Abstract:
The present invention relates to a compound of formula I 
                                 
wherein
   R 1 , R 2 , R 3 , R 4 ,   R 9 , R 10 , m and n are as defined herein, or to a pharmaceutically acceptable acid addition salt thereof. The present compounds are high potential NK-3 receptor antagonists for the treatment of depression, bipolar disorders, pain, psychosis, Parkinson&#39;s disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).

Description:
PRIORITY TO RELATED APPLICATION(S) 
     This application claims the benefit of European Patent Application No. 07110143.0, filed Jun. 13, 2007, which is hereby incorporated by reference in its entirety. 
     BACKGROUND OF THE INVENTION 
     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. 
     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). 
     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). 
     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. 
     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 Resources, 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 behavior, 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. 
     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 Resources, Inc., Waltham, Mass.). 
     SUMMARY OF THE INVENTION 
     The present invention provides a compound of formula I 
                                
wherein
     R 1  is hydrogen or lower alkyl;   R 2  is hydrogen, fluoro, hydroxy or lower alkyl;   R 3  is hydrogen or lower alkyl;   R 4  is —CHR 5 -A
       R 5  is hydrogen, lower alkyl, fluoro, CF 3 , CH 2 OH or cycloalkyl;   A is aryl or heteroaryl, each of which is unsubstituted or substituted by (R 6 ) o ;   R 6  is heteroaryl, lower alkyl, lower alkoxy, cyano, halogen, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or NR 7 R 8 , wherein when o is more than one, each R 6  is the same or different;   o is 1, 2 or 3;   R 7  and R 8  are each independently hydrogen or lower alkyl;   
       R 9  is lower alkyl;   R 10  is lower alkyl, lower alkoxy or halogen;   n is 1 or 2;   m is 1 or 2;
 
or a pharmaceutically acceptable acid addition salt thereof.
   
     The invention includes all sterioisomeric forms, including individual diastereoisomers and enantiomers of the compound of formula (I) as well as racemic and non-racemic mixtures thereof. 
     The invention also provides pharmaceutical compositions which contain a therapeutically effective compound of formula I or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. The invention further provides methods for the manufacture of the compounds and compositions of the invention. 
     The present 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). 
     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 
     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. 
     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. 
     The term “halogen” denotes chlorine, iodine, fluorine and bromine. 
     The term “lower alkyl substituted by halogen” denotes a lower 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. 
     The term “lower alkoxy” denotes a lower 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. 
     The term “lower alkoxy substituted by halogen” denotes a lower alkoxy group substituted by halogen as defined above that is attached via an oxygen atom. Preferred lower alkoxy substituted by halogen groups are groups having 1-4 carbon atoms. 
     The term “cycloalkyl” denotes a saturated carbon ring containing from 3-7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. 
     The term “aryl” denotes a cyclic aromatic hydrocarbon radical consisting of one or more fused rings containing 6-14 carbon atoms in which at least one ring is aromatic in nature, for example phenyl, benzyl, naphthyl or indanyl. Preferred is the phenyl group. 
     The term “heteroaryl” denotes a cyclic aromatic radical consisting of one or more fused rings containing 3-14 ring atoms, preferably containing 5-10 ring atoms, in which at least one ring is aromatic in nature, and which contains at least one heteroatom, selected from N, O and S, for example quinoxalinyl, dihydroisoquinolinyl, pyrazinyl, pyrazolyl, pyridinyl, pyridyl, pyrimidyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, furyl or imidazolyl. 
     Preferred heteroaryl groups are quinoxalinyl and pyridinyl. 
     “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered. 
     The term “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. 
     “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. 
     The following groups of compounds of formula IA are preferred: 
     A compound of formula IA, wherein n is 1. 
     A compound of formula IA, wherein R 2  is lower alkyl. 
     A compound of formula IA, wherein R 3  is hydrogen or lower alkyl and R 4  is —CHR 5 -A. Preferably A is an optionally substituted aryl, and particularly A is an optionally substituted phenyl. 
     The following compounds relate to this group. N-(4-chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2,N-dimethyl-butyramide, 2-(3,4-dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyramide, N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2,N-dimethyl-N-(4-methyl-benzyl)-butyramide, 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-N-(4-trifluoromethyl-benzyl)-butyramide, 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2,N-dimethyl-N-(4-trifluoromethyl-benzyl)-butyramide, N-(4-chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyramide, N-[cyclopropyl-(4-methoxy-phenyl)-methyl]-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-butyramide, N-(3,5-bis-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-N-(4-methyl-benzyl)-butyramide, N-(4-chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-butyramide, 2-(3,4-dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-butyramide, N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-butyramide, N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-N-(3-difluoromethoxy-benzyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-N-(4-trifluoromethyl-benzyl)-butyramide, 2-(3,4-dichloro-phenyl)-N-(2-fluoro-5-trifluoromethyl-benzyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, N-[1-(4-chloro-phenyl)-ethyl]-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, N-(2-chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-butyramide, 2-(3,4-dichloro-phenyl)-N-[1-(3,4-dichloro-phenyl)-ethyl]-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-N-(3-trifluoromethoxy-benzyl)-butyramide, N-(4-chloro-3-fluoro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-N-(4-trifluoromethoxy-benzyl)-butyramide, N-(4-chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-N-(4-trifluoromethyl-benzyl)-butyramide, N-(4-chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-butyramide, 2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-N-(3-trifluoromethyl-benzyl)-butyramide, N-[cyclopropyl-(4-methoxy-phenyl)-methyl]-2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-butyramide, N-(3,5-bis-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-N-(4-methyl-benzyl)-butyramide, N-(4-chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-butyramide, 2-(3,4-dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-butyramide, N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-butyramide, N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-N-(4-trifluoromethyl-benzyl)-butyramide, N-[1-(4-chloro-phenyl)-ethyl]-2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-N-[1-(3,4-dichloro-phenyl)-ethyl]-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, N-(4-chloro-3-fluoro-benzyl)-2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-N-(4-trifluoromethoxy-benzyl)-butyramide, N-(4-chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-N-(4-trifluoromethyl-benzyl)-butyramide, N-(4-chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-butyramide, 2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl-N-(3-trifluoromethyl-benzyl)-butyramide, (S)—N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, (R)—N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2,N-dimethyl-N-(3-trifluoromethyl-benzyl)-butyramide, (R or S)-2-(3,4-dichloro-phenyl)-N—((R)-2-hydroxy-1-phenyl-ethyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyramide and N—[(R)-1-(4-chloro-phenyl)-2-hydroxy-ethyl]-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyramide. 
     Preferred are further compounds of formula IA, wherein n is 2. The following compounds relate to this group. 2-(3,4-dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-N-(4-trifluoromethyl-benzyl)-butyramide, N-(4-chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-butyramide, N-(4-chloro-3-fluoro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-N-(3-fluoro-benzyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-butyramide, 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-N-(3-trifluoromethyl-benzyl)-butyramide, N-(3-chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-butyramide, 2-(3,4-dichloro-phenyl)-N-(3-fluoro-4-methoxy-benzyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-butyramide, 2-(3,4-dichloro-phenyl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-butyramide, 2-(3,4-dichloro-phenyl)-N-(4-difluoromethoxy-3-methoxy-benzyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-butyramide, 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-N-(4-methyl-benzyl)-butyramide, N-(4-chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-butyramide, 2-(3,4-dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-butyramide, N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-butyramide, N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-[1,4] diazepan-1-yl)-2-methyl-butyramide, 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-N-(4-trifluoromethyl-benzyl)-butyramide, N-(2-chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-butyramide, 2-(3,4-dichloro-phenyl)-N-[1-(3,4-dichloro-phenyl)-ethyl]-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyramide, and 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl-N-(4-pyridin-4-yl-benzyl)-butyramide. 
     The following groups of compounds of formula IB are preferred: 
     A compound of formula IB, wherein n is 1. 
     A compound of formula IB, wherein R 2  is lower alkyl. 
     A compound of formula IB, wherein R 3  is hydrogen or lower alkyl and R 4  is —CHR 5 -A. Preferably A is an optionally substituted aryl, and particularly A is an optionally substituted phenyl, for example the following compounds N—[(R)-1-(4-chloro-phenyl)-2-hydroxy-ethyl]-2-(3,4-dichloro-phenyl)-4-(1,1-dioxo-hexahydro-1λ 6 -thia-5,7a-diaza-inden-5-yl)-2-methyl-butyramide and 2-(3,4-dichloro-phenyl)-4-(1,1-dioxo-hexahydro-1λ 6 -thia-5,7a-diaza-inden-5-yl)-N—[(R)-1-(4-fluoro-phenyl)-2-hydroxy-ethyl]-2-methyl-butyramide. 
     A further embodiment of the invention are compounds of formula 
                                
wherein
     R 1  is hydrogen or lower alkyl;   R 2  is hydrogen, fluoro or lower alkyl;   R 3  is hydrogen or lower alkyl;   R 4  is —CHR 5 -A
       R 5  is hydrogen, lower alkyl, fluoro, CF 3 , CH 2 OH or cycloalkyl;   A is aryl or heteroaryl, each of which is unsubstituted or substituted by (R 6 ) o ;   R 6  is heteroaryl, lower alkyl, lower alkoxy, cyano, halogen, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or NR 7 R 8 , wherein when o is more than one, each R 6  is the same or different;   o is 1, 2 or 3;   R 7  and R 8  are each independently hydrogen or lower alkyl; and   
       n is 1 or 2;
 
or a pharmaceutically acceptable acid addition salt thereof.
   
     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. 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. 
     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. 
     The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by processes described below, which process comprises 
     cleaving off the ester group from a compound of formula 
                                
with aqueous bases, for example with NaOH or LiOH, and
 
converting the acid of formula
 
                                
with a respective amine of formula
 
                                
under coupling conditions to a compound of formula
 
                                
wherein the substituents and n have same meanings as described above, and R′ is an O— protecting group, such as alkyl (e.g. methyl) or aryl (e.g. phenyl), and
 
if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
 
     The process is described in scheme 1 and scheme 2 in more detail. 
     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 schemes. 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. 
     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 schemes 1 or 2, 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. 
     
