Abstract:
The invention relates to a compound of formula 
     
       
                 
         
             
             
         
       
     
     wherein
   Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , and R 5′  or to a pharmaceutically active salt thereof.   
 
     The compounds are high potential NK-3 receptor antagonists for the treatment of depression, pain, psychosis, Parkinson&#39;s disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).

Description:
PRIORITY TO RELATED APPLICATION(S) 
       [0001]    This application is a continuation of U.S. application Ser. No. 12/207,596, filed Sep. 10, 2008, now pending; which claims the benefit of European Patent Application No. 07116441.2, filed Sep. 14, 2007. The entire contents of the above-identified applications are hereby incorporated by reference. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    The three main mammalian tachykinins, substance P(SP), neurokinin A (NKA) and neurokinin B (NKB) belong to the family of neuropeptides sharing the common COOH-terminal pentapeptide sequence of Phe-X-Gly-Leu-Met-NH 2 . As neurotransmitters, these peptides exert their biological activity via three distinct neurokinin (NK) receptors termed as NK-1, NK-2 and NK-3. SP binds preferentially to the NK-1 receptor, NKA to the NK-2 and NKB to the NK-3 receptor. 
         [0003]    The NK-3 receptor is characterized by a predominant expression in CNS and its involvement in the modulation of the central monoaminergic system has been shown. These properties make the NK-3 receptor a potential target for central nervous system disorders such as anxiety, depression, bipolar disorders, Parkinson&#39;s disease, schizophrenia and pain ( Neurosci. Letters,  2000, 283, 185-188 ; Exp. Opin. Ther. Patents  2000, 10, 939-960 ; Neuroscience,  1996, 74, 403-414 ; Neuropeptides,  1998, 32, 481-488). 
         [0004]    Schizophrenia is one of the major neuropsychiatric disorders, characterized by severe and chronic mental impairment. This devastating disease affects about 1% of the world&#39;s population. Symptoms begin in early adulthood and are followed by a period of interpersonal and social dysfunction. Schizophrenia manifests as auditory and visual hallucinations, paranoia, delusions (positive symptoms), blunted affect, depression, anhedonia, poverty of speech, memory and attention deficits as well as social withdrawal (negative symptoms). 
         [0005]    For decades scientists and clinicians have made efforts with the aim of discovering an ideal agent for the pharmacological treatment of schizophrenia. However, the complexity of the disorders, due to a wide array of symptoms, has hampered those efforts. There are no specific focal characteristics for the diagnosis of schizophrenia and no single symptom is consistently present in all patients. Consequently, the diagnosis of schizophrenia as a single disorder or as a variety of different disorders has been discussed but not yet resolved. The major difficulty in the development of a new drug for schizophrenia is the lack of knowledge about the cause and nature of this disease. Some neurochemical hypotheses have been proposed on the basis of pharmacological studies to rationalize the development of a corresponding therapy: the dopamine, the serotonin and the glutamate hypotheses. But taking into account the complexity of schizophrenia, an appropriate multireceptor affinity profile might be required for efficacy against positive and negative signs and symptoms. Furthermore, an ideal drug against schizophrenia would preferably have a low dosage allowing once-per-day dosage, due to the low adherence of schizophrenic patients. 
         [0006]    In recent years clinical studies with selective NK1 and NK2 receptor antagonists appeared in the literature showing results for the treatment of emesis, depression, anxiety, pain and migraine (NK1) and asthma (NK2 and NK1). The most exciting data were produced in the treatment of chemotherapy-induced emesis, nausea and depression with NK1 and in asthma with NK2-receptor antagonists. In contrast, no clinical data on NK3 receptor antagonists have appeared in the literature until 2000. Osanetant (SR 142,801) from Sanofi-Synthelabo was the first identified potent and selective non-peptide antagonist described for the NK3 tachykinin receptor for the potential treatment of schizophrenia, which was reported in the literature ( Current Opinion in Investigational Drugs,  2001, 2(7), 950-956 and  Psychiatric Disorders Study  4 , Schizophrenia , June 2003, Decision Recources, Inc., Waltham, Mass.). The proposed drug SR 142,801 has been shown in a phase II trial as active on positive symptoms of schizophrenia, such as altered behaviour, delusion, hallucinations, extreme emotions, excited motor activity and incoherent speech, but inactive in the treatment of negative symptoms, which are depression, anhedonia, social isolation or memory and attention deficits. 
         [0007]    The neurokinin-3 receptor antagonists have been described as useful in pain or inflammation, as well as in schizophrenia,  Exp. Opinion. Ther. Patents  (2000), 10(6), 939-960 and  Current Opinion in Investigational Drugs,  2001, 2(7), 950-956  and Psychiatric Disorders Study  4 , Schizophrenia , June 2003, Decision Recources, Inc., Waltham, Mass.). 
       SUMMARY OF THE INVENTION 
       [0008]    The invention provides compounds of formula I 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein
   Ar 1  and Ar 2  are each independently phenyl or pyridinyl, each of which is optionally substituted by one or two substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl substituted by alkoxy, lower alkyl substituted by cyano, lower di-alkyl amino, pyridinyl and cyano;   R 1  is hydrogen, lower alkyl, —(CH 2 ) 2 O-lower alkyl or cycloalkyl:   R 2  is —S(O) 2 -lower alkyl or —C(O)-lower alkyl;
 
or R′ and R 2  together with the N-atom to which they are attached form a pyrrolidin-2-one or a piperidin-2-one group;
   R 3  is hydrogen, halogen or lower alkyl;   R 4  is hydrogen or lower alkyl;   R 5  and R 5′  are each independently hydrogen, lower alkyl, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy or cycloalkyl;
 
or R 5  and R 5′  together with the carbon-atom to which they are attached form a cycloalkyl group;
 
and pharmaceutically active salts thereof.
   
 
         [0015]    The invention includes all stereoisomeric forms, including individual diastereoisomers and enantiomers of the compound of formula (I) as well as racemic and non-racemic mixtures thereof. 
         [0016]    The present invention also provides pharmaceutical compositions containing one or more compounds of formula I. The invention further provides processes for the preparation of the compounds and compositions of the invention. 
         [0017]    The present compounds are high potential NK-3 receptor antagonists for the treatment of depression, pain, biopolar disorders, psychosis, Parkinson&#39;s disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD). 
         [0018]    The preferred indications using the compounds of the present invention are depression, psychosis, Parkinson&#39;s disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD). 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0019]    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. 
         [0020]    As used herein, the term “lower alkyl” denotes a straight- or branched-chain hydrocarbon group containing from 1-8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms. 
         [0021]    The term “halogen” denotes chlorine, iodine, fluorine and bromine. 
         [0022]    The term “lower alkyl substituted by halogen” denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example —CF 3 , —CHF 2 , —CH 2 F, CH 2 CF 3 , —CH 2 CH 2 CF 3 , —CH 2 CF 2 CF 3  and the like. Preferred lower alkyl substituted by halogen groups are groups having 1-4 carbon atoms. 
         [0023]    The term “lower alkyl substituted by hydroxy” denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by a hydroxy, for example —CH 2 OH, —CH 2 CH 2 OH, and the like. 
         [0024]    The term “lower alkyl substituted by CN” denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by a cyano group, for example —CH 2 CN, —CH 2 CH 2 CN, and the like. 
         [0025]    The term “lower alkyl substituted by alkoxy” denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by an alkoxy group as defined herein, for example —CH 2 CN, —CH 2 CH 2 CN, and the like. 
         [0026]    The term “lower alkoxy” denotes a group having an alkyl group as defined above that is attached via an oxygen atom, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy, 2-butoxy, t-butoxy and the like. Preferred alkoxy groups are groups with 1-4 carbon atoms. 
         [0027]    The term “lower alkoxy substituted by halogen” denotes an alkoxy group as defined above wherein at least one hydrogen atom on the alkyl residue is replaced by a halogen atom. Preferred lower alkoxy substituted by halogen groups are groups having 1-4 carbon atoms. 
         [0028]    The term“(C 3 -C 7 )-cycloalkyl” denotes a saturated carbocyclic group, containing 3 to 7 carbon atoms. For example, a cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and these groups may optionally be substituted by one or two (C 1 -C 4 )-alkyl substituents, for example methyl or ethyl. 
         [0029]    “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. 
         [0030]    The term “pharmaceutically acceptable acid addition salt” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. 
         [0031]    “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. 
         [0032]    The following groups of compounds of formula I are preferred: 
         [0033]    Preferred are compounds of formula I, wherein Ar 1  and Ar 2  are both phenyl. 
         [0034]    Especially preferred from this group are compounds, wherein 
         [0035]    —R 1  is methyl and R 2  is S(O) 2 CH 3 , for example
   2-(3,4-dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-4-[4-(methanesulfonyl-methyl-amino)-piperidin-1-yl]-2,N-dimethyl-butyramide,   N-(4-chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)-4-[4-(methanesulfonyl-methyl-amino)-piperidin-1-yl]-2,N-dimethyl-butyramide,   2-(3,4-dichloro-phenyl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-4-[4-(methanesulfonyl-methyl-amino)-piperidin-1-yl]-2,N-dimethyl-butyramide,   N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-[4-(methanesulfonyl-methyl-amino)-piperidin-1-yl]-2,N-dimethyl-butyramide, and   2-(3,4-dichloro-phenyl)-N-[1-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-4-[4-(methanesulfonyl-methyl-amino)-piperidin-1-yl]-2-methyl-butyramide; diastereoisomer 1.   
 
         [0041]    —R′ is cyclopropyl and R 2  is S(O) 2 CH 3 , for example
   4-[4-(cyclopropyl-methanesulfonyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-2,N-dimethyl-butyramide,   N-(4-chloro-3-trifluoromethyl-benzyl)-4-[4-(cyclopropyl-methanesulfonyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-2,N-dimethyl-butyramide,   4-[4-(cyclopropyl-methanesulfonyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-2,N-dimethyl-butyramide, and   4-[4-(cyclopropyl-methanesulfonyl-amino)-piperidin-1-yl]-N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-2,N-dimethyl-butyramide.   
 
         [0046]    —R 1  is ethyl and R 2  is S(O) 2 CH 3 , for example
   2-(3,4-dichloro-phenyl)-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-N-(3-fluoro-4-trifluoromethyl-benzyl)-2,N-dimethyl-butyramide,   N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-2,N-dimethyl-butyramide,   N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-2-methyl-butyramide,   N-(4-chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-2,N-dimethyl-butyramide,   N-(4-chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-2,N-dimethyl-butyramide,   2-(3,4-dichloro-phenyl)-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-N-(4-fluoro-3-trifluoromethyl-benzyl)-2,N-dimethyl-butyramide,   N-(3-chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-2,N-dimethyl-butyramide,   2-(3,4-dichloro-phenyl)-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-2,N-dimethyl-N-(4-trifluoromethyl-benzyl)-butyramide,   2-(3,4-dichloro-phenyl)-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-2,N-dimethyl-N-(4-methyl-benzyl)-butyramide,   N-(2-chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-2,N-dimethyl-butyramide,   2-(3,4-dichloro-phenyl)-N-[1-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-2-methyl-butyramide; diastereoisomer 1.   
 
         [0058]    —R 1  and R 2  form together with the N-atom to which they are attached a pyrrolidin-2-one group, for example
   2-(3,4-dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-2,N-dimethyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide,   N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-2,N-dimethyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide,   N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-2-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide,   N-(4-chloro-benzyl)-2-(3,4-dichloro-phenyl)-2,N-dimethyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide,   N-(4-chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)-2,N-dimethyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide,   2-(3,4-dichloro-phenyl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-2,N-dimethyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide,   N-(3-chloro-benzyl)-2-(3,4-dichloro-phenyl)-2,N-dimethyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide,   2-(3,4-dichloro-phenyl)-2,N-dimethyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-N-(4-trifluoromethyl-benzyl)-butyramide,   2-(3,4-dichloro-phenyl)-2,N-dimethyl-N-(4-methyl-benzyl)-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide,   N-(2-chloro-benzyl)-2-(3,4-dichloro-phenyl)-2,N-dimethyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide,   2-(3,4-dichloro-phenyl)-N-[-1-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide; diastereoisomer 1, 2-(3,4-dichloro-phenyl)-2-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-N-(2,2,2-trifluoro-1-phenyl-ethyl)-butyramide,   2-(3,4-dichloro-phenyl)-2-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-N-[2,2,2-trifluoro-1-(4-fluoro-phenyl)-ethyl]-butyramide,   N-(4-chloro-benzyl)-2-(3,4-dichloro-phenyl)-N-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide,   (R or S)-2-(3,4-dichloro-phenyl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-2,N-dimethyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide,   (R or S)-2-(3,4-dichloro-phenyl)-N—[(S or R)-1-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide,   2-(3,4-dichloro-phenyl)-2-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-N—((S)-1-phenyl-propyl)-butyramide,   2-(3,4-dichloro-phenyl)-N—[(R)-1-(4-fluoro-phenyl)-2-hydroxy-ethyl]-2-(R or S) methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide, and   2-(3,4-dichloro-phenyl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-2-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide.   
 
         [0077]    —R 1  is lower alkyl and R 2  is C(O)CH 3 , for example
   4-[4-(acetyl-methyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-2-methyl-butyramide,   4-[4-(acetyl-methyl-amino)-piperidin-1-yl]-N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-2,N-dimethyl-butyramide,   4-[4-(acetyl-methyl-amino)-piperidin-1-yl]-N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-2-methyl-butyramide,   4-[4-(acetyl-methyl-amino)-piperidin-1-yl]-N-(4-chloro-benzyl)-2-(3,4-dichloro-phenyl)-2,N-dimethyl-butyramide,   4-[4-(acetyl-methyl-amino)-piperidin-1-yl]-N-(4-chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)-2,N-dimethyl-butyramide,   4-[4-(acetyl-methyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-2,N-dimethyl-butyramide,   4-[4-(acetyl-methyl-amino)-piperidin-1-yl]-N-(3-chloro-benzyl)-2-(3,4-dichloro-phenyl)-2,N-dimethyl-butyramide,   4-[4-(acetyl-methyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-2,N-dimethyl-N-(4-trifluoromethyl-benzyl)-butyramide,   4-[4-(acetyl-methyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-N-[1-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-methyl-butyramide; diastereoisomer 1,   (R or S)-4-[4-(acetyl-methyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-2,N-dimethyl-butyramide,   4-[4-(acetyl-methyl-amino)-piperidin-1-yl]-N-[1-(4-chloro-phenyl)-2-hydroxy-ethyl]-2-(3,4-dichloro-phenyl)-2-methyl-butyramide (diastereoisomer 1),   4-[4-(acetyl-propyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-N—[(R)-1-(4-fluoro-phenyl)-2-hydroxy-ethyl]-2-methyl-butyramide (epimer 1),   4-[4-(acetyl-propyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-N—[(R)-1-(4-fluoro-phenyl)-2-hydroxy-ethyl]-2-methyl-butyramide (epimer 2),   4-[4-(acetyl-propyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-2-methyl-N-4-((S)-1-phenyl-propyl)-butyramide,   4-[4-(acetyl-ethyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-N—[(R)-1-(4-fluoro-phenyl)-2-hydroxy-ethyl]-2-methyl-butyramide (epimer 1), and   4-[4-(acetyl-ethyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-2-methyl-N—((S)-1-phenyl-propyl)-butyramide.   
 
