, such as binge eating disorders, anorexia nervosa and bulimia; diabetic complications such as nephropathy, neuropathy and retinopathy.
This invention relates to a method of treatment or prophylaxis of a S-HTaA-receptor-related disorder or medical condition. The method includes administering to a subject (e.g., a mammal, a human, a horse, a dog, or a cat) in need thereof an effective amount of one or more compounds of any of the formulae described above, their salt forms, or compositions that include the compounds or their salt forms.
Also v^"ithin the scope of this invention is a method for modulating (e.g., inhibiting) 5-HT2A receptor activity. The above-mentioned disorders and medical conditions may be treated with a S-HTZA antagonist. The method includes administering to a subject in need thereof an effective amount of one or more compounds of any of the formulae described above, their salt forms, or compositions that include the compounds or their salt forms.
The methods delineated herein can also include the step of identifying that the subject is in need of treatment of aforementioned disorders or medical conditions. The identification can be in the judgment of a subject or a health care professional and can be a subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).
"An effective amount" refers to an amount of a compound that confers a therapeutic effect on the treated subject. The therapeutic effect maybe objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). For cUnical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. Usually the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.2-20% by weight in pr^arations for parenteral use and preferably between 1 and 50% by weight in preparations for oral administration.

The typical dose of the active substance varies within a wide range and will depend on various factors such as, for example, the individual requirement of each patient and the route of administration, In general, oral and parenteral dosages will be in the range of 5 to 1000 mg per day of active substance, preferably 50 to 150 mg per
day.
The dose level, frequency of dosage, mode of administration, of the speC1fic compound will vary depending on a variety of factors including the potency of the speC1fic compound employed, the metabolic stability and length of action of that compound, the patient"s age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drag combination, the severity of the condition to be treated, and the patient undergoing therapy.
All references C1ted herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications.
The invention will now be illustrated with the following examples, which however, are for illustrative purposes are not intended to limit the scope of the invention.
EXAMPLES
General. NMR spectra were recorded on a Bruker DPX 400, Bruker DRX 500, Jeol 270 or on a Varian Unity Inova 400 spectrometer. Column chromatography was performed on Silica gel 60 (230-400 mesh, E. Merck). The preparative HPLC purifications were performed on a YMC OPS-AQ CombiPrep column (50 x 20 mm, i.d., 5 ytm particle size, 120 A), using various gradients of acetonitrile-water containing 0.1% TFA as eluent at a flow rate of 30 mL/min, using a LC/MS Gilson-Finnigan instrument equipped with Gilson pumps, a Dynamax UV-1 detector and a Finnigan Mass detector. Analytical reversed-phase HPLC analyses were carried out on a ACE C8 column (50 x 4.6 mm) using various gradients of acetonitrile-water, containing 0.005 M ammonium acetate, at a flow rate of 1 mL/min, using a Waters ZQ LC-MS setup. "Speed-vac" refera to a Speed-vac Plus SC250DDA or a Gene-vac

DD-4. The accurate mass analyses were determined on a Micromass LCT instrument using electrospray ionisation. The elemental analyses were performed by MikroKerai AB, Uppsala, Sweden or on an Elementar Vario EL instrument at Biovitrum AB, Stockholm, Sweden, and reported results were within ±0,4% of the theoretical values. Melting points, when given, were obtained on a Buchi Meltingpoint B-545, Electrothermal lA 9000, or a Gallenkamp MPD350 apparatus and are uncorrected. The intermediate 2-[3-(4-tertbutoxycarbonyl-1 -piperazinyl)-pyra2inyloxy]ethanol was prepared as described in WO 00/76984, Example 52, Step 2.
EXAMPLE!
1 -[2-(2-FIuoro-4-mtrophenoxy)ethyl]-3-(l -piperazinyl)-2( li;/)-pyrazinone.
Hydrochloride.
2-Fluoro-4-nitrophenol (732 mg, 4.66 mmol), 2-[3-(4-terf-butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (1.375 g, 4.240 mmol) and triphenylphosphine (1.22 g, 4.66 mmol) were dissolved in THF (8 mL) and l,r-azobis(iV,iV-dimethylformamide (TMAD; 802 mg, 4.66 mmol) was added in three portions. The reaction mixture was stirred at room temperature overnight and then centrifugated. The supernatant was concentrated in vacuo. The residue was dissolved in EtOAc and washed with 5% NaHCOj and brine. The oigmiic layer was concentrated in vacuo and the residue purified by flash-chromatography using EtOAc/toluene (4:6) as eluent to give 451 mg (23 %) of the title compoimd as its N-t-BOC derivative. The N-t-BOC mtermediate (440 mg, 0.949 mmol) was treated with trifluoroacetic aC1d (TFA)/dichloromethane/H20 (36:60:4,3.6 mL) for 45 min. The solution was concentrated in vacuo and the residue preC1pitated with ether. This material was dissolved in 50% aqueous MeOH (15 mL) and passed through an anion exchange resin (Dowex-1 X8, Cl", 4 g) eluting with 50% aqueous MeOH. Evaporation of the solvent in vacuum gave the title compound. Yield: 364 mg (96 %); mp 105-108 °C; MS-EI m/z 363 (Mf. Anal. (C16H18N5O4F • 1.1 HCl • 0.2 H2O) C, H, N.

EXAMPLE 2
l-{2-[(2-Oxo-2H"-chromen-7-yl)oxy]ethyI}-3-(I-piperazinyl)-2(li^-pyrazinone,
Hydrochloride.
Diethyl azodicarboxylate (DEAD; 0.63 mL, 4.0 mmol) was added over 20 min to a stirred mixture of 7-hydroxycouniarin (713 mg, 4.40 mmol), 2~[3-(4-tert-butoxycarbonyl- l-piperazinyl)-pyrazinyloxy]ethanoI (1.29 g, 4.00 mmol) and triphenylphosphine (1.05 g, 4.00 mmol) in THF (15 mL). The reaction mixture was stirred at room temperature overnight. Removal of solvent in vacuum and purification of the residue by repeated chromatography on silica gel using EtOAc/toluene and dichloromethane/MeOH (96:4) as eluents, respectively, gave 871 mg (46%) of the title compound as its N-t-BOC derivative. TheN-t-BOC interm:ediate (800 mg, 1.71 mmol) was treated with TFA/dichloromethane/H20 (40:55:5; 4.2 mL) for 70 min. The solution was ev£^orated and the residue preC1pitated with ether. This material (843 mg) was dissolved in 50% aqueous MeOH (10 mL) and passed through an anion exchange resin (Dowex-1 X8, CV, 5 g) eluting with 50% aqueous MeOH. The resulting hydrochloride salt of the title compound was further purified by chromatography on LiChroprep RP-18 (Merck) reversed phase silica gel (5 x 2.5 cm) eluting with 25% acetonitrile in 0.02 M HCl. The product-containing fractions were pooled, concentrated in vacuo and freeze-dried to furnish 600 mg (85%) of the title compound. MS-EI m/z 368 (M)+. Anal. (C19H20N4O4 ■ HCl ■ 0.7 H2O) C, H, N.
EXAMPLES
3-(l -Piperazinyl)-1 -[2-(2,4,5-trifluorophenoxy)ethyI]-2(l/0-pyazinone,
Hydrochloride.
2,4,5-Trifluorophenol (533 mg, 3.60 mmol), 2-[3-(4-fer^butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (972 mg, 3.00 mmol), TMAD (619 mg, 3.60 mmol) and polymer-bound triphenylphosphine (Fluka) (1.2 g, 3.6 mmol) were shaken in dichloromethane (10 mL) under nitrogen for about 21 h. The polymer was filtered off and washed with dichloromethane. The solvent was evaporated and the residue was dissolved in CHC13 and washed with 1 M NaaCOa and brine. Removal of solvent in vacuo and purification of the residue by column chromatography on silica gel using CHC13 ^ CBChMeOH (98:2) as eluent gave 791 mg (58%) of the title

compound as its N-t-BOC derivative. The N-t-BOC intennediate (700 mg, 1.54 mmol) was treated with TFA/dichloromethane/HzO (42:53:5; 4 mL) and kept at room temperature for 50 min with stirring. The solution was concentrated and the residue preC1pitated with MeOH/ether. This material was dissolved in 50% aqueous MeOH and passed through an anion exchange resin (Dowex-1 X8, C1", 4 g) eluting with 50% aqueous MeOH. Evaporation of the solvent in vacuum gave the title compound. Yield: 513 mg (85%); mp 193-195 °C; MS-EI m/z 354 (JS/Tf; HRMS m/z calcd for C16H17F3N4O2 (Mf 354.1304, found 354.1301. Anal. (C16HnF3N402 • HC1)C,H,N.
This compound, isolated as its acetate salt, has also been prepared according to the procedure of Example 65 by replaC1ng 2-(4-allyI-2-methoxy-phenoxy)-ethyl methanesulfonate with 2-(2,4,5-trifluorophenoxy)ethyl methanesulfonate.
EXAMPLE 4
3-(l-Piperazinyl)-l-[2-(2,3,5,6-tetrafluorophenoxy)ethyl]-2(l//)-pyrazinone,
Hydrochloride.
2,3,5,6-Tetrafluorophenol (556 mg, 3.35 mmol), 2-[3-(4-?erf-butoxycaibonyl-l-piperazinyl)-pyrazinyloxy]ethanol (1.01 g, 3,10 mmol) and triphenylphosphine (813 mg, 3.10 mmol) were dissolved in THE (10 mL) and TMAD (533 mg, 3.10 mmol) was added in three portions over 50 min. The reaction mixture was stirred at room temperature overnight. A small amount of a white preC1pitate was filtered off. The filtrate was evaporated, redissolved in ether and filtered again. The filtrate was washed with 5% NaHCOa and brine, concentrated in vacuo, and the residue purified by flash chromatography using EtOAc/toluene (3:7 followed by 1:4) as eluent. This gave 584 mg (40%) of the title compound as its N-t-BOC derivative. TheiV-r-iBOC intennediate (568 mg, 1.20 mmol) was treated with TFA/dichloromethane/H20 (42:53:5; 3.1 mL) at room temperature for 50 min with stirring. The solution was evaporated and the residue preC1pitated with MeOH-ether. This product was dissolved in 50% aqueous MeOH and passed through an anion exchange resin Powex-1 X8, Cr, 4 g) eluting with 50% aqueous MeOH. Evaporation of the solvent in vacuum gave the title compound. Yield: 453 mg (92%); mp 196-198 °C (dec);

MS-EI m/z ill (M)+; HRMS m/z calcd for C16H,6F4N402 (M)"" 372.1209, found 372.1196. Anal. (C16H16F4N4O2 • HCl) C, H, N.
EXAMPLES
l-[2-(2,3,4,5,6-Pentafluorophenoxy)ethyl]-3-(l-piperazinyl)-2(liy)-pyrazinone,
Hydrochloride.
Pentafluorophenol (608 mg, 3.30 mmol), 2-[3-(4-ter^butoxyC3-6bonyl-l-piperazinyl)-pyrazmyloxy]ethanol (1.01 g, 3.10 nunol) and triphenylphosphine (813 mg, 3.10 mmol) were dissolved in THF (5 mL) and TMAD (533 mg, 3.1 mmol) was added in three portions. The reaction mixture was stirred at room temperature overnight. A small amount of a white preC1pitate was filtered off. The filtrate was concentrated in vacuo and the residue was dissolved in ether, washed with 5% NaHCOa and brine. Removal of solvent in vacuo and purification of the residue by flash chromatography using toIuene/EtOAc (3:7 followed by 1 .•4) as eluent gave 332 mg (22 %) of the title compound as its N-t-BOC derivative. This material (0.677 mmol) was treated with TFA/dichlorometbane/HaO (42:53:5; 1.74 mL) for 1 h. The solution was evaporated and the residue preC1pitated with MeOH/ether. This product was dissolved in 50% aqueous MeOH and passed through an anion exchange resin (Dowex-1 X8, Cr, 4 g) eluting with 50% aqueous MeOH. Evaporation of the solvent in vacuum gave the title compound. Yield: 275 mg (92%). MS-EI m/z 390 (M)"^. HRMS m/z calcd for C16H15F5N4O2 (M)* 390.1115, found 390.1106. Anal. (C16H,5F5N402 •HC1)C,H,N.
EXAMPLE 6 l-[2-(4-Chloro-2-fluorophenoxy)ethyl]-3-(l-piperazinyl)-2(li^-pyrazinone.
l,r-Azobis(iV,A""-dimethylformamide (TMAD; 0.217 g, 1.26 mmol) was added to a stirred mixture of 2-[3-(4-tert-butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanoI (0.324 g, 1.00 mmol), triphenylphosphine (0.324 g, 1.23 mmol) and 4-chloro-fluorophenol (0.217 g, 1.48 mmol) in THF (1 mL) at room temperature. After 2 h, the reaction mixture was concentrated and the crude N-t-BOC derivative of tihe title compound was A""-deprotected with TFA/dichloromethane/H20 (45:50:5). Purification by chromatography on silica gel using EtOAc/toluene (4:6) as

eluent gave 0.123 g (35%) of the title compound as a yellow oil. HRMS m/z calcd for C,6H,8C1FN402 (Mf 352.1102, found 352.1098.
EXAMPLE? l-[2-(3-Cyanophenoxy)ethyl]-3-(l-piperazinyl)-2(l/0-pyrazinone.
~ The title compound was prepared according to the procedure described in Example 6 starting from 3-cyanophenol (0,149 g, 1,25 mmol). This gave 115 mg (35%) of the title compound as a yellow solid; mp 49-52 °C. HRMS mlz calcd for C17H19N5O2 (M)"" 325.1539, found 325.1549.
EXAMPLES l-[2-(4-CyC1opentyIphenoxy)ethyI]-3-(l-pipera2inyI)-2(l/r)-pyrazinone.
The title compound was prepared according to the procedure described in Example 6 starting from 4-cyC1opentyIphenol (0.203 g, 1.25 mmol). This gave 30 mg (8%) of the title compound as a yellow oil. HRMS m/z calcd for C21H28N4O2 (M)* 368.2212, found 368.2193
EXAMPLE 9
l-[2-(l,2-Benzisoxazol-3-yloxy)ethyIJ-3-(l-piperazinyl)-2(lH)-pyrazinone,
Dihydrochloride.
The title substance was prepared by dissolving S-hydroxj^enzisoxazole (0.324 g, 1.0 mmol), tri-n-butylphosphine (PBua; 0.360 mL, 1.46 mmol), 2-[3-(4-tert-butoxycarbonyI-l-piperazinyl)-pyrazinyIoxy]ethanol (0.324 g, 1,00 mmol) in DMF (I mL) and adding l,l"-azobis(N,N-dimethylformamide (TMAD; 0.215 g, 1.25 mmol). The reaction was heated in a Labwell microwave reactor for 1 min at 75W. The N-t-BOC derivative of the title compound was purijBed by chromatography on silica gel using MeOH/CHCU (5:95) as eluent. The subsequent iV-deprotection was carried out using TFA/dichloromethane/HaO (45:50:5). The title product was isolated as a yellow solid. Yield: 0.085 g (20%); mp 174-176°C. HRMS m/z calcd for C17H19N5O3 (M)* 341.1488, found 341.1496.

