# Patent

## Title
Benzoyl-piperazine derivatives

## Abstract

The invention relates to compounds of formula




wherein the substituents are described herein. 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.

## Background
FIELD OF THE INVENTION
The present invention relates to the treatment of CNS disorders such as schizophrenia and Alzheimer's disease. More particularly, the invention relates to inhibition of GlyT-1.
BACKGROUND OF THE INVENTION
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 D A and Lieberman J A, 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 R J and Aubrey K R., Exp. Opin. Ther. Targets, 5(4): 507-518, 2001; 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 predictors 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 D C 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 A R et al., Cell, 98: 427-236, 1999).
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, N Y; Bliss T V and Collingridge G L, Nature, 361: 31-39, 1993). Transgenic mice over expressing the NMDA NR2B subunit exhibit enhanced synaptic plasticity and superior ability in learning and memory (Tang J P et al., Nature, 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 R R 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 (1a, 1b, 1c and 1d). Only two of these isoforms have been found in rodent brain (GlyT-1a and GlyT-1b). 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., J. 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 R E and Miller D J, 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 E T et al., Prog. Neurobiol., 67: 173-202, 2002), autistic disorders (Carlsson M L, J. 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 R E and Miller D J, 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.
SUMMARY OF THE INVENTION
The present invention provides compounds of formula I per se, and pharmaceutically acceptable salts thereof. The invention also provides compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof. The invention further provides treatments for diseases related to activation of NMDA receptors via Glyt-1 inhibition, which comprises administering a therapeutically effective amount of a compound of the invention. For example, the invention provides for 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 invention further provides processes for manufacturing compounds of the invention and compositions containing them. In one aspect, the present invention relates to compounds of the general formula I




wherein

    Ar is unsubstituted or substituted aryl or 6-membered heteroaryl containing one, two or three nitrogen atoms, and wherein the substituted aryl and the substituted heteroaryl groups are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9, SO2R10, and —C(CH3)═NOR7, or are substituted by a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, which is optionally substituted by (C1-C6)-alkyl;
    R1 is hydrogen or (C1-C6)-alkyl;
    R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or by halogen, CH(CH3)—(C3-C7)-cycloalkyl, (CH2)n+1—C(O)—R9, (CH2)n+1—CN, bicyclo[2.2.1]heptyl, (CH2)n+1—O—(C1-C6)-alkyl, (CH2)n-heterocycloalkyl, (CH2)n-aryl or (CH2)n-5 or 6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
    R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O—(C3-C6)-cycloalkyl;
    R5 is NO2, CN, C(O)R9 or SO2R10;
    R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
    R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR7R8;
    R10 is (C1-C6)-alkyl optionally substituted by halogen, (CH2)n—(C3-C6)-cycloalkyl, (CH2)n—(C3-C6)-alkoxy, (CH2)n-heterocycloalkyl or NR7R8;
    
        n is 0, 1, or 2;
    
    


or a pharmaceutically acceptable acid addition salt thereof, with the proviso that

    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,
    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine,
    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine,
    4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine,
    1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine,
    4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine,
    1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine,
    1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine,
    1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine and
    4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine are excluded.


The compounds 1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine, 1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine and 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.


DETAILED DESCRIPTION OF THE INVENTION
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 “alkoxy” denotes a group wherein the alkyl residues is as defined above, and which is attached via an oxygen atom.
The term “cycloalkyl” denotes a saturated carbocyclic group containing 3-7 carbon atoms.
The term “alkenyl” denotes an unsaturated straight- or branched alkyl chain containing from 2 to 6 carbon atoms and having one or more double bonds, for example methylene, ethylene, propylene, isopropylene, and the like.
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 carbocyclic radical, for example pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or 1,3,5-triazinyl.
The term “heterocycloalkyl” denotes a non aromatic hydrocarbon radical, for example oxetanyl, tetrahydrofuranyl, 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 “alkyl, substituted by halogen” denotes for example the following groups: CF3, CHF2, CH2F, CH2CF3, CH2CHF2, CH2CH2F, CH2CH2CF3, CH2CH2CH2CF3, CH2CH2Cl, CH2CF2CF3, CH2CF2CHF2, CF2CHFCF3, C(CH3)2CF3, CH(CH3)CF3 or CH(CH2F)CH2F.
The term “alkyl, substituted by hydroxy” denotes for example the following groups: CH(OH)CH3, CH2CH(OH)CH3, CH2CH(CH3)CH2OH, (CH2)2OH, (CH2)3OH or CH2C[(CH3)]2—CH2OH.
The term “pharmaceutically acceptable acid addition salt” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric 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.
“Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
The term “therapeutically effective amount” denotes an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
In one embodiment, the invention provides compounds of the general formula




wherein

    Ar is substituted aryl or unsubstituted or substituted 6-membered heteroaryl containing one, two or three nitrogen atoms, and wherein the substituted aryl and the substituted heteroaryl groups are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9 and SO2R10;
    R1 is hydrogen or (C1-C6)-alkyl;
    R2 is (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C3-C6)-cycloalkyl, heterocycloalkyl, (C1-C6)-alkyl-(C3-C6)-cycloalkyl, (C1-C6)-alkyl-heterocycloalkyl, (C1-C6)-alkyl-C(O)—R9, (C1-C6)-alkyl-CN, (C2-C6)-alkyl-O—R13, (C2-C6)-alkyl-NR7R8, aryl, 6-membered heteroaryl containing one, two or three nitrogen atoms, (C1-C6)-alkyl-aryl, or (C1-C6)-alkyl-5 or -6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
    R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, CN, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR7R8;
    R5 is NO2, CN, C(O)R9, SO2R10 or NR11R12;
    R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
    R9 is hydroxy, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy or NR7R8;
    R10 is (C1-C6)-alkyl, (C3-C6)-cycloalkyl or NR7R8;
    R11 and R12 are each independently hydrogen, C(O)—(C1-C6)-alkyl, or SO2—(C1-C6)-alkyl, or form together with the N-atom to which they are attached a 5-membered heteroaryl group, optionally substituted by halogen, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen or (C3-C6)-cycloalkyl;
    R13 is hydroxy, (C1-C6)-alkyl or (C3-C6)-cycloalkyl;

or a pharmaceutically acceptable acid addition salt thereof, with the proviso that

    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,
    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine,
    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine,
    4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine,
    1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine,
    4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine,
    1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine,
    1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine,
    1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine and
    4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine are excluded.


In another embodiment, the present invention provides compounds of formula Ia




wherein

    R is hydrogen or halogen;
    R′ is hydrogen or halogen;
    R′′ is CN, C(O)—(C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen or S(O)2—(C1-C6)-alkyl;
    R′′′ is hydrogen;
    R5 is S(O)2—(C1-C6)-alkyl, S(O)2NH2 or NO2; and
    R2 is (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C6)-alkyl-(C3-C6)-cycloalkyl, (C1-C6)-alkyl substituted by halogen, —(CH2)2O—(C1-C6)-alkyl, benzyl or aryl, optionally substituted by halogen;

or a pharmaceutically acceptable acid addition salt thereof, with the exception of 1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine and 1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine.



A further embodiment of the invention provides those compounds of formula Ia, wherein

    R is hydrogen or fluoro;
    R′ is hydrogen or fluoro;
    R′′ is CN, C(O)CH3, CF3 or S(O)2—CH3;
    R′′′ is hydrogen;
    R5 is S(O)2—CH3, S(O)2NH2 or NO2; and
    R2 is (C1-C6)-alkyl, —CH2-cyclopropyl, cyclopentyl, —CH2—CF3, —(CH2)2—O—CH3, or is benzyl or phenyl substituted by fluoro.


Examples of such compounds are 2-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,

    [4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,
    1-{3-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone,
    4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    3-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    2-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    (2-isobutoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone and
    [4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone.


A further embodiment of the present invention provides compounds, wherein R5 is S(O)2—CH3 and R2 is CH2-cyclopropyl. An example of such compound is 4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile.
Compounds of formula Ia are further those, wherein R5 is S(O)2—CH3 and R2 is CH2CF3, for example the following compounds:

    [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-methanone and
    [4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-methanone.


Compounds of formula Ia are further those, wherein R5 is S(O)2—CH3 and R2 is cyclopentyl, for example the following compounds:

    4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile and
    4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-benzonitrile.


Preferred compounds of formula I of the present invention are those, wherein Ar is substituted phenyl, R2 is (C1-C6)-alkyl and R5 is S(O)2CH3 or S(O)2CH2CH3.
The following specific compounds relate to this group:

    1-{3-fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone,
    3-fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    2-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,
    1-{3-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone,
    4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    3-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    2-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    (2-isobutoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone,
    [4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone,
    [4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone,
    [4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,
    2,3-difluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    2,3-difluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    2,5-difluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    2,6-difluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    3,5-difluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    4-[4-(2-tert-butoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,3-difluoro-benzonitrile,
    5-chloro-2-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    4-[4-(2-tert-butoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,5-difluoro-benzonitrile,
    4-[4-(2-tert-butoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,
    (2-tert-butoxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-tert-butoxy-5-methanesulfonyl-phenyl)-[4-(2,5-difluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone,
    1-(4-{4-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoyl]-piperazin-1-yl}-3-fluoro-phenyl)-ethanone,
    4-{4-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoyl]-piperazin-1-yl}-benzonitrile,
    4-{4-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoyl]-piperazin-1-yl}-3-fluoro-benzonitrile,
    4-{4-[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoyl]-piperazin-1-yl}-2-fluoro-benzonitrile,
    [2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    [2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    [2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    [2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-[4-(2-fluoro-4-ethanesulfonyl-phenyl)-piperazin-1-yl]-methanone,
    rac-1-{4-[4-(2-sec-butoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone,
    rac-4-[4-(2-sec-butoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,
    rac-4-[4-(2-sec-butoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-benzonitrile,
    rac-(2-sec-butoxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    rac-(2-sec-butoxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethanesulfonyl-phenyl)-piperazin-1-yl]-methanone,
    (2-isobutoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethanesulfonyl-phenyl)-piperazin-1-yl]-methanone,
    2-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-5-trifluoromethyl-benzonitrile,
    1-{2-fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone,
    [4-(3-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone,
    1-{2-fluoro-4-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone,
    2-[4-(2-isobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-5-trifluoromethyl-benzonitrile,
    (5-ethanesulfonyl-2-isopropoxy-phenyl)-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    [4-(4-difluoromethyl-2-fluoro-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,
    [4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,
    3-fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzaldehyde,
    [4-(4-ethanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone,
    rac-(2-sec-butoxy-5-methanesulfonyl-phenyl)-[4-(4-ethanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone,
    [4-(4-cyclobutanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,
    [4-(4-cyclopentanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone,
    [4-(4-cyclopropanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanone and
    [4-(4-cyclopropanesulfonyl-2,5-difluoro-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone.


A further preferred group of compounds of formula I are those, wherein Ar is substituted phenyl, R2 is (CH2)n—(C3-C7)-cycloalkyl and R5 is S(O)2CH3, for example the following compounds

    1-{4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone,
    4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,
    4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-benzonitrile,
    (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    1-{4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone,
    4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,
    4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-benzonitrile,
    (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    Rac-[2-(1-cyclopropyl-ethoxy)-5-methanesulfonyl-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,3-difluoro-benzonitrile,
    4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,5-difluoro-benzonitrile,
    4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-benzonitrile,
    4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,
    (2-cyclobutylmethoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    1-{4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone,
    2-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-5-trifluoromethyl-benzonitrile,
    4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,3-difluoro-benzonitrile,
    4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,5-difluoro-benzonitrile,
    4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3,5-difluoro-benzonitrile,
    4-[4-(2-cyclobutylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,6-difluoro-benzonitrile,
    4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl-3,5-difluoro-benzonitrile,
    4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3,5-difluoro-benzonitrile,
    4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,6-difluoro-benzonitrile,
    4-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2,6-difluoro-benzonitrile,
    5-chloro-2-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    4-[4-(2-cyclohexyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile,
    4-[4-(2-cyclohexyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,
    4-[4-(2-cyclohexyloxy-5methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-benzonitrile,
    (2-cyclohexyloxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclohexyloxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclohexyloxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone,
    1-{4-[4-(2-cyclobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone,
    4-[4-(2-cyclobutoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-3-fluoro-benzonitrile,
    (2-cyclobutoxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethanesulfonyl-phenyl)-piperazin-1-yl]-methanone,
    1-{4-[4-(2-cyclopropylmethoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-2-fluoro-phenyl}-ethanone,
    2-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-5-trifluoromethyl-benzonitrile,
    (2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[4-(4-ethanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(4-ethanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclohexyloxy-5-methanesulfonyl-phenyl)-[4-(4-ethanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(4-cyclopropanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclohexyloxy-5-methanesulfonyl-phenyl)-[4-(4-cyclopropanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclobutoxy-5-methanesulfonyl-phenyl)-[4-(4-cyclopropanesulfonyl-2-fluoro-phenyl)-piperazin-1-yl]-methanone


Preferred are further compounds, wherein Ar is substituted phenyl, R2 is (C1-C6)-alkyl substituted by halogen and R5 is S(O)2CH3. The following compounds relate to this group:

    1-(3-fluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-benzoyl]-piperazin-1-yl}-phenyl)-ethanone,
    3-fluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-tri-fluoro-ethoxy)-phenyl]-methanone,
    [4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-tri-fluoro-ethoxy)-phenyl]-methanone,
    [4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-methanone,
    3-fluoro-4-{4-[5-methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    [4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-phenyl]-methanone,
    [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-phenyl]-methanone,
    1-(3-fluoro-4-{4-[5-methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoyl]-piperazin -1-yl}-phenyl)-ethanone,
    2,5-difluoro-4-[4-(5-methanesulfonyl-2-trifluoromethoxy-benzoyl)-piperazin-1-yl]-benzonitrile,
    2,3-difluoro-4-{4-[2-(2-fluoro-1-fluoromethyl-ethoxy)-5-methanesulfonyl-benzoyl]-piperazin-1-yl}-benzonitrile,
    2-fluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    [5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    2,3-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    3,5-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    2-{4-[2-(2-fluoro-1-fluoromethyl-ethoxy)-5-methanesulfonyl-benzoyl]-piperazin-1-yl}-5-trifluoromethyl-benzonitrile,
    rac-2,3-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    2-Fluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    3-fluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    [5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-phenyl]-methanone,
    2,3-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    3,5-Difluoro-4-{4-[5-methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    [4-(3,4-dichloro-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-methanone,
    rac-5-chloro-2-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    rac-3,5-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    rac-2,5-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    rac-2,6-difluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    rac-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    rac-3-fluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    rac-2-fluoro-4-{4-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoyl]-piperazin-1-yl}-benzonitrile,
    rac-5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    rac-[4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,
    rac-[4-(3-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,
    [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S or R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,
    [5-methanesulfonyl-2-((S or R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone and
    [5-methanesulfonyl-2-((R or S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone.


Preferred compounds of formula I of the present invention are further those wherein Ar is substituted phenyl, R2 is (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, CH2)n—(C3-C7)-cycloalkyl, bicycle[2.2.1]heptyl, (CH2)n—O—(C1-C6)-alkyl or CH2)n-heterocycloalkyl, and R5 is NO2. Examples of such compounds include:

    1-(3-fluoro-4-{4-[2-(2-methoxy-ethoxy)-5-nitro-benzoyl]-piperazin-1-yl}-phenyl)-ethanone,
    (2-isopropoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclopropylmethoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclobutylmethoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-butoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    [2-(2,2-dimethyl-propoxy)-5-nitro-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-isobutoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclopentyloxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (5-nitro-2-propoxy-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    (2-cyclobutoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    Rac-(2-sec-butoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    [5-nitro-2-(2,2,3,3-tetrafluoro-propoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    [5-nitro-2-(2,2,2-trifluoro-ethoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    [2-(bicyclo[2.2.1]hept-2-yloxy)-5-nitro-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone,
    [2-(2-chloro-ethoxy)-5-nitro-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone, and
    [5-nitro-2-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone.


Further preferred are compounds wherein Ar is substituted phenyl, R2 is (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen or (CH2)n—(C3-C7)-cycloalkyl and R5 is S(O)2NHCH3. Examples of such compounds include

    3-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-N-methyl-4-trifluoromethoxy-benzenesulfonamide,
    3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-N-methyl-benzenesulfonamide,
    3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzenesulfonamide,
    3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutoxy-N-methyl-benzenesulfonamide,
    3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutylmethoxy-N-methyl-benzenesulfonamide,
    3-[4-(4-cyano-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-N-methyl-benzenesulfonamide,
    3-[4-(4-cyano-phenyl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzenesulfonamide,
    3-[4-(4-cyano-phenyl)-piperazine-1-carbonyl]-4-cyclobutylmethoxy-N-methyl-benzenesulfonamide,
    3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-N-methyl-benzenesulfonamide,
    3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-(2,2-dimethyl-propoxy)-N-methyl-benzenesulfonamide,
    3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-isopropoxy-N-methyl-benzenesulfonamide,
    3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzenesulfonamide,
    3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutoxy-N-methyl-benzenesulfonamide,
    3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopropylmethoxy-N-methyl-benzenesulfonamide,
    3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutylmethoxy-N-methyl-benzenesulfonamide,
    3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-N-methyl-benzenesulfonamide,
    3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-(2,2-dimethyl-propoxy)-N-methyl-benzenesulfonamide,
    3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopentyloxy-N-methyl-benzenesulfonamide,
    3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclobutoxy-N-methyl-benzenesulfonamide,
    3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-cyclopropylmethoxy-N-methyl-benzenesulfonamide,
    4-isobutoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
    4-(2,2-dimethyl-propoxy)-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
    4-isopropoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
    4-cyclopentyloxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
    4-cyclobutoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
    4-cyclopropylmethoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
    4-cyclobutylmethoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
    N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-4-(3,3,3-trifluoro-propoxy)-benzenesulfonamide,
    3-[4-(4-cyano-2-fluoro-phenyl)-piperazine-1-carbonyl]-N-methyl-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide,
    N-methyl-4-(2,2,2-trifluoro-ethoxy)-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
    rac-N-methyl-4-(2,2,2-trifluoro-1-methyl-ethoxy)-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide,
    rac-3-[4-(4-cyano-2,5-difluoro-phenyl)-piperazine-1-carbonyl]-N-methyl-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonamide, and
    rac-3-[4-(4-cyano-2,3-difluoro-phenyl)-piperazine-1-carbonyl]-N-methyl-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonamide.


A further preferred group of compounds of formula I are those wherein Ar is a substituted 6-membered heteroaryl group containing one, two or three nitrogen atoms, R2 is (C1-C6)-alkyl or CH2)n—(C3-C7)-cycloalkyl, and R5 is SO2CH3. Examples of the compounds include:

    [4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-methanone,
    6-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-nicotinonitrile,
    (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,
    [4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanone,
    (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(6-trifluoromethyl-pyridin-3-yl)-piperazin-1-yl]-methanone,
    [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone, and
    (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone.


Further preferred are compounds of formula I, wherein Ar is a substituted 6-membered heteroaryl group containing one, two or three nitrogen atoms, R2 is (C1-C6)-alkyl substituted by halogen and R5 is SO2CH3. Examples of these compounds include:

    rac-[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,
    rac-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,
    rac-[4-(5-bromo-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,
    rac-[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,
    rac-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(6-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,
    [5-methanesulfonyl-2-((S or R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,
    [5-methanesulfonyl-2-((R or S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,
    [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone, and
    [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-phenyl]-methanone.


The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below. One such process comprises

    a) reacting a compound of formula






with a compound of formula





in the presence of an activating agent, such as TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate), to produce a compound of formula





wherein the substituents are as defined above, or

    b) reacting a compound of formula






with a compound of formula

R2OH

optionally in the presence of a catalyst, such as Cu(I)I, and a base, like potassium carbonate, cesium carbonate or sodium, to produce a compound of formula





wherein X is halogen and the other substituents are as defined above, or

    c) reacting a compound of formula






with a compound of formula

R2X

in the presence of a base and optionally in the presence of microwaves to produce 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 presence of a phosphine to produce a compound of formula





wherein the substituents are as defined above, or

    e) reacting a compound of formula






with a compound of formula

ArX

to produce a compound of formula





wherein X is halogen and the other substituents are as defined above, or

    f) reacting a compound of formula






with a corresponding amine or alcohol in the presence of an activating agent to produce a compound of formula





wherein R9 is (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy or NR7R8; and the other substituents are as defined above, or

    g) reacting a compound of formula






with a compound of formula RONH2 to produce a compound of formula





wherein R is H or alkyl and the other substituents are as defined above, or

    h) reacting a compound of formula






with a reducing agent, like sodium borohydride (when R is H), or an alkylating agent, like alkyllithium (when R is alkyl), to produce a compound of formula





wherein R is H or alkyl and the other substituents are as defined above, and if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

The compounds of formula I may be prepared in accordance with process variant a) to h) and with the following schemes 1 to 8. The starting materials are commercially available or maybe prepared in accordance with known methods.




Compounds of general formula I can be prepared by reacting piperazine derivatives of formula II with a corresponding acid of formula III in the presence of an activating agent like TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate). The acid of formula III can be prepared by reaction of an acid of formula IV with an alcohol of formula R2OH, optionally in the presence of a copper salt like Cu(I)Br. Piperazine derivatives of formula II can be prepared by heating of the corresponding piperazine with ArX or by reacting of a N-protected piperazine with ArX in the presence of palladium catalyst followed by cleavage of the protective group. The protective group is typically tert-butoxycarbonyl (Boc).




Alternatively, compounds of general formula I can be prepared by reaction of an acyl-piperazine of formula V and an alcohol of formula R2OH, optionally in the presence of a copper salt like Cu(I)I. Acylpiperazine derivatives of formula V can be prepared by reaction of an acid of formula IV with piperazine derivatives of formula II in the presence of an activating agent like TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate).




Compounds of general formula I can be prepared by reacting a compound of formula VI with an electrophile of formula R2X in the presence of base like potassium carbonate and optionally in the presence of microwaves, wherein X is halogen, mesylate or triflate.




Compounds of general formula I can be prepared by reacting phenol of formula VI with an alcohol of formula R2OH under Mitsunobu conditions, in the presence of a phosphine, like triphenylphosphine or diphenyl-2-pyridylphosphine, and a dialkylazadicarboxylate, like diethylazadicarboxylate or di-tert-butyl azodicarboxylate.
The compound of formula VI can be prepared by deprotection (for example using hydrogen) of a phenol protected as a benzyl ether (I with R2: benzyl).
Alternatively, a compound of formula VI can be prepared by reacting piperazine derivatives of formula II with an acid of formula VII in the presence of an activating agent like TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate).




Compounds of general formula I can be prepared by reacting a piperazine of formula VIII with ArX.




wherein R9 is (C1-C6)-alkoxy or NR7R8;

Compounds of general formula Ib wherein R9 is as defined above can be prepared by reacting an acid of formula Ia with a corresponding amine or alcohol in the presence of an activating agent like carbonyldimidazole.




Compounds of general formula Id can be prepared in accordance with scheme 7 by reacting a compound of formula Ic bearing a carbonyl group, with a compound of formula RONH2, wherein R is H or alkyl and R9 is (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy or NR7R8.




Compounds of general formula Ie wherein R is H or alkyd and R9 is (C1-C6)-alkyl or (C3-C6)-cycloalkyl can be prepared by reacting a compound of formula Ic bearing a carbonyl group, with a reducing agent like sodium borohydride (when R is H) or an alkylating agent like alkyllithium (when R is alkyl).
Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC.
The acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
The following 660 examples illustrate the present invention without limiting it. All temperatures are given in degree Celsius.
The following abbreviations were used in the examples:

    RT: room temperature;
    n-Boc-piperazine: tert-Butyl 1-piperazinecarboxylate,
    oxone®: (potassium peroxymonosulfate) 2KHSO5.KHSO4.K2SO4,
    EtOAc: ethyl acetate;
    THF: tetrahydrofuran;
    TBTU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate;
    DIPEA: diisopropylethylamine,
    DMF: N,N-dimetyhylformamide


EXAMPLE 1.1 
Preparation of 1-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine
(a) 4-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
A mixture of 20 mmol 1-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) 1-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine
A mixture of 9 mmol 4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in 20 ml dioxane was treated with 8.93 ml 4N HCl 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. AU aqueous phases were combined and extracted with 50 ml EtOAc. The combined organic phases were dried with MgSO4 and evaporated to yield the title compound 1.1.
1-H-NMR (300 MHz, CDCl3) δ=7.50 (d, J=13.3 Hz, 1H, H-3), 7.45 (d, J=8.8 Hz, 1H, H-5), 7.16 (dd, J1=8.8 Hz, J2=8.8 Hz, 1H, H-6), 3.5-3.2 (s, br, 1H, NH), 3.04 (m, 4H, piperazine), 2.87 (m, 4H, piperazine).
MS (m/e): 249.2 (MH+, 100%)
EXAMPLE 1.2 
Preparation of 2-isopropoxy-5-methanesulfonyl-benzoic acid
(a) 2-Chloro-5-methanesulfonyl-benzoic acid
To 99 mmol 2-chloro-5-(methylthio) 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× with 400 ml ethyl acetate, and the combined organic phases washed 2× with 300 ml 1N HCl and with 300 ml saturated aqueous NaCl solution and dried with MgSO4. Evaporation under reduced pressure yielded the title compound.
(b) 2-Isopropoxy-5-methanesulfonyl-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 volatiles were removed under vacuum, and the residue was taken up in 70 ml 1N HCl. 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 1.2(b) compounds 1.3 to 1.7 of the following table were prepared from 2-chloro-5-methanesulfonyl-benzoic acid and the appropriate alcohol:















Compound Name
Alcohol
MS (m/e)



















1.3
2-isobutoxy-5-methanesulfonyl-
isobutanol
271.1 (MH−,



benzoic acid

100%)


1.4
2-cyclopropylmethoxy-5-methanesulfonyl-
cyclopropyl-methanol
269.1 (MH−,



benzoic acid

100%)


1.5
5-methanesulfonyl-2-(2,2,2-trifluoro-
2,2,2-trifluoro-ethanol
297.0 (MH−,



ethoxy)-benzoic acid

100%)


1.6
2-cyclopentyloxy-5-methanesulfonyl-
cyclopentanol
282.9 (MH−,



benzoic acid

100%)


1.7
2-(4-fluoro-phenoxy)-5-methanesulfonyl-
4-fluoro-phenol
309.1 (MH−,



benzoic acid
(in THF)
100%)









EXAMPLE 1.8 
Preparation of 1-{3-fluoro-4-[4-(2-fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone
A solution of 0.261 mmol 2-fluoro-5-nitro-benzoyl chloride [CAS: 7304-32-7; Feng and Burgess, Chem. Europ. J. EN, 5:3261-3272 (1999)] in 1 ml dioxane was treated with 0.522 mmol triethylamine and then with a solution of 0.261 mmol 1-(3-fluoro-4-piperazin-1-yl-phenyl)-ethanone (CAS: 189763-57-3; WO 97/14,690) in 1 ml dioxane. The mixture was stirred at RT for 30 min. The solvent was removed in vacuo. The crude oil was taken up in water. The aqueous layer was extracted 3 times with CH2Cl2. The combined extracts were dried over Na2SO4, filtered, and the solvent was removed in vacuo. The crude gum was purified on silica gel (eluent: heptane/ethylacetate 0%-20% (10 min) to provide the title compound 1.8.
MS (m/e): 390.2 (MH+, 100%)
EXAMPLE 1.9 
Preparation of (2-iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone
(a) 2-Amino-5-methanesulfonyl-benzoic acid
A mixture of 4.26 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 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 HCl 1N 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 1.7 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° C., 1 hour) to yield the title compound. MS (m/e): 325.0 (M−H, 100%)
(c) (2-iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]methanone
To a solution of 9.2 mmol 2-iodo-5-methanesulfonyl-benzoic acid in 20 ml dimethylformamide 11.5 mmol TBTU, 46.0 mmol N-ethyldiisopropylamine and 11.0 mmol 1-(4-trifluoromethylphenyl)piperazine (ABCR F07741NB, [30459-17-7])were successively added. The reaction was then stirred at RT for two hours, concentrated in vacuo and purified by column chromatography (SiO2, 50 g, CH2Cl2/MeOH/NH3=100/0/0 to 95/4.5/0.5), to give the title compound 1.9. MS (m/e): 539.1 (M+H+)
EXAMPLE 5 
Preparation of [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone
A mixture of 0.05 mmol 2-isopropoxy-5-methanesulfonyl-benzoic acid (Compound 1.2), 0.06 mmol 1-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine, 0.055 mmol TBTU and 0.25 mmol DIPEA in 1 ml DMF was stirred at RT for 16 h. 0.5 ml MeOH/HCOOH 1/1 was added and the mixture was subjected to reversed phase preparative HPLC separation eluting with an acetonitrile/water gradient yielding the title compound. MS (m/e): 489.2 (MH+, 100%)
In analogy to Example 5 compounds 1 to 4, 6 to 46 and 52-54 of the following table were prepared from the acid derivatives and piperazine derivatives:













Expl.


MW found


No.
Systematic Name
Starting materials
(MH+)


















1
1-{3-fluoro-4-[4-(2-isopropoxy-5-
1-(3-fluoro-4-piperazin-1-yl-
463.2



methanesulfonyl-benzoyl)-piperazin-
phenyl)-ethanone and Compound 1.2



1-yl]-phenyl}-ethanone


2
4-[4-(2-isopropoxy-5-methanesulfonyl-
4-piperazin-1-yl-benzonitrile and
428.2



benzoyl)-piperazin-1-yl]-benzonitrile
Compound 1.2


3
3-fluoro-4-[4-(2-isopropoxy-5-
3-fluoro-4-piperazin-1-yl-benzonitrile
446.2



methanesulfonyl-benzoyl)-
and Compound 1.2



piperazin-1-yl]-benzonitrile


4
2-Fluoro-4-[4-(2-isopropoxy-5-
2-fluoro-4-piperazin-1-yl-benzonitrile
446.2



methanesulfonyl-benzoyl)-
and Compound 1.2



piperazin-1-yl]-benzonitrile


5
[4-(2-fluoro-4-trifluoromethyl-
1-(2-fluoro-4-trifluoromethyl-
489.2



phenyl)-piperazin-1-yl]-(2-
phenyl)-piperazine and



isopropoxy-5-methanesulfonyl-
Compound 1.2



phenyl)-methanone


6
[4-(3-fluoro-4-trifluoromethyl-
1-(3-fluoro-4-trifluoromethyl-
489.2



phenyl)-piperazin-1-yl]-(2-iso-
phenyl)-piperazine and



propoxy-5-methanesulfonyl-
Compound 1.2



phenyl)-methanone


7
1-{3-fluoro-4-[4-(2-isobutoxy-5-
1-(3-fluoro-4-piperazin-1-yl-
477.2



methanesulfonyl-benzoyl)-
phenyl)-ethanone and Compound 1.3



piperazin-1-yl]-phenyl}-ethanone


8
4-[4-(2-isobutoxy-5-
4-piperazin-1-yl-benzonitrile and
442.2



methanesulfonyl-benzoyl)-
Compound 1.3



piperazin-1-yl]-benzonitrile


9
3-fluoro-4-[4-(2-isobutoxy-5-
3-fluoro-4-piperazin-1-yl-
460.3



methanesulfonyl-benzoyl)-
benzonitrile and Compound 1.3



piperazin-1-yl]-benzonitrile


10
2-fluoro-4-[4-(2-isobutoxy-5-
2-fluoro-4-piperazin-1-yl-
460.3



methanesulfonyl-benzoyl)-
benzonitrile and Compound 1.3



piperazin-1-yl]-benzonitrile


11
(2-isobutoxy-5-methanesulfonyl-
1-(4-trifluoromethyl-phenyl)-
485.3



phenyl)-[4-(4-trifluoromethyl-phenyl)-
piperazine and Compound 1.3



piperazin-1-yl]-methanone


12
[4-(2-fluoro-4-trifluoromethyl-
1-(2-fluoro-4-trifluoromethyl-
503.2



phenyl)-piperazin-1-yl]-(2-isobutoxy-
phenyl)-piperazine and



5-methanesulfonyl-phenyl)-
Compound 1.3



methanone


13
[4-(3-fluoro-4-trifluoromethyl-
1-(3-fluoro-4-trifluoromethyl-
503.1



phenyl)-piperazin-1-yl]-(2-isobutoxy-
phenyl)-piperazine and



5-methanesulfonyl-phenyl)-
Compound 1.3



methanone


14
[4-(2-fluoro-4-methanesulfonyl-
1-(2-fluoro-4-methanesulfonyl-
513.3



phenyl)-piperazin-1-yl]-(2-isobutoxy-
phenyl)-piperazine and



5-methanesulfonyl-phenyl)-
Compound 1.3



methanone


15
1-{4-[4-(2-cyclopropylmethoxy-5-
1-(3-fluoro-4-piperazin-1-yl-
475.2



methanesulfonyl-benzoyl)-
phenyl)-ethanone and Compound 1.4



piperazin-1-yl]-3-fluoro-phenyl}-



ethanone


16
4-[4-(2-cyclopropylmethoxy-5-
4-piperazin-1-yl-benzonitrile and
440.3



methanesulfonyl-benzoyl)-piperazin-
Compound 1.4



1-yl]-benzonitrile


17
4-[4-(2-cyclopropylmethoxy-5-
3-fluoro-4-piperazin-1-yl-benzonitrile
458.3



methanesulfonyl-benzoyl)-piperazin-
and Compound 1.4



1-yl]-3-fluoro-benzonitrile


18
4-[4-(2-cyclopropylmethoxy-5-
2-fluoro-4-piperazin-1-yl-benzonitrile
458.3



methanesulfonyl-benzoyl)-piperazin-
and Compound 1.4



1-yl]-2-fluoro-benzonitrile


19
(2-cyclopropylmethoxy-5-methanesulfonyl-
1-(4-trifluoromethyl-phenyl)-
483.2



phenyl)-[4-(4-trifluoromethyl-
piperazine and Compound 1.4



phenyl)-piperazin-1-yl]-methanone


20
(2-cyclopropylmethoxy-5-methanesulfonyl-
1-(2-fluoro-4-trifluoromethyl-
501.2



phenyl)-[4-(2-fluoro-4-trifluoromethyl-
phenyl)-piperazine and



phenyl)-piperazin-1-yl]-methanone
Compound 1.4


21
(2-cyclopropylmethoxy-5-methanesulfonyl-
1-(3-fluoro-4-trifluoromethyl-
501.2



phenyl)-[4-(3-fluoro-4-
phenyl)-piperazine and



trifluoromethyl-phenyl)-piperazin-
Compound 1.4



1-yl]-methanone


22
(2-cyclopropylmethoxy-5-methanesulfonyl-
1-(2-fluoro-4-methanesulfonyl-
511.3



phenyl)-[4-(2-fluoro-4-
phenyl)-piperazine and



methanesulfonyl-phenyl)-piperazin-
Compound 1.4



1-yl]-methanone


23
1-(3-fluoro-4-{4-[5-methanesulfonyl-
1-(3-fluoro-4-piperazin-1-yl-
503.1



2-(2,2,2-trifluoro-ethoxy)-
phenyl)-ethanone and Compound 1.5



benzoyl]-piperazin-1-yl}-phenyl)-



ethanone


24
4-{4-[5-methanesulfonyl-2-(2,2,2-
4-piperazin-1-yl-benzonitrile and
468.1



trifluoro-ethoxy)-benzoyl]-
Compound 1.5



piperazin-1-yl}-benzonitrile


25
3-fluoro-4-{4-[5-methanesulfonyl-2-
3-fluoro-4-piperazin-1-yl-benzonitrile
468.2



(2,2,2-trifluoro-ethoxy)-benzoyl]-
and Compound 1.5



piperazin-1-yl}-benzonitrile


26
2-fluoro-4-{4-[5-methanesulfonyl-2-
2-fluoro-4-piperazin-1-yl-benzonitrile
486.2



(2,2,2-trifluoro-ethoxy)-benzoyl]-
and Compound 1.5



piperazin-1-yl}-benzonitrile


27
[5-methanesulfonyl-2-(2,2,2-trifluoro-
1-(4-trifluoromethyl-phenyl)-
511.2



ethoxy)-phenyl]-[4-(4-trifluoromethyl-
piperazine and Compound 1.5



phenyl)-piperazin-1-yl]-methanone


28
[4-(2-fluoro-4-trifluoromethyl-
1-(2-fluoro-4-trifluoromethyl-
529.2



phenyl)-piperazin-1-yl]-[5-
phenyl)-piperazine and



methanesulfonyl-2-(2,2,2-trifluoro-
Compound 1.5



ethoxy)-phenyl]-methanone


29
[4-(3-fluoro-4-trifluoromethyl-
1-(3-fluoro-4-trifluoromethyl-
529.2



phenyl)-piperazin-1-yl]-[5-methanesulfonyl-
phenyl)-piperazine and



2-(2,2,2-trifluoro-
Compound 1.5



ethoxy)-phenyl]-methanone


30
[4-(2-fluoro-4-methanesulfonyl-
1-(2-fluoro-4-methanesulfonyl-
539.2



phenyl)-piperazin-1-yl]-[5-methanesulfonyl-
phenyl)-piperazine and



2-(2,2,2-trifluoro-
Compound 1.5



ethoxy)-phenyl]-methanone


31
1-{4-[4-(2-cyclopentyloxy-5-methanesulfonyl-
1-(3-fluoro-4-piperazin-1-yl-
489.2



benzoyl)-piperazin-1-
phenyl)-ethanone and Compound 1.6



yl]-3-fluoro-phenyl}-ethanone


32
4-[4-(2-cyclopentyloxy-5-methanesulfonyl-
4-piperazin-1-yl-benzonitrile and
454.2



benzoyl)-piperazin-1-yl]-
Compound 1.6



benzonitrile


33
4-[4-(2-cyclopentyloxy-5-methanesulfonyl-
3-fluoro-4-piperazin-1-yl-
472.2



benzoyl)-piperazin-1-yl]-3-
benzonitrile and Compound 1.6



fluoro-benzonitrile


34
4-[4-(2-cyclopentyloxy-5-methanesulfonyl-
2-fluoro-4-piperazin-1-yl-
472.2



benzoyl)-piperazin-1-yl]-2-
benzonitrile and Compound 1.6



fluoro-benzonitrile


35
(2-cyclopentyloxy-5-methanesulfonyl-
1-(2-fluoro-4-trifluoromethyl-
515.2



phenyl)-[4-(2-fluoro-4-trifluoromethyl-
phenyl)-piperazine and



phenyl)-piperazin-1-yl]-methanone
Compound 1.6


36
(2-cyclopentyloxy-5-methanesulfonyl-
1-(3-fluoro-4-trifluoromethyl-
515.2



phenyl)-[4-(3-fluoro-4-
phenyl)-piperazine and



trifluoromethyl-phenyl)-piperazin-
Compound 1.6



1-yl]-methanone


37
(2-cyclopentyloxy-5-methanesulfonyl-
1-(2-fluoro-4-methanesulfonyl-
525.3



phenyl)-[4-(2-fluoro-4-
phenyl)-piperazine and



methanesulfonyl-phenyl)-piperazin-
Compound 1.6



1-yl]-methanone


38
1-(3-fluoro-4-{4-[2-(4-fluoro-phenoxy)-
1-(3-fluoro-4-piperazin-1-yl-
515.2



5-methanesulfonyl-benzoyl]-
phenyl)-ethanone and Compound 1.7



piperazin-1-yl}-phenyl)-ethanone


39
4-{4-[2-(4-fluoro-phenoxy)-5-
4-piperazin-1-yl-benzonitrile and
480.2



methanesulfonyl-benzoyl]-
Compound 1.7



piperazin-1-yl}-benzonitrile


40
3-fluoro-4-{4-[2-(4-fluoro-phenoxy)-
3-fluoro-4-piperazin-1-yl-benzonitrile
498.2



5-methanesulfonyl-benzoyl]-
and Compound 1.7



piperazin-1-yl}-benzonitrile


41
2-fluoro-4-{4-[2-(4-fluoro-phenoxy)-
2-fluoro-4-piperazin-1-yl-benzonitrile
498.2



5-methanesulfonyl-benzoyl]-
and Compound 1.7



piperazin-1-yl}-benzonitrile


42
[2-(4-fluoro-phenoxy)-5-methanesulfonyl-
1-(4-trifluoromethyl-phenyl)-
523.3



phenyl]-[4-(4-trifluoromethyl-
piperazine and Compound 1.7



phenyl)-piperazin-1-yl]-methanone


43
[2-(4-fluoro-phenoxy)-5-methanesulfonyl-
1-(2-fluoro-4-trifluoromethyl-
541.2



phenyl]-[4-(2-fluoro-4-trifluoromethyl-
phenyl)-piperazine and



phenyl)-piperazin-1-yl]-methanone
Compound 1.7


44
[2-(4-fluoro-phenoxy)-5-methanesulfonyl-
1-(3-fluoro-4-trifluoromethyl-
541.2



phenyl]-[4-(3-fluoro-4-
phenyl)-piperazine and



trifluoromethyl-phenyl)-piperazin-
Compound 1.7



1-yl]-methanone


45
[4-(2-fluoro-4-methanesulfonyl-
1-(2-fluoro-4-methanesulfonyl-
551.3



phenyl)-piperazin-1-yl]-[2-(4-
phenyl)-piperazine and



fluoro-phenoxy)-5-methanesulfonyl-
Compound 1.7



phenyl]-methanone


46
[4-(2-fluoro-4-methanesulfonyl-
1-(2-fluoro-4-methanesulfonyl-
499.2



phenyl)-piperazin-1-yl]-(2-
phenyl)-piperazine and



isopropoxy-5-methanesulfonyl-
Compound 1.2



phenyl)-methanone


52
3-[4-(4-acetyl-2-fluoro-phenyl)-
1-(3-Fluoro-4-piperazin-1-yl-
434.2



piperazine-1-carbonyl]-4-methoxy-
phenyl)-ethanone and 2-



benzenesulfonamide
methoxy-5-sulfamoyl-benzoic acid


53
3-[4-(4-acetyl-2-fluoro-phenyl)-
1-(3-Fluoro-4-piperazin-1-yl-
448.2



piperazine-1-carbonyl]-4-ethoxy-
phenyl)-ethanone and 2-Ethoxy-5-



benzenesulfonamide
sulfamoyl-benzoic acid


54
1-(3-Fluoro-4-{4-[2-(2-methoxyethoxy)-
1-(3-Fluoro-4-piperazin-1-yl-
446.1



5-nitro-benzoyl]-piperazin-
phenyl)-ethanone and 2-(2-



1-yl}-phenyl)-ethanone
Methoxyethoxy)-5-nitrobenzoic acid









EXAMPLE 47 
Preparation of 1-{3-fluoro-4-[4-(2-methoxy-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone
To a solution of 0.257 mmol 1-{3-fluoro-4-[4-(2-fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone (Compound 1.8) in 1.5 ml dioxane 102 mg sodium methoxyde was added portionwise. The mixture was stirred at 100° C. for 4 h. The reaction mixture was diluted with 10 ml water, neutralized with 1N HCl and then extracted with ethylacetate (3×10 ml). Combined organic phases were concentrated in vacuo. The residue was chromatographed on silica gel:eluent:heptane/ethylacetate 0%-30% (10 min) to provide compound 47.
MS (m/e): 402.2 (M+H+, 100%).
EXAMPLE 48 
Preparation of (2-benzyloxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone
A mixture of 0.19 mmol (2-iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (Compound 1.9), 0.037 mmol CuI, 0.37 mmol Cs2CO3, 0.074 mmol 1,10-phenanthroline and 0.4 ml benzylic alcohol was heated at 110° C. for 16 hours. The mixture was cooled to RT, diluted with ethylacetate and filtered. The organic layer was washed twice with water, dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified on silica gel, eluent: heptane/ethylacetate 0%-50% (25 min) to provide compound 48.
MS (m/e): 519.2 (M+H+, 100%)
In analogy to Example 48 compounds 49 to 51 of the following table were prepared from (2-iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (Compound 1.9) and alcohols:













Expl.


