Title of Invention

PIPERAZINE WITH OR-SUBSTITUTED PHENYL GROUP AND THEIR USE AS GLYT1 INHIBITORS

Abstract

The invention relates to compounds of formula (I) wherein the substituents are described in claim 1. The compounds may be used in the treatment of illnesses based on the glycine uptake inhibitor, such as psychoses, pain, neurodegenerative disfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease.

Full Text

PIPERAZINE WITH OR-SUBSTITUTED PHENYL GROUP AND THEIR USE AS GLYT1 INHIBITORS The present invention relates to compounds of the general formula I l-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazineand 1 - [ 5-(aminosulfonyl)-2-methoxybenzoyl] -4- [ 3-(trifluoromethyl)phenyl] -piperazine are specifically described in EP 0171636, possessing inhibiting activity towards carbonic anhydrase which plays a determining role in many physiological and pathological processes. The other excluded compounds are commercially available products. The present invention relates to compounds of general formula I, to pharmaceutical composition containing them and their use in the treatment of neurological and neuropsychiatric disorders. It has surprisingly been found that the compounds of general formula I are good inhibitors of the glycine transporter 1 (GlyT-1), and that they have a good selectivity to glycine transporter 2 (GlyT-2) inhibitors. Schizophrenia is a progressive and devastating neurological disease characterized by episodic positive symptoms such as delusions, hallucinations, thought disorders and psychosis and persistent negative symptoms such as flattened affect, impaired attention and social withdrawal, and cognitive impairments (Lewis DA and Lieberman JA, Neuron,, 28:325-33, 2000). For decades research has focused on the “dopaminergic hyperactivity” hypothesis which has led to therapeutic interventions involving blockade of the dopaminergic system (Vandenberg RJ and Aubrey KR., Exp. Opin. Ther. Targetsy 5(4): 507-518, 2001i Nakazato A and Okuyama S, et al., Exp. Opin. Ther. Patents, 10(1): 75-98, 2000). This pharmacological approach poorly address negative and cognitive symptoms which are the best redictors of functional outcome (Sharma T., Br.J. Psychiatry, 174(suppl. 28): 44-51,1999). A complementary model of schizophrenia was proposed in the mid-1960, based upon the psychotomimetic action caused by the blockade of the glutamate system by compounds like phencyclidine (PCP) and related agents (ketamine) which are non-competitive NMDA receptor antagonists. Interestingly in healthy volunteers, PCP-induced psychotomimetic action incorporates positive and negative symptoms as well as cognitive dysfunction, thus closely resembling schizophrenia in patients (Javitt DC et al., Biol. Psychiatry, 45: 668-679, 1999). Furthermore transgenic mice expressing reduced levels of the NMDAR1 subunit displays behavioral abnormalities similar to those observed in pharmacologically induced models of schizophrenia, supporting a model in which reduced NMDA receptor activity results in schizophrenia-like behavior (Mohn AR et al., Cell 98: 427-236, 1999j. Glutamate neurotransmission, in particular NMDA receptor activity, plays a critical role in synaptic plasticity, learning and memory, such as the NMDA receptors appears to serve as a graded switch for gating the threshold of synaptic plasticity and memory formation (Wiley, NY; Bliss TV and Collingridge GL, Nature, 361:31-39, 1993). Transgenic mice overexpressing the NMDA NR2B subunit exhibit enhanced synaptic plasticity and superior ability in learning and memory (Tang JP et al., Natur, 401- 63-69, 1999). Thus, if a glutamate deficit is implicate in the pathophysiology of schizophrenia, enhancing glutamate transmission, in particular via NMDA receptor activation, would be predicted to produce both anti-psychotic and cognitive enhancing effects. The amino acid glycine is known to have at least two important functions in the CNS. It acts as an inhibitory amino acid, binding to strychnine sensitive glycine receptors, and it also influences excitatory activity, acting as an essential co-agonist with glutamate for N-methyl-D-aspartate (NMDA) receptor function. While glutamate is released in an activity-dependent manner from synaptic terminals, glycine is apparently present at a more constant level and seems to modulate/control the receptor for its response to glutamate. One of the most effective ways to control synaptic concentrations of neurotransmitter is to influence their re-uptake at the synapses. Neurotransmitter transporters by removing neurotransmitters from the extracellular space, can control their extracellular lifetime and thereby modulate the magnitude of the synaptic transmission (Gainetdinov RR et al, Trends in Pharm. Sci., 23(8): 367-373, 2002). Glycine transporters, which form part of the sodium and chloride family of neurotransmitter transporters, play an important role in the termination of post-synaptic glycinergic actions and maintenance of low extracellular glycine concentration by re-uptake of glycine into presynaptic nerve terminals and surrounding fine glial processes. Two distinct glycine transporter genes have been cloned (GlyT-1 and GlyT-2) from mammalian brain, which give rise to two transporters with -50 % amino acid sequence homology. GlyT-1 presents four isoforms arising from alternative splicing and alternative promoter usage (la, lb, 1c and Id). Only two of these isoforms have been found in rodent brain (GlyT-la and GlyT-lb). GlyT-2 also presents some degree of heterogeneity. Two GlyT-2 isoforms (2a and 2b) have been identified in rodent brains. GlyT-1 is known to be located in CNS and in peripheral tissues, whereas GlyT-2 is specific to the CNS. GlyT-1 has a predominantly glial distribution and is found not only in areas corresponding to strychnine sensitive glycine receptors but also outside these areas, where it has been postulated to be involved in modulation of NMDA receptor function (Lopez-Corcuera B et al., Mol. Mem. Biol, 18:13-20, 2001). Thus, one strategy to enhance NMDA receptor activity is to elevate the glycine concentration in the local microenvironment of synaptic NMDA receptors by inhibition of GlyT-1 transporter (Bergereon R. et al., Proc. NatL Acad. Sci. USA, 95:15730-15734, 1998; Chen L. et al., /. Neurophysiol, 89(2): 691-703,2003). Glycine transporters inhibitors are suitable for the treatment of neurological and neuropsychiatric disorders. The majority of diseases states implicated are psychoses, schizophrenia (Armer RE and Miller DJ, Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001), psychotic mood disorders such as severe major depressive disorder, mood disorders associated with psychotic disorders such as acute mania or depression, associated with bipolar disorders and mood disorders, associated with schizophrenia, (Pralong ET et al., Prog. NeurobioL, 67:173-202, 2002), autistic disorders (Carlsson ML, /. Neural Trans,. 105: 525-535, 1998), cognitive disorders such as dementias, including age related dementia and senile dementia of the Alzheimer type, memory disorders in a mammal, including a human, attention deficit disorders and pain (Armer RE and Miller DJ, Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001). Thus, increasing activation of NMDA receptors via GlyT-1 inhibition may lead to agents that treat psychosis, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer’s disease. Objects of the present invention are the compounds of formula I per se, the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases related to activation of NMDA receptors via Glyt-1 inhibition, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses such as psychoses, disfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer’s disease. The preferred indications using the compounds of the present invention are schizophrenia, cognitive impairment and Alzheimer’s disease. Furthermore, the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers. As used herein, the term “alkyl” denotes a saturated straight- or branched-chain group containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred alkyl groups are groups with 1-4 carbon atoms. The term “halogen” denotes chlorine, iodine, fluorine and bromine. The term “aryl” denotes a monovalent cyclic aromatic hydrocarbon radical consisting of one or more fused rings in which at least one ring is aromatic in nature, for example phenyl, benzyl, naphthyl, biphenyl or indanyl. The term “6-membered heteroaryl containing one, two or three nitrogen atoms” denotes a monovalent aromatic carbocydic radical, for example pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or 1,3,5-triazinyL The term “heterocycloalkyl” denotes a non aromatic hydrocarbon radical, for example oxetanyl, tetrahydrofiiranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl. The term “5-membered aromatic heterocycle, containing 1-4 heteroatoms, selected from N and O” denotes for example 1,2,4-oxadiazolyl, oxazolyl, 1,3,4-oxadiazolyl or tetrazolyl. The term “5 or 6-membered heteroaryl containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen” denotes a monovalent aromatic carbocyclic radical, for example pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl or isoxazolyl. The term “pharmaceutically acceptable acid addition salts” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfiiric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like. One embodiment of the invention are compounds of the general formula optionally in the presence of a catalyst, such as Cu(I)I and a base like potassium carbonate, cesium carbonate or sodium, to a compound of formula wherein X is halogen and the other substituents are as defined above, or c) reacting a compound of formula in the presence of a base and optionally in the presence of microwaves to a compound of formula wherein X is halogen, mesylate or triflate and the other substituents are as defined above, or d) reacting a compound of formula with a compound of formula R2OH under Mitsunobu conditions in the present of a phosphine to a compound of formula A mixture of 20 mmol l-bromo-2-fluoro-4-trifluoromethyl-benzene, 24.7 mmol n-Boc-piperazine, 0.1 mmol Tris(dibenzylideneacetone)dipalladium chloroform complex, 28.8 mmol sodium-t-butoxide and 0.4 mmol 2-(dicyclohexylphosphino)biphenyl in 50 ml toluene was heated for 16 h at 80 °C. After cooling to RT the mixture was treated with 15 g Isolute HM-N and all volatiles were removed under vacuum. The residue was purified on silica eluting with a gradient of heptane / EtOAc to yield after evaporation the title compound. (b) l-(2-Fluoro-4’trifluoromethvl-phenvl)-piperazine A mixture of 9 mmol 4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine-l-carboxylic acid tert-butyl ester in 20 ml dioxane was treated with 8.93 ml 4N HC1 in dioxane for 2 h at 80°C. The mixture was concentrated and treated with 20 ml water, 20 ml 2M Na2CO3 and extracted with 50 ml EtOAc. The organic phase was washed with 30 ml saturated NaCL All aqueous phases were combined and extracted with 50 ml EtOAc. The combined organic phases were dried with MgSCU and evaporated to yield the title compound 1.1. Example 1.2 Preparation of 2-isopropoxy-5-methanesulfonyl-benzoic acid (a) 2-Chloro-5-methanesulfonyl-benzoic acid To 99 mmol 2-chloro-5-(methyIthio) benzoic acid in 400 ml methanol at 0 °C 296 mmol oxone® was added and the mixture was allowed to stir at RT for 3.5 h. