PATENT DOCUMENT

Abstract:
This invention relates to a series of substitituted amino acids of Formula I 
                                 
pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention are small molecules which bind to the erythropoietin receptor and compete with the natural ligand for binding to this receptor.

Full Description:
This application is a divisional application of U.S. application Ser. No. 09/927,111, filed Aug. 10, 2001 now U.S. Pat. No. 6,750,369 to which no matter has been added. Such earlier application is hereby incorporated into the present application by reference and which is a divisional application of U.S. application Ser. No. 09/517,976, filed Mar. 3, 2000, which is now U.S. Pat. No. 6,310,078, which is a Continuation-in-part of U.S. application Ser. No. 09/294,785, filed Apr. 19, 1999 now abandoned, which claims benefit of U.S. Provisional Application 60/082,392, filed Apr. 20, 1998. 
    
    
     This invention relates to a series of small molecules which bind to the erythropoietin receptor and compete with the natural ligand for binding to said receptor. The invention includes pharmaceutical compositions containing these mimetics, their methods of production as well as intermediates used in their synthesis. 
     Erythropoietin (EPO) is a 34,000 dalton glycoprotein hormone which is produced in the mammalian kidney. Its primary role is stimulation of mitotic cell division and differentiation of erythrocyte precursor cells. As a result this hormone regulates the production of erythrocytes, the hemoglobin contained therein and the blood&#39;s ability to carry oxygen. The commercial product Epogen® is used in the treatment of anemia. This drug is produced by recombinant techniques and is formulated in aqueous isotonic sodium chloride/sodium citrate. Even though it has been used successfully in the treatment of anemia, it is a costly drug that is administered intravenously. This method of administration is both costly and inconvenient for the patient; therefore it would be desirable to find a EPO mimetic which has the potential for oral activity. 
     A small molecule EPO mimetic has advantages over the natural protein. The immune response associated with large peptides is unlikely to occur with small molecules. In addition, the variety of pharmaceutical formulations that may be used with small molecules are technically unfeasible for proteins. Thus the use of relatively inert formulations for small molecules is possible. The most important advantage of small molecules is their potential for oral activity. Such an agent would ease administration, cost less and facilitate patient compliance. 
     Although compounds which mimic EPO are useful in stimulating red blood cell synthesis, there are diseases where the overproduction of red blood cells is a problem. Erythroleukemia and polysythemia vera are examples of such diseases. Since EPO is an agent responsible for the maturation of red blood cell precursors, an antagonist of EPO would have utility treating either of those diseases. 
     SUMMARY OF THE INVENTION 
     The disclosed invention consists of a series of small molecules which demonstrate competitive binding with the natural ligand for the EPO receptor. As such these compounds are potentially useful in the treatment of diseases or conditions associated with this receptor. In addition, the invention contemplates methods of producing these compounds and intermediates used in their production. 
     The invention includes compounds of the Formula I: 
                                
wherein:
         R 1  is the side chain of a natural or unnatural α-amino acids, where if said side chain contains a protectable group, that group may be protected with a member of the group consisting of succinyl, glutaryl, 3,3-dimethylglutaryl, C 1-5 alkyl, C 1-5 alkoxycarbonyl, acetyl, N-(9-fluorenylmethoxycarbonyl), trifluoroacetyl, omega-carboxyC 1-5 alkylcarbonyl, t-butoxycarbonyl, benzyl, benzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, phenylsulfonyl, ureido, t-butyl, cinnamoyl, trityl, 4-methyltrityl, 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl, tosyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl, phenylureido, and substituted phenylureido (where the phenyl substituents are phenoxy, halo, C 1-5 alkoxycarbonyl);   R 2  and R 3  
           may be taken together to form a six-membered aromatic ring which is fused to the depicted ring, or   are independently selected from the group consisting of hydrogen, C 1-5  alkyl, C 1-5  alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC 1-5 alkyl, phenyl C 1-5 alkoxy,   substituted phenyl (where the substituents are selected from C 1-5 alkyl, C 1-5  alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),   substituted phenoxy (where the substituents are selected from C 1-5  alkyl, C 1-5  alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),   substituted phenylC 1-5 alkyl (where the substituents are selected from C 1-5  alkyl, C 1-5  alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),   substituted phenylC 1-5 alkoxy (where the substituents are selected from C 1-5  alkyl, C 1-5  alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino), and   substituted amino (where the substituents are selected from one or more members of the group consisting of C 1-5 alkyl, halosubstitutedC 1-5 alkyl, C 1-5 alknyl, C 1-5 alkenyl, phenyl, phenylC 1-5 alkyl, C 1-5 alkylcarbonyl, halo substituted C 1-5 alkylcarbonyl, carboxyC 1-5 alkyl, C 1-5 alkoxyC 1-5 alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C 1-5 alkylsulfonyl, phenylcarbonyl, phenylC 1-5 alkylcarbonyl, phenylsulfonyl, phenylC 1-5 alkylsulfonyl substituted phenylcarbonyl, substituted phenylC 1-5 alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC 1-5 alkylsulfonyl, substituted phenyl, and substituted phenylC 1-5 alkyl [where the aromatic phenyl, phenylC 1-5 alkyl, phenylcarbonyl, phenylC 1-5 alkylcarbonyl, phenylsulfonyl, and phenylC 1-5 alkylsulfonyl substitutents are independently selected from one to five members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino]);   
           R 4  and R 5  
           may be taken together to form a six-membered aromatic ring which is fused to the depicted ring, or   are independently selected from the group consisting of hydrogen, C 1-5  alkyl, C 1-5  alkoxy, hydroxy, halo, trifluoromethyl, nitro, amino, phenyl, phenoxy, phenylC 1-5 alkyl, phenyl C 1-5 alkoxy,   substituted phenyl (where the substituents are selected from C 1-5 alkyl, C 1-5  alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),   substituted phenoxy (where the substituents are selected from C 1-5  alkyl, C 1-5  alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),   substituted phenylC 1-5 alkyl (where the substituents are selected from C 1-5  alkyl, C 1-5  alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino),   substituted phenylC 1-5 alkoxy (where the substituents are selected from C 1-5  alkyl, C 1-5  alkoxy, hydroxy, halo, trifluoromethyl, nitro, cyano, and amino), and   substituted amino (where the substituents are selected from one or more members of the group consisting of C 1-5 alkyl, halosubstitutedC 1-5 alkyl, C 1-5 alknyl, C 1-5 alkenyl, phenyl, phenylC 1-5 alkyl, C 1-5 alkylcarbonyl, halo substituted C 1-5 alkylcarbonyl, carboxyC 1-5 alkyl, C 1-5 alkoxyC 1-5 alkyl, cinnamoyl, naphthylcarbonyl, furylcarbonyl, pyridylcarbonyl, C 1-5 alkylsulfonyl, phenylcarbonyl, phenylC 1-5 alkylcarbonyl, phenylsulfonyl, phenylC 1-5 alkylsulfonyl substituted phenylcarbonyl, substituted phenylC 1-5 alkylcarbonyl, substituted phenylsulfonyl, substituted phenylC 1-5 alkylsulfonyl, substituted phenyl, and substituted phenylC 1-5 alkyl [where the aromatic phenyl, phenylC 1-5 alkyl, phenylcarbonyl, phenylC 1-5 alkylcarbonyl, phenylsulfonyl, and phenylC 1-5 alkylsulfonyl substitutents are independently selected from one to five members of the group consisting of C 1-5 alkyl, C 1-5 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino]);   
           W is selected from the group consisting of —CH═CH—, —S—, and —CH═N—;   Q is selected from the group consisting of —CH═CH—, —S—, and —CH═N—;   X is selected from the group consisting of carbonyl, C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkenylcarbonyl, and (CH 2 ) m —C(O)— where m is 2–5;   Y is selected from the group consisting of carbonyl, C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkenylcarbonyl, and (CH 2 ) m —C(O)— where m is 2–5;   n is 1, 2, or 3;   Z is selected from the group consisting of hydroxy, C 1-5  alkoxy, phenoxy, phenylC 1-5 alkoxy, amino, C 1-5 alkylamino, diC 1-5 alkylamino, phenylamino, phenylC 1-5 alkylamino, piperidin-1-yl
           substituted piperidin-1-yl (where the substituents are selected from the group consisting of C 1-5 alkyl, C 1-5 alkoxy, halo, aminocarbonyl, C 1-5 alkoxycarbonyl, and oxo;   substituted phenylC 1-5 alkylamino (where the aromatic substitutents are selected from the group consisting of C 1-5 alkyl, C 1-5 alkoxy, phenylC 1-5 alkenyloxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino),   substituted phenoxy (where the aromatic substitutents are selected from the group consisting of C 1-5 alkyl, C 1-5 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino),   substituted phenylC 1-5 alkoxy (where the aromatic substitutents are selected from the group consisting of C 1-5 alkyl, C 1-5 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino),   —OCH 2 CH 2 (OCH 2 CH 2 ) s OCH 2 CH 2 O—, —NHCH 2 CH 2 (OCH 2 CH 2 ) s OCH 2 CH 2 NH—, —NH(CH 2 ) p O(CH 2 ) q O(CH 2 ) p NH—, —NH(CH 2 ) q NCH 3 (CH 2 ) s NH—, —NH(CH 2 ) s NH—, and (NH(CH 2 ) s ) 3 N,
               where s, p, and q are independently selected from 1–7   
               with the proviso that if n is 2, Z is not hydroxy, C 1-5  alkoxy, amino, C 1-5 alkylamino, diC 1-5 alkylamino, phenylamino, phenylC 1-5 alkylamino, or piperidin-1-yl,
               with the further proviso that if n is 3, Z is (NH(CH 2 ) s ) 3 N.
 
and the salts thereof.
   
               
               
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The terms used in describing the invention are commonly used and known to those skilled in the art. “Independently” means that when there are more than one substituent, the substitutents may be different. The term “alkyl” refers to straight, cyclic and branched-chain alkyl groups and “alkoxy” refers O-alkyl where alkyl is as defined supra. “Cbz” refers to benzyloxycarbonyl. “Boc” refers to  t -butoxycarbonyl and “Ts” refers to toluenesulfonyl. “DCC” refers to 1,3-dicyclohexylcarbodiimide, “DMAP” refers to 4- N ′, N -dimethylaminopyridine and “HOBT” refers to 1-hydroxybenzotriazole hydrate. “Fmoc” refers to  N -(9-fluorenylmethoxycarbonyl), “DABCO” refers to 1,4-Diazabicyclo[2.2.2]octane, “EDCI” refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, “Dde” refers to 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl, and “TMOF” refers to trimethyl orthoformate. The side chains of α-amino acids refer to the substituents of the stereogenic carbon of an α-amino acid. For example if the amino acid is lysine, the side chain is 1-aminobutan-4-yl. The term natural amino acid refers to the 20 α-amino acids of the L configuration which are found in natural proteins. Unnatural α-amino acids include synthetic amino acids such as, α-aminoadipic acid, 4-aminobutanoic acid, 6-aminohexanoic acid, α-aminosuberic acid, 5-aminopentanoic acid, p-aminophenylalanine, α-aminopimelic acid γ-carboxyglutamic acid, p-carboxyphenylalanine, carnitine, citrulline, α,β-diaminopropionic acid, α,γ-diaminobutyric acid, homocitrulline, homoserine, and statine as well as D-configuration amino acids. The term “protectable group” refers to a hydroxy, amino, carboxy, carboxamide, guanidine, amidine or a thiol groups on an amino acid side. Compounds of the invention may be prepared by following general procedures known to those skilled in the art, and those set forth herein. 
     The compounds of the invention may be prepared by liquid phase organic synthesis techniques or by using amino acids which are bound to a number of known resins. The underlying chemistry, namely, acylation and alkylation reactions, peptide protection and deprotection reactions as well as peptide coupling reactions use similar conditions and reagents. The main distinction between the two methods is in the starting materials. While the starting materials for the liquid phase syntheses are the N-protected amino acids or the lower alkyl ester derivatives of either the N-protected or N-unprotected amino acids, the starting material for the resin syntheses are N-protected amino acids which are bound to resins by their carboxy termini. 
     General Procedure for the Solid-Phase Synthesis of Symmetrical Nα,Nα-Disubstituted Amino Acids 
     Scheme 1 
     An equivalent of an N-Fmoc-protected amino acid which is bound to a resin 1a is suspended in a suitable solvent such as DMF. This solvent is removed and the nitrogen protecting group (Fmoc) is removed by stirring the resin bound amino acid with an organic base, such as piperidine, and an addition portion of the solvent. A solution of about two to three equivalents of an appropriately substituted halide, 1b, and a suitable base such DIEA is added to the resin bound amino acid and this mixture is shaken for 18–36 h. The resulting mixture is washed with several portions of a suitable solvent and is suspended and shaken in an acidic solution, such as 50% TFA/CH 2 Cl 2 , over several hours to cleave the acid from the resin and give the N-disubstituted amino acid 1c. 
     By varying the resin bound amino acid 1a, one may obtain many of the compounds of the invention. The following resin bound amino acids may be used in Scheme I: alanine, N-g-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)arginine, β-(4-methyltrityl)asparagine, aspartic acid (β-t-butyl ester), S-(trityl)cysteine, γ-(4-methyltrityl)glutamine, glutamic acid (β-t-butyl ester), glycine, N-imidazolyl-(trityl)histidine, isoleucine, leucine, N-ε-(2-chlorobenzyloxycarbonyl)lysine, N-ε-(t-butoxycarbonyl)lysine, methionine, phenylalanine, proline, O-(t-butyl)serine, O-(t-butyl)threonine, N-indolyl-(t-butoxycarbonyl)tryptophan, O-(t-butyl)tyrosine, valine, β-alanine, α-aminoadipic acid, 4-aminobutanoic acid, 6-aminohexanoic acid, α-aminosuberic acid, 5-aminopentanoic acid, p-aminophenylalanine, α-aminopimelic acid γ-carboxyglutamic acid, p-carboxyphenylalanine, carnitine, citrulline, α,β-diaminopropionic acid, α,γ-diaminobutyric acid, homocitrulline, homoserine, and statine. In addition, the choice of “W” and “X” can be varied by using known halide derivatives of 1b. For example using benzylchloride, 2-chloromethylthiophene, or 2-chloromethylpyridine gives compounds of the invention where “W” is —CH═CH—, —S—, or —CH═N—, respectively. For variations in “X”, the use of 2-chloroethylphenyl, 3-chloro-1-propenylbenzene, or benzeneacetyl chloride as 1b, give compounds where Y is (CH 2 ) 2 , —CH═CH—CH 2 —, or —CH 2 C(O)— respectively. Still further, Scheme 1 may be used to produce combinatorial mixtures of products. Using mixtures of resin bound amino acids, 1a, with only one 1b produces said combinatorial mixtures. Alternatively, using one amino acid 1a with a mixture of 1b as well as mixture of 1a with mixtures of 1b gives a large range of combinatorial mixtures. 
     
       
                 
         
             
             
         
      
     
     General Procedure for the Solid-Phase Synthesis of Unsymmetrical Nα,Nα-Disubstituted Amino Acids 
     Scheme 2, Step A 
     An equivalent of an N-Fmoc-protected amino acid which is bound to a resin 1a is suspended in a suitable solvent such as DMF. This solvent is removed and the nitrogen protecting group (Fmoc) is removed by stirring the resin bound amino acid with an organic base, such as piperidine, and an addition portion of the solvent. Trimethyl orthoformate and an appropriately substituted aldehyde 2a (5 equivalents) is added and the mixture is shaken under N 2  overnight. This mixture is treated with a suspension of NaBH(OAc) 3  (5 equivalents) in CH 2 Cl 2  and shaken under N 2  overnight. After filtration and washing with a suitable solvent, the resulting product, resin bound Nα-monosubstituted amino acid 2b, is rinsed with a suitable solvent and its identity is confirmed by MS and or HPLC analysis after treatment of a portion of the resin with 50% TFA/CH 2 Cl 2 . 
     Scheme 2, Step B 
     The resin 2b is suspended in an appropriate solvent such as DMF and is filtered. The appropriately substituted alkyl or arylkyl halide, 2c, and an appropriate base such as DIEA are added with some additional solvent and the mixture is shaken under N 2  for 18–36 h. The resin bound Nα,Nα-disubstituted amino acid, 2d, is isolated from the suspension and the resin is cleaved with an acidic solution to give the free acid 2e. 
     
       
                 
         
             
             
         
      
     
     Scheme 3, Step C 
     A resin bound amine, 2d, where R 4  is nitro, is suspended in a suitable solvent, such as DMF, and is filtered. This mixture is treated with SnCl 2  dihydrate in DMF and shaken under N 2  overnight. The solvent is removed and the resin is washed successive portions of a suitable solvent to give the resin bound compound 3a where R 4  is amino. The resin is suspended in a suitable solvent and is combined with an organic base, such as pyridine an appropriately substituted carboxylic acid anhydride, acid chloride, or sulfonyl chloride. The mixture is shaken under N 2  overnight and is filtered to give the resin bound amino acid 3b. This material is treated with an acid and a suitable solvent to give the free amino acid 3b. 
     Scheme 3, Step D 
     The resin bound amine 3a is treated with TMOF and an appropriately substituted aldehyde 3c is added and the mixture is shaken under N 2  overnight. The resulting mixture is drained and treated with a suspension of NaBH(OAc) 3  in an appropriate solvent and this mixture is shaken under N 2  overnight. The resin bound 3-aralkylaminophenyl amino acid is identified my spectral techniques after clevage to give the free acid 3d as previously described. 
     Scheme 3, Step E 
     Resin bound, 2d, where R 1  is (CH 2 ) 4 NH(Dde) is mixed with a suitable solvent, such as DMF, and shaken with successive portions of 2% solution of hydrazine hydrate in DMF over about 30 min. The resin is filtered and treated with a suitable solvent and a cyclic anhydride derivative 3e, and a base such as DMAP and pyridine. This mixture is shaken under N 2  overnight and filtered to give the resin bound amine, 3f. This material is identified by spectral techniques after clevage to give the free acid 3f as previously described. 
     
       
                 
         
             
             
         
      
     
     Scheme 4, Step F 
     Resin bound 2b, where R 2  is nitro is suspended in CH 2 Cl 2  and is treated with an organic base, such as pyridine, and 9-fluorenylmethoxy chloride. This mixture is shaken under N 2  overnight, filtered and resuspended in a suitable solvent. This mixture is treated with SnCl 2  dihydrate in DMF and shaken under N 2  overnight. The solvent is removed and the resin is washed successive portions of a suitable solvent and filtered to give the resin bound compound 4a where R 2  is amino. The resin 4a is then suspended in a suitable solvent, such as CH 2 Cl 2 , and is combined with 0.4 mmol of pyridine and 0.25–0.4 mmol of the appropriately substituted carboxylic acid anhydride, acid chloride, or sulfonyl chloride. The mixture is shaken under N 2  overnight, filtered, and washed successively with three portions each of CH 2 Cl 2  and MeOH. This resin is suspended in DMF, filtered, and shaken under N 2  with 5 mL of a 40% solution of piperidine in DMF. After 1 h, the solvent is drained and the resin was washed successively with three portions each of suitable solvents to give the resin bound 4b. The identity of the compound was confirmed by spectral analysis after cleveage as previously described. 
     
       
                 
         
             
             
         
      
     
     Scheme 5 
     The resin 2b (0.2 mmol) is suspended in CH 2 Cl 2 , filtered, and is resuspended in CH 2 Cl 2 . This suspension is treated with diethyl phosphonoacetic acid and diisopropylcarbodiimide or other suitable carbodiimide reagent, and the mixture is shaken under N 2  overnight. The solvent is drained and the resulting resin 5a was washed successively with three portions each of CH 2 Cl 2  and MeOH. The resin is suspended in DMF and filtered. A solution of the appropriately substituted aldehyde 5b (0.6–1.0 mmol) in 3–5 mL of DMF, lithium bromide (0.6–1.0 mmol), and a suitable base such as DIEA or Et 3 N (0.6–1.0 mmol) is added and the mixture is shaken under N 2  overnight. The solvent is removed and the resin is washed successively with three portions each of DMF, CH 2 Cl 2 , and MeOH. The identity of the resin bound substituted amino acid 5c was confirmed spectral techniques. The resin bound material may be treated with 50% TFA/CH 2 Cl 2  over 1–1.5 h, to give the acid 5c. 
     
       
                 
         
             
             
         
      
     
     Scheme 6 
     To prepare compounds where n is 2 and Z is NH(CH 2 ) s NH, products of Schemes 1–5 may be used in Scheme 6. Treatment of two equivalents of the substituted amino acid 1c with an equivalent of the diamine 6a, in the presence of HOBT and a peptide coupling agent such as EDCI and a base such as DIEA at room temperature over 16 h gives the dimer 6b. 
     
       
                 
         
             
             
         
      
     
     General Procedure for the Solution-Phase Synthesis of Symmetrical Nα,Nα-Disubstituted Amino Acids 
     Scheme 7, Step A 
     A solution of of amino acid ester 7a, an appropriately substituted halide derivitive 1b, and an appropriate base such as DIEA, Na 2 CO 3 , or Cs 2 CO 3  in a suitable solvent, such as DMF, is heated at 50–100° C. under N 2  overnight, or until the starting material is exhausted, to give a mixture of the di and mono-substituted amines, 7b and 7c respectively. If the side chains of R 1  contain acid cleavable protecting groups, those groups may be cleaved by treatment with 30–80% TFA/CH 2 Cl 2 . Esters 7b and 7c may be independently converted to the corresponding acids 7d and 7e by hydrolysis with an appropriate base such as aqueous NaOH. 
     