EXAMPLE 10 l-[2-(3-Methoxyphenoxy)ethyl]-3-(l-piperazinyl)-2(l/0-pyrazinone.
TMAD (0.060 g, 0.35 mmol) was dissolved in THF (1 mL) and DMF (0.5 mL) and the solution added dropwise to a mixture of 2-[3-(4-tert-butoxycarbonyl-l-piperazinyl)-pyrazinyIoxy]ethanoI (0.100 g, 0.310 mmol), triphenylphosphine (0.092 g, 0.35 mmol) and 3-methoxyphenol (0.124 g, 1.00 mmol) in THF (0.5 mL). The reaction mixture was stirred overnight at room temperature, concentrated, and put through a silica column using toluene/EtOAc (7:3) as eluent. Solvents were removed in vacuo and the N-t-BOC derivative of the title compound was treated with dichloromethane/TFA/HaO (50:45:5; 5 mL) for 15 min. The mixture was concentrated and the residue was purified by chromatography on sihca gel using EtOAc/HOAc/MeOH/H2O (20:3:3 ;2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica coliunn using dichloromethane/MeOH (8:2) as eluent to give 40 mg (34%) of the title compound as an oil. HRMS mk calcd for C17H22N4O3 (M)^ 330.1692, found 330.1677.
EXAMPLE 11 l-[2-(3-«-Butyloxyphenoxy)ethyl]-3-(l-piperazinyl)-2(l/0-pyrazinone.
TMAD (0.060 g, 0.35 mmol) was dissolved in THF (1 mL) and DMF (0.5 mL) and the solution was added dropwise to a mixture of 2-[3-(4-/er/-butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (0.100 g, 0.310 mmol), triphenylphosphine (0.092 g, 0.35 mmol) and 3-«-butyloxyphenol (0.166 g, 1.00 mmol) in THF (0.5 mL). The reaction mixture was stirred overnight at room temperature, concentrated, and put through a silica column using toluene/EtOAc (7:3) as eluent. Solvents were removed in vacuo and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/H20 (50:45:5; 5 mL) for 15 min with stirring. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/HOAc/MeOH/HaO (20:3:3:2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica colunm using dichloromethane/MeOH (8:2) as eluent to give 97 mg (7%) of the title compound. HRMS m/z calcd for C20H28N4O3 (M)* 372.2161, found 372.2149.

EXAMPLE 12 l-[2-([l,l"-Biphenyl]-3-yloxy)ethyl]-3-(l-piperazmyl)-2(lH)-pyrazinone.
TMAD (0.060 g, 0.35 mmol) was dissolved in THF (1 mL) and DMF (0.5 mL) and the resulting solution was added dropwise to a mixture of 2-[3-(A-tert-butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (0.100 g, 0.31 mmol), triphenylphosphine (0.092 g, 0.35 mmol) and 3-phenylphenol (0.170 g, 1.00 mmol) in THF (0.5 mL). The reaction mixture was stirred overnight at room temperature, concentrated, and put through a silica column using toluene/EtOAc (7:3) as elucnt. Solvents were removed in vacuo and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/H2O (50:45.-5; 5 mL) for 15 min with stirring. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H20 (20:3:3:2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica colunm using dichloromethane/MeOH (8:2) as eluent to give 16 mg (16%) of the title compound. HRMS m/z calcd for C22H24N4O2 (M)+ 376.1899, found 376.1888.
EXAMPLE 13 3-(l-Piperazinyl)-l-[2-(2,3,4-trifluorophenoxy)ethyl]-2(lH-pyrazinone.
TMAD (0.207 g, ,1.20 mmol) was added to a solution of 2-[3-{4-tert-butoxycarbonyl-l-piperazinyI)-pyrazinyloxy]ethanol (0.324 g, l.00 mnol), triphenylphosphine (0.315 g, 1.20 mmol) and 2,3,4-trifluorophenol (0.296 g, 2.00 mmol) in THF (1 mL) at room temperature. After being stirred for 2 h, the mixture was concentrated in vacuo and put through a silica column using toluene/EtOAc (7:3) as eluent. Solvents were removed m vacuo and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/HaO (50:45:5; 5 mL) for 15 min with stirring. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/HOAc/MeOH/HaO (20:3:3:2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica column using dichloromethane/MeOH (8:2) as eluent to give 62 mg (17%) of the title compound. HRMS m/z calcd for C16Hi7F3N402(M)"" 354.1304, found 354.1321.

EXAMPLE 14 l-[2-(2,3-Dichlorophenoxy)ethyl]-3-(l-piperaziQyl)-2(l^-pyrazinone.
TMAD (0.207 g, 1.20 mmol) was added to a solution of 2-[3-(4-tert-butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (0.324 g, 1.00 mmol), triphenylphosphine (0.315 g, 1.20 mmol) and 2,3-dichlorophenol (0.326 g, 2.00 mmol) in THF (1 mL) at room temperature. After being stirred for 2 h, the mixture was concentrated in vacuo and put through a silica column using toluene/EtOAc (7:3) as eluent. Solvents were removed in vacuo and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/H20 (50:45:5; 5 mL) for 15 min with stirring. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (20:3:3:2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica column using dichloromethane/MeOH (8:2) as eluent to give 60 mg (16%) of the title compound. HRMS m/z calcd for C16H18C12N4O2 (M)^ 368.0807, found 368.0818.
EXAMPLE 15
l-[2-(l,3-Benzodioxol-5-yloxy)ethyl]-3-(l-piperazinyl)-2(lH)-pyrazinone. TMAD (0.207 g, 1.20 mmol) was added to a solution of 2-[3-(4-tert-butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (0.324 g, 1.00 mmol), triphenylphosphine (0.315 g, 1.20 mmol) and sesamol (0.173 g, 1.25 mmol) in THF (1 mL) at room temperature. After being stirred for 2 h, the reaction mixture was concentrated and put through a silica column using toluene/EtOAc (7:3) as eluent. Solvents were removed in vacuo and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/HaO (50:45:5; 5 mL) for 15 min with stirring. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/HOAc/MeOH/HaO (20:3:3:2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica column using dichloromethane/MeOH (8:2) to give 78 mg (23%) of the title compound. HRMS m/z calcd for C17H2oN404(M)+ 344.1485, found 344.1474.

EXAMPLE 16
1 -[2-(2,4-Difluorophenoxy)ethyl]-3-(l -piperazinyl)-2(lH)-pyrazinone.
TMAD (0.129 g, 0.750 mmol) was added to a solution of 2-[3-(4-tert-butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (0.200 g, 0.620 nrniol), triphenylphosphine (0.196 g, 1.23 mmol) and 2,4-difluorophenol (0.160 g, 1.23 mmol) in THF (1 mL) at room temperature. After being stirred for 2 h, the mixture was concentrated and put through a silica column using toluene/EtOAc (7:3) as eluent. Solvents were removed in vacuo and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/H2O (50:45:5; 5 mL) for 15 min with stirring. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/HOAc/MeOH/HaO (20:3:3:2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica coliunn using dichloromethane/MeOH (8:2) as eluent to give 30 mg (14%) of the title compound. HRMS m/z calcd for C16H18F2N4O2 (M)+ 336.1398, found 336.1392.
EXAMPLES 17 AND 18. GENERAL PROCEDURE:
TMAD (0.207 g, 1.20 mmol) was added to a mixture containing 2-[3-i4~tert-butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (0.325 g, 1.00 mmol), triphenylphosphine (0.328 g, 1.25 mmol) and the appropriate phenol (1,25 mmol). The reaction mixture was stirred until the starting material was consumed (by HPLC: 2-6 h) then concentrated and purified by chromatography on silica gel using toluene/EtOAc (9:1 to 1:1) as eluent. The JV-BOC derivative of the title compound was treated with dichloromethane/TFA/H20 (50:45:5; 5 mL) for 15 min with stkring. The mixture was concentrated and the residue purified by chromatography on silica gel using a gradient of dichloromethane-* dichloromethane/MeOH (8:2) as eluent to provide the title compound.

EXAMPLE 17
l-{2-[(2-Oxo-l,3-ben2;oxathiol-5-yl)oxy]ethyl}-3-(l-piperaziny])-2(li0-pyrazinone, Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 5-hydroxy-l,3-ben2oxathiol-2-one (0.210 g, 1.25 mmol). Yield: 0.147 g (30%). HRMS miz calcd for C17H18N4O4S (Mf 374.1049. found 374.1044. Anal (C17H18N4O4S • C2F3HO2) C, H, N.
EXAMPLE 18
l-[2-(3-Hydroxyphenoxy)ethyl]-3-(l-piperazinyl)-2(l/0-pyrazinone, Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from resorC1nol (0.276 g, 0.250 mmol). Yield: 0.159 g (37%). HRMS mIz calcd for C16H20N4O3 (M)"" 316.1535, found 316.1546.
EXAMPLE 19 3-(l-Piperazinyl)-l-[2-(6-quinoxalinyloxy)ethyl]-2(lJi)-pyrazinone, Hydrochloride.
TMAD (0.55 g, 3.20 mmol) was added to a stirred mixture of 2-[3-(4-^err-butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol), 6-hydroxyquinoxaline* (0.45 g, 3.08 mmol) and triphenylphosphine (0.85 g, 3.24 mmol) in THE (10 mL) at room temperature. After 20 h, the reaction mixture was concentrated and put through a silica colunrn using toluene/EtOAc (1:1) as eluent. The chromatographic procedure was repeated once. Solvents were removed in vacuo and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/HaO (50:45:5; 20 mL) for 30 min with stirring. The reaction mixture was concenfrated, dissolved in 0.1 M aqueous HCl and washed with toluene. The aqueous phase was frozen and lyophihzed, dissolved in EtOH and concentrated to give 0.843 g (70%) of the title compound. HRMS mIz calcd for C1sHaoNeOz (M)+ 352.1648, found 352.1642. *Prepared as described in J. Org. Chem. 1951,16,438-442.

EXAMPLE 20
1 - {2-[3-(H-Dimethylammo)phenoxy]ethyl}-3-(l-piperazinyl)-pyrazin-2(li:0-one,
Fumarate.
3-Dimethylaminophenol (0.97 g, 3.70 mmol), triphenylphosphine (0.97 g, 3.70 mmol) and TMAD (0.64 g, 3.70 mmol) were added to a stirred solution of 2-[3-(4-ter/-butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (1.2 g, 3.7 mmol) in dry THF (10 ToL) at room temperature. After 24 h, the reaction mixture was filtered and concentrated in vacuo. The residue was subjected to column chromatography on silica gel using toluene/EtOAc (3:1) containing 5% triethylamine as eluent to give 1.30 g (81%) of the N-t-BOC derivative of the title compound as an oil. This material (1.28 g, 2.89 mmol) was dissolved in dichloromethane (5 mL) and TFA (5 mL) was added. After being stured at room temperature for 4 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and the solution was washed sequentially with 2 M aqueous NaOH, H2O and brine. The organic layer was dried over MgS04 and concentrated in vacuo. The residue was purified by chromatography on silica gel using EtOAc/MeOH (3.5:0.5) containing 5% triethylamine as eluent to furnish 0.35 g of the free base of the title compound. This material (1.03 mmol) was dissolved in dry MeOH (3 mL) and fizmaric aC1d (0.12 g, 1.03 mmol) in dry MeOH (3 mL) was added dropwise. Diethyl ether was added dropwise. The preC1pitate formed was collected by filtration, washed with diethyl ether, dried, to give 0.37 g (22 %) of the title compound; mp. 180-191° C. Anal. (C18H25N5O2 • C4H4O4) C, H, N.
EXAMPLE 21 3-(l-Piperazinyl)-l-{2-[3-(trifluoromethyl)phenoxy]ethyl}-2(li;0-pyrazinone.
(TMAD; 129 mg, 0.75 mmol) was added to a mixture of 2-[3-(4-ferf-butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (200 mg, 0.62 mmol), triphenylphosphine (323 mg, 1.23 mmol), 3-hydroxybenzotrifluoride (199 mg, 1.23 nunol) in THF (1.5 mL). After being stirred at room temperature for 1 h, the reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel using toluene/EtOAc (7:3) as eluent. The product-containing fractions were concentrated and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/HaO (50:45:5) for 30 min with stirring. The mixture was

concentrated in a speed vac overnight and the residue purified by chromatography, on silicagel using CHCb/MeOH (9:1) as eluent to afford 109 mg (49%) of the title compound. HRMS mlz calcd for C17H19F3N4O2 (M)+ 368.1460, found 368.1465.
EXAMPLES 22-25: GENERAL PROCEDURE:
TMAD (256 mg, 1.5 mmol) was added to a mixture of 2-[2>-{4rtert-butoxycarbonyl-1 -piperazinyl)-pyrazinyloxy]ethanol (400 mg, 1.24 mmol), triphenylphosphine (646 mg, 2.46 mmol), and the appropriate phenol (1,23 mmol) in dry THF (3 mL) at room temperature. After being stirred for 4 h, the reaction mixture was concentrated in vacuo and the residue purified by chromatography on silica gel using toluene/EtOAc (8:2) as eluent. Solvents were removed in vacuo and the resulting N-t-BOC derivative of the title compound was treated with dichloromethane/TFA/H20 (50:45:5) for 30 min. The mixture was concentrated in a speed vac overnight. The residue was partitioned between 5 M aqueous NaOH/dichloromethane and the organic layer was dried over K2CO3. Removal of the solvent in vacuo and purification by chromatography on silica gel using CHClj/MeOH (9:1) as eluent gave the title compound.
EXAMPLE 22 l-[2-(3-Fluorophenoxy)ethyl]-3-(l-piperazinyI)-2(l/iO-pyrazinone.
The title compound was prepared according to the procedure described above starting from 3-fluorophenol (276 mg, 1.23 mmol). Yield: 228 mg (58%). HRMS mlz calcd for C16H19FN4O2 (M)^ 318.1492, found 318.1487.
EXAMPLE 23 l-[2-(3-Nitrophenoxy)etiiyl]-3-(l-piperazinyl)-2(lfl)-pyrazinone.
The title compound was prepared according to the general procedure described above starting firom 3-nitrophenol (342 mg, 1.23 mmol). Yield: 195 mg (46%); mp 171 °G. HRMS mlz calcd for C16H19N5O4 (M)"" 345.1437, found 345.1420.
EXAMPLE 24 l-[2.(3-Benzoylphenoxy)ethyl3-3-(l-piperazinyl)-2(l/;0-pyrazinone.