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was extracted 3 x with 400 ml ethyl acetate and the combined organic phases washed 2 x with 300 ml IN HC1 and with 300 ml saturated aqueous NaCl solution and dried with MgSO4. Evaporation under reduced pressure yielded the title compound. (b) 2-lsopropoxv-5-methanesulfonvl-benzoic acid A mixture of 2.13 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 0.64 mmol Cu(I)Br in 5 ml NEt3 and 25 ml isopropanol was heated to 120 °C for 16 h in a sealed tube. The WO 2005/014563 PCT/EP2004/008633 volatiles were removed under vacuum and the residue was taken up in 70 ml IN HC1. Extraction with ethyl acetate drying of the combined organic fractions and evaporation yielded a residue which was purified by reversed phase preparative HPLC eluting with an acetonitrile / water gradient. Evaporation of the product fractions yielded the title compound 1.2. MS (m/e): 257.0 (MH\ 100%) In analogy to Example L2(b) compounds 1.3 to 1.7 of the following table were prepared from 2-chloro-5-methanesulfonyl-benzoic acid and the appropriate alcohol: WO 2005/014563 PCT/EP2004/008633 Preparation of 5-Methanesulfonyl-2-(2-methoxy-ethoxy)-benzoic acid (a) 2-Amino-5-methanesulfonyI-benzoic acid A mixture of 4.26 mmol 2-chloro-5-methanesulfonyl-benzoic acid (compound 1.2a), 0.39 mmol Copper powder and 10 ml ammonium hydroxide 25% was heated at 125-130°C with stirring for 18 hours. Mixture was cooled to room temperature and filtered. The solid was washed with methanol. The filtrate was concentrated in vacuo. The residue was acidified with HCI IN to pH=2. The obtained solid was washed with water and dried (HV, 50°C, 1 hour) to yield the title compound. MS (m/e): 214.1 (M-H, 100%) (b) 2-Iodo-5-methanesulfonyl-benzoic acid To a suspension of 3.0 mmol 2-amino-5-methanesulfonyl-benzoic acid in a mixture of L7 ml sulfuric acid and 1.7 ml water was added dropwise a solution of 3.92 mmol sodium nitrite in 1.7 ml water at such rate that the temperature did not exceed 3°C. The mixture was stirred at 0°C for 1 hour. A solution of 3.0 mmol KI in 1.7 ml water was added dropwise at 0°C. The brown suspension was allowed to warm to rt and stirred for 30 minutes. Excess iodine was destroyed by addition of a few drops of a sodium hydrogenosulfite solution. The solid was filtered, washed with water and dried (HV, 50°O 1 hour) to yield the title compound. MS (m/e): 325.0 (M-H, 100%) WO 2005/014563 PCT/EP2004/008633 (c) 5-Methanesulfonvl-2-(2-methoxy-ethoxy)-benzoic acid To a solution of 1.6 mmol 2-iodo-5-methanesulfonyl-benzoic acid in 30 ml 2-methoxyethanol and 6 ml triethylamine were added 79 mg copper (I)bomide and the reaction mixture heated to 120°C for 4 h. The solvent was distilled off and the residue dissolved in 90 ml IN HCl. The aqueous phase was extracted twice with ethyl acetate and the pooled organic extracts washed twice with water and once with brine. The organic layer was dried with Na2SO4, filtered and evaporated to yield the title compound 1.10. MS (m/e): 273.1 (MH~, 100%). Example 1.11 Preparation of 5-Cyano-2-(2-methoxy-ethoxy)-beMoic acid (a) 2-Bromo-5-cvano-benzoic acid To a suspension of 7.1 mmol copper (II) bromide in acetonitrile (30 ml) was added dropwise 8.63 mmol tert-butylnitrite at 0°C within 2 minutes. 6.17 mmol 2-Amino-5-cyano-benzoic acid (CAS: 99767-45-0; WO9518097) was added portionwise within 10 minutes at 0°C. The mixture was stirred at 0°C for 2 hours and then at room temperature overnight. Half of the solvent was removed in vacuo. The residue was taken in HCl IN (15 ml) and ethyl acetate (30 ml). The organic layer was extracted with NaOH IN (3x10 ml). The aqueous layer was acidified with HCl 2N. The resulting solid was filtered, washed with water and dried (high vacum, 50°C) to provide the title compound MS (m/e):227.1(M+H\l00%) fb) 5-Cvano-2-(2-methoxy-ethoxv)-benzoic acid To a solution of 0.16 mmol 2-bromo-5-cyano-benzoic acid in 6 ml 2-methoxyethanol and 1.2 ml triethylamine were added 23 mg copper (I) bromide and the reaction mixture heated to 120°C for 4 h. The solvent was distilled off and the residue dissolved in 20 ml IN HCl. The aqueous phase was extracted twice with ethyl acetate and the pooled organic extracts washed twice with water and once with brine. The organic layer was dried with Na2SO4) filtered and evaporated to yield the title compound 1.11. MS (m/e): 220.4 (MH\ 100%). Example 1.12 ) Preparation of 5-Cyano-2- (2,2,2-trifluoro-ethoxy)-benzoic acid To a solution of 4-(4-Cyano-2,3-difluoro-phenyl)-piperazine-l-carboxylic acid tert-butyl ester (0.72 g) in dichloromethane (5 mL) was added trifluoroacetic acid and the reaction mixture was stirred at room temperature for 30 minutes. After such time the reaction mixture was concentrated in vacu to yield the title compound (0.63 g). MS (m/e): 224.3 (M+H+, 100%). Example 2.8 Preparation of 2,5-Difluoro-4-piperazin-1 -yl-benzonitrile-trifluoro-acetic acid Example 2.8 was prepared in analogy to Example 2.7 using 2,4,5-trifluorobenzonitrile. MS (m/e): 224.3 (M+H+, 100%). Example 2.9 Preparation of 5-Methylsirifamoyl-2-trifluoromethoxy-benzoic acid (a) 5-ChlorosulfonyI-2-trifluoromethoxy-benzoic acid A solution of 2-trifluoromethoxy benzoic acid [1979-29-9] (1.0 g) was added in small batches to chlorosulfonic acid (3.2 mL) at 0°C. After completion of the addition, the reaction mixture was stirred at 70°C for 4 hours then left at room temperature overnight and heated at 75°C for another 3 hours. After such time the reaction was slowly poured onto ice, and the precipitate was then filtered, washed with water and dried to yield the title compound as a white solid (1.2 g). MS (m/e): 303.3 (M-H, 100%). (b) 5-MethyIsulfamoYl-2-trifluoromethoxy-benzoic acid To a solution of 5-Chlorosulfonyl-2-trifluoromethoxy-benzoic acid (0.15 g) in dichloromethane (1.5 ml) was added a solution of methylamine in methanol (8M, 0.31 mL) and the reaction mixture was stirred for 2 minutes after precipitation was compele. The reaction mixture was then concentrated in vacuo and the residue was dissolved in IN NaOH (2 mL) and extracted with diethylether. The aqueous phase was then acidified using 3 N hydrochloric acid solution (2 mL) and the solution was extracted with dichloromethane (2 x 10 mL). The combined organic phases were dried with sodium sulfate and concentrated in vacuo to yield the title compound as a white solid (0.12 g). MS (m/e): 298.0 (M-H, 100%). Example 2.10 Preparation of 5-Methanesulfonyl-2-(33,3-trifluoro-propoxy)-benzoic acid (a) 5-Methanesulfonvl-2-(3,33-trifluoro-propoxv)-benzoic acid methyl ester A solution of methyl 5-(methanesulfonyl)-salicylate [101371-44-2] (50 mg), triphenylphosphine (65 mg) 3,3,3-trifluoro-l-propanol and di-tert-butyl azodicarboxylate (55 mg) in THF (3 mL) was stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo purified by column chromatography (S1O2) to yield the title compound as a white solid (65 mg). MS (m/e): 327.5 (M+H+, 100%). (b) 5-Methanesulfonvl-2-(3,3,3-trifluoro-propoxy)-benzoic acid To 5-methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoic acid methyl ester (620 mg) in ethanol at 60°C was added IN NaOH solution (3.8 mL) and the reaction mixture was stirred for 15 minutes. After such time 3.8 ml of IN HC1 was slowly added to the reaction mixture and the ethanol was evaporated in vacuo. The precipitate was then washed with water several times to give the title compound (497 mg). MS (m/e): 311.0, M-H+, 100%). Example 2.11 Preparation of 5-Methanesulfonyl-2-(tetrahydro-pyran-4-yloxy)-benzoic acid Compound 2.11 was prepared in analogy to compound 2.10 using tetrahydro-2H-pyran-4-oL MS (m/e): 299.4 (M-H, 100%). Example 2.12 Preparation of 2-Cyclobutylmethoxy-5-methanesulfonyl-benzoic acid Compound 2.12 was prepared in analogy to compound 2.10 using cyclobutyl methanol. MS (m/e): 299.4 (M-H, 100%). Example 2.13 Preparation of 3,5-Difluoro-4-piperazin-l-yl-benzonitrile trifluoro-acetic acid Compound 2.13 was prepared in analogy to compound 2.7 using 3,4,5-trifluorobenzonitrile. MS (m/e): 224.1 (M+H+, 100%). Example 2.14 Preparation of 2,6-Difluoro-4-piperazin-l-yl-benzonitrile trifluoro-acetic acid WO 2005/014563 PCT/EP2004/008633 Compound 2.14 was prepared in analogy to compound 2.7 using 2,4,6-trifluorobenzonitrile. MS (m/e): 224.1 (M+H\ 100%). Example 2.15 Preparation of 5-Methanesulfonyl-2-trifluoromethoxy-benzoic acid (a) 5-Sulfino-2-trifluoromethoxy-benzoic acid 5-chlorosulfonyl-2-trifluoromethoxy-benzoic acid (1.0 g, compound 2.9.a) was added portionwise onto a solution of sodium sulfite (3.1 g) in 16 mL of water. The reaction mixture was kept under basic conditions by the addition of the proper amount of 20% NaOH and was stirred at room temperature for 45 minutes. After such time the reaction mixture was cooled down with an ice bath and was then acidified by the addition of 20% H2SO4 solution until reaching pH 2. The solution was then extracted several times with diethyl ether and ethyl acetate. The combined organic phases were dried (sodium sulfate) and concentrated in vacuo to yield the title compound as a white solid (0.88 g). (b) 5-Methanesulfonyl-2-trifluoromethoxv-benzoic acid To 5-Sulfino-2-trifluoromethoxy-benzoic acid (0.82 g) in DMF (5 mL) was added 1.3 g of potassium carbonate and the reaction mixture was stirred for 5 minutes before methyl iodide (0.66 mL) was added. The reaction mixture was then stirred at room temperature for 60 hours. After such time the reaction mixture was concentrated in vacuo and the residue was treated with IN NaOH (10 mL) and THF (4 mL). The reaction mixture was stirred for a further 2 hours at room temperature. After such time the solution was acidified with concentrated HC1 solution. THF was then removed in vacuo and the precipitate was isolated by filtration and washed several times with water to yield the title compound. MS (m/e): 283.0 (M-H, 100%). Example 2.16 Preparation of 2,4-Difluoro-6-piperazin-l-yl-benzonitrile trifluoro-acetic acid Compound 2.16 was prepared in analogy to compound 2.7 using 2,4,6-trifluorobenzonitrile of. MS (m/e): 224.1 (M+H+, 100%). Example 2.17 Preparation of 2«(2-Fluoro-l-fluoromethyl-ethoxy)-5-methanesulfonyl-benzoic acid WO 2005/014563 PCT/EP2004/008633 Compound 2.17 was prepared in analogy to compound 2.10 using l,3-difluoro-2-propanol. MS (m/e): 293.1 (M-H, 100%). Example 2.18 Preparation of 5«Methanesulfonyl-2-(2,2,3,3,3”pentafluoro-propoxy)-benzoic acid (a) 5-Methanesulfonvl-2-(2,2,3,3,3-pentafluoro-propoxY)-benzoic acid methyl ester A solution of methyl 5-(methanesulfonyl)salicylate [101371-44-2] (0.50 g), trifluoro-methanesulfonic acid 2,2,3,3,3-pentafluoro-propyl ester (0.67 g) and potassium carbonate (0.60 g) in acetone was stirred at 60°C for 5 hours. The reaction mixture was then concentrated in vacuo and purified by column chromatography (SiO2) to yield the title compound as a white solid (0.44 g). MS (m/e): 363.1 (M+H+, 100%). (b) 5-Methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxv)-benzoicacid To 5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acid methyl ester (414 mg) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (72 mg) in water (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After such time 1.72 mL of IN aqueous hydrochloric acid solution was added. The reaction mixture was then concentrated in vacuo and the resulting precipitate was then washed several times with water to yield the title compound as a white solid (367 mg). MS (m/e): 347.1 (M-H, 100%). Example 2.19 Preparation of 2-tert-Butoxy-5-methanesulfonyl-benzoic acid (a) 2-tert-ButoxY-5-methanesulfonvl-benzoic acid methyl ester To a solution of methyl 5-(methanesulfonyl)-salicylate [101371-44-2] (0.50 g) in toluene (5 mL) was added N,N-dimethylformamide-di-ferf-butylacetal and the reaction mixture was strirred at 80°C for 1 hour. After such time the reactiom mixture was concentrated in vacuo and purified by column chromatography to yield the title compound as colourless oil (258 mg). MS (m/e): 304.4 (M+NH4+, 100%). (b) 2-tert-Butoxv-5-methanesulfonyl-benzoic acid To 2-tert-Butoxy-5-methanesulfonyl-benzoic acid methyl ester (1.58 g) in THF (25 mL) was added a solution lithium hydroxide monohydrate (0.35 g) in water (25 mL) and the WO 2005/014563 PCT/EP2004/008633 reaction mixture was stirred at room temperature for 4 hours. After such time the THF was removed in vacuo and to the remaining aqueous solution was added 8 mL of IN HC1 solution leading to precipitation of the compound. The precipitate was filtered off and washed several times with water to yield the title compound (LOO g) as a white solid. MS (m/e): 289.9 (M+NH4+). Example 2.20 Preparation of l-(2,5-Difluoro-4-methanesulfonyl-phenyl)-piperazine trifluoro-acetic acid (a) 2,4,5-Trifluoro-benzenesulfinic acid 2,4,5-Trifluoro-benzenesulfonyl chloride ([220227-21-4], 2.5 g) was added portionwise onto a solution of sodium sulfite (10.3 g) in 50 mL of water. The reaction mixture was kept under basic conditions by the addition of the proper amount of 20% NaOH and was stirred at room temperature for 1 hour. Methanol was added to the reaction mixture and the reaction mixture was stirred at room temperature for another hour. After such time the reaction mixture was cooled down with an ice bath and was then acidified by the addition of 20% H2SO4 solution until reaching pH 2. The aqueous solution was then extracted several times with diethyl ether and ethyl acetate. The aqueous solution was further extracted with etyl acetate using a Kutscher-Steudel apparatus (continuous extraction). The combined organic phases were dried (sodium sulfate) an concentrated in vacuo to yield the title compound as a white solid (2.1 g). (b) L2,4’Trifluoro-5-methanesulfonvl-benzene To 2,4,5-trifluoro-benzenesulfinic acid (2.0 g) in DMF (17 mL) was added 4.3 g of potassium carbonate and the reaction mixture was stirred for 5 minutes before methyl iodide (2.2 mL) was added. The reaction mixture was then stirred at room temperature for 60 hours. After such time water (30 mL) was poured onto the reaction mixture and the reaction mixture was extracted with diethylether several times. The combined organic phases were dried with sodium sulfate and the remaining mixture was distilled to yield the title compound as a light yellow oil (2.1 g). (c) l-(23-Difluoro-4-methanesuIfonyl-phenyl)-piperazine trifluoro-acetic acid The title compound was obtained in analogy to example 2.7 using l,2,4-Trifluoro-5-methanesulfonyl-benzene. MS (m/e): 277.1 (M+H+). WO 2005/014563 PCT/EP2004/008633 Example 2.21 Preparation of l-(3,5-Difluoro-4-methanesulfonyl-phenyl)-piperazine trifluoro-acetic acid Compound 2.21 was prepared in analogy to compound 2.20 using 2,4,6-trifluoro-benzenesulfonyl chloride [172326-59-9]. MS (m/e): 277.1 (M+H+). Example 2.22 Preparation of 5-Methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-benzoic acid Compound 2.22 was prepared in analogy to compound 2.18 using 2,2,3,3-tetrafluoro-l-propyl triflate. MS (m/e): 329.1 (M-H). Example 2.23 Preparation of l-(2,6-Difluoro-4-methanesulfonyl-phenyl)-piperazine trifluoro-acetic acid Compound 2.23 was prepared in analogy to compound 2.20 using 3,4,5-trifluoro-benzenesulfonyl chloride [351003-43-5]. MS (m/e): 277.1 (M+H+). Example 2.24 Preparation of 4-Piperazin-l-yl-6-trifluoromethyl-pyrimidine trifluoro-acetic acid Compound 2.24 was prepared in analogy to compound 2.7 using 4-chloro-6-trifluoromethyl-pyrimidine [37552-81-1]. MS (m/e): 233.1 (M+H+). Example 2.25 Preparation of 2-Piperazin- l-yl-5-trifluoromethyl-pyrimidine fa) 2-(4-Benzvl-piperazin-l-vl)-5-trifluoromethyl-pyrimidine To a solution of (3-Dimethylamino-2-trifluoromethyl-aIIylidene)”dimethyl-ammonium chloride ([176214-18-9], 0.60 g) in acetonitrile (10 mL) was added 4-Benzyl-piperazine-1-carboxamidine hydrochloride ([7773-69-5], 0.66 g) and triethylamine (0.87 mL) and the reaction mixture was stirred for 3 hours at room temperature. After such time the reaction mixture was concentrated in vacuo and purified by column chromatography to yield the title compound as a light yellow solid (0.79 g). MS (m/e): 323.4 (M+H+). (b) 2-Piperazin- l-vl-5-trifluoromethvl-pvrimidine To a solution of 2-(4-Benzyl-piperazin-l-yl)-5-trifluoromethyl«pyrimidine (0.63 g) in methanol was added Palladium-C (Degussa E101N; 5%) and the reaction mixture was heated at 60°C under hydrogen atmosphere. The reaction mixture was then allowed to cool down to room temperature, the catalyst was filtered of and solvent was removed in vacuo to yield the title compound as a colorless solid (0.41 g). MS (m/e): 233.1 (M+H+). In analogy to Example 5 compounds 108 to 280 of the following table were prepared from the acid derivatives and piperazine derivatives: Preparation of 6-Ethoxy-2-fluoro-3-methanesulfonyl-benzoic acid (a) 3-Ch.lorosulfonvl-2^6-difluoro-benzoic acid 95 mmol of 2,6-difluorobenzoic acid in 19 ml of chloro$ulfonic acid was stirred for 2 h at 1506. The mixture was poured into 200 ml of ice and stirred for 20 min. The resulting shiny was filtered, washed with water and dried (20° overnight in the dessicator) to yield the title compound as a colorless solid. MS (m/e): 279.4 (MNa,, 81%) fb) 2,6-Difluoro-3-sulfmo-benzoic acid 41 mmol of 3-chlorosulfonyI-236-difluoro-benzoic acid was slowly added over 20 min. to a solution of 310 mmol sodium sulfite in 200 ml of water. The resulting mixture was stirred for one hour at room temperature, cooled to 0° C and acidified with 20% aqueous sulforic acid. The sulfinic acid was extracted with ethyl acetate, dried over Mg$O4 and concentrated to yield the title compound as a colorless solid. MS (m/e); 220.9 (M-H, 100%) (c) 6-Ethorvr’2-fluoro-3-methanesulfonvl-benzoic acid A mixture of 27 mmol 2,6-difluoro-3-sulfino-benzoic acid and 9 mmol Na2CO3 in 110 ml methanol was treated with 72 mmol of methyl iodide. The resulting mixture was stirred overnight at 60°, concentrated and the dark residue dissolved in 100 ml of ethanol. 100 ml of 2 molar aqueous NaOH is added and the mixture was refluxed for 2 hours. Concentration to about 100 ml precipitated a yellowish solid which was filtered and WO 2005/014563 PCT/EP2004/008633 triturated with diethyl ether to give the crude title compound, which was used without further purification. Example 4.2 Preparation of l-(4-Trifluoromethanesulfonyl-phenyl)-piperazine A mixture of 1 mmol l-Bromo-4-trifluoromethanesulfonyI-benzene [Nodiff et al., J.Org.Chem. 25, 60 (I960)], 3 mmol of piperazine and 2 mmol of potassium carbonate in 5 ml of acetonitrile was refluxed for 2 hours. The resulting mixture was poured into water, extracted with ethyl acetate, dried, concentrated and purified by column chromatography (SiO2; Et20 / cyclohexane) to yield the title compound as a colorless solid. MS (m/e): 295.2 (MH\ 100%) Example 4.3 Preparation of l-(2,4-Bis-trifluoromethyl-phenyl)-piperazine hydrochloride (a) 4-f2,4-Bis-trifluoromethyl-phenvl)-piperazine’l-carboxylic acid tert-butyl ester A mixture of 5 mmol 2,4-bis(trifluoromethyl)bromobenzene, 6 mmol N-BOC-piperazine, 8 mmol NaOtBu, 0.5 mmol rac«2,21-bis(diphenylphosphino)-l,r-binaphthyl and 1 mmol tris-(dibenzylideneacetone)dipalladium chloroform complex in 20 ml toluene was stirred at 80° C for 3 hours. The mixture was then diluted with water, extracted with ethyl acetate, dried and purified by column chromatography (S1O2; cyclohexane / ethyl acetate 9:1) to yield the title compound as a yellowish oil. MS (m/e): 399.1 (MH+, 100%) (b) l-(2,4-Bis-trifluoromethyl-phenyl)-piperazine hydrochloride 3 mmol of 4-(2,4-Bis-trifluoromethyl-phenyl)-piperazine-l-carboxylic acid tert-butyl ester was stirred in 10 ml of 1,4-dioxane saturated with gaseous HCL After 4 h at room temperature, the reaction mixture was evaporated to dryness to yield the title compound as a colorless solid. MS (m/e): 299.3 (MH+, 100%) Example 4.4 Preparation of l-[4-(5-Methyl-[l,2,4]oxadiazol-3-yl)-phenyl]-piperazine hydrochloride (a) 4-f4-(5’Methvl-[L2,4ioxadiazol-3-vl)-phenyl1-pipera2ine-l-carboxvlic acid tert-butyl ester WO 2005/014563 PCT/EP2004/008633 A well stirred mixture of 0.015 mmol of bis(tri-t-butylphosphine)palladium, 0.01 mmol of cetyltrimethylammonium bromide, 2 mmol of powdered potassium hydroxide, 2mmol of 3-(4-bromo-phenyl)-5-methyl-[l,2,4]oxadiazole and 2.1 mmol of N-BOC-piperazine in 1 ml of toluene was heated under Ar to 90° C for 17 hours. The resulting reaction mixture was diluted with water, extracted with ethyl acetate and the product purified by column chromatography (SiO2; cyclohexane / ethyl acetate 7:3 ) to yield the title compound as a yellowish solid. MS (m/e): 345.3 (MH\ 100%) (b) l-[4-(5-Methyl-f l,2,4loxadiazol-3-vl)-phenvl1-piperazine hvdrochloride 1 mmol of 4-[4-(5-Methyl-[l,2,4]oxadiazol-3-yI)-phenyl]-piperazine-l-carboxylic acid tert-butyl ester was stirred in 3 ml of 1,4-dioxane saturated with gaseous HC1. After 2 h at room temperature, the reaction mixture was evaporated to dryness to yield the title compound as a colorless solid. MS (m/e): 245.1 (MH+, 100%) Example 4.5 Preparation of l-(4-Oxazol-2-yl-phenyl)-piperazine hydrochloride (a) 4-Bromo-N-(2,2-dimethoxy-ethvD-benzamide A solution of 24 mmol aminoacetaldehyde dimethylacetal was dissolved in 30 ml of water and treated with 25 mmol of potassium hydrogencarbonate. A solution of 23 mmol of 4-bromobenzoyl chloride in 50 ml of acetone was slowly added under stirring over a period of 30 min. The acetone was evaporated and the aqueous phase extracted 3 times with ethyl acetate to yield the crude title compound as a slightly brown solid. MS (m/e): 287.1 (M-H, 43%) fb) 2-(4-Bromo-phenyl)-oxazole A solution of 21 mmol of phosphorous pentoxide in 20 ml of methylsulfonic acid was treated with 7 mmol of 4-Bromo-N-(2,2-dimethoxy-ethyl)-benzamide. The reaction mixture was heated for 5 hours at 130°, cooled to room temperature and poured into ice-water. The resulting solid was filtered off and dried to yield the crude title compound as a brownish solid. MS (m/e): 224.0 (MH+, 24%) (c) 4-(4-Oxazol-2-vl-phenvl)-piperazine-l-carboxvlic acid tert-butyl ester Prepared in analogy to example 4.4 (a) from 2-(4-Bromo-phenyl)-oxazole and N-BOC-piperazine. MS (m/e): 330.3 (MH+, 100%) WO 2005/014563 PCT/EP2004/008633 (d) l-(4-OxazoI-2-vI-phenvl)-piperazine hvdrochloride Prepared in analogy to example 4.4 (b) from 4-(4-Oxazol-2-yl-phenyl)-piperazine-l-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 230.1 (MH+, 100%) Example 4.6 Preparation of l-[4-(5-Methyl-[l,3,4]oxadiazol-2-yl)-phenyl]-piperazine hydrochloride (a) 2-(4-Bromo-phenyl)-f 1,3,41 oxadiazole 12.3 mmol of 4-bromo-benzoic acid hydrazide were dissolved in 26 ml of triethyl orthoformate. The reaction mixture was stirred overnight at 140°, evaporated and the residue crystallized from ethanol to give the title compound as a colorless solid. MS (m/e): 225.0 (MH+, 100%) (b) 4-(4-f l,3,4iOxadiazol-2-yl-phenyI)-piperazine-l-carboxvlic acid tert-butyl ester Prepared in analogy to example 4.4 (a) from 2-(4-Bromo-phenyl)-[l»3,4]oxadiazole and N-BOC-piperazine. MS (m/e): 342.2 (MH\ 100%) (c) l-[4-(5-Methyl-fl,3,4loxadiazol-2-yl)-phenvn-piperazine hydrochloride Prepared in analogy to example 4.4 (b) from 4-(4-[ 1,3,4] Oxadiazol-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 245.3 (MH+, 100%) Example 4.7 Preparation of l-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine hydrochloride (a) 5-(4-Bromo-phenvl)-2-methvl-2H-tetrazole A mixture of 3.5 mmol of 5-(4-bromo-phenyl)-2H-tetrazole, 0.2 mmol of tetrabutyl ammonium bromide, 4.4 mmol of methyl iodide, 6 ml of 1M aqueous sodium hydroxide and 6 ml of dichloromethane were stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried, evaporated and the product purified by column chromatography (S1O2; cydohexane / ethyl acetate 7:3). MS (m/e): 239.1 (MHf, 29%) WO 2005/014563 PCT/EP2004/008633 (b) 4-[4-f2’Methyl-2H-tetra2ol-5-vl)-phenvn-piperazine’l-carboxvlic acid tert-butyl ester Prepared in analogy to example 4.4 (a) from 5-(4-Bromo-phenyl)-2-methyl-2H-tetrazole and N-BOC-piperazine. MS (m/e): 345.1 (MH+, 41%) (c) l”f4-(2-Methv]’2H-tetrazol-5-vl)-phenvn”piperazinehydrochloride Prepared in analogy to example 4.4 (b) from 4-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 245.1 (MH\ 100%) Example 4.8 Preparation of S^.S^-Tetrahydro-ZH-fl^’lbipyrazinyl-S’-carboxylic acid methyl ester hydrochloride (a) 23,5,6’Tetrahydro-fK2’1bipVTazinyl-4,5!