       
                 
         
             
             
         
      
     
     General Procedure for the Solution-Phase Synthesis of Unsymmetrical Nα,Nα-Disubstituted Amino Acids 
     Scheme 8, Step A 
     A solution of 1 mmol of amino acid ester 8a (or the corresponding HCl salt and 1.1 mmol of DIEA) and 1–1.5 mmol of the appropriately substituted aldehyde 2a in 3–5 mL of trimethyl orthoformate was stirred at room temperature under N 2  overnight. The solution was either concentrated and used directly for the next reaction, or was partitioned between EtOAc and water, washed with brine, dried over Na 2 SO 4 , and concentrated to give crude product, which was purified by MPLC to give mono-substituted product 8b. 
     Scheme 8, Step B 
     Amino ester 8b was dissolved in DMF, combined with 1.1–1.5 mmol of the appropriately substituted chloride or bromide 2c, and heated at 50–100° C. overnight. The reaction mixture was cooled and partitioned between water and EtOAc. The organic layer was washed three times with water and once with brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC to give pure 8c. For examples of 8c wherein the side chain R 1  contained an acid-cleavable protecting group such as t-butylcarbamate, t-butyl ester, or t-butyl ether, 8c was stirred in 30–80% TFA/CH 2 Cl 2  for 1–3 h. The reaction mixture was concentrated and optionally dissolved in HOAc and freeze-dried to give the deprotected form of 8c. For examples of 8c where R 9  was equal to t-butyl, 8c was stirred in 30–80% TFA/CH 2 Cl 2  for 1–3 h and treated as described above to give acid 8d. For examples of 8c where R 9  was equal to methyl, ethyl, or other primary or secondary alkyl esters, 8c was stirred with with 1–2 mmol of aqueous LiOH, NaOH, or KOH in MeOH, EtOH, or THF at 20–80° C. until TLC indicated the absence of 8c. The solution was acidified to pH 4–5 with aqueous citric acid or HCl and was extracted with CH 2 Cl 2  or EtOAc. The organic solution was washed with brine, dried over Na 2 SO 4 , and concentrated to give 8d. 
     Scheme 8, Step C 
     For examples of amino acid ester 8c where R 1 ═(CH 2 ) 4 NHBoc, 8c (1 mmol) was stirred in 30–80% TFA/CH 2 Cl 2  for 1–3 h. The reaction mixture was concentrated to provide 8e as the TFA salt. Optionally, the TFA salt was dissolved in CH 2 Cl 2  or EtOAc and washed with aqueous NaOH or Na 2 CO 3 , dried over Na 2 SO 4 , and concentrated to give 8e as the free base. 
     Scheme 8, Step D 
     A solution of 1 mmol of 8e, 1–4 mmol of an appropriate base such as DIEA, and 1–2 mmol of the appropriately substituted cyclic anhydride 3e was stirred in CH 2 Cl 2  or DMF under N 2  overnight. The resulting mixture was diluted with CH 2 Cl 2  or EtOAc and washed with aqueous HCl, water, and brine, was dried over Na 2 SO 4 , and concentrated to provide 8f. Alternatively, 1 mmol of 8e, 1–4 mmol of an appropriate base such as DIEA, and 1–2 mmol of the appropriately substituted carboxylic acid anhydride (R 11 CO) 2 O or acid chloride R 11 COCl was stirred in CH 2 Cl 2  or DMF under N 2  overnight and worked up as above to provide 8g. Alternatively, 1 mmol of 8e, 1–4 mmol of an appropriate base such as DIEA, and 1–2 mmol of the appropriately substituted isocyanate R 12 NCO was stirred in CH 2 Cl 2  or DMF under N 2  overnight and worked up as above to provide 8h. 
     
       
                 
         
             
             
         
      
     
     Scheme 9, Step A 
     For examples of 8c where R 5 ═NO 2 , a solution of 1 mmol of 8c (where R 2 , R 3 , R 4 , or) and 10–12 mmol of SnCl 2  dihydrate was stirred in MeOH, EtOH, or DMF at 20–80° C. for 0.5–24 h under N 2 . The solution was taken to room temperature and poured into aqueous Na 2 CO 3  with rapid stirring. The resulting mixture was extracted with EtOAc or CH 2 Cl 2  and the organic extracts were washed with brine, dried over Na 2 SO 4 , and concentrated to give the aminophenyl product 9a, which was purified by MPLC or used without further purification. 
     Scheme 9, Step B 
     A solution of 1 mmol of aminophenyl compound 9a and 1–1.5 mmol of the appropriately substituted aldehyde 2a in 3–5 mL of trimethyl orthoformate was stirred at room temperature under N 2  overnight. The solution was either concentrated and used directly for the next reaction, or was partitioned between EtOAc and water, washed with brine, dried over Na 2 SO 4 , and concentrated to give crude product, which was purified by MPLC to give 9b. For examples of 9b wherein the side chain R 1  or R 9  contained an acid-cleavable protecting group such as t-butylcarbamate, t-butyl ester, or t-butyl ether, 9b was stirred in 30–80% TFA/CH 2 Cl 2  for 1–3 h. The reaction mixture was concentrated and optionally dissolved in HOAc and freeze-dried to give the deprotected form of 9b. 
     Scheme 9, Step C 
     A solution of 1 mmol of 3-aminophenyl compound 9a, 1.1–2 mmol of pyridine, and 1–1.5 mmol of the appropriately substituted acid chloride, acid anhydride, or sulfonyl chloride in 3–5 mL of CH 2 Cl 2  or ClCH 2 CH 2 Cl was stirred at room temperature under N 2  overnight. The solution was partitioned between EtOAc and water, washed with water, saturated aqueous NaHCO 3 , and brine, dried over Na 2 SO 4 , and concentrated to give crude product which was optionally purified by MPLC to give amide or sulfonamide 9c. For examples of 9c wherein the side chain R 1  or R 9  contained an acid-cleavable protecting group such as t-butylcarbamate, t-butyl ester, or t-butyl ether, 9c was stirred in 30–80% TFA/CH 2 Cl 2  for 1–3 h. The reaction mixture was concentrated and optionally dissolved in HOAc and freeze-dried to give the deprotected form of 9c. 
     
       
                 
         
             
             
         
      
     
     General Procedure for the Solution-Phase Synthesis of Symmetrical Nα,Nα-Disubstituted Amino Amides and Their Dimers and Trimers 
     Scheme 10, Step A 
     A solution of 1 mmol of N-Cbz-protected amino acid 10a and the appropriate amine (ZH, 1 mmol), diamine (ZH 2 , 0.5 mmol), or triamine (ZH 3  0.33 mmol), was treated with 1.1 mmol of HOBt, 1.1 mmol of DIEA, and 2.1 mmol of EDCI in 3–6 mL of CH 2 Cl 2  or DMF. [Alternatively, 1 mmol of the pentafluorophenyl ester or N-hydroxysuccinimide ester of 10a was mixed with the appropriate portion of amine (ZH), diamine (ZH 2 ), or triamine (ZH 3 ) in 3–6 mL of DMF.] The solution was stirred at room temperature under N 2  for 12–24 h, and EtOAc was added. The organic solution was washed with 5% aqueous citric acid, water, saturated NaHCO 3 , and brine, dried over Na 2 SO 4 , and concentrated. The crude product was optionally purified by MPLC to afford amide 10b. Compound 10b was stirred in 30–80% TFA/CH 2 Cl 2  for 1–3 h. The reaction mixture was concentrated to provide the TFA salt which was dissolved in CH 2 Cl 2  or EtOAc and washed with aqueous NaOH or Na 2 CO 3 , dried over Na 2 SO 4 , and concentrated to give 10c as the free base. 
     Scheme 10, Step B 
     A solution of 1 mmol of amino acid ester 10c (n=1), 2.5–3 mmol of the appropriately substituted chloride or bromide 2c, and 2.5–3 mmol of an appropriate base such as DIEA, Na 2 CO 3 , or Cs 2 CO 3  in 3–5 mL of DMF was heated at 50–100° C. under N 2  for 18–24 h. (For examples of 10c where n=2 or 3, the amounts of 2c and base were increased by two- or three-fold, respectively.) The reaction mixture was cooled and partitioned between water and EtOAc. The organic layer was washed three times with water and once with brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC to give pure amide 10d. 
     Alternatively, a solution of 1 mmol of amino acid ester 10c (n=1), 2.5–3 mmol of the appropriately substituted aldehyde 2a, and 2.5–3 mmol of borane-pyridine complex in 3–5 mL of DMF or EtOH was stirred at room temperature under N 2  for 3–5 days. (For examples of 10c where n=2 or 3, the amounts of 2c and borane-pyridine complex were increased by two- or three-fold, respectively.) The mixture was concentrated to dryness and was partitioned between water and CH 2 Cl 2 , washed with brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC to give pure amide 10d. 
     Scheme 10, Step C 
     For examples of 10d where R 1 ═CH 2 CH 2 CO 2 -t-Bu or CH 2 CO 2 -t-Bu, 10d was stirred in 30–80% TFA/CH 2 Cl 2  for 1–24 h. The reaction mixture was concentrated and optionally dissolved in HOAc and freeze-dried to give acid 10e. 
     Scheme 10, Step D 
     For examples of 10d where R 1  is equal to (CH 2 ) 4 NHBoc, 10d was stirred in 30–80% TFA/CH 2 Cl 2  for 1–24 h. The reaction mixture was concentrated and optionally dissolved in HOAc and freeze-dried to give amine 10f as the TFA salt which was optionally dissolved in CH 2 Cl 2  or EtOAc, washed with aqueous NaOH or Na 2 CO 3 , dried over Na 2 SO 4 , and concentrated to give 10f as the free base. 
     Scheme 10, Step E 
     A solution of 1 mmol of 10f, 1–4 mmol of an appropriate base such as DIEA, and 1–2 mmol of the appropriately substituted cyclic anhydride 3e was stirred in CH 2 Cl 2  or DMF under N 2  overnight. The resulting mixture was diluted with CH 2 Cl 2  or EtOAc and washed with aqueous HCl, water, and brine, was dried over Na 2 SO 4 , and concentrated to provide acid 10g. Alternatively, 1 mmol of 10f, 1–4 mmol of an appropriate base such as DIEA, and 1–2 mmol of the appropriately substituted carboxylic acid anhydride (R 11 CO) 2 O or acid chloride R 11 COCl was stirred in CH 2 Cl 2  or DMF under N 2  overnight and worked up as above to provide 10h. Alternatively, 1 mmol of 8e, 1–4 mmol of an appropriate base such as DIEA, and 1–2 mmol of the appropriately substituted isocyanate R 12 NCO was stirred in CH 2 Cl 2  or DMF under N 2  overnight and worked up as above to provide 10i. 
     
       
                 
         
             
             
         
      
     
     General Procedure for the Solid-Phase Synthesis of Nα,Nα-Bis-Cinnamyl Amino Acids and Nα-Cinnamyl Amino Acids 
     Scheme 11 
     An equivalent of an N-Fmoc-protected amino acid 11a which is bound to a polystyrene resin such as Wang resin is suspended in a suitable solvent such as DMF. This solvent is removed and the nitrogen protecting group (Fmoc) is removed by stirring the resin bound amino acid with an organic base, such as piperidine, and an addition portion of the solvent. After filtration and washing with solvent, the resin is suspended in an appropriate solvent such as DMF. A solution of about 2–3 equivalents of an appropriately substituted halide 11b and a suitable base such DIEA is added to the resin bound amino acid and this mixture is shaken for 18–36 h. The resulting mixture is washed with several portions of a suitable solvent and is suspended and shaken in an acidic solution, such as 50% TFA/CH 2 Cl 2 , over several hours to cleave the acid from the resin to give a mixture of the Nα,Nα-bis-cinnamyl amino acid 11c and the Nα-cinnamyl amino acid 11d. 
     By varying the resin bound amino acid 11a, one may obtain many of the compounds of the invention. The following resin bound amino acids may be used in Scheme 11: alanine, N-g-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)arginine, β-(4-methyltrityl)asparagine, aspartic acid (β-t-butyl ester), S-(trityl)cysteine, γ-(4-methyltrityl)glutamine, glutamic acid (β-t-butyl ester), glycine, N-imidazolyl-(trityl)histidine, isoleucine, leucine, N-ε-(2-chlorobenzyloxycarbonyl)lysine, N-ε-(t-butoxycarbonyl)lysine, methionine, phenylalanine, proline, O-(t-butyl)serine, O-(t-butyl)threonine, N-indolyl-(t-butoxycarbonyl)tryptophan, O-(t-butyl)tyrosine, valine, β-alanine, α-aminoadipic acid, 4-aminobutanoic acid, 6-aminohexanoic acid, α-aminosuberic acid, 5-aminopentanoic acid, p-aminophenylalanine, α-aminopimelic acid γ-carboxyglutamic acid, p-carboxyphenylalanine, carnitine, citrulline, α,β-diaminopropionic acid, α,γ-diaminobutyric acid, homocitrulline, homoserine, and statine. 
     
       
                 
         
             
             
         
      
     
     Scheme 12, Step A 
     An equivalent of an N-Fmoc-protected amino acid which is bound to a resin 11a is suspended in a suitable solvent such as DMF. This solvent is removed and the nitrogen protecting group (Fmoc) is removed by stirring the resin bound amino acid with an organic base, such as piperidine, and an addition portion of the solvent. After filtration and washing with solvent, the resin is suspended in an appropriate solvent such as trimethyl orthoformate (TMOF), an appropriately substituted aldehyde 12a (5 equivalents) is added, and the mixture is shaken under N 2  overnight. This mixture is treated with a suspension of NaBH(OAc) 3  (5 equivalents) in CH 2 Cl 2  and shaken under N 2  overnight. After filtration and washing with a suitable solvent, the resulting product, resin bound Nα-monosubstituted amino acid 12b, is suspended and shaken in an acidic solution, such as 50% TFA/CH 2 Cl 2 , over several hours to cleave the acid from the resin to give the Nα-cinnamyl amino acid 11d. 
     Scheme 12, Step B 
     The resin 12b is suspended in an appropriate solvent such as DMF and is filtered. The appropriately substituted halide 12c and an appropriate base such as DIEA are added with some additional solvent and the mixture is shaken under N 2  for 18–36 h. The resin bound Nα,Nα-cinnamyl amino acid 12d is isolated from the suspension and the resin is cleaved with an acidic solution as described above to give the free acid 12e. 
     
       
                 
         
             
             
         
      
     
     General Procedure for the Solution-Phase Synthesis of Nα,Nα-Bis-Cinnamyl Amino Acids and Nα-Cinnamyl Amino Acids 
     Scheme 13 
     A solution of of amino acid ester 13a, an appropriately substituted halide 11b, and an appropriate base such as DIEA, Na 2 CO 3 , or Cs 2 CO 3  in a suitable solvent, such as DMF, is heated at 50–100° C. under N 2  overnight, or until the starting material is exhausted, to give a mixture of the Nα,Nα-bis-cinnamyl amino acid ester 13b and Nα-cinnamyl amino acid ester 13c. If the side chain of R 1  contains an acid-cleavable protecting group such as t-butylcarbamate, t-butyl ester, or t-butyl ether, those groups may be cleaved by treatment with an acidic solution such as 30–80% TFA/CH 2 Cl 2  or 2–4N HCl in EtOAc. For examples of 13b and 13c where the ester group R 4  is a primary alkyl group such as methyl or ethyl, esters 13b and 13c may be independently converted to the corresponding acids 11c and 11d by hydrolysis with an appropriate base such as aqueous NaOH, KOH, or LiOH. For examples of 13b and 13c where the ester group R 4  is an acid-cleavable group such as t-butyl, esters 13b and 13c may be independently converted to the corresponding acids 11c and 11d by treatment with an acidic solution such as 30–80% TFA/CH 2 Cl 2  or 2–4N HCl in EtOAc. 
     
       
                 
         
             
             
         
      
     
     Scheme 14, Step A 
     A solution of 1 mmol of amino acid ester and 1–1.5 mmol of the appropriately substituted aldehyde 12a in 3–5 mL of TMOF was stirred at room temperature under N 2  overnight. The solution was concentrated and used directly for the next reaction; optionally, the solution was partitioned between EtOAc and water, washed with brine, dried over Na 2 SO 4 , and concentrated to give crude product, which was purified by MPLC to give mono-substituted product 14a. For examples of 14a wherein the side chain R 1  contained an acid-cleavable protecting group such as t-butylcarbamate, t-butyl ester, or t-butyl ether, 8c was treated with an acidic solution such as 30–80% TFA/CH 2 Cl 2  or 2–4N HCl in EtOAc. The reaction mixture was concentrated and optionally dissolved in HOAc and freeze-dried to give the deprotected form of 14a. For examples of 14a where the ester group R 4  is a primary alkyl group such as methyl or ethyl, esters 14a may be converted to the corresponding acids 11d by hydrolysis with an appropriate base such as aqueous NaOH, KOH, or LiOH. For examples of 14a where the ester group R 4  is an acid-cleavable group such as t-butyl, esters 14a may be converted to the corresponding acids 11d by treatment with an acidic solution such as 30–80% TFA/CH 2 Cl 2  or 2–4N HCl in EtOAc. 
     Scheme 14, Step B 
     Amino ester 14a was dissolved in DMF, combined with 1.1–1.5 mmol of the appropriately substituted chloride or bromide 12c, and heated at 50–100° C. overnight. The reaction mixture was cooled and partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by MPLC to give pure 14b. For examples of 14b wherein the side chain R 1  contained an acid-cleavable protecting group such as t-butylcarbamate, t-butyl ester, or t-butyl ether, 8c was treated with an acidic solution such as 30–80% TFA/CH 2 Cl 2  or 2–4N HCl in EtOAc. The reaction mixture was concentrated and optionally dissolved in HOAc and freeze-dried to give the deprotected form of 14b. For examples of 14b where the ester group R 4  is a primary alkyl group such as methyl or ethyl, esters 14b may be converted to the corresponding acids 12e by hydrolysis with an appropriate base such as aqueous NaOH, KOH, or LiOH. For examples of 14b where the ester group R 4  is an acid-cleavable group such as t-butyl, esters 14b may be converted to the corresponding acids 12e by treatment with an acidic solution such as 30–80% TFA/CH 2 Cl 2  or 2–4N HCl in EtOAc. 
     