         [0094]    —R 1  is —(CH 2 ) 2 CH 3  and R 2  is C(O)CH 3 , for example
   4-{4-[acetyl-(2-methoxy-ethyl)-amino]-piperidin-1-yl}-2-(3,4-dichloro-phenyl)-N-[1-(4-fluoro-phenyl)-2-hydroxy-ethyl]-2-methyl-butyramide (diastereoisomer 1),   4-{4-[acetyl-(2-methoxy-ethyl)-amino]-piperidin-1-yl}-2-(3,4-dichloro-phenyl)-N-[1-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-methyl-butyramide (diastreoisomer 1),   4-{4-[acetyl-(2-methoxy-ethyl)-amino]-piperidin-1-yl}-2-(3,4-dichloro-phenyl)-N—[(R)-1-(4-fluoro-phenyl)-2-hydroxy-ethyl]-2-(R or S) methyl-butyramide, and   4-{4-[acetyl-(2-methoxy-ethyl)-amino]-piperidin-1-yl}-2-(3,4-dichloro-phenyl)-2-methyl-N—((S)-1-phenyl-propyl)-butyramide.   
 
         [0099]    The preparation of compounds of formula I of the present invention can be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following scheme 1. The skills required for carrying out the reaction and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein before unless indicated to the contrary. 
         [0100]    In more detail, the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. The reaction sequence is not limited to the one displayed in scheme 1, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art. 
         [0101]    The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by processes described below, which processes comprise 
         [0000]    a) cleaving off an O-protecting group under aqueous basic conditions from a compound of formula IV 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    and reacting a compound of formula IV under coupling conditions with an amine of formula 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    to obtain a compound of formula 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein the definitions have same meanings as described above, and
 
if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
 
         [0102]    The process is described in scheme 1 in more detail. 
       General Experimental Part 
       [0103]    
       
                 
         
             
             
         
       
     
         [0000]    R 1 , R 2 , R 3 , R 4 , R 5 , R 5′ , Ar 1  and Ar 2  are as described above and R′ is an O-protecting group, such as benzyl. 
       Step a) 
       [0104]    Phenylacetic acid ester derivatives II are commercially available or can be accessed by methods described in literature. Reaction of ester derivatives II with protected bromo alkyl aldehydes (either commercially available or synthetically accessible by methods known in the art) under basic conditions lead to aldehyde derivatives III as described analogously in literature (for reaction conditions described in literature affecting such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley &amp; Sons, New York, N.Y. 1999). However, it is convenient to react ester derivative II with the respective protected bromo alkyl aldehyde (commercially available or accessible by methods known) in the presence of a base and a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include dimethylformamide (DMF), tetrahydrofuran (THF) and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include NaH and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the aldehyde protected intermediate which can be subjected to acidic cleavage of the protecting group in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include tetrahydrofuran (THF) and the like. There is no particular restriction on the nature of the acid used in this stage, and any acid commonly used in this type of reaction may equally be employed here. Examples of such acid include HCl and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield aldehyde derivatives III. 
       Step b) 
       [0105]    Reductive aminations are widely described in literature (for reaction conditions described in literature affecting such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley &amp; Sons, New York, N.Y. 1999). However, we find it convenient to transform aldehyde derivative III with piperidine derivatives (Journal of Medicinal Chemistry (2006), 49(16), 4801-4804) under reductive conditions in the presence of a solvent to afford ester derivatives IV. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include tetrahydrofuran (THF) and the like. There is no particular restriction on the nature of the reducing agent used in this stage, and any reducing agent commonly used in this type of reaction may equally be employed here. Examples of such reducing agents include sodium triacetoxyborohydride and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield ester derivatives IV. 
       Step c) 
       [0106]    Reaction of ester derivatives II with hydroxy-protected alkyl halides (either commercially available or synthetically accessible by methods known in the art) under basic conditions lead upon cleavage of the hydroxyl protecting group to lactones V as described in literature (for reaction conditions described in literature affecting such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley &amp; Sons, New York, N.Y. 1999). However, it is convenient to react ester derivative II with 2-(2-bromoethoxy) tetrahydro-2-H-pyrane (commercially available in the presence of a base and a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include dimethylformamide (DMF), tetrahydrofuran (THF) and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include NaH and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the hydroxy protected intermediate which can be subjected to acidic cleavage of the protecting group in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include dimethylformamide (DMF), tetrahydrofuran (THF) and the like. There is no particular restriction on the nature of the acid used in this stage, and any acid commonly used in this type of reaction may equally be employed here. Examples of such acid include HCl and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield lactone derivatives V. 
       Step d) 
       [0107]    Lactone derivatives V can conveniently be transferred into the respective substituted lactone derivatives VI by reaction of lactone V with an electrophile in the presence of a base in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include dimethylformamide (DMF), tetrahydrofuran (THF) and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include NaH and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield lactone derivatives VI. 
       Step e) 
       [0108]    Lactone derivative VI can conveniently be transferred into the respective ester derivative VII by a two step reaction sequence. Any commonly used synthetic sequence is applicable however, we find it convenient to open the lactone derivative VII with HBr in the presence of an acid. Any commonly used acid which in combination with HBr affects such a reaction can be used. Examples of such acids include acetic acid and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the intermediately built acid derivative which is subjected to esterification conditions. Common procedures are described in literature, however, we find it convenient to transform the intermediately built acid into the respective ester derivative VII by reaction with SOCl 2  in methanol. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield ester derivative VII. 
       Step f) 
       [0109]    Transformation of ester derivatives VII with piperidine derivatives to access piperidine derivatives IV can be done by any commonly used procedure. However, we find it convenient to react ester derivative VII with piperidine derivatives in the presence of a solvent and a base. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include dimethylformamide (DMF), tetrahydrofuran (THF) and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include DIPEA, NEt 3  and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield piperidine derivatives IV. 
         [0110]    Step g) 
         [0111]    Transformation of piperidine derivatives IV into the final amide derivatives can be done according to procedures described in literature. However, we find it convenient to employ a two step reaction sequence in which the ester functionality in IV is cleaved under aqueous basic conditions and the liberated acid functionality converted with the respective amines under coupling conditions and to the piperidine derivatives I. There is no particular restriction on the nature of the aqueous base to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable aqueous bases include NaOH, LiOH and the like. Any commonly used co-solvent can be employed. Examples include THF and the like. The coupling of carboxylic acids with amines is widely described in literature and the procedures are known to those in the art (For reaction conditions described in literature affecting such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley &amp; Sons, New York, N.Y. 1999). The intermediately built acid can conveniently be transformed to the respective amide through coupling with an amine (either commercially available or accessible by methods described in references or by methods known in the art; as appropriate) by employing the usage of coupling reagents. For example coupling reagents like N,N′-carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and the like can equally well be employed to affect such transformation. We find it convenient to carry out the reaction in a solvent like dimethylformamide (DMF) and in the presence of a base. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: DMF, dichloromethane (DCM), dioxane, THF, and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include triethylamine and diisopropylethylamine, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield piperidine derivatives I. 
         [0112]    Where examples are said to be performed in analogy to a specific procedure, it is understood that variables within the synthesis may be optimized for the specific compound produced in accordance with knowledge within the level of skill in the art. 
       EXAMPLES 
     Intermediate 1 
     2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid 
       [0113]    
       
                 
         
             
             
         
       
     
       a) Step 1 
     3-(3,4-Dichloro-phenyl)-dihydro-furan-2-one (Commercially Available) 
       [0114]    
       
                 
         
             
             
         
       
     
         [0115]    A mixture of 30.00 g (137 mmol) (3,4-dichloro-phenyl)-acetic acid methyl ester (commercially available), 6.47 g (151 mmol) NaH (55%) and 35.80 g (171 mmol) 2-(2-bromo-ethoxy)-tetrahydro-pyran in 100 mL DMF was stirred at room temperature for 17 h. The mixture was evaporated to dryness and partitioned between water and ethyl acetate. The combined organic phases were washed with NaCl aq., dried with Na 2 SO 4  and evaporated. The residue was treated with 400 mL 4N HCl in dioxane and stirred for 16 h at room temperature. The mixture was evaporated to dryness and subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The combined product fractions were evaporated to yield 18.5 g (58%) of the title compound as yellow oil. 
       b) Step 2 
     3-(3,4-Dichloro-phenyl)-3-methyl-dihydro-furan-2-one 
       [0116]    
       
                 
         
             
             
         
       
     
         [0117]    A mixture of 18.50 g (80 mmol) 3-(3,4-dichloro-phenyl)-dihydro-furan-2-one, 3.84 g (88 mmol) NaH (55% suspension) and 14.20 g (100 mmol) iodomethane in 300 mL THF was stirred for 64 h at room temperature. NH 4 Cl aq. sat. was added and the mixture was extracted with ethyl acetate. The organic phases were washed with NaCl aq. sat. dried with Na 2 SO 4 , filtered and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were evaporated to yield 16 g (82%) of the title compound as yellow oil. MS (m/e): 246.0 (MH + ). 
       c) Step 3 
     4-Bromo-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester 
       [0118]    
       
                 
         
             
             
         
       
     
         [0119]    To a mixture of 3.30 g (13.5 mmol) 3-(3,4-dichloro-phenyl)-3-methyl-dihydro-furan-2-one in 15 mL acetic acid was added 48 mL HBr (33%) in acetic acid and after 63 h 20 mL HBr (33%) in acetic acid was added again and stirred for another 21 h at room temperature. The mixture was pored onto ice-water and extracted with ethyl ether. The combined organic phases were washed with NaCl aq. sat., dried with Na 2 SO 4 , filtered and evaporated to dryness. The residue was taken up in 150 mL toluene and 6.50 mL (89.0 mmol) thionylchloride were added. The mixture was heated to 75° C. for 4 h, cooled to 0° C., treated with 20 mL methanol and allowed to stand for 16 h at room temperature. The mixture was evaporated to dryness and subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were evaporated to yield 4.32 g (94%) of the title compound as light yellow oil. MS (m/e): 341.9 (MH + ). 
       d) Step 4 
     2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid methyl ester 
       [0120]    
       
                 
         
             
             
         
       
     
         [0121]    A mixture of 0.70 g (2.05 mmol) 4-bromo-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester and 1.83 g (10.30 mmol) N-piperidin-4-yl-methanesulfonamide (commercially available) in 30 mL N,N-dimethylacetamide was stirred for 89 h at 60° C. The mixture was evaporated to dryness and methanol, DCM and isolute was added and evaporated to dryness. The residue was subjected to column chromatography on silica eluting with a gradient formed from DCM, methanol and NH 3  aq. The product containing fractions were evaporated to yield 0.76 g (84%) of the title compound as light brown waxy solid. MS (m/e): 437.3 (MH + ). 
       e) Step 5 
       [0122]    A mixture of 0.76 g (1.7 mmol) 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid methyl ester and 0.23 g (5.4 mmol) LiOH H 2 O in 15 mL water and 15 mL THF was stirred at room temperature for 18 h. The mixture was evaporated and treated with 4N HCl aq. and evaporated to dryness. The residue was used without further purification in the subsequent step. MS (m/e): 423.1 (MH + ). 
       Intermediate 2 
     2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-butyric acid 
       [0123]    
       
                 
         
             
             
         
       
     
       a) Step 1 
     2-(3,4-Dichloro-phenyl)-4-oxo-butyric acid methyl ester 
       [0124]    
       
                 
         
             
             
         
       
     
         [0125]    A mixture of 25.0 g (114 mmol) (3,4-dichloro-phenyl)-acetic acid methyl ester (commercially available), 5.7 g (131 mmol) NaH (55%) and 23.1 g (137 mmol) bromoacetaldehyde dimethylacetal in 80 mL DMF was stirred at room temperature for 3 h. The mixture was poured onto ice/water and extracted with ethyl acetate. The combined organic phases were washed with NaCl aq., dried with Na 2 SO 4  and evaporated to dryness. The residue was dissolved in 250 mL THF and treated with 300 mL 1N HCl at room temperature for 20 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with NaCl aq., dried with Na 2 SO 4 , evaporated to dryness and subjected to column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 9.7 g (32%) of the title compound as light yellow oil. MS (m/e): 260.1/262.2 (MH + ) 
       b) Step 2 
     2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-butyric acid methyl ester 
       [0126]    
       
                 
         
             
             
         
       
     
         [0127]    A mixture of 0.89 g (3.4 mmol) 2-(3,4-dichloro-phenyl)-4-oxo-butyric acid methyl ester, 0.67 g (3.7 mmol) N-Piperidin-4-yl-methanesulfonamide (commercially available), 1.08 g (5.0 mmol) sodium triacteoxyborohydride and 0.30 g (5.0 mmol) acetic acid in 40 mL THF was stirred at room temperature for 64 h. Water and Na 2 CO 3  aq. was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with NaCl sat. aq. dried with Na 2 SO 4 , filtered and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a gradient formed from DCM, methanol and NH 3  aq. The product containing fractions were evaporated to yield 1.21 g (84%) of the title compound as off-white solid. MS (m/e): 423.1 (MH + ). 
       c) Step 3 
       [0128]    A mixture of 1.16 g (2.7 mmol) 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-butyric acid methyl ester and 0.35 g (8.2 mmol) LiOH H 2 O in 20 mL water and 20 mL THF was stirred for 69 h at room temperature and evaporated. The residue was treated with 4N HCl aq. and evaporated to dryness and dried in vacuo. The residue was used without further purification in the subsequent step. MS (m/e): 409.4 (MH + ). 
       Intermediate 3 
     2-(3,4-Dichloro-phenyl)-4-[4-(methanesulfonyl-methyl-amino)-piperidin-1-yl]-2-methyl-butyric acid 
       [0129]    
       
                 
         
             
             
         
       
     
       a) Step 1 
     2-(3,4-Dichloro-phenyl)-4-[4-(methanesulfonyl-methyl-amino)-piperidin-1-yl]-2-methyl-butyric acid methyl ester 
       [0130]    
       
                 
         
             
             
         
       
     
         [0131]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid methyl ester (intermediate 1, step 4) the title compound was prepared from 4-bromo-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester and N-methyl-N-piperidin-4-yl-methanesulfonamide (DE 2824064) as light yellow viscous oil. MS (m/e): 451.2 (MH + ). 
       b) Step 2 
       [0132]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid (intermediate 1, step 5) the title compound was prepared from 2-(3,4-dichloro-phenyl)-4-[4-(methanesulfonyl-methyl-amino)-piperidin-1-yl]-2-methyl-butyric acid methyl ester by saponification with LiOH H 2 O as off-white foam. MS (m/e): 437.1 (MH + ). 
       Intermediate 4 
     2-(3,4-Dichloro-phenyl)-2-fluoro-4-[4-(methanesulfonyl-methyl-amino)-piperidin-1-yl]-butyric acid 
       [0133]    
       
                 
         