The title compound was prepared according to the general procedure described above starting from 3-benzoylphenol (488 mg, 1.23 mmol). Yield: 120 mg (24%); mp 69-70 °C. HRMS m/z calcd for C23H24N4O3 (M)+ 404.1848, found 404.1835.
EXAMPLE 25 l-[2-(3,5-Difluorophenoxy)ethyl]-3-(l-pipera2inyl)-2(lH)-pyrazinone.
The title compound was prepared according to the general procedure , described above starting from TMAD (384 mg, 2.25 mmol), 2-[3-(4-tert-butoxycarbonyl-l-pipera2inyl)-pyrazinyloxy]ethanol (600 mg, 1.86 mmol), triphenylphosphine (969 mg, 3.69 mmol), 3,5-difluorophenol (239 mg, 1.84 mmol). Yield: 123 mg (20%); mp 119-121 °C. HRMS m/z calcd for C16H18F2N4O2 (Mf 336.1398, found 336.1409.
EXAMPLES 26-47: GENERAL PROCEDURE:
TMAD (103 mg, 0.60 mmol) was added to a mixture of 2-[3-(4-/ert-butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (97 mg, 0.30 nnnol; Examples 26-38); or 2-[3-(4-tert-butoxycarbonyl-3-methyl-l-piperazuiyl)-pyrazinyloxy]ethanol* (102 mg, 0.30 mmol; Examples 39-43); or tert-Butyl 4-[3-(2-hydroxyethoxy)pyrazin-2-yl]-l,4-diazepane-l-carboxylate** (102 mg, 0.30 mmol; Examples 44-47), triphenylphosphine (157 mg, 0.60 mmol), and the appropriate phenol (0.60 mmol) in DMF (3.2 mL). The mixture was stirred under nitrogen at room temperature for approximately 18 h. The reaction mixture was filtered through a syringe with Celite and concentrated in a speed-vac. The N-t-BOC derivative of the title compound was dissolved in acetonitrile (1 mL) and purified by preparative HPLC. The product-containing fractions were pooled and concentrated in a speed-vac. iV-Deprotection: The N-t-BOC intermediate was dissolved in dichloromethane (2 mL) and TFA (1 mL) was added at 0 °C. The temperature was allowed to rise to room temperature and the mixture was stirred for 1 h. The reaction mixture was concentrated in a speed-vac to ftumsh the title compound. *Prepared as described in Example 73. ♦♦Prepared as described in Example 75.

EXAMPLE 26 l-[2-(Phenoxy)ethyl]-3-(l-piperazinyl)-2(lH-pyrazinone, Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from phenol (56 mg, 0,60 mmol). Yield: 22 mg (18%). HPLC purity: 100%. MS m/z 301 (M+H)"". HRMS m/z calcd for C16H20N4O2 (M)+ 300.1586, found 300.1575.
EXAMPLE 27
l-[2-(2,6-Difluorophenoxy)ethyl]-3-(l-piperazinyl)-2(lH)-pyrazinone,
Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 2,6-difluorophenol (78 mg, 0,60 mmol). Yield: 55 mg (41%). HPLC purity: 99%. MS m/z 32,1 (M+H)+. HRMS m/z calcd for C16H18F2N4G2 (M)+ 336.1398, found 336.1400.
EXAMPLE 28
l-[2-(2-Cyanophenoxy)ethyl]-3-(l-piperazinyl)-2(lH)-pyrazinone, Trifluoroacetate. The title compound was prepared according to the procedure described above starting from 2-cyanophenol (71 mg, 0.60 mmol). Yield: 47 mg (36%). HPLC purity: 96%. MS m/z 326 (M+H)+. HRMS m/z calcd for C17H19N5O2 (M)+ 325.1539, found 325.1536.
EXAMPLE 29
l-[2-(4-Trifluoromethylphenoxy)ethyl]-3-(l-piperazinyl)-2(ljy)-pyrazinone,
Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 4-trifluoromethylphenol (97 mg, 0.60 mmol). Yield: 20 mg (14%). HPLC purity: 100%. MS miz 369 (M+H)^. HRMS miz calcd for C17H19F3N4O2 (M)* 368.1460, found 368.1465.

EXAMPLE 30
l-[2-(4-Bromophenoxy)ethyl]-3-(l-piperazinyl)-2(lH-pyrazmone, Trifluoroacetate. The title compound was prepared according to the procedure described above starting from 4-bromophenol (104 mg, 0.60 mmol). Yield: 29 mg (20%). HPLC purity: 99%. MS miz 380 (M+H)*. HRMS m/z calcd for C16H19BrN402 (M)+ 378.0691, found 378.0680.
EXAMPLE 31
1 -[2- {4-Phenoxy-(phenoxy)) ethyl]-3-(l -piperazinyl)-2(lH)-pyrazinone,
Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 4-phenoxyphenol (112 mg, 0.60 mmol). Yield: 20 mg (13%). HPLC purity: 96%. MS m/z 393 (M+H)*. HRMS m/z calcd for C22H24N4O3 (M)+ 392.1848, found 392.1856.
EXAMPLE 32
l-[2-(4-Fluorophenoxy)ethyl]-3-(l-piperazinyl)-2(lH)-pyrazinone, Trifluoroacetate. The title compound was prepared according to the procedure described above starting from 4-fluorophenol (67 mg, 0.60 mmol). Yield: 36 mg (28%). HPLC purity: 100%. MS m/z 319 (M+H)+ HRMS m/z calcd for C16H19FN4O2 (M)* 318.1492, found 318.1505.
EXAMPLE 33
1 -[2-(4-Isopropylphenoxy)ethyl]-3-(l -piperazinyl)-2(li0-pyrazuione,
Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 4-isopropylpheno] (82 mg, 0.60 mmol). Yield; 59 mg (43%). HPLC purity: 99%. MS m/z 343 (M+H)"". HRMS miz calcd for C19H26N4O2 (M)+ 342.2056, found 342.2062.
EXAMPLE 34 l-[2-(2,4,5-Trichlorophenoxy)ethyl]-3-(l-piperazmyl)-2(lH-pyrazinone,
Trifluoroacetate.

The title compound was prepared according to the procedure aescnoea above starting from 2,4,5-trichlorophenol (118 mg, 0.60 mmol). Yield: 2.4 mg (2%). HPLC purity: 97%. MS m/z 403 (M+H)+.
EXAMPLE 35
l-[2-(2-Methylthiophenoxy)ethyl]-3-(l-piperazinyl)-2(lH-pyrazinone,
Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 2-methylsulfanyl-phenol (84 mg, 0.60 mmol). Yield: 38 mg (36%). HPLC purity; 97%. MS m/z 347 (M+H)+. HRMS mIz calcd for C,7H22N402S (M)+ 346.1463, found 346.1471
EXAMPLE 36
l-[2-(3-Methoxyphenylthio)ethyl]-3-(l-piperazinyl)-2(lH)-pyra2inone,
Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 3-methoxy-thiophenol (84 mg, 0.60 mmol). Yield: 23 mg (22%). PIPLC purity: 85%. MS m/z 347 (M+H)* HRMS mIz calcd for C17H22N4O2S (M)* 346.1463, found 346.1468.
EXAMPLE 37
l-[2-{(4-AllyI-2-methoxy)phenoxy}ethyl]-3-(l-piperazinyl)-2(l//)-pyrazinone,
Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 4-allyI-2-methoxyphenol (99 mg, 0.60 mmol). Yield: 69 mg (47%). HPLC purity; 98%. MS mk 371 (M+H)^. HRMS mk calcd for C20H26N4O3 QAf 370.2005, found 370.2013.
EXAMPLE 38
l-[2-(5,6,7,8-Tetrahydro-naphthalen-2-yloxy)ethyl]-3-(l-piperazinyl)-2(lfl)-pyrazinone, Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 5,6,7,8-tetrahydro-naphthalen-2-ol (89 mg, 0.60 mmol). Yield: 26 mg

(19%). HPLC purity: 96%. MS m/z 355 (M+H)+. HRMS m/z calcd for C20H26N4O2 (M)+ 354.2056, found 354.2070.
EXAMPLE 39
l-[2-(2,6-Difluorophenoxy)ethyl]-3-(3-methyl-l-piperazinyl)-2(lH-pyrazinone, Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 2,6-difluorophenol (78 mg, 0.60 mmol). Yield: 71 mg (51%). HPLC purity: 99%. MS m/z 351 (M+H)+. HRMS m/z calcd for C17H20F2N4O2 (M)+ 350.1554, found 350.1539.
EXAMPLE 40
l-[2-(4-TrifluoromethyIphenoxy)ethyI]-3.(3-methyl-l-piperazinyI)-2(l/0-pyrazinone, Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 4-trifluoromethylphenol (97 mg, 0.60 mmol). Yield: 82 mg (55%). HPLC purity: 99%. MS m/z 383 (M+H)+. HRMS m/z calcd for C18H21F3N402 (M)+ 382.1617, found 382.1617.
EXAMPLE 41
l-[2-(4-Bromophenoxy)ethyl]-3-(3-methyl-l-piperazinyl)-2(lH)-pyrazinone,
Trifluoroacetate.
The titie compound was prepared according to the procedure described above starting from 4-bromophenol (104 mg, 0.60 mmol). Yield: 79 mg (52%). HPLC purity: 98%. MS m/z 394 (M+H)"". HRMS m/z calcd for C17H21BrN4O2 (Mf 392.0848, found 392.0857.
EXAMPLE 42
1 -[2-(Phenoxy)ethyl]-3-(3-methyl-l -piperazhiyl)-2(lH)-pyrazinone,
Trifluoroacetate.
The titie compound was prepared according to the procedure described above starting from phenol (56 mg, 0.60 mmol). Yield: 30 mg (32%). HPLC purity: 100%.

MS m/z 315 (M+H)^. HRMS m/z calcd for C17H22N4O2 (M)* 314.1743, found 314.1746.
EXAMPLE 43
l-[2(2,4,5-Trifluorophenoxy)ethyl]-3-(3-methyl-l-piperazinyl)-2(li7)-pyrazinone,
Trifluoroacetate.-
The title compound was prepared according to the procedure described above starting from 2,4,5-trifluoropheaol (89 mg, 0.60 mmol). Yield; 25 mg (22%). HPLC purity: 100%. MS m/z 369 (M+H)+ HRMS m/z calcd for C17H19F3NAO2 (M)+ 368.1460, found 368.1473.
EXAMPLE 44
l-[2-(2,4,5-Trifluorophenoxy)ethyl]-3-(l,4-diazepan-l-yl)-2(lJ^-pyrazinone,
Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 2,4,5-trifluorophenol (89 mg, 0.60 mmol). Yield: 56 mg (51%). HPLC purity: 98%. MS m/z 369 (M+H)^. HRMS m/z calcd for C17H19F3N4O2 (M)+ 368.1460, found 368.1454.
EXAMPLE 45
l-[2-(4-Fluorophenoxy)ethyl]-3-(l,4-diazepan-l-yl)-2(l.H)-PFa2inone,
Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 4-fluorophenol (67 mg, 0,60 mmol). Yield: 65 mg (65%), HPLC purity: 99%. MS m/z 333 (M+H). HRMS m/z calcd for C17H21FN4O2 (M)+ 332.1649, found 332.1651.
EXAMPLE 46 l.[2-(4-Isopropylphenoxy)ethyl3-3-(l,4-diazepan-l-yl)-2(lH-pyazuione,
Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 4-isopropyIphenol (82 mg, 0.60 mmol). Yield: 49 mg (46%). HPLC

purity: 99%. MS m/z 357 (M+H)+. HRMS miz calcd for C20H28N4O2 (M)+ 356.2212, found 356.2203.
EXAMPLES 47
l-[2-{(2-Methylthio)phenoxy}ethyl]-3-(l,4-diazepan-l-yl)-2(lH-pyrazinone, Trifluoroacetate.
The title compound was prepared according to the procedure described above starting from 2-naethylsulfanyl-phenol (84 mg, 0.60 namol). Yield: 51 mg (47%). HPLC purity: 98%. MS miz 361 (M+H)"". HRMS m/z calcd for C18H24N4O2S (M)+ 360.1620, found 360.1611.
EXAMPLE 48
l-(2,4,5-Trifluoroben2yl)-3-(l-piperazinyl)-2(lH/)-pyrazinone, Trifluoroacetate.
Step 1: 3-(4-tert-Butoxycarbonyl-l-piperazinyl)-2(li7)-pyrazinone.
2-Chloro-3-(4-tert-butoxycarbonyl-l-piperzinyl)pyrazine* (60 g, 0.20 mol) was added to a mixture of NaOH (100 g, 2.50 mol), water (100 mL) and DMSO (100 g) at 100 °C. After being stirred for 3 h, the mixture was allowed to cool and partitioned between toluene (100 g) and water (200 mL). Water (300 mL), crushed ice (200 g), EtOAc (600 g) and sodium chloride (100 g) were added to the aqueous layer. The layers were separated and the aqueous layer was extracted with an additional portion of BtOAc (600g). The combined organic layers were concentrated in vacuo to furnish 38 g (68%) of the title product.1H and 13C NMR data support the stated structure. HPLC purity: 100%.HRMS miz calcd for C13H20N4O3 (M)+ 280.1535, found 280.1530. *Prepared according to the procedure described in WO 00/76984, Example 52, Step 1.
Step 2. l-(2,4,5-Trifluorobenzyl)-3-(4-tert-butoxycarbonyl-l-pipera2inyl)-2(lif)-pyrazinone.
To a solution of 3-(4-tert-butoxycarbonyl-l-piperazinyl)-2(lH)-pyrazinone (obtained in Step 1 above; 1.30 g, 4.66 mmol) in THF (20 mL) was added /-BuOK (0.53 g, 4.66 mmol) and the mixture was stirred at room temperature for 10 min. The resulting solution was added dropwise to a stirred solution of 2,4,5-trifluoroben2yl bromide (1.20 g, 5.33 mmol) in THF (20 mL) at room temperature. After 2 h, the reaction mixture was cooled to 0 °C and partitioned between water (20 mL) and

