Abstract:
The present invention relates to compounds of formula I  
                         
wherein 
 
R 1 , R 2 , 
 
R 3 , 
 
R 4 , and 
X are as defined herein or to pharmaceutically acceptable acid addition salts thereof, with the exception of 4-methoxy-N-[2-oxo-2-(phenylamino)ethyl]-N-phenyl-benzamide, 4-chloro-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide, 4-chloro-N-[2-[5-chloro-2-methoxyphenyl)amino]-2-oxoethyl]-N-benzamide, 4-methyl-N-[2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide, N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide, 4-methyl-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide, 4-chloro-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide and N-[2-[(2,4-dimethoxyphenyl)amino]-2-oxoethyl]-N-[(2-fluorophenyl)methyl]-benzeneacetamide. The compounds are useful in the treatment of neurological and neuropsychiatric disorders.

Description:
PRIORITY TO RELATED APPLICATION(S)  
       [0001]     This application claims the benefit of European Patent Application No. 06119758.8, filed Aug. 30, 2006, which is hereby incorporated by reference in its entirety.  
       BACKGROUND OF THE INVENTION  
       [0002]     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,  2000, 28:325-33). 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,  2001, 5 (4): 507-518; Nakazato A and Okuyama S, et al., 2000 , Exp. Opin. Ther. Patents,  10 (1): 75-98). This pharmacological approach poorly address negative and cognitive symptoms which are the best predictors of functional outcome (Sharma T.,  Br. J. Psychiatry,  1999, 174 (suppl. 28): 44-51).  
         [0003]     A complementary model of schizophrenia was proposed in the mid-1960&#39; 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., 1999 , Biol. Psychiatry,  45: 668-679 and refs. herein). 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., 1999 , Cell,  98: 427-236).  
         [0004]     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 (Hebb D O, 1949 , The organization of behavior , Wiley, NY; Bliss T V and Collingridge G L, 1993 , Nature,  361: 31-39). Transgenic mice overexpressing the NMDA NR2B subunit exhibit enhanced synaptic plasticity and superior ability in learning and memory (Tang J P et al., 1999 , Nature:  401-63-69).  
         [0005]     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.  
         [0006]     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.  
         [0007]     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, 2002, Trends in Pharm. Sci., 23 (8): 367-373).  
         [0008]     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.  
         [0009]     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., 2001 , Mol. Mem. Biol.,  18: 13-20). 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., 1998 , Proc. Natl. Acad. Sci. USA,  95: 15730-15734; Chen L et al., 2003 , J. Neurophysiol.,  89 (2): 691-703).  
         [0010]     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, 2001 , Exp. Opin. Ther. Patents,  11 (4): 563-572), 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., 2002 , Prog. Neurobiol.,  67: 173-202), autistic disorders (Carlsson M L, 1998 , J. Neural Transm.  105: 525-535), 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, 2001 , Exp. Opin. Ther. Patents,  11 (4): 563-572).  
         [0011]     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&#39;s disease.  
       SUMMARY OF THE INVENTION  
       [0012]     The present invention provides compounds of formula I  
                         
 
 wherein 
    R 1  is lower alkyl, aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted by halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, amino, di-lower alkyl amino or morpholinyl;     R 2  is lower alkyl, —(CH 2 ) n -aryl, —(CH 2 ) n -heteroaryl or —(CH 2 ) n -cycloalkyl, wherein the aryl or heteroaryl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, cyano, or lower alkoxy;     R 3  is hydrogen or lower alkyl;     R 4  is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of halogen, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl;     X is a bond or —OCH 2 —;     n is 0, 1 or 2; 
 
 or pharmaceutically acceptable acid addition salts thereof, with the exception of 
    4-methoxy-N-[2-oxo-2-(phenylamino)ethyl]-N-phenyl-benzamide,     4-chloro-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,     4-chloro-N-[2-[5-chloro-2-methoxyphenyl)amino]-2-oxoethyl]-N-benzamide,     4-methyl-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide,     N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,     4-methyl-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,     4-chloro-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide and     N-[2-[(2,4-dimethoxyphenyl)amino]-2-oxoethyl]-N-[(2-fluorophenyl)methyl]-benzeneacetamide.    
 
         [0027]     The excepted compounds have been described in  Organic and Bio - Organic Chemistry  (1972), (7), 909-13 in a cyclisation process of α-acylamino-acids.  
         [0028]     Furthermore, the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.  
         [0029]     The present invention also provides pharmaceutical compositions containing a compound of formula I or a pharmaceutical salt thereof. The invention also provides methods for the preparation of the compounds and compositions of the invention.  
         [0030]     Compounds of general formula I are good inhibitors of the glycine transporter 1 (GlyT-1) and have a good selectivity to glycine transporter 2 (GlyT-2) inhibitors. The invention provides methods for the treatment of diseases related to activation of NMDA receptors via GlyT-1 inhibition, such as psychoses, dysfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer&#39;s disease. The preferred indications of the present invention are schizophrenia, cognitive impairment and Alzheimer&#39;s disease. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0031]     The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,” and “the” include plural forms unless the context clearly dictates otherwise.  
         [0032]     As used herein, the term “lower alkyl” denotes a saturated straight- or branched-chain hydrocarbon group containing from 1 to 7 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.  
         [0033]     The term “cycloalkyl” denotes a saturated or partially saturated carbocyclic ring containing from 3 to 7 carbon atoms, for example cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cycloheptenyl.  
         [0034]     The term “halogen” denotes chlorine, iodine, fluorine and bromine.  
         [0035]     The term “aryl” denotes a monovalent cyclic aromatic hydrocarbon radical having 6 to 12 ring atoms and consisting of one or more fused rings in which at least one ring is aromatic in nature, for example phenyl or naphthyl.  
         [0036]     The term “heteroaryl” denotes a cyclic aromatic hydrocarbon radical, containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein at least one ring is aromatic in nature, for example pyridyl, quinoxalinyl, dihydrobenzofuranyl, thiophenyl, benzothiophenyl, isoxazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and isothiazolyl.  
         [0037]     The term “lower alkyl substituted by halogen” denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by a halogen atom, for example the following groups: CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 CH 2 CF 3 , CH 2 CH 2 CH 2 CF 3 , CH 2 CH 2 Cl, CH 2 CF 2 CF 3 , CH 2 CF 2 CHF 2 , CF 2 CHFCF 3 , C(CH 3 ) 2 CF 3 , CH(CH 3 )CF 3  or CH(CH 2 F)CH 2 F.  
         [0038]     The term “lower alkoxy” denotes a alkyl group wherein the lower alkyl residue is as defined above and which is attached via an oxygen atom.  
         [0039]     The term “lower alkoxy substituted by halogen” denotes an alkoxy group, wherein at least one hydrogen atom is replaced by halogen as defined above.  
         [0040]     “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.  
         [0041]     The term “pharmaceutically acceptable acid addition salts” 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.  
         [0042]     “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.  
         [0043]     The present invention provides compounds of formula I  
                         
 
 wherein 
    R 1  is lower alkyl, aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted by halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, amino, di-lower alkyl amino or morpholinyl;     R 2  is lower alkyl, —(CH 2 ) n -aryl, —(CH 2 ) n -heteroaryl or —(CH 2 ) n -cycloalkyl, wherein the aryl or heteroaryl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, cyano, or lower alkoxy;     R 3  is hydrogen or lower alkyl;     R 4  is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of halogen, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl;     X is a bond or —OCH 2 —;     n is 0, 1 or 2; 
 
 or pharmaceutically acceptable acid addition salts thereof, with the exception of 
    4-methoxy-N-[2-oxo-2-(phenylamino)ethyl]-N-phenyl-benzamide,     4-chloro-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,     4-chloro-N-[2-[5-chloro-2-methoxyphenyl)amino]-2-oxoethyl]-N-benzamide,     4-methyl-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide,     N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,     4-methyl-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,     4-chloro-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide and     N-[2-[(2,4-dimethoxyphenyl)amino]-2-oxoethyl]-N-[(2-fluorophenyl)methyl]-benzeneacetamide.    
 
         [0058]     Preferred compounds of formula I are those, wherein X is a bond.  
         [0059]     Preferred compounds of formula I of the present invention are further those, wherein R 1  and R 4  are both monosubstituted aryl, preferably halogen substituted phenyl, for example the following compounds: 
    4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2,6-difluoro-benzyl)-benzamide,     4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2,3-difluoro-benzyl)-benzamide,     4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-fluoro-benzyl)-benzamide,     4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-thiophen-2-ylmethyl-benzamide,     4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-methoxy-benzyl)-benzamide,     4-Chloro-N-(3-chloro-benzyl)-N-[(3-chloro-phenylcarbamoyl)-methyl]-benzamide and     4-Chloro-N-(2-chloro-benzyl)-N-[(3-chloro-phenylcarbamoyl)-methyl]-benzamide.    
 
         [0067]     Further preferred compounds are those, wherein R 1  and R 4  are both monosubstituted aryl, for R 1  preferably methoxy substituted phenyl and for R 4  preferably halogen substituted phenyl, for example the following compounds: 
    N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2,6-difluoro-benzyl)-4-methoxy-benzamide and     N-(3-Chloro-benzyl)-N-[(3-chloro-phenylcarbamoyl)-methyl]-4-methoxy-benzamide.    
 