             
             
         
       
     
       a) Step 1 
     3-(3,4-Dichloro-phenyl)-3-fluoro-dihydro-furan-2-one 
       [0134]    
       
                 
         
             
             
         
       
     
         [0135]    A mixture of 4.00 g (18.7 mmol) 3-(3,4-dichloro-phenyl)-dihydro-furan-2-one (commercially available), 0.83 g (19.0 mmol) NaH (55% suspension in oil) and 6.00 g (19.0 mmol) N-fluorobenzenesulfonimide (commercially available) in 100 mL THF stirred at room temperature for 1 h. The mixture was filtered and the filtrate evaporated to dryness. DCM and isolute was added and the mixture was evaporated to dryness. The residues was subjected to column chromatography on silica eluting with a gradient formed from heptane and toluene. The product containing fraction were evaporated to yield 3.8 g (88%) of the title compound as colourless oil. MS (m/e): 248.1/250.1/251.1 (MH + ). 
       b) Step 2 
     4-Bromo-2-(3,4-dichloro-phenyl)-2-fluoro-butyric acid methyl ester 
       [0136]    
       
                 
         
             
             
         
       
     
         [0137]    In analogy to the procedure described for the preparation of 4-bromo-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester (intermediate 1, step 3) the title compound was synthesized from 3-(3,4-dichloro-phenyl)-3-fluoro-dihydro-furan-2-one by acidic bromination with acetic acid and HBr and subsequent esterification with SOCl 2  and methanol. The title compound was obtained as colourless oil. MS (m/e): 342/346/348 (MH + ). 
       c) Step 3 
     2-(3,4-Dichloro-phenyl)-2-fluoro-4-[4-(methanesulfonyl-methyl-amino)-piperidin-1-yl]-butyric acid methyl ester 
       [0138]    
       
                 
         
             
             
         
       
     
         [0139]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid methyl ester (intermediate 1, step 4) the title compound was prepared from 4-bromo-2-(3,4-dichloro-phenyl)-2-fluoro-butyric acid methyl ester and N-methyl-N-piperidin-4-yl-methanesulfonamide (DE 2824064) as light brown waxy solid. MS (m/e): 455.1 (MH + ). 
       d) Step 4 
       [0140]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid (intermediate 1, step 5) the title compound was prepared from 2-(3,4-dichloro-phenyl)-2-fluoro-4-[4-(methanesulfonyl-methyl-amino)-piperidin-1-yl]-butyric acid methyl ester by saponification with LiOH H 2 O as off-white solid. MS (m/e): 441.1 (MH + ). 
       Intermediate 5 
     N-Cyclopropyl-N-piperidin-4-yl-methanesulfonamide 
       [0141]    
       
                 
         
             
             
         
       
     
       a) Step 1 
     N-(1-Benzyl-piperidin-4-yl)-N-cyclopropyl-methanesulfonamide 
       [0142]    
       
                 
         
             
             
         
       
     
         [0143]    A mixture of 9.40 g (40.8 mmol) 1-benzyl-cyclopropylpiperidine-4-amine (commercially available), 5.14 g (44.8 mmol) methanesulfonyl chloride and 4.95 g (49.0 mmol) NEt 3  in 150 mL DCM was stirred for 17 h at room temperature. The mixture was evaporated to dryness and subjected to column chromatography on silica eluting with a gradient formed from DCM, methanol and NH 3  aq. The product containing fractions were evaporated to yield 11.40 g (90%) of the title compound as light yellow solid. MS (m/e): 309.3 (MH + ). 
       b) Step 2 
       [0144]    A mixture of 11.3 g (36.6 mmol) N-(1-benzyl-piperidin-4-yl)-N-cyclopropyl methane sulfonamide and 5.1 g Pd/C (10%) in 150 mL THF, 300 mL methanol and 31.7 mL formic acid was hydrogenated at room temperature. The mixture was filtered and evaporated to dryness. Water and Na 2 CO 3  aq. was added and the mixture was extracted with THF/ethyl acetate. The combined organic phases were washed with NaCl aq. sat., dried with Na 2 SO 4 , filtered and evaporated to dryness. The residue was taken up in DCM and subjected to flash column chromatography on silica eluting with a gradient formed from DCM, methanol and NH 3  aq. The product containing fractions were evaporated to yield 5 g (62%) of the title compound as white solid. MS (m/e): 219.1 (MH + ). 
       Intermediate 6 
     4-[4-(Cyclopropyl-methanesulfonyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid 
       [0145]    
       
                 
         
             
             
         
       
     
       a) Step 1 
     4-[4-(Cyclopropyl-methanesulfonyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester 
       [0146]    
       
                 
         
             
             
         
       
     
         [0147]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid methyl ester (intermediate 1, step 4) the title compound was prepared from 4-bromo-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester and N-cyclopropyl-N-piperidin-4-yl-methanesulfonamide as viscous colourless oil. MS (m/e): 476.9 (MH + ). 
       b) Step 2 
       [0148]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid (intermediate 1, step 5) the title compound was prepared from 4-[4-cyclopropyl-methanesulfonyl-amino)-piperidin-1-yl]dichloro-phenyl)-2-methyl-butyric acid methyl ester by saponification with LiOH H 2 O as white foam. MS (m/e): 446.1 (MH + ). 
       Intermediate 7 
     2-(3,4-Dichloro-phenyl)-2-fluoro-4-(4-methanesulfonylamino-piperidin-1-yl)-butyric acid 
       [0149]    
       
                 
         
             
             
         
       
     
       a) Step 1 
     2-(3,4-Dichloro-phenyl)-2-fluoro-4-(4-methanesulfonylamino-piperidin-1-yl)-butyric acid methyl ester 
       [0150]    
       
                 
         
             
             
         
       
     
         [0151]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid methyl ester (intermediate 1, step 4) the title compound was prepared from 4-bromo-2-(3,4-dichloro-phenyl)-2-fluoro-butyric acid methyl ester and N-piperidin-4-yl-methanesulfonamide (commercially available) as light brown waxy solid. MS (m/e): 441.1 (MH + ). 
       b) Step 2 
       [0152]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid (intermediate 1, step 5) the title compound was prepared from 2-(3,4-dichloro-phenyl)-2-fluoro-4-(4-methanesulfonylamino-piperidin-1-yl)-butyric acid methyl ester by saponification with LiOH H 2 O and conversion with HCl into the respective salt as off-white solid. MS (m/e): 427.1 (MH + ). 
       Intermediate 8 
     N-Ethyl-N-piperidin-4-yl-methanesulfonamide 
       [0153]    
       
                 
         
             
             
         
       
     
       a) Step 1 
     4-Ethylamino-piperidine-1-carboxylic acid benzyl ester 
       [0154]    
       
                 
         
             
             
         
       
     
         [0155]    A mixture of 28.93 g (124 mmol) 1-(benzyloxycarbonyl)-4-piperidinone (commercially available, 8.30 g (186 mmol) ethylamine (2N in THF), 39.42 g (186 mmol) sodium triacetoxyborohydride and 11.10 g (186 mmol) acetic acid in 300 mL THF was stirred for 68 h at room temperature. Water and Na 2 CO 3  aq. was added and extracted with ethyl acetate. The organic phases were washed with NaCl aq. sat., dried with Na 2 SO 4 , filtered and evaporated to dryness. The crude title compound was used in the consecutive step. MS (m/e): 263.0 (MH + ). 
       b) Step 2 
     4-(Ethyl-methanesulfonyl-amino)-piperidine-1-carboxylic acid benzyl ester 
       [0156]    
       
                 
         
             
             
         
       
     
         [0157]    A mixture of 32.68 g (125 mmol) 4-ethylamino-piperidine-1-carboxylic acid benzyl ester, 16.00 g (140 mmol) methanesulfonyl chloride and 19.30 (149 mmol) DIPEA in 300 mL DCM was stirred for 80 min at room temperature. The mixture was concentrated, isolute was added and evaporated to dryness. The residue was subjected to flash column chromatography on silica eluting with a gradient formed from DCM, methanol and NH 3  aq. The product containing fractions were evaporated and the residue was triturated with a mixture formed from heptane and diethyl ether. The precipitate was filtered and dried to yield 32.4 g (76%) of the title compound as white solid. MS (m/e): 341.1 (MH + ). 
       c) Step 3 
       [0158]    A solution of 32.4 g (95 mmol) 4-(ethyl-methanesulfonyl-amino)-piperidine-1-carboxylic acid benzyl ester in 400 mL THF and 300 mL methanol was hydrogenated at room temperature over 3.5 g Pd/C (10%). The mixture was filtered and evaporated to dryness to yield the crude title compound which was used without further purification in the consecutive step. MS (m/e): 207.1 (MH + ). 
       Intermediate 9 
     2-(3,4-Dichloro-phenyl)-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-2-methyl-butyric acid 
       [0159]    
       
                 
         
             
             
         
       
     
       a) Step 1 
     2-(3,4-Dichloro-phenyl)-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-2-methyl-butyric acid methyl ester 
       [0160]    
       
                 
         
             
             
         
       
     
         [0161]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid methyl ester (intermediate 1, step 4) the title compound was prepared from 4-bromo-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester and N-ethyl-N-piperidin-4-yl-methanesulfonamide (intermediate 8) as light yellow viscous oil. MS (m/e): 467.0 (MH + ). 
       b) Step 2 
       [0162]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid (intermediate 1, step 5) the title compound was prepared from 2-(3,4-dichloro-phenyl)-4-[4-(ethyl-methanesulfonyl-amino)-piperidin-1-yl]-2-methyl-butyric acid methyl ester by saponification with LiOH H 2 O and conversion with HCl into the respective salt as white foam. MS (m/e): 451.0 (MH + ). 
       Intermediate 10 
     2-(3,4-Dichloro-phenyl)-2-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyric acid 
       [0163]    
       
                 
         
             
             
         
       
     
       a) Step 1 
     2-(3,4-Dichloro-phenyl)-2-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyric acid methyl ester 
       [0164]    
       
                 
         
             
             
         
       
     
         [0165]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid methyl ester (intermediate 1, step 4) the title compound was prepared from 4-bromo-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester and 1-piperidin-4-yl-pyrrolidin-2-one (commercially available) as light yellow viscous oil. MS (m/e): 427.1 (MM. 
       b) Step 2 
       [0166]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid (intermediate 1, step 5) the title compound was prepared from 2-(3,4-dichloro-phenyl)-2-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyric acid methyl ester by saponification with LiOH H 2 O and conversion with HCl into the respective salt as white foam. MS (m/e): 415.2 (MH + ). 
       Intermediate 11 
     4-[4-(A cetyl-methyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid 
       [0167]    
       
                 
         
             
             
         
       
     
       a) Step 1 
     4-[4-(Acetyl-methyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester 
       [0168]    
       
                 
         
             
             
         
       
     
         [0169]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid methyl ester (intermediate 1, step 4) the title compound was prepared from 4-bromo-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester and N-methyl-N-piperidin-4-yl-acetamide (WO2005019194) as yellow viscous oil. MS (m/e): 415.3 (MH + ). 
       b) Step 2 
       [0170]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid (intermediate 1, step 5) the title compound was prepared from 4-[4-(acetyl-methyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester by saponification with LiOH H 2 O and conversion with HCl into the respective salt as white foam. MS (m/e): 401.1 (MH + ). 
       Intermediate 12 
     (3-Fluoro-4-trifluoromethyl-benzyl)-methyl-amine, hydrochloride 
       [0171]    
       
                 
         
             
             
         
       
     
         [0172]    A mixture of 7.65 g (39.8 mmol) 3-fluoro-4-trifluoro-benzaldehyde, 24.39 mL (49.0 mmol) methylamine (2M in THF), 3.60 mL acetic acid and 12.46 g (59.0 mmol) sodium triacetoxyborohydride in 200 mL THF was stirred for 22 h at room temperature. Water and Na 2 CO 3  aq. was added and the mixture was extracted with ethyl acetate. The organic phases were washed with NaCl aq., dried with Na 2 SO 4 , filtered and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a gradient formed from DCM, methanol and NH 3  aq. The combined product containing fractions were evaporated and treated with HCl in diethyl ether. The precipitate was filtered, washed with diethyl ether and dried to yield 4.00 g (42%) of the title compound as white solid. MS (m/e): 208.1 (MH + ). 
       Intermediate 13 
     (4-Fluoro-3-trifluoromethyl-benzyl)-methyl-amine, hydrochloride 
       [0173]    
       
                 
         
             
             
         
       
     
         [0174]    In analogy to the procedure described for the synthesis of (3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine, hydrochloride (intermediate 12) the title compound was prepared from 4-fluoro-3-trifluoro-benzaldehyde and methylamine under reductive conditions as white solid. MS (m/e): 208.3 (MH + ). 
       Intermediate 14 
     4-[4-(Acetyl-cyclopropyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid 
       [0175]    
       
                 
         
             
             
         
       
     
         [0176]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-butyric acid (intermediate 2) the title compound was prepared from 2-(3,4-dichloro-phenyl)-4-oxo-butyric acid methyl ester, N-Cyclopropyl-N-piperidin-4-yl-acetamide (intermediate 22) and subsequent saponification as exemplified in the synthesis of intermediate 2, c) Step 3. MS (m/e): 427.2 (MH + ). 
       Intermediate 15 
     4-{4-[Acetyl-(2-methoxy-ethyl)-amino]-piperidin-1-yl}-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid 
       [0177]    
       
                 
         
             
             
         
       
     
         [0178]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-butyric acid (intermediate 2) the title compound was prepared from 2-(3,4-dichloro-phenyl)-4-oxo-butyric acid methyl ester, N-(2-Methoxy-ethyl)-N-piperidin-4-yl-acetamide, hydrochloride (intermediate 23) and subsequent saponification as exemplified in the synthesis of intermediate 2, c) step 3. MS (m/e): 445.1 (MH + ). 
       Intermediate 16 
     4-(4-Acetylamino-piperidin-1-yl)-2-(3,4-dichloro-phenyl)-2-methylbutyric acid 
       [0179]    
       
                 
         
             
             
         
       
     
         [0180]    In analogy to the procedure described for the synthesis of 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-butyric acid (intermediate 2) the title compound was prepared from 2-(3,4-Dichloro-phenyl)-4-oxo-butyric acid methyl ester, 4-Acetylamino-piperidine (commercially available) and subsequent saponification as exemplified in the synthesis of intermediate 2, c) step 3. MS (m/e): 387.2 (MH + ). 
       Intermediate 17 
     4-[4-(Acetyl-propyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid 
       [0181]    
       
                 
         
             
             
         
       
     
         [0182]    In analogy to the procedure described for the synthesis of 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-butyric acid (intermediate 2) the title compound was prepared from 2-(3,4-Dichloro-phenyl)-4-oxo-butyric acid methyl ester, N-Piperidin-4-yl-N-propyl-acetamide (WO 9410146) and subsequent saponification as exemplified in the synthesis of intermediate 2, c) step 3. MS (m/e): 429.2 (MH + ). 
       Intermediate 18 
     4-[4-(Acetyl-ethyl-amino)-piperidin-1-yl]-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid 
       [0183]    
       
                 
         