EtOAc (50 mL). The organic layer was washed with brine (10 mL) and dried over
Na2SO4. Evaporation of the solvent gave 1.82 g (96%) of the title compound as an oil
which crystallized upon standing. The product can be recrystallized from tert-butyl
methyl ether. HPLC purity: 94%. 1NMR and MS analyses support the stated
structure.
Step 3. l-(2,4,5-Trifluoroben2yl)-3-(l-piperazinyl)-2(l//)-pyrazinone,
Trifluoroacetate.
To a solution of l-(2,4,5-trifluorobenzyl)-3-(4-tert-butoxycarbonyl-l-pipera2inyl)-2(lH)-pyrazinone (obtained in Step 2 above; 0.50 g, 1.18 mmol) in dichloromefhane (10 mL) was added TFA (2 mL) dropwise at 0 °C. After being stirred for 1 h at room temperature, the solvent and TFA were removed in vacuum resulting in a colorless oil. Trituration with ether gave white crystals which were filtered off after cooling the mixture to 0 °C. The crystals were washed with cold ether and dried in vacuum at 50 °C to furnish 0.50 g (98%) of the title compound. HPLC purity: 95%. "H NMR analysis supports the stated structure. HRMS m/z calcd for C15H15F3N4O (M)"" 324.1198, found 324.1195.
EXAMPLE 49
I-[3-(2,4,5-Trifluorophenyl)propyl]-3-(l-piperazinyl)-2(lH)-pyrazuione,
Trifluoroacetate.
Step 1. 3-(2,4,5-TrifluorophenyI)propionic aC1d.
3-(2,4,5-Trifluorophenyl)acrylic aC1d (3.50 g, 17.3 mmol) was dissolved in glaC1al acetic aC1d (40 mL) and treated with active carbon (~0.5 g). The mixture was stirred for 20 min, the carbon filtered off and washed with glaC1al acetic aC1d (20 mL). To the resulting solution Pd on carbon catalyst (0.45 g, 10% Pd) was added and the mixture was stirred under hydrogen at atmospheric pressure overnight. The suspension was filtered and concentrated in vacuo. Residual acetic aC1d was removed by addition of a small volume of toluene followed by concentration in vacuo. The resulting oil crystallized upon standing and this material was dried in vacuum at 50 "C to give 3.34 g (95%) of the title compound. Step 2. 3-(2,4,5-Trifluorophenyl)propan-l-ol.*
3-(2,4,5-Trifluorophenyl)propiomc aC1d (3.25 g, 16.0 mmol; from Step 1) was dissolved in THF (15 mL) and cooled to 0 °C. To this solution was added Me2S-BH3

(3.2 mL, ~32 nunol) dropwise under 30 min and the resulting mixture was then heated at 70 °C for 30 min. After cooling to 0°C, 6 M aqueous HCl (20 mL) was added dropwise. The mixture was heated at 70 °C for 1 h. After cooling to room temperature the mixture was extracted with ether (2 x 20 mL) and the combined organic layers were washed with brine and dried over Na2S04. Evaporation and drying in vacuum gave the title compound as a colorless liquid (3.17 g, 97% pure by HPLC) that was used directly in the next step. *Previously reported in EP 369812. Step 3, 3-(2,4,5-Trifluorophenyl)propyl Methanesuifonate.
Methanesulfonyl chloride (0.45 g, 3.88 mmol) was added dropwise to a solution of 3-(2,4,5-trifluorophenyI)propan-l-oI (0.46 g, 2.41 nunol; from Step 2) and triethylamine (0.71 g, 7.0 mmol) in dichloromethane (5 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. After complete disappearance of the alcohol (HPLC monitoring), dichloromethane (10 mL) and water (10 mL) were added. The aqueous phase was saturated with NaCl and extraction performed. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give 0.66 g (100%) of the title compound as a yellow oil. Purity by HPLC: 87%. This material was used directly in the next step.
Step 4:1-[3-(2,4,5-Trifluorophenyl)propyl]-3-(4-tert-butoxycarbonyl-1 -piperazinyl)-2(liiO-pyrazinone.
To a solution of 3-(4-tert-butoxycarbonyl-l-piperazinyl)-2(lH-pyrazinone (obtained in Example 48, Step 1; 0.53 g, 1.91 mmol) in THF (10 mL) was added t-BuOK (0.21 g, 1.91 mmol) and the mixture was stirred at room temperature for 10 rain. The resultant mixture was added dropwise to a solution of 3-(2,4,5-trifluorophenyOpropyl methanesulfonate (0.66 g, ~2.1 mmol; from Step 3) in THF (10 mL). The mixture was stirred at 35 °C for 3 days. Then, the solution was cooled to 0 "^C and water (20 mL) and EtOAc (25 mL) were added. The aqueous phase was saturated with NaCl (2 g) and extraction performed. After separation and repeated extraction with EtOAc (15 mL) the combined organic layers were washed with brine and dried over Na2S04. Concentration in vacuum gave 0.75 g of a yellowish oil which was purified by column chromatography on silica gel using EtOAc/n-hexane (4:1) as eluent. This gave 0.50 g (57%) of the title compound as a colorless oil. HPLC purity: 91 %, 1H NMR and MS analyses support the stated structure.

Step 5. l-[3-(2,4,5-Trifluorophenyl)propyl]-3-(l-piperazmyl)-2(l/0-pyrazmone, Trifluoroacetate.
TFA (2 mL) was added dropwise to a solution of 1 -[3-{2,4,5-trifluorophenyl)propyl]-3-(4-tert-butoxycarbonyl-l-piperazinyl)-2(lH-pyrazinone (0.46 g, 1.02 mmol; from Step 4) in dichloromethane (10 mL) at 0 "C. After being stirred for 1 h at room temperature, the solvent and TFA were removed in vacuo resulting in a colorless oil. Trituration with ether gave pale white crystals which were filtered off after cooling the mixture to 0 °C. The crystals were washed with cold ether and dried in vacuum at 50 °C to fiimish 0.38 g (79%) of &e title compound. HPLC purity: 96%. "H NMR analysis supports the stated structure. HRMS m/z calcd for C17H19F3N4O (M)+ 352.1511, found 352.1524.
EXAMPLE SO
l-(2,3-Dihydro-benzo[l,4]dioxin-2-yhnethyl)-3-(l-piperazinyl)-2(l^-pyrazinone,
Trifluoroacetate,
Step 1: l-(2,3-Dihydro-benzo[l,4]dioxin-2-ybnethyl)-3-(4-tert-butoxycarbonyl-l-pipera2inyl)-2(lH)-pyrazmone.
A mixture of 3-(4-tert-butoxycarbonyl-l-piperazinyl)-2(lH-pyrazinone (4.00 g, 14.3 mmol; from Example 48, Step 1), 2-chloromethyl-2,3-dihydro-benzo[l,4]dioxine (2.60 g, 14.3 mmol), DMF (10 g) and potassium carbonate (4.00 g, 28.9 mmol) was heated at 120 °C for 3 h. Water (100 g) and EtOAc (200 g) were added to the reaction mixture and the layers were separated. The organic layer was concentrated and the residue purified by chromatography on a MPLC column using a continuous gradient (0-100% EtOAc in heptane) as eluent. This provided 0.60 g (15%) of the title compound as an oil. 1H NMR analysis supports the stated structure.
Step 2: l-(2,3-Dihydro-benzo[l,4]dioxin-2-yhnethyl)-3-(l-piperazinyl)-2(l.H)-
pyrazinone, Trifluoroacetate.
Trifluoroacetic aC1d (5 g) was added to a mixture of l-(2,3-dihydro-
benzo[l,4]dioxin-2-yhnethyl)-3-(4-tert-butoxycarbonyl-l-piperazinyl)-2(lH)-
pyrazinone (0.6 g, 1.4 mmol; from Step 1) and dichloromethane (20 g). The mixture
was stirred overnight and then concentrated in vacuo. Metyl tert-hntyl ether (40 g)
was added to the residue and the crystals that formed instantly were collected. This

furnished 0.30 g (48 %) of the title compound as white crystals. HPLC purity: 97%. MS and NMR analyses support the stated structure. HRMS m/z calcd for C17H20N4O3 (M)+ 328.1535, found 328.1538.
EXAMPLES1
3-Piperazin-l-yl-l-[2-(2,4,5-trifluoro-phenoxy)-ethyl]-lH-quinoxalin-2-one,
Trifluoroacetate.
Step 1:4-(3-Chloro-quinoxalin-2-yl)-piperazine-l-carboxylic aC1d tert-butyl ester. Di-tert-butyI dicarbonate (5.8 g, 0.027 mol) was added to a mixture of 2-chloro-3-piperazin-1-yl-quinoxalin* (6,6 g, 0.027 mol), triethylamine (5.5 g, 0,054 mol) and dichloromethane (100 g) at 0 °C. The mixture was stirred at room temperature overnight. Toluene (300 g) and water (100 g) were added to the reaction mixture and the layers were separated. The organic layer was concentrated in vacuo to furnish 9.4 g (100%) of the title compound. "H NMR analysis supports the stated structure. ♦Reported in WO 00/76984, Example 162, Step 1.
Step 2:4-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-piperazine-l-carboxylic aC1d ten-butyl ester.
4-(3-Chloro-quinoxalin-2-yl)-piperazine-l-carboxylic aC1d- tert-butyl ester (10.0 g, 28.7 mmol; from Step 1) was added to a mixture of sodium hydroxide (40 g), water (40 g) and DMSO (40 g) at 100 °C. After being stirred for 1 h at this temperature, water (200 g) and methyl tert-butyl ether (1000 g) and sodium chloride (50 g) were added. The crystals formed from the organic layer were collected by filtration and dried. This furnished 4.0 g (42%) of the title compound as white crystals. 1H NMR analysis supports the stated structure.
Step 3:4- {3-Oxo-4-[2-(2,4,5-trifluoro-phenoxy)-ethyI]-3,4-dihydro-quinoxalin-2-yl} -piperazine-1 -carboxylic aC1d tert-butyl ester.
^BuOK (1.0 g, 8.9 mmol) was added to a mixture of 4-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-piperazine-l-carboxylic aC1d tert-\mty\ ester (1 g, 9 mmol; from Step 2), THF (20 g) and DMSO (5 g) at room temperature. This mixture is added to a solution of 2-(2,4,5-trifluorophenoxy)ethyl methanesulfonate (2.45 g, 9.00 mmol; from Example 54, Step 4) in THF (20 g). After bemg stirred at room temperature overnight, water (100 g) and EtOAc (200 g) were added to the reaction mixture. The

layers were separated and the organic layer was concentrated in vacuo. The residue was purified by chromatography on an MPLC-columnn using a continuous gradient (0-100% EtOAc in heptane) as eluent. Evaporation of solvent gave 0.5 g of the title compound as greasy crystals (npt pure). 1H NMR analysis supports the stated structure. This material was used directly in the next step.
Step 4:3-Piperazin-l-yl-I-[2-(2,4,5-trifluoro-phenoxy)-ethyl]-lH-quinoxalin-2-one, Trifluoroacetate.
Trifluoroacetic aC1d (5 g) was added to a mixture of 4-{3-oxo-4-[2-(2,4,5-trifluoro-phenoxy)-ethyI]-3,4-dihydro-quinoxalin-2-yl}-piperazine-1 -carboxylic aC1d tert-butyl ester (0,5 g, 1 mmol; from Step 3) and dichloromethane (20 g). After being stirred at room temperature for 2 h, the reaction mixture was concentrated in vacuo. The residue was purified by chromatography (prep-HPLC) to give 0.12 g (23%) of the title compound. 1H NMR and MS analyses support the stated structure. HPLC purity: 94%. HRMS m/z calcd for C20H19F3N4O2 (M)+ 404.1460, found 404.1475.
EXAMPLE 52
l-[2-(2,4,5-Trifluorophenoxy)ethyl]-3-(4-M-butyl-l-piperazinyl)-2(lH-pyrazinone.
Step 1: Methanesulfonic aC1d n-butyl ester*
Methanesulfonyl chloride (15.45 g, 0.13 mol) was added to a mixture of n-butanol
(10 g, 0.13 mol), triethylamine (26.3 g, 0.26 mol) and dichloromethane (150 g) at 10
°C. After being stirred at room temperature overnight, water (100 g) was added to the
reaction mixture and the layers were separated. The organic layer was concentrated
in vacuo at room temperature. This gave 18 g (90%) of the title mesylate as an oil. 1H
NMR analysis supports the stated structure. *Previously described in J, Amer. Chem.
Soc.1933,55,345-349.
Step 2:1 -[2-(2,4,5-Trifluorophenoxy)ethyl]-3-(4-n-butyl-1 -piperazinyl)-2(l//)-
pyrazinone.
Methanesulfonic aC1d butyl ester (0.30 g, 1,97 mmol; from Step 1) was added to a mixture of 3-(l-piperazinyl)-l-[2-(2,4,5-trifluorophenoxy)ethy1]-2(l/0-pyrazinone (0.50 g, 1.4 nunol; from the free base of Example 3) and potassium carbonate (0.10 g, 2.89 mmol) in DMSO (3 g). After being stirred for 3 h at 60 °C, water (50 g) and EtOAc (100 g) were added to the reaction mixture. The layers were separated and the

organic layer was concentrated in vacuo. The residue was purified by chromatography on a MPLC column using a continuous gradient (0-100% EtOAc in heptane) as eluent. This furnished 33 mg (8%) of the title compound as an oil. 1H NMR analysis supports the stated structure. HPLC purity: 100%. HRMS m/z calcd for C20H25F3N4O2 (M)+ 410.1930, found 410.1920.
EXAMPLE 53
l-[2-(2,4,5-Trifluorophenoxy)ethyl]-3-[4-(2-methoxyethyI)-l-piperazinyl]-2(l/0-pyrazinone, Trifluoroacetate.
Step 1: Methanesulfonic aC1d 2-methoxy-ethyl ester.*
Methanesulfonyl chloride (15 g, 0.13 mol) was added to a mixture of 2-methoxy ethanol (10 g, 0.13 mol), triethylamine (26.5 g, 0.26 mol) and dichloromethane (150 g) at 0 °C. After being stirred at room temperature overnight, water (100 g) was added tothe reaction mixture. The layers were separated and the organic layer was concentrated in vacuo at room temperature. This gave 13.1 g (65%) of the title mesylate as an oil. 1H NMR analysis supports the stated structure. *Previously reported in Tetrahedron 1995, 51,4867-4890.
Step 2: l-[2-(2,4,5-Trifluorophenoxy)ethyl]-3-[4-(2-methoxyethyl)-l-piperazinyl]-2(lH-pyrazinone, Trifluoroacetate.
Methanesulfonic aC1d 2-methoxy-ethyl ester (0.15 g, 0.97 mmol; from Step 1) was added to a mixture of 3-(l-piperazinyl)-l-[2-(2,4,5-trifluorophenoxy)ethyl]-2(lH)-pyrazinone (0.30 g, 0.85 mmol; from the free base of Example 3) and potassium carbonate (0.30 g, 2.17 mmol) in DMSO (6 g). After being stirred at 60 °C for 3 h, water (5 g) and EtOAc (30 g) were added to the reaction mixture. The layers were separated and the organic layer concentrated in vacuo. The residue (0.2 g) was purified by chromatography (prep-HPLC) to furnish 60 mg (13%) of the title compound. 1H NMR and MS analyses support the stated structure. HPLC purity: 95%.

