Abstract:
Derivatives of 2,5-piperazinedione of formula (I) are apoptotic peptidase activating factor 1 (Apaf-1) inhibitors, therefore they are useful as active pharmaceutical ingredients for the prophylaxis and/or treatment of a pathological and/or physiological condition associated with an increase of apoptosis.

Description:
[0001]    The present invention relates to compounds for the prophylaxis and/or treatment of disorders caused by apoptotic cell death or for the prevention of degenerative processes caused by apoptotic cell death. 
       STATE OF THE ART 
       [0002]    Apoptosis or programmed cell death is a complex physiological phenomenon involved in the maintenance of cell homeostasis. Apoptosis is regulated by various cell control mechanisms due to its key role in health maintenance. Many pathologies are based on apoptosis dysfunction. Therefore, an excess of apoptotic cell death can affect tissue functionality (e.g. cardiomyocyte death in the cases of myocardial infarction), whereas an excessively inhibited apoptosis entails uncontrolled cell survival (e.g. neoplastic processes). The cell components regulating apoptosis are in constant dynamic equilibrium in a healthy cell. There are at least two well characterized activation pathways for the apoptotic caspase cascade. One of them, the extrinsic pathway, is activated by extracellular signaling and requires the participation of specific membrane receptors. The intrinsic pathway corresponds to cellular stress, toxic agents, radiation, oxidizing agents, Ca 2+  overloading, DNA injury; it is activated in response to oncogenes and involves mitochondrial destabilization. In some pathophysiological conditions (for example, anoxia in cells of organs to be transplanted, treatment with toxic substances), apoptosis increases and an excessive number of cells die, crippling the functionality of the affected tissue and compromising its survival in some cases. 
         [0003]    The molecular apoptosis induction mechanisms entail the activation of proteins with protease activity called caspases which are also known as effectors of apoptosis. The formation of a molecular complex called apoptosome is necessary to enable activating the caspases. Apoptosome is formed by cytochrome c, pro-caspase-9 and the apoptotic peptidase activating factor 1 (Apaf-1). It has been demonstrated that Apaf-1 inhibition inhibits the formation of the apoptosome complex and that it causes an apoptosis inhibition (measured through caspase 3 activation). In cell assays in which apoptosis is induced by means of hypoxia (reducing the air oxygen concentration) or by means of chemical compounds, an increase of cell survival has been observed when the latter have been previously treated with apoptosis inhibitors. 
         [0004]    Likewise, during the process of removing and transplanting an organ, its cells are subjected to a hypoxia condition which can lead to cell death compromising the organ viability and functionality. Therefore, for example, only 70% of all the corneas donated for transplant are suitable to be implanted. This is due to the fact that apoptotic cell death occurs during cornea storage. A similar situation occurs during kidney and heart transplants. There are solutions on the market for transporting organs exclusively providing buffered and sterile environments but they do not contain any active molecule which prevents apoptotic cell death. 
         [0005]    The study of the mechanisms involved in apoptosis has allowed identifying different potential pharmacological targets. Therefore, inhibitors acting at different levels of the apoptotic cascade such as transcription factors, kinases, regulators of mitochondrial membrane permeabilization and inhibitors of the caspase family have been designed. 
         [0006]    Since the formation of apoptosome is a key step in the apoptotic cascade and the subsequent activation of the caspases, the inhibition of Apaf-1 activation can have a greater impact on apoptosis inhibition than other pharmacological targets studied. There are indications in the scientific literature about the therapeutic implications of Apaf-1 inhibition. Therefore the transduction of an Apaf-1 dominant negative by means of an adenovirus in an animal model of Parkinson&#39;s was more effective than the transduction of a caspase-1 dominant negative by means of an adenovirus. 
         [0007]    Document WO2007060524 describes derivative compounds of [1,4]diazepan-2,5-dione of the following formula as apoptosis inhibitors. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0008]    Document WO2008009758 describes the compounds of the following formula as UBC13-UEV interaction inhibitors which can be used in the preparation of pharmaceutical compositions for anti-tumor therapy or for the treatment and/or prophylaxis of diseases associated with metabolic pathways involving the enzyme UBC13, metabolic pathways involving transcription factor NF-kB, or pathways involving PCNA or RAD6. Although they can be considered as structurally similar to those of the present invention, they have a different use. 
         [0000]      R—(CR 1 R 2 ) q —CO—N(R 3 )—C(R 4 R 5 )—CO—NH 2  
 
         [0009]    It is therefore desirable to provide new Apaf-1 inhibitor compounds. 
     
    
     DESCRIPTION OF THE INVENTION 
       [0010]    The present invention provides new derivative compounds of 2,5-piperazinedione of formula (I) having APAF-1 inhibiting activity. 
         [0011]    Therefore, a first aspect of the invention relates to compounds of formula (I) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    and pharmaceutically acceptable salts thereof, wherein:
 
R1 and R2 are independently selected from —H, —C 1-5  alkyl, —C 2-5  alkenyl, —(CH 2 ) 0-3 -cycloalkyl, —(CH 2 ) 1-3 -heterocycle, —(CH 2 ) 0-3 -aryl, —(CH 2 ) 0-3 -heteroaryl, —(CH 2 ) 1-2 —CH(aryl) 2 , —(CH 2 ) 1-2 —CH(aryl)(heteroaryl) and —(CH 2 ) 1-2 —CH(heteroaryl) 2 ,
 
R3 is selected from —H, —C 1-5  alkyl, —C 2-5  alkenyl, —(CH 2 ) 0-3 -cycloalkyl, —(CH 2 ) 1-3 -heterocycle, —(CH 2 ) 1-3 -aryl, —(CH 2 ) 1-3 -heteroaryl, —(CH 2 ) 1-3 —CONR5R6, —(CH 2 ) 1-2 —CH(aryl) 2 , —(CH 2 ) 1-2 —CH(aryl)(heteroaryl) and —(CH 2 ) 1-2 —CH(heteroaryl) 2 ,
 
R4 is selected from —H, —C 1-5  alkyl, —(CHR7) 1-3 -CO—NR5R6, —(CHR7) 1-3 -CO—OR5, —(CH 2 ) 1-3 —NR5R6, —(CH 2 ) 1-3 —CO[NCHR7CO] m NH 2  and —(CH 2 ) 1-3 —CO[NCHR7CO] m OR5,
 
n is an integer selected from 1 and 2;
 
m is an integer selected from 1, 2 and 3;
 
R5 and R6 are independently selected from —H, —C 1-5  alkyl and —(CH 2 ) 0-3 -aryl,
 
R7 is selected from —H, —C 1-5  alkyl, —(CH 2 ) 1-3 -aryl and —(CH 2 ) 1-3 -heteroaryl, such that when m is greater than 1 the R7 substituents can be equal to or different from one another,
 
wherein the C 1-5  alkyl, C 2-5  alkenyl, cycloalkyl and heterocycle groups can be optionally substituted with one or several substituents selected independently from halogen, OR5, OCF 3 , SH, SR5, NR5R6, NHCOR5; COOH, COORS, OCOR5, aryl and heteroaryl,
 
wherein the aryl and heteroaryl groups can be optionally substituted with one or several substituents selected independently from halogen, CF3, OR5, OCF 3 , SH, SR5, NH 2 , NHCOR5; NO 2 , CN, COR5, COOR5, OCOR5, CONR5R6, —(CH 2 ) 0-3 NR5R6, SO 2 NH 2 , NHSO 2 CH 3 , C 1-5  alkyl, aryl and heteroaryl,
 
wherein the heterocycle and heteroaryl groups can be optionally substituted on a secondary nitrogen atom with
 
C 1-5  alkyl, cycloalkyl or —(CH 2 ) 0-3 -aryl,
 
on the condition that when R2 is 2-(4-fluorophenyl)ethyl, R4 is —CH 2 —CO—NH 2  and n is 1, then:
       if R1 is 2-(4-fluorophenyl)ethyl, R3 is not 2-(4-methoxyphenyl)ethyl, 2-(2-pyridyl)ethyl or 2-(2,4-dichlorophenyl)ethyl, and   if R1 is 2-(2,4-dichlorophenyl)ethyl, R3 is not 2-(4-methoxyphenyl)ethyl or 2-(2-pyridyl)ethyl.       
 
         [0014]    In a particular embodiment of the invention, R1 is —C 1-5  alkyl or —(CH 2 ) 0-3 -aryl. 
         [0015]    In another particular embodiment of the invention, R2 is —C 1-5  alkyl, —(CH 2 ) 0-3 -aryl, —(CH 2 ) 0-3 -heteroaryl or —(CH 2 ) 1-2 —CH(aryl) 2 . 
         [0016]    In another particular embodiment of the invention, R3 is —H, —C 1-5  alkyl, —(CH 2 ) 1-3 -heterocycle, —(CH 2 ) 1-3 -aryl or —(CH 2 ) 1-3 -heteroaryl. 
         [0017]    In another particular embodiment of the invention, R4 is —H, —(CHR7) 1-3 -CO—NR5R6, —(CHR7) 1-3 -CO—OR5 or —(CH 2 ) 1-3 —CO[NCHR7CO] m NH 2 . 
         [0018]    In another particular embodiment of the invention, n is 1. 
         [0019]    In another particular embodiment of the invention, m is 1. 
         [0020]    In another particular embodiment of the invention, R5 is —H or —C 1-5  alkyl. 
         [0021]    In another particular embodiment of the invention, R6 is —H. 
         [0022]    In another particular embodiment of the invention, R7 is —H, —C 1-5  alkyl, —(CH 2 ) 1-3 -aryl or —(CH 2 ) 1-3 -heteroaryl. 
         [0023]    A second aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof for use as an active pharmaceutical ingredient, particularly for use in the prophylaxis and/or treatment of a pathological and/or physiological condition associated with an increase of apoptosis, wherein the pathological and/or physiological condition associated with an increase of apoptosis is selected from organ or cell preservation, particularly transplant or conservation; cytotoxicity prevention, particularly cytotoxicity mediated by chemicals, by physical agents such as radiation, acoustic trauma, burns, or by biological agents such as hepatitis virus infection; pathologies due to hypoxia conditions, such as heart attack or cerebral infarction; eye pathologies, such as injuries caused by eye surgery, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa or glaucoma; neurodegenerative diseases, such as Alzheimer&#39;s, Huntington&#39;s, Parkinson&#39;s or amyotrophic multiple sclerosis; diabetes, particularly preservation of islets of Langerhans or diabetes-associated cytotoxicity such as, for example, nephrotoxicity; osteoarthritis; arthritis; inflammation or immunodeficiencies, such as AIDS-associated CD4 +  T lymphocyte depletion. 
         [0024]    Another aspect of the present invention relates to the use of a compound of formula (I) or of a pharmaceutically acceptable salt thereof for the manufacture of a medicament intended for the prophylaxis and/or treatment of a pathological and/or physiological condition associated with an increase of apoptosis, particularly one of the aforementioned conditions. 
         [0025]    Another aspect of the present invention relates to a method of prophylaxis and/or treatment of an individual or organ suffering or susceptible to suffering a pathological and/or physiological condition associated with an increase of apoptosis, particularly one of the aforementioned conditions, comprising the administration of a therapeutically effective amount of a compound of formula (I) or of a pharmaceutically acceptable salt thereof to said individual or organ together with sufficient amounts of pharmaceutically acceptable excipients. 
         [0026]    The compounds of formula (I) and the pharmaceutically acceptable salts thereof, particularly the compounds of formula (I) described as examples or as intermediates are preferred. 
         [0027]    The compounds of the present invention can be used alone or in combination with one or more compounds which are useful for the prophylaxis and/or treatment of a pathological and/or physiological condition associated with an increase of apoptosis, such as organ or cell preservation, particularly transplant or conservation; cytotoxicity prevention, particularly cytotoxicity mediated by chemicals, by physical agents such as radiation, acoustic trauma, burns, or by biological agents such as hepatitis virus infection; pathologies due to hypoxia conditions, such as heart attack or cerebral infarction; eye pathologies, such as injuries caused by eye surgery, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa or glaucoma; neurodegenerative diseases, such as Alzheimer&#39;s, Huntington&#39;s, Parkinson&#39;s or amyotrophic multiple sclerosis; diabetes, particularly preservation of islets of Langerhans or diabetes-associated cytotoxicity such as, for example, nephrotoxicity; osteoarthritis; arthritis; inflammation or immunodeficiencies, such as AIDS-associated CD4 +  T lymphocyte depletion. 
         [0028]    The term “C 1-5  alkyl”, alone or in combination, means a linear- or branched-chain alkyl group having 1 to 5 carbon atoms. 
         [0029]    The term “C 2-5  alkenyl”, alone or in combination, means a linear- or branched-chain group having 2 to 5 carbon atoms and having one or more unsaturated bonds. 
         [0030]    The term “cycloalkyl”, alone or in combination, refers to a stable monocyclic radical of 3 to 7 members, which is saturated or partially saturated, and which only consists of carbon and hydrogen atoms. Examples of cycloalkyl are the following: cyclopropyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, cycloheptyl. 
         [0031]    The term “heterocycle”, alone or in combination, means a saturated or partially unsaturated heterocycle of 5 to 10 links, containing one or several heteroatoms chosen from nitrogen, oxygen and sulfur. For the purposes of this invention, the heterocycle can be a monocyclic or bicyclic ring system which can include condensed ring systems. Examples of heterocycle groups are tetrahydrofuranyl (THF), dihydrofuranyl, dioxanyl, morpholyl, piperazinyl, piperidinyl, 1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolidyl, pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, and the like. 
         [0032]    The term “aryl”, alone or in combination, refers to a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic aromatic ring systems of 5-10 members, such as phenyl or naphthyl having optionally one or several substituents, preferably from one to three selected independently from halogen, CF3, OH, ORS, OCF 3 , SH, SRS, NH 2 , NHCOR5; NO 2 , CN, COR5, COOR5, OCOR5, CONR5R6, —(CH 2 ) 0-3 NR 5 R 6 , SO 2 NH 2 , NHSO 2 CH3, C 1-5  alkyl, aryl and heteroaryl. 
         [0033]    The term “heteroaryl”, alone or in combination, refers to an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S and N. Heteroaryls thus includes heteroaryls condensed to other classes of rings, such as aryls, cycloalkyls and heterocycles which are not aromatic. Examples of heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, furyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, quinazolinyl, naphthyridinyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, benzothiophenyl, tetrahydrobenzothiophenyl and the like. 
         [0034]    The expression “optionally substituted with one or several substituents” means that a group can be unsubstituted or substituted with one or several substituents, preferably with 1, 2, 3 or 4 substituents, provided that said group has 1, 2, 3 or 4 positions susceptible to be substituted. 
         [0035]    The term “pharmaceutically acceptable salts” means those salts which conserve the efficiency and the biological properties of the free bases or free acids and which do not cause discomfort in a biological sense or in any other sense. 
         [0036]    According to the invention, the compounds of formula (I) and their pharmaceutically acceptable salts are useful for the prophylaxis and/or treatment of a pathological and/or physiological condition associated with an increase of apoptosis by means of their APAF-1 inhibiting activity. 
         [0037]    Unless defined otherwise, all the technical and scientific terms used herein have the same meaning as those commonly understood by a person skilled in the field of the invention. Methods and materials which are similar or equivalent to those described herein can be used in practicing the present invention. Throughout the description and claims the word “comprises” and its variants do not aim to exclude other technical features, additives, components, steps or stereoisomers of the compounds involved. For the persons skilled in the art, other objects, advantages and features of the invention will be inferred partially from the description and partially from practicing the invention. 
         [0038]    The compounds of formula (I) can be prepared following different methods known by any person skilled in the field of organic synthesis, particularly through the general processes shown in the following schemes. The starting materials for the preparative methods are commercially available or they can be prepared by means of methods of the literature. Unless indicated otherwise, the meaning of groups R1, R2, R3, R4, R5, R6 and R7 are those described in the general formula (I). 
         [0039]    The compounds of formula (I) can be obtained from the methods and schemes described below: 
       Method A 
       [0040]    
       