       
                 
         
             
             
         
      
     
     Although the claimed compounds are useful as competitive binders to the EPO receptor, some compounds are more active than others and are either preferred or particularly preferred. 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     The particularly preferred “R 1 ”s are the side chain of lysine, ornithine, arginine, aspartic acid, glutamic acid, glutamine, cysteine, methionine, serine, and threonine. 
     The particularly preferred “R 2  and R 3 ”s are phenoxy, substituted phenoxy, benzyloxy, and substituted benzyloxy. 
     The particularly preferred “R 4  and R 5 ”s are phenoxy, substituted phenoxy, benzyloxy, and substituted benzyloxy. 
     The particularly preferred “W” is —CH═CH— 
     The particularly preferred “Q” is —CH═CH— 
     The particularly preferred “X” are C 1-5 alkenyl and CH 2 . 
     The particularly preferred “Y” are C 1-5 alkenyl and CH 2 . 
     The particularly preferred “n” are 1 and 2. 
     The particularly preferred “Z” are hydroxy, methoxy, phenethylamino, substituted phenethylamino, and —NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH—. 
     Pharmaceutically useful compositions the compounds of the present invention, may be formulated according to known methods such as by the admixture of a pharmaceutically acceptable carrier. Examples of such carriers and methods of formulation may be found in Remington&#39;s Pharmaceutical Sciences. To form a pharmaceutically acceptable composition suitable for effective administration, such compositions will contain an effective amount of the compound of the present invention. 
     Therapeutic or diagnostic compositions of the invention are administered to an individual in amounts sufficient to treat or diagnose disorders in which modulation of EPO receptor-related activity is indicated. The effective amount may vary according to a variety of factors such as the individual&#39;s condition, weight, sex and age. Other factors include the mode of administration. The pharmaceutical compositions may be provided to the individual by a variety of routes such as subcutaneous, topical, transdermal, oral and parenteral. 
     The term “chemical derivative” describes a molecule that contains additional chemical moieties which are not normally a part of the base molecule. Such moieties may improve the solubility, half-life, absorption, etc. of the base molecule. Alternatively the moieties may attenuate undesirable side effects of the base molecule or decrease the toxicity of the base molecule. Examples of such moieties are described in a variety of texts, such as Remington&#39;s Pharmaceutical Sciences. 
     Compounds disclosed herein may be used alone at appropriate dosages defined by routine testing in order to obtain optimal inhibition of the EPO receptor or its activity while minimizing any potential toxicity. In addition, co-administration or sequential administration of other agents may be desirable. 
     The present invention also has the objective of providing suitable topical, transdermal, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compositions containing compounds according to this invention as the active ingredient for use in the modulation of EPO receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for administration. For example, the compounds or modulators can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by transdermal delivery or injection. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, transdermal, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. The compounds of the present invention may be delivered by a wide variety of mechanisms, including but not limited to, transdermal delivery, or injection by needle or needle-less injection means. An effective but non-toxic amount of the compound desired can be employed as an EPO receptor modulating agent. 
     The daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per patient, per day. For oral administration, the compositions are preferably provided in the form of scored or unscored tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, and 50.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day. The range is more particularly from about 0.001 mg/kg to 10 mg/kg of body weight per day. The dosages of the EPO receptor modulators are adjusted when combined to achieve desired effects. On the other hand, dosages of these various agents may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. 
     Advantageously, compounds or modulators of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds or modulators for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. 
     For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents can be administered concurrently, or they each can be administered at separately staggered times. 
     The dosage regimen utilizing the compounds or modulators of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentrations of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug&#39;s availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug. 
     In the methods of the present invention, the compounds or modulators herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as “carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. 
     For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. 
     For liquid forms the active drug component can be combined in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired. 
     Topical preparations containing the active drug component can be admixed with a variety of carrier materials well known in the art, such as, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, PPG2 myristyl propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations. 
     The compounds or modulators of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. 
     Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds or modulators of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl-amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl-eneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds or modulators of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels, and other suitable polymers known to those skilled in the art. 
     For oral administration, the compounds or modulators may be administered in capsule, tablet, or bolus form or alternatively they can be mixed in the animals feed. The capsules, tablets, and boluses are comprised of the active ingredient in combination with an appropriate carrier vehicle such as starch, talc, magnesium stearate, or di-calcium phosphate. These unit dosage forms are prepared by intimately mixing the active ingredient with suitable finely-powdered inert ingredients including diluents, fillers, disintegrating agents, and/or binders such that a uniform mixture is obtained. An inert ingredient is one that will not react with the compounds or modulators and which is non-toxic to the animal being treated. Suitable inert ingredients include starch, lactose, talc, magnesium stearate, vegetable gums and oils, and the like. These formulations may contain a widely variable amount of the active and inactive ingredients depending on numerous factors such as the size and type of the animal species to be treated and the type and severity of the infection. The active ingredient may also be administered as an additive to the feed by simply mixing the compound with the feedstuff or by applying the compound to the surface of the feed. Alternatively the active ingredient may be mixed with an inert carrier and the resulting composition may then either be mixed with the feed or fed directly to the animal. Suitable inert carriers include corn meal, citrus meal, fermentation residues, soya grits, dried grains and the like. The active ingredients are intimately mixed with these inert carriers by grinding, stirring, milling, or tumbling such that the final composition contains from 0.001 to 5% by weight of the active ingredient. 
     The compounds or modulators may alternatively be administered parenterally via injection of a formulation consisting of the active ingredient dissolved in an inert liquid carrier. Injection may be either intramuscular, intraruminal, intratracheal, or subcutaneous, either by needle or needle-less means. The injectable formulation consists of the active ingredient mixed with an appropriate inert liquid carrier. Acceptable liquid carriers include the vegetable oils such as peanut oil, cotton seed oil, sesame oil and the like as well as organic solvents is such as solketal, glycerol formal and the like. As an alternative, aqueous parenteral formulations may also be used. The vegetable oils are the preferred liquid carriers. The formulations are prepared by dissolving or suspending the active ingredient in the liquid carrier such that the final formulation contains from 0.005 to 10% by weight of the active ingredient. 
     Topical application of the compounds or modulators is possible through the use of a liquid drench or a shampoo containing the instant compounds or modulators as an aqueous solution or suspension. These formulations generally contain a suspending agent such as bentonite and normally will also contain an antifoaming agent. Formulations containing from 0.005 to 10% by weight of the active ingredient are acceptable. Preferred formulations are those containing from 0.01 to 5% by weight of the instant compounds or modulators. 
     The compounds of Formula I may be used in pharmaceutical compositions to treat patients (humans and other mammals) with disorders or conditions associated with the production of erythropoietin or modulated by the EPO receptor. The compounds can be administered in the manner of the commercially available product or by any oral or parenteral route (including but not limited to, intravenous, intraperitoneal, intramuscular, subcutaneous, dermal patch), where the preferred route is by injection. When the method of administration is intravenous infusion, compound of Formula I may be administered in a dose range of about 0.01 to 1 mg/kg/min. For oral administration, the dose range is about 0.1 to 100 mg/kg. 
     The pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques. Oral dosage forms may be used and are elixirs, syrups, capsules, tablets and the like. Where the typical solid carrier is an inert substance such as lactose, starch, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like; and typical liquid oral excipients include ethanol, glycerol, water and the like. All excipients may be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known to those skilled in the art of preparing dosage forms. Parenteral dosage forms may be prepared using water or another sterile carrier. 
     Typically the compounds of Formula I are isolated as the free base, however when possible pharmaceutically acceptable salts can be prepared. Examples of such salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic,  p -toluenesulfonic, cyclohexanesulfamic and saccharic. 
     In order to illustrate the invention the following examples are included. These examples do not limit the invention. They are only meant to suggest a method of practicing the invention. Those knowledgeable in chemical synthesis and the treatment of EPO related disorders may find other methods of practicing the invention. However those methods are deemed to be within the scope of this invention. 
     BIOLOGICAL EXAMPLES 
     The compounds of the invention were evaluated for the ability to compete with EPO in the following immobilized EPO receptor preparation (EBP-Ig, EPO binding protein-Ig). 
     EBP-Ig fusion protein (as disclosed in WO97/27219 which is herein incorporated by reference) was purified by affinity chromatography from the conditioned media of NSO cells engineered to express a recombinant gene construct which functionally joined the N-terminal 225 amino acids of the human EPO receptor and an Ig heavy chain as described herein. The interaction of biotin and streptavidin is frequently employed to capture and effectively immobilize reagents useful in assay protocols and has been employed here as a simple method to capture and immobilize EBP-Ig. EBP-Ig is initially randomly modified with an amine reactive derivative of biotin to produce biotinylated-EBP-Ig. Use of streptavidin coated plates allows the capture of the biotinylated EBP-Ig on the surface of a scintillant impregnated coated well (Flash plates, NEN-DuPont). Upon binding of [ 125 I]EPO to the ligand binding domain, specific distance requirements are satisfied and the scintillant is induced to emit light in response to the energy emitted by the radioligand. Unbound radioligand does not produce a measurable signal because the energy from the radioactive decay is too distant from the scintillant. The amount of light produced was quantified to estimate the amount of ligand binding. The specific assay format was suitable for the multi-well plate capacity of a Packard TopCount Microplate Scintillation counter. Compounds which were capable of reducing the amount of detected signal through competitive binding with the radioligand were identified. 
     Biotinylated EBP-Ig was prepared as follows. EBP-Ig (3 mL, OD 280  2.9) was exchanged into 50 mM sodium bicarbonate, pH 8.5 using a Centriprep 10 ultrafiltration device. The final volume of the exchanged protein was 1.2 mL (OD 280  2.6, representing about 2 mg total protein). 10 μL of a 4 mg/ml solution of NHS-LC-Biotin (Pierce) was added and the reaction mixture placed on ice in the dark for two hours. Unreacted biotin was removed by exchange of the reaction buffer into PBS in a Centriprep 10 device and the protein reagent aliquoted and stored at −70° C. 
     Each individual binding well (200 μL) contained final concentrations of 1 μg/mL of biotinylated EBP-Ig, 0.5 nM of [ 125 I]EPO (NEN Research Products, Boston, 100 μCi/μg) and 0–500 μM of test compound (from a 10–50 mM stock in 100% DMSO). All wells were adjusted to a final DMSO concentration of 5%. All assay points were performed in triplicate and with each experiment a standard curve for unlabelled EPO was performed at final concentration of 2000, 62, 15, 8, 4, and 0 nM. After all additions were made, the plate was covered with an adhesive top seal and placed in the dark at room temperature overnight. The next day all liquid was aspirated from the wells to limit analyte dependent quench of the signal, and the plates were counted on a Packard TOPCOUNT Microplate Scintillation Counter. Non-specific binding (NSB) was calculated as the mean CPM of the 2000 nM EPO wells and total binding (TB) as the mean of the wells with no added unlabelled EPO. Corrected total binding (CTB) was calculated as: TB−NSB=CTB. The concentration of test compound which reduced CTB to 50% was reported as the IC 50 . Typically the IC 50  value for unlabelled EPO was ca. 2–7 nM and EMP1 was 0.1 μM. Table 1 lists the average % inhibition, and if determined the IC 50  and IC 30  values for compounds of Formula I, where the compound numbers refer to the compounds in the tables accompanying the preparative examples. 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Inhibition of EPO binding to EBP-Ig 
               
             
          
           
               
                   
                 cpd 
                 % inh @ 50 μM 
                 IC 30  μM* 
                 IC 50 , μM* 
               
               
                   
                   
               
             
          
           
               
                   
                 11 
                 70 
                 nd 
                 nd 
               
               
                   
                 12 
                 59 
                 nd 
                 nd 
               
               
                   
                 14 
                 30 
                 nd 
                 nd 
               
               
                   
                 15 
                 48 
                 nd 
                 nd 
               
               
                   
                 77 
                 52 
                 30 
                 40 
               
               
                   
                 82 
                 32 
                 nd 
                 nd 
               
               
                   
                 86 
                 37 
                 nd 
                 nd 
               
               
                   
                 100 
                 34 
                 nd 
                 nd 
               
               
                   
                 101 
                 32 
                 nd 
                 nd 
               
               
                   
                 104 
                 78 
                 10 
                 30 
               
               
                   
                 105 
                 70 
                 25 
                 35 
               
               
                   
                 107 
                 78 
                 30 
                 42 
               
               
                   
                 108 
                 81 
                 23 
                 36 
               
               
                   
                 110 
                 54 
                 6 
                 10 
               
               
                   
                 112 
                 59 
                 2 
                 10 
               
               
                   
                 114 
                 37 
                 10 
                 nd 
               
               
                   
                 115 
                 35 
                 nd 
                 nd 
               
               
                   
                 116 
                 32 
                 nd 
                 nd 
               
               
                   
                 117 
                 34 
                 nd 
                 nd 
               
               
                   
                 118 
                 36 
                 2 
                 10 
               
               
                   
                 119 
                 34 
                 nd 
                 nd 
               
               
                   
                 120 
                 35 
                 nd 
                 nd 
               
               
                   
                 121 
                 45 
                 6 
                 nd 
               
               
                   
                 137 
                 60 
                 5 
                 30 
               
               
                   
                 139 
                 46 
                 2 
                 10 
               
               
                   
                 178 
                 36 
                 nd 
                 nd 
               
               
                   
                 179 
                 30 
                 nd 
                 nd 
               
               
                   
                 183 
                 36 
                 nd 
                 nd 
               
               
                   
                 184 
                 53 
                 10 
                 nd 
               
               
                   
                 203 
                 37 
                 50 
                 nd 
               
               
                   
                 211 
                 62 
                 20 
                 65 
               
               
                   
                 220 
                 45 
                 30 
                 50 
               
               
                   
                 221 
                 48 
                 10 
                 80 
               
               
                   
                 222 
                 56 
                 5 
                 nd 
               
               
                   
                 224 
                 51 
                 25 
                 50 
               
               
                   
                 227 
                 48 
                 20 
                 50 
               
               
                   
                 230 
                 42 
                 nd 
                 nd 
               
               
                   
                 231 
                 36 
                 nd 
                 nd 
               
               
                   
                 235 
                 49 
                 20 
                 50 
               
               
                   
                 237 
                 55 
                 30 
                 70 
               
               
                   
                 238 
                 39 
                 nd 
                 nd 
               
               
                   
                 239 
                 46 
                 8 
                 50 
               
               
                   
                 243 
                 75 
                 2 
                 18 
               
               
                   
                 244 
                 66 
                 1 
                 28 
               
               
                   
                 246 
                 79 
                 10 
                 75 
               
               
                   
                 247 
                 47 
                 7 
                 18 
               
               
                   
                 248 
                 56 
                 7 
                 20 
               
               
                   
                 249 
                 72 
                 7 
                 10 
               
               
                   
                 250 
                 78 
                 7 
                 20 
               
               
                   
                 251 
                 49 
                 10 
                 45 
               
               
                   
                 261 
                 51 
                 1.5 
                 2 
               
               
                   
                 262 
                 93 
                 1 
                 1.5 
               
               
                   
                 263 
                 88 
                 1 
                 1.5 
               
               
                   
                 264 
                 89 
                 1.5 
                 8 
               
               
                   
                 265 
                 65 
                 1 
                 6 
               
               
                   
                 266 
                 82 
                 1 
                 4 
               
               
                   
                 267 
                 83 
                 2 
                 6 
               
               
                   
                 268 
                 40 
                 nd 
                 nd 
               
               
                   
                 269 
                 55 
                 8 
                 85 
               
               
                   
                 270 
                 56 
                 7 
                 100 
               
               
                   
                 271 
                 77 
                 2 
                 7 
               
               
                   
                 272 
                 78 
                 5 
                 10 
               
               
                   
                 285 
                 41 
                 nd 
                 nd 
               
               
                   
                 286 
                 46 
                 35 
                 65 
               
               
                   
                 287 
                 36 
                 nd 
                 nd 
               
               
                   
                 300 
                 57 
                 35 
                 145 
               
               
                   
                 305 
                 48 
                 35 
                 225 
               
               
                   
                 312 
                 45 
                 10 
                 85 
               
               
                   
                 321 
                 42 
                 45 
                 nd 
               
               
                   
                 363 
                 33 
                 35 
                 220 
               
               
                   
                 366 
                 38 
                 65 
                 nd 
               
               
                   
                 368 
                 40 
                 90 
                 nd 
               
               
                   
                   
               
               
                   
                 *nd = not determined 
               
             
          
         
       
