Abstract:
The invention relates to novel bis-amide derivatives and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including pharmaceutical compositions containing one or more of those compounds and their use as medicaments for the treatment or prevention of protozoal infections, such as especially malaria.

Description:
[0001]    The invention relates to novel compounds of the formula I. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the formula I and especially their use as medicaments to treat or prevent malaria infections or to treat or prevent other protozoal diseases like sleeping sickness, Chagas disease, amebiasis, giardiasis, trichomoniasis, toxoplasmosis, and leishmaniasis. 
       BACKGROUND OF THE INVENTION 
       [0002]    Numerous serious diseases affecting humans as well as domestic and livestock animal are caused by protozoal organisms such as kinetoplastida, apicomplexa, anaerobic protozoa, microsporidia and  plasmodium , for example. The clinically most relevant of these diseases is malaria. 
         [0003]    Malaria is one of the most serious and complex health problems affecting humanity in the 21 st  century. The disease affects about 300 million people worldwide, killing 1 to 1.5 million people every year. Malaria is an infectious disease caused by four species of the protozoan parasite  plasmodium, P. falciparum  being the most severe of the four. All attempts to develop vaccines against  P. falciparum  have failed so far. Therefore, therapies and preventive measures against malaria are confined to drugs. Various classes of antimalarial drugs exist. The most widely used are the quinoline antimalarials, e.g. chloroquine which has been an especially effective drug for both prophylaxis and therapy. However, resistance to many of the currently available antimalarial drugs is spreading rapidly, threatening people in areas where malaria is endemic. Reports of multi-drug resistant strains of malaria parasites render the search for new antimalarial agents especially urgent.  P. falciparum  enters the human body by way of bites of the female anophelino mosquito (it may also be transmitted by blood transfusion from asymptotic donors; almost all infected blood components including red cells, platelet concentrates, white cells, cryoprecipitates and fresh plasma can transmit malaria). The  plasmodium  parasite initially populates the liver, and during later stages of the infectious cycle reproduces in red blood cells. During this stage, the parasite degrades hemoglobin and uses the degradation products as nutrients for growth. 
         [0004]    The limitations of the current antiprotozoal chemotherapeutic arsenal underscore the need for new drugs in this therapeutic area. The present invention relates to the identification of novel low molecular weight, non-peptidic, non-quinoline compounds of formula I which are useful in the treatment and/or prevention of protozoal infections, especially in the treatment and/or prevention of malaria, in particular  plasmodium falciparum  malaria. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0005]    i) The present invention relates to novel compounds of the formula I: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein
 
R 1  represents aryl or heteroaryl, wherein these two radicals can optionally be mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, cycloalkyl, trifluoromethyl, trifluoromethoxy, and amino, wherein the amino group is optionally mono- or di-substituted with (C 1 -C 4 )alkyl or mono-substituted with (C 1 -C 4 )alkyl-carbonyl; or R 1  represents aryl wherein two adjacent carbon ring atoms of the aryl moiety are substituted with (C 1 -C 2 )alkylenedioxy, wherein the (C 1 -C 2 )alkylene moiety is optionally mono- or di-substituted, wherein the substituents are independently selected from the group consisting of halogen and (C 1 -C 4 )alkyl;
 
R 2  represents aryl or heteroaryl, wherein these two radicals can optionally be mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from the group consisting of halogen; (C 1 -C 4 )alkyl; (C 1 -C 4 )alkoxy; trifluoromethyl; trifluoromethoxy; heterocycloalkyl, that can optionally be mono-substituted on one nitrogen ring atom, if present, with (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkyl-carbonyl; and aryl or heteroaryl, wherein these two radicals can optionally be mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, trifluoromethyl, and trifluoromethoxy;
 
R 3  represents aryl or heteroaryl, wherein these two radicals can optionally be mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, trifluoromethyl, and trifluoromethoxy; or R 3  represents heterocycloalkyl that can optionally be mono-substituted on one nitrogen ring atom, if present, with (C 1 -C 4 )alkyl, cycloalkyl, (C 1 -C 4 )alkyl-carbonyl, or cycloalkyl-carbonyl; or R 3  represents 2-oxo-oxazolidin-3-yl; or R 3  represents 2,3-dioxo-2,3-dihydro-indol-1-yl that can optionally be mono-, di- or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, trifluoromethyl, and trifluoromethoxy; and
 
R 4  and R 5 , together with the nitrogen atom to which they are attached, form a morpholine ring; or together with the nitrogen atom to which they are attached, form the radicals 5,8-dihydro-6H-[1,7]naphthyridin-7-yl, 2,3-dihydro-1H-indol-1-yl, or 1,3-dihydro-1H-isoindol-2-yl, wherein these three radicals can optionally be mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, trifluoromethyl, and trifluoromethoxy;
 
or R 4  and R 5 , together with the nitrogen atom to which they are attached, form a 3-amino-pyrrolidine ring, wherein the amino group is di-substituted with (C 1 -C 4 )alkyl; or together with the nitrogen atom to which they are attached, form a 3- or 4-substituted piperidine ring, wherein the substituent is selected from the group consisting of phenyl, benzyl, pyrrolidinomethyl, piperidinomethyl, amino di-substituted with (C 1 -C 4 )alkyl, and aminomethyl wherein the amino group is di-substituted with (C 1 -C 4 )alkyl;
 
or R 4  represents hydrogen or (C 1 -C 4 )alkyl, and R 5  represents 1-benzyl-pyrrolidin-3-yl or 1-aza-bicyclo[2.2.2]oct-3-yl;
 
or R 4  represents (C 1 -C 4 )alkyl and R 5  represents the following group:
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 6  represents hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 4 )alkenyl, cyanomethyl, carbamoylmethyl, cycloalkylmethyl, or 2-benzyloxy-ethyl; or R 6  represents heteroaryl that can optionally be mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, cycloalkyl, trifluoromethyl, and trifluoromethoxy; or R 6  represents arylmethyl or heteroarylmethyl, wherein the aryl or heteroaryl moiety can optionally be mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, cyano, trifluoromethyl, difluoromethoxy, and trifluoromethoxy;
 
or R 4  represents hydrogen, (C 1 -C 4 )alkyl, or benzyl, and R 5  represents the following group:
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 7  represents (C 1 -C 4 )alkyl; and R 8  represents (C 1 -C 4 )alkyl or 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethyl; or R 8  represents arylmethyl or heteroarylmethyl, wherein the aryl or heteroaryl moiety can optionally be mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, cycloalkyl, hydroxy, hydroxymethyl, cyano, trifluoromethyl, trifluoromethoxy, —O—(CH 2 ) 2 —OH, —O—(CH 2 ) 3 —N((C 1 -C 4 )alkyl) 2 , and amino, wherein the amino group is mono- or di-substituted with substituents independently selected from (C 1 -C 4 )alkyl and hydroxy-(C 1 -C 4 )alkyl; or R 8  represents arylmethyl wherein two adjacent carbon ring atoms of the aryl moiety are substituted with (C 1 -C 2 )alkylenedioxy, wherein the (C 1 -C 2 )alkylene moiety is optionally mono- or di-substituted, wherein the substituents are independently selected from the group consisting of halogen and (C 1 -C 4 )alkyl; or R 7  and R 8 , together with the nitrogen atom to which they are attached, form a piperidine, morpholine, or azepane ring;
 
or R 4  represents (C 1 -C 4 )alkyl and R 5  represents arylmethyl or heteroarylmethyl, wherein the aryl or heteroaryl moiety can optionally be mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, trifluoromethyl, and trifluoromethoxy;
 
or R 4  represents (C 1 -C 4 )alkyl and R 5  represents the following group:
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein the amino group can be in position 2, 3 or 4; R 9  represents hydrogen, phenyl, or (C 1 -C 4 )alkyl; and R 10  represents (C 1 -C 4 )alkyl, —(CH 2 ) 2 —O—(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl-carbonyl, cycloalkyl-carbonyl, or benzoyl; or R 9  and R 10 , together with the nitrogen atom to which they are attached, form a pyrrolidin-2-one or a piperidin-2-one ring. 
         [0006]    The general terms used hereinbefore and hereinafter preferably have, within this disclosure, the following meanings, unless otherwise indicated: 
         [0007]    The term (C 1 -C 4 )alkyl, alone or in combination with other groups, means saturated, straight or branched chain groups with one to four carbon atoms, preferably one to three carbon atoms, i.e. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. The methyl, ethyl and isopropyl groups are preferred. 
         [0008]    The term (C 1 -C 4 )alkoxy, alone or in combination with other groups, refers to an R—O— group, wherein R is a (C 1 -C 4 )alkyl, i.e. methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. The methoxy group is a preferred group. 
         [0009]    The term (C 3 -C 4 )alkenyl, alone or in combination with other groups, means straight or branched chain groups comprising an olefinic bond and consisting of three to four carbon atoms, such as especially allyl. 
         [0010]    The term (C 1 -C 2 )alkylenedioxy refers to methylenedioxy and 1,2-ethylenedioxy. If R 1  or R 8  represent aryl or arylmethyl, respectively, wherein two adjacent carbon ring atoms of the aryl moiety are substituted with (C 1 -C 2 )alkylenedioxy, this means that methylenedioxy or 1,2-ethylenedioxy is attached via its oxygen atoms to the two adjacent carbon ring atoms of the aryl moiety, to form, together with the two adjacent carbon ring atoms, a 5- or 6-membered ring, respectively. 
         [0011]    The term halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine, or bromine. 
         [0012]    The term cycloalkyl, alone or in combination with other groups, means a saturated cyclic hydrocarbon ring system with 3 to 7 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The cyclopropyl group is a preferred group. 
         [0013]    The term aryl, alone or in combination with other groups, relates to a phenyl or naphthyl group, preferably a phenyl group. 
         [0014]    The term heteroaryl, alone or in combination with other groups, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing up to three, i.e. 1, 2, or 3, ring heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, and phthalazinyl. 
         [0015]    The term heterocycloalkyl, alone or in combination with other groups, means a 4-, 5-, or 6-membered saturated cyclic hydrocarbon ring system containing up to three, i.e. 1, 2, or 3, ring heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of such heterocycloalkyl groups are pyrrolidinyl, piperidyl, morpholinyl, and piperazinyl. 
         [0016]    ii) A further embodiment of the invention relates to compounds of the formula I according to embodiment i), wherein the carbon atom to which —CH 2 —R 3  is attached is in the (S)-configuration: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0017]    iii) A further embodiment of the invention relates to compounds of the formula I according to embodiment i) or ii), wherein: 
         [0000]    R 1  represents mono-substituted aryl or mono-substituted heteroaryl, wherein the substituent is selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, cycloalkyl, trifluoromethyl, and trifluoromethoxy. 
         [0018]    iv) A further embodiment of the invention relates to compounds of the formula I according to embodiment iii), wherein: 
         [0000]    R 1  represents mono-substituted aryl or mono-substituted heteroaryl, wherein the substituent is selected from the group consisting of chlorine, methyl, methoxy, and trifluoromethyl. 
         [0019]    v) A further embodiment of the invention relates to compounds of the formula I according to any one of embodiments i) to iv), wherein: 
         [0000]    R 2  represents mono-substituted aryl or mono-substituted heteroaryl, wherein the substituent is selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, and heterocycloalkyl wherein the heterocycloalkyl can optionally be mono-substituted on one nitrogen ring atom, if present, with (C 1 -C 4 )alkyl or (C 1 -C 4 )alkyl-carbonyl. 
         [0020]    vi) A further embodiment of the invention relates to compounds of the formula I according to any one of embodiments i) to v), wherein: 
         [0000]    R 3  represents phenyl, morpholin-4-yl, pyrrol-1-yl, or 1-methyl-1H-pyrazol-3-yl. 
         [0021]    vii) A further embodiment of the invention relates to compounds of the formula I according to any one of embodiments i) to vi), wherein: 
         [0000]    R 4  and R 5 , together with the nitrogen atom to which they are attached, form a 4-substituted piperidine ring, wherein the substituent is phenyl or benzyl. 
         [0022]    viii) A further embodiment of the invention relates to compounds of the formula I according to any one of embodiments i) to vi), wherein: 
         [0000]    R 4  represents (C 1 -C 4 )alkyl and R 5  represents the following group: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 6  represents hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 4 )alkenyl, cyanomethyl, carbamoylmethyl, cycloalkylmethyl, or 2-benzyloxy-ethyl; or R 6  represents heteroaryl that can optionally be mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, cycloalkyl, trifluoromethyl, and trifluoromethoxy; or R 6  represents arylmethyl or heteroarylmethyl, wherein aryl or heteroaryl moiety can optionally be mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, cyano, trifluoromethyl, difluoromethoxy, and trifluoromethoxy;
 
or R 4  represents (C 1 -C 4 )alkyl and R 5  represents the following group:
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 7  represents (C 1 -C 4 )alkyl; and R 8  represents (C 1 -C 4 )alkyl or 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethyl; or R 8  represents arylmethyl or heteroarylmethyl, wherein the aryl or heteroaryl moiety can optionally be mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, cycloalkyl, hydroxy, hydroxymethyl, cyano, trifluoromethyl, trifluoromethoxy, —O—(CH 2 ) 2 —OH, —O—(CH 2 ) 3 —N((C 1 -C 4 )alkyl) 2 , and amino, wherein the amino group is mono- or di-substituted with substituents independently selected from (C 1 -C 4 )alkyl and hydroxy-(C 1 -C 4 )alkyl; or R 8  represents arylmethyl wherein two adjacent carbon ring atoms of the aryl moiety are substituted with (C 1 -C 2 )alkylenedioxy, wherein the (C 1 -C 2 )alkylene moiety is optionally mono- or di-substituted, wherein the substituents are independently selected from the group consisting of halogen and (C 1 -C 4 )alkyl;
 
or R 4  represents (C 1 -C 4 )alkyl and R 5  represents arylmethyl or heteroarylmethyl, wherein the aryl or heteroaryl moiety can optionally be mono-, di-, tri-, or tetra-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, trifluoromethyl, and trifluoromethoxy;
 
or R 4  represents (C 1 -C 4 )alkyl and R 5  represents the following group:
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein the amino group can be in position 2, 3 or 4; R 9  represents hydrogen, phenyl, or (C 1 -C 4 )alkyl; and R 10  represents (C 1 -C 4 )alkyl, —(CH 2 ) 2 —O—(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl-carbonyl, cycloalkyl-carbonyl, or benzoyl; or R 9  and R 10 , together with the nitrogen atom to which they are attached, form a pyrrolidin-2-one or a piperidin-2-one ring. 
         [0023]    ix) In another embodiment, the present invention relates to compounds of formula I according to embodiment i) wherein: 
         [0000]    R 1  represents phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, or thiadiazolyl, wherein these radicals can optionally be mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl such as methyl, (C 1 -C 4 )alkoxy such as methoxy, and trifluoromethyl;
 
R 2  represents phenyl or pyridyl, wherein these two radicals can optionally be mono-substituted (especially in para-position), wherein the substituent is selected from the group consisting of (C 1 -C 4 )alkyl such as ethyl, morpholin-4-yl, 4-acetyl-piperazin-1-yl, pyridyl, and pyrimidyl such as pyrimidin-5-yl;
 
R 3  represents phenyl, pyrimidyl, imidazolyl, pyrrolyl, isoxazolyl, or pyrazolyl, wherein these radicals can optionally be mono-substituted with (C 1 -C 4 )alkyl such as methyl; or R 3  represents pyrrolidinyl such as pyrrolidin-1-yl, morpholinyl such as morpholin-4-yl, or piperazinyl that can optionally be mono-substituted on one nitrogen ring atom with (C 1 -C 4 )alkyl such as 4-methyl-piperazin-1-yl; or R 3  represents 2-oxo-oxazolidin-3-yl or 2,3-dioxo-2,3-dihydro-indol-1-yl; and
 
R 4  and R 5 , together with the nitrogen atom to which they are attached, form a morpholine ring; or together with the nitrogen atom to which they are attached, form the radicals 5,8-dihydro-6H-[1,7]naphthyridin-7-yl, 2,3-dihydro-1H-indol-1-yl, or 1,3-dihydro-1H-isoindol-2-yl; or R 4  and R 5 , together with the nitrogen atom to which they are attached, form a 3-amino-pyrrolidine ring, wherein the amino group is di-substituted with (C 1 -C 4 )alkyl such as methyl; or together with the nitrogen atom to which they are attached, form a 4-substituted piperidine ring, wherein the substituent is selected from the group consisting of phenyl, benzyl, pyrrolidinomethyl, amino di-substituted with (C 1 -C 4 )alkyl such as dimethylamino, and aminomethyl wherein the amino group is di-substituted with (C 1 -C 4 )alkyl such as dimethylaminomethyl;
 
or R 4  represents hydrogen or (C 1 -C 4 )alkyl such as methyl, and R 5  represents 1-benzyl-pyrrolidin-3-yl or 1-aza-bicyclo[2.2.2]oct-3-yl;
 
or R 4  represents (C 1 -C 4 )alkyl such as methyl and R 5  represents the following group:
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 6  represents hydrogen, (C 1 -C 4 )alkyl such as methyl or ethyl, (C 3 -C 4 )alkenyl such as allyl, cyanomethyl, carbamoylmethyl, cycloalkylmethyl such as cyclopropylmethyl, or 2-benzyloxy-ethyl; or R 6  represents pyrimidyl such as pyrimidin-2-yl; or R 6  represents benzyl, pyridylmethyl, furanylmethyl, isoxazolylmethyl, or benzotriazolylmethyl such as benzotriazol-5-ylmethyl, wherein these radicals can optionally be mono- or di-substituted at the ring(s), wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl such as methyl, (C 1 -C 4 )alkoxy such as methoxy, cyano, trifluoromethyl, difluoromethoxy, and trifluoromethoxy;
 
or R 4  represents hydrogen, (C 1 -C 4 )alkyl such as methyl, or benzyl, and R 5  represents the following group:
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 7  represents (C 1 -C 4 )alkyl such as methyl, isopropyl or n-butyl; and R 8  represents (C 1 -C 4 )alkyl such as methyl, isopropyl or n-butyl, or 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethyl; or R 8  represents benzyl, pyridylmethyl, pyrimidylmethyl such as pyrimidin-5-ylmethyl, furanylmethyl, thienylmethyl, thiazolylmethyl, or imidazolylmethyl, wherein these radicals can optionally be mono-, di-, or tri-substituted at the ring, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl such as methyl, (C 1 -C 4 )alkoxy such as methoxy or isopropoxy, hydroxy, hydroxymethyl, cyano, trifluoromethyl, —O—(CH 2 ) 2 —OH, —O—(CH 2 ) 3 —N((C 1 -C 4 )alkyl) 2  such as —O—(CH 2 ) 3 —N(CH 3 ) 2 , and amino, wherein the amino group is di-substituted with substituents independently selected from (C 1 -C 4 )alkyl such as methyl or ethyl, and hydroxy-(C 1 -C 4 )alkyl such as 2-hydroxy-ethyl; or R 8  represents phenylmethyl wherein two adjacent carbon ring atoms of the phenyl moiety are substituted with (C 1 -C 2 )alkylenedioxy such as benzo[1,3]dioxol-5-ylmethyl; or R 7  and R 8 , together with the nitrogen atom to which they are attached, form a piperidine, morpholine, or azepane ring;
 
or R 4  represents (C 1 -C 4 )alkyl such as methyl and R 5  represents phenylmethyl, wherein the phenyl moiety is mono-substituted with (C 1 -C 4 )alkoxy such as methoxy;
 
or R 4  represents (C 1 -C 4 )alkyl such as methyl and R 5  represents the following group:
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein the amino group is in position 4; R 9  represents hydrogen or phenyl; and R 10  represents —(CH 2 ) 2 —O—(C 1 -C 4 )alkyl such as —(CH 2 ) 2 —O—CH 3 , (C 1 -C 4 )alkyl-carbonyl such as acetyl, cycloalkyl-carbonyl such as cyclopropylcarbonyl, or benzoyl; or R 9  and R 10 , together with the nitrogen atom to which they are attached, form a pyrrolidin-2-one or a piperidin-2-one ring. 
         [0024]    x) In another embodiment, the present invention relates to compounds of formula I according to embodiment i) wherein: 
         [0000]    R 1  represents phenyl, pyridyl, pyrimidyl or pyridazinyl, wherein these four radicals are mono-substituted, wherein the substituent is selected from the group consisting of halogen, (C 1 -C 4 )alkyl such as especially methyl, (C 1 -C 4 )alkoxy such as especially methoxy, and trifluoromethyl; or R 1  represents 1-methyl-1H-pyrazol-3-yl, 1,5-dimethyl-1H-pyrazol-4-yl, 2,5-dimethyl-2H-pyrazol-3-yl, 1,3,5-trimethyl-1H-pyrazol-4-yl, 2-methyl-thiazol-4-yl, 2,4-dimethyl-thiazol-5-yl, 5-methyl-isoxazol-3-yl, 3,5-dimethyl-isoxazol-4-yl, 2,5-dimethyl-oxazol-4-yl, 2,3-dimethyl-3H-imidazol-4-yl, or [1,2,3]thiadiazol-4-yl;
 
R 2  represents phenyl or pyridyl, wherein these two radicals can optionally be mono-substituted (especially in para-position) with (C 1 -C 4 )alkyl such as especially ethyl, pyridyl, pyrimidyl such as especially pyrimidin-5-yl, morpholinyl such as especially morpholin-4-yl, or piperazinyl which is mono-substituted on one nitrogen ring atom with (C 1 -C 4 )alkyl-carbonyl such as especially 4-acetyl-piperazin-1-yl;
 
R 3  represents phenyl, morpholinyl such as morpholin-4-yl, pyrrolyl such as pyrrol-1-yl, or 1-methyl-1H-pyrazol-3-yl, such as especially phenyl or morpholin-4-yl; and
 