-dicarboxvlic acid 4-tert-butvl ester 5’- methvl ester A mixture of 17 mmol methyl-5-chloropyrazine-2-carboxylate, 18 mmol of N-BOC-piperazine and 20 mmol of K2CO3 in 20 ml of acetonitrile was heated under reflux for 3 hours. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The title compound was recrystallized from ethyl acetate to yield a colorless solid. MS (m/e): 323.4 (MH+, 100%) (b) 3A5,6-Tetrahvdro-2H-f L2’1bipyrazinyl-5T-carboxvlic acid methyl ester hydrochloride Prepared in analogy to example 4.4 (b) from 2,3,5,6-Tetrahydro-[l,2’]bipyrazinyl-4,5’-dicarboxylic acid 4-tert-butyl ester 5’-methyl ester and 1,4-dioxane saturated with gaseous HC1. MS (m/e): 223.1 (MH+, 100%) Example 4.9 Preparation of 6’-Chloro-3,4,5,6-tetrahydro-2H-[l,2,]bipyrazinyl trifluoroacetate a) 6’-Chloro-2,3,5,6-tetrahvdro-fK2f1bipyrazinvl-4-carboxvlicacid tert-butvl ester mixture of 10 mmol 2,6-dichloropyrazine and 21 mmol of N-BOC-piperazine in 15 ml icetonitrile was heated under reflux for 1.5 hours. The reaction mixture was ;oncentrated and purified by chromatography (S1O2; dichloromethane / methanol 95:5) o yield the title compound as a colorless solid. MS (m/e): 299.2 (MH+, 100%) WO 2005/014563 PCT/EP2004/008633 (b)6t-Chloro-3,4,5,6-tetrahvdro-2H4L2,1bipvrazinvltrifluoroacetate A solution of 2 mmol 6’-Chloro-2,3,5,6-tetrahydro-[l,2’]bipyrazinyl-4-carboxylic acid tert-butyl ester in 10 ml of dichloromethane was treated with 3 mmol of trifluoroacetic acid and stirred at room temperature for 17 hours. Concentration and crystallisation from diethylether yielded the title compound as a colorless solid. MS (m/e): 198.0 (M’, 100%) Example 4.10 Preparation of 3,4,5,6-Tetrahydro-2H-[l,2l]bipyra2inyl-5’-carboxylic acid amide hydrochloride (a) 5’-Carbamovl-2,3,5,6-tetrahydro-[L2’lbipyrazinvl-4-carboxylic acid tert-butyl ester 3 mmol of 2,3,5,6-Tetrahydro-[l,2’]bipyrazinyl-4,5’-dicarboxylic acid 4-tert-butyl ester 5’-methyl ester (example 1.13 (a)) was dissolved in a 7 molar solution of gaseous ammonia in methanol. The reaction vessel was tightly closed and heated overnight at 60° C. Cooling of the reaction mixtures led to crystallisation of the title compound. MS (m/e): 308.4 (MH+, 100%) (b) 3,4,5,6-Tetrahvdro-2H-[l,2’1bipyrazinyl-5l-carboxyIic acid amide hvdrochloride 0.25 mmol of 5’-Carbamoyl-2,3,5,6-tetrahydro-[l,2’]bipyrazinyl-4-carboxylic acid tert-butyl ester was stirred for 1 hour in 1 ml of dioxane saturated with gaseous HC1. Concentration of the reaction mixture led to the title compound, as a colorless solid. MS (m/e): 208.3 (MH+, 100%) Example 4,11 Preparation of Dimethyl- (4-piperazin-1 -yl- [ 1,3,5 ] triazin-2-yl) -amine (a) 4-(4-Chloro-f L3,5itriazin-2’Vl)-piperazine-l-carboxvlic acid tert-butyl ester A solution of 11 mmol of 2,4-dichlorotriazine (WO 02/083654) in 20ml of acetonitrile was chilled and treated with 11 mmol of triethylamine and 11 mmol of N-BOC-piperazine. The reaction mixture was stirred for 2 hours at 0° C then for 2 hours at room temperature. Addition of 100ml brine and extraction with ethyl acetate yielded the crude product which was purified through trituration in ethyl acetate. MS (m/e): 300.3 (MH+, 100%) WO 2005/014563 PCT/EP2004/008633 (b) 4-(4-Dimethvlamino-[L3,5itriazin-2-vl)-pipera2ine’l-carboxylic acid tert-butvl ester A solution of 2 mmol of 4-(4-Chloro-[l,3,5]triazin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester in 15 ml of 2M dimethylamine in methanol was stirred at room temperature for 1 hour. Concentration and purification by chromatography (SiO2; ethyl acetate / cydohexane 1:1) yielded the title compound as a colorless solid. MS (m/e): 309.1 (MH+, 100%) (c) Dimethvl’(4-piperazin-l-vl-[L3,5itriazin-2-vl)-amine A solution of 1 mmol of 4-(4-Dimethylamino-[l,3,5]triazin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester in 10 ml dichloromethane was chilled and treated with 14 mmol of trifluoroacetic acid. The reaction mixture was heated to 40° C for 30 min. After cooling, 50ml of 2M aqueous sodium hydroxide is added. The organic layer was separated, dried and concentrated to yield the title compound as a yellowish oil. MS (m/e): 267.0 (M+CH3COO\ 100%) Example 4.12 Preparation of 6’-Methoxy-3,4,5,6-tetrahydro-2H-[ 1,2’jbipyrazinyl (a) 6’-Methoxv-2.3,5,6-tetrahvdro-f lT2’]bipyrazinyl-4-carboxvlic acid tert-butyl ester 1 mmol of 6’-Chloro-2,3,5,6-tetrahydro-[l,2l]bipyrazinyl-4-carboxylic acid tert-butyl ester [example 4.9 (a)] was dissolved in a solution of sodium methanolate (prepared by dissolving 1 mmol of sodium in 10 ml of methanol). The mixture was heated overnight to 70°, concentrated and the product purified by chromatography (SiCh; dichloromethane / methanol 99:1) to yield the title compound as a colorless foam. MS (m/e): 295.3 (MH\ 100%) (b)6l-Methoxv-3,4,5,6-tetrahvdro-2H-rL2tlbipvrazinvl Prepared in analogy to example 4.10 (c) from 6,-Methoxy-2,3,5,6-tetrahydro-[l,2’)bipyrazinyl-4-carboxylic acid tert-butyl ester and trifluoroacetic acid. MS (m/e): 195.1 (MH+, 80%) Example 4.13 Preparation of 2-Methoxy-4-piperazin- 1-yl- [ 1,3,5] triazine (a) 4-(4-Methoxv-f L3,5itriazin-2-vl)-piperazine-l-carboxvlic acid tert-butvl ester WO 2005/014563 PCT/EP2004/008633 1 mmol of 4-(4-Chloro-[13,5]triazin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester [example 4.11 a)] was dissolved in a solution of sodium methanolate (prepared by dissolving 1 mmol of sodium in 5 ml of methanol). The mixture was stirred at room temperature for 1 hour, concentrated and the the title compound purified by recrystallisation from ethyl acetate / cyclohexane. MS (m/e): 296.3 (MH+, 100%) (b)2-MethoxY-4-piperazin-l-yI-fl,3,5itriazine Prepared in analogy to example 4.10 (c) from 4-(4-Methoxy-[l,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester and trifluoroacetic acid. MS (m/e): 196.4 (MH\ 100%) Example 4.14 Preparation of 2-Dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid (a) 2-Hydroxy-5-methanesulfonyl-benzoic acid benzyl ester 5 mmol of N-(3-dimethylaminopropyl)-Nf-ethyl-carbodiimid-hydrochloride was slowly added to a stirred suspension of 5 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid, 5 mmol of benzyl alcohol and 0.5 mmol of 4-dimethylaminopyridine in 10 ml acetonitrile. The mixture was stirred overnight at room temperature, concentrated and treated with 10 ml of water. A few drops of diluted hydrochloric acid were added to acidify the solution. The resulting solid was filtered and the purified by chromatography (SiO2; ethyl acetate / cyclohexane 3:7) to yield the title compound as a colorless solid. MS (m/e): 305.0 (M-H, 100%) (b) 2-Dimethvlcarbamoyloxv-5-methanesulfonvl-benzoic acid benzyl ester A mixture of 1 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid benzyl ester, 1.5 mmol of N-methylmorpholine and 0.2 mmol of 4-dimethylaminopyridine in 4 ml of dimethylformamide was treated with 1.3 mmol of N,N-dimethyl-carbamoylchloride. The reaction mixture was stirred at 60° for 48 hours, concentrated in vacuo and the residue taken up in 5 ml of water. Acidification with diluted hydrochloric acid and extraction with ethyl acetate yielded a crude product which was purified by chromatography ethyl acetate / cyclohexane 1.1). MS (m/e): 378.3 (MH+, 100%) (c) 2-Dimethvlcarbamovloxv-5-methanesulfonvl-benzoic acid 1 mmol of 2-dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid benzyl ester was dissolved in 5 ml of methanol 25 mg of palladium 10% on charcoal was added and the reaction mixture hydrogenated at room temperature to yield the title compound as a slightly yellowish solid. MS (m/e): 288.0 (MH+, 66%) In analogy to Example 5 compounds 327 to 355 of the following table were prepared from the acid derivatives and piperazine derivatives: WO 2005/014563 PCT/EP2004/008633 Example 356 Preparation of l-{3-Fluoro-4- [4- (2-isopropoxy-5-methanesulfonyl-benzoyl)- piperazin-l-yl]-phenyl}-ethanoneoxhne 0.12 mmol of l-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-l-yl]-phenyl}-ethanone was dissolved in 1 ml of a 1:1 mixture of ethanol and water. 0.8 mmol of hydroxylamine hydrochloride was added, followed by 8.4 mmol of sodium acetate. The resulting mixture was stirred overnight at room temperature, diluted with water, filtered, washed and dried to yield the title compound as a colorless solid. MS (m/e): 478.2 (MH+, 100%) Example 357 Preparation of l-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1 -yl] -phenyl} -ethanone O-methyl-oxime 0.12 mmol of l-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-l-yl]-phenyl}-ethanone was dissolved in 1 ml of a 1:1 mixture of ethanol and water. 0.8 mmol of O-methyl-hydroxylamine hydrochloride was added, followed by 8.4 mmol of sodium acetate. The slurry was stirred overnight at room temperature, diluted with water, extracted with ethyl acetate, dried and concentrated. The resulting gum was WO 2005/014563 PCT/EP2004/008633 triturated with diethyl ether / heptane to yield the title compound as a colorless solid. MS (m/e): 492.3 (MH\ 100%) Example 4.15 Preparation of (2,6-Difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1 -yl] -methanone (a) 3-ChlorosuIfonvI-2,6-difluoro-benzoic acid 77 mmol of 2,6-difluorobenzoic acid were dissolved in 15.5 ml of chlorosulfonic acid and stirred for 2 h at 150° C. The reaction mixture was cooled to room temperature and poured into 100 ml of ice / water. The solid was filtered and dried to yield the title compound as a colorless solid. MS (m/e): 255.1 (M-H, 44%) (b) 2,6-Difluoro-3-sulfino-benzoic acid 240 mmol of sodium sulfite were dissolved in 150 ml of water. 