     
     PREPARATIVE EXAMPLES 
     Unless otherwise noted, materials used in the examples were obtained from commercial suppliers and were used without further purification. Melting points were determined on a Thomas Hoover apparatus and are uncorrected. Proton nuclear magnetic resonance ( 1 H NMR) spectra were measured in the indicated solvent with tetramethylsilane (TMS) as the internal standard using a Bruker AC-300 NMR spectrometer. NMR chemical shifts are expressed in parts per million (ppm) downfield from internal TMS using the d scale.  1 H NMR data are tabulated in order: multiplicity, (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), number of protons, coupling constant in Hertz). Electrospray (ES) mass spectra (MS) were determined on a Hewlett Packard Series 1090 LCMS Engine. Elemental analyses were performed by Quantitative Technologies, Inc. (QTI), PO Box 470, Salem Industrial Park, Bldg #5, Whitehouse, N.J. 08888-0470. Analytical thin layer chromatography (TLC) was done with Merck Silica Gel 60 F 254  plates (250 micron). Medium pressure liquid chromatography (MPLC) was done with Merck Silica Gel 60 (230–400 mesh). 
     Example 1 
     N,N-bis(3-Phenoxycinnamyl)Glu(O-t-Bu)-OMe (cpd 96) and N-(3-phenoxycinnamyl)Glu(O-t-Bu)-OMe (cpd 334) 
     A solution of 500 mg (1.97 mmol) of H-Glu(O-t-Bu)OMe.HCl, 997 mg (3.45 mmol) of 3-phenoxycinnamyl bromide (Jackson, W. P.; Islip, P. J.; Kneen, G.; Pugh, A.; Wates, P. J.  J. Med. Chem.  31 1988; 499–500), and 0.89 mL (5.1 mmol, 660 mg) of DIEA in 5 mL of DMF was stirred under N 2  at room temperature for 40 h. The mixture was partitioned between EtOAc and water and the organic layer was washed with water and brine. After drying over Na 2 SO 4 , the organic solution was concentrated to give 1.24 g of orange oil. The crude residue was purified by MPLC using a solvent gradient ranging from 10–30% EtOAc/hexanes to give two products. The less polar product (cpd 96, 235 mg, 19% based on starting amino acid), was isolated as a pale yellow oil;  1 H NMR (CDCl 3 , 300 MHz) 1.39 (s, 9H), 2.0 (m, 2H), 2.33 (dt, 2H, J=2, 7 Hz), 3.24 (dd, 2H, J=8, 15 Hz), 3.5, (m, 3H), 3.69 (s, 3H), 6.13 (m, 2H), 6.47 (d, 2H, J=16 Hz), 6.86 (dd, 2H, J=1.5, 8 Hz), 7.0–7.4 (complex, 16H); MS (ES+) m/z 634 (MH+). 
     The more polar product (cpd 334, 422 mg, 50% based on starting amino acid) was isolated as a pale yellow oil;  1 H NMR (CDCl 3 , 300 MHz) 1.42 (s, 9H), 1.9 (m, 2H), 2.35 (t, 2H, J=7.5 Hz), 3.2–3.4 (complex, 3H), 3.71 (s, 3H), 6.17 (dt, 1H, J=16, 6 Hz), 6.46 (d, 1H, J=16 Hz), 6.87 (dd, 1H, J=1.5, 8 Hz), 7.01 (m, 3H), 7.10 (t, 2H, J=7.5 Hz), 7.2–7.4 (complex, 3H); MS (ES+) m/z 426 (MH+). Anal. Calcd for C 25 H 31 NO 5 : C, 70.57; H, 7.34; N, 3.29. Found: C, 70.29; H, 7.14; N, 3.08. 
     Example 2 
     N-(3-Phenoxycinnamyl)Glu-OMe (cpd 325) 
     A solution of 95 mg (0.22 mmol) of N-(3-phenoxycinnamyl)Glu(O-t-Bu)-OMe (cpd 334) in 3 mL of 50% TFA/CH 2 Cl 2  was stirred for 2 h at room temperature. The mixture was concentrated and the residue was dissolve in acetic acid and freeze-dried to give 117 mg of N-(3-phenoxycinnamyl)Glu-OMe (cpd 325)as an off-white solid;  1 H NMR (CD 3 OD, 300 MHz) 2.3–2.7 (complex, 4H), 3.78 (s, 3H), 3.81 (d, 2H, J=7 Hz), 4.09 (t, 1H, J=5 Hz), 6.17 (dt, 1H, J=16, 7 Hz), 6.55 (d, 1H, J=16 Hz), 6.9 (m, 4H), 7.11 (t, 2H, J=7.5 Hz), 7.3 (m, 4H); MS (ES+) m/z 370 (MH+), 209. Anal. Calcd for C 21 H 23 NO 5 .C 2 HF 3 O 2 : C, 57.14; H, 5.00; N, 2.90. Found: C, 57.07; H, 5.02; N, 2.73. 
     Example 3 
     N,N-bis(3-Phenoxycinnamyl)Asp(O-t-Bu)-O-t-Bu (cpd 106) 
     A solution of 1.00 g (3.55 mmol) of Asp(O-t-Bu)-O-t-Bu.HCl, 2.05 g (7.1 mmol) of 3-phenoxycinnamyl bromide, and 1.86 mL (10.7 mmol, 1.38 g) of DIEA in 15 mL of DMF was heated under N 2  at 60° C. overnight. Additional 3-phenoxycinnamyl bromide (1.0 g, 3.4 mmol) and DIEA (0.95 mL, 0.705 g, 5.4 mmol) were added and heating was continued for an additional 14 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was washed twice with water, once with brine, and was dried over Na 2 SO 4 . The solution was concentrated to give 3.5 g of an amber oil which was purified by MPLC using a solvent gradient ranging from 2.5–3% EtOAc/hexanes to afford 1.21 g of cpd 106 as a pale yellow oil;  1 H NMR (CDCl 3 , 300 MHz) 1.41 (s, 9H), 1.48 (s, 9H), 2.49 (dd, 1H, J=7.5, 15.5 Hz), 2.70 (dd, 1H, J=7.5, 15.5 Hz), 3.26 (dd, 2H, J=7.5, 14.5 Hz), 3.47 (dd, 2H, J=4, 14.5 Hz), 3.88 (t, 1H, J=7.5), 6.13 (m, 2H), 6.48 (d, 2H, J=16 Hz), 6.86 (dd, 2H, J=2, 8 Hz), 7.0 (m, 6H), 7.1 (m, 4H), 7.2–7.4 (complex, 6H); MS (ES+) m/z 662 (MH+). 
     Example 4 
     N,N-bis(3-Phenoxycinnamyl)Asp-OH (cpd 107) 
     A solution of 1.14 g (1.62 mmol) of cpd 106 in 16 mL of 50% TFA/CH 2 Cl 2  was stirred at room temperature for 24 h. The solution was concentrated and pumped to give 1.37 g (˜100%) cpd 107 as an amber oil;  1 H NMR (CD 3 OD, 300 MHz) 3.1 (m, 2H), 4.0 (dd, 2H, J=8, 14 Hz), 4.27 (dd, 2H, J=8, 16 Hz), 4.70 (t, 1H, J=4 Hz), 6.38 (2H, dt, J=16, 8 Hz), 6.7–7.4 (complex, 20H); MS (ES−) m/z 562 ([M−H]+). 
     Example 5 
     N,N-bis(4-Benzyloxybenzyl)Lys(Boc)-OMe (cpd 111) and N-(4-Benzyloxybenzyl)Lys(Boc)-OMe 
     A solution of 594 mg (2.0 mmol) of Lys(Boc)-OMe.HCl, 524 mg (2.25 mmol) of 4-benzyloxybenzyl chloride, 75 mg (0.5 mmol), of NaI, and 0.61 mL (3.5 mol, 452 mg) of DIEA was warmed at 50–70° C. under N 2  overnight. The mixture was cooled and partioned between EtOAc and water. The organic layer was washed twice with water, once with brine, and was dried over Na 2 SO 4 . The organic solution was concentrated to give 0.83 g of amber oil which was purified by MPLC using a solvent gradient ranging from 15–40% EtOAc/hexanes to give two products. The less polar product (296 mg), cpd 111, was isolated as a pale yellow oil;  1 H NMR (CDCl 3 , 300 MHz) 1.28 (m, 4H), 1.43 (s, 9H), 1.70 (m, 2H), 3.03 (m, 2H), 3.28 (t, 1H, J=7 Hz), 3.40 (d, 2H, J=13.5 Hz), 3.74 (s, 3H), 3.81 (d, 2H, J=13.5 Hz), 5.05 (2, 4H), 6.92 (d, 4H, J=8.5), 7.23 (d, 4H, J=8.5), 7.25–7.5 (complex, 10H); MS (ES+) m/z 653 (MH+). 
     The more polar product (406 mg), N-(4-benzyloxybenzyl)Lys(Boc)-OMe, was isolated as a white solid;  1 H NMR (CDCl 3 , 300 MHz) 1.4 (, 4H), 1.43 (s, 9H), 1.65 (m, 3H), 3.08 (m, 2H), 3.23 (t, 1H, J=6.5 Hz), 3.54 (d, 1H, J=12.5 Hz), 3.71 (s, 3H), 3.73 (d, 1H, J=12.5 Hz), 5.05 (s, 2H), 6.92 (d, 2H, J=8.5 Hz), 7.23 (d, 2H, J=8.5 Hz), 7.25–7.5 (complex, 5H); MS (ES+) m/z 457 (MH+). 
     Example 6 
     N-(4-Benzyloxybenzyl)-N-(3-nitrobenzyl)Lys(Boc)-OMe (cpd 113) 
     A solution of 374 mg (0.82 mmol) of N-(4-Benzyloxybenzyl)Lys(Boc)-OMe, 221 mg (1.03 mmol) of 4-nitrobenzyl bromide, and 197 L (1.13 mmol, 146 mg) of DIEA was warmed at 50–70° C. for 4 h, then at 40–50° C. overnight. After the addition of 0.2 mL of 1N aqueous HCl, the mixture was partioned between EtOAc and water. The organic layer was washed twice with water, once with brine, and was dried over Na 2 SO 4 . The organic solution was concentrated to give 610 mg is of an amber oil which was purified by MPLC 1:3 EtOAc/hexanes to afford 436 mg (90%) cpd 113 as a pale yellow oil;  1 H NMR (CDCl 3 , 300 MHz) 1.35 (m, 4H), 1.42 (s, 9H), 1.75 (broad q, 2H, J=8 Hz), 3.06 (broad q, 2H, J=6 Hz), 3.28 (t, 1H, J=7.5 Hz), 3.48 (d, 1H, J=13.5 Hz), 3.66 (d, 1H, J=14.5 Hz), 3.76 (s, 3H), 3.79 (d, 1H, J=13.5 Hz), 3.97 (d, 1H, J=14.5 Hz), 4.47 (broad s, 1H), 5.05 (s, 2H), 6.93 (d, 2H, J=8.5 Hz), 7.22 (d, 2H, J=8.5 Hz), 7.3–7.5 (complex, 6H), 7.65 (d, 1H, J=7.5 Hz), 8.09 (d, 1H, J=8 Hz), 8.22 (s, 1H); MS (ES+) m/z 592 (MH+). 
     Example 7 
     N-(3-Aminobenzyl)-N-(4-benzyloxybenzyl)Lys(Boc)-OMe 
     A solution of 361 mg (0.61 mmol) of cpd 113 and 835 mg (3.7 mmol) of SnCl 2  dihydrate was stirred under N 2  at room temperature for 6 h. The slightly cloudy mixture was poured into 200 mL of 5% aqueous Na 2 CO 3  with rapid stirring. The resulting milky suspension was extracted with three 75 mL portions of CH 2 Cl 2  and the combined organic layers were washed with brine and dried over Na 2 SO 4 . The extracts were concentrated to give 344 mg of colorless oil which was purified by MPLC using 1:2 EtOAc/hexanes to provide 291 mg of N-(3-aminobenzyl)-N-(4-benzyloxybenzyl)Lys(Boc)-OMe as a yellow oil;  1 H NMR (CDCl 3 , 300 MHz) 1.25 (m, 4H), 1.44 (s, 9H), 1.70 (m, 2H), 3.31 (dd, 1H, J=6, 9 Hz), 3.38 (d, 1H, J=14 Hz), 3.40 (d, 1H, J=13.5 Hz), 3.74 (s, 3H), 3.81 (d, 1H, J=14 Hz), 3.83 (d, 1H, J=13.5 Hz), 4.52 (broad s, 1H), 5.05 (s, 2H), 6.50 (broad d, 1H, J=8 Hz), 6.70 (m, 2H), 6.92 (d, 2H, J=8.5 Hz), 7.08 (t, 1H, J=7.5 Hz), 7.2–7.5 (complex, 7H); MS (ES+) m/z 562 (base, MH+), 506. 
     Example 8 
     N-(4-Benzyloxybenzyl)-N-(3-((2-furancarbonyl)amino)benzyl)Lys-OMe (cpd 117) 
     A solution of 42 mg (0.075 mmol) of N-(3-aminobenzyl)-N-(4-benzyloxybenzyl)Lys(Boc)-OMe and 12 μL (12 mg, 0.15 mmol) of pyridine in 0.5 mL of 1,2-dichloroethane was combined with 8.1 μL (11 mg, 0.083 mmol) and stirred under N 2  overnight. EtOAc (3 mL) was added and the solution was washed twice with 2 mL of water and 2 mL of saturated aqueous NaHCO 3 . The EtOAc solution was filtered through a pad of Na 2 SO 4  and concentrated to give 44 mg of N-(4-benzyloxybenzyl)-N-(3-((2-furancarbonyl)amino)benzyl)Lys(Boc)-OMe; MS (ES+) m/z 356 (MH+). The Boc-protected intermediate was stirred in 2 mL of 50% TFA/CH 2 Cl 2  for 2 h and was concentrated and pumped at high vacuum to provide 66 mg of cpd 117 as the bis-TFA salt;  1 H NMR (CD 3 OD, 300 MHz) 1.55 (m, 2H), 1.65 (m, 2H), 2.10 (m, 2H), 2.93 (t, 2H, J=7 Hz), 3.68 (t, 1H, J=7 Hz), 3.78 (s, 3H), 4.20 (m, 4H), 5.09 (s, 2H), 6.66 (dd, 1H, J=1.5, 3.5 Hz), 7.03 (d, 2H, J=8.5 Hz), 7.1–7.6 (complex, 11H), 7.76 (m, H), 8.07 (m, 1H); MS (ES+) m/z 556 (base, MH+), 360, 197. 
     Example 9 
     N,N-bis(3-Nitrobenzyl)Asp(O-t-Bu)-O-t-Bu (cpd 62) 
     A solution of 0.50 mg (1.77 mmol) of Asp(O-t-Bu)-O-t-Bu.HCl, 1.17 g (5.42 mmol) of 3-nitrobenzyl bromide, and 1.25 mL (0.93 g, 7.2 mmol) of DIEA in 6 mL of DMF was stirred at room temperature under N 2  for 24 h and was heated at 70–80° C. overnight. The reaction mixture was partitioned between EtOAc and water and the organic layer was washed twice with water and once with brine. After drying over Na 2 SO 4 , the organic solution was concentrated to give 0.86 g of a yellow oil which was purified by MPLC using 1:9 EtOAc/hexanes to afford 0.849 g (93%) cpd 62 as a pale yellow oil;  1 H NMR (CDCl 3 , 300 MHz) 1.43 (s, 9H), 1.57 (s, 9H), 2.59 (dd, 1H, J=7.5, 16 Hz), 2.76 (dd, 1H, J=7, 16 Hz), 3.72 (t, 1H, J=7.5 Hz), 3.78 (d, 2H, J=14 Hz), 3.92 (d, 2H, J=14 Hz), 7.47 (t, 2H, J=8 Hz), 7.67 (d, 2H, J=7.5 Hz), 8.09 (broad d, 2H J=8 Hz), 8.16 (broad s, 2H); MS (ES+) m/z 538 (MNa+), 516 (base, MH+), 460, 404, 237. 
     Example 10 
     N,N-bis(3-Aminobenzyl)Asp(O-t-Bu)-O-t-Bu 
     A solution of 0.644 g (1.25 mmol) of cpd 62 and 2.82 g (12.5 mmol) of SnCl 2 .2H 2 O in 12 mL of absolute EtOH was refluxed for 1.5 h. The mixture was cooled and poured into 300 mL of 5% aqueous Na 2 CO 3  with rapid stirring. The cloudy mixture was extracted with three 150 mL portions of CH 2 Cl 2  and the organic extracts were washed with brine and dried over Na 2 SO 4 . The CH 2 Cl 2  solution was concentrated to afford 210 mg (37%) of N,N-bis(3-aminobenzyl)Asp(O-t-Bu)-O-t-Bu as a cloudy yellow oil which was used without purification;  1 H NMR (CDCl 3 , 300 MHz) 1.40 (s, 9H), 1.52 (s, 9H), 2.48 (dd, 1H, J=7, 16 Hz), 2.76 (dd, 1H, J=8, 16 Hz), 3.48 (d, 2H, J=14 Hz), 3.55 (m, 1H), 3.73 (d, 2H, J=14 Hz), 6.56 (broad d, 2H J=8 Hz), 6.70 (broad s, 2H), 6.77 (d, 2H, J=7.5 Hz), 7.08 (t, 2H, J=8 Hz); MS (ES+) m/z 478 (MNa+), 456 (base, MH+), 400, 344. 
     Example 11 
     N,N-bis(3-(4-Methylbenzoyl)aminobenzyl)Asp(O-t-Bu)-O-t-Bu 
     To a solution of 109 mg (0.24 mmol) of N,N-bis(3-aminobenzyl)Asp(O-t-Bu)-O-t-Bu, 29 mg (0.24 mmol) of DMAP, 125 μL (93 mg, 0.72 mmol) of DIEA in 1 mL of CH 2 Cl 2  was added 95 μL (111 mg, 0.72 mmol) of 4-methylbenzoyl chloride. The solution was stirred under N 2  overnight and was then partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaHCO 3  and brine, dried over Na 2 SO 4 , and concentrated to give 177 mg of yellow oil. The crude material was purified by MPLC using a solvent gradient ranging from 20–25% EtOAc/hexanes to provide 87 mg of N,N-bis(3-(4-methylbenzoyl)aminobenzyl)Asp(O-t-Bu)-O-t-Bu as a pale yellow oil;  1 H NMR (CDCl 3 , 300 MHz) 1.36 (s, 9H), 1.55 (s, 9H), 2.35 (s, 6H), 2.53 (dd, 1H, J=6, 16 Hz), 2.76 (dd, 1H, J=9, 16 Hz), 3.69 (d, 2H, J=14), 3.77 (dd, 1H, J=6, 9 Hz), 3.83 (d, 2H, J=14), 7.01 (m, 6H), 7.26 (t, 2H, J=8 Hz), 7.59 (m, 6H), 8.11 (s, 2H), 8.49 (s, 2H); MS (ES+) m/z 714 (MNa+), 692 (base, MH+), 636, 580. 
     Example 12 
     N,N-bis(3-(4-Methylbenzoyl)aminobenzyl)Asp-OH (cpd 64) 
     A solution of 87 mg (0.13 mmol) of N,N-bis(3-(4-methylbenzoyl)amino-benzyl)Asp(O-t-Bu)-O-t-Bu in 1 mL of 50% TFA/CH 2 Cl 2  was stirred overnight. The mixture was concentrated and the residue was dissolved in HOAc and freeze-dried to afford 77 mg cpd 64 as a white solid;  1 H NMR (CD 3 OD, 300 MHz) 2.40 (s, 6H), 2.85 (dd, 1H, J=6, 16.5 Hz), 2.98 (dd, 1H, J=8, 16.5 Hz), 4.02 (d, 2H, J=13.5 Hz), 4.08 (d, 4H, J=13.5 Hz), 4.10 (t, 1H, J=6.5 Hz), 7.22 (m, 6H), 7.34 (t, 2H, J=7.5 Hz), 7.60 (broad d, 2H, J=9 Hz), 7.76 (d, 4H, J=8 Hz), 7.88 (broad s, 2H); MS (ES+) m/z 580 (base, MH+). 
     Example 13 
     [N-Cbz-Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2    
     To a solution of 1.69 g (5.0 mmol) of N-Cbz-Glu(O-t-Bu)-OH, 0.365 mL (0.371 g, 2.5 mmol) of 1,8-diamino-3,6-dioxaoctane, 0.743 g (5.5 mmol) of HOBT, and 1.05 mL (0.776 g, 6.0 mmol) of DIEA in 15 mL of CH 2 Cl 2  was added 1.05 g (5.5 mmol) of EDCI in one portion. After stirring at room temperature under N 2  overnight, the mixture was partitioned between EtOAc and 10% aqueous citric acid. The organic layer was washed with water, saturated NaHCO 3 , and brine, dried over Na 2 SO 4 , and concentrated to give 1.87 g of (N-Cbz-Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ) 2  as a colorless oil;  1 H NMR (CD 3 OD, 300 MHz) 1.43 (s, 18H), 1.85 (m, 2H), 2.05 (m, 2H), 2.31 (t, 4H, J=8 Hz), 3.37 (t, 4H, J=5 Hz), 3.52 (t, 4H, J=5 Hz), 3.58 (s, 4H), 4.15 (m, 2H), 5.09 (dd, 4H, J=12, 16 Hz), 7.30 (m, 10H); MS (ES+) m/z 809 (base, MNa+), 787 (MH+). 
     Example 14 
     [Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2    
     Ammonium formate (0.78 g, 12.4 mmol) and 0.16 g of 10% palladium on carbon were added to a solution of (N-Cbz-Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ) 2  in 12 mL of MeOH and the resulting suspension was stirred under N 2  at room temperature overnight. The mixture was diluted with CH 2 Cl 2  and filtered through a Celite pad. The solids were washed thoroughly with CH 2 Cl 2  and the combined organic filtrates were concentrated to dryness. The residue was partitioned between CH 2 Cl 2  and saturated aqueous NaHCO 3 , washed with brine, dried over Na 2 SO 4 , and concentrated to give 1.13 g of (Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ) 2  as a colorless oil; 1.44 (s, 18H), 1.81 (m, 2H), 2.08 (m, 2H), 2.35 (m, 4H), 3.39 (dd, 2H, J=5, 7.5 Hz), 3.47 (t, 4H, J=5 Hz), 3.58 (t, 4H, J=5 Hz), 7.53 (m, 2H). 
     Example 15 
     [N,N-bis(4-Benzyloxybenzyl)Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2  (cpd 245) 
     A solution of 199 mg (0.384 mmol) of [Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2 , 403 mg (1.73 mmol) of 4-benzyloxybenzyl chloride, 30 mg (0.2 mmol) of NaI, and 334 L (248 mg, 1.92 mmol) of DIEA was stirred under N 2  at room temperature for several days. The solution was partitioned between EtOAc and water and the organic layer was washed three times with water and once with brine. After drying over Na 2 SO 4 , the solution was concentrated to give 528 mg of yellow oil which was purified by MPLC using a solvent gradient ranging from 42–50% EtOAc/hexanes to afford 318 mg (64%) of cpd 245 as a white foam;  1 H NMR (CDCl 3 , 300 MHz) 1.42 (s, 18H), 2.01 (m, 4H), 2.38 (m, 2H), 2.55 (m, 2H), 3.03 (dd, 2H, J=5, 8 Hz), 3.31 (m, 2H), 3.4–3.6 (complex, 18H), 4.99 (s, 8H), 6.89 (d, 8H, J=8.5), 7.1–7.4 (complex, 30H). 
     Example 16 
     [N,N-bis(4-Benzyloxybenzyl)GluNHCH 2 CH 2 OCH 2 ] 2  (cpd 246) 
     A solution of 219 mg (0.168 mmol) of cpd 245 in 2 mL of 33% TFA/CH 2 Cl 2  was stirred ad room temperature overnight. The mixture was concentrated to give a crude product which was dissolved in HOAc and freeze-dried to afford 251 mg of cpd 246 as an amber oil;  1 H NMR (CD 3 OD, 300 MHz) 2.1–2.6 (complex, 8H), 3.3–3.6 (complex, 8H), 3.57 (s, 4H), 3.78 (m, 2H), 4.25 (broad d, 4H, J=14 Hz), 4.36 (broad d, 4H, J=14 Hz), 5.09 (s, 8H), 7.03 (d, 8H, J=8 Hz), 7.3–7.5 (complex, 28H); MS (ES+) m/z 1192 (MH+), 995, 596, 197 (base). 
     Example 17 
     [N-(3-Phenoxybenzyl)Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2    
     A solution of 680 mg (0.76 mmol) of [Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2  and 278 μL (317 mg, 1.6 mmol) of 3-phenoxybenzaldehyde in 3 mL of TMOF was stirred overnight at room temperature under N 2 . The mixture was concentrated and pumped at high vacuum to give a colorless oil which was dissolved in 3 mL of CH 2 Cl 2  and treated with 678 mg (3.2 mmol) of NaBH(OAc) 3 . After stirring under N 2  for 2 days, 50 mL of saturated aqueous NaHCO 3  was added and the mixture was extracted with CH 2 Cl 2 . The organic layers were combined, dried over Na 2 SO 4 , and concentrated and the crude product (1.01 g) was purified by MPLC using a solvent gradient ranging from 2–4% MeOH/CH 2 Cl 2  to afford 490 mg of [N-(3-phenoxybenzyl)Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2  as a colorless oil;  1 H NMR (CDCl 3 , 300 MHz) 1.41 (s, 18H), 1.89 (m, 4H), 2.31 (m, 4H), 3.12 (t, 2H, J=6 Hz), 3.45 (m, 8H), 3.55 (s, 4H), 3.60 (d, 2H, J=13.5 Hz), 3.73 (d, 2H, J=13.5 Hz), 6.86 (dd, 2H, J=1.5, 8 Hz), 7.00 (m, 8H), 7.2–7.4 (complex, 8H); MS (ES+) m/z 883 (MH+), 589, 442, 414, 386 (base), 183. 
     Example 18 
     [N-(3-Nitrobenzyl)-N-(3-phenoxybenzyl)-Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2    
     DIEA (269 μL, 199 mg, 1.54 mmol), 3-nitrobenzyl bromide (322 mg, 1.49 mmol), and [N-(3-phenoxybenzyl)Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2  (482 mg, 0.546 mmol) were combined in 2 mL of DMF and heated at 60–70° C. under N 2  for 2 days. The reaction mixture was cooled and partitioned between 100 mL of EtOAc and water. The organic layer was washed with three times with water and once with brine, dried over Na 2 SO 4 , and concentrated to give 661 mg (˜100%) of [N-(3-nitrobenzyl)-N-(3-phenoxybenzyl)-Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2  which was used without purification; MS (ES+) m/z 1154 (MH+), 577, 130 (base). 
     Example 19 
     [N-(3-Aminobenzyl)-N-(3-phenoxybenzyl)-Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2    
     A solution of 661 mg (0.54 mmol) of crude [N-(3-nitrobenzyl)-N-(3-phenoxy-benzyl)-Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2  and 2.71 g (12.0 mmol) of SnCl 2 . 2H 2 O in 20 mL of absolute EtOH was refluxed under N 2  for 30 min. The cooled solution was poured into 500 mL of 2.5% aqueous Na 2 CO 3  with rapid stirring and the resulting cloudy mixture was extracted thoroughly with EtOAc. The slightly cloudy organic extracts were washed twice with brine, dried over Na 2 SO 4 , and concentrated to give 604 mg of yellow oil which was purified by MPLC using 3% MeOH/CH 2 Cl 2  to provide 350 mg (59%) of [N-(3-aminobenzyl)-N-(3-phenoxybenzyl)-Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2  as a pale yellow oil;  1 H NMR (CDCl 3 , 300 MHz) 1.41 (s, 18H), 1.97 (m, 4H), 2.25 (m, 4H), 2.48 (m, 4H), 3.03 (dd, 2H, J=5, 8 Hz), 3.30 (m, 2H), 3.4–3.8 (complex, 24H), 6.47 (d, 2H, J=7.5 Hz), 6.65 (m, 4H), 6.85 (d, 2H, J=9.5 Hz), 6.9–7.15 (complex, 12H), 7.2–7.4 (complex, 8H); MS (ES+) m/z 1094 (MH+), 547 (base). 
     Example 20 
     [N-(3-Phenoxybenzyl)-N-(3-(pentanoylamino)benzyl)-Glu-NHCH 2 CH 2 OCH 2 ] 2  (cpd 247) 
     Pentanoyl chloride (16 uL, 16 mg, 0.136 mmol) was added dropwise to a solution of 68 mg (0.062 mmol) of [N-(3-aminobenzyl)-N-(3-phenoxybenzyl)-Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2 , 20 μL (20 mg, 0.25 mmol) of pyridine in 0.3 mL of 1,2-dichloroethane. The mixture was shaken under N 2  overnight and was then partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaHCO 3 , dried over Na 2 SO 4 , and concentrated to give 77 mg of [N-(3-phenoxybenzyl)-N-(3-(pentanoylamino)benzyl)-Glu(O-t-Bu)-NHCH 2 CH 2 OCH 2 ] 2 ; MS (ES+) m/z 1073, 575 (base, MH+/2). The crude product was dissolved in 1 mL of 50% TFA/CH 2 Cl 2  and allows to stand overnight. The solution was concentrated and the resulting oil was dissolved in HOAc and freeze-dried to provide 82 mg of cpd 247;  1 H NMR (CD 3 OD, 300 MHz) 3.98 (t, 6H, J=7.5 Hz), 1.39 (sextet, 4H, J=7.5 Hz), 1.66 (quintet, 4H, J=7.5 Hz), 1.65 (m, 2H), 1.78 (m, 2H), 2.35 (t, 4H, J=7.5 Hz), 2.45 (m, 4H), 3.38 (m, 4H), 3.50 (t, 2H, J=5), 3.57 (m, 4H), 4.10 (broad s, 8H), 6.9–7.25 (complex, 14H), 7.25–7.4 (complex, 10H), 7.71 (s, 2H); MS (ES+) m/z 1150 (MH+), 575 (base). 
     Example 21 
     [N-Cbz-Lys(BOC)-NHCH 2 CH 2 ] 3 N 
     A solution of 1.0 g (2.63 mmol) of N-Cbz-Lys(Boc)OH, 0.131 mL (0.128 g, 0.876 mmol) of tris(2-aminoethyl)amine, 0.391 g (2.98 mmol) of HOBt, 0.555 g (2.89 mmol) of EDCI, and 0.55 mL (0.408 g, 3.16 mmol) of DIEA in 5 mL of CH 2 Cl 2  was stirred under N 2  at room temperature overnight. The mixture was diluted with EtOAc and washed with 10% aqueous citric acid, saturated aqueous NaHCO 3 , and brine. The solution was dried over Na 2 SO 4  and concentrated to give 0.872 g of [N-Cbz-Lys(Boc)-NHCH 2 CH 2 ] 3 N as an off-white solid;  1 H NMR (CD 3 OD, 300 MHz) 135 (m, 12H), 1.40 (s, 27H), 1.60 (m, 3H), 1.72 (m, 3H), 2.51 (m, 6H), 2.99 (m, 6H), 3.10 (m, 3H), 3.21 (m, 3H), 4.12 (m, 3H), 5.00 (d, 3H, J=12.5 Hz), 5.08 (d, 3H, J=12.5 Hz), 7.29 (m, 15H); MS (ES+) m/z 1243 (base, MH+), 567, 467. 
     Example 22 
     [Lys(Boc)-NHCH 2 CH 2 ] 3 N 
     A solution of 0.841 g (0.682 mmol) [N-Cbz-Lys(Boc)-NHCH 2 CH 2 ] 3 N, 0.252 g of 10% Pd-C, and 0.774 g (12.3 mmol) of ammonium formate in 10 mL of MeOH was stirred for 5 h at room temperature under N 2 . The mixture was filtered through a Celite pad, the solids were washed with CH 2 Cl 2 , and the reslulting solution was concentrated to dryness. The residue was partitioned between CH 2 Cl 2  and brine; the organic layer was dried over Na 2 SO 4  and concentrated to provide 0.191 g of [Lys(Boc)-NHCH 2 CH 2 ] 3 N as an off-white solid;  1 H NMR (CD 3 OD, 300 MHz) 1.40 (s, 27H), 1.45 (m, 12H), 1.75 (m, 6H), 2.62 (m, 6H), 3.01 (m, 6H), 3.28 (m, 6H), 3.64 (m, 3H); MS (ES+) m/z 853 (MNa+), 831 (MH+), 266 (base). 
     Example 23 
     [N,N-bis(3-Phenoxybenzyl)Lys(Boc)-NHCH 2 CH 2 ] 3 N 
     A solution of 65 mg (0.078 mmol) of [Lys(Boc)-NHCH 2 CH 2 ] 3 N, 120 μL (140 mg, 0.70 mmol) of 3-phenoxybenzaldehyde, and 71 μL (65 mg, 0.70 mmol) of borane-pyridine complexin 3 mL of absolute EtOH was stirred for 4 days at room temperature under N 2 . The mixture was concentrated to dryness and partitioned between water and CH 2 Cl 2 . The organic layer was concentrated to give a yellow oil which was purified by MPLC using 2.5% MeOH/CH 2 Cl 2  to give 78 mg of [N,N-bis(3-phenoxybenzyl)Lys(Boc)-NHCH 2 CH 2 ] 3 N as a yellow oil; MS (ES+) m/z 872 (base, [M—C 13 H 12 O)/2]+), 611, 443. 
     Example 24 
     [N,N-bis(3-Phenoxybenzyl)Lys-NHCH 2 CH 2 ] 3 N (cpd 277) 
     A solution of 78 mg (0.048 mmol) of [N,N-bis(3-phenoxybenzyl)Lys(Boc)-NHCH 2 CH 2 ] 3 N in 2 mL of 50% TFA/CH 2 Cl 2  was stirred for 2 h at room temperature. The mixture was diluted with CH 2 Cl 2 , washed with water and 5% Na 2 CO 3 , and concentrated to give 57 mg of cpd 277 as an off-white foam;  1 H NMR (CD 3 OD, 300 MHz) 1.35 (m, 6H), 1.52 (m, 6H), 1.76 (m, 6H), 2.75 (m, 6H), 3.19 (m, 6H), 3.40 (m, 6H), 3.60 (m, 9H), 3.77 (m, 6H), 6.79 (d, 6H, J=8 Hz), 6.93 (m, 24H), 7.05 (m, 6H), 7.19 (m, 6H), 7.29 (m, 12H); MS (ES+) m/z 813 ([MH 2 /2]+), 721, 542 (base, [MH/3]+). 
     Example 25 
     N,N-bis(3-Phenoxycinnamyl)Ser(t-Bu)-OMe (cpd 290) and N-(3-phenoxycinnamyl)Ser(t-Bu)-OMe (cpd 352) 
     A solution of 423 mg (2.0 mmol) of H-Ser(t-Bu)OMe.HCl, 1.01 g (3.5 mmol) of 3-phenoxycinnamyl bromide (Jackson, W. P.; Islip, P. J.; Kneen, G.; Pugh, A.; Wates, P. J.  J. Med. Chem.  31 1988; 499–500), and 0.87 mL (5.0 mmol, 650 mg) of DIEA in 6 mL of DMF was stirred under N 2  at room temperature for 20 h. The mixture was partitioned between EtOAc and water and the organic layer was washed with water and brine. After drying over Na 2 SO 4 , the organic solution was concentrated to give 0.98 g of yellow oil. The crude residue was purified by MPLC using a solvent gradient ranging from 10–30% EtOAc/hexanes to give two products. The less polar product (168 mg, 14% based on starting amino acid), N,N-bis(3-phenoxycinnamyl)Ser(t-Bu)-OMe (cpd 290), was isolated as a pale yellow oil;  1 H NMR (CDCl 3 , 300 MHz) 1.15 (s, 9H), 3.35 (dd, 2H, J=7, 14.5 Hz), 3.53 (dd, 2H, J=5.5, 14.5 Hz), 3.6–3.8 (complex, 3H), 3.69 (s, 3H), 6.18 (dt, 2H, J=16, 6.5 Hz), 6.49 (d, 2H, J=16 Hz), 6.86 (dd, 2H, J=2, 8 Hz), 6.9–7.4 (complex, 16H); MS (ES+) m/z 614, 592 (MH+, base), 406, 384, 209. 
     The more polar product (354 mg, 46% based on starting amino acid), N-(3-phenoxycinnamyl)Ser(t-Bu)-OMe (cpd 352), was isolated as a pale yellow oil;  1 H NMR (CDCl 3 , 300 MHz) 1.15 (s, 9H), 1.98 (broad s, 1H), 3.32 (ddd, 1H, J=1.2, 6.5, 14 Hz), 3.4–3.7 (complex, 4H), 3.72 (s, 3H), 6.21 (dt, 1H, J=16, 6.5 Hz), 6.48 (d, 1H, J=16 Hz), 6.88 (dd, 1H, J=1.5, 8 Hz), 7.0–7.4 (complex, 8H); MS (ES+) m/z 789 (2M+Na+), 384 (MH+, base), 209. 
     Example 26 
     N,N-Bis(3-phenoxycinnamyl)Ser-OMe (cpd 299) 
     N,N-Bis(3-phenoxycinnamyl)Ser(t-Bu)-OMe (cpd 290, 168 mg, 0.284 mmol) was stirred in 3 mL of 50% TFA/CH 2 Cl 2  under N 2  overnight. The solvent was removed using a rotary evaporator and the crude residue was partitioned between EtOAc and saturated aqueous NaHCO 3 . After washing with brine and drying over Na 2 SO 4 , the organic layer was concentrated using a rotary evaporator and the crude product (134 mg) was purified by MPLC using 30% EtOAc/hexanes to give 44 mg (29%) of N,N-bis(3-phenoxycinnamyl)Ser-OMe (cpd 299) as a colorless oil;  1 H NMR (CDCl 3 , 300 MHz) 1.6 (broad s, 2H), 3.38 (dd, 2H, J−8, 12 Hz), 3.4–3.9 (complex, 5H), 3.72 (s, 3H), 6.13 (dt, 2H, J=16, 7 Hz), 6.50 (d, 2H, J=16 Hz), 6.8–7.4 (complex, 18H); MS (ES+) m/z 536 (MH+). 
     Example 27 
     N,N-Bis(3-phenoxycinnamyl)Ser-OH (cpd 300) 
     N,N-Bis(3-phenoxycinnamyl)Ser-OMe (cpd 299, 44 mg, 0.082 mmol) was dissolved in 0.2 mL of MeOH and was stirred with 0.090 mL of 1N aqueous NaOH. When TLC analysis revealed that starting material had been consumed, the solvent was removed by rotary evaporation and the residue was lyophilized from acetic acid to give 42 mg (88%) of N,N-bis(3-phenoxycinnamyl)Ser-OH acetate (cpd 300) as a sticky yellow solid;  1 H NMR (methanol-d 4 , 300 MHz) 1.97 (s, 3H), 3.3–4.2 (complex, 7H), 6.80 (d, 2H, J=16 Hz), 6.9–7.4 (complex, 18H); MS (ES+) m/z 522 (MH+), 209. 
     Example 28 
     N-(3-Phenoxycinnamyl)Ser-OMe (cpd 346) 
     N-(3-Phenoxycinnamyl)Ser(t-Bu)-OMe (cpd 352, 268 mg, 0.699 mmol) was stirred in 3 mL of 50% TFA/CH 2 Cl 2  under N 2  overnight. The solvent was removed using a rotary evaporator and the crude residue (256 mg) was purified by MPLC using EtOAc to give 137 mg (60%) of N-(3-phenoxycinnamyl)Ser-OMe (cpd 346) as a colorless oil;  1 H NMR (CDCl 3 , 300 MHz) 2.2 (broad s, 2H), 3.36 (dd, 1H, J=6, 14 Hz), 3.4–3.5 (complex, 2H), 3.62 (dd, 1H, J=6.5, 11 Hz), 3.74 (s, 3H), 3.80 (dd, 1H, J=4.5, 11 Hz). 6.19 (dt, 1H, J=16, 6.5 Hz), 6.48 (d, 1H, J=6 Hz), 6.88 (dd, 1H, J=1.5, 8 Hz), 7.0–7.4 (complex, 8H); MS (ES+) m/z 677 (2M+Na+), 350 (M+Na+), 328 (MH+), 209 (base). 
     Example 29 
     N-(3-phenoxycinnamyl)Ser-OH (cpd 347) 
     N-(3-Phenoxycinnamyl)Ser-OMe (cpd 346, 110 mg, 0.336 mmol) was dissolved in 1.5 mL of MeOH and was stirred with 0.50 mL of 1N aqueous NaOH. When TLC analysis revealed that starting material had been consumed, the solvent was removed by rotary evaporation. The residue was dissolved in water and acidified to pH 7–8 with 1N aqueous HCl; the resulting solids were filtered, washed with water, and dried to give 71 mg of white powder. The insoluble powder was dissolved in TFA and, after removal of excess TFA by rotary evaporation, lyophilized from acetic acid to give 82 mg (57%) of N-(3-phenoxycinnamyl)Ser-OH trifluoroacetate (cpd 347) as an amber oil;  1 H NMR (methanol-d 4 , 300 MHz) 3.88 (d, 2H, J=7H), 4.0–4.2 (complex, 3H), 6.27 (dt, 1H, J=16, 6.5), 6.83 (d, 1H, J=16 Hz), 6.9–7.4 (complex, 9H); MS (ES+) m/z 314, (MH+), 209. 
     Example 30 
     N-(3-Phenoxycinnamyl)Glu(O-t-Bu)-OH (cpd 337) 
     A mixture of 249 mg (0.585 mmol) of N-(3-phenoxycinnamyl)Glu(O-t-Bu)-OMe (cpd 334) in 3 mL of MeOH was sonicated to speed dissolution, and the resulting solution was treated with 0.585 mL of 1N aqueous NaOH. After stirring overnight, the MeOH was removed using a rotary evaporator and the residue was dissolved in water. Acidification with 0.64 mL of 1N aqueous HCl produced a 250 mg of solid material that was triturated with Et 2 O to give 111 mg (46%) of N-(3-phenoxycinnamyl)Glu(O-t-Bu)-OH (cpd 337) as a white solid;  1 H NMR (300 MHz, methanol-d 4 ) 1.43 (s, 9H), 1.9–2.2 (complex, 2H), 2.46 (t, 2H, J=7 Hz), 3.57 (dd, 1H, J=5, 7 Hz), 3.78 (dd, 1H, J=7, 13.5 Hz), 3.82 (dd, 1H, J=7, 13.5 Hz), 6.28 (dt, 1H, J=16, 7 Hz), 6.81 (d, 1H, J=16 Hz), 6.9–7.5 (complex, 9H); MS (ES+) m/z 412 (MH+, base), 356, 209. Anal. Calcd for C 24 H 29 NO 5 .0.4H 2 O: C, 68.55; H, 7.04; N, 3.24. Found: C, 68.89; H, 7.04; N, 3.24. 
     Example 31 
     N-(3-Phenoxycinnamyl)Glu-OH (cpd 326) 
     A mixture of 85 mg (0.21 mmol) of N-(3-phenoxycinnamyl)Glu(O-t-Bu)-OH (cpd 337) in was stirred in 1 mL of 50% TFA/CH 2 Cl 2  for 1 h. After solvent removal using a rotary evaporator, the residue was dissolved in acetic acid and freeze-dried to give 75 mg (76%) of N-(3-phenoxycinnamyl)Glu-OH tifluoroacetate (cpd 326) as a fluffy white solid;  1 H NMR (300 MHz, methanol-d 4 ) 2.0–2.4 (complex, 2H), 2.55 (m, 2H), 3.84 (d, 2H, J=7 Hz), 3.96 (dd, 1H, J=5, 7 Hz, 6.24 (dt, 1H, J=16, 7 Hz), 6.84 (d, 1H, J=16 Hz), 6.9–7.4 (complex, 9H); MS (ES+) m/z 356 (MH+), 209 (base). 
     