       
                 
         
             
             
         
      
     
     
       
                 
         
             
             
         
      
     
     The substituents and n have same meanings as described above, and R′ is an O— protecting group, such as alkyl (e.g. methyl) and aryl (e.g. phenyl)] 
     a) 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,  2 nd 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 can 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 can 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 can 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 can 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. Additionally, the protected aldehyde derivative can further be reacted to introduce R 2 =alkyl. For reaction conditions described in literature affecting such reactions see for example:  Comprehensive Organic Transformations: A Guide to Functional Group Preparations,  2 nd Edition,  Richard C. Larock. John Wiley &amp; Sons, New York, N.Y. 1999). However, it is convenient to react the protected aldehyde intermediate with an electophile ain 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 can 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 can 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 then can be subjected to acidic cleavage of the protecting group. The order of reaction of phenyl acetic acid derivatives consecutively with two suitable electrophiles can be chosen freely according to the reactivity of the reagents and compounds. 
     b) 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,  2 nd Edition,  Richard C. Larock. John Wiley &amp; Sons, New York, N.Y. 1999). However, we find it convenient to transform aldehyde derivative III with (homo) piperazine derivatives ( Journal of Medicinal Chemistry  (1983), 26(5), 657-61) under reductive conditions in the presence of a solvent to afford ester derivatives IV A or IV B. 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 can 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 can 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 IV. 
     c) 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,  2 nd 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 can 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 can 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 can 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 can 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. 
     d) 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 can 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 can 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. 
     e) Lactone derivative VI can conveniently 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 can 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 can 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. 
     f) Transformation of ester derivative VII with (homo) piperazine derivatives (described in literature: see for instance  Journal of Medicinal Chemistry  (1983), 26(5), 657-61) to access (homo) piperazine derivatives IV A or IV B ca be affected by any commonly used procedure. However, we find it convenient to react ester derivative VII with (homo) piperazine 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 can 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 can 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 (homo) piperazine derivatives IV A or IV B. 
     g) Transformation of (homo) piperazine derivatives IV A or IV B 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 A or IV B is cleaved under aqueous basic conditions and the liberated acid functionality converted with the respective amines under coupling conditions and to the (homo) piperazine derivatives IA or IB. 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,  2 nd 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 can 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 can 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 (homo) piperazine derivatives I A or I B. 
     h) Pyruvate derivatives VIII are commercially available or can be synthesised by methods described in literature (For reaction conditions see for example:  Comprehensive Organic Transformations: A Guide to Functional Group Preparations,  2 nd Edition,  Richard C. Larock. John Wiley &amp; Sons, New York, N.Y. 1999). However we find it convenient to react pyruvate derivative VIII with allyl bromide and indium (0) in analogy to the procedure described in Synthetic Communications 2001, 3189-3196 to yield hydroxy-ester derivatives IX. 
     i) Transformation of the allyl-moiety in hydroxy-ester derivative IX to an aldehyde moiety can be achieved by various methods as described in literature. See for example  Comprehensive Organic Transformations: A Guide to Functional Group Preparations,  2 nd Edition,  Richard C. Larock. John Wiley &amp; Sons, New York, N.Y. 1999. However, we find it convenient to di-hydroxylate the allyl-moiety with OsO 4  and treat the intermediate product with NaIO 4  (for analogous reaction see for example: J. Am Chem Soc. 2006, 128,4590-4591) to furnish the allyl moiety in derivatives III (R 2 ═OH). 
     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. 
     As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that 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. 
     Experimental Procedure 
     The compounds were investigated in accordance with the tests given hereinafter. 
     [ 3 H]SR142801 Competition Binding Assay 
     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., Zürich, 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 (K i ) 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. 
     Some results of preferred compounds of the hNK-3 receptor affinity were shown in the following Table 1. 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Example 
                 Compound name 
                 hNK 3  Ki [μM] 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 N-(4-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.1709 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-N-methyl-butyramide 
               
               
                 2 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1- 
                 0.3149 
               
               
                   
                 yl)-N-methyl-N-(4-pyridin-4-yl-benzyl)-butyramide 
               
               
                 3 
                 N-(2-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.6546 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-N-methyl-butyramide 
               
               
                 4 
                 N-Benzyl-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl- 
                 0.3554 
               
               
                   
                 piperazin-1-yl)-N-methyl-butyramide 
               
               
                 5 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1- 
                 0.1355 
               
               
                   
                 yl)-N-methyl-N-(4-trifluoromethyl-benzyl)-butyramide 
               
               
                 6 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-4-methoxy-benzyl)-4- 
                 0.6899 
               
               
                   
                 (4-methanesulfonyl-piperazin-1-yl)-N-methyl-butyramide 
               
               
                 7 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-benzyl)-4-(4- 
                 0.3878 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-N-methyl-butyramide 
               
               
                 8 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1- 
                 0.2884 
               
               
                   
                 yl)-2-methyl-N-(3-trifluoromethyl-benzyl)-butyramide 
               
               
                 9 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1- 
                 0.1896 
               
               
                   
                 yl)-2-methyl-N-(3-trifluoromethoxy-benzyl)-butyramide 
               
               
                 10 
                 N-(3-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.1453 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-2,N-dimethyl-butyramide 
               
               
                 11 
                 2-(3,4-Dichloro-phenyl)-N-(3-difluoromethoxy-benzyl)-4-(4- 
                 0.4168 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-2-methyl-butyramide 
               
               
                 12 
                 N-(4-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.0664 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-2,N-dimethyl-butyramide 
               
               
                 13 
                 2-(3,4-Dichloro-phenyl)-N-(4-difluoromethoxy-benzyl)-4-(4- 
                 0.3259 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-2-methyl-butyramide 
               
               
                 14 
                 N-[1-(4-Chloro-phenyl)-ethyl]-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.1707 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-2-methyl-butyramide 
               
               
                 15 
                 N-[Cyclopropyl-(4-methoxy-phenyl)-methyl]-2-(3,4- 
                 0.2338 
               
               
                   
                 dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2- 
               
               
                   
                 methyl-butyramide 
               
               
                 16 
                 N-(2-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.1694 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-2,N-dimethyl-butyramide 
               
               
                 17 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1- 
                 0.1464 
               
               
                   
                 yl)-2-methyl-N-(4-trifluoromethoxy-benzyl)-butyramide 
               
               
                 18 
                 N-(4-Cyano-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.4337 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-2-methyl-butyramide 
               
               
                 19 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1- 
                 0.429 
               
               
                   
                 yl)-2-methyl-N-(2-trifluoromethoxy-benzyl)-butyramide 
               
               
                 20 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl- 
                 0.0671 
               
               
                   
                 benzyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 21 
                 N-(3,4-Dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.0655 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-2-methyl-butyramide 
               
               
                 22 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1- 
                 0.0774 
               
               
                   
                 yl)-2,N-dimethyl-N-(4-methyl-benzyl)-butyramide 
               
               
                 23 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1- 
                 0.2009 
               
               
                   
                 yl)-2,N-dimethyl-N-(4-pyridin-4-yl-benzyl)-butyramide 
               
               
                 24 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-benzyl)-4-(4- 
                 0.2238 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-2,N-dimethyl-butyramide 
               
               
                 25 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-4-methoxy-benzyl)-4- 
                 0.1335 
               
               
                   
                 (4-methanesulfonyl-piperazin-1-yl)-2,N-dimethyl-butyramide 
               
               
                 26 
                 2-(3,4-Dichloro-phenyl)-N-(4-difluoromethoxy-3-methoxy- 
                 0.2748 
               
               
                   
                 benzyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 27 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1- 
                 0.082 
               
               
                   
                 yl)-2-methyl-N-(4-trifluoromethyl-benzyl)-butyramide 
               
               
                 28 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1- 
                 0.045 
               
               
                   
                 yl)-2,N-dimethyl-N-(4-trifluoromethyl-benzyl)-butyramide 
               
               
                 29 
                 N-(4-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.0984 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-2-methyl-butyramide 
               
               
                 30 
                 N-(4-Chloro-3-fluoro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.1334 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-2-methyl-butyramide 
               
               
                 31 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-4-methoxy-benzyl)-4- 
                 0.1087 
               
               
                   
                 ((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N- 
               
               
                   
                 dimethyl-butyramide 
               
               
                 32 
                 N-[Cyclopropyl-(4-methoxy-phenyl)-methyl]-2-(3,4- 
                 0.0168 
               
               
                   
                 dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl- 
               
               
                   
                 piperazin-1-yl)-2-methyl-butyramide 
               
               
                 33 
                 2-(3,4-Dichloro-phenyl)-N-(4-fluoro-3-trifluoromethyl- 
                 0.0158 
               
               
                   
                 benzyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)- 
               
               
                   
                 2,N-dimethyl-butyramide 
               
               
                 34 
                 N-(3,5-Bis-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)- 
                 0.0481 
               
               
                   
                 4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 35 
                 2-(3,4-Dichloro-phenyl)-N-(4-difluoromethoxy-3-methoxy- 
                 0.2159 
               
               
                   
                 benzyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)- 
               
               
                   
                 2,N-dimethyl-butyramide 
               
               
                 36 
                 2-(3,4-Dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl- 
                 0.0508 
               
               
                   
                 piperazin-1-yl)-2,N-dimethyl-N-(4-methyl-benzyl)- 
               
               
                   
                 butyramide 
               
               
                 37 
                 2-(3,4-Dichloro-phenyl)-N-(4-dimethylamino-benzyl)-4-((R)- 
                 0.4851 
               
               
                   
                 4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 38 
                 2-(3,4-Dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl- 
                 0.5452 
               
               
                   
                 piperazin-1-yl)-2-methyl-N-quinoxalin-6-ylmethyl- 
               
               
                   
                 butyramide 
               
               
                 39 
                 N-(4-Chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro- 
                 0.0126 
               
               
                   
                 phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)- 
               
               
                   
                 2,N-dimethyl-butyramide 
               
               
                 40 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl- 
                 0.0167 
               
               
                   
                 benzyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)- 
               
               
                   
                 2,N-dimethyl-butyramide 
               
               
                 41 
                 N-(3,4-Dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4- 
                 0.0133 
               
               
                   
                 methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 42 
                 N-(3,4-Dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4- 
                 0.0057 
               