         [0070]     Preferred compounds of formula I of the present invention are further those, wherein R 1  is heteroaryl, preferably benzothiophenyl, for example the following compounds: 
    Benzo[b]thiophene-2-carboxylic acid (2-chloro-benzyl)-[(3-trifluoromethyl-phenylcarbamoyl)-methyl]-amide,     Benzo[b]thiophene-2-carboxylic acid (2-chloro-benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide,     Benzo[b]thiophene-2-carboxylic acid (3,5-difluoro-benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide,     Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(2,6-difluoro-benzyl)-amide,     Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(2,3-difluoro-benzyl)-amide and     Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(3,5-difluoro-benzyl)-amide.    
 
         [0077]     Preferred compounds of formula I of the present invention are further those, wherein R 1  and R 4  are monosubstituted aryl, preferably halogen substituted phenyl for R 1  and CF 3  substituted phenyl for R 4 , for example the following compound: 
    N-(2-Chloro-benzyl)-4-fluoro-N-[(3-trifluoromethyl-phenylcarbamoyl)-methyl]-benzamide.    
 
         [0079]     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, which processes comprise  
         [0080]     a) reacting a compound of formula  
                         
 
 with a compound of formula 
 
R 2 —NH 2   II 
 
 and with a compound of formula  
                         
 
 in the presence of N-ethyldiisopropylamine 
 
 to produce a compound of formula  
                         
 
 wherein the substituents are as defined above, or 
 
         [0081]     b) reacting a compound of formula  
                         
 
 with a compound of formula  
                         
 
 in presence of triethylamine 
 
 to produce a compound of formula  
                         
 
 wherein the substituents are as defined above or 
 
         [0082]     c) reacting a compound of formula 
 
NHR 3 R 4   IX 
 
 with a compound of formula  
                         
 
 in the presence of N-ethyldiisopropylamine and HATU [O-(7-Azabenzotriazole-1-yl)-N, N,N′N′-tetramethyluronium hexafluorophosphate], 
 
 to produce a compound of formula  
                         
 
 wherein the substituents are as defined above, or 
 
         [0083]     d) reacting a compound of formula  
                         
 
 with a compound of formula  
                         
 
 in the presence of triethylamine, 
 
 to produce a compound of formula  
                         
 
 wherein the substituents are as defined above 
 
 and 
 
         [0084]     if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.  
         [0085]     The acid addition salts of the basic compounds of formula I can 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.  
         [0086]     The compounds of formula I can be prepared in accordance with process variant a) to d), with the following schemes and with working examples 1-128.  
         [0087]     The starting material is commercially available or can be prepared in accordance with known methods.  
         [0000]     Procedure A  
         [0088]     This procedure is used to prepare Example 34 (N-phenyl-N-(p-tolylcarbamoyl-methyl)-6-trifluoromethyl-nicotinamide).  
                         
 
         [0089]     To a compound of formula III, for example 2-bromo-N-(4-methyl-phenyl)-acetamide, in THF is added a compound of formula II, for example aniline and N-ethyldiisopropylamine, and a compound of formula IV, for example 6-trifluoromethyl-nicotynoyl chloride, and the reaction mixture is stirred over night at reflux. Then the reaction is concentrated in vacuo, and the reaction mixture is purified in conventional manner.  
         [0000]     Procedure B  
         [0090]     This procedure is used to prepare Example 30: N-[(3,4-dichloro-phenylcarbamoyl)-methyl]-N-phenyl-3-trifluoromethyl benzamide.  
                         
 
 Step 1: Compound of Formula V 
 
         [0091]     To a compound of formula III, for example 2-bromo-N-(3,4-dichloro-phenyl)-acetamide, in THF is added a compound of formula II, for example aniline and N-ethyldiisopropylamine, and the reaction mixture is stirred over night at reflux. The precipitated salt is then filtered off, and the filtrate was then concentrated in vacuo. The residue was then purified in conventional manner.  
         [0000]     Step 2: Compound of Formula I  
         [0092]     To a compound of formula V, for example N-(3,4-dichloro-phenyl)-2-phenylamino-acetamide, in THF is added triethylamine and a compound of formula IV, for example 3-trifluoromethylbenzoyl chloride, and the reaction mixture is stirred at room temperature for about 30 minutes. Water is then added to the mixture until precipitation occurred, and the mixture is stirred for 5 minutes. Then the precipitate is isolated by filtration and washed.  
         [0000]     Procedure C  
         [0093]     This procedure is used to prepare Example 30: 4-chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-fluoro-benzyl)benzamide.  
                         
 
 Step 1: Compound of Formula VII 
 
         [0094]     To a compound of formula VI, for example (2,6-dichloro-benzylamino)-acetic acid ethyl ester, in suspension THF is added triethylamine and a compound of formula IV, for example 4-methoxybenzoyl chloride, and the reaction mixture is stirred at room temperature for 10 min. Water is then added to the reaction mixture, and the aqueous phase is extracted with diethylacetate. The combined organic phases are then dried, concentrated in vacuo and purified.  
         [0000]     Step 2: Compound of Formula VIII  
         [0095]     To a compound of formula VII, for example N-(3,4-dichloro-phenyl)-2-phenylamino-acetamide, in ethanol is added NaOH, and the reaction mixture is stirred at room temperature for about 3 hours. The reaction mixture is then neutralized by addition of HCl, and the ethanol is eliminated by evaporation. Water and ethyl acetate is then added to the residue. The organic phase is separated, and the aqueous phase is extracted with ethylacetate. The combined organic phase is then washed again with water, dried and concentrated in vacuo.  
         [0000]     Step 3: Compound of Formula I  
         [0096]     To a solution of a compound of formula IX, for example 3-chloroaniline, in DMF is added N-ethyldiiopropylamine, a compound of formula VIII, for example [(2,6-dichloro-benzyl)-(4-methoxy-benzoyl)-amino]-acetic acid, and HATU; and the reaction mixture is stirred at room temperature over night. Then water is added until precipitation occurs, and the precipitate is isolated by filtration and washed with a mixture of water and ethanol to yield the title compound.  
         [0000]     Procedure D  
         [0097]     This procedure was used to prepare Example 1: 4-chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2,6-difluoro-benzyl)-benzamide.  
                         
 
         [0098]     To a compound of formula III-1, for example N-1-(3-chlorophenyl)-2-chloroacetamide, in DMF is added a compound of formula II, for example 2,6-difluorobenzylamine and triethylamine, and a compound of formula IV, such as 4-chlorobenzoyl chloride. The reaction mixture is stirred at room temperature for about 15 min and then purified.  
         [0000]     Procedure E  
         [0099]     This procedure was used to prepare Example 97: N-[(3,4-dichloro-phenylcarbamoyl)-methyl]-N-isobutyl-4-methoxy-benzamide.  
                         
 
 Step 1: Hydrobromide of a Compound of Formula V-1 
 
         [0100]     To a solution of a compound of formula III, for example 2-bromo-N-(3,4-dichloro-phenyl)-acetamide, in dichloromethane at 0° C. is slowly added isobutylamine in dichloromethane. The reaction mixture is allowed to warm up to room temperature and then stirred for another 24 hours. Then the salt is filtered off and the filtrate is concentrated in vacuo. The residue is then purified.  
         [0000]     Step 2: Compound of Formula I-1.  
         [0101]     To a solution of a compound of formula V-1, such as N-(3,4-dichloro-phenyl)-2-isobutylamino-acetamide hydrobromide, in THF are slowly added a solution of triethylamine in THF and a solution of a compound of formula IV, for example 4-methoxybenzoyl chloride, in THF, and the reaction mixture is stirred at room temperature for about 24 hours. Then water is added to the reaction mixture, and the precipitate is isolated by filtration and then purified.  
         [0102]     The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, the compounds of the present invention are good inhibitors of the glycine transporter I (GlyT-1).  
         [0103]     The compounds were investigated in accordance with the test given hereinafter.  
       Solutions and Materials  
       [0104]     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)  
         [0105]     Uptake buffer (UB): 150 mM NaCl, 10 mM Hepes-Tris, pH 7.4, 1 mM CaCl 2 , 2.5 mM KCl, 2.5 mM MgSO 4 , 10 mM (+) D-glucose.  
         [0000]     Flp-in™-CHO (Invitrogen Cat n° R758-07) cells stably transfected with mGlyT1b cDNA.  
         [0000]     Glycine Uptake Inhibition Assay (mGlyT-1b)  
         [0106]     On day 1 mammalian cells, (Flp-in™-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-well 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. IC 50 , the concentration of the competitor inhibiting glycine uptake of 50%). A solution was then immediately added containing [ 3 H]-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 was counted using a scintillation counter.  
         [0107]     The compounds described in examples 1-128 have an IC 50  data &lt;1.0 μM. The IC 50  data (&lt;0.4 μM) for representative compounds 1-128 is be provided in table 2.  
         [0108]     The present invention also provides pharmaceutical compositions containing compounds of the invention, for example compounds of formula I and their pharmaceutically suitable acid addition salts, and a pharmaceutically acceptable carrier. Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. The pharmaceutical compositions also can be in the form of suppositories or injectable solutions.  
         [0109]     The pharmaceutical compounds of the invention, in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic and 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.  
         [0110]     The pharmaceutical compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.  
         [0111]     The invention also provides a method for preparing compositions of the invention 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.  
         [0112]     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&#39;s disease. The invention provides a method for the treatment of schizophrenia, which comprises administering to an individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The invention also provides a method for the treatment of Alzheimer&#39;s disease, which comprises administering to an individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The invention further comprises a method for improving cognition, which comprises administering to an individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.  
         [0113]     The dosage at which compounds 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 can 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.                  
 
