FIELD OF THE INVENTION The present invention comprises small molecular weight, non-peptidic inhibitors of Protein Tyrosine Phosphatase 1 (PTP1) which are useful for the treatment and/or prevention of Non-Insulin Dependent Diabetes Mellitus (NIDDM).

BACKGROUND OF THE INVENTION The mechanism of insulin action depends critically upon the phosphorylation of tyrosine residues in several proteins in the insulin signaling cascade. Enzymes that dephosphorylate these proteins, protein tyrosine phosphatases (PTPs), are important negative regulators of insulin action. Therefore, the use of specific PTP inhibitors may therapeutically enhance insulin action.

The insulin resistance that is central to noninsulin-dependent diabetes mellitus (NIDDM) appears to involve a defect in an early process in insulin signal transduction rather than a structural defect in the insulin receptor itself. (J. M. Olefsky, W. T. Garvey, R. R. Henry, D.

Billon, S. Matthai and G. R. Freidenberg, G. R. (1988).) Cellular mechanisms of insulin resistance in non-insulin-dependent (Type II) diabetes. (Am. J. Med. 85: Suppl. 5A, 86-105.) A drug that improved insulin sensitivity would have several avantages over traditional therapy of NIDDM using sulfonylureas, which do not alleviate insulin resistance but instead compensate by increasing insulin secretion.

The binding of insulin to the a-subunits of the insulin receptor permits the ß-subunits to catalyze phosphorylation of target proteins on tyrosine residues. There are 22 tyrosine residues in each insulin receptor ß-subunit itself and autophosphorylation of at least 6 of these tyrosines, in 3 distinct domains, is known to be involved in insulin action. (C. R. Kahn (1994) Insulin action, diabetogenes, and the cause of type 11 diabetes. Diabetes 43: 1066-1084.) Autophosphorylation of Tyr 960 in the juxtamembrane domain is important for receptor

internalization and for the interaction of the receptor with downstream signaling molecules such as insulin receptor substrate 1 (IRS-1).) (T. J. O'Neill, A. Craparo and T. A. Gustafson (1994) Characterization of an interaction between insulin receptor substrate 1 and the insulin receptor by using the two-hybrid system. Mol. Cell Biol. 14: 6433-6442.) Autophosphorylation of tyrosine residues 1146,1150 and 1151 in the regulatory domain permits continued tyrosine kinase activity of ß-subunits, even after insulin has dissociated from the a-subunits, and activates the kinase toward other protein substrates. (R. Herrera and O. M. Rosen (1986) Autophosphorylation of the insulin receptor in vitro: designation of phosphorylation sites and correlation with receptor kinase activation. J. Biol. Chem. 261: 11980-11985.) Deletion of autophosphorylation sites at Tyrl 316 and Tyrl 322 in the C-terminal domain attenuates the metabolic actions of insulin, but augments its mitogenic actions. (H. Maegawa, D. McClain, G.

Freidenberg, J. Olefsky, M. Napier, T. Lipari, T. Dull, J. Lee, and A. Ullrich (1988) Properties of a human insulin receptor with a COOH-terminal truncation. II. Truncated receptors have normal kinase activity but are defective in signaling metabolic effects. J. Biol. Chem. 263: 8912-8917.) (Y. Takata, N. J. G. Webster, and J. M. Olefsky (1991) Mutation of the two carboxyl-terminal tyrosines results in an insulin receptor with normal metabolic signaling but enhanced mitogenic signaling properties. J. Biol. Chem. 266: 9135-9139.) Dephosphorylation of these autophosphorylated sites occurs rapidly in vivo, suggesting that a protein tyrosine phosphatase (PTPase) is involved in terminating insulin action. A compound that inhibited this PTPase, therefore, should potentiate insulin action. Indeed, vanadate potentiates insulin action, at least in part, by such a mechanism (Y. Schechter (1990). Insulin-mimetic effects of vanadate.

Possible implications for future treatment of diabetes. Diabetes 39: 1-5.) The PTPase (s) that act on the insulin receptor, however, has not been identifie definitively.

It has been estimated that the human genome encodes as many as 500 PTP enzymes (T.

Hunter (1995) Protein kinases and phosphatases: The Yin and Yang of protein phosphorylation and signaling. Cell 80: 225-236), but less than 100 have been identifie and have been grouped into 4 sub-families (E. A. Fauman and M. A. Saper (1996) Structure and function of the protein tyrosine phosphatases. Trends Biochem. Sci. 21: 413-417.) Members of the tyrosine-specific PTP sub-family are further divided into the receptor PTPases (such as CD45 and LAR) which typically have a large variable extracellular domain, a single transmembrane spanning region, and two intracellular phosphatase catalytic domains and the non-receptor PTPases. This latter group inclues PTP that resemble PTP1. (D. A. Pot and J. E. Dixon (1992) A thousand and two protein tyrosine phosphatases. Biochim. Biophys. Acta 1136: 35-43.) There is data to support

the proposition that the insulin receptor PTPase may be PTPI-like. For instance, an insulin- dependent association of PTP I with insulin receptors has been described. (D. Bandyopadhyay, A. Kursari, K. A. Kenner, F. Liu, J. Chernoff, T. A. Gustafson, J. Kusari (1997) Protein-tyrosine phosphatase 1B complexes with the insulin receptor in vivo and is tyrosine-phosphorylated in the presence of insulin. J. Biol. Chem. 272: 1639-1645; and L. Seely, et al. (1996) Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. Diabetes 45: 1379.) Furthermore, PTP 1 dephosphorylates purifie insulin receptors sequentially in the order observe in vivo (i. e., Tyr1150=Tyr1151>Tyr1146), (C. Ramachandran, R. Aebersold, N.

Tonks and D. A. Pot (1992) Sequential dephosphorylation of a multiply phosphorylated insulin receptor peptide by protein tyrosine phosphatases. Biochemistry 31: 4232-4238) and insulin acutely increases PTP1 mRNA in hepatoma cells. (N. Hashimoto and B. J. Goldstein (1992) Differential regulation of mRNAs encoding three protein-tyrosine phosphatases by insulin and activation of protein kinase C. Biochem. Biophys. Res. Commun. 188: 1305-1311.) Insulin resistance induced in Rat 1 fibroblasts by high glucose (27 mM) is preceded by an approximate doubling of cytosolic PTP I activity that is blocked by the insulin-sensitizer, pioglitazone. (H.

Maegawa, R. Ide, M. Hasegawa, S. Ugi, K. Egawa, M. Iwanishi, R. Kikkawa, Y. Shigeta, and A. Kashiwagi (1995) Thiazolidinedione derivatives ameliorate high glucose-induced insulin resistance via the normalization of protein tyrosine phosphatase activities. J. Biol. Chem. 270: 7724-7730.) Thus, a specific inhibitor of PTP1 could be used to potentiate insulin action. While there are no known small molecules that specifically inhibit PTP 1, it was found that osmotic loading of hepatoma cells with neutralizing antibodies against PTPlb (the human homologue of rat PTP1) resulted in increased autophosphorylation of insulin receptors and phosphorylation of IRS-1 in response to insulin. (F. Ahmad, P.-M. Li, J. Meyerovitch, and B. J. Goldstein (1995) Osmotic loading of neutralizing antibodies demonstrates a role for PTPase I B in negative regulation of the insulin signaling pathway. Diabetes 44: Suppl. 1 104A.) See also B. J.

Goldstein (1993) Regulation of insulin receptor signaling by protein-tyrosine dephosphorylation.

Receptor 3: 1-15.) INFORMATION DISCLOSURE International Publication No. WO 96/30332,"O-Malonyltyrosyl Compound, O- Malonyltyrosyl Compound-Containing Peptides, and Uses thereof,"published 3 October 1996, disclose non-phosphorus containing O-malonyltyrosyl compound, derivatives thereof, uses of the O-malonyltyrosyl compound in the synthesis of peptides, and O-malonyltyrosyl compound-

containing peptides. The O-malonyltyrosyl compound and O-malonyltyrosyl compound- containing peptides are disclosed as being useful as inhibitors of protein-tyrosine phosphatase; however, no specific non-peptidic compound or data is disclosed.

International Publication No. WO 96/23813,"Peptides and Compound that Bind to SH2 Domains,"published 8 August 1996, discloses tyrosine-containing peptides and compound which bind to the SH2 domain or domains of various proteins, as well as methods for identifying such peptides and compound. These peptides and compound have application as agonists and antagonists of SH2 domain containing proteins, and as diagnostic or therapeutic agents for the diagnosis or treatment of disease conditions.

International Publication No. WO 96/40113,"Phosphatase Inhibitors,"published 19 December 1996, discloses heterocyclic nitrogen containing compound, such as nitropyn'dine or nitrothiazole, capable of inhibiting protein tyrosine phosphatase activity. Such molecules are disclosed as being useful to modulate or regulate signal transduction by inhibiting protein tyrosine phosphatase activity and to treat various disease states including diabetes mellitus.

International Publication No. WO 96/40109,"Methods of Inhibiting Phosphatase Activity and Treatment of Disorders Associated Therewith Using Napthopyrones and Derivatives Thereof,"published 19 December 1996, discloses the use of naphthopyrone compound to inhibit protein tyrosine phosphatase activity. Such compound are disclosed as being useful to modulate or regulate signal transduction by inhibiting protein tyrosine phosphatase activity and to treat various disease states including diabetes mellitus.

The compound of the present invention have surprising activity in that they are small molecular weight and non-peptidic compound.

SUMMARY OF THE INVENTION One aspect of the invention provides a compound of formula I: wherein A is-C (O)- or-S02- ; whereinGl° is-R43;

wherein Gl l is a) CONR99R, b) H, c) CHZOH, or d) CH=CHR44; wherein R99 is H or C1-C6 alkyl; wherein is a)-OSO3H, b)-OCH (C02R46)2, c)-OCH2 (C02R46), d)-OCH(CO2R46)CH2CO2R46, e)-OC(CO2R46)=CHCO2446, f)-CH2CH(CO2R46)2, g)-CH=C (C02R46) 2, h)-OCH2CONHOH, i)-N (CH2Co2R46) 2, or j)-oCHF (Co2R46); wherein is alkoxy,a)-C1-C10 b) -C0-C6 alkyl-(G12)n, wherein alkyl is optionally substituted with one to three -O- C1-C4 alkyl, halo, or trifluoromethyl, and optionally interrupted with one to three -O-, -S-, or-N-, with the proviso that when G12 is phenyl, the phenyl group must be substituted by one (1) to four (4) R50 groups, provided that-COOR46 is not a substituent, alkenyl-(G12)n,c)-C2-C10 alkyl-O-(G12)n,d)-C1-C10 e)-Cl-C6 alkyl-C3-CIO cycloalkyl optionally substituted with one to three R50, or -Co-Clo alkylcarbonyl- (Glz)" wherein alkyl is optionally interrupted with one to three-0-,-S-, or-N- ; wherein R44 is

a)-C I-C 12 alkyl, optionally substituted with one to three-0-C I-C4 alkyl,-S-C I- C4 alkyl, -O-G12, -S-G12, or -OH, and optionally interrupted with one to three- or-N-,O-,-S-, b)-Cl-C4 alkyl-C3-C6 cycloalkyl, alkenyl,c)-C2-C12 alkynyl,d)-C3-C12 e) -C0-C10 alkyl (G12) n wherein alkyl is optionally interrupted with one to three -O- -N-,,-S-,or alkyl,f)-CH(CONH2)C1-C12 g) -C0-C6 alkyl-NR53R54, wherein alkyl is substituted with zero to three OH, orh)-NR54-CO-R56, i) -O-C1-C10 alkyl (G12)", wherein alkyl is optionally interrupted with one to three- 0-,-S-, or-N- ; wherein is a)-H, alkyl,orb)-C1-C10 alkyl-phenyl;c)-C1-C5 wherein R47 is alkyl,a)-C1-C10 alkyl-G12,b)-C0-C6 c)-Cl-C6 alkyl-CONH2, alkylNHCO2R46,d)-C1-C6 alkyl-OR46,e)-C1-C6 alkyl-NHSO2Me,f)-C1-C6 alkyl-O-G12,g)-C1-C6 alkyl-S-G12,orh)-C1-C6 i)-Cl-C6 alkyl-CO2R46; wherein R48 is a)-H, alkyl-G12,b)-C1-C6 alkyl-CO2R46,c)-C1-C6

d)-C I-C6 alkyl CONH2, alkylNHCO2R46,e)-C1-C6 alkyl,f)-C1-C10 g)-Cl-Clo cycloalkyl, h)-C,-C6alkyl-SR46, or alkyl-S(=O)R46;i)-C1-C6 wherein is a) phenyl substituted by zero (0) to four (4) RSO, b) naphthyl substituted by zero (0) to three (3) R or c) het1 substituted by zero (0) to three (3) R50; wherein hetl is a 5-or 6-membered saturated or unsaturated ring containing from one (1) to four (4) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, C3- C8 cycloalkyl, or another heterocycle; and optionally, the nitrogen and sulfur heteroatoms may be in oxidized form if chemically feasible; wherein R50may be any of the following: a) C1-C8 alkyl substituted by zero (0) to three (3) halo, b) C2-C8 alkenyl, c)OH, d) alkyl, e) O-Co-Cs alkyl-phenyl, f) -(CH2)n-O-C1-C5 alkyl substituted by zero (0) to three (3) hydroxy, g) -(CH2)n-O-C2-C7 alkenyl substituted by zero (0) to three (3) hydroxy, h) halo, j) amino-C-Cs alkyl, k) mono-or di-Cl-C5 alkylamino, alkyl,1)-C(O)-C1-C5 m)-CHO, n)-C (O)-Co-CS alkyl-phenyl, o)-COOR46, p)-CON (R) 2,

q)-C3-C7 cycloalkyl, r)-NO2, <BR> <BR> <BR> <BR> <BR> s)-CN,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> t)-S03H, u)-SO2N(R46)2, v)-O[(CH2)2-O]n-CH3, alkyl,w)-[CH2-O]n-C1-C3 x)-NR46(CO)-NR46, y)-CF3, alkyl,z)-NR46(CO)C1-C5 a1)-N(R46)-SO2-R46, b1)-O-C(O)-R46, c1)-S(O)-R46, d1)-SR46, el)-So2-R46, fl) phenyl, or gl) oxo; wherein R51 is a)-H, b)-CO2R46, c)-CONHOH, d) het2 substituted by zero to three R51, where in het2 is a 5-or 6-membered saturated or unsaturated ring containing from one (1) to four (4) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, e) F, OCH2CO2R46,or whereinR52 is a) H, or

b) methyl; wherein Rs3 and Rs4 are a) H, b) Cl-C6 alkyl, or alkyl-phenyl;c)C0-C6 wherein R55 is a) H, or b) CI-C4 alkyl; wherein is a) C0-C0 alkyl-phenyl, wherein alkyl is optionally substituted with one OH and phenyl is substituted with one to three OH or phenyl, or b) C0-C6 alkyl-NR55-CO-phenyl, wherein alkyl is optionally substituted with one OH and phenyl is substituted with zero to three OH or phenyl; wherein X is-CO-or-S02-or-C02- ; wherein n is zero, one, two or three; or a pharmaceutically acceptable salt thereof ; provided that when R51 is H, R42 is other than-OCH2 (C02R46); and that when (i) A is-S02- ; and/or (ii) R44 is -C0-C6 alkyl-NR53R54, wherein alkyl is substituted with zero to three OH; and/or (iii) R44 is-NR54-Co-R56; and/or (iv) R44 is -O-C1-C10 alkyl (G12)n, wherein alkyl is optionally interrupted with one to three-O-,-S-, or-N-; and/or (v) R5'is het2 other than 5- tetrazolyl; and/or (vi) R99 is Cl-C6 alkyl; then (1) R43 may also be g) -C1-C10 alkyl optionally substituted with (i) one or two-Co2R46 bonded to the same or different carbon atoms or (ii) one-CO-NH2, h)-Co-C6 alkyl-C3-C8 cycloalkyl optionally substituted with one-COZR46, i) -C0-C6 alkyl-phenyl optionally substituted with (i) one or two-Co2R46 bonded to the same or different carbon atoms or (ii)-CH2CH (CO2R46)2, orj)-CH(R48)NHXR47, and

(2) Glo may also be <BR> <BR> <BR> _49 R45,<BR> b)-NR49 wherein is a)-H, b) -C1-C18 alkyl or alkenyl, or andc)-C0-C6-alkyl-G12; wherein R49 is a) Cl)-C6 alkyl-G b) CH (R48) COZR46, c) CH (R) CH2C02R, or d) CH (R48) CoNHCH2Co2R46.

Another aspect of this invention provides a pharmaceutical composition, comprising the compound of formula I and a pharmaceutically acceptable carrier.

Another aspect of this invention provides a method for treating a patient by administering an effective amount of a compound of formula I.

Another aspect of this invention provides a method of inhibiting protein tyrosine phosphatases, comprising contacting a cell with the compound of formula I.

Another aspect of this invention provides the compound of formula I above excluding the compound disclosed in U. S. Serial No. 09/138,642 and PCT/US98/17327, which are hereby incorporated by reference.

The compound of the present invention are named according to the IUPAC or CAS nomenclature system.

The carbon atoms content of various hydrocarbon-containing moities is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i. e., the prefix Ci-Ci indicates a moiety of the integer"i"to the integer"j"carbon atoms, inclusive.

Thus, for example, C1-C3 alkyl refers to alkyl of one to three carbon atoms, inclusive, or methyl, ethyl, propyl, and isopropyl, straight and branche forms thereof.

Also, the carbon atom content of various hydrocarbon-containing moities of the present invention may be indicated by a subscripted integer representing the number of carbon and hydrogen atoms in the moiety, e. g., "CnH2n"indicates a moiety of the integer"n"carbon atoms, inclusive, and the integer"2n"hydrogen atoms, inclusive. Thus, for example,"CnH2n"wherein

n is one to three carbon atoms, inclusive, and two to six hydrogen atoms, inclusive, or methyl, ethyl, propyl and isopropyl, and all isomeric, straight and branche forms thereof.

Examples of alkyl of one to nine carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and nonyl, and all isomeric forts thereof and straight and branche forms thereof.

Examples of alkenyl of one to five carbon atoms, inclusive, are ethenyl, propenyl, butenyl, pentenyl, all isomeric forms thereof, and straight and branche forms thereof.

By"halo"is meant the typical halogen atoms, such as fluorine, chlorine, bromine, and iodine.

The present invention encompasses all possible combinations of configurations at each of the possible chiral centers. The preferred configuration for the chiral center depicted in formula I is (S).

The compound of formula I of the present invention are prepared as described in the Charts, Preparations and Examples below, or are prepared by methods analogous thereto, which are readily known and available to one of ordinary skill in the art of organic synthesis.

The present invention provides for compound of formula I or pharmacologically acceptable salts and/or hydrates thereof. Pharmacologically acceptable salts refers to those salts which would be readily apparent to a manufacturing pharmaceutical chemist to be equivalent to the parent compound in properties such as formulation, stability, patient acceptance and bioavailability. Examples of salts of the compound of formula I include lithium, sodium and potassium.

Where R46 is other than H, the compound would not be expected to have intrinsic activity, but would be expected to possess activity in vivo following hydrolysis by non-specific esterases to the corresponding carboxylic acids.

The compound of the present invention are useful for treating patients, such as human patients, with noninsulin-dependent diabetes mellitus (NIDDM) and conditions resulting from NIDDM, such as obesity. For this indication, these compound may be administered by oral, intranasal, transdermal, subcutaneous and parenteral (including intramuscular and intravenous) routes in doses of 0.1 mg to 1000 mg/kg of body weight per day.

Those skilled in the art would know how to formulate the compound of this invention into appropriate pharmaceutical dosage forms. Examples of the dosage forts include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.

When the compound in this invention are administered orally, an effective amount is from about 0.1 mg to 100 mg per kg of body weight per day. Either solid or fluid dosage forms can be prepared for oral administration. Solid compositions, such as compresse tables, are prepared by mixing the compound of this invention with conventional pharmaccutical carriers such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose, or functionally similar pharmaceutical diluents and carriers. Capsules are prepared by mixing the compound of this invention with an inert pharmaceutical diluent and placing the mixture into an appropriately sized hard gelatin capsule.

Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound of this invention with an acceptable inert oil such as vegetable oil or light liquid petrolatum.

Syrups are prepared by dissolving the compound of this invention in an aqueous vehicle and adding sugar, aromatic flavoring agents and preservatives. Elixirs are prepared using a hydroalcoholic vehicle such as ethanol, suitable sweeteners such as sugar or saccharin and an aromatic flavoring agent. Suspensions are prepared with an aqueous vehicle and a suspending agent such as acacia, tragacanth, or methyl cellulose.

When the compound of this invention are administered parenterally, they can be given by injection or by intravenous infusion. An effective amount is from about 0.1 mg to 100 mg per kg of body weight per day. Parenteral solutions are prepared by dissolving the compound of this invention in aqueous vehicle and filter sterilizing the solution before placing in a suitable sealable vial or ampule. Parenteral suspensions are prepared in substantially the same way except a sterile suspension vehicle is used and the compound of this invention are sterilized with ethylene oxide or suitable gas before it is suspende in the vehicle.

The exact route of administration, dose, or frequency of administration would be readily determined by those skilled in the art and is dependant on the age, weight, general physical condition, or other clinical symptoms specific to the patient to be treated.

The utility of representative compound of the present invention has been demonstrated in the biological assays described below: PTPl Assays: A construct, which consiste of a C-terminal truncation of rat PTP1 (amino acid residues 1-322) (cloned from a rat brain library) with an N-terminal glutathione S- transferase (GST) tag and an adjacent thrombin cleavage site, was inserted into vector plasmid pGEX-2T and transformed into E. coli strain TG-1 under the control of a lac promoter (K. L.

Guan and J. E. Dixon (1991) Eukaryotic proteins expressed in Escherichia coli: an improved thrombin cleavage and purification procedure of fusion proteins with glutathione S-transferase.

Analyt. Biochem. 192: 262-267). The GST-fusion protein was purifie on a glutathione agarose affinity column, the GST tag was cleaved with thrombin, and the active enzyme was recovered for use in an assay to identify PTP inhibitors.

The equivalent construct of human PTP 1B (amino acid residues 1-321) (cloned from a human placenta library), without the GST tag and thrombin cleavage site, was inserted into a pMB replicon and transformed into E. coli BL21 (DE3), a strain containing a chromosomal copy of the gene for T7 RNA polymerase under control of a lacLTV5 promoter. Expression of PTP1B was induced with isopropyl thiogalactose and the soluble protein was purifie by ion exchange, hydrophobic interaction and gel exclusion chromatography for use in the assay to identify PTP inhibitors.

PTP I activity is measured using either p-nitrophenol phosphate (pNPP) or a triphosphopeptide (that matches residues 1142 through 1153 ofthe-subunit and the insulin receptor) as substrate in a 96-well microtiter plate format. An assay pH of 72 in used for standard assays (measured A405=9800 at pH 7.2).

Human PTP I B, which is highly homologous to rat PTP1, was assayed exactly as described above for PTP 1. The PTP1 inhibitors described here also inhibit PTP I B with similar or identical potencies.

Standard assays are conducted at room temperature in a total volume of 0.2 ml that contains Hepes buffer (50 mM, pH 7.2), NaCI (50 mM), EDTA (1 mM), DTT (1 mM), bovine serum albumin (1 mg/ml), pNPP (1 mM) and PTP1 (35 ng/ml). Compound (2 pl of 10 mM solutions) are pipette into wells of microtiter plates followed by 198 p1 of premixed rection mix (with PTP1 and pNPP added immediately before use). The rate of change in A405 is recorde for 60 min. Two wells on each plate contain DMSO controls and two wells contain sodium orthovanadate (1 mM) which inhibits PTP I-catalyzed hydrolysis of pNPP completely.

Data are expressed as percent inhibition relative to the average of the DMSO controls measured on the same microtiter plate.

When tn*phosphopeptidel 142-1153 is used as substrate, the rate of release of inorganic phosphate is measured using a Malachite Green/phosphomolybdate rection (A. A. Baykov, O. A. Evtushenko, and S. M. Avaeva (1988) A Malachite Green procedure for orthophosphate determination and its use in alkaline phosphatase-based enzyme immunoassay. Anal. Biochem.

171: 266-270.) in a microtiter plate format. Standard assays are conducted at room temperature in a total volume of 50 pI that contains Hepes buffer (50 mM, pH 7.2), NaCI (50 mM), EDTA

(1mM),bovineserumalbumin(1mg/ml),triphosphopeptide1142-1153( 200µM)(1mM),DTT and PTP 1 (87 ng/ml). Rections are terminated with the addition of 0.15 mi of Malachite Green/ammonium molybdate reagent [I Oml Malachite Green (0.44 g in 6N H2SO4), 2.5 ml ammonium molybdate (7.5% w/v), 0.2 ml Tween 20 (11% w/v)] that is diluted with 8 parts of water immediately before use, and after 1 h absorbance at 650 nm is measured. The phosphate assay is calibrated using either KH2PO4 or pNPP (after ashing with Mg (N03) 2) which gives essentially identical standard curves. The phosphate assay is useful in the range of 1 to 10 nmol Pi.

The % inhibition of pNPP-hydrolysis by compound of the present invention are listed in Table below.

The invention is further directe to the following compound: 2-(carboxymethoxy)-5-[(2S)-3-oxo-3-(pentylamino)-2-({(2S)-2- [ (phenoxycarbonyl) amino]-3-phenylpropanoyll amino) propyl] benzoic acid; 5-((2R)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylprop anoyl}amino)-3-oxo-3- {[3-(2-oxo-1-pyrrolidinyl)propyl]amino}propyl)-2-(carboxymet hoxy)benzoicacid; 5-{(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylprop anoyl}amino)-3-oxo-3- [ (3-pyridinylmethyl) amino] propyl)-2- (carboxymethoxy) benzoic acid; 5-{(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylprop anoyl}amino)-3-[(3- isopropoxypropyl) amino]-3-oxopropyll-2- (carboxymethoxy) benzoic acid; 5-{(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylprop anoyl}amino)-3-[(3- hydroxypropyl) amino]-3-oxopropyll-2- (carboxymethoxy) benzoic acid; 2-(carboxymethoxy)-5-[(2R)-2-{[2-(2-methoxyphenyl)acetyl]ami no}-3-oxo-3- (pentylamino) propyl] benzoic acid; Methyl-2-[4-{(2S)-benzoylamino)-3-oxo-3[(4-phenylbutyl)amino ]propyl}-2-(2H- 1,2,3,4-tetrazol-5-yl) phenoxy] acetate; 2-[4-{(2S)-2-benzoylamino)-3-oxo-3-[(4-phenylbutyl)amino]pro pyl}-2-(2H-1,2,3,4- tetrazol-5-yl) phenoxy] acetic acid; 2- [4-{ (2S)-3-furoylamino)-3-oxo-3- [ (4-phenylbutyl) amino] propyl)-2- (2H-1,2,3,4- tetrazol-5-yl) phenoxy] acetic acid; 5-{(2S)-2-({(2S)-2-[(tert-butoxycarbonyl-amino]-3-phenylprop anoyl}amino)-3-oxo-3- [ (3-phenylpropoxy) amino] propyl}-2- (carboxymethoxy) benzoic acid;

5- { (2S)-2- ( f (2S)-2- [ (tert-butoxycarbonyl) amino]-3-phenylpropanoyl} amino)-3-oxo-3- [ (4-phenylbutyl) amino] propyl}-2-(carboxymethoxy) benzoic acid; 5-{(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylprop anoyl}amino)-3-[(2- hydroxyethyl) amino]-3-oxopropyll-2- (carboxymethoxy) benzoic acid; 5-{(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylprop anoyl}amino)-3-oxo-3- [ (3-phenylpropyl) amino] propyl}-2- (carboxymethoxy) benzoic acid; 5-[(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylprop anoyl}amino)-3- hydroxypropy]-2-(carboxymethoxy) benzoic acid; 2-(carboxymethoxy)-5-[(2S)-2- {[(5,(carboxymethoxy)-5-[(2S)-2- {[(5, 6-dichloro-3-pyridinyl) carbonyl] amino}-3-oxo-3- (pentylamino) propyl] benzoic acid; 5-{(2S)-2-benzoylamino)-3-oxo-3-[(4-phenylbutyl)amino]propyl }-2- (carboxymethoxy) benzoic acid; 2-(carboxymethoxy)-5-{(2S)-2-[(4-chlorobenzoyl)amino]-3-oxo- 3-[(4- phenylbutyl) amino] propyl} benzoic acid; 2-(carboxymethoxy)-5-{(2S)-3-oxo-3-[(4-phenylbutyl)amino]-2- [(3- pyridinylcarbonyl) amino] propyllbenzoic acid; 2-(carboxymethoxy)-5-{(2S)-2-(3-furoylamino)-3-oxo-3-[(4- phenylbutyl) amino] propyl}benzoic acid; 5-((2S)-2-(benzoylamino)-3-{[4-(4-chlorophenyl)butyl]amiino} -3-oxopropyl)-2- (carboxymethoxy) benzoic acid; 2-(carboxymethoxy)-5-((2S)-2-[(4-chlorobenzoyl)amino]-3-{[4- (4- chlorophenyl) butyl] amino}-3-oxopropyl) benzoic acid; 2-(carboxymethoxy)-5-[(2S)-3-{[4-(4-chlorophenyl)butyl]amino }-2-(3-furoylamino)-3- oxopropyl] benzoic acid; 2-(carboxymethoxy)-5-((2S)-2-{[(6-chloro-3-pyridinyl)carbony l]amino}-3-{[4-(4- methoxyphenyl) butyl] amino}-3-oxopropyl) benzoic acid; 2-(carboxymethoxy)-5-((2S)-3-{[4-(4-chlorophenyl) butyl] amino 1-2-f [ (2,4- diflurophenyl) sulfonyl] amino}-3-oxopropyl) benzoic acid; 2-(carboxymethoxy)-5-[(2S)-3-{[4-(4-chlorophenyl)butyl]amino }-3-oxo-2-({[(E)-2- phenylethenyl] sulfonyl} amino) propyl] benzoic acid; and 2-(carboxymethoxy)-5-{(2S)-3-oxo-3-[(3-phenoxypropyl)amino]- 2- [(phenylsulfonyl) amino] propyl} benzoic acid.