MW found


No
Systematic Name
Starting materials
(MH+)







49
(2-ethoxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-
Compound 1.9 and
457.2



phenyl)-piperazin-1-yl]-methanone
ethanol


50
(2-isopropoxy-5-methanesulfonyl-phenyl)-[4-(4-
Compound 1.9 and
471.2



trifluoromethyl-phenyl)-piperazin-1-yl]-
isopropylalcohol



methanone


51
(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-
Compound 1.9 and
497.2



[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-
cyclopentanol



methanone









EXAMPLE 1.10 
Preparation of 5-Methanesulfonyl-2-(2-methoxy-ethoxy)-benzoic acid
(a) 2-Amino-5-methanesulfonyl-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. The 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 HCl 1N 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 1.7 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° C., 1 hour) to yield the title compound. MS (m/e): 325.0 (M−H, 100%)
(c) 5-Methanesulfonyl-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 1N 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)-benzoic acid
(a) 2-Bromo-5-cyano-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 1N (15 ml) and ethyl acetate (30 ml). The organic layer was extracted with NaOH 1N (3×10 ml). The aqueous layer was acidified with HCl 2N. The resulting solid was filtered, washed with water and dried (high vacuum, 50° C.) to provide the title compound MS (m/e): 227.1 (M+H+, 100%)
(b) 5-Cyano-2-(2-methoxy-ethoxy)-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 1N 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
A mixture of 11.3 mmol sodium in 66 mmol 2,2,2-trifluoroethanol was heated to 100° C. until all sodium was dissolved (20 min.). Then a solution of 5.5 mmol 5-cyano-2-iodo-benzoic acid [CAS: 219841-92-6; WO9901455] in 2 ml N-methyl-2-pyrrolidone and 0.5 mmol copper (I) bromide were added, and the reaction mixture heated to 120° C. for 2 h. The reaction mixture was poured onto water, acidified to pH 2 with conc. HCl and extracted 3× with ethyl acetate. The pooled organic extracts were washed with brine, dried over Na2SO4 and evaporated. Flash chromatography on silica gel with heptane/ethyl acetate provided the title compound 1.12. MS (EI) (m/e): 245.1 (M+., 94%), 146.0 ([M−CF3CH2O]+., 100%).
In analogy to Example 1.12 compounds 1.13 to 1.16 of the following table were prepared from 5-cyano-2-iodo-benzoic acid and the appropriate alcohol:















Compound Name
Alcohol
MS (m/e)



















1.13
5-Cyano-2-isopropoxy-benzoic acid
isopropanol
204.1 (M − H−, 100%)


1.14
5-Cyano-2-cyclopropylmethoxy-
cyclopropyl-methanol
216.1 (M − H−, 100%)



benzoic acid


1.15
5-Cyano-2-isobutoxy-benzoic acid
isobutyl alcohol
218.3 (M − H−, 100%)


1.16
5-Cyano-2-cyclopentyloxy-benzoic acid
cyclopentanol
230.1 (M − H−, 100%)









In analogy to Example 5 compounds 55 to 61 of the following table were prepared from the acid derivatives and piperazine derivatives:













Expl.


MW found


No.
Systematic Name
Starting materials
(MH+)







55
1-(3-Fluoro-4-{4-[5-
1-(3-Fluoro-4-piperazin-1-
479.5



methanesulfonyl-2-(2-methoxyethoxy)-
yl-phenyl)-ethanone



benzoyl]-piperazin-1-yl}-
(WO9714690) and 5-



phenyl)-ethanone
Methanesulfonyl-2-(2-




methoxy-ethoxy)-benzoic




acid (compound 1.10)


56
4-(2-Methoxy-ethoxy)-3-[4-(4-
1-(4-Trifluoromethyl-
434.5



trifluoromethyl-phenyl)-
phenyl)-piperazine and 5-



piperazine-1-carbonyl]-
cyano-2-(2-methoxy-



benzonitrile
ethoxy)-benzoic acid




(compound 1.11)


57
4-(2,2,2-Trifluoro-ethoxy)-3-[4-
1-(4-trifluoromethylphenyl)
458.4



(4-trifluoromethyl-phenyl)-
piperazine and 5-Cyano-2-



piperazine-1-carbonyl]-
(2,2,2-trifluoro-ethoxy)-



benzonitrile
benzoic acid (compound 1.12)


58
4-Isopropoxy-3-[4-(4-
1-(4-trifluoromethylphenyl)
418.3



trifluoromethyl-phenyl)-
piperazine and 5-Cyano-2-



piperazine-1-carbonyl]-
isopropoxy-benzoic acid



benzonitrile
(compound 1.13)


59
4-Cyclopropylmethoxy-3-[4-(4-
1-(4-trifluoromethylphenyl)
430.6



trifluoromethyl-phenyl)-
piperazine and 5-Cyano-2-



piperazine-1-carbonyl]-
cyclopropylmethoxy-



benzonitrile
benzoic acid (compound 1.14)


60
4-Isobutoxy-3-[4-(4-
1-(4-trifluoromethylphenyl)
432.5



trifluoromethyl-phenyl)-
piperazine and 5-Cyano-2-



piperazine-1-carbonyl]-
isobutoxy-benzoic acid



benzonitrile
(compound 1.15)


61
4-Cyclopentyloxy-3-[4-(4-
1-(4-trifluoromethylphenyl)
444.5



trifluoromethyl-phenyl)-
piperazine and 5-Cyano-2-



piperazine-1-carbonyl]-
cyclopentyloxy-benzoic acid



benzonitrile
(compound 1.16)









EXAMPLE 2.1 
Preparation of (2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin 1-yl]-methanone
Compound 2.1 was prepared in analogy to Example 5 using 2-hydroxy-5-nitrobenzoic acid [96-97-9] and 1-(4-trifluoromethyl-phenyl)-piperazine. MS (m/e): 394.0 (M−H, 100%)
EXAMPLE 2.2 
Preparation of (2-Hydroxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone
Compound 2.2 was prepared in analogy to Example 5 using 2-hydroxy-5-(methylsulfonyl)benzoic acid [68029-77-6] and 1-(4-trifluoromethyl-phenyl)-piperazine. MS (m/e): 427.5 (M−H, 100%)
EXAMPLE 66 
Preparation of (2-Butoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone
A solution of (2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (50 mg), potassium carbonate (87 mg) and 1-bromobutane (0.15 mL) in dimethylacetamide (0.3 mL) was heated at 150° C. for 15 minutes in a microwave oven. The reaction mixture was then concentrated and purified by column chromatography (SiO2) to give the title compound (55 mg).
In analogy to Example 66, compounds 62 to 97 of the following table were prepared from the acid derivatives and piperazine derivatives:













Expl.


MW found


No.
Systematic Name
Starting materials
(MH+)







62
(2-Isopropoxy-5-nitro-
(2-Hydroxy-5-nitro-phenyl)-[4-
438.4



phenyl)-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and 2-




bromopropane


63
(2-Cyclopropylmethoxy-5-
(2-Hydroxy-5-nitro-phenyl)-[4-
450.5



nitro-phenyl)-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and




cyclopropylmethylbromide


64
(2-Cyclobutylmethoxy-5-
(2-Hydroxy-5-nitro-phenyl)-[4-
464.5



nitro-phenyl)-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and




Cyclobutylmethylbromide


65
(2-Allyloxy-5-
(2-Hydroxy-5-methanesulfonyl-
469.5



methanesulfonyl-phenyl)-
phenyl)-[4-(4-trifluoromethyl-



[4-(4-trifluoromethyl-
phenyl)-piperazin-1-yl]-



phenyl)-piperazin-1-yl]-
methanone (compound 2.2)



methanone
and cyclopropylbromide


66
(2-Butoxy-5-nitro-phenyl)-
(2-Hydroxy-5-nitro-phenyl)-[4-
452.4



[4-(4-trifluoromethyl-
(4-trifluoromethyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazin-1-yl]-methanone



methanone
(compound 2.1) and




bromobutane


67
Rac-[2-(2-Hydroxy-
(2-Hydroxy-5-nitro-phenyl)-[4-
454.6



propoxy)-5-nitro-phenyl]-
(4-trifluoromethyl-phenyl)-



[4-(4-trifluoromethyl-
piperazin-1-yl]-methanone



phenyl)-piperazin-1-yl]-
(compound 2.1) and rac-1-



methanone
Bromo-2-propanol


68
[2-(2,2-Dimethyl-propoxy)-
(2-Hydroxy-5-nitro-phenyl)-[4-
466.6



5-nitro-phenyl]-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and 1-Bromo-




2,2-Dimethylpropane


69
[2-(3-Methyl-butoxy)-5-
(2-Hydroxy-5-nitro-phenyl)-[4-
466.5



nitro-phenyl]-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and 1-Bromo-




3-methylbutane


70
(2-Isobutoxy-5-nitro-
(2-Hydroxy-5-nitro-phenyl)-[4-
452.5



phenyl)-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and 1-Bromo-




3-methylpropane


71
(2-Cyclopentyloxy-5-nitro-
(2-Hydroxy-5-nitro-phenyl)-[4-
464.5



phenyl)-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and




Cyclopentyl bromide


72
(5-Nitro-2-propoxy-
(2-Hydroxy-5-nitro-phenyl)-[4-
438.5



phenyl)-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and 1-




Bromopropane


73
(2-Cycloheptyloxy-5-nitro-
(2-Hydroxy-5-nitro-phenyl)-[4-
492.5



phenyl)-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and




Bromocycloheptane


74
(2-Cyclobutoxy-5-nitro-
(2-Hydroxy-5-nitro-phenyl)-[4-
450.4



phenyl)-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and




Bromocyclobutane


75
[2-(2-Ethoxy-ethoxy)-5-
(2-Hydroxy-5-nitro-phenyl)-[4-
468.5



nitro-phenyl]-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and 2-




Bromoethyl-ethylether


76
[2-((R)-3-Hydroxy-2-
(2-Hydroxy-5-nitro-phenyl)-[4-
468.4



methyl-propoxy)-5-nitro-
(4-trifluoromethyl-phenyl)-



phenyl]-[4-(4-
piperazin-1-yl]-methanone



trifluoromethyl-phenyl)-
(compound 2.1) and (R)-(−)-3-



piperazin-1-yl]-methanone
bromo-2-methyl-1-propanol


77
(2-Ethoxy-5-nitro-phenyl)-
(2-Hydroxy-5-nitro-phenyl)-[4-
424.4



[4-(4-trifluoromethyl-
(4-trifluoromethyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazin-1-yl]-methanone



methanone
(compound 2.1) and 2-Bromo-




1-ethoxy-1,1,2-trifluoro-ethane


78
Rac-(2-sec-Butoxy-5-nitro-
Rac-(2-Hydroxy-5-nitro-
452.5



phenyl)-[4-(4-
phenyl)-[4-(4-trifluoromethyl-



trifluoromethyl-phenyl)-
phenyl)-piperazin-1-yl]-



piperazin-1-yl]-methanone
methanone (compound 2.1) and




2-Bromobutane


79
[2-(2-Hydroxy-ethoxy)-5-
(2-Hydroxy-5-nitro-phenyl)-[4-
440.4



nitro-phenyl]-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and 2-Bromo-




1-ethanol


80
[5-Nitro-2-(2,2,3,3-
(2-Hydroxy-5-nitro-phenyl)-[4-
510.5



tetrafluoro-propoxy)-
(4-trifluoromethyl-phenyl)-



phenyl]-[4-(4-
piperazin-1-yl]-methanone



trifluoromethyl-phenyl)-
(compound 2.1) and 1-Iodo-



piperazin-1-yl]-methanone
2,2,3,3,-tetrafluoropropane


81
[5-Nitro-2-(4,4,4-trifluoro-
(2-Hydroxy-5-nitro-phenyl)-[4-
506.5



butoxy)-phenyl]-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and 1-Bromo-




4,4,4,-trifluorobutane


82
[2-(2-Fluoro-ethoxy)-5-
(2-Hydroxy-5-nitro-phenyl)-[4-
442.5



nitro-phenyl]-
(4-trifluoromethyl-phenyl)-



[4-(4-trifluoromethyl-
piperazin-1-yl]-methanone



phenyl)-piperazin-
(compound 2.1) and 1-Bromo-



1-yl]-methanone
2-fluoroethane


83
[2-(3-Hydroxy-2,2-
(2-Hydroxy-5-nitro-phenyl)-[4-
482.6



dimethyl-propoxy)-
(4-trifluoromethyl-phenyl)-



5-nitro-phenyl]-[4-(4-
piperazin-1-yl]-methanone



trifluoromethyl-phenyl)-
(compound 2.1) and 3-Bromo-



piperazin-1-yl]-methanone
2,2-Dimethyl-2-propan-1-ol


84
[5-Nitro-2-(2,2,2-trifluoro-
(2-Hydroxy-5-nitro-phenyl)-[4-
478.3



ethoxy)-phenyl]-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and 1,1,1-




Trifluoro-2-iodo-ethane


85
[2-(1-Ethyl-propoxy)-5-
(2-Hydroxy-5-nitro-phenyl)-[4-
466.5



nitro-phenyl]-
(4-trifluoromethyl-phenyl)-



[4-(4-trifluoromethyl-
piperazin-1-yl]-methanone



phenyl)-piperazin-
(compound 2.1) and 3-Bromo-



1-yl]-methanone
pentane


86
[5-Nitro-2-(oxetan-3-
(2-Hydroxy-5-nitro-phenyl)-[4-
452.4



yloxy)-phenyl]-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and Toluene-4-




sulfonic acid oxetan-3-yl ester




(CAS: 26272-83-3)


87
[2-(3-Hydroxy-propoxy)-5-
(2-Hydroxy-5-nitro-phenyl)-[4-
454.6



nitro-phenyl]-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and




Bromopropanole


88
[2-(Bicyclo[2.2.1]hept-2-
(2-Hydroxy-5-nitro-phenyl)-[4-
490.5



yloxy)-5-nitro-phenyl]-
(4-trifluoromethyl-phenyl)-



[4-(4-trifluoromethyl-
piperazin-1-yl]-methanone



phenyl)-piperazin-1-yl]-
(compound 2.1) and exo-2-



methanone
Bromonorbornane


89
[2-(2-Methoxy-ethoxy)-5-
(2-Hydroxy-5-nitro-phenyl)-[4-
454.5



nitro-phenyl]-
(4-trifluoromethyl-phenyl)-



[4-(4-trifluoromethyl-
piperazin-1-yl]-methanone



phenyl)-piperazin-1-yl]-
(compound 2.1) and 2-



methanone
bromoethylmethylether


90
[2-(3,3-Dimethyl-butoxy)-
(2-Hydroxy-5-nitro-phenyl)-[4-
480.8



5-nitro-phenyl]-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and 1-bromo-




3,3-dimethylbutane


91
[2-(1-Ethoxy-
(2-Hydroxy-5-nitro-phenyl)-[4-
480.6



cyclopropoxy)-5-nitro-
(4-trifluoromethyl-phenyl)-



phenyl]-[4-(4-
piperazin-1-yl]-methanone



trifluoromethyl-phenyl)-
(compound 2.1) and 1-Bromo-



piperazin-1-yl]-
1-ethoxy-cyclopropane



methanone


92
[2-(2-Chloro-ethoxy)-5-
(2-Hydroxy-5-nitro-phenyl)-[4-
458.4



nitro-phenyl]-
(4-trifluoromethyl-phenyl)-



[4-(4-trifluoromethyl-
piperazin-1-yl]-methanone



phenyl)-piperazin-
(compound 2.1) and 2-



1-yl]-methanone
Chloroethanol


93
{4-Nitro-2-[4-(4-
(2-Hydroxy-5-nitro-phenyl)-[4-
435.4



trifluoromethyl-phenyl)-
(4-trifluoromethyl-phenyl)-



piperazine-1-carbonyl]-
piperazin-1-yl]-methanone



phenoxy}-acetonitrile
(compound 2.1) and




bromoacetonitrile


94
[5-Nitro-2-(3,3,3-trifluoro-
(2-Hydroxy-5-nitro-phenyl)-[4-
492.4



propoxy)-phenyl]-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and 1,1,1-




Trifluoro-1-Iodopropan


95
[5-Nitro-2-(tetrahydro-
(2-Hydroxy-5-nitro-phenyl)-[4-
480.4



pyran-4-yloxy)-phenyl]-[4-
(4-trifluoromethyl-phenyl)-



(4-trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and 4-chloro-




tetrahydropyrane


96
[2-(2,2-Difluoro-ethoxy)-5-
(2-Hydroxy-5-nitro-phenyl)-[4-
460.5



nitro-phenyl]-[4-(4-
(4-trifluoromethyl-phenyl)-



trifluoromethyl-phenyl)-
piperazin-1-yl]-methanone



piperazin-1-yl]-methanone
(compound 2.1) and 1-bromo-




2,2-difluoroethane


97
[2-(1,1,2,3,3,3-Hexafluoro-
(2-Hydroxy-5-nitro-phenyl)-[4-
546.3



propoxy)-5-nitro-phenyl]-
(4-trifluoromethyl-phenyl)-



[4-(4-trifluoromethyl-
piperazin-1-yl]-methanone



phenyl)-piperazin-1-yl]-
(compound 2.1) and 3-



methanone
Hexafluoropropane









EXAMPLE 98 
Preparation of (2-Difluoromethoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone
In analogy to a procedure published in WO9749710, a solution of (2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (50 mg), potassium carbonate (1 eq), and ethyl chlorofluoroacetate (1 eq) in DMF (1 mL) was stirred at 65° C. for 16 hours. After such time the reaction mixture was concentrated in vacuo and purified by column chromatography (SiO2) to yield the title compound (26 mg). MS (m/e): 446.0 (M+H+, 100%).
EXAMPLE 99 
Preparation of 5-Nitro-2-(2,2,3,3-tetrafluoro-cyclobutylmethoxy)-phenyl-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone
Example 99 was prepared in analogy to Example 66 using 1-(chloromethyl)-2,2,3,3-tetrafluorocyclobutane [356-80-9]. MS (m/e): 536.3 (M+H+, 100%).
EXAMPLE 100 
Preparation of [5-Nitro-2-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone
To a refluxing solution of 50 mg of (2-hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone in acetone (2 mL) containing potassium carbonate (35 mg) was added 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (54 mg) over 10 min. The reaction mixture was refluxed for 20 hours before being concentrated in vacuo and purified by column chromatography (SiO2, CH2Cl2/MeOH) to yield the title compound as a colorless solid (66 mg). MS (m/e): 569.0 (M+H+, 100%).
EXAMPLE 101 
Preparation of [2-(2-Fluoro-1-fluoromethyl-ethoxy)-5-nitro-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone
A solution of (2-hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (50 mg), 1,3-difluoro-2-propanol [453-13-4] (27 mg), triphenylphosphine (76 mg) and diisopropylazodicarboxylate (48 mg) was refluxed overnight, concentrated in vacuo and purified by column chromatography (SiO2) to yield the title compound as a colorless solid (68 mg). MS (m/e): 474.1 (M+H+, 100%).
In analogy to Example 48, compounds 102 to 104 of the following table were prepared from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound 1.9) and an alcohol:
















MW


Expl.


found


No.
Systematic Name
Starting materials
(MH+)







102
[2-(1-Ethyl-propoxy)-5-
(2-Iodo-5-methanesulfonyl-
499.5



methanesulfonyl-phenyl]-
phenyl)-[4-(4-trifluoromethyl-



[4-(4-trifluoromethyl-
phenyl)-piperazin-1-yl]-



phenyl)-piperazin-1-yl]-
methanone (compound 1.9) and



methanone
3-Pentanol


103
[5-Methanesulfonyl-2-(3-
(2-Iodo-5-methanesulfonyl-
513.4



methyl-oxetan-3-
phenyl)-[4-(4-trifluoromethyl-



ylmethoxy)-phenyl]-[4-(4-
phenyl)-piperazin-1-yl]-



trifluoromethyl-phenyl)-
methanone (compound 1.9) and



piperazin-1-yl]-methanone
Methyloxethanemethanol


104
Rac-[2-(1-Cyclopropyl-
(2-Iodo-5-methanesulfonyl-
497.4



ethoxy)-5-methanesulfonyl-
phenyl)-[4-(4-trifluoromethyl-



phenyl]-[4-(4-
phenyl)-piperazin-1-yl]-



trifluoromethyl-phenyl)-
methanone (compound 1.9) and



piperazin-1-yl]-methanone
rac-1-cyclopropylethanol









EXAMPLE 2.3 
Preparation of (2-Fluoro-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone
Compound 2.3 was prepared in analogy to Example 5 using 2-fluoro-5-(methylsulfonyl)benzoic acid [247569-56-8] and 1-(5-trifluoromethyl-2-pyridyl)piperazine [132834-58-3]. MS (m/e): 432.4 (M+H+, 100%).
EXAMPLE 105 
Preparation of [5-Methanesulfonyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone
A solution of (2-fluoro-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone (compound 2.3) (20 mg), 2-trifluoromethyl-2-propanol (0.053 mL), potassium carbonate or cesium carbonate (3 equivalents) in dimethylacetamide was heated at 150° C. for 30 min and then at 180° C. for 1 h in a microwave oven. After such time the reaction mixture was concentrated and purified by column chromatography (SiO2) to yield the title compound as a light yellow solid (4.9 mg). MS (m/e): 540.3 (M+H+, 100%).
EXAMPLE 2.4 
Preparation of (2-Isopropoxy-5-methanesulfonyl-phenyl)-piperazin-1-yl-methanone trifluoro-acetic acid
A solution of 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2, 1.0 g), tert-butyl 1-piperazinecarboxylate (0.78 g), TBTU (1.4 g) and N-ethyldiisopropylamine (4 mL) was stirred at room temperature for 2 hours. After such time, the reaction mixture was concentrated in vacuo and purified by column chromatography (SiO2) to give 4-(2-Isopropoxy-5-methanesulfonyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester as a colorless foam (1.6 g). The latter was dissolved in dichloromethane (11 mL) and treated with trifluroacetic acid (4.2 mL) for 30 minutes. After such time the reaction mixture was concentrated in vacuo to yield the title compound (1.6 g) as light yellow oil. MS (m/e): 327.1 (M+H+, 100%).
EXAMPLE 2.5 
Preparation of 4-Chloro-6-trifluoromethyl-pyrimidine
6-Trifluoromethyl-pyrimidin-4-ol ([1546-78-7], 5 g) was refluxed in phosphorus oxychloride (17 mL) for 2 hours. The reaction mixture was carefully concentrated in vacuo and the residue was distilled (Kugelrohr) under reduced pressure (bp=30-55° C. @ 10 mbar) to yield the title compound ([37552-81-1], 1.4 g). MS (EI): 182.0 (M).
EXAMPLE 106 
Preparation of (2-Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanone
A solution of (2-isopropoxy-5-methanesulfonyl-phenyl)-piperazin-1-yl-methanone trifluoro-acetic acid (compound 2.4, 80 mg) 2-chloro-5-nitro-pyridine (29 mg), potassium carbonate (50 mg) in 1-butanol (3 mL) was stirred at 120° C. for 20 hours. After such time the solution was concentrated in vacuo, and purified by column chromatography (SiO2) to yield the title compound as white foam (81 mg). MS (m/e): 449.1 (M+H+, 100%).
EXAMPLE 107 
Preparation of (2-Isopropoxy-5-methanesulfonyl-phenyl)-[4-(6-trifluoromethyl-pyrimidin-4-yl)-piperazin-1-yl]-methanone
Example 107 was prepared in analogy to example 106 using 4-chloro-6-trifluoromethyl-pyrimidine [37552-81-1]. MS (m/e): 473.1 (M+H+, 100%).
EXAMPLE 2.6 
Preparation of 2-(4-fluorophenoxy)-5-nitrobenzoic acid
2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid can be prepared by a similar method to that described in the literature (e.g. WO9938845) by reaction of 2-Chloro-5-nitro-benzoic acid ethyl ester [16588-17-3] with 4-Fluoro-phenol [371-35-7] yielding 2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid ethyl ester. 2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid ethyl ester can then be hydrolysed with sodium hydroxide for example to yield the title compound. MS (m/e): 276.1 (M+H+, 100%).
EXAMPLE 2.7 
Preparation of 2,3-Difluoro-4-piperazin-1-yl-benzonitrile-trifluoro-acetic acid
(a) 4-(4-Cyano-2,3-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
To a solution of N-Boc-Piperazine (0.65 g) in DMA (20 mL) was slowly added a solution of 2,3,4-trifluorobenzonitrile (0.49 g) in DMA (10 mL). The reaction mixture was stirred for 2 hours at 80° C. After such time the solvent was removed in vacuo and purified by column chromatography (SiO2) to yield the title compound as white solid (0.76 g).
(b) 2,3-Difluoro-4-piperazin-1-yl-benzonitrile-trifluoro-acetic acid
To a solution of 4-(4-Cyano-2,3-difluoro-phenyl)-piperazine-1-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 vacuo 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-Methylsulfamoyl-2-trifluoromethoxy-benzoic acid
(a) 5-Chlorosulfonyl-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-Methylsulfamoyl-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 complete. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 1N 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 (2×10 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-(3,3,3-trifluoro-propoxy)-benzoic acid
(a) 5-Methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoic acid methyl ester
A solution of methyl 5-(methanesulfonyl)-salicylate [101371-44-2] (50 mg), triphenylphosphine (65 mg) 3,3,3-trifluoro-1-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 and purified by column chromatography (SiO2) to yield the title compound as a white solid (65 mg). MS (m/e): 327.5 (M+H+, 100%).
(b) 5-Methanesulfonyl-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 1N NaOH solution (3.8 mL), and the reaction mixture was stirred for 15 minutes. After such time, 3.8 ml of 1N HCl 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-1-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-1-yl-benzonitrile trifluoro-acetic acid
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-trifluoromethoxy-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 1N 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 HCl 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-1-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-1-fluoromethyl-ethoxy)-5-methanesulfonyl-benzoic acid
Compound 2.17 was prepared in analogy to compound 2.10 using 1,3-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-Methanesulfonyl-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-propoxy)-benzoic acid
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 1N 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-methanesulfonyl-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-tert-butylacetal, and the reaction mixture was stirred at 80° C. for 1 hour. After such time the reaction 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-Butoxy-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 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 1N HCl solution, leading to precipitation of the compound. The precipitate was filtered off and washed several times with water to yield the title compound (1.00 g) as a white solid. MS (m/e): 289.9 (M+NH4+).
EXAMPLE 2.20 
Preparation of 1-(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 ethyl 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) 1,2,4-Trifluoro-5-methanesulfonyl-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) 1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-piperazine trifluoro-acetic acid
The title compound was obtained in analogy to example 2.7 using 1,2,4-Trifluoro-5-methanesulfonyl-benzene. MS (m/e): 277.1 (M+H+).
EXAMPLE 2.21 
Preparation of 1-(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-1-propyl triflate. MS (m/e): 329.1 (M−H).
EXAMPLE 2.23 
Preparation of 1-(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-1-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-1-yl-5-trifluoromethyl-pyrimidine
(a) 2-(4-Benzyl-piperazin-1-yl)-5-trifluoromethyl-pyrimidine
To a solution of (3-Dimethylamino-2-trifluoromethyl-allylidene)-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-1-yl-5-trifluoromethyl-pyrimidine
To a solution of 2-(4-Benzyl-piperazin-1-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 off, 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:













Expl.


MW found


No.
Systematic Name
Starting materials
(MH+)







108
[2-(4-Fluoro-phenoxy)-
1-(4-trifluoromethyl-
490.5



5-nitro-phenyl]-
phenyl)piperazine and 2-(4-



[4-(4-trifluoromethyl-
fluorophenoxy)-5-



phenyl)-piperazin-1-yl]-
nitrobenzoic acid



methanone
(compound 2.6)


109
2,3-Difluoro-4-[4-(2-
2,3-Difluoro-4-piperazin-1-
464.3



isopropoxy-5-
yl-benzonitrile-trifluoro-



methanesulfonyl-
acetic acid (compound 2.7)



benzoyl)-piperazin-1-yl]-
and 2-Isopropoxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 1.2)


110
2,5-Difluoro-4-[4-(2-
2,5-Difluoro-4-piperazin-1-
464.1



isopropoxy-5-
yl-benzonitrile-trifluoro-



methanesulfonyl-
acetic acid (compound 2.8)



benzoyl)-piperazin-1-yl]-
and 2-Isopropoxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 1.2)


111
3-[4-(4-Cyano-3-fluoro-
2-Fluoro-4-piperazin-1-yl
487.1



phenyl)-piperazine-1-
benzonitrile (WO 9808835)



carbonyl]-N-methyl-4-
and 5-Methylsulfamoyl-2-



trifluoromethoxy-
trifluoromethoxy-benzoic



benzenesulfonamide
acid (compound 2.9)


112
3-Fluoro-4-{4-[5-
3-Fluoro-4-piperazin-1-yl-
500.3



methanesulfonyl-2-
benzonitrile (WO9625414)



(3,3,3-trifluoro-
and 5-Methanesulfonyl-2-



propoxy)-benzoyl]-
(3,3,3-trifluoro-propoxy)-



piperazin-1-yl}-benzonitrile
benzoic acid (compound 2.10)


113
4-{4-[5-
4-Piperazin-1-yl-
482.3



Methanesulfonyl-2-
benzonitrile (commercial)



(3,3,3-trifluoro-
and 5-Methanesulfonyl-2-



propoxy)-benzoyl]-
(3,3,3-trifluoro-propoxy)-



piperazin-1-yl}-benzonitrile
benzoic acid (compound 2.10)


114
2-Fluoro-4-{4-[5-
2-Fluoro-4-piperazin-1-yl-
500.3



methanesulfonyl-2-
benzonitrile (WO 9808835)



(3,3,3-trifluoro-
and 5-Methanesulfonyl-2-



propoxy)-benzoyl]-
(3,3,3-trifluoro-propoxy)-



piperazin-1-yl}-benzonitrile
benzoic acid (compound 2.10)


115
[5-Methanesulfonyl-2-
1-(4-Trifluoromethyl-
525.2



(3,3,3-trifluoro-
phenyl)-piperazine



propoxy)-phenyl]-[4-(4-
(commercial) and 5-



trifluoromethyl-phenyl)-
Methanesulfonyl-2-(3,3,3-



piperazin-1-yl]-methanone
trifluoro-propoxy)-benzoic




acid (compound 2.10)


116
[4-(3-Fluoro-4-
1-(3-Fluoro-4-
543.3



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-[5-
piperazine (compound 5.1)



methanesulfonyl-2-
and 5-Methanesulfonyl-2-



(3,3,3-trifluoro-
(3,3,3-trifluoro-propoxy)-



propoxy)-phenyl]-
benzoic acid (compound 2.10)



methanone


117
[4-(2-Fluoro-4-
1-(2-Fluoro-4-
543.2



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-[5-
piperazine (compound



methanesulfonyl-2-
1.1) and 5-Methane-



(3,3,3-trifluoro-
sulfonyl-2-(3,3,3-trifluoro-



propoxy)-phenyl]-
propoxy)-benzoic acid



methanone
(compound 2.10)


118
1-(3-Fluoro-4-{4-[5-
1-(3-Fluoro-4-piperazin-1-
517.3



methanesulfonyl-2-
yl-phenyl)-ethanone



(3,3,3-trifluoro-
(WO9714690) and 5-



propoxy)-benzoyl]-
Methanesulfonyl-2-(3,3,3-



piperazin-1-yl}-phenyl)-
trifluoro-propoxy)-benzoic



ethanone
acid (compound 2.10)


119
[4-(2-Fluoro-4-
1-(2-Fluoro-4-
553.2



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine (commercial)



[5-methanesulfonyl-2-
and 5-Methanesulfonyl-2-



(3,3,3-trifluoro-
(3,3,3-trifluoro-propoxy)-



propoxy)-phenyl]-
benzoic acid (compound 2.10)



methanone


120
4-{4-[5-
4-Piperazin-1-yl-
470.0



Methanesulfonyl-2-
benzonitrile (commercial)



(tetrahydro-pyran-4-
and 5-Methanesulfonyl-2-



yloxy)-benzoyl]-
(tetrahydro-pyran-4-yloxy)-



piperazin-1-yl}-
benzoic acid (compound 2.11)



benzonitrile


121
2-Fluoro-4-{4-[5-
2-Fluoro-4-piperazin-1-yl-
488.1



methanesulfonyl-2-
benzonitrile (WO 9808835)



(tetrahydro-pyran-4-
and 5-Methanesulfonyl-2-



yloxy)-benzoyl]-
(tetrahydro-pyran-4-yloxy)-



piperazin-1-yl}-
benzoic acid (compound 2.11)



benzonitrile


122
3-Fluoro-4-{4-[5-
3-Fluoro-4-piperazin-1-yl-
488.0



methanesulfonyl-2-
benzonitrile (WO9625414)



(tetrahydro-pyran-4-
and 5-Methanesulfonyl-2-



yloxy)-benzoyl]-
(tetrahydro-pyran-4-yloxy)-



piperazin-1-yl}-
benzoic acid (compound 2.11)



benzonitrile


123
[5-Methanesulfonyl-2-
1-(4-Trifluoromethyl-
513.3



(tetrahydro-pyran-4-
phenyl)-piperazine



yloxy)-phenyl]-[4-(4-
(commercial) and 5-



trifluoromethyl-phenyl)-
Methanesulfonyl-2-



piperazin-1-yl]-
(tetrahydro-pyran-4-yloxy)-



methanone
benzoic acid (compound 2.11)


124
[4-(3-Fluoro-4-
1-(3-Fluoro-4-
531.0



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-[5-
piperazine (compound 5.1)



methanesulfonyl-2-
and 5-Methanesulfonyl-2-



(tetrahydro-pyran-4-
(tetrahydro-pyran-4-yloxy)-



yloxy)-phenyl]-
benzoic acid (compound 2.11)



methanone


125
[4-(2-Fluoro-4-
1-(2-Fluoro-4-
531.2



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-[5-
piperazine (compound



methanesulfonyl-2-
1.1) and 5-



(tetrahydro-pyran-4-
Methanesulfonyl-2-



yloxy)-phenyl]-
(tetrahydro-pyran-4-yloxy)-



methanone
benzoic acid (compound 2.11)


126
1-(3-Fluoro-4-{4-[5-
1-(3-Fluoro-4-piperazin-1-
505.1



methanesulfonyl-2-
yl-phenyl)-ethanone



(tetrahydro-pyran-4-
(WO9714690) and 5-



yloxy)-benzoyl]-
Methanesulfonyl-2-



piperazin-1-yl}-phenyl)-
(tetrahydro-pyran-4-yloxy)-



ethanone
benzoic acid (compound 2.11)


127
[4-(2-Fluoro-4-
1-(2-Fluoro-4-
541.3



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine (commercial)



[5-methanesulfonyl-2-
and 5-Methanesulfonyl-2-



(tetrahydro-pyran-4-
(tetrahydro-pyran-4-yloxy)-



yloxy)-phenyl]-
benzoic acid (compound 2.11)



methanone


128
2,3-Difluoro-4-[4-(2-
2,3-Difluoro-4-piperazin-1-
478.1



isobutoxy-5-
yl-benzonitrile-trifluoro-



methanesulfonyl-
acetic acid (compound 2.7)



benzoyl)-piperazin-1-yl]-
and 2-Isobutoxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 1.3)


129
4-[4-(2-
2,3-Difluoro-4-piperazin-1-
476.3



Cyclopropylmethoxy-5-
yl-benzonitrile-trifluoro-



methanesulfonyl-
acetic acid (compound 2.7)



benzoyl)-piperazin-1-yl]-
and 2-Cyclopropylmethoxy-



2,3-difluoro-benzonitrile
5-methanesulfonyl-benzoic




acid (compound 1.4)


130
2,3-Difluoro-4-{4-[5-
2,3-Difluoro-4-piperazin-1-
506.4



methanesulfonyl-2-
yl-benzonitrile-trifluoro-



(tetrahydro-pyran-4-
acetic acid (compound 2.7)



yloxy)-benzoyl]-
and 5-Methanesulfonyl-2-



piperazin-1-yl}-
(tetrahydro-pyran-4-yloxy)-



benzonitrile
benzoic acid (compound 2.11)


131
4-[4-(2-Cyclopentyloxy-
2,3-Difluoro-4-piperazin-1-
490.5



5-methanesulfonyl-
yl-benzonitrile-trifluoro-



benzoyl)-piperazin-1-yl]-
acetic acid (compound 2.7)



2,3-difluoro-benzonitrile
and 2-Cyclopentyloxy-5-




methanesulfonyl-benzoic




acid (compound 1.6)


132
2,5-Difluoro-4-[4-(2-
2,5-Difluoro-4-piperazin-1-
478.4



isobutoxy-5-
yl-benzonitrile-trifluoro-



methanesulfonyl-
acetic acid (compound 2.8)



benzoyl)-piperazin-1-yl]-
and 2-Isobutoxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 1.3)


133
4-[4-(2-
2,5-Difluoro-4-piperazin-1-
476.3



Cyclopropylmethoxy-5-
yl-benzonitrile-trifluoro-



methanesulfonyl-
acetic acid (compound 2.8)



benzoyl)-piperazin-1-yl]-
and 2-Cyclopropylmethoxy-



2,5-difluoro-benzonitrile
5-methanesulfonyl-benzoic




acid (compound 1.4)


134
2,5-Difluoro-4-{4-[5-
2,5-Difluoro-4-piperazin-1-
506.4



methanesulfonyl-2-
yl-benzonitrile-trifluoro-



(tetrahydro-pyran-4-
acetic acid (compound 2.8)



yloxy)-benzoyl]-
and 5-Methanesulfonyl-2-



piperazin-1-yl}-
(tetrahydro-pyran-4-yloxy)-



benzonitrile
benzoic acid (compound 2.11)


135
4-[4-(2-Cyclopentyloxy-
2,5-Difluoro-4-piperazin-1-
490.5



5-methanesulfonyl-
yl-benzonitrile-trifluoro-



benzoyl)-piperazin-1-yl]-
acetic acid (compound 2.8)



2,5-difluoro-benzonitrile
and 2-Cyclopentyloxy-5-




methanesulfonyl-




benzoic acid (compound 1.6)


136
4-[4-(2-
4-Piperazin-1-yl-
454.6



Cyclobutylmethoxy-5-
benzonitrile (commercial)



methanesulfonyl-
and 2-Cyclobutylmethoxy-



benzoyl)-piperazin-1-yl]-
5-methanesulfonyl-benzoic



benzonitrile
acid (compound 2.12)


137
4-[4-(2-
2-Fluoro-4-piperazin-1-yl-
472.3



Cyclobutylmethoxy-5-
benzonitrile (WO 9808835)



methanesulfonyl-
and 2-Cyclobutylmethoxy-



benzoyl)-piperazin-1-yl]-
5-methanesulfonyl-benzoic



2-fluoro-benzonitrile
acid (compound 2.12)


138
4-[4-(2-
3-Fluoro-4-piperazin-1-yl-
472.3



Cyclobutylmethoxy-5-
benzonitrile (WO9625414)



methanesulfonyl-
and 2-Cyclobutylmethoxy-



benzoyl)-piperazin-1-yl]-
5-methanesulfonyl-benzoic



3-fluoro-benzonitrile
acid (compound 2.12)


139
(2-Cyclobutylmethoxy-5-
1-(4-Trifluoromethyl-
497.3



methanesulfonyl-
phenyl)-piperazine



phenyl)-[4-(4-
(commercial) and 2-



trifluoromethyl-phenyl)-
Cyclobutylmethoxy-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 2.12)


140
(2-Cyclobutylmethoxy-5-
1-(3-Fluoro-4-
515.4



methanesulfonyl-
trifluoromethyl-phenyl)-



phenyl)-[4-(3-fluoro-4-
piperazine (compound 5.1)



trifluoromethyl-phenyl)-
and 2-Cyclobutylmethoxy-



piperazin-1-yl]-
5-methanesulfonyl-benzoic



methanone
acid (compound 2.12)


141
(2-Cyclobutylmethoxy-5-
1-(2-Fluoro-4-
515.4



methanesulfonyl-
trifluoromethyl-phenyl)-



phenyl)-[4-(2-fluoro-4-
piperazine (compound



trifluoromethyl-phenyl)-
1.1) and 2-



piperazin-1-yl]-
Cyclobutylmethoxy-5-



methanone
methanesulfonyl-benzoic




acid (compound 2.12)


142
1-{4-[4-(2-
1-(3-Fluoro-4-piperazin-1-
489.5



Cyclobutylmethoxy-5-
yl-phenyl)-ethanone



methanesulfonyl-
(WO9714690) and 2-



benzoyl)-piperazin-1-yl]-
Cyclobutylmethoxy-5-



3-fluoro-phenyl}-
methanesulfonyl-benzoic



ethanone
acid (compound 2.12)


143
(2-Cyclobutylmethoxy-5-
1-(2-Fluoro-4-
525.3



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-[4-(2-fluoro-4-
piperazine (commercial)



methanesulfonyl-
and 2-Cyclobutylmethoxy-



phenyl)-piperazin-1-yl]-
5-methanesulfonyl-benzoic



methanone
acid (compound 2.12)


144
2-[4-(2-
2-Piperazin-1-yl-5-
522.4



Cyclobutylmethoxy-5-
trifluoromethyl-benzonitrile



methanesulfonyl-
(compound 5.2) and 2-



benzoyl)-piperazin-1-yl]-
Cyclobutylmethoxy-5-



5-trifluoromethyl-
methanesulfonyl-benzoic



benzonitrile
acid (compound 2.12)


145
4-[4-(2-
2,3-Difluoro-4-piperazin-1-
490.5



Cyclobutylmethoxy-5-
yl-benzonitrile-trifluoro-



methanesulfonyl-
acetic acid (compound 2.7)



benzoyl)-piperazin-1-yl]-
and 2-Cyclobutylmethoxy-



2,3-difluoro-benzonitrile
5-methanesulfonyl-benzoic




acid (compound 2.12)


146
4-[4-(2-
2,5-Difluoro-4-piperazin-1-
490.5



Cyclobutylmethoxy-5-
yl-benzonitrile-trifluoro-



methanesulfonyl-
acetic acid (compound 2.8)



benzoyl)-piperazin-1-yl]-
and 2-Cyclobutylmethoxy-



2,5-difluoro-benzonitrile
5-methanesulfonyl-benzoic




acid (compound 2.12)


147
4-[4-(2-
3,5-Difluoro-4-piperazin-1-
490.5



Cyclobutylmethoxy-5-
yl-benzonitrile trifluoro



methanesulfonyl-
acetic acid (compound 2.13)



benzoyl)-piperazin-1-yl]-
and 2-Cyclobutylmethoxy-



3,5-difluoro-benzonitrile
5-methanesulfonyl-benzoic




acid (compound 2.12)