R 4  and R 5 , together with the nitrogen atom to which they are attached, form a morpholine ring; or together with the nitrogen atom to which they are attached, form the radicals 5,8-dihydro-6H-[1,7]naphthyridin-7-yl, 2,3-dihydro-1H-indol-1-yl, or 1,3-dihydro-1H-isoindol-2-yl;
 
or R 4  and R 5 , together with the nitrogen atom to which they are attached, form a 3-amino-pyrrolidine ring, wherein the amino group is di-substituted with (C 1 -C 4 )alkyl such as especially 3-dimethylamino-pyrrolidin-1-yl; or together with the nitrogen atom to which they are attached, form a 3- or 4-substituted piperidine ring (especially 4-substituted), wherein the substituent is independently selected from the group consisting of phenyl, benzyl, pyrrolidinomethyl, amino di-substituted with (C 1 -C 4 )alkyl such as especially dimethylamino, and aminomethyl wherein the amino group is di-substituted with (C 1 -C 4 )alkyl such as especially dimethylaminomethyl;
 
or R 4  represents (C 1 -C 4 )alkyl such as especially methyl, and R 5  represents 1-benzyl-pyrrolidin-3-yl;
 
or R 4  represents (C 1 -C 4 )alkyl such as especially methyl, and R 5  represents the following group:
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 6  represents hydrogen, (C 1 -C 4 )alkyl such as especially methyl, (C 3 -C 4 )alkenyl such as especially allyl, cyanomethyl, carbamoylmethyl, cycloalkylmethyl such as especially cyclopropylmethyl, or 2-benzyloxy-ethyl; or R 6  represents pyrimidyl such as especially pyrimidin-2-yl; or R 6  represents phenylmethyl or pyridylmethyl, wherein the phenyl or pyridyl moiety can optionally be mono- or di-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl such as especially methyl, (C 1 -C 4 )alkoxy such as especially methoxy, cyano, difluoromethoxy, and trifluoromethoxy; or R 6  represents 5-trifluoromethyl-furan-3-ylmethyl, 5-methyl-isoxazol-3-ylmethyl, or 1-methyl-1H-benzotriazol-5-ylmethyl;
 
or R 4  represents (C 1 -C 4 )alkyl such as especially methyl, and R 5  represents the following group:
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 7  represents (C 1 -C 4 )alkyl such as especially methyl; and R 8  represents (C 1 -C 4 )alkyl such as especially methyl; or R 8  represents phenylmethyl or pyridylmethyl, wherein the phenyl or pyridyl moiety can optionally be mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of halogen, (C 1 -C 4 )alkyl such as especially methyl, (C 1 -C 4 )alkoxy such as especially methoxy, hydroxy, cyano, trifluoromethyl, —O—(CH 2 ) 2 —OH, —O—(CH 2 ) 3 —N((C 1 -C 4 )alkyl) 2  such as especially —O—(CH 2 ) 3 —N(CH 3 ) 2 , and amino, wherein the amino group is di-substituted wherein the substituents are independently selected from (C 1 -C 4 )alkyl and hydroxy-(C 1 -C 4 )alkyl such as diethylamino or N-(2-hydroxy-ethyl)-N-methyl-amino; or R 8  represents pyrimidylmethyl such as especially pyrimidin-5-ylmethyl; or R 8  represents furan-2-ylmethyl, furan-3-ylmethyl, 5-bromo-furan-2-ylmethyl, 5-hydroxymethyl-furan-2-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, 5-chloro-thiophen-2-ylmethyl, thiazol-2-ylmethyl, 3H-imidazol-4-ylmethyl, or 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethyl; or R 8  represents phenylmethyl, wherein two adjacent carbon ring atoms of the phenyl moiety are substituted with (C 1 -C 2 )alkylenedioxy, such as especially benzo[1,3]dioxol-5-ylmethyl;
 
or R 4  represents (C 1 -C 4 )alkyl such as especially methyl, and R 5  represents phenylmethyl, wherein the phenyl moiety is mono-substituted with (C 1 -C 4 )alkoxy such as especially methoxy;
 
or R 4  represents (C 1 -C 4 )alkyl such as especially methyl, and R 5  represents the following group:
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein the amino group can be in position 2, 3, or 4 (especially in position 4); R 9  represents hydrogen or phenyl, such as especially hydrogen; and R 10  represents —(CH 2 ) 2 —O—(C 1 -C 4 )alkyl such as especially —(CH 2 ) 2 —O—CH 3 , (C 1 -C 4 )alkyl-carbonyl such as especially acetyl, cycloalkyl-carbonyl such as especially cyclopropyl-carbonyl, or benzoyl; or R 9  and R 10 , together with the nitrogen atom to which they are attached, form a pyrrolidin-2-one or a piperidin-2-one ring. 
         [0025]    The compounds of formula I may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. The compounds of formula I may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art. 
         [0026]    Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like. 
         [0027]    Any reference hereinbefore or hereinafter to a compound of formula I is to be understood as referring also to salts, especially pharmaceutically acceptable salts, of a compound of formula I, as appropriate and expedient. 
         [0028]    The term “pharmaceutically acceptable salts” refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to “Salt selection for basic drugs”,  Int. J. Pharm.  1986, 33, 201-17. 
         [0029]    Examples of preferred compounds of formula I are selected from the group consisting of:
   (S)—N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-4-yl-benzyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-3-(2,4-dimethyl-thiazol-5-yl)-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-3-(2,5-dimethyl-oxazol-4-yl)-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-3-(6-methyl-pyridin-3-yl)-N-(4-pyridin-4-yl-benzyl)acrylamide;   (S)—N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-3-(5-methyl-pyridin-2-yl)-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-3-(6-methoxy-pyridin-3-yl)-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-4-yl-benzyl)-3-(5-trifluoromethyl-pyridin-2-yl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-3-(1,5-dimethyl-1H-pyrazol-4-yl)-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]-N-pyridin-2-ylmethyl-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-Benzyl-N-[1-benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-3-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-Benzyl-N-[1-benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[1-Benzyl-2-oxo-2-(4-phenyl-piperidin-1-yl)-ethyl]-N-(4-pyrimidin-5-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[1-Benzyl-2-oxo-2-(4-phenyl-piperidin-1-yl)-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-dimethylaminomethyl-piperidin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[1-Benzyl-2-oxo-2-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   N—-[(S)-1-Benzyl-2-((R)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   N—-[(S)-1-Benzyl-2-((S)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   N—-[(S)-1-Benzyl-2-((R)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   N—-[(S)-1-Benzyl-2-((S)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[1-Benzyl-2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-N-(4-pyrimidin-5-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-Benzyl-2-(1,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-acrylamide;   (S)-3-(2,4-Dimethyl-thiazol-5-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(5-trifluoromethyl-pyridin-2-yl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(6-methoxy-pyridin-3-yl)-N-(4-morpholin-4-yl-benzyl)-acrylamide;   (S)-3-(2,5-Dimethyl-2H-pyrazol-3-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-acrylamide;   (S)-3-(2,4-Dimethyl-thiazol-5-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(2-methyl-thiazol-4-yl)-N-(4-pyridin-2-yl-benzyl)-acrylamide;   (S)-3-(3,5-Dimethyl-isoxazol-4-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(6-methoxy-pyridazin-3-yl)-N-(4-pyridin-2-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(6-methyl-pyridin-3-yl)-N-(4-pyridin-2-yl-benzyl)-acrylamide;   (S)-3-(6-Chloro-pyridin-3-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(5-methyl-pyridin-2-yl)-N-(4-pyridin-2-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(6-methoxy-pyridin-3-yl)-N-(4-pyridin-2-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(2-trifluoromethyl-pyrimidin-5-yl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(5-trifluoromethyl-pyridin-2-yl)-acrylamide;   (S)-3-(1,5-Dimethyl-1H-pyrazol-4-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(1-methyl-1H-pyrazol-3-yl)-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)-3-(2,3-Dimethyl-3H-imidazol-4-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)-3-(2,4-Dimethyl-thiazol-5-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(2-methyl-thiazol-4-yl)-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(5-methyl-isoxazol-3-yl)-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)-3-(3,5-Dimethyl-isoxazol-4-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)-3-(2,5-Dimethyl-oxazol-4-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-4-yl-benzyl)-3-[1,2,3]thiadiazol-4-yl-acrylamide;   (S)-3-(6-Chloro-pyridin-3-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(5-methyl-pyridin-2-yl)-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(6-methoxy-pyridin-3-yl)-N-(4-pyridin-4-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-4-yl-benzyl)-3-(5-trifluoromethyl-pyridin-2-yl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-3-(2,5-dimethyl-2H-pyrazol-3-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-3-(2,4-dimethyl-thiazol-5-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-3-(6-chloro-pyridin-3-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(6-methoxy-pyridin-3-yl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(5-trifluoromethyl-pyridin-2-yl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(1-methyl-1H-pyrazol-3-yl)-N-(4-pyrimidin-5-yl-benzyl)-acrylamide;   (S)-3-(2,4-Dimethyl-thiazol-5-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyrimidin-5-yl-benzyl)-acrylamide;   (S)-3-(5-Chloro-pyridin-2-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyrimidin-5-yl-benzyl)-acrylamide;   (S)-3-(6-Chloro-pyridin-3-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyrimidin-5-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(2-methoxy-pyrimidin-5-yl)-N-(4-pyrimidin-5-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyrimidin-5-yl-benzyl)-3-(5-trifluoromethyl-pyridin-2-yl)-acrylamide;   (S)-3-(2,4-Dimethyl-thiazol-5-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-3-yl-benzyl)-acrylamide;   (S)-3-(2,5-Dimethyl-oxazol-4-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-3-yl-benzyl)-acrylamide;   (S)-3-(6-Chloro-pyridin-3-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-3-yl-benzyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(6-methoxy-pyridin-3-yl)-N-(4-pyridin-3-yl-benzyl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]-3-(4-methoxy-phenyl)-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-acrylamide;   (S)—N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-3-p-tolyl-acrylamide;   (S)—N-(1-Benzyl-2-morpholin-4-yl-2-oxo-ethyl)-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-3-p-tolyl-acrylamide;   (S)—N-(1-Benzyl-2-morpholin-4-yl-2-oxo-ethyl)-3-(4-methoxy-phenyl)-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-acrylamide;   (S)—N-[1-Benzyl-2-(5,8-dihydro-6H-[1,7]naphthyridin-7-yl)-2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-3-p-tolyl-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4-methoxy-phenyl)-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-acrylamide;   (S)—N-Benzyl-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-p-tolyl-acrylamide;   (S)—N-(4-Ethyl-benzyl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-p-tolyl-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-pyridin-2-ylmethyl-3-p-tolyl-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-pyrrol-1-yl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   N-[1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-(1-methyl-1H-pyrazol-3-yl)-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   N-[1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-(1-methyl-1H-pyrazol-4-yl)-ethyl]-N-(4-pyridin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   N-[1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-(1-methyl-1H-pyrazol-3-yl)-ethyl]-N-(4-pyridin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-{1-[(2-Dimethylamino-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   N-{1-[((S)-1-Benzyl-pyrrolidin-3-yl)-methyl-carbamoyl]-(S)-2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   N-{1-[((R)-1-Benzyl-pyrrolidin-3-yl)-methyl-carbamoyl]-(S)-2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-{1-[(2-Hydroxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-hydroxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-{1-[(4-Methoxy-benzyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(pyrimidin-2-yloxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-benzyloxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-{1-[(2-Benzyloxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(2,4-dimethyl-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(3-fluoro-4-methoxy-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(3-cyano-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(3-trifluoromethoxy-benzyloxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(3-methoxy-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(4-difluoromethoxy-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(1-methyl-1H-benzotriazol-5-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(pyridin-3-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{[2-(3-Methoxy-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-{1-[(2-Ethoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-ethoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(2,4-dimethyl-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{[2-(2,4-Dimethyl-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{[2-(3-Fluoro-4-methoxy-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{[2-(3-Cyano-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{Methyl-[2-(3-trifluoromethoxy-benzyloxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{[2-(3,5-Dimethoxy-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{[2-(3-Methoxy-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{[2-(4-Difluoromethoxy-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{Methyl-[2-(1-methyl-1H-benzotriazol-5-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{Methyl-[2-(pyridin-3-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(5-methyl-isoxazol-3-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(pyridin-4-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(5-trifluoromethyl-furan-2-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-cyclopropylmethoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(pyridin-4-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(5-methyl-isoxazol-3-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(2-benzyloxy-ethoxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-cyanomethoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-allyloxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-carbamoylmethoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(pyridin-2-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(pyridin-2-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(2-benzyloxy-ethoxy)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-cyanomethoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-allyloxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-[1-({2-[(5-Bromo-furan-2-ylmethyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{[2-(Benzyl-methyl-amino)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(6-Chloro-pyridin-3-ylmethyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{[2-(Furan-3-ylmethyl-methyl-amino)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{[2-(Furan-2-ylmethyl-methyl-amino)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{Methyl-[2-(methyl-pyridin-2-ylmethyl-amino)-ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{Methyl-[2-(methyl-thiophen-2-ylmethyl-amino)-ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(5-Chloro-thiophen-2-ylmethyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(6-Bromo-pyridin-3-ylmethyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(5-Hydroxymethyl-furan-2-ylmethyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(6-Methoxy-pyridin-3-ylmethyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-(Methyl-{2-[methyl-(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-ethyl}-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{Methyl-[2-(methyl-pyridin-3-ylmethyl-amino)-ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{Methyl-[2-(methyl-thiophen-3-ylmethyl-amino)-ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-(Methyl-{2-[methyl-(2-methyl-benzyl)-amino]-ethyl}-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(2,4-Dimethyl-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(3,5-Dimethoxy-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(3,5-dimethoxy-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-({4-[(2-hydroxy-ethyl)-methyl-amino]-benzyl}-methyl-amino)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(4-hydroxy-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(4-diethylamino-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(3-hydroxy-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(methyl-pyridin-3-ylmethyl-amino)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-{[3-(2-hydroxy-ethoxy)-benzyl]-methyl-amino}-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(3-cyano-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(4-isopropoxy-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-(methyl-{2-[methyl-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethyl)-amino]-ethyl}-carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-{[4-(3-dimethylamino-propoxy)-benzyl]-methyl-amino}-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(6-methoxy-pyridin-3-ylmethyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(methyl-thiazol-2-ylmethyl-amino)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(benzo[1,3]dioxol-5-ylmethyl-methyl-amino)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(methyl-pyrimidin-5-ylmethyl-amino)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(2,3-difluoro-4-methyl-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(3H-imidazol-4-ylmethyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2-(methyl-pyridin-4-ylmethyl-amino)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(benzyl-methyl-amino)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{[2-({4-[(2-Hydroxy-ethyl)-methyl-amino]-benzyl]-methyl-amino}-ethyl)-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(4-Hydroxy-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(4-Diethylamino-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(3-Hydroxy-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{Methyl-[2-(methyl-pyridin-3-ylmethyl-amino)-ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-{1-[(2-{[3-(2-Hydroxy-ethoxy)-benzyl]methyl-amino}-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(3-Cyano-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(4-Isopropoxy-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-(Methyl-{2-[methyl-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethyl)-amino]-ethyl}-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(6-Methoxy-pyridin-3-ylmethyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{Methyl-[2-(methyl-thiazol-2-ylmethyl-amino)-ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{[2-(Benzo[1,3]dioxol-5-ylmethyl-methyl-amino)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{Methyl-[2-(methyl-pyrimidin-5-ylmethyl-amino)-ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(2,3-Difluoro-4-methyl-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-[1-({2-[(3H-Imidazol-4-ylmethyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{Methyl-[2-(methyl-pyridin-4-ylmethyl-amino)-ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide;   (S)—N-(1-{Methyl-[4-(2-oxo-pyrrolidin-1-yl)-benzyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)-Cyclopropanecarboxylic acid (4-{[methyl-(2-{(4-morpholin-4-yl-benzyl)-[3-(6-trifluoromethyl-pyridin-3-yl)-acryloyl]-amino}-3-phenyl-propionyl)-amino]-methyl}-phenyl)-amide;   (S)—N-(1-{Methyl-[4-(2-oxo-piperidin-1-yl)-benzyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-(4-{[Methyl-(2-{(4-morpholin-4-yl-benzyl)-[3-(6-trifluoromethyl-pyridin-3-yl)-acryloyl]-amino}-3-phenyl-propionyl)-amino]-methyl}-phenyl)-benzamide;   (S)—N-(1-{[4-(Acetyl-phenyl-amino)-benzyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   (S)—N-(1-{[4-(2-Methoxy-ethylamino)-benzyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide;   N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-morpholin-4-yl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide; and   N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-pyrrol-1-yl-ethyl}-N-(4-pyridin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide.   
 
         [0226]    The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral administration, and are suitable for the treatment and/or prevention of the diseases mentioned herein, such as especially malaria. 
         [0227]    The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington,  The Science and Practice of Pharmacy,  21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams &amp; Wilkins]) by bringing the described compounds of formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants. 
         [0228]    In one embodiment, the invention relates to a method for the treatment or prevention of the diseases mentioned herein, such as especially malaria, said method comprising administering to a subject a pharmaceutically active amount of a compound of formula I. 
         [0229]    The compounds of formula I or the above-mentioned pharmaceutical compositions may also be used in combination with one or more other therapeutically useful substances e.g. with other antimalarials like quinolines (e.g. quinine, chloroquine, amodiaquine, mefloquine, primaquine, and tafenoquine), peroxide antimalarials (e.g. artemisinin, artemether, and artesunate), pyrimethamine-sulfadoxine antimalarials (e.g. Fansidar®), hydroxynaphtoquinones (e.g. atovaquone), acroline-type antimalarials (e.g. pyronaridine), and other antiprotozoal agents like ethylstibamine, hydroxystilbamidine, pentamidine, stilbamidine, quinapyramine, puromycine, propamidine, nifurtimox, melarsoprol, nimorazole, nifuroxime, aminitrozole and the like. 
         [0230]    The present invention also relates to the use of a compound of formula I for the preparation of a pharmaceutical composition, optionally for use in combination with one or more other therapeutically useful substances such as those mentioned in the preceding paragraph, for the prevention and/or treatment of the diseases mentioned herein, such as especially malaria. 
         [0231]    The compounds of the formula I of the present invention may be prepared according to the procedures described herein, especially as described in the experimental part. 
         [0232]    In general, all chemical transformations can be performed according to well-known standard methodologies as described in the literature or as described in the procedures below. 
       Preparation of Compounds of Formula I: 
     Method A: 
       [0233]    
       
                 
         
             
             
         
       
     
         [0234]    The Boc-protected amino-acid 1 can be coupled with an amine derivative 2 by the help of a coupling/activating reagent such as TBTU in a solvent such as DCM or DMF at rt in the presence of a base such as DIPEA (Hünig&#39;s base) to give the intermediate 3. Alternatively, the Cbz-protected amino-acid 1 can be coupled with the amine derivative 2 via the chloride intermediate (not depicted) generated by the help of a chlorinating agent such as the Ghosez&#39;s reagent in a solvent such as DCM at rt in the presence of a base such as TEA to give the intermediate 3. Boc-deprotection is usually achieved by reacting 3 with TFA in DCM, while Cbz-deprotection is achieved by hydrogenation with Pd/C catalyst in MeOH, to give the amine intermediate 4. Compound 4 can be refluxed with an aldehyde derivative 5 (under reductive amination conditions via the imine; not depicted) in MeOH in the presence of a base such as TEA to form an unstable imine intermediate which is reduced at rt with sodium borohydride to give the secondary amine intermediate 6. Alternatively, the reductive amination can be achieved in a solvent such as DCM in the presence of a reducing reagent such as sodium triacetoxyborohydride to give the expected secondary amine intermediate 6. Compound 6 can be acylated by either a carboxylic acid 7 by the help of a coupling/activating reagent such as TBTU or PyBop in a solvent such as DMF or MeCN at rt in the presence of a base such as DIPEA, or the corresponding acid chloride (not depicted) in a solvent such as DCM in the presence of a base such as TEA, to give the final compounds 8 of formula I. 
         [0235]    The compounds of formula I can also be prepared via method B and according to Scheme 2. 
       Method B: 
       [0236]    
       
                 
         
             
             
         
       
     
         [0237]    Reductive amination of an amino-acid methyl/ethyl ester 9 with an aldehyde derivative 5 either via the imine formation under conditions similar to those described above or in a solvent such as MeOH and in the presence of acetic acid and of a reducing reagent such as sodium cyanoborohydride gives the secondary amine intermediate 10. Compound 10 can be acylated by an acid chloride 11 in a solvent such as DCM in the presence of a base such as DIPEA or TEA to give the amide intermediate 12. The acid chloride can be generated by reaction of the corresponding carboxylic acid 7 either with oxalyl chloride in the presence of few drops of DMF or with the Ghosez&#39;s reagent, and in a solvent such as DCM. 
         [0238]    Saponification of the ester function using methods known in the art such as treatment with a base such as NaOH in solvent mixtures such as methanol/water or ethanol/water followed by acylation of the resulting acid 13 with an amine derivative 2 with the help of a coupling/activating reagent such as TBTU or PyBrop in a solvent such as DCM in the presence of a base such as DIPEA provides the final compounds 14 of formula I. 
         [0239]    The compounds of formula I wherein R 5 =—(CH 2 ) 2 —O—R 6  can also be prepared via method C and according to Scheme 3. 
       Method C: 
       [0240]    
       
                 
         
             
             
         
       
     
         [0241]    Coupling of the acid intermediate 13 with the aminoethanol derivative 15 under conditions similar to those described above followed by alkylation of the resulting hydroxyl intermediate 16 with a halide derivative 17 in the presence of a strong base such as sodium hydride and in a polar aprotic solvent such as THF provides the final compounds 18 of formula I. 
         [0242]    The compounds of formula I wherein R 4 ═R 7 , R 5 =—(CH 2 ) 2 —NR 7 R 8  and R 8 =alkyl, —CH 2 -aryl or —CH 2 -heteroaryl, can also be prepared via method D and according to Scheme 4. 
       Method D: 
       [0243]    
       
                 
         
             
             
         
       
     
         [0244]    Coupling of the acid intermediate 13 with the Boc-protected ethylenediamine derivative 20 by the help of a coupling/activating reagent such as TBTU and a catalytic amount of DMAP in a solvent such as DCM at rt in the presence of a base such as DIPEA followed by Boc-deprotection of the amide intermediate 21 under conditions similar to those described above and then reductive amination of the resulting secondary amine 22 with an appropriate aldehyde derivative 23 in a solvent such as THF or MeCN in the presence of acetic acid and of a reducing reagent such as sodium triacetoxyborohydride provides the final compounds 24 of formula I. 
         [0245]    The compounds of formula I wherein R 5 =—CH 2 —(C 6 H 4 )—NR 9 R 10  or —CH 2 —(C 6 H 4 )—N(R 11 )COR 12  can also be prepared via method E and according to Scheme 5. 
       Method E: 
       [0246]    
       
                 
         
             
             
         
       
     
         [0247]    Coupling of the acid intermediate 13 with the amine 27 prepared via a reductive amination of 2-, 3-, or 4-bromobenzaldehyde 25 with a primary amine 26, under conditions similar to those described above, followed by Buchwald-Hartwig coupling of the aryl bromide intermediate 28 with an amine derivative 29, by the help of a catalyst such as SK-CC02-A in the presence of a base such as sodium tert-butoxide in a solvent such as dioxane, provides the final compounds 30 of formula I. In addition, aryl amidation of the aryl bromide intermediate 28 with an amide derivative 31, by the help of a catalyst such as copper (I) iodide in the presence of a ligand such as N,N′-dimethylethylenediamine and an inorganic base such as potassium carbonate in a solvent such as dioxane, provides the final compounds 32 of formula I. 
         [0248]    The compounds of formula I wherein R 3 =—NR 13 R 14  can also be prepared via method F and according to Scheme 6. 
       Method F: 
       [0249]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0250]    L-serine methyl ester 33 can be refluxed with an aldehyde derivative 5 (under reductive amination conditions via the imine; not depicted) in DCM in the presence of a base such as TEA and a dessicant such as sodium sulfate to form an unstable imine intermediate which is reduced at 0° C. in MeOH with sodium borohydride to give the secondary amine intermediate 34. Protection of the hydroxy group by tert-butyldimethylsilyl chloride in the presence of a catalyst such as imidazole in a solvent such as DCM gives the protected serine derivative 35. Compound 35 can be acylated by an acid chloride 11 in a solvent such as DCM in the presence of a base such as TEA and a catalytic amount of DMAP to give the amide intermediate 36. The acid chloride 11 can be generated by reaction of the corresponding carboxylic acid 7 with oxalyl chloride in the presence of few drops of DMF and in a solvent such as DCM. 
         [0251]    TBDMS-deprotection is usually achieved by treating 36 in a solvent mixture such as acetic acid/water to give the alcohol intermediate 37. Chlorination of the hydroxy group of 37 with a chlorinating agent such as thionyl chloride in a solvent such as DCM gives the chloride intermediate 38. The elimination product 39 can be obtained by the use of a base such as TEA in a solvent such as DCM. 
         [0252]    Conjugate addition on the double bond of compound 39 with an aliphatic cyclic secondary amine 40 in the presence of a catalyst such as FeCl 3  in a solvent such as DCM, or aza-Michael addition with an aromatic amine or a carbamate or an oxo-amide 40 in the presence of a base such as potassium carbonate in a solvent such as MeCN, gives the non-natural amino-acid derivative 41. 
         [0253]    Saponification of the ester function using methods known in the art such as treatment with a base such as NaOH in solvent mixtures such as methanol/water followed by acylation of the resulting acid 42 with an amine derivative 2 with the help of a coupling/activating reagent such as TBTU in a solvent such as DCM in the presence of a base such as DIPEA provides the final compounds 43 of formula I. 
         [0254]    Carboxylic acid compounds 7 are commercially available or can be synthesized according to the following pathways: 
       Pathway A: Knoevenagel Reaction 
       [0255]    
       
