NZ334690A

NZ334690A - Substituted amino acid ester derivatives useful for inhibiting beta-amyloid peptide release and/or synthesis

Info

Publication number: NZ334690A
Application number: NZ334690A
Authority: NZ
Inventors: James J Droste; Lee H Latimer; Thomas E Mabry; Jeffrey S Nissen; Warren J Porter; Jon K Reel; Eugene D Thorsett; Jay S Tung; Jing Wu; Clark Norman Eid; William Leonard Scott; James E Audia; Thomas C Britton; Beverly K Folmer; George W Huffman; Varghese John
Original assignee: Lilly Co Eli; Elan Pharm Inc
Priority date: 1996-11-22
Filing date: 1997-11-21
Publication date: 2001-09-28
Also published as: PE16999A1; CN1238779A; CZ122899A3; TR199902937T2; TR199902938T2; AR016751A1; JP2001503782A; IL129083A0; CA2267634A1; HUP0100270A3; NO992368D0; HUP0100270A2; NO992368L; EA199900490A1; CO4910156A1; WO1998022494A2; EP0942924A2; KR20000069064A; HRP970627A2; TR199901133T2

Abstract

A substituted amino acid ester derivative of formula (I) or a pharmaceutically acceptable salt thereof is used to inhibiting b-amyloid peptide release and/or its synthesis in a cell or is used to prevent the onset of Alzheimer's disease in a patient at risk of developing Alzheimer's disease wherein: R1 is optionally substituted alkyl, alkenyl, or alkynyl or is cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclic; R2 is hydrogen, optionally substituted alkyl, alkenyl or alkynyl or is cycloalkyl, aryl, heteroaryl or heterocyclic; each R3 is independently hydrogen or methyl or R3 together with R4 can be fused to form a cyclic structure of from 3 to 8 atoms which is optionally fused with an aryl or heteroaryl group; each R4 is independently hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, or is aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic; each R5 is hydrogen or methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms; X is -C(O)Y, -C(S)Y or -CR6R6Y'; Y is optionally substituted alkyl provided that the substitution does not include a-haloalkyl, a-diazoalkyl, a-OC(O)alkyl or a-OC(O)aryl or is cycloalkyl, optionally substituted alkoxy or thioalkoxy, hydroxy, aryl, heteroaryl, heterocyclic, NR'R", -NHSO2-R8, -NR9NR10R10 or NR9[C(O)O]zR10; each R6 is independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic; Y' is hydroxyl, amino, thiol, optionally substituted alkoxy or thioalkoxy, -OC(O)R7, -S-SR7, -S-SC(O)R7; R7 is optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic; X' is hydrogen, hydroxy, or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; Z is a bond covalently linking R to -CX'Xn-, oxygen or sulphur; n is 1 or 2; z is 0 or 1 and R', R", R8, R9, R10 are as defined in the specification limited by the provisos listed in the specification.

Description

<div class="application article clearfix" id="description"> WO 98/22494 PCT/US97/20804 METHODS AND COMPOUNDS FOR INHIBITING 0-AMYLOID PEPTIDE RELEASE AND/OR ITS SYNTHESIS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the following U.S. Provisional Applications: 1. U.S. Provisional Application No. 60/ , , which was converted 5 pursuant to 37 C.F.R. §1.53(b)(2)(ii) from U.S. Patent Application No. 08/755,442, filed November 22, 1996; 2. U.S. Provisional Application No. 60/ , , which was converted pursuant to 37 C.F.R. §1.53(b)(2)(ii) from U.S. Patent Application No. 08/808,528, filed February 28, 1997; 10 3. US. Provisional Application No. 60/ , , which was converted pursuant to 37 C.F R. §1.53(b)(2)(ii) from U.S. Patent Application No. 08/807,528, filed February 28, 1997; and 4. U S. Provisional Application No. 60/ , , which was converted pursuant to 37 C.F.R. §1.53(b)(2)(ii) from U.S. Patent Application No. 08/807,427, 15 filed February 28, 1997. Each of these applications are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION 20 Field of the Invention This invention relates to methods which inhibit cellular ^-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. This invention also relates to pharmaceutical compositions comprising such compounds as well as methods for inhibiting release of 25 /3-amyloid peptide. WO 98/22494 PCT/US97/20804 - 2 - 40 BACKGROUND OF THE INVENTION Field of the Invention This invention generally relates to uses of compounds represented by formula I below which inhibit cellular 3-amyloid peptide release and/or its synthesis,, and, accordingly, have utility in treating Alzheimer's disease References 10 The following publications, patents and patent applications are cited m this application as superscript numbers: 1 Glenner, et al., "Alzheimer's Disease: Initial Report of the Purification and Charactenzation of a Novel Cerebrovascular 15 Amyloid Protein", Biochem. Biophys. Res. Commun., 120:885- 890 (1984). 2 Glenner, et al., "Polypeptide Marker for Alzheimer's Disease and its Use for Diagnosis", U.S. Patent No. 4,666,829 issued 20 May 19, 1987. 3 Selkoe, "The Molecular Pathology of Alzheimer's Disease", Neuron, 6:487-498 (1991). 25 4 Goate, et al., "Segregation of a Missense Mutation in the Amyloid Precursor Protein Gene with Familial Alzheimer's Disease", Nature, 349:704-706 (1990). 3 Chartier-Harlan, et al., "Early-Onset Alzheimer's Disease Caused 30 by Mutations at Codon 717 of the /3-Amyloid Precursor Proteing Gene", Nature, 353:844-846 (1989). 6 Murrell, et al., "A Mutation in the Amyloid Precursor Protein Associated with Hereditary Alzheimer's Disease", Science, 35 254:97-99 (1991). 7 Mullan, et al., "A Pathogenic Mutation for Probable Alzheimer's Disease in the APP Gene at the N-Terminus of jS-Amyloid, Nature Genet., 1:345-347 (1992). intellectual property office of n.z. 0 3 AUG 2001 received WO 98/22494 PCT/US97/20804 — 3 — 10 Schenk, et al., "Methods and Compositions for the Detection of Soluble /8-Amyloid Peptide", International Patent Application Publication No. WO 94/10569, published 11 May 1994. Selkoe, "Amyloid Protein and Alzheimer's Disease", Scientific American, pp. 2-8, November, 1991. Losse, et al., Tetrahedron, 27:1423-1434 (1971). 10 11 Citron, et al., "Mutation of the /3-Amyloid Precursor Protein in Familial Alzheimer's Disease Increases /3-Protein Production, Nature, 360:672-674 (1992). 12 Hansen, et al., "Reexamination and Further Development of a 15 Precise and Rapid Dye Method for Measuring Cell Growth/Cell Kill", J. lmmun. Meth.. 119:203-210 (1989). 13 P. Seubert, Nature (1992) 359:325-327 20 14 Johnson-Wood et al., PNAS USA (1997) 94:1550-1555 15 Tetrahedron Letters, 34(48), 7685 (1993)) 25 All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. 30 State of the Art Alzheimer's Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and 35 emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public 40 health problem. The disease is currendy estimated to affect about two to three Printed from Mimosa WO 98/22494 PCT/US97/20804 „ 4 - million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known. 5 The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function 10 in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type 15 (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure. 20 The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the /3-amyloid peptide (/SAP) or sometimes A/3, A/3P or /3/A4 /3-Amyloid peptide was first purified and a partial amino 25 acid sequence was provided by Glenner, et al.1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Patent No. 4,666,8292. Molecular biological and protein chemical analyses have shown that the 30 /3-amyloid peptide is a small fragment of a much larger precursor protein (APP), that is normally produced by cells in many tissues of various animals, Printed from Mimosa WO 98/22494 PCT/US97/20804 - 5 - including humans. Knowledge of the structure of the gene encoding the APP has demonstrated that /3-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s). The precise biochemical mechanism by which the /J-amyloid peptide fragment is cleaved from APP and subsequently 5 deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown. Several lines of evidence indicate that progressive cerebral deposition of /3-amyloid peptide plays a seminal role in the pathogenesis of AD and can 10 precede cognitive symptoms by years or decades. See, for example, Selkoe3. The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate, et al.4; Chartier-Harlan, 15 et al.5; and Murrell, et al.6) and is referred to as the Swedish variant. A double mutation changing lysine595-methionine596 to asparagine5M-leucine59# (with reference to the 695 isoform) found in a Swedish family was reported in 1992 (Mullan, et al.7). Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific 20 molecular cause of AD in the affected members of such families. In addition, a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the /8-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The 25 discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its /5-amyloid peptide fragment can cause AD. Despite the progress which has been made in understanding the 30 underlying mechanisms of AD and other /3-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the Printed from Mimosa WO 98/22494 PCT/US97/20804 -6- (followed by page 6a) disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting /3-amyloid peptide release and/or its synthesis in vivo. The readers attention is also directed to our related New Zealand Patent Specification No. 513278 (NZ 513278) which describes and claims compounds of formula I as herein set forth, useful in the preparation of a medicament of the present invention. 10 15 SUMMARY OF THE INVENTION The invention generally relates to the discovery of a class of compounds which inhibit (3-amyloid peptide release and/or its synthesis ana, therefore, are useful m the prevention of AD m patients susceptable to AD and/or in the treatment of patients with AD m order to inhibit further deterioration in their condition. According to one aspect of the present invention there is provided a use, m tne preparation of a medicament for inmbiting B-amyloid peptide release and/or its synthesis m a cell, of a compound or mixture of compounds represented by formula I: 25 X' X R1Z wherem R' is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cvcloalkenyl, substituted alkyl, substituted alkenyl, 30 substituted alkynyl, aryl, heteroaryl and heterocyclic; intellectual property office of n.z. 0 3 AUG 2001 received -6a- R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R3 is independently selected from the group consisting of hydrogen and methyl and R3 together with R4 can be fused to form a cyclic structure of from 3 to 8 atoms which is optionally fused with an aryl or heteroaryl group; intellectual property office of n.z. 0 3 AUG 2001 received WO 98/22494 PCT/US97/20804 "7" '5 ^ vJj V) each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; each R5 is selected from hydrogen and methyl or together with R4 forms 5 a cycloalkyl group of from 3 to 6 carbon atoms; X is selected from the group consisting of -C(0)Y and -C(S)Y where Y is selected from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl with the proviso that the substitution on said 10 substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl, or a-0C(0)aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, 15 (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R" where R' and R" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted 20 alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, 25 where when either R1 or R" are substituted alkyl, the substituted alkyl is an alkyl group of 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxyalkyl, oxyacyl, 30 intellectual property OFFICE OF NZ. 1 8 JUN 2001 received oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, mono-alkylamino, mono-(substituted alkyl)amino, di-(substituted alkyl)amino, mono-aryl amino, di-ary^j^amino, mono-heteroarylamino, di-heteroarylammo, mono-heterocyclic amino, di-heterocyclic amino and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, (j) -NHSO:-R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -ONR'fCCOJOJjR10 where z is zero or one, R9 and R10 are as defined above; intellectual property office of nz. 1 8 JUN 2001 received WO 98/22494 PCT/US97/20804 - 8 - X can also be -CR6R6Y' where each R6 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted 5 thioalkoxy, -0C(0)R7, -SSR7, -SSC(0)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X' is hydrogen, hydroxy, or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo 10 group, Z is selected from the group consisting of a bond covalently linking R1 to -CX'X"-, oxygen and sulfur; n is an integer equal to 1 or 2; and pharmaceutically acceptable salts thereof 15 with the provisos that: A. when R1 is phenyl or 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0H; B. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3 20 derived from D-threonine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0H or -C(0)0CH3; C. when R1 is phenyl, R2 is methyl, R4 is benzyl, R5 is hydrogen, X is methoxycarbonyl, X' and X" are hydrogen, Z is a bond, and n is 1, then R3 is not methyl; 25 D. when R1 is wo-propyl, R2 is -CH2C(0)NH2, R3 is hydrogen, R4 is wo-butyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH3; E. when R1 is phenyl, R2 is methyl, R5 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R3, the nitrogen atom 30 attached to R3, and R4 do not form l,2,3,4-tetrahydro«o-quinolin-2-yl or pyrroIidin-2-yl; Printed from Mimosa WO 98/22494 PCT/US97/20804 F. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R5 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not 4-amino-n-butyl; G. when R1 is 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is 5 -CH(OH)CH3, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NH2 or -CH2OH; H. when R1 is phenyl, R2 is methyl, R3 is hydrogen, Rs is hydrogen, X is -CH2OCH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not benzyl or ethyl; 10 I. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is methyl, R4 is methyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CHOH0; J. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R3 is hydrogen, X' and X" are 15 hydrogen, Z is a bond, and n is 1, then X is not -CHOH<£ or -CH2OH; K. when R, is A/-(2-pyrrolidinonyl), R2 is methyl, R3 is hydrogen, R< is benzyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH3; L. when R1 is 3,5-difluorophenyl, R2 is methyl derived from D-alanine, 20 R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NH-benzyl; M. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is hydrogen, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CH2OH; 25 N. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is 4-phenylphenyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X4s not -C(0)NHC(CHj)3; and O. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X' and X" are 30 hydrogen, Z is a bond, and n is 1, then X is not -C(0)NHCH(CH3)<£ intellectual property OFFICE OF NZ. 1 8 JUN 2001 received 10 0 (P) when R1 is ethyl, R2 is iso-butyl, R3 is hydrogen, X" and X" are hydrogen, Z is a bond and n is 1, then X is not -CH(C2H2F30)(C4H9). Because the in vivo generation of (3-amyloid peptide is associated with the pathogenesis of AD8 9, the compounds of formula I can also be employed in conjunction with a pharmaceutical composition to prophylactically and/or therapeutically prevent and/or treat AD. Accordingly a further aspect of the present invention provides a use, in the preparation of a medicament for preventing the onset of AD in a patient at risk for developing AD, of a compound or a mixture of compounds of formula I: wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R3 is independently selected from the group consisting of hydrogen and methyl and R3 together with R4 can be fused to form a cyclic structure of from 3 to 8 atoms which is optionally fused with an aryl or heteroaryl group; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; I R2 R3 intellectual property office of nz. 1 8 JUN 2001 "10a ~ 33 each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms; X is selected from the group consisting of -C(0)Y and -C(S)Y where Y is selected from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include a-haloalkyi, a-diazoalkyl, a-0C(0)alkyl, or a-0C(0)aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i)—NR'R" where R' and R" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional t heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, where when either R' or R" are substituted alkyl, the substituted alkyl is an alkyl group of 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, acylamino, amino, ammoacvl, ammocarboxy esters, cyano, cyclalkyl, halogen, hydroxyl, carboxyl, carboxyalkyl, oxyacyl, oxyacylammo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, mono-alkylamino, intellectual property office of n z. 1 8 JUN 2001 received - 10b K th ) ) . v \kJf < it. v: di-alkylamino, mono-(substituted alkyl)amino, di-(substituted alkyl)amino, mono-aryl amino, di-aryl amino, mono-heteroarylammo, di-heteroarylamino, mono-heterocyclic ammo, di-heterocyclic, amino and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, (]) -NHSO:-R8 where R4 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl. cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR^NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and 0) -0NR9[C(0)0]zR10 where z is zero or one, R9 and R10 are as defined above; X can also be -CR6R6Y' where each R6 is independently selected from the group consisung of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl. heteroaryl and heterocyclic and Y' is selected from the group consisting of hvdroxyl, ammo, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -0C(0)R7, -SSR7, -SSC(0)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl. aryl, heteroaryl and heterocyclic, X' is hydrogen, hydroxy, or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, Z is selected from the group consisung of a bond covalently linking R1 to -CX'X"-, oxygen and sulfur; n is an integer equal to 1 or 2; and pharmaceutical^ acceptable salts thereof with the provisos that: A. when R1 is phenyl or 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3, Rs is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0H; B. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3 derived from D-threonine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0H or -C(0)0CH3; intellectual property office of n.z. 1 8 JUN 2001 Dcrciwcn WO 98/22494 - 10c C. when R1 is phenyl, R2 is methyl, R4 is benzyl, R5 is hydrogen, X is methoxycarbonyl, X' and X" are hydrogen, Z is a bond, and n is 1, then R3 is not methyl; D. when R1 is iso-propyl, R2 is -CH2C(0)NH2, R3 is hydrogen, R4 is 5 iso-butyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH3; E. when R1 is phenyl, R2 is methyl, R5 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R3, the nitrogen atom attached to R3, and R4 do not form l,2,3,4-tetrahydro/j<?-quinolin-2-yl or 10 pyrrolidin-2-yl; F. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R5 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not 4-amino-n-butyl; G. when R' is 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is 15 -CH(OH)CH3, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NH2 or -CH2OH; H. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R5 is hydrogen, X is -CH2OCH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not benzyl or ethyl; 20 I. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is methyl, R4 is methyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and nisi, then X is not -CHOH<£; J. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycme, R5 is hydrogen, X' and X" are 25 hydrogen, Z is a bond, and n is 1, then X is not -CHOH© or -CH2OH; K. when R! is A^-(2-pyrrolidinonyl), R2 is methyl, R3 is hydrogen, R, is benzyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH3; L. when R1 is 3,5-difluorophenyl, R2 is methyl derived from D-alanine, 30 R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and nisi, then X is not -C(0)NH-benzyl; intellectual property OFFICE OF NZ. 1 8 JUN 2001 received PCT/US97/20804 WO 98/22494 PCT/US97/20804 lOd M. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is hydrogen, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CH2OH; N. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is 5 4-phenylphenyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NHC(CH3)3; and O. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NHCH(CH3)<£ then X is not -CH(C2H2F30)(C4H9). In yet a further aspect of the present invention provides a use, in the preparation of a medicament for treating a patient with AD in order to inhibit further deterioration in the condition of that patient of a compound or a mixture of compounds of formula I: R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, subsututed alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R3 is independently selected from the group consisting of hydrogen 30 and methyl and R3 together with R4 can be fused to form a cyclic structure of from 3 to 8 atoms which is optionally fused with an aryl or heteroaryl group: P. when R1 is ethyl, R2 is iso-butyl, R3 is 10 hydrogen, X' and X" are hydrogen, Z is a bond and n is 1, I wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, 25 substituted alkynyl. aryl, heteroaryl and heterocyclic; intellectual property OFFICE OF N Z. 1 8 JUN 2001 received WO 98/22494 PCT/US97/20804 10e J ■i-'J v- q 10 25 each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; each R3 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms; X is selected from the group consisting of -C(0)Y and -C(S)Y where Y is selected from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl, or a-0C(0)aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R" where R' and R" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, where when either R' or R" are substituted alkyl, the substituted alkyl is an alkyl group of 1 to 10 cartoon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, acylammo, ammo, ammoacyl, ammocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxyalkyl, oxyacyl, oxyacyiammo, thiol, thioalkoxy, substituted thioalkoxy, intellectual property office of n.z. 1 8 JUN 2001 received lOf A 'm 't aryl , heteroaryl, , heterocyclic, nitro, mono-alkylammo, di-alkylamino, mono-(substituted alkyl)amino, di-(substituted alkyl)amino, mono-aryl ammo, di-aryl ammo, mono-heteroarylamoni, di-'neteroarylammo, mono-heterocyclic ammo, di-heterocyclic ammo and unsymmetric di-substituted amines having different substituents selected from alKyl, substituted alkyl, aryl, heteroaryl and heterocyclic, 0") -NHS02-R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR9NRi0R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -0NR9[C(0)0]zR'° where z is zero or one, R9 and R'° are as defined above; X can also be -CR6R6Y' where each R6 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl7 heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, subsututed alkoxy, thioalkoxy, substituted thioalkoxy, -0C(0)R7, -SSR7, -SSC(0)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X' is hydrogen, hydroxy, or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, Z is selected from the group consisting of a bond covalently linking R1 to -CX'X"-, oxygen and sulfur; n is an integer equal to 1 or 2; and pharmaceutical^ acceptable salts thereof with the provisos that: intellectual property OFFICE OF N Z 1 8 JUN 2001 received - lOg - P /F*t> c: j^; L Vi' A. when R1 is phenyl or 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3, R3 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0H; B. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3 derived from D-threomne, R3 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0H or -C(0)0CH3; C. when R1 is phenyl, R2 is methyl, R4 is benzyl, R3 is hydrogen, X is methoxycarbonyl, X' and X" are hydrogen, Z is a bond, and n is 1, then R3 is not methyl; D. when R1 is wo-propyl, R2 is -CH2C(0)NH2, R3 is hydrogen, R4 is wo-butyl, R3 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH3; E. when R1 is phenyl, R2 is methyl, R5 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R3, the nitrogen atom attached to R\ and R4 do not form 1,2,3,4-tetrahydro/j0-quinolin-2-yl or pyrrolidin-2-yl; F. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R3 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not 4-amino-n-butyl; G. when R1 is 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3, R3 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NH2 or -CH2OH; H. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R3 is hydrogen, X is -CH2OCH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not benzyl or ethyl; I. when R1 is 3,5-difluorophenyl, R2 is methyl, R3 is methyl, R4 is methyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CHOH<£; intellectual property OTICE OF N 7 1 8 JUN 2001 received - lOh - J. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, Rs is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CHOH<£ or -CH2OH; K. when Rt is iV-(2-pyrrolidinonyl), R2 is methyl, R3 is hydrogen, R, is benzyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH3; L. when R1 is 3,5-difluorophenyl, R2 is methyl derived from D-alanine, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R3 is hydrogen, X' and X" are hydrogen, Z is a bond, and nisi, then X is not -C(0)NH-benzyl; M. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is hydrogen, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CH2OH; N. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is 4-phenylphenyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NHC(CH3)3; and O. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl denved from D-phenylglycine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NHCH(CH3)<£ P. when R1 is ethyl, R2 is iso-butyl, R3 is hydrogen, X' and X" are hydrogen, Z is a bond and n is 1, then X is not -CH(C2H2F30) (C4H9) . intellectual property office of nz. 1 8 JUN 2001 received Suitable compounds for use in the preparation of a medicament of the present invention include, by way of example only, the following: N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate methyl ester AHAHS^-difluorophenylacetyO-L-alaninylJ-L-histidine methyl ester N-benzyl-N'-[AK3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide Ar-2-(Ar,A/-dimethylamino)ethyl-Ar'-[W-(3,5-difiuorophenylacetyl)-L-alaninyl]-(S)-2-ammohexanamide N-(2-methoxyethyl)-Ar'-[A/-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide A7-2-(Ar,Ar-dimethylamino)ethyl-A/'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide AL(4-pyridyl)methyl-A7'-[AL(3,5-difluorophenylacetyl)-L-alarunyl]-L-phenylalaninamide N-(3-pyridyl)methyl-N'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide A''-(4-pyridyl)methyl-./V'-[A''-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide /*/-[iV-(3,5-difluorophenylacetyl)-L-aianinyl]-(S)-2-arriinohexanoate/m-butyl ester N-[N-(pent-4-enoyl)-L-alaninyl]-L-phenylalanine methyl ester AL[A'-(dec-4-enoyl)-L-alaninyl]-L-phenylalanine methyl ester N-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[3-(iV,N-dimethylamino)propoxy]phenylalanine methyl ester INTELLECTUAL PROPERTY OFFICE OF NZ. 0 3 AUG 2001 received WO 98/22494 PCT/US97/20804 - 12 - A/-[AH3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[(r£rr-butyloxycarbonyl)methoxy]phenylalanine methyl ester W-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester 5 iV-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(carboxymethoxy)phenylalanine methyl ester Ar-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-10 morpholinoethoxy)phenylalamne methyl ester A^-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-6-(jV,N-dimethylamino)hexanoate methyl ester 15 A*-[Af-(3,5-dtfluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2- pyridyl)propionate methyl ester 20 25 40 jV-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(3- pyridyl)propionate methyl ester N-|W-(3,5-difluorophenylacetyl)-L-alamnyl]-L-proline methyl ester l-[jV-(3,5-difluorophenylacetyl)-L-a]aninyl]piperidine-2-carboxylate methyl ester A^-[//-(3,5-difluorophenylacetyl)-L-aJaninyl]-(S)-2-amino-3-(4-pyridyl)propionate methyl ester iV-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-30 methoxypropionate methyl ester A'-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropionate methyl ester 35 JV-(2-methoxyethyl)-/V'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2- morpholinoethoxy)phenylalaninamide iV-(2-methoxyethyl)-A?'-[yV-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionamide A^-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]glycine methyl ester N-(2-methoxyethyl)-A'"-[N-(3,5-difluorophenylacetyl)-L-alaiiinyl]-2-amino-3-(4-pyridyl)propionamide 45 Printed from Mimosa WO 98/22494 PCT/US97/20804 - 13 - iV-(2-methoxyethyl)-iV'-[Air-(3,5-difluorophenylacetyI)-L-alaninyl]-2-amino-3-(2-pyridyl)propionamide N-[A^-(3,5-difluorophenylacetyl)-L-aIaninyl]-(S)-2-amino-3-(thlazol-4-5 yl)propionate methyl ester 2-[A^(3,5-difluorophenylacetyl)-L-aIaninyl]-l,2,3,4-tetrahydroisoquinoline-3-carboxylate methyl ester 10 tf-(3-methoxybenzyl)-./V'-[A/-(3,5-difluorophenylacetyl)-L-a]aninyl]-L- phenylalaninamide 15 40 A^-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(l-naphthyl)propionate methyl ester Ar-[A^-(3,5-difluorophenylacetyI)-L-alaninyl]-(S)-2-amino-3-(2-naphthyl)propionate methyl ester N-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-20 thienyl)propionate methyl ester N-[N-(3,5-difluorophenylacetyl)-L-alamnyl]-L-phenylalanine benzyl ester A^-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine 3-bromo-25 propyl ester Ar-[A'-(3,5-difluorophenylacetyl)-L-alaninyll-L-phenylalanine 3-lodopropyl ester 30 iV-[jV-(3,5-difluorophenylacetyI)-L-alaninyl]-L-leucine tert-butyl ester W-[7V-(3,5-difluorophenylacetyl)-L-alaniny]]-2-amino-2-(2-pyridyl)acetamide 35 W-|7V-(3,5-difluorophenylacetyl)-L-a]aninyl]-2-amino-2-(3- pyridyl)acetamide 45 AL[A^-(3,5-dxfluorophenylacetyl)-L-alaninyl]-//e-(/g/r-butoxycarbonyl)-L-lysine methyl ester methyl Ar-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-4-phenylbutanoate N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 2-phenylethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 3-phenylpropyl ester Printed from Mimosa WO 98/22494 PCT/US97/20804 - 14 -- W-(W-(3,5-difluorophenylacetyl)-L-alamnyl]-2-amino-2-(4-pyridyl)acetamide iV-[Af-(phenylacetyl)-L-alaxiinyl]-L-threonine methyl ester 5 A^-[-/V-(phenylacetyl)-L-alaninyl]-L-leucinamide ^V'-[//-(phenylacetyl)-L-alaninyl]-L-alaninamide 10 W-[7V-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide iV'-[A^-(phenylacetyl)-L-alaninyl)-L-valmamide Ar-[Af-(3,5-difluorophenylacetyl)-L-alaiiinyl]-2-amino-2-(3-pyridyl)acetate 15 ethyl ester Af-methyl-N'-|W-(phenylacetyl)-L-alaninyl]-L-leucinamide Ar,jV-dimethyl-/V'-[A'-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide 20 Ar,yV-dimethyl-Ar'-[A'-(phenylacetyl)-L-alaninyl]-L-leucinamide ;V,/V-dimethyl-/V'-[/V-(phenylacetyl)-L-alaninyl]-L-valinamide 25 A/-methyl-//'-[AHphenylacetyl)-L-alaninyl]-L-phenylalaninamide Ar-methyl-A^'-[Ar-(phenylacetyl)-L-alaninyi]-L-valinamide jV-methyl-/V'-[W-(3,5-difluorophenylacetyl)-L-alanmyl]-(S)-2-30 aminohexanamide /V,/V-dimethyl-/V'-[W-(3,5-difluorophenylacetyl)-L-alarrinylHS)-2-aminohexanamide 35 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide jV-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-methoxyphenyl)acetate methyl ester 40 N-[N-(3,5-difluorophenylacctyl)-L-alaninyl]-2-amino-2-(4- methoxyphenyl)acetate methyl ester AL[A?-(3,5-difluorophenylacetyl)-L-alamnyl]-2-amino-2-(2-pyridyl)acetate ethyl ester 45 Printed from Mimosa WO 98/22494 PCT/US97/20804 - 15 -- A^[yV-(3,5-difluorophenylacetyl)-L-aJaninyl]-2-amino-2-(4-pyridyl)acetate ethyl ester JV-[iV-(cyclohexylacetyl)-L-alaninyl]-L-phenylalanine methyl ester 5 i\^[/V-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine methyl ester iV-[iV-(cyclohex-l-enylacetyl)-L-alaninyl]-L-phenylalanine methyl ester 10 N-[N-(3,5-difluoropheny lacetyl)-L-alaninyI]-1 -aminocyclopropane-1 - carboxylate methyl ester Ar-2-(.N,.N-dimethylamino)ethy]-7V-methyl-W-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide 15 //-fyV-(cyclopropylacetyl)-L-aianinyl]-L-phenylalanine methyl ester A'-[AL(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester 20 iV-[AKisovaleryl)-L-phenylglycinyl]-L-alamne ethyl ester A'-[iV-(3-nitrophenylacetyl)-L-a]aninyl]-L-phenyIalanine methyl ester A'-[A'-(3-nitrophenylacetyl)-L-alaninyl]-L-alanine ethyl ester 25 7V-[A'-(3-nitrophenylacetyl)-L-alaninyl]g1ycine ethyl ester /V-hydroxy-iV'-fA^-CS-nitrophenylacetyO-L-alaninylJ-D.L-threoninamide 30 Af-[7V-(isova]eryl)-L-phenylglycinyl]-L-alanine wo-butyl ester N-[/v'-(3-nitrophenylacetyl)-L-alaninyl]-2-amino-3-(3-hydroxyphenyI)propionate methyl ester 35 vV-fAHS-nitrophenylacetylJ-L-alaninyij-L-tyrosine ethyl ester iV-[7V-(isovaleryl)-L-isoleucinyl]-L-alanine wo-butyl ester //-[//-[^-(isovaleryO-L-valinyll-L-phenylglycinylJ-L-alanine /jo-butyl 40 ester iV-[/V-(isovaleryl)-L-phenyIalamnyl]-L-alanine wc-butyl ester iV-(7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester 45 Printed from Mimosa WO 98/22494 PCT/US97/20804 - 16 - l-[A^-(3-nitrophenylacetyl)-L-alaninyl]-indoline-(S)-2-carboxylate ethyl ester A^'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Ar-methoxy-//-methyl-A^'-[A'_-(isovaleryl)-L-phenylglycinyl]-L-alaiiin amide iV-/jo-butyl-/V'-[A'-(3,5-difluorophenyIacetyl)-L-alaninyl]-L-alaninamide iV,iV-di-n-propyl-./V'-[A''-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide A^'-[//-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valinamide N-(4-nitrophenyl)-AT-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alamnamide A^'-[AL[A,-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-phenylalaninamide A^-[jV-(3,5-difluorophenylacetyl)-L-alariinyl]-L-phenylalanine methyl ester vV'-[jV~(3,5-difluorophenylacetyl)-L-a]aninyl]-L-phenylalaninamide A'-/jo-buty]-A^'-[A'-(isovaleryl)-L-phenylglycinyl]-L-alaninamide A'-(2-methoxyethyl)-A?'