148
4-[4-(2-
2,6-Difluoro-4-piperazin-1-
490.5



Cyclobutylmethoxy-5-
yl-benzonitrile trifluoro-



methanesulfonyl-
acetic acid (compound 2.14)



benzoyl)-piperazin-1-yl]-
and 2-Cyclobutylmethoxy-



2,6-difluoro-benzonitrile
5-methanesulfonyl-benzoic




acid (compound 2.12)


149
2,5-Difluoro-4-{4-[5-
2,5-Difluoro-4-piperazin-1-
504.0



methanesulfonyl-2-
yl-benzonitrile-trifluoro-



(2,2,2-trifluoro-ethoxy)-
acetic acid (compound 2.8)



benzoyl]-piperazin-1-yl}-
and 5-Methanesulfonyl-2-



benzonitrile
(2,2,2-trifluoro-ethoxy)-




benzoic acid (compound 1.5)


150
2,3-Difluoro-4-{4-[5-
2,3-Difluoro-4-piperazin-1-
504.1



methanesulfonyl-2-
yl-benzonitrile-trifluoro-



(2,2,2-trifluoro-ethoxy)-
acetic acid (compound 2.7)



benzoyl]-piperazin-1-yl}-
and 5-Methanesulfonyl-2-



benzonitrile
(2,2,2-trifluoro-ethoxy)-




benzoic acid (compound 1.5)


151
2,5-Difluoro-4-[4-(5-
2,5-Difluoro-4-piperazin-1-
490.0



methanesulfonyl-2-
yl-benzonitrile-trifluoro-



trifluoromethoxy-
acetic acid (compound 2.8)



benzoyl)-piperazin-1-yl]-
and 5-Methanesulfonyl-2-



benzonitrile
trifluoromethoxy-benzoic




acid (compound 2.15)


152
4-[4-(5-
4-Piperazin-1-yl-
454.3



Methanesulfonyl-2-
benzonitrile (commercial)



trifluoromethoxy-
and 5-Methanesulfonyl-2-



benzoyl)-piperazin-1-yl]-
trifluoromethoxy-benzoic



benzonitrile
acid (compound 2.15)


153
2-Fluoro-4-[4-(5-
2-Fluoro-4-piperazin-1-yl-
472.1



methanesulfonyl-2-
benzonitrile (WO 9808835)



trifluoromethoxy-
and 5-Methanesulfonyl-2-



benzoyl)-piperazin-1-yl]-
trifluoromethoxy-benzoic



benzonitrile
acid (compound 2.15)


154
3-Fluoro-4-[4-(5-
3-Fluoro-4-piperazin-1-yl-
472.0



methanesulfonyl-2-
benzonitrile (WO9625414)



trifluoromethoxy-
and 5-Methanesulfonyl-2-



benzoyl)-piperazin-1-yl]-
trifluoromethoxy-benzoic



benzonitrile
acid (compound 2.15)


155
(5-Methanesulfonyl-2-
1-(4-Trifluoromethyl-
514.2



trifluoromethoxy-
phenyl)-piperazine
(M + NH4+)



phenyl)-[4-(4-
(commercial) and 5-



trifluoromethyl-phenyl)-
Methanesulfonyl-2-



piperazin-1-yl]-
trifluoromethoxy-benzoic



methanone
acid (compound 2.15)


156
[4-(3-Fluoro-4-
1-(3-Fluoro-4-
532.2



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-
(M + NH4+)



piperazin-1-yl]-(5-
piperazine (compound 5.1)



methanesulfonyl-2-
and 5-Methanesulfonyl-2-



trifluoromethoxy-
trifluoromethoxy-benzoic



phenyl)-methanone
acid (compound 2.15)


157
[4-(2-Fluoro-4-
1-(2-Fluoro-4-
515.3



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-(5-
piperazine (compound



methanesulfonyl-2-
1.1) and 5-



trifluoromethoxy
Methanesulfonyl-2-



phenyl)-methanone
trifluoromethoxy-benzoic




acid (compound 2.15)


158
2,3-Difluoro-4-[4-(5-
2,3-Difluoro-4-piperazin-1-
507.4



methanesulfonyl-2-
yl-benzonitrile-trifluoro-
(M + NH4+)



trifluoromethoxy-
acetic acid (compound 2.7)



benzoyl)-piperazin-1-yl]-
and 5-Methanesulfonyl-2-



benzonitrile
trifluoromethoxy-benzoic




acid (compound 2.15)


159
3,5-Difluoro-4-[4-(5
3,5-Difluoro-4-piperazin-1-
507.3



methanesulfonyl-2-
yl-benzonitrile trifluoro-
(M + NH4+)



trifluoromethoxy-
acetic acid (compound 2.13)



benzoyl)-piperazin-1-yl]-
and 5-Methanesulfonyl-2-



benzonitrile
trifluoromethoxy-benzoic




acid (compound 2.15)


160
2,6-Difluoro-4-[4-(5-
2,6-Difluoro-4-piperazin-1-
507.4



methanesulfonyl-2-
yl-benzonitrile trifluoro-
(M + NH4+)



trifluoromethoxy-
acetic acid (compound 2.14)



benzoyl)-piperazin-1-yl]-
and 5-Methanesulfonyl-2-



benzonitrile
trifluoromethoxy-benzoic




acid (compound 2.15)


161
[4-(2-Fluoro-4-
1-(2-Fluoro-4-
542.0



methanesulfonyl-
methanesulfonyl-phenyl)-
(M + NH4+)



phenyl)-piperazin-1-yl]-
piperazine (commercial)



(5-methanesulfonyl-2-
and 5-Methanesulfonyl-2-



trifluoromethoxy-
trifluoromethoxy-benzoic



phenyl)-methanone
acid (compound 2.15)


162
2-[4-(5-
2-Piperazin-1-yl-5-
539.2



Methanesulfonyl-2-
trifluoromethyl-benzonitrile
(M + NH4+)



trifluoromethoxy-
(compound 5.2)and 5-



benzoyl)-piperazin-1-yl]-
Methanesulfonyl-2-



5-trifluoromethyl-
trifluoromethoxy-benzoic



benzonitrile
acid (compound 2.15)


163
3,5-Difluoro-4-[4-(2-
3,5-Difluoro-4-piperazin-1-
464.1



isopropoxy-5-
yl-benzonitrile trifluoro-



methanesulfonyl-
acetic acid (compound 2.13)



benzoyl)-piperazin-1-yl]-
and 2-Isopropoxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 1.2)


164
3,5-Difluoro-4-[4-(2-
3,5-Difluoro-4-piperazin-1-
478.0



isobutoxy-5-
yl-benzonitrile trifluoro-



methanesulfonyl-
acetic acid (compound 2.13)



benzoyl)-piperazin-1-yl]-
and 2-Isobutoxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 1.3)


165
4-[4-(2-
3,5-Difluoro-4-piperazin-1-
476.1



Cyclopropylmethoxy-5-
yl-benzonitrile trifluoro-



methanesulfonyl-
acetic acid (compound 2.13)



benzoyl)-piperazin-1-yl]-
and 2-Cyclopropylmethoxy-



3,5-difluoro-benzonitrile
5-methanesulfonyl-benzoic




acid (compound 1.4)


166
3,5-Difluoro-4-{4-[5-
3,5-Difluoro-4-piperazin-1-
504.1



methanesulfonyl-2-
yl-benzonitrile trifluoro-



(2,2,2-trifluoro-ethoxy)-
acetic acid (compound 2.13)



benzoyl]-piperazin-1-yl}-
and 5-Methanesulfonyl-2-



benzonitrile
(2,2,2-trifluoro-ethoxy)-




benzoic acid (compound 1.5)


167
4-[4-(2-Cyclopentyloxy-
3,5-Difluoro-4-piperazin-1-
490.3



5-methanesulfonyl-
yl-benzonitrile trifluoro-



benzoyl)-piperazin-1-yl]-
acetic acid (compound 2.13)



3,5-difluoro-benzonitrile
and 2-Cyclopentyloxy-5-




methanesulfonyl-




benzoic acid (compound 1.6)


168
2,6-Difluoro-4-[4-(2-
2,6-Difluoro-4-piperazin-1-
481.1



isopropoxy-5-
yl-benzonitrile trifluoro-
(M + NH4+)



methanesulfonyl-
acetic acid (compound 2.14)



benzoyl)-piperazin-1-yl]-
and 2-Isopropoxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 1.2)


169
2,6-Difluoro-4-[4-(2-
2,6-Difluoro-4-piperazin-1-
495.0



isobutoxy-5-
yl-benzonitrile trifluoro-
(M + NH4+)



methanesulfonyl-
acetic acid (compound 2.14)



benzoyl)-piperazin-1-yl]-
and 2-Isobutoxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 1.3)


170
4-[4-(2-
2,6-Difluoro-4-piperazin-1-
493.0



Cyclopropylmethoxy-5-
yl-benzonitrile trifluoro-
(M + NH4+)



methanesulfonyl-
acetic acid (compound 2.14)



benzoyl)-piperazin-1-yl]-
and 2-Cyclopropylmethoxy-



2,6-difluoro-benzonitrile
5-methanesulfonyl-benzoic




acid (compound 1.4)


171
2,6-Difluoro-4-{4-[5-
2,6-Difluoro-4-piperazin-1-
521.3



methanesulfonyl-2-
yl-benzonitrile trifluoro-
(M + NH4+)



(2,2,2-trifluoro-ethoxy)-
acetic acid (compound 2.14)



benzoyl]-piperazin-1-yl}-
and 5-Methanesulfonyl-2-



benzonitrile
(2,2,2-trifluoro-ethoxy)-




benzoic acid (compound 1.5)


172
4-[4-(2-Cyclopentyloxy-
2,6-Difluoro-4-piperazin-1-
507.3



5-methanesulfonyl-
yl-benzonitrile trifluoro-
(M + NH4+)



benzoyl)-piperazin-1-yl]-
acetic acid (compound 2.14)



2,6-difluoro-benzonitrile
and 2-Cyclopentyloxy-5-




methanesulfonyl-




benzoic acid (compound 1.6)


173
2,4-Difluoro-6-[4-(2-
2,4-Difluoro-6-piperazin-1-
581.4



isopropoxy-5-
yl-benzonitrile trifluoro-
(M + NH4+)



methanesulfonyl-
acetic acid (compound 2.16)



benzoyl)-piperazin-1-yl]-
and 2-Isopropoxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 1.2)


174
2-Fluoro-4-{4-[2-(2-
2-Fluoro-4-piperazin-1-yl-
482.3



fluoro-1-fluoromethyl-
benzonitrile (WO 9808835)



ethoxy)-5-
and 2-(2-Fluoro-1-



methanesulfonyl-
fluoromethyl-ethoxy)-5-



benzoyl]-piperazin-1-yl}-
methanesulfonyl-benzoic



benzonitrile
acid (compound 2.17)


175
3-Fluoro-4-{4-[2-(2-
3-Fluoro-4-piperazin-1-yl-
482.4



fluoro-1-fluoromethyl-
benzonitrile (WO9625414)



ethoxy)-5-
and 2-(2-Fluoro-1-



methanesulfonyl-
fluoromethyl-ethoxy)-5-



benzoyl]-piperazin-1-yl}-
methanesulfonyl-benzoic



benzonitrile
acid (compound 2.17)


176
2,3-Difluoro-4{4-[2-(2-
2,3-Difluoro-4-piperazin-1-
500.3



fluoro-1-fluoromethyl-
yl-benzonitrile-trifluoro-



ethoxy)-5-
acetic acid (compound 2.7)



methanesulfonyl-
and 2-(2-Fluoro-1-



benzoyl]-piperazin-1-yl}-
fluoromethyl-ethoxy)-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 2.17)


177
2,5-Difluoro-4-{4-[2-(2-
2,5-Difluoro-4-piperazin-1-
500.3



fluoro-1-fluoromethyl-
yl-benzonitrile-trifluoro-



ethoxy)-5-
acetic acid (compound 2.8)



methanesulfonyl-
and 2-(2-Fluoro-1-



benzoyl]-piperazin-1-yl}-
fluoromethyl-ethoxy)-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 2.17)


178
3-5-Difluoro-4-{4-[2-(2-
3,5-Difluoro-4-piperazin-1-
500.3



fluoro-1-fluoromethyl-
yl-benzonitrile trifluoro-



ethoxy)-5-
acetic acid (compound 2.13)



methanesulfonyl-
and 2-(2-Fluoro-1-



benzoyl]-piperazin-1-yl}-
fluoromethyl-ethoxy)-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 2.17)


179
2,6-Difluoro-4-{4-[2-(2-
2,6-Difluoro-4-piperazin-1-
500.3



fluoro-1-fluoromethyl-
yl-benzonitrile trifluoro-



ethoxy)-5-
acetic acid (compound 2.14)



methanesulfonyl-
and 2-(2-Fluoro-1-



benzoyl]-piperazin-1-yl}-
fluoromethyl-ethoxy)-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 2.17)


180
2-Fluoro-4-{4-[5-
2-Fluoro-4-piperazin-1-yl
536.3



methanesulfonyl-2-
benzonitrile (WO 9808835)



(2,2,3,3,3-pentafluoro-
and 5-Methanesulfonyl-2-



propoxy)-benzoyl]-
(2,2,3,3,3-pentafluoro-



piperazin-1-yl}-
propoxy)-benzoic acid



benzonitrile
(compound 2.18)


181
3-Fluoro-4-{4-[5-
3-Fluoro-4-piperazin-1-yl-
536.3



methanesulfonyl-2-
benzonitrile (WO9625414)



(2,2,3,3,3-pentafluoro-
and 5-Methanesulfonyl-2-



propoxy)-benzoyl]-
(2,2,3,3,3-pentafluoro-



piperazin-1-yl}-
propoxy)-benzoic acid



benzonitrile
(compound 2.18)


182
[5-Methanesulfonyl-2-
1-(4-Trifluoromethyl-
561.3



(2,2,3,3,3-pentafluoro-
phenyl)-piperazine



propoxy)-phenyl]-[4-(4-
(commercial) and 5-



trifluoromethyl-phenyl)-
Methanesulfonyl-2-



piperazin-1-yl]-
(2,2,3,3,3-pentafluoro-



methanone
propoxy)-benzoic acid




(compound 2.18)


183
[4-(3-Fluoro-4-
1-(3-Fluoro-4-
579.0



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-[5-
piperazine (compound 5.1)



methanesulfonyl-2-
and 5-Methanesulfonyl-2-



(2,2,3,3,3-pentafluoro-
(2,2,3,3,3-pentafluoro-



propoxy)-phenyl]-
propoxy)-benzoic acid



methanone
(compound 2.18)


184
2,3-Difluoro-4-{4-[5-
2,3-Difluoro-4-piperazin-1-
554.0



methanesulfonyl-2-
yl-benzonitrile-trifluoro-



(2,2,3,3,3-pentafluoro-
acetic acid (compound 2.7)



propoxy)-benzoyl]-
and 5-Methanesulfonyl-2-



piperazin-1-yl}-
(2,2,3,3,3-pentafluoro-



benzonitrile
propoxy)-benzoic acid




(compound 2.18)


185
2,5-Difluoro-4-{4-[5-
2,5-Difluoro-4-piperazin-1-
554.0



methanesulfonyl-2-
yl-benzonitrile-trifluoro-



(2,2,3,3,3-pentafluoro-
acetic acid (compound 2.8)



propoxy)-benzoyl]-
and 5-Methanesulfonyl-2-



piperazin-1-yl}-
(2,2,3,3,3-pentafluoro-



benzonitrile
propoxy)-benzoic acid




(compound 2.18)


186
3,5-Difluoro-4-{4-[5-
3,5-Difluoro-4-piperazin-1-
554.0



methanesulfonyl-2-
yl-benzonitrile trifluoro-



(2,2,3,3,3-pentafluoro-
acetic acid (compound 2.13)



propoxy)-benzoyl]-
and 5-Methanesulfonyl-2-



piperazin-1-yl}-
(2,2,3,3,3-pentafluoro-



benzonitrile
propoxy)-benzoic acid




(compound 2.18)


187
2,6-Difluoro-4-{4-[5-
2,6-Difluoro-4-piperazin-1-
571.2



methanesulfonyl-2-
yl-benzonitrile trifluoro-
(M + NH4+)



(2,2,3,3,3-pentafluoro-
acetic acid (compound 2.14)



propoxy)-benzoyl]-
and 5-Methanesulfonyl-2-



piperazin-1-yl}-
(2,2,3,3,3-pentafluoro-



benzonitrile
propoxy)-benzoic acid




(compound 2.18)


188
[4-(2-Fluoro-4-
1-(2-Fluoro-4-
589.3



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine (commercial)



[5-methanesulfonyl-2-
and 5-Methanesulfonyl-2-



(2,2,3,3,3-pentafluoro-
(2,2,3,3,3-pentafluoro-



propoxy)-phenyl]-
propoxy)-benzoic acid



methanone
(compound 2.18)


189
4-{4-[2-(2-Fluoro-1-
4-Piperazin-1-yl-
464.1



fluoromethyl-ethoxy)-5-
benzonitrile (commercial)



methanesulfonyl-
and 2-(2-Fluoro-1-



benzoyl]-piperazin-1-yl}-
fluoromethyl-ethoxy)-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 2.17)


190
[2-(2-Fluoro-1-
1-(4-Trifluoromethyl-
507.3



fluoromethyl-ethoxy)-5-
phenyl)-piperazine



methanesulfonyl-
(commercial) and 2-(2-



phenyl]-[4-(4-
Fluoro-1-fluoromethyl-



trifluoromethyl-phenyl)-
ethoxy)-5-methanesulfonyl-



piperazin-1-yl]-
benzoic acid (compound 2.17)



methanone


191
[2-(2-Fluoro-1-
1-(3-Fluoro-4-
525.2



fluoromethyl-ethoxy)-5-
trifluoromethyl-phenyl)-



methanesulfonyl-
piperazine (compound 5.1)



phenyl]-[4-(3-fluoro-4-
and 2-(2-Fluoro-1-



trifluoromethyl-phenyl)-
fluoromethyl-ethoxy)-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 2.17)


192
[2-(2-Fluoro-1-
1-(2-Fluoro-4-
525.0



fluoromethyl-ethoxy)-5-
trifluoromethyl-phenyl)-



methanesulfonyl-
piperazine (compound



phenyl]-[4-(2-fluoro-4-
1.1) and 2-(2-Fluoro-1-



trifluoromethyl-phenyl)-
fluoromethyl-ethoxy)-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 2.17)


193
[2-(2-Fluoro-1-
1-(2-Fluoro-4-
535.3



fluoromethyl-ethoxy)-5-
methanesulfonyl-phenyl)-



methanesulfonyl-
piperazine (commercial)



phenyl]-[4-(2-fluoro-4-
and 2-(2-Fluoro-1-



methanesulfonyl-
fluoromethyl-ethoxy)-5-



phenyl)-piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 2.17)


194
2-{4-[2-(2-Fluoro-1-
2-Piperazin-1-yl-5-
532.2



fluoromethyl-ethoxy)-5-
trifluoromethyl-benzonitrile



methanesulfonyl-
(compound 5.2) and 2-(2-



benzoyl]-piperazin-1-yl}-
Fluoro-1-fluoromethyl-



5-trifluoromethyl-
ethoxy)-5-methanesulfonyl-



benzonitrile
benzoic acid (compound 2.17)


195
[4-(2,3-Difluoro-4-
1-(2,3-Difluoro-4-
553.2



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine (compound 5.3)



[2-(2-fluoro-1-
and 2-(2-Fluoro-1-



fluoromethyl-ethoxy)-5-
fluoromethyl-ethoxy)-5-



methanesulfonyl-
methanesulfonyl-benzoic



phenyl]-methanone
acid (compound 2.17)


196
4-[4-(2-tert-Butoxy-5-
2,3-Difluoro-4-piperazin-1-
478.3



methanesulfonyl-
yl-benzonitrile-trifluoro-



benzoyl)-piperazin-1-yl]-
acetic acid (compound 2.7)



2,3-difluoro-benzonitrile
and 2-tert-Butoxy-5-




methanesulfonyl-benzoic




acid (compound 2.19)


197
[4-(2,5-Difluoro-4-
1-(2,5-Difluoro-4-
534.3



methanesulfonyl-
methanesulfonyl-phenyl)-
(M + NH4+)



phenyl)-piperazin-1-yl]-
piperazine trifluoro-acetic



(2-isopropoxy-5-
acid (compound 2.20) and



methanesulfonyl-
2-Isopropoxy-5-



phenyl)-methanone
methanesulfonyl-benzoic




acid (compound 1.2)


198
[4-(3,5-Difluoro-4-
1-(3,5-Difluoro-4-
534.3



methanesulfonyl-
methanesulfonyl-phenyl)-
(M + NH4+)



phenyl)-piperazin-1-yl]-
piperazine trifluoro-acetic



(2-isopropoxy-5-
acid (compound 2.21) and



methanesulfonyl-
2-Isopropoxy-5-



phenyl)-methanone
methanesulfonyl-benzoic




acid (compound 1.2)


199
2-[4-(2-Isopropoxy-5-
2-Piperazin-1-yl-
428.5



methanesulfonyl-
benzonitrile (commercial)



benzoyl)-piperazin-1-yl]-
and 2-Isopropoxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 1.2)


200
[4-(2-Fluoro-phenyl)-
1-(2-Fluoro-phenyl)-
421.3



piperazin-1-yl]-(2-
piperazine (commercial)



isopropoxy-5-
and 2-Isopropoxy-5-



methanesulfonyl-
methanesulfonyl-benzoic



phenyl)-methanone
acid (compound 1.2)


201
[4-(4-Chloro-phenyl)-
1-(4-Chloro-phenyl)-
437.3



piperazin-1-yl]-(2-
piperazine (commercial)



isopropoxy-5-
and 2-Isopropoxy-5-



methanesulfonyl-
methanesulfonyl-benzoic



phenyl)-methanone
acid (compound 1.2)


202
5-Chloro-2-[4-(2-
5-Chloro-2-piperazin-1-yl-
462.1



isopropoxy-5-
benzonitrile (WO9625414)



methanesulfonyl-
and 2-Isopropoxy-5-



benzoyl)-piperazin-1-yl]-
methanesulfonyl-benzoic



benzonitrile
acid (compound 1.2)


203
[4-(4-Chloro-2-fluoro-
1-(4-Chloro-2-fluoro-
455.4



phenyl)-piperazin-1-yl]-
phenyl)-piperazine



(2-isopropoxy-5-
hydrochloride (commercial)



methanesulfonyl-
and 2-Isopropoxy-5-



phenyl)-methanone
methanesulfonyl-benzoic




acid (compound 1.2)


204
[4-(4-Chloro-3-
1-(4-Chloro-3-
505.3



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-(2-
piperazine (commercial)



isopropoxy-5-
and 2-Isopropoxy-5-



methanesulfonyl-
methanesulfonyl-benzoic



phenyl)-methanone
acid (compound 1.2)


205
[4-(3,4-Dichloro-
1-(3,4-Dichloro-phenyl)-
471.0



phenyl)-piperazin-1-yl]-
piperazine (commercial)



(2-isopropoxy-5-
and 2-Isopropoxy-5-



methanesulfonyl-
methanesulfonyl-benzoic



phenyl)-methanone
acid (compound 1.2)


206
[4-(2-Fluoro-4-methyl-
1-(2-Fluoro-4-methyl-
435.3



phenyl)-piperazin-1-yl]-
phenyl)-piperazine



(2-isopropoxy-5-
(compound 5.4) and 2-



methanesulfonyl-
Isopropoxy-5-



phenyl)-methanone
methanesulfonyl-benzoic




acid (compound 1.2)


207
rac-2,3-Difluoro-4-{4-[5-
2,3-Difluoro-4-piperazin-1-
535.3



methanesulfonyl-2-
yl-benzonitrile-trifluoro-
(M + NH4+)



(2,2,2-trifluoro-1-
acetic acid (compound 2.7)



methyl-ethoxy)-
and rac-5-Methanesulfonyl-



benzoyl]-piperazin-1-yl}-
2-(2,2,2-trifluoro-1-methyl-



benzonitrile
ethoxy)-benzoic acid




(compound 3.1)


208
(2-Isopropoxy-5-
1-(4-Trifluoromethoxy-
487.3



methanesulfonyl-
phenyl)-piperazine



phenyl)-[4-(4-
(WO03007954) and 2-



trifluoromethoxy-
Isopropoxy-5-



phenyl)-piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 1.2)


209
2-Fluoro-4-{4-[5-
2-Fluoro-4-piperazin-1-yl-
535.3



methanesulfonyl-2-
benzonitrile (WO 9808835)
(M + NH4+)



(2,2,3,3-tetrafluoro-
and 5-Methanesulfonyl-2-



propoxy)-benzoyl]-
(2,2,3,3-tetrafluoro-



piperazin-1-yl}-
propoxy)-benzoic acid



benzonitrile
(compound 2.22)


210
3-Fluoro-4-{4-[5-
3-Fluoro-4-piperazin-1-yl-
535.5



methanesulfonyl-2-
benzonitrile (WO9625414)
(M + NH4+)



(2,2,3,3-tetrafluoro-
and 5-Methanesulfonyl-2-



propoxy)-benzoyl]-
(2,2,3,3-tetrafluoro-



piperazin-1-yl}-
propoxy)-benzoic acid



benzonitrile
(compound 2.22)


211
[5-Methanesulfonyl-2-
1-(4-Trifluoromethyl-
560.3



(2,2,3,3-tetrafluoro-
phenyl)-piperazine
(M + NH4+)



propoxy)-phenyl]-[4-(4-
(commercial) and 5-



trifluoromethyl-phenyl)-
Methanesulfonyl-2-(2,2,3,3-



piperazin-1-yl]-
tetrafluoro-propoxy)-



methanone
benzoic acid (compound 2.22)


212
[4-(2-Fluoro-4-
1-(2-Fluoro-4-
578.2



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-
(M + NH4+)



piperazin-1-yl]-[5-
piperazine (compound



methanesulfonyl-2-
1.1) and 5-



(2,2,3,3-tetrafluoro-
Methanesulfonyl-2-(2,2,3,3-



propoxy)-phenyl]-
tetrafluoro-propoxy)-



methanone
benzoic acid (compound 2.22)


213
2,3-Difluoro-4-{4-[5-
2,3-Difluoro-4-piperazin-1-
553.2



methanesulfonyl-2-
yl-benzonitrile-trifluoro-
(M + NH4+)



(2,2,3,3-tetrafluoro-
acetic acid (compound 2.7)



propoxy)-benzoyl]-
and 5-Methanesulfonyl-2-



piperazin-1-yl}-
(2,2,3,3-tetrafluoro-



benzonitrile
propoxy)-benzoic acid




(compound 2.22)


214
2,5-Difluoro-4-{4-[5-
2,5-Difluoro-4-piperazin-1-
553.2



methanesulfonyl-2-
yl-benzonitrile-trifluoro-
(M + NH4+)



(2,2,3,3-tetrafluoro-
acetic acid (compound 2.8)



propoxy)-benzoyl]-
and 5-Methanesulfonyl-2-



piperazin-1-yl}-
(2,2,3,3-tetrafluoro-



benzonitrile
propoxy)-benzoic acid




(compound 2.22)


215
3,5-Difluoro-4-{4-[5-
3,5-Difluoro-4-piperazin-1-
553.0



methanesulfonyl-2-
yl-benzonitrile trifluoro-
(M + NH4+)



(2,2,3,3-tetrafluoro-
acetic acid (compound 2.13)



propoxy)-benzoyl]-
and 5-Methanesulfonyl-2-



piperazin-1-yl}-
(2,2,3,3-tetrafluoro-



benzonitrile
propoxy)-benzoic acid




(compound 2.22)


216
2,6-Difluoro-4-{4-[5-
2,6-Difluoro-4-piperazin-1-
553.2



methanesulfonyl-2-
yl-benzonitrile trifluoro-
(M + NH4+)



(2,2,3,3-tetrafluoro-
acetic acid (compound 2.14)



propoxy)-benzoyl]-
and 5-Methanesulfonyl-2-



piperazin-1-yl}-
(2,2,3,3-tetrafluoro-



benzonitrile
propoxy)-benzoic acid




(compound 2.22)


217
[4-(2-Fluoro-4-
1-(2-Fluoro-4-
588.3



methanesulfonyl-
methanesulfonyl-phenyl)-
(M + NH4+)



phenyl)-piperazin-1-yl]-
piperazin (commercial)



[5-methanesulfonyl-2-
and 5-Methanesulfonyl-2-



(2,2,3,3-tetrafluoro-
(2,2,3,3-tetrafluoro-



propoxy)-phenyl]-
propoxy)-benzoic acid



methanone
(compound 2.22)


218
[4-(2,6-Difluoro-4-
1-(2,6-Difluoro-4-
517.3



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine trifluoro-acetic



(2-isopropoxy-5-
acid (compound 2.23) and



methanesulfonyl-
2-Isopropoxy-5-



phenyl)-methanone
methanesulfonyl-benzoic




acid (compound 1.2)


219
3-Chloro-4-[4-(2-
3-Chloro-4-piperazin-1-yl-
462.3



isopropoxy-5-
benzonitrile (WO 9625414)



methanesulfonyl-
and 2-Isopropoxy-5-



benzoyl)-piperazin-1-yl]-
methanesulfonyl-benzoic



benzonitrile
acid (compound 1.2)


220
[4-(2-Chloro-4-nitro-
1-(2-Chloro-4-nitro-
482.3



phenyl)-piperazin-1-yl]-
phenyl)-piperazine (EP



(2-isopropoxy-5-
257864) and 2-Isopropoxy-



methanesulfonyl-
5-methanesulfonyl-benzoic



phenyl)-methanone
acid (compound 1.2)


221
3-[4-(2-Isopropoxy-5-
3-Piperazin-1-yl-
428.4



methanesulfonyl-
benzonitrile (WO02068399)



benzoyl)-piperazin-1-yl]-
and 2-Isopropoxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 1.2)


222
[4-(3,5-Dichloro-
1-(3,5-Dichloro-pyridin-4-
474.0



pyridin-4-yl)-piperazin-
yl)-piperazine (commercial)



1-yl]-(2-isopropoxy-5-
and 2-Isopropoxy-5-



methanesulfonyl-
methanesulfonyl-benzoic



phenyl)-methanone
acid (compound 1.2)


223
5-Chloro-2-{4-[5-
5-Chloro-2-piperazin-1-yl-
502.1



methanesulfonyl-2-
benzonitrile (WO9625414)



(2,2,2-trifluoro-ethoxy)-
and 5-Methanesulfonyl-2-



benzoyl]-piperazin-1-yl}-
(2,2,2-trifluoro-ethoxy)-



benzonitrile
benzoic acid (compound 1.5)


224
[4-(4-Chloro-2-fluoro-
1-(4-Chloro-2-fluoro-
495.4



phenyl)-piperazin-1-yl]-
phenyl)-piperazine



[5-methanesulfonyl-2-
hydrochloride (commercial)



(2,2,2-trifluoro-ethoxy)-
and 5-Methanesulfonyl-2-



phenyl]-methanone
(2,2,2-trifluoro-ethoxy)-




benzoic acid (compound 1.5)


225
[4-(4-Chloro-3-
1-(4-Chloro-3-
545.3



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-[5-
piperazine (commercial)



methanesulfonyl-2-
and 5-Methanesulfonyl-2-



(2,2,2-trifluoro-ethoxy)-
(2,2,2-trifluoro-ethoxy)-



phenyl]-methanone
benzoic acid (compound 1.5)


226
[4-(2,5-Difluoro-4-
1-(2,5-Difluoro-4-
574.3



methanesulfonyl-
methanesulfonyl-phenyl)-
(M + NH4+)



phenyl)-piperazin-1-yl]-
piperazine trifluoro-acetic



[5-methanesulfonyl-2-
acid (compound 2.20) and



(2,2,2-trifluoro-ethoxy)-
5-Methanesulfonyl-2-(2,2,2-



phenyl]-methanone
trifluoro-ethoxy)-benzoic




acid (compound 1.5)


227
[4-(2,6-Difluoro-4-
1-(2,6-Difluoro-4-
557.4



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine trifluoro-acetic



[5-methanesulfonyl-2-
acid (compound 2.23) and



(2,2,2-trifluoro-ethoxy)-
5-Methanesulfonyl-2-(2,2,2-



phenyl]-methanone
trifluoro-ethoxy)-benzoic




acid (compound 1.5)


228
5-Chloro-2-[4-(2-
5-Chloro-2-piperazin-1-yl-
474.1



cyclopropylmethoxy-5-
benzonitrile (WO9625414)



methanesulfonyl-
and 2-Cyclopropylmethoxy-



benzoyl)-piperazin-1-yl]-
5-methanesulfonyl-benzoic



benzonitrile
acid (compound 1.4)


229
[4-(4-Chloro-2-fluoro-
1-(4-Chloro-2-fluoro-
467.3



phenyl)-piperazin-1-yl]-
phenyl)-piperazine



(2-cyclopropylmethoxy-
hydrochloride (commercial)



5-methanesulfonyl-
and 2-Cyclopropylmethoxy-



phenyl)-methanone
5-methanesulfonyl-benzoic




acid (compound 1.4)


230
(2-Cyclopropylmethoxy-
1-(3,4-Dichloro-phenyl)-
483.3



5-methanesulfonyl-
piperazine (commercial)



phenyl)-[4-(3,4-
and 2-Cyclopropylmethoxy-



dichloro-phenyl)-
5-methanesulfonyl-benzoic



piperazin-1-yl]-
acid (compound 1.4)



methanone


231
[4-(4-Chloro-3-
1-(4-Chloro-3-
517.0



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-(2-
piperazine (commercial)



cyclopropylmethoxy-5-
and 2-Cyclopropylmethoxy-



methanesulfonyl-
5-methanesulfonyl-benzoic



phenyl)-methanone
acid (compound 1.4)


232
(2-Cyclopropylmethoxy-
1-(2,5-Difluoro-4-
546.3



5-methanesulfonyl-
methanesulfonyl-phenyl)-
(M + NH4+)



phenyl)-[4-(2,5-difluoro-
piperazine trifluoro-acetic



4-methanesulfonyl-
acid (compound 2.20) and



phenyl)-piperazin-1-yl]-
2-Cyclopropylmethoxy-5-



methanone
methanesulfonyl-benzoic




acid (compound 1.4)


233
(2-Cyclopropylmethoxy-
1-(2,6-Difluoro-4-
546.3



5-methanesulfonyl-
methanesulfonyl-phenyl)-
(M + NH4+)



phenyl)-[4-(2,6-difluoro-
piperazine trifluoro-acetic



4-methanesulfonyl-
acid (compound 2.23) and



phenyl)-piperazin-1-yl]-
2-Cyclopropylmethoxy-5-



methanone
methanesulfonyl-benzoic




acid (compound 1.4)


234
4-[4-(2-tert-Butoxy-5-
2,5-Difluoro-4-piperazin-1-
478.1



methanesulfonyl-
yl-benzonitrile-trifluoro-



benzoyl)-piperazin-1-yl]-
acetic acid (compound 2.8)



2,5-difluoro-benzonitrile
and 2-tert-Butoxy-5-




methanesulfonyl-benzoic




acid (compound 2.19)


235
4-[4-(2-tert-Butoxy-5-
3,5-Difluoro-4-piperazin-1-
478.1



methanesulfonyl-
yl-benzonitrile trifluoro



benzoyl)-piperazin-1-yl]-
acetic acid (compound 2.13)



3,5-difluoro-benzonitrile
and 2-tert-Butoxy-5-




methanesulfonyl-benzoic




acid (compound 2.19)


236
4-[4-(2-tert-Butoxy-5-
2,6-Difluoro-4-piperazin-1-
478.1



methanesulfonyl-
yl-benzonitrile trifluoro-



benzoyl)-piperazin-1-yl]-
acetic acid (compound 2.14)



2,6-difluoro-benzonitrile
and 2-tert-Butoxy-5-




methanesulfonyl-benzoic




acid (compound 2.19)


237
(2-tert-Butoxy-5-
1-(2-Fluoro-4-
530.2



methanesulfonyl-
methanesulfonyl-phenyl)-
(M + NH4+)



phenyl)-[4-(2-fluoro-4-
piperazine (commercial)



methanesulfonyl-
and 2-tert-Butoxy-5-



phenyl)-piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 2.19)


238
2-[4-(2-tert-Butoxy-5-
2-Piperazin-1-yl-5-
527.3



methanesulfonyl-
trifluoromethyl-benzonitrile
(M + NH4+)



benzoyl)-piperazin-1-yl]-
(compound 5.2) and 2-tert-



5-trifluoromethyl-
Butoxy-5-methanesulfonyl-



benzonitrile
benzoic acid (compound 2.19)


239
(2-tert-Butoxy-5-
1-(2,3-Difluoro-4-
548.3



methanesulfonyl-
methanesulfonyl-phenyl)-
(M + NH4+)



phenyl)-[4-(2,3-difluoro-
piperazine (compound 5.3)



4-methanesulfonyl-
and 2-tert-Butoxy-5-



phenyl)-piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 2.19)


240
(2-tert-Butoxy-5-
1-(3-Chloro-5-
520.3



methanesulfonyl-
trifluoromethyl-pyridin-2-



phenyl)-[4-(3-chloro-5-
yl)-piperazine (commercial)



trifluoromethyl-pyridin-
and 2-tert-Butoxy-5-



2-yl)-piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 2.19)


241
(2-tert-Butoxy-5-
1-(5-Chloro-pyridin-2-yl)-
452.3



methanesulfonyl-
piperazine (WO01062751)



phenyl)-[4-(5-chloro-
and 2-tert-Butoxy-5-



pyridin-2-yl)-piperazin-
methanesulfonyl-benzoic



1-yl]-methanone
acid (compound 2.19)


242
(2-tert-Butoxy-5-
1-(5-Trifluoromethyl-
486.4



methanesulfonyl-
pyridin-2-yl)-



phenyl)-[4-(5-
piperazine (commercial)



trifluoromethyl-pyridin-
and 2-tert-Butoxy-5-



2-yl)-piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 2.19)


243
4-[4-(2-tert-Butoxy-5-
2-Fluoro-4-piperazin-1-yl-
460.3



methanesulfonyl-
benzonitrile (WO 9808835)



benzoyl)-piperazin-1-yl]-
and 2-tert-Butoxy-5-



2-fluoro-benzonitrile
methanesulfonyl-benzoic




acid (compound 2.19)


244
4-[4-(2-tert-Butoxy-5-
3-Fluoro-4-piperazin-1-yl-
460.3



methanesulfonyl-
benzonitrile (WO9625414)



benzoyl)-piperazin-1-yl]
and 2-tert-Butoxy-5-



3-fluoro-benzonitrile
methanesulfonyl-benzoic




acid (compound 2.19)


245
(2-tert-Butoxy-5-
1-(4-Trifluoromethyl-
485.5



methanesulfonyl-
phenyl)-piperazine



phenyl)-[4-(4-
(commercial) and 2-tert-



trifluoromethyl-phenyl)-
Butoxy-5-methanesulfonyl-



piperazin-1-yl]-
benzoic acid (compound 2.19)



methanone


246
(2-tert-Butoxy-5-
1-(3-Fluoro-4-
503.1



methanesulfonyl-
trifluoromethyl-phenyl)-



phenyl)-[4-(3-fluoro-4-
piperazine (compound 5.1)



trifluoromethyl-phenyl)-
and 2-tert-Butoxy-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 2.19)


247
(2-tert-Butoxy-5-
1-(2-Fluoro-4-
503.3



methanesulfonyl-
trifluoromethyl-phenyl)-



phenyl)-[4-(2-fluoro-4-
piperazine (compound 1.1)



trifluoromethyl-phenyl)-
and 2-tert-Butoxy-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 2.19)


248
6-[4-(2-tert-Butoxy-5-
6-Piperazin-1-yl-
443.4



methanesulfonyl-
nicotinonitrile



benzoyl)-piperazin-1-yl]-
(commercial) and 2-tert-



nicotinonitrile
Butoxy-5-methanesulfonyl-




benzoic acid (compound 2.19)


249
(2-tert-Butoxy-5-
1-(2,5-Difluoro-4-
548.3



methanesulfonyl-
methanesulfonyl-phenyl)-
(M + NH4+)



phenyl)-[4-(2,5-difluoro-
piperazine trifluoro-acetic



4-methanesulfonyl-
acid (compound 2.20) and



phenyl)-piperazin-1-yl]-
2-tert-Butoxy-5-



methanone
methanesulfonyl-benzoic




acid (compound 2.19)


250
(2-tert-Butoxy-5-
1-(2,6-Difluoro-4-
548.3



methanesulfonyl-
methanesulfonyl-phenyl)-
(M + NH4+)



phenyl)-[4-(2,6-difluoro-
piperazine trifluoro-acetic



4-methanesulfonyl-
acid (compound 2.23) and



phenyl)-piperazin-1-yl]-
2-tert-Butoxy-5-



methanone
methanesulfonyl-benzoic




acid (compound 2.19)


251
[4-(3,4-Dichloro-
1-(3,4-Dichloro-phenyl)-
511.0



phenyl)-piperazin-1-yl]-
piperazine (commercial)



[5-methanesulfonyl-2-
and 5-Methanesulfonyl-2-



(2,2,2-trifluoro-ethoxy)-
(2,2,2-trifluoro-ethoxy)-



phenyl]-methanone
benzoic acid (compound 1.5)


252
2-[4-(2-Isopropoxy-5-
2-Piperazin-1-yl-
429.5



methanesulfonyl-
nicotinonitrile



benzoyl)-piperazin-1-yl]-
(commercial) and 2-



nicotinonitrile
Isopropoxy-5-




methanesulfonyl-benzoic




acid (compound 1.2)


253
(2-Isopropoxy-5-
2-Piperazin-1-yl-4-
473.0



methanesulfonyl-
trifluoromethyl-



phenyl)-[4-(4-
pyrimidine (commercial)



trifluoromethyl-
and 2-Isopropoxy-5-



pyrimidin-2-yl)-
methanesulfonyl-benzoic



piperazin-1-yl]-
acid (compound 1.2)



methanone


254
rac-[4-(2,5-Difluoro-4-
1-(2,5-Difluoro-4-
571.0



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine trifluoro-acetic



[5-methanesulfonyl-2-
acid (compound 2.20) and



(2,2,2-trifluoro-1-
rac-5-Methanesulfonyl-2-



methyl-ethoxy)-phenyl]-
(2,2,2-trifluoro-1-methyl-



methanone
ethoxy)-benzoic acid




(compound 3.1)


255
rac-[4-(2,6-Difluoro-4-
1-(2,6-Difluoro-4-
571.2



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine trifluoro-acetic



[5-methanesulfonyl-2-
acid (compound 2.23) and



(2,2,2-trifluoro-1-
rac-5-Methanesulfonyl-2-



methyl-ethoxy)-phenyl]-
(2,2,2-trifluoro-1-methyl-



methanone
ethoxy)-benzoic acid




(compound 3.1)


256
rac-5-Chloro-2-{4-[5-
5-Chloro-2-piperazin-1-yl-
516.2



methanesulfonyl-2-
benzonitrile (WO9625414)



(2,2,2-trifluoro-1-
and rac-5-Methanesulfonyl-



methyl-ethoxy)-
2-(2,2,2-trifluoro-1-methyl-



benzoyl]-piperazin-1-yl}-
ethoxy)-benzoic acid



benzonitrile
(compound 3.1)