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 R 1  (amino 
                   
                   
                   
               
               
                 cpd 
                 % inh 
                 acid side chain) 
                 R 2   
                 R 3   
                 W, Q 
               
               
                   
               
               
                 11 
                 70 
                 Asn, Asp, Gln, Glu 
                 3-PhO 
                   
                 CH═CH 
               
               
                 12 
                 59 
                 Cys, Met, Ser, Thr 
                 3-PhO 
                   
                 CH═CH 
               
               
                 13 
                 nd 
                 Arg, Gly, His, Pro 
                 3-PhO 
                   
                 CH═CH 
               
               
                 14 
                 30 
                 Lys(2-Cl—Cbz), 
                 3-PhO 
                   
                 CH═CH 
               
               
                   
                   
                 Phe, Trp, Tyr 
               
               
                 15 
                 48 
                 Ala, Ile, Leu, Val 
                 3-PhO 
                   
                 CH═CH 
               
               
                 16 
                 nd 
                 Glu, Asp 
                 2,3-benzo 
                   
                 CH═CH 
               
               
                 17 
                 nd 
                 Cys, Met 
                 2,3-benzo 
                   
                 CH═CH 
               
               
                 18 
                 nd 
                 Ser, Thr 
                 2,3-benzo 
                   
                 CH═CH 
               
               
                 19 
                 nd 
                 His, Arg(Mtr) 
                 2,3-benzo 
                   
                 CH═CH 
               
               
                 20 
                 nd 
                 Pro, Gly 
                 2,3-benzo 
                   
                 CH═CH 
               
               
                 21 
                 nd 
                 Phe, Tyr 
                 2,3-benzo 
                   
                 CH═CH 
               
               
                 22 
                 nd 
                 Trp, Lys(2-Cl—Cbz) 
                 2,3-benzo 
                   
                 CH═CH 
               
               
                 23 
                 nd 
                 Ile, Ala 
                 2,3-benzo 
                   
                 CH═CH 
               
               
                 24 
                 nd 
                 Val, Leu 
                 2,3-benzo 
                   
                 CH═CH 
               
               
                 25 
                 nd 
                 Asn, Lys 
                 2,3-benzo 
                   
                 CH═CH 
               
               
                 26 
                 nd 
                 Ala, Ile 
                   
                 3,4-benzo 
                 CH═CH 
               
               
                 27 
                 nd 
                 Arg(Mtr), 
                   
                 3,4-benzo 
                 CH═CH 
               
               
                   
                   
                 Lys(2-Cl—Cbz) 
               
               
                 28 
                 nd 
                 Asp, Glu 
                   
                 3,4-benzo 
                 CH═CH 
               
               
                 29 
                 nd 
                 Cys, Met 
                   
                 3,4-benzo 
                 CH═CH 
               
               
                 30 
                 nd 
                 Gly, Pro 
                   
                 3,4-benzo 
                 CH═CH 
               
               
                 31 
                 nd 
                 His, Lys 
                   
                 3,4-benzo 
                 CH═CH 
               
               
                 32 
                 nd 
                 Leu, Val 
                   
                 3,4-benzo 
                 CH═CH 
               
               
                 33 
                 nd 
                 Lys(2-Cl—Cbz), 
                   
                 3,4-benzo 
                 CH═CH 
               
               
                   
                   
                 Phe 
               
               
                 34 
                 nd 
                 Ser, Thr 
                   
                 3,4-benzo 
                 CH═CH 
               
               
                 35 
                 nd 
                 Trp, Tyr 
                   
                 3,4-benzo 
                 CH═CH 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/EBP-Ig 
                   
                   
                   
                   
                   
               
               
                 cpd 
                 % inh @ 50 μM 
                 R 1   
                 R 2   
                 R 9   
                 W, Q 
                 MS MH+ 
               
               
                   
               
               
                 36 
                 nd 
                 CH 3   
                 4-CF 3   
                 H 
                 CH═CH 
                 458 
               
               
                 37 
                 19 
                 H 
                 4-CF 3   
                 H 
                 CH═CH 
                 430 
               
               
                 38 
                 nd 
                 (CH 2 ) 4 NH(2-Cl—Cbz) 
                 4-F 
                 H 
                 CH═CH 
                 448 
               
               
                 40 
                 nd 
                 CH 3   
                 4-F 
                 H 
                 CH═CH 
                 223 
               
               
                 41 
                 nd 
                 CH 2 CO 2 H 
                 4-F 
                 H 
                 CH═CH 
                 266 
               
               
                 42 
                 nd 
                 CH 2 CH 2 CO 2 H 
                 4-F 
                 H 
                 CH═CH 
                 281 
               
               
                 43 
                 nd 
                 (CH 2 ) 3 NHC(═NH)NH 2   
                 4-F 
                 H 
                 CH═CH 
                 308 
               
               
                 45 
                 nd 
                 PhCH 2   
                 4-F 
                 H 
                 CH═CH 
                 299 
               
               
                 46 
                 nd 
                 4-HO—PhCH 2   
                 4-F 
                 H 
                 CH═CH 
                 315 
               
               
                 47 
                 nd 
                 CH 2 OH 
                 4-F 
                 H 
                 CH═CH 
                 238 
               
               
                 48 
                 nd 
                 CH(OH)CH 3   
                 4-F 
                 H 
                 CH═CH 
                 253 
               
               
                 49 
                  1 
                 (CH 2 ) 3 NHC(═NH)NH 2   
                 H 
                 H 
                 S 
                 419 
               
               
                 50 
                 −6 
                 (CH 2 ) 4 NH 2   
                 H 
                 H 
                 S 
                 391 
               
               
                 51 
                 nd 
                 CH(CH 3 )CH 2 CH 3   
                 H 
                 H 
                 S 
                 376 
               
               
                 52 
                 21 
                 CH 2 CH 2 CO 2 H 
                 H 
                 H 
                 S 
                 392 
               
               
                 53 
                 14 
                 CH 2 CO 2 H 
                 H 
                 H 
                 S 
                 378 
               
               
                 54 
                 18 
                 CH 3   
                 H 
                 H 
                 S 
                 334 
               
               
                 55 
                  4 
                 CH 2 CH 2 CONH 2   
                 H 
                 H 
                 S 
                 391 
               