-[A''-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide /V-(4-nitrobenzyl)-;V'-[A'-(3,5-dif]uorophenylacetyI)-L-alaninyl]-L-alaninamide A'-(4-nitrophenyl)-A''-[A'-[A^-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-alaiunamide N-(4-nitrophenyl)-A^'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide A^-benzyl-A'-methyl-/V"-fAr-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide A^-(3,5-difluorobenzyl)-A/'-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide //-(3-nitrobenzyl)-A^'-[A'-(3,5-difluorophenylacetyl)-L-alaiiinyl]-L-alaninamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 17 -- W-benzyl-W-[7V-(3,5-difluorophenylacetyl)-L-alaninyI]-L-alaninamide N-(4-nitrobenzyl)-Af'-|W-(3,5-difluorophenylacetyl)-L-alaiiinyI]-L-phenylalaninamide Af-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophan methyl ester AH4-methoxybenzyl)-iV'-[iV-(3,5-difluorophenylacetyl)-L-aIaninyl]-L-alaninamide ^-[A^CphenylacetyO-L-phenylglycinylJ-L-alanine ethyl ester iVr-[iV-[A'-(3,5-difluorophenyIacetyI)-L-alaninyl]-L-phenylalaninyl]-L-phenylglycine methyl ester iV-[N-(cyclohexylacetyl)-L-phenylglycinyl]-L-alanine ethyl ester N-f/V-^.S-difluorophenylacetylVL-alaninyll-L-phenylglycine methyl ester 20 N-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]-L- phenylglycine methyl ester 10 15 25 30 35 Ar-(2-phenylethyl)-N'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Ar'-[/V-(3,5-difluorophenylacetyl)-L-a]aninyl]L-tryptophanamide N-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-cyclohexylpropionate methyl ester Ar-(2-methoxyethyl)-A''-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-nitrophenyl)propionamide A^-[jV-(3-nitrophenylacetyl)-L-alaninyl]-L-serine ethyl ester A',-[(R)-a-methylbenzyl]-/V'-[A'-(3,5-difluorophenyIacetyl)-L-alaninyl]-L-alaninamide iV-[(S)-a-methylbenzyl]-.W-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-40 alaninamide iV-(4-fluorobenzyl)-iV'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide 45 A^-(4-pyridylmethyl)-/V'-[Ac-(3,5-difluorophenylacetyl)-L-alaninyl]-L- alaninamide Printed from Mimosa 5 10 15 20 25 30 35 40 45 WO 98/22494 PCT/US97/20804 - 18 - N-(4-trifluoromethylbenzyl)-W-(7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide N-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-phenylpropionate ethyl ester Ar-[JV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine/e/T-butyl ester jV-[jV-(3,5-difluorophenylacetyI)-L-alaninyl]-2-amino-2-methylpropionate methyl ester iV-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-cyclohexylacetate ethyl ester A?-(2-methoxyethyl)-A^'-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide A^-[A^-(isovaleryl)-2-amino-2-cyclohexyIacetyl]-L-alanine ethyl ester .N-2-(A/,A/-dimethylamino)ethyl-jV'-[Af-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide Ar-(2-pyridylmethyl)-Ar'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide A^-[Ar-(3-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl ester Af-[vV-(2-pyndylacetyl)~L-alaninyl]-L-phenylalanine methyl ester Ar-[jV-(4-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl ester /V-[jV-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-fluorophenyl)acetate ethyl ester N- [N- (3,5-difluoropheny lacetyl)-L-alaniny 1]-2-ammo-2-(2-fluorophenyl)acetate ethyl ester ^-[^-(S^-difluorophenylacetyO-L-phenylglycinylJ-L-alanineethyl ester Af-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-phthalimidopropionate ethyl ester AT-[A/-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine neopentyl ester Printed from Mimosa WO 98/22494 PCT/US97/20804 - 19 - A'-rm-butyl-Ar'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide Af-[JV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine /erf-butyl ester Af'-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide 4-[Ar-tjV-(3-nitrophenylacetyl)-L-alaninyl]-L-valinyI]morpholine A^-[/V-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ethyl ester Af-[iV-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine methyl ester 15 Af-[AH3.5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methyl ester 10 20 4-|W-[A/r-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-amino-3-/err-butoxybutyryljmorpholine 4-[/V-[AH3-nitrophenylacetyl)-L-alaninyl]-L-isoleucinyl]moipholine A'-[A'-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine methyl ester 25 Af-(W-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine A'-[A'-[A'-(3-nitrophenylacetyl)-L-alaninyl]-L-threoninyl]-L-valine ethyl ester 30 N-[W-(3-nitrophenylacetyl)-L-alaninyI]-(S)-2-aminopentanoate methyl ester Ar-[Af-(3-nitrophenylacetyl)-L-alaninyl]-L-leucine methyl ester 35 /V-|W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine methyl ester jV-2-methoxyethyl-jV'-fjV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide 40 yV-2-(Ar,/V-dimethylamino)ethyl-/V'-[A':(3,5-difluorophenylacetyl)-L- alaninyl]-L-alaninamide iV-cyclohexyl-./V'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide 45 Ar-neopentyl-//'-[//-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 20 - A^tetrahydrofurfuryl-N'-[A/'-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide iV-2-pyridy lmethyl-N '-[iV-(3,5-difluorophenylacety l)-L-alaninyl] -L-S alaninamide 3-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]thiazolidine •N-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methyl 10 ester iV-fAr-(3-nitrophenylacetyl)-L-alamnyl]-(S)-2-aminobutanoate methyl ester iV-(R)-jlec-butyl-A''-[A^(3,5-difluorophenylacetyl)-L-alaninyl]-L-15 alaninamide l-[W-[yV-(3,5-difluarophenylacetyl)-L-alaninyl]-L-alaninyl]pyiTolidine 2V-(S)-sec-butyl-iV'-|W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-20 alaninamide N-[./V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valine methyl ester Af-2-fluoroethyl-W-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-25 alaninamide Ar-[(S)-6-methyl-3-oxohept-2-yl]-/V'-(3,5-difluorophenylacetyl)-L-alaninamide 30 //-4-nitrobenzyl-/V'-[A'L(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2- aminobutyramide 35 AM-nitrobenzyl-W-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanamide N-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-fluorophenyl)acetate methyl ester N'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-40 thienyl)acetamide yV-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiophen-2-yl)acetate methyl ester 45 A'-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-2- yl)acetate ethyl ester Printed from Mimosa WO 98/22494 PCT/US97/20804 -21 JV-[A/-(3,5-difluorophenylacetyl)-L-alamnyl]-2-amino-2-(benzothiophen-3-yl)acetate methyl ester iV-|W-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-thienyl)acetate 5 methyl ester N-[jV-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-5-yl)acetate ethyl ester 10 Ar-[Ar-(3,5-difIuorophenylacetyl)-L-alaniny]]-(S)-2-aminc>-2-(2- thienyl)acetate methyl ester /V-[AH3,5-difluorophenylacetyl)-L-aIaninyI]-(S)-2-amino-2-(2-thienyl)acetate /m-butyl ester iV-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetic acid 15 ./V-(W-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(l//-tetrazol-5-20 yl)acetate methyl ester Ar-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(6-methoxy-2-naphthyl)acetate methyl ester 25 Ar-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3- trifluoromethylphenytyacetate methyl ester 30 yV-[7V'-(3,5-difluorc>phenylacetyl)-L-alaninyl]-2-arnino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetate methyl ester iV-(7V-(3,5-dif[uorophenylacetyl)-L-alaninyl]-2-amino-2-(thieno[2,3-i]thiophen-2-yl)acetate methyl ester Ar-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-methylthiazol-35 4-yl)acetate methyl ester (3S,4S)-A'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-4-amino-3-hydroxy-5-phenylpentanoate methyl ester 40 Af-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-4-enoate methyl ester N-(7V-(cyclopropylacetyl)-L-alajiinyI]-L-phenylglycine tert-butyl ester 45 //-/err-butyI-/V'-[iV-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2- (4-phenylphenyl)acetamide Printed from Mimosa WO 98/22494 -22 - PCT/US97/20804 iV-[iV-(3,5-difluorophenylacetyl)-(S)-2-aminobutanoyl]-L-phenylglycine ferr-Butyl Ester N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine tert-butyl 5 ester A^-[iV-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycine methyl ester 10 //-[//-(S^-difluorophenylacetylJ-L-valinylJ-L-phenylglycine methyl ester iV-(7V-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-pheiiylgIycine methyl ester 15 N-|W-(3,5-difluorophenylacetyl)-L-leucinyl]-L-phenylglycine methyl ester jV-ITV-^S-difluorophenylacetyO-L-phenylalaninylJ-L-phenylglycine methyl ester 20 N-f/V-(3,5-difluorophenylacetyl)glycinyl]-L-phenylglycine methyl ester N- [N- (3,5 -difluorophenylacetyl)-L-phenylglyciny l]-L-phenylglycine methyl ester 25 iV-[7V-(phenyIacetyI)-L-alaninyl]-L-alanine methyl ester A^-[^/-(phenylacetyl)-L-alaninyl]-L-leucine methyl ester Ar-[A'-(phenylacetyl)-L-alaninyl]-L-isoleucine methyl ester 30 N-[jV-(phenylacetyl)-L-alaninyl]-L-prohne methyl ester jV-[jV-(phenylacetyl)-L-a]aninyl]-L-phenylalanme methyl ester 35 TV-fA^phenylacetyQ-L-alaninylj-A^-f/erf-butoxycarbonyO-L-lysine methyl ester iV-[Af-(phenylacetyl)-L-alaninyl]-glycine methyl ester 40 A^-[/V-(phenylacetyl)-L-alaninyl]-L-valine methyl ester A'-[jV-(phenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methyl ester iV-[AHphenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methyl ester 45 Af-[jV-(3-nitrophenylacetyl)-L-alaninyl]-L-valine Printed from Mimosa WO 98/22494 PCT/US97/20804 -23- 2V-[7V-(phenylacetyl)-L-alaninyl]-L-W-methylalamne methyl ester A^[jV-(isovaleryl)-L-phenylglycinyl]-L-alanine wo-butyl ester 5 A/-[/V-(isovaleryl)-L-isoleucinyl]-L-alanine wo-butyl ester A^-Cyclohexyl-A^'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide 10 N-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-hydroxyproLine ethyl ester N-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-lysine methyl ester 15 A^-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-glutamide l-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxylate methyl ester 20 yV-[(S)-3-hydroxy-6-methylhept-2-yl]-N'-(3,5-difluorophenylacetyl)-L- alaninamide 25 40 JV-[(S)-2-hydroxy-1 -phenyleth-1 -yl]-N' -(3,5-difluorophenylacetyl)-L-alaninamide JV-[W-(3,5-difluorophenyl-ar-fluoroacetyl)-L-alaniny]-L-phenylglycine rm-butyl ester 7V-[A?-(3,5-difluorophenyIacetyl)-2-(S)-aminocyclohexylacetyl]-L-30 phenylglycine methyl ester iV-[(lR,2S)-l-hydroxy-l-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide 35 JV-[( 1 R,2S)-1 -hydroxy-1,2-diphenyleth-2-yl]-2V'-(3,5- difluorophenylacetyl)-L-alaninamide A,-[(lS,2R)-l-hydroxy-l-phenylprop-2-yl]-/V'-(3,5-difluorophenylacetyl)-L-alaninamide Ar-2-methoxyethyl-A''-[A^-(3,5-difluorophenyIacetyl)-L-alaninyl]-glycinamide A^-[(S)-a-hydroxy-a-phenyl-wo-propyl]-N'-(3,5-difluorophenylacetyl)-L-45 alaninamide Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 24 - iV-[(S)-2-hydroxy-l,2-diphenylethyl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide Af-[(S)-l-hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide 5 Ar-[a-hydroxy-a'-(4-hydroxyphenyl)-/50-propyl]-N'-(3,5-difluorophenylacetyl)-L-alajunamide Ar-2-pyridylmethyl-A''-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-10 phenylalaninamide iV-[a!