257
rac-[4-(4-Chloro-2-
1-(4-Chloro-2-fluoro-
509.3



fluoro-phenyl)-
phenyl)-piperazine



piperazin-1-yl]-[5-
hydrochloride (commercial)



methanesulfonyl-2-
and rac-5-Methanesulfonyl-



(2,2,2-trifluoro-1-
2-(2,2,2-trifluoro-1-methyl-



methyl-ethoxy)-phenyl]-
ethoxy)-benzoic acid



methanone
(compound 3.1)


258
rac-[4-(3,4-Dichloro-
1-(3,4-Dichloro-phenyl)-
525.2



phenyl)-piperazin-1-yl]-
piperazine (commercial)



[5-methanesulfonyl-2-
and rac-5-Methanesulfonyl-



(2,2,2-trifluoro-1-
2-(2,2,2-trifluoro-1-methyl-



methyl-ethoxy)-phenyl]-
ethoxy)-benzoic acid



methanone
(compound 3.1)


259
rac-[4-(4-Chloro-3-
1-(4-Chloro-3-
559.0



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-[5-
piperazine (commercial)



methanesulfonyl-2-
and rac-5-Methanesulfonyl-



(2,2,2-trifluoro-1-
2-(2,2,2-trifluoro-1-methyl-



methyl-ethoxy)-phenyl]-
ethoxy)-benzoic acid



methanone
(compound 3.1)


260
rac-3,5-Difluoro-4-{4-[5-
3,5-Difluoro-4-piperazin-1-
518.2



methanesulfonyl-2-
yl-benzonitrile trifluoro-



(2,2,2-trifluoro-1-
acetic acid (compound 2.13)



methyl-ethoxy)-
and rac-5-Methanesulfonyl-



benzoyl]-piperazin-1-yl}-
2-(2,2,2-trifluoro-1-methyl-



benzonitrile
ethoxy)-benzoic acid




(compound 3.1)


261
rac-2,5-Difluoro-4-{4-[5-
2,5-Difluoro-4-piperazin-1-
518.0



methanesulfonyl-2-
yl-benzonitrile-trifluoro-



(2,2,2-trifluoro-1-
acetic acid (compound 2.8)



methyl-ethoxy)-
and rac-5-Methanesulfonyl-



benzoyl]-piperazin-1-yl-}-
2-(2,2,2-trifluoro-1-methyl-



benzonitrile
ethoxy)-benzoic acid




(compound 3.1)


262
rac-2,6-Difluoro-4-{4-[5-
2,6-Difluoro-4-piperazin-1-
517.8



methanesulfonyl-2-
yl-benzonitrile trifluoro-



(2,2,2-trifluoro-1-
acetic acid (compound 2.14)



methyl-ethoxy)-
and rac-5-Methanesulfonyl-



benzoyl]-piperazin-1-yl}-
2-(2,2,2-trifluoro-1-methyl-



benzonitrile
ethoxy)-benzoic acid




(compound 3.1)


263
(2-Cyclopropylmethoxy-
2-Piperazin-1-yl-4-
485.1



5-methanesulfonyl-
trifluoromethyl-pyrimidine



phenyl)-[4-(4-
(commercial) and 2-



trifluoromethyl-
Cyclopropylmethoxy-5-



pyrimidin-2-yl)-
methanesulfonyl-benzoic



piperazin-1-yl]-
acid (compound 1.4)



methanone


264
(2-Isopropoxy-5-
4-Piperazin-1-yl-2-
473.1



methanesulfonyl-
trifluoromethyl-pyrimidine



phenyl)-[4-(2-
trifluoro-acetic acid



trifluoromethyl-
(WO030249) and 2-



pyrimidin-4-yl)-
Isopropoxy-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 1.2)


265
(2-tert-Butoxy-5-
1-(3-Fluoro-5-
504.0



methanesulfonyl-
trifluoromethyl-pyridin-2-



phenyl)-[4-(3-fluoro-5-
yl)-piperazine (compound



trifluoromethyl-pyridin-
5.5) and 2-tert-Butoxy-5-



2-yl)-piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 2.19)


266
(2-tert-Butoxy-5-
2-Piperazin-1-yl-4-
487.1



methanesulfonyl-
trifluoromethyl-



phenyl)-[4-(4-
pyrimidine (commercial)



trifluoromethyl-
and 2-tert-Butoxy-5-



pyrimidin-2-yl)-
methanesulfonyl-benzoic



piperazin-1-yl]-
acid (compound 2.19)



methanone


267
[5-Methanesulfonyl-2-
2-Piperazin-1-yl-4-
513.3



(2,2,2-trifluoro-ethoxy)-
trifluoromethyl-



phenyl]-[4-(4-
pyrimidine (commercial)



trifluoromethyl-
and 5-Methanesulfonyl-2-



pyrimidin-2-yl)-
(2,2,2-trifluoro-ethoxy)-



piperazin-1-yl]-
benzoic acid (compound 1.5)



methanone


268
rac-[5-Methanesulfonyl-
2-Piperazin-1-yl-4-
527.0



2-(2,2,2-trifluoro-1-
trifluoromethyl-



methyl-ethoxy)-phenyl]-
pyrimidine (commercial)



[4-(4-trifluoromethyl-
and rac-5-Methanesulfonyl-



pyrimidin-2-yl)-
2-(2,2,2-trifluoro-1-methyl-



piperazin-1-yl]-
ethoxy)-benzoic acid



methanone
(compound 3.1)


269
[4-(2,5-Difluoro-4-
1-(2,5-Difluoro-4-
571.0



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine trifluoro-acetic



[5-methanesulfonyl-2-
acid and 5-



((S)-2,2,2-trifluoro-1-
Methanesulfonyl-2-((S)-



methyl-ethoxy)-phenyl]-
2,2,2-trifluoro-1-methyl-



methanone
ethoxy)-benzoic acid




(compound 5.6)


270
[4-(2,5-Difluoro-4-
1-(2,5-Difluoro-4-
571.0



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine trifluoro-acetic



[5-methanesulfonyl-2-
acid (compound 2.20) and



((R)-2,2,2-trifluoro-1-
5-Methanesulfonyl-2-((R)-



methyl-ethoxy)-phenyl]-
2,2,2-trifluoro-1-methyl-



methanone
ethoxy)-benzoic acid




(compound 5.7)


271
[4-(2,6-Difluoro-4-
1-(2,6-Difluoro-4-
571.2



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine trifluoro-acetic



[5-methanesulfonyl-2-
acid (compound 2.23) and



((S)-2,2,2-trifluoro-1-
5-Methanesulfonyl-2-((S)-



methyl-ethoxy)-phenyl]-
2,2,2-trifluoro-1-methyl-



methanone
ethoxy)-benzoic acid




(compound 5.6)


272
[4-(2,6-Difluoro-4-
1-(2,6-Difluoro-4-
571.2



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine trifluoro-acetic



[5-methanesulfonyl-2-
acid (compound 2.23) and



((R)-2,2,2-trifluoro-1-
5-Methanesulfonyl-2-((R)-



methyl-ethoxy)-phenyl]-
2,2,2-trifluoro-1-methyl-



methanone
ethoxy)-benzoic acid




(compound 5.7)


273
rac-[5-Methanesulfonyl-
4-Piperazin-1-yl-2-
527.0



2-(2,2,2-trifluoro-1-
trifluoromethyl-pyrimidine



methyl-ethoxy)-phenyl]-
trifluoro-acetic acid



[4-(2-trifluoromethyl-
(WO030249) and rac-5-



pyrimidin-4-yl)-
Methanesulfonyl-2-(2,2,2-



piperazin-1-yl]-
trifluoro-1-methyl-ethoxy)-



methanone
benzoic acid (compound 3.1)


274
rac-[5-Methanesulfonyl-
4-Piperazin-1-yl-6-
527.2



2-(2,2,2-trifluoro-1-
trifluoromethyl-pyrimidine



methyl-ethoxy)-phenyl]-
trifluoro-acetic acid



[4-(6-trifluoromethyl-
(compound 2.24) and rac-5-



pyrimidin-4-yl)-
Methanesulfonyl-2-(2,2,2-



piperazin-1-yl]-
trifluoro-1-methyl-ethoxy)-



methanone
benzoic acid (compound 3.1)


275
rac-[5-Methanesulfonyl-
2-Piperazin-1-yl-5-
527.2



2-(2,2,2-trifluoro-1-
trifluoromethyl-pyrimidine



methyl-ethoxy)-phenyl]-
(compound 2.25) and rac-5-



[4-(5-trifluoromethyl-
Methanesulfonyl-2-(2,2,2-



pyrimidin-2-yl)-
trifluoro-1-methyl-ethoxy)-



piperazin-1-yl]-
benzoic acid (compound 3.1)



methanone


276
(2-Isopropoxy-5-
2-Piperazin-1-yl-5-
473.1



methanesulfonyl-
trifluoromethyl-pyrimidine



phenyl)-[4-(5-
(compound 2.25) and 2-



trifluoromethyl-
Isopropoxy-5-



pyrimidin-2-yl)-
methanesulfonyl-benzoic



piperazin-1-yl]-
acid (compound 1.2)



methanone


277
(2-Cyclopropylmethoxy-
4-Piperazin-1-yl-2-
485.1



5-methanesulfonyl-
trifluoromethyl-pyrimidine



phenyl)-[4-(2-
trifluoro-acetic acid



trifluoromethyl-
(WO030249) and 2-



pyrimidin-4-yl)-
Cyclopropylmethoxy-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 1.4)


278
(2-Cyclopropylmethoxy-
4-Piperazin-1-yl-6-
485.5



5-methanesulfonyl-
trifluoromethyl-pyrimidine



phenyl)-[4-(6-
trifluoro-acetic acid



trifluoromethyl-
(compound 2.24) and 2-



pyrimidin-4-yl)-
Cyclopropylmethoxy-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 1.4)


279
[5-Methanesulfonyl-2-
4-Piperazin-1-yl-2-
513.3



(2,2,2-trifluoro-ethoxy)-
trifluoromethyl-pyrimidine



phenyl]-[4-(2-
trifluoro-acetic acid



trifluoromethyl-
(WO030249) and 5-



pyrimidin-4-yl)-
Methanesulfonyl-2-(2,2,2-



piperazin-1-yl]-
trifluoro-ethoxy)-benzoic



methanone
acid (compound 1.5)


280
[5-Methanesulfonyl-2-
4-Piperazin-1-yl-6-
513.3



(2,2,2-trifluoro-ethoxy)-
trifluoromethyl-pyrimidine



phenyl]-[4-(6-
trifluoro-acetic acid



trifluoromethyl-
(compound 2.24) and 5-



pyrimidin-4-yl)-
Methanesulfonyl-2-(2,2,2-



piperazin-1-yl]-
trifluoro-ethoxy)-benzoic



methanone
acid (compound 1.5)









In analogy to Example 1.2 (b) compounds 3.1 to 3.5 of the following table were prepared from 2-chloro-5-methanesulfonyl-benzoic acid and the appropriate alcohol:













Expl.





No
Compound Name
Alcohol
MS (m/e)







3.1
rac-5-Methanesulfonyl-
rac-1,1,1-Trifluoro-
311.3 (MH−)



2-(2,2,2-trifluoro-1-
propan-2-ol



methyl ethoxy)-benzoic



acid (compound 3.1)


3.2
2-Cyclohexyloxy-5-
Cyclohexanol
297.3 (MH−)



methanesulfonyl-benzoic



acid (compound 3.2)


3.3
2-(2,2-Dimethyl-
2,2-Dimethyl-
285.1 (MH−)



propoxy)-5-
propan-1-ol



methanesulfonyl-benzoic



acid (compound 3.3)


3.4
2-Cyclobutoxy-5-
cyclobutanol
269.3 (MH−)



methanesulfonyl-benzoic



acid (compound 3.4)


3.5
rac-2-sec-Butoxy-5-
Butan-2-ol
271.4 (MH−)



methanesulfonyl-benzoic



acid (compound 3.5)









In analogy to Example 5 compounds 281 to 326 of the following table were prepared from the acid derivatives and piperazine derivatives.













Expl.


MW found


No.
Systematic Name
Starting materials
(MH+)







281
1-{4-[4-(2-
1-(3-Fluoro-4-piperazin-1-
503.5



Cyclohexyloxy-5-
yl-phenyl)-ethanone



methanesulfonyl-
(WO9714690) and 2-



benzoyl)-piperazin-1-yl]-
Cyclohexyloxy-5-



3-fluoro-phenyl}-
methanesulfonyl-benzoic



ethanone
acid (compound 3.2)


282
4-[4-(2-Cyclohexyloxy-
4-Piperazin-1-yl-
468.5



5-methanesulfonyl-
benzonitrile (commercial)



benzoyl)-piperazin-1-yl]-
and 2-Cyclohexyloxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 3.2)


283
4-[4-(2-Cyclohexyloxy-
3-Fluoro-4-piperazin-1-yl-
486.5



5-methanesulfonyl-
benzonitrile (WO9625414)



benzoyl)-piperazin-1-yl]-
and 2-Cyclohexyloxy-5-



3-fluoro-benzonitrile
methanesulfonyl-benzoic




acid (compound 3.2)


284
4-[4-(2-Cyclohexyloxy-
2-Fluoro-4-piperazin-1-yl-
486.5



5methanesulfonyl-
benzonitrile (WO 9808835)



benzoyl)-piperazin-1-yl]-
and 2-Cyclohexyloxy-5-



2-fluoro-benzonitrile
methanesulfonyl-benzoic




acid (compound 3.2)


285
(2-Cyclohexyloxy-5-
1-(4-Trifluoromethyl-
511.5



methanesulfonyl-
phenyl)-piperazine



phenyl)-[4-(4-
(commercial) and 2-



trifluoromethyl-phenyl)-
Cyclohexyloxy-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 3.2)


286
(2-Cyclohexyloxy-5-
1-(2-Fluoro-4-
529.5



methanesulfonyl-
trifluoromethyl-phenyl)-



phenyl)-[4-(2-fluoro-4-
piperazine (compound



trifluoromethyl-phenyl)-
1.1) and 2-Cyclohexyloxy-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 3.2)


287
(2-Cyclohexyloxy-5-
1-(3-Fluoro-4-
529.3



methanesulfonyl-
trifluoromethyl-phenyl)-



phenyl)-[4-(3-fluoro-4-
piperazine (compound 5.1)



trifluoromethyl-phenyl)-
and 2-Cyclohexyloxy-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 3.2)


288
(2-Cyclohexyloxy-5-
1-(2-Fluoro-4-
539.5



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-[4-(2-fluoro-4-
piperazine (commercial)



methanesulfonyl-
and 2-Cyclohexyloxy-5-



phenyl)-piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 3.2)


289
1-(4-{4-[2-(2,2-
1-(3-Fluoro-4-piperazin-1-
491.5



Dimethyl-propoxy)-5-
yl-phenyl)-ethanone



methanesulfonyl-
(WO9714690) and 2-(2,2-



benzoyl]-piperazin-
Dimethyl-propoxy)-5-



1-yl}-3-fluoro-phenyl)-
methanesulfonyl-benzoic



methanone
acid (compound 3.3)


290
4-{4-[2-(2,2-Dimethyl-
4-Piperazin-1-yl-
456.6



propoxy)-5-methanesulfonyl-
benzonitrile (commercial)



benzoyl]-piperazin-1-
and 2-(2,2-Dimethyl-



yl}-benzonitrile
propoxy)-5-




methanesulfonyl-benzoic




acid (compound 3.3)


291
4-{4-[2-(2,2-Dimethyl-
3-Fluoro-4-piperazin-1-yl-
474.4



propoxy)-5-
benzonitrile (WO9625414)



methanesulfonyl-
and 2-(2,2-Dimethyl-



benzoyl]-piperazin-1-yl}-
propoxy)-5-



3-fluoro-benzonitrile
methanesulfonyl-benzoic




acid (compound 3.3)


292
4-{4-[2-(2,2-Dimethyl-
2-Fluoro-4-piperazin-1-yl-
474.5



propoxy)-5-methanesulfonyl-
benzonitrile (WO 9808835)



benzoyl]-piperazin-1-
and 2-(2,2-Dimethyl-



yl}-2-fluoro-benzonitrile
propoxy)-5-




methanesulfonyl-benzoic




acid (compound 3.3)


293
[2-(2,2-Dimethyl-
1-(4-Trifluoromethyl-
499.4



propoxy)-5-
phenyl)-piperazine



methanesulfonyl-
(commercial) and 2-(2,2-



phenyl]-[4-(4-
Dimethyl-propoxy)-5-



trifluoromethyl-phenyl)-
methanesulfonyl-benzoic



piperazin-1-yl]-
acid (compound 3.3)



methanone


294
[2-(2,2-Dimethyl-
1-(2-Fluoro-4-
517.5



propoxy)-5-methanesulfonyl-
trifluoromethyl-phenyl)-



phenyl]-[4-(2-
piperazine (compound



fluoro-4-trifluoromethyl-
1.1) and 2-(2,2-Dimethyl-



phenyl)-piperazin-1-yl]-
propoxy)-5-



methanone
methanesulfonyl-benzoic




acid (compound 3.3)


295
[2-(2,2-Dimethyl-
1-(3-Fluoro-4-
517.5



propoxy)-5-methane
trifluoromethyl-phenyl)-



sulfonyl-phenyl]-[4-(3-
piperazine (compound 5.1)



fluoro-4-trifluoromethyl-
and 2-(2,2-Dimethyl-



phenyl)-piperazin-1-yl]-
propoxy)-5-



methanone
methanesulfonyl-benzoic




acid (compound 3.3)


296
[2-(2,2-Dimethyl-
1-(2-Fluoro-4-
527.3



propoxy)-5-
methanesulfonyl-phenyl)-



methanesulfonyl-
piperazine (commercial)



phenyl]-[4-(2-fluoro-4-
and 2-(2,2-Dimethyl-



methanesulfonyl-
propoxy)-5-



phenyl)-piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 3.3)


297
rac-1-(3-Fluoro-4-{4-[5-
1-(3-Fluoro-4-piperazin-1-
517.5



methanesulfonyl-2-
yl-phenyl)-ethanone



(2,2,2-trifluoro-1-
(WO9714690)and rac-5-



methyl-ethoxy)-
Methanesulfonyl-2-(2,2,2-



benzoyl]-piperazin-1-yl}-
trifluoro-1-methyl-ethoxy)-



phenyl)-ethanone
benzoic acid (compound 3.1)


298
rac-4-{4-[5-
4-Piperazin-1-yl-
482.5



Methanesulfonyl-2-
benzonitrile (commercial)



(2,2,2-trifluoro-1-
and rac-5-Methanesulfonyl-



methyl-ethoxy)-
2-(2,2,2-trifluoro-1-methyl-



benzoyl]-piperazin-1-yl}-
ethoxy)-benzoic acid



benzonitrile
(compound 3.1)


299
rac-3-Fluoro-4-{4-[5-
3-Fluoro-4-piperazin-1-yl-
500.4



methanesulfonyl-2-
benzonitrile (WO9625414)



(2,2,2-trifluoro-1-
and rac-5-Methanesulfonyl-



methyl-ethoxy)-
2-(2,2,2-trifluoro-1-methyl-



benzoyl]-piperazin-1-yl}-
ethoxy)-benzoic acid



benzonitrile
(compound 3.1)


300
rac-2-Fluoro-4-{4-[5-
2-Fluoro-4-piperazin-1-yl
500.4



methanesulfonyl-2-
benzonitrile (WO 9808835)



(2,2,2-trifluoro-1-
and rac-5-Methanesulfonyl-



methyl-ethoxy)-
2-(2,2,2-trifluoro-1-methyl-



benzoyl]-piperazin-1-yl}-
ethoxy)-benzoic acid



benzonitrile
(compound 3.1)


301
rac-5-Methanesulfonyl-
1-(4-Trifluoromethyl-
525.3



2-(2,2,2-trifluoro-1-
phenyl)-piperazine



methyl-ethoxy)-phenyl]-
(commercial) and rac-5-



[4-(4-trifluoromethyl-
Methanesulfonyl-2-(2,2,2-



phenyl)-piperazin-1-yl]-
trifluoro-1-methyl-ethoxy)-



methanone
benzoic acid (compound 3.1)


302
rac-[4-(2-Fluoro-4-
1-(2-Fluoro-4-
543.5



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-[5-
piperazine (compound



methanesulfonyl-2-
1.1) and rac-5-Methanesulfonyl-



(2,2,2-trifluoro-1-
2-(2,2,2-trifluoro-



methyl-ethoxy)-phenyl]-
1-methyl-ethoxy)-benzoic



methanone
acid (compound 3.1)


303
rac-[4-(3-Fluoro-4-
1-(3-Fluoro-4-
543.5



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-[5-
piperazine (compound 5.1)



methanesulfonyl-2-
and rac-5-Methanesulfonyl-



(2,2,2-trifluoro-1-
2-(2,2,2-trifluoro-1-methyl-



methyl-ethoxy)-phenyl]-
ethoxy)-benzoic acid



methanone
(compound 3.1)


304
rac-[4-(2-Fluoro-4-
1-(2-Fluoro-4-
553.0



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine (commercial)



[5-methanesulfonyl-2-
and rac-5-Methanesulfonyl-



(2,2,2-trifluoro-1-
2-(2,2,2-trifluoro-1-methyl-



methyl-ethoxy)-phenyl]-
ethoxy)-benzoic acid



methanone
(compound 3.1)


305
4-{4-[5-Methanesulfonyl-
4-Piperazin-1-yl-
444.3



2-(2-methoxy-ethoxy)-
benzonitrile (commercial)



benzoyl]-piperazin-1-yl}-
and 5-Methanesulfonyl-2-



benzonitrile
(2-methoxy-ethoxy)-




benzoic acid (compound 1.10)


306
3-Fluoro-4-{4-[5-
3-Fluoro-4-piperazin-1-yl-
462.5



methanesulfonyl-2-
benzonitrile (WO9625414)



(2-methoxy-ethoxy)-
and 5-Methanesulfonyl-2-



benzoyl]-piperazin-1-yl}-
(2-methoxy-ethoxy)-



benzonitrile
benzoic acid (compound 1.10)


307
2-Fluoro-4-{4-[5-
2-Fluoro-4-piperazin-1-yl-
462.5



methanesulfonyl-2-
benzonitrile (WO 9808835)



(2-methoxy-ethoxy)-
and 5-Methanesulfonyl-2-



benzoyl]-piperazin-1-yl}-
(2-methoxy-ethoxy)-



benzonitrile
benzoic acid (compound 1.10)


308
[4-(2-Fluoro-4-
1-(2-Fluoro-4-
505.5



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-[5-
piperazine (compound 1.1)



methanesulfonyl-2-(2-
and 5-Methanesulfonyl-2-(2-



methoxy-ethoxy)-
methoxy-ethoxy)-benzoic



phenyl]-methanone
acid (compound 1.10)


309
[4-(3-Fluoro-4-
1-(3-Fluoro-4-
505.5



trifluoromethyl-phenyl)-
trifluoromethyl-phenyl)-



piperazin-1-yl]-[5-
piperazine (compound 5.1)



methanesulfonyl-2-(2-
and 5-Methanesulfonyl-2-



methoxy-ethoxy)-
(2-methoxy-ethoxy)-



phenyl]-methanone
benzoic acid (compound 1.10)


310
[4-(2-Fluoro-4-
1-(2-Fluoro-4-
515.5



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-yl]-
piperazine (commercial)



[5-methanesulfonyl-2-
and 5-Methanesulfonyl-2-



(2-methoxy-ethoxy)-
(2-methoxy-ethoxy)-



phenyl]-methanone
benzoic acid (compound 1.10)


311
1-{4-[4-(2-Cyclobutoxy-
1-(3-Fluoro-4-piperazin-1-
475.4



5-methanesulfonyl-
yl-phenyl)-ethanone



benzoyl)-piperazin-1-yl]-
(WO9714690) and 2-



3-fluoro-phenyl}-
Cyclobutoxy-5-



ethanone
methanesulfonyl-benzoic




acid (compound 3.4)


312
4-[4-(2-Cyclobutoxy-5-
4-Piperazin-1-yl-
440.5



methanesulfonyl-
benzonitrile (commercial)



benzoyl)-piperazin-1-yl]-
and 2-Cyclobutoxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 3.4)


313
4-[4-(2-Cyclobutoxy-5-
3-Fluoro-4-piperazin-1-yl-
458.5



methanesulfonyl-
benzonitrile (WO9625414)



benzoyl)-piperazin-1-yl]-
and 2-Cyclobutoxy-5-



3-fluoro-benzonitrile
methanesulfonyl-benzoic




acid (compound 3.4)


314
4-[4-(2-Cyclobutoxy-5-
2-Fluoro-4-piperazin-1-yl-
458.5



methanesulfonyl-
benzonitrile (WO 9808835)



benzoyl)-piperazin-1-yl]-
and 2-Cyclobutoxy-5-



2-fluoro-benzonitrile
methanesulfonyl-benzoic




acid (compound 3.4)


315
(2-Cyclobutoxy-5-
1-(4-Trifluoromethyl-
483.5



methanesulfonyl-
phenyl)-piperazine



phenyl)-[4-(4-
(commercial) and 2-



trifluoromethyl-phenyl)-
Cyclobutoxy-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 3.4)


316
(2-Cyclobutoxy-5-
1-(2-Fluoro-4-
501.5



methanesulfonyl-
trifluoromethyl-phenyl)-



phenyl)-[4-(2-fluoro-4-
piperazine (compound



trifluoromethyl-phenyl)-
1.1) and 2-Cyclobutoxy-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 3.4)


317
(2-Cyclobutoxy-5-
1-(3-Fluoro-4-
501.5



methanesulfonyl-
trifluoromethyl-phenyl)-



phenyl)-[4-(3-fluoro-4-
piperazine (compound 5.1)



trifluoromethyl-phenyl)-
and 2-Cyclobutoxy-5-



piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 3.4)


318
(2-Cyclobutoxy-5-
1-(2-Fluoro-4-
511.5



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-[4-(2-fluoro-4-
piperazine (commercial)



methanesulfonyl-
and 2-Cyclobutoxy-5-



phenyl)-piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 3.4)


319
rac-1-{4-[4-(2-sec-
1-(3-Fluoro-4-piperazin-1-
477.4



Butoxy-5-
yl-phenyl)-ethanone



methanesulfonyl-
(WO9714690) and rac-2-



benzoyl)-piperazin-1-yl]-
sec-Butoxy-5-



3-fluoro-phenyl}-
methanesulfonyl-benzoic



ethanone
acid (compound 3.5)


320
rac-4-[4-(2-sec-Butoxy-
4-Piperazin-1-yl-
442.5



5-methanesulfonyl-
benzonitrile (commercial)



benzoyl)-piperazin-1-yl]-
and rac-2-sec-Butoxy-5-



benzonitrile
methanesulfonyl-benzoic




acid (compound 3.5)


321
rac-4-[4-(2-sec-Butoxy-
3-Fluoro-4-piperazin-1-yl-
460.5



5-methanesulfonyl-
benzonitrile (WO9625414)



benzoyl)-piperazin-1-yl]-
and rac-2-sec-Butoxy-5-



3-fluoro-benzonitrile
methanesulfonyl-benzoic




acid (compound 3.5)


322
rac-4-[4-(2-sec-Butoxy-
2-Fluoro-4-piperazin-1-yl-
460.5



5-methanesulfonyl-
benzonitrile (WO 9808835)



benzoyl)-piperazin-1-yl]-
and rac-2-sec-Butoxy-5-



2-fluoro-benzonitrile
methanesulfonyl-benzoic




acid (compound 3.5)


323
rac-(2-sec-Butoxy-5-
1-(4-Trifluoromethyl-
485.5



methanesulfonyl-
phenyl)-piperazine



phenyl)-[4-(4-
(commercial) and rac-2-sec-



trifluoromethyl-phenyl)-
Butoxy-5-methanesulfonyl-



piperazin-1-yl]-
benzoic acid (compound 3.5)



methanone


324
rac-(2-sec-Butoxy-5-
1-(2-Fluoro-4-
503.3



methanesulfonyl-
trifluoromethyl-phenyl)-



phenyl)-[4-(2-fluoro-4-
piperazine (compound



trifluoromethyl-
1.1) and rac-2-sec-Butoxy-



phenyl)-piperazin-1-yl]-
5-methanesulfonyl-benzoic



methanone
acid (compound 3.5)


325
rac-(2-sec-Butoxy-5-
1-(3-Fluoro-4-
503.3



methanesulfonyl-
trifluoromethyl-phenyl)-



phenyl)-[4-(3-fluoro-4-
piperazine (compound 5.1)



trifluoromethyl-
and rac-2-sec-Butoxy-5-



phenyl)-piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 3.5)


326
rac-(2-sec-Butoxy-5-
1-(2-Fluoro-4-
513.5



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-[4-(2-fluoro-4-
piperazine (commercial)



methanesulfonyl-
and rac-2-sec-Butoxy-5-



phenyl)-piperazin-1-yl]-
methanesulfonyl-benzoic



methanone
acid (compound 3.5)









EXAMPLE 4.1 
Preparation of 6-Ethoxy-2-fluoro-3-methanesulfonyl-benzoic acid
(a) 3-Chlorosulfonyl-2,6-difluoro-benzoic acid
95 mmol of 2,6-difluorobenzoic acid in 19 ml of chorosulfonic acid was stirred for 2 h at 150°. The mixture was poured into 200 ml of ice and stirred for 20 min. The resulting slurry 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%)
(b) 2,6-Difluoro-3-sulfino-benzoic acid
41 mmol of 3-chlorosulfonyl-2,6-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 sulfuric acid. The sulfinic acid was extracted with ethyl acetate, dried over MgSO4 and concentrated to yield the title compound as a colorless solid. MS (m/e): 220.9 (M−H, 100%)
(c) 6-Ethoxy-2-fluoro-3-methanesulfonyl-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 was added, and the mixture was refluxed for 2 hours. Concentration to about 100 ml precipitated a yellowish solid which was filtered and triturated with diethyl ether to give the crude title compound, which was used without further purification.
EXAMPLE 4.2 
Preparation of 1-(4-Trifluoromethanesulfonyl-phenyl)-piperazine
A mixture of 1 mmol 1-Bromo-4-trifluoromethanesulfonyl-benzene [Nodiff et al., J. Org. Chem. 25, 60 (1960)], 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; Et2O/cyclohexane) to yield the title compound as a colorless solid. MS (m/e): 295.2 (MH+, 100%)
EXAMPLE 4.3 
Preparation of 1-(2,4-Bis-trifluoromethyl-phenyl)-piperazine hydrochloride
(a) 4-(2,4-Bis-trifluoromethyl-phenyl)-piperazine-1-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-2,2′-bis(diphenylphosphino)-1,1′-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 (SiO2; cyclohexane/ethyl acetate 9:1) to yield the title compound as a yellowish oil.
MS (m/e): 399.1 (MH+, 100%)
(b) 1-(2,4-Bis-trifluoromethyl-phenyl)-piperazine hydrochloride
3 mmol of 4-(2,4-Bis-trifluoromethyl-phenyl)-piperazine-1-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 1-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazine hydrochloride
(a) 4-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester
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, 2 mmol of 3-(4-bromo-phenyl)-5-methyl-[1,2,4]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) 1-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazine hydrochloride
1 mmol of 4-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester was stirred in 3 ml of 1,4-dioxane saturated with gaseous HCl. After 2 h at room temperature, the reaction mixture was evaporated to dryness to yield the tide compound as a colorless solid. MS (m/e): 245.1 (MH+, 100%)
EXAMPLE 4.5 
Preparation of 1-(4-Oxazol-2-yl-phenyl)-piperazine hydrochloride
(a) 4-Bromo-N-(2,2-dimethoxy-ethyl)-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 was 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%)
(b) 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-yl-phenyl)-piperazine-1-carboxylic 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%)
(d) 1-(4-Oxazol-2-yl-phenyl)-piperazine hydrochloride
Prepared in analogy to example 4.4 (b) from 4-(4-Oxazol-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 230.1 (MH+, 100%)
EXAMPLE 4.6 
Preparation of 1-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-piperazine hydrochloride
(a) 2-(4-Bromo-phenyl)-[1,3,4]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-[1,3,4]Oxadiazol-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
Prepared in analogy to example 4.4 (a) from 2-(4-Bromo-phenyl)-[1,3,4]oxadiazole and N-BOC-piperazine.
MS (m/e): 342.2 (MH+, 100%)
(c) 1-[4-(5-Methyl-[1.3,4]oxadiazol-2-yl)-phenyl]-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 1-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine hydrochloride
(a) 5-(4-Bromo-phenyl)-2-methyl-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 (SiO2; cyclohexane/ethyl acetate 7:3). MS (m/e): 239.1 (MH+, 29%)
(b) 4-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine-1-carboxylic 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) 1-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine hydrochloride
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 3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester hydrochloride
(a) 2,3,5,6-Tetrahydro-[1,2′]bipyrazinyl-4,5′-dicarboxylic acid 4-tert-butyl ester 5′-methyl 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) 3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester hydrochloride
Prepared in analogy to example 4.4 (b) from 2,3,5,6-Tetrahydro-[1,2′]bipyrazinyl-4,5′-dicarboxylic acid 4-tert-butyl ester 5′-methyl ester and 1,4-dioxane saturated with gaseous HCl. MS (m/e): 223.1 (MH+, 100%)
EXAMPLE 4.9 
Preparation of 6′-Chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl trifluoroacetate
(a) 6′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester
A mixture of 10 mmol 2,6-dichloropyrazine and 21 mmol of N-BOC-piperazine in 15 ml acetonitrile was heated under reflux for 1.5 hours. The reaction mixture was concentrated and purified by chromatography (SiO2; dichloromethane/methanol 95:5) to yield the title compound as a colorless solid. MS (m/e): 299.2 (MH+, 100%)
(b) 6′-Chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl trifluoroacetate
A solution of 2 mmol 6′-Chloro-2,3,5,6-tetrahydro-[1,2′]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-[1,2′]bipyrazinyl-5′-carboxylic acid amide hydrochloride
(a) 5′-Carbamoyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester
3 mmol of 2,3,5,6-Tetrahydro-[1,2′]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-Tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid amide hydrochloride
0.25 mmol of 5′-Carbamoyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester was stirred for 1 hour in 1 ml of dioxane saturated with gaseous HCl. 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-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester
A solution of 11 mmol of 2,4-dichlorotriazine (WO 02/083654) in 20 ml 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 100 ml 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%)
(b) 4-(4-Dimethylamino-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester
A solution of 2 mmol of 4-(4-Chloro-[1,3,5]triazin-2-yl)-piperazine-1-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/cyclohexane 1:1) yielded the title compound as a colorless solid. MS (m/e): 309.1 (MH+, 100%)
(c) Dimethyl-(4-piperazin-1-yl-[1,3,5]triazin-2-yl)-amine
A solution of 1 mmol of 4-(4-Dimethylamino-[1,3,5]triazin-2-yl)-piperazine-1-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, 50 ml of 2M aqueous sodium hydroxide was 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′]bipyrazinyl
(a) 6′-Methoxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester
1 mmol of 6′-Chloro-2,3,5,6-tetrahydro-[1,2′]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 (SiO2; dichloromethane/methanol 99:1) to yield the title compound as a colorless foam. MS (m/e): 295.3 (MH+, 100%)
(b) 6′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl
Prepared in analogy to example 4.10 (c) from 6′-Methoxy-2,3,5,6-tetrahydro-[1,2′]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-Methoxy-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester
1 mmol of 4-(4-Chloro-[1,3,5]triazin-2-yl)-piperazine-1-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 title compound purified by recrystallisation from ethyl acetate/cyclohexane. MS (m/e): 296.3 (MH+, 100%)
(b) 2-Methoxy-4-piperazin-1-yl-[1,3,5]triazine
Prepared in analogy to example 4.10 (c) from 4-(4-Methoxy-[1,3,5]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)-N′-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 then 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-Dimethylcarbamoyloxy-5-methanesulfonyl-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 (SiO2; ethyl acetate/cyclohexane 1.1). MS (m/e): 378.3 (MH+, 100%)
(c) 2-Dimethylcarbamoyloxy-5-methanesulfonyl-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:













Expl.


MW found


No.
Systematic Name
Starting materials
(MH+)







327
(6-Ethoxy-2-fluoro-3-
1-(4-Methanesulfonyl-phenyl)-
485.4



methanesulfonyl-
piperazine (commercial) and



phenyl)-[4-(4-
6-Ethoxy-2-fluoro-3-



methanesulfonyl-
methanesulfonyl-benzoic acid



phenyl)-piperazin-1-
(compound 4.1)



yl]-methanone


328
(2-Isopropoxy-5-
1-(4-Trifluoromethanesulfonyl-
552.0



methanesulfonyl-
phenyl)-piperazine
(M + NH4+)



phenyl)-[4-(4-
(compound 4.2) and 2-



trifluoromethanesulfonyl-
Isopropoxy-5-



phenyl)-piperazin-1-yl]-
methanesulfonyl-benzoic acid



methanone
(compound 1.2)


329
(2-Cyclopentyloxy-5-
1-(4-Trifluoromethanesulfonyl-
578.0



methanesulfonyl-
phenyl)-piperazine
(M + NH4+)



phenyl)-[4-(4-
(compound 4.2) and 2-



trifluoromethanesulfonyl-
Cyclopentyloxy-5-methanesulfonyl-



phenyl)-piperazin-1-yl]-
benzoic acid (compound 1.6)



methanone


330
(2-Isobutoxy-5-
1-(4-Trifluoromethanesulfonyl-
566.1



methanesulfonyl-
phenyl)-piperazine
(M + NH4+)



phenyl)-[4-(4-
(compound 4.2) and 2-



trifluoromethanesulfonyl-
Isobutoxy-5-methanesulfonyl-



phenyl)-piperazin-1-yl]-
benzoic acid (compound 1.3)



methanone


331
[4-(2,4-Bis-
1-(2,4-Bis-trifluoromethyl-
539.2



trifluoromethyl-
phenyl)-piperazine



phenyl)-piperazin-1-
hydrochloride (compound 4.3)



yl]-(2-isopropoxy-5-
and 2-Isopropoxy-5-



methanesulfonyl-
methanesulfonyl-benzoic acid



phenyl)-methanone
(compound 1.2)


332
[4-(2,4-Bis-
1-(2,4-Bis-trifluoromethyl-
565.3



trifluoromethyl-
phenyl)-piperazine



phenyl)-piperazin-1-
hydrochloride (compound 4.3)



yl]-(2-cyclopentyloxy-
and 2-Cyclopentyloxy-5-



5-methanesulfonyl-
methanesulfonyl-



phenyl)-methanone
benzoic acid (compound 1.6)


333
[4-(2,4-Bis-
1-(2,4-Bis-trifluoromethyl-
553.2



trifluoromethyl-
phenyl)-piperazine



phenyl)-piperazin-1-
hydrochloride (compound 4.3)



yl]-(2-isobutoxy-5-
and 2-Isobutoxy-5-



methanesulfonyl-
methanesulfonyl-benzoic acid



phenyl)-methanone
(compound 1.3)


334
(2-Isobutoxy-5-
1-[4-(5-Methyl-
499.1



methanesulfonyl-
[1,2,4]oxadiazol-3-yl)-phenyl]-



phenyl)-{4-[4-(5-
piperazine hydrochloride



methyl-
(compound 4.4) and 2-



[1,2,4]oxadiazol-3-yl)-
Isobutoxy-5-methanesulfonyl-



phenyl]-piperazin-1-
benzoic acid (compound 1.3)



yl}-methanone


335
(2-Cyclopentyloxy-5-
1-[4-(5-Methyl-
511.4



methanesulfonyl-
[1,2,4]oxadiazol-3-yl)-phenyl]-



phenyl)-{4-[4-(5-
piperazine hydrochloride



methyl-
(compound 4.4) and 2-



[1,2,4]oxadiazol-3-yl)-
Cyclopentyloxy-5-



phenyl]-piperazin-1-
methanesulfonyl-



yl}-methanone
benzoic acid (compound 1.6)


336
(2-Isobutoxy-5-
1-(4-Oxazol-2-yl-phenyl)-
484.4



methanesulfonyl-
piperazine; hydrochloride



phenyl)-[4-(4-oxazol-
(compound 4.5) and 2-



2-yl-phenyl)-
Isobutoxy-5-methanesulfonyl-



piperazin-1-yl]-
benzoic acid (compound 1.3)



methanone


337
(2-Cyclopentyloxy-5-
1-(4-Oxazol-2-yl-phenyl)-
496.4



methanesulfonyl-
piperazine; hydrochloride



phenyl)-[4-(4-oxazol-
(compound 4.5) and 2-



2-yl-phenyl)-
Cyclopentyloxy-5-



piperazin-1-yl]-
methanesulfonyl-



methanone
benzoic acid (compound 1.6)


338
(2-Isopropoxy-5-
1-[4-(5-Methyl-[1,3,4]
485.3



methanesulfonyl-
oxadiazol-2-yl)-phenyl]-



phenyl)-{4-[4-(5-
piperazine hydrochloride



methyl-
(compound 4.6) and 2-



[1,3,4]oxadiazol-2-yl)-
Isopropoxy-5-methane



phenyl]-piperazin-1-
sulfonyl-benzoic acid



yl}-methanone
(compound 1.2)


339
(2-Isobutoxy-5-
1-[4-(5-Methyl-[1,3,4]
499.2



methanesulfonyl-
oxadiazol-2-yl)-phenyl]-



phenyl)-{4-[4-(5-
piperazine hydrochloride



methyl-
(compound 4.6) and 2-



[1,3,4]oxadiazol-2-yl)-
Isobutoxy-5-methanesulfonyl-



phenyl]-piperazin-1-
benzoic acid (compound 1.3)



yl}-methanone


340
(2-Cyclopentyloxy-5-
1-[4-(5-Methyl-
511.3



methanesulfonyl-
[1,3,4]oxadiazol-2-yl)-phenyl]-



phenyl)-{4-[4-(5-
piperazine hydrochloride



methyl-
(compound 4.6) and 2-



[1,3,4]oxadiazol-2-yl)-
Cyclopentyloxy-5-



phenyl]-piperazin-1-
methanesulfonyl-



yl}-methanone
benzoic acid (compound 1.6)


341
(2-Isobutoxy-5-
1-[4-(2-Methyl-2H-tetrazol-5-
499.1



methanesulfonyl-
yl)-phenyl]-piperazine;



phenyl)-{4-[4-(2-
hydrochloride (compound



methyl-2H!-tetrazol-
4.7) and 2-Isobutoxy-5-



5-yl)-phenyl]-
methanesulfonyl-benzoic acid



piperazin-1-yl}-
(compound 1.3)



methanone


342
4-(2-Isopropoxy-5-
3,4,5,6-Tetrahydro-2H-
463.4



methanesulfonyl-
[1,2′]bipyrazinyl-5′-carboxylic



benzoyl)-3,4,5,6-
acid methyl ester;



tetrahydro-2H-
hydrochloride (compound



[1,2′]bipyrazinyl-5′-
4.8) and 2-Isopropoxy-5-



carboxylic acid methyl
methanesulfonyl-benzoic acid



ester
(compound 1.2)


343
4-(2-Isobutoxy-5-
3,4,5,6-Tetrahydro-2H-
477.1



methanesulfonyl-
[1,2′]bipyrazinyl-5′-carboxylic



benzoyl)-3,4,5,6-
acid methyl ester;



tetrahydro-2H-
hydrochloride (compound



[1,2′]bipyrazinyl-5′-
4.8) and 2-Isobutoxy-5-



carboxylic acid methyl
methanesulfonyl-benzoic acid



ester
(compound 1.3)