                 
         
             
             
         
       
     
       Pathway B: Horner-Emmons Reaction 
       [0256]    
       
                 
         
             
             
         
       
     
       Pathway C: Heck Reaction 
       [0257]    
       
                 
         
             
             
         
       
     
         [0258]    Pathway A: By reaction of an aldehyde 44 with malonic acid in the presence of a strong base such as piperidine in refluxing pyridine furnishes the desired carboxylic acid 7 (WO 00/66566). 
         [0259]    Pathway B: By reaction of an aldehyde 44 with trimethyl phosphoacetate in the presence of a strong base such as KOtBu in an aprotic solvent such as THF followed by saponification of the resulting methyl ester with 1N NaOH in MeOH furnishes the desired carboxylic acid 7. 
         [0260]    Pathway C: By reaction of a halide 45 with methyl acrylate in the presence of a base such as potassium carbonate, a palladium catalyst such as palladium (II) acetate and a phase-transfer catalyst TBAC in DMF followed by saponification of the resulting methyl ester with 1N NaOH in MeOH provides the desired carboxylic acid 7 (EP 0 702 014 A1). 
         [0261]    Non-natural amino-acid derivatives 9 used in method B can be synthesized according to the following pathways: 
       Pathway D: Paal-Knorr Pyrrole Synthesis 
       [0262]    
       
                 
         
             
             
         
       
     
       Pathway E: Horner-Emmons Reaction 
       [0263]    
       
                 
         
             
             
         
       
     
       Pathway F: Nucleophilic Substitution 
       [0264]    
       
                 
         
             
             
         
       
     
         [0265]    Pathway D: By reaction of the free amine Cbz-L-2,3-diaminopropionic acid methyl ester, prepared from the acid 46 by methylation ( Helv. Chim. Acta  1989, 72, 1043-51), with 2,5-dimethoxytetrahydrofuran in AcOH at 100° C. ( Acta Chem. Scand.  1952, 6, 867-74), followed by Cbz-deprotection of the resulting protected pyrrole amino-acid by hydrogenation with Pd/C catalyst in MeOH furnishes the methyl ester pyrrole amino-acid 47. 
         [0266]    Pathway E: By reaction of an aldehyde 48 with (+/−)-Cbz-α-phosphonoglycine trimethyl ester in the presence of a strong base such as DBU in an aprotic solvent such as DCM, followed by reduction of the resulting double bond and Cbz-deprotection (one pot) by hydrogenation with Pd/C catalyst in MeOH furnishes the desired methyl ester amino-acid 49 (WO 2007/070826). 
         [0267]    Pathway F: By reaction of a chloride 51 in the presence of lithium iodide or a mesylate 53 generated from an alcohol 52 (with mesyl chloride in an aprotic solvent such as THF) with the anion of N-(diphenylmethylene)-glycine ethyl ester 50 in a DMF/THF mixture, followed by deprotection of the resulting imine-protected amino-acid 54 in an AcOH/H 2 O/THF mixture provides the desired ethyl ester amino-acid 55 (WO 2006/045613, WO 2005/016883, WO 01/68591). 
         [0268]    The following examples illustrate the invention but do not limit the scope thereof. All temperatures are stated in ° C. 
       Abbreviations (as Used Herein): 
       [0000]    
       
         AcOH acetic acid 
         Alk alkyl 
         aq. aqueous 
         Boc tert.-butyloxycarbonyl 
         Boc 2 O di-tert-butyldicarbonate 
         cat. catalytic 
         Cbz benzyloxycarbonyl 
         conc. concentrated 
         DAD diode array detection 
         DBU 1,8-diazabicyclo[5.4.0]undec-7-ene 
         DCM dichloromethane 
         DIPEA N,N-diisopropylethylamine 
         DMAP N,N-dimethyl-4-aminopyridine 
         DMF dimethylformamide 
         DMSO dimethylsulfoxide 
         EA ethyl acetate 
         ELSD evaporative light scattering detection 
         eq equivalent(s) 
         ESI electrospray ionization 
         Et ethyl 
         EtOH ethanol 
         Ex. example 
         FC flash chromatography 
         h hour(s) 
         HPLC high performance liquid chromatography 
         KOtBu potassium tert-butoxide 
         LC-MS liquid chromatography-mass spectroscopy 
         Me methyl 
         MeCN acetonitrile 
         MeOH methanol 
         min minute(s) 
         MS mass spectroscopy 
         Ms mesyl 
         MsCl mesyl chloride 
         No. number 
         OAc acetate 
         PBS phosphate buffered saline 
         PG protecting group 
         Ph phenyl 
         PyBop benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate 
         PyBrop bromo-tris-pyrrolidinophosphonium hexafluorophosphate 
         quant. quantitative 
         rt room temperature 
         sat. saturated 
         SK-CC02-A 2-(dimethylamino)-ferrocen-1-yl-palladium(11)-chloride dinorbornylphosphine complex (Fluke 44696) 
         TBAC tetra-n-butylammonium chloride 
         TBDMS tert-butyldimethylsilyl 
         TBDMSCl tert-butyldimethylsilyl chloride 
         TBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate 
         TEA triethylamine 
         TFA trifluoroacetic acid 
         THF tetrahydrofuran 
         t R  retention time 
         UV ultra violet 
         V is visible 
       
     
       General Procedures and Examples: 
     HPLC Conditions: 
     Analytic: 
       [0324]    (A) Agilent 1100 series with UV/Vis and MS detection (MS: Thermo Finnigan single quadrupole). Columns (4.6×50 mm, 5 μm): Zorbax SB-AQ, Zorbax Extend C18 or Waters X-Bridge C18. Acidic conditions: eluents: A: MeCN, B: H 2 O+0.04% TFA. Basic conditions: eluents: A: MeCN, B: conc. NH 3  in water (1.0 mL/L). Gradient 5 to 95% A over 1.5 min. Flow rate: 4.5 mL/min. 
         [0325]    (B) Agilent 1100 series with DAD, ELSD and MS detection (MS: ESI + /ESI − , AB Sciex Instruments API 2000 triple quadrupole). Column: Onyx monolithic C18 (100×3 mm). Conditions: eluents: A: MeCN, B: H 2 O+0.05% formic acid. Gradient 10 to 90% A over 4.0 min. Flow rate: 1.8 mL/min. 
       Preparative: 
       [0326]    Gilson with UV/Vis+MS or UV/Vis+ELSD detection. Acidic conditions: eluents: A: MeCN, B: H 2 O+0.5% formic acid. Basic conditions: eluents: A: MeCN, B: H 2 O+0.5% NH 3  (25% aq.). 
         [0327]    (A) Waters X-Bridge column, 19×50 mm, 5 μm. Gradient: 20 to 90% A over 5 min. Flow rate: 40 mL/min. 
         [0328]    (B) Waters X-Bridge column, 30×75 mm, 10 μm. Gradient: 20 to 90% A over 6 min. Flow rate: 75 mL/min. 
       Preparation of Compounds of Formula I Via Method A: 
     Step 1 
     General Procedure 1 
       [0329]    
       
                 
         
             
             
         
       
     
         [0330]    To a solution of the acid Boc-L-phenylalanine (1 eq) in dry DCM or DMF (1 mL/mmol) were added TBTU (1 eq) and DIPEA (5 eq). The resulting white suspension was stirred at rt for 30 min, then a solution of the amine NHR 4 R 5  (1 eq) in dry DCM or DMF (0.5 mL/mmol) was added. The reaction mixture was stirred at rt overnight under nitrogen atmosphere, then concentrated in vacuo. The resulting residue was diluted in EA. The organic layer was washed with water, sat. NaHCO 3  solution and brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure. FC (n-heptane/EA system) afforded the pure amide. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Chemical name 
                 Yield 
                      LC-MS*    t R  (min)  [M + H] +   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-{1-[(2-Methoxy-ethyl)-methyl- carbamoyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester 
                 97% 
                 0.96 
                 337.48 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-[1-Benzyl-2-(4-benzyl-piperidin-1- yl)-2-oxo-ethyl]-carbamic acid tert- butyl ester 
                 98% 
                 1.09 
                 423.24 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-[1-Benzyl-2-oxo-2-(4-phenyl- piperidin-1-yl)-ethyl]-carbamic acid tert-butyl ester 
                 94% 
                 1.07 
                 409.21 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-[1-Benzyl-2-(2,3-dihydro-indol-1- yl)-2-oxo-ethyl]-carbamic acid tert- butyl ester 
                 80% 
                 1.04 
                 367.14 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-[1-Benzyl-2-oxo-2-(1,3,3a,7a- tetrahydro-isoindol-2-yl)-ethyl]- carbamic acid tert-butyl ester 
                 61% 
                 1.00 
                 367.15 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       General Procedure 2 
       [0331]    
       
                 
         
             
             
         
       
     
         [0332]    To an ice-cooled solution of the acid Cbz-L-phenylalanine (1 eq) in dry DCM (2.5 mL/mmol) was added 1-chloro-N,N-2-trimethylpropenylamine (Ghosez&#39;s reagent, 1 eq). The resulting mixture was stirred at 0° C. for 10 min, then the amine NHR 4 R 5  (1 eq) and TEA (1 eq) were added. The reaction mixture was stirred at rt overnight, then diluted with DCM, washed with a sat. NaHCO 3  solution, dried (MgSO 4 ), filtered and concentrated under reduced pressure. FC (DCM/MeOH system) afforded the pure amide. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Chemical name 
                 Yield 
                      LC-MS*    t R  (min)  [M + H] +   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-[1-Benzyl-2-(4-dimethylamino- piperidin-1-yl)-2-oxo-ethyl]-carbamic acid benzyl ester 
                 crude 
                 0.69 
                 410.12 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-[1-Benzyl-2-(4- dimethylaminomethyl-piperidin-1-yl)-2- oxo-ethyl]-carbamic acid benzyl ester 
                 crude 
                 0.74 
                 424.24 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-[1-Benzyl-2-oxo-2-(4-pyrrolidin-1- ylmethyl-piperidin-1-yl)-ethyl]- carbamic acid benzyl ester 
                 32% 
                 0.77 
                 450.12 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S,R)-[1-Benzyl-2-(3-dimethylamino- pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid benzyl ester 
                 79% 
                 0.69 
                 396.16 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S,S)-[1-Benzyl-2-(3-dimethylamino- pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid benzyl ester 
                 78% 
                 0.71 
                 396.16 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       Step 2 
     General Procedure 1 
       [0333]    
       
                 
         
             
             
         
       
     
         [0334]    To an ice-cooled solution of the Boc-protected amine (1 eq) in dry DCM (15 mL/mmol) was added dropwise TFA (10 eq). The resulting reaction mixture was stirred at rt for 2 h under nitrogen atmosphere and then concentrated in vacuo. The resulting residue was dissolved in DCM, washed with a sat. NaHCO 3  solution, and the aq. phase was extracted twice with DCM. The combined organic extracts were washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure to afford the free primary amine, which was used for the next step without further purification. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Chemical name 
                 Yield 
                      LC-MS*    t R  (min)  [M + H] +   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-Amino-N-(2-methoxy-ethyl)-N- methyl-3-phenyl-propionamide 
                 83% 
                 0.59 
                 237.18 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-Amino-1-(4-benzyl-piperidin-1- yl)-3-phenyl-propan-1-one 
                 95% 
                 0.81 
                 323.18 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-Amino-3-phenyl-1-(4-phenyl- piperidin-1-yl)-propan-1-one 
                 87% 
                 0.75 
                 309.14 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-Amino-1-(2,3-dihydro-indol-1-yl)- 3-phenyl-propan-1-one 
                 98% 
                 0.73 
                 267.09 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-Amino-3-phenyl-1-(1,3,3a,7a- tetrahydro-isoindol-2-yl)-propan-1-one 
                 86% 
                 0.71 
                 267.08 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       General Procedure 2 
       [0335]    
       
                 
         
             
             
         
       
     
         [0336]    To a purged solution of the Cbz-protected amine (1 eq) in dry MeOH (2.5 mL/mmol) was added 10% Pd/C (10% w/w) under nitrogen atmosphere. The flask was evacuated and refilled with hydrogen (3×). The black suspension was stirred at rt overnight under hydrogen atmosphere, then filtered over Celite and concentrated under reduced pressure to afford the crude primary amine, which was used for the next step without further purification. 
         [0000]    
       
         
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Chemical name 
                      LC-MS*    t R  (min)  [M + H] +   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-Amino-1-(4- dimethylamino-piperidin-1- yl)-3-phenyl-propan-1-one 
                 0.33 
                 276.46 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-Amino-1-(4- dimethylaminomethyl- piperidin-1-yl)-3-phenyl- propan-1-one 
                 0.42 
                 290.16 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-Amino-3-phenyl- 1-(4-pyrrolidin-1-ylmethyl- piperidin-1-yl)-propan-1-one 
                 0.49 
                 316.20 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S,R)-2-Amino-1-(3- dimethylamino-pyrrolidin-1- yl)-3-phenyl-propan-1-one 
                 0.28 
                 262.11 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S,S)-2-Amino-1-(3- dimethylamino-pyrrolidin-1- yl)-3-phenyl-propan-1-one 
                 0.28 
                 262.12 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       Step 3 
       [0337]    
       
                 
         
             
             
         
       
     
       General Procedure 1 
       [0338]    To a solution of the amine (1 eq) in dry MeOH (4 mL/mmol) was added the aldehyde R 2 CHO (1 eq). The resulting mixture was refluxed overnight under nitrogen atmosphere. After cooling to 0° C., sodium borohydride (2 eq) was added portionwise. The reaction mixture was stirred at rt for 1 h, then quenched with a sat. NaHCO 3  solution and extracted twice with EA. The combined organic extracts were washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure. FC (EA, EA/MeOH, DCM/MeOH or DCM/MeOH+1% NH 4 OH system) afforded the pure secondary amine. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 2   
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-N-(2-Methoxy-ethyl)-N-methyl-3- phenyl-2-(4-pyridin-2-yl- benzylamino)-propionamide 
                 83% 
                 0.66 
                 404.27 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-N-(2-Methoxy-ethyl)-N-methyl-3- phenyl-2-(4-pyridin-3-yl- benzylamino)-propionamide 
                 62% 
                 0.63 
                 404.08 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-N-(2-Methoxy-ethyl)-N-methyl-3- phenyl-2-(4-pyridin-4-yl- benzylamino)-propionamide 
                 41% 
                 0.61 
                 404.09 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-N-(2-Methoxy-ethyl)-N-methyl-3- phenyl-2-(4-pyrimidin-5-yl- benzylamino)-propionamide 
                 89% 
                 0.72 
                 405.09 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-[4-(4-Acetyl-piperazin-1-yl)- benzylamino]-N-(2-methoxy-ethyl)- N-methyl-3-phenyl-propionamide 
                 91% 
                 0.77 
                 453.77 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-N-(2-Methoxy-ethyl)-N-methyl-2- (4-morpholin-4-yl-benzylamino)-3- phenyl-propionamide 
                 82% 
                 0.76 
                 412.61 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 2   
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-1-(4-Dimethylamino-piperidin-1- yl)-3-phenyl-2-(4-pyridin-2-yl- benzylamino)-propan-1-one 
                 87% 
                 0.51 
                 442.93 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-1-(4-Dimethylamino-piperidin-1- yl)-3-phenyl-2-(4-pyridin-4-yl- benzylamino)-propan-1-one 
                 79% 
                 0.49 
                 442.87 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-1-(4-Dimethylamino-piperidin-1- yl)-3-phenyl-2-(4-pyrimidin-5-yl- benzylamino)-propan-1-one 
                 95% 
                 0.57 
                 444.12 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-[4-(4-Acetyl-piperazin-1-yl)- benzylamino]-1-(4-dimethylamino- piperidin-1-yl)-3-phenyl-propan-1- one 
                 92% 
                 0.56 
                 492.17 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-1-(4-Dimethylamino-piperidin-1- yl)-2-(4-morpholin-4-yl- benzylamino)-3-phenyl-propan-1- one 
                 62% 
                 0.60 
                 451.66 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Chemical name 
                 Yield 
                 t R   (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-1-(4-Dimethyl- aminomethyl- piperidin-1-yl)-3- phenyl- 2-(4-pyridin-2- yl-benzylamino)- propan-1-one 
                 53% 
                 0.54 
                 457.30 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Phenyl-2- (4-pyridin-2-yl- benzylamino)-1- (4-pyrrolidin-1- ylmethyl-piperidin- 1-yl)-propan-1-one 
                 49% 
                 0.56 
                 483.21 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S,R)-1-(3-Dimethyl- amino-pyrrolidin- 1-yl)-3-phenyl-2- (4-pyridin-2-yl- benzylamino)- propan-1-one 
                 86% 
                 0.52 
                 429.23 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S,S)-1-(3-Dimethyl- amino-pyrrolidin- 1-yl)-3-phenyl-2- (4-pyridin-2-yl- benzylamino)- propan-1-one 
                 99% 
                 0.53 
                 429.22 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       General Procedure 2 
       [0339]    To a solution of the amine (1 eq) in dry DCM (20 mL/mmol) were added successively the aldehyde R 2 CHO (1 eq) and sodium triacetoxyborohydride (3 eq). The reaction mixture was stirred at rt overnight under nitrogen atmosphere, then quenched with a sat. NH 4 Cl solution and extracted twice with EA. The combined organic extracts were washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure to afford the crude secondary amine. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                   
                 Chemical  
                   
                 t R    
                   
               
               
                 R 2   
                 name 
                 Yield 
                 (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2- Benzylamino- 1-(4-benzyl- piperidin-1-yl)- 3-phenyl- propan-1- one 
                 quant. 
                 0.91 
                 413.24 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-1-(4-Benzyl- piperidin-1-yl)- 3-phenyl-2- [(pyridin- 2-ylmethyl)- amino]- propan- 1-one 
                 quant. 
                 0.87 
                 414.24 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-1-(4- Benzyl- piperidin- 1-yl)-3- phenyl-2-(4- pyridin-2-yl- benzylamino)- propan-1-one 
                 81% 
                 0.84 
                 490.24 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-1-(4- Benzyl- piperidin-1- yl)-3- phenyl-2-(4- pyridin-3-yl- benzylamino)- propan-1-one 
                 87% 
                 0.80 
                 490.26 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                   
                 Chemical  
                   
                 t R   
                   
               
               
                 R 2   
                 name 
                 Yield 
                 (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Phenyl-1- (4-phenyl- piperidin-1-yl)- 2-(4-pyridin-2- yl-benzylamino)- propan-1-one 
                 95% 
                 0.85 
                 476.27 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Phenyl-1- (4-phenyl- piperidin-1- yl)-2-(4- pyrimidin-5- yl- benzylamino)- propan-1-one 
                 95% 
                 0.89 
                 477.26 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 2   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-1-(2,3-Dihydro-indol-1-yl)- 3-phenyl-2-(4-pyrimidin-5-yl- benzylamino)-propan-1-one 
                 quant. 
                 0.81 
                 435.12 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Phenyl-2-(4-pyridin-2- yl-benzylamino)-1-(1,3,3a,7a- tetrahydro-isoindol-2-yl)- propan-1-one 
                 43% 
                 0.73 
                 434.14 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       Step 4 
       [0340]    
       
                 
         
             
             
         
       
     
       General Procedure 1 
       [0341]    To the cinnamic acid (1 eq) were added successively a solution of TBTU or PyBop (1 eq) in dry MeCN or DMF (5 mL/mmol), and DIPEA (5 eq). The resulting mixture was stirred at rt for 30 min and then a solution of the amine (1 eq) in dry MeCN or DMF (5 mL/mmol) was added. The reaction mixture was stirred at rt or at 60° C. overnight under nitrogen atmosphere, then directly purified by preparative HPLC to afford the pure final compound. 
       General Procedure 2 
       [0342]    To an ice-cooled solution of the cinnamic acid (1 eq) in dry DCM (30 mL/mmol) was added 1-chloro-N,N-2-trimethylpropenylamine (Ghosez&#39;s reagent, 1 eq). The resulting mixture was stirred at 0° C. for 10 min, then the amine (1 eq) and TEA (1.1 eq) were added. The reaction mixture was stirred at rt overnight, then diluted with DCM, washed with a sat. NaHCO 3  solution, dried (MgSO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford the pure final compound. 
         [0000]    
       
         
               
               
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                 Example 
                   
                 LC-MS* 
               
             
          
           
               
                 number 
                 Chemical name 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
             
          
           
               
                 1 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.80 
                 613.19 
               
               
                   
                 oxo-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(1,3,5- 
               
               
                   
                 trimethyl-1H-pyrazol-4-yl)-acrylamide 
               
               
                 2 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.82 
                 616.08 
               
               
                   
                 oxo-ethyl]-3-(2,4-dimethyl-thiazol-5-yl)-N-(4-morpholin- 
               
               
                   
                 4-yl-benzyl)-acrylamide 
               
               
                 3 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.81 
                 600.24 
               
               
                   
                 oxo-ethyl]-3-(3,5-dimethyl-isoxazol-4-yl)-N-(4- 
               
               
                   
                 morpholin-4-yl-benzyl)-acrylamide 
               
               
                 4 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.87 
                 650.77 
               
               
                   
                 oxo-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(5- 
               
               
                   
                 trifluoromethyl-pyridin-2-yl)-acrylamide 
               
               
                 5 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.82 
                 612.21 
               
               
                   
                 oxo-ethyl]-3-(6-methoxy-pyridin-3-yl)-N-(4-morpholin-4- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 6 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.81 
                 641.32 
               
               
                   
                 oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl- 
               
               
                   
                 phenyl)-acrylamide 
               
               
                 7 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.77 
                 642.18 
               
               
                   
                 oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(6-trifluoromethyl- 
               
               
                   
                 pyridin-3-yl)-acrylamide 
               
               
                 8 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.75 
                 591.54 
               
               
                   
                 oxo-ethyl]-3-(2,5-dimethyl-2H-pyrazol-3-yl)-N-(4-pyridin- 
               
               
                   
                 2-yl-benzyl)-acrylamide 
               
               
                 9 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.75 
                 605.18 
               
               
                   
                 oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(1,3,5-trimethyl- 
               
               
                   
                 1H-pyrazol-4-yl)-acrylamide 
               
               
                 10 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.76 
                 608.02 
               
               
                   
                 oxo-ethyl]-3-(2,4-dimethyl-thiazol-5-yl)-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 11 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.74 
                 593.89 
               
               
                   
                 oxo-ethyl]-3-(2-methyl-thiazol-4-yl)-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 12 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.76 
                 592.33 
               
               
                   
                 oxo-ethyl]-3-(3,5-dimethyl-isoxazol-4-yl)-N-(4-pyridin-2- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 13 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.74 
                 592.13 
               
               
                   
                 oxo-ethyl]-3-(2,5-dimethyl-oxazol-4-yl)-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 14 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.77 
                 608.13 
               
               
                   
                 oxo-ethyl]-3-(6-chloro-pyridin-3-yl)-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 15 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.71 
                 588.32 
               
               
                   
                 oxo-ethyl]-3-(5-methyl-pyridin-2-yl)-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 16 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.77 
                 604.31 
               
               
                   
                 oxo-ethyl]-3-(6-methoxy-pyridin-3-yl)-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 17 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.81 
                 642.09 
               
               
                   
                 oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(5-trifluoromethyl- 
               
               
                   
                 pyridin-2-yl)-acrylamide 
               
               
                 18 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.73 
                 591.37 
               
               
                   
                 oxo-ethyl]-3-(1,5-dimethyl-1H-pyrazol-4-yl)-N-(4-pyridin- 
               
               
                   