-hydroxy-a;'-pyrid-2-yl-«0-propyl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide 15 A/-[a-hydroxy-Q('-pyrid-4-yl-/5o-propyl]-N'-(3,5-difluorophenyiacetyl)-L- alaninamide 20 25 30 A'-[(S)-l-hydroxy-4-methylpent-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide Af-[or-methoxy-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide N-[ 1 -hydroxy-3-methyl-but-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alamnamide A'-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(6-aminopyrid-2-yl)acetate methyl ester A^[l-hydroxy-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide 2V-[(S)-2-methoxy-l-phenyleth-l-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide Ar-[(S)-l-methoxy-2-phenyl-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-35 alaninamide /V-[(S)-1 -acetoxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide iV- [(S)-1 -<7m-butylcarbonyloxy)-hex-2-yl]-N' -(3,5-difluorophenylacetyl)-40 L-alaninamide //-[2-hydroxy-1 -(thien-2-yl)ethyl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide 45 //-[(S)-2-hydroxy-2-methyl-l-phenylprop-l-yl]-N'-(3,5- difluorophenylacetyl)-L-alamnamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 25 - A'-[/V-(3,5-difluorophenylacetyl)-L-(thien-2-yI)glycinyl]-L-phenylalanine rerr-butyl ester Af-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinol 5 iV-[iV-(cyclopropaneacetyl)-L-phenylglycinyl]-L-phenylglycinol N-[iV-(cyclopentaneacetyl)-L-phenylglycinyl]-L-phenylglycinol 10 N- [/V-(3,5-difluorophenylacetyl)-D, L-phenylglycinyl]-D ,L- phenylglycinamide //-[iV-(3,5-difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamide 15 N-[iV-(2-thienylacetyl)-L-alaninyl]-L-phenylglycinamide jV-[iV-(n-caprotyl)-L-alamnyl]-L-phenylglycinamide Af-|W-(3,5-difluorophenylacetyl)-L-norleucinyl]-L-phenylglycine methyl 20 ester N-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-L-phenylglycine methyl ester 25 /V-[/V-(3,5-difluorophenylacetyl)-L-/m-leucinyl]-L-phenylglycine methyl ester 30 7V-[W-(3,5-difluorophenyIacetyl)-L-isoleucinyl]-L-phenylglycine methyl ester /V-[A^-(3,5-difluorophenylacetyl)-L-cyclohexylalaninyl]-L-phenylglycine methyl ester //-[A^-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-35 phenylglycine methyl ester iV-[Ar-(3,5-difluorophenylacetyI)-(S)-2-amino-2-(thien-3-yl)acetyl]-L-phenylglycine methyl ester 40 Ar-[A^-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-2-yl)acetyl]-L- phenylglycine methyl ester 45 Ar-[iV-(3,5-difluorophenylacetyl)-L-(4-fluorophenyl)glycinyl]-L-phenylglycine methyl ester Printed from Mimosa WO 98/22494 PCT/US97/20804 - 26 - Af-[AH3,5-difluorophenylacetyl)-D-(4-fluorophenyl)gIycinyl]-L-phenylglycine methyl ester /V-[AH3,5-difiuorophenylacetyl)-L-(4-methoxyphenyl)glycinyl]-L-5 phenylglycine methyl ester A^-[/V-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-butyl ester 10 Af-[iV-(cyclopropylacetyl)-L-phenylglycinyl]-L-phenylglycine re/T-butyl ester 15 20 35 iV-[/V-(cycIopentylacetyl)-L-phenylglycinyl]-L-phenylglycine/m-butyl ester A'-[.'V-(/m-butylacetyl)-L-alaninyl]-L-phenylglycinamide A'-^rr-butyl-A"-[yV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(5-bromothien-2-yl)glycinamide A^rgrf-butyl-A^'-[A^-(3,5-difluorophenylacetyl)-L-alamnyl]-D-(5-bromothien-2-yl)glycinamide A'-/^rr-butyl-iV'-[//-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-25 bromothien-2-yl)glycinamide A'-/err-butyl-A''-[/V-(3,5-difluorophenylacetyl)-L-alainnyl]-L-(thien-2-yl)glycinamide 30 A^-rerr-butyl-Ar'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2- yl)g]ycinamide iV-/m-butyl-/V'-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-3-yl)glycinamide jV-/e/?-butyl-7V'-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide Ar-fer/-butyl-Ar'-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-D-40 phenylglycinamide iV-/er7-butyl-/V'-[A'-(3,5-difluorophenylacetyl)-L-alariinyl]-L-phenylglycinamide 45 A^-/m-butyl-jV'-[A^-(3,5-difluorophenylacetyl)-L-a]aninyl]-D,L-(5- chlorothien-2-yl)glycinamide Printed from Mimosa 98/22494 PCT/US97/20804 — 27 - /V-Cyclohexyl-W-[A/-(3,5-difluorophenylacetyl)-L-alaninyl]-D-4-(phenyl)phenylglycinamide N-/erf-butyl-Ar'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenoxy)phenylglycinamide iV-(S)-(-)-o(-methylbenzyl-A^'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide ■N-/err-butyl-./V'-[yV-(3,5-dif]uorophenylacetyl)-L-alaninyl]-L-3-(phenyl)phenylglycinamide iV-rerr-butyl-jV'-[7V-(3,5-difluorophenylacetyl)-L-alajiinyl]-L-4-(ethyl)phenylglycinamide //-rm-butyl-/V'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(phenyl)phenylglycinamide //-/e/t-butyl-N'-[JV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(benzyl)phenylgiycinamide Af-/err-butyl-W-[Af-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-bromophenylglycinamide /V-rm-butyl-/V'-[A':(3,5-difluorophenylacetyl)-L-alaniny]]-L-4-(cyclohexyl)phenylglycinamide A^-rerr-butyl-Ar'-[yV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(4-ethylphenyOphenylglycinamide N-rerr-butyl-Ar'-[jV-(3,5-difluorophenylacetyl)-L-alaiiiriyl]-D,L-4-(/ert-butyl)phenylglycinamide jV-/e^f-butyl-A^'-[/V-(3,5-difluorophenylacetyl)-L-alarinyl]-D,L-3-(4-chlorophenoxy)phenylglycinamide A?-cyclohexyl-A^'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(phenyl)phenylglycinamide iV-[W-(3,5-difIuorophenyl-a-hydroxyacetyl)-L-a]aninyl]-L-phenylglycine rm-butyl ester iV-fen,-butyl-A^'-[Ar-(3,5-difIuorophenyl-a,a-difluoroacetyl)-L-aIaninyl]-L-phenylglycinamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 28- AT-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine/err-butyl ester A^-[(S)-l-oxo-l-phenylprop-2-yl]-//'-(3,5-difluorophenylacetyl)-L-5 alaninamide N-[N-(3,5-difluorophenylacetyl)-L-alamnyl]-D}L-(pyrid-3-yl)glycinerm- butyl ester 10 [/V-IW-P.S-difluorophenylacety^-L-alanmylJ-DjL- phenylglyciny 1] morpholine N-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(2-methoxy)phenylglycine methyl ester //-[./V-^S-difluorophenylacety^-L-alaninylj-D.L-phenylglycine N-tert-butoxycarbonyl(hydroxyl amine) ester 15 N-neopentyl-./V'-|7V-(3,5-difluorophenylacetyl)-L-aIaninyl]-D,L-20 phenylglycinamide /V-tetrahydrofurfuryl-Ar'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide 25 7V-methoxy~W-|W-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L- phenylglycinamide 30 [AL[A'-(3,5-difluorophenylacetyI)-L-alaninyl]-D,L-phenylglycinyl] azetidine Ar-/jo-butyl-A?'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide N-cyclopropanemethyl-A''-[A'-(3,5-difluorophenylacetyl)-L-a]aninyl]-D,L-35 phenylglycinamide Ar-methoxy-Ar-methyl-A''-[A''-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide 40 Af-2-methylprop-2-enyl-A,'-[//-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L- phenylglycinamide A'-(pyrid-3-yl)methyl-jV'-[//-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide 45 Printed from Mimosa WO 98/22494 PCT/US97/20804 - 29 - A^-(pyrid-4-yl)methyl-vV-[A/-(3,5-difluorophenylacetyl)-L-alaninyI]-D,L-phenylglycinamide 2V-furfuryl-W-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-5 phenylglycinamide N-cyclopentyl-iV'-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide 10 N-l-benzylpiperidin-4-yl-W-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]- D ,L-phenylglycinamide 15 30 N,/V-dimethyl-A','-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide jV-2,2,6,6-tetramethylpipendin-4-yl-N'-[jV-(3,5-difluorophenylacetyl)-L-alaninyl]-D ,L-phenylglycinamide jV-2-methylcyclohexyl-Ar'-[//-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-20 phenylglycinamide iV-4-methylcyclohexyl-A/'-[A/-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycmamide 25 7V-l-ethoxycarbonylpiperidin-4-yl-AT'-[JV-(3,5-difluorophenylacetyl)-L- aJaninyl]-D,L-phenylglycinamide //-methyl-N'-[A^-(3,5-difluorophenylacety])-L-alaninyl]-L-phenylglycinamide //-/err-butoxy-A^'-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide ./V-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]~D,L-phenylglycine N-zm-35 butyl(hydroxylamme) ester A''-[A''-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyIglycinehydrazide N-( 1 -ethoxyethen-1 -yl)-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-40 phenylglycine hydrazide A'-[A'-(pheny]acetyl)-L-a]aniny]]-L-phenylglycine /erf-butyl ester A-4-(phenyl)butyl-W-|W-(3,5-difluorophenylacetyl)-L-a]aninyl]-L-45 phenylglycinamide Printed from Mimosa 98/22494 PCT/US97/20804 -- 30 - AT-3-(4~iodophenoxy)propyl-Af'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide iV-6-(amino)hexyl-iV-[//-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide Hydrochloride AM-(phthalimido)pent-2-yl-W-(3,5-difluorophenylacetyl)-L-alaninamide iV-[7V-(3,5-difluorophenylacetyl)-L-(3,5-difluorophenyl)glycinyl]-L-(3,5-difluorophenyl)glycine methyl ester AT-[iV-(3,5-difluorophenylacetyl)-L-aIaninyl]-L-norleucine A^[A^-(cyclopentaneacetyI)-L-alaninyl]-L-phenylglycine rerf-butyl ester /V-[/V-(3,5-difluorophenylacetyl)-L-alariinyl]-L-4-fluorophenylglycine iso-propyl ester JV-(isopropyl) A^'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide 7V-|7V-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine rm-butyl ester A^-[//-(cyclopropylacetyl)-L-alaninyl]-L-phenylalanine rerr-butyl ester iV-[AH3,5-Difluorophenylacetyl)-L-alanjnyl]-L-phenylglycine /jo-butyl ester Ar-[7V-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-phenylglycine methyl ester Ar-[A'L(3,5-Difluorophenylacetyl)-L-alaninyl]-L-(3-Q;-phenyl)proline methyl ester /V-[/V-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-azetidine methyl ester N-ITV-^.S-difluorophenylacetyO-L-alaninyl^-amino-S-CS-chlorobenzothiophen-2-yl)acetate methyl ester Ar-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)propionate tert-butyl ester iV-[7V-(3,5-difluorophenylacetyl)-L-a]aniriyl]-L-phenylglycinamide cm-butyl ester 7V-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 31 - A^[AK3,4~dichlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide N-[//-(3-chlorophenylacetyl)-L-alaninyI]-D-phenylglycinamide 5 A^t/V-(3"bromophenylacetyl)-L-alaninyl]-D-phenylglycinamide A^-[A^(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide 10 2V-[Af-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide N-[JV-(3-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide //-[Ar-(4-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide 15 A/-[A^-(3-trifluoromethylphenylacetyl)-L-alaninyl]-D-phenylglycinamide /V-[Af-(3-methoxyphenylacetyl)-L-alaninyl]-D-phenylglycinamide 20 iV-[/\/-(2-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide /V-[jV-(l-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide iV-[Af-(2-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide 25 W-[W-(phenylacetyl)-L-alaninyl]-D-phenyIglycinamide /V-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine 30 Af-[Af-(3,5-difluorophenylacety])-L-alaninyl]-D-pheny]glycinamide iy'-[jV-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-furanyl)acetamide 35 //'-[iV-(3,5-difluorophenylacetyl)-D-aIaninyl]-D-phenylglycinamide N'-[A'L(3,4-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide /V'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanin-N-40 methylsulfonamide Af"-methyl-N"-phenyl-/V'-|W-(3,5-difluorophenyIacetyl)-L-a]amnyl]-glycinamide 45 A?"