344
(6′-Chloro-2,3,5,6-
6′-Chloro-3,4,5,6-tetrahydro-
439.1



tetrahydro-
2H-[1,2′]bipyrazinyl; trifluoro-



[1,2′]bipyrazinyl-4-
acetic acid (compound 4.9)



yl)-(2-isopropoxy-5-
and 2-Isopropoxy-5-



methanesulfonyl-
methanesulfonyl-benzoic acid



phenyl)-methanone
(compound 1.2)


345
4-(2-Isopropoxy-5-
3,4,5,6-Tetrahydro-2H-
448.3



methanesulfonyl-
[1,2′]bipyrazinyl-5′-carboxylic



benzoyl)-3,4,5,6-
acid amide; hydrochloride



tetrahydro-2H-
(compound 4.10) and 2-



[1,2′]bipyrazinyl-5′-
Isopropoxy-5-methanesulfonyl-



carboxylic acid amide
benzoic acid (compound 1.2)


346
4-(2-Isobutoxy-5-
3,4,5,6-Tetrahydro-2H-
462.3



methanesulfonyl-
[1,2′]bipyrazinyl-5′-carboxylic



benzoyl)-3,4,5,6-
acid amide; hydrochloride



tetrahydro-2H-
(compound 4.10) and 2-



[1,2′]bipyrazinyl-5′-
Isobutoxy-5-methanesulfonyl-



carboxylic acid amide
benzoic acid (compound 1.3)


347
[4-(4-Dimethylamino-
Dimethyl-(4-piperazin-1-yl-
463.3



[1,3,5]triazin-2-yl)-
[1,3,5]triazin-2-yl)-amine



piperazin-1-yl]-(2-
(compound 4.11) and 2-



isobutoxy-5-
Isobutoxy-5-methanesulfonyl-



methanesulfonyl-
benzoic acid (compound 1.3)



phenyl)-methanone


348
[4-(4-Dimethylamino-
Dimethyl-(4-piperazin-1-yl-
449.3



[1,3,5]triazin-2-yl)-
[1,3,5]triazin-2-yl)-amine



piperazin-1-yl]-(2-
(compound 4.11) and 2-



isopropoxy-5-
Isopropoxy-5-methane



methanesulfonyl-
sulfonyl-benzoic acid



phenyl)-methanone
(compound 1.2)


349
(2-Isopropoxy-5-
6′-Methoxy-3,4,5,6-tetrahydro-
435.2



methanesulfonyl-
2H-[1,2′]bipyrazinyl; trifluoro-



phenyl)-(6′-methoxy-
acetic acid (compound 4.12)



2,3,5,6-tetrahydro-
and 2-Isopropoxy-5-methanesulfonyl-



[1,2′]bipyrazinyl-4-
benzoic acid (compound 1.2)



yl)-methanone


350
(2-Isopropoxy-5-
2-Methoxy-4-piperazin-1-yl-
436.4



methanesulfonyl-
[1,3,5]triazine (compound



phenyl)-[4-(4-methoxy-
4.13) and 2-Isopropoxy-5-



[1,3,5]triazin-2-yl)-
methanesulfonyl-benzoic acid



piperazin-1-yl]-
(compound 1.2)



methanone


351
Dimethyl-carbamic
1-(4-Trifluoromethyl-phenyl)-
500.4



acid 4-methanesulfonyl-
piperazine (commercial) and



2-[4-(4-trifluoromethyl-
2-Dimethylcarbamoyloxy-5-



phenyl)-piperazine-1-
methanesulfonyl-benzoic acid



carbonyl]-phenyl ester
(compound 4.14)


352
Dimethyl-carbamic
1-(2-Fluoro-4-methane
528.3



acid 2-[4-(2-fluoro-4-
sulfonyl-phenyl)-piperazine



methanesulfonyl-
(commercial) and 2-



phenyl)-piperazine-1-
Dimethylcarbamoyloxy-5-



carbonyl]-4-
methanesulfonyl-benzoic acid



methanesulfonyl-
(compound 4.14)



phenyl ester


353
(2-Cyclopropylmethoxy-
1-Phenyl-piperazine
415.5



5-methanesulfonyl-
(commercial) and 2-



phenyl)-(4-
Cyclopropylmethoxy-5-



phenyl-piperazin-1-
methanesulfonyl-benzoic acid



yl)-methanone
(compound 1.4)


354
(2-Cyclopropylmethoxy-
1-(4-Methoxy-phenyl)-
445.3



5-methanesulfonyl-
piperazine (commercial) and



phenyl)-[4-(4-
2-Cyclopropylmethoxy-5-



methoxy-phenyl)-
methanesulfonyl-benzoic acid



piperazin-1-yl]-
(compound 1.4)



methanone


355
(2-Cyclopropylmethoxy-
4-Piperazin-1-yl-phenol
431.4



5-methanesulfonyl-
(commercial) and 2-



phenyl)-[4-(4-
Cyclopropylmethoxy-5-



hydroxy-phenyl)-
methanesulfonyl-benzoic acid



piperazin-1-yl]-
(compound 1.4)



methanone









EXAMPLE 356 
Preparation of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone oxime
0.12 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-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 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone O-methyl-oxime
0.12 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-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 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-Chlorosulfonyl-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-methanesulfonyl-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-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone
This compound was prepared in analogy to example 5 from 1-(2-fluoro-4-methanesulfonyl-phenyl)-piperazine and 2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m/e): 477.0 (MH+, 67%)
EXAMPLE 4.16 
Preparation of 4-[4-(2,6-Difluoro-3-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile
Prepared in analogy to example 5 from 4-piperazin-1-yl-benzonitrile and 2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m/e): 406.3 (MH+, 84%)
EXAMPLE 358 
Preparation of (2-Cyclopentyloxy-6-ethoxy-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-1-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 (SiO2; 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-1-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 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-Cyclopentyloxy-2-fluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-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-1-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-1-yl]-benzonitrile and sodium isopropanolate. MS (m/e): 446.0 (MH+, 49%)
EXAMPLE 5.1 
Preparation of 1-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine
(a) 4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic 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) 1-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine
A mixture of 2.87 mmol 4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-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%)
EXAMPLE 5.2 
Preparation of 2-Piperazin-1-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 1-(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 1-(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 1-(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-1-methyl-ethoxy)-benzoic acid
(a) rac-5-Methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl 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-1-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.
(b) 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester
The title compound was obtained by separation of rac-5-Methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester by chiral HPLC (Chiralcel OD, 15% ethanol/Heptane, flow 35 ml, 220 nm, retention time: 86 min.).
(c) 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid
The compound was prepared in analogy to compound 2.10(b) from 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-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-1-methyl-ethoxy)-benzoic acid
(a) 5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester
The title compound was obtained by separation of rac-5-Methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester by chiral HPLC (Chiralcel OD, 15% ethanol/Heptane, flow 35 ml, 220 nm, retention time: 74 min.).
(b) 5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid
The compound was prepared in analogy to compound 2.10(b) from 5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-1-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 1-(2-Fluoro-4-piperazin-1-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 1-(3-Fluoro-4-methanesulfonyl-phenyl)-piperazine
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 1-(4-Fluoro-2-piperazin-1-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 5.12 
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-Ethanesulfonyl-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 1-(4-Difluoromethyl-2-fluoro-phenyl)-piperazine
(a) 1-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.
(b) 1-(4-Difluoromethyl-2-fluoro-phenyl)-piperazine
The compound was prepared in analogy to compound 1.1 from 1-Chloro-4-difluoromethyl-2-fluoro-benzene. MS (m/e): 231.2 (M+H+, 100%)
EXAMPLE 5.15 
Preparation of 1-(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-1-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 1-(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-trifluoromethyl-pyridine [615579-78-1] (WO03087056). MS (m/e): 227 (M+H+, 100%)
EXAMPLE 5.18 
Preparation of 1-(6-Methyl-pyridin-3-yl)-piperazine
The compound was prepared in analogy to compound 1.1 from 5-Bromo-2-methyl-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:













Expl.


MW found


No.
Systematic Name
Starting materials
(MH+)







363
2-[4-(2-Isopropoxy-5-
2-Piperazin-1-yl-5-
496.3



methanesulfonyl-
trifluoromethyl-benzonitrile



benzoyl)-piperazin-1-
(compound 5.2) and 2-



yl]-5-trifluoromethyl-
Isopropoxy-5-methanesulfonyl-



benzonitrile
benzoic acid (compound 1.2)


364
4-[4-(2-Isopropoxy-5-
4-Piperazin-1-yl-2-
496.3



methanesulfonyl-
trifluoromethyl-benzonitrile



benzoyl)-piperazin-1-
(WO0017163) and 2-



yl]-2-trifluoromethyl-
Isopropoxy-5-methanesulfonyl-



benzonitrile
benzoic acid (compound 1.2)


365
1-{4-[4-(2-Isopropoxy-
1-(4-Piperazin-1-yl-2-
513.4



5-methanesulfonyl-
trifluoromethyl-phenyl)-



benzoyl)-piperazin-1-
ethanone (WO0210277) and



yl]-2-trifluoromethyl-
2-Isopropoxy-5-methanesulfonyl-



phenyl}-ethanone
benzoic acid (compound 1.2)


366
2-Chloro-4-[4-(2-
2-Chloro-4-piperazin-1-yl-
462.3



isopropoxy-5-
benzonitrile (compound 5.8)



methanesulfonyl-
and 2-Isopropoxy-5-



benzoyl)-piperazin-1-
methanesulfonyl-benzoic acid



yl]-benzonitrile
(compound 1.2)


367
1-{2-Fluoro-4-[4-(2-
1-(2-Fluoro-4-piperazin-1-yl-
463.4



isopropoxy-5-
phenyl)-ethanone (compound



methanesulfonyl-
5.9) and 2-Isopropoxy-5-



benzoyl)-piperazin-1-
methanesulfonyl-benzoic acid



yl]-phenyl}-ethanone
(compound 1.2)


368
[4-(3-Fluoro-4-
1-(3-Fluoro-4-
499.3



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-
piperazine (compound 5.10)



yl]-(2-isopropoxy-5-
and 2-Isopropoxy-5-



methanesulfonyl-
methanesulfonyl-benzoic acid



phenyl)-methanone
(compound 1.2)


369
1-{4-[4-(2-Cyclopropyl
1-(2-Fluoro-4-piperazin-1-yl-
475.4



methoxy-5-methanesulfonyl-
phenyl)-ethanone (compound



benzoyl)-piperazin-1-yl]-2-
5.9) and 2-Cyclopropyl



fluoro-phenyl}-ethanone
methoxy-5-methanesulfonyl-




benzoic acid (compound 1.4)


370
(2-Cyclopropyl
1-(3-Fluoro-4-methanesulfonyl-
511.4



methoxy-5-methanesulfonyl-
phenyl)-piperazine



phenyl)-[4-(3-fluoro-4-
(compound 5.10) and 2-



methanesulfonyl-phenyl)-
Cyclopropylmethoxy-5-



piperazin-1-yl]methanone-
methanesulfonyl-benzoic acid




(compound 1.4)


371
[4-(3-Fluoro-4-
1-(3-Fluoro-4-methanesulfonyl-
513.4



methanesulfonyl-
phenyl)-piperazine



phenyl)-piperazin-1-
(compound 5.10) and 2-



yl]-(2-isobutoxy-5-
Isobutoxy-5-methanesulfonyl-



methanesulfonyl-
benzoic acid (compound 1.3)



phenyl)-methanone


372
1-{2-Fluoro-4-[4-(2-
1-(2-Fluoro-4-piperazin-1-yl-
477.3



isobutoxy-5-
phenyl)-ethanone (compound



methanesulfonyl-
5.9) and 2-Isobutoxy-5-



benzoyl)-piperazin-1-
methanesulfonyl-benzoic acid



yl]-phenyl}-ethanone
(compound 1.3)


373
2-[4-(2-
2-Piperazin-1-yl-5-
522.4



Cyclopentyloxy-5-
trifluoromethyl-benzonitrile



methanesulfonyl-
(compound 5.2) and 2-



benzoyl)-piperazin-1-
Cyclopentyloxy-5-methanesulfonyl-



yl]-5-trifluoromethyl-
benzoic acid (compound 1.6)



benzonitrile


374
2-[4-(2-Cyclopropyl
2-Piperazin-1-yl-5-trifluoromethyl-
508.6



methoxy-5-methanesulfonyl-
benzonitrile (compound 5.2) and 2-



benzoyl)-piperazin-1-yl]-5-
Cyclopropylmethoxy-5-



trifluoromethyl-
methanesulfonyl-benzoic acid



benzonitrile
(compound 1.4)


375
2-[4-(2-Isobutoxy-5-
2-Piperazin-1-yl-5-trifluoromethyl-
510.6



methanesulfonyl-
benzonitrile (compound 5.2) and 2-



benzoyl)-piperazin-1-
Isobutoxy-5-methanesulfonyl-



yl]-5-trifluoromethyl-
benzoic acid (compound 1.3)



benzonitrile


376
2-{4-[5-Methanesulfonyl-
2-Piperazin-1-yl-5-trifluoromethyl-
536.5



2-(2,2,2-
benzonitrile



trifluoro-ethoxy)-
(compound 5.2) and 5-



benzoyl]-piperazin-1-
Methanesulfonyl-2-(2,2,2-



yl}-5-trifluoromethyl-
trifluoro-ethoxy)-benzoic acid



benzonitrile
(compound 1.5)


377
rac-[4-(3-Fluoro-4-
1-(3-Fluoro-4-methanesulfonyl-
553.2



methanesulfonyl-
phenyl)-piperazine



phenyl)-piperazin-1-
(compound 5.10) and rac-5-



yl]-[5-methanesulfonyl-
Methanesulfonyl-2-(2,2,2-



2-(2,2,2-trifluoro-1-
trifluoro-1-methyl-ethoxy)-



methyl-ethoxy)-
benzoic acid (compound 3.1)



phenyl]-methanone


378
rac-1-(2-Fluoro-4-{4-
1-(2-Fluoro-4-piperazin-1-yl-
517.4



[5-methanesulfonyl-2-
phenyl)-ethanone (compound



(2,2,2-trifluoro-1-
5.9) and rac-5-Methanesulfonyl-



methyl-ethoxy)-
2-(2,2,2-trifluoro-1-



benzoyl]-piperazin-1-
methyl-ethoxy)-benzoic acid



yl}-phenyl)-ethanone
(compound 3.1)


379
1-{4-Fluoro-2-[4-(2-
1-(4-Fluoro-2-piperazin-1 yl-
463.4



isopropoxy-5-
phenyl)-ethanone (compound



methanesulfonyl-
5.11) and 2-Isopropoxy-5-



benzoyl)-piperazin-1-
methanesulfonyl-benzoic acid



yl]-phenyl}-ethanone
(compound 1.2)


380
3-[4-(2-Fluoro-4-
1-(2-Fluoro-4-trifluoromethyl-
454.6



trifluoromethyl-
phenyl)-piperazine (compound



phenyl)-piperazine-1-
1.1) and 6-Isopropoxy-



carbonyl]-4-
isophthalamic acid (compound 5.12)



isopropoxy-benzamide


381
4-Isopropoxy-3-[4-(4-
1-(4-Trifluoromethyl-phenyl)-
436.4



trifluoromethyl-
piperazine (commercial) and



phenyl)-piperazine-1-
6-Isopropoxy-isophthalamic



carbonyl]-benzamide
acid (compound 5.12)


382
3-[4-(3-Fluoro-4-
1-(3-Fluoro-4-trifluoromethyl-
454.6



trifluoromethyl-
phenyl)-piperazine (compound



phenyl)-piperazine-1-
5.1) and 6-Isopropoxy-



carbonyl]-4-
isophthalamic acid (compound 5.12)



isopropoxy-benzamide


383
3-[4-(2-Fluoro-4-
1-(2-Fluoro-4-methanesulfonyl-
464.4



methanesulfonyl-
phenyl)-piperazine



phenyl)-piperazine-1-
(commercial) and 6-



carbonyl]-4-
Isopropoxy-isophthalamic acid



isopropoxy-benzamide
(compound 5.12)


384
3-[4-(2-Cyano-4-
2-Piperazin-1-yl-5-trifluoromethyl-
461.4



trifluoromethyl-
benzonitrile



phenyl)-piperazine-1-
(compound 5.2) and 6-



carbonyl]-4-
Isopropoxy-isophthalamic acid



isopropoxy-benzamide
(compound 5.12)


385
3-[4-(4-Cyano-phenyl)-
4-Piperazin-1-yl-benzonitrile
393.2



piperazine-1-carbonyl]-
(commercial) and 6-



4-isopropoxy-benzamide
Isopropoxy-isophthalamic acid




(compound 5.12)


386
3-[4-(4-Cyano-2-
3-Fluoro-4-piperazin-1-yl-
411.4



fluoro-phenyl)-
benzonitrile (WO9625414) and



piperazine-1-carbonyl]-
6-Isopropoxy-isophthalamic



4-isopropoxy-benzamide
acid (compound 5.12)


387
3-[4-(4-Cyano-3-
2-Fluoro-4-piperazin-1-yl-
411.4



fluoro-phenyl)-
benzonitrile (WO 9808835)



piperazine-1-carbonyl]-
and 6-Isopropoxy-



4-isopropoxy-benzamide
isophthalamic acid (compound 5.12)


388
3-[4-(4-Acetyl-2-
1-(3-Fluoro-4-piperazin-1-yl-
428.6



fluoro-phenyl)-
phenyl)-ethanone



piperazine-1-carbonyl]-
(WO9714690) and 6-



4-isopropoxy-
Isopropoxy-isophthalamic acid



benzamide
(compound 5.12)


389
[4-(2,3-Difluoro-4-
1-(2,3-Difluoro-4-
517.4



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-
piperazine (compound 5.3)



yl]-(2-isopropoxy-5-
and 2-Isopropoxy-5-



methanesulfonyl-
methanesulfonyl-benzoic acid



phenyl)-methanone
(compound 1.2)


390
(5-Ethanesulfonyl-2-
1-(4-Trifluoromethyl-phenyl)-
485.5



isopropoxy-phenyl)-[4-
piperazine (commercial) and



(4-trifluoromethyl-
5-Ethanesulfonyl-2-



phenyl)-piperazin-1-
isopropoxy-benzoic acid



yl]-methanone
(compound 5.13)


391
(5-Ethanesulfonyl-2-
1-(2-Fluoro-4-
513.4



isopropoxy-phenyl)-[4-
methanesulfonyl-phenyl)-



(2-fluoro-4-
piperazine (commercial) and



methanesulfonyl-
5-Ethanesulfonyl-2-



phenyl)-piperazin-1-
isopropoxy-benzoic acid



yl]-methanone
(compound 5.13)


392
4-[4-(5-Ethanesulfonyl-
3-Fluoro-4-piperazin-1-yl-
460.5



2-isopropoxy-benzoyl)-
benzonitrile (WO9625414) and



piperazin-1-yl]-3-
5-Ethanesulfonyl-2-



fluoro-benzonitrile
isopropoxy-benzoic acid




(compound 5.13)


393
(5-Ethanesulfonyl-2-
1-(2-Fluoro-4-trifluoromethyl-
503.3



isopropoxy-phenyl)-[4-
phenyl)-piperazine (compound



(2-fluoro-4-
1.1) and 5-Ethanesulfonyl-2-



trifluoromethyl-
isopropoxy-benzoic acid



phenyl)-piperazin-1-
(compound 5.13)



yl]-methanone


394
[4-(2,3-Difluoro-4-
1-(2,3-Difluoro-4-
531.3



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-
piperazine (compound 5.3)



yl]-(5-ethanesulfonyl-2-
and 5-Ethanesulfonyl-2-



isopropoxy-phenyl)-
isopropoxy-benzoic acid



methanone
(compound 5.13)


395
(2-Cyclopentyloxy-5-
1-(2,3-Difluoro-4-
542.1



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-[4-(2,3-
piperazine (compound 5.3)



difluoro-4-
and 2-Cyclopentyloxy-5-



methanesulfonyl-
methanesulfonyl-



phenyl)-piperazin-1-
benzoic acid (compound 1.6)



yl]-methanone


396
(2-Cyclopropylmethoxy-
1-(2,3-Difluoro-4-
529.3



5-methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-[4-(2,3-difluoro-
piperazine (compound 5.3)



4-methanesulfonyl-
and 2-Cyclopropylmethoxy-5-



phenyl)-piperazin-1-
methanesulfonyl-benzoic acid



yl]-methanone
(compound 1.4)


397
[4-(2,3-Difluoro-4-
1-(2,3-Difluoro-4-
557.2



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-
piperazine (compound 5.3)



yl]-[5-methanesulfonyl-
and 5-Methanesulfonyl-2-



2-(2,2,2-trifluoro-
(2,2,2-trifluoro-ethoxy)-



ethoxy)-phenyl]-
benzoic acid (compound 1.5)



methanone


398
rac-[4-(2,3-Difluoro-4-
1-(2,3-Difluoro-4-
571.3



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-
piperazine (compound 5.3)



yl]-[5-methanesulfonyl-
and rac-5-Methanesulfonyl-2-



2-(2,2,2-trifluoro-1-
(2,2,2-trifluoro-1-methyl-



methyl-ethoxy)-
ethoxy)-benzoic acid



phenyl]-methanone
(compound 3.1)


399
[4-(2,3-Difluoro-4-
1-(2,3-Difluoro-4-
543.2



methanesulfonyl-
methanesulfonyl-phenyl)-



phenyl)-piperazin-1-
piperazine (compound 5.3)



yl]-(5-methanesulfonyl-
and 5-Methanesulfonyl-2-



2-trifluoromethoxy-
trifluoromethoxy-benzoic acid



phenyl)-methanone
(compound 2.15)


400
[4-(4-Difluoromethyl-
1-(4-Difluoromethyl-2-fluoro-
471.1



2-fluoro-phenyl)-
phenyl)-piperazine (compound



piperazin-1-yl]-(2-
5.14) and 2-Isopropoxy-5-



isopropoxy-5-
methanesulfonyl-benzoic acid



methanesulfonyl-
(compound 1.2)



phenyl)-methanone


401
[4-(3-Chloro-5-
1-(3-Chloro-5-trifluoromethyl-
546.3



trifluoromethyl-
pyridin-2-yl)-



pyridin-2-yl)-piperazin-
piperazine (commercial) and



1-yl]-[5-methanesulfonyl-
5-Methanesulfonyl-2-(2,2,2-



2-(2,2,2-trifluoro-ethoxy)-
trifluoro-ethoxy)-benzoic acid



phenyl]-methanone
(compound 1.5)


402
[5-Methanesulfonyl-2-
1-(5-Trifluoromethyl-pyridin-
512.4



(2,2,2-trifluoro-
2-yl)-piperazine (commercial)



ethoxy)-phenyl]-[4-(5-
and 5-Methanesulfonyl-2-



trifluoromethyl-
(2,2,2-trifluoro-ethoxy)-



pyridin-2-yl)-piperazin-
benzoic acid (compound 1.5)



1-yl]-methanone


403
6-{4-[5-Methanesulfonyl-
6-Piperazin-1-yl-nicotinonitrile
469.3



2-(2,2,2-trifluoro-ethoxy)-
(commercial) and 5-



benzoyl]-piperazin-1-
Methanesulfonyl-2-(2,2,2-



yl}-nicotinonitrile
trifluoro-ethoxy)-benzoic acid




(compound 1.5)


404
6-[4-(2-Cyclopropylmethoxy-
6-Piperazin-1-yl-nicotinonitrile
441.4



5-methanesulfonyl-benzoyl)-
(commercial) and 2-



piperazin-1-yl]-nicotinonitrile
Cyclopropylmethoxy-5-




methanesulfonyl-benzoic acid




(compound 1.4)


405
(2-Cyclopropylmethoxy-5-
1-(5-Trifluoromethyl-pyridin-
484.5



methanesulfonyl-
2-yl)-piperazine (commercial)



phenyl)-[4-(5-trifluoromethyl-
and 2-Cyclopropylmethoxy-5-



pyridin-2-yl)-piperazin-
methanesulfonyl-benzoic acid



1-yl]-methanone
(compound 1.4)


406
[4-(3-Chloro-5-
1-(3-Chloro-5-trifluoromethyl-
518.3



trifluoromethyl-
pyridin-2-yl)-



pyridin-2-yl)-piperazin-
piperazine (commercial) and



1-yl]-(2-cyclopropylmethoxy-
2-Cyclopropylmethoxy-5-



5-methanesulfonyl-
methanesulfonyl-benzoic acid



phenyl)-methanone
(compound 1.4)


407
rac-[4-(3-Chloro-5-
1-(3-Chloro-5-trifluoromethyl-
560.3



trifluoromethyl-
pyridin-2-yl)-



pyridin-2-yl)-piperazin-
piperazine (commercial) and



1-yl]-[5-methanesulfonyl-
rac-5-Methanesulfonyl-2-



2-(2,2,2-
(2,2,2-trifluoro-1-methyl-



trifluoro-1-methyl-
ethoxy)-benzoic acid



ethoxy)-phenyl]-
(compound 3.1)



methanone


408
rac-[5-Methanesulfonyl-
1-(5-Trifluoromethyl-pyridin-
526.2



2-(2,2,2-
2-yl)-piperazine (commercial)



trifluoro-1-methyl-
and rac-5-Methanesulfonyl-2-



ethoxy)-phenyl]-[4-(5-
(2,2,2-trifluoro-1-methyl-



trifluoromethyl-
ethoxy)-benzoic acid



pyridin-2-yl)-piperazin-
(compound 3.1)



1-yl]-methanone


409
rac-6-{4-[5-
6-Piperazin-1-yl-nicotinonitrile
483.4



Methanesulfonyl-2-
(commercial) and rac-5-



(2,2,2-trifluoro-1-
Methanesulfonyl-2-(2,2,2-



methyl-ethoxy)-
trifluoro-1-methyl-ethoxy)-



benzoyl]-piperazin-1-
benzoic acid (compound 3.1)



yl}-nicotinonitrile


410
[4-(6-Chloro-5-
1-(6-Chloro-5-trifluoromethyl-
518.3



trifluoromethyl-
pyridin-2-yl)-



pyridin-2-yl)-piperazin-
piperazine (WO03097636) and



1-yl]-(2-cyclopropyl
2-Cyclopropylmethoxy-5-



methoxy-5-methanesulfonyl-
methanesulfonyl-benzoic acid



phenyl)-methanone
(compound 1.4)


411
6-[4-(2-
6-Piperazin-1-yl-nicotino
455.5



Cyclopentyloxy-5-
nitrile (commercial) and 2-



methanesulfonyl-
Cyclopentyloxy-5-methanesulfonyl-



benzoyl)-piperazin-1-
benzoic acid (compound 1.6)



yl]-nicotinonitrile


412
(2-Cyclopentyloxy-5-
1-(5-Trifluoromethyl-pyridin-
498.3



methanesulfonyl-
2-yl)-piperazine (commercial)



phenyl)-[4-(5-
and 2-Cyclopentyloxy-5-



trifluoromethyl
methanesulfonyl-benzoic acid



pyridin-2-yl)-piperazin-
(compound 1.6)



1-yl]-methanone


413
[4-(3-Chloro-5-
1-(3-Chloro-5-trifluoromethyl-
532.3



trifluoromethyl-
pyridin-2-yl)-



pyridin-2-yl)-piperazin-
piperazine (commercial) and



1-yl]-(2-
2-Cyclopentyloxy-5-



cyclopentyloxy-5-
methanesulfonyl-benzoic acid



methanesulfonyl-
(compound 1.6)



phenyl)-methanone


414
[4-(6-Chloro-5-
1-(6-Chloro-5-trifluoromethyl-
506.3



trifluoromethyl-
pyridin-2-yl)-



pyridin-2-yl)-piperazin-
piperazine (WO03097636) and



1-yl]-(2-isopropoxy-5-
2-Isopropoxy-5-methanesulfonyl-



methanesulfonyl-
benzoic acid (compound 1.2)



phenyl)-methanone


415
(2-Isopropoxy-5-
1-(5-Trifluoromethyl-pyridin-
472.2



methanesulfonyl-
2-yl)-piperazine (commercial)



phenyl)-[4-(5-
and 2-Isopropoxy-5-methanesulfonyl-



trifluoromethyl-
benzoic acid (compound 1.2)



pyridin-2-yl)-piperazin-



1-yl]-methanone


416
6-[4-(2-Isopropoxy-5-
6-Piperazin-1-yl-nicotinonitrile
429.5



methanesulfonyl-
(commercial) and 2-



benzoyl)-piperazin-1-
Isopropoxy-5-methanesulfonyl-



yl]-nicotinonitrile
benzoic acid (compound 1.2)


417
[4-(3-Chloro-5-
1-(3-Chloro-5-trifluoromethyl-
506.3



trifluoromethyl-
pyridin-2-yl)-



pyridin-2-yl)-piperazin-
piperazine (commercial) and



1-yl]-(2-isopropoxy-5-
2-Isopropoxy-5-methanesulfonyl-



methanesulfonyl-
benzoic acid (compound 1.2)



phenyl)-methanone


418
rac-[4-(5-Chloro-
1-(5-Chloro-pyridin-2-yl)-
492.3



pyridin-2-yl)-piperazin-
piperazine (WO01062751) and



1-yl]-[5-methanesulfonyl-
rac-5-Methanesulfonyl-2-



2-(2,2,2-trifluoro-1-methyl-
(2,2,2-trifluoro-1-methyl-



ethoxy)-phenyl]-
ethoxy)-benzoic acid



methanone
(compound 3.1)


419
[4-(5-Chloro-pyridin-
1-(5-Chloro-pyridin-2-yl)-
464.3



2-yl)-piperazin-1-yl]-
piperazine (WO01062751) and



(2-cyclopentyloxy-5-
2-Cyclopentyloxy-5-



methanesulfonyl-
methanesulfonyl-benzoic acid



phenyl)-methanone
(compound 1.6)


420
[4-(5-Chloro-pyridin-
1-(5-Chloro-pyridin-2-yl)-
450.4



2-yl)-piperazin-1-yl]-
piperazine (WO01062751) and



(2-cyclopropylmethoxy-
2-Cyclopropylmethoxy-5-



5-methanesulfonyl-
methanesulfonyl-benzoic acid



phenyl)-methanone
(compound 1.4)


421
[4-(5-Chloro-pyridin-
1-(5-Chloro-pyridin-2-yl)-
478.2



2-yl)-piperazin-1-yl]-
piperazine (WO01062751) and



[5-methanesulfonyl-2-
5-Methanesulfonyl-2-(2,2,2-



(2,2,2-trifluoro-
trifluoro-ethoxy)-benzoic acid



ethoxy)-phenyl]-
(compound 1.5)



methanone


422
[4-(5-Chloro-pyridin-
1-(5-Chloro-pyridin-2-yl)-
438.3



2-yl)-piperazin-1-yl]-
piperazine (WO01062751) and



(2-isopropoxy-5-
2-Isopropoxy-5-methanesulfonyl-



methanesulfonyl-
benzoic acid (compound 1.2)



phenyl)-methanone


423
Rac-[4-(6-Chloro-
3-Chloro-6-piperazin-1-yl-
493.3



pyridazin-3-yl)-
pyridazine (WO02030405) and



piperazin-1-yl]-[5-
rac-5-Methanesulfonyl-2-



methanesulfonyl-2-
(2,2,2-trifluoro-1-methyl-



(2,2,2-trifluoro-1-
ethoxy)-benzoic acid



methyl-ethoxy)-
(compound 3.1)



phenyl]-methanone


424
[4-(6-Chloro-
3-Chloro-6-piperazin-1-yl-
465.4



pyridazin-3-yl)-
pyridazine (WO02030405) and



piperazin-1-yl]-(2-
2-Cyclopentyloxy-5-



cyclopentyloxy-5-
methanesulfonyl-benzoic acid



methanesulfonyl-
(compound 1.6)



phenyl)-methanone


425
(2-Isopropoxy-5-
1-(6-Trifluoromethyl-pyridin-
472.2



methanesulfonyl-
3-yl)-piperazine (compound



phenyl)-[4-(6-
5.15) and 2-Isopropoxy-5-



trifluoromethyl-
methanesulfonyl-benzoic acid



pyridin-3-yl)-piperazin-
(compound 1.2)



1-yl]-methanone


426
[5-Methanesulfonyl-2-
1-(6-Trifluoromethyl-pyridin-
512.4



(2,2,2-trifluoro-
3-yl)-piperazine (compound



ethoxy)-phenyl]-[4-(6-
5.15) and 5-Methanesulfonyl-



trifluoromethyl-
2-(2,2,2-trifluoro-ethoxy)-



pyridin-3-yl)-piperazin-
benzoic acid (compound 1.5)



1-yl]-methanone


427
rac-[5-Methanesulfonyl-
1-(6-Trifluoromethyl-pyridin-
526.2



2-(2,2,2-
3-yl)-piperazine (compound



trifluoro-1-methyl-
5.15) and rac-5-Methanesulfonyl-



ethoxy)-phenyl]-[4-(6-
2-(2,2,2-trifluoro-1-



trifluoromethyl-
methyl-ethoxy)-benzoic acid



pyridin-3-yl)-piperazin-
(compound 3.1)



1-yl]-methanone


428
3-Fluoro-4-[4-(2-
3-Fluoro-4-piperazin-1-yl-
493.4



isopropoxy-5-methanesulfonyl-
benzoic acid ethyl ester



benzoyl)-piperazin-1-yl]-
(compound 5.16) and 2-



benzoic acid ethyl ester
Isopropoxy-5-methanesulfonyl-




benzoic acid (compound 1.2)


429
[4-(5-Bromo-pyridin-
1-(5-Bromo-pyridin-2-yl)-
482.4



2-yl)-piperazin-1-yl]-
piperazine (WO9534555) and



(2-isopropoxy-5-
2-Isopropoxy-5-methanesulfonyl-



methanesulfonyl-
benzoic acid (compound 1.2)



phenyl)-methanone


430
(2-Cyclopentyloxy-5-
1-(6-Trifluoromethyl-pyridin-
498.3



methanesulfonyl-
3-yl)-piperazine (compound



phenyl)-[4-(6-trifluoromethyl-
5.15) and 2-Cyclopentyloxy-5-



pyridin-3-yl)-
methanesulfonyl-benzoic acid



piperazin-1-yl]-
(compound 1.6)



methanone


431
(2-Cyclopropyl
1-(6-Trifluoromethyl-pyridin-
484.5



methoxy-5-methanesulfonyl-
3-yl)-piperazine (compound



phenyl)-[4-(6-
5.15) and 2-Cyclopropyl



trifluoromethyl-
methoxy-5-methanesulfonyl-



pyridin-3-yl)-piperazin-
benzoic acid (compound 1.4)



1-yl]-methanone


432
[4-(5-Bromo-pyridin-
1-(5-Bromo-pyridin-2-yl)-
522.2



2-yl)-piperazin-1-yl]-
piperazine (WO 9534555) and



[5-methanesulfonyl-2-
5-Methanesulfonyl-2-(2,2,2-



(2,2,2-trifluoro-
trifluoro-ethoxy)-benzoic acid



ethoxy)-phenyl]-
(compound 1.5)



methanone


433
[5-Methanesulfonyl-2-
1-(2-Trifluoromethyl-pyridin-
512.4



(2,2,2-trifluoro-
4-yl)-piperazine (compound



ethoxy)-phenyl]-[4-(2-
5.17) and 5-Methanesulfonyl-



trifluoromethyl-
2-(2,2,2-trifluoro-ethoxy)-



pyridin-4-yl)-piperazin-
benzoic acid (compound 1.5)



1-yl]-methanone


434
(2-Isopropoxy-5-
1-(2-Trifluoromethyl-pyridin-
472.2



methanesulfonyl-
4-yl)-piperazine (compound



phenyl)-[4-(2-
5.17) and 2-Isopropoxy-5-



trifluoromethyl-
methanesulfonyl-benzoic acid



pyridin-4-yl)-piperazin-
(compound 1.2)



1-yl]-methanone


435
rac-[4-(5-Bromo-
1-(5-Bromo-pyridin-2-yl)-
536.3



pyridin-2-yl)-piperazin-
piperazine (WO 9534555) and



1-yl]-[5-methanesulfonyl-
rac-5-Methanesulfonyl-2-



2-(2,2,2-
(2,2,2-trifluoro-1-methyl-



trifluoro-1-methyl-
ethoxy)-benzoic acid



ethoxy)-phenyl]-
(compound 3.1)



methanone


436
[4-(3-Fluoro-5-
1-(3-Fluoro-5-trifluoromethyl-
530.3



trifluoromethyl-
pyridin-2-yl)-piperazine



pyridin-2-yl)-piperazin-
(compound 5.5) and 5-



1-yl]-[5-methanesulfonyl-
Methanesulfonyl-2-(2,2,2-



2-(2,2,2-
trifluoro-ethoxy)-benzoic acid



trifluoro-ethoxy)-
(compound 1.5)



phenyl]-methanone


437
[4-(3-Fluoro-5-
1-(3-Fluoro-5-trifluoromethyl-
490.4



trifluoromethyl-
pyridin-2-yl)-piperazine



pyridin-2-yl)-piperazin-
(compound 5.5) and 2-



1-yl]-(2-isopropoxy-5-
Isopropoxy-5-methanesulfonyl-



methanesulfonyl-
benzoic acid (compound 1.2)



phenyl)-methanone


438
rac-[4-(3-Fluoro-5-
1-(3-Fluoro-5-trifluoromethyl-
544.3



trifluoromethyl-
pyridin-2-yl)-piperazine



pyridin-2-yl)-piperazin-
(compound 5.5) and rac-5-



1-yl]-[5-methanesulfonyl-
Methanesulfonyl-2-(2,2,2-



2-(2,2,2-trifluoro-
trifluoro-1-methyl-ethoxy)-



1-methyl-ethoxy)-
benzoic acid (compound 3.1)



phenyl]-methanone


439
(2-Cyclopentyloxy-5-
1-(3-Fluoro-5-trifluoromethyl-
516.4



methanesulfonyl-
pyridin-2-yl)-piperazine



phenyl)-[4-(3-fluoro-5-
(compound 5.5) and 2-



trifluoromethyl-
Cyclopentyloxy-5-methanesulfonyl-



pyridin-2-yl)-piperazin-
benzoic acid (compound 1.6)



1-yl]-methanone


440
(2-Cyclopropylmethoxy-
1-(3-Fluoro-5-trifluoromethyl-
502.3



5-methanesulfonyl-
pyridin-2-yl)-piperazine



phenyl)-[4-(3-fluoro-5-
(compound 5.5) and 2-



trifluoromethyl-
Cyclopropylmethoxy-5-



pyridin-2-yl)-piperazin-
methanesulfonyl-benzoic acid



1-yl]-methanone
(compound 1.4)


441
rac-[5-Methanesulfonyl-
1-(2-Trifluoromethyl-pyridin-
526.2



2-(2,2,2-
4-yl)-piperazine (compound



trifluoro-1-methyl-
5.17) and rac-5-Methanesulfonyl-



ethoxy)-phenyl]-[4-(2-
2-(2,2,2-trifluoro-1-



trifluoromethyl-
methyl-ethoxy)-benzoic acid



pyridin-4-yl)-piperazin-
(compound 3.1)



1-yl]-methanone


442
[5-Methanesulfonyl-2-
1-(6-Methyl-pyridin-3-yl)-
458.4



(2,2,2-trifluoro-
piperazine (compound 5.18)



ethoxy)-phenyl]-[4-(6-
and 5-Methanesulfonyl-2-



methyl-pyridin-3-yl)-
(2,2,2-trifluoro-ethoxy)-



piperazin-1-yl]-
benzoic acid (compound 1.5)



methanone


443
(2-Isopropoxy-5-
1-(6-Methyl-pyridin-3-yl)-
418.3



methanesulfonyl-
piperazine (compound 5.18)



phenyl)-[4-(6-methyl-
and 2-Isopropoxy-5-



pyridin-3-yl)-piperazin-
methanesulfonyl-benzoic acid



1-yl]-methanone
(compound 1.2)


444
(2-Cyclopentyloxy-5-
1-(6-Methyl-pyridin-3-yl)-
444.4



methanesulfonyl-
piperazine (compound 5.18)



phenyl)-[4-(6-methyl-
and 2-Cyclopentyloxy-5-



pyridin-3-yl)-piperazin-
methanesulfonyl-benzoic acid



1-yl]-methanone
(compound 1.6)


445
(2-Cyclopropyl
1-(6-Methyl-pyridin-3-yl)-
430.5



methoxy-5-methanesulfonyl-
piperazine (compound 5.18)



phenyl)-[4-(6-
and 2-Cyclopropylmethoxy-5-



methyl-pyridin-3-yl)-
methanesulfonyl-benzoic acid



piperazin-1-yl]-methanone
(compound 1.4)


446
[5-Methanesulfonyl-2-
1-(5-Methyl-pyridin-2-yl)-
458.0



(2,2,2-trifluoro-
piperazine (WO03032996) and



ethoxy)-phenyl]-[4-(5-
5-Methanesulfonyl-2-(2,2,2-



methyl-pyridin-2-yl)-
trifluoro-ethoxy)-benzoic acid



piperazin-1-yl]-methanone
(compound 1.5)


447
(2-Isopropoxy-5-
1-(5-Methyl-pyridin-2-yl)-
418.3



methanesulfonyl-
piperazine (WO03032996) and



phenyl)-[4-(5-methyl-
2-Isopropoxy-5-methanesulfonyl-



pyridin-2-yl)-piperazin-
benzoic acid (compound 1.2)



1-yl]-methanone


448
(2-Cyclopropylmethoxy-
1-(5-Methyl-pyridin-2-yl)-
430.5



5-methanesulfonyl-
piperazine (WO03032996) and



phenyl)-[4-(5-
2-Cyclopropylmethoxy-5-



methyl-pyridin-2-yl)-
methanesulfonyl-benzoic acid



piperazin-1-yl]-methanone
(compound 1.4)


449
rac-[5-Methanesulfonyl-
1-(5-Methyl-pyridin-2-yl-
472.3



2-(2,2,2-
piperazine (WO03032996) and



trifluoro-1-methyl-
rac-5-Methanesulfonyl-2-



ethoxy)-phenyl]-[4-(5-
(2,2,2-trifluoro-1-methyl-



methyl-pyridin-2-yl)-
ethoxy)-benzoic acid



piperazin-1-yl]-methanone
(compound 3.1)


450
rac-[5-Methanesulfonyl-
1-(6-Methyl-pyridin-3-yl)-
472.2



2-(2,2,2-
piperazine (compound 5.18)



trifluoro-1-methyl-
and rac-5-Methanesulfonyl-2-



ethoxy)-phenyl]-[4-(6-
(2,2,2-trifluoro-1-methyl-



methyl-pyridin-3-yl)-
ethoxy)-benzoic acid



piperazin-1-yl]-methanone
(compound 3.1)


451
[5-Methanesulfonyl-2-
1-(4-Trifluoromethyl-pyridin-
512.4



(2,2,2-trifluoro-
2-yl)-piperazine



ethoxy)-phenyl]-[4-(4-
(WO02002529) and 5-



trifluoromethyl-
Methanesulfonyl-2-(2,2,2-



pyridin-2-yl)-piperazin-
trifluoro-ethoxy)-benzoic acid



1-yl]-methanone
(compound 1.5)


452
(2-Isopropoxy-5-
1-(4-Trifluoromethyl-pyridin-
472.3



methanesulfonyl-
2-yl)-piperazine



phenyl)-[4-(4-
(WO02002529) and 2-



trifluoromethyl-
Isopropoxy-5-methanesulfonyl-



pyridin-2-yl)-piperazin-
benzoic acid (compound 1.2)



1-yl]-methanone


453
(2-tert-Butoxy-5-
1-(4-Trifluoromethyl-pyridin-
486.2



methanesulfonyl-
2-yl)-piperazine



phenyl)-[4-(4-
(WO02002529) and 2-tert-



trifluoromethyl-
Butoxy-5-methanesulfonyl-



pyridin-2-yl)-piperazin-
benzoic acid (compound 2.19)



1-yl]-methanone


454
[4-(2-Fluoro-4-
1-(2-Fluoro-4-methane
570.4



methanesulfonyl-
sulfonyl-phenyl)-piperazine
(M + NH4+)



phenyl)-piperazin-1-
(commercial) and 5-Methane



yl]-[5-methanesulfonyl-
sulfonyl-2-((S)-2,2,2-trifluoro-



2-((S)-2,2,2-trifluoro-1-
1-methyl-ethoxy)-benzoic acid



methyl-ethoxy)-
(compound 5.6)



phenyl]-methanone


455
rac-[5-Methanesulfonyl-
1-(4-Trifluoromethyl-pyridin-
526.0



2-(2,2,2-
2-yl)-piperazine



trifluoro-1-methyl-
(WO02002529) and rac-5-



ethoxy)-phenyl]-[4-(4-
Methanesulfonyl-2-(2,2,2-



trifluoromethyl-
trifluoro-1-methyl-ethoxy)-



pyridin-2-yl)-piperazin-
benzoic acid (compound 3.1)



1-yl]-methanone


456
[4-(2-Fluoro-4-
1-(2-Fluoro-4-
570.4



methanesulfonyl-
methanesulfonyl-phenyl)-
(M + NH4+)



phenyl)-piperazin-1-
piperazine (commercial) and



yl]-[5-methanesulfonyl-
5-Methanesulfonyl-2-((R)-



2-((R)-2,2,2-trifluoro-
2,2,2-trifluoro-1-methyl-



1-methyl-ethoxy)-
ethoxy)-benzoic acid



phenyl]-methanone
(compound 5.7)


457
(2-Cyclopentyloxy-5-
1-(4-Trifluoromethyl-pyridin-
498.2



methanesulfonyl-
2-yl)-piperazine



phenyl)-[4-(4-
(WO02002529) and 2-



trifluoromethyl-
Cyclopentyloxy-5-



pyridin-2-yl)-piperazin-
methanesulfonyl-



1-yl]-methanone
benzoic acid (compound 1.6)


458
(2-Isopropoxy-5-
1-(6-Trifluoromethyl-pyridin-
472.1



methanesulfonyl-phenyl)-
2-yl)-piperazine (EP 462638)



[4-(6-trifluoromethyl-
and 2-Isopropoxy-5-methanesulfonyl-



pyridin-2-yl)-piperazin-
benzoic acid (compound 1.2)



1-yl]-methanone


459
rac-[5-Methanesulfonyl-
1-(6-Trifluoromethyl-pyridin-
526.0



2-(2,2,2-
2-yl)-piperazine (EP 462638)



trifluoro-1-methyl-
and rac-5-Methanesulfonyl-2-



ethoxy)-phenyl]-[4-(6-
(2,2,2-trifluoro-1-methyl-



trifluoromethyl-
ethoxy)-benzoic acid



pyridin-2-yl)-piperazin-
(compound 3.1)



1-yl]-methanone


460
[5-Methanesulfonyl-2-
1-(6-Trifluoromethyl-pyridin-
512.2



(2,2,2-trifluoro-
2-yl)-piperazine (EP 462638)



ethoxy)-phenyl]-[4-(6-
and 5-Methanesulfonyl-2-



trifluoromethyl-
(2,2,2-trifluoro-ethoxy)-



pyridin-2-yl)-piperazin-
benzoic acid (compound 1.5)



1-yl]-methanone


461
3-Fluoro-4-[4-(2-
1-(4-Difluoromethyl-2-fluoro-
449.1



isopropoxy-5-
phenyl)-piperazine (compound



methanesulfonyl-
5.14) and 2-Isopropoxy-5-



benzoyl)-piperazin-1-
methanesulfonyl-benzoic acid



yl]-benzaldehyde
(compound 1.2)









EXAMPLE 462 
Preparation of rac-{4-[2-Fluoro-4-(1-hydroxy-ethyl)-phenyl]-piperazin-1-yl}-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone
0.086 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-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 HCl 1N and extracted 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/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
To a solution of 0.173 mmol 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-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% NH4Cl 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:














Expl.