EXAMPLE 54
l-[2-(2,4,5-Trifluorophenoxy)ethyl]-3-(4-methyl-l-piperazinyl)-2(lH-pyrazinone. Step 1. l-(3-Chloro-2-pyrazinyl)-4-methylpiperazine.*
A mixture of 2,3-dichloropyrazme (5.0 g, 34 mmol), iV-methylpiperazine (5.1 g, 51 mmol) and potassium carbonate (7.0 g, 51 mmol) in acetonitrile (100 mL) was stirred at ambient temperature for 2 h. Addition of hexane, followed by filtration and concentration of the filtrate gave 7.3 g of the crude product as an orange liquid. Purification by filtration through silica using heptane/EtOAc (3:1) followed by EtOAc/acetone (1:1) gave 4.1 g (57%) of the title compound as a yellow oil which solidified upon cooling. HPLC purity: 100%. MS m/z 213 (M+H)"^. *Reported in WO 00/76984, Example 169, Step 1. Step 2.3-(4-Methyl-l-piperazmyl)-2(lH-pyrazinone.
To a solution of NaOH (5.4 g, 125 mmol) in a mixture of water/DMSO (1:1; 15 mL) at 80 °C was added l-(3-chloro-2-pyrazinyl)-4-methyIpiperazine (obtained in Step 1 above; 2.5 g, 12 mmol). After being stirred for 2 h, the dark red solution was cooled to room temperature, extracted with EtOAc overnight to give, after drying and solvent removal in vacuo, 0.96 g (43%) of the title compound as an off-white solid. HPLC purity: 88%. MS m/z 195 (M+H). HRMS m/z calcd for C9H14N4O(M)+ 194.1168, found 194.1159. Step 3.2-(2,4,5-Trifluorophenoxy)ethanoI.
t-BuOK (3.0 g, 27 mmol) was added to a mixture of 1,2,4,5-tetrafluorobenzene (2.0 g, 13.3 namol) and ethylene glycol (7.5 mL, 133 mmol) in DMSO (50 mL) and heated at 80 °C for 1 h and then at 60 °C overnight. EtOAc was added and the resulting solution was washed several times with water. The organic layer was dried (Na2S04) and concentrated carefiiUy in vacuo at 30 °C to fiimish 1.5 g (containing ~14% EtOAc) of the title compound as a white semisolid. NMR analysis supports the stated structure. This material was used directly in the next step. Step 4.2-(2,4,5-Trifluorophenoxy)ethyl Methanesulfonate.
Triethylamine (1.8 mL, 13.2 mmol) was added to a cold (0 °C) solution of a mixture of the 2-(2,4,5-trifluorophraioxy)ethanol (1.3 g, 6.6 mmol; from Step 3) and methanesulfonyl chloride (0.61 mL, 7.9 mmol) in dichloromethane (40 mL). After being stirred for 1.5 h, water was added and the mixture was concentrated. The residue was dissolved in EtOAc and the solution was washed with 1 M KHSO4, then

with brine, dried (Na2SO4) and concentrated to give 1.78 g (quantitative yield) of the title compound as an orange oil. NMR analysis supports the stated structure. This material was used directly in the next step.
Step 5.1-[2-(2,4,5-Trifluorophenoxy)ethyl]-3-(4-methyl-l-piperazinyl)-2(lH-pyrazinone.
A mixture of 3-(4-methyl-l-piperazinyl)-2(l/f)-pyrazinone (obtained in Step 2 above; 0.5 g, 2.6 mmol) and t-BuOK (440 mg, 3.90 mmol) in THF (40 mL) was stirred until the mixture became thick (about 10 min), and then a solution of 2-(2,4,5-trifluorophenoxy)ethyl methanesulfonate (0.90 g, 2.2 mmol; from Step 4) in THF (10 mL) was added. After being stirred for 5 days at ambient temp, HPLC showed only 50% conversion. The reaction solution was then heated to 60 °C overnight which gave almost full conversion. The reaction was worked up according to the following: water was added, THF was evaorated off and the aqueous mixture was extracted twice with EtOAc, dried (Na2SO4) and concentrated to yield 1.08 g of the crude product as a yellow oil. Purification by chromatography on silica gel [eluent: 2% MeOH in CHCl3 + NH3 (g)] gave the title compound as a yellow oil, which solidified upon cooling. Yield: 304 mg (32%). HPLC purity: 100%. MS m/z 369 (M+H)+. HRMS miz calcd for C17H19F3N4O2 (M)"" 368.1460, found 368.1462.
EXAMPLE 55
l-[2-(2,4,5-Trifluorophenoxy)ethyl]-3-(4-isopropyl-l-piperazinyl)-2(lH)-
pyrazinone.
Step 1; 2-Chloro-3-(4-isopropylpiperazin-l-yl)pyrazine.
A mixture 2,3-dichloro-pyrazine (5.0 g, 34 mmol), l-isopropylpiperazine (6.5 g, 51 mmol) and potassium carbonate (7.0 g, 51 mmol) in acetonitrile (100 mL) was stirred at ambient temperature for 2 h. Addition of hexane, followed by filtration and concentration of the filtrate gave 9.5 g of crude material as an orange liquid. Purification by filtration through silica using heptane/EtOAc (3:1), followed by EtOAc/acetone (1:1), provided 6.5 g (79%) of the title compound as a yellow oil which solidified upon cooling. HPLC purity: 98%. MS m/z 241 (M+H)+. HRMS m/z calcd for C11H17ClN4 (M)+ 240.1142, found 240.1138.
Step 2:3-(4-Isopropyl-l-piperazinyl)-2(l/r)-pyrazinone.

To a solution of NaOH (5.4 g, 125 mmol) in amixture of water/DMSO (1:1; 15 mL) was added 2-chloro-3-(4-isopropylpipera2in-l-yl)pyrazine (2.66 g, 12 nunol; from Stqj 1). After being stirred at 80 °C for 2 h, the dark red solution was cooled to room temperature, extracted with EtOAc overnight to give, after drying and solvent removal in vacuo, 2.6 g (70%) of the title compound as a white solid. HPLC purity: 87%. MS m/z 223 (M+H)+. HRMS m/z calcd for CnHi8N40 (M)+ 222.1481, found 222.1489.
Step 3:1 -[2-(2,4,5-Trifluorophenoxy)ethyl]-3-(4-isopropyl-1 -piperazinyl)-2(lH-pyrazinone.
A mixture of 3-(4-isopropyl-l-piperazinyl)-2(lH)-pyrazinone (0.58 g, 2.6 mmol; from Step 2) and t-BuOK (440 mg, 3.90 mmol) in THF (40 mL) was stirred until the mixture became thick (about 10 min), and then a solution of 2-(2,4,5-trifluorophenoxy)ethyl methanesulfonate (0.90 g, 2.2 mmol; from Example 54, Step 4) in THF (10 mL) was added. After being stirred for 5 days at ambient temperature, HPLC showed only 25% conversion. The reaction solution was then heated to 60 °C overnight which gave almost full conversion. The reaction was worked up according to the following: water was added, THF was evaporated off and the aqueous mixture was extracted twice with EtOAc, dried (Na2S04) and concentrated to yield 1.18 g of the crude product as a yellow oil. Purification by chromatography on silica gel (eluent; 2.5% MeOH in CHCl3 + NH3 (g)) gave the title compound as a colourless oil, which solidified upon cooling. Yield: 120 mg (14%). HPLC purity: 99%. MS m/z 397 (M+H)+ HRMS mlz calcd for C19H23F3N4O2 (M)+ 396.1773, found 396.1771.
EXAMPLE 56
1 - {2-[(5-Methyl[l ,2,4]triazolo[ 1,5-α]pyrimidin-7-yl)oxy]ethyl} -3-(l -piperazinyl)-
2(lH)-pyrazinone, Hydrochloride.
DEAD (0.485 µL, 3.08 nunol) was added to a stirred solution of 2-[3-(4-tert-
butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol), 5-methyl-
s-triazolo[l,5-a]pyrimidin-7-ol (0.465 g, 3.08 mmol) and triphenylphosphine (0.85 g,
3.24 mmol) in THF (10 ml). After being stirred for 2 h, the reaction mixture was
concentrated and put through a silica column using toluene/EtOAc (1:1) as eluent.
The obtained 7H-B0C derivative of the title compound was treated with

dichloromethane/TFA/H2O (50:45:5; 10 mL) for 45 minutes, concentrated, dissolved in 0.1 M aqueous HCl and washed with toluene. The water phase was concentrated to give 0.21 g (17 %) of the title compound. Pos-EI-MS shows M* +11 ions supporting the stated structure. HRMS mlz calcd for C16H20N8O2 (Mf 356.1709, found 356.1719.
EXAMPLE 57
1 -[2-(4-Cyanophenoxy)ethyl]-3-(l -piperazinyl)-2(lH)-pyrazinone, Maleate. Step 1: tert-Butyl 4-(4-[2-(4-cyanophenoxy)ethyI]-3-oxo-3,4-dihydro-2-pyrazuiyl}-1 -piperazinecarboxylate.
DEAD (0.520 ml, 3,3 mmol) was added to a slurry of 2-[3-(4-tert-butoxycarbonyl-l-piperazinyl)-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol), 4-cyanophenol (0.381 g, 3.20 mmol) and resin bound triphenylphosphine (1,1 g, 3.3 mmol) in dichloromethane (10 mL) and shaken overnight. The reaction mixture was filtered, concentrated and purified by chromatography on silica gel using toluene/EtOAc (1:1) as eluent to give 0.168 g (13%) of the title compound. 1 NMR and MS analyses support the stated structure. HKMS mlz calcd for C22H27N5O4 (M)+ 425.2063, found 425.2075. Step 2; l-[2-(4-Cyanophenoxy)ethyl]-3-(l-piperazinyl)-2(li;/)-pyrazinone, Maleate. tert-Butyl4-{4-[2-(4-cyanophenoxy)ethyl]-3-oxo-3,4-dihydro-2-pyrazinyl}-l-piperazinecarboxylate (0,145 g, 0.34 mmol; from Step 1) was treated with dichloromethane/TFA/H20 (50:45:5; 5 mL) for 30 minutes and poured into 5% aqueous NaOH and extracted with diethyl ether. The ether phase was dried and concentrated to give 0.104 g of the free base of the title compound. This material and maleic aC1d (0.037 g, 0.32 mmol) were dissolved in MeOH and concentrated to give 0.133 g (88%) of the title compound. Pos-EI-MS shows M+ + 11 ions supporting the stated structure. HRMS mlz calcd for C17H19N5O2 (M)"" 325.1539, found 325.1531.
EXAMPLE 58 l-[4-(2,4,5-Trifluorophenoxy)butyl]-3-(l-piperazinyl)-2(lH-pyrazinone,
Trifluoroacetate.
Step 1:4-(2,4,5-Trifluoro-phenoxy)butan-l-ol.
To a mixture of 1,4-butanediol (15 g, 0.17 mol) and t-BuOK (8.0 g, 0.071 mol) were
added 1,2,4,5-tetrafluorobenzene (5.0 g, 33 mmol) and DMSO (50 g) at 60 "C. After

being stirred at this temperature for 18 h, toluene (200 mL), water (50 mL) and sodium chloride (10 g) were added to the reaction mixture. The layers were separated and the organic layer was concentrated in vacuo giving the title compound. This material was used directly in the next step.
Step 2: Methanesulfonic aC1d 4-(2,4,5-trifluoro-phenoxy)butyl ester. Triethylamine (2.5 mL, 18.2 mmol) was added to a cold (0 °C) solution of a mixture of 4-(2,4,5-trifluorophenoxy)butan-l-ol (2.0 g, 9.1 mmol; from Step 1) and methanesulfonyl chloride (0.77 mL, 10 mmol) in dichloromethane (40 mL). After being stirred for 1 h, water was added and the organic phase isolated, dried and concentrated to give 2.45 g (90 %) of the title mesylate as a colorless oil. Its structure was confirmed by 1H NMR analysis.
Step 3: tert-B\xty\ 4-{4-[4-(2,4,5-trifluorophenoxy)butyl]-3-oxo-3,4-dihydro-2-pyrazinyl} -1 -piperazinecarboxylate.
A mixture of 3-(4-tert-butoxycarbonyl-l-piperazinyl)-2(lH)-pyrazinone (1.20 g, 4.30 mmol; from Example 48, Step 1) and t-BuOK (730 mg, 6.50 mmol) in THF (10 mL) was stirred for 10 min, and then added to a solution of methanesulfonic aC1d 4-(2,4,5-trifluoro-phenoxy)butyl ester (1.23 g, 4.3 mmol; from Step 2) in THF (50 mL). After being stirred at room temperature for 1 day, HPLC showed about 30% conversion. After 3 days, the reaction was worked up: water was added, THF was evaporated off and the aqueous mixture was extracted twice with EtOAc, dried and concentrated to yield 2.21 g of the crude product as a yellow oil. HPLC analysis showed a 5/1 ratio between the title product and the isomeric 0-alkylated product.* Purification by chromatography on silica gel using EtOAc/hexane (1/2 to 1/1) as eluent gave 870 mg (42%) of tile title product as a colorless oil. HPLC purity: 95%. MS m/z 483 (M+H)"*". *Assigmnents were based on NMR analysis.
Step 4: l-[4-(2,4,5-Trifluorophenoxy)butyl]-3-(l-piperazmyl)-2(l/0-pyrazinone, Trifluoroacetate.
?ert-Butyl 4-{4-[4-(2,4,5-trifluorophenoxy)butyl]-3-oxo-3,4-dihydro-2-pyrazinyl} -1-piperazinecarboxylate (830 mg, 1.80 mmol; from Step 3) was N-deprotected by reaction with TFA (4 mL) in dichloromethane (15 mL) over 1.5 h at room temperature. Evaporation of excess TFA and solvent followed by addition of diethyl ether gave, after filtration and washing with ether, the titie compound as a light pink