               
                   
                 methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 43 
                 2-(3,4-Dichloro-phenyl)-N-(3-difluoromethoxy-benzyl)-4- 
                 0.0999 
               
               
                   
                 ((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 44 
                 2-(3,4-Dichloro-phenyl)-N-(5-fluoro-2-trifluoromethyl- 
                 0.2123 
               
               
                   
                 benzyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)- 
               
               
                   
                 2-methyl-butyramide 
               
               
                 45 
                 2-(3,4-Dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl- 
                 0.0333 
               
               
                   
                 piperazin-1-yl)-2-methyl-N-(4-trifluoromethyl-benzyl)- 
               
               
                   
                 butyramide 
               
               
                 46 
                 2-(3,4-Dichloro-phenyl)-N-(2-fluoro-5-trifluoromethyl- 
                 0.0995 
               
               
                   
                 benzyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)- 
               
               
                   
                 2-methyl-butyramide 
               
               
                 47 
                 N-[1-(4-Chloro-phenyl)-ethyl]-2-(3,4-dichloro-phenyl)-4- 
                 0.0159 
               
               
                   
                 ((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 48 
                 2-(3,4-Dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl- 
                 0.2629 
               
               
                   
                 piperazin-1-yl)-N-(3-methoxy-benzyl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 49 
                 N-(2-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4- 
                 0.088 
               
               
                   
                 methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 50 
                 2-(3,4-Dichloro-phenyl)-N-[1-(3,4-dichloro-phenyl)-ethyl]-4- 
                 0.0258 
               
               
                   
                 ((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 51 
                 2-(3,4-Dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl- 
                 0.0146 
               
               
                   
                 piperazin-1-yl)-2-methyl-N-(3-trifluoromethoxy-benzyl)- 
               
               
                   
                 butyramide 
               
               
                 52 
                 N-(4-Chloro-3-fluoro-benzyl)-2-(3,4-dichloro-phenyl)-4- 
                 0.0464 
               
               
                   
                 ((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 53 
                 2-(3,4-Dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl- 
                 0.0228 
               
               
                   
                 piperazin-1-yl)-2-methyl-N-(4-trifluoromethoxy-benzyl)- 
               
               
                   
                 butyramide 
               
               
                 54 
                 N-(4-Chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro- 
                 0.0175 
               
               
                   
                 phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)- 
               
               
                   
                 2-methyl-butyramide 
               
               
                 55 
                 2-(3,4-Dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl- 
                 0.0169 
               
               
                   
                 piperazin-1-yl)-2,N-dimethyl-N-(4-trifluoromethyl-benzyl)- 
               
               
                   
                 butyramide 
               
               
                 56 
                 N-(4-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4- 
                 0.0265 
               
               
                   
                 methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 57 
                 N-(4-Cyano-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4- 
                 0.1611 
               
               
                   
                 methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 58 
                 2-(3,4-Dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl- 
                 0.0562 
               
               
                   
                 piperazin-1-yl)-2,N-dimethyl-N-(3-trifluoromethyl-benzyl)- 
               
               
                   
                 butyramide 
               
               
                 59 
                 N-(3-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4- 
                 0.1032 
               
               
                   
                 methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 60 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-benzyl)-4-((R)-4- 
                 0.1305 
               
               
                   
                 methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 61 
                 2-(3,4-Dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl- 
                 0.2468 
               
               
                   
                 piperazin-1-yl)-2,N-dimethyl-N-(4-pyridin-4-yl-benzyl)- 
               
               
                   
                 butyramide 
               
               
                 62 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-4-methoxy-benzyl)-4- 
                 0.2156 
               
               
                   
                 ((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2,N- 
               
               
                   
                 dimethyl-butyramide 
               
               
                 63 
                 N-[Cyclopropyl-(4-methoxy-phenyl)-methyl]-2-(3,4- 
                 0.0657 
               
               
                   
                 dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl- 
               
               
                   
                 piperazin-1-yl)-2-methyl-butyramide 
               
               
                 64 
                 2-(3,4-Dichloro-phenyl)-N-(4-fluoro-3-trifluoromethyl- 
                 0.0168 
               
               
                   
                 benzyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)- 
               
               
                   
                 2,N-dimethyl-butyramide 
               
               
                 65 
                 N-(3,5-Bis-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)- 
                 0.0846 
               
               
                   
                 4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 66 
                 2-(3,4-Dichloro-phenyl)-N-(4-difluoromethoxy-3-methoxy- 
                 0.2767 
               
               
                   
                 benzyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)- 
               
               
                   
                 2,N-dimethyl-butyramide 
               
               
                 67 
                 2-(3,4-Dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl- 
                 0.0992 
               
               
                   
                 piperazin-1-yl)-2,N-dimethyl-N-(4-methyl-benzyl)- 
               
               
                   
                 butyramide 
               
               
                 68 
                 2-(3,4-Dichloro-phenyl)-N-(4-dimethylamino-benzyl)-4-((S)- 
                 0.7341 
               
               
                   
                 4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 69 
                 N-(4-Chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro- 
                 0.0114 
               
               
                   
                 phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)- 
               
               
                   
                 2,N-dimethyl-butyramide 
               
               
                 70 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl- 
                 0.0192 
               
               
                   
                 benzyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)- 
               
               
                   
                 2,N-dimethyl-butyramide 
               
               
                 71 
                 N-(3,4-Dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((S)-4- 
                 0.0125 
               
               
                   
                 methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 72 
                 N-(3,4-Dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((S)-4- 
                 0.0429 
               
               
                   
                 methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 73 
                 2-(3,4-Dichloro-phenyl)-N-(3-difluoromethoxy-benzyl)-4- 
                 0.2998 
               
               
                   
                 ((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 74 
                 2-(3,4-Dichloro-phenyl)-N-(5-fluoro-2-trifluoromethyl- 
                 0.4962 
               
               
                   
                 benzyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2- 
               
               
                   
                 methyl-butyramide 
               
               
                 75 
                 2-(3,4-Dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl- 
                 0.0681 
               
               
                   
                 piperazin-1-yl)-2-methyl-N-(4-trifluoromethyl-benzyl)- 
               
               
                   
                 butyramide 
               
               
                 76 
                 2-(3,4-Dichloro-phenyl)-N-(2-fluoro-5-trifluoromethyl- 
                 0.311 
               
               
                   
                 benzyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2- 
               
               
                   
                 methyl-butyramide 
               
               
                 77 
                 N-[1-(4-Chloro-phenyl)-ethyl]-2-(3,4-dichloro-phenyl)-4- 
                 0.0674 
               
               
                   
                 ((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 78 
                 2-(3,4-Dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl- 
                 0.6112 
               
               
                   
                 piperazin-1-yl)-N-(3-methoxy-benzyl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 79 
                 N-(2-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((S)-4- 
                 0.1677 
               
               
                   
                 methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 80 
                 2-(3,4-Dichloro-phenyl)-N-[1-(3,4-dichloro-phenyl)-ethyl]-4- 
                 0.0162 
               
               
                   
                 ((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 81 
                 2-(3,4-Dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl- 
                 0.1259 
               
               
                   
                 piperazin-1-yl)-2-methyl-N-(3-trifluoromethoxy-benzyl)- 
               
               
                   
                 butyramide 
               
               
                 82 
                 N-(4-Chloro-3-fluoro-benzyl)-2-(3,4-dichloro-phenyl)-4-((S)- 
                 0.0942 
               
               
                   
                 4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 83 
                 2-(3,4-Dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl- 
                 0.0571 
               
               
                   
                 piperazin-1-yl)-2-methyl-N-(4-trifluoromethoxy-benzyl)- 
               
               
                   
                 butyramide 
               
               
                 84 
                 N-(4-Chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro- 
                 0.0452 
               
               
                   
                 phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)- 
               
               
                   
                 2-methyl-butyramide 
               
               
                 85 
                 2-(3,4-Dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl- 
                 0.0277 
               
               
                   
                 piperazin-1-yl)-2,N-dimethyl-N-(4-trifluoromethyl-benzyl)- 
               
               
                   
                 butyramide 
               
               
                 86 
                 N-(4-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((S)-4- 
                 0.0663 
               
               
                   
                 methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 87 
                 2-(3,4-Dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl- 
                 0.052 
               
               
                   
                 piperazin-1-yl)-2,N-dimethyl-N-(3-trifluoromethyl-benzyl)- 
               
               
                   
                 butyramide 
               
               
                 88 
                 N-(3-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((S)-4- 
                 0.1069 
               
               
                   
                 methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 89 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-benzyl)-4-((S)-4- 
                 0.2656 
               
               
                   
                 methanesulfonyl-3-methyl-piperazin-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 90 
                 2-(3,4-Dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl- 
                 0.5251 
               
               
                   
                 piperazin-1-yl)-2,N-dimethyl-N-(6-trifluoromethyl-pyridin-3- 
               
               
                   
                 ylmethyl)-butyramide 
               
               
                 91 
                 2-(3,4-Dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl- 
                 0.9063 
               
               
                   
                 piperazin-1-yl)-2-methyl-N-(6-trifluoromethyl-pyridin-3- 
               
               
                   
                 ylmethyl)-butyramide 
               
               
                 92 
                 2-(3,4-Dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl- 
                 0.5821 
               
               
                   
                 piperazin-1-yl)-2-methyl-N-(6-trifluoromethyl-pyridin-3- 
               
               
                   
                 ylmethyl)-butyramide 
               
               
                 93 
                 (S or R)—N-(3,4-Dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4- 
                 0.0192 
               
               
                   
                 ((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 94 
                 (R or S)—N-(3,4-Dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4- 
                 0.112 
               
               
                   
                 ((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 95 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl- 
                 0.0643 
               
               
                   
                 benzyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 96 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan- 
                 0.0245 
               
               
                   
                 1-yl)-2,N-dimethyl-N-(4-trifluoromethyl-benzyl)-butyramide 
               
               
                 97 
                 N-(4-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.0299 
               
               
                   
                 methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 98 
                 N-(4-Chloro-3-fluoro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.066 
               
               
                   
                 methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyramide 
               
               
                 99 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan- 
                 0.1277 
               