                 
         
             
             
         
       
     
         [0041]    According to Method A, once the fluorenemethyloxycarbonyl group is deprotected, the amine II bound to the solid support is acylated with an acylating agent III, wherein X represents a leaving group, for example a halogen and Y represents OH or halogen. When Y represents a halogen, for example chloroacetyl chloride, the reaction can be performed in the presence of a base such as triethylamine. When Y represents —OH, for example bromoacetic acid, the reaction can be carried out in the presence of a suitable coupling agent, for example N,N′-diisopropylcarbodiimide. In both cases the reaction can be performed in an inert solvent which is capable of swelling the resin, such as N,N-dimethylformamide or methylene chloride and at room temperature or under microwave irradiation to minimize the reaction time. Then, the amine IVa is coupled using a tertiary amine as a base. The reaction can be carried out at room temperature or under microwave irradiation. 
         [0042]    A carboxylic acid VI, wherein PG represents a protecting group, such as allyl, is reacted with the amine V to obtain the amide VII, using a coupling agent, such as for example the combination of N,N′-diisopropylcarbodiimide and 1-hydroxybenzotriazole. An amine IVb is then added, by means of Michael reaction using a base and a solvent, such as N,N-dimethylformamide or dimethyl sulfoxide to obtain the intermediate VIII after cleavage from the resin using a mixture of trifluoroacetic acid, dichloromethane and water. The intermediate VIII is cyclized (intermediate IX) and deprotected in basic medium yielding the intermediate acid X. 
         [0043]    The intermediate X can alternatively be prepared in the solid phase according to scheme 2, wherein the amine V′ can be prepared from the amine IVa either by means of a reductive amination reaction with a glyoxylate in THF-AcOH using a reducing agent such as NaBH 3 CN, or alternatively by means of alkylation with a bromoacetate or a bromoacetamide using a tertiary amine as a base. Subsequently, it is coupled to the acid VI to obtain the amide VII′. An amine IVb is then added and by means of Michael reaction and subsequent in situ cyclization produces the intermediate ester IX which through basic treatment yields compound X. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0044]    A compound of formula Ia can be obtained from the intermediate X by coupling with an amine bound to a solid support Va or Va′, obtained according to the methodology indicated above, in the presence of a coupling agent such as, for example, the combination of HATU and HOBT. The compound of formula Ib can be obtained in the manner similar to the synthesis of compound Ia, except in the case of solid phase in which the starting solid support (IIb) has a halogen group instead of an amino group, such as for example, the chlorotrityl resin, obtaining an acid after cleavage from the resin. The ester Ic can be synthesized by esterification of the corresponding acid Ib by means of common esterification methods in organic synthesis, such as for example, using methanol in an acid medium such as sulfuric acid. In the case of Ib, it can be obtained by means of saponifying the ester Ic. The compounds of formula Id can be obtained by reacting the intermediate X with a primary amine IVc. 
         [0045]    An alternative strategy for obtaining the compounds of formula I can be carried out by means of acylating the amine II with an amino acid of formula XI (Method B). 
       Method B 
       [0046]    
       
                 
         
             
             
         
       
     
         [0047]    As is obvious for a person skilled in the field of the invention, it is possible to combine some of the steps of method A with some of the steps of method B to obtain a compound of formula I. 
         [0048]    Alternatively, it is possible to obtain the compounds of formula Ie and If as shown in the scheme described below. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0049]    The peptide XIII and the pseudopeptide XIV which will be bound to the acid X can be obtained by means of standard peptide synthesis reactions. Therefore, the amine IIa (Z═NH 2 ) or chloride IIb (Z═Cl) resin can be reacted with a suitably protected amino acid (XII), using a suitable coupling agent. Optionally the process can sequentially be repeated, previously deprotecting the amine, to obtain the peptide XIII. The carboxylic acid X then reacts with XIII to obtain the compound Ie. 
         [0000]    By combining the amino acid units (XIII) with a glycine unit (following method A or B), the pseudopeptide XIV is obtained, which will lead to obtaining If in the manner similar to that described above. 
         [0050]    The primary amines used IVa, IVb and IVc are commercially available or can be obtained by means of known methods (March, Advanced Organic Chemistry, 1991, Ed. John Wiley &amp; Sons) or by using, for example, the schemes described below. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0051]    An amine can be obtained by Mitsunobu reaction starting from alcohol and potassium phthalimide in the presence of, for example, diethyl azodicarboxylate (DEAD) and triphenylphosphine in tetrahydrofuran as solvent and the subsequent release with hydrazine hydrate. (Mitsunobu,  J. Am. Chem. Soc.  1972, 94, 679-680) 
         [0052]    The N-substituted glycines V and XI can be synthesized by means of some of the methods shown below, such as for example, reductive amination of the corresponding glycine with a suitable aldehyde (Scheme 5) using reducing agents such as NaBH 4 , NaBH 3 CN or NaBH(AcO) 3  or by the nucleophilic substitution of an ester with an amine R—NH 2  (Scheme 6). 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
       EXAMPLES 
     Abbreviations 
       [0000]    
       
         AcOEt Ethyl acetate 
         Brine Saturated NaCl solution 
         DCM Dichloromethane 
         DIC N,N′-diisopropylcarbodiimide 
         DIPEA N,N-diisopropylethylamine 
         DMF N,N-dimethylformamide 
         DMSO Dimethyl sulfoxide 
         EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 
         Eq. Molar equivalent 
         Et 3 N Triethylamine 
         Fmoc 9-fluorenylmethoxycarbonyl 
         IPA Isopropyl alcohol 
         HATU 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate 
         HOBT 1-hydroxybenzotriazole 
         HPLC High performance liquid chromatography 
         HRMS High resolution mass spectrometry 
         MeOH Methanol 
         PyBOP Benzotriazol-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate 
         RP Reverse phase 
         rt Room temperature 
         tr Retention time 
         UV Ultraviolet 
         TFA Trifluoroacetic acid 
       
     
         [0076]    The following examples serve to better illustrate the invention but they must not be considered as limiting the same. 
         [0077]    The nomenclature used in the present document is based on the CFW_CHEMICAL_NAME function in Chemdraw for Excel version 12. 
       General Data: 
       [0078]    The compounds were synthesized using a polystyrene AM RAM resin acquired from Rapp Polymere GmbH (Germany). In the reactions polystyrene syringes with a polyethylene disc were used using an HS501 digital IKA Labortechnik stirrer. In the reactions carried out by microwaves, a CEM Discover model with 10 ml glass reactors was used. 
         [0000]    The products were analyzed by:
       Method A: By means of an RP-HPLC using a Hewlett Packard Series 1100 (UV detector 1315A) equipment using an X-Terra C18 (15×0.46 cm, 5 μm) reverse phase column. The wavelength used for the UV detection was 210 nm. Mixtures of CH 3 CN—H 2 O with 0.1% TFA at 1 ml/min were used as mobile phase. The analyses were conducted with a gradient from 20% to 70% of CH 3 CN (10 min), and from 70% to 100% (8 min).   Method B: The products were analyzed using an Agilent 1100 HPLC equipment, provided with a UV detector of variable wavelength and a mass spectrometer model 1100 VL. The wavelength used for the UV detection was 210 nm, whereas the MS detector has been operated in positive electrospray ionization mode and a 100 to 1300 m/z scan has been performed. Concerning chromatographic separation, the column used was a Kromasil 100 C18 (4.0×40 mm, 3.5 μm) set at 50° C., and 5 μl have been injected. For the elution one of the two solvent gradients described below was followed: 5-100% B in 7 min, 5% B 7-8.5 min. The flow rate of the mobile phase is 1.4 ml/min. Solvent A consists of 0.2% formic acid in water, whereas B is 0.2% formic acid in acetonitrile.   Method C: using Waters HPLC-UV-MS equipment provided with a detector having diodes in series and a mass spectrometer model EMD1000. The wavelength used for UV detection was 210 nm, whereas the MS detector has been operated in a positive electrospray ionization mode and a 100 to 1000 m/z scan has been performed. Concerning chromatographic separation, the column used was a Kromasil C18 (2.1×50 mm, 3.5 μm) set at 50° C. and 2 μl have been injected. For the elution, the following gradient was followed: 5-100% B, 0-5 min, 100% B, 5-6.5 min, 5% B, 6.5-8 min. The flow rate of the mobile phase is 0.5 ml/min.       
 
         [0082]    The high resolution mass spectrometry was carried out by HPLC-HRMS using a Waters Acquity HPLC equipment coupled to a Waters orthogonal acceleration time of flight mass spectrometer model LCT Premier XE. The chromatographic analysis was conducted by means of a Waters Acquity C18 column (10×2.1 mm, 1.7 μm). 
         [0083]    Mixtures of CH 3 CN—H 2 O with 20 mM formic acid at 0.3 ml/min were used as the mobile phase. The analyses were conducted with a gradient from 50% to 100% of CH 3 CN in 6 min. 
       Intermediate VI 
     VI: (Z)-2-butenedioic acid allyl ester 
       [0084]    1.8 ml allyl alcohol (26 mmol, 1.3 eq.) were added to a 2 g solution of maleic anhydride (20 mmol) in chloroform. The reaction mixture was stirred at reflux for 5 h. The resulting solution was treated with 1N HCl and was extracted with chloroform. The organic extracts were washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate and filtered. The solvent was evaporated at reduced pressure, and the residue obtained was identified as intermediate VI in the form of an oil (95% purity, 85% yield). 
       Intermediates X 
     X.1: 2-(4-(2,4-dichlorophenethyl)-1-(3,3-diphenylpropyl)-3,6-dioxopiperazin-2-yl)acetic acid 
       [0085]    
       
                 
         
             
             
         
       
     
         [0086]    A mixture of 2 g of Fmoc-Rink Amide AM polystyrene resin (0.61 mmol/g resin, 1.22 mmol) and 12 ml of 20% piperidine in DMF was stirred in a microwave reactor for 2 min at 35° C. The resin was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). The resin was treated with a solution of bromoacetic acid (III, 840 mg, 5 eq.) and N,N′-diisopropylcarbodiimide (1.15 ml, 5 eq.) in DMF (12 ml). The reaction mixture was stirred for 2 min at 60° C. in a microwave reactor. The resin was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). A solution of 2,4-dichlorophenethylamine (IVa, 1.035 ml, 5 eq.) and triethylamine (0.85 ml, 5 eq.) in 12 ml of DMF was added to the resin and the suspension was stirred for 2 min at 90° C. activated by microwaves. The supernatant was removed and the reaction was repeated in the same conditions. The resin V obtained was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). Then, the resin was treated with a solution of (Z)-2-butenedioic acid allyl ester (VI, 957 mg, 5 eq.), HOBT (825 mg, 5 eq.) and DIC (770 μL, 5 eq.) in DCM:DMF (2:1, 123 ml). The reaction mixture was stirred at room temperature for 30 min and was filtered. The resin was dried and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). Then, a solution of 3,3-diphenylpropylamine (IVb, 1.29 g, 5 eq.) and triethylamine (0.85 ml, 5 eq.) in 12 ml of DMF was added to the resin and the suspension was stirred for 3 h at room temperature. The resin was filtered and the reaction was repeated for 16 h at the same temperature. The supernatant was removed and the resin was dried and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). Cleavage from the solid phase was performed by treatment with a 60:40:2 TFA/DCM/water mixture (20 ml) for 30 min at room temperature. The reaction mixture was filtered and the solvents were evaporated at reduced pressure. Cyclization was then performed by treating the residue obtained with 20 ml of dioxane for 1.5 h at reflux (monitoring the reaction by HPLC). A 1:2 solution (9 ml) of 4N sodium hydroxide and allyl alcohol was then added and the mixture was stirred for 45 min at reflux. The crude reaction product was acidified with 1N hydrochloric acid and the solvent was evaporated. The resulting solution was extracted with ethyl acetate (3×50 ml) and the organic extracts were washed with a saturated NaCl solution (2×100 ml); they were dried on anhydrous MgSO4 and were evaporated at reduced pressure to obtain 450 mg of the desired product (X, 70% purity, 95% yield at 210 nm). HRMS (M+H) +  calculated for C 29 H 29 Cl 2 N 2 O 4 , 539.1504, experimental, 539.1514. 
         [0087]    The following compounds were prepared by following a method similar to that described in the example above but by using different amines: 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 HRMS (M + H) + : 
               
             
          
           
               
                 Ex. 
                 Structure 
                 Compound 
                 Calculated 
                 Experim. 
               