                 2-yl-benzyl)-acrylamide 
               
               
                 19 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.70 
                 577.05 
               
               
                   
                 oxo-ethyl]-3-(1-methyl-1H-pyrazol-3-yl)-N-(4-pyridin-4- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 20 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.73 
                 591.47 
               
               
                   
                 oxo-ethyl]-3-(2,5-dimethyl-2H-pyrazol-3-yl)-N-(4-pyridin- 
               
               
                   
                 4-yl-benzyl)-acrylamide 
               
               
                 21 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.72 
                 605.18 
               
               
                   
                 oxo-ethyl]-N-(4-pyridin-4-yl-benzyl)-3-(1,3,5-trimethyl- 
               
               
                   
                 1H-pyrazol-4-yl)-acrylamide 
               
               
                 22 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.73 
                 607.40 
               
               
                   
                 oxo-ethyl]-3-(2,4-dimethyl-thiazol-5-yl)-N-(4-pyridin-4-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 23 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.72 
                 594.31 
               
               
                   
                 oxo-ethyl]-3-(2-methyl-thiazol-4-yl)-N-(4-pyridin-4-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 24 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.73 
                 592.91 
               
               
                   
                 oxo-ethyl]-3-(3,5-dimethyl-isoxazol-4-yl)-N-(4-pyridin-4- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 25 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.72 
                 592.63 
               
               
                   
                 oxo-ethyl]-3-(2,5-dimethyl-oxazol-4-yl)-N-(4-pyridin-4-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 26 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.72 
                 605.14 
               
               
                   
                 oxo-ethyl]-3-(6-methoxy-pyridazin-3-yl)-N-(4-pyridin-4- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 27 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.65 
                 588.34 
               
               
                   
                 oxo-ethyl]-3-(6-methyl-pyridin-3-yl)-N-(4-pyridin-4-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 28 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.69 
                 588.37 
               
               
                   
                 oxo-ethyl]-3-(5-methyl-pyridin-2-yl)-N-(4-pyridin-4-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 29 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.74 
                 604.21 
               
               
                   
                 oxo-ethyl]-3-(6-methoxy-pyridin-3-yl)-N-(4-pyridin-4-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 30 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.78 
                 642.09 
               
               
                   
                 oxo-ethyl]-N-(4-pyridin-4-yl-benzyl)-3-(5-trifluoromethyl- 
               
               
                   
                 pyridin-2-yl)-acrylamide 
               
               
                 31 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.71 
                 591.27 
               
               
                   
                 oxo-ethyl]-3-(1,5-dimethyl-1H-pyrazol-4-yl)-N-(4-pyridin- 
               
               
                   
                 4-yl-benzyl)-acrylamide 
               
               
                 32 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.71 
                 605.45 
               
               
                   
                 oxo-ethyl]-3-(2-methoxy-pyrimidin-5-yl)-N-(4-pyridin-4- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 33 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2- 
                 0.75 
                 654.22 
               
               
                   
                 (4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-3-(1,3,5- 
               
               
                   
                 trimethyl-1H-pyrazol-4-yl)-acrylamide 
               
               
                 34 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2- 
                 0.78 
                 653.28 
               
               
                   
                 (4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-3-(6- 
               
               
                   
                 methoxy-pyridin-3-yl)-acrylamide 
               
               
                 35 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-benzyl-2- 
                 0.82 
                 691.23 
               
               
                   
                 (4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-3-(5- 
               
               
                   
                 trifluoromethyl-pyridin-2-yl)-acrylamide 
               
               
                 36 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.80 
                 606.18 
               
               
                   
                 oxo-ethyl]-N-(4-pyrimidin-5-yl-benzyl)-3-(1,3,5-trimethyl- 
               
               
                   
                 1H-pyrazol-4-yl)-acrylamide 
               
               
                 37 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.81 
                 609.20 
               
               
                   
                 oxo-ethyl]-3-(2,4-dimethyl-thiazol-5-yl)-N-(4-pyrimidin-5- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 38 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.82 
                 593.25 
               
               
                   
                 oxo-ethyl]-3-(3,5-dimethyl-isoxazol-4-yl)-N-(4-pyrimidin- 
               
               
                   
                 5-yl-benzyl)-acrylamide 
               
               
                 39 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.85 
                 609.18 
               
               
                   
                 oxo-ethyl]-3-(5-chloro-pyridin-2-yl)-N-(4-pyrimidin-5-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 40 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.84 
                 609.17 
               
               
                   
                 oxo-ethyl]-3-(6-chloro-pyridin-3-yl)-N-(4-pyrimidin-5-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 41 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.83 
                 605.22 
               
               
                   
                 oxo-ethyl]-3-(6-methoxy-pyridin-3-yl)-N-(4-pyrimidin-5- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 42 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.88 
                 642.88 
               
               
                   
                 oxo-ethyl]-N-(4-pyrimidin-5-yl-benzyl)-3-(5- 
               
               
                   
                 trifluoromethyl-pyridin-2-yl)-acrylamide 
               
               
                 43 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.79 
                 592.28 
               
               
                   
                 oxo-ethyl]-3-(1,5-dimethyl-1H-pyrazol-4-yl)-N-(4- 
               
               
                   
                 pyrimidin-5-yl-benzyl)-acrylamide 
               
               
                 44 
                 (S)-N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]- 
                 1.04 
                 612.30 
               
               
                   
                 N-pyridin-2-ylmethyl-3-(4-trifluoromethyl-phenyl)- 
               
               
                   
                 acrylamide 
               
               
                 45 
                 (S)-N-Benzyl-N-[1-benzyl-2-(4-benzyl-piperidin-1-yl)-2- 
                 1.23 
                 611.10 
               
               
                   
                 oxo-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 46 
                 (S)-N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]- 
                 1.10 
                 688.32 
               
               
                   
                 N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)- 
               
               
                   
                 acrylamide 
               
               
                 47 
                 (S)-N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]- 
                 1.01 
                 689.30 
               
               
                   
                 N-(4-pyridin-3-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3- 
               
               
                   
                 yl)-acrylamide 
               
               
                 48 
                 (S)-N-Benzyl-N-[1-benzyl-2-(4-benzyl-piperidin-1-yl)-2- 
                 1.16 
                 612.30 
               
               
                   
                 oxo-ethyl]-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                 49 
                 (S)-N-[1-Benzyl-2-oxo-2-(4-phenyl-piperidin-1-yl)-ethyl]- 
                 1.00 
                 675.20 
               
               
                   
                 N-(4-pyrimidin-5-yl-benzyl)-3-(6-trifluoromethyl-pyridin- 
               
               
                   
                 3-yl)-acrylamide 
               
               
                 50 
                 (S)-N-[1-Benzyl-2-oxo-2-(4-phenyl-piperidin-1-yl)-ethyl]- 
                 0.99 
                 675.22 
               
               
                   
                 N-(4-pyridin-2-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3- 
               
               
                   
                 yl)-acrylamide 
               
               
                 51 
                 (S)-N-[1-Benzyl-2-(4-dimethylaminomethyl-piperidin-1- 
                 0.77 
                 656.32 
               
               
                   
                 yl)-2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(6- 
               
               
                   
                 trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                 52 
                 (S)-N-[1-Benzyl-2-oxo-2-(4-pyrrolidin-1-ylmethyl- 
                 0.83 
                 681.28 
               
               
                   
                 piperidin-1-yl)-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 53 
                 N-[(S)-1-Benzyl-2-((R)-3-dimethylamino-pyrrolidin-1-yl)- 
                 0.81 
                 627.35 
               
               
                   
                 2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 54 
                 N-[(S)-1-Benzyl-2-((S)-3-dimethylamino-pyrrolidin-1-yl)- 
                 0.81 
                 627.26 
               
               
                   
                 2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 55 
                 N-[(S)-1-Benzyl-2-((R)-3-dimethylamino-pyrrolidin-1-yl)- 
                 0.76 
                 628.29 
               
               
                   
                 2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(6- 
               
               
                   
                 trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                 56 
                 N-[(S)-1-Benzyl-2-((S)-3-dimethylamino-pyrrolidin-1-yl)- 
                 0.76 
                 628.25 
               
               
                   
                 2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(6- 
               
               
                   
                 trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                 57 
                 (S)-N-[1-Benzyl-2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]- 
                 1.25 
                 633.24 
               
               
                   
                 N-(4-pyrimidin-5-yl-benzyl)-3-(4-trifluoromethyl-phenyl)- 
               
               
                   
                 acrylamide 
               
               
                 58 
                 (S)-N-[1-Benzyl-2-(1,3-dihydro-isoindol-2-yl)-2-oxo- 
                 0.97 
                 633.23 
               
               
                   
                 ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(6-trifluoromethyl- 
               
               
                   
                 pyridin-3-yl)-acrylamide 
               
               
                 59 
                 (S)-3-(2,5-Dimethyl-2H-pyrazol-3-yl)-N-{1-[(2-methoxy- 
                 0.96 
                 560.48 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4- 
               
               
                   
                 morpholin-4-yl-benzyl)-acrylamide 
               
               
                 60 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.94 
                 574.45 
               
               
                   
                 phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(1,3,5- 
               
               
                   
                 trimethyl-1H-pyrazol-4-yl)-acrylamide 
               
               
                 61 
                 (S)-3-(2,3-Dimethyl-3H-imidazol-4-yl)-N-{1-[(2-methoxy- 
                 0.77 
                 560.43 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4- 
               
               
                   
                 morpholin-4-yl-benzyl)-acrylamide 
               
               
                 62 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.94 
                 563.44 
               
               
                   
                 phenyl-ethyl}-3-(2-methyl-thiazol-4-yl)-N-(4-morpholin- 
               
               
                   
                 4-yl-benzyl)-acrylamide 
               
               
                 63 
                 (S)-3-(2,4-Dimethyl-thiazol-5-yl)-N-{1-[(2-methoxy- 
                 0.98 
                 577.56 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4- 
               
               
                   
                 morpholin-4-yl-benzyl)-acrylamide 
               
               
                 64 
                 (S)-3-(3,5-Dimethyl-isoxazol-4-yl)-N-{1-[(2-methoxy- 
                 0.96 
                 561.14 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4- 
               
               
                   
                 morpholin-4-yl-benzyl)-acrylamide 
               
               
                 65 
                 (S)-3-(2,5-Dimethyl-oxazol-4-yl)-N-{1-[(2-methoxy- 
                 0.93 
                 561.23 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4- 
               
               
                   
                 morpholin-4-yl-benzyl)-acrylamide 
               
               
                 66 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.94 
                 550.16 
               
               
                   
                 phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3- 
               
               
                   
                 [1,2,3]thiadiazol-4-yl-acrylamide 
               
               
                 67 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 1.03 
                 611.18 
               
               
                   
                 phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(5- 
               
               
                   
                 trifluoromethyl-pyridin-2-yl)-acrylamide 
               
               
                 68 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.84 
                 557.37 
               
               
                   
                 phenyl-ethyl}-3-(5-methyl-pyridin-2-yl)-N-(4-morpholin- 
               
               
                   
                 4-yl-benzyl)-acrylamide 
               
               
                 69 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.78 
                 557.29 
               
               
                   
                 phenyl-ethyl}-3-(6-methyl-pyridin-3-yl)-N-(4-morpholin- 
               
               
                   
                 4-yl-benzyl)-acrylamide 
               
               
                 70 
                 (S)-3-(6-Chloro-pyridin-3-yl)-N-{1-[(2-methoxy-ethyl)- 
                 0.98 
                 576.77 
               
               
                   
                 methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 71 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.98 
                 573.32 
               
               
                   
                 phenyl-ethyl}-3-(6-methoxy-pyridin-3-yl)-N-(4- 
               
               
                   
                 morpholin-4-yl-benzyl)-acrylamide 
               
               
                 72 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.92 
                 574.14 
               
               
                   
                 phenyl-ethyl}-3-(2-methoxy-pyrimidin-5-yl)-N-(4- 
               
               
                   
                 morpholin-4-yl-benzyl)-acrylamide 
               
               
                 73 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.78 
                 538.19 
               
               
                   
                 phenyl-ethyl}-3-(1-methyl-1H-pyrazol-3-yl)-N-(4-pyridin- 
               
               
                   
                 2-yl-benzyl)-acrylamide 
               
               
                 74 
                 (S)-3-(2,5-Dimethyl-2H-pyrazol-3-yl)-N-{1-[(2-methoxy- 
                 0.82 
                 552.22 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 75 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.79 
                 566.21 
               
               
                   
                 phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(1,3,5- 
               
               
                   
                 trimethyl-1H-pyrazol-4-yl)-acrylamide 
               
               
                 76 
                 (S)-3-(2,3-Dimethyl-3H-imidazol-4-yl)-N-{1-[(2-methoxy- 
                 0.67 
                 552.22 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 77 
                 (S)-3-(2,4-Dimethyl-thiazol-5-yl)-N-{1-[(2-methoxy- 
                 0.85 
                 569.15 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 78 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.82 
                 555.15 
               
               
                   
                 phenyl-ethyl}-3-(2-methyl-thiazol-4-yl)-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 79 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.83 
                 539.19 
               
               
                   
                 phenyl-ethyl}-3-(5-methyl-isoxazol-3-yl)-N-(4-pyridin-2- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 80 
                 (S)-3-(3,5-Dimethyl-isoxazol-4-yl)-N-{1-[(2-methoxy- 
                 0.83 
                 553.18 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 81 
                 (S)-3-(2,5-Dimethyl-oxazol-4-yl)-N-{1-[(2-methoxy- 
                 0.81 
                 553.19 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 82 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.75 
                 566.19 
               
               
                   
                 phenyl-ethyl}-3-(6-methoxy-pyridazin-3-yl)-N-(4-pyridin- 
               
               
                   
                 2-yl-benzyl)-acrylamide 
               
               
                 83 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.78 
                 550.20 
               
               
                   
                 phenyl-ethyl}-3-(2-methyl-pyrimidin-5-yl)-N-(4-pyridin-2- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 84 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.69 
                 549.19 
               
               
                   
                 phenyl-ethyl}-3-(6-methyl-pyridin-3-yl)-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 85 
                 (S)-3-(6-Chloro-pyridin-3-yl)-N-{1-[(2-methoxy-ethyl)- 
                 0.85 
                 569.16 
               
               
                   
                 methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 86 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.74 
                 549.20 
               
               
                   
                 phenyl-ethyl}-3-(5-methyl-pyridin-2-yl)-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 87 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.84 
                 565.20 
               
               
                   
                 phenyl-ethyl}-3-(6-methoxy-pyridin-3-yl)-N-(4-pyridin-2- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 88 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.88 
                 604.14 
               
               
                   
                 phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(2- 
               
               
                   
                 trifluoromethyl-pyrimidin-5-yl)-acrylamide 
               
               
                 89 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.89 
                 603.14 
               
               
                   
                 phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(5- 
               
               
                   
                 trifluoromethyl-pyridin-2-yl)-acrylamide 
               
               
                 90 
                 (S)-3-(1,5-Dimethyl-1H-pyrazol-4-yl)-N-{1-[(2-methoxy- 
                 0.80 
                 552.19 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-2- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 91 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.76 
                 538.20 
               
               
                   
                 phenyl-ethyl}-3-(1-methyl-1H-pyrazol-3-yl)-N-(4-pyridin- 
               
               
                   
                 4-yl-benzyl)-acrylamide 
               
               
                 92 
                 (S)-3-(2,3-Dimethyl-3H-imidazol-4-yl)-N-{1-[(2-methoxy- 
                 0.65 
                 552.15 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-4- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 93 
                 (S)-3-(2,4-Dimethyl-thiazol-5-yl)-N-{1-[(2-methoxy- 
                 0.77 
                 569.06 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-4- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 94 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.80 
                 555.15 
               
               
                   
                 phenyl-ethyl}-3-(2-methyl-thiazol-4-yl)-N-(4-pyridin-4-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 95 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.81 
                 539.17 
               
               
                   
                 phenyl-ethyl}-3-(5-methyl-isoxazol-3-yl)-N-(4-pyridin-4- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 96 
                 (S)-3-(3,5-Dimethyl-isoxazol-4-yl)-N-{1-[(2-methoxy- 
                 0.81 
                 553.18 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-4- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 97 
                 (S)-3-(2,5-Dimethyl-oxazol-4-yl)-N-{1-[(2-methoxy- 
                 0.79 
                 553.18 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-4- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 98 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.78 
                 542.12 
               
               
                   
                 phenyl-ethyl}-N-(4-pyridin-4-yl-benzyl)-3- 
               
               
                   
                 [1,2,3]thiadiazol-4-yl-acrylamide 
               
               
                 99 
                 (S)-3-(6-Chloro-pyridin-3-yl)-N-{1-[(2-methoxy-ethyl)- 
                 0.83 
                 569.14 
               
               
                   
                 methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-4-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 100 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.72 
                 549.23 
               
               
                   
                 phenyl-ethyl}-3-(5-methyl-pyridin-2-yl)-N-(4-pyridin-4-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 101 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.82 
                 565.22 
               
               
                   
                 phenyl-ethyl}-3-(6-methoxy-pyridin-3-yl)-N-(4-pyridin-4- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 102 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.86 
                 603.16 
               
               
                   
                 phenyl-ethyl}-N-(4-pyridin-4-yl-benzyl)-3-(5- 
               
               
                   
                 trifluoromethyl-pyridin-2-yl)-acrylamide 
               
               
                 103 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 0.86 
                 587.20 
               
               
                   
                 methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(1- 
               
               
                   
                 methyl-1H-pyrazol-3-yl)-acrylamide 
               
               
                 104 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-3-(2,5- 
                 0.91 
                 601.23 
               
               
                   
                 dimethyl-2H-pyrazol-3-yl)-N-{1-[(2-methoxy-ethyl)- 
               
               
                   
                 methyl-carbamoyl]-2-phenyl-ethyl}-acrylamide 
               
               
                 105 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 0.90 
                 615.25 
               
               
                   
                 methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3- 
               
               
                   
                 (1,3,5-trimethyl-1H-pyrazol-4-yl)-acrylamide 
               
               
                 106 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-3-(2,3- 
                 0.73 
                 601.24 
               
               
                   
                 dimethyl-3H-imidazol-4-yl)-N-{1-[(2-methoxy-ethyl)- 
               
               
                   
                 methyl-carbamoyl]-2-phenyl-ethyl}-acrylamide 
               
               
                 107 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-3-(2,4- 
                 0.94 
                 618.11 
               
               
                   
                 dimethyl-thiazol-5-yl)-N-{1-[(2-methoxy-ethyl)-methyl- 
               
               
                   
                 carbamoyl]-2-phenyl-ethyl}-acrylamide 
               
               
                 108 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 0.91 
                 604.20 
               
               
                   
                 methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(2- 
               
               
                   
                 methyl-thiazol-4-yl)-acrylamide 
               
               
                 109 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-3-(3,5- 
                 0.93 
                 602.23 
               
               
                   
                 dimethyl-isoxazol-4-yl)-N-{1-[(2-methoxy-ethyl)-methyl- 
               
               
                   
                 carbamoyl]-2-phenyl-ethyl}-acrylamide 
               
               
                 110 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-3-(2,5- 
                 0.90 
                 602.23 
               
               
                   
                 dimethyl-oxazol-4-yl)-N-{1-[(2-methoxy-ethyl)-methyl- 
               
               
                   
                 carbamoyl]-2-phenyl-ethyl}-acrylamide 
               
               
                 111 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 0.88 
                 615.20 
               
               
                   
                 methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(6- 
               
               
                   
                 methoxy-pyridazin-3-yl)-acrylamide 
               
               
                 112 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 0.75 
                 598.29 
               
               
                   
                 methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(6- 
               
               
                   
                 methyl-pyridin-3-yl)-acrylamide 
               
               
                 113 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-3-(6-chloro- 
                 0.95 
                 618.14 
               
               
                   
                 pyridin-3-yl)-N-{1-[(2-methoxy-ethyl)-methyl-carbamoyl]- 
               
               
                   
                 2-phenyl-ethyl}-acrylamide 
               
               
                 114 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 0.80 
                 598.21 
               
               
                   
                 methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(5- 
               
               
                   
                 methyl-pyridin-2-yl)-acrylamide 
               
               
                 115 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 0.94 
                 614.21 
               
               
                   
                 methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(6- 
               
               
                   
                 methoxy-pyridin-3-yl)-acrylamide 
               
               
                 116 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 0.99 
                 652.18 
               
               
                   
                 methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(5- 
               
               
                   
                 trifluoromethyl-pyridin-2-yl)-acrylamide 
               
               
                 117 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-3-(1,5- 
                 0.88 
                 601.24 
               
               
                   
                 dimethyl-1H-pyrazol-4-yl)-N-{1-[(2-methoxy-ethyl)- 
               
               
                   
                 methyl-carbamoyl]-2-phenyl-ethyl}-acrylamide 
               
               
                 118 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 0.88 
                 615.21 
               
               
                   
                 methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(2- 
               
               
                   
                 methoxy-pyrimidin-5-yl)-acrylamide 
               
               
                 119 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.95 
                 539.18 
               
               
                   
                 phenyl-ethyl}-3-(1-methyl-1H-pyrazol-3-yl)-N-(4- 
               
               
                   
                 pyrimidin-5-yl-benzyl)-acrylamide 
               
               
                 120 
                 (S)-3-(2,3-Dimethyl-3H-imidazol-4-yl)-N-{1-[(2-methoxy- 
                 0.76 
                 553.20 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4- 
               
               
                   
                 pyrimidin-5-yl-benzyl)-acrylamide 
               
               
                 121 
                 (S)-3-(2,4-Dimethyl-thiazol-5-yl)-N-{1-[(2-methoxy- 
                 1.05 
                 570.17 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4- 
               
               
                   
                 pyrimidin-5-yl-benzyl)-acrylamide 
               
               
                 122 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 1.00 
                 556.13 
               
               
                   
                 phenyl-ethyl}-3-(2-methyl-thiazol-4-yl)-N-(4-pyrimidin-5- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 123 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 1.01 
                 540.17 
               
               
                   
                 phenyl-ethyl}-3-(5-methyl-isoxazol-3-yl)-N-(4-pyrimidin- 
               
               
                   
                 5-yl-benzyl)-acrylamide 
               
               
                 124 
                 (S)-3-(3,5-Dimethyl-isoxazol-4-yl)-N-{1-[(2-methoxy- 
                 1.03 
                 554.17 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4- 
               
               
                   
                 pyrimidin-5-yl-benzyl)-acrylamide 
               
               
                 125 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.99 
                 542.84 
               
               
                   
                 phenyl-ethyl}-N-(4-pyrimidin-5-yl-benzyl)-3- 
               
               
                   
                 [1,2,3]thiadiazol-4-yl-acrylamide 
               
               
                 126 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.97 
                 567.03 
               
               
                   
                 phenyl-ethyl}-3-(6-methoxy-pyridazin-3-yl)-N-(4- 
               
               
                   
                 pyrimidin-5-yl-benzyl)-acrylamide 
               
               
                 127 
                 (S)-3-(5-Chloro-pyridin-2-yl)-N-{1-[(2-methoxy-ethyl)- 
                 1.07 
                 570.15 
               
               
                   
                 methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyrimidin-5-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 128 
                 (S)-3-(6-Chloro-pyridin-3-yl)-N-{1-[(2-methoxy-ethyl)- 
                 1.05 
                 570.12 
               
               
                   
                 methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyrimidin-5-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 129 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 1.04 
                 566.10 
               
               
                   
                 phenyl-ethyl}-3-(2-methoxy-pyrimidin-5-yl)-N-(4- 
               
               
                   
                 pyrimidin-5-yl-benzyl)-acrylamide 
               
               
                 130 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 1.09 
                 604.13 
               