         [0114]     The following examples illustrate the present invention without limiting it. All temperatures are given in degree Celsius.  
         [0000]     Procedure A  
         [0115]     This procedure is used to prepare Example 34  
       N-Phenyl-N-(p-tolylcarbamoyl-methyl)-6-trifluoromethyl-nicotinamide  
       [0116]     To 2-bromo-N-(4-methyl-phenyl)-acetamide (100 mg) in THF (3.0 mL) was added aniline (41 mg) and N-ethyldiisopropylamine and 6-trifluoromethyl-nicotynoyl chloride (110 mg) the reaction mixture was stirred over night at reflux. Then the reaction was concentrated in vacuo and the reaction mixture was purified by column chromatography to yield the title compound as a light brown solid (127 mg, 70%).  
         [0000]     Procedure B  
         [0117]     This procedure was used to prepare Example 30  
       N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-phenyl-3-trifluoromethyl benzamide  
     Step 1: N-(3,4-Dichloro-phenyl)-2-phenylamino-acetamide  
       [0118]     To 2-bromo-N-(3,4-dichloro-phenyl)-acetamide (2 g) in THF (80 mL) was added aniline (41 mg) and N-ethyldiisopropylamine and the reaction mixture was stirred over night at reflux. The precipitated salt was then filtered off and the filtrate was then concentrated in vacuo. The residue was then purified by column chromatography to give the title compound as a light brown solid (1.3 g, mp=110-112° C.).  
       Step 2: N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-phenyl-3-trifluoromethyl benzamide  
       [0119]     To N-(3,4-dichloro-phenyl)-2-phenylamino-acetamide (73 mg) in THF (3.1 mL) was added tiethylamine (52 μL) and 3-trifluoromethylbenzoyl chloride (62 mg) and the reaction mixture was stirred at room temperature for 30 minutes. To the mixture was then added water under precipitation occurred and the mixture was stirred for 5 minutes. Then the precipitate was isolated by filtration and washed with a mixture water-ethanol (1:1) to yield the title compound as a white solid (64 mg, mp=130-132° C.).  
         [0000]     Procedure C  
         [0120]     This procedure was used to prepare Example 30  
       4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-fluoro-benzyl)benzamide  
     Step 1: N-(3,4-Dichloro-phenyl)-2-phenylamino-acetamide  
       [0121]     To (2,6-dichloro-benzylamino)-acetic acid ethyl ester (100 mg) in suspension THF (5 mL) was added triethylamine (0.08 mL) and 4-methoxybenzoyl chloride (78 mg) and the reaction mixture was stirred at room temperature for 10 min. After such time the water was added to the reaction mixture and the aqueous phase was extracted with diethylacetate. The combined organic phases were then dried over sodium sulfate, concentrated vacuo and purified by column chromatography to yield the title (128 mg). MS (m/e): 396.3 (M+H + )  
       Step 2: [(2,6-Dichloro-benzyl)-(4-methoxy-benzoyl)-amino]-acetic acid  
       [0122]     To N-(3,4-dichloro-phenyl)-2-phenylamino-acetamide in ethanol (10 mL) was added 1N NaOH (0.38 μL) and the reaction mixture was stirred at room temperature for 3 hours. After such time the reaction mixture was neutralized by addition of 3N HCl and the ethanol was eliminated by evaporation. To the residue was added more water and ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethylacetate. The combined organic phase was then washed again with water, dried over sodium sulfate and concentrated in vacuo to yield the title compound (90 mg). MS (m/e): 366.0 (M−H).  
       Step 3: 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-fluoro-benzyl)benzamide  
       [0123]     To a solution of 3-chloroaniline (20 mg) in DMF (1.5 mL) was added N-ethyldiiopropylamine (137 μL), [(2,6-Dichloro-benzyl)-(4-methoxy-benzoyl)-amino]-acetic acid (58 mg) and HATU (Across 365312) and the reaction mixture was stirred at room temperature over night. Then water was added until the precipitation occurs and the precipitate was isolated by filtration and washed with a mixture of water and ethanol (2:1) to yield the title compound (35 mg). MS (m/e): 479.2 (M+H + ).  
         [0000]     Procedure D  
         [0124]     This procedure was used to prepare Example 1  
       4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2,6-difluoro-benzyl)-benzamide  
       [0125]     To N1-(3-chlorophenyl)-2-chloroacetamide (61 mg) in DMF (1 mL) was added 2,6-difluorobenzylamine (38 mg) and triethylamine (0.1 mL) and 4-chlorobenzoyl chloride (58 mg) the reaction mixture was stirred at room temperature for 15 min and then purified by HPLC preparative to yield the title compound (55 mg). MS (m/e): 447.0 (M−H).  
         [0000]     Procedure E  
         [0126]     This procedure was used to prepare Example 97  
       N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-isobutyl-4-methoxy-benzamide  
     Step 1: N-(3,4-Dichloro-phenyl)-2-isobutylamino-acetamide hydrobromide  
       [0127]     To a solution of 2-bromo-N-(3,4-dichloro-phenyl)-acetamide (0.1 g) in dichloromethane (80 mL) at 0° C. was slowly added of isobutylamine (52 mg) in dichloromethane. The reaction mixture was allowed to warm up to room temperature and then stirred for another 24 hours. Then the salt was filtered off and the filtrate was concentrated in vacuo. The residue was then purified by column chromatography to yield the title compound as a white solid (0.1 g). MS (m/e): 357.1 (M+H + ).  
       Step 2: N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-isobutyl-4-methoxy-benzamide  
       [0128]     To a solution of N-(3,4-dichloro-phenyl)-2-isobutylamino-acetamide hydrobromide (0.090 g) in THF were slowly added a solution of triethylamine (0.064 mg) in THF (5 mL) and a solution of 4-methoxybenzoyl chloride (47 mg) in THF (5 mL) and the reaction mixture was stirred at room temperature for 24 hours. Then water was added to the reaction mixture and the precipitate was isolated by filtration and then purified by column chromatography to yield the title compound (78 mg). MS (m/e): 409.2 (M−H, 100%).  
         [0129]     The following starting materials for preparation of compounds of formula I have been used:  
                                                     TABLE 1                               Amine/   Chloro amide or           Exp   Procedure   Aniline   bromo amide   Acyl chloride                                1   D   2,6-   N1-(3-Chlorophenyl)-   4-Chlorobenzoyl               Difluorobenzylamine   2-chloroacetamide   chloride       2   D   3,4-   N1-(3-Chlorophenyl)-   4-Chlorobenzoyl               Difluorobenzylamine   2-chloroacetamide   chloride       3   D   3,5-   N1-(3-Chlorophenyl)-   4-Chlorobenzoyl               Difluorobenzylamine   2-chloroacetamide   chloride       4   D   2,3-   N1-(3-Chlorophenyl)-   4-Chlorobenzoyl               Difluorobenzylamine   2-chloroacetamide   chloride       5   D   2,4-   N1-(3-Chlorophenyl)-   4-Chlorobenzoyl               Difluorobenzylamine   2-chloroacetamide   chloride       6   D   2,5-   N1-(3-Chlorophenyl)-   4-Chlorobenzoyl               Difluorobenzylamine   2-chloroacetamide   chloride       7   D   4-Fluorobenzylamine   N1-(3-Chlorophenyl)-   4-Chlorobenzoyl                   2-chloroacetamide   chloride       8   D   3-Fluorobenzylamine   N1-(3-Chlorophenyl)-   4-Chlorobenzoyl                   2-chloroacetamide   chloride       9   D   2-Fluorobenzylamine   N1-(3-Chlorophenyl)-   4-Chlorobenzoyl                   2-chloroacetamide   chloride       10   D   Thiophen-3-yl-   N1-(3-Chlorophenyl)-   4-Methoxybenzoyl               methylamine   2-chloroacetamide   chloride       11   D   2,6-   N1-(3-Chlorophenyl)-   4-Methoxybenzoyl               Difluorobenzylamine   2-chloroacetamide   chloride       12   D   3,5-   N1-(3-Chlorophenyl)-   4-Methoxybenzoyl               Dichlorobenzylamine   2-chloroacetamide   chloride       13   D   2,6-   N1-(3-Chlorophenyl)-   4-Methoxybenzoyl               Dichlorobenzylamine   2-chloroacetamide   chloride       14   D   3-Chlorobenzylamine   N1-(3-Chlorophenyl)-   4-Methoxybenzoyl                   2-chloroacetamide   chloride       15   D   Benzylamine   N1-(3-Chlorophenyl)-   4-Fluorobenzoyl chloride                   2-chloroacetamide       16   D   benzylamine   N1-(3-Chlorophenyl)-   4-Chlorobenzoyl                   2-chloroacetamide   chloride       17   D   Thiophen-2-yl-   N1-(3-Chlorophenyl)-   4-Chlorobenzoyl               methylamine   2-chloroacetamide   chloride       18   D   Thiophen-2-yl-   N1-(3-Chlorophenyl)-   4-Methoxybenzoyl               methylamine   2-chloroacetamide   chloride       19   C   (2,6-Dichloro-   3-Chloro aniline   4-Methoxybenzoyl               benzylamino)-acetic       chloride               acid ethyl ester       20   D   3-Fluoroaniline   2-Bromo-N-(3,4-   4-Methoxybenzoyl                   dichloro-phenyl)-   chloride                   acetamide       21   D   2-Fluoroaniline   2-Bromo-N-(3,4-   4-Methoxybenzoyl                   dichloro-phenyl)-   chloride                   acetamide       22   B   Aniline   2-Bromo-N-(3,4-   4-Methoxybenzoyl                   dichloro-phenyl)-   chloride                   acetamide       23   C   Phenylamino-acetic   3-Chloro-2-   4-Methoxybenzoyl               acid ethyl ester   Fluoroaniline   chloride       24   C   Phenylamino-acetic   5-Amino-2,2-difluoro-   4-Methoxybenzoyl               acid ethyl ester   1,3-benzodioxole   chloride       25   C   Phenylamino-acetic   3-   4-Methoxybenzoyl               acid ethyl ester   (Trifluoromethoxy)aniline   chloride       26   C   Phenylamino-acetic   m-Toluidine   4-Methoxybenzoyl               acid ethyl ester       chloride       27   C   Phenylamino-acetic   3-   4-Methoxybenzoyl               acid ethyl ester   Aminobenzotrifluoride   chloride       28   C   Phenylamino-acetic   3-Chloroaniline   4-Methoxybenzoyl               acid ethyl ester       chloride       29   C   Phenylamino-acetic   3-methoxybenzonitrile   4-Methoxybenzoyl               acid ethyl ester       chloride       30   B   Aniline   2-Bromo-N-(3,4-   3-trifluoromethylbenzoyl                   dichloro-phenyl)-   chloride                   acetamide       31   B   Aniline   2-Bromo-N-(3,4-   3-cyanobenzoyl chloride                   dichloro-phenyl)-                   acetamide       32   B   Aniline   2-Bromo-N-(3,4-   2-Methoxybenzoyl                   dichloro-phenyl)-   chloride                   acetamide       33   B   Aniline   2-Bromo-N-(3,4-   3-Methylbenzoyl                   dichloro-phenyl)-   chloride                   acetamide       34   A   Aniline   2-Bromo-N-(4-methyl-   6-trifluoromethyl-                   phenyl)-acetamide   nicotynoyl chloride       35   B   Aniline   2-Bromo-N-(3,4-   3-Chlorobenzoyl                   dichloro-phenyl)-   chloride                   acetamide       36   A   Aniline   2-Bromo-N-(4-fluoro-   6-trifluoromethyl-                   phenyl)-acetamide   nicotynoyl chloride       37   B   Aniline   2-Bromo-N-(3,4-   6-Trifluoromethyl-                   dichloro-phenyl)-   nicotinoyl chloride                   acetamide       38   B   Aniline   2-Bromo-N-(3,4-   4-cyanobenzoyl chloride                   dichloro-phenyl)-                   acetamide       39   B   Aniline   2-Bromo-N-(3,4-   2-Fluorobenzoyl chloride                   dichloro-phenyl)-                   acetamide       40   B   Aniline   2-Bromo-N-(3,4-   3-fluorobenzoyl chloride                   