DESCRIPTION OF PREFERRED EMBODIMENTS EXAMPLE 1: (Chart A, Formula A-7) 2- [4- f (2S)-2- (benzoylamino)-3-oxo-3- [ (4- phenylbutyl) amino]-propyl}-2-(2H-1, 2,3,4-tetrazol-5-yl) phenoxy] acetic acid PREPARATION OF A-2: To a stirring solution of A-1 (0.25 g, 0.61 mmol) in CH2Cl2 (4 mL) was added 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.13 g, 0.67 mmol) and 4-phenylbutylamine (107 µL, 0.67 mmol) at 0 °C. The mixture was strirred at ambient temperature over night, and then extracted with 1 M aqueous HCI (2 x 2 mL) and brine (4 mL). The organic layer was dried (Na2SO4) and concentrated. The crude material was purifie by flash chromatography (SiO2, EtOAc/iso-hexane 1: 1) which furnished 0.28 g (85%) of A-2 as a colorless oil. 1H NMR 500 Mz (CDCI3) 6 1.41 (s, 9H), 1.43 (ion, 2H), 1.54 (ion, 2H), 2.59 (dd, 2H), 2.92 (ion, 2H), 3.18 (ion, 2H), 4.18 (m, 1H), 5.07 (br s, 1H), 5.81 (br s, 1H), 6.85 (d, 1H, J= 8,1 Hz), 7.05 (dd, 1H, J= 8.1,1.6 Hz), 7.13-7.49 (ion, 6H); 13C NMR (CDC13) b 28.3, 28.4,29.0,35.4,37.3,39.4,40.5,56.1,65.3,80.4,85.4,115.1,125. 8,128. 3,128.4, 131. 0, 138.9,141.9,154.2,155.4,170.9. IR 3312,3010,2932,1660,1500,1367 crri I. MS (ESI) 537 (M-H). HRMS (EI) calcd for C24H31IN204 538.1329, found 538.1315.

PREPARATION OF A-3: To a solution of A-2 (7.0 g, 13 mmol) in THF (50 mL) was added zinc cyanide (1.83 g, 15.6 mmol), Pd (PPh3) 4 (0.75g, 0.65 mmol) and copper (I) iodide (0.25 g, 1. 30 mmol). The mixture was refluxed (75 °C) over night, under nitrogen atmosphere.

The rection mixture was cooled to ambient temperature, diluted with EtOAc and filtered through a pad of celite. The filtrate was concentrated and purifie by flash chromatography (Si02, gradient: EtOAc/iso-hexan 1: 3 to EtOAc/iso-hexane 1: 1) which furnished 1.40 g of a mixture of starting material and product, and 2.51 g of A-3 (44%) as a white solid. OH NMR 400 MHz (MeOH) # 1.37 (s, 9H), 1.46 (ion, 2H), 1.57 (ion, 2H), 2.60 (m, 2H), 2.74 (dd, 1H, J= 8.8, 13.8), 2.96 (dd, 1H, J= 6.3,13.8), 3. 12 and 3. 18 (m, 2H), 4.16 (m, 1H), 6.87 (d, IH, J= 8.5), 7.11-736 (m, 7H) ; 13C NMR (OH) 8 28.6,29.9,30.94,36.4,38.2,40.2,40.8,57.3,80.7, 100.5,117.1,117.9,126.7,129.3,129.4,130.2,134.9,136.8,143.5, 157.5,160.4,173.7. MS 436 (M-H).

PREPARATION OF A-4: To a solution of A-3 (2.51 g, 5.74 mmol) in acetone (30 mL) was added methyl bromoacetate (1.09 mL, 11.47 mmol) and grounded K2CO3 (1.59 g, 11.47).

The mixture was stirred at 50 °C over night and then cooled to ambient temperature. Water (20 mL) was added and the mixture was extracted with EtOAc (2 x 20 mL), the organic layer was dried (Na2S04) and concentrated. The crude material was purifie by flash chromatography

(SiO2, EtOAc/iso-hexane 1: 1) which furnished 2.21 g (76%) of A-4 as a white solid. Mp 94-96 OC.'H NMR 500 MHz (CDCl3) 6 1.40 (s, 9H), 1.46 (ion, 2H), 1.58 (ion, 2H), 2.61 (ion, 2H), 2.95 (dd, 1H, J= 6.9,14.1), 3.05 (dd, 1H, J= 6.9,14.1), 3.22 (ion, 2H), 3.79 (s, 3H), 4.21 (m, 1H), 4.71 (s, 2H), 5.01 (br s, 1H), 5.96 (br m, 1H), 6.73 (d, 1H, J= 8.5), 7.14-7. 28 (m, 5H), 7.35 (dd, 1H, J= 8.5,2.2), 7.42 (d, 1H, J= 2.2); 13C NMR (CDCl3) 6 28.2,28.4,29.0,29.8,35.3,35.5, 37.1,39.4,40.5,52.4,55.6,65.7,80.5,102.7,112.5,115.8,125.8,1 28.4,130.9,134.5,135.2, 142.1, 158. 4,168.2,170.4. IR 3338,2932,2863,2224 (CN signal), 1754,1681,1646. MS (ESI) 508 (M-H). Anal. Calcd for C28H35N3O6 : C, 65.99; H, 6.92; N, 8.25. Found: C, 66.9; H, 7.0; N, 8.2.

PREPARATION OF A-5: Trifluoroacetic acid (2.1 mL) was carefully added to a stirring solution of A-4 (0.93 g, 1.82 mmol) in CH2Cl2 (17 mL) at 0°C. The mixture was stirred for 3h allowing the solution to warm to ambient temperature. The volatiles were removed by evaporation in vacuo, and the residue was partitioned between EtOAc (15 mL) and saturated aqueous NaHC03 (2x10 mL). The organic layer was dried (Na2SO4) and concentrated to give 0.90 g (>100%) of the crude amine as a yellowish oil. The amine was dissolve in CH2C12 (15 mL) and cooled with ice. Benzoic acid (0.22 g, 1.82 mmol), 1-hydroxybenzotriazole (0.25 g, 1.82 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.35 g, 1.82 mmol) was added to the solution, which was then stirred at room temperature over night.

The rection mixture was diluted with CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and concentrated.

The residue was purifie by column chromatography (SiO2, EtOAc) which gave 0.65 g (69%) of A-5 as a white solid. Mp = 125-128'C.'H NA4R 500 MHz (CDCl3) # 1.43 (ion, 2H), 1.54 (ion, 2H), 2.55 (t, 2H, J= 7.2,15.1 Hz), 3.13 (ion, 3H), 3.21 (ion, 1H), 3.77 (s, 3H), 4.68 (s, 2H), 4.86 (m, 1H), 6.48 (br t, 1H), 6.71 (d, 1H, J= 8.8 Hz), 7.10 (d, 3H), 7.15 (m, 1H), 7.24 (ion, 2H), 7. 39 (ion, 3H), 7.49 (ion, 1H), 7.71 (ion, 2H); 13C NMR (CDCl3) 6 28.4,28.9,35.3,37.4,39.4,52.4, 54.7,65.6,102.6,112.5,115.8,125.8,127.0,128.3,128.7,130.8,13 2.0,133.4,134.7,135.2, 141.9,158.5,167.4,168.1,170.4. IR 3278,2932,2855,2224 (CN signal), 1750,1630,1500.

MS (ESI) 512 (M-H). Anal. Calcd for C30H31N3O5 : C, 70.16; H, 6.08; N, 8. 18. Found: C, 70.3; H, 6.1; N, 8.2.

PREPARATION OF A-6: To a suspension of A-5 (0.21 g, 0.42 mmol) in toluene (4 mL) in a Heck vial was added trimethylsilyl azide (165 µL, 1.25 mmol) and dibutyltin oxide (10.3 mg, 0.042 mmol). The flask was flushed with nitrogen, tightly sealed, and stirred at 95 °C over night. Some more trimethylsilyl azide (3 eq.) and dibutyltin oxide (0.1 eq.) was added two times

and the mixture was continuously stirred at 95 °C, After 48 h the rection mixture was cooled to ambient temperature, and the volatiles were evaporated in vacuo. The residue was partitioned between EtOAc (5 mL) and 1 M aqueous HCl (3 mL). The organic layer was washed with brine (3 mL), dried (Na2SO4), and concentrated. The material was purifie by flash chromatography (Si02, gradient system: EtOAc/iso-hexane 1: 1 to 3: 1) which furnished 49 mg (21 %) of A-6 as a white solid. Mp = 183-186 °C. 1H NMR 500 MHz (MeOH) # 1.46 (ion, 2H), 1.53 (ion, 2H), 2.53 (t, 2H, J= 7.2,14.8), 3.07-3.16 (ion, 2H), 3.23 (ion, 2H), 3.79 (s, 3H), 4.80 (m, 1H, hidden behind solvent peak), 4.93 (s, 2H), 7.06 (d, 1H), 7.11 (ion, 3H), 7.19 (ion, 2H), 7.40 (ion, 2H), 7.45-7.51 (ion, 2H), 7.75 (ion, 2H), 8.18 (d, 1H); 13C NMR (MeOH) # 29.7,29.9,36.3,38.2,40.2,53.0,56.7, 66.8,114.3,115.5,126.7,128.5,129.3,129.4,129.5,131.7,132.8,1 35.0,135.2,143.5,153.3, 155.6,170.1,171.5,173.2. IR 3286,2924,2855,1742,1634,1500. MS (ESI) 555 (M-H). Anal.

Calcd for C30H32N6O5: C, 64.74; H, 5.79; N, 15.10. Found: C, 64.8; H, 5.8; N, 15.1.

PREPARATION OF A-7: To a solution of A-6 (33 mg, 0.060 mmol) in THF (0.8 mL) was added 2.5 M aqueous LiOH (72 µL, 0.18 mol). The mixture was stirred at room temperature for 4 h, and then quenched with 1 M aqueous HCl. The mixture was diluted with EtOAc (3 mL). Some precipitate was formed which was filtered off by a glass funnel. The filtrate was washed with brine (3 mL) and the organic layer was dried (Na2SO4), and concentrated in vacuo, which furnished a white solid. This material was combine with the precipitate, which totally gave 28 mg (84%) of A-7 as a white solid. Mp = 223-225 °C, 1H NMR 500 MHz (MeOH) # 1.44 (m, 2H), 1.53 (m, 2H), 2.53 (t, 2H, J= 7.5,15.3 Hz), 3.08-3.17 (m, 2H), 3.21-3.26 (m, 2H), 4.79 (m, 1H, partly hidden behind solvent peak), 4.89 (s, 2H), 7.09 (m, 4H), 7.19 (m, 2H), 7.40 (ion, 2H), 7.49 (m, 2H), 7.76 (ion, 2H), 8.20 (d, 1H); 13 C NMR (MeOH) # 29.7,29.9,36.3,38.2,40.2,56.7,67.0,114.1,114.8,126.7,128.5,1 29.3,129.5,131.5,132.8, 133.0,135.2,135.3,143.5,153.1,155.8,170.1,173.1,173.2. IR 3286,3062,2924,1655,1630, 1539,1496,1242. MS (ESI) 541 (M-H). Anal. Calcd for C29H30N6O5 # 1/4 H2O: C, 62.13; H, 5.75; N, 14.99. Found: C, 62.4; H, 5.4; N, 14.8.

EXAMPLE 2: (Chart B, Formula B-4) 2- [4- { (2S)-2- (3-furoylamino)-3-oxo-3- [ (4- phenylbutyl) amino]-propyl}-2- (2H-1, 2,3,4-tetrazol-5-yl) phenoxy] acetic acid PREPARATION OF B-2: Trifluoroacetic acid (1.9 mL) was carefully added to a stirring solution of A-4 (0.85 g, 1.66 mmol) in CHOC12 (10 mL) at 0 OC. The mixture was stirred for 3h allowing the solution to warm to ambient temperature. The volatiles were removed by

evaporation in vacuo, and the residue was partitioned between EtOAc (10 mL) and saturated aqueous NaHC03 (2x5 mL). The organic layer was dried (Na2SO4) and concentrated to give 0.71 g (>100%) of the crude amine as a yellowish oil. The amine was dissolve in CH2Cl2 (8 mL) and cooled with ice. 3-Furoic acid (0.21 g, 1.83 mmol), 1-hydroxybenzotriazole (0.25 g, 1.83 mmol) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.35 g, 1.82 mmol) was added to the solution, which was then stirred at room temperature over night.

The rection mixture was diluted with CH2Cl2 (5 mL) and washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purifie by column chromatography (SiO2, EtOAc/iso-hexane 1: 1 to 3: 1), which gave 0.51 g (62%) of B-2 as a colorless oil. 1H NMR 500 MHz (CDCl3) 6 1.44 (ion, 2H), 1.56 (ion, 2H), 2.57 (t, 2H, J= 7.3,15.1 Hz), 3.06 (t, 2H, partly hidden behind multiplet), 3.13 (ion, 1H), 3.24 (m, 1H), 3.76 (s, 3H), 4.68 (s, 2H), 4.82 (m, 1H), 6.61 (d, 1H), 6.72 (m, 1H), 7.11-7.17 (ion, 3H), 7.24 (t, 2H), 7.34-7.38 (ion, 2H), 7.48 (d, 1H), 7.91 (d, 1H); 13C NMR (CDC13) 8 28.5, 28.9,35.3,37.1,39.5,52.4,54.6,65.6,102.6,108.3,112.5,115.8,1 21.8,125.8,128.3,130.9, 134.7, 135. 2,141.9,143.8,145.3,158.4,162.8,168.1, 171. 0. MS (ESI) 502 (M-H). Anal. Calcd for C28H29N306: C, 66.79; H, 5.80; N, 8. 34. Found: C, 66.6; H, 5.9; N, 8.3.

PREPARATION OF B-3: To a suspension of B-2 (0.44 g, 0.88 mmol) in toluene (5 mL) in a Heck vial was added trimethylsilyl azide (349 µL, 2.64 mmol) and dibutyltin oxide (22 mg, 0.088 mmol). The flask was flushed with nitrogen, tightly sealed, and stirred at 95 °C over night. Some more trimethylsilyl azide (3 eq.) and dibutyltin oxide (0.1 eq.) was added two times and the mixture was continuously stirred at 95 °C. After 48 h the rection mixture was cooled to ambient temperature, and the volatiles were evaporated in vacuo. The residue was partitioned between EtOAc (5 mL) and 1 M aqueous HCI (3 mL). The organic layer was washed with brine (3 mL), dried (Na2SO4), and concentrated. The material was purifie by flash chromatography (Si02, gradient system: EtOAc/iso-hexane 1: 1 to 3: 1) which furnished 52 mg (11%) of B-3 as a white solid. Mp = 152-154 °C. 1H NMR 500 MHz (MeOH) # 1.44 (ion, 2H), 1.53 (ion, 2H), 2.53 (t, 2H), 3.05-3.25 (ion, 4H), 3.81 (s, 3H), 4.78 (m, 1H), 4.91 (s, 2H), 6.79 (s, 1H), 7.05-7.23 (ion, 6H), 7.48 (ion, 2H), 8.07 (s, 1H), 8.21 (s, 1H); 13C NMR (MeOH) # 29.7,29.8,36.3, 38. 1,40.2, 53.0,56.2,66.7,109.7,113.9,114.4,123.2,126.7,129.2,129.3,131 .5,132.9,135.1,143.4, 145.1,146.8,152.9,155.5,164.9,171.4,173.1. IR 3140,2933,2860,2367,1736,1653,1617, 1493. MS (ESI) 545 (M-H). Anal. Calcd for C28H3oN606: C, 61.53; H, 5.53; N, 15.38. Found: C, 61.4; H, 5.8; N, 15.4.

PREPARATION OF B-4: To a solution of B-3 (40 mg, 0.073 mmol) in THF (0.8 mL) was added 2.5 M aqueous LiOH (88 µL, 0.22 mmol). The mixture was stirred at room temperature for 4 h, and then washed with EtOAc (2 mL). The aqueous layer was acidifie with 1 M aqueous HCI and extracted with EtOAc (2 x 3 mL). Some precipitate was formed which was filtered off by a glass funnel. The filtrate was washed with brine (3 mL) and the organic layer was dried (Na2SO4), and concentrated in vacuo, which furnished a white solid. This material was combine with the precipitate, which totally gave 14 mg (37%) of B-4 as a white solid. Mp = 230-233 °C. 1H NMR 500 MHz (MeOH) # 1.42 (m, 2H), 1.50 (ion, 2H), 2.51 (t, 2H, J= 7.5,15.1 Hz), 3.07-3.13 (ion, 2H), 3.19-3.23 (ion, 2H), 4.75 (ion, 1H), 4.91 (s, 2H), 6.78 (d, 1H, J= 2.5), 7.07-7.20 (ion, 2H), 7.47 (dd, 1 H), 7. 53 (t, 1H), 8.06 (s, 1H), 8.17 (d, 1H, J= 2.5); 13C NMR 8 29.7,29.8, 36. 3, 38. 1,40.2, 56. 2,66.9,109.7,111.0,114.0,114.7,123.2,126.7,129.3, 129.4,131.4,132.9,135.2,143.5,145.2,146.8,155.7,173.0,173.1. IR 3300,2940,2867,1637, 1543,1497,1173. MS (ESI) 531 (M-H). Anal. Calcd for C27H28N6O6 # 1/4 H2O : C, 60.38; H, 5.25; N, 15.65. Found: C, 60.2; H, 5.2; N, 15.4.

EXAMPLE 3: (Chart C, Formula C-3) 5- [ (2S)-2- ( { (2S)-2- [ (tert- butoxycarbony)-amino]-3-phenylpropanoyl}amino)-3-hydroxyprop yl]-2- (carboxymethoxy) benzoic acid PREPARATION OF C-2: Methyl 5- [(2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl}amino)-3-hydroxypropyl]-2-(2-methoxy-2-oxoet hoxy) benzoate: To a solution of II-1 (1.24 g, 2.24 mmol) in dry THF (10 mL) is added 1, l'-carbonyldiimidazole (CDI, 0.54 g, 3.35 mmol). The solution is stirred at room temperature over night under nitrogen atmosphere.

The rection mixture is cooled with ice and a solution of NaBH4 (0.21 g, 5.59 mmol) in H20 (5 mL) is slowly added. After addition is complete, the mixture is stirred at room temperature for 10 min. The mixture is quenched with 10% aqueous HCl, and extracted with EtOAc. The organic layer is dried (Na2SO4) and concentrated. The residue is purifie by flash chromatography (SiO2, EtOAc) which furnished 160 mg (13%) of C-2 as a sticky foam, 1H NMR 400 MHz (CDC13) 8 1.38,2.49,2.68,2.73,3.00,3.42,3.57,3.78,3.87,4.05,4.27,4.68, 6.80,7.13-7.30,7.61 ; 13C NMR (CDC13) 6 28.2,33.2,38.5,52.1,56.2,58.2,60.9,62.8,66.7, 71.9,80.6,114.6,121.0,126.9,128.6,128.9,131.1,131.5,132.5,13 4.1,136.6,156. 2,166.2, 169.0,171.6. MS (ESI) 543 (M-H). Anal. Calcd for CZgH36N2O9: C, 61.75; H, 6.66; N, 5.14.

Found; C, 61.5; H, 6.6; N, 5.3.

PREPARATION OF C-3: 5-[(2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl}amino)-3-hydroxypropyl]-2-(carboxymethoxy) benzoic acid: To a solution of C-2 (36 mg, 0.066 mmol) in THF (1.5 mL) was added a 2.5 M aqueous solution of LiOH (106 µL, 0.26 mmol). The mixture was stirred at room temperature for 4 h, and then acidifie with 10% aqueous HCl and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to afford 33 mg (96%) of C-3 as a white solid. Mp = 168.8-172.3 OC.'H NMR 400 MHz (MeOH) 6 1.35,2.31,2.64-2.97,3.52,4.06,4.22,4.78,7.00,7.11-7.27,7.43, 7.77; 13c NMR (MeOH) # 20.7,28.6,30.9,36.8,39.5,57.3,67.5,80.6,111.0115.6,121.3,127 .6,129.3, 130. 3,133.6,134.0,136.1,138.6,157.5,169.1,172.2,174.1. MS (ESI) 516 (M-H). Anal. Calcd for C26H32N209 * H20: C, 59,42; H, 6.33; N, 5.33. Found; C, 59.4; H, 6.3; N, 5.35.4.

EXAMPLE 4: (Chart D, Formula D-5) 2- [4- [ (2S)-2- (f (2S)-2- [ (Tert- butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-oxo-3- (pentylamino) propyl]-2-(3-hydroxy-5-isoxazolyl) phenoxy] acetic acid PREPARATION OF D-2: Methyl 2-{4-[(2S)-2-[(tert-butoxycarbonyl) amino]-3-oXo-3- (pentylamino) propyl]-2-iodophenoxy} acetate: Prepared from D-1 (2.24 g, 4.70 mmol) by the general method as described for A-4, which afforded 2.29 g (89%) of the title compound as a white solid. 1H NMR 400 MHz (CDCI3) 6 0.88 (t, 3H, J= 7.1,14.4), 1. 20 (m, 2H), 1.29 (ion, 2H), 138 (m, 2H), 1.43 (s, 9H), 2.96 (ion, 2H), 3.17 (ion, 2H), 3.81 (s, 3H), 4.19 (m, 1H), 4.67 (s, 2H), 5.06 (br s, 1H), 5.79 (br s, 1H), 6.63 (d, 1H, J = 8.4), 7.12 (dd, 1H, J = 2.1,8.4), 7.64 (d, 1H, J = 2.1); 13C NMR (CDCI3) X 14.0,22.3, 28.3,28.9,29.1,37.2,39.5,52.4,56.0,66.3,80.3,86.6,112. 3,130.4,132.3,140.5,155.4,155.7, 168.8,170.6. MS (ESI) 544 (M-H). Anal. Calcd for C22H33N206I: C, 48.18; H, 6.06. Found: C, 48.3; H, 6.2.

PREPARATION OF D-3: Ethyl 3-[5-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-oxo-3- (pentylamino)propyl]-2- (2-methoxy-2-oxoethoxy) phenyl-2-propynoate: Ethyl propiolate (1.94 mL, 19.2 mmol) was added to a suspension of copper (I) oxide (0.61 g, 6.39 mmol) in anhydrous DMF (3 mL) under nitrogen atmosphere. A solution of D-2 (4.38 g, 7,99 mmol) in DMF (40 mL) was added. The rection flask was flushed with nitrogen, tightly sealed, and stirred at 110 °C for 16 h. The rection mixture was filtered through a short pad of SiO2 and washed with EtOAc. The organic layer was washed with 1 M aqueous HCI (20 mL), brine (20 mL), saturated aqueous NaHC03 (20 mL), dried (Na2SO4) and concentrated. The

residue was purifie by column chromatography (SiO4, EtOAc/hexane 1: 2 to 1: 1) which afforded 1.93 g (47%) of D-3 as a white solid. Mp = 133.9-135.1 OC.'H NMR 400 MHz (CDCI3) 6 0.87 (t, 3H, J = 7.1,14.4), 1.22 (ion, 2H), 1.29 (ion, 2H), 1.35 (t, 3H, J = 7.1), 1.41 (s and m, 11H), 2.97 (app t, 2H, J = 6.7,13.2), 3.17 (ion, 2H), 3.80 (s, 3H), 4.21 (m, 1H), 4.29 (q, 2H, J = 7.1), 4.72 (s, 2H), 5.06 (br s, 1H), 5.91 (m, 1H), 6.70 (d, 1H, J = 8.6), 7.22 (dd, 1H, J = 2.1,8.6), 7.38 (d, 1H, J = 2.1); 13C NMR (CDCI3) 6 13.9,14.1,22.2,28.2,28.9,29.1,37.4,39.5, 52.3,55.9,62.0,65.9,80.3,82.1,85.0,109.9,112.6,130.3,133.0,1 35.7,154.0,155.3,158.8, 168.7,170.6. MS (ESI) 517 (M-H). Anal. Calcd for C27H38N208 H2O : C, 60.43; H, 7.33; N, 5.22. Found: C, 60.7; H, 7.4; N, 5.3.

PREPARATION OF D-4: Ethyl 3- [5- [ (2S)-2- ( { (2S)-2- [ (tert-butoxycarbonyl) amino]-3- phenylpropanoyl}amino)-3-oxo-3-(pentylamino)propyl]-2-(2-met hoxy-2-oxoethoxy)phenyl]-2- propynoate: Prepared from D-3 (1.01 g, 1.95 mmol) by the general method as described for A-5, which afforded 1.09 g (84%) of the title compound as a white solid. Mp = 121.8-123. 1 °C. 1H NMR 400 MHz (CDCI3) 6 0.87 (t, 3H, J = 7.1,14.4), 1.14-1.41 (ion, 6H), 1.34 (t, 3H, J = 7.1), 1.35 (s, 9H), 2.81 (m, 1H), 3.01-3.09 (ion, 4H), 3.15 (m, 1H), 3.77 (s, 3H), 4.27 (m, 1H), 4.29 (q, 2H, J= 7.1), 4.56 (m, 1H), 4.69 (s, 2H), 4.97 (d, 1H, J = 6.3), 6.17 (br m, 1H), 6.41 (br m, 1H), 6.66 (d, 1H, J = 8.6), 7.10-7.19 (ion, 4H), 7.25-7.34 (ion, 3H); 13C NMR (CDC13) 6 13.9,14.1,22.2, 28. 1, 28.9,36.4,37.7,39.6,52.2,53.6,56.1,62.0,65.8,80.6,82.0,85.0, 109.8,112.6,127.2,128.8, 129.2,129.9,133.1,135.5,136.0,153.9,158.8,168.6,169.6,170.9. MS (ESI) 664 (M-H). Anal.

Calcd for C36H47N309: C, 64.95; H, 7.12; N, 6. 31. Found: C, 64.9; H, 7.0; N, 6,3, PREPARATION OF D-5: 2-[4-[(2S)-2-({(2S)-2-[(Tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3-oxo-3- (pentylamino) propyl]-2- (3-hydroxy-5- isoxazolyl) phenoxy] acetic acid: 2.5 M aqueous NaOH (670 µL, 1.68 mmol) was added to hydroxylamine hydrochloride (61 mg, 0.87 mmol). This mixture was added to a solution of D-4 (446 mg, 0.67 mmol) in ethanol/THF (1 mL : 2mL). The clear yellow solution was stirred over night at ambient temperature, and then acidifie with 1 M aqueous HCI. The rection mixture was extracted with EtOAc (2x4 mL), and the organic layer was washed with brine (4 mL), dried (Na2SO4) and concentrated which afforded 418 mg of a crude material as a yellowish solid. This material was a mixture of the target compound and the corresponding hydroxamic acid analogs. Separation by reverse phase HPLC furnished 82 mg (19%) of pure title compound D-5 as a white solid. Melting point:

sublimented above 260 °C. Accurate mass: Calculated 638.2952; Found 638.2957. MS (ESI) 637 (M-H). Anal. Calcd for C33H42N409 H2O: C, 60.35; H, 6.75; N, 8.53. Found: C, 60.2; H, 6.6; N, 8.6.

EXAMPLE 5: (Chart E, Formula E-6) 2- [4- [ (2S)-2- (1 (2S)-2- [ (tert- butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-oxo-3- (pentylamino)propyl]-2- (2-hydroxy-3, 4-dioxo- I-cyclobuten-I- yl) phenoxyJacetic acid PREPARATION OF E-2: (2S)-2-amino-3- (4-hydroxy-3-iodophenyl)-N- pentylpropanamide (E-1) (8.64 g, 14.30 mmol) was dissolve in CHOC12 and stirred at 0 °C under N2. Then EDC (2.74 g, 14.30 mmol), HOBt (1.93 g, 14.30 mmol) and Boc-L-Phe (3.79g, 14.30 mmol) were added simultaneously. Et3N (3.98 mL, 28.6 mmol) was added dropwise. The resulting mixture was stirred overnight. EtOAc (200 mL) was added and the organic layer was washed with 5% aqueous HCI (2 x 100 mL). The aqueous phases were combine and extracted with EtOAc (100 mL). The combine organic phases were washed with 10% aqueous NaHC03, (100 mL). Drying (Na2SO4), filtration and evaporation of volatiles gave an yellowish solid. Column chromatography of the crude product on silica using CHCl3/MeOH (95: 5) and then EtOAc/light petroleum (1: 1) as eluent gave 3.58 g 43% of a pale white solid: TLC Rf = 0.08 (Si02, CHC13/MeOH 99: 1); Mp 162-164 °C. 1H NMR (CDC13) 5 7. 38-7. 16 (ion, 6H), 6.92-6.87 (m, 1H), 6.84 (d, J= 8.16 Hz, 1H), 6.28 (brs, 1H), 6.13 (brs, 1H), 6.0 (brs, 1H) 4.89 (d, J= 5.97 Hz, 1H), 4.57-4.50 (m, 1H), 4.29-4.23 (ion, 1H), 3.20-2.95 (ion, 5 H), 2.72-2.62 (ion, 1H), 1.45-1.15 (ion, 15H), 0.87 (tr, J= 7.22 Hz, 3H); 13CNMR (CDC13) 8 170.80,169.87,155.73,154.25,138.82, 135. 92,131.09,130.09,129.24,128.97,127.37,115.1 9,85.49,80.89,56.19,53.53,39.76,37.59,36.07,28.99,28.95,28.1 0,22.29,13.94; IR (KBr disc) 1690,1655 cm-1; MS (ESI) m/z 624 (m+H),; Anal. Calcd for C28H38IN3O5#0. 25 H20: C, 53.17; H, 6.06; N, 6.64; Found: C, 52.95; H, 5.95; N, 6.00.

PREPARATION OF E-3: A mixture of E-2 (463 mg 0.742 mmol), methyl bromoacetate (206 µL, 2.23 mmol) and K2C03 (308 mg, 2.23 mmol) in CH3CN (4 mL) was stirred at 40 °C overnight. The rection mixture was filtered and the solid was washed with CH3CN. The organic phase was concentrated to give a crude solid. The solid was dissolve in CHOC13 and purifie by column chromatography on Si02 using EtOAc/pentane (1: 1) as eluent to give 0.446 g (86%) of the product as a white solid: TLC Rf = 0.11 (Si02, CHC13/MeOH 99: 1); Mp 141-142 OC.'H NMR (CDC13) 6 7.45-7.25 (ion, partly obscure by solvent signal, 6H), 7.02 (ion, 2H), 7.02 (d, d,

J= 1.89 and 8.48 Hz, 1H) 6.60 (d, J= 8.48 Hz, 1H), 6.24 (brs, 1H), 610 (brs, 1H), 4.83 (m, 1H), 4.64 (s, 2H), 4.57-4.47 (m, 1H), 4.30-4.21 (m, 1H), 3.79 (s, 3H), 3.20-2.95 (m, 5H), 2.78-2.70 (ion, 1H), 1.43-1.15 (ion, 15H), 0.87 (tr, J= 7.22 Hz, 3H); 13C NMR (CDCI3) 6 170.74,169.65,168.59,155.90,140.35,135.97,131.82,130.43,129. 21,128.97,128.85,127.3 5,112.44,86.54,80.83,66.34,56.27,53.54,52.28,39.71,39.58,37. 65,36.14,28.99,28.95,28.

12,22.27; IR (KBr disc) 1690,1645 cm-1; MS (ESI) m/z 694 (m-H),; Anal. Calcd for C31H42IN3O7: C, 53.53; H, 6.09; N, 6.04; Found: C, 53.40; H, 6.15; N, 6.00.