               
                   
                 1-yl)-2-methyl-N-(4-trifluoromethoxy-benzyl)-butyramide 
               
               
                 100 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-benzyl)-4-(4- 
                 0.0965 
               
               
                   
                 methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 101 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl- 
                 0.0184 
               
               
                   
                 [1,4]diazepam-1-yl)-2,N-dimethyl-N-(3-trifluoromethyl- 
               
               
                   
                 benzyl)-butyramide 
               
               
                 102 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan- 
                 0.1229 
               
               
                   
                 1-yl)-2-methyl-N-(3-trifluoromethoxy-benzyl)-butyramide 
               
               
                 103 
                 N-(3-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.0418 
               
               
                   
                 methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 104 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-4-methoxy-benzyl)-4- 
                 0.0602 
               
               
                   
                 (4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 105 
                 N-[Cyclopropyl-(4-methoxy-phenyl)-methyl]-2-(3,4- 
                 0.1345 
               
               
                   
                 dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2- 
               
               
                   
                 methyl-butyramide 
               
               
                 106 
                 2-(3,4-Dichloro-phenyl)-N-(4-fluoro-3-trifluoromethyl- 
                 0.0092 
               
               
                   
                 benzyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N- 
               
               
                   
                 dimethyl-butyramide 
               
               
                 107 
                 N-(3,5-Bis-trifluoromethyl-benzyl)-2-(3,4-dichloro-phenyl)- 
                 0.2094 
               
               
                   
                 4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 108 
                 2-(3,4-Dichloro-phenyl)-N-(4-difluoromethoxy-3-methoxy- 
                 0.0895 
               
               
                   
                 benzyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N- 
               
               
                   
                 dimethyl-butyramide 
               
               
                 109 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan- 
                 0.0335 
               
               
                   
                 1-yl)-2,N-dimethyl-N-(4-methyl-benzyl)-butyramide 
               
               
                 110 
                 2-(3,4-Dichloro-phenyl)-N-(4-dimethylamino-benzyl)-4-(4- 
                 0.2908 
               
               
                   
                 methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyramide 
               
               
                 111 
                 N-(4-Chloro-3-trifluoromethyl-benzyl)-2-(3,4-dichloro- 
                 0.0067 
               
               
                   
                 phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N- 
               
               
                   
                 dimethyl-butyramide 
               
               
                 112 
                 2-(3,4-Dichloro-phenyl)-N-(3-fluoro-4-trifluoromethyl- 
                 0.0162 
               
               
                   
                 benzyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2,N- 
               
               
                   
                 dimethyl-butyramide 
               
               
                 113 
                 N-(3,4-Dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.0101 
               
               
                   
                 methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 114 
                 N-(3,4-Dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.0399 
               
               
                   
                 methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyramide 
               
               
                 115 
                 2-(3,4-Dichloro-phenyl)-N-(3-difluoromethoxy-benzyl)-4-(4- 
                 0.1832 
               
               
                   
                 methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyramide 
               
               
                 116 
                 2-(3,4-Dichloro-phenyl)-N-(5-fluoro-2-trifluoromethyl- 
                 0.5751 
               
               
                   
                 benzyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 117 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan- 
                 0.0496 
               
               
                   
                 1-yl)-2-methyl-N-(4-trifluoromethyl-benzyl)-butyramide 
               
               
                 118 
                 2-(3,4-Dichloro-phenyl)-N-(2-fluoro-5-trifluoromethyl- 
                 0.1358 
               
               
                   
                 benzyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 119 
                 N-[1-(4-Chloro-phenyl)-ethyl]-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.1212 
               
               
                   
                 methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyramide 
               
               
                 120 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan- 
                 0.1079 
               
               
                   
                 1-yl)-N-(3-methoxy-benzyl)-2,N-dimethyl-butyramide 
               
               
                 121 
                 N-(2-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.0312 
               
               
                   
                 methanesulfonyl-[1,4]diazepan-1-yl)-2,N-dimethyl- 
               
               
                   
                 butyramide 
               
               
                 122 
                 2-(3,4-Dichloro-phenyl)-N-[1-(3,4-dichloro-phenyl)-ethyl]-4- 
                 0.0434 
               
               
                   
                 (4-methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyramide 
               
               
                 123 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan- 
                 0.0934 
               
               
                   
                 1-yl)-2,N-dimethyl-N-(4-pyridin-4-yl-benzyl)-butyramide 
               
               
                 124 
                 N-(4-Cyano-benzyl)-2-(3,4-dichloro-phenyl)-4-(4- 
                 0.1074 
               
               
                   
                 methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyramide 
               
               
                 125 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan- 
                 0.2751 
               
               
                   
                 1-yl)-2,N-dimethyl-N-(6-trifluoromethyl-pyridin-3-ylmethyl)- 
               
               
                   
                 butyramide 
               
               
                 126 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan- 
                 0.9486 
               
               
                   
                 1-yl)-2-methyl-N-(6-trifluoromethyl-pyridin-3-ylmethyl)- 
               
               
                   
                 butyramide 
               
               
                 127 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1- 
                 0.0784 
               
               
                   
                 yl)-2,N-dimethyl-N-(3-trifluoromethyl-benzyl)-butyramide 
               
               
                 128 
                 (R or S)-2-(3,4-Dichloro-phenyl)-N-((R)-2-hydroxy-1- 
                 0.0406 
               
               
                   
                 phenyl-ethyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 129 
                 (S or R)-2-(3,4-Dichloro-phenyl)-N-((R)-2-hydroxy-1- 
                 0.3338 
               
               
                   
                 phenyl-ethyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl- 
               
               
                   
                 butyramide 
               
               
                 130 
                 N-[(R)-1-(4-Chloro-phenyl)-2-hydroxy-ethyl]-2-(3,4- 
                 0.0399 
               
               
                   
                 dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2- 
               
               
                   
                 methyl-butyramide 
               
               
                 131 
                 N-[(S)-1-(4-Chloro-phenyl)-2-hydroxy-ethyl]-2-(3,4- 
                 0.1863 
               
               
                   
                 dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2- 
               
               
                   
                 methyl-butyramide 
               
               
                 132 
                 2-(3,4-Dichloro-phenyl)-N-[(R)-1-(4-fluoro-phenyl)-2- 
                 0.1463 
               
               
                   
                 hydroxy-ethyl]-4-(4-methanesulfonyl-piperazin-1-yl)-2- 
               
               
                   
                 methyl-butyramide 
               
               
                 133 
                 2-(3,4-Dichloro-phenyl)-N-[(S)-1-(4-fluoro-phenyl)-2- 
                 0.3972 
               
               
                   
                 hydroxy-ethyl]-4-(4-methanesulfonyl-piperazin-1-yl)-2- 
               
               
                   
                 methyl-butyramide 
               
               
                 134 
                 2-(3,4-Dichloro-phenyl)-N-[1-(4-fluoro-phenyl)-ethyl]-4-(4- 
                 0.2287 
               
               
                   
                 methanesulfonyl-piperazin-1-yl)-2-methyl-butyramide 
               
               
                 135 
                 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1- 
                 0.1961 
               
               
                   
                 yl)-2-methyl-N-[2,2,2-trifluoro-1-(4-fluoro-phenyl)-ethyl]- 
               
               
                   
                 butyramide 
               
               
                 136 
                 N-[(R)-1-(4-Chloro-phenyl)-2-hydroxy-ethyl]-2-(3,4- 
                 0.0154 
               
               
                   
                 dichloro-phenyl)-4-(1,1-dioxo-hexahydro-1λ 6 -thia-5,7a-diaza- 
               
               
                   
                 inden-5-yl)-2-methyl-butyramide 
               
               
                 137 
                 2-(3,4-Dichloro-phenyl)-4-(1,1-dioxo-hexahydro-1λ 6 -thia- 
                 0.0305 
               
               
                   
                 5,7a-diaza-inden-5-yl)-N-[(R)-1-(4-fluoro-phenyl)-2- 
               
               
                   
                 hydroxy-ethyl]-2-methyl-butyramide 
               
               
                   
               
             
          
         
       
     
     In addition, the present compounds showed high selective affinity to the hNK-3 receptor compared with the hNK-1 and hNK-2 receptors. 
     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. 
     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. 
     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. 
     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 
     Tablets of the following composition can be manufactured in the usual manner: 
     
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 mg/tablet 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Active substance 
                 5 
               
               
                   
                 Lactose 
                 45 
               
               
                   
                 Corn starch 
                 15 
               
               
                   
                 Microcrystalline cellulose 
                 34 
               
               
                   
                 Magnesium stearate 
                 1 
               
               
                   
                 Tablet weight 
                 100 
               
               
                   
                   
               
             
          
         
       
     
     EXAMPLE B 
     Capsules of the following composition can be manufactured: 
     
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 mg/capsule 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Active substance 
                 10 
               
               
                   
                 Lactose 
                 155 
               
               
                   
                 Corn starch 
                 30 
               
               
                   
                 Talc 
                 5 
               
               
                   
                 Capsule fill weight 
                 200 
               
               
                   
                   
               
             
          
         
       
     
     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 can be filled by machine into hard gelatin capsules. 
     EXAMPLE C 
     Suppositories of the following composition can be manufactured: 
     
       
         
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 mg/supp. 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Active substance 
                  15 
               
               
                   
                 Suppository mass 
                 1285 
               
               
                   
                 Total 
                 1300 
               
               
                   
                   
               
             
          
         
       
     
     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, left to cool, the suppositories then can be removed from the moulds and packed individually in wax paper or metal foil. 
     The following Examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius. 
     Abbreviations 
     
         
         DCM=dichloromethane; 
         DIPEA=N,N-diisopropylethylamine; 
         DMA=N,N-dimethylacetamido; 
         DMF=N,N-dimethylformamide; 
         HPLC=high-performance liquid chromatography; 
         MS=mass spectroscopy; 
         TBTU=O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate; 
         THF=tetrahydrofurane. 
       