32 mmol of 3-Chlorosulfonyl-2,6-difluoro-benzoic acid was added under stirring over a period of about 20 min. After stirring for an additional hour at room temperature, the mixture was chilled and acidified with 20% aqueous sulfuric acid. The product was extracted with ethyl acetate to yield the title compound as a colorless solid. MS (m/e): 221.3 (M-H, 34%) (c) 2,6-Difluoro-3-methanesulfonvl-benzoic acid A suspension of 18 mmol sodium carbonate and 9 mmol 2,6-Difluoro-3-sulfino-benzoic acid in 30 ml of methanol was stirred at room temperature for 30 min, then heated to 60° C. 24 mmol of methyl iodide were added and the reaction mixture heated overnight at 60° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was discarded and the aqueous phase acidified by addition of concentrated hydrochloric acid. Extraction with ethyl acetate yielded the title compound as a slightly brownish solid. MS (m/e): 235.1 (M-H, 16%) (d) (2,6-Difluoro-3-methanesulfonvl-phenvl)-[4-(2-fluoro-4-methanesulfonvl-phenvl)- piperazin-l-vli-methanone This compound was prepared in analogy to example 5 from l-(2-fluoro-4-methanesulfonyl-phenyl)-piperazine and 2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m/e): 477.0 (MH+, 67%) WO 2005/014563 PCT/EP2004/008633 Example 4.16 Preparation of 4-[4-(2,6-Difluoro-3-methanesulfonyl-benzoyl)-piperazin-l-yl]- benzonitrile Prepared in analogy to example 5 from 4-piperazin-l-yl-benzonitrile and 2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m/e): 406.3 (MH+, 84%) Example 358 Preparation of (2-Cydopentyloxy-6-ethxy-3-methanesulfonyl-phenyl)- [4-(4-methanesulfonyl-phenyl)-piperazin- 1-yl] -methanone 0.12 mmol of (6-Ethoxy-2-fluoro-3-methanesulfonyl-phenyl)-[4-(4-methanesulfonyl-phenyl)-piperazin-l-yl] -methanone (example 55) was added to a solution of sodium cyclopentanolate (prepared from 1 mmol sodium dissolved in 1 ml of cyclopentanol). The mixture was heated for 1 hour at 80° C, poured on ice / water and extracted with ethyl acetate. Chromatography (S1O2; ethyl acetate) yielded the title compound as a slightly yellow solid. MS (m/e): 551.1 (MH+, 29%) Example 359 Preparation of (2,6-diisopropoxy-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin- 1-yl] -methanone 0.27 mmol of 2,6-difluoro-3-methanesulfonyl-phenyl)- [4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone (example 4.15) was added to a solution of sodium isopropanolate (prepared by dissolving 3 mmol of sodium in 2 ml of isopropanol). The reaction mixture was heated under reflux for 5 hours, cooled, diluted with water and extracted with ethyl acetate, yielding the title compound as a slightly yellow solid. MS (m/e): 557.3 (MH\ 66%) Example 360 Preparation of (2-Fluoro-6-isopropoxy-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4- methanesulfonyl-phenyl)-piperazin-l-yl)-methanone 0.2 mmol of{2,6-difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin- 1-yl] -methanone were dissolved in a solution of sodium isopropanolate (prepared by dissolving 0.2 mmol of sodium in 1 ml of isopropanol). The reaction mixture was heated to 50° C for 2 hours, then stirred at room temperature for 48 hours. The solution was diluted with water and extracted with ethyl acetate. The product WO 2005/014563 PCT/EP2004/008633 was purified by chromatography (SiO2, ethyl acetate / cyclohexane 9:1) to yield the title compound as a colorless solid. MS (m/e): 517.1 (MH+, 100%) Example 361 Preparation of (6-Cydopentyloxy-2-fluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4- methanesulfonyl-phenyl)-piperazin-l-yl]-methanone The compound was prepared in analogy to example 358 from [2,6-difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-l-yl]-methanone and sodium cyclopentanolate. MS (m/e): 560.5 (MNH4+, 43%) Example 362 Preparation of 4-[4-(2-Fluoro-6-isopropoxy-3-methanesulfonyl-benzoyl)-piperazin-1- yl]-benzonitrile The compound was prepared in analogy to example 359 from 4-[4-(2,6-difluoro-3-methanesulfonyl-benzoyl)-piperazin-l-yl]-benzonitrile and sodium isopropanolate. MS (m/e): 446.0 (MH\ 49%) Example 5-1 Preparation of l-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine (a) 4-(3-Fluoro-4-trifluoromethvl-phenyl)-piperazine-l-carboxvlic acid tert-butyl ester A mixture of 4.9 mmol 4-chloro-2-fluorobenzotrifluoride, 5.9 mmol n-Boc-piperazine, 0.05 mmol palladium acetate, 6.9 mmol sodium-t-butoxide and 0.49 mmol 2-(di-t-butylphosphino)biphenyl in 10 ml toluene was heated for 16 h at 80 °C. After cooling to RT, the mixture was diluted with ether, the suspension was filtered over decalite and the filtrate evaporated. The residue was purified on silica eluting with a gradient of heptane / EtOAc to yield after evaporation the title compound. (b) l-(3-Fluoro-4-trifluoromethvl-phenyl)-piperazine A mixture of 2.87 mmol 4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-l-carboxylic acid tert-butyl ester in 10 ml dichloromethane was treated with 14.4 mmol trifluoroacetic acid and refluxed for 3 h. The mixture was concentrated and treated with 10 ml water, NaOH and extracted with dichloromethane. The combined organic phases were dried with MgSO4 and evaporated to yield the title compound 5.1. MS (m/e): 249.2 (MH+, 100%) WO 2005/014563 PCT/EP2004/008633 Example 5.2] Preparation of 2-Piperazin-l-yl-5-trifluoromethyl-benzonitrile The compound was prepared in analogy to compound 5.1 from 2-Chloro-5-trifluoromethyl-benzonitrile (DE2550262). MS (m/e): 256.0 (MH+, 100%) Example 5.3 Preparation of l-(2,3-Difluoro-4-methanesulfonyl-phenyl)-piperazine The compound was prepared in analogy to compound 2.20 from 2,3,4-Trifluoro-benzenesulfonyl chloride (commercial). MS (m/e): 277.2 (MH\ 100%) Example 5.4 Preparation of l-(2-Fluoro-4-methyl-phenyl)-piperazine The compound was prepared in analogy to compound 1.1 from 4-bromo-3-fluorotoluene (commercial). MS (m/e): 195.3 (MH+, 100%) Example 5.5 Preparation of l-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazine The compound was prepared in analogy to compound 2.7 from 2,3-Difluoro-5-trifluoromethyl-pyridine (EP0104715). MS (m/e): 250.2 (MH\ 100%) Example 5.6 Preparation of 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid (a) rac-5-Methanesulfonvl-2-(2,2,2-trifluoro-l-methvl’ethoxv)-benzoic acid methvl ester A mixture of 21.7 mmol 2-Hydroxy-5-methanesulfonyl-benzoic acid methyl ester [68029-77-6], 32.5 mmol trifluoro-methanesulfonic acid 2,2,2-trifluoro-l -methyl-ethyl ester [212556-43-9], 43.4 mmol potassium carbonate in 87 ml DMF was stirred at 80 °C for 48 hours. After cooling to RT, the mixture was concentrated in vacuo, taken in water and stirred for 1 hour. Filtration yielded the title compound. fb) 5-Methanesulfonvl-2-((S)-2,2,2-trifluoro-l-methvl-ethoxvVbenzoic acid methyl ester The title compound was obtained by separation of rac-5-Methanesulfonyl-2-(2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid methyl ester by chiral HPLC (Chiralcel OD, 15 % ethanol/ Heptane, flow 35 ml, 220 nm, retention time: 86 min.). WO 2005/014563 PCT/EP2004/008633 (c) 5-Methanesulfonvl-2-f(S)-2,2,2-trifluoro-l-methvl-ethoxv)-benzoicacid The compound was prepared in analogy to compound 2.10(b) from 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid methyl ester MS (m/e): 311.0 (M-H, 100%) Example 5.7 Preparation of 5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid (a) 5-Methanesulfonvl-2-((R)-2,2,2-trifluoro-l-methvl-ethoxy),benzoic acid methyl ester The title compound was obtained by separation of trifluoro-l-inethyl-ethoxy^benzoic acid methyl ester by chiral HPLC (Chiralcel OD, 15 % ethanol/ Heptane, flow 35 ml, 220 nm, retention time: 74 min.). (c) 5-Methanesulfonvl’2-((R)-2,2,2-trifluoro-l-methvl-ethoxyVbenzoicacid The compound was prepared in analogy to compound 2.10(b) from 5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid methyl ester MS (m/e): 311.0 (M-H, 100%) Example 5.8 Preparation of 2-Chloro-4-piperazin- 1-yl-benzonitrile A mixture of 7.0 mmol 2-chloro-4-fluorobenzonitrile (commercial), 10.5 mmol piperazine in 4 ml N,N-dimethylacetamide was heated for 1 h at 85 °C. After cooling to RT and evaporation in vacuo, the mixture was diluted with dichloromethane and purified on silica eluting with a gradient of dichloromethane / MeOH to yield after evaporation the title compound.MS (m/e): 222.1 (MH+, 100%) Example 5.9 Preparation of l-(2-Fluoro-4-piperazin-l-yl-phenyl)-ethanone The compound was prepared in analogy to compound 5.8 from 2,4-difluoroacetophenone (commercial). MS (m/e): 223.2 (M-H, 100%) Example 5.10 Preparation of l-(3-Fluoro-4-methanesulfonyl-phenyl)-piperazine WO 2005/014563 PCT/EP2004/008633 The compound was prepared in analogy to compound 2.20 from 2,4-difluorobenzenesulfonylchloride (commercial). MS (m/e): 259.1 (MH+, 100%) Example 5.11 Preparation of l-(4-Fluoro-2-piperazin-l-yl-phenyl)-ethanone 5 The compound was prepared in analogy to compound 5.8 from 2,4-difluoroacetophenone (commercial). MS (m/e): 223.2 (M-H, 100%) Example 5.12 Preparation of 6-Isopropoxy-isophthalamic acid The compound was prepared in analogy to compound 2.10 from 6-Hydroxy-\ isophthalamic acid methyl ester [89366-34-7]. MS (m/e): 222.1 (M-H, 100%) Example 5.13 Preparation of 5-Ethanesulfonyl-2-isopropoxy-benzoic acid (a) 5-EthanesuIfonyl-2-hydroxy-benzoic acid methyl ester The compound was prepared in analogy to compound 2.20(b) from 2-Hydroxy-5-sulfino-benzoic acid [19479-88-0] and ethyliodide (b) 5-Ethanesulfonyl-2-isopropoxy-benzoic acid The compound was prepared in analogy to compound 2.10 from 5-Ethanesulfonyl-2-hydroxy-benzoic acid methyl ester, MS (m/e): 271.1 (M-H, 100%) Example 5.14 Preparation of l-(4-Difluoromethyl-2-fluoro-phenyl)-piperazine (a) l-Chloro-4-difluoromethyl-2-fluoro-benzene 24.7 mmol 4-Chloro-3-fluorobenzaldehyde was dissolved in DAST (5.1 ml) under nitrogen. The mixture was stirred at room temperature for 3 hours, at 50°C for 2 hours and then at room temperature for 65 hours. The solution was added dropwise to a saturated.bicarbonate solution (150 ml) under cooling. The aqueous layer was extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified on silica eluting with heptane to yield after evaporation the title compound. WO 2005/014563 PCT/EP2004/008633 fb) l-(4-Difluoromethvl-2-fluoro-phenyl)-piperazine The compound was prepared in analogy to compound 1.1 from l-Chloro-4-difluoromethyl-2-fluoro-benzene. MS (m/e): 231.2 (M+H+, 100%) Example 5.15 Preparation of l-(6-Trifluoromethyl-pyridin-3-yl)-piperazine The compound was prepared in analogy to compound 1.1 from 5-Bromo-2-trifluoromethyl-pyridine [436799-32-5]. MS (m/e): 232.1 (M+H\ 100%) Example 5.16 Preparation of 3-Fluoro-4-piperazin-l-yl-benzoic acid ethyl ester The compound was prepared in analogy to compound 5.8 from Ethyl-3,4-difluorobenzoate (commercial). MS (m/e): 253.2 (M+H+, 100%) Example 5.17 Preparation of l-(2-Trifluoromethyl-pyridin-4-yl)-piperazine The compound can be prepared from 4-Nitro-2-trifluoromethyl-pyridine 1-oxide [147149-97-1] in analogy to the procedure used for the preparation of 4-Bromo-2-methyl-6-trifluoromethyI-pyridine [615579-78-1] (WO03087056). MS (m/e): 227 (M+H\ 100%) Example 5.18 Preparation of l-(6-Methyl-pyridin-3-yl)-piperazine The compound was prepared in analogy to compound 1.1 from 5-Bromo-2-methyll-pyridine (commercial). MS (m/e): 178.1 (M+H+, 100%) In analogy to Example 5 compounds 363 to 461 of the following table were prepared from the acid derivatives and piperazine derivatives: Example 462 Preparation of rac-{4-[2-Fluoro-4-(l-hydroxy-ethyl)-phenyl]-piperazin-l-yl}-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone 5 0.086 mmol of l-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-l-yl]-phenyl}-ethanone was dissolved in 1 ml ethanol and 0.26 mmol sodium borohydride was added. The mixture was refluxed for 40 min., cooled to room temperature, quenched with water, acidified with HC1 IN