PREPARATION OF E-4: A mixture of E-3 (508.0 mg 0.7303 mmol), 3-isopropoxy-4- (tri-n-butylstannyl)-3-cyclobutene-1, 2-dione (prepared from 3,4-diisopropoxycyclobutenediones using the protocol of Liebeskind, L. S.; Fengl, R. W., J. Org. Chem., 1990,55,5359-5364.313.4 mg, 0.7303 mol), Pd2 (dba) 3 (16.7 mg, 0.0292 mmol), and AsPh3 (35. 8 mg, 0.1168 mmol) in degassed DMF was stirred at room temperature. After 5 min, Cul (11.12 mg, 0.058 mmol), and the mixture was stirred at 50 °C for 24 h. Additional Pd2 (dba) 3 (16.7 mg, 0.0292 mmol), and AsPh3 (35. 8 mg, 0.1168 mmol), CuI (11.12 mg, 0.058 mmol) were added and the rection was run for another 48 h. The rection mixture was diluted with EtOH (10 mL) and filtered through celite. The mixture was concentrated and partioned between water and CHC13. The organic phase was filtered and concentrated. The crude residue was purifie by flash chromatography on silica by first using gradient elution (CHCL3# CHCL3/MeOH) and then by using CHCL3 + 2.5% MeOH. This gave 215 mg (44%) of the product as yellowish solid: TLC Rf = 0.1 (SiO2, CHC13/McOH 99: 1); Mp 175-178 °C. IH NMR (CDCl3) 8 7.74-7.71 (m, 1H) 7.35-7.16 (ion., partly obscure by solvent signal, 7H), 6.78 (d, J= 8.48 Hz, I H), 6.57-6. 50 (m, 1H), 5.65 (h, J= 6.28 Hz, 1H), 5.46 (brs, 1H), 4.68 (d, J= 3.77 Hz, 2H), 4.28-4.23 (m, 1H), 3.79 (s, 3H), 3.26- 2.86 (ion, 7H), 1.49 (d, J = 6.28 Hz, 6H), 1.45-1.17 (ion, 15H), 0.87 (tr, J= 7.22 Hz, 3H) ; 13C NMR (CDCI3) 6 194.23,193.12,193.03,171.91,171.28,169.74,168.33,154.28,136. 53,135.15,130.28,129.7 3,129.24,128.75,128.68,127.01,117.77,113.11,79.44,65.71,57.0 4,52.26,39.75,37.54,28.9 1,28.12,28.03,22.90,22.26,13. 91. not all signals are visible in the 13C NMR spectrum; IR (KBr disc) 3291,1644 cm-1; MS (ESI) m/z 694 (M-isopropyl); HPLC: chemical purity 90.6%; Anal. Calcd for C38H49N3010 1.0 H20: C, 62.88; H, 7.08; N, 5.78; Found: C, 62.85; H, 6.90; N, 5.90.

PREPARATION OF E-5: E-4 was dissolve in warm THF (10 mL). 6M aqueous HCI (0.5 mL) was added and the solution was stirred at room temperature 3 days and then at 50 °C

for 2h. The rection mixture was concentrated to give 1.48 g of a yellow solid. The solid was triturated first with ether then with acetone/water to give 503 mg of a yellow solid. The solid was then purifie on a reverse phase preparative HPLC system to give 406 mg (71 %) of the pure compound: Mp 210-decomp. 1H NMR (DMSO-d6) 8 15.14 (brs, 1H), 8.75 (d, J= 8.48 Hz, 1H), 8.16 (d, J= 2.20 Hz, 1H), 8.03 (ion, 3H), 7.35-7.13 (m, 5H), 6.97 (d, J= 8.48 Hz, 1H), 4.69 (s, 2H), 4.48 (m, 1H), 4.10 (m, 1H), 3.15-2.70 (m, 5H), 1.40-1.10 (m, 5H), 0.83 (tr, J= 7.54 Hz, 3H); 13c NMR (DMSO-d6) 8 210.87,196.94,172.81,169.68,169.42,167.72,155.16,151.39,139. 50,134.79,131.26,129.4 8,128.40,127.01,126.67,120.82,111.76,65.53,54.39,53.23,38.46 ,37.31,36.95,28.58,28.53 , 21.74,13.80; MS (ESI) m/z 552 (M+H); HPLC: 97% chemical purity.

PREPARATION OF E-6: To a stirred solution of E-5 (386.4 mg, 0.657 mol), in 1M NaOH (3mL), dioxane (5mL) and water (4mL) was added di-t-butyldicarbonate at 0 °C. The rection mixture was then stirred for 10 h. The mixture was acidifie with 2M KHSO4, and the dioxane was evaporated (precipitation of starting material). The rection mixture was filtered and extracted with EtOAc. The organic phase was dried (Na2S04) and concentrated. The purity of the crude residue on a reverse phase HPLC system shows a purity of 64% with no major side products. Ms (ESI) shows the right molecular ion 650 (M-H). The solid was then purifie on a reverse phase preparative HPLC system using the same conditions as in the analytical expriment (mobile phase CHCN/aq. 0.1 % TFA gradient 10: 90o95: 5). An analytical sample was then run on the purest fraction (96% purity). Something happens with the product during workup. The worked up fraction seem to be more impure than the crude fraction. The workup consiste of carefully evaporate the organic phase and then lyophilize the product. The product seem to be very sensitive towards TFA.

EXAMPLE 6: (Chart F, R = pyridine, Formula F-2) Methyl 2- (2-methoxy-2- oxoethoxy)-5-{(2S)-3-oxo-3-(pentylamino)-2-[(3- pyridinylcarbonyl) amino] propyl} b enzo ate PREPARATION OF F-2 (General Procedure A: Amide Coupling): Triethylamine was added dropwise to a stirred solution of F-1 (200mg, 0.44mmol) in dichloromethane (3. 3ml) at 0°C until neural. EDC (85mg, 0.44mmol), HOBT (60mg, 0.44mmol) and nicotinic acid (47mg, 0.44mmol) were then added in single portions to the stirred solution again at 0°C under nitrogen.

The mixture was then allowed to warm to room temperature where it was stirred for 3hr. The yellow mixture was then diluted with EtOAc (20mol) and the organic solution washed with HCI

(2M, 1 Oml). The acidic layer was basified with NaOH and extracted with EtOAc (3 x 1 Oml) and the combine organic layers washed with NaHC03 (1 x 1 Oml), dried (MgS04) and concentrated under reduced pressure to give a cloudy oil. The crude product was purifie by column chromatography on silica gel using petrol: EtOAc: MeOH (4: 2: 1) as eluent to give a white solid, F-2 (120mg), 1H NMR (270MHz, MeOH) # 8.90 (1H, s), 8.66 (1H, d, J = 4.95 Hz), 8.15 (1H, dt, J= 2.31,8.04Hz), 7.72 (1H, d, J= 2. 31Hz), 7.51 (1H, dd, J= 4.95,7.92Hz),. 7.41 (1H, dd, J = 2.31,6.27Hz), 6.93 (1H, d, J= 8.58Hz), 4.75 (2H, s), 4.73 (1H, obscure ion), 3.83 (3H, s), 3.74 (3H, s), 3.58-2.97 (4H, ion), 1.45-1.20 (6H, ion), 0.88 (3H, t, J= 6.93Hz).

EXAMPLE 7: (Chart F, R = pyridine, Formula F-3) 5-[(2S)-2-({(2R)-2-[(tert- butoxycarbonyl) amino]-3-phenylpropyl} amino)-3-oxo-3- (pentylamino) propyl]-2- (carboxymethoxy) benzoic acid dihydrochloride PREPARATION OF F-3 (General Procedure B: Ester Hydrolysis): Lithium hydroxide (15mg, 0. 64mmol) was added to a stirred solution of F-2 (100mg, 0. 21mmol) in THF (20mol) and the mixture stirred at room temperature for 3hr. The solvent was removed in vacuo and the residue dissolve in water (20mol) and acidifie with HCI (10% aqueous). The solution became cloudy and was extracted with EtOAc (3 x I Oml). The combine organic phases were dried (NaS04) and concentrated under reduced pressure to give a white solid F-3 (40mg, 0.09mol, 42%) m. p. 168-170°C ; #max(cm-1) 3288, 3073,2931,1731,1639,1545,1498 ; 1H NMR (500 MHz, DMSO) 8 8.96 (1H, s), 8.80 (1H, d, J= 8.17Hz), 8.71 (1H, br s), 8.16 (1H, d, J= 7.85 Hz), 8.08 (1H, t, J= 5.65Hz),. 7.70 (1H, d, J= 2. 20Hz), 7. 5o (1H, dd, J4.71,7.85Hz), 7.43 (1H, dd, J 2. 51,8.79Hz), 6.92 (1H, d, J = 8.47Hz), 4.70 (2H, s), 4.64-4.55 (1H,m), 3.12-3. O 1 ( 4H, m), 1. 44-1. 16 (6H, m), 0.85 (3H, t, J= 7.22Hz) ; 13C NMR (500mHz, CD30D) 172.90, 167.81,157.65,152.58,149.00,137.36,136.06,133.87,132.10,115. 83,67.95,56.76,40.51, 37.95,30.89,30.02,29.80,23.25,14.30; MS (ESI) 456.2 (M-H+), 458.2 (M+H+).

EXAMPLE 8: (Chart F, R = 2-methoxybenzyl, Formula F-S) 2- (carboxymethoxy)-5- [(2R)-2- { [2-(2-methoxyphenyl) acetyl] amino I-3-oxo-3- (pentylamino) propyl] benzoic acid (a) PREPARATION OF F-4: Methyl 2- (2-methoxy-2-oxoethoxy)-5- [ (2R)-2- { [2- (2- methoxyphenyl) acetyl]-amino}-3-oxo-3-(pentylamino) propyl] benzoate: By general procedure A, a solution of F-1 (500mg, 1.2mmol) in dichloromethane (8ml) was treated with EDC (230mg, 1.2mmol), HOBT (162mg, 1. 2mmol), triethylamine (243mg,

2.4mmol) 2- (2-methoxyphenyl) acetic acid (199mg, 1.2mmol) at room temperature overnight.

The mixture was then diluted with EtOAc (20mol) and the organic layer washed with HCI (5%, 1x15ml). The aqueous layer was then extracted with EtOAc (3xlOml) and the combine organic layers washed with NaHCO3 (sat. aq.), dried (MgS04) and concentrated to give a yellow oil. The crude product was purifie by column chromatography using dichoromethane: MeOH (20: 1) as eluent to give a white solid, F-4 (320mg, 0.6mmol, 50%) m. p. 145-6; #max(cm-1). 3282,2954, 1755,1731,1642,1547,1497,1437; IH NMR (500MHz, CD30D) 8 7.57 (1H, d, J= 2.2Hz), 7.24-7.19 (2H, ion), 7.08 (1 H, d, J 7.22Hz), 6.92-6.84 (3H, m), 4.75 (2H, s) 4.52 (1H, m), 3.85 (3H, s), 3.77 (3H, s), 3.74 (3H, s), 3.52 (1H, d (AB), J= 14.76Hz), 3.45 (1H, d (AB), J= 14.76Hz), 3.16-3.03 (2H, ion), 3.00 (1H, dd, J6. 6,14. 3Hz), 2.86 (1H, dd, J7. 84,13.82Hz), 1-43- 1.17 (6H, ion), 0.88 (3H, t, J7. 22Hz) ; 13C NMR (500MHz, CD30D) 6 173.83,172.80,170.84, 168.04,158.75,157.76,135.45, 133.36, 131.87,131.36,129.72,124.75,121.87,121.76,115.38, 111.80,67.09,55.96,55.74,52.60,52.52,40.44,38.69,38.17,30.11 ,29.93,23.33,14.29; MS (ESI) 529.1 (M+H+); Anal. Calculated for C28H36N208: C, 63.6; H, 6.9; N, 5. 3 ; Found: C, 63.6; H, 6.9; N, 5.3%.

(b) PREPARATION OF F-5: By general procedure B, a solution of F-4 (280mg, 0.53mmol) in THF' (Sml) and water (5mol) was treated with lithium hydroxide (100mg, 1. lmmol) at room temperature overnight. The crude product was recrystallised from acetonitrile to give a white crystalline solid, F-5 (130mg, 0.26mmol, 50%) m. p. 146-8°C; #max(cm-1). 3296,2929,1736,1643,1547,1495;'H NMR (500MHz, CD30D) 6 7.71 (1H, br d, J= 6.2Hz), 7.23 (2H, ion), 7.09 (1H, d, J = 7.04Hz), 6.93- 6.86 (3H, ion), 4.79 (2H, s), 4.55 (1H, br t, J= 7.45Hz), 3.75 (3H, s), 3.55 (1H, d (AB), J= 14.48Hz), 3.45 (1 H, d (AB), J= 15.3Hz), 3.18-3.06 (2H, ion), 3.02 (1 H, dd, J= 6.20,14.07Hz), 2.87 (1H, dd, J= 7.45,13.66Hz), 1.44-1.20 (6H, ion), 0.88 (3H, t, J= 7.45Hz) ; 1H NMR (500MHz, CD30D) 6 172.84,172.75,172.20,168.96,158.71,157.73,135.99,134.03,131. 88, 131.84,129.77,124.70,121.79,121.30,115.50,111.84,67.41, 55. 98,55.67,40.45, 38. 70, 38.19,30.11,29.94,23.32,14.29; MS (ESI) 499.0 (M-H+); Anal. Calculated for C26H32N208: C, 62.4; H, 6.4; N, 5.6; Found: C, 62.2; H, 6.4; N, 5.6%.

EXAMPLE 9: Two-dimensional library of 5-substituted-2-carbomethoxybenzoic acids Scheme 1 HO 0 O 'NHFmoc CI H i 'CH3R NH i I H Na O N. + w O DIC/HOB 3 DMF/NaBH (OAc) 3 H O O Step 3 HO O 1 2 3 4 0 0 C HC3 ° °ACHCH3 2 3 4 5 3 R3 R3 N O N O 0 N O H. N O NHFmoc pPeridine'' Ste H R2 LipH HRZ TFA H, R2 H 2) DIC/HOBT THF : MeOH \ OH i O O RZC02H Step 6 Sep 7 0 Step 5 po OH O OH 0 0 CH CH3 0 c-F3 H3 6 7 8 9

Chemistry Summary The combination solid-phase/solution-phase synthetic sequence was designed to prepare a 6xl l two-dimensional library of 5-substituted-2-carboxymethoxybenzoic acids in a 96-well format as illustrated in Scheme 1. The synthesis was based on the use of the AMEBA linker (acid sensitive methoxybenzaldehyde, 3), selected due to its ease of cleavage and versatility in the reductive amination step. The intermediate 5 was synthesized in a seven step sequence described in"Intermediate Synthesis"below. The key resin 3 was synthesized by treating Merrifield resin with 2-methoxy-4-hydroxybenzaldehyde according to the literature procedure (Fivush, A. M.; Willson, T. M. Tetrahedron Lett. 1997,38,7151. Sarantakis, D.; Bicksler, J. J.

Tetrahedron Lett., 1997,38,7325). The functionalized resin 3 was treated with the first diversity element, a primary amine, and sodium triacetoxyborohydride to provide six different secondary amine resins, 4. Attachment of 5 to each individual resin was performed utilizing the standard conditions of DIC/HOBt in DMF. A deprotection/ condensation protocol was followed to attach the next diversity element to give 7. Hydrolysis of the diester was then followed by removal of the products from the resin with 20% TFA/CH2CI2.

Scheme 2-Intermediate Synthesis

PhO O HO O HO O PhO O tBu II tBu N O NH2 Boc20 Np'tBu B DBU N CO (g)/ Pd Catalyst H i I NaOH/THF, + CH3CN i EtOH/DMF I I u 56-60% I' 1 78-83% OH 0 I I OH O OH OH OH 3 10 11 12 13 14 Ph O O O Ph O>O Ph O 0 HO 0 N110tBu NH2 NHFmoc NHFmoc BrCH2COOEt H 20% TFA Fmocci H2 - K2C0 w I pHZCIZ Na2 Pd/C O o Dioxane 70-80/o 0 01 0 0, ss-sro 0 01 0 0l 0'-OCH3H3 O''OC 3H3 O'-OCH3H3 O'-OCH3H3 15 16 17 5 The tyrosine scaffold (5) was prepared in seven steps with an overall yield of 23% on a multi- gram scale. Commercially available 3-iodotyrosine (10) was treated with di-t-butylcarbonate to afford 11 (92-95%), treatment of 11 with DBU (1,5-diazobicyclo [5.4.0.]-undec-5-ene) and benzyl bromide (12) gave 13 (56-60%). Carbonylation of 13 in ethanol gave the corresponding ethyl ester 14 in 93% yield. Treatment of 14 with ethyl bromoacetate in potassium carbonate gave the diethyl ester 15 (93%). Deprotection of the Boc group was carried out using 20% TFA to afford the amine 16 (87%), which was protected with Fmoc-Cl to give 17 (66-76%), followed by hydrogenation to afford the acid 5 (70-80%). <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>(2S)-2- [ (tert-Butoxycarbonyl) amino)-3- (4-hydroxy-3-iodophenyl) propanoic Acid (11) To a solution of 3-iodo-L-tyrosine (10) (5.00 g, 16.3 mmol) in 1.0 M NaOH (16.3 mL), H20 (16 mL) and THF 32 mL was added di-tert-butyl dicarbonate (3.95 g, 18.1 mmol). After 1.5 hr at rt, the rection was concentrated in vacuo to remove THF, diluted with H20 (25 mL), and washed with Et2O (3 x 25 mL). The aqueous phase was brought to pH 4 with 1 M citric acid, extracted with CHOC12 (3 x 50 mL), and dried (Na2S04). Removal of the solvent in vacuo afforded 11 (6.30 g, 95%) as a white foam (Rzeszotarska, B.; Nadolska, B.; Tarnawski, J. Liebigs Ann. Chemin.

1981,7, 1294). 1H NMR (300 MHz, DMF-d7) # 7. 67 (s, 1 H), 7.18 (d, J= 8 Hz, 1 H), 6.92 (d, J = 8 Hz, 1 H), 4.29-4.24 (m, 1 H), 3.08 (dd, J= 9,14 Hz, 1 H), 2.88-2.84 (m, 1 H), 1.37 (s, 9 H).

Benzyl (2S)-2- [ (tert-Butoxycarbonyl) amino]-3- (4-hydroxy-3-iodophenyl) propanoate (13).

A solution of acid 11 (17.6 g, 43.3 mmol) in 150 mL of CH3CN was treated DBU (6.8 mL, 45

mmol) and benzylbromide (12) (5.4 mL, 45 mmol). The rection mixture was stirred at rt for 18 h, then concentrated to remove CH3CN, diluted with 300 mL of CH2CI2, washed with I N HCI (2x 150 mL), 100 mL of water, dried over NaSO4 and condense. Purifie by chromatography (20% EtOAc: Heptane) to yield 13 as an oil (21.5 g, 24.3 mmol, 56% yield). UV #max 228 (10800,95% ETHANOL) ; 1H NMR (CDC13) 6 7.41-7.31 (ion, 6 H), 6. 88 (d, J= 8 Hz, 1 H), 6.79 (d, J= 8 Hz, 1 H), 5.95 (br s, 1 H), 5. 22-5, 10 (ion, 3 H), 4. 59-4. 13 (m, 1 H), 3.02-2.96 (ion, 2 H), 1.45 (s, 9 H); 13C NMR (75 MHz, CDC13) 8 171.6,155.2,154.2,139.1,135.0,131.0,129.8, 128.7,128.6,115.1,85.4,80.3,67.3,54.6,36.9,28.4; IR (drift) 3457,3362,1737,1683,1528, 1503,1350,1294,1281,1206,1195,1169,810,753,701 cm-1; MS (EI) m/z 497 (M+), 380, 233,107,106,92,91,77,65,57,51. Anal. Calcd for C21H24INO5 : C, 50.72; H, 4.86; N, 2.82.

Found: C, 50.87; H, 4.70; N, 2.72.

Ethyl 5- { (2S)-3- (Benzyloxy)-2- [ (tert-butoxycarbonyl) amino]-3-oxopropyl}-2- hydroxybenzoate (14) A solution of 13 (12.1 g, 24.3 mmol) in 50 mL of EtOH and 120 mL of DMF was treated with Pd (II) Acetate (270 mg, 1.20 mmol), triethylamine (6.8 mL, 48.8 mmol).

The rection atmosphere was replace with CO (g) at 1 atm. and stirred at 60-70°C for 18 h.

The rection mixture was diluted with 300 mL of EtOAc, washed with 1 N HCl (3x 100 mL) and 100 mL of water. The organics were dried over Na2S04 and condense. Purifie by chromatography (20% EtOAc: heptane) to give product 14 as white crystals (8.44 g, 19.0 mmol, 78% yield). UV #max 228 (10800,95% EtOH) ; IH NMR (CDCl3) 6 10.73 (s, 1 H), 7.61 (d, J= 2 Hz, 1 H), 7.38-7.36 (m, 3 H), 7.32-7.28 (m, 2 H), 7.11 (br d, J=8 Hz, 1 H), 6.84 (d, J= 8 Hz, I H), 5.18 (d, J= 12 Hz, 1 H), 5.13 (d, J= 12 Hz, 1 H), 5.06 (br d, 1 H), 4.62-4. 59 (m, 1 H), 4.39 (q, J= 7 Hz, 2 H), 3.09-3.00 (ion, 2 H), 1.43 (s, 9 H), 1.41 (t, J= 7 Hz, 3 H); 13C NMR (75 MHz, CDC13) 6 171.6,170.0,160.7,155.0,136.6,135.0,130.4,128.6,128.6,128.5, 126.5,117.8, 112.5,80.0,67.2,61.5,54.5,37.4,28.3,14.2; IR (drift) 3357,1732,1687,1528,1493,1371, 1292,1270,1252,1207,1191,1169,1088,792,699 cm-1; MS (EI) m/z 443 (M+), 326,180, 179,134,133,91,77,65,57, 51. Anal. Calcd for C24H29NO7: C, 65.00; H, 6.59; N, 3.16.

Found: C, 64.93; H, 6.48; N, 3.11.

Ethyl 5-{(2S)-3-(Benzyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopr opyl}-2-(2-ethoxy-2- oxoethoxy) benzoate (15) A solution of 14 (5.76 g, 13.0 mmol) in 100 mL of CH3CN was treated with solid K2CO3 (9.0 g, 65.1 mol), ethylbromoacetate (1.7 mL, 15.3 mmol). The

rection mixture was stirred at rt for 14 h, additional ethylbromoacetate (0.5 mL, 4.5 mmol) added, then refluxed for 1 h. The rection solution was filtered to remove K2CO3 with fine filter paper to yield 15 as an orange oil. Purifie by chromatography (20% EtOAc/heptane) to yield a clear colorless oil (6.37 g, 12.0 mmol, 93%). [a] 15 D = 5° (c 0.78, chloroform); UV #max 228 (10800,95% EtOH); 1H NMR (CDCl3) 8 7.58 (s, 1 H), 7.36-7.28 (ion, 5 H), 7.10 (d, J= 8 Hz, 1 H), 6.74 (d, J = 8 Hz, 1 H), 5.12 (d, J = 2 Hz, 2 H), 5.06 (d, J = 9 Hz, 1 H), 4.64 (s, 2 H), 4.60- 4.57 (m, 1 H), 4.34 (q, J = 7 Hz, 2 H), 4.25 (q, J = 7 Hz, 2 H), 3.10-3. 01 (m, 2 H), 1.40 (s, 9 H), 1.36 (t, J= 7 Hz, 3 H), 1.27 (t, J= 7 Hz, 3 H); 13c NMR (75 MHz, CDCI3) 6 171.5,168.5, 165.6,156.6,155.0,135.1,134.0,132.6,129.4,128.6,128.5,121.5, 114.7,79.9,67.2,66.9, 61. 3,60.9,54.4,37.2,31.9,28.3,22.7,14.2; IR (liq.) 2980,1717,1500,1456,1446,1392,1379, 1367,1303,1254,1200,1166,1090,1068,1022 cm~l ; MS (EI ) m/z 529 (M+), 266,265,220, 192,179,133,91,59,57,56. Anal. Calcd for C28H35NOg: C, 63.50; H, 6.66; N, 2.64. Found: C, 63.86; H, 6.76; N, 2.63.

Ethyl 5-[(2S)-2-Amino-3-(benzyloxy)-3-oxopropyl]-2-(2-ethoxy-2-oxo ethoxy) benzoate (16) A solution of 15 (10.0 g, 18.9 mmol) in 100 mL of 20% TFA/CH2C12 was stirred at rt for 2 h.

The rection mixture was condense; the oil was redissolved in 400 mL of CH2CI2 and washed with NaHC03 and dried over NaSO4, condense to yield product 16 as an oil (8.12 g, 17.0 mmol, 90% yield). [α]25D=-3° (c 0.52, methanol); UV #max 227 (9410, MeOH); 1H NMR (400 MHz, CDCl3) # 7. 66 (d, J = 2 Hz, 1 H), 7.32 (m, 6 H), 6.78 (d, 1 H), 5.14 (s, 2 H), 4.66 (s, 2 H), 4.35 (q, J= 7 Hz, 2 H), 4.26 (q, J= 7 Hz, 2 H), 3.75 (dd, J= 6, 8 Hz, 1 H), 3.05 (dd, J = 5, 14 Hz, 2 H), 2.87 (dd, J = 8, 14 Hz, 2 H), 1. 38 (t, J = 7 Hz, 3 H), 1.29 (t, J = 7 Hz, 3 H); 13CNMR (100 MHz, CD30D) 6 174.6,169.3,166.7,156.7,136.0,138.4,132.1,130.4,128.6,128.4, 128. 3,121.5,114.6,66.7,66.3,61.3,61.2,55.7,39.7,13.6,13.5; IR (liq.) 2982,1757,1731, 1500,1455,1445,1367,1302,1254,1200,1172,1091,1023,754,700 cm~l ; MS (FAB) m/z (rel. intensity) 430 (MH+, 4), 430 (4), 265 (4), 133 (7), 92 (8), 91 (99), 81 (4), 69 (8), 55 (5), 41 (4), 29 (4). HRMS (FAB) calcd for C23H27NO7+H1 430.1866, found 430.1860.

Ethyl 5-((2S)-3-(Benzyloxy)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]a mino}-3-oxopropyl)- 2-(2-ethoxy-2-oxoethoxy) benzoate (17) A solution of 16 (6.93 g, 16.1 mmol) in 50 mL of dioxane was treated with Na2CO3 (5.47g 44.1 mmol) and 44 mL of water and then cooled to 0°C. To the cooled rection mixture was added 9-fluorenylcarbonylchloride (4.57 g, 17.7 mmol)

portionwise. After 30 min the rection mixture was warmed to rt for 5 h. The rection mixture was concentrated to remove dioxane, then partitioned between water and CH2Cl2, organics dried over Na2SO4, and condense. Purifie by chromatography (20% EtOAc/heptane to 50% EtOAc/heptane) to yield 17 as a gummy clear oil (6.97 g, 10.7 mmol, 66% yield). 1H NMR (400 MHz, CDCI3) 6 7.77 (d, J= 8 Hz, 2 H), 7.63 (s, 1 H), 7.59 (t, J= 6 Hz, 1 H), 7.36 (ion, 9 H), 7.08 (d, J = 8 Hz, 1 H), 6.75 (d, J = 9 Hz, 2 H), 5.38 (d, J = 8 Hz, 1 H), 5.17 (s, 2 H), 4.72 (m, 1 H), 4.65 (s, 2 H), 4.36 (m, 4 H), 4.24 (q, J= 9 Hz, 2 H), 4.21 (m, 1 H), 3.11 (m, 2 H), 1.35 (t, J = 7 Hz, 3 H), 1.27 (t, J= 5 Hz, 3 H).

(2S)-3-[3-(Ethoxycarbonyl)-4-(2-ethoxy-2-oxoethoxy)phenyl ]-2-{[(9H-fluoren-9- ylmethoxy) carbonyllaminolpropanoic acid (5) To 17 (6.97 g, 10.7 mmol) was added 504 mg of Pd/C followed by the addition of 250 mL of MeOH. The rection mixture was stirred at rt under 1 atm of H2 (g) for 18 h. The rection mixture was filtered through celite, condense.

Purifie by chromatography (1% AcOH, 5% MeOH, CH2Cl2) to yield 5 as a white solid (4.19 g, 7.45 mmol, 70% yield). The product can be recrystallized in toluene/heptane. [α]25D= 3° (c 0.99, methanol); W lx 264 (18800, MeOH) ; IH NMR (400 MHz, CDCI3) 6 8.95 (s, 1 H), 7.75 (d, J = 7 Hz, 2 H), 7.67 (s, 1 H), 7. 55 (t, J = 8 Hz, 2 H), 7. 39 (t, J = 7 Hz, 2 H), 7.24 (ion, 3 H), 7.22 (m, 1 H), 6.79 (d, J= 8 Hz, 1 H), 5.41 (d, J= 8 Hz, 1 H), 4.68 (m, 1 H), 4.64 (s, 2 H), 4.26 (m, 6 H), 3.20 (ion, 1 H), 3.08 (m, 1 H), 1.34 (t, J = 7 Hz, 3 H), 1.27 (t, J = 7 Hz, 3 H) ; 13C NMR (100 MHz, CDC13) 6 174.8,168.6,166.1,15 6.5,155.8,143.7,141.2,134.1,132.6,129.1, 127.7,127.1,125.0,121.6,119.9,114.6,67.2,66.8,61.4,61.2,54.5 ,47.1,36.7,14.2,14.1; IR (drift) 3337,3318,1754,1744,1694,1543,1445,1295,1269,1255,1203,1167, 1090,764,741 cm~l ; HRMS (FAB) calcd for C31H31NO9+H1 562.2077, found 562.2070.

Diversity Elements N-TerminalN-TerminalCarboxylic Acids available); Name # nicotinic acid 18 2-pyrazinecarboxylic acid 19 4-chlorobenzoic acid 20 6-chloronicotinic acid 21 2,3,5, 6-tetrafluorobenzoic acid 22 S-methoxyindole-2-carboxylic 23 acid 3-furoic acid 24 5,6-dichloronicotinic acid 25 cycloheptanecarboxylic acid 26 benzoic acid 27 N-acetyl- (L)-phenylalanine 28 (S)- (-)-3- (benzyloxycarbonyl)- 29 4-oxazolidinecarboxylicacid

C-Terminal Amines: a) Commercially available: Name # n-propylamine 30 n-amylamine31 4-phenylbutylamine 32 b) Synthesized:

Three of the six amines used in this library were commercially available, the remaining three amines 36a, 36b and 38 were prepared synthetically. Wolff-Kishner reduction of 4-(p-

chlorophenyl)-4-oxobutanoic acid gave 4- (p-chlorophenyl) butanoic acid (34a) in 96% yield, which was converted to 35a (55%). 4- (p-Methoxyphenyl) butylamine (36b) was similarly synthesized with equal results from commercially available 34b. Benzyl ethylamine ether (38) was prepared in one step from ethanolamine and benzyl chloride in 10% yield.