               
                   
                 phenyl-ethyl}-N-(4-pyrimidin-5-yl-benzyl)-3-(5- 
               
               
                   
                 trifluoromethyl-pyridin-2-yl)-acrylamide 
               
               
                 131 
                 (S)-3-(2,3-Dimethyl-3H-imidazol-4-yl)-N-{1-[(2-methoxy- 
                 0.66 
                 552.18 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-3- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 132 
                 (S)-3-(2,4-Dimethyl-thiazol-5-yl)-N-{1-[(2-methoxy- 
                 0.83 
                 569.12 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-3- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 133 
                 (S)-3-(2,5-Dimethyl-oxazol-4-yl)-N-{1-[(2-methoxy- 
                 0.81 
                 553.16 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-3- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                 134 
                 (S)-3-(6-Chloro-pyridin-3-yl)-N-{1-[(2-methoxy-ethyl)- 
                 0.84 
                 569.10 
               
               
                   
                 methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin-3-yl- 
               
               
                   
                 benzyl)-acrylamide 
               
               
                 135 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.83 
                 565.16 
               
               
                   
                 phenyl-ethyl}-3-(6-methoxy-pyridin-3-yl)-N-(4-pyridin-3- 
               
               
                   
                 yl-benzyl)-acrylamide 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       Preparation of Compounds of Formula I Via Method B: 
     Step 1 
     General Procedure 1 
       [0343]    
       
                 
         
             
             
         
       
     
         [0344]    To a solution of L-phenylalanine-methylester hydrochloride (1 eq), and TEA (1 eq) in dry MeOH (5 mL/mmol) was added in one portion the aldehyde R 2 CHO (1 eq). The resulting mixture was refluxed overnight under nitrogen atmosphere. After cooling to 0° C., sodium borohydride (1.5 eq) was added portionwise. The reaction mixture was stirred at rt for 1 h, then quenched with a sat. NaHCO 3  solution and extracted twice with EA. The combined organic extracts were washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure to afford the crude secondary amine, which was used for the next step without further purification. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                   
                   
                   
                 t R    
                   
               
               
                 R 2   
                 Chemical name 
                 Yield 
                 (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-Benzylamino-3-phenyl- propionic acid methyl ester 
                 14% 
                 0.78 
                 270.15 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-(4-Ethyl-benzylamino)-3- phenyl-propionic acid methyl ester 
                 11% 
                 0.83 
                 298.18 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Phenyl-2-[(pyridin-2-ylmethyl)- amino]-propionic acid methyl ester 
                 47% 
                 0.72 
                 271.16 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Phenyl-2-(4-pyridin-2-yl- benzylamino)-propionic acid methyl ester 
                 99% 
                 0.70 
                 347.40 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-[4-(4-Acetyl-piperazin-1-yl)- benzylamino]-3-phenyl-propionic acid methyl ester 
                 89% 
                 0.74 
                 396.40 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-(4-Morpholin-4-yl- benzylamino)-3-phenyl-propionic acid methyl ester 
                 84% 
                 0.76 
                 355.30 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-[(6-Morpholin-4-yl-pyridin-3- ylmethyl)-amino]-3-phenyl-propionic acid methyl ester 
                 89% 
                 0.81 
                 356.08 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       General Procedure 2 
       [0345]    
       
                 
         
             
             
         
       
     
         [0346]    To a solution of the amino-acid methyl/ethyl ester (1 eq) in dry MeOH (5 mL/mmol) at 0° C. were added successively the aldehyde R 2 CHO (1 eq), sodium cyanoborohydride (1 eq) and acetic acid (1 eq). The reaction mixture was stirred at rt for 1 h under nitrogen atmosphere and then concentrated in vacuo. The resulting residue was dissolved in a small amount of water, basified with a 10% Na 2 CO 3  solution and extracted twice with DCM. The combined organic extracts were dried (MgSO 4 ) and concentrated under reduced pressure to afford the crude secondary amine, which was used for the next step without further purification. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 LC-MS* 
               
             
          
           
               
                   
                   
                 t R    
                   
               
               
                 R 3   
                 Chemical name 
                 (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-(4-Pyridin-2-yl- benzylamino)-3-pyrrol-1-yl- propionic acid methyl ester 
                 2.20 
                 336.30 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(1-Methyl-1H-pyrazol- 4-yl)-2-(4-pyridin-2-yl- benzylamino)-propionic  acid methyl ester 
                 1.36 
                 351.10 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(1-Methyl-1H-pyrazol- 3-yl)-2-(4-pyridin-2-yl- benzylamino)-propionic  acid methyl ester 
                 1.83 
                 351.20 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(2-Methyl-2H-pyrazol- 3-yl)-2-(4-pyridin-2-yl- benzylamino)-propionic  acid methyl ester 
                 1.82 
                 351.20 
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                   
                   
                   
                 t R    
                   
               
               
                 R 3   
                 Alk 
                 Chemical name 
                 (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 rac-3-(1-Methyl-1H- pyrazol-4-yl)-2-(4- pyridin- 4-yl-benzylamino)- propionic  acid methyl ester 
                 0.61 
                 351.10 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 rac-3-(1-Methyl-1H- pyrazol-3-yl)-2-(4- pyridin-4-yl-benzylamino)- propionic acid methyl ester 
                 0.61 
                 351.20 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 rac-3-(2-Methyl-2H- pyrazol-3-yl)-2-(4- pyridin- 4-yl-benzylamino)- propionic acid methyl ester 
                 0.61 
                 351.10 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Et 
                 rac-3-Isoxazol-3-yl-2- (4-pyridin-4-yl- benzylamino)-propionic  acid ethyl ester 
                 1.02 
                 352.30 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Et 
                 rac-2-(4-Pyridin-4- yl-benzylamino)-3- pyrimidin-2-yl-propionic acid ethyl ester 
                 0.60 
                 363.20 
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
       Step 2 
     General Procedure 1 
       [0347]    
       
                 
         
             
             
         
       
     
         [0348]    To an ice-cooled solution of the cinnamic acid (1 eq) in a mixture of dry DCM (1 mL/mmol) and DMF (few drops) was added dropwise oxalyl chloride (1.1 eq). The reaction mixture was stirred at 0° C. for 3 h and concentrated in vacuo to yield the crude acid chloride. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0349]    To an ice-cooled solution of the secondary amine (1 eq) and DIPEA (2 eq) in dry DCM (4 mL/mmol) was added dropwise a solution of the acid chloride (1 eq) in dry DCM (4 mL/mmol). The reaction mixture was stirred at 0° C. for 1 h and then concentrated in vacuo. The resulting residue was taken up in EA, washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure. FC (n-heptane/EA or DCM/MeOH system) afforded the pure amide. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LC-MS 
               
             
          
           
               
                   
                   
                   
                 t R    
                   
                   
               
               
                 R 1   
                 Chemical name 
                 Yield 
                 (min) 
                 [M + H] +   
                 conditions 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-{(6-Morpholin-4-yl-pyridin- 3-ylmethyl)-[3-(4-trifluoromethyl- phenyl)-acryloyl]-amino}-3- phenyl-propionic acid methyl ester 
                 45% 
                 0.93 
                 554.21 
                 analytic A Zorbax SB-AQ acidic 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-{(6-Morpholin-4-yl-pyridin- 3-ylmethyl)-[3-(6-trifluoromethyl- pyridin-3-yl)-acryloyl]-amino}-3- phenyl-propionic acid methyl ester 
                 79% 
                 0.91 
                 554.79 
                 analytic A Zorbax Extend basic 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-[(6-Morpholin-4-yl-pyridin- 3-ylmethyl)-(3-p-tolyl-acryloyl)- amino]-3-phenyl-propionic acid methyl  ester 
                 crude 
                 0.84 
                 500.26 
                 analytic A Zorbax SB-AQ acidic 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-[[3-(4-Methoxy-phenyl)- acryloyl]-(6-morpholin-4-yl- pyridin-3-ylmethyl)-amino]-3- phenyl-propionic acid methyl ester 
                 quant. 
                 0.91 
                 516.02 
                 analytic A Zorbax Extend basic 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                   
                   
                   
                   
                 t R    
                   
               
               
                 R 2   
                 Y 
                 Chemical name 
                 Yield 
                 (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 (S)-3-Phenyl-2-{(4-pyridin-2-yl- benzyl)-[3-(4-trifluoromethyl- phenyl)-acryloyl]-amino}-propionic acid methyl ester 
                 89% 
                 0.96 
                 545.32 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 (S)-2-{[4-(4-Acetyl-piperazin-1-yl)- benzyl]-[3-(4-trifluoromethyl- phenyl)-acryloyl]-amino}-3-phenyl- propionic acid methyl ester 
                 70% 
                 1.12 
                 594.35 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 (S)-2-{(4-Morpholin-4-yl-benzyl)- [3-(4-trifluoromethyl-phenyl)- acryloyl]-amino}-3-phenyl- propionic acid methyl ester 
                 74% 
                 1.12 
                 553.14 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N 
                 (S)-2-{[4-(4-Acetyl-piperazin-1-yl)- benzyl]-[3-(6-trifluoromethyl- pyridin-3-yl)-acryloyl]-amino}-3- phenyl-propionic acid methyl ester 
                 34% 
                 1.06 
                 595.24 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N 
                 (S)-2-{(4-Morpholin-4-yl-benzyl)- [3-(6-trifluoromethyl-pyridin-3-yl)- acryloyl]-amino}-3-phenyl- propionic acid methyl ester 
                 39% 
                 1.07 
                 553.91 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                   
                   
                   
                 t R    
                   
               
               
                 R 2   
                 Chemical name 
                 Yield 
                 (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-[Benzyl-(3- p-tolyl-acryloyl)- amino]-3- phenyl-propionic  acid methyl ester 
                 81% 
                 1.14 
                 414.10 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-[(4-Ethyl- benzyl)- (3-p-tolyl-acryloyl)- amino]-3-phenyl- propionic  acid methyl ester 
                 95% 
                 1.18 
                 442.10 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Phenyl-2- [pyridin- 2-ylmethyl-(3-p- tolyl-acryloyl)- amino]-propionic acid methyl ester 
                 96% 
                 0.91 
                 415.05 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       General Procedure 2 
       [0350]    
       
                 
         
             
             
         
       
     
         [0351]    To an ice-cooled solution of 4-(trifluoromethyl)cinnamic acid (1.05 eq) in a mixture of dry DCM (2 mL/mmol) and DMF (few drops) was added dropwise oxalyl chloride (1.1 eq). The reaction mixture was stirred at 0° C. for 15 min under nitrogen atmosphere, then allowed to warm at rt for 30 min. 
         [0352]    To this mixture at 0° C. was added a solution of the secondary amine (1 eq), TEA (2 eq) and DMAP (0.05 eq) in dry DCM (2 mL/mmol). The reaction mixture was stirred at rt overnight under nitrogen atmosphere, then diluted with DCM and washed with water. The aq. phase was separated and extracted with DCM. The combined organic extracts were washed with a sat. NaHCO 3  solution, dried (MgSO 4 ), filtered and concentrated under reduced pressure. FC (n-heptane/EA or EA/MeOH system) afforded the pure amide. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                   
                   
                   
                 t R    
                   
               
               
                 R 3   
                 Chemical name 
                 Yield 
                 (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-{(4-Pyridin- 2-yl-benzyl)-[3-(4- trifluoromethyl-phenyl)- acryloyl]-amino}-3- pyrrol-1-yl-propionic  acid methyl ester 
                 72% 
                 3.58 
                 534.30 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(1-Methyl-1H- pyrazol-4-yl)-2-{(4- pyridin-2-yl-benzyl)-[3- (trifluoromethyl-phenyl)- acryloyl]-amino}-propionic  acid methyl ester 
                 76% 
                 3.17 
                 549.30 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(1-Methyl-1H- pyrazol-3-yl)-2-{(4- pyridin-2-yl-benzyl)-[3- (4-trifluoromethyl-phenyl)- acryloyl]-amino}-propionic  acid methyl ester 
                 69% 
                 3.20 
                 549.30 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(2-Methyl-2H- pyrazol-3-yl)-2-{(4- pyridin-2-yl-benzyl)- [3-(4-trifluoromethyl- phenyl)-acryloyl]-amino}- propionic acid methyl ester 
                 61% 
                 3.22 
                 549.40 
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                   
                   
                   
                   
                 t R    
                   
               
               
                 R 3   
                 Alk 
                 Chemical name 
                 Yield 
                 (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 rac-3-(1-Methyl- 1H-pyrazol-4-yl)-2- {(4-pyridin-4-yl- benzyl)-[3-(4- trifluoromethyl- phenyl)- acryloyl]-amino}- propionic acid  methyl ester 
                 72% 
                 2.69 
                 549.40 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 rac-3-(1-Methyl- 1H-pyrazol-3-yl)-2- {(4-pyridin-4-yl- benzyl)-[3-(4- trifluoromethyl- phenyl)- acryloyl]-amino}- propionic acid  methyl ester 
                 67% 
                 2.74 
                 549.30 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 rac-3-(2-Methyl- 2H-pyrazol-3-yl)-2- {(4-pyridin-4-yl- benzyl)-[3-(4- trifluoromethyl- phenyl)- acryloyl]-amino}- propionic acid  methyl ester 
                 61% 
                 2.74 
                 549.30 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Et 
                 rac-3-Isoxazol-3-yl- 2-{(4-pyridin-4-yl- benzyl)-[3-(4- trifluoromethyl- phenyl)- acryloyl]-amino}- propionic acid ethyl ester 
                 56% 
                 2.91 
                 550.40 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Et 
                 rac-2-{(4-Pyridin- 4-yl-benzyl)-[3-(4- trifluoromethyl- phenyl)- acryloyl]-amino}- 3-pyrimidin-2-yl- propionic acid ethyl ester 
                 78% 
                 2.78 
                 561.40 
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
       Step 3 
       [0353]    
       
                 
         
             
             
         
       
     
         [0354]    To a solution of the ester (1 eq) in MeOH (for methyl ester) or EtOH (for ethyl ester) (15 mL/mmol) was added dropwise aq. 2N NaOH (3.5 eq). The reaction mixture was stirred at rt for 1-14 h, then water was added and the solvent was removed in vacuo. The residue was acidified with aq. 1N HCl until pH &lt;6. Solid NaCl was added until the aq. phase was saturated and then extracted with EA or DCM. The combined organic extracts were dried (MgSO 4 ), filtered and concentrated to afford the acid. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LC-MS 
               
             
          
           
               
                   
                   
                   
                 t R    
                   
                   
               
               
                 R 1   
                 Chemical name 
                 Yield 
                 (min) 
                 [M + H] +   
                 conditions 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-{(6-Morpholin-4-yl-pyridin- 3-ylmethyl)-3-(4-trifluoromethyl- phenyl)-acryloyl]-amino}-3- phenyl-propionic acid 
                 93% 
                 0.61 
                 539.95 
                 analytic A Zorbax Extend basic 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-{(6-Morpholin-4-yl-pyridin- 3-ylmethyl)-[3-(6-trifluoromethyl- pyridin-3-yl)-acryloyl]-amino}-3- phenyl-propionic acid 
                 97% 
                 0.83 
                 541.03 
                 analytic A Zorbax SB-AQ acidic 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-[(6-Morpholin-4-yl-pyridin- 3-ylmethyl)-(3-p-tolyl-acryloyl)- amino]-3-phenyl-propionic acid 
                 crude 
                 0.85 
                 486.15 
                 analytic A Zorbax SB-AQ acidic 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-[[3-(4-Methoxy-phenyl)- acryloyl]-(6-morpholin-4-yl- pyridin-3-ylmethyl)-amino]-3- phenyl-propionic acid 
                 99% 
                 0.83 
                 502.15 
                 analytic A Zorbax SB-AQ acidic 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                   
                   
                   
                   
                 t R    
                   
               
               
                 R 2   
                 Y 
                 Chemical name 
                 Yield 
                 (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 (S)-3-Phenyl-2-{(4-pyridin-2-yl- benzyl)-[3-(4-trifluoromethyl- phenyl)-acryloyl]-amino}- propionic acid 
                 quant. 
                 0.91 
                 531.25 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 (S)-2-{[4-(4-Acetyl-piperazin-1- yl)-benzyl]-[3-(4- trifluoromethyl-phenyl)- acryloyl]-amino}-3-phenyl- propionic acid 
                 95% 
                 1.04 
                 580.00 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 (S)-2-{(4-Morpholin-4-yl- benzyl)-[3-(4-trifluoromethyl- phenyl)-acryloyl]-amino}-3- phenyl-propionic acid 
                 89% 
                 1.04 
                 539.13 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N 
                 (S)-2-{[4-(4-Acetyl-piperazin-1- yl)-benzyl]-[3-(6- trifluoromethyl-pyridin-3-yl)- acryloyl]-amino}-3-phenyl- propionic acid 
                 quant. 
                 0.98 
                 581.05 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N 
                 (S)-2-{(4-Morpholin-4-yl- benzyl)-[3-(6-trifluoromethyl- pyridin-3-yl)-acryloyl]-amino}- 3-phenyl-propionic acid 
                 95% 
                 0.99 
                 539.94 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                   
                   
                   
                 t R    
                   
               
               
                 R 2   
                 Chemical name 
                 Yield 
                 (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-[Benzyl-(3-p- tolyl- acryloyl)-amino]-3- phenyl-propionic acid 
                 99% 
                 1.07 
                 400.06 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-[(4-Ethyl- benzyl)- (3-p-tolyl-acryloyl)- amino]-3-phenyl- propionic acid 
                 99% 
                 1.11 
                 428.10 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Phenyl-2- [pyridin-2-ylmethyl- (3-p-tolyl-acryloyl)- amino]-propionic acid 
                 81% 
                 0.94 
                 401.07 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 3   
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-2-{(4-Pyridin-2-yl-benzyl)-[3-(4- trifluoromethyl-phenyl)-acryloyl]-amino}-3- pyrrol-1-yl-propionic acid, hydrochloride salt 
                 quant. 
                 3.41 
                 520.40 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(1-Methyl-1H-pyrazol-4-yl)-2-{(4-pyridin- 2-yl-benzyl)-[3-(4-trifluoromethyl-phenyl)- acryloyl]-amino}-propionic acid, dihydrochloride salt  
                 90% 
                 2.90 
                 535.50 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(1-Methyl-1H-pyrazol-3-yl)-2-{(4-pyridin- 2-yl-benzyl)-[3-(4-trifluoromethyl-phenyl)- acryloyl]-amino}-propionic acid, dihydrochloride salt  
                 85% 
                 2.95 
                 535.40 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(2-Methyl-2H-pyrazol-3-yl)-2-{(4-pyridin- 2-yl-benzyl)-[3-(4-trifluoromethyl-phenyl)- acryloyl]-amino}-propionic acid, dihydrochloride salt 
                 crude 
                 2.93 
                 535.50 
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 3   
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(1-Methyl-1H-pyrazol-4-yl)-2-{(4-pyridin- 4-yl-benzyl)-[3-(4-trifluoromethyl-phenyl)- acryloyl]-amino}-propionic acid, dihydrochloride salt  
                 crude 
                 2.53 
                 535.50 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(1-Methyl-1H-pyrazol-3-yl)-2-{(4-pyridin- 4-yl-benzyl)-[3-(4-trifluoromethyl-phenyl)- acryloyl]-amino}-propionic acid, dihydrochloride salt  
                 crude 
                 2.57 
                 535.50 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(2-Methyl-2H-pyrazol-3-yl)-2-{(4-pyridin- 4-yl-benzyl)-[3-(4-trifluoromethyl-phenyl)- acryloyl]-amino}-propionic acid, dihydrochloride  
                 crude 
                 2.57 
                 535.50 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-Isoxazol-3-yl-2-{(4-pyridin-4-yl-benzyl)- [3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}- propionic acid, hydrochloride salt  
                 86% 
                 2.65 
                 522.20 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-2-{(4-Pyridin-4-yl-benzyl)-[3-(4- trifluoromethyl-phenyl)-acryloyl]-amino}-3- pyrimidin-2-yl-propionic acid, hydrochloride salt 
                 67% 
                 2.51 
                 533.50 
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
       Step 4 
       [0355]    
       
                 
         
             
             
         
       
     
       General Procedure 1 
       [0356]    A mixture of the acid (1 eq), TBTU (1.1 eq), and DIPEA (5 eq) in dry DMF (5 mL/mmol) was stirred at rt for 30 min. Then a solution of the amine NHR 4 R 5  (1.05 eq) in dry DMF (5 mL/mmol) was added and the reaction mixture was stirred at rt overnight, then directly purified by preparative HPLC to afford the pure final compound. 
       General Procedure 2 
       [0357]    To an ice-cooled solution of the acid (1 eq) and the amine NHR 4 R 5  (1.1 eq) in dry DCM (5 mL/mmol) were added successively a solution of PyBrop (1.1 eq) in dry DCM (5 mL/mmol) and DIPEA (2 eq). The reaction mixture was stirred at rt for 30 min, then the solvent was removed in vacuo and the crude product purified by preparative HPLC to afford the pure final compound. 
         [0000]    
       
         
               
               
             
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 LC-MS (analytic A) 
               
             
          
           
               
                 Ex. 
                   
                 t R   
                   
                   
               
               
                 No. 
                 Chemical name 
                 (min) 
                 [M + H] +   
                 HPLC 
               
               
                   
               
               
                 136 
                 (S)-N-[1-Benzyl-2-(4-dimethylamino-piperidin-1-yl)-2- 
                 0.80 
                 649.92 
                 Zorbax 
               
               
                   
                 oxo-ethyl]-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-3-(4- 
                   
                   
                 SB-AQ 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 137 
                 rac-N-[2-(4-Dimethylamino-piperidin-1-yl)-1-(1-methyl- 
                 0.88 
                 645.15 
                 XBridge 
               
               
                   
                 1H-pyrazol-4-ylmethyl)-2-oxo-ethyl]-N-(4-pyridin-2-yl- 
                   
                   
                 basic 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 138 
                 rac-N-[2-(4-Dimethylamino-piperidin-1-yl)-1-(1-methyl- 
                 0.89 
                 645.14 
                 XBridge 
               
               
                   
                 1H-pyrazol-3-ylmethyl)-2-oxo-ethyl]-N-(4-pyridin-2-yl- 
                   
                   
                 basic 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 139 
                 rac-N-[2-(4-Dimethylamino-piperidin-1-yl)-1-(1-methyl- 
                 0.84 
                 645.16 
                 XBridge 
               
               
                   
                 1H-pyrazol-4-ylmethyl)-2-oxo-ethyl]-N-(4-pyridin-4-yl- 
                   
                   
                 basic 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 140 
                 rac-N-[2-(4-Dimethylamino-piperidin-1-yl)-1-(1-methyl- 
                 0.85 
                 645.11 
                 XBridge 
               
               
                   
                 1H-pyrazol-3-ylmethyl)-2-oxo-ethyl]-N-(4-pyridin-4-yl- 
                   
                   
                 basic 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 141 
                 rac-N-[2-(4-Dimethylamino-piperidin-1-yl)-1-(2-methyl- 
                 0.85 
                 645.13 
                 XBridge 
               
               
                   
                 2H-pyrazol-3-ylmethyl)-2-oxo-ethyl]-N-(4-pyridin-4-yl- 
                   
                   
                 basic 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 142 
                 rac-N-[2-(4-Dimethylamino-piperidin-1-yl)-1-(2-methyl- 
                 0.90 
                 645.12 
                 XBridge 
               
               
                   
                 2H-pyrazol-3-ylmethyl)-2-oxo-ethyl]-N-(4-pyridin-2-yl- 
                   
                   
                 basic 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 143 
                 (S)-N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo- 
                 1.04 
                 697.19 
                 Zorbax 
               