dichloro-phenyl)-                   acetamide       41   B   Aniline   2-Bromo-N-(3,4-   4-methoxybenzoyl                   dichloro-phenyl)-   chloride                   acetamide       42   B   Aniline   2-Bromo-N-(3,4-   4-fluorobenzoyl chloride                   dichloro-phenyl)-                   acetamide       43   D   2-Chloro-benzylamine   2-Chloro-N-(3-   3-Methylbenzoyl                   trifluoromethyl-   chloride                   phenyl)-acetamide       44   D   2-Chloro-benzylamine   2-Chloro-N-(3-   6-trifluoromethyl-                   trifluoromethyl-   nicotynoyl chloride                   phenyl)-acetamide       45   D   3,5-difluoro-   2-Chloro-N-(3-   3-Chlorobenzoyl               benzylamine   trifluoromethyl-   chloride                   phenyl)-acetamide       46   D   3,5-difluoro-   2-Chloro-N-(3-   6-trifluoromethyl-               benzylamine   trifluoromethyl-   nicotynoyl chloride                   phenyl)-acetamide       47   D   3,5-difluoro-   2-Chloro-N-(3-   6-Trifluoromethyl-               benzylamine   trifluoromethyl-   nicotinoyl chloride                   phenyl)-acetamide       48   D   3,5-difluoro-   2-Chloro-N-(3-   4-cyanobenzoyl chloride               benzylamine   trifluoromethyl-                   phenyl)-acetamide       49   D   3,5-difluoro-   2-Chloro-N-(3-   2-Fluorobenzoyl chloride               benzylamine   trifluoromethyl-                   phenyl)-acetamide       50   D   3,5-difluoro-   2-Chloro-N-(3-   4-cyanobenzoyl chloride               benzylamine   trifluoromethyl-                   phenyl)-acetamide       51   D   2-Chloro-benzylamine   2-Chloro-N-(3-   Benzo[b]thiophene-2-                   trifluoromethyl-   carbonyl chloride                   phenyl)-acetamide       52   D   2-Chloro-benzylamine   2-Chloro-N-(3-   3-fluorobenzoyl chloride                   trifluoromethyl-                   phenyl)-acetamide       53   D   2-Chloro-benzylamine   2-Chloro-N-(3-   4-Chlorobenzoyl                   trifluoromethyl-   chloride                   phenyl)-acetamide       54   D   2-Chloro-benzylamine   2-Chloro-N-(3-   4-                   trifluoromethyl-   trifluoromethoxybenzoyl                   phenyl)-acetamide   chloride       55   D   2-Chloro-benzylamine   2-Chloro-N-(3-   4-Fluorobenzoyl chloride                   trifluoromethyl-                   phenyl)-acetamide       56   D   3,5-difluoro-   2-Chloro-N-(3-   6-trifluoromethyl benzyl               benzylamine   trifluoromethyl-   chloride                   phenyl)-acetamide       57   D   2-Chloro-benzylamine   2-Chloro-N-(3-fluoro-   Benzo[b]thiophene-2-                   phenyl)-acetamide   carbonyl chloride       58   D   2-Chloro-benzylamine   2-Chloro-N-(3-fluoro-   3-fluorobenzoyl chloride                   phenyl)-acetamide       59   D   2-Chloro-benzylamine   2-Chloro-N-(3-fluoro-   3-Methylbenzoyl                   phenyl)-acetamide   chloride       60   D   2-Chloro-benzylamine   2-Chloro-N-(3-fluoro-   4-                   phenyl)-acetamide   trifluoromethoxybenzoyl                       chloride       61   D   2-Chloro-benzylamine   2-Chloro-N-(3-fluoro-   4-Fluorobenzoyl chloride                   phenyl)-acetamide       62   D   2-Chloro-benzylamine   2-Chloro-N-(3-fluoro-   4-cyanobenzoyl chloride                   phenyl)-acetamide       63   D   3,5-difluoro-   2-Chloro-N-(3-fluoro-   Benzo[b]thiophene-2-               benzylamine   phenyl)-acetamide   carbonyl chloride       64   D   3,5-difluoro-   2-Chloro-N-(3-fluoro-   3-Methylbenzoyl               benzylamine   phenyl)-acetamide   chloride       65   D   3,5-difluoro-   2-Chloro-N-(3-fluoro-   4-               benzylamine   phenyl)-acetamide   trifluoromethoxybenzoyl                       chloride       66   D   3,4-difluoro-   2-Chloro-N-(3-fluoro-   Benzo[b]thiophene-2-               benzylamine   phenyl)-acetamide   carbonyl chloride       67   D   3,4-difluoro-   2-Chloro-N-(3-fluoro-   3-Methylbenzoyl               benzylamine   phenyl)-acetamide   chloride       68   D   3,4-difluoro-   2-Chloro-N-(3-fluoro-   4-               benzylamine   phenyl)-acetamide   trifluoromethoxybenzoyl                       chloride       69   D   2,6-difluoro-   2-Chloro-N-(3-   Benzo[b]thiophene-2-               benzylamine   Chloro,4-fluoro-   carbonyl chloride                   phenyl)-acetamide       70   D   2,6-difluoro-   2-Chloro-N-(3-   3-Methylbenzoyl               benzylamine   Chloro,4-fluoro-   chloride                   phenyl)-acetamide       71   D   2,6-difluoro-   2-Chloro-N-(3-   4-               benzylamine   Chloro,4-fluoro-   trifluoromethoxybenzoyl                   phenyl)-acetamide   chloride       72   D   2-Chloro-benzylamine   2-Chloro-N-(3-   Benzo[b]thiophene-2-                   Chloro,4-fluoro-   carbonyl chloride                   phenyl)-acetamide       73   D   2-Chloro-benzylamine   2-Chloro-N-(3-   3-fluorobenzoyl chloride                   Chloro,4-fluoro-                   phenyl)-acetamide       74   D   2-Chloro-benzylamine   2-Chloro-N-(3-   4-Chlrorobenzoyl                   Chloro,4-fluoro-   chloride                   phenyl)-acetamide       75   D   2-Chloro-benzylamine   2-Chloro-N-(3-   4-                   Chloro,4-fluoro-   trifluoromethoxybenzoyl                   phenyl)-acetamide   chloride       76   D   2-Chloro-benzylamine   2-Chloro-N-(3-   4-Fluorobenzoyl chloride                   Chloro,4-fluoro-                   phenyl)-acetamide       77   D   2-Chloro-benzylamine   2-Chloro-N-(3-   4-cyanobenzoyl chloride                   Chloro,4-fluoro-                   phenyl)-acetamide       78   D   2,6-difluoro-   2-Chloro-N-(3-   4-Fluorobenzoyl chloride               benzylamine   Chloro,4-fluoro-                   phenyl)-acetamide       79   D   2-Chloro-benzylamine   2-Chloro-N-(3-   6-trifluoromethyl benzyl                   Chloro,4-fluoro-   chloride                   phenyl)-acetamide       80   D   2,3-Difluoro-   2-Chloro-N-(3-   Benzo[b]thiophene-2-               benzylamine   Chloro,4-fluoro-   carbonyl chloride                   phenyl)-acetamide       81   D   2,3-Difluoro-   2-Chloro-N-(3-   3-fluorobenzoyl chloride               benzylamine   Chloro,4-fluoro-                   phenyl)-acetamide       82   D   2,3-Difluoro-   2-Chloro-N-(3-   4-Chlrorobenzoyl               benzylamine   Chloro,4-fluoro-   chloride                   phenyl)-acetamide       83   D   2,3-Difluoro-   2-Chloro-N-(3-   4-               benzylamine   Chloro,4-fluoro-   trifluoromethoxybenzoyl                   phenyl)-acetamide   chloride       84   D   2,3-Difluoro-   2-Chloro-N-(3-   4-Fluorobenzoyl chloride               benzylamine   Chloro,4-fluoro-                   phenyl)-acetamide       85   D   2,3-Difluoro-   2-Chloro-N-(3-   4-cyanobenzoyl chloride               benzylamine   Chloro,4-fluoro-                   phenyl)-acetamide       86   D   2,3-Difluoro-   2-Chloro-N-(3-   6-trifluoromethyl benzyl               benzylamine   Chloro,4-fluoro-   chloride                   phenyl)-acetamide       87   D   2,3-Difluoro-   2-Chloro-N-(3-   Benzo[b]thiophene-2-               benzylamine   Chloro,4-fluoro-   carbonyl chloride                   phenyl)-acetamide       88   D   2,6-difluoro-   2-Chloro-N-(3-   4-cyanobenzoyl chloride               benzylamine   Chloro,4-fluoro-                   phenyl)-acetamide       89   D   2,3-Difluoro-   2-Chloro-N-(3-   3-Methylbenzoyl               benzylamine   Chloro,4-fluoro-   chloride                   phenyl)-acetamide       90   D   3,5-difluoro-   2-Chloro-N-(3-   4-               benzylamine   Chloro,4-fluoro-   trifluoromethoxybenzoyl                   phenyl)-acetamide   chloride       91   D   3,5-difluoro-   2-Chloro-N-(3-   4-Fluorobenzoyl chloride               benzylamine   Chloro,4-fluoro-                   phenyl)-acetamide       92   D   3,5-difluoro-   2-Chloro-N-(3-   4-cyanobenzoyl chloride               benzylamine   Chloro,4-fluoro-                   phenyl)-acetamide       93   D   3,5-difluoro-   2-Chloro-N-(3-   6-trifluoromethyl benzyl               benzylamine   Chloro,4-fluoro-   chloride                   phenyl)-acetamide       94   D   3,4-Difluoro-   2-Chloro-N-(3-   Benzo[b]thiophene-2-               benzylamine   Chloro,4-fluoro-   carbonyl chloride                   phenyl)-acetamide       95   D   2,2-simethyl   2-Chloro-N-(3-Chloro   4-Chlrorobenzoyl               propylamine   phenyl)-acetamide   chloride       96   D   3,3-dimethyl   2-Chloro-N-(3-Chloro   4-Chlrorobenzoyl               butylamine   phenyl)-acetamide   chloride       97   E   iso butylamine   2-Bromo-N-(3,4-   4-Methoxybenzoyl                   dichloro phenyl)-   chloride                   acetamide       98   E   3-methyl butylamine   2-Bromo-N-(3,4-   4-Methoxybenzoyl                   dichloro phenyl)-   chloride                   acetamide       99   B   benzylamine   2-Bromo-N-(3,4-   4-Methoxybenzoyl                   dichloro phenyl)-   chloride                   acetamide       100   D   3-cyano-benzylamine   2-Chloro-N-(3-chloro-   4-Chlorobenzoyl                   phenyl)-acetamide   chloride       101   D   3-methoxy-   2-Chloro-N-(3-chloro-   4-Chlorobenzoyl               benzylamine   phenyl)-acetamide   chloride       102   D   2-methoxy-   2-Chloro-N-(3-chloro-   4-Chlorobenzoyl               benzylamine   phenyl)-acetamide   chloride       103   D   3-methyl-benzylamine   2-Chloro-N-(3-chloro-   4-Chlorobenzoyl                   phenyl)-acetamide   chloride       104   D   2-methyl-benzylamine   2-Chloro-N-(3-chloro-   4-Chlorobenzoyl                   phenyl)-acetamide   chloride       105   D   3-Chloro-benzylamine   2-Chloro-N-(3-chloro-   4-Chlorobenzoyl                   phenyl)-acetamide   chloride       106   D   2-Chloro-benzylamine   2-Chloro-N-(3-chloro-   4-Chlorobenzoyl                   phenyl)-acetamide   chloride       107   D   C-Furan-2-yl-   2-Chloro-N-(3-chloro-   4-Chlorobenzoyl               methylamine   phenyl)-acetamide   chloride       108   C   Phenylamino-acetic   2-Bromo-N-(3,4-   4-methoxy benzoyl               acid ethyl ester   dichloro phenyl)-   chloride                   acetamide       119   B   2-fluoro-benzylamine   3-Chloro aniline   6-Morpholin-4-yl-                       nicotinoyl chloride       120   B   2-fluoro-benzylamine   3-Chloro aniline   6-Chloro-nicotinoyl                       chloride       121   B   2-Fluoro-benzylamine   3-Chloro aniline   2-Chloro-isonicotinoyl                       chloride       122   B   2-Fluoro-benzylamine   3-Chloro aniline   2,6-Dichloro-                       isonicotinoyl chloride       123   A   C-Cyclohexyl-   2-Chloro-N-(3-chloro-   4-chlorobenzoyl chloride               methylamine   phenyl)-acetamide       124   A   C-Cyclohexyl-   2-Chloro-N-(3-chloro-   4-Chlorobenzoyl               methylamine   phenyl)-acetamide   chloride       125   A   C-Cyclohexyl-   2-Chloro-N-(3-chloro-   4-Fluorobenzoyl chloride               methylamine   phenyl)-acetamide       126   A   Cyclopentylamine   2,4-Dichloro-N-(3-   4-Methoxybenzoyl                   chloro-phenyl)-   chloride                   acetamide       127   A   Cyclopropylamine   2,4-Dichloro-N-(3-   4-Methoxybenzoyl                   chloro-phenyl)-   chloride                   acetamide       128   A   Cyclohexylamine   2,4-Dichloro-N-(3-   4-Methoxybenzoyl                   chloro-phenyl)-   chloride                   acetamide                  
 