4- (p-chlorophenyl) butanoic acid (34a) A mixture of 3- (4-chlorobenzoyl) propionic acid (33) (2.50 g, 12.0 mmol), KOH (s) (1.75 g, 31.2 mmol), and hydrazine monohydrate (1.25 mL, 25.8 mmol) in 12.5 mL of diethylene glycol was refluxed azeotropically at 120-130°C for 90 min to remove water. The rection mixture was then refluxed at 170°C for 3 h, cooled to RT, diluted with 12.5 mL of water, and poured into 15 mL 2.5 N HCI (aq). The precipate was filtered off, dissolve in CH2Cl2, and the solvent removed to give 34a (2.23 g, 96%) as a white solid. UV #max 223 (8980, 95% ETHANOL); 1H NMR (400 MHz, CDCl3) 6 7.26 (d, J= 7 Hz, 2 H), 7.12 (d, J= 8 Hz, 2 H), 2.66 (t, J= 4 Hz, 2 H), 2.38 (t, J= 4 Hz, 2 H), 1.96 (ion, 2 H); 13C NMR (CDC13) 6 179.3, 140.0,132.2,130.2,128.9,34.7,33.4,26.4; IR (drift) 3063 (s), 3051 (s), 2955 (s), 2923 (s, b), 2905 (s), 2814,2797,2493 (b), 2466,2413,2367 (b), 2321,1706 (s), 1492 (s), 1212 (s), cm-1; MS (EI) m/z (rel. intensity) 198 (M+, 22), 200 (7), 198 (22), 140 (32), 139 (17), 138 (99), 127 (15), 125 (48), 103 (10), 89 (13), 60 (9); HRMS (EI) calcd for 198.0448, found 198.0441.

4- (p-chlorophenyl) butanamide (35a) A mixture of 34a (1.880 g, 10.1 mmol) and thionyl chloride (3.0 mL, 40.9 mmol) in 15 mL CHOC13 was stirred at reflux (75°C) for 4 h. Solvent and excess thionyl chloride were removed in vacuo, and residue was twice diluted with 7.5 mL toluene and evaporated to remove traces of thionyl chloride. To a solution of the residue in 3 mL toluene was slowly added 9 mL of cold concentrated NH40H. The precipitate was filtered off and recrystallized in CHCI3/heptane to give 35a (1.02 g, 55%) as a white solid. W 4lax 224 (9300,95% ETHANOL). 1H NMR (400 MHz, CDCl3) 6 7.25 (d, J= 8 Hz, 2 H), 7.12 (d, J= 8 Hz, 2 H), 5.31 (s, 2H), 2.66 (t, J= 8 Hz, 2 H), 2.23 (t, J= 7 Hz, 2 H), 1.98 (ion, 2 H); 13C NMR (CDC13) 6 175.4,140.2,134.5,130.2,128.9,35.1,34.8,27.0; IR (drift) 3434,2948,2282 (w), 1901 (w), 1655 (s), 1607,1491,1420,1306,1094,1016,836 (s), 825,804,666, cm-1. Calcd for C1oH12C1N0: C, 60.76; H, 6.12; N, 7.09; Cl, 17.94. Found: C, 60.60; H, 6.11; N, 6.96.

4- (p-chlorophenyl) butylamine (36a) (Ali, F. E.; Dandridge, P. A.; Gleason, J. G.; Krell, R. D.; Kruse, C. H.; Lavanchy, P. G; Snader, K. M. J. Med. Chem., 1982,25,947) To a stirred suspension of lithium aluminum hydride (2.40 g, 63.2 mmol) in 65 mL diethyl ether was added slowly a solution of (3.12 g 15.8 mmol) of 35a in 28 mL THF, and stirred at rt for 1 h. To the rection mixture was slowly added 4 mL water, 4 mL 5 N NaOH (aq), and 12 mL water. The organics were removed from the mulsion which was dissolve in water and extracted with ether. The organic portions were dried over Na2SO4(8), and condense to give 36a (2.76 g, 95%) as an oil. UV k. 224 (7600,95% ETHANOL). 1H NMR (400 MHz, <BR> <BR> <BR> <BR> 7.23(m,2H),7.10(d,J=8Hz,2H),2.74(t,J=7Hz,2H),2.60(t,J=8Hz,2H ),CDCl3# 2.25 (s, 2 H), 1.64 (ion, 2 H), 1.49 (ion, 2 H). 13C NMR (CDCI3) 6 141.2,131.8,130.1,128.8,42.3, 35.4,33.6,29.0; IR (liq.) 3365 (b), 3296 (b), 3026,2933 (s), 2858 (s), 2170 (w), 1996 (w), 1576, 1492 (s), 1460,1093 (s), 1016 (s), 831,821,804, crri'; HRMS (FAB) calcd for ClOH14CIN +Hl 184.0893, found 184.0879.

4- (p-methoxyphenyl) butanamide (35b) A mixture of 4- (p-methoxyphenyl) butyric acid (34b) (6.50 g, 33.5 mmol) and thionyl chloride (10.0 mL, 137 mmol) in 50 mL CHOC13 was stirred at reflux for 5.5 h. Solvent and excess thionyl chloride were removed in vacuo, and residue was twice diluted with 25 mL toluene and evaporated to remove traces of thionyl chloride. To a solution of the residue in 10 mL toluene was added slowly 30 mL of cold concentrated NH40H. The precipitate was filtered off and recrystallized in CHCl3/heptane to give 35b (3.68 g, 57%) as a white solid. W kmax 223 (10200,95% EtOH); 1H NMR (400 MHz, CDCl3) # 7.10 (d, J = 9 Hz, 2 H), 6.84 (d, J = 9 Hz, 2 H), 5.44 (s, 2 H), 3.80 (s, 3 H), 2.63 (t, J = 7 Hz, 2 H), 2.23 (d, J = 8 Hz, 2 H), 1.96 (in, 2 H); 13C NMR (CDC13) 6 175.5,158.3,133.8,129.7,114.2,55.6,35.4,34.5,27.4; IR (drift) 3366 (s), 2479 (w), 2355 (w), 2285 (w), 2053 (w), 1993 (w), 1656 (s), 1628 (s), 1512 (s), 1416 (s), 1304 (s), 1243 (s), 1230 (s), 1031 (s), 838 (s), cm~l. Anal. Calcd for C, IH15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.42; H, 8.03; N, 7.24.

4- (p-methoxyphenyl) butylamine (36b) (Ali, F. E.; Dandridge, P. A.; Gleason, J. G.; Krell, R. D.; Kruse, C. H.; Lavanchy, P. G; Snader, K. M. J. Med. Chem., 1982,25,947) To a stirred suspension of lithium aluminium hydride (4.40 g, 116 mmol) in 120 mL diethyl ether was added dropwise a solution of 35b (5.60 g, 29.0 mmol) in 10 mL THF, and

stirred at rt for 1 h. To the rection mixture was added 7.5 mL water, 7.5 mL 5 N NaOH (aq), and 20 mL water. The organics were removed from the mulsion which was dissolve in water and extracted with ether. The organic portions were dried over Na2SO4(s), and condense to give 36b (5.10 g, 98%) as an oil. UV #max 223 (9410,95% EtOH). (400 MHz, CDCI3) 6 7.10 (d, J = 9 Hz, 2 H), 6.83 (d, J=9 Hz, 2 H), 3.79 (s, 3 H), 2.71 (t, J = 7 Hz, 2H), 2.58 (t, J = 7 Hz, 2 H), 1.63 (ion, 2 H), 1.48 (ion, 2 H); IR (li.) 2933 (s), 2856,2145 (w), 2059 (w), 1996 (w), 1612 (s), 1584, 1513 (s), 1461,1442,1246 (s), 1178, 1034 (s), 827,822, cm-1 NMRS (FAB) calcd for Ci iHl7NO +Hi 180.1388, found 180.1387. NHBn, 1. NaH/THF HO 2. Benzyl chlonde w w HO HO 2. Benzyl chlondep < (major) U + HO~N iJ(major 37 38 39 40 2-(benzyloxy)(benzyloxy) ethylamine (38) (Hu, X. E.; Cassady, J. M. Synthetic Comm., 1995,25,907) To a solution of distille ethanolamine (37) (1. 81mL, 30.0 mmol) in 30 mL of dry THF, was added NaH (1.2 g 30.0 mmol) as a 60% dispersion in mineral oil, in small portions at rt. The mixture was stirred at reflux for 30 min., benzyl chloride (2.88 mL, 25.0 mmol) was added, and stirred at reflux for an additional 4.5 h. The mixture was cooled to rt, 10 mL water was added, and solvent evaporated in vacuo. The residue was partitioned between 1 N HCl (aq) and CH2C12.

The aqueous layer was extracted with CH2CI2 to remove side product 39. The aqueous portion was adjusted to pH 13 with 10% NaOH (aq) and extracted with CHOC12. The extracts were condense and purifie by flash chromatography (10% MeOH (saturated with NH3)/CH2CI2) to give 38 (0.24 g, 10%) as a yellow oil. Rf(10% MeOH (saturated with NH3)/CH2Cl2) = 0.47; LTV #max 251 (162, 95% ETHANOL); 1H NMR (400 MHz, CDCl3) # 7.31 (ion, 5 H), 4.55 (s, 2 H), 3.53 (t, J = 5 Hz, 2 H), 2.90 (t, J = 5, 2 H), 1.68 (s, 2 H); 13C NMR (CDCl3) # 138.7,128.8, 128.1,128.0,73.5,72.9,42.3; IR (liq.) 3371,3302 (b), 3030,2924 (b), 2860 (s), 2202 (w), 1955 (w), 1496,1453 (s), 1356,1101 (s), 1069,1028,739 (s), 698 (s), cm-1. HRMS (FAB) calcd for C9Hz3NO +Hl 152.1075, found 152.1074.

Library Synthesis The production of this library required seven steps using solid support. Three steps were carried out in a 96 well format. The AMEBA (acid sensitive methoxy benzaldehyde) linker was

prepared by reacting Merrifield resin and 4-hydroxy-2-methoxybenzaldehyde with sodium methoxide (see Scheme I). The AMEBA resin was then treated with the corresponding amine and NaBH (OAc) 3 to give the corresponding reductive amination product. The tyrosine scaffold (5) was then coupled to the various amine resins using DIC and HOBT in DMF. The Fmoc protecting group was then removed with piperidine/DMF (1: 1). The resin was then plated in a 96 well Robbins block then coupled to the corresponding acid with DIC and HOBT in DMF.

The diethyl ester was hydrolyzed with excess LiOH in THF: MeOH (1: 1) for 5-14 h at rt to yield the dicarboxylic acid on resin. The use of THF: MeOH (1: 1) is crucial for this hydrolysis. The use of excess LiOH and neat OH, TUF and DMF failed to yield the diacid. The product was then cleaved from the resin with 20% TFA/CH2CI2 solution. The resin was cleaved twice to yield the maximum possible product. The second cleavage resulted in approximately 10-20% more product without any change in purity levels.

Step 1: Preparation of AMEBA Linker A suspension of Merrifield resin (2.10g, 3.47 mmol) in 50 mL of DMF was treated with solid sodium methoxide (560 mg, 10.4 mol). To the solution was added 4-hydroxy-2-methoxybenzaldehyde (1.58 g, 10.4 mmol). The rection mixture was heated to 60-70°C for 24 h. The resin was then washed with DMF, MeOH, water, MeOH, CH2CI2, and MeOH (3x 10 mL). IR indicated strong absorption at 1681 cri'.

Step 2: Reductive Amination A suspension of AMEBA (1.04g 1.12 mmol) in 25 mL of C2H4CI2 was treated with phenylbutyl amine (0.36 mL, 2.3 mmol) and NaBH (OAc) 3 (479 mg, 2.26 mmol). The rection mixture was stirred at rt for 3 h. The resin was then washed with CH- 2CI2, DMF, MeOH and CH2C12 (3x 10 mL). IR indicated disappearance of strong absorption at 1681 cl-1.

Step 3: Coupling Resin to Intermediate 5 A suspension of resin (734 mg, 0.751 mmol) in 20 mL of DMF was treated with tyrosine scaffold 5 (632 mg, 1.13 mol), hydroxybenzotriazole (HOBT) (24 mg, 0.18 mmol), diisopropyl carbodiimide (DIC) (175 pL, 1.12 mmol). The rection mixture was stirred at rt for 2 h. The resin was tested for the presence of any secondary amine using the choral'l test. A semple of resin 1-5 mg was mixed with one drop of 2% acetaldehyde in DMF and one drop of 2% chloranil in DMF. After 5 min the resin showed no color change; a control containing a secondary amine stained blue (Rzeszotarska, B.; Nadolska,

B.; Tarnawski, J. Liebigs Ann. Chem. 1981,7,1294). The resin was washed with DMF, CH- ZC12, MeOH, CH2C12 (3x 10 mL).

Step 4: Fmoc Removal Resin (1.14 g, 0.751 mmol) was suspende in 10 mL of piperidine/ DMF (1: 5) and stirred for 30 min. at rt. The resin was washed with DMF, CH2CI2, MeOH, CH- 2CI2 (3x 10 mol).

Step 5: Coupling Resin to Acid The resin was plated in a 96 well Robbins block (approx. 35 mg, 0.027 mmol). To each well was added as a slurry of DMF/CH2CI2 and the resin was dried.

Standard solutions of acid (1.26 mmol) in 7.5 mL of DMF, HOBT (119 mg, 0.88 mmol) in 20mL of DMF and DIC (1.3 mL, 8.4 mmol) in 20 mL DMF were prepared. To the resin in each well was added the standard acid solution (0.50 mL, 0.084 mmol), DIC (0.20 mL DMF, 0.084 mmol) and HOBT (0.20 mL DMF, 0.009 mol). The Robbins plate was then rotated for 5 h.

The resin was washed with DMF, CH2Cl2, MeOH, CH2Cl2 (3x 1 mL).

Step 6: Hydrolysis of Esters A standard solution of LiOH (2.26 g, 53.9 mmol) in 25 mL of MeOH and 25 mL of THF was prepared. The resin (approx. 35 mg, 0.027 mmol) in each well was treated with 0.5 mL of standard LiOH solution (0.62 mol). The Robbins plate was rotated for 14 h. The resin was washed with DMF, CH2Cl2, MeOH, CH2Cl2 (3x 1 mL).

Step 7: Cleavage The resin (approx. 35 mg, 0.027 mmol) in each well was treated with 0.50 mL of TFA/CH2C12 (1: 5). The robbins block was rotated for 30 min. The resin was washed with CH2Cl2 (3x 0.2 mL) and the filtrate collecte. This process was repeated to insure all the product was cleaved from the resin.

Purification The entire library was purifie by reverse phase HPLC. The average purity after purification of the eleven samples was >99%. All samples tested indicated a purity >98% by analytical HPLC. The average yield after purification was 17% (2-3 mg per well on average).

The preparative HPLC system used a Gilson 215 liquid robotics autosampler/fraction collector.

The chromatography utilized a three-pump system of Rainin pump heads equipped with 10 mL/min or 50 mL/min pump solvent delivery heads and a Gilson solvent mixing chamber. Two pumps were used for solvent delivery, and one was used for flushing the system at the

completion of the series of chromatography runs. W absorbance was monitored using a Knauer variable wavelength UV detector equipped with a 10 mm path length analytical flow cell. The entire system was controlled by Gilson Unipoint software v. 1.65 which was used for data acquisition and analysis.

Samples were prepared for injection by dissolving each in 1-2 mL MeOH and housing them in 96 deep-well microtiter plates (2 mL/well). Injections for the chromatography loaded the entire sample into a 2.0 mL injection loop installe on the Gilson 819/Rheodyne Injector Module.

The HPLC method used in this study is as follows: Column. YMC GuardPack C8 (20 X 50 mm, 5,120 A) Mobile A: water + 0.05% tiifluoroacetic acid (TFA) MobileB: acetonitrile Flow Rate. 10 mL/min Gradient: 10% B 0-2 min, 10-100% B 2-23 min, 100% B 23-25 min, re-equilibrate for 3 min Detection: LTV absorbance at 220 nm, Knauer UV detector with 10 mm flow cell Fraction Collection: Gilson 215,15% AUFS threshold, 9 mL maximum/tube in 13 X 100 mm disposable tubes Mass Spectrometry The entre library was analyzed by mass spectrometry after reverse phase HPLC. All of the 64 recovered compound were positively identifie by a molecular ion peak.

Library Compound (Examples 9-1 to 9-64) Table A Ex. No. Compound Name Mol. Wt. Mass DATA Post Purification Ret (M+) HPLC Analysis Tim 9-1 2-(carboxymethoxy)-5-[(2S)-2-[[(6-chloro- 491.93 493.1 3-pyridinyl)carbonyl]amino}-3-oxo-3- (pentylamino)propyl]benzoic acid 9-2 2-(carboxymethoxy)-5-[p(2S)-2-{[(5,6- 526.38 544 (M + dichloro-3-pyridinyl)carbonyl]amino}-3-oxo- NH3)+ 3-(pentylamino)propyl]benzoc acid 9-3 2-(carboxymethoxy)-5-{(2S)-3-oxo-3- 458.48 459.1 (pentylamino)-2-[(2- pyrazinylcarbonyl)amino]propyl}benzoic acid 9-4 2-(carboxymethoxy)-5-[(2S)-2-(3- 446.46 447.2 furoylamino)-3-oxo-3- (pentylamino)propyl]benzoic acid 9-5 2-(carboxymethoxy)-5-[(2S)-2-{[(5- 525.56 526.1 >98% 3 methoxy-1H-indol-2-yl)carbonyl]amino]-3- oxo-3-(pentylamino)propyl]benzoic acid 9-6 5-[(2S)-2-{[(2S)-2-(acetylamino)-3- 541.61 542.2 phenylpropanoyl]amino}-3-oxo-3- (pentylamino)propyl]-2- (carboxymethoxy)benzoic acid 9-7 2-(carboxymethoxy)-5-[(2S)-2- 538.65 539.2 [(cycloheptylcarbonyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 9-8 5-((2S)-2-(benzoylamino)-3-oxo-3-[(4- 518.57 519.2 phenylbutyl)amino]propyl}-2- (carboxymethoxy)benzoic acid 9-9 2-(carboxymethoxy)-5-{(2S)-2-[(4- 553.02 554.1 >98% 4 chlorobenzoyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 9-10 2-(carboxymethoxy)-5-{(2S)-3-oxo-3-[(4- 590.53 591.0 phenylbutyl)amino]-2-[(2,3,5,6- tetrafluorobenzoyl)amino]propyl}benzoic acid 9-11 2-(carboxymethoxy)-5-{(2S)-3-oxo-3-[(4- 519.56 520.2 phenylbutyl)amino]-2-[(3- pyridinylcarbonyl)amino]propyl}benzoic acid 9-12 2-(carboxymethoxy)-5-[(2S)-2-{[(6-chloro- 554 555.1 3-pyridinyl)carbonyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 9-13 2-(carboxymethoxy)-5-{(2S)-2-{[(5,6- 588.45 589.9 dichloro-3-pyridinyl)carbonyl]amino}-3-oxo- 3-[(4-phenylbutyl)amino]propyl}benzoic acid 9-14 2-(carboxymethoxy)-5-{(2S)-3-oxo-3-[(4- 520.55 521.1 phenylbutyl)amino]-2-[(2- pyrazinylcarbonyl)amino]propyl}benzoic acid 9-15 2-(carboxymethoxy)-5-{(2S)-2-(3- 508.53 509.1 >98% 4 furoylamino)-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 9-16 2-(carboxymethoxy)-5-{(2S)-2-{[(5- 587.64 588.1 methoxy-1H-indol-2-yl)carbonyl]amino}-3- oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 9-17 5-{(2S)-2-{[(2S)-2-(acetylamino)-3- 603.68 604.1 phenylpropanoyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}-2- (carboxymethoxy)benzoic acid 9-18 2-(carboxymethoxy)-5-{(2S)-3-{[4-(4- 573.09 574.1 chlorophenyl)butyl]amino}-2- [(cycloheptylcarbonyl)amino]-3- oxopropyl}benzoic acid 9-19 5-((2S)-2-(benzoylamino)-3-{[4-(4- 553.02 554.2 chlorophenyl)butyl]amino}-3-oxopropyl)-2- (carboxymethoxy)benzoic acid 9-20 2-(carboxymethoxy)-5-((2S)-2-[(4- 587.46 589.0 chlorobenzoyl)amino]-3-{[4-(4- chlorophenyl)butyl]amino}-3- oxopropyl)benzoic acid 9-21 2-(carboxymethoxy)-5-{(2S)-3-{[4-(4- 624.98 626.2 >98% 3 chlorophenyl)butyl]amino}-3-oxo-2- [(2,3,5,6- tetrafluorobenzoyl)amino]propyl}benzoic acid 9-22 2-(carboxymethoxy)-5-{(2S)-3-{[4-(4- 554 555.1 chlorophenyl)butyl]amino}-3-oxo-2-[(3- pyridinylcarbonyl)amino]propyl}benzoic acid 9-23 2-(carboxymethoxy)-5-((2S)-3-{[4-(4- 588.45 589.1 chlorophenyl)butyl]amino}-2-{[(6-chloro-3- pyridinyl)carbonyl]amino}-3- oxopropyl)benzoic acid 9-24 2-(carboxymethoxy)-5-((2S)-3-{[4-(4- 622.89 623.9 chlorophenyl)butyl]amino}-2-{[(5,6- dichloro-3-pyridinyl)carbonyl]amino}-3- oxopropyl)benzoic acid 9-25 2-(carboxymethoxy)-5-{(2S)-3-{[4-(4- 554.99 556.1 >98% 4 chlorophenyl)butyl]amino}-3-oxo-2-[(2- pyrazinylcarbonyl)amino]propyl}benzoic acid 9-26 2-(carboxymethoxy)-5-[(2S)-3-[[4-(4- 542.98 544.1 chlorophenyl)butyl]amino}-2-(3- furoylamino)-3-oxopropyl]benzoic acid 9-27 2-(carboxymethoxy)-5-((2S)-3-{[4-(4- 622.08 623.1 chlorophenyl)butyl]amino)-2-{[(5-methoxy- 1H-indol-2-yl)carbonyl]amino}-3- oxopropyl)benzoic acid 9-28 5-((2S)-2-{[(2S)-2-(acetylamino)-3- 638.12 639.2 phenylpropanoyl]amino}-3-{[4-(4- chlorophenyl)butyl]amino}-3-oxopropyl)-2- (carboxymethoxy)benzoic acid 9-29 2-(carboxymethoxy)-5-((2S)-2- 568.67 569.1 [(cycloheptylcarbonyl)amino]-3-{[4-(4- methoxyphenyl)butyl]amino]-3- oxopropyl)benzoic acid 9-30 5-((2S)-2-(benzoylamino)-3-{[4-(4- 548.6 549.1 methoxyphenyl)butyl]amino}-3-oxopropyl)- 2-(carboxymethoxy)benzoic acid 9-31 2-(carboxymethoxy)-5-((2S)-2-[(4- 583.04 584.3 chlorobenzoyl)amino]-3-{[4-(4- methoxyphenyl)butyl]amino}-3- oxopropyl)benzoic acid 9-32 2-(carboxymethoxy)-5-{(2S)-3-{[4-(4- 620.56 621.0 methoxyphenyl)butyl]amino}-3-oxo-2- [(2,3,5,6- tetrafulorobenzoyl)amino]propyl}benzoic acid 9-33 2-(carboxymethoxy)-5-{(2S)-3-{[4-(4- 549.59 550.1 >98% 3 methoxyphenyl)butyl]amino}-3-oxo-2-[(3- pyridinylcarbonyl)amino]propyl}benzoic acid 9-34 2-(carboxymethoxy)-5-((2S)-2-{[(6-chloro- 584.03 585.2 3-pyridinyl)carbonyl]amino}-3-{[4-(4- methoxyphenyl)butyl]amino}-3- oxopropyl)benzoic acid 9-35 2-(carboxymethoxy)-5-((2S)-2-{[(5,6 618.48 619.9 >98% 4 dichloro-3-pyridinyl)carbonyl]amino}-3-{[4- (4-methoxyphenyl)butyl]amino}-3- oxopropyl)benzoic acid 9-36 2-(carboxymethoxy)-5-{(2S)-3-{[4-(4- 550.57 551.1 methoxyphenyl)butyl]amino}-3-oxo-2-[(2- pyrazinylcarbonyl)amino]propyl}benzoic acid 9-37 2-(carboxymethoxy)-5-((2S)-2-(3- 538.56 539.1 furoylamino)-3-{[4-(4- methoxyphenyl)butyl]amino}-3- oxopropyl)benzoic acid 9-38 2-(carboxymethoxy)-5-((2S)-2-{[(5- 617.66 618.1 methoxy-1H-indol-2-yl)carbonyl]amino}-3- {[4-(4-methoxyphenyl)butyl]amino}-3- oxopropyl)benzoic acid 9-39 5-((2S)-2-{[(2S)-2-(acetylamino)-3- 633.7 634.1 phenylpropanoyl]amino}-3-{[4-(4- methoxyphenyl)butyl]amino}-3-oxopropyl)- 2-(carboxymethoxy)benzoic acid 9-40 5-{(2S)-3-{[2-(benzyloxy)ethyl]amino}-2- 540.62 541.2 [(cycloheptylcarbonyl)amino]-3-oxopropyl}- 2-(carboxymethoxy)benzoic acid 9-41 5-((2S)-2-(benzoylamino)-3-{[2- 520.54 521.1 (benzyloxy)ethyl]amino}-3-oxopropyl)-2- (carboxymethoxy)benzoic acid 9-42 5-{(2S)-3-{[2-(benzyloxy)ethyl]amino}-2- 554.99 556.0 [(4-chlorobenzoyl)amino]-3-oxopropyl}-2- (carboxymethoxy)benzoic acid 9-43 5-{(2S)-3-{[2-(benzyloxy)ethyl]amino}-3- 592.51 593.0 oxo-2-[(2,3,5,6- tetrafluorobenzoyl)amino]propyl}-2- (carboxymethoxy)benzoic acid 9-44 5-{(2S)-3-{[2-(benzyloxy)ethyl]amino}-3- 521.53 522.1 oxo-2-[(3-pyridinylcarbonyl)amino]propyl}- 2-(carboxymethoxy)benzoic acid 9-45 5-((2S)-3-{[2-(benzyloxy)ethyl]amino}-2- 555.98 557.1 >98% 3 {[(6-chloro-3-pyridinyl)carbonyl]amino}-3- oxopropyl)-2-(carboxymethoxy)benzoic acid 9-46 5-((2S)-3-{[2-(benzyloxy)ethyl]amino}-2- 590.42 592.0 {[(5,6-dichloro-3-pyridinyl)carbonyl]amino}- 3-oxopropyl)-2-(carboxymethoxy)benzoic acid 9-47 5-((2S)-3-{[2-(benzyloxy)ethyl]amino}-3- 522.52 523.1 oxo-2-[(2-pyrazinylcarbonyl)amino]propyl}- 2-(carboxymethoxy)benzoic acid 9-48 5-[(2S)-3-{[2-(benzyloxy)ethyl]amino}-2- 510.51 511.1 (3-furoylamino)-3-oxopropyl]-2- (carboxymethoxy)benzoic acid 9-49 5-((2S)-3-{[2-(benzyloxy)ethyl]amino}-2- 589.61 590.0 {[(5-methoxy-1H-indol-2- yl)carbonyl]amino}-3-oxopropyl)-2- (carboxymethoxy)benzoic acid 9-50 5-((2S)-2-{[(2S)-2-(acetylamino)-3- 605.65 606.0 phenylpropanoyl]amino}-3-{[2- (benzyloxy)ethyl]amino}-3-oxopropyl)-2- (carboxymethoxy)benzoic acid 9-51 5-[(2S)-2-(benzoylamino)-3-oxo-3- 428.45 429.2 (propylamino)propyl]-2- (carboxymethoxy)benzoic acid 9-52 2-(carboxymethoxy)-5-[(2S)-2-[(4- 462.89 463.1 chlorobenzoyl)amino]-3-oxo-3- (propylamino)propyl]benzoic acid 9-53 2-(carboxymethoxy)-5-{(2S)-3-oxo-3- 500.41 501.1 (propylamino)-2-[(2,3,5,6- tetrafluorobenzoyl)amino]propyl}benzoic acid 9-54 2-(carboxymethoxy)-5-{(2S)-3-oxo-3- 429.43 430.2 (propylamino)-2-[(3- pyridinylcarbonyl)amino]propyl}benzoic acid 9-55 2-(carboxymethoxy)-5-[(2S)-2-{[(6-chloro- 463.88 464.1 3-pyridinyl)carbonyl]amino}-3-oxo-3- (propylamino)propyl]benzoic acid 9-56 2-(carboxymethoxy)-5-[(2S)-2-{[(5,6- 498.32 516 (M + dichloro-3-pyridinyl)carbonyl]amino}-3-oxo- NH3)+ 3-(propylamino)propyl]benzoic acid 9-57 2-(carboxymethoxy)-5-{(2S)-3-oxo-3- 430.42 431.2 (propylamino)-2-[(2- pyrazinylcarbonyl)amino]propyl}benzoic acid 9-58 2-(carboxymethoxy)-5-[(2S)-2-(3- 418.41 419.1 furoylamino)-3-oxo-3- (propylamino)propyl]benzoic acid 9-59 2-(carboxymethoxy)-5-[(2S)-2-{[(5- 497.51 498.1 methoxy-1H-indol-2-yl)carbonyl]amino}-3- oxo-3-(propylamino)propyl]benzoic acid 9-60 2-(carboxymethoxy)-5-[(2S)-2- 476.57 477.2 [(cycloheptylcarbonyl)amino]-3-oxo-3- (pentylamino)propyl]benzoic acid 9-61 5-[(2S)-2-(benzoylamino)-3-oxo-3- 456.5 457.2 >98% 3 (pentylamino)propyl]-2- (carboxymethoxy)benzoic acid 9-62 2-(carboxymethoxy)-5-[(2S)-2-[(4- 490.94 491.1 chlorobenzoyl)amino]-3-oxo-3- (pentylamino)propyl]benzoic acid 9-63 2-(carboxymethoxy)-5-{(2S)-3-oxo-3- 528.46 529.1 (pentylamino)-2-[(2,3,5,6- tetrafluorobenzoyl)amino]propyl}benzoic acid 9-64 2-(carboxymethoxy)-5-{(2S)-3-oxo-3- 457.49 458.2 (pentylamino)-2-[(3- pyridinylcarbonyl)amino]propyl}benzoic acid

The following NMR data were determined Ex. 9-64; 1H NMR (300 MHz, DMSO-d6) 6 8.97 (d, J= 5 Hz, 1 H), 8.77 (d, J= 3 Hz, 2 H), 8.12 (t, J = 2 Hz, 1 H), 7.81 (m, 2 H), 7.40 (dd, J = 2,6 Hz, 1 H), 6.89 (d, J = 6 Hz, 1 H), 4.6 9 (s, 2 H), 4.62 (m, 1 H), 3.07 (m, 3 H), 2.94 (m, 1 H), 1.40 (m, 2 H), 1.26 (m, 4 H),. 85 (J= 5 Hz, 3H).