               
                   
               
               
                 X.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophenethyl)- 1-(4-fluorobenzyl)-3,6- dioxopiperazin-2-yl)acetic acid 
                 C 21 H 19 Cl 2 FN 2 O 4  453.0784 
                 453.0782 
               
               
                   
               
               
                 X.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 4-(2,4-dichlorophenethyl)-2- (1-(2-(1H-indol-3-yl)ethyl)- 3,6-dioxopiperazin-2-yl) acetic acid 
                 C 24 H 23 Cl 2 N 3 O 4  488.1144 
                 488.1131 
               
               
                   
               
               
                 X.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophenethyl)- 3,6-dioxo-1-(2-(thiophen-2- yl)ethyl)piperazin-2-yl) acetic acid 
                 C 20 H 20 Cl 2 N 2 O 4 S 455.0599 
                 455.0594 
               
               
                   
               
               
                 X.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophenethyl)- 1-(2-(5-methoxy-1H-indol-3- yl)ethyl)-3,6-dioxopiperazin- 2-yl) acetic acid 
                 C 25 H 25 Cl 2 N 3 O 5  518.1250 
                 518.1270 
               
               
                   
               
               
                 X.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(1-(2-([1,1′-biphenyl]-4- yl)ethyl)-4-(2,4- dichlorophenethyl)-3,6- dioxopiperazin-2-yl) acetic acid 
                 C 28 H 26 Cl 2 N 2 O 4  515.1348 
                 525.1348 
               
               
                   
               
               
                 X.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophenethyl)- 3,6-dioxo-1-(4- (trifluoromethyl)benzyl)pipera zin-2-yl) acetic acid 
                 C 22 H 19 Cl 2 F 3 N 2 O 4  503.0752 
                 503.0757 
               
               
                   
               
             
          
         
       
     
       X.13:2-(4-(2,4-dichlorophenethyl)-3,6-dioxo-1-(4-(trifluoromethyl)benzyl)piperazin-2-yl)acetic acid 
       [0088]    
       
                 
         
             
             
         
       
     
       Step 1 Intermediate V′ 
       [0089]    7.55 mL of Et 3 N and 2.50 g (27 mmol) of bromoacetamide were added to a solution of 5 g (41 mmol) of 2-(2-pyridyeethylamine in 300 mL of dioxane. The resulting mixture is heated to reflux overnight. The solution is evaporated to dryness and purified in silica gel using a mixture of AcOEt:MeOH:NH 3  (10:1:0.01) as eluent, yielding 2.39 g of the intermediate V′. Method B: tr: 0.261, m/z: 180. 
       Step 2: Intermediate VII′ 
       [0090]    4.90 mL of Et 3 N, 3.24 g (24 mmol) of HOBT, 4.60 g (24 mmol) of EDC and the product of step 1 are added to a solution consisting of 2.31 g (16.0 mmol) of maleic acid monoethyl ester in 100 mL of DMF. The suspension formed is kept under stirring at rt for 18 h. It is then treated with water and AcOEt is added, the organic phase is separated and the aqueous phase is extracted one more time with AcOEt. The organic phases are pooled and are successively washed with saturated NaHCO 3  solution and brine. It is subsequently dried on anhydrous Na 2 SO 4 , the solvent is filtered and evaporated at reduced pressure. 1.5 g of the compound identified as example VII′.13 are obtained. Method B: tr: 1.094, m/z: 306. 
       Step 3: Intermediate IX 
       [0091]    0.8 mL (5.89 mmol) of Et 3 N and 1.5 g of the intermediate VII′.13 (4.91 mmol) were added to a solution of 2-thiophenylethylamine (0.63 mL, 5.4 mmol) in 40 mL of dioxane and the resulting solution was stirred for 18 h at reflux. The solution was evaporated to dryness and was purified by means of silica gel column chromatography, using a (10:1:0.01) mixture of AcOEt:MeOH:NH 3  as eluent, yielding 510 mg of an oil identified as intermediate IX.13 ethyl (2-(3,6-dioxo-4-(2-(pyridin-2-yeethyl)-1-(2-(thiophen-2-yeethyl)piperazin-2-yeacetate). Method A: tr: 2.289, m/z: 416. 
         [0092]    The following intermediates were prepared in the manner similar to intermediate IX.13: 
         [0000]    
       
         
               
               
               
               
               
               
             
           
               
                   
               
               
                 Int. 
                 structure 
                 name 
                 method 
                 tr 
                 m/z 
               
               
                   
               
             
             
               
                 IX.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(1-(2-(1H-indol-3- yl)ethyl)-4-(2,4- dichlorophenethyl)-3,6- dioxopiperazin-2-yl)acetate 
                 B 
                 4.100 
                 516 518 
               
               
                   
               
               
                 IX.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Methyl 2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetate 
                 B 
                 3.984 
                 469 471 
               
               
                   
               
               
                 IX.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Allyl 2-(4-(4- chlorophenethyl)-3,6- dioxo-1-(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetate 
                 B 
                 4.019 
                 461 463 
               
               
                   
               
               
                 IX.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Allyl 2-(4-(4- methoxyphenethyl)-3,6- dioxo-1-(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetate 
                 B 
                 3.734 
                 457 
               
               
                   
               
               
                 IX.10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(4-(2,4- dichlorophenethyl)-1-(2- methoxyethyl)-3,6- dioxopiperazin-2-yl)acetate 
                 B 
                 3.637 
                 431 433 
               
               
                   
               
               
                 IX.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(4-(2,4- dichlorophenethyl)-1-(3- morpholinopropyl)-3,6- dioxopiperazin-2-yl)acetate 
                 B 
                 2.737 
                 500 502 
               
               
                   
               
               
                 IX.12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(1-(3-(1H- imidazol-1-yl)propyl)-4- (2,4-dichlorophenethyl)- 3,6-dioxopiperazin-2- yl)acetate 
                 B 
                 2.739 
                 482 484 
               
               
                   
               
               
                 IX.14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(3,6-dioxo-4- phenethyl-1-(2-(thiophen- 2-yl)ethyl)piperazin-2- yl)acetate 
                 B 
                 3.665 
                 415 
               
               
                   
               
               
                 IX.15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(4-(2- methoxyethyl)-3,6-dioxo-1- (2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetate 
                 B 
                 2.858 
                 369 
               
               
                   
               
               
                 IX.16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(3,6-dioxo-1,4- bis(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetate 
                 B 
                 3.560 
                 421 
               
               
                   
               
               
                 IX.17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(4-benzyl-3,6- dioxo-1-(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetate 
                 B 
                 3.538 
                 401 
               
               
                   
               
               
                 IX.18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(4-(4- chlorobenzyl)-3,6-dioxo-1- (2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetate 
                 B 
                 4.358 
                 435 
               
               
                   
               
               
                 IX.19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(prop-2-yn-1- yl)piperazin-2-yl)acetate 
                 C 
                 4.233 
                 411 
               
               
                   
               
               
                 IX.22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(pyridin-4- ylmethyl)piperazin-2- yl)acetate 
                 C 
                 3.412 
                 464 
               
               
                   
               
             
          
         
       
     
       Step 4: intermediate X 
       [0093]    1.6 mL of a solution of 1N LiOH were added to a solution of 550 mg (1.32 mmol) of intermediate IX.13 in 15 mL of a MeOH:THF mixture (1:3), and it was left to stir at rt the overnight. It is then diluted in AcOEt and washed with water, the aqueous phase is acidified with a 1N HCl solution until pH=7 and is extracted with AcOEt. Finally, the organic phases are pooled, dried on anhydrous Na 2 SO 4 , filtered and the solvent is evaporated at reduced pressure. 330 mg of a colorless oil identified as intermediate X.13 are obtained. 
       Method B: tr: 1.768, m/z: 388 
       [0094]    The following intermediates were prepared in the manner similar to intermediate X.13: 
         [0000]    
       
         
               
               
               
               
               
               
             
           
               
                   
               
               
                 Int. 
                 structure 
                 name 
                 method 
                 tr 
                 m/z 
               
               
                   
               
             
             
               
                 X.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(4- chlorophenethyl)-3,6- dioxo-1-1(2-(thiophen- 2-yl)ethyl)piperazin-2- yl) acetic acid 
                 B 
                 3.314 
                 4214 23 
               
               
                   
               
               
                 X.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(4- methoxyphenethyl)- 3,6-dioxo-1-(2- (thiophen-2- yl)ethyl)piperazin-2-yl) acetic acid 
                 B 
                 3.007 
                 417 
               
               
                   
               
               
                 X.10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4- dichlorophenethyl)-1- (2-methoxyethyl)-3,6- dioxpiperazin-2-yl) acetic acid 
                 B 
                 2.979 
                 403 405 
               
               
                   
               
               
                 X.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4- dichlorophenethyl)-1- (3-morpholinopropyl)- 3,6-dioxopiperazin-2- yl) acetic acid 
                 B 
                 2.359 
                 472 474 
               
               
                   
               
               
                 X.12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(1-(3-(1H-imidazol- 1-yl)propyl)-4-(2,4- dichlorophenethyl)-3,6- dioxopiperaizn-2-yl) acetic acid 
                 B 
                 2.302 
                 454 
               
               
                   
               
               
                 X.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-4-(2- (pyridin-2-yl)ethyl)-1- (2-(thiophen-2- yl)ethyl)piperazin-2-yl) acetic acid 
                 B 
                 1.768 
                 388 
               
               
                   
               
               
                 X.14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-4- phenethyl-1-(2- (thiophen-2- yl)ethyl)piperazin-2-yl) acetic acid 
                 B 
                 3.028 
                 387 
               
               
                   
               
               
                 X.15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2-methoxyethyl)- 3,6-dioxo-1-(2- (thiophen-2- yl)ethyl)piperazin-2-yl) acetic acid 
                 B 
                 2.221 
                 341 
               
               
                   
               
               
                 X.16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-1,4-bis(2- (thiophen-2- yl)ethyl)piperazin-2-yl) acetic acid 
                 B 
                 2.933 
                 393 
               
               
                   
               
               
                 X.17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo- 1-(2-(thiophen-2- yl)ethyl)piperazin-2-yl) acetic acid 
                 C 
                 3.474 
                 373 
               
               
                   
               
               
                 X.19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(prop-2-yn-1- yl)piperazin-2-yl) acetic acid 
                 C 
                 3.615 
                 383 385 
               
               
                   
               
               
                 X.22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(pyridin-4- ylmethyl)piperazin-2- yl) acetic acid 
                 C 
                 2.995 
                 436 438 
               
               
                   
               
             
          
         
       
     
       Compounds of Formula Ia 
     a) Ia.1.2: N-(2-amino-2-oxoethyl)-N-(2,4-dichlorophenethyl)-2-(4-(2,4-dichlorophenethyl)-1-(3,3-diphenylpropyl)-3,6-dioxopiperazin-2-yl)acetamide 
       [0095]    
       
                 
         
             
             
         
       
     
         [0096]    The acid X.1 (100 mg, 1.1 eq.), HOBt (40 mg, 1.5 eq.), HATU (105 mg, 1.5 eq.) and DIPEA (95 μA, 3 eq.) were added to a suspension of resin Va (0.61 mmol/g resin, 0.17 mmol) with the suitable amine and previously swelled with a 2:1 DCM:DMF solution (3 ml). The reaction mixture was stirred at room temperature for 16 h. The resin was dried and washed with DMF (3×3 ml), isopropyl alcohol (3×3 ml) and DCM (3×3 ml) and was subsequently treated with a mixture of 60:40:2 TFA/DCM/water (5 ml) for 30 min at room temperature. The resin was filtered and the filtrate was evaporated at reduced pressure to obtain 73 mg of the desired compound (Ia.1.2, 51% yield, 91% purity). HRMS (M+H) +  calculated for C 39 H 39 Cl 4 N 4 O 4 , 767.1725, experimental, 767.1741. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 HRMS (M + H) + : 
               
             
          
           
               
                 Ex 
                 Structure 
                 Compound 
                 Calculated 
                 Experimental 
               
               
                   
               
               
                 Ia.1.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-N-(4- chlorophenethyl)-2-(4-(2,4- dichlorophenethyl)-1-(3,3- diphenylpropyl)-3,6- dioxopiperazin-2-yl)acetamide 
                 C 3 H 39 Cl 3 N 4 O 4  733.2115 
                 733.2090 
               
               
                   
               
               
                 Ia.1.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3-(1H-imidazol-1- yl)propyl)-N-(2-amino-2- oxoethyl)-2-(4-(2,4- dichlorophenethyl)-1-(3,3- diphenylpropyl)-3,6- dioxopiperaizn-2-yl)acetamide 
                 C 37 H 40 Cl 2 N 6 O 4  703.2566 
                 703.2582 
               
               
                   
               
               
                 Ia.1.16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-2-(4- (2,4-dichlorophenethyl)-1- (3,3-diphenylpropyl)-3,6- dioxopiperazin-2-yl)-N-(2- (pyridin-2-yl)ethyl)acetamide 
                 C 38 H 39 Cl 2 N 5 O 4  700.2457 
                 700.2480 
               
               
                   
               
               
                 Ia.1.20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-N- (sec-butyl)-2-(4-(2,4- dichlorophenethyl)-1-(3,3- diphenylpropyl)-3,6- dioxopiperazin-2-yl)acetamide 
                 C 35 H 40 Cl 2 N 4 O 4  651.2505 
                 651.2517 
               
               
                   
               
               
                 Ia.1.21 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-2-(4- (2,4-dichlorophenethyl)-1- (3,3-diphenylpropyl)-3,6- dioxopiperazin-2-yl)-N- ((tetrahydrofuran-2- yl)methyl)acetamide 
                 C 40 H 40 Cl 2 N 4 O 6  743.2403 
                 743.2405 
               
               
                   
               
               
                 Ia.1.22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-2-(4- (2,4-dichlorophenethyl)-1- (3,3-diphenylpropyl)-3,6- dioxopiperazin-2-yl)-N- phenethylacetamide 
                 C 36 H 40 Cl 2 N 4 O 5  679.2454 
                 679.2455 
               
               
                   
               
               
                 Ia.1.23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-2-(4- (2,4-dichlorophenethyl)-1- (3,3-diphenylpropyl)-3,6- dioxopiperazin-2-yl)-N- (thiophen-2- ylmethyl)acetamide 
                 C 39 H 40 Cl 2 N 4 O 4  699.2505 
                 699.2540 
               
               
                   
               
               
                 Ia.1.24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-N- (sec-butyl)-2-(4-(2,4- dichlorophenethyl)-1-(3,3- diphenylpropyl)-3,6- dioxopiperazin-2-yl)acetamide 
                 C 36 H 36 Cl 2 N 4 O 4 S 691.1913 
                 691.1913 
               
               
                   
               
               