             
             
         
       
     
         [0184]    In analogy to the procedure described for the synthesis of 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-butyric acid (intermediate 2) the title compound was prepared from 2-(3,4-Dichloro-phenyl)-4-oxo-butyric acid methyl ester, N-Ethyl-N-piperidin-4-yl-acetamide (EP 457686) and subsequent saponification as exemplified in the synthesis of intermediate 2, c) step 3. MS (m/e): 415.2 (MH + ). 
       Intermediate 19 
     1-(4-Fluoro-3-trifluoromethyl-phenyl)-ethylamine; hydrochloride 
       [0185]    
       
                 
         
             
             
         
       
     
         [0186]    A mixture of 10 g (49 mmol) 4-Fluoro-3-(trifluoromethyl)acetopheneone (commercially available), 27.5 g (97 mmol) titanium tetraisopropoxide and 34 mL (243 mmol) 7 N ammonia in MeOH at 0° C. was stirred over the weekend at 20° C. Subsequently, 5.5 g (146 mmol) sodium borohydride was added and the mixture allowed to come from 0° C. to room temperature over night. Water and ammonia was added and the mixture was filtered through decalit and washed with ethyl acetate. The aqueous phase was separated washed with ethyl acetate and the combined organic phases washed with NaCL sat. aq., dried with Na 2 SO 4  and evaporated to dryness. The residue was purified by column chromatography eluting with a gradient formed from DCM, methanol and ammonia. The product containing fractions were evaporated to dryness and transformed with HCl in diethyl ether to the respective hydrochloride salt. Yield: 4.4 g (37%). MS (m/e): 207.9 (MH + ). 
       Intermediate 20 
     1-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl-methyl amine; hydrochloride 
       [0187]    
       
                 
         
             
             
         
       
     
         [0188]    In analogy to the procedure described for the synthesis of Intermediate 20, 1-(4-Fluoro-3-trifluoromethyl-phenyl)-ethylamine; hydrochloride the title compound was prepared from 4-fluoro-3-(trifluoromethyl)acetopheneone (commercially available) and methylamine. MS (m/e): 191.2/222.1 (MH + ). 
       Intermediate 21 
     N-Cyclopropyl-N-piperidin-4-yl-acetamide 
       [0189]    
       
                 
         
             
             
         
       
     
         [0190]    A mixture of 6.25 g (27 mmol) 1-(benzyloxycarbonyl)-4-piperidinone (commercially available, 1.83 g (32 mmol) cyclopropyl amine, 2.3 mL acetic acid and 8.51 g (40 mmol) sodium triacetoxyborohydride was stirred from 0° C. to room temperature over night. Water and Na 2 CO 3  aq. was added and the mixture extracted with ethyl acetate. The organic phase was washed with NaCl sat. aq., dried with Na 2 SO 4  and evaporated to dryness. The residue was taken up in 100 mL DCM and 4.48 mL (32 mmol) NEt 3  and 2.09 mL acetyl chloride was added and allowed to stir at 0° C. for 2 h. The mixture was evaporated and isolute was added and the residue was purified by column chromatography on silica eluting with a gradient formed from DCM, methanol and ammonia. The product containing fractions were evaporated and the residue taken up in methanol and hydrogenated over Pd/C with H 2 . Filtration and evaporation yielded 4.5 g (92%) of the title compound as light yellow solid. MS (m/e): 183.2 (MH + ). 
       Intermediate 22 
     N-(2-Methoxy-ethyl)-N-piperidin-4-yl-acetamide, hydrochloride 
       [0191]    
       
                 
         
             
             
         
       
     
         [0192]    In analogy to the procedure described for the synthesis of N-cyclopropyl-N-piperidin-4-yl-acetamide (intermediate 22) the title compound was prepared from 1-(benzyloxycarbonyl)-4-piperidinone (commercially available and 2-methoxyethyloamine. 
         [0193]    The title compound was obtained as hydrochloride salt by treatment of the free base with HCl. MS (m/e): 201.1 (MH + ). 
       Example 1 
     2-(3,4-Dichloro-phenyl)-N-(3-fluoro-4-methoxy-benzyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2,N-dimethyl-butyramide 
       [0194]    
       
                 
         
             
             
         
       
     
         [0195]    A mixture of 30 mg crude 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2-methyl-butyric acid, 14 mg (0.068 mmol) (3-fluoro-4-methoxy-benzyl)-methyl-amine, hydrochloride, 0.33 mL TBTU/DMF (0.2N) and 50 uL DIPEA in 1.2 mL DMF was stirred at room temperature for 16 h. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt 3 . The product containing fractions were evaporated to yield 6.5 mg of the title compound. MS (m/e): 574.3 (MH + ). 
         [0196]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-N-(3-fluoro-4-methoxy-benzyl)-4-(4-methanesulfonylamino-piperidin-1-yl)-2,N-dimethyl-butyramide (example 1) further piperidine derivatives have been prepared from the starting materials listed in table 1. Optionally diastereoisomeric mixture have been separated by column chromatography. Table 1 comprises example 2-example 110. 
         [0000]    
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 MW 
                 hNK3 
               
               
                   
                   
                   
                   
                   
                 found 
                 Ki 
               
               
                 No 
                 structure 
                 MW 
                 Systematic Name 
                 starting materials 
                 (MH+) 
                 (uM) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                  1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 574.5 
                 2-(3,4-Dichloro- phenyl)-N-(3- fluoro-4-methoxy- benzyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and (3-Fluoro-4- methoxy-benzyl)- methyl-amine (commercially available) 
                 574.3 
                 0.1872 
               
               
                   
               
               
                  2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 582.6 
                 N-[Cyclopropyl-(4- methoxy-phenyl)- methyl]-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and C- Cyclopropyl-C-(4- methoxy-phenyl)- methylamine (commercially available) 
                 584.3 
                 0.7035 
               
               
                   
               
               
                  3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 612.5 
                 2-(3,4-Dichloro- phenyl)-N-(4- fluoro-3- trifluoromethyl- benzyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and (4-Fluoro-3- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 13) 
                 612.1 
                 0.0232 
               
               
                   
               
               
                  4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 648.5 
                 N-(3,5-Bis- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and 3,5-Bis- trifluoromethyl- benzylamine (commercially available) 
                 648.3 
                 0.1396 
               
               
                   
               
               
                  5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 622.6 
                 2-(3,4-Dichloro- phenyl)-N-(4- difluoromethoxy-3- methoxy-benzyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and (4- Difluoromethoxy- 3-methoxy-benzyl)- methyl-amine (commercially available) 
                 622.2 
                 0.2716 
               
               
                   
               
               
                  6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 540.6 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-2,N- dimethyl-N-(4- methyl-benzyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and Methyl-(4- methyl-benzyl)- amine (commercially available) 
                 540.4 
                 0.0774 
               
               
                   
               
               
                  7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 555.6 
                 2-(3,4-Dichloro- phenyl)-N-(4- dimethylamino- benzyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and (4- Aminomethyl- phenyl)-dimethyl- amine (commercially available) 
                 555.3 
                 0.6205 
               
               
                   
               
               
                  8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 629.0 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and (4-Chloro-3- trifluoromethyl- benzyl)-methyl- amine (commercially available) 
                 630.3 
                 0.0226 
               
               
                   
               
               
                  9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 612.5 
                 2-(3,4-Dichloro- phenyl)-N-(3- fluoro-4- trifluoromethyl- benzyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and (3-Fluoro-4- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 12) 
                 612.3 
                 0.03 
               
               
                   
               
               
                 10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 595.4 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and (3,4- Dichloro-benzyl)- methyl-amine (commercially available) 
                 596.1 
                 0.024 
               
               
                   
               
               
                 11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 581.4 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and 3,4- Dichloro- benzylamine (commercially available) 
                 582 
                 0.0442 
               
               
                   
               
               
                 12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 578.5 
                 2-(3,4-Dichloro- phenyl)-N-(3- difluoromethoxy- benzyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and 3- Difluoromethoxy- benzylamine (commercially available) 
                 578.1 
                 0.3094 
               
               
                   
               
               
                 13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 598.5 
                 2-(3,4-Dichloro- phenyl)-N-(5- fluoro-2- trifluoromethyl- benzyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and 5-Fluoro-2- trifluoromethyl- benzylamine (commercially available) 
                 598.1 
                 0.5804 
               
               
                   
               
               
                 14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 580.5 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-2-methyl- N-(4- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and 4- Trifluoromethyl- benzylamine (commercially available) 
                 580 
                 0.058 
               
               
                   
               
               
                 15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 598.5 
                 2-(3,4-Dichloro- phenyl)-N-(2- fluoro-5- trifluoromethyl- benzyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and 2-Fluoro-5- trifluoromethyl- benzylamine (commercially available) 
                 598.3 
                 0.1661 
               
               
                   
               
               
                 16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 561.0 
                 N-[1-(4-Chloro- phenyl)-ethyl]-2- (3,4-dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and 1-(4-Chloro- phenyl)-ethylamine (commercially available) 
                 562.5 
                 0.1735 
               
               
                   
               
               
                 17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 556.6 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-N-(3- methoxy- benzyl)-2,N- dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and (3-Methoxy- benzyl)-methyl- amine (commercially available) 
                 556.1 
                 0.2127 
               
               
                   
               
               
                 18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 561.0 
                 N-(2-Chloro- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and (2-Chloro- benzyl)-methyl- amine (commercially available) 
                 560.2 
                 0.0333 
               
               
                   
               
               
                 19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 595.4 
                 2-(3,4-Dichloro- phenyl)-N-[1-(3,4- dichloro-phenyl)- ethyl]-4-(4- methanesulfonyl- amino-piperidin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and 1-(3,4- Dichloro-phenyl)- ethylamine (commercially available) 
                 596.3 
                 0.0599 
               
               
                   
               
               
                 20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 603.6 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-2,N- dimethyl-N-(4- pyridin-4-yl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and Methyl-(4- pyridin-4-yl- benzyl)-amine (commercially available) 
                 603.3 
                 0.2032 
               
               
                   
               
               
                 21 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 596.5 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-2- methyl-N-(3- trifluoromethoxy- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and 3- Trifluoromethoxy- benzylamine (commercially available) 
                 596.2 
                 0.1468 
               
               
                   
               
               
                 22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 564.9 
                 N-(4-Chloro-3- fluoro-benzyl)-2- (3,4-dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and 4-Chloro-3- fluoro-benzylamine (commercially available) 
                 566.3 
                 0.0708 
               
               
                   
               
               
                 23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 596.5 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-2- methyl-N-(4- trifluoromethoxy- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and 4- Trifluoromethoxy- benzylamine (commercially available) 
                 596.2 
                 0.1403 
               
               
                   
               
               
                 24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 614.9 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and 4-Chloro-3- trifluoromethyl- benzylamine (commercially available) 
                 616.3 
                 0.0714 
               
               
                   
               
               
                 25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 594.5 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-2,N- dimethyl-N-(4- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and Methyl-(4- trifluoromethyl- benzyl)-amine (commercially available) 
                 594.2 
                 0.0287 
               
               
                   
               
               
                 26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 561.0 
                 N-(4-Chloro- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin- 1-yl)-2,N- dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and (4-Chloro- benzyl)-methyl- amine (commercially available) 
                 560.3 
                 0.0265 
               
               
                   
               
               
                 27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 537.5 
                 N-(4-Cyano- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and 4- Aminomethyl- benzonitrile (commercially available) 
                 537.3 
                 0.2633 
               
               
                   
               
               
                 28 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 594.5 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-2,N- dimethyl-N-(3- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and Methyl-(3- trifluoromethyl- benzyl)-amine (commercially available) 
                 594.2 
                 0.0217 
               
               
                   
               
               
                 29 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 561.0 
                 N-(3-Chloro- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and (3-Chloro- benzyl)-methyl- amine (commercially available) 
                 560.5 
                 0.0485 
               
               
                   
               
               
                 30 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 544.5 
                 2-(3,4-Dichloro- phenyl)-N-(3- fluoro-benzyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and (3-Fluoro- benzyl)-methyl- amine (commercially available) 
                 544.2 
                 0.1233 
               
               
                   
               
               
                 31 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 595.5 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-2,N- dimethyl-N-(6- trifluoromethyl- pyridin-3- ylmethyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- 2-methyl-butyric acid (intermediate 1) and Methyl-(6- trifluoromethyl- pyridin-3- ylmethyl)-amine (commercially available) 
                 595.2 
                 0.5004 
               
               
                   
               
               
                 32 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 598.5 
                 2-(3,4-Dichloro- phenyl)-N-(3- fluoro-4- trifluoromethyl- benzyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 2) and (3-Fluoro-4- tnfluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 12) 
                 598.3 
                 0.0617 
               
               
                   
               
               
                 33 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 580.5 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-N- methyl-N-(4- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 2) and Methyl-(4- trifluoromethyl- benzyl)-amine (commercially available) 
                 580.3 
                 0.0816 
               
               
                   
               
               
                 34 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 581.4 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 2) and (3,4-Dichloro- benzyl)-methyl- amine (commercially available) 
                 582.1 
                 0.0775 
               
               
                   
               
               
                 35 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 614.9 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-butyric acid (intermediate 2) and (4-Chloro-3- trifluoromethyl- benzyl)- methyl-amine (commercially available) 
                 616.1 
                 0.1494 
               
               
                   
               
               
                 36 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 600.9 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 2) and 4-Chloro-3- trifluoromethyl- benzylamine (commercially available) 
                 600.2 
                 0.3541 
               
               
                   
               
               
                 37 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 546.9 
                 N-(4-Chloro- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino -piperidin-1-yl)- butyric acid (intermediate 2) and (4-Chloro- benzyl)-methyl- amine (commercially available) 
                 546.2 
                 0.0787 
               
               
                   
               
               
                 38 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 526.5 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-N-methyl- N-(4-methyl- benzyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 2) and Methyl-(4- methyl-benzyl)- amine (commercially available) 
                 526.4 
                 0.0929 
               
               
                   
               
               
                 39 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 546.9 
                 N-(3-Chloro- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 2) and (3-Chloro- benzyl)-methyl- amine (commercially available) 
                 546.2 
                 0.2126 
               
               
                   
               
               
                 40 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 580.5 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-N-methyl- N-(3- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-butyric acid (intermediate 2) and Methyl-(3- trifluoromethyl- benzyl)-amine (commercially available) 
                 580.3 
                 0.2801 
               
               
                   
               
               
                 41 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 546.9 
                 N-(2-Chloro- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 2) and (2-Chloro- benzyl)-methyl- amine (commercially available) 
                 546.2 
                 0.2588 
               
               
                   
               
               
                 42 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 567.4 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4- (4- methanesulfonyl- amino-piperidin-1- yl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 2) and 3,4-Dichloro- benzylamine (commercially available) 
                 568.3 
                 0.1919 
               
               
                   
               
               
                 43 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 530.5 
                 2-(3,4-Dichloro- phenyl)-N-(3- fluoro-benzyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 2) and (3-Fluoro- benzyl)-methyl- amine (commercially available) 
                 530.1 
                 0.2544 
               
               
                   
               
               