Ex-9-3 ; 1H NMR (300 MHz, DMSO-d6) 8 9.10 (s, 1 H), 8.87 (d, J= 2 Hz, 1 H), 8.72 (m, 1 H), 8.65 (d, J = 6 Hz, 1 H), 8. 15 (m, 1 H), 7.53 (d, J = 2 Hz, 1 H), 7.30 (dd, J = 2,6 Hz, 1 H), 6.87 (d, J = 6 Hz, 1 H), 4.69 (s, 2 H), 4.65 (m, 1 H), 3.06 (m, 4 H), 1. 38 (m, 2 H), 12.3 (m, 4 H), 0.84 (t,J= 6 Hz, 3 H).

Ex. 9-62; 1H NMR (300 MHz, DMSO-d6) 6 8.62 (d, J= 6 Hz, 1 H), 8.05 (m, 1 H), 7.80 (d, J= 9 Hz, 2 H), 7.66 (d, J = 2 Hz, 1 H), 7.49 (d, J = 8 Hz, 2 H), 7.41 (dd, J = 2,6 Hz, 1 H), 6. 88 (d, J = 6 Hz, 1 H), 4.68 (s, 2 H), 4.58 (m, 1 H), 3.00 (m, 4 H), 13 8 (m, 2 H), 1.23 (m, 4 H), 0.83 (t, J= 6 Hz, 3 H).

Ex. 9-1 ; 1H NMR (300 MHz, DMSO-d6) 8 8.88 (d, J= 6 Hz, 1 H), 8.73 (d, J= 2 Hz, 1 H), 8.16 (dd, J= 3,6 Hz, 1 H), 8. 10 (m, 1 H), 7.66 (s, 1 H), 7.59 (d, J= 8 Hz, 1 H), 7.39 (dd, J= 2,7 Hz, 1 H), 6.88 (d, J= 9 Hz, 1 H), 4.68 (s, 2 H), 4.58 (m, 1 H), 2.90 (m, 4 H), 1.37 (m, 2 H), 1.23 (m, 4 H), 0.83 (t, J= 5 Hz, 3 H) Ex. 9-2; 1H NMR (300 MHz, DMSO-d6) 8 8.70 (d, J= 6 Hz, 1 H), 8.53 (s, 1 H), 8.26 (s, 1 H), 8.07 (m, 1 H), 7.68 (s, 1 H), 7.40 (m, 1 H), 6.90 (d, J= 6 Hz, 1 H), 4.70 (s, 2 H), 4. 58 (m, 1 H), 3.03 (m, 2 H), 2.89 (m, 1 H), 1.38 (m, 1 H), 1.25 (m, 4 H), 0.84 (t, J= 6 Hz, 3H).

Ex. 9-4; 1H NMR (400 MHz, DMSO-d6) 6 8.27 (d, J= 10 Hz, 1 H), 8.16 (s, 1 H), 8.03 (m, 1 H), 7.67 (m, 2 H), 7.39 (m, 1 H), 6.89 (d, J= 10 Hz, 1 H), 6.83 (s, 1 H), 4.70 (s, 2 H), 4.56 (m, 1 H), 3.03 (m, 2 H), 2.96 (m, 1 H), 2.85 (m, 1 H), 1.37 (m, 2 H), 1.23 (m, 4 H), 0.84 (t, 3 H). IH NMR.

EXAMPLE 10: One-dimensional library of 5-substituted-2-carbomethoxybenzoic acids Scheme 3 o CI p I H NHZ 0 w. CH3/ + CH3 DMF, HO CH DMF NaBH (OAc) 3 Sep 2 1 2 3 Ph Ph HO 0 Ph N O NHFmoc II NHFmoc 1) piperidine N R2 + ( DIC/HOBT i Step 4 i NH O 01 St I 0 2) DIC/HOBT RZCOOH O O 16 1- H3 0 0 Step 5 4 5 O''O^CH3H3 O'OCH3H3 6 7 Ph Ph LN O O H, N O O LiOH NR2 NR THF: MeOH. H TFA H i i Step 6 0 CH2C12 C 4° Step 7 0 0 OH O OH 0 OH 0 OH 8 9

Chemistry Summary The combination solid-phase/solution-phase synthetic sequence was designed to prepare an 88-member one-dimensional library of 5-substituted-2-carboxymethoxybenzoic acids in a 96- well format as illustrated in Scheme 3. The synthesis was based on the use of the AMEBA linker (acid sensitive methoxybenzaldehyde, 3), selected due to its ease of cleavage and versatility in the reductive amination step, and the intermediate 5, synthesized in a seven step sequence as described below. The key resin 3 was synthesized by treating Merrifield resin with 2-methoxy-4-hydroxybenzaldehyde according to the literature procedure (Fivush, A. M.; Willson, T. M. Tetrahedron Lett. 1997,38,7151. Sarantakis, D.; Bicksler, J. J. Tetrahedron Lett., 1997,38,7325e). The functionalized resin 3 was treated with 4-phenylbutyl amine and sodium triacetoxyborohydride to provide resin 4. Attachment of the scaffold 5 to the resin was performed utilizing the standard conditions of DIC/HOBt in DMF. A deprotection/

condensation protocol was followed to attach the diversity element to give 7. Hydrolysis of the diester was then followed by removal of the products from the resin with 20% TFA/CH2Cl2.

Intermediate Synthesis Scaffold 5 (see Scheme 3 above), (2S)-3- [3-ethyoxycarbonyl)-4- (2-ethoxy-2- oxoethoxy)phenyl]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino }propanoic acid, was prepared as described in Example 9 above.

Diversity Elements Compound Name benzoic acid diethylphosphonoacetic acid pentafluoropropionic acid S-benzylthioglycolic acid 2-methyl-6-nitrobenzoic acid 2-formylphenoxyacetic acid 4-cyanocinnamic acid benzoylformic acid 1-phenyl-1-cyclopentylcarboxylicacid 2-cyanobenzoic acid 4-oxo-2-thioxo-3-thiazolidineacetic acid pivalic acid p-chlorophenylpropiolicacid 2-benzoylbenzoic acid 3,4-dihydro-2,2-dimethyl-4-oxo-2H-pyran-6-carboxylic acid isonicotinic acid cyclopropanecarboxylic acid 3-cyclopentylpropionic acid 1-methyl-1-cyclohexanecarboxylic acid 2,5-dimethoxybenzoic acid 2-biphenylcarboxylic acid 2-acetylbenzoic acid o-toluic acid 3-fluorobenzoicacid 3,4-dichlorobenzoicacid m-anisicacid 3,4-dimethoxybenzoicacid 3,4,5-trimethoxybenzoicacid 3,5-dimethoxybenzoicacid 4-bromobenzoicacid 4-chloro-o-anisic acid 4-dimethylaminobenzoicacid 4- (trifluoromethoxy) benzoic acid 4-butoxybenzoicacid 4-biphenylcarboxylicacid 4-acetylbenzoicacid α,α,α-trifluoro-p-toluicacid 4-tert-butylbenzoicacid p-toluicacid 3-methoxy-4-methylbenzoicacid hydrocinnamicacid 3- (4-methoxyphenyl) propionic acid 3-benzoylpropionicacid 1-methylpyrrole-2-carboxylicacid 5-bromo-2-furoicacid 2-naphthoicacid <BR> <BR> <BR> <BR> (R)-(+)-α-methoxy-α-(trifluoromethyl)phenylaceticacid (R)-(-)-a-methoxyphenylacetic acid 4-fluorophenoxyaceticacid phenylaceticacid 2-chlorophenylaceticacid 2-methoxyphenylaceticacid o-tolylaceticacid 3-chlorophenylaceticacid m-methoxyphenylaceticacid (α,α,α-trifluoro-m-tolyl)aceticacid p-chlorophenylacetic acid 4-methoxyphenylacetic acid (a, α,α-trifluoro-p-tolyl) acetic acid 4-phenylbutyric acid 4- (4-methoxyphenyl) butyric acid 4-benzoylbutyric acid 5-phenylvaleric acid undecylenic acid 3-methyl-2-thiophenecarboxylic acid 4- (2-thienyl) butyric acid 3-thiophenecarboxylic acid 1-methylindole-2-carboxylic acid piperonylic acid picolinic acid 3-quinolinecarboxylic acid coumarin-3-carboxylic acid 4- (methylsulfonyl) benzoic acid 2-methoxy-4- (methylthio) benzoic acid (2-pyrimidylthio) acetic acid 2-fluoro-4- (trifluoromethyl) benzoic acid 3-pyridylacetic acid hydrochloride 2-methylnicotinic acid 2,3,5,6-tetramethyl-benzoic acid ß-(p-chlorophenyl)propionicacid (3,5-dimethoxyphenyl) acetic acid 3- (3,4-methylenedioxyphenyl) propionic acid 6-methylpicolinic acid 1-acetylpiperidine-4-carboxylicacid 4-cyclohexylbenzoic acid 5-chloro-2-thiophenecarboxylicacid 3-methylindene-2-carboxylic acid

8-quinolinecarboxylic acid 3,5-dimethylisoxazole-4-carboxylic acid 2,4-dimethylthiazole-5-carboxylic acid 3- (4-fluorophenyl) propionic acid 7-chlorobenzofuran-2-carboxylic acid (S)-(-)-a-methoxy-a-(trifluoromethyl) phenylacetic acid ()-camphorcarboxylic acid pinonic acid 1-adamantanecarboxylic acid tetrahydro-3-furoic acid 3-fluoro-2-methyl-benzoic acid 2,6-dimethoxynicotinic acid 1,4-benzodioxan-2-carboxylic acid 2-fluoro-5-methylbenzoic acid 2-norbornaneacetic acid 2-phenoxypropionic acid anti-3-oxotricyclo (2.2.1.02,6) heptane-7-carboxylic acid Library Synthesis The production of the library required seven steps using solid support. Three steps were carried out in a 96 well format. The AMEBA (acid sensitive methoxy benzaldehyde) linker was prepared by reacting Merrifield resin and 4-hydroxy-2-methoxybenzaldehyde with sodium methoxide (see Scheme 3). The AMEBA resin was then treated with 4-phenylbutyl amine and NaBH (OAc) 3 to give the corresponding reductive amination product. The tyrosine scaffold (5) was then coupled to this amine resin using DIC and HOBT in DMF. The Fmoc protecting group was then removed with piperidine/DMF (1: 1). The resin was then plated in a 96 well Robbins block and coupled to the corresponding acid with DIC and HOBT in DMF. After thorough washing, the resin was subjected to the coupling conditions a second time. The diethyl ester was hydrolyzed with excess LiOH in THF: MeOH (1: 1) for 5-14 h at rt to yield the dicarboxylic acid on resin. The product was then cleaved from the resin with 20% TFA/ CH2Cl2 solution. The resin was cleaved twice to yield the maximum possible product. The second cleavage resulted in approximately 10-20% more product without any change in purity levels.

Step 1: Preparation of AMEBA Linker A suspension of Merrifield resin (10.3g, 12.9 mmol) in 200 mL of DMF was treated with solid sodium methoxide (2.08 g, 38.5 mmol) and 4- hydroxy-2-methoxybenzaldehyde (5.81 g, 38.2 mmol). The rection mixture was heated to 60°C for 24 h. The resin was then washed with DMF, MeOH, water, MeOH, CH2Cl2, and MeOH (3x 50 mL), and dried to a constant weight (9.31 g) under high vacuum. IR indicated strong absorption at 1681 cm~l.

Step 2: Reductive Amination A suspension of AMEBA (0.804 g 0.878 mmol) in 25 mL of 1,2-dichloroethane was treated with 4-phenylbutyl amine (0.29 mL, 1.8 mmol) and NaBH (OAc) 3 (394 mg, 1.86 mmol). After stirring at room temperature for 4h, the resin was washed with CH2Cl2, DMF, MeOH and CH2Cl2 (3x each) and dried under high vacuum to a constant mass (0.807g). IR indicated disappearance of strong absorption at 1681 crri I.

Step 3: Coupling Resin to Intermediate 5 A suspension of resin (0.724 g, 0.689 mmol) in 20 mL of DMF was treated with tyrosine scaffold 5 (0.584 g, 1.04 mol), hydroxybenzotriazole (HOBt) (32 mg, 0.24 mmol), diisopropyl carbodiimide (DIC) (0.13 mL, 0.24 mmol). The rection mixture was stirred at rt for 2.5 h. The resin was tested for the presence of any secondary amine using the choranil test (a sample of resin 1-5 mg was mixed with one drop of 2% acetaldehyde in DMF and one drop of 2% chloranil in DMF). After 5 min the resin showed no color change; a control containing a secondary amine stained blue (Vojkovsky T. Peptide Research 1995,4,236). The resin was washed with DMF, CHZC12, MeOH, CHZCIz (3x each) and dried under high vacuum to constant mass (0.857 g).

Step 4: Fmoc Removal Resin (0.855 g, 0.0.537 mmol) was suspende in 10 mL of piperidine/ DMF (1: 5) and stirred for 45 min. at rt. The resin was washed with DMF, CH2Cl2, MeOH, CH- 2C12 (3x 10 mL) and dried under high vacuum to constant mass (0.528 g).

Step 5: Coupling Resin to Acid The resin was plated into a 96 well Robbins block (approx. 60 mg, 0.045 mmol/well) as a suspension in DMF/CH2C12 and dried. Standard solutions of acid (0.50 mL of a 0.27M stock in DMF), HOBt (200 IL of a 0.0675M stock in DMF) and DIC (200pL of a 0.675M stock in DMF) were added to each well. The Robbins block was then rotated for 18 h at ambient temperature. The resin was washed with DMF, CH2Cl2, MeOH, CH-

2Cl2 (3x each). The coupling was repeated by adding the same amounts of reagents as above, rotating for an additional 18h, and washing as above.

Step 6: Hydrolysis of Esters A standard solution of 0.90M LiOH in 1: 1 MEOIPTBF was prepared. The resin (approx. 60 mg, 0.045 mmol) in each well was treated with 1.0 mL of standard LiOH solution (0.90 mmol). The Robbins plate was rotated for 6h, and the resin was washed with MeOH/CH2Cl2 (3x).

Step 7: Cleavage The resin (approx. 60 mg, 0.045 mmol) in each well was treated with 0.50 mL of TFA/CH2CI2 (1: 5). The Robbins block was rotated for 30 min. The resin was washed with CH2Cl2 (3x 0.2 mL) and the filtrate collecte. This process was repeated to ensure complete cleavage from the resin.

Purification The entire library from the first cleavage iteration was purifie by reverse phase HPLC.

Based on HPLC analysis of 54 randomly chosen samples, the average purity of these compound was 98%. The average yield after purification was 3% (0.6 mg per well on average).

The recovered weight of each compound was determined by transferring the appropriate fraction (s) to a tared vial and removing the solvent in a Savant concentrator.

The preparative HPLC system used a Gilson 215 liquid robotics autosampler/fraction collector.

The chromatography utilized a three-pump system of Rainin pump heads equipped with 10 mL/min or 50 mL/min pump solvent delivery heads and a Gilson solvent mixing chamber. Two pumps were used for solvent delivery, and one was used for flushing the system at the completion of the series of chromatography runs. IJV absorbance was monitored using a Knauer variable wavelength IJV detector equipped with a 10 mm path length analytical flow cell. The entire system was controlled by Gilson Unipoint software v. 1.65 which was used for data acquisition and analysis.

Samples were prepared for injection by dissolving each in 1-2 mL MeOH and housing them in 96 deep-well microtiter plates (2 mL/well). No filtering was performed on those amples. Injections for the chromatography loaded the entire sample into a 2.0 mL injection loop installe on the Gilson 819/Rheodyne Injector Module.

The HPLC method used in this study is as follows: Column. YMC GuardPack C8 (20 X 50 mm, 5 Il, 120 A) Mobile A: water + 0.05% trifluoroacetic acid (TFA) Mobile B: acetonitrile Flow Rate. 10 mL/min Gradient: 10% B 0-2 min, 10-100% B 2-23 min, 100% B 23-25 min, re-equilibrate for 3 min Detection: W absorbance at 220 nm, Knauer LYV detector with 10 mm flow cell Fraction Collection: Gilson 215,15% AUFS threshold, 9 mL maximum/tube in 13 X 100 mm disposable tubes Mass Spectrometry The entire library was analyzed by mass spectrometry after reverse phase HPLC. All but five of the 85 recovered compound were positively identifie by a molecular ion peak.

Library Compound (Examples 10-1 to 10-80) The following compound were obtained in the library.

Table B Amount of Observed compound Ex. No. Compound Name M.W. Molecular ion (g) (after) (ES-) HPLC) (2 10-1 2-(carboxymethoxy)-5-{(2S)-2-[(3- 538.64 537.3 0.0010 cyclopentylpropanoyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-2 2-(carboxymethoxy)-5-{(2S)-2-{[(1- 538.64 537.3 0.0012 methylcyclohexyl)carbonyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-3 2-(carboxymethoxy)-5-{(2S)-2-[(2,5- 578.62 577.2 0.0013 dimethoxybenzoyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-4 5-{(2S)-2-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-oxo-3- 594.67 593.3 0.0022 [(4-phenylbutyl)amino]propyl}-2- (carboxymethoxy)benzoic acid 10-5 2-(carboxymethoxy)-5-{(2S)-2-[(2- 532.60 531.2 0.0008 methylbenzoyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-6 2-(carboxymethoxy)-5-{(2S)-2-[(3-fluorobenzoyl)amino]- 536.56 535.1 0.0006 3-oxo-3-[(4-phenylbutyl)amino]propyl}benzoic acid 10-7 2-(carboxymethoxy)-5-{(2S)-2-[(3,4- 587.46 585.0 0.0019 dichlorobenzoyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-8 2-(carboxymethoxy)-5-{(2S)-2-[(3- 548.59 547.2 0.0015 methoxybenzoyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-9 2-(carboxymethoxy)-5-{(2S)-2-[(3,4- 578.62 577.0 0.0008 dimethoxybenzoyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-10 2-(carboxymethoxy)-5-{(2S)-3-oxo-3-[(4- 608.65 607.2 0.0004 phenylbutyl)amino]-2-[(3,4,5- trimethoxybenzoyl)amino]propyl}benzoic acid 10-11 2-(carboxymethoxy)-5-{(2S)-2-[(3,5- 578.62 576.9 0.0001 dimethoxybenzoyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-12 5-{(2S)-2-[(4-bromobenzoyl)amino]-3-oxo-3-[(4- 597.47 596.8 0.0008 phenylbutyl)amino]propyl}-2-(carboxymethoxy)benzoic acid 10-13 2-(carboxymethoxy)-5-{(2S)-2-[(4-chloro-2- 583.04 581.0 0.0011 methoxybenzoyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-14 2-(carboxymethoxy)-5-{(2S)-2-{[4- 561.64 560.0 0.0004 (dimethylamino)benzoyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-15 2-(carboxymethoxy)-5-((2S)-3-oxo-3-[(4- 602.57 600.9 0.0003 phenylbutyl)amino]-2-{[4- (trifluoromethoxy)benzoyl]amino}propyl)benzoic acid 10-16 5-{(2S)-2-[(4-butoxybenzoyl)amino]-3-oxo-3-[(4- 590.68 589.2 0.0008 phenylbutyl)amino]propyl}-2-(carboxymethoxy)benzoic acid 10-17 5-{(2S)-2-[([1,1'-biphenyl]-4-ylcarbonyl)amino]-3-oxo-3- 594.67 539.0 0.0005 [(4-phenylbutyl)amino]propyl}-2- (carboxymethoxy)benzoic acid 10-18 5-{(2S)-2-[(4-acetylbenzoyl)amino]-3-oxo-3-[(4- 560.61 559.1 0.0005 phenylbutyl)amino]propyl}-2-(carboxymethoxy)benzoic acid 10-19 2-(carboxymethoxy)-5-((2S)-3-oxo-3-[(4- 586.57 585.0 0.0002 phenylbutyl)amino]-2-{[4- (trifluoromethyl)benzoyl]amino}propyl)benzoic acid 10-20 5-{(2S)-2-{[4-(tert-butyl)benzoyl]amino}-3-oxo-3-[(4- 574.68 573.1 0.0015 phenylbutyl)amino]propyl}-2-(carboxymethoxy)benzoic acid 10-21 2-(carboxymethoxy)-5-{(2S)-2-[(4- 532.60 531.1 0.0010 methylbenzoyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-22 2-(carboxymethoxy)-5-{(2S)-2-[(3-methoxy-4- 562.62 561.0 0.0005 methylbenzoyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-23 2-(carboxymethoxy)-5-{(2S)-3-oxo-3-[(4- 546.62 544.9 0.0006 phenylbutyl)amino]-2-[(3- phenylpropanoyl)amino]propyl}benzoic acid 10-24 2-(carboxymethoxy)-5-{(2S)-2-{[3-(4- 576.65 575.0 0.0001 methoxyphenyl)propanoyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-25 2-(carboxymethoxy)-5-[(2S)-3-oxo-2-[(4-oxo-4- 574.63 573.1 0.0007 phenylbutanoyl)amino]-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-26 2-(carboxymethoxy)-5-{(2S)-2-{[(1-methyl-1H-pyrrol-2- 521.57 520.1 0.0002 yl)carbonyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-27 5-{(2S)-2-[(5-bromo-2-furoyl)amino]-3-oxo-3-[(4- 587.43 585.0 0.0007 phenylbutyl)amino]propyl}-2-(carboxymethoxy)benzoic acid 10-28 2-(carboxymethoxy)-5-{(2S)-2-(2-naphthoylamino)-3- 568.63 567.0 0.0005 oxo-3-[(4-phenylbutyl)amino]propyl}benzoic acid 10-29 2-(carboxymethoxy)-5-((2S)-3-oxo-3-[(4- 630.62 628.9 0.0001 phenylbutyl]amino]-2-{[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]amino}propyl)benzoic acid 10-30 2-(carboxymethoxy)-5-{(2S)-2-{[(2R)-2-methoxy-2- 562.62 561.1 0.0005 phenylethanoyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-31 2-(carboxymethoxy)-5-{(2S)-2-{[2-(4- 566.59 565.2 0.0005 fluorophenoxy)acetyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-32 2-(carboxymethoxy)-5-{(2S)-3-oxo-2-[(2- 532.60 531.2 0.0004 phenylacetyl)amino]-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-33 2-(carboxymethoxy)-5-{(2S)-2-{[2-(2- 567.04 565.1 0.0013 chlorophenyl)acetyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-34 2-(carboxymethoxy)-5-{(2S)-2-{[2-(2- 562.62 561.0 0.0003 methoxyphenyl)acetyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-35 2-(carboxymethoxy)-5-{(2S)-2-{[2-(2- 546.62 545.2 0.0007 methylphenyl)acetyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-36 2-(carboxymethoxy)-5-{(2S)-2-{[2-(3- 567.04 565.1 0.0005 chlorophenyl)acetyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-37 2-(carboxymethoxy)-5-{(2S)-2-{[2-(3- 562.62 561.0 0.0001 methoxyphenyl)acetyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-38 2-(carboxymethoxy)-5-[(2S)-3-oxo-3-[(4- 600.59 599.0 0.0002 phenylbutyl)amino]-2-({2-[3- (trifluoromethyl)phenyl]acetyl}amino)propyl]benzoic acid 10-39 2-(carboxymethoxy)-5-{(2S)-2-{[2-(4- 567.04 565.0 0.0002 chlorophenyl)acetyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-40 2-(carboxymethoxy)-5-((2S)-2-{[2-(4- 562.62 561.0 0.0003 methoxyphenyl)acetyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-41 2-(carboxymethoxy)-5-[(2S)-3-oxo-3-[(4- 600.59 598.9 0.0002 phenylbutyl)amino]-2-({2-[4- (trifluoromethyl)phenyl]acetyl}amino)propyl]benzoic acid 10-42 2-(carboxymethoxy)-5-{(2S)-3-oxo-2-[(4- 560.65 559.1 0.0017 phenylbutanoyl)amino]-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-43 2-(carboxymethoxy)-5-{(2S)-2-{[4-(4- 590.68 589.1 0.0005 methoxyphenyl)butanoyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-44 2-(carboxymethoxy)-5-{(2S)-3-oxo-2-[(5-oxo-5- 588.66 586.9 0.0001 phenylpentanoyl)amino]-3-[(4- phenylbutyl)amino]propyl}benzoic acid 155-45 2-(carboxymethoxy)-5-{(2S)-3-oxo-3-[(4- 574.68 573.0 0.0001 phenylbutyl)amino]-2-[(5- phenylpentanoyl)amino]propyl}benzoic acid 10-46 2-(carboxymethoxy)-5-[(2S)-3-oxo-3-[(4- 580.72 579.1 0.0005 phenylbutyl)amino]-2-(10- undecenoylamino)propyl]benzoic acid 10-47 2-(carboxymethoxy)-5-{(2S)-2-{[(3-methyl-2- 538.62 537.0 0.0005 thienyl)carbonyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-48 2-(carboxymethoxy)-5-((2S)-3-oxo-3-[(4- 566.68 565.0 0.0004 phenylbutyl)amino]-2-{[4-(2- thienyl)butanoyl]amino}propyl)benzoic acid 10-49 2-(carboxymethoxy)-5-{(2S)-3-oxo-3-[(4- 524.59 523.0 0.0004 phenylbutyl)amino]-2-[(3- thienylcarbonyl)amino]propyl}benzoic acid 10-50 5-{(2S)-2-[(1,3-benzodioxol-5-ylcarbonyl)amino]-3-oxo- 562.58 561.1 0.0002 3-[(4-phenylbutyl)amino]propyl}-2- (carboxymethoxy)benzoic acid 10-51 2-(carboxymethoxy)-5-{(2S)-3-oxo-3-[(4- 569.62 568.0 0.0003 phenylbutyl)amino]-2-[(3- quinolinylcarbonyl)amino]propyl}benzoic acid 10-52 2-(carboxymethoxy)-5-{(2S)-3-oxo-2-{[(2-oxo-2H- 586.60 585.0 0.0007 chromen-3-yl)carbonyl]amino}-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-53 2-(carboxymethoxy)-5-{(2S)-2-{[4- 596.66 594.9 0.0001 (methylsulfonyl)benzoyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-54 2-(carboxymethoxy)-5-{(2S)-2-{[2-methoxy-4- 594.69 593.1 0.0013 (methylsulfanyl)benzoyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-55 2-(carboxymethoxy)-5-((2S)-3-oxo-3-[(4- 566.63 565.0 0.0004 phenylbutyl)amino]-2-{[2-(2- pyrimidinylsulfanyl)acetyl]amino}propyl)benzoic acid 10-56 2-(carboxymethoxy)-5-{(2S)-2-{[3-(4- 581.07 579.0 0.0002 chlorophenyl)propanoyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-57 2-(carboxymethoxy)-5-{(2S)-2-{[2-(3,5- 592.65 590.9 0.0001 dimethoxyphenyl)acetyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic aicd 10-58 5-{(2S)-2-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}-3- 590.63 589.1 0.0001 oxo-3-[(4-phenylbutyl)amino]propyl}-2- (carboxymethoxy)benzoic acid 10-59 2-(carboxymethoxy)-5-{(2S)-2-{[(6-methyl-2- 533.58 532.0 0.0000 pyridinyl)carbonyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-60 5-f (2S)-2- [ (1-acetyl-4-piperidinyl) carbonyl] amino}-3- 567.64 566.0 0.0002 | oxo-3- [ (4-phenylbutyl) amino] propyl}-2- carbox methox benzoic acid 10-61 2-(carboxymethoxy)-5-{(2S)-2-[(4-600.(carboxymethoxy)-5-{(2S )-2-[(4-600. 71 599.2 0.0014 99 9.01 cyclohexylbenzoyl)amino]-3-oxo-3- [ (4- hen Ibut I amino ro I benzoicacid 10-62 2- (carboxymethoxy)-5- { (2S)-2- { [ (5-chloro-2- 559. 04 557.0 0.0002 99 7.07 thienyl) carbonyl] aminol-3-oxo-3- [ (4- hen Ibut I amino ro I benzoic acid 10-63 2-(carboxymethoxy)-5-{(2S)-2-{[(3-methyl-1 H-inden-2-570. 64 569. 0 0. 0001 J 99 j 7. 44 yl)carbonyl] amino}-3-oxo-3-[(4- hen Ibut I amino ro I benzoic acid 10-64 2- (carboxymethoxy)-5-{(2S)-3-oxo-3-[(4-569. 62 568. 1 0.0011 96. 9 6. 4 phenylbutyl)amino]-2- [ (8- uinolin Icarbon I amino ro I benzoic acid l l 10-65 2- (carboxymethoxy)-5- { (2S)-2- { [ (3, 5-dimethyl-4- 537.57 536.0 0.0001 99 5.67 isoxazolyl) carbonyl] amino}-3-oxo-3- [ (4- hen Ibut I amino ro I benzoicacid 10-66 2- (carboxymethoxy)-5-J (2S)-2- { [ (2,4-dimethyl-1,3- 553.64 554.0 (ES+) 0.0001 | thiazol-5-yl) carbonyl] aminol-3-oxo-3- [ (4- hen Ibut I amino ro I benzoic acid l l 10-67 2- (carboxymethoxy)-5-{(2S)-2-{[3-(4-564. 61 563.1 0.0002 99 6. 75 fluorophenyl)propanoyljaminol-3-oxo-3- [ (4- hen Ibut I amino ro I benzoic acid 9-9--77.- 10-68 2- (carboxymethoxy)-5-{(2S)-2-{[(7-chloro-1-benzofuran-593. 03 590. 9 0.0007 99 7. 57 2-yl)carbonyl] amino}-3-oxo-3-[(4- hen Ibut I amino ro I benzoicacid 10-69 2- (carboxymethoxy)-5- ( (2S)-3-oxo-3- ( (4- 630.62 629.0 0.0004 | l X phenylbutyl)aminoj-2- { [ (2S)-3,3,3-trifluoro-2-methoxy-2- hen I ro ano I amino ro I benzoic acid _. 10-70 2-(carboxymethoxy)-5-((2S)-3-oxo-3-[(4- 592.69 591.1 0.009 phenylbutyl)amino]-2-{[(4,7,7-trimethyl-3- oxobicyclo[2.2.1]hept-2- yl)carbonyl]amino}propyl)benzoic acid 10-71 5-{(2S)-2-{[2-(3-acetyl-2,2- 580.68 579.1 0.0001 dimethylcyclobutyl)acetyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}-2-(carboxymethoxy)benzoic acid 10-72 5-{(2S)-2-[(1-adamantylcarbonyl)amino]-3-oxo-3-[(4- 576.69 575.2 0.0014 phenylbutyl)amino]propyl}-2-(carboxymethoxy)benzoic acid 10-73 2-(carboxymethoxy)-5-{(2S)-3-oxo-3-[(4- 512.56 511.1 0.0004 phenylbutyl0amino]-2-[(tetrahydro-3- furanylcarbonyl)amino]propyl}benzoic acid 10-74 2-(carboxymethoxy)-5-{(2S)-2-[(3-fluoro-2- 550.59 549.2 0.0020 methylbenzoyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-75 2-(carboxymethoxy)-5-{(2S)-2-{[(2,6-dimethoxy-3- 579.61 578.2 0.0029 pyridinyl)carbonyl]amino}-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-76 2-(carboxymethoxy)-5-{(2S)-2-[(2,3-dihydro-1,4- 576.61 575.0 0.0006 benzodioxin-2-ylcarbonyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl]-benzoic acid 10-77 2-(carboxymethoxy)-5-{(2S)-2-[(2-fluoro-5- 550.59 549.2 0.0007 methylbenzoyl)amino]-3-oxo-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-78 5-{(2S)-2-({2-[(1S,4S)bicyclo[2.2.1]hept-2- 550.65 549.1 0.0004 yl]acetyl}amino)-3-oxo-3-[(4-phenylbutyl)amino]propyl}- 2-(carboxymethoxy)benzoic acid 10-79 2-(carboxymethoxy)-5-{(2S)-3-oxo-2-[(2- 562.62 561.2 0.0009 phenoxypropanoyl)amino]-3-[(4- phenylbutyl)amino]propyl}benzoic acid 10-80 2-(carboxymethoxy)-5-{(2S)-3-oxo-2-({[(1R,2S,3S,4S)- 548.59 547.1 0.0012 5-oxotricyclo[2.2.1.0#2,6#]hept-3-yl]carbonyl}amino)-3- [(4-phenylbutyl)amino]propyl}benzoic acid EXAMPLE 11: Two-dimensional library of 5-substituted-2-carbomethoxybenzoic acids Scheme 4 HO 0 0 NHFmoc Zon i i H _NaOMe O \ OH3 Rt R3 + W I O DIC/HOBT O&H DMF 10 NaBH (OAC) 3 N'H + P Ste 1 Step 2 O OCH3H3 1 2 3 4 5 R3 R3 R3 N O N p H. N O 1) piperidine N'% % N'R2 H 0 H N v Step 4'/i TFA H O ZON z z 0 O p RZS02CI Step 6 0 OH Step 7 OH O OH Step 5 CH3 O'-OCH3H3 O'_OH O O CH3 O''OH 6 7 8 9

Chemistry Summary The combination solid-phase/solution-phase synthetic sequence was designed to prepare a 6x10 two-dimensional library of 5-substituted-2-carboxymethoxybenzoic acids in a 96-well format as illustrated in Scheme 4. The synthesis was based on the use of the AMEBA linker (acid sensitive methoxybenzaldehyde, 3), selected due to its ease of cleavage and versatility in the reductive amination step, and the intermediate 5, synthesized in a seven step sequence as described below. The key resin 3 was synthesized by treating Merrifield resin with 2-methoxy- 4-hydroxybenzaldehyde according to the literature procedure (Fivush, A. M.; Willson, T. M.