                 Ia.1.25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-2-(4- (2,4-dichlorophenethyl)-1- (3,3-diphenylpropyl)-3,6- dioxopiperazin-2-yl)-N- ((tetrahydrofuran-2- yl)methyl)acetamide 
                 C 39 H 39 Cl 2 FN 4 O 4  717.2411 
                 717.2441 
               
               
                   
               
               
                 Ia.6.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(1-(2-([1,1′-biphenyl]-4- yl)ethyl)-4-(2,4- dichlorophenethyl)-3,6- dioxopiperazin-2-yl)-N-(2- amino-2-oxoethyl)-N-(2,4- dichlorophenethyl)acetamide 
                 C 38 H 36 Cl 4 N 4 O 4  753.1569 
                 753.4000 
               
               
                   
               
               
                 Ia.7.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-N- (2,4-dichlorophenethyl)-2-(4- (2,4-dichlorophenethyl)-3,6- dioxo-1-(4- (trifluoromethyl)benzyl)pipera zin-2-yl)acetamide 
                 C 32 H 29 Cl 4 F 3 N 4 O 4  731.0973 
                 731.0995 
               
               
                   
               
               
                 Ia.20.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-N- (2,4-dichlorophenethyl)-2-(4- (2,4-dichlorophenethyl)-1- isopentyl-3,6-dioxopiperazin- 2-yl)acetamide 
                 C 29 H 34 Cl 4 N 4 O 4  643.1412 
                 643.1398 
               
               
                   
               
               
                 Ia.21.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-N- (2,4-dichlorophenethyl)-2-(4- (2,4-dichlorophenethyl)-1-(2- (naphthalen-1-yl)ethyl)-3,6- dioxopiperazin-2-yl)acetamide 
                 C 36 H 34 Cl 4 N 4 O 4  727.1412 
                 727.1428 
               
               
                   
               
               
                 Ia.23.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-N- (2,4-dichlorophenethyl)-2-(1- (3,3-diphenylpropyl)-3,6- dioxo-4-phenethylpiperazin-2- yl)acetamide 
                 C 39 H 40 Cl 2 N 4 O 4  699.2505 
                 699.2509 
               
               
                   
               
               
                 Ia.24.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-2-(4- (4-chlorophenethyl)-1-(3,3- diphenylpropyl)-3,6- dioxopiperazin-2-yl)-N-(2,4- dichlorophenethyl)acetamide 
                 C 39 H 39 Cl 3 N 4 O 4  733.2115 
                 755.1927 (Na+) 
               
               
                   
               
               
                 Ia.25.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-N- (2,4-dichlorophenethyl)-2-(1- (3,3-diphenylpropyl)-4- isopentyl-3,6-dioxopiperazin- 2-yl)acetamide 
                 C 36 H 42 Cl 2 N 4 O 4  665.2661 
                 665.2656 
               
               
                   
               
               
                 Ia.26.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)-N- (2,4-dichlorophenethyl)-2-(4- (2,4-dichlorophenethyl)-1- (2,2-diphenylethyl)-3,6- dioxopiperazin-2-yl)acetamide 
                 C 38 H 36 Cl 4 N 4 O 4  753.1569 
                 753.1569 
               
               
                   
               
             
          
         
       
     
       b) Ia.2.1: N-(2-amino-2-oxoethyl)-N-(2,4-dichlorophenethyl)-2-(4-(2,4-dichlorophenethyl)-1-(4-fluorobenzyl)-3,6-dioxopiperazin-2-yl)acetamide 
       [0097]    
       
                 
         
             
             
         
       
     
         [0098]    The acid X.2 (100 mg, 1 eq.) was added to a solution of 2-(4-fluorobenzylamino)acetamide (IVc, 28 μL, 1 eq.), DIC (85 μL, 3 eq.) and triethylamine (80 μL, 3 eq.) in 2 ml of DCM and the reaction mixture was stirred at room temperature for 3 h. The crude reaction product was neutralized with NaOH and was extracted with DCM. The organic extracts were washed with saturated sodium chloride, they were dried on anhydrous MgSO 4  and were evaporated at reduced pressure to obtain 96 mg of the desired compound 
       Ia.2.1. 
     Method A: tr:13.239, m/z: 681 
       [0099]    The following intermediates were prepared in the manner similar to compound Ia.2.1: 
         [0000]    
       
         
               
               
               
               
               
               
             
           
               
                   
               
               
                 Ex 
                 Structure 
                 Compound 
                 method 
                 tr 
                 m/z 
               
               
                   
               
             
             
               
                 Ia.3.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(1-(2-(1H-indol-3- yl)ethyl)-4-(2,4- dichlorophenethyl)-3,6- dioxopiperazin-2-yl)-N-(2- amino-2-oxoethyl)-N-(2,4- dichlorophenthyl)acetamide 
                 A 
                 13.961 
                 — 
               
               
                   
               
               
                 Ia.4.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)- N-(2,4-dichlorophenethyl)- 2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetamide 
                 A 
                 13.228 
                 683 
               
               
                   
               
               
                 Ia.11.19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-amino-2-oxoethyl)- N-benzyl-2-(4-(2,4- dichlorophenethyl)-1-(3- morpholinopropyl)-3,6- dioxopiperazin-2- yl)acetamide 
                 B 
                 2.786 
                 618 620 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
         
       
     
       Compounds of formula Ib 
     a) Ib.1.2 2-(N-(2,4-dichlorophenethyl)-2-(4-(2,4-dichlorophenethyl)-1-(3,3-diphenylpropyl)-3,6-dioxopiperazin-2-yl)acetamido) acetic acid 
       [0100]    
       
                 
         
             
             
         
       
     
         [0101]    A solution of bromoacetic acid (275 mg, 5 eq.) and DIPEA (345.5 eq.) in DMF (3 ml) was added to 200 mg of 2-chlorotrityl chloride resin (1.6 mmol/g Cl/g resin, 0.17 mmol) and the suspension was stirred at room temperature for 1 h. The resin was filtered and washed with DMF (3×3 ml), isopropyl alcohol (3×3 ml) and DCM (3×3 ml). The resin was then treated with methanol (3 ml) for 10 min to remove the unreacted Cl atoms. The supernatant was removed and the residue was washed with DCM (3×3 ml), isopropyl alcohol (3×3 ml) and DMF (3×3 ml). A solution of 2,4-dichlorophenethylamine (IVa, 340 μL, 5 eq.) and triethylamine (280 μL, 5 eq.) in 3 ml of DMF was then added to the resin and the suspension was stirred at room temperature for 3 h. After filtering and washing with DMF (3×3 ml), isopropyl alcohol (3×3 ml) and DCM (3×3 ml), acid X (100 mg, 1.1 eq.) was added to the resin in the presence of HOBT (40 mg, 1.5 eq.), HATU (105 mg, 1.5 eq.) and DIPEA (95 μA, 3 eq.) in 2:1 DCM:DMF (3 ml). The reaction mixture was stirred at room temperature for 16 h and was filtered. The resin was dried and washed with DMF (3×3 ml), isopropyl alcohol (3×3 ml) and DCM (3×3 ml). Finally, the resin was treated with a mixture of 5:95 TFA:DCM (5 ml) for 30 min at room temperature, obtaining a crude reaction product which was filtered. The solvent of the filtrate was removed at reduced pressure to obtain 60 mg of the desired compound (Ib.1.2, 42% yield, 91% purity). HRMS (M+H) +  calculated for C 39 H 38 Cl 4 N 3 O 5 , 768.1576, experimental, 768.1573. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                   
                   
                   
                 HRMS (M + H) + : 
               
             
          
           
               
                   
                   
                   
                   
                 Experi- 
               
               
                 Ex 
                 Structure 
                 Compound 
                 Calculated 
                 mental 
               
               
                   
               
               
                 Ib.2.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(N-(2,4-dichlorophenethyl)-2- (4-(2,4-dichlorophenethyl)-1-(4- fluorobenzyl)-3,6- dioxopiperazin-2-yl)acetamido) acetic acid 
                 C 31 H 28 Cl 4 FN 3 O 5  682.0845 
                 682.0841 
               
               
                   
               
               
                 Ib.3.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(2-(1-(2-(1H-indol-3-yl)ethyl)- 4-(2,4-dichlorophenethyl)-3,6- dioxopiperazin-2-yl)-N-(2,4- dichlorophenethyl)acetamido) acetic acid 
                 C 34 H 32 Cl 4 N 4 O 5  717.1205 
                 717.1216 
               
               
                   
               
               
                 Ib.7.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(N-(2,4-dichlorophenethyl)-2- (4-(2,4-dichlorophenethyl)-3,6- dioxo-1-(4-(tri- fluoromethyl)benzyl)piperazin- 2-yl)acetamido) acetic acid 
                 C 32 H 28 Cl 4 F 3 N 3 O 5  732.0813 
                 732.0827 
               
               
                   
               
               
                 Ib.4.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(N-(2,4-dichlorophenethyl)-2- (4-(2,4-dichlorophenethyl)-3,6- dioxo-1-(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetamido) acetic acid 
                 C 30 H 29 Cl 4 N 3 O 5 S 684.066 
                 684.0661 
               
               
                   
               
               
                 Ib.5.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(N-(2,4-dichlorophenethyl)-2- (4-(2,4-dichlorophenethyl)-1-(2- (5-methoxy-1H-indol-3- yl)ethyl)-3,6-dioxopiperazin-2- yl)acetamido) acetic acid 
                 C 35 H 34 Cl 4 N 4 O 6  747.1311 
                 747.1272 
               
               
                   
               
               
                 Ib.6.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(2-(1-(2-([1,1′-biphenyl]-4- yl)ethyl)-4-(2,4- dichlorophenethyl)-3,6- dioxopiperazin-2-yl)-N-(2,4- dichlorophenethyl)acetamido) acetic acid 
                 C 38 H 35 Cl 4 N 3 O 5  754.1409 
                 754.1389 
               
               
                   
               
             
          
         
       
     
       Compounds of formula Ic 
     Ic.1.2. Methyl 2-(N-(2,4-dichlorophenethyl)-2-(4-(2,4-dichlorophenethyl)-1-(3,3-diphenylpropyl)-3,6-dioxopiperazin-2-yl)acetamido)acetate 
       [0102]    
       
                 
         
             
             
         
       
     
         [0103]    A mixture of acid Ib.1.2 (30 mg, 1 eq.), methanol (7.5 ml) and H 2 SO 4  (20 μl, 1 eq.) was reacted for 15 h at room temperature. The crude reaction product was neutralized with NaOH and was extracted with DCM. The organic extracts were washed with saturated sodium chloride, dried on anhydrous MgSO 4  and evaporated at reduced pressure to obtain 22 mg of the desired compound Ic.1.2 (72% yield, 86% purity). HRMS (M+H) + calculated for C 40 H 39 Cl 4 N 3 O 5 , 782.1722, experimental, 782.1216. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                   
                   
                 HRMS (M + H) + : 
               
             
          
           
               
                   
                   
                   
                   
                 Experi- 
               
               
                 Ex 
                 Structure 
                 Compound 
                 Calculated 
                 mental 
               
               
                   
               
               
                 Ic.2.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Methyl 2-(N- (2,4-dichloro phenethyl)- 2-(4-(2,4- dichloro- phenethyl)-1- (4-fluoro- benzyl)- 3,6-dioxo- piperazin-2- yl)acetamido) acetate 
                 C 32 H 30 Cl 4 FN 3 O 5  696.1002 
                 696.1052 
               
               
                   
               
               
                 Ic.3.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Methyl  2-(2-(1-(2- (1H-indol-3- yl)ethyl)-4- (2,4- dichloro- phenethyl)- 3,6-dioxo- piperazin- 2-yl)-N-(2,4- dichloro- phenethyl) acetamido) acetate 
                 C 35 H 34 Cl 4 N 4 O 5  731.1362 
                 731.1321 
               
               
                   
               
               
                 Ic.4.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Methyl 2-(N- (2,4- dichloro- phenethyl)- 2-(4-(2,4- dichloro- phenethyl)- 3,6-dioxo- 1-(2-(thio- phen-2-yl) ethyl) piperazin-2- yl) acetamido) acetate 
                 C 31 H 31 Cl 4 N 3 O 5 S 698.0817 
                 698.0849 
               
               
                   
               
               
                 Ic.5.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Methyl 2-(N- (2,4-dichloro- phenethyl)- 2-(4-(2,4- dichloro- phenethyl)- 1-(2-(5- methoxy- 1H-indol-3- yl)ethyl)-3,6- dioxo- piperazin-2- yl) acetamido) acetate 
                 C 36 H 36 Cl 4 N 4 O 6  761.1467 
                 761.1437 
               
               
                   
               
               
                 Ic.6.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Methyl 2-(2- (1-(2-([1,1′- bi- phenyl]-4-yl) ethyl)-4- (2,4- dichloro- phenethyl)- 3,6-dioxo- piperazin- 2-yl)-N- (2,4- dichloro- phenethyl) acetamido) acetate 
                 C 39 H 37 Cl 4 N 3 O 5  768.1566 
                 768.1570 
               
               
                   
               
               
                 Ic.7.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Methyl 2- (N-(2,4- dichloro- phenethyl)- 2-(4-(2,4- dichloro- phenethyl)- 3,6-dioxo-1- (4-(trifluoro- methyl) benzyl) piperazin- 2-yl) acetamido) acetate 
                 C 33 H 30 Cl 4 F 3 N 3 O 5  746.097 
                 746.0955 
               
               
                   
               
             
          
           
               
                 Ex 
                 Structure 
                 Compound 
                 method 
                 tr 
                 m/z 
               
               
                   
               
               
                 Ic.4.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4-(2,4- dichloro- phenethyl)- 3,6-dioxo-1- (2-(thio- phen-2-yl) ethyl) piperazin- 2-yl)-N-(4- hydroxy- phenethyl) acetamido) acetate 
                 B 
                 3.374 
                 660 662 
               
               
                   
               
               
                 Ic.4.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 3,6-dioxo-1- (2- (thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(3,4- dimethoxy- phenethyl) acetamido) acetate 
                 B 
                 4.349 
                 704 706 
               
               
                   
               
               
                 Ic.4.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(4- sulfamoyl- phenethyl) acetamido) acetate 
                 B 
                 3.950 
                 723 725 
               
               
                   
               
               
                 Ic.4.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(4- nitrophenyl) acetamido) acetate 
                 B 
                 4.476 
                 689 691 
               
               
                   
               
               
                 Ic.4.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (3-(1H- imidazol-1- yl) propyl)-2-(4- (2,4- dichloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 3.174 
                 648 650 
               
               
                   
               
               