solid. Yield: 800 mg (9l%) mp 113.4-116.6 (dec). HPLC purity: 100%MS m/z 383 (M+E)+. HRMS m/z calcd for C18H21F3N4O2 (Mf 382.1617, found 382.1622.
EXAMPLE 59
l-[3-(2,4,5-Trifluorophenoxy)propyl]-3-(l-piperazinyl)-2(1H-pyrazinone,
Trifluoroacetate.
Step 1; 3-(2,4,5-Trifluoro-phenoxy)propan-l-ol.
To a mixture of 1,3-propanediol (15 g, 0.20 mol) and /-BuOK (8.0 g, 0.071 mol) were added 1,2,4,5-tetrafluorobenzene (5.0 g, 33 mol) and DMSO (50 g) at 60 °C. After being stirred at this temperature for 18 h, toluene (200 mL), water (50 mL) and sodium chloride (10 g) were added to the reaction mixture. The layers were separated and the organic layer was concentrated in vacuo to the title compound that was used directly in the next step.
Step 2: Methanesulfonic aC1d 3-(2,4,5-trifluoro-phenoxy)-propyl ester. Triethylamine (1.36 mL, 9.80 mmol) was added to a cold (0 °C) solution of a mixture of the 3-(2,4,5-trifIuott)phenoxy)propan-l-o] (1.0 g, 4.9 mmol; from Step 1) and mesyl chloride (0.418 mL, 5.40 mmol) in dichloromethane (20 mL). After being stirred for 1 h, water was added and the organic phase isolated, dried and concentrated to give 1,35 g (97 %) of the title mesylate as a colorless oil. Step 3: tert-Butyl 4-{4-[3-(2,4,5-trifluorophenoxy)propyl3-3-oxo-3,4-dihydro-2-pyrazinyl} -1 -piperazinecarboxylate.
A mixture of 3-(4-tert-butoxycarbonyl-l-piperazinyl)-2(lH-pyrazinone (0.83 g, 3.0 mmol; from Example 48, Step 1) and t-BuOK (497 mg, 4.4 mmol) in THF (5 mL) was stirred for 10 min, and then added to methanesulfonic aC1d 3-(2,4,5-trifluoro-phenoxy)-propyl ester (0.80 g, 3.0 mmol; from Step 2) in THF (50 mL). After being stirred at room temperature for 1 day, HPLC showed about 20% conversion. After 6 days, the reaction was worked up; water was added, THF was evaporated and the aqueous mixture was extracted twice with EtOAc, dried and concentrated to yield 1.33 g of the crude product as a yellow oil. HPLC analysis showed a 1/1 ratio between the title product and the isomeric O-alkylated product. Purification by chromatography on silica gel using EtOAc/hexane (1/3 to 1/1.7) as eluent gave 427

mg (30%) of the title product as a colorless oil. HPLC purity: 96%. MS m/z 469
(M+H)+.
Step 4:1 -[3-(2,4,5-Trifluorophenoxy)propyl]-3-(l -piperazinyl)-2(lH)-pyrazinone,
Trifluoroacetate.
tert-butyl 4- {4-[3-(2,4,5-trifluorophenoxy)propyl]-3-oxo-3,4-dihydro-2-pyrazinyl} -
I-piperazinecarboxylate (395 mg, 0.84 mmol; from Step 3) was A/"-deprotected by
reaction with TFA (2 mL) in dichloromethane (10 mL) over 1.5 h at room
temperature. Evaporation of excess TFA and solvent followed by addition of diethyl
ether gave, after filtration, washing with ether and drying, the title compound as a
light pink solid. Yield: 350 mg (73%); mp. 100.3-100.9 (dec); HPLC purity: 100%;
MS m/z 369 (U+H)+ fIRMS m/z calcd for C17H19F3N4O2 (M)+ 368.1460, found
368.1466.
EXAMPLE 60
3-[4-(l-Phenylethyl)piperazin-l-yl]-l-[2-(2,4,5-trifluorophenoxy)ethyl]pyrazin-2i\H)-ono, Hydrochloride (racemic)
A mixture of 3-(l-piperazinyl)-l-[2-(2,4,5-trifluorophenoxy)ethyl]-2(lH)-pyrazinone (354 mg, 1.00 mmol; from the free base of Example 3), 1-bromo-l-phenylethane (204 mg, 1.10 mmol) and K2CO3 (276 mg, 2.00 mmol) in acetonitrile (10 mL) was stirred at 30 °C overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified on a SiO2 column using dichloromethane MeOH (95:5) as eluent. The product was isolated as HCl salt. Yield: 0,26 g (50 %); HPLC purity: >99%; mp 137-139 "C. HRMS calc for C24H25F3N4O2 (M)"" 458.1930, found 458.1933.
EXAMPLE 61
3-[4-(2-Phenoxyethyl)piperazin-l-yl]-l-[2-(2,4,5-trifluorophenoxy)ethyl]pyrazin-2(H)-one, Hydrochloride.
The title compound was prepared according to the procedure of Example 60 starting from 3-(l-piperazinyl)-l-[2-(2,4,5-trifluorophenoxy)ethyl]-2(lH)-pyrazinone (0.35 g, 1.0 mmol; from the free base of Example 3) and 2-bromoethyl phenyl ether (0.22

g, 1.1 mmol). Yield 0.14 g (27 %). HPLC purity: 99%. HRMS calc for C24H25F3N4O3 (M)+ 474.1879, found 474.1887.
EXAMPLE 62
3-[4-(2-Phenylethyl)piperazin-l-yl]-l-[2-(2,4,5-trifluorophenoxy)ethyl]pyrazm-2(lif)-one, Hydrochloride.
The title compound was prepared according to the procedure of Example 60 starting from 3-(l-piperazinyl)-l-[2-(2,4,5-trifluorophenoxy)ethyl]-2(li;0-pyrazinone (0.71 g, 2.0 mmol; from the free base of Example 3) and (2-bromoethyl)benzene (0.41 g, 2.2 mmol). Yield: 0.20 g (20 %). HPLC purity: 96%. HRMS calc for C24H25F3N4O2 (M)+ 458.1930, found 458.1928.
EXAMPLE 63
3-(4-Benzylpiperazin-l-yl)-l-[2-(2,4,5-trifluorophenoxy)ethyl]pyrazin-2(lH)-one
hydrochloride.
The title compound was prepared according to the procedure of Example 60 starting from 3-(l-piperazinyl)-l-[2-(2,4,5-trifluorophenoxy)ethyl]-2H-pyrazinone (0.35 g, 1.0 mmol; from the free base of Example 3) and benzyl bromide (0.19 g, 1.1 mmol) Yield: 0.17 g (35 %); HPLC purity; 99%; mp 214-214.5 "C. HRMS calc for C23H23F3N4O2 (M)+ 444.1773, found 444.1789.
EXAMPLE 64
3-[(2/i!)-2-Methylpiperazin-l-yl]-l-[2-(2,4,5-trifluorophenoxy)ethyl]pyrazm-2(l/f)-one, Trifluoroacetate.
To a solution of tert-bxiXyl (3R)-4-[3-(2-hydroxyethoxy)pyrazin-2-yl]-3-methylpiperazine-l-carboxylate (from Example 74; 338 mg, 1.00 mmol), 2,4,5-trifluorophenol (178 mg, 1.2 mmol) and triphenylphosphine (315 mg, 1.20 mmol) in THF (5 mL) was added DEAD (210 mg, 1.2 mmol) and the resulting mixture left stirring at room temperature for 4 h. The mixture was concentrated and the residue put through a silica column using dichloromethane -» dichloromethane /MeOH (95:5) as eluent. The purified material, the N-t-BOC derivative of the title compound, was dissolved in dichloromethane (5 mL) and TEA (1 mL) was added. The mixtur-e

was stirred at room temperature for 60 h, concentrated in vacuo, and the residue purified by preparative HPLC to get 125 mg (25%) of the title product. HPLC purity: 95%. HRMS mlz calc for C17H19F3N402 (M)+ 368.1460, found 368.1448.
EXAMPLE 65
l-[2-(4-Allyl-2-methoxyphenoxy)ethyl]-3-piperazin-l-ylpyrazin-2(lH)-one,
Maleate.*
3-(4-tert-Butoxycarbonyl-l-piperazinyl)-2(lH-pyrazinone (from Example 48, Step 1; 3.08 g, 11.0 mmol) was dissolved in THF (20 mL). t-BuOK (1.23 g, 11 mmol) was added and the mixture stirred for 10 min at room temperature before adding a solution of 2-(4-allyl-2-methoxy-phenoxy)-ethylmethanesulfonate** (3.15 g, 11 mmol) in THF (15 mL). The resulting mixture was left stirring over the weekend. EtOAc (150 mL) and brine (30 mL) were added and the mixture stirred for a few minutes. The organic layer was dried with Na2SO4 and concentrated to get an oily residue that was purified on a SiOa column eluting with dichloromethane --> dichloromethane/MeOH (97.5:2.5). The fractions containing the N-t-BOC derivative of the title compound were combined and concentrated. This gave 1.46 g of an oil that was redissolved in dichloromethane (60 mL) and TEA (8 g) was added. After being stirred for 2 h, the mixture was concentrated and the residue dissolved in water, added Na2C03 (s) and dichloromethane; stirred for 5 min; separated the dichloromethane phase; dried (Na2S04) and concentrated to get a greenish oil (900 mg). This material was purified on a Si02 column using dichloromethane /MeOH (97.5:2.5 --> 90:10) as eluent. The obtained product was isolated as the maleate salt. Yield; 0.46 g (9 %); HPLC purity: 93%; mp 158-160°C; MS m/z 371 (M+H)+. HRMS mIzcaXc for C20H26N4O3 (M)+ 370.2005, found 370.2005. *This compound, as its trifluoroacetate salt, has been prepared by an alternative method in Example 37. **Prepared according to the general procedure described in Example 76.
EXAMPLE 66 3-Piperazin-l-yl-l-[2-(3-thienyl)ethyl]pyrazin-2(lH-one, Maleate.
The title compound was prepared according to the procedure of Example 65 starting from 3-(4-tert-butoxycarbonyl-l-piperazinyl)-2(lH-pyrazinone (2.24 g, 8.0 mmol;

from Example 48, Stq) 1), 2-(3-thienyl)ethyl methanesulfonate* (1.65 g, 8.00 mmol) and f-BuOK (1.35 g, 12.0 mmol). Yield: 0.48 g (20 %). HPLC purity: 96%. MS m/z 291 (M+H)+ HRMS mlz calc for C14H18N4OS (M)^ 290.1201, found 290.1208." ♦Prepared according to the procedure of Example 76 and previously reported in J. Am. Chem. Soc. 1987,109, 1858-1859.
EXAMPLE 67 3-Piperazin-l-yl-l-[2-(2-thienyl)ethyl]pyrazin-2(lfl)-one,TTifluoToacetate.
t
The title compound was prepared according to the procedure of Example 65 starting from 3-(4-fert-butoxycarbonyl-l-piperazinyl)-2(l/H)-pyrazinone (2.24 g, 8.0 mmol; from Example 48, Step 1), 2-(2-thienyI)ethyl methanesulfonate* (1.65 g, 8.00 mmol) and t-BuOK (1.35 g, 12.0 mmol). Yield: 0.62 g (19 %). HPLC purity: 96 %. MS m/z 291 (M+H)+ HRMS mlz calc for C14H18N40S (M)+ 290.1201, found 290.1203. *Prepared according to the procedure of Example 76 and previously reported in J. Med. Chem. 1989,32,1108-1118.
EXAMPLE 68
1 -[2-( lH-Indol-3 -yl)ethyl] -3 -piperazin-1 -ylpyrazin-2( lif)-one, Trifluoroacetate.
The title compound was prepared according to the procedure of Example 65 starting from 3-(4-tert-butoxycarbonyl-l-piperazmyl)-2(l/f)-pyrazinone (0.93 g, 3.4 mmol; from Example 48, Step 1), 2-(indol-3-yl) ethyl methanesulphonate* (1.1 g, 3.4 mmol) and t-BuOK (0.38 g, 3.4 mmol). Yield: 22 mg (2 %). HPLC purity: 95%. HRMS mlz calc for C18H21N5O (M)+ 323.1746, found 323.1754. *Prepared according to the procedure of Example 76.
EXAMPLE 69
l-[2-(2,3-Dihydro-l,4-benzodioxin-5-yloxy)ethyl]-3-piperazin-l-ylpyrazin-2(l/r)-one, Trifluoroacetate.
The title compound was prepared according to the procedure of Example 65 starting from 3-(4-tert-butoxycarbonyl-l-piperazinyI)-2(l/0-pyazinone (0.72 g, 2.6 mmol; from Example 48, Step 1), 2-(2,3-dihydro-l,4-benzodioxin-5-yIoxy)ethyl

methanesulphonate* (0.86 g, 2.6 mmol) and t-BuOK (0.29 g, 2.6 mmol). Yield: 185 mg (15 %). HPLC purity: 99%. HRMS miz calc for C18H22N4O4 (M)""358.1641, found 358.1650. *Prepared according to the procedure of Example 76. The corresponding alcohol 2-(2,3-dihydro-l,4-benzodioxin-5-yloxy)ethanol was prepared according to the general procedure described in WO 00/76984, Example 91, Step 1.
EXAMPLE 70
1 -[2-(Phenylthio)ethyl]-3-piperazin-l -ylpyrazin-2(lH)-one, Trifluoroacetate.
The title compound was prepared according to the procedure of Example 65 starting from 3-(4-tert-butoxycarbonyl-l-piperazinyI)-2(lH)-pyrazinone (2,41 g, 8.62 mmol; from Example 48, Step 1), 2-phenylsulfanyl-ethyl methanesulfonate* (2.00 g, 8.62 mmol) and t-BuOK (0.97 g, 8.62 mmol). Yield: 80 mg (2 %). HPLC purity: 99%. HRMS m/z calc for C16H20N4OS (M)+ 316.1358, found 316.1357. *Prepared according to the procedure of Example 76.
EXAMPLE 71
l-(3-Oxo-3-phenylpropyl)-3-piperazin-l-ylpyrazin-2(lF)-one, Trifluoroacetate.
The title compound was prepared according to the procedure of Example 65 starting from 3-(4-tert-butoxycarbonyl-l-piperazinyl)2(lH)-Pyazinone (0.56 g, 2.00 mmol; from Example 48, Step 1), commerC1ally available 3-chloro-l-phenyl-propan-l-one (0.34 g, 2.0 mmol) and /-BuOK (0.22 g, 2.0 mmol). Yield: 0.45 g (52 %). HPLC purity: 97%. MS m/z 313 (M+H)+. HRMS m/z calc for C17H20N4O2 (M)+ 312.1586, found 312.1587.
EXAMPLE 72
l-[3-(4-Fluorophenyl)-3-oxopropyl]-3-piperazin-l-ylpyrazin-2(lH-one,
Trifluoroacetate.
The title compound was prepared according to the procedure of Example 65 starting from 3-(4-tert-butoxycarbonyl-l-piperazinyI)-2(lH-pyrazinone (0.56 g, 2.00 mmol; from Example 48, Step 1), commerC1ally available 3-chloro-l-(4-fluoro-phenyl)-propan-1-one (0.37 g, 2.0 mmol) and t-BuOK (0.22 g, 2.0 mmol). Yield: 0.14 g (15