Tetrahedron Lett. 1997,38,7151. Sarantakis, D.; Bicksler, J. J. Tetrahedron Lett., 1997,38, 7325). The functionalized resin 3 was treated with the first diversity element, a primary amine, and sodium triacetoxyborohydride to provide six different secondary amine resins, 4.

Attachment of 5 to each individual resin was performed utilizing the standard conditions of DIC/HOBt in DMF. A deprotection/sulfonamide formation (Kim, S. W.; Hong, C. Y.; Lee, K.; Lee, E. J.; Koh, J. S. Bio. and Med. Chem. Lettes. 1998,8,735) protocol was followed to attach the next diversity element to give 7. Hydrolysis of the diester was then followed by removal of the products from the resin with 20% TFA/CH2CI2-

Intermediate Synthesis Scaffold 5 (see Scheme 4 above), (2S)-3- [3-ethyoxycarbonyl)-4- (2-ethoxy-2- oxoethoxy)phenyl]-2-{[(9H-fluoren-9-ylmethoxy) carbonyl] amino} propanoic acid, was prepared as described in Example 9 above.

Diversity Elements Chlorides(commerciallyavailable):N-TerminalSulfonyl Name Cpd# benzene sulfonyl chloride 18 2,4-difluorobenzene sulfonyl chloride 19 1-methylimidazole-4-sulfonyl chloride 20 4- (n-butoxy) benzene sulfonyl chloride 21 naphthalene sulfonyl chloride 22 2-nitrobenzene sulfonyl chloride 23 octane sulfonyl chloride 24 8-quinoline sulfonyl chloride 25 2,3,5,6-tetramethylbenzene sulfonyl chloride 26 trans- (3-styrene sulfonyl chloride 27 N-acetylsulfanilylchloride 28 benzo-2,1,3-thiadiazole-4-sulfonyl chloride 29 4-cyanobenzene sulfonyl chloride 30 3,4-dimethoxybenzene sulfonyl chloride 31

C-Terminal Amines: a) Commercially available: Name # n-amylamine 32 4-phenylbutylamine 33 b) Synthesized

Two of the six amines used in this library were commercially available, the remaining four amines 37a, 37b, 39 and 44 were prepared synthetically. Wolff-Kishner reduction of 4- (P- chlorophenyl)-4-oxobutanoic acid gave 4- (p-chlorophenyl) butanoic acid (35a) in 96% yield, which was converted to 36a (55%). 4- (p-Methoxyphenyl) butylamine (37b) was similarly synthesized with equal results from commercially available 35b. Benzyl ethylamine ether (39) was prepared in one step from ethanolamine and benzyl chloride in 10% yield.

4- (p-chlorophenyl) butanoic acid (35a). A mixture of 3- (4-chlorobenzoyl) propionic acid (34) (2.50 g, 12.0 mmol), KOH (s) (1.75 g, 31.2 mmol), and hydrazine monohydrate (1.25 mL, 25.8 mmol) in 12.5 mL of diethylene glycol was refluxed azeotropically at 120-130°C for 90 min to remove water. The rection mixture was then refluxed at 170°C for 3 h, cooled to RT, diluted with 12.5 mL of water, and poured into 15 mL 2.5 N HCl (aq). The precipate was filtered off, dissolve in CH2Cl2, and the solvent removed to give 35a (2.23 g, 96%) as a white solid. UV Xmax 223 (8980,95% ETHANOL) ; 1H NMR (400 MHz, CDCl3) 6 7.26 (d, J= 7 Hz, 2 H), 7.12 (d, J= 8 Hz, 2 H), 2.66 (t, J= 4 Hz, 2 H), 238 (t, J= 4 Hz, 2 H), 1.96 (m, 2 H); 13C NMR (CDCl3) 6 179.3,140.0,132.2,130.2,128.9,34.7,33.4,26.4; IR (drift) 3063 (s), 3051 (s), 2955 (s), 2923 (s,b), 2905 (s), 2814,2797,2493 (b), 2466,2413,2367 (b), 2321,1706 (s), 1492 (s), 1212 (s), cm-l; MS (EI) m/z (rel. intensity) 198 (M+, 22), 200 (7), 198 (22), 140 (32), 139 (17), 138 (99), 127 (15), 125 (48), 103 (10), 89 (13), 60 (9); HRMS (EI) calcd for 198.0448, found 198.0441.

4- (p-chlorophenyl) butanamide (36a). A mixture of 35a (1.880 g, 10.1 mmol) and thionyl chloride (3.0 mL, 40.9 mmol) in 15 mL CHOC13 was stirred at reflux (75°C) for 4 h. Solvent and excess thionyl chloride were removed in vacuo, and residue was twice diluted with 7.5 mL toluene and evaporated to remove traces of thionyl chloride. To a solution of the residue in 3 mL toluene was slowly added 9 mL of cold concentrated NH40H. The precipitate was filtered off and recrystallized in CHCl3/heptane to give 36a (1.02 g, 55%) as a white solid. UV #max 224 (9300,95% ETHANOL).'H NMR (400 MHz, CDCl3) 6 7.25 (d, J = 8 Hz, 2 H), 7.12 (d, J = 8

Hz, 2 H), 5 31 (s, 2H), 2.66 (t, J = 8 Hz, 2 H), 2.23 (t, J = 7 Hz, 2 H), 1.98 (in, 2 H); 13C NMR (CDCl3) 6 175.4,140.2,134.5,130.2,128.9,35.1,34.8,27.0; IR (drift) 3434,2948,2282 (w), 1901 (w), 1655 (s), 1607,1491,1420,1306,1094,1016,836 (s), 825,804,666, cm-1. Calcd for CloHl2ClNO: C, 60.76; H, 6.12; N, 7.09; Cl, 17.94. Found: C, 60.60; H, 6.11; N, 6.96.

4- (p-chlorophenyl) butylamine (37a). (Ali, F. E.; Dandridge, P. A.; Gleason, J. G.; Krell, R. D.; Kruse, C. H.; Lavanchy, P. G; Snader, K. M. J Med. Chem., 1982,25,947). To a stirred suspension of lithium aluminum hydrie (2.40 g, 63.2 mmol) in 65 mL diethyl ether was added slowly a solution of (3.12 g 15.8 mmol) of 36a in 28 mL THF, and stirred at rt for 1 h. To the rection mixture was slowly added 4 mL water, 4 mL 5 N NaOH (aq), and 12 mL water. The organics were removed from the mulsion which was dissolve in water and extracted with ether. The organic portions were dried over Na2SO4 (s), and condense to give 37a (2.76 g, 95%) as an oil. W 4lax 224 (7600,95% ETHANOL). 1H NMR (400 MHz, CDCl3) # 7.23 (ion, 2 H), 7.10 (d, J = 8 Hz, 2 H), 2.74 (t, J = 7 Hz, 2 H), 2.60 (t, J = 8 Hz, 2 H), 2.25 (s, 2 H), 1.64 (ion, 2 H), 1.49 (ion, 2 H). 13C NMR (CDCl3) 6 141.2,131.8,130.1,128.8,42.3,35.4,33.6,29.0; IR (liq.) 3365 (b), 3296 (b), 3026,2933 (s), 2858 (s), 2170 (w), 1996 (w), 1576,1492 (s), 1460, 1093 (s), 1016 (s), 831,821,804, crri 1 ; HRMS (FAB) calcd for CloHl4ClN +Hl 184.0893, found 184.0879.

4- (p-methoxyphenyl) butanamide (36b). A mixture of 4-(p-methoxyphenyl)butyric acid (35b) (6.50 g, 33.5 mmol) and thionyl chloride (10.0 mL, 137 mmol) in 50 mL CHOC13 was stirred at reflux for 5.5 h. Solvent and excess thionyl chloride were removed in vacuo, and residue was twice diluted with 25 mL toluene and evaporated to remove traces of thionyl chloride. To a solution of the residue in 10 mL toluene was added slowly 30 mL of cold concentrated NH40H.

The precipitate was filtered off and recrystallized in CHCl3/heptane to give 36b (3.68 g, 57%) as a white solid. W 4lax 223 (10200,95% EtOH) ; IH NMR (400 MHz, CDC13) # 7.10 (d, J = 9 Hz, 2 H), 6.84 (d, J = 9 Hz, 2 H), 5.44 (s, 2 H), 3.80 (s, 3 H), 2.63 (t, J = 7 Hz, 2 H), 2.23 (d, J = 8 Hz, 2 H), 1.96 (ion, 2 H); 13C NMR (CDC13) 6 175.5,158.3,133.8,129.7,114.2,55.6,35.4, 34.5,27.4; IR (drift) 3366 (s), 2479 (w), 2355 (w), 2285 (w), 2053 (w), 1993 (w), 1656 (s), 1628 (s), 1512 (s), 1416 (s), 1304 (s), 1243 (s), 1230 (s), 1031 (s), 838 (s), cm~l. Anal. Calcd for CIIH15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.42; H, 8.03; N, 7.24.

4- (p-methoxyphenyl) butylamine (37b). (Ali, F. E.; Dandridge, P. A.; Gleason, J. G.; Krell, R. D.; Kruse, C. H.; Lavanchy, P. G; Snader, K. M. J. Med. Chem., 1982,25,947). To a stirred suspension of lithium aluminum hydride (4.40 g, 116 mmol) in 120 mL diethyl ether was added dropwise a solution of 36b (5.60 g, 29.0 mmol) in 10 mL THF, and stirred at rt for 1 h. To the rection mixture was added 7.5 mL water, 7.5 mL 5 N NaOH (aq), and 20 mL water. The organics were removed from the mulsion which was dissolve in water and extracted with ether. The organic portions were dried over Na2SO4 (s), and condense to give 37b (5.10 g, 98%) as an oil. LJV, ax 223 (9410,95% EtOH). (400 MHz, CDCl3) 6 7.10 (d, J= 9 Hz, 2 H), 6.83 (d, J = 9 Hz, 2 H), 3.79 (s, 3 H), 2.71 (t, J = 7 Hz, 2 H), 2.58 (t, J = 7 Hz, 2 H), 1.63 (m, 2 H), 1.48 (ion, 2 H); IR (liq.) 2933 (s), 2856,2145 (w), 2059 (w), 1996 (w), 1612 (s), 1584,1513 (s), 1461,1442,1246 (s), 1178,1034 (s), 827,822, cm~ HRMS (FAB) calcd for CIIH17NO +Hl 180.1388, found 180.1387. /,,-.-NHBn NH. NaH/THF HO ~ 2. Benzyl chlonde w + w + HO (major) 38 39 40 41 2- (benzyloxy) ethylamine (39). (Hu, X. E.; Cassady, J. M. Synthetic Comm., 1995,25,907). To a solution of distille ethanolamine (38) (1. 81mL, 30.0 mmol) in 30 mL of dry THF, was added NaH (1.2 g 30.0 mmol) as a 60% dispersion in mineral oil, in small portions at rt. The mixture was stirred at reflux for 30 min., benzyl chloride (2.88 mL, 25.0 mmol) was added, and stirred at reflux for an additional 4.5 h. The mixture was cooled to rt, 10 mL water was added, and solvent evaporated in vacuo. The residue was partitioned between 1 N HCl (aq) and CH2C12. The aqueous layer was extracted with CH2C12 to remove side product 40. The aqueous portion was adjusted to pH 13 with 10% NaOH (aq) and extracted with CH2Cl2. The extracts were condense and purifie by flash chromatography (10% MeOH (saturated with NH3)/CH2Cl2) to give 39 (0.24 g, 10%) as a yellow oil. Rf(10% MeOH (saturated with NH3)/CH2Cl2) = 0.47; UV #max 251 (162,95% ETHANOL); 1H NMR (400 MHz, (CDCl3) # 7.31 (m, 5 H), 4.55 (s, 2 H), 3.53 (t, J = 5 Hz, 2 H), 2.90 (t, J = 5,2 H), 1.68 (s, 2 H) ; 13C NMR (CDC13) 6 138.7,128.8,128.1,128.0, 73.5,72.9,42.3; IR (liq.) 3371,3302 (b), 3030,2924 (b), 2860 (s), 2202 (w), 1955 (w), 1496, 1453 (s), 1356,1101 (s), 1069,1028,739 (s), 698 (s), cm~l. HRMS (FAB) calcd for C9HI3NO +HI 152.1075, found 152.1074.

3-Phenoxypropylphthalimide (44). A mixture of 7.41 g (40.0 mmol) of potassium phthalimide and 6.30 mL (40.0 mmol) of 3-phenoxypropylbromide in 100 mL DMF was stirred at reflux (165°C) under N2 (g) for 90 min. Mixture was cooled and filtered, filtrate was condense in vacuo. Residue was recrystallized from 95% ethanol to give 44 (6.68 g, 58%) as a white solid.

W Xmax 222 (41700,95% ETHANOL). 1H NMR (400 MHz, CDCl3) # 7.85 (ion, 2 H), 7.72 (ion, 2H), 7.24 (t, J = 10 Hz, 2 H), 6.92 (t, J=7Hz, 4H), 6.82 (d, J=4Hz, 2H), 4.03 (t, J=6Hz, 2 H), 3.92 (t, J = 4 Hz, 2 H), 2.20 (t, J = 3 Hz, 2 H); 13C NMR (CDCl3) # 168.7,134.7,134.3, 132.6,129.7,124.0,123.6,121.1,114.9,65.9, 35. 9,28.7; IR (drift) 2474 (w), 2431 (w), 2417 (w), 2339 (w), 2305 (w), 1770,1705 (s), 1600,1397,1388,1249 (s), 1233,756,721 (s), 712, crri 1. HRMS (FAB) calcd for C17Hl5NO3+Hl 282.1130, found 282.1129.

3-Phenoxypropylamine hydrochloride (45). (Lever, O. W., Jr.; Bell, L. N.; McGuire, H. M.; Ferone, R. J Med. Chem., 1985,281,1873). A mixture of 6.95 g (24.8 mmol) of 44 and 3.12 mL (99.3 mmol) of 98% hydrazine in 80 mL 95% ethanol was stirred at reflux (85°C) under N2 (g) for 3 h. Mixture was cooled and white precipitate was dissolve in 250 mL water, mixed with 20 mL 10% NaOH (aq), extracted with diethyl ether. Ether extracts were washed with water, acidifie with 60 mL 1 N HCl (aq), and condense in vacuo. Residue was recrystallized from ethanol-ether to give 45 (2.02 g, 43%) as a white solid. LJV,. 222 (41700,95% ETHANOL). 1H NMR (400 MHz, DMSO-d6) 8 8.00 (s), 7.29 (t, J= 4 Hz, 2 H), 6.93 (ion, 3 H), 4.05 (t, J= 3 Hz, 2 H), 3.31 (s, 2 H), 2.94 (s, 2 H), 2.02 (ion, 2 H) ; 13C NMR (DMSO-d6) # 159.1,130. 3,121.5,115.3,65.3,37.1,27.7; IR (drift) 3036 (s), 3029 (s, b), 3009 (s, b), 2963 (s, b), 2938 (s), 2925 (s), 2428 (w), 2351 (w), 2256 (w), 2203 (w), 2052 (w), 1598 (s), 1258 (s), 749 (s), 696 (s), cm-1. Anal. Calcd for C9Hl3NO. HCI: C, 57.60; H, 7.52; N, 7.46; Cl, 18.89. Found: C, 57.45; H, 7.75; N, 7.36.

Library Synthesis The production of the library required seven steps using solid support. Three steps were carried out in a 96 well format. The AMEBA (acid sensitive methoxy benzaldehyde) linker was prepared by reacting Merrifield resin and 4-hydroxy-2-methoxybenzaldehyde with sodium methoxide (see Scheme 4). The AMEBA resin was then treated with the corresponding amine and NaBH (OAc) 3 to give the corresponding reductive animation product. The tyrosine scaffold (5) was then coupled to the various amine resins using DIC and HOBT in DMF. The Fmoc protecting group was then removed with piperidine/DMF (1: 1). The resin was then plated in a 96 well Robbins block then coupled to the corresponding sulfonyl chloride with DIEA in CH2CI2. The diethyl ester was hydrolyzed with excess LiOH inTHF: MeOH (1: 1) for 16 h at rt to yield the dicarboxylic acid on resin. The use of THF: MeOH (1 : 1) is believed to be crucial for this hydrolysis. The product was then cleaved from the resin with 20% TFA/CH2Cl2 solution. The resin was cleaved twice to yield the maximum possible product. The second cleavage resulted in approximately 10-20% more product without any change in purity levels.

Step 1: Preparation of AMEBA Linker A suspension of Merrifield resin (2.10g, 3.47 mmol) in 50 mL of DMF was treated with solid sodium methoxide (560 mg, 10.4 mmol). To the solution was added 4-hydroxy-2-methoxybenzaldehyde (1.58 g, 10.4 mmol). The rection mixture was heated to 60-70°C for 24 h. The resin was then washed with DMF, MeOH, water, MeOH, CHZC12, and MeOH (3x 10 mL). IR indicated strong absorption at 1681 cm~l.

Step 2: Reductive Amination A suspension of AMEBA (1.04g 1.12 mmol) in 25 mL of C2H4CI2 was treated with phenylbutyl amine (0.36 mL, 2.3 mmol) and NaBH (OAc) 3 (479 mg, 2.26 mmol). The rection mixture was stirred at rt for 3 h. The resin was then washed with CH- 2CI2, DMF, MeOH and CH2C12 (3x 10 mL). IR indicated disappearance of strong absorption at 1681 cri'.

Step 3: Coupling Resin to Intermediate 5 A suspension of resin (734 mg, 0.751 mmol) in 20 mL of DMF was treated with tyrosine scaffold 5 (632 mg, 1.13 mmol), hydroxybenzotriazole (HOBT) (24 mg, 0.18 mmol), diisopropyl carbodiimide (DIC) (175 pL, 1.12 mmol). The rection mixture was stirred at rt for 2 h. The resin was tested for the presence of any secondary amine using the choranil test. A sample of resin 1-5 mg was mixed with one drop of 2% acetaldehyde in DMF and one drop of 2% chloranil in DMF. After 5 min the resin showed no

color change; a control containing a secondary amine stained blue (Vojkovsky T. Peptide Research 1995,4,236). The resin was washed with DMF, CH2Cl2, MeOH, CH2Cl2 (3x 10 mL).

Step 4: Fmoc Removal Resin (1.14 g, 0.751 mmol) was suspende in 10 mL of piperidine/ DMF (1: 5) and stirred for 30 min. at rt. The resin was washed with DMF, CH2Cl2, MeOH, CH- 2C12 (3x 10 mL).

Step 5: Coupling Resin to Sulfonyl Chloride The resin was plated in a 96 well Robbins block (approx. 62 mg, 0.045 mmol), added to each well as a slurry in DMF/CH2Cl2. The resin was filtered and dried. Standard solutions of sulfonyl chloride (0.9 M in CH2Cl2) and DIEA (1.8 M in CH2Cl2) were prepared. To the resin in each well was added 0.5 mL CH2Cl2,0.25 mL DIEA solution, and then 0.25 mL of the standard sulfonyl chloride solution. The Robbins block was then rotated at rt for 2.5 h. The resin was filtered and washed with CH2Cl2, DMF, MeOH (2x 1 mL), then 1 mL CH2C12.

Step 6: Hydrolysis of Esters A standard solution of LiOH (0.9 M in 1: 1 THF/MeOH) was prepared. The resin in each well was treated with 1 mL of standard LiOH solution. The Robbins block was rotated at rt for 16 h.

The resin was filtered and washed with CH2Cl2, DMF, MeOH (2x 1 mL), then 1 mL CH2Cl2.

Step 7: Cleavage The resin (approx. 62 mg, 0.045 mmol) in each well was treated with 0.50 mL of TFA/ CH2Cl2 (1: 5). The Robbins block was rotated for 30 min. The resin was washed with CH2Cl2 (0.75 mL) collecting the filtrate. Resin was rinsed a second time into a second collection plate with CH2Cl2 (1.0 mol).

Purification The entire library was purifie by reverse phase HPLC. Half of the library was, however, lost during purification. The average purity, based on four original and six different standards, after purification of the library average purity was 75#13% by analytical HPLC. The average yield after purification was 10% (1-2 mg per well on average). The preparative HPLC system used a Gilson 215 liquid robotics autosampler/fraction collector. The chromatography utilized a

three-pump system of Rainin pump heads equipped with 10 mL/min or 50 mL/min pump solvent delivery heads and a Gilson solvent mixing chamber. Two pumps were used for solvent delivery, and one was used for flushing the system at the completion of the series of chromatography runs : UV absorbance was monitored using a Knauer variable wavelength W detector equipped with a 10 mm path length analytical flow cell. The entire system was controlled by Gilson Unipoint software v. 1.65 which was used for data acquisition and analysis.

Samples were prepared for injection by dissolving each in 1 mL MeOH and housing them in 96-well microtiter plates (2 mL/well). Injections for the chromatography loaded the entire sample into a 2.0 mL injection loop installe on the Gilson 819/Rheodyne Injector Module.

The HPLC method used in this study is as follows: Column. YMC GuardPack C8 (20 X 50 mm, 5,120 A) Mobile A: water + 0.05% trifluoroacetic acid (TFA) Mobile B: acetonitrile Flow Rate. 10 mL/min Gradient: 10% B 0-2 min, 10-100% B 2-23 min, 100% B 23-25 min, re-equilibrate for 3 min Detection: LJV absorbance at 220 nm, Knauer LJV detector with 10 mm flow cell Fraction Collection: Gilson 215,15% AUFS threshold, 9 mL maximum/tube in 13 X 100 mm disposable tubes Mass Spectrometry Each of the recovered compound was analyzed by mass spectrometry after reverse phase HPLC. Only 28 compound having a covered mass greater than 0.1 mg were positively identifie by a molecular ion peak.

Library Compound (Examples 11-1 to 11-28) The following compound were obtained in the library Table C Fln MS (ES+) Mass HPL Ex. No. Compound Name Mol Wt. lon Recovered, Purity Observed g 220 11-1 2-(carboxymethoxy)-5-((2S)-3-{[4-(4- 625.05 626.3 0.0014 chlorophenyl)butyl]amino}-2-{[(2,4- difluorophenyl)sulfonyl]amino}-3-oxopropyl)benzoic acid 11-2 5-((2S)-2-{[(4-butoxyphenyl)sulfonyl]amino]-3-{[4-(4- 661.17 662.4 0.0015 chlorophenyl)butyl]amino}-3-oxopropyl)-2- (carboxymethoxy)benzoic acid 11-3 2-(carboxymethoxy)-5-{(2S)-3-{[4-(4- 639.13 640.3 0.0018 chlorophenyl)butyl]amino}-2-[(1-naphthylsulfonyl)amino]-3- oxopropyl}benzoic acid 11-4 2-(carboxymethoxy)-5-((2S)-3-{[4-(4- 634.06 635.3 0.0015 chlorophenyl)butyl]amino}-2-{[(2- nitrophenyl)sulfonyl]amino}-3-oxopropyl)benzoic acid 11-5 2-(carboxymethoxy)-5-{(2S)-3-{[4-(4- 640.11 641.2 0.0018 chlorophenyl)butyl]amino}-3-oxo-2-[(8- quinolinylsulfonyl)amino]propyl}benzoic acid 11-6 2-(carboxymethoxy)-5-((2S)-3-{[4-(4- 645.17 646.4 0.0009 78.31 chlorophenyl)butyl]amino}-3-oxo-2-{[(2,3,5,6- tetramethylphenyl)sulfonyl]amino}propyl)benzoic acid 11-7 2-(carboxymethoxy)-5-[(2S)-3-{[(4-(4- 615.10 616.3 0.0009 59.93 chlorophenyl)butyl]amino}-3-oxo-2-({[(E)-2- phenylethenyl]sulfonyl}amino)propyl]benzoic acid 11-8 2-(carboxymethoxy)-5-{(2S)-3-{[4-(4- 584.65 585.2 0.0014 82.81 methoxyphenyl)butyl]amino}-3-oxo-2- [(phenylsulfonyl)amino]propyl}benzoic acid 11-9 2-(carboxymethoxy)-5-((2S)-2-{[(2,4- 620.63 621.2 0.0018 83.33 difluorophenyl)sulfonyl]amino}-3-{[4-(4- methoxyphenyl)butyl]amino}-3-oxopropyl)benzoic acid 11-10 5-((2S)-2-{[(4-butoxyphenyl)sulfonyl]amino}-3-{[4-(4- 656.75 657.2 0.0015 methoxyphenyl)butyl]amino}-3-oxoipropyl)-2- (carboxymethoxy)benzoic acid 11-11 2-(carboxymethoxy)-5-{(2S)-3-{[4-(4- 634.71 635.2 0.0010 methoxyphenyl)butyl]amino}-2-[(1-naphthylsulfonyl)amino]- 3-oxopropyl}benzoic acid 11-12 2-(carboxymethoxy)-5-((2S)-3-{[4-(4- 629.65 630.1 0.0011 methoxyphenyl)butyl]amino}-2-{[(2- nitrophenyl)sulfonyl]amino]-3-oxopropyl)benzoic acid 11-13 2-(carboxymethoxy)-5-{(2S)-3-{[4-(4- 635.70 636.2 0.0020 71.51 methoxyphenyl)butyl]amino}-3-oxo-2-[(8- quinolinylsulfonyl)amino]propyl}benzoic acid 11-14 2-(carboxymethoxy)-5-((2S)-3-{[4-(4- 640.76 641.2 0.0012 methoxyphenyl)butyl]amino]-3-oxo-2-{[(2,3,5,6- tetramethylphenyl)sulfonyl]amino}propyl)benzoic acid 11-15 2-(carboxymethoxy)-5-[(2S)-3-{[4-(4- 610.69 611.2 0.0011 methoxyphenyl)butyl]amino}-3-oxo-2-({[(E)-2- phenylethenyl]sulfonyl}amino)propyl]benzoic acid 11-16 2-(carboxymethoxy)-5-{(2S)-3-oxo-3-[(3- 556.59 557.2 0.0012 phenoxypropyl)amino]-2- [(phenylsulfonyl)amino]propyl]benzoic acid 11-17 2-(carboxymethoxy)-5-{(2S)-2-{[(2,4- 592.57 593.1 0.0002 difluorophenyl)sulfonyl]amino}-3-oxo-3-[(3- phenoxypropyl)amino]propyl}benzoic acid 11-18 5-{(2S)-2-{[(4-butoxyphenyl)sulfonyl]amino}-3-oxo-3-[(3- 628.70 629.2 0.0010 98.74 phenoxypropyl)amino]propyl}-2-(carboxymethoxy)benzoic acid 11-19 2-(carboxymethoxy)-5-{(2S)-2-[(1- 606.65 607.2 0.0007 naphthylsulfonyl)amino]-3-oxo-3-[(3- phenoxypropyl)amino]propyl}benzoic acid 11-20 2-(carboxymethoxy)-5-{(2S)-2-{[(2- 601.59 602.1 0.0010 95.31 nitrophenyl)sulfonyl]amino}-3-oxo-3-[(3- phenoxypropyl)amino]propyl}benzoic acid 11-21 2-(carboxymethoxy)-5-((2S)-3-oxo-3-[(3- 612.70 613.2 0.0006 phenoxypropyl)amino]-2-{[(2,3,5,6- tetramethylphenyl)sulfonyl]amino}propyl)benzoic acid 11-23 5-{(2S)-3-{[2-(benzyloxy)ethyl]amino}-3-oxo-2- 556.59 557.2 0.0012 [(phenylsulfonyl)amino]propyl}-2-(carboxymethoxy)benzoic acid 11-24 5-((2S)-3-{[2-(benzyloxy)ethyl]amino}-2-{[(2,4- 592.57 593.1 0.0004 difluorophenyl)sulfonyl]amino}-3-oxopropyl)-2- (carboxymethoxy)benzoic acid 11-25 5-{(2S)-3-{[2-(benzyloxy)ethyl]amino}-2-[(1- 606.65 607.1 0.0002 85.21 naphthylsulfonyl)amino]-3-oxopropyl}-2- (carboxymethoxy)benzoic acid 11-26 5-((2S)-3-{[2-(benzyloxy)ethyl]amino}-2-{[(2- 601.59 602.2 0.0008 nitrophenyl)sulfonyl]amino}-3-oxopropyl)-2- (carboxymethoxy)benzoic acid 11-27 5-{(2S)-3-{[2-(benzyloxy)ethyl]amino}-3-oxo-2-[(8- 607.64 608.2 0.0003 quinolinylsulfonyl)amino]propyl}-2- (carboxymethoxy)benzoic acid 11-28 5-((2S)-3-{[2-(benzyloxy)ethyl]amino}-3-oxo-2-{[(2,3,5,6- 612.70 613.2 0.0002 tetramethylphenyl)sulfonyl]amino}propyl)-2- (carboxymethoxy)benzoic acid

EXAMPLE 12 General Methods. NMR spectra were recorde on a Varian spectrometer and chemical shifts are given in ppm using CD30D d 3.31 as an internal standard at 25 °C. Only selected data are reporte. HPLC analysis was performed using a Hypersil C-18 column (50 x 4.6 mm, 3 m) with a flow of 1 ml/min on a HP 1100 system with monitoring at 214 and 254 mu.