                 Ic.4.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(N-(2- (1H-indol-3- yl)ethyl)- 2-(4- (2,4- dichloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin-2- yl) acetamido) acetate 
                 B 
                 4.426 
                 683 685 
               
               
                   
               
               
                 Ic.4.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin-2- yl)-N-(2-(5- methoxy- 1H-indol-3- yl)ethyl) acetamido) acetate 
                 B 
                 4.348 
                 713 715 
               
               
                   
               
               
                 Ic.4.12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Methyl 2-(2- (4-(2,4- dichloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin-2- yl)-N- methyl- acetamido) acetate 
                 B 
                 3.795 
                 540 542 
               
               
                   
               
               
                 Ic.4.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(2- methoxy- ethyl) acetamido) acetate 
                 B 
                 4.104 
                 598 600 
               
               
                   
               
               
                 Ic.4.14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 3,6-dioxo- 1-(2-(thio- phen-2-yl) ethyl) piperazin- 2-yl)-N-(3- morpholino- propyl) acetamido) acetate 
                 B 
                 3.183 
                 667 669 
               
               
                   
               
               
                 Ic.4.15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(3- (2-oxo- pyrrolidin- 1-yl)propyl) acetamido) acetate 
                 B 
                 3.813 
                 665 667 
               
               
                   
               
               
                 Ic.8.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (4-chloro- phenethyl)- 2-(4-(4- chloro- phenethyl)- 3,6-di- oxo-1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 4.520 
                 644 646 
               
               
                   
               
               
                 Ic.8.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (4-chloro- phenethyl)- 3,6-dioxo-1- (2- (thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(4- hydroxy- phenethyl) acetamido) acetate 
                 B 
                 3.844 
                 626 628 
               
               
                   
               
               
                 Ic.8.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (4-chloro- phenethyl)- 3,6-dioxo- 1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(4- methoxy- phenethyl) acetamido) acetate 
                 B 
                 4.299 
                 391 
               
               
                   
               
               
                 Ic.8.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (4-chloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin-2- yl)-N-(3,4- di- methoxy- phenethyl) acetamido) acetate 
                 B 
                 4.126 
                 670 672 
               
               
                   
               
               
                 Ic.8.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (4-chloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(4- sulfamoyl- phenethyl) acetamido) acetate 
                 B 
                 3.736 
                 689 691 
               
               
                   
               
               
                 Ic.8.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (3-(1H- imidazol-1- yl)propyl)-2- (4-(4-chloro- phenethyl)- 3,6-dioxo- 1-(2-(thio- phen-2-yl) ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 2.993 
                 614 616 
               
               
                   
               
               
                 Ic.8.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(N-(2- (1H-indol-3- yl)ethyl)-2- (4-(4-chloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin-2- yl)acetamido) acetate 
                 B 
                 4.210 
                 649 651 
               
               
                   
               
               
                 Ic.8.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (4-chloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin-2- yl)-N-(2-(5- methoxy-1H- indol- 3-yl)ethyl) acetamido) acetate 
                 B 
                 4.131 
                 679 681 
               
               
                   
               
               
                 Ic.8.12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Methyl  2-(2-(4-(4- chloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin- 2-yl)-N- methyl- acetamido) acetate 
                 B 
                 3.540 
                 506 508 
               
               
                   
               
               
                 Ic.8.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4-(4- chloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin- 2-yl)-N- (2-methoxy- ethyl) acetamido) acetate 
                 B 
                 3.855 
                 564 566 
               
               
                   
               
               
                 Ic.8.14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4-(4- chloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(3- morpholino- propyl) acetamido) acetate 
                 B 
                 2.992 
                 633 635 
               
               
                   
               
               
                 Ic.8.15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4-(4- chloro- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(3- (2-oxo- pyrrolidin- 1-yl)propyl) acetamido) acetate 
                 B 
                 3.585 
                 631 633 
               
               
                   
               
               
                 Ic.9.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(N-(4- chloro- phenethyl)- 2-(4-(4- methoxy- phenethyl)- 3,6-dioxo- 1-(2-(thio- phen-2-yl) ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 4.297 
                 640 642 
               
               
                   
               
               
                 Ic.9.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2,4- dichloro- phenethyl)- 2-(4-(4- methoxy- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin-2- yl) acetamido) acetate 
                 B 
                 4.504 
                 674 676 
               
               
                   
               
               
                 Ic.9.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (4-hydroxy- phenethyl)- 2-(4-(4- methoxy- phenethyl)- 3,6- dioxo-1-(2- (thiophen-2- yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 3.590 
                 622 
               
               
                   
               
               
                 Ic.9.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (4-methoxy- phenethyl)- 2-(4-(4- methoxy- phenethyl)- 3,6-dioxo- 1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 4.052 
                 636 
               
               
                   
               
               
                 Ic.9.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (3,4- dimethoxy- phenethyl)- 2-(4-(4- methoxy- phenethyl)- 3,6- dioxo-1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 3.870 
                 666 
               
               
                   
               
               
                 Ic.9.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (4-methoxy- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin- 2-yl)-N- (4- sulfamoyl- phenethyl) acetamido) acetate 
                 B 
                 3.486 
                 685 
               
               
                   
               
               
                 Ic.9.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (4-methoxy- phenethyl)- 3,6-dioxo-1- (2-(thio- phen-2-yl) ethyl) piperazin- 2-yl)-N-(4- nitro- phenethyl) acetamido) acetate 
                 B 
                 4.026 
                 651 
               
               
                   
               
               
                 Ic.9.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (3-(1H- imidazol- 1-yl)propyl)- 2-(4-(4- methoxy- phenethyl)- 3,6- dioxo-1-(2- (thiophen-2- yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 2.757 
                 610 
               
               
                   
               
               
                 Ic.9.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2-(1H- indol-3-yl) ethyl)-2-(4- (4-methoxy- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 3.964 
                 645 
               
               
                   
               
               
                 Ic.9.10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2- (5-hydroxy- 1H-indol- 3-yl)ethyl)- 2-(4- (4-methoxy- phenethyl)- 3,6-dioxo-1- (2- (thiophen- 2-yl)ethyl) piperazin-2- yl) acetamido) acetate 
                 B 
                 3.488 
                 661 
               
               
                   
               
               
                 Ic.9.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2-(5- methoxy-1H- indol-3-yl) ethyl)-2-(4- (4-methoxy- phen- ethyl)-3,6- dioxo-1-(2- (thiophen-2- yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 3.888 
                 675 
               
               
                   
               
               
                 Ic.9.12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Methyl 2-(2- (4- (4-methoxy- phenethyl)- 3,6-dioxo-1- (2-(thiophen- 2-yl) ethyl) piperazin-2- yl)- N-methyl- acetamido) acetate 
                 B 
                 3.233 
                 502 
               
               
                   
               
               
                 Ic.9.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(N-(2- methoxy- ethyl)- 2-(4-(4- methoxy- phenethyl)- 3,6-dioxo- 1-(2-(thio- phen-2-yl) ethyl) piperazin-2- yl) acetamido) acetate 
                 B 
                 3.568 
                 560 
               
               
                   
               
               
                 Ic.9.14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (4-methoxy- phenethyl)- 3,6-dioxo- 1-(2- (thiophen- 2-yl)ethyl) piperazin-2- yl)-N-(3- morpholino- propyl) acetamido) acetate 
                 B 
                 2.772 
                 629 
               
               
                   
               
               
                 Ic.9.15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (4-methoxy- phenethyl)- 3,6-dioxo- 1-(2-(thio- phen- 2-yl)ethyl) pipera- zin-2-yl)-N- (3-(2- oxopyr- rolidin-1- yl)propyl) acetamido) acetate 
                   
                 3.316 
                 627 
               
               
                   
               
               
                 Ic.10.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (4-chloro- phenethyl)- 2-(4-(2,4- dichloro- phenethyl)- 1-(2- methoxy- ethyl)- 3,6-dioxo- piperazin- 2-yl) acetamido) acetate 
                 B 
                 4.376 
                 626 628 
               
               
                   
               
               
                 Ic.10.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2,4- dichloro- phenethyl)- 2-(4-(2,4-di- chloro- phenethyl)- 1-(2- methoxy- ethyl)-3,6- dioxopipe- razin-2-yl) acetamido) acetate 
                 B 
                 4.621 
                 660 662 
               
               
                   
               
               
                 Ic.10.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4-(2,4- dichloro- phenethyl)- 1- (2-methoxy- ethyl)- 3,6-dioxo- piperazin-2- yl)-N-(4- hydroxy- phenethyl) acetamido) acetate 
                 B 
                 3.637 
                 608 610 
               
               
                   
               
               
                 Ic.10.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4-(2,4- dichloro- phenethyl)- 1- (2-methoxy- ethyl)-3,6- dioxo- piperazin- 2-yl)-N-(4- methoxy- phenethyl) acetamido) acetate 
                 B 
                 4.110 
                 622 624 
               
               
                   
               
               
                 Ic.10.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 1-(2- methoxy- ethyl)-3,6- dioxo- piperazin- 2-yl)-N- (3,4- dimethoxy- phenethyl) acetamido) acetate 
                 B 
                 3.917 
                 652 654 
               
               
                   
               
               
                 Ic.10.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 1-(2- methoxy- ethyl)-3,6- dioxo- piperazin- 2- yl)-N-(4- sulfamoyl- phenethyl) acetamido) acetate 
                 B 
                 3.511 
                 671 673 
               
               
                   
               
               
                 Ic.10.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (4-(2,4- dichloro- phenethyl)- 1-(2- methoxy- ethyl)-3,6- dioxo- piperazin- 2-yl)-N-(4- nitro- phenethyl) acetamido) acetate 
                 B 
                 4.084 
                 637 639 
               
               
                   
               
               
                 Ic.10.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(N-(3- (1H- imidazol- 1-yl) propyl)- 2-(4-(2,4- di- chloro- phenethyl)- 1-(2- methoxy- ethyl)-3,6- dioxo- piperazin- 2-yl) acetamido) acetate 
                 B 
                 2.759 
                 596 598 
               
               
                   
               
               
                 Ic.10.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2-(1H- indol-3- yl)ethyl)-2- (4-(2,4- dichloro- phenethyl)- 1- (2-methoxy- ethyl)-3,6- dioxo- piperazin-2- yl) acetamido) acetate 
                 B 
                 4.021 
                 631 633 
               
               
                   
               
               
                 Ic.10.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2- (2-(4-(2,4- dichloro- phenethyl)- 1-(2- methoxy- ethyl)-3,6- dioxo- piperazin- 2-yl)-N-(2- (5-methoxy- 1H- indol-3-yl) ethyl) acetamido) acetate 
                 B 
                 3.941 
                 661 663 
               
               
                   
               
               
                 Ic.10.14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2- (N-(3-(1H- imidazol- 1-yl) propyl)-2- (4-(2,4-di- chloro- phenethyl)- 1-(3- morpholino- propyl)- 3,6- dioxo- piperazin- 2-yl) acetamido) acetate 
                 B 
                 2.188 
                 665 667 
               
               
                   
               
               
                 Ic.11.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (4- chlorophen- ethyl)-2-(4- (2,4- dichloro- phenethyl)- 1-(3- morpholino- propyl)-3,6- dioxo- piperazin- 2-yl) acetamido) acetate 
                 B 
                 3.461 
                 695 697 
               
               
                   
               
               
                 Ic.11.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2,4- dichloro- phenethyl)- 2- (4-(2,4- dichloro- phenethyl)- 1-(3- morpholino- propyl)-3,6- dioxo- piperazin- 2-yl) acetamido) acetate 
                 B 
                 3.590 
                 729 731 
               
               
                   
               
               
                 Ic.11.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (4-(2,4- dichloro- phenethyl)- 1-(3- morpholino- propyl)-3,6- dioxo- piperazin- 2-yl)-N-(4- hydroxy- phenethyl) acetamido) acetate 
                 B 
                 2.970 
                 677 679 
               
               
                   
               
               
                 Ic.11.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 1-(3- morpholino- propyl)-3,6- dioxo- piperazin- 2-yl)-N- (4-meth- oxy- phenethyl) acetamido) acetate 
                 B 
                 3.295 
                 691 693 
               
               
                   
               
               
                 Ic.11.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 1-(3- morpholino- propyl)-3,6- dioxo- piperazin- 2-yl)-N- (3,4- dimethoxy- phenethyl) acetamido) acetate 
                 B 
                 3.150 
                 721 723 
               
               
                   
               
               
                 Ic.11.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 1-(3- morpholino- propyl)- 3,6-dioxo- piperazin- 2-yl)-N-(4- sulfamoyl- phenethyl) acetamido) acetate 
                 B 
                 2.867 
                 527 529 
               
               
                   
               
               
                 Ic.11.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 1-(3- morpholino- propyl)-3,6- dioxo- piperazin- 2-yl)-N-(4- nitro- phenethyl) acetamido) acetate 
                 B 
                 3.291 
                 706 708 
               
               
                   
               
               
                 Ic.11.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2-(1H- indol-3-yl) ethyl)-2-(4- (2,4- dichloro- phenethyl)- 1-(3- morpholino- propyl)-3,6- dioxo- piperazin- 2-yl) acetamido) acetate 
                 B 
                 3.234 
                 700 702 
               
               
                   
               
               
                 Ic.11.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4- (2,4- dichloro- phenethyl)- 1-(3- morpholino- propyl)-3,6- dioxo- piperazin- 2-yl)-N-(2- (5-methoxy- 1H-indol-3- yl)ethyl) acetamido) acetate 
                 B 
                 3.164 
                 730 732 
               
               
                   
               
               
                 Ic.11.16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (4-(2,4- dichloro- phenethyl)- 1-(3- morpholino- propyl)-3,6- dioxo- piperazin- 2-yl)-N-(2- (pyridin-2- yl)ethyl) acetamido) acetate 
                 B 
                 2.500 
                 662 664 
               
               
                   
               
               
                 Ic.11.17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Methyl 3- (N-(4- (benzyloxy) benzyl)-2-(4- (2,4- dichloro- phenethyl)- 1-(3- morpholino- propyl)-3,6- dioxo- piperazin-2- yl) acetamido) propanoate 
                 B 
                 3.551 
                 735 737 
               
               
                   
               
               
                 Ic.11.18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (4-(2,4- dichloro- phenethyl)- 1-(3- morpholino- propyl)-3,6- dioxo- piperazin- 2-yl)-N-(4- hydroxy- benzyl) acetamido) acetate 
                 B 
                 2.787 
                 663 665 
               