               
                   
                 ethyl]-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-3-(4- 
                   
                   
                 SB-AQ 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 144 
                 (S)-N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo- 
                 1.01 
                 698.16 
                 Zorbax 
               
               
                   
                 ethyl]-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-3-(6- 
                   
                   
                 SB-AQ 
               
               
                   
                 trifluoromethyl-pyridin-3-yl)-acrylamide 
                   
                   
                 acidic 
               
               
                 145 
                 (S)-N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo- 
                 1.00 
                 659.16 
                 Zorbax 
               
               
                   
                 ethyl]-3-(4-methoxy-phenyl)-N-(6-morpholin-4-yl- 
                   
                   
                 SB-AQ 
               
               
                   
                 pyridin-3-ylmethyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 146 
                 (S)-N-[1-Benzyl-2-(4-benzyl-piperidin-1-yl)-2-oxo- 
                 1.02 
                 643.11 
                 Zorbax 
               
               
                   
                 ethyl]-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-3-p-tolyl- 
                   
                   
                 SB-AQ 
               
               
                   
                 acrylamide 
                   
                   
                 acidic 
               
               
                 147 
                 (S)-N-(1-Benzyl-2-morpholin-4-yl-2-oxo-ethyl)-N-(6- 
                 0.88 
                 555.00 
                 Zorbax 
               
               
                   
                 morpholin-4-yl-pyridin-3-ylmethyl)-3-p-tolyl-acrylamide 
                   
                   
                 SB-AQ 
               
               
                   
                   
                   
                   
                 acidic 
               
               
                 148 
                 (S)-N-(1-Benzyl-2-morpholin-4-yl-2-oxo-ethyl)-3-(4- 
                 0.85 
                 570.98 
                 Zorbax 
               
               
                   
                 methoxy-phenyl)-N-(6-morpholin-4-yl-pyridin-3- 
                   
                   
                 SB-AQ 
               
               
                   
                 ylmethyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 149 
                 (S)-N-[1-Benzyl-2-(5,8-dihydro-6H-[1,7]naphthyridin-7- 
                 0.88 
                 647.23 
                 Zorbax 
               
               
                   
                 yl)-2-oxo-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4- 
                   
                   
                 SB-AQ 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 150 
                 (S)-N-[1-(2-Dibutylamino-ethylcarbamoyl)-2-phenyl- 
                 0.92 
                 685.51 
                 Zorbax 
               
               
                   
                 ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl- 
                   
                   
                 SB-AQ 
               
               
                   
                 phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 151 
                 (S)-N-[1-(2-Morpholin-4-yl-ethylcarbamoyl)-2-phenyl- 
                 0.81 
                 643.42 
                 Zorbax 
               
               
                   
                 ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl- 
                   
                   
                 SB-AQ 
               
               
                   
                 phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 152 
                 N-[1-(rac-1-Aza-bicyclo[2.2.2]oct-3-ylcarbamoyl)-(S)-2- 
                 0.80 
                 639.40 
                 Zorbax 
               
               
                   
                 phenyl-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4- 
                   
                   
                 SB-AQ 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 153 
                 (S)-N-[2-Phenyl-1-(2-piperidin-1-yl-ethylcarbamoyl)- 
                 0.83 
                 641.44 
                 Zorbax 
               
               
                   
                 ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl- 
                   
                   
                 SB-AQ 
               
               
                   
                 phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 154 
                 (S)-N-[1-(2-Azepan-1-yl-ethylcarbamoyl)-2-phenyl- 
                 0.86 
                 655.43 
                 Zorbax 
               
               
                   
                 ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl- 
                   
                   
                 SB-AQ 
               
               
                   
                 phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 155 
                 (S)-N-[1-(2-Diisopropylamino-ethylcarbamoyl)-2- 
                 0.85 
                 657.46 
                 Zorbax 
               
               
                   
                 phenyl-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4- 
                   
                   
                 SB-AQ 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 156 
                 (S)-N-[1-(2-Dimethylamino-ethylcarbamoyl)-2-phenyl- 
                 0.80 
                 601.41 
                 Zorbax 
               
               
                   
                 ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4-trifluoromethyl- 
                   
                   
                 SB-AQ 
               
               
                   
                 phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 157 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.92 
                 610.93 
                 Zorbax 
               
               
                   
                 phenyl-ethyl}-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)- 
                   
                   
                 SB-AQ 
               
               
                   
                 3-(4-trifluoromethyl-phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 158 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.90 
                 557.01 
                 Zorbax 
               
               
                   
                 phenyl-ethyl}-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)- 
                   
                   
                 SB-AQ 
               
               
                   
                 3-p-tolyl-acrylamide 
                   
                   
                 acidic 
               
               
                 159 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.88 
                 573.01 
                 Zorbax 
               
               
                   
                 phenyl-ethyl}-3-(4-methoxy-phenyl)-N-(6-morpholin-4- 
                   
                   
                 SB-AQ 
               
               
                   
                 yl-pyridin-3-ylmethyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 160 
                 (S)-N-Benzyl-N-{1-[(2-methoxy-ethyl)-methyl- 
                 1.12 
                 471.63 
                 Zorbax 
               
               
                   
                 carbamoyl]-2-phenyl-ethyl}-3-p-tolyl-acrylamide 
                   
                   
                 SB-AQ 
               
               
                   
                   
                   
                   
                 acidic 
               
               
                 161 
                 (S)-N-(4-Ethyl-benzyl)-N-{1-[(2-methoxy-ethyl)-methyl- 
                 1.16 
                 499.70 
                 Zorbax 
               
               
                   
                 carbamoyl]-2-phenyl-ethyl}-3-p-tolyl-acrylamide 
                   
                   
                 SB-AQ 
               
               
                   
                   
                   
                   
                 acidic 
               
               
                 162 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.90 
                 472.68 
                 Zorbax 
               
               
                   
                 phenyl-ethyl}-N-pyridin-2-ylmethyl-3-p-tolyl-acrylamide, 
                   
                   
                 SB-AQ 
               
               
                   
                 formic acid 
                   
                   
                 acidic 
               
               
                 163 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.99 
                 591.10 
                 XBridge 
               
               
                   
                 pyrrol-1-yl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(4- 
                   
                   
                 basic 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 164 
                 rac-N-[1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-(1- 
                 0.90 
                 606.11 
                 XBridge 
               
               
                   
                 methyl-1H-pyrazol-4-yl)-ethyl]-N-(4-pyridin-2-yl- 
                   
                   
                 basic 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 165 
                 rac-N-[1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-(1- 
                 0.91 
                 606.10 
                 XBridge 
               
               
                   
                 methyl-1H-pyrazol-3-yl)-ethyl]-N-(4-pyridin-2-yl- 
                   
                   
                 basic 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 166 
                 rac-N-[1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-(1- 
                 0.86 
                 606.08 
                 XBridge 
               
               
                   
                 methyl-1H-pyrazol-4-yl)-ethyl]-N-(4-pyridin-4-yl- 
                   
                   
                 basic 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 167 
                 rac-N-[1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-(1- 
                 0.87 
                 606.07 
                 XBridge 
               
               
                   
                 methyl-1H-pyrazol-3-yl)-ethyl]-N-(4-pyridin-4-yl- 
                   
                   
                 basic 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 168 
                 rac-N-[1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-(2- 
                 0.87 
                 606.07 
                 XBridge 
               
               
                   
                 methyl-2H-pyrazol-3-yl)-ethyl]-N-(4-pyridin-4-yl- 
                   
                   
                 basic 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 169 
                 rac-N-{2-Isoxazol-3-yl-1-[(2-methoxy-ethyl)-methyl- 
                 0.90 
                 592.98 
                 XBridge 
               
               
                   
                 carbamoyl]-ethyl}-N-(4-pyridin-4-yl-benzyl)-3-(4- 
                   
                   
                 basic 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 170 
                 rac-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2- 
                 0.86 
                 604.03 
                 XBridge 
               
               
                   
                 pyrimidin-2-yl-ethyl}-N-(4-pyridin-4-yl-benzyl)-3-(4- 
                   
                   
                 basic 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 171 
                 (S)-N-{1-[(2-Dimethylamino-ethyl)-methyl-carbamoyl]- 
                 0.82 
                 615.52 
                 Zorbax 
               
               
                   
                 2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(4- 
                   
                   
                 SB-AQ 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 172 
                 N-{1-[((S)-1-Benzyl-pyrrolidin-3-yl)-methyl-carbamoyl]- 
                 0.90 
                 703.52 
                 Zorbax 
               
               
                   
                 (S)-2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(4- 
                   
                   
                 SB-AQ 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 173 
                 N-{1-[((R)-1-Benzyl-pyrrolidin-3-yl)-methyl-carbamoyl]- 
                 0.89 
                 703.40 
                 Zorbax 
               
               
                   
                 (S)-2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(4- 
                   
                   
                 SB-AQ 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 174 
                 (S)-N-{1-[Benzyl-(2-dimethylamino-ethyl)-carbamoyl]- 
                 0.90 
                 691.43 
                 Zorbax 
               
               
                   
                 2-phenyl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(4- 
                   
                   
                 SB-AQ 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 175 
                 (S)-N-{1-[(2-Hydroxy-ethyl)-methyl-carbamoyl]-2- 
                 1.00 
                 596.17 
                 Zorbax 
               
               
                   
                 phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(4- 
                   
                   
                 SB-AQ 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 176 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 1.00 
                 637.28 
                 Zorbax 
               
               
                   
                 hydroxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4- 
                   
                   
                 SB-AQ 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
                   
                   
                 acidic 
               
               
                 177 
                 (S)-N-{1-[(4-Methoxy-benzyl)-methyl-carbamoyl]-2- 
                 1.11 
                 672.46 
                 Zorbax 
               
               
                   
                 phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(6- 
                   
                   
                 SB-AQ 
               
               
                   
                 trifluoromethyl-pyridin-3-yl)-acrylamide 
                   
                   
                 acidic 
               
               
                   
               
             
          
         
       
     
       Preparation of Compounds of Formula I Via Method C: 
     Step 1 
       [0358]    
       
                 
         
             
             
         
       
     
         [0359]    To a mixture of the acid (1 eq) and TBTU (2 eq) in dry DCM (25 mL/mmol) was added DIPEA (3 eq). The resulting mixture was stirred at rt for 15 min and then 2-(methylamino)ethanol (2 eq) was added. The reaction mixture was stirred at rt overnight under nitrogen atmosphere, then concentrated in vacuo. The resulting residue was taken up in a mixture of EA and a sat. NH 4 Cl solution. The organic layer was separated and washed 4 times with sat. NH 4 Cl. The combined aq. phases were extracted twice with EA. The combined organic layers were washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure. FC (n-heptane/EA/MeOH or DCM/MeOH system) afforded the pure amide. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 2   
                 Y 
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 (S)-N-{1-[(2-Hydroxy-ethyl)- methyl-carbamoyl]-2-phenyl- ethyl}-N-(4-morpholin-4-yl- benzyl)-3-(4-trifluoromethyl- phenyl)-acrylamide 
                 91% 
                 1.00 
                 596.17 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CH 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)- benzyl]-N-{1-[(2-hydroxy-ethyl)- methyl-carbamoyl]-2-phenyl- ethyl}-3-(4-trifluoromethyl-phenyl)- acrylamide  
                 64% 
                 1.00 
                 637.28 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)- benzyl]-N-{1-[(2-hydroxy-ethyl)- methyl-carbamoyl]-2-phenyl- ethyl}-3-(6-trifluoromethyl-pyridin- 3-yl)-acrylamide 
                 66% 
                 0.93 
                 638.09 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       Step 2 
       [0360]    
       
                 
         
             
             
         
       
     
         [0361]    To a stirred solution of the alcohol (1 eq) in dry THF (5 ml/mmol) was added NaH (1.5 eq). Then was added the halide R 6 X (1 eq) in the resulting orange mixture. The reaction mixture was stirred at rt overnight, then quenched with a small amount of water. The solvent was removed in vacuo and the crude product purified by preparative HPLC to afford the pure final compound. 
         [0000]    
       
         
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                 Example 
                   
                 LC-MS* 
               
             
          
           
               
                 number 
                 Chemical name 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
               
                 178 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 1.07 
                 651.24 
               
               
                   
                 methoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 179 
                 (S)-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-phenyl- 
                 1.07 
                 610.27 
               
               
                   
                 ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl- 
               
               
                   
                 phenyl)-acrylamide, formic acid 
               
               
                 180 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 1.03 
                 715.27 
               
               
                   
                 (pyrimidin-2-yloxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 181 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 1.12 
                 727.36 
               
               
                   
                 benzyloxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 182 
                 (S)-N-{1-[(2-Benzyloxy-ethyl)-methyl-carbamoyl]-2- 
                 1.14 
                 686.25 
               
               
                   
                 phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 183 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(2,4- 
                 1.19 
                 755.22 
               
               
                   
                 dimethyl-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl- 
               
               
                   
                 ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide, formic acid 
               
               
                 184 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(3- 
                 1.15 
                 775.13 
               
               
                   
                 fluoro-4-methoxy-benzyloxy)-ethyl]-methyl-carbamoyl}-2- 
               
               
                   
                 phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide, 
               
               
                   
                 formic acid 
               
               
                 185 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(3- 
                 1.14 
                 752.19 
               
               
                   
                 cyano-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl- 
               
               
                   
                 ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide, formic acid 
               
               
                 186 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 1.20 
                 811.12 
               
               
                   
                 (3-trifluoromethoxy-benzyloxy)-ethyl]-carbamoyl}-2- 
               
               
                   
                 phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide, 
               
               
                   
                 formic acid 
               
               
                 187 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(3- 
                 1.15 
                 757.19 
               
               
                   
                 methoxy-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl- 
               
               
                   
                 ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide, formic acid 
               
               
                 188 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(4- 
                 1.16 
                 793.14 
               
               
                   
                 difluoromethoxy-benzyloxy)-ethyl]-methyl-carbamoyl}-2- 
               
               
                   
                 phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide, 
               
               
                   
                 formic acid 
               
               
                 189 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 1.10 
                 782.20 
               
               
                   
                 (1-methyl-1H-benzotriazol-5-ylmethoxy)-ethyl]- 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)- 
               
               
                   
                 acrylamide, formic acid 
               
               
                 190 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 0.93 
                 728.20 
               
               
                   
                 (pyridin-3-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide, formic acid 
               
               
                 191 
                 (S)-N-(1-{[2-(3-Methoxy-benzyloxy)-ethyl]-methyl- 
                 1.12 
                 716.30 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide, formic acid 
               
               
                 192 
                 (S)-N-{1-[(2-Ethoxy-ethyl)-methyl-carbamoyl]-2-phenyl- 
                 1.10 
                 623.84 
               
               
                   
                 ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl- 
               
               
                   
                 phenyl)-acrylamide 
               
               
                 193 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-ethoxy- 
                 1.10 
                 664.99 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 194 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(2,4- 
                 1.20 
                 754.94 
               
               
                   
                 dimethyl-benzyloxy)-ethyl]-methyl-carbamoyl}-2-phenyl- 
               
               
                   
                 ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 195 
                 (S)-N-(1-{[2-(2,4-Dimethyl-benzyloxy)-ethyl]-methyl- 
                 1.19 
                 714.01 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 196 
                 (S)-N-(1-{[2-(3-Fluoro-4-methoxy-benzyloxy)-ethyl]- 
                 1.15 
                 733.98 
               
               
                   
                 methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl- 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 197 
                 (S)-N-(1-{[2-(3-Cyano-benzyloxy)-ethyl]-methyl- 
                 1.14 
                 710.98 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 198 
                 (S)-N-(1-{Methyl-[2-(3-trifluoromethoxy-benzyloxy)-ethyl]- 
                 1.20 
                 770.03 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 199 
                 (S)-N-(1-{[2-(3,5-Dimethoxy-benzyloxy)-ethyl]-methyl- 
                 1.15 
                 745.99 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 200 
                 (S)-N-(1-{[2-(3-Methoxy-benzyloxy)-ethyl]-methyl- 
                 1.15 
                 716.03 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 201 
                 (S)-N-(1-{[2-(4-Difluoromethoxy-benzyloxy)-ethyl]-methyl- 
                 1.16 
                 751.93 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 202 
                 (S)-N-(1-{Methyl-[2-(1-methyl-1H-benzotriazol-5- 
                 1.10 
                 741.08 
               
               
                   
                 ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4- 
               
               
                   
                 morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)- 
               
               
                   
                 acrylamide 
               
               
                 203 
                 (S)-N-(1-{Methyl-[2-(pyridin-3-ylmethoxy)-ethyl]- 
                 0.93 
                 686.98 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 204 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 1.10 
                 731.97 
               
               
                   
                 (5-methyl-isoxazol-3-ylmethoxy)-ethyl]-carbamoyl}-2- 
               
               
                   
                 phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 205 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 0.92 
                 727.99 
               
               
                   
                 (pyridin-4-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 206 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 1.18 
                 784.87 
               
               
                   
                 (5-trifluoromethyl-furan-2-ylmethoxy)-ethyl]-carbamoyl}-2- 
               
               
                   
                 phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 207 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 1.13 
                 691.03 
               
               
                   
                 cyclopropylmethoxy-ethyl)-methyl-carbamoyl]-2-phenyl- 
               
               
                   
                 ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 208 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 0.87 
                 728.97 
               
               
                   
                 (pyridin-4-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3- 
               
               
                   
                 (6-trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                 209 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 1.05 
                 732.97 
               
               
                   
                 (5-methyl-isoxazol-3-ylmethoxy)-ethyl]-carbamoyl}-2- 
               
               
                   
                 phenyl-ethyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                 210 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(2- 
                 1.16 
                 770.83 
               
               
                   
                 benzyloxy-ethoxy)-ethyl]-methyl-carbamoyl}-2-phenyl- 
               
               
                   
                 ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 211 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 1.08 
                 676.00 
               
               
                   
                 cyanomethoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}- 
               
               
                   
                 3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 212 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-allyloxy- 
                 1.12 
                 677.10 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 213 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 1.00 
                 693.99 
               
               
                   
                 carbamoylmethoxy-ethyl)-methyl-carbamoyl]-2-phenyl- 
               
               
                   
                 ethyl}-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 214 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 0.94 
                 728.00 
               
               
                   
                 (pyridin-2-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 215 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 0.89 
                 728.98 
               
               
                   
                 (pyridin-2-ylmethoxy)-ethyl]-carbamoyl}-2-phenyl-ethyl)-3- 
               
               
                   
                 (6-trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                 216 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(2- 
                 1.12 
                 771.89 
               
               
                   
                 benzyloxy-ethoxy)-ethyl]-methyl-carbamoyl}-2-phenyl- 
               
               
                   
                 ethyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                 217 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2- 
                 1.02 
                 677.00 
               
               
                   
                 cyanomethoxy-ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}- 
               
               
                   
                 3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                 218 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-allyloxy- 
                 1.07 
                 677.97 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-3-(6- 
               
               
                   
                 trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       Preparation of Compounds of Formula I Via Method D: 
     Preparation of Methyl-(2-methylamino-ethyl)-carbamic acid tert-butyl ester 
       [0362]    
       
                 
         
             
             
         
       
     
         [0363]    To an ice-cooled solution of N,N′-dimethyethylenediamine (10 mL, 91.0 mmol) in dry THF (150 mL) was added a solution of Boc 2 O (4.97 g, 22.8 mmol) in dry THF (50 mL) over 30 minutes. The reaction mixture was stirred for 1 h at 0° C. then at rt overnight, and concentrated in vacuo. The resulting residue was taken up in a mixture of EA and a sat. NH 4 Cl solution. The organic layer was separated, washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure. FC (10% MeOH in DCM) afforded the title compound as a yellow oil (2.90 g, 17%). 
         [0364]    LC-MS (analytic A, Zorbax SB-AQ column, acidic conditions): t R =0.50 min; [M+H] + =189.40. 
       Step 1 
       [0365]    
       
                 
         
             
             
         
       
     
         [0366]    To a mixture of the acid (1 eq), TBTU (2 eq), and cat. DMAP in dry DCM (25 mL/mmol) was added DIPEA (3 eq). The resulting mixture was stirred at rt for 15 min and then methyl-(2-methylamino-ethyl)-carbamic acid tert-butyl ester (1 eq) was added. The reaction mixture was stirred at rt overnight under nitrogen atmosphere, then concentrated in vacuo. The resulting residue was taken up in a mixture of EA and a sat. NH 4 Cl solution. The organic layer was separated and washed 4 times with sat. NH 4 Cl. The combined aq. phases were extracted twice with EA. The combined organic layers were washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure. FC (n-heptane/EA or EA/MeOH system) afforded the pure amide. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 2   
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-Methyl-{2-[methyl-(3-phenyl-2-{(4- pyridin-2-yl-benzyl)-[3-(4- trifluoromethyl-phenyl)-acryloyl]-amino}- propionyl)-amino]-ethyl}-carbamic acid tert-butyl ester  
                 77% 
                 0.98 
                 701.74 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-Methyl-{2-[methyl-(2-{(4-morpholin- 4-yl-benzyl)-[3-(4-trifluoromethyl- phenyl)-acryloyl]-amino}-3-phenyl- propionyl)-amino]-ethyl}-carbamic acid tert-butyl ester  
                 74% 
                 1.14 
                 709.27 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-{2-[(2-{[4-(4-Acetyl-piperazin-1-yl)- benzyl]-[3-(4-trifluoromethyl-phenyl)- acryloyl]-amino}-3-phenyl-propionyl)- methyl-amino]-ethyl}-methyl-carbamic acid tert-butyl ester 
                 69% 
                 1.14 
                 750.29 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       Step 2 
       [0367]    
       
                 
         
             
             
         
       
     
         [0368]    To an ice-cooled solution of the Boc-protected amine (1 eq) in dry DCM (10 mL/mmol) was added dropwise TFA (10 eq). The resulting reaction mixture was stirred at 0° C. for 30 min, then at rt for 5 h under nitrogen atmosphere and then concentrated in vacuo. The resulting residue was dissolved in EA and washed with a 2N NaOH solution. The organic extract was dried (MgSO 4 ), filtered and concentrated under reduced pressure. FC (DCM/MeOH/NH 4 OH system) afforded the free secondary amine. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 2   
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-N-{1-[Methyl-(2-methylamino-ethyl)- carbamoyl]-2-phenyl-ethyl}-N-(4-pyridin- 2-yl-benzyl)-3-(4-trifluoromethyl- phenyl)-acrylamide  
                 70% 
                 0.80 
                 601.64 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-N-{1-[Methyl-(2-methylamino-ethyl)- carbamoyl]-2-phenyl-ethyl}-N-(4- morpholin-4-yl-benzyl)-3-(4- trifluoromethyl-phenyl)-acrylamide  
                 58% 
                 0.91 
                 609.09 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)- benzyl]-N-{1-[methyl-(2-methylamino- ethyl)-carbamoyl]-2-phenyl-ethyl}-3-(4- trifluoromethyl-phenyl)-acrylamide 
                 61% 
                 0.90 
                 650.32 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       Step 3 
       [0369]    
       
                 
         
             
             
         
       
     
         [0370]    A mixture of the amine (1 eq), the aldehyde (2 eq), sodium triacetoxyborohydride (2.5 eq), and acetic acid (2 eq) in dry THF or MeCN (10 ml/mmol) was stirred at rt overnight, then directly purified by preparative HPLC to afford the pure final compound. 
         [0000]    
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 LC-MS* 
               
             
          
           
               
                   
                   
                 t R   
                   
               
               
                 Ex. No. 
                 Chemical name 
                 (min) 
                 [M + H] +   
               
               
                   
               
               
                 219 
                 (S)-N-[1-({2-[(5-Bromo-furan-2-ylmethyl)-methyl-amino]- 
                 0.89 
                 761.68 
               
               
                   