For preparative HPLC purification a Vydac C-18 column (250 x 22 mm, 10u) was used on a Gilson system with a flow of 15 ml/min. LCMS chromatograms and spectra were recorde on a Perkin Elmer Sciex system using a YMC-Pack FL-ODS column (50 x 4.6 mm, 5 u, 120A) with a flow of 4 ml/min. IR spectra were recorde on a Perkin Elmer Spectrum 1000 FTIR spectrometer. HRMS and FRMS spectra were recorde on a LCT instrument with electrospray.

Synthetic Method A. (2S)-2- ( { (2S)-2- [ (tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2- oxoethoxy) phenyl] propanoic acid (100 mg, 0.18 mmol) was weighed into 10 screw-capped tubes and dissolve in dichloromethane (500 uL). 1-Hydroxybenzotriazole (0.23 mmol) in dimethylformamide (100 uL) was added to each tube followed by a set of 10 amines (0.29 mmol). The mixtures were cooled in an ice bath and 1-ethyl-3- (3-dimethylamino- propyl) carbodiimide hydrochloride (0.23 mmol) in dichloromethane (2 mL) was added to each tube. The mixtures were left in room temperature for 3h and were then applied on small silica gel columns (5 ml) packed in dichloromethane. The products were eluted with dichloromethane followed by, dichloromethane-acetonitrile (1: 1) and finally acetonitrile. The amide containing fractions were concentrated and dried under vacuum. The amides were then dissolve in tetrahydrofuran-methanol (2: 1,3 mL) and sodium hydroxide (1.5 mL, 2%, aq) was added. The mixtures were shaken at room temperature 5-7 h. Acetic acid (40 uL) was added and the mixtures were concentrated until approximately 2 mL was left in each tube.

The materials were analyzed by HPLC and LC-MS and were then purifie by reverse phase HPLC (Vydac C-18 column) using acetonitrile-water gradients containing 0.1 % trifluoroacetic acid. After HPLC analysis the purest fractions were collecte and lyophilized.

Synthetic Method B. To eight solutions of (2S)-2-( {(2S)-2-[(tert- butoxycarbonyl) amino]-3-phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy- 2-oxoethoxy) phenyl] propanoic acid (100 mg, 0.18 mmol) in dichloromethane (500 uL) in

screw-capped tubes was added a set of eight amines (0.29 mmol). 1-Hydroxybenzotriazole (0.23 mmol) in dimethylformamide (100 uL) was added and the mixtures were cooled in an ice bath. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 mmol) in dichloromethane (2 ml) was added to each tube and the rection mixtures were left in room temperature over night. The mixtures were then applied on small silica gel columns (6 ml) packed in chloroform. The products were eluted with a step-wise chloroform-methanol gradient. The amide containing fractions were concentrated and dried under vacuum. The amides were then dissolve in methanol (1 mL) and sodium hydroxide (1.2 mL, 2%, aq) was added. When necessary tetrahydrofuran (500 uL) was added. The mixtures were left in room temperature for 5-7 h. Dowex H+ was added and after analysis by HPLC and LC/MS the materials were purifie by reverse phase HPLC (Vydac C-18 column) using acetonitrile- water gradients. After HPLC analysis the purest fractions were collecte and lyophilized.

Synthetic Method C. (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (typically 100 mg, 1 eq) was weighed into 10 screw-capped tubes and dissolve in dichloromethane (500 uL). A set of 10 amines (1.2 eq) was dissolve in dichloromethane (1 mL) and triethylamine (2 equivalents to the amines) was added. The amine solutions were added to the carboxylic acid solutions and the mixtures were cooled in an ice bath. 1- Hydroxybenzotriazole (1.2 eq) in dimethylformamide (100 uL) was added followed by 1-ethyl- 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 mmol) in dichloromethane (2 mL).

The mixtures were left in room temperature over night. The mixtures were then applied on small silica gel columns (5-7 ml) packed in chloroform. The products were eluted with a stepwise chloroform-methanol gradient. The amide containing fractions were concentrated and dried under vacuum. The amides were then dissolve in tetrahydrofuran-methanol (1: 1,2 mL) and sodium hydroxide (1 mL, 2%, aq) was added. The mixtures were left in room temperature over night. Dowex H+ was added and the mixtures were concentrated until approximately 2 mL was left. The materials were either lyophilized directly or purifie by reverse phase HPLC (Vydac C-18 column) using acetonitrile-water gradients. After HPLC analysis the purest fractions were collecte and lyophilized.

Example 12-1: 5-{(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3-oxo-3- [ (3-phenylpropyl) amino] propyl}-2- (carboxymethoxy) benzoic acid

Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid and 3-pnenylpropylamine (41 uL) according to Method A to give the title compound (48 mg). IH-NA4R (400 MHz, CD30D) d 7.79 (s, 1H), 7.40 (d, J=8.5 Hz, 1 H), 7.26-7.13 (m, 10H), 6.99 (d, J=8.5 Hz, 1H), 4.72 (s, 2H), 4.52 (t, J=6.8 Hz, 1H), 4.25 (dd, J=5.3 Hz, J=9.2 Hz, 1H), 3.18 (m, 1H), 3.09-2.92 (ion, 4H), 2.77 (dd, J=9.5 Hz, J=13.5 Hz, 1H), 2.50 (t, J=7.7 Hz, 2H), 1.69 (ion, 2H), 1.34 (s, 9H); IR (KBr) 3302,2926,1736,1686,1646 cm-1 ; HRMS m/z 647.2823 (calc. of monoisotopic mass for C35H41N3O9 gives 647.2823).

Example 12-2: 5-{(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-oxo-3-[(4-phenylbutyl)amino]propyl} -2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2- oxoethoxy) phenyl] propanoic acid and 4-phenylbutylamine (46 uL) according to Method A to give the title compound (34 mg). 1H-NMR (400 MHz, CD30D) d 7.76 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.26-7.11 (m, 10H), 6.98 (d, J=8.5 Hz, 1H), 4.76 (s, 2H), 4.50 (t, J=6.9 Hz, 1H), 4.23 (dd, J=5.2 Hz, J=9.3 Hz, 1H), 3.17 (m, 1H), 3.09-2.91 (ion, 4H), 2.75 (dd, J=9.4 Hz, J=13.6 Hz, 1H), 2.58 (t, J=7.5 Hz, 2H), 1.54 (ion, 2H), 1.42 (m 2H), 1.34 (s, 9H); IR (KBr) 3296,2925,1738,1687,1643 cm-1; HRMS m/z 661.2987 (calc. of monoisotopic mass for C36H43N3O9 gives 661.2999).

5-{(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3-Example 12-3: phenylpropanoyl} amino)-3- [ (2-hydroxyethyl) amino]-3-oxopropyl}-2- (carboxymethoxy) benzoic Synthesis was performed from PNU-181049 and ethanolamine (18 uL) according to Method A to give the title compound (58 mg). 1H-NMR (400 MHz, CD30D) d 7.76 (s, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.27-7.17 (m, 5H), 7.02 (d, J=8.5 Hz, 1H), 4.80 (s, 2H), 4.55 (m, 1H), 4.24 (dd, J=5.0 Hz, J=9.4 Hz, 1H), 3.52 (ion, 2H), 3.25 (ion, 2H), 3.10 (dd, J=6.1 Hz, J=13.7 Hz, 1H), 3.02 (dd, J=4.9 Hz, J=13.9 Hz, 1H), 2.95 (dd, J=7.9 Hz, J=13.8 Hz, 1H), 2.74 (dd, J=9.5 Hz, J=13.4 Hz, 1H), 1.35 (s, 9H); IR (KBr) 3339,3298,2961,1743,1714,

1686 cm~l; HRMS m/z 573.2325 (calc. of monoisotopic mass for C28H35N3010 gives 573.2322).

Example12-4:-{(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino ]-3- phenylpropanoyl} amino)-3-[(2,[(2, 3-dihydroxypropyl) aminol-3-oxopropyll-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2- oxoethoxy) phenyl] propanoic acid and 3-amino-1,2-propanediol 22 (uL) according to Method A to give the title compound (46 mg). 1H-NMR (400 MHz, CD30D) d 7.78 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.28-7.20 (m, 5H), 7.03 (d, J=8.5 Hz, 1H), 4.81 (s, 2H), 4.57 (in, IH), 4.24 (dd, J=4.8 Hz, J=9.3 Hz, 1H), 3.69-3.56 (ion, 2H), 2.74 (dd, J=9.0 Hz, J=13.4 Hz, 1H), 1.34 (s, 9H); IR (KBr) 3292,2932,1686,1652 cm-1 ; HRMS m/z 603.2412 (calc. of monoisotopic mass for C29H37N3011 gives 603.2428).

Example 12-5: Disodium 5-{(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-oxo-3-[(1-phenylethyl)amino]propyl} -2-(2-oxido-2- oxoethoxy) benzoate Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyll amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid and 1-phenylethylamine (38 uL) according to Method A to give a material which was re- purifie by reverse phase C-18 HPLC in absence of trifluoroacetic acid and then passed through a column with Dowex Na+. After lyophilizing, the title compound (34 mg) was obtained as a diasteromeiic mixture with a 2: 1 ratio of the components (HPLC). (KBr) 3291, 2971,1691,1642 cm-3; HRMS m/z 633.2682 (cale. of monoisotopic mass for C34H39N309 gives 633.2686).

Example 12-6: 5-((2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino-3-{[1-(hydroxymethyl)pentyl]amino}-3-o xopropyl)-2- (carboxymethoxy) benzoic acid

Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2 - oxoethoxy) phenyl] propanoic acid and D, L-2-amino-1-hexanol (37 uL) according to Method A with the difference that after the hydrolysis, the rection mixture was neutralized by Dowex H+. Thereafter the obtained solution was lyophilized to give the title compound (95 mg) as a diasteromeric mixture with a 1: 1 ratio of the components (HPLC). 1H-NMR (400 MHz, CD30D) d 7.76 (s, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.27-7.17 (m, 5H) 7.02 (d, J=8.5 Hz, 1H), 4.82 (s, 2H), 4.51 (t, J=6.8 Hz, 1H), 4.23 (m, 1H), 3.16 (m, 1H), 2.76 (dd, J=9.3 Hz, J=13.8 Hz, 1H), 1.51 (ion, 2H), 1.34 (s, 9H); (KBr) 3293,2931,1689,1645 cm-1 ; HRMS m/z 629.2943 (calc. of monoisotopic mass for C32H43N3O10 gives 629.2948).

Example 12-7: 5-[(2S)-3-(Benzylamino)-2-({(2S)-2-[(tert-butoxycarbonyl)ami no]-3-phenyl- propa-noyl} amino)-3-oxopropyl)-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid and benzylamine (31 µL) according to Method A to give a material which was re-purified by reverse phase C-18 HPLC in absence of trifluoroacetic acid to give the title compund (29 mg). 1H-NMR (400 MHz, CD30D) d 7.78 (s, 1H), 7.36 (dd, J=2.0 Hz, J=8.6 Hz, 1H), 7.30-7.13 (m, 10H), 6.96 (d, J=8.5 Hz, 1H), 4.79 (s, 2H), 4.58 (t, J=6.9 Hz, 1H), 3.11-2.94 (ion, 4H), 2.76 (dd, J=10 Hz, J=13.4 Hz, 1H), 1.33 (s, 9H); IR (KBr) 3304,2979,1694,1640 crri 1 ; HRMS m/z 619.2511 (calc. of monoisotopic mass for C33H37N309 gives 619. 2530).

Example 12-8: 5-{(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-[(6-hydroxyhexyl)amino]-3-oxopropyl }-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-( {(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2- oxoethoxy) phenyl] propanoic acid and 6-amino-1-hexanol (34 mg) according to Method A to give the title compound (64 mg). 1H-NMR (400 MHz, CD30D) d 7.79 (s, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.27-7.18 (ion, 5H), 7.02 (dd, J=7.0 Hz, J=8.5 Hz, 1H), 4.80 (s, 2H), 4. 57 (m, 1H), 4.25 (dd, J=4.8 Hz, J=9.5 Hz, 1H), 3.77 (m, 1H), 2.74 (dd, J=10.2 Hz, J=13.2 Hz, 1H), 1.34 (s, 9H); IR (KBr) 3291,2932,1691,1647 cm~l; HRMS m/z 629.2948 (calc. of monoisotopic mass for C32H43N3010 gives 629.2948).

Example 12-9: 5-((2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-{[(1R)-1-(hydroxymethyl)-3-methylbu tyl]amino}-3- oxopropyl)-2-(carboxymethoxy)benzoicacid Synthesis was performed from (2S)-2- ( { (2S)-2- [ (tert-butoxycarbonyl) amino]-3- phenylpropanoyl) amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2- oxoethoxy) phenyl] propanoic acid and D-leucinol (37 uL) according to Method A to give the title compund (51 mg), 1H-NMR (400 MHz, CD30D) d 7.79 (s, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.29-7.18 (m, 5H), 7.04 (d, J=8.5 Hz, 1H), 4.80 (s, 2H), 4.55 (t, J=7.0 Hz, 1H), 4.25 (dd, J=4.8 Hz, J=9.5 Hz, 1H), 3.86 (m, 1H), 2.75 (dd, J=9.5 Hz, J=13.5 Hz, 1H), 1.35 (s, 9H), 0.82 (ion, 6H); IR (KBr) 3312,2958,1639 crri 1 ; HRMS m/z 629.2926 (calc. of monoisotopic mass for C32H43N3O10 gives 629.2948).

Example5-[(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-oxo-3-(phenethylamino)propyl]-2-(ca rboxymethoxy)benzoic acid Synthesis was performed performed from (2S)-2-( {(2S)-2-[(tert- butoxycarbonyl) amino]-3-phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2- oxoethoxy) phenyl] propanoic acid and phenetylamine (38 uL) according to Method A to give the title compound (57 mg). 1H-NMR (400 MHz, CD30D) d 7.76 (s, 1H), 7.36 (dd, J=1.9 Hz, J=8.3 Hz, 1H), 7.28-7.15 (m, 10H), 7.00 (d, J=8.7 Hz, 1H), 4.79 (s, 2H), 4.50 (t, J=6.8 Hz, 1H), ), 4.25 (dd, J=5.1 Hz, J=9.4 Hz, 1H), 3.40 (m, 1H), 3.02 (m 2H), 2.90 (dd, J=7.7 Hz, J=13. 6 Hz, 1H), 1.36 (s, 9H); (KBr) 3297,2979,1728,1688,1645 cm-1; HRMS m/z 633.2660 (calc. of monoisotopic mass for C34H39N309 gives 633.2686).

Example5-{(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3- Disodium phenylpropanoyl}amino)-3-[(5-hydroxypentyl)amino]-3-oxopropy l}-2-(2-oxido-2- oxoethoxy) benzoate Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid and 5-amino-1-pentanol (31 mg) according to Method A to give a material which was re- purifie by reverse phase C-18 HPLC in absence of trifluoroacetic acid and then passed

through a column with Dowex Na+. After lyophilizing, the title compound (34 mg) was obtained. 1H-NMR (400 MHz, CD30D) d 7.56 (s, 1H), 7.30-7.17 (ion, 6H), 7.04 (d, J=8.5 Hz, 1H), 4.57-4.50 (ion, 3H), 4.24 (dd, J=5.0 Hz, J=9.7 Hz, 1H), 3.52 (t, J=13.2 Hz, 2H), 3.14 (ion, 1 H), 3.07-2.92 (ion, 4H), 2.72 (dd, J=9.8 Hz, J=13.6 Hz, 1 H), 1.50 (ion, 2H), 1.35 (s, 9H), 1.28 (ion, 2H); (KBr) 3318,2934,1686,1647 cm-1; HRMS m/z 615.2821 (calc. of monoisotopic mass for C31H4lN3Olo gives 615.2792).

Example 12-12: 5- ((2R)-2-({(2S)-2-[(tert-Butoxycarbonyl) amino]-3- phenylpropanoyl}amino)-3-oxo-3-{[3-(2-oxo-1-pyrrolidinyl) propyl] amino} propyl)-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- <BR> <BR> <BR> <BR> phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenylJpropanoic acid (100 mg, 0.18 mmol) and N-(3'-aminopropyl)-2-pyrrolidinone (42 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (26 mg). 1H-NMR (400 MHz, CD30D) 8 1.35 (s, 9H) 1.6 (ion, 2H) 2.03 (ion, 2H) 2.37 (t, 2H) 2.76 (m, 1H) 2.92-3.10 (m, SH) 3.14 (t, 2H) 3.42 (t, 2H) 4.25 (m, 1H) 4.5 (m, 1H) 4.78 (s, 2H) 7.05 (d, 1H) 7.23 (dd, SH) 7.42 (d, 1H) 7.72 (s, 1H); HR-MS m/z 654.2880 (calc. Of monoisotop mass for C33H42N4O10 gives 654.2901).

Example5-((2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-{[2-(dimethylamino)ethyl]amino}-3-o xopropyl)-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3- phenylpropanoyll amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid and N, N-dimethylenediamine (26 mg) according to Method B to give the title compound (7.2 mg). 1H-NMR (400 MHz, CD30D) d 7.50 (s, 1H), 7.35 (m, 1H), 7.29-7.20 (m, 5H), 7.13 (d, J=8.5 Hz, 1H), 4.69 (s, 2H), 4.39 (t, J=7.3 Hz, 1H), 4.29 (dd, J=5.3 Hz, J=9.2 Hz, 1H), 3.37 (ion, 2H), 3.07 (dd, J=5.1 Hz, J=13.9 Hz, 1H), 2.99 (ion, 4H), 2.85 (s, 6H), 2.79 (dd, J=9.0 Hz, J=13. 6 Hz, 1 H), 1.36 (s, 9H); FIRMES m/z 600.2774 (calc. of monoisotopic mass for C3oH4ON409 gives 600.2795).

Example5-{(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-oxo-3-[(3-pyridinylmethyl)amino]pro pyl}-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid and 3- (aminomethyl) pyridine (31 mg) according to Method B to give the title compound (14 mg). HRMS m/z 620.2471 (calc. of monoisotopic mass for C32H36N409 gives 620.2482).

Example 12-15: 5-((2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-{[3-(isopropylamino)propyl]amino}-3 -oxopropyl)-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid and N-isopropyl-1,3-propanediamine (34 mg) according to Method B to give the title compound (26 mg). 1H-NMR (400 MHz, CD30D) d 7.46 (d, J=2.2 Hz, 1H), 7.36 (dd, J=2.2 Hz, J=6.2 Hz, 1H), 7.29-7.20 (m, 5H), 7.08 (d, J=8.4 Hz, 1H), 4.68 (s, 2H), 4.44 (dd, J=5.7 Hz, J=9.9 Hz, 1 H), 4.30 (dd, J=5.5 Hz, J=9.2 Hz, 1H), 3.27 (ion, 2H), 3.06 (ion, 2H), 2.89 (dd, J=10. 1 Hz, J=13.0 Hz, 1H), 2.80 (ion, 2H), 2.65 (ion, 2H), 1.30 (dd, J=2.9 Hz, J=6.6 Hz); IR (KBr) cm~l ; HRMS m/z 628.3082 (calc. of monoisotopic mass for C32H44N409 gives 628.3108).

Example5-{(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-[(3-isopropoxypropyl)amino]-3-oxopr opyl}-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl) amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid and 3-isopropoxypropylamine (34 mg) according to Method B to give the title compound (34 mg). 1H-NMR (400 MHz, CD30D) d 7.76 (s, 1H), 7.40 (d, J=8.3Hz, 1H), 7.28-7.17 (ion, 5H), 7.03 (d, J=8.6 Hz, 1H), 4.80 (s, 2H), 4.50 (m, 1H), 4.24 (dd, J=5.1 Hz, J=93 Hz, 1H), 3.54 (t, J=6.1 Hz, 1H), 3. 35 (m, 2H), 3.23 (m, 1H), 3.14 (m, 1H), 3.08-2.91 (ion, 3H), 2.75 (dd, J=9.6 Hz, J=13.5 Hz, (1H), 1.63 (ion, 2H), 1.35 (s, 9H), 1.12 (dd, J=2.0 Hz, J=6.1 Hz); IR (KBr) cm~l ; HRMS m/z 629.2946 (calc. of monoisotopic mass for C32H43N3010 gives 629.2948).

Example 12-17: 5-((2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-oxo-3-{[2-(2-pyridinyl)ethyl]amino} propyl)-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl]propanoic acid and 2- (2-aminoethyl) pyridine (35 mg) according to Method B to give the title compound (56 mg). IH-NMK (400 MHz, CD30D) d 8.52 (d, J=4.6 Hz, 1H), 7.97 (ion, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.46-7.17 (ion, 8H), 7.03 (d, J=8.6 Hz, 1H), 4.78 (s, 2H), 4.46 (m, 1H), 4.23 (dd, J=5.2 Hz, J=9.4 Hz, 1H), 3.41 (m, 1H), 2.74 (dd, J=8.9 Hz, J=13.6 Hz, 1H), 1.35 (s, 9H); HRMS m/z 634.2651 (calc. of monoisotopic mass for C33H38N409 gives 634.2639).

Example 12-18: 5-((2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-oxo-3-{[2-(1-piperazinyl)ethyl]amin o}propyl)-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyllarnino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid and N-2-aminoethyl) piperazine (37 mg) according to Method B to give the title compound (5.8 mg). lH-NMR (400 MHz, CD30D) d 7.58 (s, 1H), 7.37 (dd, J=2.0 Hz, J=8.4 Hz, 1H), 7.26- 7.18 (m, 5H), 7.13 (d, J=8.5 Hz, 1H), 4.68 (s, 2H), 4.50 (t, J=7.3 Hz, 1H), 4.28 (dd, J=5.3 Hz, J=9.0 Hz, 1H), 3.68 (m, 1H), 3.56 (m, 1H), 2.80 (dd, J=9.3 Hz, J=13.2 Hz, 1H), 2. 37 (m, 1H), 1.37 (s, 9H); HRMS m/z 641.3032 (calc. of monoisotopic mass for C32H43N509 gives 641.3061).

Example 12-19: 5- [(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl) amino]-3- phenylpropanoyl}amino)-3-({2-[(2-hydroxypropyl)amino]ethyl}a mino)-3-oxopropyl]-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid and N- (2-hydroxypropyl) ethylenediamine (34 mg) according to Method B to give the title compound (26 mg). 1H-NMR (400 MHz, CD30D) d 7.56 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.28-7.17 (m, 5H), 7.05 (d, J=8.5 Hz, 1H), 4. 37 (m, 1H), 4.27 (dd, J=5.2 Hz, J=8.9 Hz, 1H), 1.35 (s, 9H), 1.22 (dd, J=1.8 Hz, J=6.2 Hz, 3H); HRMS m/z 630.2883 (calc. of monoisotopic mass for C3lH42N4010 gives 630.2901).

Example 12-20: 5-{(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl) amino]-3- phenylpropanoyl}amino)-3-[(4-methoxybenzyl)amino]-3-oxopropy l}-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2- ( { (2S)-2- [ (tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid and 4-methoxybenzylamine (40 mg) according to Method B to give the title compound (33 mg). 1H-NMR (400 MHz, CD30D) d 7.75 (s, 1H), 7.34 (dd, 1H), 7.26-7.18 (m, 5H), 7.05 (d, J=8.6 Hz, 1H), 6.94 (d, J=8.6 Hz, 2H), 6.82 (m, 2H), 4.77 (s, 2H), 4.56 (m, 1H), 4.15 (dd, J=5.1 Hz, J=14.7 Hz, 1H), 3.76 (s, 3H), 3.08-2.94 (m, 3H), 2.76 (dd, J=9.6 Hz, J=13.7 Hz, 1H), 1.33 (s, 9H); HRMS m/z 649.2615 (calc. of monoisotopic mass for C34H39N3O10 gives 649.2635).

Example 12-21: 5-{(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl} amino)-3- [ (3-hydroxypropyl) amino)-3-oxopropyl}-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid and 3-amino-1-propanol (18 ul) according to Method A to give material was re-purified by reverse phase HPLC in absence of trifluoroacetic acid to give the title compound (11 mg). 1H- NMR (400 MHz, CD30D) d 7.84 (s, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.27-7.17 (m, 5H), 7.04 (d, J=8.5 Hz, 1H), 4.79 (s, 2H), 4.51 (m, 1H), 4.23 (dd, J=5.2 Hz, J=9.3 Hz, 1H), 3.25 (m, 1H), 3.15 (m, 1H), 2.75 (m, 1H), 1.62 (m, 2H), 1.36 (s, 9H); HRMS m/z 587.2493 (calc. of monoisotopic mass for C29H37N3010 gives 587.2479).

Example 12-22: 5-{(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-[2-(3-hydroxy-3-phenylpropanoyl)hyd razino]-3-oxopropyl}-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2- ( { (2S)-2- [ (tert-butoxycarbonyl) amino-3- phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2 -oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and 3-phenylhydracrylic acid hydrazide (39 mg, 0.22 mmol) according to Method C with HPLC purification to give the title compound (58 mg) as a diasteromeric mixture, 1H-NMR (400 MHz, CD30D) d 7.77 (1H), S. l 1 (dd, J=4.6 Hz, J=8.6 Hz, 1H), 4.78 (2H), 4.70 (m, 1H), 4.24 (dd, J=5.0 Hz, J=9.3 Hz, 1H), 1.34 (s, 9H); IR (KBr) 3274,

1681,1652,1608 cm-1; HRMS m/z 692.2670 (calc. of monoisotopic mass for C35H4oN401, gives 692.2694).

Example 12-23: 5-((2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- Phenylpropanoyl}amino)-3-{2-[(2-hydroxy[1,1'-biphenyl]-3-yl) carbonyl]hydrazino}-3- oxopropyl)-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2- ( { (2S)-2- [ (tert-butoxycarbonyl) amino-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (93 mg, 0.17 mmol) and 3-phenylsalicylic acid hydrazide (45 mg, 0.20 mmol) according to Method C with HPLC purification to give the title compound (30 mg). 1H-NMR (400 MHz, CD30D) d 4.80 (s, 2H), 4.27 (dd, J=4.9 Hz, J=9.8 Hz, 1 H), 3.04 (m, 1H), 2.94 (m, 1H), 2.72 (dd, J=9.3 Hz, J=13.7 Hz, 1H), 134 (s, 9H); IR (KBr) 3280,1694,1653 cm-1; HRMS m/z 740.2666 (calc. of monoisotopic mass for C39H4oN401, gives 740.2694).

Example 12-24: 5-[(2S)-3-{2-[2-(Benzoylamino)acetyl]hydrazino}-2-({(2S)-2-[ (tert-butoxy- carbonyl) amino]-3-phenylpropanoyl) amino)-3-oxopropyll-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (100 mg, 0.18 mmol) and hippuric acid hydrazide (42 mg, 0.22 mmol) according to Method C with HPLC purification to give the title compound (24 mg). IR (KBr) 3274,1652,1616 cm-1; HRMS m/z 705.2640 (calc. of monoisotopic mass for C35H39Ns011 gives 705.2646).

Example 12-25: 5-[(2S)-3-({2-[5-(Benzyloxy)-1H-indol-3-yl]-1-methylethyl}am ino)-2-({(2S)- 2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-ox opropyl]-2-(carboxy- methoxy) benzoic acid Synthesis was performed from (2S)-2- (f (2S)-2- [ (tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl]propanoic acid (68 mg, 0.12 mmol) and 3- (2-aminopropyl)-5- (benzyloxy)-indole hydrochloride (46 mg, 0.15 mmol) according to Method C with HPLC purification to give the title compound (32 mg) as a diasteromeric mixture. IR (KBr) 3409,1681,1652 cm~l ; HRMS m/z 792.3360 (calc. of monoisotopic mass for C44H48N4O10 gives 792.3370).

Example 12-26: 5-{(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-[(3,4-diphenylpropoxy)amino]-3-oxop ropyl}-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (85 mg, 0.15 mmol) and 3,3-diphenylpropoxyamine hydrochloride (48 mg, 0.18 mmol) according to Method C with HPLC purification to give the title compound (29 mg). 7.75 (s, 1H), 7.33 (d, J=9.5 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 4.71 (s, 2H), 4.39 (dd, 1H), 4.25 (m, 1H), 4.11 (t, J=8.0 Hz, 1H), 3.57 (ion, 2H), 3.01 (ion, 2H), 2.93 (ion, 1H), 2.75 (ion, 1H), 2.24 (ion, 2H), 1.35 (s, 9H); IR (KBr) 3274,2978,1684,1651 cm~1 ; HRMS m/z 739.3126 (calc. of monoisotopic mass for C41H4sN301o gives 739.3105).

Example 12-27: 5-[(2S)-2-{[3-(Benzylanilino)-2-hydroxypropyl]amino}-2-({(2S )-2-[(tert- butoxycarbonyl)amino]-3-phenylpropanoyl]amino)-3-oxopropyl]- 2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl]propanoic acid (85 mg, 0.15 mmol) and 1-amino-3- (N-benzylanilino)-2-propanol (47 mg, 0.18 mmol) according to Method C with HPLC purification to the title compound (23 mg) as a diasteromeric mixture. IR (KBr) 3414,1654 cm~l ; HRMS m/z 768.33 82 (cale. of monoisotopic mass for C42H48N4010 gives 768.3370).

Example 12-28: 5-{(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl) amino]-3- phenylpropanoyl}amino)-3-oxo-3-[(3-phenylpropoxy)amino]propy l}-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (100 mg, 0.18 mmol) and 3-phenylpropoxyamine (41 mg, 0.22 mmol) according to Method C with HPLC purification to give the title compound (53 mg). 1H-NMR (400 MHz, CD30D) d 7.57 (s, 1H), 6.94 (d, J=8.3 Hz, 1H), 4.28 (m, 1H), 3.65 (ion, 2H), 3.04 (dd, J=4.9 Hz, J=13.9 Hz, 1H), 2.97 (m, 1H), 2.73 (dd, J=9.6 Hz, J=13.8 Hz, 1H), 2.65 (t, J=7.7 Hz, 2H), 1.78 (ion, 2H), 1.37 (s, 3H), 1.36 (s, 6H); IR (KBr) 3293,2949,1681,1651 cm-1; HRMS m/z 663.2806 (calc. of monoisotopic mass for C3sH4lN3olo gives 663.2792).