               
                   
               
               
                 Ic.13.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (4-chloro- phenethyl)- 2-(3,6- dioxo-4-(2- (pyridin- 2-yl)ethyl)- 1-(2-(thio- phen-2-yl) ethyl)pipe- razin-2-yl) acetamido) acetate 
                 C 
                 3.763 
                 611 613 
               
               
                   
               
               
                 Ic.13.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2,4-di- chlorophen- ethyl)-2- (3,6-dioxo- 4-(2- (pyridin-2- yl)ethyl)- 1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 C 
                 3.957 
                 645 647 
               
               
                   
               
               
                 Ic.13.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (3,4- dimethoxy- phenethyl)- 2-(3,6- dioxo-4-(2- (pyridin- 2-yl)ethyl)- 1-(2- (thiophen- 2-yl)ethyl) piperazin-2- yl) acetamido) acetate 
                 C 
                 3.378 
                 637 
               
               
                   
               
               
                 Ic.13.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (3,6- dioxo-4-(2- (pyridin-2- yl)ethyl)-1- (2-(thio- phen- 2-yl)ethyl) piperazin- 2-yl)-N-(4- nitro- phenethyl) acetamido) acetate 
                 C 
                 3.528 
                 622 
               
               
                   
               
               
                 Ic.13.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl-2-(N- (2-(1H- indol-3-yl) ethyl)-2- (3,6- dioxo-4-(2- (pyridin- 2-yl)ethyl)- 1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 C 
                 3.480 
                 616 
               
               
                   
               
               
                 Ic.13.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (3,6-dioxo- 4-(2-(pyri- din-2-yl) ethyl)-1-(2- (thiophen-2- yl)ethyl) piperazin- 2-yl)-N-(2- (5-methoxy- 1H-indol-3- yl)ethyl) acetamido) acetate 
                 B 
                 2.914 
                 646 
               
               
                   
               
               
                 Ic.14.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (4-chloro- phenethyl)- 2-(3,6- dioxo- 4-phenethyl- 1-(2-(thio- phen-2-yl) ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 4.331 
                 610 612 
               
               
                   
               
               
                 Ic.14.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2,4- dichloro- phenethyl)- 2-(3,6- dioxo- 4-phenethyl- 1-(2-(thio- phen-2-yl) ethyl) piperazin-2- yl) acetamido) acetate 
                 C 
                 5.072 
                 644 646 
               
               
                   
               
               
                 Ic.14.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (3,6- dioxo-4- phenthyl-1- (2- (thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(4- methoxy- phenethyl) acetamido) acetate 
                 B 
                 4.101 
                 606 
               
               
                   
               
               
                 Ic.14.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (3,4- dimethoxy- phenethyl)- 2-(3,6- dioxo-4- phenethyl- 1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 C 
                 4.432 
                 636 
               
               
                   
               
               
                 Ic.14.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (3,6-dioxo- 4-phenethyl- 1-(2- (thiophen- 2-yl)ethyl) piperazin-2- yl)-N-(4- sulfamoyl- phenethyl) acetamido) acetate 
                 B 
                 3.522 
                 655 
               
               
                   
               
               
                 Ic.14.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (3,6-dioxo- 4-phenethyl- 1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(4- nitro- phenethyl) acetamido) acetate 
                 C 
                 4.578 
                 621 
               
               
                   
               
               
                 Ic.14.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2- (1H-indol-3- yl)ethyl)-2- (3,6-dioxo-4- phenethyl-1- (2-(thiophen- 2-yl)ethyl) piperazin-2- yl) acetamido) acetate 
                 B 
                 3.996 
                 616 
               
               
                   
               
               
                 Ic.14.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (3,6- dioxo-4- phenethyl- 1-(2- (thiophen- 2-yl)ethyl) piperazin-2- yl)-N-(2-(5- methoxy- 1H-indol-3- yl)ethyl) acetamido) acetate 
                 C 
                 4.447 
                 645 
               
               
                   
               
               
                 Ic.14.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (3,6-dioxo- 4-phenethyl- 1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl)-N- (2-methoxy- ethyl) acetamido) acetate 
                 B 
                 3.610 
                 530 
               
               
                   
               
               
                 Ic.14.19.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 3-(N- benzyl-2- (3,6-dioxo- 4-phenethyl- 1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) propanoate 
                 B 
                 4.108 
                 576 
               
               
                   
               
               
                 Ic.15.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (4-chloro- phenethyl)- 2-(4-(2- methoxy- ethyl)-3,6- dioxo-1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 C 
                 4.337 
                 564 566 
               
               
                   
               
               
                 Ic.15.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2,4- dichloro- phenethyl)- 2-(4-(2- methoxy- ethyl)-3,6- dioxo-1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 C 
                 4.580 
                 598 600 
               
               
                   
               
               
                 Ic.15.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4-(2- methoxy- ethyl)-3,6- dioxo-1-(2- (thiophen- 2-yl)ethyl) piperazin-2- yl)-N-(4- methoxy- phenethyl) acetamido) acetate 
                 B 
                 3.548 
                 560 
               
               
                   
               
               
                 Ic.15.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (3,4- dimethoxy- phenethyl)- 2-(4-(2- methoxy- ethyl)- 3,6-dioxo- 1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 3.885 
                 590 
               
               
                   
               
               
                 Ic.15.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(4-(2- methoxy- ethyl)-3,6- dioxo-1-(2- (thiophen- 2-yl)ethyl) piperazin-2- yl)-N-(4- sulfamoyl- phenethyl) acetamido) acetate 
                 B 
                 2.923 
                 609 
               
               
                   
               
               
                 Ic.15.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (4-(2- methoxy- ethyl)-3,6- dioxo- 1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(4- nitro- phenethyl) acetamido) acetate 
                 C 
                 4.057 
                 575 
               
               
                   
               
               
                 Ic.15.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2-(1H- indol- 3-yl)ethyl)- 2-(4-(2- methoxy- ethyl)- 3,6-dioxo- 1-(2-(thio- phen-2-yl) ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 3.462 
                 569 
               
               
                   
               
               
                 Ic.15.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2-(5- methoxy- 1H- indol-3-yl) ethyl)-2-(4- (2-methoxy- ethyl)- 3,6-dioxo-1- (2- (thiophen- 2-yl)ethyl) piperazin-2- yl) acetamido) acetate 
                 B 
                 3.383 
                 599 
               
               
                   
               
               
                 Ic.15.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2-methoxy- ethyl)- 2-(4-(2- methoxy- ethyl)-3,6- dioxo- 1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 2.916 
                 484 
               
               
                   
               
               
                 Ic.15.19.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 3-(N- benzyl-2-(4- (2-methoxy- ethyl)-3,6- dioxo-1-(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) propanoate 
                 B 
                 3.526 
                 530 
               
               
                   
               
               
                 Ic.16.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (4- chlorophen- ethyl)-2- (3,6-dioxo- 1,4-bis(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 C 
                 4.793 
                 616 618 
               
               
                   
               
               
                 Ic.16.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2,4- dichloro- phenethyl)- 2-(3,6- dioxo- 1,4-bis(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 C 
                 5.008 
                 650 652 
               
               
                   
               
               
                 Ic.16.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl  2-(2-(3,6- dioxo- 1,4-bis(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(4- hydroxy- phenethyl) acetamido) acetate 
                 B 
                 3.569 
                 598 
               
               
                   
               
               
                 Ic.16.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (3,4- dimethoxy- phenethyl)- 2-(3,6- dioxo- 1,4-bis(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 3.836 
                 642 
               
               
                   
               
               
                 Ic.16.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (3,6-dioxo- 1,4-bis (2- (thiophen- 2-yl)ethyl) piperazin-2- yl)-N-(4- sulfamoyl- phenethyl) acetamido) acetate 
                 B 
                 3.450 
                 660 
               
               
                   
               
               
                 Ic.16.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (3,6-dioxo- 1,4-bis(2- (thiophen-2- yl)ethyl) piperazin- 2-yl)-N-(4- nitro- phenethyl) acetamido) acetate 
                 C 
                 4.522 
                 627 
               
               
                   
               
               
                 Ic.16.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (3-(1H- imidazol- 1-yl)propyl)- 2-(3,6- dioxo- 1,4-bis(2- (thiophen- 2-yl)ethyl) piperazin-2- yl) acetamido) acetate 
                 B 
                 2.709 
                 586 
               
               
                   
               
               
                 Ic.16.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(N- (2- (1H-indol- 3-yl)ethyl)- 2-(3,6- dioxo- 1,4-bis(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) acetate 
                 B 
                 3.937 
                 621 
               
               
                   
               
               
                 Ic.16.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (3,6-dioxo- 1,4-bis (2- (thiophen- 2-yl)ethyl) piperazin- 2-yl)-N-(2- (5-methoxy- 1H-indol- 3-yl)ethyl) acetamido) acetate 
                 B 
                 3.857 
                 651 
               
               
                   
               
               
                 Ic.16.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 2-(2- (3,6-dioxo- 1,4-bis(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl)-N- (2-methoxy- ethyl) acetamido) acetate 
                 B 
                 3.530 
                 536 
               
               
                   
               
               
                 Ic.16.19.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 3-(N- benzyl-2- (3,6-dioxo- 1,4-bis(2- (thiophen- 2-yl)ethyl) piperazin- 2-yl) acetamido) propanoate 
                 B 
                 4.040 
                 582 
               
               
                   
               
               
                 Ic.21.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Methyl 2- (N-(2,4- dichloro- phenethyl)- 2-(4-(2,4- dichloro- phenethyl)- 1-(2- (naphthalen- 1-yl)ethyl)- 3,6-dioxo- piperazin- 2-yl) acetamido) acetate 
                 B 
                 5.087 
                 743 745 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
         
       
     
       Compounds of formula Id 
     Id.1.2 N-(2,4-dichlorophenethyl)-2-(4-(2,4-dichlorophenethyl)-1-(3,3-diphenylpropyl)-3,6-dioxopiperazin-2-yl)acetamide 
       [0104]    
       
                 
         
             
             
         
       
     
         [0105]    Acid X.1 (100 mg, 1 eq.) was added to a solution of 2,4-dichlorophenethylamine (IVc, 28 μL, 1 eq.), DIC (85 μL, 3 eq.) and triethylamine (80 μL, 3 eq.) in 2 ml of DCM and the reaction mixture was stirred at room temperature for 3 h. The crude reaction product was neutralized with NaOH and was extracted with DCM. The organic extracts were washed with saturated sodium chloride, dried on anhydrous MgSO 4  and evaporated at reduced pressure to obtain 96 mg of the desired compound Id.1.2 (73% yield, 89% purity). HRMS (M+H) +  calculated for C 37 H 36 Cl 4 N 3 O 3 , 710.1511, experimental, 710.1522. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                   
                   
                 HRMS (M + H) + : 
               
             
          
           
               
                   
                   
                   
                   
                 Experi- 
               
               
                 Ex 
                 Structure 
                 Compound 
                 Calculated 
                 mental 
               
               
                   
               
               
                 Id.2.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2,4-dichlorophen- ethyl)-2-(4- (2,4-dichlorophen- ethyl)-1-(4- fluorobenzyl)-3,6- dioxopiperazin-2- yl)acetamide 
                 C 29 H 26 Cl 4 FN 3 O 3  624.0791 
                 624.25 
               
               
                   
               
               
                 Id.3.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(1-(2-(1H-indol-3- yl)ethyl)-4- (2,4-dichlorophen- ethyl)-3,6- dioxopiperazin-2-yl)- N-(2,4-dichlorophen- ethyl)acetamide 
                 C 32 H 30 Cl 4 N 4 O 3  659.115 
                 659.1163 
               
               
                   
               
               
                 Id.4.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2,4-dichlorophen- ethyl)-2-(4- (2,4-dichlorophen- ethyl)-3,6-dioxo-1- (2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetamide 
                 C 28 H 27 Cl 4 N 3 O 3 S 626.0605 
                 626.0589 
               
               
                   
               
               
                 Id.5.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2,4-dichlorophen- ethyl)-2-(4-(2,4- dichlorophenethyl)-1- (2-(5-methoxy-1H- indol-3-yl)ethyl)- 3,6-dioxopiperazin-2- yl)acetamide 
                 C 33 H 32 Cl 4 N 4 O 4  689.1256 
                 689.30 
               
               
                   
               
               
                 Id.6.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(1-(2-([1,1′-biphenyl]- 4-yl)ethyl)-4-(2,4- dichlorophenethyl)-3,6- dioxopiperazin-2-yl)- N-(2,4-dichlorophen- ethyl)acetamide 
                 C 36 H 33 Cl 4 N 3 O 3  696.1354  
                 696.1335 
               
               
                   
               
               
                 Id.7.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2,4-dichlorophen- ethyl)-2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(4- (trifluoromethyl)benzyl) piperazin-2-yl)acetamide 
                 C 30 H 26 Cl 4 F 3 N 3 O 3  674.0759  
                 674.35 
               
               
                   
               
             
          
           
               
                 Ex. 
                 Structure 
                 Compound 
                 method 
                 tr 
                 m/z 
               
               
                   
               
               
                 Id.4.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-chlorophen- ethyl)-2-(4-(2,4- dichlorophenethyl)- 3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2- yl)acetamide 
                 C 
                 4.869 
                 592 594 
               
               
                   
               
               
                 Id.4.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- hydroxyphenethyl) acetamide 
                 C 
                 4.193 
                 574 576 
               
               
                   
               
               
                 Id.4.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- methoxyphenethyl) acetamide 
                 C 
                 4.62 
                 588 590 
               
               
                   
               
               
                 Id.4.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-( 2,4-dichlorophen- ethyl)-3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N- (3,4-dimethoxy- phenethyl)acetamide 
                 C 
                 4.455 
                 618 620 
               
               
                   
               
               
                 Id.4.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- sulfamoylphenethyl) acetamide 
                 C 
                 4.079 
                 637 639 
               
               
                   
               
               
                 Id.4.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- nitrophenethyl) acetamide 
                 C 
                 4.599 
                 603 605 
               
               
                   
               
               
                 Id.4.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3-(1H-imidazol-1- yl)propyl)-2-(4-(2,4- dichlorophenethyl)- 3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl) acetamide 
                 C 
                 3.410 
                 543 545 
               
               
                   
               
               
                 Id.4.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-(1H-indol-3-yl) ethyl)-2-(4-(2,4- dichlorophenethyl)- 3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl) acetamide 
                 C 
                 4.565 
                 597 599 
               