                 ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 220 
                 (S)-N-(1-{[2-(Benzyl-methyl-amino)-ethyl]-methyl- 
                 0.89 
                 691.79 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 221 
                 (S)-N-[1-({2-[(6-Chloro-pyridin-3-ylmethyl)-methyl-amino]- 
                 0.87 
                 726.73 
               
               
                   
                 ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 222 
                 (S)-N-(1-{[2-(Furan-3-ylmethyl-methyl-amino)-ethyl]-methyl- 
                 0.87 
                 681.77 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 223 
                 (S)-N-(1-{[2-(Furan-2-ylmethyl-methyl-amino)-ethyl]-methyl- 
                 0.87 
                 681.76 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 224 
                 (S)-N-(1-{Methyl-[2-(methyl-pyridin-2-ylmethyl-amino)-ethyl]- 
                 0.87 
                 692.79 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 225 
                 (S)-N-(1-{Methyl-[2-(methyl-thiophen-2-ylmethyl-amino)- 
                 0.88 
                 697.74 
               
               
                   
                 ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)- 
               
               
                   
                 3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 226 
                 (S)-N-[1-({2-[(5-Chloro-thiophen-2-ylmethyl)-methyl-amino]- 
                 0.90 
                 731.70 
               
               
                   
                 ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 227 
                 (S)-N-[1-({2-[(6-Bromo-pyridin-3-ylmethyl)-methyl-amino]- 
                 0.87 
                 772.70 
               
               
                   
                 ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 228 
                 (S)-N-[1-({2-[(5-Hydroxymethyl-furan-2-ylmethyl)-methyl- 
                 0.85 
                 711.33 
               
               
                   
                 amino]-ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4- 
               
               
                   
                 pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 229 
                 (S)-N-[1-({2-[(6-Methoxy-pyridin-3-ylmethyl)-methyl-amino]- 
                 0.87 
                 722.71 
               
               
                   
                 ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl- 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 230 
                 (S)-N-[1-(Methyl-{2-[methyl-(6-trifluoromethyl-pyridin-3- 
                 0.89 
                 760.71 
               
               
                   
                 ylmethyl)-amino]-ethyl}-carbamoyl)-2-phenyl-ethyl]-N-(4- 
               
               
                   
                 pyridin-2-yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 231 
                 (S)-N-(1-{Methyl-[2-(methyl-pyridin-3-ylmethyl-amino)-ethyl]- 
                 0.81 
                 692.73 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 232 
                 (S)-N-(1-{Methyl-[2-(methyl-thiophen-3-ylmethyl-amino)- 
                 0.88 
                 697.63 
               
               
                   
                 ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-pyridin-2-yl-benzyl)- 
               
               
                   
                 3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 233 
                 (S)-N-[1-(Methyl-{2-[methyl-(2-methyl-benzyl)-amino]-ethyl}- 
                 0.91 
                 705.68 
               
               
                   
                 carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 234 
                 (S)-N-[1-({2-[(2,4-Dimethyl-benzyl)-methyl-amino]-ethyl}- 
                 0.93 
                 719.69 
               
               
                   
                 methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-pyridin-2-yl-benzyl)- 
               
               
                   
                 3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 235 
                 (S)-N-[1-({2-[(3,5-Dimethoxy-benzyl)-methyl-amino]-ethyl}- 
                 1.02 
                 759.37 
               
               
                   
                 methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl- 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 236 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(3,5- 
                 1.01 
                 799.34 
               
               
                   
                 dimethoxy-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)- 
               
               
                   
                 2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 237 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-({4-[(2- 
                 0.95 
                 813.34 
               
               
                   
                 hydroxy-ethyl)-methyl-amino]-benzyl}-methyl-amino)-ethyl]- 
               
               
                   
                 methyl-carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl- 
               
               
                   
                 phenyl)-acrylamide 
               
               
                 238 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(4- 
                 0.96 
                 756.30 
               
               
                   
                 hydroxy-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2- 
               
               
                   
                 phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 239 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(4- 
                 0.95 
                 811.35 
               
               
                   
                 diethylamino-benzyl)-methyl-amino]-ethyl}-methyl- 
               
               
                   
                 carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)- 
               
               
                   
                 acrylamide 
               
               
                 240 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(3- 
                 0.96 
                 756.31 
               
               
                   
                 hydroxy-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2- 
               
               
                   
                 phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 241 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 0.92 
                 741.37 
               
               
                   
                 (methyl-pyridin-3-ylmethyl-amino)-ethyl]-carbamoyl}-2- 
               
               
                   
                 phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 242 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-{[3-(2- 
                 0.95 
                 799.46 
               
               
                   
                 hydroxy-ethoxy)-benzyl]-methyl-amino}-ethyl)-methyl- 
               
               
                   
                 carbamoyl]-2-phenyl-ethyl}-3-(4-trifluoromethyl-phenyl)- 
               
               
                   
                 acrylamide 
               
               
                 243 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(3-cyano- 
                 0.99 
                 765.27 
               
               
                   
                 benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)-2-phenyl- 
               
               
                   
                 ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 244 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(4- 
                 1.03 
                 798.25 
               
               
                   
                 isopropoxy-benzyl)-methyl-amino]-ethyl}-methyl-carbamoyl)- 
               
               
                   
                 2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 245 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-(methyl-{2- 
                 1.01 
                 811.31 
               
               
                   
                 [methyl-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7- 
               
               
                   
                 ylmethyl)-amino]-ethyl}-carbamoyl)-2-phenyl-ethyl]-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 246 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-{1-[(2-{[4-(3- 
                 0.87 
                 841.37 
               
               
                   
                 dimethylamino-propoxy)-benzyl]-methyl-amino}-ethyl)- 
               
               
                   
                 methyl-carbamoyl]-2-phenyl-ethyl}-3-(4-trifluoromethyl- 
               
               
                   
                 phenyl)-acrylamide 
               
               
                 247 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(6- 
                 0.97 
                 771.15 
               
               
                   
                 methoxy-pyridin-3-ylmethyl)-methyl-amino]-ethyl}-methyl- 
               
               
                   
                 carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)- 
               
               
                   
                 acrylamide 
               
               
                 248 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 0.95 
                 747.27 
               
               
                   
                 (methyl-thiazol-2-ylmethyl-amino)-ethyl]-carbamoyl}-2- 
               
               
                   
                 phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 249 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2- 
                 1.00 
                 784.23 
               
               
                   
                 (benzo[1,3]dioxol-5-ylmethyl-methyl-amino)-ethyl]-methyl- 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)- 
               
               
                   
                 acrylamide 
               
               
                 250 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 0.88 
                 742.40 
               
               
                   
                 (methyl-pyrimidin-5-ylmethyl-amino)-ethyl]-carbamoyl}-2- 
               
               
                   
                 phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 251 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(2,3- 
                 0.99 
                 790.40 
               
               
                   
                 difluoro-4-methyl-benzyl)-methyl-amino]-ethyl}-methyl- 
               
               
                   
                 carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)- 
               
               
                   
                 acrylamide 
               
               
                 252 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-[1-({2-[(3H- 
                 0.82 
                 730.40 
               
               
                   
                 imidazol-4-ylmethyl)-methyl-amino]-ethyl}-methyl- 
               
               
                   
                 carbamoyl)-2-phenyl-ethyl]-3-(4-trifluoromethyl-phenyl)- 
               
               
                   
                 acrylamide 
               
               
                 253 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{methyl-[2- 
                 0.87 
                 741.40 
               
               
                   
                 (methyl-pyridin-4-ylmethyl-amino)-ethyl]-carbamoyl}-2- 
               
               
                   
                 phenyl-ethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 254 
                 (S)-N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-(1-{[2-(benzyl- 
                 0.96 
                 740.40 
               
               
                   
                 methyl-amino)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 255 
                 (S)-N-(1-{[2-({4-[(2-Hydroxy-ethyl)-methyl-amino]-benzyl}- 
                 0.97 
                 772.30 
               
               
                   
                 methyl-amino)-ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N- 
               
               
                   
                 (4-morpholin-4-yl-benzyl)-3-(4-trifluoromethyl-phenyl)- 
               
               
                   
                 acrylamide 
               
               
                 256 
                 (S)-N-[1-({2-[(4-Hydroxy-benzyl)-methyl-amino]-ethyl}- 
                 0.97 
                 715.30 
               
               
                   
                 methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl- 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 257 
                 (S)-N-[1-({2-[(4-Diethylamino-benzyl)-methyl-amino]-ethyl}- 
                 0.94 
                 770.30 
               
               
                   
                 methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl- 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 258 
                 (S)-N-[1-({2-[(3-Hydroxy-benzyl)-methyl-amino]-ethyl}- 
                 0.97 
                 715.30 
               
               
                   
                 methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl- 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 259 
                 (S)-N-(1-{Methyl-[2-(methyl-pyridin-3-ylmethyl-amino)-ethyl]- 
                 0.92 
                 700.40 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 260 
                 (S)-N-{1-[(2-{[3-(2-Hydroxy-ethoxy)-benzyl]-methyl-amino}- 
                 0.96 
                 759.30 
               
               
                   
                 ethyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4- 
               
               
                   
                 yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 261 
                 (S)-N-[1-({2-[(3-Cyano-benzyl)-methyl-amino]-ethyl}-methyl- 
                 1.00 
                 724.30 
               
               
                   
                 carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 262 
                 (S)-N-[1-({2-[(4-Isopropoxy-benzyl)-methyl-amino]-ethyl}- 
                 1.05 
                 757.30 
               
               
                   
                 methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl- 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 263 
                 (S)-N-[1-(Methyl-{2-[methyl-(4-methyl-3,4-dihydro-2H- 
                 1.02 
                 770.30 
               
               
                   
                 benzo[1,4]oxazin-7-ylmethyl)-amino]-ethyl}-carbamoyl)-2- 
               
               
                   
                 phenyl-ethyl]-N-(4-morpholin-4-yl-benzyl)-3-(4- 
               
               
                   
                 trifluoromethyl-phenyl)-acrylamide 
               
               
                 264 
                 (S)-N-[1-({2-[(6-Methoxy-pyridin-3-ylmethyl)-methyl-amino]- 
                 0.98 
                 730.30 
               
               
                   
                 ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4- 
               
               
                   
                 yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 265 
                 (S)-N-(1-{Methyl-[2-(methyl-thiazol-2-ylmethyl-amino)-ethyl]- 
                 0.96 
                 706.30 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 266 
                 (S)-N-(1-{[2-(Benzo[1,3]dioxol-5-ylmethyl-methyl-amino)- 
                 1.01 
                 743.20 
               
               
                   
                 ethyl]-methyl-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4- 
               
               
                   
                 yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 267 
                 (S)-N-(1-{Methyl-[2-(methyl-pyrimidin-5-ylmethyl-amino)- 
                 0.92 
                 701.30 
               
               
                   
                 ethyl]-carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl- 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 268 
                 (S)-N-[1-({2-[(2,3-Difluoro-4-methyl-benzyl)-methyl-amino]- 
                 1.03 
                 749.30 
               
               
                   
                 ethyl}-methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4- 
               
               
                   
                 yl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 269 
                 (S)-N-[1-({2-[(3H-Imidazol-4-ylmethyl)-methyl-amino]-ethyl}- 
                 0.85 
                 689.30 
               
               
                   
                 methyl-carbamoyl)-2-phenyl-ethyl]-N-(4-morpholin-4-yl- 
               
               
                   
                 benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide 
               
               
                 270 
                 (S)-N-(1-{Methyl-[2-(methyl-pyridin-4-ylmethyl-amino)-ethyl]- 
                 0.92 
                 700.40 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl-benzyl)-3- 
               
               
                   
                 (4-trifluoromethyl-phenyl)-acrylamide 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       Preparation of Compounds of Formula I Via Method E: 
     Preparation of (4-Bromo-benzyl)-methyl-amine 
       [0371]    
       
                 
         
             
             
         
       
     
         [0372]    In an autoclave, a mixture of 4-bromobenzaldehyde (2.08 g, 11.15 mmol) and methylamine 2M solution in methanol (25 mL, 33.44 mmol) was stirred at 65° C. for 4 h. After cooling to rt, sodium borohydride (633 mg, 16.72 mmol) was added portionwise. The reaction mixture was stirred at rt for 30 min, then concentrated in vacuo. The resulting residue was dissolved in EA (30 mL) and the organic layer washed with a sat. NaHCO 3  solution (10 mL). The aq. phase was basified with few drops of 1N NaOH (pH=13) and extracted twice with EA. The combined organic extracts were washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure to afford the title compound as a colorless oil (2.04 g, 91%), which was used for the next step without further purification. 
         [0373]    LC-MS (analytic A, Zorbax SB-AQ column, acidic conditions): t R =0.61 min; [M+H] + =241.06 (MeCN adduct). 
       Step 1 
       [0374]    
       
                 
         
             
             
         
       
     
         [0375]    To a mixture of (S)-2-{(4-morpholin-4-yl-benzyl)-[3-(6-trifluoromethyl-pyridin-3-yl)-acryloyl]-amino}-3-phenyl-propionic acid (4.00 g, 7.41 mmol), TBTU (4.76 g, 14.83 mmol), and cat. DMAP in dry DCM (45 mL) was added DIPEA (3.8 mL, 22.24 mmol). The resulting mixture was stirred at rt for 10 min and then (4-bromo-benzyl)-methyl-amine (1.48 g, 7.41 mmol) was added. The reaction mixture was stirred at rt overnight under nitrogen atmosphere, then concentrated in vacuo. The resulting residue was taken up in EA. The organic layer was washed with water (5×) and brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure. FC (n-heptane/EA 5:5) afforded the N-{1-[(4-bromo-benzyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide as a yellow foam (2.38 g, 44%). 
         [0376]    LC-MS (analytic A, Zorbax SB-AQ column, acidic conditions): t R =1.16 min; [M+H] + =722.76. 
       Step 2 
     General Procedure 1 
       [0377]    
       
                 
         
             
             
         
       
     
         [0378]    A mixture of N-{1-[(4-bromo-benzyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide (1 eq), the amine NHR 9 R 10  (1.5 eq), and sodium tert-butylate (1.5 eq) in dry dioxane (14 mL/mmol) was degassed with argon for 10 min and stirred at 105° C. Then a degassed solution (with argon) of the catalyst Solvias SK-CC02-A (0.06 eq in 125 mL/mmol dioxane) is added. The reaction mixture was stirred at 105° C. overnight then concentrated in vacuo. The resulting residue was taken up in EA, filtered over isolute and purified by preparative HPLC to afford the pure final compound. 
       General Procedure 2 
       [0379]    
       
                 
         
             
             
         
       
     
         [0380]    A mixture of N-{1-[(4-bromo-benzyl)-methyl-carbamoyl]-2-phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide (1 eq), the amide NH(R 11 )COR 12  (1.2 eq), potassium carbonate (2 eq), copper (I) iodide (0.05 eq), and N,N′-dimethylethylenediamine (0.1 eq) in dry dioxane (14 mL/mmol) was stirred at 120° C. overnight under nitrogen atmosphere. The reaction mixture was filtered over isolute using EA as solvent, then purified by preparative HPLC to afford the pure final compound. 
         [0000]    
       
         
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 LC-MS* 
               
             
          
           
               
                 Ex. No. 
                 Chemical name 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
               
                 271 
                 (S)-N-{1-[(4-Acetylamino-benzyl)-methyl-carbamoyl]-2- 
                 1.03 
                 699.94 
               
               
                   
                 phenyl-ethyl}-N-(4-morpholin-4-yl-benzyl)-3-(6- 
               
               
                   
                 trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                 272 
                 (S)-N-(1-{Methyl-[4-(2-oxo-pyrrolidin-1-yl)-benzyl]- 
                 1.07 
                 725.90 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl- 
               
               
                   
                 benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                 273 
                 (S)-Cyclopropanecarboxylic acid (4-{[methyl-(2-{(4- 
                 1.07 
                 726.99 
               
               
                   
                 morpholin-4-yl-benzyl)-[3-(6-trifluoromethyl-pyridin-3- 
               
               
                   
                 yl)-acryloyl]-amino}-3-phenyl-propionyl)-amino]- 
               
               
                   
                 methyl}-phenyl)-amide 
               
               
                 274 
                 (S)-N-(1-{Methyl-[4-(2-oxo-piperidin-1-yl)-benzyl]- 
                 1.05 
                 739.88 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl- 
               
               
                   
                 benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                 275 
                 (S)-N-(4-{[Methyl-(2-{(4-morpholin-4-yl-benzyl)-[3-(6- 
                 1.11 
                 762.99 
               
               
                   
                 trifluoromethyl-pyridin-3-yl)-acryloyl]-amino}-3-phenyl- 
               
               
                   
                 propionyl)-amino]-methyl}-phenyl)-benzamide 
               
               
                 276 
                 (S)-N-(1-{[4-(Acetyl-phenyl-amino)-benzyl]-methyl- 
                 1.10 
                 776.00 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl- 
               
               
                   
                 benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                 277 
                 (S)-N-(1-{[4-(2-Methoxy-ethylamino)-benzyl]-methyl- 
                 1.00 
                 716.00 
               
               
                   
                 carbamoyl}-2-phenyl-ethyl)-N-(4-morpholin-4-yl- 
               
               
                   
                 benzyl)-3-(6-trifluoromethyl-pyridin-3-yl)-acrylamide 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       Preparation of Compounds of Formula I Via Method F: 
     Step 1 
       [0381]    
       
                 
         
             
             
         
       
     
         [0382]    To a stirred suspension of L-serine methyl ester hydrochloride (1 eq) in dry DCM (1.5 mL/mmol) and TEA (1.1 eq) at rt were added successively anhydrous sodium sulfate (250 mg/mmol) and the aldehyde R 2 CHO (1 eq). The reaction mixture was stirred at rt for 20 h under nitrogen atmosphere, then filtered and concentrated in vacuo. The resulting solid was dissolved in dry MeOH (1.5 mL/mmol) and cooled to 0° C. before sodium borohydride (1.1 eq) was added. The reaction mixture was stirred at 0° C. for 2 h, then quenched with water and the MeOH was removed in vacuo. The resulting aq. solution was extracted with EA (3×) and the combined organic extracts were washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure to afford the secondary amine, which was used for the next step without further purification. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 2   
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Hydroxy-2-(4-pyridin-2-yl- benzylamino)-propionic acid methyl ester  
                 98% 
                 0.70 
                 287.21 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Hydroxy-2-(4-pyridin-4-yl- benzylamino)-propionic acid methyl ester 
                 quant. 
                 0.66 
                 287.23 
               
               
                   
               
               
                 *Analytic A, Waters X-Bridge column, basic conditions 
               
             
          
         
       
     
       Step 2 
       [0383]    
       
                 
         
             
             
         
       
     
         [0384]    To a stirred solution of the serine derivative (1 eq) in dry DCM (4 mL/mmol) at 0° C. were added successively imidazole (1.5 eq) and TBDMSCl (1.1 eq). The reaction mixture was stirred at rt for 20 h under nitrogen atmosphere, then were added a sat. NH 4 Cl solution and DCM. The aq. phase was separated and extracted twice with DCM. The combined organic extracts were dried (MgSO 4 ), filtered and concentrated under reduced pressure. FC (n-heptane/EA system) afforded the pure TBDMS-protected serine derivative. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 2   
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-(tert-Butyl-dimethyl-silanyloxy)-2- (4-pyridin-2-yl-benzylamino)-propionic acid methyl ester 
                 85% 
                 2.74 
                 401.30 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-(tert-Butyl-dimethyl-silanyloxy)-2- (4-pyridin-4-yl-benzylamino)-propionic acid methyl ester 
                 68% 
                 2.42 
                 401.40 
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
       Step 3 
       [0385]    
       
                 
         
             
             
         
       
     
         [0386]    To a mixture of 4-(trifluoromethyl)cinnamic acid (1.05 eq) and DMF (few drops) in dry DCM (2.25 mL/mmol) was added dropwise oxalyl chloride (1.1 eq) at 0° C. The reaction mixture was stirred at 0° C. for 30 min then at rt for 4 h under nitrogen atmosphere. It was then cooled to 0° C. and treated with a solution of the amine (1 eq), TEA (2 eq), and DMAP (0.05 eq) in dry DCM (0.45 mL/mmol). The reaction mixture was stirred at rt for 17 h under nitrogen atmosphere, then water was added. The aq. phase was separated and extracted twice with DCM. The combined organic extracts were washed with a sat. NaHCO 3  solution, dried (MgSO 4 ), filtered and concentrated under reduced pressure. FC (n-heptane/EA system) afforded the pure amide. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 2   
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-(tert-Butyl-dimethyl-silanyloxy)-2- {(4-pyridin-2-yl-benzyl)-[3-(4- trifluoromethyl-phenyl)-acryloyl]-amino}- propionic acid methyl ester  
                 60% 
                 1.10 
                 599.79 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-(tert-Butyl-dimethyl-silanyloxy)-2- {(4-pyridin-4-yl-benzyl)-[3-(4- trifluoromethyl-phenyl)-acryloyl]-amino}- propionic acid methyl ester 
                 96% 
                 1.05 
                 599.71 
               
               
                   
               
               
                 *Analytic A, Zorbax SB-AQ column, acidic conditions 
               
             
          
         
       
     
       Step 4 
       [0387]    
       
                 
         
             
             
         
       
     
         [0388]    A mixture of the TBDMS-protected alcohol (1 eq) in AcOH/H 2 O 2:1 (20 mL/mmol) was stirred at rt under nitrogen atmosphere for 1-3 days. 
         [0389]    The solvent was removed in vacuo and the resulting residue dissolved in DCM and washed with a sat. NaHCO 3  solution. The aq. phase was extracted with DCM (3×). The combined organic extracts were dried (MgSO 4 ), filtered and concentrated under reduced pressure. Recrystallization in MeOH or EtOH afforded the pure alcohol. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 2   
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Hydroxy-2-{(4-pyridin-2-yl-benzyl)- [3-(4-trifluoromethyl-phenyl)-acryloyl]- amino}-propionic acid methyl ester  
                 93% 
                 3.02 
                 485.00 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Hydroxy-2-{(4-pyridin-4-yl-benzyl)- [3-(4-trifluoromethyl-phenyl)-acryloyl]- amino}-propionic acid methyl ester 
                 94% 
                 2.56 
                 484.90 
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
       Step 5 
       [0390]    
       
                 
         
             
             
         
       
     
         [0391]    To a stirred suspension of the alcohol (1 eq) in dry DCM (14 mL/mmol) was added thionyl chloride (1.1 eq). The resulting yellow mixture was stirred at rt for 12 h under nitrogen atmosphere. The solution was washed with water and brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure to afford the crude chloride derivative, which was used for the next step without further purification. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 2   
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Chloro-2-{(4-pyridin-2-yl-benzyl)- [3-(4-trifluoromethyl-phenyl)-acryloyl]- amino}-propionic acid methyl ester 
                 98% 
                 3.55 
                 503.40 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 (S)-3-Chloro-2-{(4-pyridin-4-yl-benzyl)- [3-(4-trifluoromethyl-phenyl)-acryloyl]- amino}-propionic acid methyl ester 
                 quant. 
                 2.96 
                 503.40 
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
       Step 6 
       [0392]    
       
                 
         
             
             
         
       
     
         [0393]    A mixture of the chloride (1 eq) and TEA (2 eq) in DCM (14 mL/mmol) was stirred at rt for 20 h under nitrogen atmosphere, then washed with water and brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure to afford the crude elimination product, which was used for the next step without further purification. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 LC-MS* 
               
             
          
           
               