-methyl-A'"-phenyl-iV'-[jV-(3,5-difluorophenylacetyl)-L-alaninyl]-L- alaninamide Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 32 - N'- [TV-(3,5 -difluorophenylacetyl)-L- methioninyl] -L-phenylglycinamide JV"-methyl-^V"-benzyl-iV'-[^V-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamide 5 A^"-4-fluorobenzyl-iV'-[A/'-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide N'-[A'-(3,5-difluorophenylacetyl)-L-a]aninyl]-L-(4-fluoro)phenylglycine 10 neopentyl ester N- [N- (2,3, ■4,5,6-pentafluorophenylacety l)-L-alaninyl] -L- (py rid-3-yl)glycine methyl ester 15 Af-[7V-(3,5-difluoropheny]acetyI)-L-alaninyl]-L-(pynd-3-yl)glycine/«/t- butyl ester 20 N-[N-(3,5-difluorophenylacetyl)-L-(0-benzyl)serinyl]-L-phenylglycine methyl ester iV-[7V-(3,5-difluorophenylacetyl)-L-(0-benzyl)threoninyl]-L-phenylglycine methyl ester A^-[jV-(3,5-difluorophenylacetyl)-L-threoninyl]-L-phenylglycine methyl 25 ester ./V-|W-(3,5-difluorophenylacetyI)-L-serinyl]-L-phenylglycine methyl ester /V"-4-methylphenyl-/V '-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-30 phenylglycinamide /V"-tetrahydrofurfuryl-iV'-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide 35 iV'-[Af-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenyl- glycinamide A^'-[A^-(3,5-difluorophenylacetyl)-L-methionyl]-L-phenylglycinamide 40 AL[A/-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamide Ar'-[A^-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenyIglycinamide Ar-[/V-(3,5-difluorophenylacetyl)-L-valinyl]-L-pheriylglycinamide 45 Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 33 - 2V-[(R)-a-methylbenzyl]-W-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide N-[l-phenyl-2-oxo-3-methylbutan-l-yl]-.W-(3,5-difluorophenylacetyl)-L-5 alaninamide N- [ 1 -pheny 1-2-oxo-propan-1 -y 1] - A/ '-(3,5-difluorophenylacetyl)-L-alaninamide 10 N- [ 1 -phenyl-2-oxo-pentan-1 -yl]-N'-(3,5-difluorophenylacetyl)-L- alaninamide Af-[l-phenyl-2-oxo-2-phenyl-ethan-1 -yl]-A"-(3,5-difluorophenyl-acetyl)-L-alanmamide 15 /V-[l-phenyl-2-oxo-butan-l-yl]-/V'-(3,5-difluorophenyl-acetyl)-L-alamnamide A^[l-phenyl-2-oxo-4-methylpentan-l-yl]-iV'-(3,5-difluorophenyl-acetyl)-20 L-alaninamide iV'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-a-hydroxyphenylalanine methyl ester 25 Ar-[4-((2-hydroxy-4-azido)-phenyl)-NHC(0)-)butyl] N'~[N-(3,5- difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide A^[(S)-l-phenyl-2-oxo-2-phenyl-ethan-l-yl]-A^'-(3,5-difluorophenyl-acetyl)-L-alaninamide 30 W-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycine rert-butyl ester ;V'-[jV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-phenylphenylglycine 35 /m-butyl ester [7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(2,3-benzo[b]proline) methyl ester 40 A/"-/m-butyl-W-[W-(3,5-difluorophenylacetyI)-L-alaninyl]-L-4-rt- butylphenylglycmamide jV"-/m-butyl-./V'-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(phenylacetenyl)phenylglycinamide 45 iV'-17V-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 34 - ,/V-[l,3-diphenyl-2-oxo-propan-l-yl]-W-(3,5-difluorophenylacetyl)-L-alaninamide iV-[ 1 -phenyl-2-oxo-2-cyclopentylethan-1 -yl]-W-(3,5-difluorophenylacetyl)-L-alaninamide N-[ 1 -phenyl-2-oxo-hexan-1 -yl]-N'-(3,5-difluorophenylacetyl)-L-alamnamide N-[l-phenyl-2-oxo-3-methylpentan-l-yl]-W-(3,5-difluorophenylacetyl)-L-alaninamide 7V"-n-hexyl-6-biotinamidyl-/V'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D ,L-phenylglycinthioamide A^'-[iV-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionine W-[W-(2-rm-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycine methyl ester N"-tert-butyl jV'-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-fluorophenylglycinamide N'-[W-(3,5-difluorophenylacetyl)-L-aJarunyl]-D,L-2-phenylglycirie methyl ester AT-[(S)-l-phenyl-2-oxo-3-phenylpropan-l-yl]-W-(3,5-difluorophenylacetyl)-L-alaninamide Af'-[/V-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycine A^'-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycine tert-butyl ester W-[/V-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycine A/'-[A';-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycine tert-butyl ester iV-[2-hydroxy-1 -(S)phenyleth-1 -yl]-W-[(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alaninamide A/-[2-hydroxyeth-l-yl]-A/'-[(3,5-difluorophenylacetyl)-L-alaninyl]-L- phenylglycinamide Printed from Mimosa wo 98/22494 PCT/US97/20804 "35" ^ A (R IP) r - 10 J ^ sjj iV'-[A^-(3,5-difluorophenyl-2-oxo-acetyl)-L-alaninyl]-L-2-phenylglycine rm-butyl ester [jV-(2,5-dichlorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl ester [N-(3,5-difluorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl ester [^-(3,4-dichlorothiophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl ester [AH3-aminoproprionyl)-L-alaninyl]-L-phenylglycine tert-butyl ester [7V-(3-ferr-butoxycarbonylamino)propionyl)-L-alaninyl]-L-phenylglycine /err-butyl ester 15 20 In formula I above, X" is preferably hydrogen and X' is preferably hydrogen or fluoro. In formula I above, Z is preferably a covalent bond linking R1 to -CX'X"-. In formula I above, preferred R1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like. 30 Preferred R1 substituted aryl groups include, for example, monosubsti- tuted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3,5 substituents); and trisubstituted phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not include more than 3 substituents. intellectual property OFFICE OF NZ. 1 8 JUN 2001 received WO 98/22494 PCT/US97/20804 - 36 -- Examples of substituted phenyls include, for instance, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxy-phenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2-hydroxy-5 phenyl, 2-methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 3,4-dibromophenyl, 3,4-dichlorophenyl, 3,4-methylene-dioxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2,4-dichlorophenyl, and 2,5-difluorophenyl. 10 Preferred R1 alkaryl groups include, by way of example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, and the like. Preferred R1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups include, by way of example, iso-propyl, n-propyl, n-butyl, 15 iso-butyl, sec-butyl, rm-butyl, -CH2CH=CH2, -CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexy], -CH2CH2-cyclopentyl, aminomethyl, N-/m-butoxycarbonylaminomethyl, and the like. 20 Preferred R1 heteroaryls and substituted heteroaryls include, by way of example, pynd-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyndyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yI, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-25 2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-l ,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, and the like. Preferably R2 is selected from the group consisting of hydrogen, alkyl, 30 substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. Particularly preferred R2 substituents include, by way of example, methyl, ethyl, /i-propyl, Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 37 - iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, 4-fluorophenyl, 3,5-difluoro-phenyl, 4-methoxyphenyl, benzyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, thien-2-yl, thien-3-yl, -CH2CH2SCH3, -CH2OCH20, -CH(CH3)OCH2<£, -CH(OH)CH3, -CH2OH and the like. As noted below, R2 5 (as well as R4) is preferably the side chain of an L-amino acid. Preferably, R3 is hydrogen, methyl or together with R4 and the nitrogen to which R3 is attached forms pyrrolidin-2-yl, 2,3-dihydroindol-2-yl, piperidin-2-yl, 4-hydroxy-pyrrolidin-2-yl, l,2,3,4-tetrahydroisoquinolin-3-yl, and the like. 10 Preferred R4 substituents include, for example, hydrogen, methyl, ethyl, iso-propyl, ^-propyl, «-butyl, sec-butyl, /so-butyl, cyclopentyl, cyclohexyl, allyl, /so-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2-indol-3-yl, phenyl, />-(phenyl)phenyl, w?-(phenyl)phenyl o-fluorophenyl, 15 wj-fluorophenyl, p-fluorophenyl, p-bromophenyl, /n-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, />-hydroxybenzyl, /j-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH20-benzyl, /7-(CH3)3C0C(0)CH20-benzyl, /?-phenylphenyl, 3,5-difluorophenyl, p-(HOOCCH20)-benzyl, 2-aminopyrid-6-yl, 4-(N-morpholino-CH2CH20)-20 benzyl, -CH2CH2C(0)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thien-2-yl, -CH2-thiazol-4-yl, -CH2(l-methyl)cyclopropyl, -CH2-thien-3-yl, thien-3-yl, thien-2-yl, -CH2-C(0)0-r-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, 2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -(CH2)2SCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2i -CH2CH=CHCH3 (cis and trans), 25 -CH2OH, -CH(OH)CH3, -CH(0-f-butyI)CH3, -CH2OCH3, -(CH^NH-Boc, -(CH2)4NH2, -(CH2)4N(CH3)2, -CH2-pyndyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyndyl), -CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), -CH2-(N-morphohno), p-(N-morpholino-CH2CH20)-benzyl, benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-30 chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, Printed from Mimosa WO 98/22494 PCT/US97/20804 -38 - benzo[b]thiophen-3-yl, tetrazol-5-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2-N-phthalimidyl, 2-methylthiazol-4-yl, and tiueno[2,3-Z>]thiophen-2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl, 5-chlorothien-2-yl, 3-phenoxyphenyl, 5 2-phenoxyphenyl, 4-ethylphenyl, 2-benzylphenyl, (4-ethylphenyl)phenyl, 4-terr-butylphenyl, 4-/i-butylphenyl, o-(4-chlorophenoxy)phenyl, furan-2-yl, 4-phenylacetylenylphenyl and the like. Preferably, R5 is hydrogen. However, in another embodiment, R4 and 10 R5 are fused to form a cycloalkyl group including, for example, cyclopropyl, cyclobutyl, and the like. One preferred X substituent is -C(0)Y. Preferably Y is hydroxy, alkoxy or substituted alkoxy such as methoxy, ethoxy, /j-propoxy, wo-propoxy, 15 n-butoxy, zso-butoxy, /m-butoxy, neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-«-propoxy, 3-iodo-/i-propoxy, 4-bromo-/i-butoxy, -0NHC(0)0C(CH3)3, -ONHC(CH3)3 and the like. Another preferred Y group is -NR'R" where R' and R" are as defined above. Such preferred Y groups include, by way of example, amino (-NH2), -NH(/jo-butyl), -NH(sec-butyl), N-methylamino, N,N-20 dimethylamino, N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidmyl, N-hexamethyleneimino, N-heptamethylene-imino, N-pyrrolidinyl, -NH-methallyl, -NHCH2-(furan-2-yl), -NHCH2-cyclopropyl, -NH(zm-butyl), -NH(p-methylpheny 1), -NHOCH3, -NHCH2(p-fluorophenyl), -NHCH2CH2OCH3, -NH-cyclopentyl, -NH-cyclohexyl, -NHCH2CH2N(CH3)2, -NHCH2C(CH3)3, 25 -NHCH2-(pyrid-2-yl), -NHCH2-(pyrid-3-yl), -NHCH2-(pynd-4-yl), N-thiazolindinyl, -N(CH2CH2CH3)2, -N[CH2CH(CH3)2]2, -NHOH, -NH(p-NOr<f>), -NHCH2O-NO2-0), -NHCH2(m-NO2-0), -N(CH3)OCH3, -N(CH3)CH2-<A, -NHCH2-(3,5-di-fluorophenyl), -NHCH2CH2F, -NHCH2(p-CH30-</>), -NHCH2(m-CH3O-0), -NHCH2(/>CF3-<£), -N(CH3)CH2CH2OCH3, 30 -NHCH2CH2<t>, -NHCH(CH3)<p, -NHCHr(p-F-<£), -N(CH3)CH2CH2N(CH3)2, -NHCH2-(tetrahydrofuran-2-yl), -NHCH2(p-trifluoromethylphenyl), Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 39 - v-1 -NHCH2C(CH3)=CH2) -NH-[(p-benzyl)pyrid-4-yl], -NH-[(2,6-dimethyl)pyrid-4-yl], -NH-(2-methylcyclohexyl), -NH-(4-methylcyclohexyl), -NH-[N-ethoxycarbonyl]-piperidin-4-yl, -NHOC(CH3)3, -NHCH2CH2CH2CH2-<£, -C(0)NH(CH2)30-(p-CH3)<^, -0(0)^(^2)^2, -NH-(tetrahydrofuran-2-yl), 5 -N(CH3)4>, -NH(CH2)4NHC(0)-(2-hydroxy-4-azido)-phenyl, -NHCCH^-(biotinamidyl), and the like. Another preferred Y group is an alkyl group such as methyl, ethyl, /jo-propyl, fl-propyl, z'jo-butyl, n-butyl, sec-butyl, /err-butyl, 10 -CH2CH2CH(CH3)2, -CHj-pyridy-2-yl, -CH2-pyridy-3-yl, -CH2-pyridy-4-yl, -CH2-fur-2-yl, and the like; a substituted alkyl group such as benzyl; a cycloalkyl group such as cyclopentyl; and an aryl group such as phenyl. Still another preferred Y group is -NHS02-R where R is selected from 15 alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic. Such groups are exemplified by NH-S02-CH3. Preferred Y' groups include a substituted alkyl group such as -CH2OH, -CH(OH)CH2CH2CH(CH3)2, -CH(OH)<*>, -CH(0H)CH2C(0)0CH3, 20 -C(OH)(CH3)2, -CH2OCH3, -CH20C(0)0CH3, -CH20C(0)C(CH3)3, and the like. intellectual property 0"TE OF f17 1 8 JUN 2001 received - 39a - NZ 513278 describes and claims a compound represented by formula: x' x" o Rt ,R5 R1Z if I J' ° R2 R3 wherein R: is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, hcteioaryl and heterocyclic; R* is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R' is independently selected fiom the group consisting of hydrogen and methyl and R3 together with Rs can be fused to form a cyclic structure of from 3 to 8 atoms winch is optionally fused with an aryl or heteroaryl group; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl, each R5 is selected from hydrogen and methyl or together with R" forms a cycloalkyl group of from 3 to 6 carbon atoms; X is selected fiom the group consisting of -C(0)Y and -C(S)Y where Y is selected Trom the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl with the proviso that the substitution, on said substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-OC(0)alkyl, or