                 44 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 598.5 
                 2-(3,4-Dichloro- phenyl)-N-(4- fluoro-3- trifluoromethyl- benzyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- amino-piperidin- 1-yl)-butyric acid (intermediate 2) and (4-Fluoro-3- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 13) 
                 598.3 
                 0.1323 
               
               
                   
               
               
                 45 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 626.5 
                 2-(3,4-Dichloro- phenyl)-N-(3- fluoro-4- trifluoromethyl- benzyl)-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]- 2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]- 2-methyl-butyric acid (intermediate 3) and (3-Fluoro-4- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 12) 
                 625.8 
                 0.0085 
               
               
                   
               
               
                 46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 643.0 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4- [4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2,N- dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2- methyl-butyric acid (intermediate 3) and (4-Chloro-3- trifluoromethyl- benzyl)- methyl-amine (commercially available) 
                 641.8 
                 0.0024 
               
               
                   
               
               
                 47 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 626.5 
                 2-(3,4-Dichloro- phenyl)-N-(4- fluoro-3- trifluoromethyl- benzyl)-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2,N- dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2- methyl-butyric acid (intermediate 3) and (4-Fluoro-3- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 13) 
                 625.7 
                 0.0021 
               
               
                   
               
               
                 48 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 609.4 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4- [4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2,N- dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2- methyl-butyric acid (intermediate 3) and (3,4-Dichloro- benzyl)-methyl- amine (commercially available) 
                 609.5 
                 0.0036 
               
               
                   
               
               
                 49 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 625.4 
                 2-(3,4-Dichloro- phenyl)-N-[1-(3,4- dichloro-phenyl)-2- hydroxy-ethyl]-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2- methyl-butyramide; diastereoisomer 1 
                 2-(3,4-Dichloro- phenyl)-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2- methyl-butyric acid (intermediate 3) and 2-Amino-2- (3,4-dichloro- phenyl)-ethanol (WO 2005058892) 
                 626.2 
                 0.0055 
               
               
                   
               
               
                 50 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 625.4 
                 2-(3,4-Dichloro- phenyl)-N-[1-(3,4- dichloro-phenyl)-2- hydroxy-ethyl]-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2- methyl-butyramide; diastereoisomer 2 
                 2-(3,4-Dichloro- phenyl)-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2- methyl-butyric acid (intermediate 3) and 2-Amino-2- (3,4-dichloro- phenyl)-ethanol (WO 2005058892) 
                 626.2 
                 0.0521 
               
               
                   
               
               
                 51 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 594.5 
                 2-(3,4-Dichloro- phenyl)-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2- methyl-N-(2,2,2- trifluoro-1-phenyl- ethyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2- methyl-butyric acid (intermediate 3) and 2,2,2- Trifluoro- 1-phenyl- ethylamine (commercially available) 
                 594.3 
                 0.0187 
               
               
                   
               
               
                 52 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 526.5 
                 N-Benzyl-2-(3,4- dichloro-phenyl)-4- [4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-2- methyl-butyric acid (intermediate 3) and benzylamine (commercially available) 
                 525.8 
                 0.0648 
               
               
                   
               
               
                 53 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 630.5 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-N- (3-fluoro-4- trifluoromethyl- benzyl)-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-N- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- [4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]- butyric acid (intermediate 4) and (3-Fluoro-4- trifluoromethyl benzyl)-methyl- amine, hydrochloride (intermediate 12) 
                 629.8 
                 0.0183 
               
               
                   
               
               
                 54 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 647.0 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-2- fluoro-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-N- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- [4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]- butyric acid (intermediate 4) and (4-Chloro-3- trifluoromethyl- benzyl)-methyl- amine (commercially available) 
                 645.7 
                 0.0245 
               
               
                   
               
               
                 55 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 630.5 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-N- (4-fluoro-3- trifluoromethyl- benzyl)-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-N- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- [4- (methanesulfonyl- methyl-amino)- piperidin-1-yl] butyric acid (intermediate 4) and (4-Fluoro-3- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 13) 
                 629.8 
                 0.0234 
               
               
                   
               
               
                 56 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 613.4 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-2- fluoro-4-[4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]-N- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- [4- (methanesulfonyl- methyl-amino)- piperidin-1-yl]- butyric acid (intermediate 4) and (3,4-Dichloro- benzyl)-methyl- amine (commercially available) 
                 613.7 
                 0.0228 
               
               
                   
               
               
                 57 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 652.6 
                 4-[4-(Cyclopropyl- methanesulfonyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-N-(3- fluoro-4- trifluoromethyl- benzyl)-2,N- dimethyl- butyramide 
                 4-(4-(Cyclopropyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-(3,4- dichloro-phenyl)-2- methyl-butyric acid (intermediate 6) and (3-Fluoro-4- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 12) 
                 653.8 
                 0.0059 
               
               
                   
               
               
                 58 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 669.0 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-4-[4- (cyclopropyl- methanesulfonyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2,N- dimethyl- butyramide 
                 4-[4-(Cyclopropyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-(3,4- dichloro-phenyl)-2- methyl-butyric acid (intermediate 6) and (4-Chloro-3- trifluoromethyl- benzyl)-methyl- amine (commercially available) 
                 669.8 
                 0.0036 
               
               
                   
               
               
                 59 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 652.6 
                 4-[4-(Cyclopropyl- methanesulfonyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-N-(4- fluoro-3- trifluoromethyl- benzyl)-2,N- dimethyl- butyramide 
                 4-[4-(Cyclopropyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-(3,4- dichloro-phenyl)-2- methyl-butyric acid (intermediate 6) and (4-Fluoro-3- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 13) 
                 653.7 
                 0.0043 
               
               
                   
               
               
                 60 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 635.5 
                 4-[4-(Cyclopropyl- methanesulfonyl- amino)-piperidin-1- yl]-N-(3,4-dichloro- benzyl)-2-(3,4- dichloro-phenyl)- 2,N-dimethyl- butyramide 
                 4-[4-(Cyclopropyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-(3,4- dichloro-phenyl)-2- methyl-butyric acid (intermediate 6) and (3,4-Dichloro- benzyl)-methyl- amine (commercially available) 
                 635.5 
                 0.0026 
               
               
                   
               
               
                 61 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 616.5 
                 2-(3,4-Dichloro- phenyl)-2-fluoro- N-(3-fluoro-4- trifluoromethyl- benzyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- (4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 7) and (3-Fluoro-4- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 12) 
                 616.1 
                 0.08 
               
               
                   
               
               
                 62 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 564.9 
                 N-(4-Chloro- benzyl)-2-(3,4- dichloro-phenyl)-2- fluoro-4-(4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- (4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 7) and (4-Chloro- benzyl)-methyl- amine (commercially available) 
                 564.2 
                 0.1052 
               
               
                   
               
               
                 63 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 632.9 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-2- fluoro-4-(4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- (4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 7) and (4-Chloro-3- trifluoromethyl- benzyl)-methyl- amine (commercially available) 
                 632.2 
                 0.1169 
               
               
                   
               
               
                 64 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 616.5 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-N- (4-fluoro-3- trifluoromethyl- benzyl)-4-(4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- (4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 7) and (4-Fluoro-3- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 13) 
                 616.1 
                 0.1219 
               
               
                   
               
               
                 65 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 564.9 
                 N-(3-Chloro benzyl)-2-(3,4- dichloro-phenyl)-2- fluoro-4-(4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- (4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 7) and (3-Chloro- benzyl)-methyl- amine (commercially available) 
                 564.2 
                 0.3067 
               
               
                   
               
               
                 66 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 598.5 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- (4- methanesulfonyl- amino-piperidin- 1-yl)-N-methyl- N-(4- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- (4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 7) and Methyl-(4- trifluoromethyl- benzyl)-amine (commercially available) 
                 598.3 
                 0.0843 
               
               
                   
               
               
                 67 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 544.5 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- (4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl-N-(4- methyl-benzyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- (4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 7) and Methyl-(4- methyl-benzyl)- amine (commercially available) 
                 546.2 
                 0.3227 
               
               
                   
               
               
                 68 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 564.9 
                 N-(2-Chloro- benzyl)-2-(3,4- dichloro-phenyl)-2- fluoro-4-(4- methanesulfonyl- amino-piperidin-1- yl)-N-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-fluoro-4- (4- methanesulfonyl- amino- piperidin-1-yl)- butyric acid (intermediate 7) and (2-Chloro- benzyl)-methyl- amine (commercially available) 
                 564.2 
                 0.1585 
               
               
                   
               
               
                 69 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 640.6 
                 2-(3,4-Dichloro- phenyl)-4-[4-(ethyl- methanesulfonyl- amino)-piperidin-1- yl]-N-(3-fluoro-4- trifluoromethyl- benzyl)-2,N- dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (ethyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-methyl- butyric acid (intermediate 9) and (3-Fluoro-4- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 12) 
                 640.3 
                 0.0024 
               
               
                   
               
               
                 70 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 623.5 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4- [4-(ethyl- methanesulfonyl- amino)-piperidin-1- yl]-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- (ethyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-methyl- butyric acid (intermediate 9) and (3,4-Dichloro- benzyl)-methyl- amine (commercially available) 
                 624.3 
                 0.0012 
               
               
                   
               
               
                 71 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 609.4 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4- [4-(ethyl- methanesulfonyl- amino)-piperidin-1- yl]-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (ethyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-methyl- butyric acid (intermediate 9) and 3,4-Dichloro- benzylamine (commercially available) 
                 610.1 
                 0.0028 
               
               
                   
               
               
                 72 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 589.0 
                 N-(4-Chloro- benzyl)-2-(3,4- dichloro-phenyl)-4- [4-(ethyl- methanesulfonyl- amino)-piperidin-1- yl]-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (ethyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-methyl- butyric acid (intermediate 9) and (4-Chloro- benzyl)-methyl- amine (commercially available) 
                 590.2 
                 0.0022 
               
               
                   
               
               
                 73 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 657.0 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4- [4-(ethyl- methanesulfonyl- amino)-piperidin-1- yl]-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (ethyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-methyl- butyric acid (intermediate 9) and 4-Chloro-3- trifluoromethyl- benzylamine (commercially available) 
                 658.3 
                 0.0015 
               
               
                   
               
               
                 74 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 640.6 
                 2-(3,4-Dichloro- phenyl)-4-[4-(ethyl- methanesulfonyl- amino)-piperidin-1- yl]-N-(4-fluoro-3- trifluoromethyl- benzyl)-2,N- dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (ethyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-methyl- butyric acid (intermediate 9) and (4-Fluoro-3- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 13) 
                 640.2 
                 0.0013 
               
               
                   
               
               
                 75 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 589.0 
                 N-(3-Chloro- benzyl)-2-(3,4- dichloro-phenyl)-4- [4-(ethyl- methanesulfonyl- amino)-piperidin-1- yl]-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (ethyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-methyl- butyric acid (intermediate 9) and (3-Chloro- benzyl)-methyl- amine (commercially available) 
                 590.2 
                 0.0039 
               
               
                   
               
               
                 76 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 622.6 
                 2-(3,4-Dichloro- phenyl)-4-[4-(ethyl- methanesulfonyl- amino)-piperidin-1- yl]-2,N-dimethyl-N- (4-trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (ethyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-methyl- butyric acid (intermediate 9) and Methyl-(4- trifluoromethyl- benzyl)-amine (commercially available) 
                 622.4 
                 0.0017 
               
               
                   
               
               
                 77 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 568.6 
                 2-(3,4-Dichloro- phenyl)-4-[4-(ethyl- methanesulfonyl- amino)-piperidin-1- yl]-2,N-dimethyl-N- (4-methyl-benzyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (ethyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-methyl- butyric acid (intermediate 9) and Methyl-(4- methyl-benzyl)- amine (commercially available) 
                 568.3 
                 0.0031 
               
               
                   
               
               
                 78 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 589.0 
                 N-(2-Chloro- benzyl)-2-(3,4- dichloro-phenyl)-4- [4-(ethyl- methanesulfonyl- amino)-piperidin-1- yl]-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-[4- (ethyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-methyl- butyric acid (intermediate 9) and (2-Chloro- benzyl)-methyl- amine (commercially available) 
                 590.2 
                 0.0036 
               
               
                   
               
               
                 79 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 639.5 
                 2-(3,4-Dichloro- phenyl)-N-[1-(3,4- dichloro-phenyl)-2- hydroxy-ethyl]-4-[4- (ethyl- methanesulfonyl- amino)-piperidin-1- yl]-2-methyl- butyramide; diastereoisomer 1 
                 2-(3,4-Dichloro- phenyl)-4-[4- (ethyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-methyl- butyric acid (intermediate 9) and 2-Amino-2- (3,4-dichloro- phenyl)-ethanol (WO 2005058892) 
                 640.3 
                 0.0015 
               
               
                   
               
               
                 80 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 639.5 
                 2-(3,4-Dichloro- phenyl)-N-[1-(3,4- dichloro-phenyl)-2- hydroxy-ethyl]-4-[4- (ethyl- methanesulfonyl- amino)-piperidin-1- yl]-2-methyl- butyramide; diastereoisomer 2 
                 2-(3,4-Dichloro- phenyl)-4-[4- (ethyl- methanesulfonyl- amino)-piperidin- 1-yl]-2-methyl- butyric acid (intermediate 9) and 2-Amino-2- (3,4-dichloro- phenyl)-ethanol (WO 2005058892) 
                 640.2 
                 0.0133 
               
               
                   
               
               
                 81 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 602.5 
                 2-(3,4-Dichloro- phenyl)-N-(3- fluoro-4- trifluoromethyl- benzyl)-2,N- dimethyl-4-[4-(2- oxo-pyrrolidin-1- yl)-piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and (3-Fluoro-4- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 12) 
                 601.9 
                 0.003 
               
               
                   
               
               
                 82 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 585.4 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)- 2,N-dimethyl-4-[4- (2-oxo-pyrrolidin-1- yl)-piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-Oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and (3,4-Dichloro- benzyl)-methyl- amine (commercially available) 
                 585.7 
                 0.0012 
               
               
                   
               
               
                 83 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 571.4 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-2- methyl-4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and 3,4-Dichloro- benzylamine (commercially available) 
                 569.7 
                 0.0023 
               
               
                   
               
               
                 84 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 551.0 
                 N-(4-Chloro- benzyl)-2-(3,4- dichloro-phenyl)- 2,N-dimethyl-4-[4- (2-oxo-pyrrolidin 1- yl)-piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and (4-Chloro- benzyl)-methyl- amine (commercially available) 
                 549.9 
                 0.0021 
               
               
                   
               
               
                 85 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 619.0 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)- 2,N-dimethyl-4-[4- (2-oxo-pyrrolidin-1- yl)-piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-Oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and 4-Chloro-3- trifluoromethyl- benzylamine (commercially available) 
                 619.7 
                 0.0014 
               
               
                   
               
               
                 86 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 602.5 
                 2-(3,4-Dichloro phenyl)-N-(4- fluoro-3- trifluoromethyl- benzyl)-2,N- dimethyl-4-[4-(2- oxo-pyrrolidin-1- yl)-piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and (4-Fluoro-3- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 13) 
                 601.9 
                 0.0014 
               
               
                   
               
               