%). HPLC purity: 98%. MS m/z 331 (M+H)+ HRMS m/z calc for C17H19FN4O2 (M)+ 330.1492, found 330.1498.
EXAMPLE 73 (INTERMEDIATED
2-[3-(4-tert-Butoxycarbonyl-3-methyl-l-piperazinyl)-pyrazinyloxy]ethanol. Step 1.2-ChIoro-3-(3-methyIpiperazin-l-yl)pyrazine.
A mixture of 2,3-dichloropyrazine (2.80 g, 18.8 mmol), racemic 2-methylpiperazine (1.88 g, 18.8 mmol) and K2CO3 (3.90 g, 28.2 mmol) in acetonitrile (25 mL) was heated at 65 °C for 15 h with stirring. The reaction mixture was filtered and concentrated. The crude product was purified by flash chromatography on silica gel using CHCl3/MeOH (15:1) as eluent to give 3.2 g (79%) of the title compound. MS m/z 213(M+H)+. Step 2. tert"Butyl 4-(3-chloropyrazin-2-yl)-2-methylpiperazine-l-carboxyIate.
Triethylamine (1.82 g, 17.9 mmol) was added to a solution of 2-chloro-3-(3-methylpiperazin-l-yl)pyrazine (3.18 g, 15.0 mmol; from Step 1) in dichloromethane (20 mL) at 0 °C. Di-tert-butyl dicarbonate (3.92 g, 17.9 mmol) in dichloromethane (20 mL) was added dropwise and the resulting mixture was stirred at 0 °C for 30 min. The mixture was allowed to warm to room temperature and stirring was continued for a further 15 h. The reaction mixture was washed with water, the organic layer dried over MgSO4, and concentrated in vacuo to give 3.12 g (67%) of the title compound. MS m/z 313 (M+H)+. Step 3.2-[3-(4-tert-Butoxycarbonyl-3-methyl-l-piperazinyl)-pyrazinyloxy]- ethanol.
To a mixture of tert-butyl 4-(3-chloropyrazin-2-yl)-2-methylpiperazine-l-carboxylate (3.0 g, 9.6 mmol; from Step 2) in ethylene glycol (10 mL) and dioxane (30 mL) was added t-BuOK (1.18 g, 10.6 mmol). The resulting mixture was stirred at 90 °C, under N2, overnight. Water (10 mL) was added to the light brown reaction mixture and extracted with dichloromethane (3 x 20 mL). The organic layer was dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography using toluene/EtOAc (2:3) as eluent to furnish 3.19 g (98%) of the title compound. HPLC purity: 99%, MS m/z 339 (M+Kf. HRMS m/z calcd for C16H26N404(M)+ 338.1954, found 338.1953.
EXAMPLE 74 (INTERMEDIATE)

tert-Butyl (3R)-4-[3-(2-hydroxyethoxy)pyrazin-2-yI]-3-methylpiperazine-1 -carboxylate.
A mixture of tert-hutyl (3R)-4-(3-chloropyrazin-2-yl)-3-methyipipera2;ine-l-carboxylate* (35 g, 0.11 mol), ethylene glycol (100 g, 1.61 mol) and t-BuOK (25 g, 0.22 mol) in DMSO (150 g) was stirred at 50 °C for 3 h. After this time, the reaction mixture was partitioned between EtOAc (500 g) and water (500 g) and sodium chloride (20 g) was added. The organic layer was concentrated in vacuo to furnish 32,5 g (87%) of the title product. HPLC purity: 75%. HRMS m/z calcd for C16H26N404(M)"" 338.1954, found 338.1959. *Described in WO 00/76984, Example 172, Step 2.
EXAMPLE 75 (INTERMEDIATE)
tert-Butyl4-[3-(2-hydroxyethoxy)pyrazin-2-yl]-l,4-diazepane-l-carboxylate. Step 1: tert-Butyl 4-(3-chloropyrazin-2-yl)-l,4-diazepane-l-carboxylate. To a stirred mixture of 2,3-dichloropyrazine (1,91 g, 12.8 mmol) and iV-/-BOC-homopiperazine, (2.57 g, 12,8 mmol) in acetonitrile (25 mL), was added K2CO3 (2.65 g, 19.2 mmol). The mixtxure was heated in an oilbath (65 °C) overnight. The solution was filtered and the solvent evaporated. The oil contained a white preC1pitate, so this was dissolved in acetonitrile and filtered again. The crude mixture was purified by flash chromatography using toluene/EtOAc (7:3) as eluent. 1H NMR analysis supports the stated structure. Yield: 2.13 g (53%). HPLC purity: 97%. Step 2: tert-Butyl 4-[3-(2-hydroxyethoxy)pyrazin-2-yl]-l,4-diazepane-l-carboxylate. To a stirred mixture of tert-hutyl 4-(3-chloropyrazin-2-yl)-l,4-diazepane-l-carboxyiate (2.5 g, 8.0 mmol; Srom Step 1) in ethylene glycol (8 mL) and dioxane (25 mL), was added t-BuOK (0.99 g, 8.8 mmol). The mixture was heated at 90 °C with condenser, under N2, overnight. Water (10 mL) was added to the ligjit brown mixture and extracted with dichloromethane (3 x 20 mL). The organic phase was dried over MgSO4. The solution was filtered and the solvent evaporated. The residue was purified by chromatography on silica gel using toluene/EtOAc (2:3) as eluent. 1H NMR analysis supports the stated structure. Yield: 1.66 g (61%). HPLC purity: 100%.MS m/z 339(M+H)+.

EXAMPLE
General procedure for the preparation of the mesylates used in Examples 65-70: The starting alcohol (1 equiv) and triethylamine (2 equiv) were dissolved in dichloromethane; the solution cooled on ice/water; methanesulphonyl chloride (1.5 equiv) was added dropwise under stirring; the mixture stirred at room temperature for 1 h; diluted the mixture with dichloromethane; washed with water; dried with Na2S04 and concentrated to get the mesylate. The crude mesylate contains residual triethylamine (up to 0.6 mol equiv).
PREPARATION OF A PHARMACEUTICAL COMPOSITION
EXAMPLE: Preparation of tablets

The active ingredient 1 is mixed with ingredients 2,3,4 and 5 for about 10 minutes. The magnesium stearate is then added, and the resultant mixture is mixed for about 5 minutes and compressed into tablet form with or without film-coating.
Pharmacological methods
The ability of a compound of the invention to bind or act at speC1fic 5-HT receptor subtypes can be determined using in vitro and in vivo assays known in the art. The biological activity of compounds prepared in the Examples was tested using different tests.

Affinity assay
The 5-HT2A receptor affinity of compounds in the Examples was detemiined in competition experiments, where the ability of each compound in serial dilution to displace 3H-labeled lysergic diethyl amide (LSD), bound to membranes prepared from a transfected CHO cell line stably expressing the human 5-HT2A receptor protein, was measured after rapid filtration through glass fiber filters. Non-speC1fic binding was defined using mianserin (5 µM). The 5-HT2A receptor affinity values are expressed as Ki values. Results obtained for exemplary compounds of the invention are illustrated in Table 1 below. The K, values for the compounds towards the human 5-HT2A realtor were in the range 0.1-1500 nM.
Table 1. Human 5-HT2A receptor Affinity

In vitro functional assay
The antagonist activity at the 5-HT2A receptor of the compounds in the Examples of the present invention was judged from their inability to mobilise intracellular calC1um in transfected CHO cells, stably expressing the human 5-HT2A receptor protein, using the calC1um-chelating fluorescent dye FLUO-3 (Sigma, St. Louis, MO, U.S.A.) at a substrate concentration of 1 pM. Additionally, the antagonist activity at the 5-HT2A receptor of the said compounds could be verified by

their ability to inhibit 5-HT-induced calC1um release in transfected CHO cells, stably expressing the human 5-HT2A receptor protein, using cumulative dose-response
techniques. From these experiments, the apparent functional inhibitory constant Kb could be estimated.


WE CLAIM:
1. Piperazinyl pyrazinone derivatives of the general formula (I):

wherein
m is 1 or 2;
n is O, 1,2, 3 or 4;
R1 is H, C1.6-alkyl, aryl-C1-Cj-alkyl, heteroaryl-C1-C3-alkyl, 2-hydroxyethyl, methoxy-C2-C4-alkyl, C1-C4-alkoxycarbonyl, aryloxy-C2-C3-alkyl, or heteroaryloxy-C2-C3-alkyl; wherein
any aryl or heteroaryl residue may be substituted with C1-4-
alkyl, C1-4-alkoxy, C1-4-alkylthio, halogen, trifluoromethyl,
trifluoromethoxy or cyano;
R2and R3 each, independently, represent H or CH3;
R4 and R5 each, independently, represent H, halogen, methyl, or together with the ring, to which carbon atoms they are attached, form a IH-quinoxalin-2-one nucleus; and
R6 represents aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-NH, heteroaryl-NH, aryl, arylcarbonyl, heteroaryl, or heteroarylcarbonyl; wherein
any aryl or heteroaryl residue, alone or as part of another
group, may be unsubstituted or substituted with one, two, three, four
or five substituents, independently selected from aryl, aryl-C1-2-alkyl,
arylcarbonyl, heteroaryl, heteroaryl-C1-2-alkyl, heteroarylcarbonyl.

aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylamino, heteroarylamino, C3-6-cycloalkyl, C3-6-cycloalkyloxy, C3.6-cycloalkylcarbonyl, C1^-alkyl, C2-6-alkanoyl, C2-6-alkynyl, C2-6-alkenyl, or fluoro-C2-4-alkyloxy, halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, trifluoromethylthio, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylamino, C1-4-dialkylamino, hydroxy or 0x0; wherein
any aryl or heteroaryl residue as substitueivts on aryl or heteroaryl, alone or as part of anoflier group, in turn may be substituted in one or more positions, independently of each other, by C1-4-alkyl, Cu-alkoxy, C1-4-alkylthio, halogen, trifluoromethyl, trifluoromethoxy or cyano;
and pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, A""-oxides and prodrug forms thereof, with the provisos that:
R2 and R3 are not both CH3;
when R1, R2 R4 and R5 are H and R3 is H or CH3, then R6 is not 3-pyridyloxy, 6-methyl-2-nitro-3-pyrjdyloxy, or 2-chloro-3-pyridyloxy;
when n = 0, then R6 is not aiyloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-NH orheteroaryl-NH; and
the compound of formula (I) is not l-ben2yl-3-(4-methyl-piperazin-l-yl)- lH-quinoxalin-2-one.
2. The compound according to claim 1, wherein
any aryl or heteroaryl residue, alone or as part of another group, is substituted with one or two non-halogen substituents.
3. The compound according to claim 1, wherein
any aryl or heteroaryl residue, alone or as part of another group, is substituted with at least one halogen substituent.

4. The compound according to claim 1 or 2, wherein any ajyl or heteroaryl residue that is a substituent on another aryl or heteroaryl, alone or as part of another group, in turn is substituted in one position.
5. The compound according to claim 1, wherein
n=l;
R1 R2 R3 R4 and R5 each are H; and
R6 is phenoxy, where the phenyl ring of the said phenoxy group may be unsubstituted or substituted with one, two, three, four or five substituents.
6. The compound according to claim 5, wherein the phenyl ring of R6 is
substituted with one, two, three, four or five substituents independently
selected from
halogen,
2-propenyl,
C1-C6-alkyl,
C1-C6-alkoxy,
trifluoromethyl,
phenyl,
phenoxy,
benzoyl, and
C3-6-cycloalkyl;
wherein the phenyl, phenoxy or benzoyl substituent in turn may be substituted in one or more positions, independently of each other, by C1-4-alkcyl, Cu-alkoxy, C1-4-alkylthio, halogen, trifluoromethyl, trifluoromethoxy or cyano.
7. The compound according to claim 6, wherein the phenyl ring of R6 is substituted with one or two non-halogen substituents.
8. The compound according to claim 6, wherein the halogen substituent is fluorine.

The compound according to claim 1, wherein n=l;
R1 is methoxy-C2-C4-alkyl or straight-chained C]-C4-alkyl; R2 R3 R4 and R5 each are H; and R6 is 2,4,5-trifluorophenoxy.
0. The compound according to claim 1, wherein
n=l;
R1 R2 R3 R4 and R5 each are H; and
R* is 2-0X0-l,3-benzoxathiol-5-yloxy.
1. The compoimd according to claim 1 wherein
n = 0;
R1, R2 R3 R4 and R5 each are H; and
R6 is phenyl, where the said phenyl may be substituted with halogen, in one, two, three, four or five positions.
12. The compound according to claim 11 wherein the halogen is fluorine.
13. The compoimd according to anyone of claims 1 to 12, which is selected from the group consisting of;

• l-[2-(2-fluoro-4-nitrophenoxy)ethyl]-3-(l-piperazinyl)-2(li?)-pyrazinone,
• l-{2-[(2-oxo-2i/-chromen-7-yl)oxy]ethyl}-3-(l-piperazinyl)-2(l/0-pyrazinone,
• 3-(l -piperazinyl)-1 -[2-(2,4,5-trifluorophenoxy)ethyl]-2(l/i0-pyrazinone,
• 3-(l -piperazinyl)-1 -[2-(2,3,5,6-tetrafluorophenoxy)ethyl3-2( IH)-pyrazinone,
• l-[2-(2,3,4,5,6-pentai[luorophenoxy)ethyl]-3-(l-piperazinyl)-2(l//)-pyrazinone,
• i-[2-(4-chloro-2-fluorophenoxy)e1hyl]-3-(l-piperazinyl)-2(l/0-pyrazinone,
• l-[2-(3-cyanophenoxy)ethyl]-3-(l-piperazinyl)-2(l/0-pyrazinone,
• i-(2-(4-cyclopentylphenoxy)ethyl]-3-(l-piper^inyl)-2(li;r)-pyrazinone,