               
                 56 
                 nd 
                 (CH 2 ) 4 NHCbz 
                 H 
                 Me 
                 S 
                 539 
               
               
                 57 
                  0 
                 (CH 2 ) 4 NHCbz 
                 H 
                 CH 2 Ph 
                 S 
                 615 
               
               
                 58 
                 nd 
                 CH 2 (indol-3-yl) 
                 H 
                 Me 
                 S 
                 463 
               
               
                 59 
                 26 
                 CH 2 CH 2 CO 2 -t-Bu 
                 H 
                 Me 
                 S 
                 462 
               
               
                 60 
                  9 
                 CH 2 CH 2 CO 2 Et 
                 H 
                 Me 
                 S 
                 434 
               
               
                 61 
                 14 
                 CH 2 CH 2 CO 2 H 
                 H 
                 Me 
                 S 
                 406 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/EBP-Ig 
                   
                   
                   
                   
                   
               
               
                 cpd 
                 % inh @ 50 μM 
                 R a   
                 R 2   
                 R 4   
                 R 9   
                 MS, MH+ 
               
               
                   
               
               
                 62 
                 nd 
                 t-Bu 
                 NO 2   
                 NO 2   
                 t-Bu 
                 516 
               
               
                 63 
                 20 
                 H 
                 PhCH 2 NH 
                 PhO 
                 H 
                 511 
               
               
                 64 
                 −4 
                 H 
                 4-MePhCONH 
                 4-MePhCONH 
                 H 
                 580 
               
               
                 65 
                 −7 
                 H 
                 4-MePhSO 2 NH 
                 4-MePhSO 2 NH 
                 H 
                 652 
               
               
                 66 
                 −16  
                 H 
                 3-ClPhCH 2 NH 
                 PhO 
                 H 
                 546 
               
               
                 67 
                 −8 
                 H 
                 3-BrPhCH 2 NH 
                 PhO 
                 H 
                 590 
               
               
                 68 
                 −13  
                 H 
                 2-FPhCH 2 NH 
                 PhO 
                 H 
                 529 
               
               
                 69 
                 −13  
                 H 
                 2-MePhCH 2 NH 
                 PhO 
                 H 
                 525 
               
               
                 70 
                 −8 
                 H 
                 4-FPhCH 2 NH 
                 PhO 
                 H 
                 529 
               
               
                 71 
                 −6 
                 H 
                 3-ClPhCH 2 NH 
                 4-Me—PhO 
                 H 
                 560 
               
               
                 72 
                 −14  
                 H 
                 F 5 —PhCH 2 NH 
                 4-Me—PhO 
                 H 
                 615 
               
               
                 73 
                 −13  
                 H 
                 2-FPhCH 2 NH 
                 4-Me—PhO 
                 H 
                 543 
               
               
                 74 
                 −7 
                 H 
                 3-CNPhCH 2 NH 
                 4-Me—PhO 
                 H 
                 550 
               
               
                 75 
                 −2 
                 H 
                 PhCH 2 NH 
                 4-Me—PhO 
                 H 
                 525 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/EBP-Ig 
                   
                   
                   
                   
                   
                   
                   
                 MS, 
               
               
                 cpd 
                 % inh @ 50 μM 
                 R a   
                 R 2   
                 R 3   
                 R 4   
                 R 5   
                 R 9   
                 n 
                 MH+ 
               
               
                   
               
               
                 76 
                 25 
                 t-Bu 
                 PhO 
                 H 
                 PhO 
                 H 
                 t-Bu 
                 1 
                 636 
               
               
                 77 
                 52 
                 H 
                 PhO 
                 H 
                 PhO 
                 H 
                 H 
                 1 
                 524 
               
               
                 78 
                 nd 
                 H 
                 H 
                 4-MePhCONH 
                 H 
                 BnO 
                 H 
                 2 
                 593 
               
               
                 79 
                 nd 
                 H 
                 H 
                 n-BuCONH 
                 H 
                 BnO 
                 H 
                 2 
                 559 
               
               
                 80 
                 nd 
                 H 
                 H 
                 2-naphthyl CONH 
                 H 
                 BnO 
                 H 
                 2 
                 629 
               
               
                 81 
                 nd 
                 H 
                 H 
                 2-furyl CONH 
                 H 
                 BnO 
                 H 
                 2 
                 569 
               
               
                 82 
                 32 
                 H 
                 H 
                 4-MeO—PhCONH 
                 H 
                 BnO 
                 H 
                 2 
                 609 
               
               
                 83 
                 18 
                 H 
                 H 
                 HO 2 C(CH 2 ) 3 CONH 
                 H 
                 BnO 
                 H 
                 2 
                 589 
               
               
                 84 
                 14 
                 H 
                 H 
                 C 2 F 5 CONH 
                 H 
                 BnO 
                 H 
                 2 
                 621 
               
               
                 85 
                 20 
                 H 
                 H 
                 CF 3 CONH 
                 H 
                 BnO 
                 H 
                 2 
                 571 
               
               
                 86 
                 37 
                 H 
                 H 
                 4-pyridyl-CONH 
                 H 
                 BnO 
                 H 
                 2 
                 580 
               
               
                 87 
                 23 
                 H 
                 H 
                 4-MePhSO 2 NH 
                 H 
                 BnO 
                 H 
                 2 
                 629 
               
               
                 88 
                   10.3 
                 H 
                 H 
                 HO 2 CCH 2 (1,1- 
                 H 
                 BnO 
                 H 
                 2 
                 643 
               
               
                   
                   
                   
                   
                 cyclopentyl) 
               
               
                   
                   
                   
                   
                 CH 2 CONH 
               
               
                 89 
                 22 
                 H 
                 H 
                 PhOCONH 
                 H 
                 BnO 
                 H 
                 2 
                 595 
               
               
                 90 
                 29 
                 H 
                 H 
                 4-Ph—PhCONH 
                 H 
                 BnO 
                 H 
                 2 
                 655 
               
               
                 91 
                 19 
                 H 
                 H 
                 4-NO 2 —PhCONH 
                 H 
                 BnO 
                 H 
                 2 
                 624 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/EBP-Ig 
                   
                   
                   
                   
                   
                   
                   
                 MS, 
               
               
                 cpd 
                 % inh @ 50 μM 
                 R a   
                 R 2   
                 R 3   
                 R 4   
                 R 5   
                 n 
                 R 9   
                 MH+ 
               
               
                   
               
             
          
           
               
                 92 
                 20 
                 H 
                 H 
                 H 
                 H 
                 H 
                 2 
                 Me 
                 394 
               
               
                 93 
                 20 
                 t-Bu 
                 H 
                 H 
                 H 
                 H 
                 2 
                 Me 
                 450 
               
               
                 94 
                 25 
                 Et 
                 H 
                 H 
                 H 
                 H 
                 2 
                 Me 
                 422 
               
               
                 95 
                 15 
                 t-Bu 
                 2,3-benzo 
                   
                 2,3-benzo 
                   
                 2 
                 Me 
                 550 
               
               
                 96 
                 −5 
                 t-Bu 
                 PhO 
                 H 
                 PhO 
                 H 
                 2 
                 Me 
                 634 
               
               
                 97 
                 14 
                 t-Bu 
                 3,4-benzo 
                   
                 3,4-benzo 
                   
                 2 
                 H 
                 536 
               
               
                 98 
                 12 
                 t-Bu 
                 H 
                 Ph 
                 H 
                   
                 2 
                 Me 
                 602 
               
               
                 99 
                 13 
                 t-Bu 
                 3,4-di-Cl—PhO 
                 H 
                 3,4-di-Cl—PhO 
                 H 
                 2 
                 Me 
                 772 
               
               
                 100 
                 34 
                 H 
                 H 
                 Ph 
                 H 
                   
                 2 
                 Me 
                 546 
               
               
                 101 
                 32 
                 H 
                 3,4-di-Cl—PhO 
                 H 
                 3,4-di-Cl—PhO 
                 H 
                 2 
                 Me 
                 716 
               
               
                 102 
                 5 
                 t-Bu 
                 4-t-Bu—PhO 
                 H 
                 4-t-Bu—PhO 
                 H 
                 2 
                 t-Bu 
                 789 
               
               
                 103 
                 17 
                 t-Bu 
                 3-CF3—PhO 
                 H 
                 3-CF3—PhO 
                 H 
                 2 
                 t-Bu 
                 812 
               
               
                 104 
                 78 
                 H 
                 4-t-Bu—PhO 
                 H 
                 4-t-Bu—PhO 
                 H 
                 2 
                 H 
                 676 
               
               
                 105 
                 70 
                 H 
                 3-CF3—PhO 
                 H 
                 3-CF3—PhO 
                 H 
                 2 
                 H 
                 700 
               
               
                 106 
                 20 
                 t-Bu 
                 PhO 
                 H 
                 PhO 
                 H 
                 1 
                 t-Bu 
                 662 
               
               
                 107 
                 78 
                 H 
                 PhO 
                 H 
                 PhO 
                 H 
                 2 
                 H 
                  562* 
               
               
                 108 
                 81 
                 H 
                 PhO 
                 H 
                 PhO 
                 H 
                 1 
                 H 
                 550 
               
               
                   
               
               
                 *[M—H] −   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/ 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 EBP-Ig 
               
               
                   
                 % inh 
                   
                   
                   
                   
                   
                   
                 MS, 
               
               
                   
                 @ 50 
                   
                   
                   
                   
                   
                   
                 MH 
               
               
                 cpd 
                 μM 
                 R a   
                 R 2   
                 R 3   
                 R 4   
                 R 5   
                 R 9   
                 + 
               
               
                   
               
               
                 109 
                  7 
                 Boc 
                 BnO 
                 H 
                 BnO 
                 H 
                 Me 
                 653 
               
               
                 110 
                 54 
                 H 
                 H 
                 BnO 
                 H 
                 BnO 
                 Me 
                 553 
               
               
                 111 
                  5 
                 Boc 
                 H 
                 BnO 
                 H 
                 BnO 
                 Me 
                 653 
               
               
                 112 
                 59 
                 H 
                 BnO 
                 H 
                 BnO 
                 H 
                 Me 
                 553 
               
               
                 113 
                 24 
                 Boc 
                 H 
                 BnO 
                 NO 2   
                 H 
                 Me 
                 592 
               
               
                 114 
                 37 
                 H 
                 H 
                 BnO 
                 NO 2   
                 H 
                 Me 
                 492 
               
               
                 115 
                 35 
                 H 
                 H 
                 BnO 
                 NH 2   
                 H 
                 Me 
                 462 
               
               
                 116 
                 32 
                 H 
                 H 
                 BnO 
                 n-BuCONH 
                 H 
                 Me 
                 546 
               
               
                 117 
                 34 
                 H 
                 H 
                 BnO 
                 2-furylCONH 
                 H 
                 Me 
                 556 
               
               
                 118 
                 36 
                 H 
                 H 
                 BnO 
                 4-MePhCONH 
                 H 
                 Me 
                 580 
               
               
                 119 
                 34 
                 H 
                 H 
                 BnO 
                 i-Pr—CONH 
                 H 
                 Me 
                 532 
               
               
                 120 
                 35 
                 H 
                 H 
                 BnO 
                 4-pyridyl- 
                 H 
                 Me 
                 567 
               
               
                   
                   
                   
                   
                   
                 CONH 
               
               
                 121 
                 45 
                 H 
                 H 
                 BnO 
                 2-naphthyl- 
                 H 
                 Me 
                 616 
               
               
                   
                   
                   
                   
                   
                 CONH 
               
               
                 122 
                 nd 
                 Boc 
                 PhCH 2 NH 
                 H 
                 PhCH 2 NH 
                 H 
                 Me 
                 651 
               
               
                 123 
                 nd 
                 Boc 
                 2-MePhCH 2 NH 
                 H 
                 2-MePhCH 2 NH 
                 H 
                 Me 
                 679 
               
               
                 124 
                 nd 
                 Boc 
                 4-MeO— 
                 H 
                 4-MeO— 
                 H 
                 Me 
                 711 
               
               
                   
                   
                   
                 PhCH 2 NH 
                   
                 PhCH 2 NH 
               
               
                 125 
                 nd 
                 Boc 
                 3,4-di-MeO— 
                 H 
                 3,4-di-MeO— 
                 H 
                 Me 
                 771 
               
               
                   
                   
                   
                 PhCH 2 NH 
                   
                 PhCH 2 NH 
               
               
                 126 
                 nd 
                 Boc 
                 —NH 2   
                 H 
                 —NH 2   
                 H 
                 Me 
                 471 
               
               
                 127 
                 nd 
                 H 
                 PhCH 2 NH 
                 H 
                 PhCH 2 NH 
                 H 
                 Me 
                 551 
               
               
                 128 
                 nd 
                 H 
                 2-MePhCH 2 NH 
                 H 
                 2-MePhCH 2 NH 
                 H 
                 Me 
                 579 
               
               
                 129 
                 nd 
                 H 
                 4-MeO— 
                 H 
                 4-MeO— 
                 H 
                 Me 
                 611 
               
               
                   
                   
                   
                 PhCH 2 NH 
                   
                 PhCH 2 NH 
               
               
                 130 
                 nd 
                 H 
                 3,4-di-MeO— 
                 H 
                 3,4-di-MeO— 
                 H 
                 Me 
                 671 
               
               
                   
                   
                   
                 PhCH 2 NH 
                   
                 PhCH 2 NH 
               
               
                 131 
                 nd 
                 H 
                 PhCH 2 CH 2 NH 
                 H 
                 PhCH 2 CH 2 NH 
                 H 
                 Me 
                 579 
               
               
                 132 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 PhCH 2 NH 
                 H 
                 PhCH 2 NH 
                 H 
                 Me 
                 651 
               
               
                 133 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 2-MePhCH 2 NH 
                 H 
                 2-MePhCH 2 NH 
                 H 
                 Me 
                 679 
               
               
                 134 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-MeO— 
                 H 
                 4-MeO— 
                 H 
                 Me 
                 711 
               
               
                   
                   
                   
                 PhCH 2 NH 
                   
                 PhCH 2 NH 
               
               
                 135 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 3,4-di-MeO— 
                 H 
                 3,4-di-MeO— 
                 H 
                 Me 
                 771 
               
               
                   
                   
                   
                 PhCH 2 NH 
                   
                 PhCH 2 NH 
               
               
                 136 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 PhCH 2 CH 2 NH 
                 H 
                 PhCH 2 CH 2 NH 
                 H 
                 Me 
                 679 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/EBP-Ig 
                   
                   
                   
                   
                   
                   
               
               
                   
                 % inh @ 50 
                   
                   
                   
                   
                   
                 MS, 
               
               
                 cpd 
                 μM 
                 R a   
                 R 2   
                 R 4   
                 R 5   
                 R 9   
                 MH+ 
               
               
                   
               
               
                 137 
                 nd 
                 H 
                 PhO 
                 PhO 
                 H 
                 Me 
                 551 
               
               
                 138 
                 nd 
                 Boc 
                 4-t-Bu—PhO 
                 BnO 
                 H 
                 Me 
                 721 
               
               
                 139 
                 nd 
                 H 
                 4-t-Bu—PhO 
                 BnO 
                 H 
                 Me 
                 621 
               
               
                 140 
                 nd 
                 H 
                 (CF 3 CO) 2 N 
                 BnO 
                 H 
                 H 
                 666 
               
               
                 141 
                 nd 
                 H 
                 PhCONH 
                 BnO 
                 H 
                 H 
                 578 
               
               
                 142 
                 nd 
                 H 
                 4-pyridyl-CONH 
                 BnO 
                 H 
                 H 
                 579 
               
               
                 143 
                 nd 
                 H 
                 (CF 3 CO) 2 N 
                 PhO 
                 H 
                 H 
                 652 
               
               
                 144 
                 nd 
                 H 
                 PhCONH 
                 PhO 
                 H 
                 H 
                 564 
               
               
                 145 
                 nd 
                 H 
                 4-pyridyl-CONH 
                 PhO 
                 H 
                 H 
                 565 
               
               
                 146 
                 nd 
                 H 
                 (CF 3 CO) 2 N 
                 MeO 
                 MeO 
                 H 
                 620 
               
               
                 147 
                 nd 
                 H 
                 PhCONH 
                 MeO 
                 MeO 
                 H 
                 532 
               
               
                 148 
                 nd 
                 H 
                 4-pyridyl-CONH 
                 MeO 
                 MeO 
                 H 
                 533 
               
               
                 149 
                 nd 
                 H 
                 (CF 3 CO) 2 N 
                 H 
                 PhO 
                 H 
                 652 
               
               
                 150 
                 nd 
                 H 
                 PhCONH 
                 H 
                 PhO 
                 H 
                 564 
               
               
                 151 
                 nd 
                 H 
                 4-pyridyl-CONH 
                 H 
                 PhO 
                 H 
                 565 
               
               
                 152 
                 nd 
                 H 
                 PhCONH 
                 H 
                 BnO 
                 H 
                 578 
               
               
                 153 
                 nd 
                 H 
                 4-pyridyl-CONH 
                 H 
                 BnO 
                 H 
                 579 
               
               
                 154 
                 nd 
                 H 
                 (CF 3 CO) 2 N 
                 H 
                 BnO 
                 H 
                 666 
               
               
                 155 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-MeO—PhCONH 
                 PhO 
                 H 
                 H 
                 694 
               
               
                 156 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 PhCONH 
                 PhO 
                 H 
                 H 
                 664 
               
               
                 157 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 2-naphthyl- 
                 PhO 
                 H 
                 H 
                 714 
               
               
                   
                   
                   
                 CONH 
               
               
                 158 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-Me—PhSO 2 NH 
                 PhO 
                 H 
                 H 
                 714 
               
               
                 159 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-MeO—PhCONH 
                 2,3- 
                   
                 H 
                 652 
               
               
                   
                   
                   
                   
                 benzo 
               
               
                 160 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 PhCONH 
                 2,3- 
                   
                 H 
                 622 
               
               
                   
                   
                   
                   
                 benzo 
               
               
                 161 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 2-naphthyl- 
                 2,3- 
                   
                 H 
                 672 
               
               
                   
                   
                   
                 CONH 
                 benzo 
               
               
                 162 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-Me—PhSO 2 NH 
                 2,3- 
                   
                 H 
                 672 
               
               
                   
                   
                   
                   
                 benzo 
               
               
                 163 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-MeO—PhCONH 
                 H 
                 F 
                 H 
                 620 
               
               
                 164 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 PhCONH 
                 H 
                 F 
                 H 
                 590 
               
               
                 165 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 2-naphthyl- 
                 H 
                 F 
                 H 
                 640 
               
               
                   
                   
                   
                 CONH 
               
               
                 166 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-Me—PhSO 2 NH 
                 H 
                 F 
                 H 
                 640 
               
               
                 167 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-MeO—PhCONH 
                 BnO 
                 H 
                 H 
                 708 
               
               
                 168 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 PhCONH 
                 BnO 
                 H 
                 H 
                 678 
               
               
                 169 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 2-naphthyl- 
                 BnO 
                 H 
                 H 
                 728 
               
               
                   
                   
                   
                 CONH 
               
               
                 170 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-Me—PhSO 2 NH 
                 BnO 
                 H 
                 H 
                 728 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/ 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 EBP- 
               
               
                   
                 Ig 
               
               
                   
                 % inh 
                   
                   
                   
                   
                   
                   
                 MS, 
               
               
                   
                 @ 50 
                   
                   
                   
                   
                   
                   
                 MH 
               
               
                 cpd 
                 μM 
                 R a   
                 R 2   
                 R 3   
                 R 4   
                 R 5   
                 R 9   
                 + 
               
               
                   
               
               
                 171 
                 nb 
                 Cbz 
                 H 
                 H 
                 H 
                 H 
                 Me 
                 527 
               
               
                 172 
                 15 
                 Cbz 
                 H 
                 H 
                 H 
                 H 
                 H 
                 513 
               
               
                 173 
                  5 
                 Cbz 
                 H 
                 H 
                 H 
                 H 
                 t- 
                 569 
               
               
                   
                   
                   
                   
                   
                   
                   
                 Bu 
               
               
                 174 
                 23 
                 Cbz 
                 H 
                 MeO 
                 H 
                 MeO 
                 Me 
                 587 
               
               
                 175 
                  1 
                 Cbz 
                   
                 3,4- 
                   
                 3,4- 
                 Me 
                 627 
               
               
                   
                   
                   
                   
                 benzo 
                   
                 benzo 
               
               
                 176 
                 −4 
                 Cbz 
                 PhO 
                 H 
                 PhO 
                 H 
                 Me 
                 711 
               
               
                 177 
                 nd 
                 Cbz 
                 2,3-benzo 
                   
                 2,3-benzo 
                   
                 Me 
                 627 
               
               
                 178 
                 36 
                 Boc 
                 H 
                 NO 2   
                 H 
                 NO 2   
                 Me 
                 583 
               
               
                 179 
                 30 
                 Boc 
                 H 
                 NO 2   
                 H 
                 NO 2   
                 H 
                 569 
               
               
                 180 
                 −4 
                 Boc 
                 PhO 
                 H 
                 PhO 
                 H 
                 Me 
                 677 
               
               
                 181 
                 −9 
                 Boc 
                 4-t-Bu—PhO 
                 H 
                 4-t-Bu—PhO 
                 H 
                 Me 
                 790 
               