and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and the solvent was 10 removed in vacuo. The residue was purified on silica eluting with heptane/ethylacetate to yield after evaporation the title compound. MS (m/e): 465.4 (M+H+, 100%) Example 463 Preparation of {4- [2-Fluoro-4- (1 -hydroxy-1 -methyl-ethyl)-phenyl] -piperazin-1 -yl}-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone WO 2005/014563 PCT/EP2004/008633 To a solution of 0.173 mmol H3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-l-yl]-phenyl}-ethanone in tetrahydrofuran (2 ml) was added dropwise 0.190 mmol 1.6M Methyllithium solution in ether at -75°C The mixture was stirred for 2 hours and then allowed to warm to 0°C. The mixture was quenched with a 20% NH4C1 solution and extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified on silica eluting with dichloromethane/MeOH to yield after evaporation the title compound. MS (m/e): 479.5 (M+H\ 100%) The examples 464-471 have been prepared by separation of the racemic material by chiral HPLC: Preparation of 2-isobutoxy-5-methylsulfamoyl-benzoic acid (a) 5-Chlorosulfonvl-2-hvdroxv-benzoic acid To 3.26 mol chlorosulfonic acid at 0 °C was added 652 mmol salicylic acid in small portions and the mixture was then allowed to stir at RT for 1 h, then at 50 °C for 1 h, and finally at 70 °C for 1 h. The mixture was then added dropwise to 1000 ml ice-water with stirring and stirring continued for an additional 30 min. The ensuing white crystals were collected by filtration, washed three times with water, and then dried in vacuo at 45 °C for 16 h to yield the title compound. MS (m/e): 236.8 ([{37C1}M-H]\ 33%), 235.0 ([{37C1}M-H]\ 100%) (b) 2-HydroxY-5-methvIsulfamoyl-benzoic acid To 63 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 120 ml dichloromethane at RT was added dropwise 317 mmol methylamine (8 M solution in ethanol) and the mixture was allowed to stir at RT for 1 h. The mixture was then concentrated in vacuo. The residue was suspended in 1 M aq NaOH solution and extracted twice with ether. The aqueous phase was acidified with 5 M aq HC1, saturated with NaCl, and extracted 3 times WO 2005/014563 PCT/EP2004/008633 with THF. The combined THF extracts were washed twice with saturated aqueous NaCl solution and dried with Na2SO4. Evaporation in vacuo yielded the title compound. MS (m/e): 249.0 (M+NH4\ 100%), 231.9 (M+H+, 63%) (c) 2-Hvdroxv-5~methvlsulfamoyl-benzoic acid methyl ester To 77 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid in 300 ml THF was added 85 mmol CDI and the mixture heated at 70 °C for 1 h. 770 mmol methanol was then added and the mixture was heated at 70 °C for 16 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane/dichloromethane 45:45:10) to afford the title compound. MS (m/e): 244.1 ([M-H]\ 100%) (d) 2-Isobutoxv-5-methylsulfamovl-benzoic acid methyl ester To 2.9 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester, 3.1 mmol 2-methyl- 1-propanol and 3.3 mmol triphenylphosphine in 10 ml THF was added 3.1 mmol di-tert-butyl azodicarboxylate and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 2:3) to afford the title compound. MS (m/e): 300.2 ([M-H], 100%) (e) 2-IsobutoxY-5-methvlsulfamoyl-benzoic acid To 3.3 mmol 2-isobutoxy-5-methylsulfamoyl-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH and the mixture was heated at 50 °C for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether afforded the title compound. MS (m/e): 286.2 ([M-H], 100%) In analogy to Example 6.1(d) and (e), compounds 6.2 to 6.10 of the following table were prepared from 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and the appropriate alcohol, followed by hydrolysis with aqueous sodium hydroxide: WO 2005/014563 PCT/EP2004/008633 (a) 5-Methvlsulfamovl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid methvl ester To 3.3 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 3.3 mmol potassium carbonate in 50 ml acetone was added dropwise 4.9 mmol 2,2,2-trifluoro-ethyl trifluoromethanesulfonate and the mixture was heated at 60 °C for 16 h. The mixture was then concentrated in vacuo. The residue was suspended in dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 3:7) to afford the title compound. MS (m/e): 328.0 (M+H+, 100%) (b) 5-Methvlsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid To 2.3 mmol 5-methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH and the mixture was heated at 50 °C for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether afforded the title compound. MS (m/e): 312.0 ([M-H]\ 100%) Example 6.19 Preparation of rac-5-methylsulfamoyl-2-(2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid (a) rac-5-Methvlsulfamoyl-2-(2,2,2-trifluoro-l-methvl-ethoxv)-benzoic acid methvl ester To 4.1 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 4.1 mmol potassium carbonate in 5 ml DMF was added dropwise 6.1 mmol trifluoro-methanesulfonic acid 2,2,2-trifluoro-l-methyl-ethyl ester and the mixture was heated at 90 °C for 16 h. The mixture was then cooled to RT, poured onto water and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Eva-poration in vacuo followed by chromatography on silica gel (eluant: dichloromethane) afforded the title compound. MS (m/e): 359.2 (M+NH/, 80%), 342.0 (M+H+, 100%) rac-5-Methvlsulfamoyl’2-(2,2,2-trifluoro-l’methyl-ethoxv)-benzoicacid To 1.6 mmol 5-methylsulfamoyl-2-(2,2,2-trifluoro-l-methyl-ethoxy)-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH and the mixture was heated at 50 °C for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted twice with WO 2005/014563 PCT/EP2004/008633 ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether and hexane afforded the title compound. MS (m/e): 326.2 ([M-H]\ 100%) Example 6.14 Preparation of 5-cyclopropanesulfonyl-2-isopropoxy-benzoic acid (a) 2-Hydroxy-5-sulfino-benzoic acid To 317 mmol sodium sulfite in 200 ml water at RT was added dropwise over 30 min a solution of 42.3 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 80 ml dioxane and stirring continued for a further 30 min. 5 M aq NaOH was then added dropwise until the reaction mixture was pH 14 and the mixture was then allowed to stir at RT for a further 2 h. The mixture was then cooled to 0 °C and concentrated H2SO4 added until the reaction mixture was pH 1. Ethyl acetate was added and the phases were separated. The organic phase was dried with Na2SO4. Evaporation in vacuo yielded the title compound. MS (m/e): 201.0 ([M-H]\ 100%) (b) 5-(3-Chloro-propane-l-sulfonyl)-2-hydroxy-benzoic acid To 16.7 mmol 2-hydroxy-5-sulfino-benzoic acid and 41.7 mmol triethylamine in 40 ml DMF was added 18.3 mmol l-chloro-3-iodopropane and the mixture heated at 40 °C for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: dichloromethane/methanol/acetic acid gradient) to afford the title compound. MS (m/e): 279.1 ([{37C1}M-H]\ 33%), 277.0 ([{35Cl}M-H]M00%) (c) 5-CvclopropanesuIfonyl”2-hydroxy-benzoic acid To 8.0 mmol 5-(3-chloro-propane-l-sulfonyl)-2-hydroxy-benzoic acid in 30 ml THF at -78 °C was added dropwise over 30 min 23.9 mmol of a 0.9 M solution of potassium bis(trimethylsilyl)amide in toluene. The reaction mixture was then allowed to warm to RT and stirring continued for a further 30 min at RT. The mixture was then diluted with THF/ethyl acetate (1:1) and washed sequentially with 1 M aq HCl and saturated aqueous NaCl solution dried with Na2SO4, and concentrated in vacuo. The residue was triturated in ether/pentane to afford the title compound. MS (m/e): 241.2 ([M-H]\ 100%) (d) 5-Cyclopropanesulfonvl-2-hvdroxy-benzoic acid methyl ester WO 2005/014563 PCT/EP2004/008633 To 7.2 mmol 5-cyclopropanesulfonyl-2-hydroxy-benzoic acid in 20 ml dichloroethane containing a few drops of DMF was added dropwise 8.7 mmol oxalyl chloride. After stirring for 90 min at RT, the reaction mixture was cooled to 0 °C and then 144 mmol methanol was added followed by 72 mmol pyridine and stirring continued at RT for 1 h. The mixture was then washed with 1 M aq HCl, dried with Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 255.2 ([M-H]\ 100%) (e) 5-CvclopropanesulfonyI-2-isopropoxv-benzoic acid To 0.6 mmol 5-cyclopropanesulfonyl-2-hydroxy-benzoic acid methyl ester, 3.7 mmol 2-propanoi and 0.9 mmol diphenyl-2-pyridylphosphine in 8 ml THF was added 0.9 mmol di-tert-butyl azodicarboxylate and the mixture was stirred at RT for 3 h. 4 mmol 5 M aq NaOH solution was then added and the mixture heated at 60 °C for 1 h. The mixture was then concentrated in vacuo. The residue was resuspended in ethyl acetate and washed twice with 1 M aq NaOH solution. The combined aqueous phases were then acidified to pH 1 by addition of 25% aq HCl and extracted three times with ethyl acetate. The combined organic extracts were then dried with Na2SO4, and concentrated in vacuo to afford the title compound MS (m/e): 282.9 ([M-H]\ 100%) In analogy to Example 6.14 (e), compounds 6.15 to 6.18 of the following table were prepared from 5-cyclopropanesulfonyl-2-hydroxy-benzoic acid methyl ester and the appropriate alcohol, followed by hydrolysis with aqueous sodium hydroxide: WO 2005/014563 PCT/EP2004/008633 Example 6.12 Preparation of l-(4-ethanesulfonyl-2-fluoro-phenyl)-piperazine (a) 3,4-Difluoro-benzenesulfinic acid To 2.47 mol sodium sulfite in 1120 ml water at RT was added dropwise over 20 min a solution of 329 mmol 3,4-difluoro-benzenesulfonyl chloride in 560 ml dioxane and stirring continued for a further 30 min. 1 M aq NaOH was then added dropwise until the reaction mixture was pH 14 and the mixture was then allowed to stir at RT for a further 16 h. The mixture was then cooled to 0 °C and concentrated H2SO4 added until the reaction mixture was pH 1. The mixture was extracted three times with ethyl acetate and the combined organic phases washed with saturated aq NaCl solution and then dried with Na2SO4. Evaporation in vacuo yielded the title compound. MS (m/e): 177.1 ([M-H]~, 100%) (b) 4-EthanesulfonyI-1,2-difluoro-benzene To 3.0 mmol 3,4-difluoro-benzenesulfinic acid and 3.0 mmol triethylamine in 10 ml DMF was added 7.5 mmol iodoethane and the mixture heated at 90 °C for 9 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:7) to afford the title compound. MS (m/e): 206.9 (M+H+, 100%) (c) l-(4-Ethanesulfonyl-2-fluoro-phenyl)-piperazine To 2.0 mmol 4-ethanesulfonyl-l,2-difluoro-benzene in 5 ml N,N-dimethylacetamide was added 5.6 mmol piperazine and the mixture was heated at 80 °C for 45 min. The mixture was then concentrated in vacuo to afford the title compound. MS (m/e): 273.0 (M+H+, 100%) WO 2005/014563 PCT/EP2004/008633 In analogy to Example 6.12 (b) and (c), compounds 6.13, and 6.21 to 6.23 of the following table were prepared from 3,4-difluoro-benzenesulfinic acid and the indicated alkyl halides, followed by reaction with piperazine: Example 6.20 Preparation of l-(4-Cydopropanesulfonyl-2-fluoro-phenyl)-piperazine (a) 4-f3-Chloro-propane-1 -sulfonvl)-1,2-difluoro-benzene To 28.3 mmol 3,4-difluoro-benzenesulfinic acid and 36.8 mmol triethylamine in 100 ml DMF was added 70.7 mmol l-chloro-3-iodopropane and the mixture stirred at RT for 1 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 257.2 ({37C1}M+H+, 33%), 255.1({35C1}M+H+, 100%), fb) 4-CyclopropanesuIfonyl-l,2-difluoro-benzene WO 2005/014563 PCT/EP2004/008633 To 11.8 mmol 4-(3-chloro-propane-l-sulfonyl)-l,2-difluoro-benzene in 400 ml THF at -78 °C was added dropwise over 30 min 14.2 mmol of a 0.9 M solution of potassium