• 1 -[2-(l ,2-benzisoxazol-3-yloxy)ethyl]-3-(l -piperazmyl)-2(lH-
pyrazinone,
• 1 -[2-(3-methoxyphenoxy)ethyl]-3-(l-piperazrayl)-2(lH)-pyrazinone,
• l-[2-(3-M-butyloxyphenoxy)ethyl]-3-(l-piperazinyl)-2(lH)-pyrazmone,
• l-[2-([l,r-biphenyl]-3-yloxy)ethyl]-3-(l-piperazinyl)-2(lH)-pyra2inone,
• 3-(l-piperazinyl)-l-[2-(2,3,4-trifluorophenoxy)ethyl]-2(lii)-pyrazinone,
• l-[2-(2,3-dichlorophenoxy)ethyl]-3-(l-piperazinyl)-2(l/0-pyrazinone,
• 1 -[2-( 1,3-benzodioxol-5-yloxy)ethyl]-3-(l -piperazinyl)-2(li;f)-pyrazinone,
• 1 -[2-(2,4-difluorophenoxy)ethyl]-3-(l -piperazmyl)-2(l/i/)-pyraziTione,
• l-{2-[(2-oxo-l,3-benzoxathiol-5-yl)oxy]ethyl}-3-(l-piperazinyl)-2(l^-pyrazinone,
• l-[2-(3-hydroxyphenoxy)ethyl]-3-(l-piperazinyl)-2(lH)-pyrazinone,
• 3 -(1 -piperazinyl)-1 -[2-(6-quinoxalinyloxy)ethyl] -2(1H-pyrazinone,
• l-{2-[3-(7\r,Ar-dimethylamino)phenoxy]ethyl}-3-(l-piperazinyl)-pyrazin-2(li;0-one,
• 3-(l -piperazinyl)-! - {2"[3-(trifluoromethyI)phenoxy]ethyl}-2(lH)-pyrazinone,
• 1 -[2-(3-fluorophenoxy)ethyl]-3-(l -piperazinyl)-2(l/^-pyrazinone,
• 1 -[2-(3 -nitrophenoxy)ethyl] -3 -(1 -piperazinyl)-2(l//)-pyrazinone,
• 1 -[2-(3-benzoylphenoxy)ethyl]-3-(l -piperazinyl)-2(li;/)-pyraziuone,
• l-[2-(3,5-difluorophenoxy)ethyl]-3-(l-piperazinyl)-2(lfl)-pyrazinone,
• 1 -[2-(phenoxy)ethyl]-3-(l -piperazinyl)-2(lH-pyrazinone,
• 1 -[2-(2,6-difluorophenoxy)ethyl]-3-(l -piperazinyl)-2(lH-pyrazinone,
• 1 -[2-(2-cyanophenoxy)etliyl]-3-(l -piperazinyl)-2(li:/)-pyi"azinone,
• l-[2-(4-trifluoTomethylphenoxy)ethylT|-3-(l-piperazinyl)-2(lH)-pyrazinone,
• l-[2-(4-bromophenoxy)ethyl]-3-(l-piperazinyl)-2(li3f)-pyra2inone,
• 1 -[2- {4-phenoxy-(phenoxy)} ethyl].3-(l -piperazinyl)-2(l//)-pyra2inone,
• l-[2-(4-fluorophenoxy)ethyl]-3-(l-piperazinyl)-2(lH)-pyrazinone,
• l-[2-(4-isopropylphenoxy)ethyl]-3-(l-piperazinyl)-2(lH)-pyrazinone,
• l-[2-(2,4,5-trichlorophenoxy)ethyl]-3-(l-piperazinyl)-2(li7)-pyrazinone,
• l-[2-(2-methylthiophenoxy)ethyl]-3-(l-pip6razinyl)-2(l/y)-pyrazinone,

• l-[2-(3-methoxyphenylthio)ethyl]-3-(l-piperazinyl)-2(l//)-pyrazinone,
• 1 -[2- {(4-allyl-2-methoxy)phenoxy} ethyl]-3-(l -pipera2inyl)-2(l/f)-
pyrazinone,
• 1 -[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)e1hyl]-3-(l-piperazinyl)-
2(l/0-pyrazmone,
• l-[2-(2,6-difluorophenoxy)ethyl]-3-(3-methyl-l-piperazinyl)-2(li/)-
pyrazinone,
• 1 -[2-(4-trifluoromethylphenoxy)ethyl]-3-(3-methyl-l -piperazinyl)-2(lH}-
pyrazinone,
• l-[2-(4-bromophenoxy)ethyl]-3-(3-methyl-l-piperazmyl)-2(lH-
pyrazinone,
• l-[2-(phenoxy)ethyI]-3-(3-methyl-l-piperazinyl)-2(l/0-pyrazinone,
• l-[2-(2,4,5-trifluorophenoxy)ethyl]-3-(3-methyl-l-piperazinyl)-2(1H)-pyrazinone,
• l-[2-(2,4,5-trifluorophenoxy)ethyl]-3-(l,4-diazepan-l-yl)-2(lH- " pyrazinone,
• l-[2-(4-fluorophenoxy)ethyl]-3-(l,4-dia2epan-l-yl)-2(lH-pyrazinone,
• l-[2-(4-isopropyIphenoxy)ethyl]-3-(l,4-diazepan-l-yl)-2(lH-pyrazinone,
• l-[2-(2-inethyItl\iophenoxy)ethyI]-3-(l,4-diazepan-l-yl)-2(lH-pyrazinone,
• 1 -(2,4,5-trifluorobenzyl)-3-(l -piperazinyl)-2(l//)-pyrazinone,
• 1 -[3-(2,4,5-trifluorophenyl)propyl]-3-(l -piperazinyl)-2(lH)-pyrazmone,
• l-(2,3-dihydro-benzo[l,4]dioxin-2-ylmethyl)-3-(l-piperazinyl)-2(lH)-pyrazinone,
• 3-piperazin-i-yl-l[2-(2,4,5-trifluoro-phenoxy)-ethyl]-liy-qumoxalin-2-one,
• l-[2-(2,4,5-trifluoroph«ioxy)ethyl]-3-(4-n-butyl-l-piperazinyl)-2(lH)-pyrazinone,
• l-[2-(2,4,5-trifluorophenoxy)ethyl]-3-[4-(2-methoxyethyl)-l-piperazinyl]-2(lH)-pyrazinone,
• l-[2-(2,4,5-trifluorophenoxy)ethyl]-3-(4-methyl-l-piperazinyl)-2(l/0-pyrazinone,

• 1 -[2-(2,4,5-trifluorophenoxy)ethyl]-3-(4-isopropyl-1 -piperazinyl)-2(liiO-pyrazinone,
• l-{2-[(5-methyl[l,2,4]triazolo[l,5-a]pyrimidin-7-yl)oxy]ethyI}-3-(l-piperazinyl)-2(lJy)-pyrazinone,
• l-[2-(4-Cyanophenoxy)ethyl]-3-(l-piperazinyl)-2(l-H)-pyrazmone,
• l-[4-(2,4,5-trifluorophenoxy)butyl]-3-(l-piperazmyl)-2(l/0-pyrazmone,
• l-[3-(2,4,5-trifluorophenoxy)propyl]-3-(l-piperazinyl)-2(l//)-pyrazinone,
• 3-[4-(l-plieliylethyl)piperazin-l-yl]-l-[2-(2,4,5-trifluorophenoxy)ethyl]-pyrazin-2( 1 H-one,
• 3-[4-(2-phenoxyethyl)piperazin-l-yl]-l-[2-(2,4,5-trifluorophenoxy)ethyl]-pyrazin-2(lH)-one,
• 3-[4-(2-Phenylethyl)piperazin-l-yl]-l-[2-(2,4,5-trifluorophenoxy)ethyl3pyrazin-2(l/0-one, hydrochloride,
• 3-(4-Benzylpiperazin-l-yl)-l-[2-(2,4,5-trifluorophenoxy)ethyl3pyrazin-2(lH)-one hydrochloride,
• 3-[(2/?)-2-methylpiperazin-l-yl]-l-[2-(2,4,5-trifluorophenoxy)ethyl]-pyrazin-2(lH)-one,
• 3-piperazin-l-yl-l-[2-(3-thienyl)ethyl]pyrazin-2(lH-one,
• 3-pipera2in-l-yl-l-[2-(2-thienyl)ethyl]pyrazin-2(lH-one,
• l-[2-(lH-indol-3-yl)ethyl]-3-piperazin-l-ylpyrazin-2(lH-one,
• 1 -[2-(2,3 -dihydro-1,4-benzodioxin-5-yloxy)ethylj-3 -piperazin-1 -yIpyrazm-2(l//)-one,
• l-[2-(phenyIthio)ethyl]-3-piperazin-l-ylpyrazin-2(lH)-one,
• l-(3-oxo-3-phenylpropyl)-3-piperazin-l-ylpyrazin-2(lfl)-one, and
• l-[3-(4-fluorophenyl)-3-oxopropyl]-3-piperazin-l-ylpyrazm-2(lii)-one, and their pharmacologically acceptable salts and solvates,
14. A pharmaceutical composition comprising a compoimd according to any one of claims 1 to 13 as an active ingredient, together with a pharmaceutically acceptable carrier.

15. A process for preparing a compound of formula (I) according to any one of claims 1 to 10 and 13,
wherein R6 is selected from aryloxy, heteroaryloxy, arylthio, heteroarylthio,
ary]-NH, or heteroaiyl-NH,
by reacting a compound of the following formula (II):

wherein
m is 1 or 2; n is 1 or 2; X is OH;

R1 is H, C1.6-alkyl, aryl-C1-6-alkyl, heteroaryl-C1-C3-alkyl. 2-hydroxyethyl, methoxy-C2-C4-alkyl, C1-C4-alkoxycarbonyl, aryloxy-C2-C3-alkyl, or heteroaryloxy-C2-C3-alkyl; wherein
any aryl or heteroaryl residue may be substituted with C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, halogen, trifluoromethyl, trifluoromethoxy or cyano; R1 and R3 each, independently, represent H or CH3; and
R4 and R5 each, independently, represent H, halogen, methyl, or together with the ring, to which carbon atoms they are attached, form a li?-quinoxalin-2-one nucleus; with an optionally substituted phenol or thiophenol; in a solvent.
16.The process according to claim 15 for tine preparation of compounds of formula
(I) where R1 is H, wherein R1 in the corresponding intermediate of formula
(II) is a protecting group selected from tert-butoxycarbonyl (t-BOC) or trityl.
17. The process according to any one of claims 15 and 16, wherein the intermediate
of formula (II) is selected from:
2-[3-(4-tert-butoxycarbonyl-3-methyl-l-piperazinyl)-pyrazinyloxy]ethanol; rerr-Butyl(3i?)-4-[3-(2-hydroxyethoxy)pyrazin-2-yl]-3-methylpiperazine-l-caiboxylate; and /err-Butyl4-[3-(2-hydroxyethoxy)pyrazin-2-yl]-I,4-diazepane-l-carboxylate.
18. A process of preparing a compound of formula (I) according to any one of claims 1 to 13,
wherein R^ is selected Srom aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-NH, heteroaryl-NH, aryl, arylcarbonyl, heteroaryl, or heteroarylcarbonyl, by reacting a compound of the following formula (IV),


wherein
m is 1 or 2;
Hal is halogen;
R is H, C1-6-alkyl, aryl-C1-C3-alkyl, heteroaryl-C1-C3-alkyl, 2-. hydroxyethyl, methoxy-C2-C4-alkyl, C1-C4-alkoxycarbonyl, aryloxy-C2-C3-alkyl, orheteroaryloxy-C2-C3-alkyl; wherein
any aryl or heteroaryl residue may be substituted with C1-4-
alkyl, C1-4-alkoxy, C1-4-alkylthio, halogen, trifluoromethyl,
trifluoromethoxy or cyano;
R2 and R3 each, independently, represent H or CH3; and
R4 and R5 each, independently, represent H, halogen, methyl, or together with the ring, to which carbon atoms they are attached, form a IH-quinoxalin-2-one nucleus;
with an alkali metal or alkaline earth metal basic salt, in aqueous media, at 25 to 150°C, to produce a compound of formula (V),

wherein
m is 1 or 2;
R1 is H or C1-6-alkyl, aryl-C1-C3-alkyl, heteroaryl-C1-C3-alkyl, 2-hydroxyethyl, methoxy-C2-C4-alkyI, C1-C4-alkoxycarbonyl, aryloxy-C2-C3-alkyl, or heteroaryloxy-C2-C3-alkyl; wherein

any aryl or heteroaryl residue may be substituted with C1-4-
alkyl, C1-4-alkoxy, C1-4-alkylthio, halogen, trifluoromethyl,
trifluorbmethoxy or cyano;
each, independently, represent H or CH3; and
R4" and R5 each, independently, represent H, halogen, methyl, or together with the ring, to which carbon atoms they are attached, form a IH-quinoxalin-2-one nucleus;
followed by N-alkylation of the compound of formula (V) by reaction with a compoimd of formula (VI),
R^-CH3-(CH,)-Y
wherein
n is O, 1,2,3 or 4; Y is a leaving group; and
R6 represents aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-NH, heteroaryl-NH, aryl, arylcarbonyl, heteroaryl, or heteroarylcarbonyl; and wherein any aryl or heteroaryl residue, alone or as part of another group, may be unsubstituted or substituted. Where substituted, one, two, three, four or five substituents may be present, prefera;bly one or two for non-halogen substituents, and are independently selected from aryl, aryl-C1.2-alkyl, arylcarbonyl, heteroaryl, heteroaryl-C1.2-alkyl, heteroarylcarbonyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, arylamino, heteroarylamino, C3-6-cycloalkyl, C3.6-cycloalkyloxy, C3-6-cycloalkylcarbonyl, C1.6-alkyl, C2-6-alkanoyl, C2-6-alkynyl, C2-6-alkenyl, or fluoro-C2-4-alkyloxy, halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, trifluoromethylthio, C1-6-alkoxy, C1-6-alkylthio, C1-e-alkylamino, C1-4-dialkylamino, hydroxy or 0x0;
wherein any aryl or heteroaryl residue as substituents on aryl or heteroaryl, alone or as part of another group, in turn may be substituted in one or more positions, preferably one, independently of each other by C1-4-alkyl, C1-4-alkoxy, C1-4-

alkylthio, halogen, trifluoromethyl, trifluoromethoxy, or cyano; in the presence of a base in a suitable solvent at an elevated temperature.
19. The process according to claim 18 for the preparation of compounds of formula
(I) where R1 is H, wherein R1 in the corresponding intermediate of formula (V) is a protecting group selected fcom tert-butoxycarbonyl (t-BOC) or trityl.

Documents:

26-chenp-2005-abstract-dupltcate.pdf

26-chenp-2005-abstract.pdf

26-chenp-2005-claims-dupltcate.pdf

26-chenp-2005-claims.pdf

26-chenp-2005-correspondence-others.pdf

26-chenp-2005-correspondence-po.pdf

26-chenp-2005-description(complete)-dupltcate.pdf

26-chenp-2005-description-(complete).pdf

26-chenp-2005-form-1.pdf

26-chenp-2005-form-13.pdf

26-chenp-2005-form-18.pdf

26-chenp-2005-form-26.pdf

26-chenp-2005-form-3.pdf

26-chenp-2005-form-5.pdf

26-chenp-2005-other-document.pdf

26-chenp-2005-others.pdf

26-chenp-2005-pct.pdf


Patent Number 215364
Indian Patent Application Number 26/CHENP/2005
PG Journal Number 13/2008
Publication Date 31-Mar-2008
Grant Date 26-Feb-2008
Date of Filing 18-Jan-2005
Name of Patentee BIOVITRUM AB
Applicant Address SE-112 76, Stockholm,
Inventors:
# Inventor's Name Inventor's Address
1 NILSSON, Bjorn Igeldammsgatan 20, 5 Trp, S-112 76 Stockholm,
2 THOR, Markus Spakbacken, SE-741 94 Knivsta,
3 CERNERUD, Magnus Nybrogatan 68, SE-114 41 Stockholm,
4 LUNDSTRoM, Helena Mjolnerbacken 15, 1 trp, Se-174 48 Sundbyberg,
PCT International Classification Number C07D 408/02
PCT International Application Number PCT/SE03/01102
PCT International Filing date 2003-06-25
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0202287-9 2002-07-19 Sweden
2 60/426,240 2002-11-14 Sweden