         [0130]     The following compounds have been prepared in accordance with table 1:  
                                                                                   TABLE 2                                                                                  Procedure   R 1     R 2     R 3     R 4     X   IC 50     Exp                                                        D                                                               H                                 bond   0.052   1               D                                                               H                                 bond   0.265   2               D                                                               H                                 bond   0.184   3               D                                                               H                                 bond   0.074   4               D                                                               H                                 bond   0.16   5               D                                                               H                                 bond   0.165   6               D                                                               H                                 bond       7               D                                                               H                                 bond   0.128   8               D                                                               H                                 bond   0.074   9               D                                                               H                                 bond   0.285   10               D                                                               H                                 bond   0.1   11               D                                                               H                                 bond   0.243   12               D                                                               H                                 bond   0.122   13               D                                                               H                                 bond   0.024   14               D                                                               H                                 bond   0.312   15               D                                                               H                                 bond   0.156   16               D                                                               H                                 bond   0.077   17               D                                                               H                                 bond   0.257   18               C                                                               H                                 bond   0.164   19               D                                                               H                                 bond       20               D                                                               H                                 bond   0.315   21               B                                                               H                                 bond       22               C                                                               H                                 bond       23               C                                                               H                                 bond       24               C                                                               H                                 bond       25               C                                                               H                                 bond       26               C                                                               H                                 bond   0.148   27               C                                                               H                                 bond   0.267   28               C                                                               H                                 bond       29               B                                                               H                                 bond       30               B                                                               H                                 bond   0.35   31               B                                                               H                                 bond       32               B                                                               H                                 bond       33               A                                                               H                                 bond       34               B                                                               H                                 bond       35               A                                                               H                                 bond       36               B                                                               H                                 bond   0.154   37               B                                                               H                                 bond       38               B                                                               H                                 bond   0.291   39               B                                                               H                                 bond       40               B                                                               H                                 bond   0.276   41               B                                                               H                                 bond       42               D                                                               H                                 bond   0.339   43               D                                                               H                                 bond       44               D                                                               H                                 bond   0.298   45               D                                                               H                                 bond       46               D                                                               H                                 bond       47               D                                                               H                                 bond       48               D                                                               H                                 bond       49               D                                                               H                                 bond       50               D                                                               H                                 bond   0.06   51               D                                                               H                                 bond   0.153   52               D                                                               H                                 bond   0.241   53               D                                                               H                                 bond   0.196   54               D                                                               H                                 bond   0.097   55               D                                                               H                                 bond       56               D                                                               H                                 bond   0.088   57               D                                                               H                                 bond       58               D                                                               H                                 bond   0.166   59               D                                                               H                                 bond   0.107   60               D                                                               H                                 bond       61               D                                                               H                                 bond   0.357   62               D                                                               H                                 bond   0.07    63               D                                                               H                                 bond       64               D                                                               H                                 bond   0.278   65               D                                                               H                                 bond   0.167   66               D                                                               H                                 bond       67               D                                                               H                                 bond       68               D                                                               H                                 bond   0.09   69               D                                                               H                                 bond       70               D                                                               H                                 bond   0.107   71               D                                                               H                                 bond   0.205   72               D                                                               H                                 bond       73               D                                                               H                                 bond   0.142   74               D                                                               H                                 bond   0.259   75               D                                                               H                                 bond   0.159   76               D                                                               H                                 bond   0.182   77               D                                                               H                                 bond   0.282   78               D                                                               H                                 bond       79               D                                                               H                                 bond   0.066   80               D                                                               H                                 bond       81               D                                                               H                                 bond   0.108   82               D                                                               H                                 bond   0.078   83               D                                                               H                                 bond   0.178   84               D                                                               H                                 bond   0.123   85               D                                                               H                                 bond       86               D                                                               H                                 bond   0.036   87               D                                                               H                                 bond   0.199   88               D                                                               H                                 bond   0.306   89               D                                                               H                                 bond   0.288   90               D                                                               H                                 bond       91               D                                                               H                                 bond       92               D                                                               H                                 bond       93               D                                                               H                                 bond       94               D                                                               H                                 bond       95               D                                                               H                                 bond   0.359   96               E                                                               H                                 bond       97               E                                                               H                                 bond       98               B                                                               H                                 bond       99               D                                                               H                                 bond   0.192   100               D                                                               H                                 bond       101               D                                                               H                                 bond   0.06   102               D                                                               H                                 bond   0.142   103               D                                                               H                                 bond   0.209   104               D                                                               H                                 bond   0.021   105               D                                                               H                                 bond   0.025   106               D                                                               H                                 bond   0.199   107               C                                                               H                                 bond   0.182   108               C                                                               H                                 bond       109               C                                                               H                                 bond   0.369   110               C                                                               H                                 bond       111               C                                                               H                                 bond       112               B                                                               H                                 bond   0.15   113               B                                                               H                                 bond   0.091   114               B                                                               H                                 bond       115               B                                                               H                                 bond   0.191   116               B                                                               H                                 bond   0.21   117               B                                                               H                                 OCH 2     0.259   118               B                                                               H                                 bond   0.355   119               B                                                               H                                 bond   0.182   120               B                                                               H                                 bond       121               B                                                               H                                 bond       122               A                                                               CH 3                                   bond       123               A                                                               H                                 bond       124               A                                                               H                                 bond       125               A                                                               H                                 bond   0.357   126               A                                                               H                                 bond       127               A                                                               H                                 bond       128                  
 