                 87 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 551.0 
                 N-(3-Chloro- benzyl)-2-(3,4- dichloro-phenyl)- 2,N-dimethyl-4-[4- (2-oxo-pyrrolidin-1- yl)-piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and (3-Chloro- benzyl)-methyl- amine (commercially available) 
                 549.9 
                 0.0046 
               
               
                   
               
               
                 88 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 584.5 
                 2-(3,4-Dichloro- phenyl)-2,N- dimethyl-4-[4-(2- oxo-pyrrolidin-1- yl)-piperidin-1-yl]- N-(4- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-Oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and Methyl-(4- trifluoromethyl- benzyl)-amine (commercially available) 
                 583.7 
                 0.0018 
               
               
                   
               
               
                 89 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 530.5 
                 2-(3,4-Dichloro- phenyl)-2,N- dimethyl-N-(4- methyl-benzyl)-4- [4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and Methyl-(4- methyl-benzyl)- amine (commercially available) 
                 529.9 
                 0.0053 
               
               
                   
               
               
                 90 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 551.0 
                 N-(2-Chloro- benzyl)-2-(3,4- dichloro-phenyl)- 2,N-dimethyl-4-[4- (2-oxo-pyrrolidin-1- yl)-piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and (3-Chloro- benzyl)-methyl- amine (commercially available) 
                 551.8 
                 0.0025 
               
               
                   
               
               
                 91 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 516.5 
                 2-(3,4-Dichloro- phenyl)-2-methyl-4- [4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]-N- (1-phenyl-ethyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-Oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and 1-Phenyl- ethylamine (commercially available) 
                 516.2 
                 0.0512 
               
               
                   
               
               
                 92 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 530.5 
                 2-(3,4-Dichloro- phenyl)-2-methyl- N-(1-methyl-1- phenyl-ethyl)-4-[4- (2-oxo-pyrrolidin-1- yl)-piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and 1-Methyl-1- phenyl-ethylamine (commercially available) 
                 530.2 
                 0.9912 
               
               
                   
               
               
                 93 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 528.5 
                 2-(3,4-Dichloro phenyl)-2-methyl-4- [4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]-N- (1-phenyl- cyclopropyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and 1-Phenyl- cyclopropylamine (commercially available) 
                 528.1 
                 0.1842 
               
               
                   
               
               
                 94 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 601.4 
                 2-(3,4-Dichloro- phenyl)-N-[-1-(3,4- dichloro-phenyl)-2- hydroxy-ethyl]-2- methyl-4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyramide; diastereoisomer 1 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and 2-Amino-2- (3,4-dichloro- phenyl)-ethanol (WO 2005058892) 
                 602.1 
                 0.003 
               
               
                   
               
               
                 95 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 570.5 
                 2-(3,4-Dichloro- phenyl)-2-methyl-4- [4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]-N- (2,2,2-trifluoro-1- phenyl-ethyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and 2,2,2-Trifluoro- 1-phenyl- ethylamine (commercially available) 
                 572.2 
                 0.0047 
               
               
                   
               
               
                 96 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 588.5 
                 2-(3,4-Dichloro- phenyl)-2-methyl-4- [4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]-N- [2,2,2-trifluoro-1-(4- fluoro-phenyl)- ethyl]-butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and 2,2,2-Trifluoro- 1-(4-fluoro-phenyl)- ethylamine (commercially available) 
                 588.3 
                 0.0072 
               
               
                   
               
               
                 97 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 638.5 
                 2-(3,4-Dichloro- phenyl)-2-methyl-4- [4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]-N- [2,2,2-trifluoro-1-(4- trifluoromethyl- phenyl)-ethyl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-Oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and 2,2,2-Trifluoro- l-(4- trifluoromethyl- phenyl)-ethylamine (commercially available) 
                 638.2 
                 0.0081 
               
               
                   
               
               
                 98 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 601.4 
                 2-(3,4-Dichloro- phenyl)-N-[1-(3,4- dichloro-phenyl)-2- hydroxy-ethyl]-2- methyl-4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyramide; diastereoisomer 2 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyric acid (intermediate 10) and 2-Amino-2- (3,4-dichloro- phenyl)-ethanol (WO 2005058892) 
                 602.1 
                 0.0499 
               
               
                   
               
               
                 99 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 590.5 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-N-(3- fluoro-4- trifluoromethyl- benzyl)-2-methyl- butyramide 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and 3-Fluoro-4- trifluoromethyl- benzylamine (commercially available) 
                 590.3 
                 0.0058 
               
               
                   
               
               
                 100  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 573.4 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-N-(3,4-dichloro- benzyl)-2-(3,4- dichloro-phenyl)- 2,N-dimethyl- butyramide 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and (3,4-Dichloro- benzyl)-methyl- amine (commercially available) 
                 574.2 
                 0.003 
               
               
                   
               
               
                 101  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 559.4 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-N-(3,4-dichloro- benzyl)-2-(3,4- dichloro-phenyl)-2- methyl-butyramide 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and 3,4-Dichloro- benzylamine (commercially available) 
                 560.2 
                 0.0068 
               
               
                   
               
               
                 102  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 539.0 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-N-(4-chloro- benzyl)-2-(3,4- dichloro-phenyl)- 2,N-dimethyl- butyramide 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and (4-Chloro- benzyl)-methyl- amine (commercially available) 
                 538.3 
                 0.0051 
               
               
                   
               
               
                 103  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 606.9 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-N-(4-chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)- 2,N-dimethyl- butyramide 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and (4-Chloro-3- trifluoromethyl- benzyl)- methyl-amine (commercially available) 
                 608.2 
                 0.0022 
               
               
                   
               
               
                 104  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 590.5 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-N-(4- fluoro-3- trifluoromethyl- benzyl)-2,N- dimethyl- butyramide 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and (4-Fluoro-3- trifluoromethyl- benzyl)-methyl- amine, hydrochloride (intermediate 13) 
                 590.3 
                 0.0023 
               
               
                   
               
               
                 105  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 539.0 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-N-(3-chloro- benzyl)-2-(3,4- dichloro-phenyl)- 2,N-dimethyl- butyramide 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and (3-Chloro- benzyl)-methyl- amine (commercially available) 
                 538.3 
                 0.0087 
               
               
                   
               
               
                 106  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 572.5 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2,N- dimethyl-N-(4- trifluoromethyl- benzyl)-butyramide 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and Methyl-(4- trifluoromethyl- benzyl)-amine (commercially available) 
                 572.2 
                 0.0051 
               
               
                   
               
               
                 107  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 518.5 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2,N- dimethyl-N-(4- methyl-benzyl)- butyramide 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and Methyl-(4- methyl-benzyl)- amine (commercially available) 
                 518.4 
                 0.0106 
               
               
                   
               
               
                 108  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 539.0 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-N-(2-chloro- benzyl)-2-(3,4- dichloro-phenyl)- 2,N-dimethyl- butyramide 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and (2-Chloro- benzyl)-methyl- amine (commercially available) 
                 538.5 
                 0.012 
               
               
                   
               
               
                 109  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 589.4 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-N-[1-(3,4- dichloro-phenyl)-2- hydroxy-ethyl]-2- methyl-butyramide; diastereoisomer 1 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and 2-Amino-2- (3,4-dichloro- phenyl)-ethanol (WO 2005058892) 
                 590.2 
                 0.0056 
               
               
                   
               
               
                 110  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 589.4 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-N-[1-(3,4- dichloro-phenyl)-2- hydroxy-ethyl]-2- methyl-butyramide; diastereoisomer 2 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and 2-Amino-2- (3,4-dichloro- phenyl)-ethanol (WO 2005058892) 
                 590.2 
                 0.1103 
               
               
                   
               
             
          
         
       
     
       Example 111 
     N-(4-Chloro-benzyl)-2-(4-fluoro-phenyl)-N-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide 
       [0197]    
       
                 
         
             
             
         
       
     
       a) Step 1 
     N-(4-Chloro-benzyl)-2-(4-fluoro-phenyl)-N-methyl-acetamide 
       [0198]    
       
                 
         
             
             
         
       
     
         [0199]    A mixture of 1.09 g (7 mmol) 4-fluorophenylacetic acid, 1.37 g (9 mmol) (4-chloro-benzyl)-methyl-amine, 2.84 g (9 mmol) TBTU and 6 mL (35 mmol) DIPEA in 50 mL DMF was stirred at room temperature for 16 h. After evaporation of all volatiles Na 2 CO 3  aq. was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with NaCl aq., dried with Na 2 SO 4 , filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were evaporated to yield 1.35 g (65%) of the title compound as yellow oil. MS (m/e): 292.2 (MH + ). 
       b) Step 2 
     N-(4-Chloro-benzyl)-2-(4-fluoro-phenyl)-N-methyl-4-oxo-butyramide 
       [0200]    
       
                 
         
             
             
         
       
     
         [0201]    A solution of 1.10 g (3.78 mmol) N-(4-chloro-benzyl)-2-(4-fluoro-phenyl)-N-methyl-acetamide in 10 mL DMF at 0° C. was treated with 0.18 g (4 mmol) NaH (55% in oil) and allowed to stir at 40-50° C. for 3 h. After cooling to 0° C. the mixture was treated with 0.80 g (5 mmol) bromoacetaldehyde dimethylacetal in 10 mL DMF and the mixture was stirred at room temperature for 16 h. After evaporation of all volatiles the residue was treated with water and THF and 1N HCl aq. was added. The mixture was stirred at room temperature for 2 h and extracted with ethyl acetate. The combined organic phases were washed with NaCl aq. sat., dried with Na 2 SO 4 , filtered and evaporated. The residue was purified by column chromatography on silica eluting with a gradient formed from tert.-butylmethyl ether and heptane. The product containing fractions were evaporated to yield 0.90 g of the title compound which was used without further purification in the consecutive step. MS (m/e): 332.4 (MH + ). 
       c) Step 3 
       [0202]    A mixture of 237 mg (0.71 mmol) N-(4-chloro-benzyl)-2-(4-fluoro-phenyl)-N-methyl-4-oxo-butyramide, 131 mg (0.77 mmol) 1-piperidin-4-yl-pyrrolidin-2-one, 0.226 (10.7 mmol) sodium triacetoxyborohydride and 64 mg acetic acid in 10 mL THF was stirred at room temperature for 17 h. Water and Na 2 CO 3  aq. was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with NaCl aq. sat., dried with Na 2 SO 4 , filtered and evaporated. The residue was purified by column chromatography on silica eluting with a gradient formed from DCM, methanol and NH 3  aq. The product containing fractions were evaporated to yield 277 mg (0.57 mmol) of the title compound as white foam. MS (m/e): 486.4 (MH + ). 
         [0203]    In analogy to the procedure described for the synthesis of N-(4-chloro-benzyl)-2-(4-fluoro-phenyl)-N-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide (example 111) further piperidine derivatives have been synthesized from the starting materials listed in table 2. Table 2 comprises example 112-117. 
         [0000]    
       
         
               
               
               
               
               
               
               
             
           
               
                 Table 2 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 MW 
                 hNK3 
               
               
                   
                   
                   
                 Systematic 
                   
                 found 
                 Ki 
               
               
                 No 
                 structure 
                 MW 
                 Name 
                 starting materials 
                 (MH+) 
                 (uM) 
               
               
                   
               
             
             
               
                 111 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 486.0 
                 N-(4-Chloro- benzyl)-2-(4- fluoro- phenyl)-N- methyl-4-[4- (2-oxo- pyrrolidin-1- yl)-piperidin- 1-yl]- butyramide 
                 4-Fluorophenylacetic acid, (4-Chloro- benzyl)-methyl- amine, bromoaetaldehyde dimethylacetal and 1- Piperidin-4-yl- pyrrolidin-2-one 
                 486.4 
                 0.4084 
               
               
                   
               
               
                 112 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 536.9 
                 N-(4-Chloro- benzyl)-2- (2,4-dichloro- phenyl)-N- methyl-4-[4- (2-oxo- pyrrolidin-1- yl)-piperidin- 1-yl]- butyramide 
                 2,4- Dichlorophenylacetic acid, (4-Chloro- benzyl)-methyl- amine, bromoaetaldehyde dimethylacetal and 1- Piperidin-4-yl- pyrrolidin-2-one 
                 536.2 
                 0.1281 
               
               
                   
               
               
                 113 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 498.1 
                 N-(4-Chloro- benzyl)-2-(4- methoxy- phenyl)-N- methyl-4-[4- (2-oxo- pyrrolidin-1- yl)-piperidin- 1-yl]- butyramide 
                 4- Methoxyphenylacetic acid, (4-Chloro- benzyl)-methyl- amine, bromoaetaldehyde dimethylacetal and 1- Piperidin-4-yl- pyrrolidin-2-one 
                 498.1 
                 0.7748 
               
               
                   
               
               
                 114 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 468.0 
                 N-(4-Chloro- benzyl)-N- methyl-4-[4- (2-oxo- pyrrolidin-1- yl)-piperidin- 1-yl]-2- phenyl- butyramide 
                 Phenylacetic acid, (4- Chloro-benzyl)- methyl-amine, bromoaetaldehyde dimethylacetal and 1- Piperidin-4-yl- pyrrolidin-2-one 
                 468.3 
                 0.5603 
               
               
                   
               
               
                 115 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 536.9 
                 N-(4-Chloro- benzyl)-2- (3,4-dichloro- phenyl)-N- methyl-4-[4- (2-oxo- pyrrolidin-1- yl)-piperidin- 1-yl]- butyramide 
                 3,4- Dichlorophenylacetic acid, (4-Chloro- benzyl)-methyl- amine, bromoaetaldehyde dimethylacetal and 1- Piperidin-4-yl- pyrrolidin-2-one 
                 536.1 
                 0.0081 
               
               
                   
               
               
                 116 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 504.0 
                 N-(4-Chloro- benzyl)-2- (3,4-difluoro- phenyl)-N- methyl-4-[4- (2-oxo- pyrrolidin-1- yl)-piperidin- 1-yl]- butyramide 
                 3,4- Difluorophenylacetic acid, (4-Chloro- benzyl)-methyl- amine, bromoaetaldehyde dimethylacetal and 1- Piperidin-4-yl- pyrrolidin-2-one 
                 504.2 
                 0.1977 
               
               
                   
               
               
                 117 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 503.5 
                 N-(4-Chloro- benzyl)-2-(6- chloro- pyridin-3-yl)- N-methyl-4- [4-(2-oxo- pyrrolidin-1- yl)-piperidin- 1-yl]- butyramide 
                 (6-Chloro-pyridin-3- yl)-acetic acid, (4- Chloro-benzyl)- methyl-amine, bromoaetaldehyde dimethylacetal and 1- Piperidin-4-yl- pyrrolidin-2-one 
                 503.2 
                 0.3872 
               
               
                   
               
             
          
         
       
     
         [0204]    Enantiomers were accessed from their respective starting materials (as listed in table 3) by column chromatography on appropriate chiral phase. Isolated compounds were optionally transferred into their respective salts by treatment with acid. Table 3 comprises example 118-124. 
         [0000]    
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 MW 
                 hNK3 
               
               
                   
                   
                   