               
                   
               
               
                 Id.4.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 3-(2-(3-(2-aminoethyl)-5- methoxy-1H-indol-1- yl)-2-oxoethyl)-1-(2,4- dichlorophenethyl)-4- (2-(thiophen-2- yl)ethyl)piperazine- 2,5-dione 
                 C 
                 4.498 
                 627 629 
               
               
                   
               
               
                 Id.4.12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N- methylacetamide 
                 C 
                 3.988 
                 468 470 
               
               
                   
               
               
                 Id.4.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(2-  methoxyethyl)acetamide  
                 C 
                 4.086 
                 512 514 
               
               
                   
               
               
                 Id.4.14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(3- morpholinopropyl) acetamide 
                 C 
                 3.440 
                 581 583 
               
               
                   
               
               
                 Id.4.15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(3- (2-oxopyrrolidin-1- yl)propyl)acetamide 
                 C 
                 3.953 
                 579 581 
               
               
                   
               
               
                 Id.4.19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-benzyl-2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetamide 
                 C 
                 4.584 
                 544 546 
               
               
                   
               
               
                 Id.4.23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N- phenethylacetamide 
                 C 
                 4.661 
                 558 560 
               
               
                   
               
               
                 Id.4.24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N- (thiophen-2-ylmethyl) acetamide 
                 C 
                 4.501 
                 550 552 
               
               
                   
               
               
                 Id.4.25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N-(3- phenylpropyl) acetamide 
                 C 
                 4.796 
                 572 574 
               
               
                   
               
               
                 Id.4.26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N- (prop-2-yn-1-yl) acetamide 
                 C 
                 4.175 
                 492 494 
               
               
                   
               
               
                 Id.4.27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-allyl-2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(2-(thiophen- 2-yl)ethyl)piperazin- 2-yl)acetamide 
                 C 
                 4.269 
                 494 496 
               
               
                   
               
               
                 Id.13.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-chlorophenethyl)-2- (3,6-dioxo-4-(2- (pyridin-2-yl)ethyl)-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl) acetamide 
                 C 
                 3.382 
                 525 
               
               
                   
               
               
                 Id.13.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2,4-dichlorophen- ethyl)-2-(3,6-dioxo-4- (2-(pyridin-2-yl)ethyl)- 1-(2-(thiophen-2-yl) ethyl)piperazin-2-yl) acetamide 
                 C 
                 3.561 
                 559 561 
               
               
                   
               
               
                 Id.13.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,4-dimethoxyphen- ethyl)-2-(3,6-dioxo- 4-(2-(pyridin-2-yl) ethyl)-1-(2-(thiophen- 2-yl)ethyl)piperazin- 2-yl)acetamide 
                 C 
                 3.018 
                 551 
               
               
                   
               
               
                 Id.13.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-4-(2- (pyridin-2-yl)ethyl)- 1-(2-(thiophen-2-yl) ethyl)piperazin-2-yl)- N-(4-nitrophenethyl) acetamide 
                 C 
                 3.149 
                 536 
               
               
                   
               
               
                 Id.13.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-(1H-indol-3-yl) ethyl)-2-(3,6-dioxo-4- (2-(pyridin-2-yl)ethyl)- 1-(2-(thiophen-2-yl) ethyl)piperazin-2-yl) acetamide 
                 C 
                 3.170 
                 530 
               
               
                   
               
               
                 Id.13.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-4-(2- (pyridin-2-yl)ethyl)- 1-(2-(thiophen-2-yl) ethyl)piperazin-2-yl)- N-(2-(5-methoxy-1H- indol-3-yl)ethyl) acetamide 
                 C 
                 3.123 
                 560 
               
               
                   
               
               
                 Id.14.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-chlorophenethyl)-2- (3,6-dioxo-4-phenethyl- 1-(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetamide 
                 B 
                 3.931 
                 524 526 
               
               
                   
               
               
                 Id.14.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2,4-dichlorophen- ethyl)-2-(3,6-dioxo- 4-phenethyl-1-(2- (thiophen-2- yl)ethyl)piperazin-2- yl)acetamide 
                 B 
                 4.163 
                 558 560 
               
               
                   
               
               
                 Id.14.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-4-phenethyl- 1-(2-(thiophen-2- yl)ethyl)piperazin-2-yl)- N-(4-hydroxyphen- ethyl)acetamide 
                 B 
                 3.225 
                 506 
               
               
                   
               
               
                 Id.14.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-4- phenethyl-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- methoxyphenethyl) acetamide 
                 B 
                 3.671 
                 520 
               
               
                   
               
               
                 Id.14.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,4-dimethoxyphen- ethyl)-2-(3,6-dioxo-4- phenethyl-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl) acetamide 
                 B 
                 3.487 
                 550 
               
               
                   
               
               
                 Id.14.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-4- phenethyl-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- sulfamoylphenethyl) acetamide 
                 B 
                 3.112 
                 569 
               
               
                   
               
               
                 Id.14.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-4-phenethyl- 1-(2-(thiophen-2-yl) ethyl)piperazin-2-yl)- N-(4-nitrophenethyl) acetamide 
                 B 
                 4.184 
                 535 
               
               
                   
               
               
                 Id.14.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3-(1H-imidazol-1- yl)propyl)-2-(3,6-dioxo- 4-phenethyl-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl) acetamide 
                 B 
                 2.456 
                 494 
               
               
                   
               
               
                 Id.14.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-(1H-indol-3-yl) ethyl)-2-(3,6-dioxo-4- phenethyl-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl) acetamide 
                 B 
                 3.626 
                 529 
               
               
                   
               
               
                 Id.14.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-4-phenethyl- 1-(2-(thiophen-2- yl)ethyl)piperazin-2-yl)- N-(2-(5-methoxy-1H- indol-3-yl)ethyl) acetamide 
                 B 
                 3.552 
                 559 
               
               
                   
               
               
                 Id.14.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-4-phen- ethyl-1-(2-(thiophen- 2-yl)ethyl)piperazin- 2-yl)-N-(2-methoxy- ethyl)acetamide 
                 B 
                 3.044 
                 444 
               
               
                   
               
               
                 Id.14.19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-benzyl-2-(3,6-dioxo-4- phenethyl-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl) acetamide 
                 B 
                 3.600 
                 476 
               
               
                   
               
               
                 Id.15.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-chlorophenethyl)- 2-(4-(2-methoxyethyl)- 3,6-dioxo-1-(2-(thiophen- 2-yl)ethyl)piperazin- 2-yl)acetamide 
                 B 
                 3.346 
                 478 480 
               
               
                   
               
               
                 Id.15.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2,4-dichlorophen- ethyl)-2-(4-(2- methoxyethyl)-3,6- dioxo-1-(2-(thiophen- 2-yl)ethyl)piperazin- 2-yl)acetamide 
                 B 
                 3.596 
                 512 514 
               
               
                   
               
               
                 Id.15.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-hydroxyphenethyl)- 2-(4-(2-methoxyethyl)- 3,6-dioxo-1-(2-(thiophen- 2-yl)ethyl)piperazin- 2-yl)acetamide 
                 B 
                 2.547 
                 460 
               
               
                   
               
               
                 Id.15.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2-methoxyethyl)- 3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N- (4-methoxyphen- ethyl)acetamide 
                 B 
                 3.046 
                 474 
               
               
                   
               
               
                 Id.15.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,4-dimethoxyphen- ethyl)-2-(4-(2- methoxyethyl)-3,6- dioxo-1-(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetamide 
                 B 
                 2.850 
                 504 
               
               
                   
               
               
                 Id.15.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2-methoxyethyl)- 3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- sulfamoylphenethyl) acetamide 
                 B 
                 2.433 
                 523 
               
               
                   
               
               
                 Id.15.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2-methoxyethyl)- 3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- nitrophenethyl) acetamide 
                 B  
                 3.041 
                 489 
               
               
                   
               
               
                 Id.15.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3-(1H-imidazol-1- yl)propyl)-2-(4-(2- methoxyethyl)-3,6-dioxo- 1-(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetamide 
                 B 
                 1.847 
                 448 
               
               
                   
               
               
                 Id.15.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-(1H-indol-3-yl) ethyl)-2-(4-(2-methoxy- ethyl)-3,6-dioxo-1- (2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetamide 
                 B 
                 3.033 
                 483 
               
               
                   
               
               
                 Id.15.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-(5-methoxy-1H- indol-3-yl)ethyl)-2-(4- (2-methoxyethyl)-3,6- dioxo-1-(2-(thiophen- 2-yl)ethyl)piperazin- 2-yl)acetamide 
                 B 
                 2.962 
                 513 
               
               
                   
               
               
                 Id.15.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-methoxyethyl)-2-(4- (2-methoxyethyl)-3,6- dioxo-1-(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetamide 
                 B 
                 2.275 
                 398 
               
               
                   
               
               
                 Id.15.19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-benzyl-2-(4-(2- methoxyethyl)-3,6- dioxo-1-(2-(thiophen- 2-yl)ethyl)piperazin- 2-yl)acetamide 
                 B 
                 2.919 
                 430 
               
               
                   
               
               
                 Id.16.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-chlorophenethyl)-2- (3,6-dioxo-1,4-bis (2-(thiophen-2-yl)ethyl) piperazin-2-yl)acetamide 
                 B 
                 3.861 
                 530 532 
               
               
                   
               
               
                 Id.16.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2,4-dichlorophen- ethyl)-2-(3,6-dioxo- 1,4-bis(2-(thiophen- 2-yl)ethyl)piperazin- 2-yl)acetamide 
                 B 
                 4.094 
                 564 566 
               
               
                   
               
               
                 Id.16.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-1,4-bis(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- hydroxyphenethyl) acetamide 
                 B 
                 3.145 
                 512 
               
               
                   
               
               
                 Id.16.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-1,4-bis(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- methoxyphenethyl) acetamide 
                 B 
                 3.600 
                 526 
               
               
                   
               
               
                 Id.16.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3,4-dimethoxyphen- ethyl)-2-(3,6-dioxo-1,4- bis(2-(thiophen-2- yl)ethyl)piperazin-2-yl) acetamide 
                 B 
                 3.409 
                 556 
               
               
                   
               
               
                 Id.16.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-1,4-bis(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- sulfamoylphenethyl) acetamide 
                 B 
                 3.029 
                 575 
               
               
                   
               
               
                 Id.16.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-1,4-bis(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- nitrophenethyl) acetamide 
                 B 
                 3.578 
                 541 
               
               
                   
               
               
                 Id.16.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3-(1H-imidazol-1- yl)propyl)-2-(3,6- dioxo-1,4-bis(2- (thiophen-2-yl)ethyl) piperazin-2-yl) acetamide 
                 B 
                 2.377 
                 500 
               
               
                   
               
               
                 Id.16.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-(1H-indol-3-yl) ethyl)-2-(3,6-dioxo- 1,4-bis(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetamide 
                 B 
                 3.554 
                 535 
               
               
                   
               
               
                 Id.16.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-1,4-bis (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(2- (5-methoxy-1H-indol-3- yl)ethyl)acetamide 
                 B 
                 3.481 
                 565 
               
               
                   
               
               
                 Id.16.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(3,6-dioxo-1,4-bis(2- (thiophen-2-yl)ethyl) piperazin-2-yl)-N-(2- methoxyethyl) acetamide 
                 B 
                 2.948 
                 450 
               
               
                   
               
               
                 Id.16.19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-benzyl-2-(3,6-dioxo- 1,4-bis(2-(thiophen-2- yl)ethyl)piperazin-2-yl) acetamide 
                 B 
                 3.519 
                 482 
               
               
                   
               
               
                 Id.17.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo- 1-(2-(thiophen-2-yl) ethyl)piperazin-2-yl)- N-(4-chlorophenethyl) acetamide 
                 C 
                 4.354 
                 510 512 
               
               
                   
               
               
                 Id.17.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 3-(2-(3-(2-aminoethyl)-5- methoxy-1H-indol-1-yl)- 2-oxoethyl)-1-benzyl-4- (2-(thiophen-2-yl)ethyl) piperazin-2,5-dione 
                 C 
                 3.984 
                 545 
               
               
                   
               
               
                 Id.17.12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo- 1-(2-(thiophen-2- yl)ethyl)piperazin-2-yl)- N-methylacetamide 
                 C 
                 3.355 
                 386 
               
               
                   
               
               
                 Id.17.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo- 1-(2-(thiophen-2- yl)ethyl)piperazin-2-yl)- N-(2-methoxyethyl) acetamide 
                 C 
                 3.472 
                 430 
               
               
                   
               
               
                 Id.17.14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(3- morpholinopropyl) acetamide 
                 C 
                 2.984 
                 499 
               
               
                   
               
               
                 Id.17.15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(3- (2-oxopyrrolidin-1-yl) propyl)acetamide 
                 C 
                 3.407 
                 497 
               
               
                   
               
               
                 Id.17.19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-benzyl-2-(4-benzyl- 3,6-dioxo-1-(2-(thiophen- 2-yl)ethyl)piperazin-2-yl) acetamide 
                 C 
                 4.021 
                 462 
               
               
                   
               
               
                 Id.17.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(2,4- dichlorophenethyl) acetamide 
                 C 
                 4.596 
                 544 546 
               
               
                   
               
               
                 Id.17.23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N- phenethylacetamide 
                 C 
                 4.131 
                 476 
               
               
                   
               
               
                 Id.17.24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo- 1-(2-(thiophen-2-yl) ethyl)piperazin-2-yl)- N-(thiophen-2- ylmethyl)acetamide 
                 C 
                 3.936 
                 468 
               
               
                   
               
               
                 Id.17.25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(3- phenylpropyl)acetamide 
                 C 
                 4.294 
                 490 
               
               
                   
               
               
                 Id.17.26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N- (prop-2-yn-1-yl) acetamide 
                 C 
                 3.568 
                 410 
               
               
                   
               
               
                 Id.17.27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-allyl-2-(4-benzyl-3,6- dioxo-1-(2-(thiophen-2- yl)ethyl)piperazin-2-yl) acetamide 
                 C 
                 3.651 
                 412 
               
               
                   
               
               
                 Id.17.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- hydroxyphenethyl) acetamide 
                 C 
                 3.656 
                 492 
               
               
                   
               
               
                 Id.17.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo-1- (2-(thiophen-2-yl) ethyl)piperazin-2-yl)- N-(4-methoxyphen- ethyl)acetamide 
                 C 
                 4.091 
                 506 
               
               
                   
               
               