    
     Intermediate 1 
     2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-butyric acid 
     
       
                 
         
             
             
         
      
     
     a) step 1: 2-(3,4-Dichloro-phenyl)-4-oxo-butyric acid methyl ester 
     
       
                 
         
             
             
         
      
     
     A mixture of 25 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-methanesulfonyl-piperazin-1-yl)-butyric acid methyl ester 
     
       
                 
         
             
             
         
      
     
     A mixture of 1.07 g (4.1 mmol) 2-(3,4-dichloro-phenyl)-4-oxo-butyric acid methyl ester, 0.74 g (4.5 mmol) 1-methanesolfonyl-piperazine, 1.3 g (6.1 mmol) sodium triacteoxyborohydride and 0.37 g (6.1 mmol) acetic acid in 40 mL THF was stirred at room temperature for 17 h. Water and Na 2 CO 3  aq. (10%) was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with NaCl sat. aq. dried with MgSO 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 1.42 g (85%) of the title compound as colorless waxy solid. MS(m/e): 409.3 (MH + ). 
     c) step 3: 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-butyric acid 
     A mixture of 1.42 g (3.4 mmol) 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-butyric acid methyl ester and 0.182 g (4.3 mmol) LiOH.H 2 O in 30 mL water and 30 mL THF was heated to reflux for 1 h. The mixture was treated with 4N HCl aq. and evaporated to dryness. The residue was used without further purification in the subsequent step. MS(m/e): 395.0 (MH + ). 
     Intermediate 2 
     2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyric acid 
     
       
                 
         
             
             
         
      
     
     a) step 1: 3-(3,4-Dichloro-phenyl)-dihydro-furan-2-one (commercially available) 
     
       
                 
         
             
             
         
      
     
     A mixture of 30 g (137 mmol) (3,4-dichloro-phenyl)-acetic acid methyl ester (commercially available), 6.47 g (151 mmol) NaH (55%) and 35.8 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 in 250 mL methanol 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 
     
       
                 
         
             
             
         
      
     
     A mixture of 18.5 g (80 mmol) 3-(3,4-dichloro-phenyl)-dihydro-furan-2-one, 3.84 g (88 mmol) NaH (55% suspension) and 14.2 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 
     
       
                 
         
             
             
         
      
     
     To a mixture of 3.3 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 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 6.5 mL (89 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-methanesulfonyl-piperazin-1-yl)-2-methyl-butyric acid methyl ester 
     
       
                 
         
             
             
         
      
     
     A mixture of 0.325 g (0.95 mmol) 4-bromo-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester, 0.667 g (4 mmol) 1-methanesulfonyl piperazine (commercially available) and 0.154 g (1.2 mmol) N,N-diisopropylethylamine in 2.5 mL DMF was heated to 50° C. for 42 h. 
     Another mixture of 1.2 g (3.5 mmol) 4-bromo-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester, 2.32 g (14 mmol) 1-methanesulfonyl piperazine (commercially available) and 0.722 g (5.5 mmol) N,N-diisopropylethylamine in 30 mL DMF was heated to 55° C. for 84 h. The two mixtures were combined, evaporated to dryness, suspended in a mixture formed from methanol and DCM and filtered. The precipitate was washed with DCM, 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 1.16 g (61%) of the title compound as light yellow viscous oil. MS(m/e): 423.1 (MH + ). 
     e) step 5: 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyric acid 
     A mixture of 1.15 g (2.7 mmol) 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyric acid methyl ester and 0.171 g (4.08 mmol) LiOH.H 2 O in 25 mL water and 25 mL THF was stirred at room temperature for 16 h. The mixture was treated with 4N HCl aq. and evaporated to dryness. The residue was used without further purification in the subsequent step. MS(m/e): 409.2 (MH + ). 
     Intermediate 3 
     2-(3,4-Dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyric acid 
     
       
                 
         
             
             
         
      
     
     a) step 1: 2-(3,4-Dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyric acid methyl ester 
     
       
                 
         
             
             
         
      
     
     In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyric acid methyl ester (intermediate 2, step 4) the title compound was prepared from 4-bromo-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester (intermediate 2, step 3) and (R)-1-methanesulfonyl-2-methyl-piperazine (commercially available) in DMA as light brown viscous oil. 
     MS(m/e): 437.0 (MH + ). 
     b) step 2: 2-(3,4-Dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyric acid 
     In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyric acid (intermediate 2, step 5) the title compound was prepared from 2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyric acid methyl ester by saponification with LiOH.H 2 O as yellow foam. MS(m/e): 423.1 (MH + ). 
     Intermediate 4 
     2-(3,4-Dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyric acid 
     
       
                 
         
             
             
         
      
     
     a) step 1: 2-(3,4-Dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyric acid methyl ester 
     
       
                 
         
             
             
         
      
     
     In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyric acid methyl ester (intermediate 2, step 4) the title compound was prepared from 4-bromo-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester (intermediate 2, step 3) and (S)-1-methanesulfonyl-2-methyl-piperazine (commercially available) in DMA as light brown viscous oil. 
     MS(m/e): 437.0 (MH + ). 
     b) step 2: 2-(3,4-Dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyric acid 
     In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyric acid (intermediate 2, step 5) the title compound was prepared from 2-(3,4-dichloro-phenyl)-4-((S)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyric acid methyl ester by saponification with LiOH.H 2 O as yellow foam. MS(m/e): 423.1 (MH + ). 
     Intermediate 5 
     2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyric acid 
     
       
                 
         
             
             
         
      
     
     a) step 1: 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyric acid methyl ester 
     
       
                 
         
             
             
         
      
     
     In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyric acid methyl ester (intermediate 2, step 4) the title compound was prepared from 4-bromo-2-(3,4-dichloro-phenyl)-2-methyl-butyric acid methyl ester (intermediate 2, step 3) and 1-methanesulfonyl-[1,4]diazepane (commercially available) in DMA as light brown viscous oil. MS(m/e): 437.2 (MH + ). 
     b) step 2: 2-(3,4-Dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyric acid 
     In analogy to the procedure described for the synthesis of 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyric acid (intermediate 2, step 5) the title compound was prepared from 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-[1,4]diazepan-1-yl)-2-methyl-butyric acid methyl ester by saponification with LiOH.H 2 O as yellow foam. MS(m/e): 423.1 (MH + ). 
     Intermediate 6 
     2-(3,4-Dichloro-phenyl)-4-(1,1-dioxo-hexahydro-1λ 6 -thia-5,7a-diaza-inden-5-yl)-2-methyl-butyric acid 
     
       
                 
         
             
             
         
      
     
     a) step 1: 2-(3,4-Dichloro-phenyl)-4,4-dimethoxy-2-methyl-butyric acid methyl ester 
     
       
                 
         
             
             
         
      
     
     A mixture of 35 g (150 mmol) 2-(3,4-dichloro-phenyl)-propionic acid methyl ester ( Journal of Medicinal Chemistry  (2004), 47(23), 5753-5765), 31.7 g (188 mmol) bromoacetaldehyde dimethyl acetal (commercially available and 6.6 g (165 mmol) NaH (55%) in 100 mL DMF was stirred at room temperature and afterwards evaporated to dryness. Ice water and ethyl acetate was added and the organic fraction was washed with sat. NaCl aq., dried with Na 2 SO 4  and evaporated. The residue was purified by column chromatography on silica eluting with a mixture of ethyl acetate and hexane. The product containing fractions were evaporated to yield 29.6 g (61%) of the title compound as yellow liquid. 
     b) step 2: 2-(3,4-Dichloro-phenyl)-2-methyl-4-oxo-butyric acid methyl ester 
     
       
                 
         
             
             
         
      
     
     A mixture of 6 g (19 mmol) 2-(3,4-dichloro-phenyl)-4,4-dimethoxy-2-methyl-butyric acid methyl ester and 28 mL 2N HCl aq. in 60 mL THF and 60 mL water was stirred at room temperature for 20 h. The mixture was extracted with diethyl ether. The combined organic phases were washed with sat. NaCl aq., dried with Na 2 SO 4  and evaporated to dryness. The residue was subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and hexane. The product containing fractions were evaporated to yield 3 g (58%) of the title compound as light yellow oil. 
     c) step 3: 2-(3,4-Dichloro-phenyl)-4-(1,1-dioxo-hexahydro-1λ 6 -thia-5,7a-diaza-inden-5-yl)-2-methyl-butyric acid methyl ester 
     
       
                 
         
             
             
         
      
     
     A mixture of 0.8 g (2.9 mmol) 2-(3,4-dichloro-phenyl)-2-methyl-4-oxo-butyric acid methyl ester, 0.742 g (3.48 mmol) 2H-isothiazolo[2,3-a]pyrazine, hexahydro-1,1-dioxide (WO 2007/028654), 0.924 g (4.36 mmol) sodium triacetoxyborohydride, 0.26 g (4.3 mmol) acetic acid and 0.353 g (3.5 mmol) NEt 3  in 80 mL DCM was stirred at room temperature. Na 2 CO 3  aq. (10%) was added and the organic phase was washed with sat. NaCl aq., dried with Na 2 SO 4  and evaporated. The residue was subjected to column chromatography on silica eluting with a gradient formed from DCM, methanol and NH 3  aq. (2N). The product containing fractrions were evaporated to yield 1.18 g (92%) of the title compound as colorless viscous oil. MS(m/e): 435.2 (MH + ). 
     d) step 4: 2-(3,4-Dichloro-phenyl)-4-(1,1-dioxo-hexahydro-1λ 6 -thia-5,7a-diaza-inden-5-yl)-2-methyl-butyric acid 
     A mixture of 1.16 g (2.6 mmol) 2-(3,4-dichloro-phenyl)-4-(1,1-dioxo-hexahydro-1λ 6 -thia-5,7a-diaza-inden-5-yl)-2-methyl-butyric acid methyl ester and 0.123 g (2.9 mmol) LiOH.H 2 O in 40 mL water and 40 mL THF was stirred at room temperature for 48 h. After evaporation of THF the pH was adjusted to pH=2 with 2N HCl aq., evaporated to dryness, taken up in acetonitrile and evaporated (3×), The residue was dried at 60° C. under high vacuum and used without further purification in the consecutive amide coupling step. MS(m/e): 421.0 (MH + ). 
     EXAMPLE 1 
     N-(4-Chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-N-methyl-butyramide 
     
       
                 
         
             
             
         
      
     
     A mixture of 25 mg 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-butyric acid (intermediate 1), 24.1 mg (0.075 mmol) TBTU, 11.67 mg (0.075 mmol) (4-chloro-benzyl)-methyl-amine (commercially available) and 0.06 mL N,N-diisopropyl ethylamine in 0.75 mL DMF was shaken at room temperature and subsequently 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 20.7 mg (67%) of the title compound as yellow viscous oil. MS(m/e): 534.2 (MH + ). 
     In analogy to the procedure described for the synthesis of N-(4-chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-N-methyl-butyramide (example 1) further piperazine derivatives have been synthesized from the starting materials listed in Table 2. Table 2 comprises examples 2-92. 
     