Example5-((2S)-2-({(2R)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-oxo-3-{[2-(1-pyrrolidinyl) ethyl] amino} propyl)-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyll amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2- oxoethoxy) phenyl] propanoic acid (100 mg, 0.18 mmol) and N- (2-aminoethyl) pyrrolidinone (33 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (10 mg). IH-NMR (400 MHz, CD30D) 6 1.36 (s, 9H) 2.05 (s, 4H) 2.68-3.20 (ion, 8H) 3.39 (ion, 4H) 4.28 (m, 1H) 4.39 (ion, 1H) 4.69 (s, 2H) 7.05-7.40 (ion, 7H) 7.52 (s, 1H); HRMS m/z 626.2929 (calc. of monoisotopic mass for C32H42N4O9 gives 626.2952).

Example 12-30: 5-{(2S)-2-({(2R)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-[(3,4-dimethoxyphenethyl)amino]-3-o xopropyl}-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (100 mg, 0.18 mmol) and 3, 4-dimethoxyphenethylamine (52 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (12 mg). 1H-NMR (400 MHz, CD30D) 8 1.38 (s, 9H) 2.68 (t, 2H) 2.72-3.09 (ion, 4H) 3.29-3.44 (ion, 2H) 3.80 (s, 3H) 3.85 (s, 3H) 4.25 (m, 1H), 4.52 (m, 1H) 4.79 (s, 2H) 6.74 (d, 1H) 6.84 (s, 1H) 6.87 (d, 1H) 7.06 (d, 1H) 7.17-7.38 (ion, 6H) 7.73 (s, 1H); HRMS m/z 693.2904 (calc ofmonoisotopic mass for C36H43N301l gives 693.2898).

Example 12-31: 5-((2S)-2-({(2R)-2-[(tert-Butoxycarbonyl) amino]-3- phenylpropanoyl}amino)-3-{[2-hydroxy-2-(1-phenyl-1H-indol-3- yl)ethyl]amino}-3- oxopropyl)-2-(carboxymethoxy)benzoicacid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (49 mg, 0.08 mmol) and N-phenyl-3-(1-hydroxy-2-aminoethyl) indole malonate (45 mg, 0.14 mmol) according to Method C with HPLC purification to give the title compound (13 mg).

1H-NMR (400 MHz, CD30D) 6 1.30-1.31 (d, 9H) 2.65 (m, 1H) 2.80-3.06 (ion, 3H) 3.45 (m, 1H)

3.72 (m, 1H) 4.19 (m, 1H) 4.52 (m, 1H) 4.67 (d, 2H) 5.03 (m, 1H) 7.0-7.8 (m, 18H); HRMS m/z 764.3073 (calc. of monoisotopic mass for C42H44M4O10 gives 764.3057).

Example 12-32: 5-[(2S)-2-({(2R)-2-[(tert-Butoxycarbonyl) amino]-3- phenylpropanoyl}amino)-3-oxo-3-({5-[(phenylsulfonyl)amino]pe ntyl}amino)propyl]-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2- ( { (2S)-2- [ (tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (45 mg) and N-(5-aminopentyl)-benzenesulphonamide malonate (45 mg, 0.08 mmol) according to Method C with HPLC purification to give the title compound (4.2 mg, 0.13 mmol).

1H-NMR (400 MHz, CD3OD) # 0.97 (m, 1H) 1.16-1.49 (m, 16H) 2.73-3.16 (m, 6H) 4.26 (m, 1H) 4.50 (m, 1H) 4.68 (s, 2H) 7.09-7.9 (m, 13 H); HRMS 754.2859 (calc of monoisotopic mass for C37H46N401 IS gives 754.2884).

Example 12-33: 5-[(2S)-3-{2-[2-(Benzoylamino)-3-methylbutanoyl]hydrazno}-2- ({(2R)-2- [(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-oxop ropyl]-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyllamino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (66 mg, 0.12 mmol) and N-benzoylvaline hydrazide (45 mg, 0.19 mmol) according to Method C with HPLC purification to give the title compound (3.5 mg). 1H-NMR (400 MHz, CD30D) 6 1.10 (m, 6H) 1.35 (s, 9H) 1.43 (m, 1H) 2.25 (m, 1H) 2.68 (m, 1H) 2.90 (m, 2H) 3.51 (m, 1H) 4.24 (m, 1H) 4.51 (m, 1H) 4.70 (m, 2H) 7.02-8.0 (m, 13H); HRMS m/z 747.3098 (calc of monoisotopic mass for C38H45N5011 gives 747.3116).

Example 12-34: 5-[2-({2-[(tert-Butoxycarbonyl)amino]-3-phenylpropanoyl}amin o)-3- (dipentylamino)-3-oxopropyl]-2-(carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl]propanoic acid (100 mg, 0.18 mmol) and dipentylamine (46 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (64 mg). 1H-NMR (400 MHz, CD30D) 8 0.90 (m, 6H) 1.14-1.53 (m, 21H) 2.65-2.82 (m, 1H) 2.86-3.38 (m, 7H) 4.30 (m, 1H) 4.80 (d, 2H) 4.94 (m,

1H) 7.02 (in, 1H) 7.21 (m, SH) 7.35-7.45 (dd, 1H) 7.76 (dd, 1H); HRMS m/z 669.3634 (calc. of monoisotopic mass for C36H51N3O9 gives 669.3625); mp 87-90 OC.

Example 12-35: 5-{(2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-[(4-hydroxybutyl)amino]-3-oxopropyl }-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid and 4-amino-1-butanol (21 ul) according to Method A to give a material which was re- purifie by reverse phase C-18 HPLC in absence of trifluoroacetic acid to give the title compound (19 mg). 1H-NMR (400 MHz, CD30D) d 7.75 (s, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.28- 7.18 (m, 5H), 7.04 (d, J=8.8 Hz, 1H), 4.79 (s, 2H), 4.51 (m, 1H), 4.24 (dd, J=5.2 Hz, J=9.2 Hz, 1H), 3.52 (m, 1H), 3.18 (m, 1H), 3.09-2.92 (ion, 4H), 2.75 (m, 1H), 1.45 (ion, 4H), 1. 36 (s, 9H); HRMS m/z 601.2616 (calc. of monoisotopic mass for C30H39N301o gives 601.2635).

Example5-((2S)-2-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3- phenylpropanoyl}amino)-3-{[2-(2-fluoro[1,1'-biphenyl]-4-yl)p ropyl]amino}-3-oxopropyl)- 2-(carboxymethoxy)benzoicacid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (79 mg, 0.14 mmol) and 2-fluoro-3-methyl-4-biphenylethylamine hydrochloride (45 mg, 0.17 mmol) according to Method C to give the title compound (44 mg).'H-NNM (400 MHz, CD3OD) d 7.75 (s, (s,1H),4.57(s,1H),4.51(m,1H),4.22(m,1H),3,52(m,1H),4.78 3.41 (m, 1H), 3.22 (m, 1H), 3.06-2.85 (ion, 4H), 2.72 (m, 1H), 1.35 (s, 9H), 1.20 (dd, J=7.0 Hz, J=15. 7 Hz, 4H); HRMS m/z 741.3094 (calc. of monoisotopic mass for C41H44FN309 gives 741.3062).

Example 12-37: 5-((2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl}amino)-3-{[2-hydroxy-2-(3-phenoxyphenyl)ethy l]amino}-3-oxopropyl)-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (96 mg, 0.16 mmol) and 2-amino-1- (3-phenoxyphenyl)-1-etanol (45 mg, 0.20 mmol)

according to Method C with HPLC purification to give the title compound (25 mg) as a diasteromeric mixture. 1H-NMR (400 MHz, CD30D) d 7.59 (d, J=1.7 Hz, 1H), 6.87 (dd, J=1.2 Hz, J=8.3 Hz, 1H), 4.66 (m, 3H), 4.55 (t, J=7.0 Hz, 1H), 4.23 (m, 1H), 3.02 (m, 2H), 3.52 (m, 1H), 2.90 (m, 1H), 2 : 69 (m, 1H), 1.34 (s, 9H); HRMS m/z 741.2925 (calc. of monoisotopic mass for C40H43N3O11 gives 741.2898).

Example 12-38: 5- ( (2S)-2- ( { (2S)-2- [ (tert-butoxycarbonyl) amino)-3- phenylpropanoyl}amino)-3-{[(4-hydroxy-2-phenyl-3,4-dihydro-2 H-chromen-4- yl) methyllaminol-3-oxopropyl)-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (82 mg, 0.15 mmol) and 4-(aminomethyl)-2-phenyl-4-chromanol (45 mg, 0.18 mmol) according to Method C with HPLC purification to give the title compound (15 mg). 1H-NMR (400 MHz, CD30D) d 7.64 (s, 1H), 6.84 (dd, J=1.0 Hz, J=8.3 Hz, 1H), 5.33 (d, J=12.0 Hz, 1H), 4.64 (s, 2H), 4.63 (m, 1H), 4.28 (m, 1H), 3.95 (m, 1H), 3.19 (m, 1H), 1.35 (s, 3H), 1.32 (s, 6H); HRMS m/z 767. 3084 (calc. of monoisotopic mass for C42H45N3O11 gives 767.3054).

Example 12-39: 5-[(2S)-3-({2-[2-(benzyloxy)-5-chlorophenyl]-2-hydroxyethyl} amino)-2- ({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amin o)-3-oxopropyl]-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (75 mg, 0.13 mmol) and 2-amino-I- [2- (benzyloxy)-5-chlorophenyl]-I-ethanol (45 mg, 0.16 mmol) according to Method C to give the title compound (66 mg) as a diasteromeric mixture.

H-NMR (400 MHz, CD30D) d 4.77 (s, 1H), 4.75 (s, 1H), 4.55 (m, 1H), 4.22 (m, 1H), 1.33- 1.32 (9H); FIRMES m/z 789.2713 (calc. of monoisotopic mass for C41H44C1N3O11 gives 789.2664).

Example 12-40: 5-[(2S)-3-{[2-(1-benzyl-1H-indol-3-yl)ethyl]amino}-2-({(2S)- 2-[(tert- butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-oxopropyl]- 2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic

acid (73 mg, 0.13 mmol) and 2-(1-benzyl-1H-indol-3-yl) ethylamine hydrochloride (45 mg, 0.16 mmol) according to Method C to give the title compound (48 mg). IH-NMR (400 MHz, CD30D) d 7.56 (d, J=7.6 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 5.28 (s, 2H), 4.69 (s, 2H), 4.48 (ion, 1H), 4.22 (dd, J=5.2 Hz, J=9.2 Hz, 1H), 3.52 (m, 1H), 3.38 (m, 1H), 2.98 (ion, 2H), 2.86 (ion, 3H), 2.72 (dd, J=9.3 Hz, J=13.8 Hz, 1H), 1.33 (s, 9H); HRMS m/z 762.3292 (calc. of monoisotopic mass for C43H46N409 gives 762.3265).

Example 12-41: 5-{2-({2-[(tert-Butoxycarbonyl)amino]-3-phenylpropanoyl} amino)-3- [methyl (pentyl) amino)-3-oxopropyl}-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (100 mg, 0.18 mmol) and N-methylamylamine (29 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (33 mg). 1H-NMR (400 MHz, CD30D) d 7.76 (s, 1H), 7.5-7.15 (ion, 6H), 7.04 (d, 1H), 5.02 (m, 1H), 4.81 (s, 2H), 4.28 (m, 1H), 3.25-2.7 (ion, 9H), 1.10-1.5 (ion, 15H), 0.89 (t, 3H); HRMS m/z 613.2982 (calc. of monoisotopic mass for C32H43N309 gives 613.2999).

Example 12-42: 5-[(2S)-3-{[2-(Benzylsulfanyl)ethyl]amino}-2-({(2S)-2-[(tert -butoxycar- bonyl) amino]-3-phenylpropanoyl}amino)-3-oxopropyl]-2-(carboxymetho xy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (100 mg, 0.18 mmol) and 2-(benzylsulfanyl)-1-ethanamine hydrochloride (44 mg, 0.22 mmol) according to Method C with HPLC purification to give the title compound (15 mg). 1H- NMR (400 MHz, CD30D) d 7.76 (s, 1H), 6.97 (d, J=8.6 Hz, 1H), 4.77 (s, 2H), 4.51 (m, 1H), 4.24 (dd, J=5.1 Hz, J=9.3 Hz, 1H), 3.71 (s, 2H), 3.19 (m, 1H), 2.74 (m, 1H), 2.41 (ion, 2H), 1.35 (s, 9H); HRMS nl/z 679.2542 (calc. of monoisotopic mass for C34H41N3O9S gives 679.2564).

Example 12-43: 5-[(2S)-3-[([1,1'-Biphenyl]-4-ylmethoxy)amino]-2-({(2S)-2-[( tert-butoxy- carbonyl)amino]-3-phenylpropanoyl]amino)-3-oxopropyl]-2-(car boxymethoxy)benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (91 mg, 0.16 mmol) and 4-[(aminooxy)methyl]-1,1'-biphenyl hydrochloride (46 mg, 0.20 mmol) according to Method C with HPLC purification to give the title compound (47 mg). 1H-

NMR (400 MHz, CD30D-Me2SO-d6) d 7.74-7.16 (17H), 4.84 (1H), 4.76 (1H), 4.64 (s, 2H), 4.32 (m, 1H), 3.03 (m, 3H), 1.41 (s, 9H); IR (KBr) 3272,2978,1681,1652 cm~l; HRMS m/z 711.2831 (calc. of monoisotopic mass for C39H4lN3010 gives 711.2792).

Example 12-44: 5-[(2S)-3-{[2-(Benzylamino)-2-phenylethyl]amino}-2-({(2S)-2- [(tert- butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-oxopropyl]- 2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)_2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl] propanoic acid (70 mg, 0.13 mmol) and N1-benzyl-1-phenyl-1, 2-ethandiamine dihydrochloride (45 mg, 0.15 mmol) according to Method C with HPLC purification to give the title compound (11 mg) as a diastereomeric mixture. IH-NMR (400 MHz, CD30D) d 7.50 (1H), 7.45-7.03 (17H), 4.40 (in, IH), 4.25 (in, 1H), 4.06 (in, IH), 3.80 (s, 2H), 3.03 (in, 1H), 1.33 (s, 9H); HRMS m/z 738.3281 (calc. of monoisotopic mass for C41H46N409 gives 738.3265).

Example 12-45: 5-{(2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl}amino)-3-[(1-methyl-3,3-diphenylpropyl)amino ]-3-oxopropyl]-2- (carboxymethoxy) benzoic acid Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3- phenylpropanoyl amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2-oxoethoxy) phenyl]propanoic acid (88 mg, 0.16 mmol) and 1-methyl-3,3-diphenylpropylamine (45 mg, 0.19 mmol) according to Method C with HPLC purification to give the title compound (31 mg) as a diastereomeric mixture in a 2: 1 ratio. HRMS m/z 737.3312 (calc. of monoisotopic mass for C42H47N309 gives 737.3329).

Preparation of starting material: (2S)-2-({(2S)-2-[(tert-butoxycarbonyl) amino]-3- phenylpropanoyl} amino)-3- [3- (methoxycarbonyl)-4- (2-methoxy-2- oxoethoxy) phenyl] propanoic acid General. All experiments were carried out under N2-atmosphere, except the hydrogenation and carbonylation rections. Melting points were determined in open glass capillaries on a Gallenkamp apparats and were not corrected. 1H NMR and 13C NMR were recorde on a Bruker Avance DPX 400 spectrometer at 400.1 and 100.6 MHz, respectively or on a Bruker

DRX 500 at 500 MHz and at 125.7 MHz, respectively. IH NMR and 13C NMR spectra were referenced to interna tetramethylsilane. IR spectra were recorde on a Perkin-Elmer Spectrum 1000 FT-IR spectrophotometer. Ionspray MS spectra were obtained on a Perkin Liner API 150EX mass spectrometer. Thin-layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Column chromatography was performed on silica using Kieselgel 60 (230-400 mesh), E. Merck. The elemental analyses were performed by Mikro Kemi AB, Uppsala, Sweden. a) Benzyl (2S)-2-amino-3- (4-hydroxy)-3-iodophenyl) propanoate hydrochloride 3-Iodo-L-tyrosine (5.0 g, 16.3 mmol) was suspende in benzyl alcohol (100 mL) and at 0 °C, thionyl chloride (20 mL) was added dropwise over a 20-min period. The temperature was raised to 80 °C and HCl (g) started to evolve. The rection mixture became yellow turbid and turned to clear colorless after 30 min. After 8 h of heating, the mixture was stirred overnight at ambient temperature. Dry diethyl ether (150 mL) was added and the flask was stored overnight at-10 °C. The white product was collecte on a glass-sintered funnel and dried (1.91 g). An additional amount of 2.65 g was obtained after the addition of i-hexane and storage at - 10 °C, The combine material was taken up in S% NaHC03 (200 mL) and extracted with ethyl acetate (3 x 150 mL). The combine organic layers were dried (Na2S04) and evaporated in vacuo leaving a crude yellow oil (4.00 g; 64 %). Mp (HCl salt): 187-188 °C; IH NMR (HCl salt, CD30D) 6 3.02 (d, J= 6.8,2H), 4.22 (t, J= 6.8,1H), 5.15 (q, J1 = 15 9, J2= 3.9,2H), 6.68 (d, J= 8.3, 1H), 6.91, (dd, J1 = 8.3, J2 = 2.2,1H), 7.23-7.31 (m, 5H), 7.51 (d, J= 2.2, 1H) ; 13C NMR (HC1 salt, CD30D) 8 36.44,55.61,69.60,85.56,116.48,128.11,130.14, 130.22,130.28,131.99,136.49,141.55,158.35,170.34; MS (Ionspray, [M+H] +) m/z 396.2; Anal. Calcd. (found) for C16H16INO3 # HCl: C 44.3 (44. 7) % H 4.0 (3.9) % N 3.2 (3.2) %. b) (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropano yl}amino)-3-(4- hydroxy-3-iodophenyl) propanoate The free base of benzyl (2S)-2-amino-3- (4-hydroxy)-3-iodophenyl) propanoate hydrochloride (3.97 g, 10. 0 mmol) was dissolve in dichloromethane (75 mL) and stirred at 0 °C under N2-atmosphere. Then, EDC (1.92 g, 10.0 mmol), HOBT (1.35 g, 10.0 mmol)) and BOC- L-Phe (2.65 g, 10.0 mmol) were added simultaneously and triethylamine 1.39 mL, 10.0 mmol) was added dropwise. This rection mixture was stirred for 15 h allowing to warm to ambient

temperature. Ethyl acetate (200 mL) was added and the organic layer was washed with 5 % HCl (2 x 200 mL). The combine aqueous phases were extracted with ethyl acetate (100 mL) after which the combine organic layers were washed with 10% NaHCO3 (100 mL). Drying (Na2SO4), filtration and evaporation in vacuo gave an off-white foam (6.01 g, 93%). The product was purifie by flash column chromatography on silica gel eluting with chloroform giving a 4.88 g (76%) of a white foam. Mp: 81. 6-82. 7 °C; 1H NMR õ 1.39 (s, 9H), 2.89-2.98 (ion, 2H), 3.03 (d, J= 6.5,2H), 4. 33 (m, 1H), 4.75 (m, 1H), 4.94 (br s, 1H), 5.10 (s, 2H), 5.60 (br s, 1H), 6.37 (d, J= 8.0,1H), 6.73, (s, 1H), 7.17-7.39 (m, 11H); 13C NMR # 28. 24, 36. 52, 38. 26, 53. 34, 55,85, 67.36,85.47,115.02,128.59,128.66,128.71,128.75,129.30,129.58 ,131.04, 134.86,136.39,138.79,154.04,170.58,170.91; MS (Ionspray, [M-H] +) m/z 643.2; Anal. Calcd.

(found) for C3pH332o6 C 55.9 (56.3) % H 5.2 (5.2) % N 4.4 (4.7) % c) Methyl5- [ (2S)-3- (benzyloxy)-2- ( { (2S)-2- [ (tert-butoxycarbonyl) amino-3- phenylpropanoyl}amino)-3-oxopropyl]-2-hydroxybenzoate A mixture (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-benzyl phenylpropanoyl}amino)-3-(4-hydroxy-3-iodophenyl) propanoate (4.43 g, 6.87 mmol), Pd (OAc) 2 (50 mg, 3.3 mol%) and DPPF (230 mg, 6.2 mol%) in acetonitrile (20 mL) was treated with trietylamine (1.9 mL, 13.74 mmol) and methanol (4.4 mL). A carbon monoxide atmosphere was established and the rection mixture was heated at 70 °C (Essential! Solvent vapour displaces CO if temperature is too high) for 16 h. The darkbrown rection mixture was directly coated on silica gel and subjected to colum-n chromatography (3 x 20 cm) eluting with chloroform. Pure fractions were pooled giving 2.45 g (62%) off-white solid after evaporation of the eluent. Pure material can be obtained by recrystallization from abs. ethanol. 1H NMR 8 138 (s, 9H), 2.98-3.05 (m, 4H), 3.87 (s, 3H), 4.37 (br s, 1H), 4.78 (q, J1 = 13. 2, J2= 7.2, 1H), 4.99 (br s, 1 H), 5.08 (s, 2H), 6.43 (d, J= 7.5,1 H), 6.76 (d, J= 8.5,1 H), 6.95 (dd, Jl = 8.5, J2 = 2.2, 1 H), 7.16-7. 37 (m, 10H) 7.46 (d, J= 2.2, 1H), 10.62 (s, 1H); 13C NMR 6 28.19,3 6.97,3 8.19, 52. 30, 53.35, 55. 71,67.28,80.27,112.11,117.77,126.20,126.99,128.50,128.60, 128. 66, 129.28,130. 30,134.84,136.45,136.68,155.33,160.58,170.20,170.65,170.87; MS (Ionspray, [M-H] +) m/z 575.2; Anal. Calcd. (found) for C32H36N208 0. 25 H2O: C 66.1 (66.0) % H 6.3 (6.5) % N 4.8 (4.9) %

d) 5-[(2S)-3-(benzyloxy)-2-({(2S)-2-[(tert-butoxycarbonyl)amino ]-3- phenylpropanoyl}amino)-3-oxopropyl]-2-(2-methoxy-2-oxoethoxy )benzoate A mixture of methyl 5-[(2S)-3-(benzyloxy)-2-({(2S)-2-[(tert- butoxycarbonyl) amino]-3-phenylpropanoyl} amino)-3-oxopropyl]-2-hydroxybenzoate (1.68 g, 2.91 mol), methyl bromoacetate (0.83 uL, 3 eq.) and K2CO3 (activated, 1.20 g, 3 eq.) in acetone (20 mL) was heated at 50 °C covernight. TLC showed complete conversion and water (20 mL) was added. Extraction with dichloromethane (3 x 25 mL), drying (Na2SO4) and removal of the solvent at the rotavapor afforded 2.27 g of a yellow oil. Flash column chromatography on silica gel (2 x 20 cm) eluting with chloroform gave 1.17 g (62%) of a pure colorless oil, that solidifie on standing. An additional amount (0.45 g) impure colorless oil was isolated. 1H NMR # 1.36 (s, 9H), 2.95-3.11 (ion, 4H), 3.78 (s, 3H), 3.85 (s, 3H), 4.36 (br s, 1H), 4.66 (s, 2H), 4.80 (q, 1H), 5.09 (s, 2H), 5.11 (br s, 1H), 6.57 (d, 1H), 6.66 (d, 1H), 7.00 (dd, 1H), 7.17-7.37 (m, 10H) 7.48 (d, 1H); 13C NMR 8 28.06,36.69,38.01,52.02,52.15,53.12,55.62, 66.45,67.20,80.05,114.27,120.75,126.79,128.34,128.43,128.48, 128.50,128.90,129.16, 132.65,134.12,136.49,156.40,165.86,168.82,170.48,170.87; MS (Ionspray, [M-H] +) m/z 647.4; Anal. Calcd. (found) for C35H40N2O10#0. 25 H20: C 64.4 (64.1) % H 6.3 (6.2) % N 4.3 (4.3) %. e) (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropano yl}amino)-3-[3- (methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy) phenyl] propanoic acid Methyl 5-[(2S)-3-(benzyloxy)-2-({(2S)-2-[(tert-butoxycarbonyl)amino ]-3- phenylpropanoyl}amino)-3-oxopropyl]-2-(2-methoxy-2-oxoethoxy ) benzoate (0.97 g, 1.50 mmol) was hydrogenated (atmospheric pressure) in abs ethanol (30 mL) over 10% Pd/C (100 mg) for 3 h. Filtration over diatomaceous earth and evaporation in vacuo of the filtrate yielded 0.76 g (91%) of a light-grey foam. IH NMR (CD30D) 8 1.33 (s, 9H), 2.62-2.75 (ion, 1H), 2.98- 3.08 (ion, 2H), 3.17-3.22 (m, 1H), 3.74 (s, 3H), 3.83 (s, 3H), 4.27 (m, 1H), 4.64 (m, 1H), 4.76 (s, 2H), 6.93 (d, 1H), 7.18-7.27 (m, SH) 7. 35 (d, 1H), 7.64 (s, 1H); 13C NMR (CD30D) 6 28.12, 36.82,38.71,52.08,54. 32,56.96,66.52,80.16,114.89,121.30,127.15,128.87,129.81,130. 92, 133.06,135.20,138.16,157.31,167.67,170.37,173.49,173.66; MS (Ionspray, [M-H] +) m/z 557. 2; Anal. Calcd. (found) for C28H34N2O10#0.25 H2O : C 59. 7 (59. 6) % H 6.2 (6.1) % N 5.0 (4.9) %

EXAMPLE 13: 2-(Carboxymethoxy)-5-[(2S)-3-oxo-3-(pentylamino)-2-({(2S)-2- [ (phenoxycarbou yl) amino]-3-phenylpropanoyl}amino)propyl]benzoic acid The title compound was prepared in analogy with the preparation of the compound of Example 6 above. MS (FAB) m/z (rel. intensity) 620 (MH+, 18), 620 (18), 231 (52), 155 (33), 154 (99), 137 (65), 109 (18), 91 (16), 57 (11), 45 (11), 43 (11). Anal. Calcd for C33H37N3Og : C, 63.96, H, 6.02; N, 6.78. Found: C, 64.06, H, 6.27; N, 6.53.

EXAMPLE 14: 2-(Carboxymethoxy)-5-[(2S)-2-{[(3R)-3-carboxy-4- phenylbutanoyl] amino)-3-oxo-3- (pentylamino) propyllbenzoic acid The title compound was prepared in analogy with the preparation of the compound of Example 6 above. MS (FAB) m/z (rel. intensity) 543 (mu+, 25), 544 (9), 543 (25), 309 (15), 263 (9), 233 (10), 231 (48), 154 (99), 137 (58), 109 (15), 91 (16). MS (FAB) m/z (rel. intensity) 543 (MH+, 99), 565 (20), 544 (33), 543 (99), 238 (25), 117 (16), 107 (16), 88 (58), 43 (23), 41 (16), 23 (17). HRMS (FAB) calcd for C28H34N209+Hl 543.2343, found 543.2353. Anal.

Calcd for C2gH34N209: C, 61.98; H, 6.32; N, 5.16. Found: C, 60. 35; H, 6.35; N, 4.89.

CHARMA HZN OH I OH Zn2CN EDC Pd (PPh3) 4 cat.Cul O NH CHZCi2 O N N H o (85%) H o 9 (4i%) A-1 A-2 N OH N Methylbromoacetate O 1) TFA K2C03 CHZCI2 O N acétone acetone N 1 2) Benzoic acid O EDC/HOBT CHOC12 A-3 A-4 (69%) N'No N ion N O N 0 0 0 N 4 O N N <TMS-N3 cat. Bu2Sn0 nu toluene) 110oC \ I H Ip % ji H ° U toluene, 110°C 9 H o <A-6A-5(21%) A-6 14-No N_NNH N iN O LIOH , n vTHF J (84%) N / O A-7

CHARTB 1)TFA N O CH2CI2 N O 4° 2) 3-Furoic acid 0 H O U fEDC/HOBT U CH2CI2 O N N I (62%)/ N NH o I p B-4 B-2 NNON N iN O TMS-N3 0 LIOH cat.Bu2Sn0 toluene, 110°C i° T THF (11%) l/ N N/ (37%) I H O \ B-3 (/)--"H 0 t i ° ZOO 0 H I/ N I B-4 CHARS C CHARS D OH Methyl bromoacetate 0 /KzC03/Ethyl propiolate CuzO O N N acetone, 50oC NH (89%) H DMF, 110oC I (47%) D-1 D-2 C7 i O O i0 \ 1) TFA/CHZCl2 2) Boc-Phe-OH HOBT/EDC / CHZCIZ I/ N (84%) I INH NF/ H O II N I O v O D-3 (8 D-4 OH N _ 0s 0 NH2OH HCI 0 NAOH EtOH/THF X 1 l O v O(19%) H O \ D-5 CHARTE OH OH EDC, HOBt \ Boc-L-Phe O I BrCHZCOOMe CHZCIzp NH N Et3N II NH p acetone E-1 E-2 ffi J-'O \ O Sn (Bu) 3, O p I NH AN o io 0 0 $ONH (NHSNHv ONHJuNH NH>/ O p Pdz (dba) 3 O \^ O Cul, AsPh3 X DMF E-3 E-4 HO 0 HO \ O HO 4=O "OH O/Wi 6M aq. HCI, THF II v Boc20, 1 M aq. NaOH HCI x H2NsANH>NH N HUI dioxane E-5 I HO \ O ho°sAOH O w o T O'NH"NH NV-l// OUZO E-6 CHARTF pyridine;F-2R=pyridine;F-3R= <BR> <BR> F-1 2-methoxybenzyl;F-4R=2-methoxybenzyl;F-4R= Table 1 Example Number Concentration % Inhibition Ki (UM) 100 97 0.87 13 10 85 1 43 100 95 12-12 76 1 27 100 94 12-14 10 67 1 20 100 97 12-16 83 1 38 100 95 12-21 10 73 1 24 100 30 810 1 120 246 12-28 0.4 100 98 12-2 10 93 64 100 94 12-3 72 1 22 100 97 12-1 84 1 39 100 80 31310 1 5 100 95 9-2 10 72 1 23 100 97 9-8 10 81 30 100 97 9-9 10 85 137 100 95 9-11 10 73 1 22 100 97 9-15 10 31 1 80 10098 9-19 10 85 1 40 10098 9-20 10 79 1 27 10097 9-26 10 78 1 30 10096 9-34 10 77 1 26 10095 9-1 10 69 1 18 100 95 11-7 10 69 1 18 10095 11-16 10 72 1 20 The Ki values were calculated from IC50-values obtained from a dose-response curve prepared using the inhibition assay described above.