                 Id.17.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(3,4- dimethoxyphenethyl) acetamide 
                 C 
                 3.917 
                 536 
               
               
                   
               
               
                 Id.17.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- sulfamoylphenethyl) acetamide 
                 C 
                 3.548 
                 555 
               
               
                   
               
               
                 Id.17.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-benzyl-3,6-dioxo-1- (2-(thiophen-2-yl)ethyl) piperazin-2-yl)-N-(4- nitrophenethyl) acetamide 
                 C 
                 4.086 
                 521 
               
               
                   
               
               
                 Id.17.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3-(1H-imidazol-1- yl)propyl)-2-(4-benzyl- 3,6-dioxo-1-(2- (thiophen-2-yl)ethyl) piperazin-2-yl)acetamide 
                 C 
                 3.000 
                 480 
               
               
                   
               
               
                 Id.17.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-(1H-indol-3-yl) ethyl)-2-(4-benzyl-3,6- dioxo-1-(2-(thiophen-2- yl)ethyl)piperazin-2- yl)acetamide 
                 C 
                 4.059 
                 515 
               
               
                   
               
               
                 Id.19.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-chlorophenethyl)-2- (4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1-(prop- 2-yn-1-yl)piperazin-2- yl)acetamide 
                 C 
                 4.548 
                 520 522 
               
               
                   
               
               
                 Id.19.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N-(2- (5-methoxy-1H-indol-3- yl)ethyl)acetamide 
                 C 
                 4.166 
                 555 557 
               
               
                   
               
               
                 Id.19.12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N- methylacetamide 
                 C 
                 3.552 
                 396 398 
               
               
                   
               
               
                 Id.19.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N-(2- methoxyethyl)acetamide 
                 C 
                 3.670 
                 440 442 
               
               
                   
               
               
                 Id.19.14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N-(3- morpholinopropyl) acetamide 
                 C 
                 3.081 
                 509 511 
               
               
                   
               
               
                 Id.19.15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N-(3- (2-oxopyrrolidin-1-yl) propyl)acetamide 
                 C 
                 3.579 
                 507 509 
               
               
                   
               
               
                 Id.19.19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-benzyl-2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(prop-2-yn-1- yl)piperazin-2-yl) acetamide 
                 C 
                 4.214 
                 472 474 
               
               
                   
               
               
                 Id.19.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2,4-dichlorophen- ethyl)-2-(4-(2,4- dichlorophenethyl)- 3,6-dioxo-1-(prop-2- yn-1-yl)piperazin-2- yl)acetamide 
                 C 
                 4.798 
                 554 556 558 
               
               
                   
               
               
                 Id.19.23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N- phenethylacetamide 
                 C 
                 4.329 
                 486 488 
               
               
                   
               
               
                 Id.19.24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N- (thiophen-2-ylmethyl) acetamide 
                 C 
                 4.147 
                 478 480 
               
               
                   
               
               
                 Id.19.25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N- (3-phenylpropyl) acetamide 
                 C 
                 4.493 
                 500 502 
               
               
                   
               
               
                 Id.19.26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N- (prop-2-yn-1-yl)acetamide 
                 C 
                 3.779 
                 420 422 
               
               
                   
               
               
                 Id.19.27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-allyl-2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(prop-2-yn-1-yl) piperazin-2-yl) acetamide 
                 C 
                 3.864 
                 422 424 
               
               
                   
               
               
                 Id.19.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N-(4- hydroxyphenethyl) acetamide 
                 C 
                 3.840 
                 502 504 
               
               
                   
               
               
                 Id.19.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N-(4- methoxyphenethyl) acetamide 
                 C 
                 4.289 
                 516 518 
               
               
                   
               
               
                 Id.19.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N-(3,4- dimethoxyphenethyl) acetamide 
                 C 
                 4.109 
                 546 548 
               
               
                   
               
               
                 Id.19.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N-(4- sulfamoylphenethyl) acetamide 
                 C 
                 3.717 
                 565 567 
               
               
                   
               
               
                 Id.19.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (prop-2-yn-1-yl) piperazin-2-yl)-N-(4-  nitrophenethyl)acetamide  
                 C 
                 4.275 
                 531 533 
               
               
                   
               
               
                 Id.19.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3-(1H-imidazol-1- yl)propyl)-2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(prop-2-yn- 1-yl)piperazin-2-yl) acetamide 
                 C 
                 3.099 
                 490 492 
               
               
                   
               
               
                 Id.19.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-(1H-indol-3-yl) ethyl)-2-(4-(2,4-dichloro- phenethyl)-3,6-dioxo- 1-(prop-2-yn-1-yl) piperazin-2-yl)acetamide 
                 C  
                 4.245 
                 525 527 
               
               
                   
               
               
                 Id.22.1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(4-chlorophenethyl)-2- (4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl) acetamide 
                 C 
                 3.822 
                 573 575 
               
               
                   
               
               
                 Id.22.11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N-(2- (5-methoxy-1H-indol - 3-yl)ethyl)acetamide 
                 C 
                 3.511 
                 608 610 
               
               
                   
               
               
                 Id.22.12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N- methylacetamide 
                 C 
                 3.015 
                 449 451 
               
               
                   
               
               
                 Id.22.13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N-(2- methoxyethyl)acetamide 
                 C 
                 3.103 
                 493 495 
               
               
                   
               
               
                 Id.22.14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N-(3- morpholinopropyl) acetamide 
                 C 
                 2.680 
                 562 564 
               
               
                   
               
               
                 Id.22.15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N-(3- (2-oxopyrrolidin-1-yl) propyl)acetamide 
                 C 
                 3.098 
                 560 562 
               
               
                   
               
               
                 Id.22.19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-benzyl-2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(pyridin-4- ylmethyl)piperazin-2- yl)acetamide 
                 C 
                 3.524 
                 525 527 
               
               
                   
               
               
                 Id.22.2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2,4-dichlorophen- ethyl)-2-(4-(2,4-dichloro- phenethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl) acetamide 
                 C 
                 4.012 
                 607 609 
               
               
                   
               
               
                 Id.22.23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N- phenethylacetamide 
                 C 
                 3.545 
                 539 542 
               
               
                   
               
               
                 Id.22.24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N- (thiophen-2-ylmethyl) acetamide 
                 C 
                 3.441 
                 531 533 
               
               
                   
               
               
                 Id.22.25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N-(3- phenylpropyl)acetamide 
                 C 
                 3.732 
                 553 555 
               
               
                   
               
               
                 Id.22.26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N- (prop-2-yn-1-yl) acetamide 
                 C 
                 3.143 
                 473 475 
               
               
                   
               
               
                 Id.22.27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-allyl-2-(4-(2,4-dichloro- phenethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)acetamide 
                 C 
                 3.227 
                 475 477 
               
               
                   
               
               
                 Id.22.3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N-(4- hydroxyphenethyl) acetamide 
                 C 
                 3.273 
                 555 557 
               
               
                   
               
               
                 Id.22.4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N-(4- methoxyphenethyl) acetamide 
                 C 
                 3.603 
                 569 571 
               
               
                   
               
               
                 Id.22.5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N-(3,4- dimethoxyphenethyl) acetamide 
                 C 
                 3.466 
                 599 601 
               
               
                   
               
               
                 Id.22.6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N-(4- sulfamoylphenethyl) acetamide 
                 C 
                 3.173 
                 618 620 
               
               
                   
               
               
                 Id.22.7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-(4-(2,4-dichlorophen- ethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl)-N-(4- nitrophenethyl) acetamide 
                 C 
                 3.607 
                 584 586 
               
               
                   
               
               
                 Id.22.8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3-(1H-imidazol-1- yl)propyl)-2-(4-(2,4- dichlorophenethyl)-3,6- dioxo-1-(pyridin-4- ylmethyl)piperazin-2- yl)acetamide 
                 C 
                 2.668 
                 543 545 
               
               
                   
               
               
                 Id.22.9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(2-(1H-indol-3-yl) ethyl)-2-(4-(2,4-dichloro- phenethyl)-3,6-dioxo-1- (pyridin-4-ylmethyl) piperazin-2-yl) acetamide 
                 C 
                 3.569 
                 578 580 
               
               
                   
               
             
          
         
       
     
       Compounds of formula Ie 
     Ie.1 6-amino-2-(2-(4-(2,4-dichlorophenethyl)-1-(3,3-diphenylpropyl)-3,6-dioxopiperazin-2-yl)acetamido)hexanamide 
       [0106]    
       
                 
         
             
             
         
       
     
         [0107]    Rink amide-Fmoc resin (II, 500 mg, 0.305 mmol) was deprotected with 5 ml of 20% piperidine in DMF stirring in a microwave reactor for 2 min at 60° C. The resin was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). The Fmoc-L-Lys(Boc)-OH amino acid (XI, 286 mg, 2 eq.) was then bound to the resin using HOBT (82 mg, 2 eq.) and DIC (96 μL, 2 eq.) in 5 ml of DMF. The mixture was stirred at room temperature for 1 h. The resin was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). Once the Fmoc group was removed with 5 ml of 20% piperidine in DMF for 20 min, the resin was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). Subsequently the resin was treated with a solution of acid X (181 mg, 1.1 eq.), HATU (348 mg, 3 eq.), HOBT (123 mg, 3 eq.) and DIPEA (0.313 ml, 6 eq.) in 5 ml of DMF. The reaction mixture was stirred at room temperature for 16 h. The resin was dried and washed with DMF (3×3 ml), isopropyl alcohol (3×3 ml) and DCM (3×3 ml) and was subsequently treated with a mixture of 80:20:2.5:2.5 TFA/DCM/water/triisopropylsilane (5 ml) for 30 min at room temperature. The resin was filtered and the filtrate was evaporated at reduced pressure. The residue obtained is purified by normal phase chromatography using a gradient of a dichloromethane-methanol-ammonia mixture to obtain 15 mg of the desired compound (Ie.1, 8% yield, 100% purity). MS (M+H) +  calculated for C 35 H 41 Cl 2 N 5 O 4 , 666.26, experimental, 666.40. 
       Compounds of formula If 
     If.1.2 6-amino-2-(2-(N-(2,4-dichlorophenethyl)-2-(4-(2,4-dichlorophenethyl)-1-(3,3-diphenylpropyl)-3,6-dioxopiperazin-2-yl)acetamido)acetamido)hexanamide 
       [0108]    
       
                 
         
             
             
         
       
     
         [0109]    Rink amide-Fmoc resin (II, 800 mg, 0.42 mmol) was deprotected with 8 ml of 20% piperidine in DMF stirring in a microwave reactor for 2 min at 60° C. The resin was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). The Fmoc-L-Lys(Boc)-OH amino acid (XII, 497 mg, 2 eq.) was the bound to the resin using HOBT (143 mg, 2 eq.) and DIC (165 μL, 2 eq.) in 8 ml of DMF. The mixture was stirred at room temperature for 1 h. The resin was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). Once the Fmoc group was removed with 8 ml of 20% piperidine in DMF for 20 min, the resin was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). The resin was treated with a solution of bromoacetic acid (III, 295 mg, 4 eq.) and DIC (0.33 ml, 4 eq.) in 1:2 DMF:DCM (8 ml) and the mixture was stirred for 20 min at room temperature. The resin was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml). A solution of 2,4-dichlorophenethylamine (IVd, 0.32 ml, 4 eq.) and triethylamine (0.295 ml, 4 eq.) in 12 ml of DMF was added to the resin and the suspension was stirred for 3 h at room temperature. The supernatant was removed and the reaction was repeated in the same conditions. The resin was filtered and washed with DMF (3×15 ml), isopropyl alcohol (3×15 ml) and DCM (3×15 ml) to obtain the resin XIV, which was treated with a solution of acid X (274 mg, 2 eq.), HATU (116 mg, 1.6 eq.), HOBT and DIPEA (0.295 ml, 3.2 eq.) in 8 ml of DMF. The reaction mixture was stirred at room temperature for 3 h. The resin was dried and washed with DMF (3×3 ml), isopropyl alcohol (3×3 ml) and DCM (3×3 ml) and was subsequently treated with a mixture of 80:20:2.5:2.5 TFA/DCM/water/triisopropylsilane (5 ml) for 30 min at room temperature. The resin was filtered and the filtrate was evaporated at reduced pressure. The residue obtained was purified by semi-preparative RP-HPLC using a gradient of an acetonitrile-water mixture to obtain 128 mg of the desired compound (If.1.2, 34% yield, 99% purity). HRMS (M+H) + calculated for C 45 H 50 Cl 4 N 6 O 5 , 895.2675; experimental, 895.2648. 
       Pharmacological Examples 
     In Vitro Apoptosome Formation Inhibition Assay 
       [0110]    Recombinant Apaf-1 produced in insect cells (rApaf-1) was incubated in the presence (at a concentration of 10 μM) or absence (as control) of the compounds to be evaluated in the assay buffer (20 mM Hepes-KOH pH 7.5, 10 mM KCl, 1.5 mM MgCl 2 , 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 0.1 mM PMSF) for 15 minutes at 30° C. The final rApaf-1 concentration was 40 nM. dATP/Mg (Sigma) and purified horse cytochrome c (Sigma) were then added achieving final concentrations of 100 μM and 0.1 μM, respectively. It was incubated for 60 minutes at 30° C. and recombinant procaspase-9 produced in  E. coli  (rprocaspase-9, final concentration 0.1 μM) was then added and it was incubated for 10 minutes at 30° C. before adding the caspase-9 fluorogenic substrate Ac-LEDH-afc (final concentration 50 μM). The total assay volume was 200 μL. The caspase activity was continuously monitored by means of the afc release at 37° C. in a Wallac 1420 Workstation (λ exc =390 nm, λ em =510 nm). 
         [0111]    The activity values of some compounds described in the examples are indicated in the following table expressed as the percentage of Apaf-1 inhibition. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 Example 
                 % Apaf-1 inhibition 
               
               
                   
                   
               
             
             
               
                   
                 I.1.20 
                 36 
               
               
                   
                 I.1.16 
                 46 
               
               
                   
                 I.1.25 
                 26 
               
               
                   
                 Ia.6.2 
                 29 
               
               
                   
                 Ib.1.2 
                 72 
               
               
                   
                 Ib.2.2 
                 28 
               
               
                   
                 Ib.3.2 
                 48 
               
               
                   
                 Ic.3.2 
                 29 
               
               
                   
                 Ic.5.2 
                 23 
               
               
                   
                 Id.5.2 
                 40 
               
               
                   
                 If.1.2 
                 80