         [0131]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                   
               
               
                   
                   
                 MS 
                 MS 
                   
               
               
                 Compound name 
                 MW 
                 result 
                 mode 
                 Example 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 449.28 
                 447.0 
                 neg 
                 1 
               
               
                 N-(2,6-difluoro-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 449.28 
                 447.0 
                 neg 
                 2 
               
               
                 N-(3,4-difluoro-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 449.28 
                 447.0 
                 neg 
                 3 
               
               
                 N-(3,5-difluoro-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 449.28 
                 449.2 
                 pos 
                 4 
               
               
                 N-(2,3-difluoro-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 449.28 
                 449.2 
                 pos 
                 5 
               
               
                 N-(2,4-difluoro-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 449.28 
                 449.2 
                 pos 
                 6 
               
               
                 N-(2,5-difluoro-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 431.29 
                 431.4 
                 pos 
                 7 
               
               
                 N-(4-fluoro-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 431.29 
                 431.4 
                 pos 
                 8 
               
               
                 N-(3-fluoro-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 431.29 
                 431.4 
                 pos 
                 9 
               
               
                 N-(2-fluoro-benzyl)-benzamide 
               
               
                 N-[(3-Chloro-phenylcarbamoyl)-methyl]-4- 
                 414.9 
                 415.3 
                 pos 
                 10 
               
               
                 methoxy-N-thiophen-3-ylmethyl-benzamide 
               
               
                 N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2,6- 
                 444.9 
                 443.2 
                 neg 
                 11 
               
               
                 difluoro-benzyl)-4-methoxy-benzamide 
               
               
                 N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(3,5- 
                 477.8 
                 477.1 
                 pos 
                 12 
               
               
                 dichloro-benzyl)-4-methoxy-benzamide 
               
               
                 N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2,5- 
                 477.8 
                 479.2 
                 pos 
                 13 
               
               
                 dichloro-benzyl)-4-methoxy-benzamide 
               
               
                 N-(3-Chloro-benzyl)-N-[(3-chloro- 
                 443.3 
                 443.3 
                 pos 
                 14 
               
               
                 phenylcarbamoyl)-methyl]-4-methoxy-benzamide 
               
               
                 N-Benzyl-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 496.8 
                 497.1 
                 pos 
                 15 
               
               
                 4-fluoro-benzamide 
               
               
                 N-Benzyl-4-chloro-N-[(3-chloro-phenylcarbamoyl)- 
                 413.3 
                 413.2 
                 pos 
                 16 
               
               
                 methyl]-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 419.3 
                 419.1 
                 pos 
                 17 
               
               
                 N-thiophen-2-ylmethyl-benzamide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4- 
                 449.4 
                 449.1 
                 pos 
                 18 
               
               
                 methoxy-N-thiophen-2-ylmethyl-benzamide 
               
               
                 N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2,6- 
                 477.8 
                 479.2 
                 pos 
                 19 
               
               
                 dichloro-benzyl)-4-methoxy-benzamide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-(3- 
                 447.3 
                 447.1 
                 pos 
                 20 
               
               
                 fluoro-phenyl)-4-methoxy-benzamide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-(2- 
                 447.3 
                 447.1 
                 pos 
                 21 
               
               
                 fluoro-phenyl)-4-methoxy-benzamide 
               
               
                 Pentanoic acid [(3,4-dichloro-phenylcarbamoyl)- 
                 379.3 
                 379.3 
                 pos 
                 22 
               
               
                 methyl]-phenyl-amide 
               
               
                 N-[(3-Chloro-2-fluoro-phenylcarbamoyl)-methyl]- 
                 412.8 
                 413.4 
                 pos 
                 23 
               
               
                 4-methoxy-N-phenyl-benzamide 
               
               
                 N-[(2,2-Difluoro-benzo[1,3]dioxol-5-ylcarbamoyl)- 
                 440.4 
                 441.0 
                 pos 
                 24 
               
               
                 methyl]-4-methoxy-N-phenyl-benzamide 
               
               
                 4-Methoxy-N-phenyl-N-[(3-trifluoromethoxy- 
                 444.4 
                 445.1 
                 pos 
                 25 
               
               
                 phenylcarbamoyl)-methyl]-benzamide 
               
               
                 4-Methoxy-N-phenyl-N-(m-tolylcarbamoyl- 
                 374.4 
                 375.1 
                 pos 
                 26 
               
               
                 methyl)-benzamide 
               
               
                 4-Methoxy-N-phenyl-N-[(3-trifluoromethyl- 
                 428.4 
                 429.0 
                 pos 
                 27 
               
               
                 phenylcarbamoyl)-methyl]-benzamide 
               
               
                 N-[(3-Chloro-phenylcarbamoyl)-methyl]-4- 
                 394.9 
                 395.0 
                 pos 
                 28 
               
               
                 methoxy-N-phenyl-benzamide 
               
               
                 4-Methoxy-N-[(3-methoxy-phenylcarbamoyl)- 
                 390.4 
                 391.3 
                 pos 
                 29 
               
               
                 methyl]-N-phenyl-benzamide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N- 
                 467.3 
                 467.0 
                 pos 
                 30 
               
               
                 phenyl-3-trifluoromethyl-benzamide 
               
               
                 3-Cyano-N-[(3,4-dichloro-phenylcarbamoyl)- 
                 424.3 
                 467.0 
                 pos 
                 31 
               
               
                 methyl]-N-phenyl-benzamide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-2- 
                 429.3 
                 429.2 
                 pos 
                 32 
               
               
                 methoxy-N-phenyl-benzamide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-3- 
                 413.3 
                 413.2 
                 pos 
                 33 
               
               
                 methyl-N-phenyl-benzamide 
               
               
                 N-Phenyl-N-(p-tolylcarbamoyl-methyl)-6- 
                 413.4 
                 414.4 
                 pos 
                 34 
               
               
                 trifluoromethyl-nicotinamide 
               
               
                 3-Chloro-N-[(3,4-dichloro-phenylcarbamoyl)- 
                 433.7 
                 433.0 
                 pos 
                 35 
               
               
                 methyl]-N-phenyl-benzamide 
               
               
                 N-[(4-Fluoro-phenylcarbamoyl)-methyl]-N-phenyl- 
                 417.4 
                 418.0 
                 pos 
                 36 
               
               
                 6-trifluoromethyl-nicotinamide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N- 
                 468.3 
                 468.1 
                 pos 
                 37 
               
               
                 phenyl-6-trifluoromethyl-nicotinamide 
               
               
                 4-Cyano-N-[(3,4-dichloro-phenylcarbamoyl)- 
                 424.3 
                 424.0 
                 pos 
                 38 
               
               
                 methyl]-N-phenyl-benzamide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-2- 
                 417.3 
                 417.3 
                 pos 
                 39 
               
               
                 fluoro-N-phenyl-benzamide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-3- 
                 417.3 
                 417.1 
                 pos 
                 40 
               