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 MW 
               
               
                   
                   
                   
                 Systematic 
                 starting 
                 found 
               
               
                 No 
                 MW 
                 structure 
                 Name 
                 materials 
                 MH+ 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 2 
                 575.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-N- methyl-N-(4-pyridin- 4-yl-benzyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)- butyric acid (intermediate 1) and Methyl-(4-pyridin-4- yl-benzyl)-amine (commercially available) 
                 575.3 
               
               
                   
               
               
                 3 
                 532.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-Chloro-benzyl)- 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-N- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)- butyric acid (intermediate 1) and (2-Chloro-benzyl)- methyl-amine (commercially available) 
                 534.2 
               
               
                   
               
               
                 4 
                 498.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-Benzyl-2-(3,4- dichloro-phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-N- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)- butyric acid (intermediate 1) and Benzyl-methyl-amine (commercially available) 
                 498.3 
               
               
                   
               
               
                 5 
                 566.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-N- methyl-N-(4- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)- butyric acid (intermediate 1) and Methyl-(4- trifluoromethyl- benzyl)-amine (commercially available) 
                 566.3 
               
               
                   
               
               
                 6 
                 546.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- 4-methoxy-benzyl)-4- (4-methanesulfonyl- piperazin-1-yl)-N- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)- butyric acid (intermediate 1) and (3-Fluoro-4- methoxy-benzyl)- methyl-amine (commercially available) 
                 546.1 
               
               
                   
               
               
                 7 
                 516.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- benzyl)-4-(4- methanesulfonyl- piperazin-1-yl)-N- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)- butyric acid (intermediate 1) and (3-Fluoro-benzyl)- methyl-amine (commercially available) 
                 516.2 
               
               
                   
               
               
                 8 
                 566.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-N-(3- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 3-Trifluoromethyl- benzylamine (commercially available) 
                 566.3 
               
               
                   
               
               
                 9 
                 582.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-N-(3- trifluoromethoxy- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 3-Trifluoromethoxy- benzylamine (commercially available) 
                 582.2 
               
               
                   
               
               
                 10 
                 546.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3-Chloro-benzyl)- 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2,N- dimethyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and (3-Chloro-benzyl)- methyl-amine (commercially available) 
                 546.2 
               
               
                   
               
               
                 11 
                 564.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3- difluoromethoxy- benzyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 3-Difluoromethoxy- benzylamine (commercially available) 
                 564.2 
               
               
                   
               
               
                 12 
                 546.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-benzyl)- 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2,N- dimethyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and (4-Chloro-benzyl)- methyl-amine (commercially available) 
                 546.1 
               
               
                   
               
               
                 13 
                 564.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(4- difluoromethoxy- benzyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 4-Difluoromethoxy- benzylamine (commercially available) 
                 564.2 
               
               
                   
               
               
                 14 
                 546.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Chloro- phenyl)-ethyl]-2-(3,4- dichloro-phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 1-(4-Chloro- phenyl)-ethylamine (commercially available) 
                 546.2 
               
               
                   
               
               
                 15 
                 568.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-[Cyclopropyl-(4- methoxy-phenyl)- methyl]-2-(3,4- dichloro-phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and C-Cyclopropyl-C-(4- methoxy-phenyl)- methylamine (commercially available) 
                 568.4 
               
               
                   
               
               
                 16 
                 546.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-Chloro-benzyl)- 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2,N- dimethyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and (2-Chloro-benzyl)- methyl-amine (commercially available) 
                 546.2 
               
               
                   
               
               
                 17 
                 582.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-N-(4- trifluoromethoxy- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 4-Trifluoromethoxy- benzylamine (commercially available) 
                 582 
               
               
                   
               
               
                 18 
                 523.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Cyano-benzyl)- 2-(3,4-dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 4-Aminomethyl- benzonitrile (commercially available) 
                 523.3 
               
               
                   
               
               
                 19 
                 582.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-N-(2- trifluoromethoxy- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 2-Trifluoromethoxy- benzylamine (commercially available) 
                 582.2 
               
               
                   
               
               
                 20 
                 584.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- 4-trifluoromethyl- benzyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 3-Fluoro-4- trifluoromethyl- benzylamine (commercially available) 
                 584 
               
               
                   
               
               
                 21 
                 567.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 3,4-Dichloro- benzylamine (commercially available) 
                 568 
               
               
                   
               
               
                 22 
                 526.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2,N- dimethyl-N-(4- methyl-benzyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and Methyl-(4-methyl- benzyl)-amine (commercially available) 
                 526.3 
               
               
                   
               
               
                 23 
                 589.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2,N- dimethyl-N-(4- pyridin-4-yl-benzyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and Methyl-(4-pyridin-4- yl-benzyl)-amine (commercially available) 
                 589.3 
               
               
                   
               
               
                 24 
                 530.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- benzyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2,N- dimethyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 3-Fluoro-benzyl)- methyl-amine (commercially available) 
                 530.2 
               
               
                   
               
               
                 25 
                 560.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- 4-methoxy-benzyl)-4- (4-methanesulfonyl- piperazin-1-yl)-2,N- dimethyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and (3-Fluoro-4- methoxy-benzyl)- methyl-amine (commercially available) 
                 560.3 
               
               
                   
               
               
                 26 
                 608.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(4- difluoromethoxy-3- methoxy-benzyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2,N- dimethyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and (4-Difluoromethoxy- 3-methoxy-benzyl)- methyl-amine (commercially available) 
                 608 
               
               
                   
               
               
                 27 
                 566.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-N-(4- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 4-Trifluoromethyl- benzylamine (commercially available) 
                 566.3 
               
               
                   
               
               
                 28 
                 580.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2,N- dimethyl-N-(4- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and Methyl-(4- trifluoromethyl- benzyl)-amine (commercially available) 
                 580.3 
               
               
                   
               
               
                 29 
                 532.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-benzyl)- 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 4-Chloro- benzylamine (commercially available) 
                 534 
               
               
                   
               
               
                 30 
                 550.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-3-fluoro- benzyl)-2-(3,4- dichloro-phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 4-Chloro-3-fluoro- benzylamine (commercially available) 
                 552.3 
               
               
                   
               
               
                 31 
                 574.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- 4-methoxy-benzyl)-4- ((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (3-Fluoro-4- methoxy-benzyl)- methyl- amine (commercially available) 
                 574.3 
               
               
                   
               
               
                 32 
                 582.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-[Cyclopropyl-(4- methoxy-phenyl)- methyl]-2-(3,4- dichloro-phenyl)-4- ((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and C-Cyclopropyl- C-(4-methoxy- phenyl)- methylamine (commercially available) 
                 584.1 
               
               
                   
               
               
                 33 
                 612.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(4-fluoro- 3-trifluoromethyl- benzyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (4-Fluoro-3- trifluoromethyl- benzyl)-methyl- amine (commercially available) 
                 612.2 
               
               
                   
               
               
                 34 
                 648.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,5-Bis- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4- ((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and 3,5-Bis- trifluoromethyl- benzylamine (commercially available) 
                 648.1 
               
               
                   
               
               
                 35 
                 622.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(4- difluoromethoxy-3- methoxy-benzyl)-4- ((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (4- Difluoromethoxy-3- methoxy-benzyl)- methyl-amine (commercially available) 
                 622.2 
               
               
                   
               
               
                 36 
                 540.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl-N- (4-methyl-benzyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and Methyl-(4- methyl-benzyl)- amine (commercially available) 
                 540.4 
               
               
                   
               
               
                 37 
                 555.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(4- dimethylamino- benzyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (4- Aminomethyl- phenyl)-dimethyl- amine (commercially available) 
                 555.2 
               
               
                   
               
               
                 38 
                 564.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-N- quinoxalin-6- ylmethyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and C-Quinoxalin-6- yl-methylamine (commercially available) 
                 564.3 
               
               
                   
               
               
                 39 
                 629.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4- ((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (4-Chloro-3- trifluoromethyl- benzyl)- methyl-amine (commercially available) 
                 628.2 
               
               
                   
               
               
                 40 
                 612.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- 4-trifluoromethyl- benzyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (3-Fluoro-4- trifluoromethyl- benzyl)-methyl- amine (commercially available) 
                 612.2 
               
               
                   
               
               
                 41 
                 595.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4- ((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (3,4-Dichloro- benzyl)-methyl- amine (commercially available) 
                 596.1 
               
               
                   
               
               
                 42 
                 581.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4- ((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and 3,4-Dichloro- benzylamine (commercially available) 
                 582 
               
               
                   
               
               
                 43 
                 578.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3- difluoromethoxy- benzyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and 3- Difluoromethoxy- benzylamine (commercially available) 
                 578.1 
               
               
                   
               
               
                 44 
                 598.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(5-fluoro- 2-trifluoromethyl- benzyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and 5-Fluoro-2- trifluoromethyl- benzylamine (commercially available) 
                 598.2 
               
               
                   
               
               
                 45 
                 580.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-N-(4- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and 4- Trifluoromethyl- benzylamine (commercially available) 
                 580.1 
               
               
                   
               
               
                 46 
                 598.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(2-fluoro- 5-trifluoromethyl- benzyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and 2-Fluoro-5- trifluoromethyl- benzylamine (commercially available) 
                 598.1 
               
               
                   
               
               
                 47 
                 561.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Chloro- phenyl)-ethyl]-2-(3,4- dichloro-phenyl)-4- ((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and 1-(4-Chloro- phenyl)-ethylamine (commercially available) 
                 562.5 
               