Separation
MW found


No.
Systematic Name
Starting materials
Conditions
(MH+)







464
[5-Methanesulfonyl-
rac-[5-
Chiralpak AD,
525.8



2-((S or R)-2,2,2-
Methanesulfonyl-2-
20%
(M)



trifluoro-1-methyl-
(2,2,2-trifluoro-1-
Isopropanol/



ethoxy)-phenyl]-[4-
methyl-ethoxy)-
Heptane, flow



(5-trifluoromethyl-
phenyl]-[4-(5-
35 ml, 254 nm,



pyridin-2-yl)-
trifluoromethyl-
170 min.



piperazin-1-yl]-
pyridin-2-yl)-



methanone
piperazin-1-yl]-




methanone (example




408)


465
[5-Methanesulfonyl-
rac-[5-Methanesulfonyl-
Chiralpak AD,
525.3



2-((R or S)-2,2,2-
2-(2,2,2-
20%
(M)



trifluoro-1-methyl-
trifluoro-1-methyl-
Isopropanol/



ethoxy)-phenyl]-[4-
ethoxy)-phenyl]-[4-
Heptane, flow



(5-trifluoromethyl-
(5-trifluoromethyl-
35 ml, 254 nm,



pyridin-2-yl)-
pyridin-2-yl)-
245 min.



piperazin-1-yl]-
piperazin-1-yl]-



methanone
methanone (example




408)


466
[4-(2-Fluoro-4-
rac-[4-(2-Fluoro-4-
Chiralpak AD,
543.2



trifluoromethyl-
trifluoromethyl-
25%



phenyl)-piperazin-1-
phenyl)-piperazin-1-
Isopropanol/



yl]-[5-
yl]-[5-methanesulfonyl-
Heptane, flow



methanesulfonyl-2-
2-(2,2,2-
35 ml 220 nm,



((S or R)-2,2,2-
trifluoro-1-methyl-
141 min.



trifluoro-1-methyl-
ethoxy)-phenyl]-



ethoxy)-phenyl]-
methanone (example



methanone
302)


467
[4-(2-Fluoro-4-
rac-[4-(2-Fluoro-4-
Chiralpak AD,
543.2



trifluoromethyl-
trifluoromethyl-
25%



phenyl)-piperazin-1-
phenyl)-piperazin-1-
Isopropanol/



yl]-[5-
yl]-[5-methanesulfonyl-
Heptane, flow



methanesulfonyl-2-
2-(2,2,2-
35 ml, 220 nm,



((R or S)-2,2,2-
trifluoro-1-methyl-
199 min.



trifluoro-1-methyl-
ethoxy)-phenyl]-



ethoxy)-phenyl]-
methanone (example



methanone
302)


468
[5-Methanesulfonyl-
rac-5-Methanesulfonyl-
Chiralpak AD,
525.2



2-((S or R)-2,2,2-
2-(2,2,2-
25%



trifluoro-1-methyl-
trifluoro-1-methyl-
Isopropanol/



ethoxy)-phenyl]-[4-
ethoxy)-phenyl]-[4-
Heptane, flow



(4-trifluoromethyl-
(4-trifluoromethyl-
35 ml, 220 nm,



phenyl)-piperazin-1-
phenyl)-piperazin-1-
197 min.



yl]-methanone
yl]-methanone




(example 301)


469
[5-Methanesulfonyl-
rac-5-Methanesulfonyl-
Chiralpak AD,
525.2



2-((R or S)-2,2,2-
2-(2,2,2-
25%



trifluoro-1-methyl-
trifluoro-1-methyl-
Isopropanol/



ethoxy)-phenyl]-[4-
ethoxy)-phenyl]-[4-
Heptane, flow



(4-trifluoromethyl-
(4-trifluoromethyl-
35 ml, 220 nm,



phenyl)-piperazin-1-
phenyl)-piperazin-1-
280 min.



yl]-methanone
yl]-methanone




(example 301)


470
[4-(3-Fluoro-5-
rac-[4-(3-Fluoro-5-
Chiralpak AD,
544.3



trifluoromethyl-
trifluoromethyl-
20%



pyridin-2-yl)-
pyridin-2-yl)-
Isopropanol/



piperazin-1-yl]-[5-
piperazin-1-yl]-[5-
Heptane, flow



methanesulfonyl-2-
methanesulfonyl-2-
35 ml, 254 nm,



((S)-2,2,2-trifluoro-
(2,2,2-trifluoro-1-
110 min.



1-methyl-ethoxy)-
methyl-ethoxy)-



phenyl]-methanone
phenyl]-methanone




(example 438)


471
[4-(3-Fluoro-5-
rac-[4-(3-Fluoro-5-
Chiralpak AD,
544.0



trifluoromethyl-
trifluoromethyl-
20%



pyridin-2-yl)-
pyridin-2-yl)-
Isopropanol/



piperazin-1-yl]-[5-
piperazin-1-yl]-[5-
Heptane, flow



methanesulfonyl-2-
methanesulfonyl-2-
35 ml, 254 nm,



((R)-2,2,2-trifluoro-
(2,2,2-trifluoro-1-
145 min.



1-methyl-ethoxy)
methyl-ethoxy)-



phenyl]-methanone
phenyl]-methanone




(example 438)









EXAMPLE 6.1 
Preparation of 2-isobutoxy-5-methylsulfamoyl-benzoic acid
(a) 5-Chlorosulfonyl-2-hydroxy-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 ([{37Cl}M−H]−, 33%), 235.0 ([{37Cl}M−H]−, 100%)
(b) 2-Hydroxy-5-methylsulfamoyl-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 HCl, saturated with NaCl, and extracted 3 times 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-Hydroxy-5-methylsulfamoyl-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-Isobutoxy-5-methylsulfamoyl-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-methylsulfamoyl-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:













Expl.





No
Systematic Name
alcohol
MS (M/e)







6.2
2-(2,2-Dimethyl-propoxy)-5-
2,2-Dimethyl-1-
300.2



methylsulfamoyl-benzoic acid
propanol
(M − H)


6.3
2-Isopropoxy-5-
2-Propanol
272.2



methylsulfamoyl-benzoic acid

(M − H)


6.4
2-Cyclopentyloxy-5-
Cyclopentanol
298.2



methylsulfamoyl-benzoic acid

(M − H)


6.5
2-Cyclobutoxy-5-
Cyclobutanol
284.1



methylsulfamoyl-benzoic acid

(M − H)


6.6
2-Cyclopropylmethoxy-5-
Cyclopropyl-methanol
284.1



methylsulfamoyl-benzoic acid

(M − H)


6.7
2-Cyclobutylmethoxy-5-
Cyclobutyl-methanol
298.2



methylsulfamoyl-benzoic acid

(M − H)


6.8
5-Methylsulfamoyl-2-
Tetrahydro-2H-pyran-
314.1



(tetrahydro-pyran-4-yloxy)-
4-ol
(M − H)



benzoic acid


6.9
2-(2-Methoxy-ethoxy)-5-
2-Methoxy-ethanol
288.1



methylsulfamoyl-benzoic acid

(M − H)


6.10
5-Methylsulfamoyl-2-(3,3,3-
3,3,3-Trifluoro-1-
326.2



trifluoro-propoxy)-benzoic
propanol
(M − H)



acid









EXAMPLE 6.11 
Preparation of 5-methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid
(a) 5-Methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl 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 tide compound. MS (m/e): 328.0 (M+H+, 100%)
(b) 5-Methylsulfamoyl-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 tide compound. MS (m/e): 312.0 ([M−H]−, 100%)
EXAMPLE 6.19 
Preparation of rac-5-methylsulfamoyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid
(a) rac-5-Methylsulfamoyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl 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-1-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. Evaporation in vacuo followed by chromatography on silica gel (eluant: dichloromethane) afforded the title compound.
MS (m/e): 359.2 (M+NH4+, 80%), 342.0 (M+H+, 100%)
(b) rac-5-Methylsulfamoyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid
To 1.6 mmol 5-methylsulfamoyl-2-(2,2,2-trifluoro-1-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 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-1-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 1-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 ([{37Cl}M−H]−, 33%), 277.0 ([{35Cl}M−H]−, 100%)
(c) 5-Cyclopropanesulfonyl-2-hydroxy-benzoic acid
To 8.0 mmol 5-(3-chloro-propane-1-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-Cyclopropanesulfonyl-2-hydroxy-benzoic acid methyl ester
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-Cyclopropanesulfonyl-2-isopropoxy-benzoic acid
To 0.6 mmol 5-cyclopropanesulfonyl-2-hydroxy-benzoic acid methyl ester, 3.7 mmol 2-propanol 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 tide 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:













Expl. No
Systematic Name
alcohol
MS (m/e)







6.15
5-Cyclopropanesulfonyl-
2-Methyl-1-propanol
297.1



2-isobutoxy-benzoic acid

(M − H)


6.16
2-Cyclopentyloxy-5-
Cyclopentanol
309.1



cyclopropanesulfonyl-

(M − H)



benzoic acid


6.17
5-Cyclopropanesulfonyl-
Cyclopropyl-methanol
295.2



2-cyclopropylmethoxy-

(M − H)



benzoic acid


6.18
2-Cyclobutoxy-5-
Cyclobutanol
295.2



cyclopropanesulfonyl-

(M − H)



benzoic acid









EXAMPLE 6.12 
Preparation of 1-(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-Ethanesulfonyl-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) 1-(4-Ethanesulfonyl-2-fluoro-phenyl)-piperazine
To 2.0 mmol 4-ethanesulfonyl-1,2-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%)
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:
















MW


Expl.


found


No.
Systematic Name
alkyl halide
(M + H+)







6.13
1-[4-(Butane-1-sulfonyl)-2-
Iodobutane
301.1



fluoro-phenyl]-piperazine


6.21
1-[2-Fluoro-4-(propane-2-
2-Iodopropane
287.0



sulfonyl)-phenyl]-piperazine


6.22
1-(4-
Bromomethyl-
299.2



Cyclopropylmethanesulfonyl-2-
cylopropane and



fluoro-phenyl)-piperazine
NaI


6.23
1-[2-Fluoro-4-(2-methoxy-
1-Iodo-2-methoxy-
303.1



ethanesulfonyl)-phenyl]-
ethane



piperazine









EXAMPLE 6.20 
Preparation of 1-(4-Cyclopropanesulfonyl-2-fluoro-phenyl)-piperazine
(a) 4-(3-Chloro-propane-1-sulfonyl)-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 1-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 ({37Cl}M+H+, 33%), 255.1({35Cl}M+H+, 100%),
(b) 4-Cyclopropanesulfonyl-1,2-difluoro-benzene
To 11.8 mmol 4-(3-chloro-propane-1-sulfonyl)-1,2-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 HCl 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) 1-(4-Cyclopropanesulfonyl-2-fluoro-phenyl)-piperazine
To 0.2 mmol 4-cyclopropanesulfonyl-1,2-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 1-(4-cyclobutanesulfonyl-2-fluoro-phenyl)-piperazine hydrochloride
(a) 4-Cyclobutanesulfonyl-1,2-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) 1-(4-Cyclobutanesulfonyl-2-fluoro-phenyl)-piperazine hydrochloride
To 2.8 mmol 4-cyclobutanesulfonyl-1,2-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 HCl (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.
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 HCl in dioxane:
















MW found


Expl. No
Systematic Name
Starting Materials
(M + H+)







6.25
1-(4-
difluoro-
313.3



Cyclopentanesulfonyl-2-
benzenesulfinic acid



fluoro-phenyl)-piperazine
and



hydrochloride)
bromocyclopentane









EXAMPLE 6.26 
Preparation of 1-[2-fluoro-4-(3,3,3-trifluoro-propane-1-sulfonyl)-phenyl]-piperazine
(a) 1,2-Difluoro-4-(3,3,3-trifluoro-propylsulfanyl)-benzene
To 3.4 mmol 3,4-difluoro-thiophenol and 5.1 mmol 1-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 vacuo to afford the title compound. MS (m/e): 243.1 (M+H+, 100%)
(b) 1,2-Difluoro-4-(3,3,3-trifluoro-propane-1-sulfonyl)-benzene
To 3.0 mmol 1,2-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%)
(c) 1-[2-Fluoro-4-(3,3,3-trifluoro-propane-1-sulfonyl)-phenyl]-piperazine
To 0.5 mmol 1,2-difluoro-4-(3,3,3-trifluoro-propane-1-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:
















MW found


Expl No
Systematic name
Alkylating agent
(M + H+)







6.27
1-[2-Fluoro-4-
Toluene-4-sulfonic acid
329.1



(tetrahydro-pyran-4-
tetrahydro-pyran-4-yl



sulfonyl)-phenyl]-
ester



piperazine


6.28
1-(4-
Iodocyclohexane
327.3



Cyclohexanesulfonyl-



2-fluoro-phenyl)-



piperazine









EXAMPLE 6.29 
Preparation of 1-[2,3-difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine hydrochloride
(a) 1,2,3-Trifluoro-4-(propane-2-sulfonyl)-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%)
(b) 4-[2,3-Difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester
To 7.6 mmol 1,2,3-trifluoro-4-(propane-2-sulfonyl)-benzene in 20 ml N,N-dimethylacetamide was added 15.9 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: ethyl acetate/heptane 1:2) to afford the title compound.
MS (m/e): 405.2 (M+H+, 100%)
(c) 1-[2,3-Difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine hydrochloride
To 7.5 mmol 4-[2,3-difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester in 100 ml dioxane was added 30.2 mmol HCl (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 HCl in dioxane:
















MW


Expl.


found


No
Systematic Name
starting materials
(M + H)







6.30
1-(4-Ethanesulfonyl-2,3-
2,3,4-trifluoro-
291.2



difluoro-phenyl)-piperazine
benzenesulfinic acid and



hydrochloride
iodoethane


6.32
1-[2,5-Difluoro-4-
2,4,5-Trifluoro-
305.1



(propane-2-sulfonyl)-
benzenesulfinic acid and



phenyl]-piperazine
2-iodopropane



hydrochloride


6.33
1-(4-Ethanesulfonyl-2,5-
2,4,5-Trifluoro-
291.1



difluoro-phenyl)-piperazine
benzenesulfinic acid and



hydrochloride
iodoethane









EXAMPLE 6.31 
Preparation of 1-(4-cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine hydrochloride
(a) 1-(3-Chloro-propane-1-sulfonyl)-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 1-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/e): 275.2 ({37Cl}M+H+, 33%), 273.1({35Cl}M+H+, 100%),
(b) 1-Cyclopropanesulfonyl-2,3,4-trifluoro-benzene
To 5.9 mmol 1-(3-chloro-propane-1-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 HCl 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/e): 237.2 (M+H+, 100%)
(c) 4-(4-Cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
To 4.2 mmol 1-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-Cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine hydrochloride
To 3.7 mmol 4-(4-Cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in 100 ml dioxane was added 14.9 mmol HCl (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 HCl in dioxane:
















MW


Expl.


found


No
Systematic Name
starting materials
(M + H)







6.34
1-(4-Cyclopropanesulfonyl-2,5-
2,4,5-Trifluoro-
303.1



difluoro-phenyl)-piperazine
benzenesulfinic



hydrochloride
acid and 2-




iodopropane









EXAMPLE 6.35 
Preparation of rac-2-Methyl-1-(4-trifluoromethyl-phenyl)-piperazine hydrochloride
(a) rac-3-Methyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
To 1-bromo-4-trifluoromethyl-benzene (1 g), rac-3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (1 g), in toluene (10 mL) was added sodium tert-butylate (0.6 g), 2-(dicyclohexylphosphino)biphenyl (31 mg), and tris(dibenzylideneacetone)Pd-CHCl3 (23 mg). 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-Methyl-1-(4-trifluoromethyl-phenyl)-piperazine hydrochloride
To 0.58 mmol rac-3-methyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in 3 ml dioxane was added 8.7 mmol HCl (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 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-Acetyl-2-isopropoxy-benzoic acid
To 25.8 mmol 5-acetyl-2-isopropoxy-benzoic acid methyl ester in 100 ml THF was 400 mmol 2 M aq NaOH, and the mixture was heated at 80° C. for 2 h. The mixture en cooled to RT and extracted twice with ether. The aqueous phase was acidified with q hydrochloric acid and extracted 3 times with ethyl acetate. The combined organic were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether ed 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 ed from the acid derivatives and piperazine derivatives:













Expl.


MW found


No.
Systematic Name
Starting materials
(MH+)







472
3-[4-(4-Cyano-2-fluoro-
3-Fluoro-4-piperazin-1-yl-
433.2



phenyl)-piperazine-1-
benzonitrile (WO9625414) and 2-



carbonyl]-4-ethoxy-
Ethoxy-5-sulfamoyl-benzoic acid



benzenesulfonamide
(JP53050139)


473
3-[4-(4-Cyano-3-fluoro-
2-Fluoro-4-piperazin-1-yl-
431.3



phenyl)-piperazine-1-
benzonitrile (WO 9808835) and 2-
(M − H)



carbonyl]-4-ethoxy-
Ethoxy-5-sulfamoyl-benzoic acid



benzenesulfonamide
(JP53050139)


474
3-[4-(4-Cyano-phenyl)-
4-Piperazin-1-yl-benzonitrile
413.3



piperazine-1-carbonyl]-
(commercial) and 2-Ethoxy-5-
(M − H)



4-ethoxy-
sulfamoyl-benzoic acid (JP53050139)



benzenesulfonamide


475
3-[4-(4-Cyano-3-fluoro-
2-Fluoro-4-piperazin-1-yl-
475.1



phenyl)-piperazine-1-
benzonitrile (WO 9808835) and 2-



carbonyl]-4-isobutoxy-
Isobutoxy-5-methylsulfamoyl-



N-methyl-
benzoic acid (compound 6.1)



benzenesulfonamide


476
3-[4-(4-Cyano-3-fluoro-
2-Fluoro-4-piperazin-1-yl-
489.3



phenyl)-piperazine-1-
benzonitrile (WO 9808835) and 2-



carbonyl]-4-(2,2-
(2,2-Dimethyl-propoxy)-5-



dimethyl-propoxy)-N-
methylsulfamoyl-benzoic acid



methyl-
(compound 6.2)



benzenesulfonamide


477
3-[4-(4-Cyano-3-fluoro-
2-Fluoro-4-piperazin-1-yl-
461.2



phenyl)-piperazine-1-
benzonitrile (WO 9808835) and 2-



carbonyl]-4-isopropoxy-
Isopropoxy-5-methylsulfamoyl-



N-methyl-
benzoic acid (compound 6.3)



benzenesulfonamide


478
3-[4-(4-Cyano-3-fluoro-
2-Fluoro-4-piperazin-1-yl-
487.3



phenyl)-piperazine-1-
benzonitrile (WO 9808835) and 2-



carbonyl]-4-
Cyclopentyloxy-5-methylsulfamoyl-



cyclopentyloxy-N-
benzoic acid (compound 6.4)



methyl-benzenesulfonamide


479
3-[4-(4-Cyano-3-fluoro-
2-Fluoro-4-piperazin-1-yl-
473.1



phenyl)-piperazine-1-
benzonitrile (WO 9808835) and 2-



carbonyl]-4-cyclobutoxy-
Cyclobutoxy-5-methylsulfamoyl-



N-methyl-
benzoic acid (compound 6.5)



benzenesulfonamide


480
3-[4-(4-Cyano-3-fluoro-
2-Fluoro-4-piperazin-1-yl-
473.2



phenyl)-piperazine-1-
benzonitrile (WO 9808835) and 2-



carbonyl]-4-
Cyclopropylmethoxy-5-



cyclopropylmethoxy-N-
methylsulfamoyl-benzoic acid



methyl-benzenesulfonamide
(compound 6.6)


481
3-[4-(4-Cyano-3-fluoro-
2-Fluoro-4-piperazin-1-yl-
487.3



phenyl)-piperazine-1-
benzonitrile (WO 9808835) and 2-



carbonyl]-4-
Cyclobutylmethoxy-5-



cyclobutylmethoxy-N-
methylsulfamoyl-benzoic acid



methyl-benzenesulfonamide
(compound 6.7)


482
3-[4-(4-Cyano-3-fluoro-
2-Fluoro-4-piperazin-1-yl-
503.2



phenyl)-piperazine-1-
benzonitrile (WO 9808835) and 5-



carbonyl]-N-methyl-4-
Methylsulfamoyl-2-(tetrahydro-



(tetrahydro-pyran-4-
pyran-4-yloxy)-benzoic acid



yloxy)-benzenesulfonamide
(compound 6.8)


483
3-[4-(4-Cyano-3-fluoro-
2-Fluoro-4-piperazin-1-yl-
477.3



phenyl)-piperazine-1-
benzonitrile (WO 9808835) and 2-



carbonyl]-4-(2-methoxy-
(2-Methoxy-ethoxy)-5-



ethoxy)-N-methyl-
methylsulfamoyl-benzoic acid



benzenesulfonamide
(compound 6.9)


484
3-[4-(4-Cyano-3-fluoro-
2-Fluoro-4-piperazin-1-yl-
515.2



phenyl)-piperazine-1-
benzonitrile (WO 9808835) and 5-



carbonyl]-N-methyl-4-
Methylsulfamoyl-2-(3,3,3-trifluoro-



(3,3,3-trifluoro-
propoxy)-benzoic acid (compound



propoxy)-
6.10)



benzenesulfonamide


485
3-[4-(4-Cyano-phenyl)-
4-Piperazin-1-yl-benzonitrile
459.1



piperazine-1-carbonyl]-
(commercial) and 2-(2-Methoxy-



4-(2-methoxy-ethoxy)-
ethoxy)-5-methylsulfamoyl-benzoic



N-methyl-
acid (compound 6.9)



benzenesulfonamide


486
3-[4-(4-Cyano-phenyl)-
4-Piperazin-1-yl-benzonitrile
497.0



piperazine-1-carbonyl]-
(commercial) and 5-



N-methyl-4-(3,3,3-
Methylsulfamoyl-2-(3,3,3-trifluoro-



trifluoro-propoxy)-
propoxy)-benzoic acid (compound



benzenesulfonamide
6.10)


487
3-[4-(4-Cyano-phenyl)-
4-Piperazin-1-yl-benzonitrile
485.2



piperazine-1-carbonyl]-
(commercial) and 5-



N-methyl-4-(tetrahydro-
Methylsulfamoyl-2-(tetrahydro-



pyran-4-yloxy)-
pyran-4-yloxy)-benzoic acid



benzenesulfonamide
(compound 6.8)


488
3-[4-(4-Cyano-phenyl)-
4-Piperazin-1-yl-benzonitrile
457.3



piperazine-1-carbonyl]-
(commercial) and 2-Isobutoxy-5-



4-isobutoxy-N-methyl-
methylsulfamoyl-benzoic acid



benzenesulfonamide
(compound 6.1)


489
3-[4-(4-Cyano-phenyl)-
4-Piperazin-1-yl-benzonitrile
471.1



piperazine-1-carbonyl]-
(commercial) and 2-(2,2-Dimethyl-



4-(2,2-dimethyl-
propoxy)-5-methylsulfamoyl-



propoxy)-N-methyl-
benzoic acid (compound 6.2)



benzenesulfonamide


490
3-[4-(4-Cyano-phenyl)-
4-Piperazin-1-yl-benzonitrile
443.2



piperazine-1-carbonyl]-
(commercial) and 2-Isopropoxy-5-



4-isopropoxy-N-methyl-
methylsulfamoyl-benzoic acid



benzenesulfonamide
(compound 6.3)


491
3-[4-(4-Cyano-phenyl)-
4-Piperazin-1-yl-benzonitrile
469.2



piperazine-1-carbonyl]-
(commercial) and 2-Cyclopentyloxy-



4-cyclopentyloxy-N-
5-methylsulfamoyl-benzoic acid



methyl-benzenesulfonamide
(compound 6.4)


492
3-[4-(4-Cyano-phenyl)-
4-Piperazin-1-yl-benzonitrile
455.3



piperazine-1-carbonyl]-
(commercial) and 2-Cyclobutoxy-5-



4-cyclobutoxy-N-methyl-
methylsulfamoyl-benzoic acid



benzenesulfonamide
(compound 6.5)


493
3-[4-(4-Cyano-phenyl)-
4-Piperazin-1-yl-benzonitrile
455.3



piperazine-1-carbonyl]-
(commercial) and 2-



4-cyclopropylmethoxy-
Cyclopropylmethoxy-5-



N-methyl-
methylsulfamoyl-benzoic acid



benzenesulfonamide
(compound 6.6)


494
3-[4-(4-Cyano-phenyl)-
4-Piperazin-1-yl-benzonitrile
469.2



piperazine-1-carbonyl]-
(commercial) and 2-



4-cyclobutylmethoxy-N-
Cyclobutylmethoxy-5-



methyl-benzenesulfonamide
methylsulfamoyl-benzoic acid




(compound 6.7)


495
3-[4-(2-Fluoro-4-
1-(2-Fluoro-4-methanesulfonyl-
528.0



methanesulfonyl-
phenyl)-piperazine (commercial)



phenyl)-piperazine-1-
and 2-Isobutoxy-5-



carbonyl]-4-isobutoxy-
methylsulfamoyl-benzoic acid



N-methyl-
(compound 6.1)



benzenesulfonamide


496
4-(2,2-Dimethyl-
1-(2-Fluoro-4-methanesulfonyl-
559.2



propoxy)-3-[4-(2-fluoro-
phenyl)-piperazine (commercial)
(M + NH4+)



4-methanesulfonyl-
and 2-(2,2-Dimethyl-propoxy)-5-



phenyl)-piperazine-1-
methylsulfamoyl-benzoic acid



carbonyl]-N-methyl-
(compound 6.2)



benzenesulfonamide


497
3-[4-(2-Fluoro-4-
1-(2-Fluoro-4-methanesulfonyl-
514.1



methanesulfonyl-
phenyl)-piperazine (commercial)



phenyl)-piperazine-1-
and 2-Isopropoxy-5-



carbonyl]-4-isopropoxy-
methylsulfamoyl-benzoic acid



N-methyl-
(compound 6.3)



benzenesulfonamide


498
4-Cyclopentyloxy-3-[4-
1-(2-Fluoro-4-methanesulfonyl-
557.0



(2-fluoro-4-
phenyl)-piperazine (commercial)
(M + NH4+)



methanesulfonyl-
and 2-Cyclopentyloxy-5-



phenyl)-piperazine-1-
methylsulfamoyl-benzoic acid



carbonyl]-N-methyl-
(compound 6.4)



benzenesulfonamide


499
4-Cyclobutoxy-3-[4-(2-
1-(2-Fluoro-4-methanesulfonyl-
526.0



fluoro-4-
phenyl)-piperazine (commercial)



methanesulfonyl-
and 2-Cyclobutoxy-5-



phenyl)-piperazine-1-
methylsulfamoyl-benzoic acid



carbonyl]-N-methyl-
(compound 6.5)



beuzenesulfonamide


500
4-Cyclopropylmethoxy-
1-(2-Fluoro-4-methanesulfonyl-
526.0



3-[4-(2-fluoro-4-
phenyl)-piperazine (commercial)



methanesulfonyl-
and 2-Cyclopropylmethoxy-5-



phenyl)-piperazine-1-
methylsulfamoyl-benzoic acid



carbonyl]-N-methyl-
(compound 6.6)



benzenesulfonamide


501
4-Cyclobutylmethoxy-3-
1-(2-Fluoro-4-methanesulfonyl-
557.0



[4-(2-fluoro-4-
phenyl)-piperazine (commercial)
(M + NH4+)



methanesulfonyl-
and 2-Cyclobutylmethoxy-5-



phenyl)-piperazine-1-
methylsulfamoyl-benzoic acid



carbonyl]-N-methyl-
(compound 6.7)



benzenesulfonamide


502
3-[4-(2-Fluoro-4-
1-(2-Fluoro-4-methanesulfonyl-
530.1



methanesulfonyl-
phenyl)-piperazine (commercial)



phenyl)-piperazine-1-
and 2-(2-Methoxy-ethoxy)-5-



carbonyl]-4-(2-methoxy-
methylsulfamoyl-benzoic acid



ethoxy)-N-methyl-
(compound 6.9)



benzenesulfonamide


503
3-[4-(2-Fluoro-4-
1-(2-Fluoro-4-methanesulfonyl-
585.0



methanesulfonyl-
phenyl)-piperazine (commercial)
(M + NH4+)



phenyl)-piperazine-1-
and 5-Methylsulfamoyl-2-(3,3,3-



carbonyl]-N-methyl-4-
trifluoro-propoxy)-benzoic acid



(3,3,3-trifluoro-propoxy)-
(compound 6.10)



benzenesulfonamide


504
3-[4-(4-Cyano-2-fluoro-
3-Fluoro-4-piperazin-1-yl-
475.0



phenyl)-piperazine-1-
benzonitrile (WO9625414) and 2-



carbonyl]-4-isobutoxy-
Isobutoxy-5-methylsulfamoyl-



N-methyl-
benzoic acid (compound 6.1)



benzenesulfonamide


505
3-[4-(4-Cyano-2-fluoro-
3-Fluoro-4-piperazin-1-yl-
489.0



phenyl)-piperazine-1-
benzonitrile (WO9625414) and 2-



carbonyl]-4-(2,2-
(2,2-Dimethyl-propoxy)-5-



dimethyl-propoxy)-N-
methylsulfamoyl-benzoic acid



methyl-benzenesulfonamide
(compound 6.2)


506
3-[4-(4-Cyano-2-fluoro-
3-Fluoro-4-piperazin-1-yl-
478.0



phenyl)-piperazine-1-
benzonitrile (WO9625414) and 2-
(M + NH4+)



carbonyl]-4-isopropoxy-
Isopropoxy-5-methylsulfamoyl-



N-methyl-
benzoic acid (compound 6.3)



benzenesulfonamide


507
3-[4-(4-Cyano-2-fluoro-
3-Fluoro-4-piperazin-1-yl-
487.1



phenyl)-piperazine-1-
benzonitrile (WO9625414) and 2-



carbonyl]-4-
Cyclopentyloxy-5-methylsulfamoyl-



cyclopentyloxy-N-methyl-
benzoic acid (compound 6.4)



benzenesulfonamide


508
3-[4-(4-Cyano-2-fluoro-
3-Fluoro-4-piperazin-1-yl-
472.8



phenyl)-piperazine-1-
benzonitrile (WO9625414) and



carbonyl]-4-cyclobutoxy-
Cyclobutoxy-5-methylsulfamoyl-



N-methyl-
benzoic acid (compound 6.5)



benzenesulfonamide


509
3-[4-(4-Cyano-2-fluoro-
3-Fluoro-4-piperazin-1-yl-
472.8



phenyl)-piperazine-1-
benzonitrile (WO9625414) and 2-



carbonyl]-4-
Cyclopropylmethoxy-5-



cyclopropylmethoxy-N-
methylsulfamoyl-benzoic acid



methyl-benzenesulfonamide
(compound 6.6)


510
3-[4-(4-Cyano-2-fluoro-
3-Fluoro-4-piperazin-1-yl-
487.1



phenyl)-piperazine-1-
benzonitrile (WO9625414) and 2-



carbonyl]-4-
Cyclobutylmethoxy-5-



cyclobutylmethoxy-N-
methylsulfamoyl-benzoic acid



methyl-benzenesulfonamide
(compound 6.7)


511
3-[4-(4-Cyano-2-fluoro-
3-Fluoro-4-piperazin-1-yl-
503.0



phenyl)-piperazine-1-
benzonitrile (WO9625414) and 5-



carbonyl]-N-methyl-4-
Methylsulfamoyl-2-(tetrahydro-



(tetrahydro-pyran-4-
pyran-4-yloxy)-benzoic acid



yloxy)-benzenesulfonamide
(compound 6.8)


512
3-[4-(4-Cyano-2-fluoro-
3-Fluoro-4-piperazin-1-yl-
477.1



phenyl)-piperazine-1-
benzonitrile (WO9625414) and 2-(2-



carbonyl]-4-(2-methoxy-
Methoxy-ethoxy)-5-



ethoxy)-N-methyl-
methylsulfamoyl-benzoic acid



benzenesulfonamide
(compound 6.9)


513
3-[4-(4-Cyano-2-fluoro-
3-Fluoro-4-piperazin-1-yl-
515.1



phenyl)-piperazine-1-
benzonitrile (WO9625414) and 5-



carbonyl]-N-methyl-4-
Methylsulfamoyl-2-(3,3,3-trifluoro-



(3,3,3-trifluoro-propoxy)-
propoxy)-benzoic acid (compound 6.10)



benzenesulfonamide


514
3-[4-(4-Acetyl-2-fluoro-
1-(3-Fluoro-4-piperazin-1-yl-
492.1



phenyl)-piperazine-1-
phenyl)-ethanone (WO9714690) and



carbonyl]-4-isobutoxy-
2-Isobutoxy-5-methylsulfamoyl-



N-methyl-benzenesulfonamide
benzoic acid (compound 6.1)


515
3-[4-(4-Acetyl-2-fluoro-
1-(3-Fluoro-4-piperazin-1-yl-
506.3



phenyl)-piperazine-1-
phenyl)-ethanone (WO9714690) and



carbonyl]-4-(2,2-
2-(2,2-Dimethyl-propoxy)-5-



dimethyl-propoxy)-N-
methylsulfamoyl-benzoic acid



methyl-benzenesulfonamide
(compound 6.2)


516
3-[4-(4-Acetyl-2-fluoro-
1-(3-Fluoro-4-piperazin-1-yl-
478.2



phenyl)-piperazine-1-
phenyl)-ethanone (WO9714690) and



carbonyl]-4-isopropoxy-
2-Isopropoxy-5-methylsulfamoyl-



N-methyl-benzenesulfonamide
benzoic acid (compound 6.3)


517
3-[4-(4-Acetyl-2-fluoro-
1-(3-Fluoro-4-piperazin-1-yl-
504.2



phenyl)-piperazine-1-
phenyl)-ethanone (WO9714690) and



carbonyl]-4-
2-Cyclopentyloxy-5-



cyclopentyloxy-N-
methylsulfamoyl-benzoic acid



methyl-benzenesulfonamide
(compound 6.4)


518
3-[4-(4-Acetyl-2-fluoro-
1-(3-Fluoro-4-piperazin-1-yl-
590.6



phenyl)-piperazine-1-
phenyl)-ethanone (WO9714690) and



carbonyl]-4-cyclobutoxy-
2-Cyclobutoxy-5-methylsulfamoyl-



N-methyl-benzenesulfonamide
benzoic acid (compound 6.5)


519
3-[4-(4-Acetyl-2-fluoro-
1-(3-Fluoro-4-piperazin-1-yl-
490.2



phenyl)-piperazine-1-
phenyl)-ethanone (WO9714690) and



carbonyl]-4-
2-Cyclopropylmethoxy-5-



cyclopropylmethoxy-N-
methylsulfamoyl-benzoic acid



methyl-benzenesulfonamide
(compound 6.6)


520
3-[4-(4-Acetyl-2-fluoro-
1-(3-Fluoro-4-piperazin-1-yl-
504.2



phenyl)-piperazine-1-
phenyl)-ethanone (WO9714690) and



carbonyl]-4-
2-Cyclobutylmethoxy-5-



cyclobutylmethoxy-N-
methylsulfamoyl-benzoic acid



methyl-benzenesulfonamide
(compound 6.7)


521
3-[4-(4-Acetyl-2-fluoro-
1-(3-Fluoro-4-piperazin-1-yl-
520.3



phenyl)-piperazine-1-
phenyl)-ethanone (WO9714690) and



carbonyl]-N-methyl-4-
5-Methylsulfamoyl-2-(tetrahydro-



(tetrahydro-pyran-4-
pyran-4-yloxy)-benzoic acid



yloxy)-benzenesulfonamide
(compound 6.8)


522
3-[4-(4-Acetyl-2-fluoro-
1-(3-Fluoro-4-piperazin-1-yl-
494.2



phenyl)-piperazine-1-
phenyl)-ethanone (WO9714690) and



carbonyl]-4-(2-methoxy-
2-(2-Methoxy-ethoxy)-5-



ethoxy)-N-methyl-
methylsulfamoyl-benzoic acid



benzenesulfonamide
(compound 6.9)


523
3-[4-(4-Acetyl-2-fluoro-
1-(3-Fluoro-4-piperazin-1-yl-
532.2



phenyl)-piperazine-1-
phenyl)-ethanone (WO9714690) and



carbonyl]-N-methyl-4-
5-Methylsulfamoyl-2-(3,3,3-



(3,3,3-trifluoro-
trifluoro-propoxy)-benzoic acid



propoxy)-benzenesulfonamide
(compound 6.10)


524
4-Isobutoxy-N-methyl-3-
1-(4-Trifluoromethyl-phenyl)-
500.2



[4-(4-trifluoromethyl-
piperazine (commercial) and 2-



phenyl)-piperazine-1-
Isobutoxy-5-methylsulfamoyl-



carbonyl]-benzenesulfonamide
benzoic acid (compound 6.1)


525
4-(2,2-Dimethyl-
1-(4-Trifluoromethyl-phenyl)-
514.2



propoxy)-N-methyl-3-
piperazine (commercial) and



[4-(4-trifluoromethyl-
2-(2,2-Dimethyl-propoxy)-5-



phenyl)-piperazine-1-
methylsulfamoyl-benzoic acid



carbonyl]-benzenesulfonamide
(compound 6.2)


526
4-Isopropoxy-N-methyl-
1-(4-Trifluoromethyl-phenyl)-
486.2



3-[4-(4-trifluoromethyl-
piperazine (commercial) and 2-



phenyl)-piperazine-1-
Isopropoxy-5-methylsulfamoyl-



carbonyl]-benzenesulfonamide
benzoic acid (compound 6.3)


527
4-Cyclopentyloxy-N-
1-(4-Trifluoromethyl-phenyl)-
512.3



methyl-3-[4-(4-
piperazine (commercial) and 2-



trifluoromethyl-phenyl)-
Cyclopentyloxy-5-methylsulfamoyl-



piperazine-1-carbonyl]-
benzoic acid (compound 6.4)



benzenesulfonamide


528
4-Cyclobutoxy-N-
1-(4-Trifluoromethyl-phenyl)-
498.2



methyl-3-[4-(4-
piperazine (commercial) and 2-



trifluoromethyl-phenyl)-
Cyclobutoxy-5-methylsulfamoyl-



piperazine-1-carbonyl]-
benzoic acid (compound 6.5)



benzenesulfonamide


529
4-Cyclopropylmethoxy-
1-(4-Trifluoromethyl-phenyl)-
498.2



N-methyl-3-[4-(4-
piperazine (commercial) and 2-



trifluoromethyl-phenyl)-
Cyclopropylmethoxy-5-



piperazine-1-carbonyl]-
methylsulfamoyl-benzoic acid



benzenesulfonamide
(compound 6.6)