bis(trimethylsilyl)amide in THF. The reaction mixture was then allowed to warm to RT and stirring continued for a further 30 min at RT. The mixture was then quenched by addition of 1 M aq HC1 and extracted three times with ethyl acetate. The combined organic phases were dried with Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:5) to afford the title compound. MS (m/e): 219.2 (M+H+, 100%) (c) l-(4-Cvdopropanesulfonvl-2-fluoro-phenvl)-piperazine To 0.2 mmol 4-cyclopropanesulfonyl-l,2-difluoro-benzene in 5 ml N,N-dimethylacetamide was added 0.5 mmol piperazine and the mixture was heated at 80 °C for 90 min. The mixture was then concentrated in vacuo to afford the title compound. MS (m/e): 285.0 (M+H\ 100%) Example 6.24 Preparation of l-(4-cydobutanesulfonyl-2-fluoro-phenyl)-piperazine hydrochloride (a)4-Cyclobutanesulfonyl-l,2-difluoro-benzene To 5.6 mmol 3,4-difluoro-benzenesulfinic acid and 6.2 mmol triethylamine in 10 ml DMF were added 8.4 mmol bromocyclobutane and 0.2 mmol sodium iodide and the mixture heated at 100 °C for 48 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 233.1 (M+H+, 100%) (b) l-(4-Cvclobutanesulfonvl-2-fluoro-phenyl)-piperazine hydrochloride To 2.8 mmol 4-cyclobutanesuIfonyl-l,2-difluoro-benzene in 20 ml N,N-dimethylacetamide was added 8.3 mmol piperazine and the mixture was heated at 80 °C for 45 min. The mixture was then concentrated in vacuo and the residue was chromatographed on silica gel (eluant: ethyl acetate/methanol gradient). The product-containing fractions were combined and concentrated in vacuo. The residue was resuspended in 100 ml dioxane and 6.0 mmol HC1 (as a 4 M solution in dioxane) was added. After stirring for 10 min, the ensuing white crystals were collected by filtration, washing twice with ether, to afford the title compound. WO 2005/014563 PCT/EP2004/008633 MS (m/e): 299.1 (M+H\ 100%) In analogy to Example 6.24 (a) and (b), compound 6.25 of the following table was prepared from the 3,4-difluoro-benzenesulfinic acid, bromocyclobutane and sodium iodide, followed by reaction with piperazine and subsequent treatment with HC1 in dioxane: Example 6.26 Preparation of l-[2-fluoro-4-(3,3,3-trifluoro-propane-l-sulfonyl)-phenyl]”piperazine (a) L2-Difluoro-4-(333-trifluoro-propylsulfanyl)-benzene To 3.4 mmol 3,4-difluoro-thiophenol and 5.1 mmol l-iodo-3,3,3-trifluoropropane in 5 ml acetone was added 3.7 mmol potassium carbonate and the mixture heated at 140 °C for 3 h under microwave irradiation. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in,yacuo to afford the title compound. MS (m/e): 243.1 (M+H\ 100%) (b) L2’Difluoro-4-(3,3,3-trifluoro-propane-l-sulfonyl)-benzene To 3.0 mmol l,2-difluoro-4-(3,3,3-trifluoro-propylsulfanyl)-benzene in 5 ml dichloromethane was added 8.3 mmol m-chloroperbenzoic acid and the mixture heated at 50 °C for 48 h.. The reaction mixture was then cooled to room temperature and diluted with dichloromethane and washed three times with saturated aq NaHCO3 solution. The organic phase was then washed with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 275.1 (M+H+, 100%) WO 2005/014563 PCT/EP2004/008633 To 0.5 mmol l,2-difluoro-4-(3,3,3-trifluoro-propane-l-sulfonyl)-benzene in 5 ml N,N-dimethylacetamide was added 1.5 mmol piperazine and the mixture was heated at 80 °C for 90 min. The mixture was then concentrated in vacuo and the residue was chromatographed on silica gel (eluant: methanol/dichloromethane gradient) to afford the title compound. MS (m/e): 341.2 (M+H\ 100%) In analogy to Example 6.26 (a) to (c), compounds 6.27 and 6.28 of the following table were prepared from 3,4-difluoro-thiophenol and the indicated alkylating agent, followed by oxidation with m-chloroperbenzoic acid and reaction with piperazine: Example 6,29 Preparation of l-[2,3-difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine hydrochloride (a) L23-Trifluoro-4-(propane-2-sulfonvl)-benzene To 20.4 mmol 2,3,4-trifluoro-benzenesulfinic acid (prepared in analogy to example 2.20(a) from 2,3,4-trifluoro-benzenesulfonyl chloride) and 61.2 mmol triethylamine in 20 ml DMF was added 40.8 mmol 2-iodopropane and the mixture stirred at room temperature for 16 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue, was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS (m/e): 239.1 (M+H+, 100%) WO 2005/014563 PCT/EP2004/008633 (b) 4-[23-Difluoro-4-(propane-2-sulfonvl)-phenvll-piperazine-l-carboxylic acid tert- butyl ester To 7.6 mmol l,2,3-trifluoro-4-(propane-2-sulfonyI)-benzene in 20 ml N,N-dimethylacetarnide was added 15.9 mmol tert-butyl-1-piperazine carboxylate and the 5 mixture was heated at 90 °C for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:2) to afford the title compound..MS (m/e): 405.2 (M+H\ 100%) (c) l-[23-Pifluoro-4-(propane’2’Sulfonyl)-phenyn”piperazinehydrochloride To 7.5 mmol 4-[2,3-difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine-l-carboxylic acid tert-butyl ester in 100 ml dioxane was added 30.2 mmol HC1 (as a 4 M solution in dioxane) and the mixture was heated at 80 °C for 1 h. The mixture was then cooled to room temperature and the ensuing white crystals were collected by filtration, washing twice with ether, to afford the title compound. MS (m/e): 305.2 (M+H+, 100%) In analogy to Example 6.29 (a) to (c), compounds 6.30,6.32 and 6.33 of the following table were prepared from the indicated sulfinic acids and alkyl halides, followed by reaction with tert-butyl- 1-piperazine carboxylate and hydrolysis with HC1 in dioxane: WO 2005/014563 PCT/EP2004/008633 Example 6.31 Preparation of l-(4-cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine hydrochloride (a) l-(3-Chloro-propane-l-sulfonvl)-2,3,4-trifluoro-benzene To 30.6 mmol 2,3,4-trifluoro-benzenesulfinic acid (acid (prepared in analogy to example 2.20(a) from 2,3,4-trifluoro-benzenesulfonyl chloride) and 91.8 mmol triethylamine in 20 ml DMF was added 61.2 mmol l-chloro-3-iodopropane and the mixture stirred at room temperature for 1 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS (m/c): 275.2 ({37C1}M+H\ 33%), 273.1({33C1}M+H\ 100%), (b) 1 -Cvclopropanesulfonyl-2,3,4-trifluoro-benzene To 5.9 mmol l-(3’Chloro-propane-l-sulfonyl)-2,3,4-trifluoro-benzene in 200 ml THF at -78 °C was added dropwise over 30 min 7.0 mmol of a 0.9 M solution of potassium bis(trimethylsilyl)amide in THF. The reaction mixture was then allowed to warm to RT and stirring continued for a further 30 min at RT. The mixture was then quenched by addition of 1 M aq HC1 and extracted three times with ethyl acetate. The combined organic phases were dried with Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS (m/c): 237.2 (M+H+, 100%) (c) 4-(4-Cvclopropanesulfonvl’2,3-difluoro-phenyn-piperazine-l-carboxylic acid tert- butvl ester To 4.2 mmol l-cyclopropanesulfonyl-2,3,4-trifluoro-benzene in 20 ml N,N-dimethylacetamide was added 8.9 mmol tert-butyl-1-piperazine carboxylate and the mixture was heated at 90 °C for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: dichloromethane/ethyl acetate gradient) to afford the title compound. MS (m/e): 403.3 (M+H\ 100%) (d) 1 -(4-Cyclopropanesulfonvl-23-difluoro-phenyl)-piperazine hvdrochloride WO 2005/014563 PCT/EP2004/008633 To 3.7 mmol 4-(4-Cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine’l-carboxylic acid tert-butyl ester in 100 ml dioxane was added 14.9 mmol HC1 (as a 4 M solution in dioxane) and the mixture was heated at 80 °C for 1 h. The mixture was then cooled to room temperature and the ensuing white crystals were collected by filtration, washing twice with ether, to afford the title compound. MS (m/e): 303.2 (M+H+, 100%) In analogy to Example 6.31 (a) to (d), compound 6.34 of the following table was prepared from the indicated sulfinic acid and alkyl halide, followed by treatment with potassium bis(trimethylsilyl)amide, reaction with tert-butyl-1-piperazine carboxylate and deprotection with HC1 in dioxane: Example 6.35 Preparation of rac-2-Methyl-l-(4-trifluoromethyl-phenyl)-piperazine hydrochloride (a) rac-3-Methvl-4-(4-trifluoromethyl-phenvl)-piperazine-l-carboxvlic acid tert-butvl ester To l-bromo-4-trifluoromethyl-benzene (1 g), rac-3-Methyl-piperazine-l-carboxylic acid tert-butyl ester (1 g), in toluene (10 mL) was added sodium fert-butylate (0.6 g), 2-(dicyclohexylphosphino)biphenyl (31 mg), and tris(dibenzylideneacetone)Pd-CHCl3 (23 ing). The reaction mixture was then stirred at 80°C overnight. Ethyl acetate was then added to the reaction mixture. Solids were filtered off. The filtrate was then concentrated in vacuo and the residue was purified by column chromatography to yield 0.46 g of the title compound.MS (m/e): 345.2 (M+H\ 100%) (b) rac-2-MethvI-l-(4-trifluoromethyl-phenyl)-piperazinehvdrochloride To 0.58 mmol rac-3-methyl-4-(4-trifluoromethyl-phenyl)-piperazine-l-carboxylic acid tert-butyl ester in 3 ml dioxane was added 8.7 mmol HC1 (as a 4 M solution in dioxane) and the mixture was heated at 90 °C for 3 h. The mixture was then cooled 0 °C and WO 2005/014563 PCT/EP2004/008633 diluted with 10 ml ether. The ensuing white crystals were collected by filtration, washing with ether, and dried in vacuo to afford the title compound. MS (m/e): 245.1 (M+H+, 100%) Example 6.36 Preparation of 5-Acetyl-2-isopropoxy-benzoic acid (a) 5-Acetyl-2-isopropoxy-benzoic acid methyl ester To 25.8 mmol methyl-5-acetyl-2-hydroxybenzoate, 28.3 mmol 2-propanol and 29.6 mmol triphenylphosphine in 100 ml THF was added 28.3 mmol di-tert-butyl azodicarboxylate and the mixture was stirred at RT for 90 min. The mixture was then concentrated in vacuo to afford the title compound. MS (m/e): 237.1 (M+H\ 100%) (b) 5-Acetvl-2-isopropoxy-benzoic acid To 25.8 mmol 5-acetyl-2-isopropoxy-benzoic acid methyl ester in 100 ml THF was added 400 mmol 2 M aq NaOH and the mixture was heated at 80 °C for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 15% aq hydrochloric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether afforded the title compound. MS (m/e): 221.2 ([M-H]\ 100%) In analogy to Example 5 compounds 472 to 619 of the following table were prepared from the acid derivatives and piperazine derivatives: WO 2005/014563 PCT/EP2004/008633 residue purified by chromatography on silica gel (eluant: methanol/dichloromethane 5:95) to afford the title compound.MS (m/e): 435.3 ([M-H]”, 100%) Example 620 Preparation of 4-isopropoxy-3-[4-(4-txifluoromethyl-phenyl)-piperazine-l- carbonyl] -benzoic acid methyl ester To 0.3 mmol 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-l-carbonyl]-benzoic acid in 2 ml DMF was added 0.4 mmol CDI and the mixture heated at 50 °C for 30 min. 5.2 mmol methanol was then added and the mixture was stirred at RT for 16 h. The mixture was then cooled to room temperature, concentrated in vacuo, and the residue chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS (m/e): 451.2 (M+H\ 100%) Example 621 Preparation of 4-isopropoxy-N-methyl-3-[4-(4-trifluoromethyl”phenyl)- piperazine-1 -carbonyl] -benzamide To 0.3 mmol 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-l-carbonyl]-benzoic acid in 2 ml DMF was added 0.4 mmol CDI and the mixture heated at 50 °C for 30 min. 5.2 mmol methylamine (41% aq solution) was then added and the mixture was stirred at RT for 16 h. The mixture was then cooled to room temperature, concentrated in vacuo, and the residue chromatographed on silica gel (eluant: ethyl acetate) to afford the title compound. MS (m/e): 450.1 (M+H+, 100%) Example 6.38 