               
                   
               
               
                 48 
                 556.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-N-(3-methoxy- benzyl)-2,N-dimethyl butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (3-Methoxy- benzyl)-methyl- (commercially available) 
                 556.3 
               
               
                   
               
               
                 49 
                 561.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-Chloro-benzyl)- 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (2-Chloro- benzyl)-methyl- amine (commercially available) 
                 560.3 
               
               
                   
               
               
                 50 
                 595.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-[1-(3,4- dichloro-phenyl)- ethyl]-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and 1-(3,4-Dichloro- phenyl)-ethylamine (commercially available) 
                 596.3 
               
               
                   
               
               
                 51 
                 596.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-N-(3- trifluoromethoxy- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and 3- Trifluoromethoxy- benzylamine (commercially available) 
                 596.2 
               
               
                   
               
               
                 52 
                 564.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-3-fluoro- benzyl)-2-(3,4- dichloro-phenyl)-4- ((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and 3-Chloro-4- fluoro-benzylamine (commercially available) 
                 564.3 
               
               
                   
               
               
                 53 
                 596.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-N-(4- trifluoromethoxy- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and 4- Trifluoromethoxy- benzylamine (commercially available) 
                 596.2 
               
               
                   
               
               
                 54 
                 614.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4- ((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and 4-Chloro-3- trifluoromethyl- benzylamine (commercially available) 
                 614.3 
               
               
                   
               
               
                 55 
                 594.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl-N- (4-trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and Methyl-(4- trifluoromethyl- benzyl)-amine (commercially available) 
                 594.2 
               
               
                   
               
               
                 56 
                 561.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-benzyl)- 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (4-Chloro- benzyl)-methyl- amine (commercially available) 
                 560.3 
               
               
                   
               
               
                 57 
                 537.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Cyano-benzyl)- 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and 4-Aminomethyl- benzonitrile (commercially available) 
                 537.3 
               
               
                   
               
               
                 58 
                 594.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl-N- (3-trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and Methyl-(3- trifluoromethyl- benzyl)-amine (commercially available) 
                 594.2 
               
               
                   
               
               
                 59 
                 561.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3-Chloro-benzyl)- 2-(3,4-dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (3-Chloro- benzyl)-methyl- amine (commercially available) 
                 562.5 
               
               
                   
               
               
                 60 
                 544.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- benzyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (3-Fluoro- benzyl)-methyl- amine (commercially available) 
                 544.2 
               
               
                   
               
               
                 61 
                 603.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl-N- (4-pyridin-4-yl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and Methyl-(4- pyridin-4-yl-benzyl)- amine (commercially available) 
                 603.3 
               
               
                   
               
               
                 62 
                 574.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- 4-methoxy-benzyl)-4- ((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and (3-Fluoro-4- methoxy-benzyl)- methyl-amine (commercially available) 
                 574.3 
               
               
                   
               
               
                 63 
                 582.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-[Cyclopropyl-(4- methoxy-phenyl)- methyl]-2-(3,4- dichloro-phenyl)-4- ((S)-4- methanesulfonly-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and C-Cyclopropyl- C-(4-methoxy- phenyl)- methylamine (commercially available) 
                 584.2 
               
               
                   
               
               
                 64 
                 612.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(4-fluoro- 3-trifluoromethyl- benzyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and (4-Fluoro-3- trifluoromethyl- benzyl)-methyl- amine (commercially acid available) 
                 612.3 
               
               
                   
               
               
                 65 
                 648.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,5-Bis- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4- ((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and 3,5-Bis- trifluoromethyl- benzylamine (commercially available) 
                 648.2 
               
               
                   
               
               
                 66 
                 622.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(4- difluoromethoxy-3- methoxy-benzyl)-4- ((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (4- Difluoromethoxy-3- methoxy-benzyl)- methyl-amine (commercially available) 
                 622.3 
               
               
                   
               
               
                 67 
                 540.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl-N- (4-methyl-benzyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and Methyl-(4- methyl-benzyl)- amine (commercially available) 
                 540.4 
               
               
                   
               
               
                 68 
                 555.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(4- dimethylamino- benzyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and (4- Aminomethyl- phenyl)-dimethyl- amine (commercially available) 
                 555.2 
               
               
                   
               
               
                 69 
                 629.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4- ((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and (4-Chloro-3- trifluoromethyl- benzyl)-methyl- amine (commercially available) 
                 630.3 
               
               
                   
               
               
                 70 
                 612.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- 4-trifluoromethyl- benzyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and (3-Fluoro-4- trifluoromethyl- benzyl)-methyl- amine (commercially available) 
                 612.1 
               
               
                   
               
               
                 71 
                 595.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4- ((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and (3,4-Dichloro- benzyl)-methyl- amine (commercially available) 
                 596.2 
               
               
                   
               
               
                 72 
                 581.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4- ((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and 3,4-Dichloro- benzylamine (commercially available) 
                 582 
               
               
                   
               
               
                 73 
                 578.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3- difluoromethoxy- benzyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and 3- Difluoromethoxy- benzylamine (commercially available) 
                 578.1 
               
               
                   
               
               
                 74 
                 598.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(5-fluoro- 2-trifluoromethyl- benzyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and 5-Fluoro-2- trifluoromethyl- benzylamine (commercially available) 
                 598.3 
               
               
                   
               
               
                 75 
                 580.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-N-(4- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and 4- Trifluoromethyl- benzylamine (commercially available) 
                 580 
               
               
                   
               
               
                 76 
                 598.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(2-fluoro- 5-trifluoromethyl- benzyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and 2-Fluoro-5- trifluoromethyl- benzylamine (commercially available) 
                 598.1 
               
               
                   
               
               
                 77 
                 561.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Chloro- phenyl)-ethyl]-2-(3,4- dichloro-phenyl)-4- ((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and 1-(4-Chloro- phenyl)-ethylamine (commercially available) 
                 560.3 
               
               
                   
               
               
                 78 
                 556.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-N-(3-methoxy- benzyl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and (3-Methoxy- benzyl)-methyl- amine (commercially available) 
                 556.1 
               
               
                   
               
               
                 79 
                 561.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-Chloro-benzyl)- 2-(3,4-dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and (2-Chloro- benzyl)-methyl- amine (commercially available) 
                 562.3 
               
               
                   
               
               
                 80 
                 595.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-[1-(3,4- dichloro-phenyl)- ethyl]-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and 1-(3,4-Dichloro- phenyl)-ethylamine (commercially available) 
                 596.2 
               
               
                   
               
               
                 81 
                 596.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-N-(3- trifluoromethoxy- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and 3- Trifluoromethoxy- benzylamine (commercially available) 
                 596.3 
               
               
                   
               
               
                 82 
                 564.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-3-fluoro- benzyl)-2-(3,4- dichloro-phenyl)-4- ((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and 3-Chloro-4- fluoro-benzylamine (commercially available) 
                 566.3 
               
               
                   
               
               
                 83 
                 596.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-N-(4- trifluoromethoxy- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and 4- Trifluoromethoxy- benzylamine (commercially available) 
                 596.2 
               
               
                   
               
               
                 84 
                 614.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4- ((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and 4-Chloro-3- trifluoromethyl- benzylamine (commercially available) 
                 614.3 
               
               
                   
               
               
                 85 
                 594.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl-N- (4-trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and Methyl-(4- trifluoromethyl- benzyl)-amine (commercially available) 
                 594.2 
               
               
                   
               
               
                 86 
                 561.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-benzyl)- 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and (4-Chloro- benzyl)-methyl- amine (commercially available) 
                 562.5 
               
               
                   
               
               
                 87 
                 594.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl-N- (3-trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and Methyl-(3- trifluoromethyl- benzyl)-amine (commercially available) 
                 594.3 
               
               
                   
               
               
                 88 
                 561.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3-Chloro-benzyl)- 2-(3,4-dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and (3-Chloro- benzyl)-methyl- amine (commercially available) 
                 560.3 
               
               
                   
               
               
                 89 
                 544.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- benzyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and (3-Fluoro- benzyl)-methyl- amine (commercially available) 
                 544.2 
               
               
                   
               
               
                 90 
                 595.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2,N-dimethyl-N- (6-trifluoromethyl- pyridin-3-ylmethyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and C-(6- Trifluoromethyl- pyridin-3-yl)- methylamine (commercially available) 
                 595.2 
               
               
                   
               
               
                 91 
                 581.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-N-(6- trifluoromethyl- pyridin-3-ylmethyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((S)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 4) and C-(6- Trifluoromethyl- pyridin-3-yl)- methylamine (commercially available) 
                 581 
               
               
                   
               
               
                 92 
                 581.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-N-(6- trifluoromethyl- pyridin-3-ylmethyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-((R)-4- methanesulfonyl-3- methyl-piperazin-1- yl)-2-methyl-butyric acid (intermediate 3) and (commercially available) 
                 581 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 93 
     (S or R)—N-(3,4-Dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide MS(m/e): 581.4 (MH + ) (or diastereoisomer) 
     
       
                 
         
             
             
         
      
     
     EXAMPLE 94 
     (R or S)—N-(3,4-Dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide MS(m/e): 581.5 (MH + ) (or diastereoisomer) 
     
       
                 
         
             
             
         
      
     
     The title compounds were isolated from N-(3,4-dichloro-benzyl)-2-(3,4-dichloro-phenyl)-4-((R)-4-methanesulfonyl-3-methyl-piperazin-1-yl)-2-methyl-butyramide (example 42) through column chromatography on chiral phase. 
     In analogy to the procedure described for the synthesis of N-(4-chloro-benzyl)-2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-N-methyl-butyramide (example 1) further (homo)-piperazine derivatives have been synthesized from the starting materials listed in Table 3. Table 3 comprises examples 95-137. 
     