a-0C(0)aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R" where R' and R" are independently selected from hydrogen, alkyl. alkenyl, alkynyl. substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, aryl, heteioaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" arc joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional hcteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, where when either R' or R" are substituted alkyl. the substituted alkyl is an alkyl group of 1 to 10 carbon atoms, having from 1 to 3 substituents selected from die group consisting of alkoxy, substituted alkoxy, aryloxy, hcteroaryloxy, heterocyclyloxy, acylamino, amino, ammoacyl, aminocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, intellectual PROPERTY office OF n.z. 0 3 AUG 2001 received carboxyalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, mono-alkylamino, di-alkylamino, mono-(substitutcd alkyl)amino, di-(substituted alkyl)ammo, mono-aryl ammo, di-aryl ammo, mono-hcteroarylamino, di-hcteroarylamino, mono-heterocyclic ammo, di-hetcrocyclic amino and unsymmetric di-subsututed amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, (j) -NHSO:-R3 where R8 is selected from alkyl, substituted alkyl, alkenyl, substiluted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR9NR10R10 where R9 is hydrogen or alkyl, and each R'° is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -0NR'[C(0)0]iRl° where z is zero or one, R9 and R10 are as defined above; X can also be -CRf,R6Y' where cach R6 is independently selected fiom the group consisting ofhvdrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected fiom the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted tiuoalkoxy, phthalunido, -0C(0)R\ -SSR7, -SSC(0)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, Z is selected from the group consisting of a bond covalently linking R1 to -CX'X"-, oxygen and sulfur; and n is an integei equal to 1 or 2; with the proviso that. A. when R1 is phenyl or 3-nitrophenyl, R2 is methyl, R1 is hydrogen, R4 is -CH(OH)CH3, R5 is hydrogen, X' and X" are h>drosen, Z is a bond, and n is 1, then X is not -C(0)0H; B. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CII3 derived from D-thrconinc, RJ is hydrogen, X' and X" arc hydrogen, Z is a bond, and n is 1, then X is not -C(0)OH or -C(0)0CH3; C. when R1 is phenyl, R2 is methyl. R4 is benzyl, RJ is hydrogen, X is methoxycarbonyl, X' and X" are hydrogen, Z is a bond, and n is 1, then R3 is not methyl; D when R1 is tfc-propyl, R2 is -CH2C(0)NH2, R3 is hydrogen, R4 is /jo-buty], R5 is hydrogen, X' and X" arc hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH:; E. when R1 is phenyl, R2 is methyl, R5 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and nisi, then R3, the nitrogen atom attached to R3, and R4 do not form l,2,3.4-tetrahydro/ii9-quinolin-2-yl or pyrrohdin-2-yl; F. when R1 is phenyl, R: is methyl, R3 is hydrogen, R5 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not 4-amino-n-butyl; G. when Rl is 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH,, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NH2 or -CH:OH; H. when R1 is phenyl, R: is methyl, R3 is hydrogen, R5 is hydrogen, X is -CI-I2OCII3, X' and X" are hydiogen, Z is a bond, and n is 1, then R4 is not benzyl or ethyl; intellectual property office of n z. 1 8 JUN 2001 received - 39c - ;'*•>? /; r? 0: f\ I. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is methyl, R4 is methyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CHOHcf); J. when R' is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phcnylglycine, R5 is hydrogen, X' and X" are hydiogen, Z is a bond, and n is 1, then X is not -CHOHcJ) or -CH:OH, K when R, is iV-(2-pyrrolidinonyl), R2 is methyl, R3 is hydrogen, R4 is benzyl, Rs is hydrogen, X' and X" arc hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH3; L, when R1 is 3,5-difluorophenyl, R2 is methyl derived from D-alanine, RJ is hydrogen, R4 is phenyl derived from D-phenylglycmc, Rs is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NH-ben/.yl; M. when Rl is 5,5-difluorophcnyl, R2 is methyl, R3 is hydrogen, R4 is hydrogen, RJ is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CH2OH; N. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is 4-phenylphenyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NHC(CH3),, 0, when R' is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R3 is hydrogen, X' and X" arc hydrogen. Z is a bond, and n is 1, then X is not -C(0)NHCH(CH3)<|>; P. when R1 is ethyl, R2 is /so-butyl, R3 is hydrogen, X' and X" are hydrogen, Z is a bond and n is 1, then X is not -CH(C2H2F30)(CilH9); and Q. when R1 is phenyl, R2 is hydrogen or methyl. R3 is hydrogen, R4 is methyl, R5 is hydrogen, X' and X" arc hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH3; with the further proviso that the compounds of die formulas below are excluded wherein R1 is selected from the group consisting of. (a) aryl group substituted with from 1 to 3 substituents selected from the gruup consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy. alkenyl, alkynyl, ammo, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomediyl provided lhat at least one of said substituents is selected from acyl, acyloxy, intellectual property office of n z. 1 8 JUN 2001 received - 39d - — ' A* fa /,-n i/?\ \J_Jl ^ ^ alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, fiunro and heteroaryl, (b) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting hydioxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nicro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and heteroaryl, (c) cycloalkenyl, (d) substituted alkyl provided that the substiruent is not aryl and/or heteroaryl groups, (e) substituted alkenyl provided that the substiruent is not aralkenyl or hetcroaralkenyl, (f) substinued alkynyl provided that the substituent is not aralkynyl or heicroaralkynyl, and (h) heterocyclic; R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl, each R5 is selected from hydrogen and mcihyl or together with R4 forms a cycloalkyl croup of jrom 3 to 6 carbon atoms; X is -C(0)Y or -C(S)Y where Y is selected from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl with the proviso that the substitution on said subsututed alkyl do noL include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl or a-0C(0)aryl gioups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (0 aryl, (g) hetcroaiyl, (h) heterocyclic, (i) -NR'R" where R' and R" are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 caibon atoms optionally containing 1 to 2 additional heteroaioms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups, intellectual property office of NZ 1 8 JUN 2001 received (j) -NHSOrR8 where R8 is sclectcd from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR9NR10R10 where R9 is hydrogen or alkyl, and cach R;0 is independently sclectcd from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aiyl, heteroaryl, heterocyclic, and (1) -0NR5[C(0)0]zR10 where z is zero or one, R9 and R'° arc as defined above; X can also be -CRGR6Y' where each R6 is independently selected from the group consisting of liydiogcn, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is sclectcd from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, phihalimido, -0C(0)R7, -SSR7, -SSC(0)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X' is hydrogen, hydroxy or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, and n is an integer equal to 1 or 2, with the proviso excluding the following known compound: when R1 is o-fluorophenyl, R2 is 3,4-dichlorophenyl or cdiyl, R4 and R5 are hydrogen, X' and X" arc hydrogen, then X is not -C(0)OCH3; wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substiruted alkenyl, substimied alkynyl, aryl, heteroaryl and heterocyclic; R2 is selected from the group consisting of (a) substituted alkyl provided that such substituted alkyl groups do not include aryl or heteroaryl substituted alkyl, or a side-chain of a naturally occurring amino acid, (b) substituted alkenyl provided that such substituted alkenyl groups do not include aryl or heteroaryl subsututed alkenyl, (c) substituted alkynyl provided that such substituted alkynyl groups do not include aiyl oi heteroaryl substituted alkynyl, (d) heterocyclic, intellectual property office of nz. 1 8 JUN 2001 received (e) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl. acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitio, heteroaryl, and tnhalomethyl provided lhat at least one of said subsiituenis is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aiyloxy, carboxyl, carboxylalkyl, carboxylamido, and heteroaryl, and (f) a hetcioaryl group substituted with 1 to 3 substituents selecicd from the group consisting of alkyl, alkoxy, aryl, alkaryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that if there is an alkyl substituent on the substituted heteroaryl group then there is at least one other substituent which is not alkyl; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkcnyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; each Rs is selected from hydrogen and methyl or together wilh R" forms a cycloalkyl group of from 3 to 6 carbon atoms; X is -C(0)Y or -C(S)Y where Y is selected from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl with the proviso that Lhe substitution on said substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl or a-0C(0)aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (0 aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R" where R' and R" are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, hcceioaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups, (j) -NHSO,-Rs where R3 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR'NR^R10 where R9 is hydrogen or alkyl, and cach R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -ONR5[C(0)OJ7R'° where z is zero or one, R9 and R10 are as defined above; X can also be -CR6RSY' where each R6 is independently selected from the group consisting of hydiogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, intellectual property office of nz. 1 8 JUN 2001 received - 39g - phthalimido, -0C(0)R7, -SSR\ -SSC(0)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X' is hydrogen, hydroxy or fluoro; X" is hydrogen, hydroxy or lluoro, or X' and X" together form an oxo group, and n is an inccger equal co 1 or 2, wherein Rl is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkcnyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; R2 is selected from the group consisting of alkyl, subsumted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; R4 is selected from the croup consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl. cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl provided that at lease one R4 is selected to be: (a) substituted alkyl provided that such substituted alkyl groups do not include aryl or heteroaryl substituted alkyl. or a side-chain of a naturally occurring amino acid, (b) substituted alkenyl provided that such substituted alkenyl groups do not include aryl or heteroaryl substituted alkenyl, (c) substiiuted alkynyl provided Lhat such subsiituted alkynyl groups do not include aryl or heteroaryl substituted alkynyl, (d) heterocyclic, (c) aryl group substituted with fiom 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl. carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyi provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, caiboxyl, carboxylalkyl, carboxylamido, and heteroaryl, and (f) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, alkaryi, aryloxy, halo, nitro, heteroaryl, thioalkoxy, X' X' o