               
                 fluoro-N-phenyl-benzamide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4- 
                 429.3 
                 429.3 
                 pos 
                 41 
               
               
                 methoxy-N-phenyl-benzamide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4- 
                 417.3 
                 417.1 
                 pos 
                 42 
               
               
                 fluoro-N-phenyl-benzamide 
               
               
                 N-(2-Chloro-benzyl)-4-cyano-N-[(3- 
                 471.9 
                 472.2 
                 pos 
                 43 
               
               
                 trifluoromethyl-phenylcarbamoyl)-methyl]- 
               
               
                 benzamide 
               
               
                 N-(2-Chloro-benzyl)-3-trifluoromethyl-N-[(3- 
                 514.9 
                 515.2 
                 pos 
                 44 
               
               
                 trifluoromethyl-phenylcarbamoyl)-methyl]- 
               
               
                 benzamide 
               
               
                 Benzo[b]thiophene-2-carboxylic acid (3,5-difluoro- 
                 504.5 
                 506.2 
                 pos 
                 45 
               
               
                 benzyl)-[(3-trifluoromethyl-phenylcarbamoyl)- 
               
               
                 methyl]-amide 
               
               
                 N-(3,5-Difluoro-benzyl)-3-fluoro-N-[(3- 
                 466.4 
                 467.2 
                 pos 
                 46 
               
               
                 trifluoromethyl-phenylcarbamoyl)-methyl]- 
               
               
                 benzamide 
               
               
                 4-Chloro-N-(3,5-difluoro-benzyl)-N-[(3- 
                 482.8 
                 483.4 
                 pos 
                 47 
               
               
                 trifluoromethyl-phenylcarbamoyl)-methyl]- 
               
               
                 benzamide 
               
               
                 N-(3,5-Difluoro-benzyl)-4-trifluoromethoxy-N-[(3- 
                 432.4 
                 433.2 
                 pos 
                 48 
               
               
                 trifluoromethyl-phenylcarbamoyl)-methyl]- 
               
               
                 benzamide 
               
               
                 N-(3,5-Difluoro-benzyl)-4-fluoro-N-[(3- 
                 466.4 
                 467.2 
                 pos 
                 49 
               
               
                 trifluoromethyl-phenylcarbamoyl)-methyl]- 
               
               
                 benzamide 
               
               
                 4-Cyano-N-(3,5-difluoro-benzyl)-N-[(3- 
                 473.4 
                 474.2 
                 pos 
                 50 
               
               
                 trifluoromethyl-phenylcarbamoyl)-methyl]- 
               
               
                 benzamide 
               
               
                 Benzo[b]thiophene-2-carboxylic acid (2-chloro- 
                 502.9 
                 503.1 
                 pos 
                 51 
               
               
                 benzyl)-[(3-trifluoromethyl-phenylcarbamoyl)- 
               
               
                 methyl]-amide 
               
               
                 N-(2-Chloro-benzyl)-3-fluoro-N-[(3- 
                 464.9 
                 465.3 
                 pos 
                 52 
               
               
                 trifluoromethyl-phenylcarbamoyl)-methyl]- 
               
               
                 benzamide 
               
               
                 4-Chloro-N-(2-chloro-benzyl)-N-[(3- 
                 481.3 
                 481.2 
                 pos 
                 53 
               
               
                 trifluoromethyl-phenylcarbamoyl)-methyl]- 
               
               
                 benzamide 
               
               
                 #N!-(2-Chloro-benzyl)-4-trifluoromethoxy-#N!-[(3- 
                 530.9 
                 531.1 
                 pos 
                 54 
               
               
                 trifluoromethyl-phenylcarbamoyl)-methyl]- 
               
               
                 benzamide 
               
               
                 N-(2-Chloro-benzyl)-4-fluoro-N-[(3- 
                 464.9 
                 465.3 
                 pos 
                 55 
               
               
                 trifluoromethyl-phenylcarbamoyl)-methyl]- 
               
               
                 benzamide 
               
               
                 N-(3,5-Difluoro-benzyl)-3-trifluoromethyl-N-[(3- 
                 516.4 
                 517.2 
                 pos 
                 56 
               
               
                 trifluoromethyl-phenylcarbamoyl)-methyl]- 
               
               
                 benzamide 
               
               
                 Benzo[b]thiophene-2-carboxylic acid (2-chloro- 
                 452.9 
                 453.0 
                 pos 
                 57 
               
               
                 benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide 
               
               
                 N-(2-Chloro-benzyl)-3-fluoro-N-[(3-fluoro- 
                 414.8 
                 415.3 
                 pos 
                 58 
               
               
                 phenylcarbamoyl)-methyl]-benzamide 
               
               
                 4-Chloro-N-(2-chloro-benzyl)-N-[(3-fluoro- 
                 431.3 
                 431.1 
                 pos 
                 59 
               
               
                 phenylcarbamoyl)-methyl]-benzamide 
               
               
                 N-(2-Chloro-benzyl)-N-[(3-fluoro- 
                 480.8 
                 481.1 
                 pos 
                 60 
               
               
                 phenylcarbamoyl)-methyl]-4-trifluoromethoxy- 
               
               
                 benzamide 
               
               
                 N-(2-Chloro-benzyl)-4-fluoro-N-[(3-fluoro- 
                 414.8 
                 415.2 
                 pos 
                 61 
               
               
                 phenylcarbamoyl)-methyl]-benzamide 
               
               
                 N-(2-Chloro-benzyl)-4-cyano-N-[(3-fluoro- 
                 421.9 
                 422.1 
                 pos 
                 62 
               
               
                 phenylcarbamoyl)-methyl]-benzamide 
               
               
                 Benzo[b]thiophene-2-carboxylic acid (3,5-difluoro- 
                 454.5 
                 455.2 
                 pos 
                 63 
               
               
                 benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide 
               
               
                 4-Chloro-N-(3,5-difluoro-benzyl)-N-[(3-fluoro- 
                 432.8 
                 433.2 
                 pos 
                 64 
               
               
                 phenylcarbamoyl)-methyl]-benzamide 
               
               
                 N-(3,5-Difluoro-benzyl)-N-[(3-fluoro- 
                 482.4 
                 483.1 
                 pos 
                 65 
               
               
                 phenylcarbamoyl)-methyl]-4-trifluoromethoxy- 
               
               
                 benzamide 
               
               
                 Benzo[b]thiophene-2-carboxylic acid (3,4-difluoro- 
                 454.5 
                 455.2 
                 pos 
                 66 
               
               
                 benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide 
               
               
                 4-Chloro-N-(3,4-difluoro-benzyl)-N-[(3-fluoro- 
                 432.8 
                 433.2 
                 pos 
                 67 
               
               
                 phenylcarbamoyl)-methyl]-benzamide 
               
               
                 N-(3,4-Difluoro-benzyl)-N-[(3-fluoro- 
                 482.4 
                 483.4 
                 pos 
                 68 
               
               
                 phenylcarbamoyl)-methyl]-4-trifluoromethoxy- 
               
               
                 benzamide 
               
               
                 Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4- 
                 488.9 
                 489.1 
                 pos 
                 69 
               
               
                 fluoro-phenylcarbamoyl)-methyl]-(2,6-difluoro- 
               
               
                 benzyl)-amide 
               
               
                 4-Chloro-N-[(3-chloro-4-fluoro-phenylcarbamoyl)- 
                 467.3 
                 467.1 
                 pos 
                 70 
               
               
                 methyl]-N-(2,6-difluoro-benzyl)-benzamide 
               
               
                 N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 
                 518.8 
                 517.1 
                 pos 
                 71 
               
               
                 N-(2,6-difluoro-benzyl)-4-trifluoromethoxy- 
               
               
                 benzamide 
               
               
                 Benzo[b]thiophene-2-carboxylic acid (2-chloro- 
                 487.4 
                 487.2 
                 pos 
                 72 
               
               
                 benzyl)-[(3-chloro-4-fluoro-phenylcarbamoyl)- 
               
               
                 methyl]-amide 
               
               
                 N!-(2-Chloro-benzyl)-N!-[(3-chloro-4-fluoro- 
                 449.3 
                 449.1 
                 pos 
                 73 
               
               
                 phenylcarbamoyl)-methyl]-3-fluoro-benzamide 
               
               
                 4-Chloro-N-(2-chloro-benzyl)-N-[(3-chloro-4- 
                 465.7 
                 465.2 
                 pos 
                 74 
               
               
                 fluoro-phenylcarbamoyl)-methyl]-benzamide 
               
               
                 N-(2-Chloro-benzyl)-N-[(3-chloro-4-fluoro- 
                 515.3 
                 512.3 
                 pos 
                 75 
               
               
                 phenylcarbamoyl)-methyl]-4-trifluoromethoxy- 
               
               
                 benzamide 
               
               
                 N-(2-Chloro-benzyl)-N-[(3-chloro-4-fluoro- 
                 449.3 
                 449.1 
                 pos 
                 76 
               
               
                 phenylcarbamoyl)-methyl]-4-fluoro-benzamide 
               
               
                 N-(2-Chloro-benzyl)-N-[(3-chloro-4-fluoro- 
                 456.3 
                 456.3 
                 pos 
                 77 
               
               
                 phenylcarbamoyl)-methyl]-4-cyano-benzamide 
               
               
                 N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 
                 450.8 
                 451.1 
                 pos 
                 78 
               