               
                 182 
                 18 
                 H 
                 4-t-Bu—PhO 
                 H 
                 4-t-Bu—PhO 
                 H 
                 Me 
                 689 
               
               
                 183 
                 36 
                 Boc 
                 NO 2   
                 H 
                 NO 2   
                 H 
                 Me 
                 583 
               
               
                 184 
                 53 
                 H 
                 NO 2   
                 H 
                 NO 2   
                 H 
                 Me 
                 483 
               
               
                 185 
                 29 
                 H 
                 NH 2   
                 H 
                 NH 2   
                 H 
                 Me 
                 423 
               
               
                 186 
                 nd 
                 H 
                 n-Bu—CONH 
                 H 
                 n-Bu—CONH 
                 H 
                 Me 
                 591 
               
               
                 187 
                 nd 
                 H 
                 2-furyl-CONH 
                 H 
                 2-furyl-CONH 
                 H 
                 Me 
                 611 
               
               
                 188 
                 nd 
                 H 
                 PhCONH 
                 H 
                 PhCONH 
                 H 
                 Me 
                 631 
               
               
                 189 
                 nd 
                 H 
                 4-Me—PhCONH 
                 H 
                 4-Me—PhCONH 
                 H 
                 Me 
                 659 
               
               
                 190 
                 nd 
                 H 
                 4-NO 2 —PhCONH 
                 H 
                 4-NO 2 —PhCONH 
                 H 
                 Me 
                 721 
               
               
                 191 
                 nd 
                 H 
                 4-Me—PhSO 2 NH 
                 H 
                 4-Me—PhSO 2 NH 
                 H 
                 Me 
                 731 
               
               
                 192 
                 nd 
                 H 
                 Cbz—NH 
                 H 
                 Cbz—NH 
                 H 
                 Me 
                 691 
               
               
                 193 
                 nd 
                 H 
                 4-Br—PhCONH 
                 H 
                 4-Br—PhCO 
                 H 
                 Me 
                 789 
               
               
                 194 
                 nd 
                 H 
                 2-MeO—PhCONH 
                 H 
                 2-MeO—PhCONH 
                 H 
                 Me 
                 691 
               
               
                 195 
                 nd 
                 H 
                 3-MeO—PhCONH 
                 H 
                 3-MeO—PhCONH 
                 H 
                 Me 
                 691 
               
               
                 196 
                 nd 
                 H 
                 4-MeO—PhCONH 
                 H 
                 4-MeO—PhCONH 
                 H 
                 Me 
                 691 
               
               
                 197 
                 nd 
                 H 
                 CH 3 CH═CHCONH 
                 H 
                 CH 3 CH═CHCONH 
                 H 
                 Me 
                 559 
               
               
                 198 
                 nd 
                 H 
                 C 2 F 5 CONH 
                 H 
                 C 2 F 5 CONH 
                 H 
                 Me 
                 715 
               
               
                 199 
                 nd 
                 H 
                 2-naphthyl- 
                 H 
                 2-naphthyl- 
                 H 
                 Me 
                 731 
               
               
                   
                   
                   
                 CONH 
                   
                 CONH 
               
               
                 200 
                 nd 
                 H 
                 EtO 2 CCH 2 CH 2 CONH 
                 H 
                 EtO 2 CCH 2 CH 2 CONH 
                 H 
                 Me 
                 679 
               
               
                 201 
                 nd 
                 H 
                 CF 3 CONH 
                 H 
                 CF 3 CONH 
                 H 
                 Me 
                 615 
               
               
                 202 
                 nd 
                 H 
                 MeSO 2 NH 
                 H 
                 MeSO 2 NH 
                 H 
                 Me 
                 579 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/ 
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 EBP-Ig 
                   
                   
                   
                   
                   
                   
                 MS, 
               
               
                   
                 % inh @ 
                   
                   
                   
                   
                   
                   
                 MH 
               
               
                 cpd 
                 50 μM 
                 R a   
                 R 2   
                 R 3   
                 R 4   
                 R 5   
                 Z 
                 + 
               
               
                   
               
               
                 203 
                 37 
                 Boc 
                 H 
                 H 
                 H 
                 H 
                 4-(MeCOCH 2 CH 2 )—PhNH 
                 640 
               
               
                 204 
                 −6 
                 H 
                 H 
                 H 
                 H 
                 H 
                 4-(MeCOCH 2 CH 2 )—PhNH 
                 540 
               
               
                 205 
                 26 
                 H 
                 H 
                 H 
                 H 
                 H 
                 n-Bu—NH 
                 434 
               
               
                 206 
                 17 
                 2-MeO—PhCO 
                 H 
                 H 
                 H 
                 H 
                 n-Bu—NH 
                 568 
               
               
                 207 
                 20 
                 4-MeO—PhCO 
                 H 
                 H 
                 H 
                 H 
                 n-Bu—NH 
                 568 
               
               
                 208 
                 22 
                 PhCO 
                 H 
                 H 
                 H 
                 H 
                 n-Bu—NH 
                 538 
               
               
                 209 
                 25 
                 2-MeO—PhCO 
                 H 
                 H 
                 H 
                 H 
                 n-Bu—NH 
                 568 
               
               
                 210 
                 nd 
                 Boc 
                 H 
                 H 
                 H 
                 H 
                 4-MeO—PhCH 2 CH 2 NH 
                 612 
               
               
                 211 
                 62 
                 H 
                 H 
                 H 
                 H 
                 H 
                 4-MeO—PhCH 2 CH 2 NH 
                 512 
               
               
                 212 
                 −10  
                 H 
                 H 
                 H 
                 H 
                 H 
                 n-Pr—NH 
                 420 
               
               
                 214 
                 nd 
                 Boc 
                 H 
                 H 
                 H 
                 H 
                 3,4-di-MeO— 
                 642 
               
               
                   
                   
                   
                   
                   
                   
                   
                 PhCH 2 CH 2 NH 
               
               
                 215 
                 nd 
                 Boc 
                 H 
                 H 
                 H 
                 H 
                 3-MeO—PhCH 2 CH 2 NH 
                 612 
               
               
                 216 
                 10 
                 Boc 
                 H 
                 H 
                 H 
                 H 
                 4-(PhCH═CHCH 2 O)— 
                 700 
               
               
                   
                   
                   
                   
                   
                   
                   
                 PhCH 2 NH 
               
               
                 217 
                 nd 
                 Boc 
                 H 
                 H 
                 H 
                 H 
                 4-HO—PhCH 2 NH 
                 584 
               
               
                 218 
                 nd 
                 Boc 
                 H 
                 H 
                 H 
                 H 
                 EtNH 
                 506 
               
               
                 219 
                 nd 
                 Boc 
                 H 
                 H 
                 H 
                 H 
                 MeNH 
                 492 
               
               
                 220 
                 45 
                 H 
                 H 
                 H 
                 H 
                 H 
                 4-(PhCH═CHCH 2 O)— 
                 600 
               
               
                   
                   
                   
                   
                   
                   
                   
                 PhCH 2 NH 
               
               
                 221 
                 48 
                 H 
                 H 
                 H 
                 H 
                 H 
                 3,4-di-MeO— 
                 542 
               
               
                   
                   
                   
                   
                   
                   
                   
                 PhCH 2 CH 2 NH 
               
               
                 222 
                 56 
                 H 
                 H 
                 H 
                 H 
                 H 
                 3-MeO—PhCH 2 CH 2 NH 
                 512 
               
               
                 223 
                 nd 
                 Boc 
                 H 
                 H 
                 H 
                 H 
                 2-MeO—PhCH 2 CH 2 NH 
                 612 
               
               
                 224 
                 51 
                 H 
                 H 
                 H 
                 H 
                 H 
                 2-MeO—PhCH 2 CH 2 NH 
                 512 
               
               
                 225 
                 10 
                 Boc 
                 PhO 
                 H 
                 PhO 
                 H 
                 4-MeO—PhCH 2 CH 2 NH 
                 797 
               
               
                 226 
                 nd 
                 Boc 
                 H 
                 H 
                 H 
                 H 
                 PhCH 2 CH 2 NH 
                 582 
               
               
                 227 
                 48 
                 H 
                 H 
                 H 
                 H 
                 H 
                 PbCH 2 CH 2 NH 
                 482 
               
               
                 228 
                 21 
                 PhNHCO 
                 PhO 
                 H 
                 PhO 
                 H 
                 4-MeO—PhCH 2 CH 2 NH 
                 816 
               
               
                 229 
                 22 
                 4-PhO— 
                 H 
                 H 
                 H 
                 H 
                 4-MeO—PhCH 2 CH 2 NH 
                 723 
               
               
                   
                   
                 PhNHCO 
               
               
                 230 
                 42 
                 3,4-di-Cl— 
                 H 
                 H 
                 H 
                 H 
                 4-MeO—PhCH 2 CH 2 NH 
                 700 
               
               
                   
                   
                 PhNHCO 
               
               
                 231 
                 36 
                 4-EtO2C— 
                 H 
                 H 
                 H 
                 H 
                 4-MeO—PhCH 2 CH 2 NH 
                 703 
               
               
                   
                   
                 PhNHCO 
               
               
                 232 
                 14 
                 4-PhO— 
                 PhO 
                 H 
                 PhO 
                 H 
                 4-MeO—PhCH 2 CH 2 NH 
                 908 
               
               
                   
                   
                 PhNHCO 
               
               
                 233 
                 18 
                 H 
                 H 
                 NO2 
                 H 
                 NO2 
                 3-MeO—PhCH 2 CH 2 NH 
                 602 
               
               
                 234 
                 nd 
                 Boc 
                 H 
                 H 
                 H 
                 H 
                 PbCH 2 NH 
                 568 
               
               
                 235 
                 49 
                 H 
                 H 
                 H 
                 H 
                 H 
                 PhCH 2 NH 
                 468 
               
               
                 236 
                 nd 
                 Boc 
                 H 
                 Ph 
                 H 
                 Ph 
                 4-MeO—PhCH 2 CH 2 NH 
                 765 
               
               
                 237 
                 55 
                 HO 2 CCH 2 CH 2 CO 
                 H 
                 H 
                 H 
                 H 
                 3-MeO—PhCH 2 CH 2 NH 
                 612 
               
               
                 238 
                 39 
                 H 
                 H 
                 Ph 
                 H 
                 Ph 
                 4-MeO—PhCH 2 CH 2 NH 
                 664 
               
               
                 239 
                 46 
                 H 
                 PhO 
                 H 
                 PhO 
                 H 
                 PhCH 2 CH 2 NH 
                 666 
               
               
                 240 
                 nd 
                 HO 2 CCH 2 CH 2 CH 2 CO 
                 PhO 
                 H 
                 PhO 
                 H 
                 PhCH 2 CH 2 NH 
                 780 
               
               
                 285 
                 40 
                 H 
                 H 
                 H 
                 H 
                 H 
                 4-(NH 2 CO)piperidin-1-yl 
                 489 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/ 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 EBP-Ig 
               
               
                   
                 % inh @ 
                   
                   
                   
                   
                   
                   
                   
                 MS, 
               
               
                 cpd 
                 50 μM 
                 R a   
                 R 2   
                 R 3   
                 R 4   
                 R 5   
                 Z 
                 r 
                 [MH 2 /2]+ 
               
               
                   
               
             
          
           
               
                 241 
                 2 
                 t-Bu 
                 H 
                 BnO 
                 H 
                 BnO 
                 NH(CH 2 ) 3 O(CH 2 ) 4 O(CH 2 ) 3 NH 
                 1 
                 666 
               
               
                 242 
                 1 
                 t-Bu 
                 H 
                 BnO 
                 H 
                 BnO 
                 NH(CH 2 ) 3 O(CH 2 CH 2 O) 2 (CH 2 ) 3 NH 
                 1 
                 674 
               
               
                 243 
                 75 
                 H 
                 H 
                 BnO 
                 H 
                 BnO 
                 NH(CH 2 ) 3 O(CH 2 ) 4 O(CH 2 ) 3 NH 
                 1 
                 610 
               
               
                 244 
                 66 
                 H 
                 H 
                 BnO 
                 H 
                 BnO 
                 NH(CH 2 ) 3 O(CH 2 CH 2 O) 2 (CH 2 ) 3 NH 
                 1 
                 618 
               
               
                 245 
                 0 
                 t-Bu 
                 H 
                 BnO 
                 H 
                 BnO 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 2 
                 652 
               
               
                 246 
                 79 
                 H 
                 H 
                 BnO 
                 H 
                 BnO 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 2 
                 596 
               
               
                 247 
                 47 
                 H 
                 n-Bu— 
                 H 
                 PhO 
                 H 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 2 
                 575 
               
               
                   
                   
                   
                 CONH 
               
               
                 248 
                 56 
                 H 
                 2-furyl- 
                 H 
                 PhO 
                 H 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 2 
                 585 
               
               
                   
                   
                   
                 CONH 
               
               
                 249 
                 72 
                 H 
                 4-Me— 
                 H 
                 PhO 
                 H 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 2 
                 609 
               
               
                   
                   
                   
                 PhCONH 
               
               
                 250 
                 78 
                 H 
                 4-Me— 
                 H 
                 PhO 
                 H 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 2 
                 645 
               
               
                   
                   
                   
                 PhSO 2 NH 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 12 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/EBP-Ig 
                   
                   
                   
                   
                   
                   
               
               
                   
                 % inh @ 50 
                   
                   
                   
                   
                   
                 MS, 
               
               
                 cpd 
                 μM 
                 R a   
                 R 2   
                 R 4   
                 Z 
                 r 
                 [MH 2 /2]+ 
               
               
                   
               
               
                 251 
                 49 
                 H 
                 H 
                 H 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 2 
                 436 
               
               
                 252 
                 −4 
                 t-Bu 
                 4-t-Bu— 
                 4-t-Bu—PhO 
                 NH(CH 2 ) 3 O(CH 2 ) 4 O(CH 2 ) 3 NH 
                 1 
                 803 
               
               
                   
                   
                   
                 PhO 
               
               
                 253 
                 −5 
                 t-Bu 
                 4-t-Bu— 
                 4-t-Bu—PhO 
                 NH(CH 2 ) 3 O(CH 2 CH 2 O) 2 (CH 2 ) 3 NH 
                 1 
                 811 
               
               
                   
                   
                   
                 PhO 
               
               
                 254 
                 −9 
                 t-Bu 
                 4-t-Bu— 
                 4-t-Bu—PhO 
                 NH(CH 2 ) 10 NH 
                 1 
                 787 
               
               
                   
                   
                   
                 PhO 
               
               
                 255 
                  0 
                 t-Bu 
                 4-t-Bu— 
                 4-t-Bu—PhO 
                 NH(CH 2 ) 12 NH 
                 1 
                 801 
               
               
                   
                   
                   
                 PhO 
               
               
                 256 
                 10 
                 t-Bu 
                 4-t-Bu— 
                 4-t-Bu—PhO 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 1 
                 789 
               
               
                   
                   
                   
                 PhO 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 13 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/EBP-Ig 
                   
                   
                 MS, 
               
               
                 cpd 
                 % inh @ 50 μM 
                 R a   
                 Z 
                 [MH 2 /2]+ 
               
               
                   
               
             
          
           
               
                 257 
                 −26 
                 Boc 
                 NH(CH 2 ) 3 O(CH 2 CH 2 O) 2 (CH 2 ) 3 NH 
                 731 
               
               
                 258 
                 −24 
                 Boc 
                 NH(CH 2 ) 3 O(CH 2 ) 4 O(CH 2 ) 3 NH 
                 723 
               
               
                 259 
                 −13 
                 Boc 
                 NH(CH 2 ) 12 NH 
                 721 
               
               
                 260 
                 −12 
                 Boc 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 695 
               
               
                 261 
                 51 
                 H 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 595 
               
               
                 262 
                 93 
                 HO 2 CCH 2 CH 2 CO 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 695 
               
               
                 263 
                 88 
                 HO 2 C(CH 2 ) 3 CO 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 709 
               
               
                 264 
                 89 
                 HO 2 CCH 2 CMe 2 CH 2 CO 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 737 
               
               
                 265 
                 65 
                 HO 2 CCH 2 CH 2 CO 
                 NH(CH 2 ) 3 O(CH 2 ) 4 O(CH 2 ) 3 NH 
                 723 
               
               
                 266 
                 82 
                 HO 2 C(CH 2 ) 3 CO 
                 NH(CH 2 ) 3 O(CH 2 ) 4 O(CH 2 ) 3 NH 
                 737 
               
               
                 267 
                 83 
                 HO 2 CCH 2 CMe 2 CH 2 CO 
                 NH(CH 2 ) 3 O(CH 2 ) 4 O(CH 2 ) 3 NH 
                 765 
               
               
                 268 
                 40 
                 HO 2 CCH 2 CMe2CH 2 CO 
                 NH(CH 2 ) 12 NH 
                 764 
               
               
                 269 
                 55 
                 HO 2 CCH 2 CH 2 CH 2 CO 
                 NH(CH 2 ) 12 NH 
                 735 
               
               
                 270 
                 56 
                 HO 2 CCH 2 CH 2 CO 
                 NH(CH 2 ) 12 NH 
                 721 
               
               
                 271 
                 77 
                 HO 2 CCH 2 CH 2 CO 
                 NH(CH 2 ) 3 O(CH 2 CH 2 O) 2 (CH 2 ) 3 NH 
                 731 
               
               
                 272 
                 78 
                 HO 2 CCH 2 CH 2 CH 2 CO 
                 NH(CH 2 ) 3 O(CH 2 CH 2 O) 2 (CH 2 ) 3 NH 
                 745 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 14 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/ 
                   
                   
                   
                   
                   
                   
               
               
                   
                 EBP-Ig 
                   
                   
                   
                   
                   
                 MS, 
               
               
                   
                 % inh @ 
                   
                   
                   
                   
                   
                 [MH 2 /2] 
               
               
                 cpd 
                 50 μM 
                 R a   
                 R 2   
                 R 4   
                 Z 
                 n 
                 + 
               
               
                   
               
               
                 273 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-Me—PhO 
                 4-Me—PhO 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 2 
                 695 
               
               
                 274 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 PhO 
                 PhO 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 2 
                 667 
               
               
                 275 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-MeO— 
                 4-MeO— 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 2 
                 727 
               
               
                   
                   
                   
                 PhO 
                 PhO 
               
               
                 276 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-t-Bu— 
                 4-t-Bu— 
                 NH(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NH 
                 2 
                 780 
               
               
                   
                   
                   
                 PhO 
                 PhO 
               
               
                 277 
                 nd 
                 H 
                 PhO 
                 PhO 
                 (NHCH 2 CH 2 ) 3 N 
                 3 
                 813 
               
               
                 278 
                 nd 
                 H 
                 4-Me—PhO 
                 4-Me—PhO 
                 (NHCH 2 CH 2 ) 3 N 
                 3 
                 855 
               
               
                 279 
                 nd 
                 H 
                 4-MeO— 
                 4-MeO— 
                 (NHCH 2 CH 2 ) 3 N 
                 3 
                 903 
               
               
                   
                   
                   
                 PhO 
                 PhO 
               
               
                 280 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-MeO— 
                 4-MeO— 
                 (NHCH 2 CH 2 ) 3 N 
                 3 
                 1053  
               
               
                   
                   
                   
                 PhO 
                 PhO 
               
               
                 281 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 4-Me—PhO 
                 4-Me—PhO 
                 (NHCH 2 CH 2 ) 3 N 
                 3 
                 1005  
               
               
                 282 
                 nd 
                 HO 2 CCH 2 CH 2 CO 
                 PhO 
                 PhO 
                 (NHCH 2 CH 2 ) 3 N 
                 3 
                 963 
               
               
                 283 
                 nd 
                 Boc 
                 PhO 
                 PhO 
                 NH(CH 2 ) 3 NMe(CH 2 ) 3 NH 
                 2 
                 666 
               
               
                 284 
                 nd 
                 Boc 
                 4-Me—PhO 
                 4-Me—PhO 
                 NH(CH 2 ) 3 NMe(CH 2 ) 3 NH 
                 2 
                 694 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 15 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/EBP-Ig 
                   
                   
                   
                   
               
               
                 cpd 
                 % inh @ 50 μM 
                 R 1   
                 R 2   
                 R 3   
                 MS, MH+ 
               
               
                   
               
               
                 285 
                 −28  
                 Me 
                 H 
                 H 
                 473 
               
               
                 286 
                 46 
                 H 
                 BnO 
                 H 
                 565 
               
               
                 287 
                 36 
                 H 
                 4-Me—PhO 
                 H 
                 565 
               
               
                 288 
                 27 
                 H 
                 4-tBu—PhO 
                 H 
                 607 
               
               
                 289 
                 20 
                 H 
                 H 
                 PhO 
                 551 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 16A 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/EBP-Ig 
                   
                   
                   
                   
               
               
                 cpd 
                 % inh @ 50 μM 
                 R 1   
                 R 2   
                 R 3   
                 R 4   
               
               
                   
               
               
                 290 
                  0 
                 Me 
                 PhO 
                 H 
                 t-Bu 
               
               
                 291 
                 17 
                 Me 
                 H 
                 Ph 
                 t-Bu 
               
               
                 292 
                 11 
                 Me 
                 3-CF3—C6H4O 
                 H 
                 t-Bu 
               
               
                 293 
                 14 
                 Me 
                 3,4-Cl2—C6H3O 
                 H 
                 t-Bu 
               