                   
                 starting 
                 found 
                 Ki 
               
               
                 No 
                 structure 
                 MW 
                 Systematic Name 
                 materials 
                 (MH+) 
                 (uM) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 118 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 639.0 
                 (S or R)-2-(3,4- Dichloro-phenyl)-N- (4-fluoro-3- trifluoromethyl- benzyl)-2,N-dimethyl- 4-[4-(2-oxo-pyrrolidin- 1-yl)-piperidin-1-yl]- butyramide; hydrochloride 
                 chiral separation from example 86 
                 602.4 
                 0.1709 
               
               
                   
               
               
                 119 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 639.0 
                 (R or S)-2-(3,4- Dichloro-phenyl)-N- (4-fluoro-3- trifluoromethyl- benzyl)-2,N-dimethyl- 4-[4-(2-oxo-pyrrolidin- 1-yl)-piperidin-1-yl]- butyramide; hydrochloride 
                 chiral separation from example 86 
                 602.4 
                 0.0008 
               
               
                   
               
               
                 120 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 601.4 
                 (R or S)-2-(3,4- Dichloro-phenyl)-N- [(S or R)-1-(3,4- dichloro-phenyl)-2- hydroxy-ethyl]-2- methyl-4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyramide 
                 chiral separation from example 94 
                 602.4 
                 0.002 
               
               
                   
               
               
                 121 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 590.5 
                 (S or R)-4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2-(3,4- dichloro-phenyl)-N-(4- fluoro-3- trifluoromethyl- benzyl)-2,N-dimethyl- butyramide 
                 chiral separation from example 104 
                 590.3 
                 0.1735 
               
               
                   
               
               
                 122 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 590.5 
                 (R or S)-4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2-(3,4- dichloro-phenyl)-N-(4- fluoro-3- trifluoromethyl- benzyl)-2,N-dimethyl- butyramide 
                 chiral separation from example 104 
                 590.3 
                 0.0015 
               
               
                   
               
               
                 123 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 612.5 
                 (S or R)-2-(3,4- Dichloro-phenyl)-N- (3-fluoro-4- trifluoromethyl- benzyl)-4-(4- methanesulfonylamino- piperidin-1-yl)-2,N- dimethyl-butyramide 
                 chiral separation from example 45 
                 612.2 
                 0.8004 
               
               
                   
               
               
                 124 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 612.5 
                 (R or S)-2-(3,4- Dichloro-phenyl)-N- (3-fluoro-4- trifluoromethyl- benzyl)-4-(4- methanesulfonylamino- piperidin-1-yl)-2,N- dimethyl-butyramide 
                 chiral separation from example 45 
                 612.2 
                 0.0188 
               
               
                   
               
             
          
         
       
     
       Example 125 
     2-(3,4-Dichloro-phenyl)-N-[1-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-2-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide 
       [0205]    
       
                 
         
             
             
         
       
     
         [0206]    A mixture of 0.1 g (0.22 mmol) 2-(3,4-dichloro-phenyl)-2-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyric acid (intermediate 10), 0.068 g (0.027 mmol) 1-(4-Fluoro-3-trifluoromethyl-phenyl)-ethylamine; hydrochloride (intermediate 20), 0.016 g (0.027 mmol) HATU and 0.23 mL DIPEA in 1.5 mL DMF was stirred at room temperature over night. The mixture was subjected to purification by reversed phase HPLC eluting with a gradient formed from acetonitrile, water and NEt 3 , the product containing fractions were evaporated to yield 0.079 g (59%) of the title compound as light yellow viscous oil. MS (m/e): 601.9 (MH + ). 
         [0207]    In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-N-[1-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-2-methyl-4-[4-(2-oxo-pyrrolidin-1-yl)-piperidin-1-yl]-butyramide (example 125) further piperidine derivatives have been prepared from the starting materials listed in table 4. Optionally diastereoisomeric/epimeric mixture have been separated by column chromatography. Table 4 comprises example 125-example 169. 
         [0000]    
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 MW 
                 hNK3 
               
               
                   
                   
                   
                   
                   
                 found 
                 Ki 
               
               
                 No 
                 structure 
                 MW 
                 Systematic Name 
                 starting materials 
                 (MH+) 
                 (uM) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 125 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 602.497 
                 2-(3,4-Dichloro- phenyl)-N-[1-(4- fluoro-3- trifluoromethyl- phenyl)-ethyl]-2- methyl-4-[4-(2- oxo-pyrrolidin-1- yl)-piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl-4- [4-(2-oxo-pyrrolidin- 1-yl)-piperidin-1-yl]- butyric acid (intermediate 10) and 1-(4-Fluoro-3- trifluoromethyl- phenyl)-ethylamine; hydrochloride (intermediate 19) 
                 601.9 
                 0.0254 
               
               
                   
               
               
                 126 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 616.523 
                 2-(3,4-Dichloro- phenyl)-N-[1-(4- fluoro-3- trifluoromethyl- phenyl)-ethyl]-2,N- dimethyl-4-[4-(2- oxo-pyrrolidin-1- yl)-piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl-4- [4-(2-oxo-pyrrolidin- 1-yl)-piperidin-1-yl]- butyric acid (intermediate 10) and 1-(4-Fluoro-3- trifluoromethyl- phenyl)-ethyl-methyl amine; hydrochloride (Intermediate 20) 
                 615.9 
                 0.0303 
               
               
                   
               
               
                 127 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 530.536 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]-N- ((S)-1-phenyl- propyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl-4- [4-(2-oxo-pyrrolidin- 1-yl)-piperidin-1-yl]- butyric acid (intermediate 10) and (S)-(−)-1- phenylpropylamine (commercially available) 
                 530.2 
                 0.0052 
               
               
                   
               
               
                 128 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 530.536 
                 2-(3,4-Dichloro- phenyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]-N- ((R)-1-phenyl- propyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl-4- [4-(2-oxo-pyrrolidin- 1-yl)-piperidin-1-yl]- butyric acid (intermediate 10) and (R)-(+)-1- phenylpropylamine (commercially available) 
                 530.2 
                 0.0902 
               
               
                   
               
               
                 129 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 550.499 
                 2-(3,4-Dichloro- phenyl)-N-[(R)-1- (4-fluoro-phenyl)- 2-hydroxy-ethyl]-2- (R or S) methyl-4- [4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl-4- [4-(2-oxo-pyrrolidin- 1-yl)-piperidin-1-yl]- butyric acid (intermediate 10) and (R)-2-Amino-2-(4- fluoro-phenyl)- ethanol (commercially available) 
                 550.4 
                 0.0082 
               
               
                   
               
               
                 130 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 550.499 
                 2-(3,4-Dichloro- phenyl)-N-[(R)-1- (4-fluoro-phenyl)- 2-hydroxy-ethyl]-2- (S or R) methyl-4- [4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl-4- [4-(2-oxo-pyrrolidin- 1-yl)-piperidin-1-yl]- butyric acid (intermediate 10) 
                 550.4 
                 0.1007 
               
               
                   
               
               
                 131 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 588.47 
                 2-(3,4-Dichloro- phenyl)-N-(4- fluoro-3- trifluoromethyl- benzyl)-2-methyl- 4-[4-(2-oxo- pyrrolidin-1-yl)- piperidin-1-yl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-2-methyl-4- [4-(2-oxo-pyrrolidin- 1-yl)-piperidin-1-yl]- butyric acid (intermediate 10) and 4-fluoro-3- (trifluoromethyl) benzylamine (commercially available 
                 588.1 
                 0.0034 
               
               
                   
               
               
                 132 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 590.486 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-N-[1-(4- fluoro-3- trifluoromethyl- phenyl)-ethyl]-2- methyl-butyramide 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and 1-(4-Fluoro-3- trifluoromethyl- phenyl)-ethylamine; hydrochloride (intermediate 19) 
                 589.9 
                 0.0462 
               
               
                   
               
               
                 133 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 520.497 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-N-((S)-2- hydroxy-1-phenyl- ethyl)-2-methyl- butyramide 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and (S)-(−)-1- phenylpropylamine (commercially available) 
                 520.2 
                 0.5257 
               
               
                   
               
               
                 134 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 520.497 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-N-((R)-2- hydroxy-1-phenyl- ethyl)-2-methyl- butyramide 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and (R)-(−)-1- phenylpropylamine (commercially available) 
                 520.3 
                 0.0356 
               
               
                   
               
               
                 135 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 576.459 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- N-[2,2,2-trifluoro- 1-(4-fluoro- phenyl)-ethyl]- butyramide 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and 2,2,2-Trifluoro-1-(4- fluorophenyl)ethyl- amine (commercially available) 
                 575.8 
                 0.0126 
               
               
                   
               
               
                 136 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 554.943 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-N- [1-(4-chloro- phenyl)-2-hydroxy- ethyl]-2-(3,4- dichloro-phenyl)-2- methyl-butyramide (diastereosisomer 1) 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and 4- Chlorophenylglycinol (commercially available) 
                 553.7 
                 0.0096 
               
               
                   
               
               
                 137 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 554.943 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-N- [1-(4-chloro- phenyl)-2-hydroxy- ethyl]-2-(3,4- dichloro-phenyl)-2- methyl-butyramide (diastereosisomer 2) 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and 4- Chlorophenylglycinol (commercially available) 
                 553.7 
                 0.056 
               
               
                   
               
               
                 138 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 538.488 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-N-[1-(4- fluoro-phenyl)-2- hydroxy-ethyl]-2- methyl-butyramide (diastereoisomer 1) 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and 4- Fluorophenylglycinol (commercially available) 
                 538 
                 0.0293 
               
               
                   
               
               
                 139 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 538.488 
                 4-[4-(Acetyl- methyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-N-[1-(4- fluoro-phenyl)-2- hydroxy-ethyl]-2- methyl-butyramide (diastereoisomer 2) 
                 4-[4-(Acetyl-methyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 11) and 4- Fluorophenylglycinol (commercially available) 
                 538 
                 0.1415 
               
               
                   
               
               
                 140 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 564.53 
                 4-[4-(Acetyl- cyclopropyl- amino)-piperidin- 1-yl]-2-(3,4- dichloro-phenyl)- N-[1-(4-fluoro- phenyl)-2-hydroxy- ethyl]-2-methyl- butyramide (diastereoisomer 1) 
                 4-[4-(Acetyl- cyclopropyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 14) and 4- Fluorophenylglycinol (commercially available) 
                 564.4 
                 0.0333 
               
               
                   
               
               
                 141 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 564.53 
                 4-[4-(Acetyl- cyclopropyl- amino)-piperidin- 1-yl]-2-(3,4- dichloro-phenyl)- N-[1-(4-fluoro- phenyl)-2-hydroxy- ethyl]-2-methyl- butyramide (diastereoisomer 2) 
                 4-[4-(Acetyl- cyclopropyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 14) and 4- Fluorophenylglycinol (commercially available) 
                 564.4 
                 0.1648 
               
               
                   
               
               
                 142 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 580.98 
                 4-[4-(Acetyl- cyclopropyl- amino)-piperidin- 1-yl]-N-[1-(4- chloro-phenyl)-2- hydroxy-ethyl]-2- (3,4-dichloro- phenyl)-2-methyl- butyramide (diastereoisomer 1) 
                 4-[4-(Acetyl- cyclopropyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 14) and 4- Chlorophenylglycinol (commercially available) 
                 580.4 
                 0.0109 
               
               
                   
               
               
                 143 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 580.98 
                 4-[4-(Acetyl- cyclopropyl- amino)-piperidin- 1-yl]-N-[1-(4- chloro-phenyl)-2- hydroxy-ethyl]-2- (3,4-dichloro- phenyl)-2-methyl- butyramide (diastereoisomer 2) 
                 4-[4-(Acetyl- cyclopropyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 14) and 4- Chlorophenylglycinol (commercially available) 
                 580.4 
                 0.0877 
               
               
                   
               
               
                 144 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 615.43 
                 4-[4-(Acetyl- cyclopropyl- amino)-piperidin- 1-yl]-2-(3,4- dichloro-phenyl)- N-[1-(3,4-dichloro- phenyl)-2-hydroxy- ethyl]-2-methyl- butyramide (diastereoisomer 1) 
                 4-[4-(Acetyl- cyclopropyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 14) and 3,4-di- Chlorophenylglycinol (commercially available) 
                 616.2 
                 0.0101 
               
               
                   
               
               
                 145 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 615.43 
                 4-[4-(Acetyl- cyclopropyl- amino)-piperidin- 1-yl]-2-(3,4- dichloro-phenyl)- N-[1-(3,4-dichloro- phenyl)-2-hydroxy- ethyl]-2-methyl- butyramide (diastereoisomer 2) 
                 4-[4-(Acetyl- cyclopropyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 14) and 3,4-di- Chlorophenylglycinol (commercially available) 
                 616.2 
                 0.0502 
               
               
                   
               
               
                 146 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 582.54 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin- 1-yl}-2-(3,4- dichloro-phenyl)- N-[1-(4-fluoro- phenyl)-2-hydroxy- ethyl]-2-methyl- butyramide (diastereoisomer 1) 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin-1- yl}-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 15) and 4- Fluorophenylglycinol (commercially available) 
                 582.2 
                 0.0007 
               
               
                   
               
               
                 147 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 598.995 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin- 1-yl}-N-[1-(4- chloro-phenyl)-2- hydroxy-ethyl]-2- (3,4-dichloro- phenyl)-2-methyl- butyramide 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin-1- yl}-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 15) and 4- Chlorophenylglycinol (commercially available) 
                 598.3 
                 0.3824 
               
               
                   
               
               
                 148 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 633.44 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin- 1-yl}-2-(3,4- dichloro-phenyl)- N-[1-(3,4-dichloro- phenyl)-2-hydroxy- ethyl]-2-methyl- butyramide (diastreoisomer 1) 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin-1- yl}-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 15) and 3,4-di- Chlorophenylglycinol (commercially available) 
                 634.2 
                 0.0038 
               
               
                   
               
               
                 149 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 633.44 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin- 1-yl}-2-(3,4- dichloro-phenyl)- N-[(S)-1-(3,4- dichloro-phenyl)-2- hydroxy-ethyl]-2- methyl-butyramide (diastreoisomer 2) 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin-1- yl}-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 15) and 3,4-di- Chlorophenylglycinol (commercially available) 
                 634.3 
                 0.0194 
               
               
                   
               
               
                 150 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 582.54 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin- 1-yl}-2-(3,4- dichloro-phenyl)- N-[(R)-1-(4-fluoro- phenyl)-2-hydroxy- ethyl]-2-(R or S) methyl-butyramide 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin-1- yl}-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 15) and (R)-4- Fluorophenylglycinol (commercially available) 
                 582.2 
                 0.0017 
               
               
                   
               
               
                 151 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 582.54 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin- 1-yl}-2-(3,4- dichloro-phenyl)- N-[(R)-1-(4-fluoro- phenyl)-2-hydroxy- ethyl]-2-(S or R) methyl-butyramide 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin-1- yl}-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 15) and (R)-4- Fluorophenylglycinol (commercially available) 
                 582.2 
                 0.0211 
               
               
                   
               
               