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 MW 
               
               
                   
                   
                   
                 Systematic 
                 starting 
                 found 
               
               
                 No 
                 MW 
                 structure 
                 Name 
                 materials 
                 MH+ 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 95 
                 598.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- 4-trifluoromethyl- benzyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and 3-Fluoro-4- trifluoromethyl- benzylamine (commercially available) 
                 598.3 
               
               
                   
               
               
                 96 
                 594.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl-N-(4- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and Methyl-(4- trifluoromethyl- benzyl)-amine (commercially available) 
                 594.3 
               
               
                   
               
               
                 97 
                 561.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-benzyl)- 2-(3,4-dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and (4-Chloro- benzyl)-methyl- amine(commercially available) 
                 562.2 
               
               
                   
               
               
                 98 
                 564.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-3-fluoro- benzyl)-2-(3,4- dichloro-phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and 3-Chloro-4- fluoro-benzylamine (commercially available) 
                 566.3 
               
               
                   
               
               
                 99 
                 596.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-N-(4- trifluoromethoxy- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and 4- Trifluoromethoxy- benzylamine (commercially available) 
                 596.2 
               
               
                   
               
               
                 100 
                 544.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- benzyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and (3-Fluoro- benzyl)-methyl- amine (commercially available) 
                 544.3 
               
               
                   
               
               
                 101 
                 594.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl-N-(3- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and Methyl-(3- trifluoromethyl- benzyl)-amine (commercially available) 
                 594.3 
               
               
                   
               
               
                 102 
                 596.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-N-(3- trifluoromethoxy- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and 3- Trifluoromethoxy- benzylamine (commercially available) 
                 596.2 
               
               
                   
               
               
                 103 
                 561.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3-Chloro-benzyl)- 2-(3,4-dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and (3-Chloro- benzyl)-methyl- amine (commercially available) 
                 562.2 
               
               
                   
               
               
                 104 
                 574.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- 4-methoxy-benzyl)-4- (4-methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and (3-Fluoro-4- methoxy-benzyl)- methyl-amine (commercially available) 
                 574.3 
               
               
                   
               
               
                 105 
                 582.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-[Cyclopropyl-(4- methoxy-phenyl)- methyl]-2-(3,4- dichloro-phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and C-Cyclopropyl- C-(4-methoxy- phenyl)- methylamine (commercially available) 
                 584.1 
               
               
                   
               
               
                 106 
                 612.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(4-fluoro- 3-trifluoromethyl- benzyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and (4-Fluoro-3- trifluoromethyl- benzyl)-methyl- amine (commercially available) 
                 612.1 
               
               
                   
               
               
                 107 
                 648.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,5-Bis- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and 3,5-Bis- trifluoromethyl- benzylamine (commercially available) 
                 648.2 
               
               
                   
               
               
                 108 
                 622.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(4- difluoromethoxy-3- methoxy-benzyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and (4- Difluoromethoxy-3- methoxy-benzyl)- methyl-amine (commercially available) 
                 622.1 
               
               
                   
               
               
                 109 
                 540.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl-N-(4- methyl-benzyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and Methyl-(4- methyl-benzyl)- amine (commercially available) 
                 540.3 
               
               
                   
               
               
                 110 
                 555.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(4- dimethylamino- benzyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and (4- Aminomethyl- phenyl)-dimethyl- amine (commercially available) 
                 555.3 
               
               
                   
               
               
                 111 
                 629.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Chloro-3- trifluoromethyl- benzyl)-2-(3,4- dichloro-phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and (4-Chloro-3- trifluoromethyl- benzyl)-methyl- amine (commercially available) 
                 630.2 
               
               
                   
               
               
                 112 
                 612.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3-fluoro- 4-trifluoromethyl- benzyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and (3-Fluoro-4- trifluoromethyl- benzyl)- methyl-amine (commercially available) 
                 612.3 
               
               
                   
               
               
                 113 
                 595.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and (3,4-Dichloro- benzyl)-methyl- amine (commercially available) 
                 596.2 
               
               
                   
               
               
                 114 
                 581.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,4-Dichloro- benzyl)-2-(3,4- dichloro-phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and 3,4-Dichloro- benzylamine (commercially available) 
                 582.2 
               
               
                   
               
               
                 115 
                 578.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(3- difluoromethoxy- benzyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and 3- Difluoromethoxy- benzylamine (commercially available) 
                 578.5 
               
               
                   
               
               
                 116 
                 598.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(5-fluoro- 2-trifluoromethyl- benzyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and 5-Fluoro-2- trifluoromethyl- benzylamine (commercially available) 
                 598.1 
               
               
                   
               
               
                 117 
                 580.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-N-(4- trifluoromethyl- benzyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and 4- Trifluoromethyl- benzylamine (commercially available) 
                 580.1 
               
               
                   
               
               
                 118 
                 598.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-(2-fluoro- 5-trifluoromethyl- benzyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and 2-Fluoro-5- trifluoromethyl- benzylamine (commercially available) 
                 598.3 
               
               
                   
               
               
                 119 
                 561.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-[1-(4-Chloro- phenyl)-ethyl]-2-(3,4- dichloro-phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and 1-(4-Chloro- phenyl)-ethylamine (commercially available) 
                 560.3 
               
               
                   
               
               
                 120 
                 556.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-N- (3-methoxy-benzyl)- 2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and (3-Methoxy- benzyl)-methyl amine (commercially available) 
                 556.2 
               
               
                   
               
               
                 121 
                 561.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-Chloro-benzyl)- 2-(3,4-dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and (2-Chloro- benzyl)-methyl- amine (commercially available) 
                 560.3 
               
               
                   
               
               
                 122 
                 595.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-[1-(3,4- dichloro-phenyl)- ethyl]-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and 1-(3,4-Dichloro- phenyl)-ethylamine (commercially available) 
                 596.3 
               
               
                   
               
               
                 123 
                 603.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl-N-(4- pyridin-4-yl-benzyl- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and Methyl-(4- pyridin-4-yl-benzyl)- amine (commercially available) 
                 603.2 
               
               
                   
               
               
                 124 
                 537.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-Cyano-benzyl)- 2-(3,4-dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and 4-Aminomethyl- benzonitrile (commercially available) 
                 537.3 
               
               
                   
               
               
                 125 
                 595.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2,N-dimethyl-N-(6- trifluoromethyl- pyridin-3-ylmethyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)- 2-methyl-butyric acid (intermediate 5) and C-(6- Trifluoromethyl- pyridin-3-yl)- methylamine (commercially available) 
                 595.3 
               
               
                   
               
               
                 126 
                 581.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro-phenyl)- 4-(4-methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-N-(6- trifluoromethyl-pyridin- 3-ylmethyl)-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- [1,4]diazepan-1-yl)-2- methyl-butyric acid (intermediate 5) and C-(6-Trifluoromethyl- pyridin-3-yl)- methylamine (commercially available) 
                 581 
               
               
                   
               
               
                 127 
                 580.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2,N- dimethyl-N-(3- trifluoromethyl-benzyl)- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and Methyl-(3- trifluoromethyl- benzyl)-amine (commercially available) 
                 580.2 
               
               
                   
               
               
                 128 
                 528.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (R or S)-2-(3,4- Dichloro-phenyl)-N- ((R)-2-hydroxy-1- phenyl-ethyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl-2- methyl-butyric acid (intermediate 2) and (R)-2-Amino-2- phenyl-ethanol (commercially available) 
                 528.3 
               
               
                   
               
               
                 129 
                 528.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S or R)-2-(3,4- Dichloro-phenyl)-N- ((R)-2-hydroxy-1- phenyl-ethyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and (R)-2-Amino-2- phenyl-ethanol (commercially available) 
                 528.3 
               
               
                   
               
               
                 130 
                 562.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-[(R)-1-(4-Chloro- phenyl)-2-hydroxy- ethyl]-2-(3,4-dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and (R)-2-Amino-2-(4- chloro-phenyl-ethanol (commercially available) 
                 564.3 
               
               
                   
               
               
                 131 
                 562.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-[(S)-1-(4-Chloro- phenyl)-2-hydroxy- ethyl]-2-(3,4-dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and (S)-2-Amino-2-(4- chloro-phenyl)-ethanol (commercially available) 
                 564.3 
               
               
                   
               
               
                 132 
                 546.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-[(R)-1-(4- fluoro-phenyl)-2- hydroxy-ethyl]-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and (R)-2-Amino-2-(4- fluoro-phenyl)-ethanol (commercially available) 
                 548.3 
               
               
                   
               
               
                 133 
                 546.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-[(S)-1-(4- fluoro-phenyl)-2- hydroxy-ethyl]-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and (S)-2-Amino-2-(4- fluoro-phenyl)-ethanol (commercially available) 
                 548.4 
               
               
                   
               
               
                 134 
                 530.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-N-[1-(4-fluoro- phenyl)-ethyl]-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 1-(4-Fluoro-phenyl)- ethylamine (commercially available) 
                 530.3 
               
               
                   
               
               
                 135 
                 584.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-N-[2,2,2- trifluoro-1-(4-fluoro- phenyl)-ethyl]- butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(4- methanesulfonyl- piperazin-1-yl)-2- methyl-butyric acid (intermediate 2) and 2,2,2-Trifluoro-1-(4- fluoro-phenyl)- ethylamine (commercially available) 
                 584.1 
               
               
                   
               
               
                 136 
                 575.0 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-[(R)-1-(4-Chloro- phenyl)-2-hydroxy- ethyl]-2-(3,4-dichloro- phenyl)-4-(1,1-dioxo- hexahydro-1λ 6 -thia-5,7a- diaza-inden-5-yl)-2- methyl-butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(1,1-dioxo- hexahydro- 1lambda*6*-thia-5,7a- diaza-inden-5-yl)-2- methyl-butyric acid(intermediate 6) and (R)-2-Amino-2-(4- chloro-phenyl)-ethanol (commercially available) 
                 574.1 
               
               
                   
               
               
                 137 
                 558.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,4-Dichloro- phenyl)-(1,1-dioxo- hexahydro-1λ 6 -thia-5,7a- diaza-inden-5-yl)-N- [(R)-1-(4-fluoro- phenyl)-2-hydroxy- ethyl]-2-methyl butyramide 
                 2-(3,4-Dichloro- phenyl)-4-(1,1-dioxo- hexahydro- 1lambda*6*-thia-5,7a- diaza-inden-5-yl)-2- methyl-butyric acid(intermediate 6) and (R)-2-Amino-2-(4- fluoro-phenyl)-ethanol (commercially available) 
                 558