Preparation of 3-[4-(4»Cyano-3-fluoro«phenyI)-piperazine-l-carbonyl]-4-hydroxy- benzenesulfonamide (a) 2-Hvdroxy-5-sulfamoyl-ben2oic acid Ammonia gas was bubbled through a solution of 107 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 250 ml acetone at 0 °C for 2 h. Argon gas was then bubbled through the reaction mixture for 1 h to purge excess ammonia. The mixture was then diluted with water, the pH adjusted to pH 14 by addition of 5 M aq NaOH solution, and the mixture was then extracted with ether/ethyl acetate (1:1). The aqueous phase was acidified with concentrated HC1, saturated with NaCl, and extracted twice with THF. The combined THF extracts were dried with Na2SO4. Evaporation of the solvent in vacuo followed by WO 2005/014563 PCT/EP2004/008633 drying of the residue by heating at 60 °C overnight in vacuo yielded the title compound. MS (m/e): 216.1 ([M-H], 100%) (b) 2-Hvdroxv-5-sulfamovl-benzoic acid methyl ester To 62 mmol 2-hydroxy-5-sulfamoyl-benzoic acid in 80 ml THF was added 80 mmol CDI and the mixture heated at 50 °C for 1 h. 616 mmol methanol was then added and the mixture was heated at 50 °C for 16 h. The mixture was then cooled to room temperature, concentrated in vacuo, and the residue chromatographed on silica gel (eluant: dichloromethane/methanol 20:1). The product containg fractions were concentrated in vacuo and the residue suspended in ethyl acetate and washed with aq NaHCO3 solution. The organic phase was dried dried with Na2SO4 and concentrated in vacuo to afford the title compound. MS (m/e): 230.2 ([M-H]”, 100%) (c) 2-(4-Methoxv-benzyloxy)-5-sulfamovI-benzoic acid methyl ester To 4.8 mmol 2-hydroxy-5-sulfamoyl-benzoic acid methyl ester, 5.2 mmol 4-methoxybenzyl alcohol and 5.2 mmol triphenylphosphine in 8 ml THF was added 5.2 mmol di-tert-butyl azodicarboxylate and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 350.2 ([M-H]”, 100%) (d) 2-(4-Methoxv-benzvIoxy)-5-sulfamovl-benzoic acid To 2.5 mmol 2-(4-methoxy-benzyloxy)-5-sulfamoyl-benzoic acid methyl ester in 6 ml THF was added 5 mmol 2 M aq NaOH and the mixture was heated at 60 °C for 30 min. The mixture was then cooled to RT and extracted twice with ethyl acetate. The aqueous phase was acidified to pH 1 with 5 M aq HC1 and extracted with ethyl acetate. The combined organic phases were washed with saturated aq NaCl and dried with Na2SO4. Evaporation in vacuo afforded the title compound. MS (m/e): 336.1 ([M-H]”, 100%) (e) (3-f4-(4-Cvano-3-fluoro-phenvl)-piperazine-l-carbonyl]-4-(4-methoxy-benzvloxv)- benzenesulfonamide To a solution of 3.5 mmol 2-(4-methoxy-benzyloxy)-5-sulfamoyl-benzoic acid in 4 ml dimethylformamide and 12 ml THF were added 5.3 mmol TBTU, 17.5 mmol N-ethyldiisopropylamine and 3.5 mmol 3-fluoro-4-piperazin-l-yl-benzonitrile (WO9625414). The reaction was then stirred at RT for 1 h, concentrated in vacuo, and WO 2005/014563 PCT/EP2004/008633 Example 7.1: Preparation of 3-Piperazin- l-yl-5-trifluoromethyl-pyridazine (a)-3-Chloro-5-trifluoromethvl-pvridazine 5-Trifluoromethyl-pyridazin-3-ol [244268-34-6 (lg) was added to a stirred solution of phosphoryloxychloride and the reaction mixture was stirred at 80°C for 1 hour. After such time, the reaction mixture was allowed to cool to room temperature, poured onto ice and after 5 minutes was extracted twice from the aqueous solution with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The residue was distilled in a Kugelrohr apparatus (bp = 80-100°C @ 12 mBar) to yield the title compound (0.26g). MS (m/e): 182.0 (b) 4-(5-Trifluoromethvl-pvridazin-3-yl)-piperazine-l-carboxvlic acid tert-butvl ester 3-Chloro-5-trifluoromethyl-pyridazine (200mg) was added to piperazine-1-carboxylic acid tert-butyl ester (231mg) in dimethylacetamide (3mL) and the reaction mixture was stirred at 100°C for 3 hours. After such time the reaction mixture was allowed to cool down to room temperature and diluted with ethyl acetate. The solid was filtered off and washed with ethyl acetate. The filtrate was then concentrated in vacuo and then purified by column chrornatography (SiO2, Heptane/EtOAc) to yield the title compound as a white solid (364mg). MS (m/e): 333.4 (M+H+, 100%) (c) 3-Piperazin-l-Yl-5-trifluoromethyl-pyridazine 4-(5-Trifluoromethyl-pyridazin-3-yl)-piperazine-l-carboxylic acid tert-butyl ester (45mg) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid was added (0.5 mL). The reaction mixture was stirred for 30 minutes before being concentrated in vacuo to afford the crude title compound which was used directly in the next step without further purification or analysis. Example 7.2: Preparation of 5-Methanesulfonyl-2-(2,2,2-trifluoro-l,l-dimethyl-ethoxy)-benzoic acid To 2-Fluoro-5-methanesulfonyl-benzoic acid (247569-56-8) (600 mg) in dimethylacetamide (10 mL) was added cesium carbonate at 170°C. 2-trifluoromethyl-propanol (0.94 mL) was first added to the reaction mixture followed by additionally 0.47 mL every 24 hours. After a total of 72 hours, the reaction mixture was acidified by WO 2005/014563 PCT/EP2004/008633 addition of formic acid, concentrated in vacuo and purified by preparative HPLC to yield the title compound as a light brown solid (897 mg). MS (m/e): 325.3. (M-H, 100%) Example 7.3: Preparation of 5-Methanesulfonyl-2-piperazin- 1-yl-pyrimidine (a) 3-DimethvIamino-2-methanesulfonyl-alIvlidene-dimethvl’ammonium; chloride To sulfonyl-acetic acid (L5g) in dimethylformamide was slowly added phosphorus oxychloride over 5 minutes and the reaction was then stirred at 70°C for 1 hour and then at room temperature overnight. The reaction mixture was then directly poured over a short column chromatography (SiO2,100 g) eluting successively with 500 mL of EtOAc, THF, EtOAc/EtOH (50/50), EtOH and finally MeOH to yield the title compound (1.58g). MS (m/e): 204.9 (M+). (b) 5-Methanesulfonvl-2-piperazin-l-vl-pvrimidine The title compound was prepared in analogy to Example 2.25 using 3-Dimethylamino-2-methanesulfonyl-allylidene-dimethyl-ammonium; chloride as starting material. MS (m/e): 243.1 (M+H\ 100%). Example 7.4: Preparation of l-(5-Methanesulfonyl-pyridin-2-yl)-piperazine trifluoro-acetic acid The title compound was prepared in analogy to Example 7.1 (b-c) from 2-bromo-5-(methanesulfonyl) pyridine and piperazine-1-carboxylic acid fert-butyl ester. MS (m/e): 242.1 (M+H+, 100%) In analogy to Example 5, compounds 633 to 644 of the following table were prepared from the acid derivatives and piperazine derivatives: WO 2005/014563 PCT/EP2004/008633 Example 646 Preparation of (2-Benzyloxy-5-methanesulfonyl-phenyl)- [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1 -yl] -methanone The title compound was prepared in analogy to example 5 from l-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazine (compound 5.5) and 2-Benzyloxy-5-methanesulfonyl-benzoic acid (compound 7.5). MS (m/e): 538.4 (MH+, 100%) Example 647 Preparation of (2-Benzyloxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1 -yl] -methanone The title compound was prepared in analogy to example 5 from l-(2-Fluoro-4-methanesulfonyl-pheny l)-piperazine (commercial) and 2-Benzyloxy-5-methanesulfonyl-benzoic acid (compound 7.5). MS (m/e): 547.4 (MH+, 100%) Example 648 Preparation of [4-(2-Fluoro-4-methanesulfonyl-phenyl)-piperazin-l-yl]-(2-hydroxy-5-methanesulfonyl-phenyl)-methanone A mixture of 0.915 mmol (2-benzyloxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-l-yl]-methanone,0.05 mmol palladium on charcoal (10%) in 12.5 ml methanol was hydrogenated at atmospheric pressure at room temperature for 2 hours. After addition of chloroform, the mixture was filtered and the solvent was evaporated to provide the title compound. MS (m/e): 474.3 (M+NH4+, 100%) Example 7.6 Preparation of 5-Piperazin-l-yl-2-trifluoromethyl-pyrimidine (a) 5-Chloro-2-trifluoromethyI-pyrimidine To a solution of 38 mmol trifluoroacetamidine in 70 ml acetonitrile was added 37.92 mmol ((Z)-2-Chloro-3-dimethylamino-allylidene)-dimethyI-ammonium hexafluoro phosphate (CAS: 291756-76-8) followed by 45.5 mmol triethylamine. The yellow solution was stirred at room temperature for 5 hours, then poured onto water and extracted 3 times with ether. The combined extracts were dried over sodium sulfate, WO 2005/014563 PCT/EP2004/008633 filtered and distilled at 760 mm Hg to provide the title compound. MS (m/e): 182.2 (M+, 100%) (b) 4-(2-Trifluoromethvl-pvrimidin-5’yl)-pipera2ine-l-carboxvlic acid tert-butyl ester 0.26 mmol 5-CWoro-2-trifluoromethyl-pyrimidine was added to 0.26 mmol piperazine-1-carboxylic acid tert-butyl ester in 1.5 ml dimethylacetamide and the reaction mixture was stirred at 150°C for 10 min. in a microwave oven. After such time the reaction mixture was concentrated and the residue was then purified by column chromatography (SiO2, Heptane/EtOAc) to yield the title compound. MS (m/e): 333.2 (M+H\ 100%) (c) 5-Piperazin-1 -yI-2-trifluoromethvl-pvrimidine The title compound was prepared in analogy to Example 7.1 (c) from 4-(2-trifluoromethyl-pyrimidin-5-yl)-piperazine-l-carboxylic acid tert-butyl ester MS (m/e): 233.0 (M+H\ 100%) Example 7.7 Preparation of S’-Tri (a) 2-Bromo-5-trifluoromethvl-pvrazine To a suspension of 0.423 mmol copper (II) bromide in THF (1 ml) was added dropwise 0.51 mmol tert-butylnitrite at 0°C within 2 minutes. 0.37 mmol 5-Trifluoromethyl-pyrazin-2-ylamine (CAS: 69816-38-2; WO9518097) in solution in THF (0.5 ml) was added dropwise within 5 minutes at 0°C. The mixture was stirred at 0°C for 1 hour, at room temperature for 21 hours and quenched with water. The aqueous phase was extracted with ether. The combined extracts were dried over sodium sulfate and filtered and concentrated at atmospheric pressure. The residue was then purified by column chromatography (SiO2 ether) to yield the title compound. The title compound was prepared in analogy to Example 7.6 (b-c) from 2-Bromo-5-trifluoromethyl-pyrazine MS (m/e): 233.0 (M+H+, 100%) Example 7,8 Preparation of 3-Piperazin-1 -yl-6-trifluoromethyl-pyridazine The title compound was prepared in analogy to Example 7.6 (b-c) from 3-Chloro-6-trifluoromethyl-pyridazine (CAS: 258506-68-2). MS (m/e): 233.0 (M+H+, 100%) WO 2005/014563 PCT/EP2004/008633 The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are good inhibitors of the glycine transporter I (GlyT-1). The compounds were investigated in accordance with the test given hereinafter. Solutions and materials DMEM complete medium: Nutrient mixture F-12 (Gibco Life-technologies), fetal bovine serum (FBS) 5 %, (Gibco life technologies), Penicillin/Streptomycin 1 % (Gibco life technologies), Hygromycin 0.6 mg/ml (Gibco life technologies), Glutamine 1 mM Gibco life technologies) The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions. The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose,corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers. The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of schizophrenia, cognitive impairment and Alzheimer’s disease. The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated. Manufacturing Procedure 1. Mix items 1, 2,3 and 4 and granulate with purified water. 2. Dry the granules at 50°C 3. Pass the granules through suitable milling equipment. 4. Add item 5 and mix for three minutes; compress on a suitable press. Manufacturing Procedure 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add items 4 and 5 and mix for 3 minutes. 3. Fill into a suitable capsule.

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