                 R 2   
                 Chemical name 
                 Yield 
                 t R  (min) 
                 [M + H] +   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-{(4-Pyridin-2-yl-benzyl)-[3-(4- trifluoromethyl-phenyl)-acryloyl]-amino}- acrylic acid methyl ester  
                 crude 
                 3.41 
                 467.10 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-{(4-Pyridin-4-yl-benzyl)-[3-(4- trifluoromethyl-phenyl)-acryloyl]-amino}- acrylic acid methyl ester 
                 crude 
                 2.89 
                 467.20 
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
       Step 7 
       [0394]    
       
                 
         
             
             
         
       
     
       General Procedure 1 
       [0395]    A mixture of the acrylic acid methyl ester derivative (1 eq), the aliphatic cyclic amine NHR 13 R 14  (2 eq), and FeCl 3  (0.1 eq) in dry DCM (5 mL/mmol) was stirred at rt for 60 h under nitrogen atmosphere. The reaction mixture was then washed with an aq. 1M Na 2 SO 4  solution to eliminate iron species and the aq. phase extracted twice with DCM. The combined organic extracts were dried (MgSO 4 ), filtered and concentrated under reduced pressure. FC (n-heptane/EA or DCM/MeOH system) afforded the pure amino-acid derivative. 
       General Procedure 2 
       [0396]    To a stirred solution of the acrylic acid methyl ester derivative (1 eq) in dry MeCN (10 mL/mmol) was added potassium carbonate (6 eq) followed by the aromatic amine or carbamate or oxo-amide NHR 13 R 14  (1.1 eq). The reaction mixture was stirred at rt for 4-15 h or was refluxed for 20-30 h under nitrogen atmosphere, then filtered and concentrated in under reduced pressure. FC (n-heptane/EA or DCM/MeOH system) afforded the pure amino-acid derivative. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                       Chemical name 
                       Yield 
                         LC-MS*     t R  (min) [M + H] +   
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-2-{(4-Pyridin-2-yl-benzyl)-[3-(4- trifluoromethyl-phenyl)-acryloyl]-amino}-3- pyrrolidin-1-yl-propionic acid methyl ester  
                 quant. 
                 2.66 
                 538.20 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-Piperidin-1-yl-2-{(4-pyridin-2-yl-benzyl)-[3- (4-trifluoromethyl-phenyl)-acryloyl]-amino}- propionic acid methyl ester  
                 83% 
                 2.70 
                 554.30 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(4-Methyl-piperazin-1-yl)-2-{(4-pyridin-2- yl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]- amino}-propionic acid methyl ester  
                 72% 
                 2.58 
                 567.50 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-Imidazol-1-yl-2-{(4-pyridin-2-yl-benzyl)-[3- (4-trifluoromethyl-phenyl)-acryloyl]-amino}- propionic acid methyl ester 
                 84% 
                 2.57 
                 535.40 
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                       Chemical name 
                       Yield 
                         LC-MS*     t R  (min) [M + H] +   
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-2-{(4-Pyridin-4-yl-benzyl)-[3-(4- trifluoromethyl-phenyl)-acryloyl)-amino}-3- pyrrol-1-yl-propionic acid methyl ester  
                 85% 
                 3.09 
                 534.30 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(2-Oxo-oxazolidin-3-yl)-2-{(4-pyridin-4-yl- benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]- amino}-propionic acid methyl ester  
                 76% 
                 2.65 
                 554.20 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(2,3-Dioxo-2,3-dihydro-indol-1-yl)-2-{(4- pyridin-4-yl-benzyl)-[3-(4-trifluoromethyl- phenyl)-acryloyl]-amino}-propionic acid methyl ester 
                 84% 
                 2.92 
                 614.10 
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
       Step 8 
       [0397]    
       
                 
         
             
             
         
       
     
         [0398]    To a solution of the ester (1 eq) in MeOH (15 mL/mmol) was added dropwise aq. 2N NaOH (2-3.5 eq). The reaction mixture was stirred at rt for 2-4 h, then a few amount of water was added and the solvent was removed in vacuo. The residue was acidified with aq. 2N HCl until pH=2-3. The aq. phase was concentrated under reduced pressure to afford the crude acid, which was used for the next step without further purification. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                       Chemical name 
                       Yield 
                         LC-MS*     t R  (min) [M + H] +   
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-2-{(4-Pyridin-2-yl-benzyl)-[3-(4- trifluoromethyl-phenyl)-acryloyl]-amino}-3- pyrrolidin-1-yl-propionic acid, dihydrochloride salt  
                 crude 
                  2.62 
                 524.10  
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-Piperidin-1-yl-2-{(4-pyridin-2-yl-benzyl)-[3- (4-trifluoromethyl-phenyl)-acryloyl]-amino}- propionic acid, dihydrochloride salt  
                 71% 
                  2.64 
                 540.20  
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(4-Methyl-piperazin-1-yl)-2-{(4-pyridin-2- yl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]- amino}-propionic acid, trihydrochloride salt  
                 58% 
                  2.49 
                 553.30  
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-Imidazol-1-yl-2-{(4-pyridin-2-yl-benzyl)-[3- (4-trifluoromethyl-phenyl)-acryloyl)-amino}- propionic acid, dihydrochloride salt 
                 quant. 
                  2.50 
                 521.30  
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                       Chemical name 
                       Yield 
                         LC-MS*     t R  (min) [M + H] +   
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-2-{(4-Pyridin-4-yl-benzyl)-[3-(4- trifluoromethyl-phenyl)-acryloyl]-amino}-3- pyrrol-1-yl-propionic acid, hydrochloride salt  
                 quant. 
                 2.89 
                 520.50 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(2-Oxo-oxazolidin-3-yl)-2-{(4-pyridin-4-yl- benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]- amino}-propionic acid, hydrochloride salt  
                 91% 
                 2.49 
                 540.00 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 rac-3-(2,3-Dioxo-2,3-dihydro-indol-1-yl)-2-{(4- pyridin-4-yl-benzyl)-[3-(4-trifluoromethyl- phenyl)-acryloyl]-amino}-propionic acid, hydrochloride salt 
                 crude 
                 2.69 
                 600.30 
               
               
                   
               
               
                 *Analytic B 
               
             
          
         
       
     
       Step 9 
       [0399]    
       
                 
         
             
             
         
       
     
         [0400]    To a mixture of the acid (1 eq) and DIPEA (5 eq) in dry DCM (20 mL/mmol) was added TBTU (1.1 eq). After stirring at rt for 30 min under nitrogen atmosphere, N-(2-methoxyethyl)methylamine (1 eq) was added. The reaction mixture was stirred at rt under nitrogen atmosphere for 15-72 h, then water was added and the aq. phase extracted with DCM (2-5×). The combined organic extracts were washed with a sat. NaHCO 3  solution, dried (MgSO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford the pure final compound. 
         [0401]    Note: In the case of example 281, the imidazole elimination occurred. Thus, the aza-Michael addition of imidazole was repeated on the crude product according to the procedure 2 of step 7. 
         [0000]                                                          LC-MS*            Ex. No.   Chemical name   t R  (min)   [M + H] +                 278   rac-N-[1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-(4-   0.90   624.24           methyl-piperazin-1-yl)-ethyl]-N-(4-pyridin-2-yl-benzyl)-3-           (4-trifluoromethyl-phenyl)-acrylamide       279   rac-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-   0.93   611.25           morpholin-4-yl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(4-           trifluoromethyl-phenyl)-acrylamide       280   rac-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-   0.99   595.10           pyrrolidin-1-yl-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(4-           trifluoromethyl-phenyl)-acrylamide       281   rac-N-{2-Imidazol-1-yl-1-[(2-methoxy-ethyl)-methyl-   0.89   592.12           carbamoyl]-ethyl}-N-(4-pyridin-2-yl-benzyl)-3-(4-           trifluoromethyl-phenyl)-acrylamide       282   rac-N-{1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-pyrrol-   0.96   591.14           1-yl-ethyl}-N-(4-pyridin-4-yl-benzyl)-3-(4-trifluoromethyl-           phenyl)-acrylamide       283   rac-N-{2-(2,3-Dioxo-2,3-dihydro-indol-1-yl)-1-[(2-   0.93   671.08           methoxy-ethyl)-methyl-carbamoyl]-ethyl}-N-(4-pyridin-4-           yl-benzyl)-3-(4-trifluoromethyl-phenyl)acrylamide       284   rac-N-[1-[(2-Methoxy-ethyl)-methyl-carbamoyl]-2-(2-oxo-   0.86   611.12           oxazolidin-3-yl)-ethyl]-N-(4-pyridin-4-yl-benzyl)-3-(4-           trifluoromethyl-phenyl)-acrylamide               *Analytic A, Waters X-Bridge column, basic conditions            
In Vitro Antimalarial Activity:  Plasmodium falciparum  In Vitro Assay
 
         [0402]    In vitro activity against erythrocytic stages of  P. falciparum  is determined using a [ 3 H] hypoxanthine incorporation assay. One strain resistant to chloroquine and pyrimethamine ( P. falciparum  K1) is used in the assays, and all test compounds are compared for activity with the standard drugs chloroquine (sigma C6628) and artemisinin (sigma-36, 159-3). Compounds are diluted in DMSO to 1 mM and added to parasite cultures incubated in RPMI 1640 medium without hypoxanthine, supplemented with HEPES (5.94 g/L), NaHCO 3  (2.1 g/L), neomycin (100 U/mL), Albumax (5 g/L) and washed human red cells at 2.5% haematocrit (0.3% parasitaemia). Seven serial doubling dilutions of each compound are prepared in 96-well microtitre plates and incubated in a humidifying atmosphere at 37° C.; 4% CO 2 , 3% O 2 , 93% N 2 . 
         [0403]    After 48 h, 50 μl of [3H] hypoxanthine (0.5 μCi) is added to each well of a plate. The plates are incubated for a further 24 h under the same conditions. The plates are then harvested with a Betaplate cell harvester (Wallac) and washed with distilled water. The dried filters are inserted into a plastic foil with 10 mL of scintillation fluid, and counted in a Betaplate liquid scintillation counter. IC 50  values are calculated from sigmoidal inhibition curves using Microsoft Excel. Inhibition activities (IC 50  values) of the 284 exemplified compounds are in the range of 1-494 nM with an average of 110 nM with respect to the  Plasmodium falciparum  strain K1. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 IC 50  values (nM) for the compounds of Examples 1-284: 
               
             
          
           
               
                   
                 Compound of 
                   
               
               
                   
                 Example No.: 
                 IC 50  (nM) on K1 
               
               
                   
                   
               
             
          
           
               
                   
                  1 
                 211 
               
               
                   
                  2 
                 466 
               
               
                   
                  3 
                 436 
               
               
                   
                  4 
                 323 
               
               
                   
                  5 
                 319 
               
               
                   
                  6 
                 54 
               
               
                   
                  7 
                 14 
               
               
                   
                  8 
                 381 
               
               
                   
                  9 
                 69 
               
               
                   
                  10 
                 176 
               
               
                   
                  11 
                 315 
               
               
                   
                  12 
                 220 
               
               
                   
                  13 
                 355 
               
               
                   
                  14 
                 226 
               
               
                   
                  15 
                 163 
               
               
                   
                  16 
                 115 
               
               
                   
                  17 
                 113 
               
               
                   
                  18 
                 273 
               
               
                   
                  19 
                 250 
               
               
                   
                  20 
                 116 
               
               
                   
                  21 
                 14 
               
               
                   
                  22 
                 60 
               
               
                   
                  23 
                 141 
               
               
                   
                  24 
                 103 
               
               
                   
                  25 
                 90 
               
               
                   
                  26 
                 465 
               
               
                   
                  27 
                 67 
               
               
                   
                  28 
                 81 
               
               
                   
                  29 
                 34 
               
               
                   
                  30 
                 34 
               
               
                   
                  31 
                 54 
               
               
                   
                  32 
                 298 
               
               
                   
                  33 
                 319 
               
               
                   
                  34 
                 433 
               
               
                   
                  35 
                 317 
               
               
                   
                  36 
                 173 
               
               
                   
                  37 
                 279 
               
               
                   
                  38 
                 417 
               
               
                   
                  39 
                 170 
               
               
                   
                  40 
                 490 
               
               
                   
                  41 
                 169 
               
               
                   
                  42 
                 104 
               
               
                   
                  43 
                 354 
               
               
                   
                  44 
                 14 
               
               
                   
                  45 
                 4 
               
               
                   
                  46 
                 1 
               
               
                   
                  47 
                 1 
               
               
                   
                  48 
                 8 
               
               
                   
                  49 
                 43 
               
               
                   
                  50 
                 13 
               
               
                   
                  51 
                 90 
               
               
                   
                  52 
                 92 
               
               
                   
                  53 
                 14 
               
               
                   
                  54 
                 17 
               
               
                   
                  55 
                 65 
               
               
                   
                  56 
                 58 
               
               
                   
                  57 
                 89 
               
               
                   
                  58 
                 50 
               
               
                   
                  59 
                 121 
               
               
                   
                  60 
                 48 
               
               
                   
                  61 
                 464 
               
               
                   
                  62 
                 138 
               
               
                   
                  63 
                 87 
               
               
                   
                  64 
                 180 
               
               
                   
                  65 
                 269 
               
               
                   
                  66 
                 494 
               
               
                   
                  67 
                 &lt;8 
               
               
                   
                  68 
                 156 
               
               
                   
                  69 
                 169 
               
               
                   
                  70 
                 144 
               
               
                   
                  71 
                 54 
               
               
                   
                  72 
                 344 
               
               
                   
                  73 
                 156 
               
               
                   
                  74 
                 40 
               
               
                   
                  75 
                 11 
               
               
                   
                  76 
                 163 
               
               
                   
                  77 
                 23 
               
               
                   
                  78 
                 47 
               
               
                   
                  79 
                 288 
               
               
                   
                  80 
                 44 
               
               
                   
                  81 
                 102 
               
               
                   
                  82 
                 99 
               
               
                   
                  83 
                 209 
               
               
                   
                  84 
                 27 
               
               
                   
                  85 
                 31 
               
               
                   
                  86 
                 27 
               
               
                   
                  87 
                 &lt;8 
               
               
                   
                  88 
                 45 
               
               
                   
                  89 
                 &lt;8 
               
               
                   
                  90 
                 43 
               
               
                   
                  91 
                 26 
               
               
                   
                  92 
                 23 
               
               
                   
                  93 
                 13 
               
               
                   
                  94 
                 15 
               
               
                   
                  95 
                 33 
               
               
                   
                  96 
                 20 
               
               
                   
                  97 
                 15 
               
               
                   
                  98 
                 98 
               
               
                   
                  99 
                 17 
               
               
                   
                 100 
                 12 
               
               
                   
                 101 
                 8 
               
               
                   
                 102 
                 6 
               
               
                   
                 103 
                 438 
               
               
                   
                 104 
                 45 
               
               
                   
                 105 
                 44 
               
               
                   
                 106 
                 470 
               
               
                   
                 107 
                 70 
               
               
                   
                 108 
                 225 
               
               
                   
                 109 
                 100 
               
               
                   
                 110 
                 324 
               
               
                   
                 111 
                 214 
               
               
                   
                 112 
                 153 
               
               
                   
                 113 
                 84 
               
               
                   
                 114 
                 107 
               
               
                   
                 115 
                 32 
               
               
                   
                 116 
                 &lt;8 
               
               
                   
                 117 
                 117 
               
               
                   
                 118 
                 104 
               
               
                   
                 119 
                 81 
               
               
                   
                 120 
                 285 
               
               
                   
                 121 
                 28 
               
               
                   
                 122 
                 156 
               
               
                   
                 123 
                 296 
               
               
                   
                 124 
                 110 
               
               
                   
                 125 
                 439 
               
               
                   
                 126 
                 160 
               
               
                   
                 127 
                 21 
               
               
                   
                 128 
                 94 
               
               
                   
                 129 
                 19 
               
               
                   
                 130 
                 &lt;8 
               
               
                   
                 131 
                 282 
               
               
                   
                 132 
                 28 
               
               
                   
                 133 
                 82 
               
               
                   
                 134 
                 33 
               
               
                   
                 135 
                 &lt;8 
               
               
                   
                 136 
                 74 
               
               
                   
                 137 
                 413 
               
               
                   
                 138 
                 340 
               
               
                   
                 139 
                 155 
               
               
                   
                 140 
                 191 
               
               
                   
                 141 
                 339 
               
               
                   
                 142 
                 460 
               
               
                   
                 143 
                 5 
               
               
                   
                 144 
                 24 
               
               
                   
                 145 
                 5 
               
               
                   
                 146 
                 9 
               
               
                   
                 147 
                 77 
               
               
                   
                 148 
                 65 
               
               
                   
                 149 
                 26 
               
               
                   
                 150 
                 319 
               
               
                   
                 151 
                 373 
               
               
                   
                 152 
                 242 
               
               
                   
                 153 
                 268 
               
               
                   
                 154 
                 420 
               
               
                   
                 155 
                 327 
               
               
                   
                 156 
                 382 
               
               
                   
                 157 
                 10 
               
               
                   
                 158 
                 24 
               
               
                   
                 159 
                 49 
               
               
                   
                 160 
                 93 
               
               
                   
                 161 
                 49 
               
               
                   
                 162 
                 45 
               
               
                   
                 163 
                 37 
               
               
                   
                 164 
                 247 
               
               
                   
                 165 
                 76 
               
               
                   
                 166 
                 96 
               
               
                   
                 167 
                 41 
               
               
                   
                 168 
                 349 
               
               
                   
                 169 
                 312 
               
               
                   
                 170 
                 192 
               
               
                   
                 171 
                 80 
               
               
                   
                 172 
                 89 
               
               
                   
                 173 
                 52 
               
               
                   
                 174 
                 430 
               
               
                   
                 175 
                 88 
               
               
                   
                 176 
                 51 
               
               
                   
                 177 
                 84 
               
               
                   
                 178 
                 10 
               
               
                   
                 179 
                 9 
               
               
                   
                 180 
                 38 
               
               
                   
                 181 
                 10 
               
               
                   
                 182 
                 18 
               
               
                   
                 183 
                 60 
               
               
                   
                 184 
                 13 
               
               
                   
                 185 
                 19 
               
               
                   
                 186 
                 58 
               
               
                   
                 187 
                 7 
               
               
                   
                 188 
                 53 
               
               
                   
                 189 
                 9 
               
               
                   
                 190 
                 7 
               
               
                   
                 191 
                 11 
               
               
                   
                 192 
                 19 
               
               
                   
                 193 
                 20 
               
               
                   
                 194 
                 89 
               
               
                   
                 195 
                 81 
               
               
                   
                 196 
                 16 
               
               
                   
                 197 
                 29 
               
               
                   
                 198 
                 65 
               
               
                   
                 199 
                 34 
               
               
                   
                 200 
                 11 
               
               
                   
                 201 
                 32 
               
               
                   
                 202 
                 14 
               
               
                   
                 203 
                 12 
               
               
                   
                 204 
                 9 
               
               
                   
                 205 
                 16 
               
               
                   
                 206 
                 81 
               
               
                   
                 207 
                 40 
               
               
                   
                 208 
                 57 
               
               
                   
                 209 
                 31 
               
               
                   
                 210 
                 28 
               
               
                   
                 211 
                 18 
               
               
                   
                 212 
                 20 
               
               
                   
                 213 
                 72 
               
               
                   
                 214 
                 23 
               
               
                   
                 215 
                 86 
               
               
                   
                 216 
                 94 
               
               
                   
                 217 
                 32 
               
               
                   
                 218 
                 40 
               
               
                   
                 219 
                 52 
               
               
                   
                 220 
                 29 
               
               
                   
                 221 
                 20 
               
               
                   
                 222 
                 13 
               
               
                   
                 223 
                 25 
               
               
                   
                 224 
                 29 
               
               
                   
                 225 
                 20 
               
               
                   
                 226 
                 75 
               
               
                   
                 227 
                 18 
               
               
                   
                 228 
                 9 
               
               
                   
                 229 
                 9 
               
               
                   
                 230 
                 10 
               
               
                   
                 231 
                 30 
               
               
                   
                 232 
                 33 
               
               
                   
                 233 
                 53 
               
               
                   
                 234 
                 64 
               
               
                   
                 235 
                 58 
               
               
                   
                 236 
                 68 
               
               
                   
                 237 
                 55 
               
               
                   
                 238 
                 27 
               
               
                   
                 239 
                 61 
               
               
                   
                 240 
                 28 
               
               
                   
                 241 
                 27 
               
               
                   
                 242 
                 14 
               
               
                   
                 243 
                 52 
               
               
                   
                 244 
                 19 
               
               
                   
                 245 
                 87 
               
               
                   
                 246 
                 64 
               
               
                   
                 247 
                 26 
               
               
                   
                 248 
                 21 
               
               
                   
                 249 
                 39 
               
               
                   
                 250 
                 27 
               
               
                   
                 251 
                 53 
               
               
                   
                 252 
                 80 
               
               
                   
                 253 
                 19 
               
               
                   
                 254 
                 76 
               
               
                   
                 255 
                 59 
               
               
                   
                 256 
                 39 
               
               
                   
                 257 
                 65 
               
               
                   
                 258 
                 43 
               
               
                   
                 259 
                 32 
               
               
                   
                 260 
                 14 
               
               
                   
                 261 
                 48 
               
               
                   
                 262 
                 17 
               
               
                   
                 263 
                 72 
               
               
                   
                 264 
                 39 
               
               
                   
                 265 
                 36 
               
               
                   
                 266 
                 58 
               
               
                   
                 267 
                 40 
               
               
                   
                 268 
                 80 
               
               
                   
                 269 
                 63 
               
               
                   
                 270 
                 25 
               
               
                   
                 271 
                 100 
               
               
                   
                 272 
                 80 
               
               
                   
                 273 
                 75 
               
               
                   
                 274 
                 63 
               
               
                   
                 275 
                 59 
               
               
                   
                 276 
                 65 
               
               
                   
                 277 
                 47 
               
               
                   
                 278 
                 137 
               
               
                   
                 279 
                 &lt;8 
               
               
                   
                 280 
                 219 
               
               
                   
                 281 
                 448 
               
               
                   
                 282 
                 35 
               
               
                   
                 283 
                 324 
               
               
                   
                 284 
                 362 
               
               
                   
                 Chloroquine 
                 194 
               
               
                   
                 Artemisinin 
                 3 
               
               
                   
                   
               
             
          
         
       
     
       In Vivo Antimalarial Efficacy Studies 
       [0404]    In vivo antimalarial activity is assessed for groups of three female NMRI mice (20-22 g) intravenously infected on day 0 with  P. berghei  strain GFP-ANKA (0.2 mL heparinized saline suspension containing 2×10 7  parasitized erythrocytes). In control mice, parasitaemia typically rise to approximately 40% by day 3 after infection, and control mice die between day 5 and day 7 after infection. For the mice treated with compounds, the compounds are either formulated in an aqueous-gelatine vehicle with 3 mg/mL compounds or in tween 80/ethanol (7%/3%) with 5 mg/mL. 
         [0405]    Compounds are administered intraperitonealy or subcoutaneously either as two consecutive twice-daily dosings (BID) (2×75 mg/kg BID, 24 and 48 hours after infection) or as four consecutive daily doses (4×10 mg/kg or 4×50 mg/kg, 3, 24, 48 and 72 hours after infection). With the double BID-dose regimen, 24 h after the last drug treatment, 1 μl tail blood is taken, resuspended in 1 mL PBS buffer and parasitemia determined with a FACScan (Becton Dickinson) by counting 100 000 red blood cells. Tail blood samples for the quadruple-dose regimen are processed on day 4 after infection. Activity is calculated as the difference between the mean value of the control and treated groups expressed as a percent relative to the control group. For parasetimias lower than 0.1%, the presence of parasites in the FACS gate is checked visually. The survival days of infected mice treated with compound is also recorded for each compound. Mice surviving for 30 days are checked for parasitemia and subsequently euthanised. A compound is considered curative if the animal survives to day 30 post-infection with no detectable parasites.