530
4-Cyclobutylmethoxy-N-
1-(4-Trifluoromethyl-phenyl)-
512.3



methyl-3-[4-(4-
piperazine (commercial) and 2-



trifluoromethyl-phenyl)-
Cyclobutylmethoxy-5-



piperazine-1-carbonyl]-
methylsulfamoyl-benzoic acid



benzenesulfonamide
(compound 6.7)


531
N-Methyl-3-[4-(4-
1-(4-Trifluoromethyl-phenyl)-
540.2



trifluoromethyl-phenyl)-
piperazine (commercial) and 5-



piperazine-1-carbonyl]-
Methylsulfamoyl-2-(3,3,3-trifluoro-



4-(3,3,3-trifluoro-
propoxy)-benzoic acid (compound 6.10)



propoxy)-benzenesulfonamide


532
3-[4-(4-Cyano-3-fluoro-
2-Fluoro-4-piperazin-1-yl-
501.1



phenyl)-piperazine-1-
benzonitrile (WO 9808835) and 5-



carbonyl]-N-methyl-4-
Methylsulfamoyl-2-(2,2,2-trifluoro-



(2,2,2-trifluoro-ethoxy)-
ethoxy)-benzoic acid (compound 6.11)



benzenesulfonamide


533
3-[4-(4-Cyano-phenyl)-
4-Piperazin-1-yl-benzonitrile
483.3



piperazine-1-carbonyl]-
(commercial) and 5-



N-methyl-4-(2,2,2-
Methylsulfamoyl-2-(2,2,2-trifluoro-



trifluoro-ethoxy)-
ethoxy)-benzoic acid (compound 6.11)



benzenesulfonamide


534
3-[4-(4-Cyano-2-fluoro-
3-Fluoro-4-piperazin-1-yl-
501.1



phenyl)-piperazine-1-
benzonitrile (WO9625414) and 5-



carbonyl]-N-methyl-4-
Methylsulfamoyl-2-(2,2,2-trifluoro-



(2,2,2-trifluoro-ethoxy)-
ethoxy)-benzoic acid (compound 6.11)



benzenesulfonamide


535
3-[4-(4-Acetyl-2-fluoro-
1-(3-Fluoro-4-piperazin-1-yl-
518.2



phenyl)-piperazine-1-
phenyl)-ethanone (WO9714690) and



carbonyl]-N-methyl-4-
5-Methylsulfamoyl-2-(2,2,2-



(2,2,2-trifluoro-ethoxy)-
trifluoro-ethoxy)-benzoic acid



benzenesulfonamide
(compound 6.11)


536
3-[4-(2-Fluoro-4-
1-(2-Fluoro-4-methanesulfonyl-
554.1



methanesulfonyl-
phenyl)-piperazine (commercial)



phenyl)-piperazine-1-
and 5-Methylsulfamoyl-2-(2,2,2-



carbonyl]-N-methyl-4-
trifluoro-ethoxy)-benzoic acid



(2,2,2-trifluoro-ethoxy)-
(compound 6.11)



benzenesulfonamide


537
N-Methyl-4-(2,2,2-
1-(4-Trifluoromethyl-phenyl)-
526.0



trifluoro-ethoxy)-3-[4-
piperazine (commercial) and 5-



(4-trifluoromethyl-
Methylsulfamoyl-2-(2,2,2-trifluoro-



phenyl)-piperazine-1-
ethoxy)-benzoic acid (compound 6.11)



carbonyl]-benzene



sulfonamide


538
[4-(4-Ethanesulfonyl-2-
1-(4-Ethanesulfonyl-2-fluoro-
513.3



fluoro-phenyl)-
phenyl)-piperazine (compound 6.12)



piperazin-1-yl]-(2-
and 2-Isopropoxy-5-



isopropoxy-5-
methanesulfonyl-benzoic acid



methanesulfonyl-
(compound 1.2)



phenyl)-methanone


539
{4-[4-(Butane-1-
1-[4-(Butane-1-sulfonyl)-2-fluoro-
541.0



sulfonyl)-2-fluoro-
phenyl]-piperazine (compound 6.13)



phenyl]-piperazin-1-yl}-
and 2-Isopropoxy-5-



(2-isopropoxy-5-
methanesulfonyl-benzoic acid



methanesulfonyl-
(compound 1.2)



phenyl)-methanone


540
4-[4-(5-
3-Fluoro-4-piperazin-1-yl-
472.3



Cyclopropanesulfonyl-2-
benzonitrile (WO9625414) and 5-



isopropoxy-benzoyl)-
Cyclopropanesulfonyl-2-isopropoxy-



piperazin-1-yl]-3-fluoro-
benzoic acid (compound 6.14)



benzonitrile


541
(5-Cyclopropane
1-(2-Fluoro-4-trifluoromethyl-phenyl)-
515.4



sulfonyl-2-isopropoxy-
piperazine (compound 1.1) and 5-



phenyl)-[4-(2-fluoro-4-
Cyclopropanesulfonyl-2-isopropoxy-



trifluoro methyl-phenyl)-
benzoic acid (compound 6.14)



piperazin-1-yl]-methanone


542
(5-Cyclopropanesulfonyl-
1-(2-Fluoro-4-methanesulfonyl-
539.5



2-isobutoxy-
phenyl)-piperazine (commercial)



phenyl)-[4-(2-fluoro-4-
and 5-Cyclopropanesulfonyl-2-



methane sulfonyl-
isobutoxy-benzoic acid (compound 6.15)



phenyl)-piperazin-1-yl]-



methanone


543
4-[4-(5-Cyclopropanesulfonyl-
3-Fluoro-4-piperazin-1-yl-
486.5



2-isobutoxy-
benzonitrile (WO9625414) and 5-



benzoyl)-piperazin-1-yl]-
Cyclopropanesulfonyl-2-isobutoxy-



3-fluoro-benzonitrile
benzoic acid (compound 6.15)


544
(5-Cyclopropanesulfonyl-
1-(2-Fluoro-4-trifluoromethyl-phenyl)-
529.4



2-isobutoxy-
piperazine (compound 1.1) and 5-



phenyl)-[4-(2-fluoro-4-
Cyclopropanesulfonyl-2-isobutoxy-



trifluoromethyl-phenyl)-
benzoic acid (compound 6.15)



piperazin-1-yl]-methanone


545
(2-Cyclopentyloxy-5-
1-(2-Fluoro-4-methanesulfonyl-
551.3



cyclopropanesulfonyl-
phenyl)-piperazine (commercial)



phenyl)-[4-(2-fluoro-4-
and 2-Cyclopentyloxy-5-



methanesulfonyl-
cyclopropanesulfonyl-benzoic acid



phenyl)-piperazin-1-yl]-
(compound 6.16)



methanone


546
4-[4-(2-Cyclopentyloxy-
3-Fluoro-4-piperazin-1-yl-
498.3



5-cyclopropanesulfonyl-
benzonitrile (WO9625414) and 2-



benzoyl)-piperazin-1-yl]-
Cyclopentyloxy-5-cyclopropane



3-fluoro-benzonitrile
sulfonyl-benzoic acid (compound 6.16)


547
(2-Cyclopentyloxy-5-
1-(2-Fluoro-4-trifluoromethyl-phenyl)-
541.3



cyclopropanesulfonyl-
piperazine (compound 1.1) and 2-



phenyl)-[4-(2-fluoro-4-
Cyclopentyloxy-5-



trifluoromethyl-phenyl)-
cyclopropanesulfonyl-benzoic acid



piperazin-1-yl]-methanone
(compound 6.16)


548
(5-Cyclopropanesulfonyl-
1-(2-Fluoro-4-methanesulfonyl-
537.4



2-cyclopropylmethoxy-
phenyl)-piperazine (commercial)



phenyl)-[4-(2-fluoro-4-
and 5-Cyclopropanesulfonyl-2-



methanesulfonyl-phenyl)-
cyclopropylmethoxy-benzoic acid



piperazin-1-yl]-methanone
(compound 6.17)


549
4-[4-(5-Cyclopropanesulfonyl-
3-Fluoro-4-piperazin-1-yl-
484.5



2-cyclopropylmethoxy-
benzonitrile (WO9625414) and 5-



benzoyl)-piperazin-1-yl]-
Cyclopropanesulfonyl-2-



3-fluoro-benzonitrile
cyclopropylmethoxy-benzoic acid




(compound 6.17)


550
(5-Cyclopropanesulfonyl-
1-(2-Fluoro-4-trifluoromethyl-phenyl)-
527.3



2-cyclopropylmethoxy-
piperazine (compound 1.1) and 5-



phenyl)-[4-(2-
Cyclopropanesulfonyl-2-



fluoro-4-trifluoromethyl-
cyclopropylmethoxy-benzoic acid



phenyl)-piperazin-1-yl]-
(compound 6.17)



methanone


551
(2-Cyclobutoxy-5-
1-(2-Fluoro-4-methanesulfonyl-
537.4



cyclopropanesulfonyl-
phenyl)-piperazine (commercial)



phenyl)-[4-(2-fluoro-4-
and 2-Cyclobutoxy-5-



methanesulfonyl-
cyclopropanesulfonyl-benzoic acid



phenyl)-piperazin-1-yl]-
(compound 6.18)



methanone


552
(5-Cyclopropanesulfonyl-
1-(2-Fluoro-4-methanesulfonyl-
525.3



2-isopropoxy-
phenyl)-piperazine (commercial)



phenyl)-[4-(2-fluoro-4-
and 5-Cyclopropanesulfonyl-2-



methanesulfonyl-
isopropoxy-benzoic acid



phenyl)-piperazin-1-yl]-
(compound 6.14)



methanone


553
rac-3-[4-(2-Fluoro-4-
1-(2-Fluoro-4-methanesulfonyl-
585.1



methanesulfonyl-
phenyl)-piperazine (commercial)
(M + NH4+)



phenyl)-piperazine-1-
and rac-5-Methylsulfamoyl-2-(2,2,2-



carbonyl]-N-methyl-4-
trifluoro-1-methyl-ethoxy)-benzoic



(2,2,2-trifluoro-1-
acid (compound 6.19)



methyl-ethoxy)-



benzenesulfonamide


554
rac-N-Methyl-4-(2,2,2-
1-(4-Trifluoromethyl-phenyl)-
557.2



trifluoro-1-methyl-
piperazine (commercial) and rac-5-
(M + NH4+)



ethoxy)-3-[4-(4-
Methylsulfamoyl-2-(2,2,2-trifluoro-



trifluoromethyl-phenyl)-
1-methyl-ethoxy)-benzoic acid



piperazine-1-carbonyl]-
(compound 6.19)



benzenesulfonamide


555
rac-3-[4-(4-Cyano-2-
3-Fluoro-4-piperazin-1-yl-
532.3



fluoro-phenyl)-
benzonitrile (WO9625414) and rac-
(M + NH4+)



piperazine-1-carbonyl]-
5-Methylsulfamoyl-2-(2,2,2-



N-methyl-4-(2,2,2-
trifluoro-1-methyl-ethoxy)-benzoic



trifluoro-1-methyl-
acid (compound 6.19)



ethoxy)-benzene



sulfonamide


556
[4-(4-Cyclopropane
1-(4-Cyclopropanesulfonyl-2-fluoro-
542.2



sulfonyl-2-fluoro-
phenyl)-piperazine (compound 6.20)
(M + NH4+)



phenyl)-piperazin-1-yl]-
and 2-Isopropoxy-5-methanesulfonyl-



(2-isopropoxy-5-
benzoic acid (compound 1.2)



methanesulfonyl-



phenyl)-methanone


557
rac-3-[4-(4-Cyano-2,5-
2,5-Difluoro-4-piperazin-1-yl-
550.1



difluoro-phenyl)-
benzonitrile-trifluoro-acetic acid
(M + NH4+)



piperazine-1-carbonyl]-
(compound 2.8) and rac-5-



N-methyl-4-(2,2,2-
Methylsulfamoyl-2-(2,2,2-trifluoro-



trifluoro-1-methyl-ethoxy)-
1-methyl-ethoxy)-benzoic acid



benzene sulfonamide
(compound 6.19)


558
rac-3-[4-(4-Cyano-2,3-
2,3-Difluoro-4-piperazin-1-yl-
550.1



difluoro-phenyl)-
benzonitrile-trifluoro-acetic acid
(M + NH4+)



piperazine-1-carbonyl]-
(compound 2.7) and rac-5-



N-methyl-4-(2,2,2-
Methylsulfamoyl-2-(2,2,2-trifluoro-



trifluoro-1-methyl-ethoxy)-
1-methyl-ethoxy)-benzoic acid



benzene sulfonamide
(compound 6.19)


559
{4-[2-Fluoro-4-
1-[2-Fluoro-4-(propane-2-sulfonyl)-
544.3



(propane-2-sulfonyl)-
phenyl]-piperazine (compound 6.21)
(M + NH4+)



phenyl]-piperazin-1-yl}
and 2-Isopropoxy-5-methanesulfonyl-



(2-isopropoxy-5-
benzoic acid (compound 1.2)



methanesulfonyl-



phenyl)-methanone


560
[4-(4-
1-(4-Cyclopropylmethanesulfonyl-2-
556.2



Cyclopropylmethanesulfonyl-
fluoro-phenyl)-piperazine
(M + NH4+)



2-fluoro-phenyl)-
(compound 6.22) and 2-Isopropoxy-



piperazin-1-yl]-(2-
5-methanesulfonyl-benzoic acid



isopropoxy-5-
(compound 1.2)



methanesulfonyl-



phenyl)-methanone


561
{4-[2-Fluoro-4-(2-methoxy-
1-[2-Fluoro-4-(2-methoxy-
560.3



ethanesulfonyl)-phenyl]-
ethanesulfonyl)-phenyl]-piperazine
(M + NH4+)



piperazin-1-yl}-(2-
(compound 6.23) and 2-Isopropoxy-



isopropoxy-5-
5-methanesulfonyl-benzoic acid



methanesulfonyl-
(compound 1.2)



phenyl)-methanone


562
(2-Cyclopropylmethoxy-
1-(4-Ethanesulfonyl-2-fluoro-
542.2



5-methanesulfonyl-
phenyl)-piperazine (compound 6.12)
(M + NH4+)



phenyl)-[4-(4-
and 2-Cyclopropylmethoxy-5-



ethanesulfonyl-2-fluoro-
methanesulfonyl-benzoic acid



phenyl)-piperazin-1-yl]-
(compound 1.4)



methanone


563
(2-Cyclopentyloxy-5-
1-(4-Ethanesulfonyl-2-fluoro-
556.1



methanesulfonyl-
phenyl)-piperazine (compound 6.12)
(M + NH4+)



phenyl)-[4-(4-
and 2-Cyclopentyloxy-5-



ethanesulfonyl-2-fluoro-
methanesulfonyl-benzoic acid



phenyl)-piperazin-1-yl]-
(compound 1.6)



methanone


564
(2-Cyclohexyloxy-5-
1-(4-Ethanesulfonyl-2-fluoro-
570.2



methanesulfonyl-
phenyl)-piperazine (compound 6.12)
(M + NH4+)



phenyl)-[4-(4-
and 2-Cyclohexyloxy-5-



ethanesulfonyl-2-fluoro-
methanesulfonyl-benzoic acid



phenyl)-piperazin-1-yl]-
(compound 3.2)



methanone


565
[2-(2,2-Dimethyl-
1-(4-Ethanesulfonyl-2-fluoro-
558.2 (M + NH4+)



propoxy)-5-
phenyl)-piperazine (compound 6.12)



methanesulfonyl-
and 2-(2,2-Dimethyl-propoxy)-5-



phenyl]-[4-(4-
methanesulfonyl-benzoic acid



ethanesulfonyl-2-fluoro-
(compound 3.3)



phenyl)-piperazin-1-yl]-



methanone


566
[4-(4-Ethanesulfonyl-2-
1-(4-Ethanesulfonyl-2-fluoro-
544.2 (M + NH4+)



fluoro-phenyl)-
phenyl)-piperazine (compound 6.12)



piperazin-1-yl]-(2-
and 2-Isobutoxy-5-methanesulfonyl-



isobutoxy-5-
benzoic acid (compound 1.3)



methanesulfonyl-



phenyl)-methanone


567
(2-Cyclobutoxy-5-
1-(4-Ethanesulfonyl-2-fluoro-
542.3



methanesulfonyl-
phenyl)-piperazine (compound 6.12)
(M + NH4+)



phenyl)-[4-(4-
and 2-Cyclobutoxy-5-



ethanesulfonyl-2-fluoro-
methanesulfonyl-benzoic acid



phenyl)-piperazin-1-yl]-
(compound 3.4)



methanone


568
rac-(2-sec-Butoxy-5-
1-(4-Ethanesulfonyl-2-fluoro-
544.2



methanesulfonyl-
phenyl)-piperazine (compound 6.12)
(M + NH4+)



phenyl)-[4-(4-
and rac-2-sec-Butoxy-5-



ethanesulfonyl-2-fluoro-
methanesulfonyl-benzoic acid



phenyl)-piperazin-1-yl]-
(compound 3.5)



methanone


569
(2-Cyclobutylmethoxy-5-
1-(4-Ethanesulfonyl-2-fluoro-
556.1



methanesulfonyl-
phenyl)-piperazine (compound 6.12)
(M + NH4+)



phenyl)-[4-(4-
and 2-Cyclobutylmethoxy-5-



ethanesulfonyl-2-fluoro-
methanesulfonyl-benzoic acid



phenyl)-piperazin-1-yl]-
(compound 2.12)



methanone


570
[4-(4-Cyclobutanesulfonyl-
1-(4-Cyclobutanesulfonyl-2-fluoro-
556.1



2-fluoro-phenyl)-piperazin-
phenyl)-piperazine hydrochloride
(M + NH4+)



1-yl]-(2-isopropoxy-
(compound 6.24) and 2-Isopropoxy-



5-methanesulfonyl-
5-methanesulfonyl-benzoic acid



phenyl)-methanone
(compound 1.2)


571
[4-(4-Cyclopentanesulfonyl-2-
1-(4-Cyclopentanesulfonyl-2-fluoro-
570.3



fluoro-phenyl)-piperazin-1-yl]-
phenyl)-piperazine hydrochloride
(M + NH4+)



(2-isopropoxy-5-
(compound 6.25) and 2-Isopropoxy-



methanesulfonyl-
5-methanesulfonyl-benzoic acid



phenyl)-methanone
(compound 1.2)


572
[4-(4-Cyclopropane
1-(4-Cyclopropanesulfonyl-2-fluoro-
537.2



sulfonyl-2-fluoro-
phenyl)-piperazine (compound 6.20)



phenyl)-piperazin-1-yl]-
and 2-Cyclopropylmethoxy-5-



(2-cyclopropylmethoxy-
methanesulfonyl-benzoic acid



5-methanesulfonyl-
(compound 1.4)



phenyl)-methanone


573
(2-Cyclopentyloxy-5-
1-(4-Cyclopropanesulfonyl-2-fluoro-
568.0



methanesulfonyl-
phenyl)-piperazine (compound 6.20)
(M + NH4+)



phenyl)-[4-(4-
and 2-Cyclopentyloxy-5-



cyclopropanesulfonyl-2-
methanesulfonyl-benzoic acid



fluoro-phenyl)-
(compound 1.6)



piperazin-1-yl]-methanone


574
(2-Cyclohexyloxy-5-
1-(4-Cyclopropanesulfonyl-2-fluoro-
582.1



methanesulfonyl-
phenyl)-piperazine (compound 6.20)
(M + NH4+)



phenyl)-[4-(4-
and 2-Cyclohexyloxy-5-methanesulfonyl-



cyclopropanesulfonyl-2-
benzoic acid (compound 3.2)



fluoro-phenyl)-



piperazin-1-yl]-methanone


575
[4-(4-Cyclopropanesulfonyl-
1-(4-Cyclopropanesulfonyl-2-fluoro-
570.2



2-fluoro-
phenyl)-piperazine (compound 6.20)
(M + NH4+)



phenyl)-piperazin-1-yl]-
and 2-(2,2-Dimethyl-propoxy)-5-



[2-(2,2-dimethyl-
methanesulfonyl-benzoic acid



propoxy)-5-
(compound 3.3)



methanesulfonyl-



phenyl]-methanone


576
(2-Cyclobutoxy-5-
1-(4-Cyclopropanesulfonyl-2-fluoro-
536.9



methanesulfonyl-
phenyl)-piperazine (compound 6.20)



phenyl)-[4-(4-
and 2-Cyclobutoxy-5-methane



cyclopropanesulfonyl-2-
sulfonyl-benzoic acid (compound 3.4)



fluoro-phenyl)-



piperazin-1-yl]-



methanone


577
{4-[2-Fluoro-4-(3,3,3-
1-[2-Fluoro-4-(3,3,3-trifluoro-
581.0



trifluoro-propane-1-
propane-1-sulfonyl)-phenyl]-



sulfonyl)-phenyl]-
piperazine (compound 6.26) and 2-



piperazin-1-yl}-(2-
Isopropoxy-5-methanesulfonyl-



isopropoxy-5-
benzoic acid (compound 1.2)



methanesulfonyl-



phenyl)-methanone


578
[4-(4-Cyclopropane
1-(4-Cyclopropanesulfonyl-2-fluoro-
556.1



sulfonyl-2-fluoro-
phenyl)-piperazine (compound 6.20)
(M + NH4+)



phenyl)-piperazin-1-yl]-
and 2-Isobutoxy-5-methanesulfonyl-



(2-isobutoxy-5-
benzoic acid (compound 1.3)



methanesulfonyl-



phenyl)-methanone


579
{4-[2-Fluoro-4-
1-[2-Fluoro-4-(tetrahydro-pyran-4-
586.2



(tetrahydro-pyran-4-
sulfonyl)-phenyl]-piperazine
(M + NH4+)



sulfonyl)-phenyl]-
(compound 6.27) and 2-



piperazin-1-yl}-(2-
Isopropoxy-5-methanesulfonyl-



isopropoxy-5-
benzoic acid (compound 1.2)



methanesulfonyl-



phenyl)-methanone


580
(2-tert-Butoxy-5-
1-[2-Fluoro-4-(propane-2-sulfonyl)-
558.2



methanesulfonyl-
phenyl]-piperazine (compound 6.21)
(M + NH4+)



phenyl)-{4-[2-fluoro-4-
and 2-tert-Butoxy-5-methane



(propane-2-sulfonyl)-
sulfonyl-benzoic acid (compound 2.19)



phenyl]-piperazin-1-yl-}-



methanone


581
(2-tert-Butoxy-5-
1-(4-Ethanesulfonyl-2-fluoro-
544.2



methanesulfonyl-
phenyl)-piperazine (compound 6.12)
(M + NH4+)



phenyl)-[4-(4-
and 2-tert-Butoxy-5-methane



ethanesulfonyl-2-fluoro-
sulfonyl-benzoic acid (compound 2.19)



phenyl)-piperazin-1-yl]-



methanone


582
(2-tert-Butoxy-5-
1-(4-Cyclopropanesulfonyl-2-fluoro-
556.1



methanesulfonyl-
phenyl)-piperazine (compound 6.20)
(M + NH4+)



phenyl)-[4-(4-
and 2-tert-Butoxy-5-methane



cyclopropanesulfonyl-2-
sulfonyl-benzoic acid (compound 2.19)



fluoro-phenyl)-



piperazin-1-yl]-methanone


583
{4-[2-Fluoro-4-
1-[2-Fluoro-4-(propane-2-sulfonyl)-
584.1



(propane-2-sulfonyl)-
phenyl]-piperazine (compound 6.21)
(M + NH4+)



phenyl]-piperazin-1-yl}-
and 5-Methanesulfonyl-2-(2,2,2-



[5-methanesulfonyl-2-
trifluoro-ethoxy)-benzoic acid



(2,2,2-trifluoro-ethoxy)-
(compound 1.5)



phenyl]-methanone


584
[4-(4-Ethanesulfonyl-2-
1-(4-Ethanesulfonyl-2-fluoro-
570.3



fluoro-phenyl)-
phenyl)-piperazine (compound 6.12)
(M + NH4+)



piperazin-1-yl]-[5-
and 5-Methanesulfonyl-2-(2,2,2-



methanesulfonyl-2-
trifluoro-ethoxy)-benzoic acid



(2,2,2-trifluoro-ethoxy)-
(compound 1.5)



phenyl]-methanone


585
[4-(4-Cyclopropanesulfonyl-
1-(4-Cyclopropanesulfonyl-2-fluoro-
582.1



2-fluoro-
phenyl)-piperazine (compound 6.20)
(M + NH4+)



phenyl)-piperazin-1-yl]-
and 5-Methanesulfonyl-2-(2,2,2-



[5-methanesulfonyl-2-
trifluoro-ethoxy)-benzoic acid



(2,2,2-trifluoro-ethoxy)-
(compound 1.5)



phenyl]-methanone


586
rac{4-[2-Fluoro-4-
1-[2-Fluoro-4-(propane-2-sulfonyl)-
598.2



(propane-2-sulfonyl)-
phenyl]-piperazine (compound 6.21)
(M + NH4+)



phenyl]-piperazin-1-yl}-
and rac-5-Methanesulfonyl-2-(2,2,2-



[5-methanesulfonyl-2-
trifluoro-1-methyl-ethoxy)-benzoic



(2,2,2-trifluoro-1-
acid (compound 3.1)



methyl-ethoxy)-phenyl]-



methanone


587
rac-[4-(4-Ethanesulfonyl-
1-(4-Ethanesulfonyl-2-fluoro-
584.1



2-fluoro-phenyl)-piperazin-
phenyl)-piperazine (compound 6.12)
(M + NH4+)



1-yl]-[5-methanesulfonyl-2-
and rac-5-Methanesulfonyl-2-(2,2,2-



(2,2,2-trifluoro-1-
trifluoro-1-methyl-ethoxy)-benzoic



methyl-ethoxy)-phenyl]-
acid (compound 3.1)



methanone


588
rac-[4-(4-Cyclopropanesulfonyl-
1-(4-Cyclopropanesulfonyl-2-fluoro-
596.2



2-fluoro-phenyl)-piperazin-
phenyl)-piperazine (compound 6.20)
(M + NH4+)



1-yl]-[5-methanesulfonyl-2-
and rac-5-Methanesulfonyl-2-(2,2,2-



(2,2,2-trifluoro-1-
trifluoro-1-methyl-ethoxy)-benzoic



methyl-ethoxy)-phenyl]-
acid (compound 3.1)



methanone


589
[4-(4-Cyclohexanesulfonyl-
1-(4-Cyclohexanesulfonyl-2-fluoro-
584.3



2-fluoro-phenyl)-piperazin-
phenyl)-piperazine (compound 6.28)
(M + NH4+)



1-yl]-(2-isopropoxy-5-
and 2-Isopropoxy-5-methanesulfonyl-



methanesulfonyl-
benzoic acid (compound 1.2)



phenyl)-methanone


590
{4-[2,3-Difluoro-4-
1-[2,3-Difluoro-4-(propane-2-
545.2



(propane-2-sulfonyl)-
sulfonyl)-phenyl]-piperazine



phenyl]-piperazin-1-yl}-
hydrochloride (compound 6.29) and



(2-isopropoxy-5-
2-Isopropoxy-5-methanesulfonyl-



methanesulfonyl-
benzoic acid (compound 1.2)



phenyl)-methanone


591
[4-(4-Ethanesulfonyl-
1-(4-Ethanesulfonyl-2,3-difluoro-
531.1



2,3-difluoro-phenyl)-
phenyl)-piperazine hydrochloride



piperazin-1-yl]-(2-
(compound 6.30) and 2-Isopropoxy-



isopropoxy-5-
5-methanesulfonyl-benzoic acid



methanesulfonyl-
(compound 1.2)



phenyl)-methanone


592
[4-(4-Cyclopropanesulfonyl-
1-(4-Cyclopropanesulfonyl-2,3-
543.3



2,3-difluoro-
difluoro-phenyl)-piperazine



phenyl)-piperazin-1-yl]-
hydrochloride (compound 6.31) and



(2-isopropoxy-5-
2-Isopropoxy-5-methanesulfonyl-



methanesulfonyl-
benzoic acid (compound 1.2)



phenyl)-methanone


593
{4-[2,5-Difluoro-4-
1-[2,5-Difluoro-4-(propane-2-
545.2



(propane-2-sulfonyl)-
sulfonyl)-phenyl]-piperazine



phenyl]-piperazin-1-yl}-
hydrochloride (compound 6.32) and



(2-isopropoxy-5-
2-Isopropoxy-5-methanesulfonyl-



methanesulfonyl-
benzoic acid (compound 1.2)



phenyl)-methanone


594
[4-(4-Ethanesulfonyl-
1-(4-Ethanesulfonyl-2,5-difluoro-
531.1



2,5-difluoro-phenyl)-
phenyl)-piperazine hydrochloride



piperazin-1-yl]-(2-
(compound 6.33) and 2-Isopropoxy-



isopropoxy-5-
5-methanesulfonyl-benzoic acid



methanesulfonyl-
(compound 1.2)



phenyl)-methanone


595
[4-(4-Cyclopropanesulfonyl-
1-(4-Cyclopropanesulfonyl-2,5-
543.3



2,5-difluoro-
difluoro-phenyl)-piperazine



phenyl)-piperazin-1-yl]-
hydrochloride (compound 6.34) and



(2-isopropoxy-5-
2-Isopropoxy-5-methanesulfonyl-



methanesulfonyl-
benzoic acid (compound 1.2)



phenyl)-methanone


596
(2-tert-Butoxy-5-
1-(4-Cyclobutanesulfonyl-2-fluoro-
553.6



methanesulfonyl-
phenyl)-piperazine hydrochloride



phenyl)-[4-(4-
(compound 6.24) and 2-tert-Butoxy-



cyclobutanesulfonyl-2-
5-methanesulfonyl-benzoic acid



fluoro-phenyl)-
(compound 2.19)



piperazin-1-yl]-methanone


597
(2-tert-Butoxy-5-
1-[2,3-Difluoro-4-(propane-2-
503.1



methanesulfonyl-
sulfonyl)-phenyl]-piperazine
(M-tBu + H)



phenyl)-{4-[2,3-difluoro-
hydrochloride (compound 6.29) and



4-(propane-2-sulfonyl)-
2-tert-Butoxy-5-methanesulfonyl-



phenyl]-piperazin-1-yl}-
benzoic acid (compound 2.19)



methanone


598
(2-tert-Butoxy-5-
1-(4-Ethanesulfonyl-2,3-difluoro-
489.2



methanesulfonyl-
phenyl)-piperazine hydrochloride
(M-tBu + H)



phenyl)-[4-(4-
(compound 6.30) and 2-tert-Butoxy-



ethanesulfonyl-2,3-
5-methanesulfonyl-benzoic acid



difluoro-phenyl)-
(compound 2.19)



piperazin-1-yl]-methanone


599
(2-tert-Butoxy-5-
1-(4-Cyclopropanesulfonyl-2,3-
501.1



methanesulfonyl-
difluoro-phenyl)-piperazine
(M-tBu + H)



phenyl)-[4-(4-
hydrochloride (compound 6.31) and



cyclopropanesulfonyl-
2-tert-Butoxy-5-methanesulfonyl-



2,3-difluoro-phenyl)-
benzoic acid (compound 2.19)



piperazin-1-yl]-methanone


600
(2-tert-Butoxy-5-
1-[2,5-Difluoro-4-(propane-2-
503.2



methanesulfonyl-
sulfonyl)-phenyl]-piperazine
(M-tBu + H)



phenyl)-{4-[2,5-difluoro-
hydrochloride (compound 6.32) and



4-(propane-2-sulfonyl)-
2-tert-Butoxy-5-methanesulfonyl-



phenyl]-piperazin-1-yl}-
benzoic acid (compound 2.19)



methanone


601
(2-tert-Butoxy-5-
1-(4-Ethanesulfonyl-2,5-difluoro-
489.1



methanesulfonyl-
phenyl)-piperazine hydrochloride
(M-tBu + H)



phenyl)-[4-(4-
(compound 6.33) and 2-tert-Butoxy-



ethanesulfonyl-2,5-
5-methanesulfonyl-benzoic acid



difluoro-phenyl)-
(compound 2.19)



piperazin-1-yl]-methanone


602
(2-tert-Butoxy-5-
1-(4-Cyclopropanesulfonyl-2,5-
501.3



methanesulfonyl-
difluoro-phenyl)-piperazine
(M-tBu + H)



phenyl)-[4-(4-
hydrochloride (compound 6.34) and



cyclopropanesulfonyl-
2-tert-Butoxy-5-methanesulfonyl-



2,5-difluoro-phenyl)-
benzoic acid (compound 2.19)



piperazin-1-yl]-methanone


603
[4-(4-Cyclobutanesulfonyl-
1-(4-Cyclobutanesulfonyl-2-fluoro-
579.1



2-fluoro-
phenyl)-piperazine hydrochloride



phenyl)-piperazin-1-yl]-
(compound 6.24) and 5-



[5-methanesulfonyl-2-
Methanesulfonyl-2-(2,2,2-trifluoro-



(2,2,2-trifluoro-ethoxy)-
ethoxy)-benzoic acid (compound 1.5)



phenyl]-methanone


604
{4-[2,3-Difluoro-4-
1-[2,3-Difluoro-4-(propane-2-
602.2



(propane-2-sulfonyl)-
sulfonyl)-phenyl]-piperazine
(M + NH4+)



phenyl]-piperazin-1-yl}-
hydrochloride (compound 6.29) and



[5-methanesulfonyl-2-
5-Methanesulfonyl-2-(2,2,2-



(2,2,2-trifluoro-ethoxy)-
trifluoro-ethoxy)-benzoic acid



phenyl]-methanone
(compound 1.5)


605
[4-(4-Ethanesulfonyl-
1-(4-Ethanesulfonyl-2,3-difluoro-
571.2



2,3-difluoro-phenyl)-
phenyl)-piperazine hydrochloride



piperazin-1-yl]-[5-
(compound 6.30) and 5-



methanesulfonyl-2-
Methanesulfonyl-2-(2,2,2-trifluoro-



(2,2,2-trifluoro-ethoxy)-
ethoxy)-benzoic acid (compound 1.5)



phenyl]-methanone


606
[4-(4-Cyclopropanesulfonyl-
1-(4-Cyclopropanesulfonyl-2,3-
600.2



2,3-difluoro-
difluoro-phenyl)-piperazine
(M + NH4+)



phenyl)-piperazin-1-yl]-
hydrochloride (compound 6.31) and



[5-methanesulfonyl-2-
5-Methanesulfonyl-2-(2,2,2-



(2,2,2-trifluoro-ethoxy)-
trifluoro-ethoxy)-benzoic acid



phenyl]-methanone
(compound 1.5)


607
{4-[2,5-Difluoro-4-
1-[2,5-Difluoro-4-(propane-2-
602.3



(propane-2-sulfonyl)-
sulfonyl)-phenyl]-piperazine
(M + NH4+)



phenyl]-piperazin-1-yl}-
hydrochloride (compound 6.32) and



[5-methanesulfonyl-2-
5-Methanesulfonyl-2-(2,2,2-



(2,2,2-trifluoro-ethoxy)-
trifluoro-ethoxy)-benzoic acid



phenyl]-methanone
(compound 1.5)


608
[4-(4-Ethanesulfonyl-
1-(4-Ethanesulfonyl-2,5-difluoro-
588.3



2,5-difluoro-phenyl)-
phenyl)-piperazine hydrochloride
(M + NH4+)



piperazin-1-yl]-[5-
(compound 6.33) and 5-Methanesulfonyl-



methanesulfonyl-2-
2-(2,2,2-trifluoro-ethoxy)-



(2,2,2-trifluoro-ethoxy)-
benzoic acid (compound 1.5)



phenyl]-methanone


609
[4-(4-Cyclopropanesulfonyl-
1-(4-Cyclopropanesulfonyl-2,5-
600.2



2,5-difluoro-
difluoro-phenyl)-piperazine
(M + NH4+)



phenyl)-piperazin-1-yl]-
hydrochloride (compound 6.34) and



[5-methanesulfonyl-2-
5-Methanesulfonyl-2-(2,2,2-



(2,2,2-trifluoro-ethoxy)-
trifluoro-ethoxy)-benzoic acid



phenyl]-methanone
(compound 1.5)


610
rac-[4-(4-Cyclobutanesulfonyl-
1-(4-Cyclobutanesulfonyl-2-fluoro-
593.2



2-fluoro-
phenyl)-piperazine hydrochloride



phenyl)-piperazin-1-yl]-
(compound 6.24) and rac-5-



[5-methanesulfonyl-2-
Methanesulfonyl-2-(2,2,2-trifluoro-



(2,2,2-trifluoro-1-
1-methyl-ethoxy)-benzoic acid



methyl-ethoxy)-phenyl]-
(compound 3.1)



methanone


611
rac-{4-[2,3-Difluoro-4-
1-[2,3-Difluoro-4-(propane-2-
599.2



(propane-2-sulfonyl)-
sulfonyl)-phenyl]-piperazine



phenyl]-piperazin-1-yl}-
hydrochloride (compound 6.29) and



[5-methanesulfonyl-2-
rac-5-Methanesulfonyl-2-(2,2,2-



(2,2,2-trifluoro-1-
trifluoro-1-methyl-ethoxy)-benzoic



methyl-ethoxy)-phenyl]-
acid (compound 3.1)



methanone


612
rac-[4-(4-
1-(4-Ethanesulfonyl-2,3-difluoro-
602.2



Ethanesulfonyl-2,3-
phenyl)-piperazine hydrochloride
(M + NH4+)



difluoro-phenyl)-
(compound 6.30) and rac-5-



piperazin-1-yl]-[5-
Methanesulfonyl-2-(2,2,2-trifluoro-



methanesulfonyl-2-
1-methyl-ethoxy)-benzoic acid



(2,2,2-trifluoro-1-
(compound 3.1)



methyl-ethoxy)-phenyl]-



methanone


613
rac-[4-(4-
1-(4-Cyclopropanesulfonyl-2,3-
614.3(M + NH4+)



Cyclopropanesulfonyl-
difluoro-phenyl)-piperazine



2,3-difluoro-phenyl)-
hydrochloride (compound 6.31) and



piperazin-1-yl]-[5-
rac-5-Methanesulfonyl-2-(2,2,2-



methanesulfonyl-2-
trifluoro-1-methyl-ethoxy)-benzoic



(2,2,2-trifluoro-1-
acid (compound 3.1)



methyl-ethoxy)-phenyl]-



methanone


614
rac-4-[2,5-Difluoro-4-
1-[2,5-Difluoro-4-(propane-2-
616.2



(propane-2-sulfonyl)-
sulfonyl)-phenyl]-piperazine
(M + NH4+)



phenyl]-piperazin-1-yl}-
hydrochloride (compound 6.32) and



[5-methanesulfonyl-2-
rac-5-Methanesulfonyl-2-(2,2,2-



(2,2,2-trifluoro-1-
trifluoro-1-methyl-ethoxy)-benzoic



methyl-ethoxy)-phenyl]-
acid (compound 3.1)



methanone


615
rac-[4-(4-
1-(4-Ethanesulfonyl-2,5-difluoro-
602.3



Ethanesulfonyl-2,5-
phenyl)-piperazine hydrochloride
(M + NH4+)



difluoro-phenyl)-
(compound 6.33) and rac-5-



piperazin-1-yl]-[5-
Methanesulfonyl-2-(2,2,2-trifluoro-



methanesulfonyl-2-
1-methyl-ethoxy)-benzoic acid



(2,2,2-trifluoro-1-
(compound 3.1)



methyl-ethoxy)-phenyl]-



methanone


616
rac-[4-(4-
1-(4-Cyclopropanesulfonyl-2,5-
614.3



Cyclopropanesulfonyl-
difluoro-phenyl)-piperazine
(M + NH4+)



2,5-difluoro-phenyl)-
hydrochloride (compound 6.34) and



piperazin-1-yl]-[5-
rac-5-Methanesulfonyl-2-(2,2,2-



methanesulfonyl-2-
trifluoro-1-methyl-ethoxy)-benzoic



(2,2,2-trifluoro-1-
acid (compound 3.1)



methyl-ethoxy)-phenyl]-



methanone


617
[4-(4-Hydroxy-phenyl)-
4-Piperazin-1-yl-phenol
419.1



piperazin-1-yl]-(2-
(commercial) and 2-Isopropoxy-5-



isopropoxy-5-
methanesulfonyl-benzoic acid



methanesulfonyl-
(compound 1.2)



phenyl)-methanone


618
rac-(2-Isopropoxy-5-
rac-2-Methyl-1-(4-trifluoromethyl-
485.2



methanesulfonyl-
phenyl)-piperazine hydrochloride



phenyl)-[3-methyl-4-(4-
(compound 6.35) and 2-



trifluoromethyl-phenyl)-
Isopropoxy-5-methanesulfonyl-



piperazin-1-yl]-methanone
benzoic acid (compound 1.2)


619
1-{4-Isopropoxy-3-[4-(4-
1-(4-Trifluoromethyl-phenyl)-
435.2



trifluoromethyl-phenyl)-
piperazine (commercial) and 5-



piperazine-1-carbonyl]-
Acetyl-2-isopropoxy-benzoic acid



phenyl}-ethanone
(compound 6.36)









EXAMPLE 6.37 
Preparation of 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoic acid
(a) 4-Isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzonitrile
To a solution of 3.6 mmol 5-cyano-2-isopropoxy-benzoic acid (compound 1.13) in 20 ml THF were added 4.0 mmol TBTU, 21.6 mmol N-ethyldiisopropylamine and 4.0 mmol 1-(4-trifluoromethyl-phenyl)-piperazine (commercial). The reaction was then stirred at RT for 16 h, concentrated in vacuo, and purified by chromatography on silica gel (eluant: ethyl acetate/heptane 1:1) to afford the title compound. MS (m/e): 418.3 (M+H+, 100%)
(b) 4-Isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoic acid
To 3.2 mmol 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzonitrile in 15 ml ethanol was added 30 mmol 2 M aq NaOH and the mixture was heated at 85° C. for 16 h. The mixture was then cooled to RT, diluted with water and acidified to pH 1 with conc HCl, and then extracted three times with ethyl acetate. The combined organic phases were dried with Na2SO4, concentrated in vacuo, and the 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-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoic acid methyl ester
To 0.3 mmol 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-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-1-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-phenyl)-piperazine-1-carbonyl]-4-hydroxy-benzenesulfonamide
(a) 2-Hydroxy-5-sulfamoyl-benzoic 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 HCl, saturated with NaCl, and extracted twice with THF. The combined THF extracts were dried with Na2SO4. Evaporation of the solvent in vacuo followed by 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-Hydroxy-5-sulfamoyl-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 containing fractions were concentrated in vacuo and the residue suspended in ethyl acetate and washed with aq NaHCO3 solution. The organic phase was dried with Na2SO4 and concentrated in vacuo to afford the title compound. MS (m/e): 230.2 ([M−H]−, 100%)
(c) 2-(4-Methoxy-benzyloxy)-5-sulfamoyl-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-Methoxy-benzyloxy)-5-sulfamoyl-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 HCl 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-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-(4-methoxy-benzyloxy)-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-1-yl-benzonitrile (WO9625414). The reaction was then stirred at RT for 1 h, concentrated in vacuo, and purified by chromatography on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 525.1 (M+H+)
(f) (3-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-hydroxy-benzenesulfonamide
Hydrogen gas was bubbled through a solution of 1.0 mmol (3-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-(4-methoxy-benzyloxy)-benzenesulfonamide in 40 ml THF containing 50 mg 10% palladioum on charcoal and a few drops of acetic acid for 6 h at RT. The reaction mixture was then purged with argon, filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: methanol/dichloromethane gradient) to afford the title compound. MS (m/e): 403.1 ([M−H]−, 100%)
In analogy to Example 6.38(e) and (f), compounds 6.39 and 6.40 of the following table were prepared from 2-(4-methoxy-benzyloxy)-5-sulfamoyl-benzoic acid and the appropriate piperazine, followed by hydrogenolysis with catalytic palladium on charcoal:













Expl.