               
                 N-(2,6-difluoro-benzyl)-4-fluoro-benzamide 
               
               
                 N-(2-Chloro-benzyl)-N-[(3-chloro-4-fluoro- 
                 499.3 
                 499.2 
                 pos 
                 79 
               
               
                 phenylcarbamoyl)-methyl]-3-trifluoromethyl- 
               
               
                 benzamide 
               
               
                 Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4- 
                 488.9 
                 489.2 
                 pos 
                 80 
               
               
                 fluoro-phenylcarbamoyl)-methyl]-(2,3-difluoro- 
               
               
                 benzyl)-amide 
               
               
                 N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 
                 450.8 
                 451.1 
                 pos 
                 81 
               
               
                 N-(2,3-difluoro-benzyl)-3-fluoro-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-4-fluoro-phenylcarbamoyl)- 
                 467.3 
                 467.2 
                 pos 
                 82 
               
               
                 methyl]-N-(2,3-difluoro-benzyl)-benzamide 
               
               
                 N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 
                 516.8 
                 517.1 
                 pos 
                 83 
               
               
                 N-(2,3-difluoro-benzyl)-4-trifluoromethoxy- 
               
               
                 benzamide 
               
               
                 N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 
                 450.8 
                 451.1 
                 pos 
                 84 
               
               
                 N-(2,3-difluoro-benzyl)-4-fluoro-benzamide 
               
               
                 N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 
                 457.8 
                 458.3 
                 pos 
                 85 
               
               
                 4-cyano-N-(2,3-difluoro-benzyl)-benzamide 
               
               
                 N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 
                 500.8 
                 501.1 
                 pos 
                 86 
               
               
                 N-(2,3-difluoro-benzyl)-3-trifluoromethyl- 
               
               
                 benzamide 
               
               
                 Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4- 
                 488.9 
                 499.1 
                 pos 
                 87 
               
               
                 fluoro-phenylcarbamoyl)-methyl]-(3,5-difluoro- 
               
               
                 benzyl)-amide 
               
               
                 N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 
                 457.8 
                 458.3 
                 pos 
                 88 
               
               
                 4-cyano-N-(2,6-difluoro-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-4-fluoro-phenylcarbamoyl)- 
                 467.3 
                 467.4 
                 pos 
                 89 
               
               
                 methyl]-N-(3,5-difluoro-benzyl)-benzamide 
               
               
                 N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 
                 516.8 
                 517.1 
                 pos 
                 90 
               
               
                 N-(3,5-difluoro-benzyl)-4-trifluoromethoxy- 
               
               
                 benzamide 
               
               
                 N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 
                 450.8 
                 451.1 
                 pos 
                 91 
               
               
                 N-(3,5-difluoro-benzyl)-4-fluoro-benzamide 
               
               
                 N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 
                 457.8 
                 458.3 
                 pos 
                 92 
               
               
                 4-cyano-N-(3,5-difluoro-benzyl)-benzamide 
               
               
                 N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 
                 500.8 
                 501.1 
                 pos 
                 93 
               
               
                 N-(3,5-difluoro-benzyl)-3-trifluoromethyl- 
               
               
                 benzamide 
               
               
                 Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4- 
                 488.9 
                 489.1 
                 pos 
                 94 
               
               
                 fluoro-phenylcarbamoyl)-methyl]-(3,4-difluoro- 
               
               
                 benzyl)-amide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 393.3 
                 393.1 
                 neg 
                 95 
               
               
                 N-(2,2-dimethyl-propyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 407.3 
                 408.3 
                 neg 
                 96 
               
               
                 N-(3,3-dimethyl-butyl)-benzamide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N- 
                 409.3 
                 409.2 
                 neg 
                 97 
               
               
                 isobutyl-4-methoxy-benzamide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4- 
                 423.3 
                 421.0 
                 neg 
                 98 
               
               
                 methoxy-N-(3-methyl-butyl)-benzamide 
               
               
                 N-Benzyl-N-[(3,4-dichloro-phenylcarbamoyl)- 
                 443.3 
                 441.2 
                 neg 
                 99 
               
               
                 methyl]-4-methoxy-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 438.3 
                 436.0 
                 neg 
                 100 
               
               
                 N-(3-cyano-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 443.3 
                 440.9 
                 neg 
                 101 
               
               
                 N-(3-methoxy-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 443.3 
                 440.9 
                 neg 
                 102 
               
               
                 N-(2-methoxy-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 427.3 
                 446.8 
                 neg 
                 103 
               
               
                 N-(3-methyl-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 427.3 
                 424.9 
                 neg 
                 104 
               
               
                 N-(2-methyl-benzyl)-benzamide 
               
               
                 4-Chloro-N-(3-chloro-benzyl)-N-[(3-chloro- 
                 447.8 
                 446.8 
                 neg 
                 105 
               
               
                 phenylcarbamoyl)-methyl]-benzamide 
               
               
                 4-Chloro-N-(2-chloro-benzyl)-N-[(3-chloro- 
                 447.8 
                 446.8 
                 neg 
                 106 
               
               
                 phenylcarbamoyl)-methyl]-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 403.3 
                 401.0 
                 neg 
                 107 
               
               
                 N-furan-2-ylmethyl-benzamide 
               
               
                 N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]- 
                 412.9 
                 413.0 
                 pos 
                 108 
               
               
                 4-methoxy-N-phenyl-benzamide 
               
               
                 N-[(5-Chloro-2-methyl-phenylcarbamoyl)-methyl]- 
                 408.9 
                 409.2 
                 pos 
                 109 
               
               
                 4-methoxy-N-phenyl-benzamide 
               
               
                 N-[(3-Chloro-4-methyl-phenylcarbamoyl)-methyl]- 
                 408.9 
                 409.2 
                 pos 
                 110 
               
               
                 4-methoxy-N-phenyl-benzamide 
               
               
                 N-[(3,5-Dichloro-phenylcarbamoyl)-methyl]-4- 
                 429.3 
                 429.3 
                 pos 
                 111 
               
               
                 methoxy-N-phenyl-benzamide 
               
               
                 N-[(4-Bromo-3-chloro-phenylcarbamoyl)-methyl]- 
                 473.8 
                 472.9 
                 pos 
                 112 
               
               
                 4-methoxy-N-phenyl-benzamide 
               
               
                 Benzo[b]thiophene-2-carboxylic acid [(3,4-dichloro- 
                 455.4 
                 454.9 
                 pos 
                 113 
               
               
                 phenylcarbamoyl)-methyl]-phenyl-amide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N- 
                 483.3 
                 482.9 
                 pos 
                 114 
               
               
                 phenyl-4-trifluoromethoxy-benzamide 
               
               
                 Isoxazole-5-carboxylic acid [(3,4-dichloro- 
                 390.2 
                 390.0 
                 pos 
                 115 
               
               
                 phenylcarbamoyl)-methyl]-phenyl-amide 
               
               
                 N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4- 
                 442.3 
                 442.0 
                 pos 
                 116 
               
               
                 dimethylamino-N-phenyl-benzamide 
               
               
                 N-(3-Chloro-phenyl)-N-[(3,4-dichloro- 
                 463.7 
                 462.8 
                 pos 
                 117 
               
               
                 phenylcarbamoyl)-methyl]-4-methoxy-benzamide 
               
               
                 2-(4-Chloro-phenoxy)-N-[(3,4-dichloro- 
                 463.7 
                 462.8 
                 pos 
                 118 
               
               
                 phenylcarbamoyl)-methyl]-N-phenyl-acetamide 
               
               
                 N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2- 
                 462.9 
                 483.5 
                 pos 
                 119 
               
               
                 fluoro-benzyl)-6-morpholin-4-yl-nicotinamide 
               
               
                 6-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 432.3 
                 432.2 
                 pos 
                 120 
               
               
                 N-(2-fluoro-benzyl)-nicotinamide 
               
               
                 2-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 432.3 
                 432.1 
                 pos 
                 121 
               
               
                 N-(2-fluoro-benzyl)-isonicotinamide 
               
               
                 2,6-Dichloro-N-[(3-chloro-phenylcarbamoyl)- 
                 466.7 
                 468.1 
                 pos 
                 122 
               
               
                 methyl]-N-(2-fluoro-benzyl)-isonicotinamide 
               
               
                 4-Chloro-N-{[(3-chloro-phenyl)-methyl- 
                 445.3 
                 445.4 
                 pos 
                 123 
               
               
                 carbamoyl]-methyl}-N-(3-fluoro-benzyl)-benzamide 
               
               
                 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]- 
                 419.4 
                 419.1 
                 pos 
                 124 
               
               
                 N-cyclohexylmethyl-benzamide 
               
               
                 N-[(3-Chloro-phenylcarbamoyl)-methyl]-N- 
                 402.9 
                 403.3 
                 pos 
                 125 
               
               
                 cyclohexylmethyl-4-fluoro-benzamide 
               
               
                 N-Cyclopentyl-N-[(3,4-dichloro-phenylcarbamoyl)- 
                 421.3 
                 420.9 
                 pos 
                 126 
               
               
                 methyl]-4-methoxy-benzamide 
               
               
                 N-Cyclopropyl-N-[(3,4-dichloro-phenylcarbamoyl)- 
                 393.3 
                 393.0 
                 pos 
                 127 
               
               
                 methyl]-4-methoxy-benzamide 
               
               
                 N-Cyclohexyl-N-[(3,4-dichloro-phenylcarbamoyl)- 
                 435.3 
                 435.1 
                 pos 
                 128 
               
               
                 methyl]-4-methoxy-benzamide