               
                 294 
                  9 
                 Me 
                 4-t-Bu—C6H4O 
                 H 
                 t-Bu 
               
               
                 295 
                 10 
                 Me 
                 H 
                 Ph 
                 H 
               
               
                 296 
                  0 
                 Me 
                 3,4-Cl2—C6H3O 
                 H 
                 H 
               
               
                 297 
                  0 
                 Me 
                 3-CF3—C6H4O 
                 H 
                 H 
               
               
                 298 
                  1 
                 Me 
                 4-t-Bu—C6H4O 
                 H 
                 H 
               
               
                 299 
                 nd 
                 Me 
                 PhO 
                 H 
                 H 
               
               
                 300 
                 57 
                 H 
                 PhO 
                 H 
                 H 
               
               
                 301 
                 25 
                 H 
                 H 
                 Ph 
                 t-Bu 
               
               
                 302 
                 30 
                 H 
                 3,4-Cl2—C6H3O 
                 H 
                 t-Bu 
               
               
                 303 
                 21 
                 H 
                 3-CF3—C6H4O 
                 H 
                 t-Bu 
               
               
                 304 
                 19 
                 H 
                 4-t-Bu—C6H4O 
                 H 
                 t-Bu 
               
               
                 305 
                 48 
                 H 
                 H 
                 Ph 
                 H 
               
               
                 306 
                 21 
                 Me 
                 H 
                 H 
                 t-Bu 
               
               
                 307 
                 25 
                 H 
                 3,4-Cl2—C6H3O 
                 H 
                 H 
               
               
                 308 
                 25 
                 H 
                 3-CF3—C6H4O 
                 H 
                 H 
               
               
                 309 
                 13 
                 H 
                 4-t-Bu—C6H4O 
                 H 
                 H 
               
               
                 310 
                 34 
                 Me 
                 H 
                 H 
                 H 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 16B 
               
               
                   
               
               
                 cpd 
                 MPLC solvent 
                 appearance 
                 empirical formula 
                 MS, MH+ 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 290 
                 10–30% 
                 pale yellow oil 
                 C38H41NO5 
                 592 
               
               
                   
                 EtOAc/hex 
               
               
                 291 
                 1:5 EtOAc/hex 
                 yellow oil 
                 C38H41NO3 
                 560 
               
               
                 292 
                 1:5 EtOAc/hex 
                 yellow oil 
                 C40H39F6NO5 
                 728 
               
               
                 293 
                 1:5 EtOAc/hex 
                 yellow oil 
                 C38H37Cl4NO5 
                 728 
               
               
                 294 
                 1:5 EtOAc/hex 
                 yellow oil 
                 C46H57NO5 
                 704 
               
               
                 295 
                   
                 off-white solid 
                 C34H33NO3/1 
                 504 
               
               
                   
                   
                   
                 C2H4O2 
               
               
                 296 
                   
                 amber solid 
                 C34H29Cl4NO5/1 
                 672 
               
               
                   
                   
                   
                 C2H4O2 
               
               
                 297 
                   
                 amber oil 
                 C36H31F6NO5/1 
                 672 
               
               
                   
                   
                   
                 C2H4O2 
               
               
                 298 
                   
                 off-white solid 
                 C42H49NO5/1 
                 648 
               
               
                   
                   
                   
                 C2H4O2 
               
               
                 299 
                 30% EtOAc/hex 
                 colorless oil 
                 C34H33NO5 
                 536 
               
               
                 300 
                   
                 sticky yellow solid 
                 C33H31NO5/1 
                 522 
               
               
                   
                   
                   
                 C2H4O2 
               
               
                 301 
                   
                 yellow solid 
                 C37H39NO3 
                 546 
               
               
                 302 
                   
                 amber oil 
                 C37H35Cl4NO5 
                 714 
               
               
                 303 
                   
                 amber oil 
                 C39H37F6NO5 
                 714 
               
               
                 304 
                   
                 amber oil 
                 C45H55NO5 
                 690 
               
               
                 305 
                   
                 amber solid 
                 C33H31NO2/1 
                 490 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 306 
                   
                 light-yellow oil 
                 C26H33NO3/0.25 
                 408 
               
               
                   
                   
                   
                 H2O 
               
               
                 307 
                   
                 amber solid 
                 C33H27Cl4NO5/1 
                 658 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 308 
                   
                 amber oil 
                 C35H29F6NO5/1 
                 658 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 309 
                   
                 off-white solid 
                 C41H47NO5/1 
                 634 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 310 
                   
                 light yellow oil 
                 C22H25NO3/1 
                 352 
               
               
                   
                   
                   
                 C2H4O2 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 17A 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 EPO/EBP-Ig 
                   
                   
                   
               
               
                   
                 cpd 
                 % inh @ 50 μM 
                 R 1   
                 R 2   
                 R 3   
               
               
                   
                   
               
             
          
           
               
                   
                 311 
                 5.3 
                 t-Bu 
                 PhO 
                 H 
               
               
                   
                 312 
                 45 
                 H 
                 PhO 
                 H 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
               
               
               
               
             
           
               
                 TABLE 17B 
               
               
                   
               
               
                 cpd 
                 MPLC solvent 
                 appearance 
                 empirical formula 
                 MS, MH+ 
               
               
                   
               
             
             
               
                 311 
                 10% EtOAc/hex 
                 pale yellow oil 
                 C36H37NO4 
                 548 
               
               
                 312 
                   
                 sticky brown 
                 C32H29NO4/1 
                 492 
               
               
                   
                   
                 solid 
                 C2HF3O2 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 18A 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/ 
                   
                   
                   
                   
               
               
                   
                 EBP-Ig, 
               
               
                   
                 % inh @ 
               
               
                 cpd 
                 50 μM 
                 R 1   
                 R 2   
                 R 3   
                 R 4   
               
               
                   
               
               
                 313 
                 28 
                 H 
                 H 
                 CF3 
                 (CH2)4NH(2-Cl— 
               
               
                   
                   
                   
                   
                   
                 Cbz) 
               
               
                 314 
                 12 
                 Me 
                 H 
                 CO2H 
                 (CH2)4NH2 
               
               
                 315 
                 nd 
                 Me 
                 H 
                 NO2 
                 (CH2)4NHBoc 
               
               
                 316 
                 20 
                 Me 
                 OPh 
                 H 
                 (CH2)4NHBoc 
               
               
                 317 
                 13 
                 Me 
                 4-t-Bu— 
                 H 
                 (CH2)4NHBoc 
               
               
                   
                   
                   
                 C6H4O 
               
               
                 318 
                 14 
                 Me 
                 H 
                 H 
                 (CH2)4NHCbz 
               
               
                 319 
                 nd 
                 Me 
                 H 
                 H 
                 (CH2)4NHCbz 
               
               
                 320 
                 17 
                 Me 
                 H 
                 OMe 
                 (CH2)4NHCbz 
               
               
                 321 
                 42 
                 Me 
                 CO2Me 
                 H 
                 (CH2)4NHCbz 
               
               
                 322 
                 nd 
                 Me 
                 H 
                 2,3-benzo 
                 (CH2)4NHCbz 
               
               
                 323 
                  6 
                 Me 
                 H 
                 CO2H 
                 (CH2)4NHCbz 
               
               
                 324 
                 nd 
                 Me 
                 H 
                 CO2Me 
                 nd 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 18B 
               
               
                   
               
               
                 cpd 
                 MPLC solvent 
                 appearance 
                 empirical formula 
                 MS, MH+ 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 313 
                   
                 yellow oil 
                 C25H28ClF3N2O4\1 
                 499 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 314 
                   
                 yellow oil 
                 C17H24N2O4 
                 321 
               
               
                 315 
                 30% EtOAc/hex 
                 dark yellow gum 
                 C21H31N3O6 
                 422 
               
               
                 316 
                 20–50% EtOAc/hex 
                 pale yellow oil 
                 C27H36N2O5 
                 469 
               
               
                 317 
                   
                 pale yellow oil 
                 C31H44N2O5 
                 525 
               
               
                 318 
                   
                 gum 
                 C24H30N2O4 
                 411 
               
               
                 319 
                   
                 pale yellow oil 
                 C24H30N2O4 
                 411 
               
               
                 320 
                 2% MeOH/CH2Cl2 
                 yellow oil 
                 C25H32N2O5 
                 441 
               
               
                 321 
                   
                 yellow oil 
                 C26H32N2O6\1 
                 469 
               
               
                   
                   
                   
                 C2H4O2 
               
               
                 322 
                 25–50% EtOAc/hex 
                 clear residue 
                 C28H32N2O4 
                 461 
               
               
                 323 
                   
                 yellow oil 
                 C25H30N2O6 
                 455 
               
               
                 324 
                   
                 yellow oil 
                 C26H32N2O6 
                 469 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 19A 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/ 
                   
                   
                   
                   
               
               
                   
                 EBP-Ig 
               
               
                   
                 % inh @ 
               
               
                 cpd 
                 50 μM 
                 R 1   
                 R 2   
                 R 3   
                 R 4   
               
               
                   
               
               
                 325 
                  6 
                 Me 
                 OPh 
                 H 
                 CH2CH2CO2H 
               
               
                 326 
                  0 
                 H 
                 OPh 
                 H 
                 CH2CH2CO2H 
               
               
                 327 
                 11 
                 Me 
                 H 
                 Ph 
                 CH2CH2CO2H 
               
               
                 328 
                 33 
                 Me 
                 3,4-Cl2—C6H3O 
                 H 
                 CH2CH2CO2H 
               
               
                 329 
                 13 
                 H 
                 H 
                 Ph 
                 CH2CH2CO2H 
               
               
                 330 
                 12 
                 H 
                 3-CF3—C6H4O 
                 H 
                 CH2CH2CO2H 
               
               
                 331 
                 18 
                 H 
                 4-t-Bu—C6H4O 
                 H 
                 CH2CH2CO2H 
               
               
                 332 
                 17 
                 H 
                 3,4-Cl2—C6H3O 
                 H 
                 CH2CH2CO2H 
               
               
                 333 
                 16 
                 Me 
                 3,4-benzo 
                   
                 CH2CH2CO2-t-Bu 
               
               
                 334 
                  6 
                 Me 
                 OPh 
                 H 
                 CH2CH2CO2-t-Bu 
               
               
                 335 
                 25 
                 Me 
                 H 
                 Ph 
                 CH2CH2CO2-t-Bu 
               
               
                 336 
                 32 
                 Me 
                 3,4-Cl2—C6H3O 
                 H 
                 CH2CH2CO2-t-Bu 
               
               
                 337 
                  0 
                 H 
                 OPh 
                 H 
                 CH2CH2CO2-t-Bu 
               
               
                 338 
                 23 
                 t-Bu 
                 3-CF3—C6H4O 
                 H 
                 CH2CH2CO2-t-Bu 
               
               
                 339 
                 10 
                 t-Bu 
                 4-t-Bu—C6H4O 
                 H 
                 CH2CH2CO2-t-Bu 
               
               
                 340 
                 14 
                 H 
                 H 
                 Ph 
                 CH2CH2CO2-t-Bu 
               
               
                 341 
                 19 
                 H 
                 3,4-Cl2—C6H3O 
                 H 
                 CH2CH2CO2-t-Bu 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 19B 
               
               
                   
               
               
                 cpd 
                 MPLC solvent 
                 appearance 
                 empirical formula 
                 MS, MH+ 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 325 
                   
                 off-white solid 
                 C21H23NO5\1 
                 370 
               
               
                   
                   
                   
                 C2F3HO2 
               
               
                 326 
                   
                 fluffy white 
                 C20H21NO5\1 
                 356 
               
               
                   
                   
                 solid 
                 C2HF3O2 
               
               
                 327 
                   
                 off-white solid 
                 C21H23NO4\1 
                 354 
               
               
                   
                   
                   
                 C2F3HO2 
               
               
                 328 
                   
                 amber oil 
                 C21H21Cl2NO5\1 
                 438 
               
               
                   
                   
                   
                 C2F3HO2 
               
               
                 329 
                   
                 amber solid 
                 C20H21NO4\1 
                 340 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 330 
                   
                 amber oil 
                 C21H20F3NO5\1 
                 424 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 331 
                   
                 amber oil 
                 C24H29NO5\1 
                 412 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 332 
                   
                 amber oil 
                 C20H19CL2NO5\1 
                 424 
               
               
                   
                   
                   
                 C2HF3O2 
                 424 
               
               
                 333 
                 10–25% EtOAc/hex 
                 yellow oil 
                 C23H29NO4 
                 384 
               
               
                 334 
                 10–30% EtOAc/hex 
                 pale yellow oil 
                 C25H31NO5 
                 426 
               
               
                 335 
                 1:5 EtOAc/hex 
                 yellow oil 
                 C25H31NO4 
                 410 
               
               
                 336 
                 1:5 EtOAc/hex 
                 yellow oil 
                 C25H29C12NO5 
                 494 
               
               
                 337 
                   
                 white powder 
                 C24H29NO5\0.4 
                 412 
               
               
                   
                   
                   
                 H2O 
               
               
                 338 
                 1:5 EtOAc/hex 
                 yellow oil 
                 C29H36F3NO5 
                 536 
               
               
                 339 
                 1:5 EtOAc/hex 
                 yellow oil 
                 C32H45NO5 
                 524 
               
               
                 340 
                   
                 yellow solid 
                 C24H29NO4 
                 396 
               
               
                 341 
                   
                 white solid 
                 C24H27C12NO5 
                 480 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 20A 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/EBP-Ig 
                   
                   
                   
                   
               
               
                 cpd 
                 % inh @ 50 μM 
                 R 1   
                 R 2   
                 R 3   
                 R 4   
               
               
                   
               
               
                 342 
                  0 
                 Me 
                 H 
                 Ph 
                 CH2OH 
               
               
                 343 
                 37 
                 Me 
                 4-t-Bu—C6H4O 
                 H 
                 CH2OH 
               
               
                 344 
                  4 
                 Me 
                 3-CF3—C6H4O 
                 H 
                 CH2OH 
               
               
                 345 
                 40 
                 Me 
                 3,4-Cl2—C6H3O 
                 H 
                 CH2OH 
               
               
                 346 
                 28 
                 Me 
                 OPh 
                 H 
                 CH2OH 
               
               
                 347 
                 23 
                 H 
                 OPh 
                 H 
                 CH2OH 
               
               
                 348 
                 21 
                 H 
                 H 
                 Ph 
                 CH2OH 
               
               
                 349 
                 23 
                 H 
                 3,4-Cl2—C6H3O 
                 H 
                 CH2OH 
               
               
                 350 
                 23 
                 H 
                 3-CF3—C6H4O 
                 H 
                 CH2OH 
               
               
                 351 
                 29 
                 H 
                 4-t-Bu—C6H4O 
                 H 
                 CH2OH 
               
               
                 352 
                  8 
                 Me 
                 OPh 
                 H 
                 CH2O-t-Bu 
               
               
                 353 
                 24 
                 Me 
                 H 
                 Ph 
                 CH2O-t-Bu 
               
               
                 354 
                 31 
                 Me 
                 3,4-Cl2—C6H3O 
                 H 
                 CH2O-t-Bu 
               
               
                 355 
                 22 
                 Me 
                 3-CF3—C6H4O 
                 H 
                 CH2O-t-Bu 
               
               
                 356 
                 23 
                 Me 
                 4-t-Bu—C6H4O 
                 H 
                 CH2O-t-Bu 
               
               
                 357 
                 12 
                 H 
                 3-CF3—C6H4O 
                 H 
                 CH2O-t-Bu 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 20B 
               
               
                   
               
               
                 cpd 
                 MPLC solvent 
                 appearance 
                 empirical formula 
                 MS, MH+ 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 342 
                   
                 off-white solid 
                 C19H21NO3\1 
                 312 
               
               
                   
                   
                   
                 C2F3HO2 
               
               
                 343 
                   
                 amber oil 
                 C23H29NO4\1 
                 384 
               
               
                   
                   
                   
                 C2F3HO2 
               
               
                 344 
                   
                 amber oil 
                 C20H20F3NO4\1 
                 396 
               
               
                   
                   
                   
                 C2F3HO2 
               
               
                 345 
                   
                 amber oil 
                 C19H19Cl2NO4\1 
                 396 
               
               
                   
                   
                   
                 C2F3HO2 
               
               
                 346 
                 EtOAc 
                 pale yellow oil 
                 C19H21NO4 
                 328 
               
               
                 347 
                   
                 amber oil 
                 C18H19NO4\1 
                 314 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 348 
                   
                 yellow solid 
                 C18H19NO3\1 
                 298 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 349 
                   
                 amber oil 
                 C18H17Cl2NO4\1 
                 382 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 350 
                   
                 amber oil 
                 C19H18F3NO4\1 
                 382 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 351 
                   
                 amber oil 
                 C22H27NO4\1 
                 370 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 352 
                 10–30% EtOAc/hex 
                 pale yellow oil 
                 C23H29NO4 
                 384 
               
               
                 353 
                 20% EtOAc/hex 
                 off-white solid 
                 C23H29NO3 
                 368 
               
               
                 354 
                 20% EtOAc/hex 
                 yellow oil 
                 C23H27Cl2NO4 
                 452 
               
               
                 355 
                 20% EtOAc/hex 
                 yellow oil 
                 C24H28F3NO4 
                 452 
               
               
                 356 
                 20% EtOAc/hex 
                 yellow oil 
                 C27H37NO4 
                 440 
               
               
                 357 
                   
                 white solid 
                 C23H26F3NO4 
                 438 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 21A 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 EPO/EBP-Ig 
                   
                   
                   
                   
               
               
                 cpd 
                 % inh @ 50 μM 
                 R 1   
                 R 2   
                 R 3   
                 R 4   
               
               
                   
               
             
          
           
               
                 358 
                 0 
                 H 
                 H 
                 CF3 
                 (s)-CH(OH)CH3 
               
               
                 359 
                 25 
                 Me 
                 CO2Me 
                 H 
                 (s)-CH(OMe)CH3 
               
               
                 360 
                 18 
                 Me 
                 H 
                 H 
                 Bn 
               
               
                 361 
                 24 
                 Me 
                 CO2Me 
                 H 
                 Bn 
               
               
                 362 
                 0 
                 H 
                 H 
                 CF3 
                 CH2(4-HOC6H4) 
               
               
                 363 
                 33 
                 Me 
                 CO2Me 
                 H 
                 CH2(4-MeOC6H4) 
               
               
                 364 
                 16 
                 Me 
                 H 
                 H 
                 CH2(indol-3-yl) 
               
               
                 365 
                 0 
                 H 
                 H 
                 CF3 
                 CH2CH2SMe 
               
               
                 366 
                 38 
                 Me 
                 CO2Me 
                 H 
                 CH2CO2Me 
               
               
                 367 
                 0 
                 H 
                 H 
                 CF3 
                 CH2CONH2 
               
               
                 368 
                 40 
                 Me 
                 CO2Me 
                 H 
                 CH2SBn 
               
               
                 369 
                 12 
                 H 
                 H 
                 CF3 
                 i-Bu 
               
               
                 370 
                 0 
                 H 
                 H 
                 CF3 
                 i-Pr 
               
               
                 371 
                 16 
                 Me 
                 CO2Me 
                 H 
                 i-Pr 
               
               
                 372 
                 0 
                 Me 
                 H 
                 H 
                 Me 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 21B 
               
               
                   
               
               
                 cpd 
                 MPLC solvent 
                 appearance 
                 empirical formula 
                 MS, MH+ 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 358 
                   
                 amber oil 
                 C14H16F3NO3\1 
                 304 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 359 
                   
                 amber oil 
                 C17H23NO5\1 
                 322 
               
               
                   
                   
                   
                 C2H4O2 
               
               
                 360 
                 20% EtOAc/hex 
                 light-yellow oil 
                 C19H21NO2 
                 296 
               
               
                 361 
                   
                 amber oil 
                 C22H25NO5\1 
                 354 
               
               
                   
                   
                   
                 C2H4O2 
               
               
                 362 
                   
                 amber oil 
                 C19H18F3NO3\1 
                 366 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 363 
                   
                 amber oil 
                 C22H25NO5\1 
                 384 
               
               
                   
                   
                   
                 C2H4O2 
               
               
                 364 
                 1:2 EtOAc/hex 
                 tan solid 
                 C21H22N2O2 
                 335 
               
               
                 365 
                   
                 amber oil 
                 C15H18F3NO2S\1 
                 334 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 366 
                   
                 amber oil 
                 C17H21NO6\1 
                 336 
               
               
                   
                   
                   
                 C2H4O2 
               
               
                 367 
                   
                 amber oil 
                 C14H15F3N2O3\1 
                 317 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 368 
                   
                 amber oil 
                 C22H25NO4S\1 
                 400 
               
               
                   
                   
                   
                 C2H4O2 
               
               
                 369 
                   
                 amber oil 
                 C17H22F3NO2\1 
                 316 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 370 
                   
                 amber oil 
                 C15H18F3NO2\1 
                 302 
               
               
                   
                   
                   
                 C2HF3O2 
               
               
                 371 
                   
                 amber oil 
                 C17H23NO4\1 
                 306 
               
               
                   
                   
                   
                 C2H4O2 
               
               
                 372 
                 20% EtOAc/hex 
                 yellow oil 
                 C13H17NO2\0.10 
                 220 
               
               
                   
                   
                   
                 C4H8O2