MS


No
name
piperazine
(m/e)







6.39
3-[4-(4-Cyano-2-fluoro-
3-Fluoro-4-piperazin-
403.1



phenyl)-piperazine-1-
1-yl-benzonitrile
(M − H)



carbonyl]-4-hydroxy-
(WO9625414)



benzenesulfonamide


6.40
3-[4-(2-Fluoro-4-
1-(2-Fluoro-4-
456.2



methanesulfonyl-phenyl)-
methanesulfonyl-
(M − H)



piperazine-1-carbonyl]-4-
phenyl)-piperazine



hydroxy-benzenesulfonamide
(commercial)









EXAMPLE 622 
Preparation of 3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-benzenesulfonamide
To 0.1 mmol (3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-hydroxy benzenesulfonamide (compound 6.38), 0.5 mmol 2-methyl-1-propanol and 0.3 mmol diphenyl-2-pyridylphosphine in 4 ml THF was added 0.3 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at 60° C. for 4 h. The mixture was then diluted with ethyl acetate and washed twice with 5 M aq HCl and then with saturated aq NaCl solution. The organic phase was then dried with Na2SO4, and concentrated in vacuo. The residue was triturated in ether to afford the title compound. MS (m/e): 459.2 ([M−H]−, 100%)
In analogy to Example 622, compounds 623 to 632 of the following table were prepared from compounds 6.38 to 6.40 and the appropriate alcohol:
















MW


Expl.


found


No.
name
Starting materials
(MH+)







623
3-[4-(4-Cyano-3-
3-[4-(4-Cyano-3-fluoro-
471.3



fluoro-phenyl)-
phenyl)-piperazine-1-
(M − H)



piperazine-1-carbonyl]-
carbonyl]-4-hydroxy-



4-cyclopentyloxy-
benzenesulfonamide



benzenesulfonamide
(compound 6.38) and




cyclopentanol


624
3-[4-(4-Cyano-2-
3-[4-(4-Cyano-2-fluoro-
445.2



fluoro-phenyl)-
phenyl)-piperazine-1-
(M − H)



piperazine-1-carbonyl]-
carbonyl]-4-hydroxy-



4-isopropoxy-
benzenesulfonamide



benzenesulfonamide
(compound 6.39) and 2-




propanol


625
3-[4-(4-Cyano-2-
3-[4-(4-Cyano-2-fluoro-
459.2



fluoro-phenyl)-
phenyl)-piperazine-1-
(M − H)



piperazine-1-carbonyl]-
carbonyl]-4-hydroxy-



4-isobutoxy-
benzenesulfonamide



benzenesulfonamide
(compound 6.39) and




2-methyl-1-propanol


626
3-[4-(4-Cyano-2-
3-[4-(4-Cyano-2-fluoro-
471.3



fluoro-phenyl)-
phenyl)-piperazine-1-
(M − H)



piperazine-1-carbonyl]-
carbonyl]-4-hydroxy-



4-cyclopentyloxy-
benzenesulfonamide



benzenesulfonamide
(compound 6.39) and




cyclopentanol


627
3-[4-(2-Fluoro-4-
3-[4-(2-Fluoro-4-
512.3



methanesulfonyl-
methanesulfonyl-phenyl)-
(M − H)



phenyl)-piperazine-1-
piperazine-1-



carbonyl]-4-isobutoxy-
carbonyl]-4-hydroxy-



benzenesulfonamide
benzenesulfonamide




(compound 6.40) and




2-methyl-1-propanol


628
4-Cyclopentyloxy-3-[4-
3-[4-(2-Fluoro-4-
524.5



(2-fluoro-4-
methanesulfonyl-phenyl)-
(M − H)



methanesulfonyl-
piperazine-1-



phenyl)-piperazine-1-
carbonyl]-4-hydroxy-



carbonyl]-
benzenesulfonamide



benzenesulfonamide
(compound 6.40) and




cyclopentanol


629
3-[4-(4-Cyano-3-
3-[4-(4-Cyano-3-fluoro-
445.1



fluoro-phenyl)-
phenyl)-piperazine-1-
(M − H)



piperazine-1-carbonyl]-
carbonyl]-4-hydroxy-



4-isopropoxy-
benzenesulfonamide



benzenesulfonamide
(compound 6.38) and 2-




propanol


630
3-[4-(4-Cyano-3-
3-[4-(4-Cyano-3-fluoro-
471.3



fluoro-phenyl)-
phenyl)-piperazine-1-
(M − H)



piperazine-1-carbonyl]-
carbonyl]-4-hydroxy-



4-cyclobutylmethoxy-
benzenesulfonamide



benzenesulfonamide
(compound 6.38) and




cyclobutanemethanol


631
3-[4-(2-Fluoro-4-
3-[4-(2-Fluoro-4-
498.4



methanesulfonyl-
methanesulfonyl-phenyl)-
(M − H)



phenyl)-piperazine-1-
piperazine-1-



carbonyl]-4-
carbonyl]-4-hydroxy-



isopropoxy-
benzenesulfonamide



benzenesulfonamide
(compound 6.40) and 2-




propanol


632
4-Cyclobutylmethoxy-
3-[4-(2-Fluoro-4-
524.5



3-[4-(2-fluoro-4-
methanesulfonyl-phenyl)-
(M − H)



methanesulfonyl-
piperazine-1-



phenyl)-piperazine-1-
carbonyl]-4-hydroxy-



carbonyl]-
benzenesulfonamide



benzenesulfonamide
(compound 6.40) and




cyclobutanemethanol









EXAMPLE 7.1
Preparation of 3-Piperazin-1-yl-5-trifluoromethyl-pyridazine
(a)-3-Chloro-5-trifluoromethyl-pyridazine
5-Trifluoromethyl-pyridazin-3-ol [244268-34-6 (1 g) 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 (0.26 g). MS (m/e): 182.0
(b) 4-(5-Trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester
3-Chloro-5-trifluoromethyl-pyridazine (200 mg) was added to piperazine-1-carboxylic acid tert-butyl ester (231 mg) in dimethylacetamide (3 mL), 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 chromatography (SiO2, Heptane/EtOAc) to yield the title compound as a white solid (364 mg). MS (m/e): 333.4 (M+H+, 100%)
(c) 3-Piperazin-1-yl-5-trifluoromethyl-pyridazine
4-(5-Trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (45 mg) 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-1,1-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 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-Dimethylamino-2-methanesulfonyl-allylidene-dimethyl-ammonium; chloride
To sulfonyl-acetic acid (1.5 g) 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 (1.58 g). MS (m/e): 204.9 (M+).
(b) 5-Methanesulfonyl-2-piperazin-1-yl-pyrimidine
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 1-(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 tert-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:
















MW


Expl.


found


No.
Systematic Name
Starting materials
(MH+)







633
rac-[5-Methanesulfonyl-2-
3-Piperazin-1-yl-5-
527.0



(2,2,2-trifluoro-1-methyl-
trifluoromethyl-



ethoxy)-phenyl]-[4-(5-
pyridazine (compound



trifluoromethyl-pyridazin-
7.1) and rac-5-



3-yl)-piperazin-1-yl]-
Methanesulfonyl-2-



methanone
(2,2,2-trifluoro-1-




methyl-ethoxy)-benzoic




acid (compound 3.1)


634
[5-Methanesulfonyl-2-
2-Piperazin-1-yl-5-
541.0



(2,2,2-trifluoro-1,1-
trifluoromethyl-



dimethyl-ethoxy)-phenyl]-
pyrimidine (compound



[4-(5-trifluoromethyl-
2.25) and 5-



pyrimidin-2-yl)-piperazin-
Methanesulfonyl-



1-yl]-methanone
2-(2,2,2-trifluoro-1,1-




dimethyl-ethoxy)-benzoic




acid (compound 7.2)


635
[5-Methanesulfonyl-2-
2-Piperazin-1-yl-5-
527.2



((S)-2,2,2-trifluoro-1-
trifluoromethyl-



methyl-ethoxy)-phenyl]-
pyrimidine (compound



[4-(5-trifluoromethyl-
2.25) and 5-



pyrimidin-2-yl)-piperazin-
Methanesulfonyl-



1-yl]-methanone
2-((S)-2,2,2-trifluoro-1-




methyl-ethoxy)-benzoic




acid (compound 5.6)


636
[5-Methanesulfonyl-2-
2-Piperazin-1-yl-5-
527.2



((R)-2,2,2-trifluoro-1-
trifluoromethyl-



methyl-ethoxy)-phenyl]-
pyrimidine (compound



[4-(5-trifluoromethyl-
2.25) and 5-



pyrimidin-2-yl)-piperazin-
Methanesulfonyl-



1-yl]-methanone
2-((R)-2,2,2-trifluoro-1-




methyl-ethoxy)-benzoic




acid (compound 5.7)


637
[4-(3-Fluoro-5-
1-(3-Fluoro-5-
558.2



trifluoromethyl-pyridin-2-
trifluoromethyl-pyridin-



yl)-piperazin-1-yl]-[5-
2-yl)-piperazine



methanesulfonyl-2-(2,2,2-
(compound 5.5) and 5-



trifluoro-1,1-dimethyl-
Methanesulfonyl-2-



ethoxy)-phenyl]-
(2,2,2-trifluoro-1,1-



methanone
dimethyl-ethoxy)-benzoic




acid (compound 7.2)


638
[5-Methanesulfonyl-2-
2-Piperazin-1-yl-5-
513.3



(2,2,2-trifluoro-ethoxy)-
trifluoromethyl-



phenyl]-[4-(5-
pyrimidine (compound



trifluoromethyl-
2.25) and 5-



pyrimidin-2-yl)-piperazin-
Methanesulfonyl-



1-yl]-methanone
2-(2,2,2-trifluoro-




ethoxy)-benzoic




acid (compound 1.5)


639
(2-Cyclopropylmethoxy-5-
2-Piperazin-1-yl-5-
485.4



methanesulfonyl-phenyl)-
trifluoromethyl-



[4-(5-trifluoromethyl-
pyrimidine (compound



pyrimidin-2-yl)-piperazin-
2.25) and 2-



1-yl]-methanone
Cyclopropylmethoxy-5-




methanesulfonyl-benzoic




acid (compound 1.4)


640
[4-(2,5-Difluoro-4-
1-(2,5-Difluoro-4-
585.3



methanesulfonyl-phenyl)-
methanesulfonyl-phenyl)-



piperazin-1-yl]-[5-
piperazine trifluoro-



methanesulfonyl-2-(2,2,2-
acetic acid



trifluoro-1,1-dimethyl-
(compound 2.20) and



ethoxy)-phenyl]-
5-Methanesulfonyl-



methanone
2-(2,2,2-trifluoro-1,1-




dimethyl-ethoxy)-benzoic




acid (compound 7.2)


641
[4-(2,3-Difluoro-4-
1-(2,3-Difluoro-4-
585.3



methanesulfonyl-phenyl)-
methanesulfonyl-phenyl)-



piperazin-1-yl]-[5-
piperazine (compound



methanesulfonyl-2-(2,2,2-
5.3) and 5-



trifluoro-1,1-dimethyl-
Methanesulfonyl-



ethoxy)-phenyl]-
2-(2,2,2-trifluoro-1,1-



methanone
dimethyl-ethoxy)-benzoic




acid (compound 7.2)


642
[4-(2,6-Difluoro-4-
1-(2,6-Difluoro-4-
585.2



methanesulfonyl-phenyl)-
methanesulfonyl-phenyl)-



piperazin-1-yl]-[5-
piperazine trifluoro-



methanesulfonyl-2-(2,2,2-
acetic acid



trifluoro-1,1-dimethyl-
(compound 2.23) and



ethoxy)-phenyl]-
5-Methanesulfonyl-



methanone
2-(2,2,2-trifluoro-1,1-




dimethyl-ethoxy)-




benzoic acid




(compound 7.2)


643
rac-[4-(5-Methane
5-Methanesulfonyl-2-
537.3



sulfonyl-pyrimidin-2-yl)-
piperazin-1-yl-pyrimidine



piperazin-1-yl]-[5-
(compound 7.3) and



methanesulfonyl-2-(2,2,2-
rac-5-Methanesulfonyl-2-



trifluoro-1-methyl-
(2,2,2-trifluoro-1-methyl-



ethoxy)-phenyl]-
ethoxy)-benzoic acid



methanone
(compound 3.1)


644
rac-[4-(5-
1-(5-Methanesulfonyl-
536.3



Methanesulfonyl-pyridin-
pyridin-2-yl)-piperazine



2-yl)-piperazin-1-yl]-[5-
trifluoro-acetic acid



methanesulfonyl-2-(2,2,2-
(compound 7.4) and



trifluoro-1-methyl-
rac-5-Methanesulfonyl-



ethoxy)-phenyl]-
2-(2,2,2-trifluoro-1-



methanone
methyl-ethoxy)-benzoic




acid (compound 3.1)









EXAMPLE 645 
Preparation of (2-Allyloxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone
The title compound was prepared in analogy to example 62 from (2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound 2.1) and cyclopropyl bromide. MS (m/e): 436.5 (MH+, 100%)
EXAMPLE 7.5
Preparation of 2-Benzyloxy-5-methanesulfonyl-benzoic acid
The title compound was prepared in analogy to example 2.10 from methyl 5-(methanesulfonyl)salicylate and benzylalcohol. MS (m/e): 305.3 (M−H, 100%)
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 1-(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 1-(2-Fluoro-4-methanesulfonyl-phenyl)-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-1-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-1-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-1-yl-2-trifluoromethyl-pyrimidine
(a) 5-Chloro-2-trifluoromethyl-pyrimidine
To a solution of 38 mmol trifluoroacetamidine in 70 ml acetonitrile was added 37.92 mmol ((Z)-2-Chloro-3-dimethylamino-allylidene)-dimethyl-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, filtered and distilled at 760 mm Hg to provide the title compound. MS (m/e): 182.2 (M+, 100%)
(b) 4-(2-Trifluoromethyl-pyrimidin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester
0.26 mmol 5-Chloro-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-yl-2-trifluoromethyl-pyrimidine
The title compound was prepared in analogy to Example 7.1 (c) from 4-(2-trifluoromethyl-pyrimidin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester MS (m/e): 233.0 (M+H+, 100%)
EXAMPLE 7.7 
Preparation of 5′-Trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl
(a) 2-Bromo-5-trifluoromethyl-pyrazine
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.
(b) 5′-Trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl
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%)
In analogy to Example 5, compounds 649 to 660 of the following table were prepared from the acid derivatives and piperazine derivatives:
















MW


Expl.


found


No.
Systematic Name
Starting materials
(MH+)







649
[5-Methanesulfonyl-2-
5-Piperazin-1-yl-2-
527.2



((S)-2,2,2-trifluoro-1-
trifluoromethyl-pyrimidine



methyl-ethoxy)-
(compound 7.6) and 5-



phenyl]-[4-(2-
Methanesulfonyl-2-((S)-2,2,2-



trifluoromethyl-
trifluoro-1-methyl-ethoxy)-



pyrimidin-5-yl)-
benzoic acid (compound 5.6)



piperazin-1-yl]-



methanone


650
[5-Methanesulfonyl-2-
5-Piperazin-1-yl-2-
527.0



((R)-2,2,2-trifluoro-1-
trifluoromethyl-pyrimidine



methyl-ethoxy)-
(compound 7.6) and 5-



phenyl]-[4-
Methanesulfonyl-2-((R)-2,2,2-



(2-trifluoromethyl-
trifluoro-1-methyl-ethoxy)-



pyrimidin-5-yl)-
benzoic acid (compound 5.7)



piperazin-1-yl]-



methanone


651
(2-Isopropoxy-5-
5-Piperazin-1-yl-2-
473.0



methanesulfonyl-
trifluoromethyl-pyrimidine



phenyl)-[4-(2-
(compound 7.6) and 2-



trifluoromethyl-
Isopropoxy-5-methane



pyrimidin-5-yl)-
sulfonyl-benzoic acid



piperazin-1-yl]-
(compound 1.2)



methanone


652
[5-Methanesulfonyl-2-
5′-Trifluoromethyl-3,4,5,6-
527.2



((S)-2,2,2-trifluoro-1-
tetrahydro-2H-



methyl-ethoxy)-
[1,2′]bipyrazinyl (compound



phenyl]-(5′-
7.7) and 5-Methanesulfonyl-2-



trifluoromethyl-
((S)-2,2,2-trifluoro-1-methyl-



2,3,5,6-tetrahydro-
ethoxy)-benzoic acid



[1,2′]bipyrazinyl-4-yl)-
(compound 5.6)



methanone


653
[5-Methanesulfonyl-2-
5′-Trifluoromethyl-3,4,5,6-
527.2



((R)-2,2,2-trifluoro-1-
tetrahydro-2H-



methyl-ethoxy)-
[1,2′]bipyrazinyl (compound



phenyl]-(5′-
7.7) and 5-Methanesulfonyl-



trifluoromethyl-
2-((R)-2,2,2-trifluoro-1-



2,3,5,6-tetrahydro-
methyl-ethoxy)-benzoic acid



[1,2′]bipyrazinyl-4-yl)-
(compound 5.7)



methanone


654
(2-Isopropoxy-5-
5′-Trifluoromethyl-3,4,5,6-
473.4



methanesulfonyl-
tetrahydro-2H-



phenyl)-(5′-
[1,2′]bipyrazinyl (compound



trifluoromethyl-
7.7) and 2-Isopropoxy-5-



2,3,5,6-tetrahydro-
methanesulfonyl-benzoic acid



[1,2′]bipyrazinyl-4-yl)-
(compound 1.2)



methanone


655
[5-Methanesulfonyl-2-
3-Piperazin-1-yl-6-
527.3



((S)-2,2,2-trifluoro-1-
trifluoromethyl-pyridazine



methyl-ethoxy)-
(compound 7.8) and 5-



phenyl]-[4-(6-
Methanesulfonyl-2-((S)-2,2,2-



trifluoromethyl-
trifluoro-1-methyl-ethoxy)-



pyridazin-3-yl)-
benzoic acid (compound 5.6)



piperazin-1-yl]-



methanone


656
(2-Isopropoxy-5-
3-Piperazin-1-yl-6-
473.3



methanesulfonyl-
trifluoromethyl-pyridazine



phenyl)-[4-(6-
(compound 7.8) and 2-



trifluoromethyl-
Isopropoxy-5-methane



pyridazin-3-yl)-
sulfonyl-benzoic acid



piperazin-1-yl]-
(compound 1.2)



methanone


657
[5-Methanesulfonyl-2-
3-Piperazin-1-yl-6-
527.3



((R)-2,2,2-trifluoro-1-
trifluoromethyl-pyridazine



methyl-ethoxy)-
(compound 7.8) and 5-



phenyl]-[4-(6-
Methanesulfonyl-2-((R)-2,2,2-



trifluoromethyl-
trifluoro-1-methyl-ethoxy)-



pyridazin-3-yl)-
benzoic acid (compound 5.7)



piperazin-1-yl]-



methanone


658
[5-Methanesulfonyl-2-
5-Piperazin-1-yl-2-
541.3



(2,2,2-trifluoro-1,1-
trifluoromethyl-pyrimidine



dimethyl-ethoxy)-
(compound 7.6) and 5-



phenyl]-[4-(2-
Methanesulfonyl-2-(2,2,2-



trifluoromethyl-
trifluoro-1,1-dimethyl-



pyrimidin-5-yl)-
ethoxy)-benzoic acid



piperazin-1-yl]-
(compound 7.2)



methanone


659
[5-Methanesulfonyl-2-
3-Piperazin-1-yl-6-
541.3



(2,2,2-trifluoro-1,1-
trifluoromethyl-pyridazine



dimethyl-ethoxy)-
(compound 7.8) and 5-



phenyl]-[4-(6-
Methanesulfonyl-2-(2,2,2-



trifluoromethyl-
trifluoro-1,1-dimethyl-



pyridazin-3-yl)-
ethoxy)-benzoic acid



piperazin-1-yl]-
(compound 7.2)



methanone


660
[5-Methanesulfonyl-2-
5′-Trifluoromethyl-3,4,5,6-
541.3



(2,2,2-trifluoro-1,1-
tetrahydro-2H-



dimethyl-ethoxy)-
[1,2′]bipyrazinyl (compound



phenyl]-(5′-
7.7) and 5-Methanesulfonyl-2-



trifluoromethyl-
(2,2,2-trifluoro-1,1-dimethyl-



2,3,5,6-tetrahydro-
ethoxy)-benzoic acid



[1,2′]bipyrazinyl-4-yl)-
(compound 7.2)



methanone









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)

Uptake Buffer (UB): 150 mM NaCl, 10 mM Hepes-Tris, pH 7.4, 1 mM CaCl2, 2.5 mM KCl, 2.5 mM MgSO4, 10 mM (+) D-glucose.

Flp-inTM-CHO (Invitrogen Cat n° R758-07)cells stably transfected with mGlyT1b cDNA.
Glycine Uptake Inhibition Assay (mGlyT-1b)
On day 1 mammalian cells, (Flp-inTM-CHO), transfected with mGlyT-1b cDNA, were plated at the density of 40,000 cells/well in complete F-12 medium, without hygromycin in 96-culture plates. On day 2, the medium was aspirated, and the cells were washed twice with uptake buffer (UB). The cells were then incubated for 20 min at 22° C. with either (i) no potential competitor, (ii) 10 mM non-radioactive glycine, (iii) a concentration of a potential inhibitor. A range of concentrations of the potential inhibitor was used to generate data for calculating the concentration of inhibitor resulting in 50% of the effect (e.g. IC50, the concentration of the competitor inhibiting glycine uptake of 50%). A solution was then immediately added containing [3H]-glycine 60 nM (11-16 Ci/mmol) and 25 μM non-radioactive glycine. The plates were incubated with gentle shaking, and the reaction was stopped by aspiration of the mixture and washing (three times) with ice-cold UB. The cells were lysed with scintillation liquid, shaken 3 hours and the radioactivity in the cells counted using a scintillation counter.
The prepared compounds show an IC50 (μM) at GlyT-1 in the range of 0.006-5.0.
The preferred compounds show an IC50 (μM) at GlyT-1 in the range of 0.006-0.05, as shown in the table below.














Example No.
IC50 (μM)



















1
0.039



5
0.012



15
0.015



28
0.012



54
0.05



62
0.017



63
0.028



64
0.025



66
0.032



68
0.008



70
0.008



71
0.008



72
0.026



74
0.016



78
0.012



80
0.029



84
0.04



88
0.007



92
0.05



95
0.035



100
0.02



104
0.046



105
0.039



109
0.021



111
0.035



112
0.024



116
0.019



117
0.044



118
0.024



128
0.02



131
0.03



132
0.038



135
0.041



136
0.027



137
0.027



138
0.017



139
0.024



142
0.034



144
0.045



145
0.015



146
0.019



147
0.031



148
0.036



164
0.019



165
0.47



167
0.016



169
0.012



170
0.031



172
0.019



180
0.036



182
0.03



184
0.022



186
0.048



194
0.047



196
0.041



202
0.024



207
0.023



209
0.041



210
0.039



211
0.043



212
0.029



213
0.021



215
0.049



228
0.047



234
0.043



244
0.042



247
0.03



249
0.032



250
0.061



251
0.032



256
0.032



258
0.086



260
0.043



261
0.043



262
0.042



281
0.021



282
0.027



283
0.008



284
0.01



285
0.042



287
0.033



288
0.025



289
0.018



290
0.017



291
0.013



292
0.021



293
0.034



294
0.037



295
0.016



296
0.043



298
0.021



299
0.044



300
0.016



301
0.03



302
0.013



303
0.006



311
0.045



313
0.018



317
0.041



319
0.031



321
0.018



322
0.028



324
0.039



325
0.033



328
0.032



329
0.016



330
0.018



363
0.008



367
0.036



369
0.032



371
0.041



372
0.006



373
0.035



375
0.035



393
0.032



400
0.023



407
0.027



408
0.037



411
0.045



412
0.033



413
0.03



417
0.046



430
0.037



435
0.029



437
0.026



438
0.047



439
0.021



459
0.04



461
0.046



464
0.02



465
0.04



466
0.026



468
0.02



469
0.02



470
0.03



475
0.04



481
0.03



488
0.039



491
0.037



494
0.03



504
0.025



505
0.024



506
0.046



507
0.031



408
0.026



509
0.03



510
0.015



514
0.045



515
0.04



517
0.035



518
0.033



519
0.035



524
0.012



525
0.021



526
0.009



527
0.006



528
0.015



529
0.013



530
0.0057



531
0.028



534
0.049



537
0.03



546
0.035



554
0.019



557
0.042



558
0.029



561
0.038



562
0.044



563
0.043



564
0.041



566
0.03



568
0.044



570
0.046



571
0.05



573
0.037



574
0.034



576
0.039



578
0.041



589
0.032



595
0.049



637
0.047










The present invention also provides pharmaceutical compositions containing compounds of formula I or pharmaceutically acceptable salts of the compounds of formula I and a pharmaceutically acceptable carrier. Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. The pharmaceutical compositions also can be in the form of suppositories or injectable solutions.
The pharmaceutical compositions of the invention, in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier. Suitable pharmaceutical acceptable carriers include pharmaceutically inert, inorganic or organic carriers. 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, dragées 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.
In addition, the pharmaceutical compositions can 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.
Thus, pharmaceutical compositions 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.
Thus, the invention also provides a method of inhibiting glycine uptake comprising administering to an individual a glycine inhibiting amount of one or more compounds of formula I. The invention further provides a method of inhibiting glycine uptake which comprises administering to an individual a glycine inhibiting amount of one of the following compounds

    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,
    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine,
    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine,
    4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine,
    1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine,
    4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine,
    1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine,
    1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine,
    1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine or
    4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine.


The invention provides a method of treating an illness selected from the group consisting of psychoses, pain, disfunction in memory and learning, schizophrenia, dementia, attention deficit disorders, and Alzheimer's disease, which method comprises administering to an individual an effective amount of one or more compounds of formula I. The invention further provides a method of treating an illness selected from the group consisting of psychoses, pain, disfunction in memory and learning, schizophrenia, dementia, attention deficit disorders, and Alzheimer's disease, which method comprises administering to an individual an effective amount of one or more compounds of the following compounds 1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,

    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine,
    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine,
    4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine,
    1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine,
    4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine,
    1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine,
    1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine,
    1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine or
    4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine.


In particular, the method provides a method of treating schizophrenia, which method comprises administering to an individual an effective amount of one or more compounds of formula I. The invention further provides a method of treating schizophrenia, which method comprises administering to an individual an effective amount of one or more compounds of the following compounds

    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,
    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine,
    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine,
    4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine,
    1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine,
    4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine,
    1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine,
    1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine,
    1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine or
    4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine.


In particular, the method provides a method of treating Alzheimer's disease, which method comprises administering to an individual an effective amount of one or more compounds of formula I. The invention further provides a method of treating Alzhemier's disease, which method comprises administering to an individual an effective amount of one or more compounds of the following compounds

    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,
    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine,
    1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine,
    4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine,
    1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine,
    4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine,
    1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine,
    1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine,
    1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine or
    4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine.


The compounds and compositions of the present invention can be administered in a conventional manner, for example, orally, rectally, or parenterally. The pharmaceutical compositions of the invention can be administered orally, for example, in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. The pharmaceutical compositions also can be administered rectally, for example, in the form of suppositories or parenterally, for example, in the form of injectable solutions.
The dosage at which a compound of the invention can be administered 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.










Tablet Formulation (Wet Granulation)









mg/tablet












Item
Ingredients
5 mg
25 mg
100 mg
500 mg















1.
Compound of formula I
5
25
100
500


2.
Lactose Anhydrous DTG
125
105
30
150


3.
Sta-Rx 1500
6
6
6
30


4.
Microcrystalline Cellulose
30
30
30
150


5.
Magnesium Stearate
1
1
1
1



Total
167
167
167
831









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.












Capsule Formulation









mg/capsule












Item
Ingredients
5 mg
25 mg
100 mg
500 mg















1.
Compound of formula I
5
25
100
500


2.
Hydrous Lactose
159
123
148
—


3.
Corn Starch
25
35
40
70


4.
Talc
10
15
10
25


5.
Magnesium Stearate
1
2
2
5



Total
200
200
300
600









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.

## Claims

1. A compound of formula




wherein
Ar is unsubstituted or substituted aryl or 6-membered heteroaryl containing one, two or three nitrogen atoms, wherein the substituted aryl and the substituted heteroaryl groups are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9, SO2R10, and —C(CH3)═NOR7, or are substituted by a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, which is optionally substituted by (C1-C6)-alkyl;
R1 is hydrogen or (C1-C6)-alkyl;
R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or by halogen, CH(CH3)—(C3-C7)-cycloalkyl, (CH2)n+1—C(O)—R9, (CH2)n+1—CN, bicyclo[2.2.1]heptyl, (CH2)n+1—O—(C1-C6)-alkyl, (CH2)n-heterocycloalkyl, (CH2)n-aryl or (CH2)n-5 or 6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O—(C3-C6)-cycloalkyl;
R5 is NO2, CN, C(O)R9 or SO2R10;
R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR7R8;
R10 is (C1-C6)-alkyl optionally substituted by halogen, (CH2)n—(C3-C6)-cycloalkyl, (CH2)n—(C3-C6)-alkoxy, (CH2)n-heterocycloalkyl or NR7R8;
n is 0, 1, or 2;
or a pharmaceutically acceptable acid addition salt thereof.

2. A compound of formula




wherein
Ar is substituted aryl or unsubstituted or substituted 6-membered heteroaryl containing one, two or three nitrogen atoms, and wherein the substituted aryl and the substituted heteroaryl groups are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9 and SO2R10;
R1 is hydrogen or (C1-C6)-alkyl;
R2 is (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C3-C6)-cycloalkyl, heterocycloalkyl, (C1-C6)-alkyl-(C3-C6)-cycloalkyl, (C1-C6)-alkyl-heterocycloalkyl, (C1-C6)-alkyl-C(O)—R9, (C1-C6)-alkyl-CN, (C2-C6)-alkyl-O—R13, (C2-C6)-alkyl-NR7R8, aryl, 6-membered heteroaryl containing one, two or three nitrogen atoms, (C1-C6)-alkyl-aryl or (C1-C6)-alkyl-5 or -6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, CN, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR7R8;
R5 is NO2, CN, C(O)R9, SO2R10 or NR11R12;
R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
R9 is hydroxy, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy or NR7R8;
R10 is (C1-C6)-alkyl, (C3-C6)-cycloalkyl or NR7R8;
R11 and R12 are each independently hydrogen, C(O)—(C1-C6)-alkyl, or SO2—(C1-C6)-alkyl, or form together with the N-atom to which they are attached a 5-membered heteroaryl group, optionally substituted by halogen, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen or (C3-C6)-cycloalkyl;
R13 is hydroxy, (C1-C6)-alkyl or (C3-C6)-cycloalkyl;
or a pharmaceutically acceptable acid addition salt thereof.

3. A compound of formula I according to claim 1, wherein Ar is a substituted 6-membered heteroaryl group containing one, two or three nitrogen atoms, R2 is (C1-C6)-alkyl or CH2)n—(C3-C7)-cycloalkyl, and R5 is SO2CH3.

4. A compound of formula I according to claim 3, wherein the compound is selected from the group consisting of
[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-cyclopropylmethoxy-5-methanesulfonyl-phenyl)-methanone,
6-[4-(2-cyclopentyloxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-nicotinonitrile, (2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,
[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-methanone,
(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(6-trifluoromethyl-pyridin-3-yl)-piperazin-1-yl]-methanone,
[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone and
(2-cyclopentyloxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone.

5. A compound of formula I according to claim 1, wherein Ar is a substituted 6-membered heteroaryl group containing one, two or three nitrogen atoms, R2 is (C1-C6)-alkyl substituted by halogen and R5 is SO2CH3.

6. A compound of formula I according to claim 5, wherein the compound is selected from the group consisting of
rac-[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,
rac-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,
rac-[4-(5-bromo-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,
rac-[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,
rac-[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(6-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,
[5-methanesulfonyl-2-((S or R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,
[5-methanesulfonyl-2-((R or S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone,
[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone and
[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-phenyl]-methanone.

7. A process for preparing a compound of formula




wherein
Ar is unsubstituted or substituted aryl or 6-membered heteroaryl containing one, two or three nitrogen atoms, wherein the substituted aryl and the substituted heteroaryl groups are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9, SO2R10, and —C(CH3)═NOR7, or are substituted by a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, which is optionally substituted by (C1-C6)-alkyl;
R1 is hydrogen or (C1-C6)-alkyl;
R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or by halogen, CH(CH3)—(C3-C7)-cycloalkyl, (CH2)n+1—C(O)—R9, (CH2)n+1—CN, bicyclo [2.2.1]heptyl, (CH2)n+1—O—(C1-C6)-alkyl, (CH2)n-heterocycloalkyl, (CH2)n-aryl or (CH2)n-5 or 6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O—(C3-C6)-cycloalkyl;
R5 is NO2, CN, C(O)R9 or SO2R10;
R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR7R8;
R10 is (C1-C6)-alkyl optionally substituted by halogen, (CH2)n—(C3-C6)-cycloalkyl, (CH2)n—(C3-C6)-alkoxy, (CH2)n-heterocycloalkyl or NR7R8;
n is 0, 1, or 2;
or a pharmaceutically acceptable acid addition salt thereof,
which process comprises reacting a compound of formula




with a compound of formula




in the presence of an activating agent to produce a compound of formula




wherein the substituents are as defined above.

8. A process according to claim 7, wherein the activating agent is TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoro borate).

9. A process for preparing a compound of formula




wherein
Ar is unsubstituted or substituted aryl or 6-membered heteroaryl containing one, two or three nitrogen atoms, wherein the substituted heteroaryl groups are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9, SO2R10, and —C(CH3)═NOR7, or are substituted by a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, which is optionally substituted by (C1-C6)-alkyl;
R1 is hydrogen or (C1-C6)-alkyl;
R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or by halogen, CH(CH3)—(C3-C7)-cycloalkyl, (CH2)n+1—C(O)—R9, (CH2)n+1—CN, bicyclo [2.2.1]heptyl, (CH2)n+1—O—(C1-C6)-alkyl, (CH2)n-heterocycloalkyl, (CH2)n-aryl or (CH2)n-5 or 6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O—(C3-C6)-cycloalkyl;
R5 is NO2, CN, C(O)R9 or SO2R10;
R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR7R8;
R10 is (C1-C6)-alkyl optionally substituted by halogen, (CH2)n—(C3-C6)-cycloalkyl, (CH2)n—(C3-C6)-alkoxy, (CH2)n-heterocycloalkyl or NR7R8;
n is 0, 1, or 2;
or a pharmaceutically acceptable acid addition salt thereof,
which process comprises reacting a compound of formula




with a compound of formula


R2OH


optionally in the presence of a catalyst and a base to produce a compound of formula





wherein X is halogen and the other substituents are as defined above.

10. The process according to claim 9 wherein the catalyst is Cu(I)I and the base is potassium carbonate, cesium carbonate or sodium.

11. A process for preparing a compound of formula




wherein
Ar is unsubstituted or substituted aryl or 6-membered heteroaryl containing one, two or three nitrogen atoms, wherein the substituted heteroaryl groups are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9, SO2R10, and —C(CH3)═NOR7, or are substituted by a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, which is optionally substituted by (C1-C6)-alkyl;
R1 is hydrogen or (C1-C6)-alkyl;
R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or by halogen, CH(CH3)—(C3-C7)-cycloalkyl, (CH2)n+1—C(O)—R9, (CH2)n+1—CN, bicyclo[2.2.1]heptyl, (CH2)n+1—O—(C1-C6)-alkyl, (CH2)n-heterocycloalkyl, (CH2)n-aryl or (CH2)n-5 or 6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O—(C3-C6)-cycloalkyl;
R5 is NO2, CN, C(O)R9 or SO2R10;
R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR7R8;
R10 is (C1-C6)-alkyl optionally substituted by halogen, (CH2)n—(C3-C6)-cycloalkyl, (CH2)n—(C3-C6)-alkoxy, (CH2)n-heterocycloalkyl or NR7R8;
n is 0, 1, or 2;
or a pharmaceutically acceptable acid addition salt thereof,
which process comprises reacting a compound of formula




with a compound of formula


R2X


in the presence of a base and optionally in the presence of microwaves to produce a compound of formula




wherein X is halogen, mesylate or triflate and the other substituents are as defined above.

12. A process for preparing a compound of formula




wherein
Ar is unsubstituted or substituted aryl or 6-membered heteroaryl containing one, two or three nitrogen atoms, wherein the substituted heteroaryl groups are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9, SO2R10, and —C(CH3)═NOR7, or are substituted by a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, which is optionally substituted by (C1-C6)-alkyl;
R1 is hydrogen or (C1-C6)-alkyl;
R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or by halogen, CH(CH3)—(C3-C7)-cycloalkyl, (CH2)n+1—C(O)—R9, (CH2)n+1—CN, bicyclo[2.2.1]heptyl, (CH2)n+1—O—(C1-C6)-alkyl, (CH2)n-heterocycloalkyl, (CH2)n-aryl or (CH2)n-5 or 6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O—(C3-C6)-cycloalkyl;
R5 is NO2, CN, C(O)R9 or SO2R10;
R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR7R8;
R10 is (C1-C6)-alkyl optionally substituted by halogen, (CH2)n—(C3-C6)-cycloalkyl, (CH2)n—(C3-C6)-alkoxy, (CH2)n-heterocycloalkyl or NR7R8;
n is 0, 1, or 2;
or a pharmaceutically acceptable acid addition salt thereof,
which process comprises reacting a compound of formula




with a compound of formula


R2OH


under Mitsunobu conditions in the presence of a phosphine to produce a compound of formula




wherein the substituents are as defined above.

13. A process for preparing a compound of formula




wherein
Ar is unsubstituted or substituted aryl or 6-membered heteroaryl containing one, two or three nitrogen atoms, wherein the substituted aryl and the substituted heteroaryl groups are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9, SO2R10, and —C(CH3)═NOR7, or are substituted by a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, which is optionally substituted by (C1-C6)-alkyl;
R1 is hydrogen or (C1-C6)-alkyl;
R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or by halogen, CH(CH3)—(C3-C7)-cycloalkyl, (CH2)n+1—C(O)—R9, (CH2)n+1—CN, bicyclo[2.2.1]heptyl, (CH2)n+1—O—(C1-C6)-alkyl, (CH2)n-heterocycloalkyl, (CH2)n-aryl or (CH2)n-5 or 6-membered heteroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or O—(C3-C6)-cycloalkyl;
R5 is NO2, CN, C(O)R9 or SO2R10,
R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR7R8;
R10 is (C1-C6)-alkyl optionally substituted by halogen, (CH2)n—(C3-C6)-cycloalkyl, (CH2)n—(C3-C6)-alkoxy, (CH2)n-heterocycloalkyl or NR7R8;
n is 0, 1, or 2;
or a pharmaceutically acceptable acid addition salt thereof,
which process comprises reacting a compound of formula




with a compound of formula


ArX


to produce a compound of formula




wherein X is halogen and the other substituents are as defined above.

14. A composition comprising one or more compounds of formula




wherein
Ar is unsubstituted or substituted 6-membered heteroaryl containing one, two or three nitrogen atoms, wherein the substituted heteroaryl groups are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9, SO2R10, and —C(CH3)═NOR7, or are substituted by a 5-membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, which is optionally substituted by (C1-C6)-alkyl;
R1 is hydrogen or (C1-C6)-alkyl;
R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C, C6)-alkyl substituted by hydroxy, (CH2)n—(C3-C7)-cycloalkyl optionally substituted by (C1-C6)-alkoxy or by halogen, CH(CH3—(C3-C7)-cycloalkyl, (CH2)n+−C(O)—R9, (CH2)n+1−—CN, bicyclo(2.2.1]heptyl, (CH2)n+1—O—(C1-C6)-alkyl, (CH2)n-heterocycloalkyl, (CH2)n-aryl or (CH2)n-5 or 6-membered heteroaryl containing one, two or three heteroatorns selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C6)-alkoxy;
R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6)-allcoxy or O—(C3-C6)-cycloalkyl;
R5 is NO2, CN, C(O)R9or S2R10;
R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-allcoxy or NR7R8;
R10 is (C1-C6)-alkyl optionally substituted by halogen, (CH2)n—(C3-C6)-cycloalkyl (CH2)n—(C3-C6)-alkoxy, (CH2)n-heterocycloalkyl or NR7R8;
n is 0, 1 , or2;
or a pharmaceutically acceptable acid addition salt thereof,
and a pharmaceutically acceptable excipient.

15. A method of treating schizophrenia which comprises administering to an individual an effective amount of one or more compounds of formula




wherein
Ar is unsubstituted or substituted 6-membered heteroaryl containing one, two or three nitrogen atoms, wherein the substituted heteroaryl groups are substituted by one or more substituents selected from the group consisting of hydroxy, halogen, NO2, CN, (C1-C6)-alkyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C1-C6)-alkoxy, (C1-C6)-alkoxy substituted by halogen, NR7R8, C(O)R9, SO2R10, and —C(CH3)═NOR7, or are substituted by a 5-membered aromatic heterocycle containing 1-4 heteroatorns selected from N and O, which is optionally substituted by (C1-C6)-alkyl;
R1 is hydrogen or (C1-C6)-alkyl;
R2 is hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C1-C6)-alkyl substituted by halogen, (C1-C6)-alkyl substituted by hydroxy, (CH2)n—(C3-C7)-cycloalkyl optionally substituted by (C1-C6) -alkoxy or by halogen, CH(CH3)—(C3-C7)-cycloalkyl, (CH2)n+—C(O)—R9, (CH2)n+1—CN, bicyclo[2.2.1]heptyl, (CH2)n+1—O—(C1-C6)-alkyl, (CH2)n-heterocycloalkyl, (CH2)n-aryl or (CH2)n-5 or 6-membered hetaroaryl containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein aryl, heterocycloalkyl and heteroaryl are unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, halogen, (C1-C6)-alkyl and (C1-C1)-alkoxy;
R3, R4 and R6 are each independently hydrogen, hydroxy, halogen, (C1-C6)-alkyl, (C1-C6) -alkoxy or O—(C3-C6)-cycloalkyl;
R5 is NO2, CN, C(O)R9 or SO2R10;
R7 and R8 are each independently hydrogen or (C1-C6)-alkyl;
R9 is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkoxy or NR7R8;
R10 is (C1-C6)-alkyl optionally substituted by halogen, (CH2)n—(C3-C6)-cycloalkyl, (CH2)n—(C3-C6)-alkoxy, (CH2)n-heterocycloalkyl or NR7R8;
n is 0, 1, or 2;
or a pharmaceutically acceptable acid addition salt thereof.