                 152 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 562.578 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin- 1-yl}-2-(3,4- dichloro-phenyl)-2- methyl-N-((S)-1- phenyl-propyl)- butyramide 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin-1- yl}-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 15) and (S)-(−)-1- phenylpropylamine (commercially available) 
                 562.2 
                 0.0011 
               
               
                   
               
               
                 153 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 562.578 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin- 1-yl}-2-(3,4- dichloro-phenyl)-2- methyl-N-((R)-1- phenyl-propyl)- butyramide 
                 4-{4-[Acetyl-(2- methoxy-ethyl)- amino]-piperidin-1- yl}-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 15) and (R)-(+)-1- phenylpropylamine (commercially available) 
                 562.2 
                 0.0609 
               
               
                   
               
               
                 154 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 524.46 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-N-[1-(4- fluoro-phenyl)-2- hydroxy-ethyl]-2- methyl-butyramide (diastereoisomer 1) 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-2- methylbutyric acid (intermediate 16) and 4- Fluorophenylglycinol (commercially available) 
                 524.3 
                 0.1703 
               
               
                   
               
               
                 155 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 524.46 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-N-[1-(4- fluoro-phenyl)-2- hydroxy-ethyl]-2- methyl-butyramide (diastereoisomer 2) 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-2- methylbutyric acid (intermediate 16) and 4- Fluorophenylglycinol (commercially available) 
                 524.3 
                 0.0138 
               
               
                   
               
               
                 156 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 540.916 
                 4-(4-Acetylamino- piperidin-1-yl)-N- [1-(4-chloro- phenyl)-2-hydroxy- ethyl]-2-(3,4- dichloro-phenyl)-2- methyl-butyramide (diastereoisomer 1) 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-2- methylbutyric acid (intermediate 16) and 4- Chlorophenylglycinol (commercially available) 
                 540.3 
                 0.0505 
               
               
                   
               
               
                 157 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 540.916 
                 4-(4-Acetylamino- piperidin-1-yl)-N- [1-(4-chloro- phenyl)-2-hydroxy- ethyl]-2-(3,4- dichloro-phenyl)-2- methyl-butyramide (diastereoisomer 2) 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-2- methylbutyric acid (intermediate 16) and 4- Chlorophenylglycinol (commercially available) 
                 540.3 
                 0.7727 
               
               
                   
               
               
                 158 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 575.36 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-N-[(R)-1- (3,4-dichloro- phenyl)-2-hydroxy- ethyl]-2-methyl- butyramide (diastereoisomer 1) 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-2- methylbutyric acid (intermediate 16) and 3,4-di- Chlorophenylglycinol (commercially available) 
                 576.3 
                 0.0346 
               
               
                   
               
               
                 159 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 575.36 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-N-[(S)-1- (3,4-dichloro- phenyl)-2-hydroxy- ethyl]-2-methyl- butyramide (diastereoisomer 2) 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-2- methylbutyric acid (intermediate 16) and 3,4-di- Chlorophenylglycinol (commercially available) 
                 576.3 
                 0.2582 
               
               
                   
               
               
                 160 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 524.461 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-N-[(R)-1- (4-fluoro-phenyl)- 2-hydroxy-ethyl]-2- methyl-butyramide 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-2- methylbutyric acid (intermediate 16) and (R)-4- Fluorophenylglycinol (commercially available) 
                 524.4 
                 0.1998 
               
               
                   
               
               
                 161 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 504.498 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-2-methyl- N-((S)-1-phenyl- propyl)-butyramide 
                 4-(4-Acetylamino- piperidin-1-yl)-2- (3,4-dichloro- phenyl)-2- methylbutyric acid (intermediate 16) and (S)-(−)-1- phenylpropylamine (commercially available) 
                 504.2 
                 0.0442 
               
               
                   
               
               
                 162 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 566.541 
                 4-[4-(Acetyl- propyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-N-[(R)-1- (4-fluoro-phenyl)- 2-hydroxy-ethyl]-2- methyl-butyramide (epimer 1) 
                 4-[4-(Acetyl-propyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 17) and (R)-4- Fluorophenylglycinol (commercially available) 
                 566.4 
                 0.0005 
               
               
                   
               
               
                 163 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 566.541 
                 4-[4-(Acetyl- propyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-N-[(R)-1- (4-fluoro-phenyl)- 2-hydroxy-ethyl]-2- methyl-butyramide (epimer 2) 
                 4-[4-(Acetyl-propyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 17) and (R)-4- Fluorophenylglycinol (commercially available) 
                 566.4 
                 0.0056 
               
               
                   
               
               
                 164 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 546.579 
                 4-[4-(Acetyl- propyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- N-((S)-1-phenyl- propyl)-butyramide 
                 4-[4-(Acetyl-propyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 17) and (S)-(−)-1- phenylpropylamine (commercially available) 
                 546.2 
                 0.0008 
               
               
                   
               
               
                 165 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 546.579 
                 4-[4-(Acetyl- propyl-amino)- piperidin-1-yl]-2- (3,4-dichloro- phenyl)-2-methyl- N-((R)-1-phenyl- propyl)-butyramide 
                 4-[4-(Acetyl-propyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 17) and (R)-(+)-1- phenylpropylamine (commercially available) 
                 546.2 
                 0.0145 
               
               
                   
               
               
                 166 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 552.514 
                 4-[4-(Acetyl-ethyl- amino)-piperidin- 1-yl]-2-(3,4- dichloro-phenyl)- N-[(R)-1-(4-fluoro- phenyl)-2-hydroxy- ethyl]-2-methyl- butyramide (epimer 1) 
                 4-[4-(Acetyl-ethyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 18) and (R)-4- Fluorophenylglycinol (commercially available) 
                 552.4 
                 0.0022 
               
               
                   
               
               
                 167 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 552.514 
                 4-[4-(Acetyl-ethyl- amino)-piperidin- 1-yl]-2-(3,4- dichloro-phenyl)- N-[(R)-1-(4-fluoro- phenyl)-2-hydroxy- ethyl]-2-methyl- butyramide (epimer 2) 
                 4-[4-(Acetyl-ethyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 18) and (R)-4- Fluorophenylglycinol (commercially available) 
                 552.4 
                 0.0349 
               
               
                   
               
               
                 168 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 532.552 
                 4-[4-(Acetyl-ethyl- amino)-piperidin- 1-yl]-2-(3,4- dichloro-phenyl)-2- methyl-N-((S)-1- phenyl-propyl)- butyramide 
                 4-[4-(Acetyl-ethyl- amino)-piperidin-1- yl]-2-(3,4-dichloro- phenyl)-2-methyl- butyric acid (intermediate 18) and (S)-(−)-1- phenylpropylamine (commercially available) 
                 532.2 
                 0.003 
               
               
                   
               
               
                 169 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 532.552 
                 4-[4-(Acetyl-ethyl- amino)-piperidin- 1-yl]-2-(3,4- dichloro-phenyl)-2- methyl-N-((R)-1- phenyl-propyl)- butyramide 
                 4-[4-(Acetyl-ethyl- amino)-piperidin-1- yl]-2-(3,4 dichloro- phenyl)-2-methyl- butyric acid (intermediate 18) and (R)-(+)-1- phenylpropylamine (commercially available) 
                 532.3 
                 0.0576 
               
               
                   
               
             
          
         
       
     
         [0208]    The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methan-sulphonates, p-toluenesulphonates and the like are examples of such salts. 
         [0209]    As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. The compounds of the present invention are antagonists of neurokinin 3 (NK-3) receptors. The compounds were investigated in accordance with the tests given hereinafter. 
       [ 3 H]SR142801 Competition Binding Assay 
       [0210]    hNK3 receptor binding experiment were performed using [ 3 H]SR142801 (Catalog No. TRK1035, specific activity: 74.0 Ci/mmol, Amersham, GE Healthcare UK limited, Buckinghamshire, UK) and membrane isolated from HEK293 cells transiently expressing recombinant human NK3 receptor. After thawing, the membrane homogenates were centrifuged at 48,000×g for 10 min at 4° C., the pellets were resuspended in the 50 mM Tris-HCl, 4 mM MnCl 2 , 1 μM phosphoramidon, 0.1% BSA binding buffer at pH 7.4 to a final assay concentration of 5 μg protein/well. For inhibition experiments, membranes were incubated with [ 3 H]SR142801 at a concentration equal to K D  value of radioligand and 10 concentrations of the inhibitory compound (0.0003-10 μM) (in a total reaction volume of 500 μl) for 75 min at room temperature (RT). At the end of the incubation, membranes were filtered onto unitfilter (96-well white microplate with bonded GF/C filter preincubated 1 h in 0.3% PEI+0.3% BSA, Packard BioScience, Meriden, Conn.) with a Filtermate 196 harvester (Packard BioScience) and washed 4 times with ice-cold 50 mM Tris-HCl, pH 7.4 buffer. Nonspecific binding was measured in the presence of 10 μM SB222200 for both radioligands. The radioactivity on the filter was counted (5 min) on a Packard Top-count microplate scintillation counter with quenching correction after addition of 45 μl of microscint 40 (Canberra Packard S. A., Zurich, Switzerland) and shaking for 1 h. Inhibition curves were fitted according to the Hill equation: y=100/(1+(x/IC 50 ) nH ), where n H =slope factor using Excel-fit 4 software (Microsoft). IC 50  values were derived from the inhibition curve and the affinity constant (IQ values were calculated using the Cheng-Prussoff equation K i =IC 50 /(1+[L]/K D ) where [L] is the concentration of radioligand and K D  is its dissociation constant at the receptor, derived from the saturation isotherm. All experiments were performed in duplicate and the mean±standard error (SEM) of the individual K i  values was calculated. 
         [0211]    Results of some representative compounds of the hNK-3 receptor affinity are shown in the following Table: 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 Example No. 
                 K i  NK3 h (μM) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 45 
                 0.0085 
               
               
                   
                 46 
                 0.0024 
               
               
                   
                 47 
                 0.0021 
               
               
                   
                 48 
                 0.0036 
               
               
                   
                 49 
                 0.0055 
               
               
                   
                 57 
                 0.0059 
               
               
                   
                 58 
                 0.0036 
               
               
                   
                 59 
                 0.0043 
               
               
                   
                 60 
                 0.0026 
               
               
                   
                 69 
                 0.0024 
               
               
                   
                 70 
                 0.0012 
               
               
                   
                 71 
                 0.0028 
               
               
                   
                 72 
                 0.0022 
               
               
                   
                 73 
                 0.0015 
               
               
                   
                 74 
                 0.0013 
               
               
                   
                 75 
                 0.0039 
               
               
                   
                 76 
                 0.0017 
               
               
                   
                 77 
                 0.0031 
               
               
                   
                 78 
                 0.0036 
               
               
                   
                 79 
                 0.0015 
               
               
                   
                 81 
                 0.003 
               
               
                   
                 82 
                 0.0012 
               
               
                   
                 83 
                 0.0023 
               
               
                   
                 84 
                 0.0021 
               
               
                   
                 85 
                 0.0014 
               
               
                   
                 86 
                 0.0014 
               
               
                   
                 87 
                 0.0046 
               
               
                   
                 88 
                 0.0018 
               
               
                   
                 89 
                 0.0053 
               
               
                   
                 90 
                 0.0025 
               
               
                   
                 94 
                 0.003 
               
               
                   
                 95 
                 0.0047 
               
               
                   
                 96 
                 0.0072 
               
               
                   
                 99 
                 0.0058 
               
               
                   
                 100 
                 0.003 
               
               
                   
                 101 
                 0.0068 
               
               
                   
                 102 
                 0.0051 
               
               
                   
                 103 
                 0.0022 
               
               
                   
                 104 
                 0.0023 
               
               
                   
                 105 
                 0.0087 
               
               
                   
                 106 
                 0.0051 
               
               
                   
                 109 
                 0.0056 
               
               
                   
                 115 
                 0.0081 
               
               
                   
                 119 
                 0.0008 
               
               
                   
                 120 
                 0.002 
               
               
                   
                 122 
                 0.0015 
               
               
                   
                 127 
                 0.0052 
               
               
                   
                 129 
                 0.0082 
               
               
                   
                 131 
                 0.0034 
               
               
                   
                 136 
                 0.0096 
               
               
                   
                 146 
                 0.0007 
               
               
                   
                 148 
                 0.0038 
               
               
                   
                 150 
                 0.0017 
               
               
                   
                 152 
                 0.0011 
               
               
                   
                 162 
                 0.0005 
               
               
                   
                 163 
                 0.0056 
               
               
                   
                 164 
                 0.0008 
               
               
                   
                 166 
                 0.0022 
               
               
                   
                 168 
                 0.003 
               
               
                   
                   
               
             
          
         
       
     
         [0212]    The present invention also provides pharmaceutical compositions containing compounds of the invention, for example, compounds of formula I or pharmaceutically acceptable salts thereof 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. 
         [0213]    The pharmaceutical compositions 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 or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragées and hard gelatin capsules. Suitable excipients for soft gelatin capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc. Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc. Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc. Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc. 
         [0214]    Moreover, the pharmaceutical compositions can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. 
         [0215]    The present invention also provides a method for the manufacture of pharmaceutical compositions. Such process comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers. 
         [0216]    The compounds and compositions of the present invention can be administered in a conventional manner, for example, orally, rectally, or parenterally. The pharmaceutical compositions of the invention can be administered orally, for example, in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions, or suspensions. The pharmaceutical compositions also can be administered rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injectable solutions. 
         [0217]    The dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary. 
       Example A 
       [0218]    Tablets of the following composition are manufactured in the usual manner: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 mg/tablet 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Active substance 
                 5 
               
               
                   
                 Lactose 
                 45 
               
               
                   
                 Corn starch 
                 15 
               
               
                   
                 Microcrystalline cellulose 
                 34 
               
               
                   
                 Magnesium stearate 
                 1 
               
               
                   
                 Tablet weight 
                 100 
               
               
                   
                   
               
             
          
         
       
     
       Example B 
       [0219]    Capsules of the following composition are manufactured: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 mg/capsule 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Active substance 
                 10 
               
               
                   
                 Lactose 
                 155 
               
               
                   
                 Corn starch 
                 30 
               
               
                   
                 Talc 
                 5 
               
               
                   
                 Capsule fill weight 
                 200 
               
               
                   
                   
               
             
          
         
       
     
         [0220]    The active substance, lactose and corn starch can be firstly mixed in a mixer and then in a comminuting machine. The mixture can be returned to the mixer, the talc can be added thereto and mixed thoroughly. The mixture then can be filled by machine into hard gelatin capsules. 
       Example C 
       [0221]    Suppositories of the following composition are manufactured: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 mg/supp. 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Active substance 
                 15 
               
               
                   
                 Suppository mass 
                 1285 
               
               
                   
                 Total 
                 1300 
               
               
                   
                   
               
             
          
         
       
     
         [0222]    The suppository mass can be melted in a glass or steel vessel, mixed thoroughly and cooled to 45° C. Thereupon, the finely powdered active substance can be added thereto and stirred until it has dispersed completely. The mixture can be poured into suppository moulds of suitable size and left to cool. The suppositories then can be removed from the moulds and packed individually in wax paper or metal foil.