R: -R5 intellectual property 1 OFFICE OF N7 1 1 8 JUN 2001 I - 39h - 34 6' thioaryloxy provided thai if there is an alkyl substituent on fhe substituted heteroaryl group then there is at least one other substituent which is not alkyl; each R3 is selected from hydrogen and meihyl 01 together with R4 forms a cycloalkyl gtoup of from 3 to 6 carbon atoms; X is -C(0)Y or -C(S)Y where Y is selected from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl with ihe proviso lhat the substitution on said substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl or a-0C(0)aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (c) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R" where R' and R" are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" arc joined to form a cyclic group having from 2 ro 8 carbon atoms optionally contaming 1 to 2 additional hcieroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups, (j) -NHSO;-R3 where R5 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR9NR1UR10 wheie R5 is hydrogen or alkyl, and each R!0 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl. heteroaryl, heterocyclic, and (1) -0NR9[C(0)0],.R10 where z is zero or, one, R9 and R10 are as defined above, X can also be -CRl5Rl3Y' where each R6 is independently selected from die group consisting of hydrogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaiyl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthalimido, -0C(0)R7, -SSR\ -SSC(0)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, and n ih an integer equal to 1 or 2, a:.d intelllctual phoperty ophce of nz 1 8 JUN 2001 received X' X" 0 R1 .R5 XrMVH^ o 1 R2 wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, subsututed alkynyl, aiyl, heteroaryl and heterocyclic; R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, subsututed alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryT heteioaryl ard heterocyclic; each R4 is independently selected frcn the group consisting of Hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; each R3 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms; X is selected from the group consisting of (a) -C(0)-alkyl. (b) -C(0)-substituted alkoxy or substituted tmoalkoxy provided that the substituted alkoxy groups do not include benzyl and phenethyl, (e) -C(0)-aryl wherein the aryl group is substituted with from 1 to 3 substituents selected from the group consisting of hydroxy acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aiyloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitio, heteroaryl, and trihalomethyl. (d) -C(0)-hcteroaryl wherein the heteioaryl group is substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, alkaryl, aryloxy, halo, nii.ro, heteroaryl, thioalkoxy and thioaryloxy (e) -C(0)-NR'R" where R' and R" are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional hetcroatoms selected from oxygen, sulfur and nitrogen and optionally substituted widi one or more alkyl or alkoxy groups, and X can also be -CR^'V where ea<"h Rc ;s independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryi, heteroaiyl and heterocyclic and Y' is selected from die gioup consisting of amino, thiol, alkoxy, phthalimido, -0C(0)R7, -SSR7, -SSC(0)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, provided that R' and R" are not both independendy selected from hydrogen, alkyl, phenyl, benzyl and phenethyl; X' is hydrogen, hydroxy or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, and n is an integer equal to 1 or 2; with, the proviso that: when R1 is ^-propyl, R2 is phenyl, R4 is methyl, R5 is hydrogen, X' and X" are hydrogen, n is 2, and the second R" at the carboxy terminus is meihvl. dien X is not -C(0)NH- - 393 - NZ 513278 also describes and claims a pharmaceutical composition comprising a pharmaceutical^ acceptable carrier and a pharmaceutical^ acceptable amount of a compound of the formula: wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heieroaryl and heierocyclic; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R3 is independently selected from the group consisting of hydrogen and methyl and R- together with R* can be fused to form a cyclic structure of from 3 to 8 atoms which is optionally fused with an aiyl or heteioaryl group; each R~ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; each R3 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms; X is selected from the group consisting of -C(0)Y and -C(S)Y where Y is selecied from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl widi the proviso that the substitution on said substituted alkyl do tiol include a-haloalkyl, a-duxoalkyl, a-0C(0)alkyl, or a-0C(0)aryl groups, (c) alkoxy or thioalkoxy, intellectual property office of n.z. 0 3 AUG 2001 received - 39k - (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aiyl, (g) heteroaryl, (h) hctcrocychc, (i) -NR'R" where R' and R" are independently sclcctcd from hydrogen, alkyl. alkenyl, alkynyl, substituted alkyl, substituted alkenyi, substituted alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional hctcroatoms sclcctcd from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, (j) -NHSOrR8 where R8 is selected from alkyl, subsiituied alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, kereroary! and heterocyclic, (k) -NR'JNR10R!0 where R9 is hydrogen or alkyl, and each R'r' is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteioaryl, heterocyclic, and (1) -0NR9[C(0)0Jj.R'° where z o zero oi one, R0 and R10 are as defined above; X can also be -CR^'Y' wheie each R6 is independently selected from the group consisting of hydrogen, alky], substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, phthalimido, -0C(0)R7, -SSR7, -SSC(0)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X' is hydrogen, hydroxy or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, Z is sclcctcd from the group consisting o' a bond ccvalentlv linking R1 to -CX'X"-, oxygen and sulfur; and n is an integer equal to 1 or 2, widi the proviso that: A. when R1 is phenyl or 3-nitrophenyl, R2 is methyl, R3 is hydiogen, R* is -CH(OH)CH3, Rs is hydrogen, X' and X" are hydiogen, Z is a bond, and n is 1, then X is not -C(0)0II; 13. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3 derived from D-threonmc, R3 is hydrogen X' and X" are hydrogen, Z is a bond, and nisi, then X is not -C(0)0H or -C(0)0CH3,~ C. when R1 is phenyl, R2 is methyl, R4 is benzyl, R5 is hydrogen, X is meihoxycarbonyl, X' and X" are hydrogen, Z is a bond, and n is i, then R' is not methyl; D. when R1 is /.so-propyl, R2 L -CK,C(0)NH2, R3 is hydrogen, R" is zjo-butyl, R5 is hydrogen, X' and X" are hydrogen, 7. is a bond, and n is 1, Lhen X is not -C(0)0CH3; 391 A kJ E. when R1 is phenyl, R2 is methyl, R5 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R\ the nitrogen atom attached to R\ and R4 do not form l,2,3,4-tetrahydroi\5'o-quinolin-2-yl or pyrrolidin-2-yl, F. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R5 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not 4-amino-/?-butyl; G. when R1 is 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3, R5 is hydrogen, X' and X" are hydtogen, Z is a bond, and n is 1, then X is not -C(0)NH2 or -CH2OH; II. when R' is phenyl, R2 is methyl, R3 is hydrogen, R5 is hydrogen, X is -CII2OCII3, X' and X" are hydrogen, Z is a bond, and n is 1, then R" is not ben/.yl or ethyl, I. when Rl is 5,5-difluorophenyl, R2 is methyl, R3 is methyl, R4 is methyl, R5 is hydrogen, X' and X" arc hydrogen, Z is a bond, and r: is 1, then X is not -CHOHc}); J. when Rl is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen. R4 is phenyl derived from D-phenylglycine, R5 is nydrogen, X' and X" are hydiogen, Z i<= a bond, and n is 1, then X is not -CHOHcj) or -CH2OH; K, when R, is al(2-pyrr0hdin0Lyl)i R2 is methyl, R3 is hydrogen, R4 is benzyl, Rs is hydiogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH3; I., when R1 is 3,5-difIuorophenyl, R: is methyl derived from D-alanine, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, Rs is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NH-benzyl, M. V'hcn R' ir, 5,5-difluoroohcnyl, R2 is methyl, R3 is hydrogen, R4 is hydrogen, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CH2OH, N, when R1 is 5,5-difluorophenyl, R2 is rriethyi, R3 is hydrogen, R4 is 4-phenylphenyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and ma 1, then X is not -C(0)NHC(CH3)3; and 0. when R1 is 5,5-difluorophenvI, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NHCH(CH3)(J); with the further proviso that the compounds of the formulas below are excluded- X' X' 0 r; 3s o wherein R' is selected from the group consisting of: - 39m - (a) aryl group substituted with from 1 to 3 subsiiiucnis selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaiyl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomcihyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and heteroaryl, (b) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, ammo, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, niiro, heteroaryl, and trihalomeihyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and heteroaryl, (c) cycloalkenyl, (d) substituted alkyl provided that the subsiiiuent is not aiyl and/oi heteroaryl groups, (e) substituted alkenyl provided that the subsiiiuent is not aralkenyl or heteroaralkenyl, (t) substituted alkynyl provided that the substituent is not aralkynyl or heteioaralkynyl, and (h) heterocyclic; R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; each R5 is sclcctcd from hydrogen and methyl or together with R* forms a cycloalkyl group of from 3 to 6 carbon atoms; X is -C(0)Y or -C(S)Y where Y is selected from the group consisting of (a) alkyl ci cycloalkyl, (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-0C(0)aIkyl o. a-0C(0)aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substitMted mioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R" where R' and R" are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional hctcroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups, (j) -NHS02-R3 wheie R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR'NR10R10 where R° is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkeny!, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -0NR°[C(0)0]2RU1 where z is zero or one, Ry and R10 are as defined above; X can also be -CR6RcY' where each R5 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from die group consisting of hydroxy 1, amino, thiol, alkoxy, substituted alkoxy, phthalimido, -0C(0)R\ -SSR\ -SSC(0)R7 whe'e R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X' is hydrogen, hydroxy or fluoro; X" is hydrogen, hydroxy or fluoro, or X' md X" together lonn an oxo group, and n is an integer equal to 1 or 2; with the proviso excluding the following known compound; when Rl is o-fluorophenyl, RJ is 3,4-dichlorophenyl or ethyl, R4 and R3 are hydrogen, X' and X" are hydrogen, then X is not -C(0)0CH3; wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; R2 is selected from the group consisting of (a) substituted alkyl provided that such biibsntuted alkyl groups do noi include aryl or heteroaryl substituted alkyl, or a sidc-chain of a naturally occurring amino acid, (b) substituted alkenyl provided that such substituted alkenyl groups do not include aryl or heteroaryl subbtiLuted alkenyl. (c) substituted alkynyl provided that such substituted alkynyl groups do not include aryl or hctcroaiyl substituted alkynyl, (d) heterocyclic, (e) aryl gioup substituted with from I to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaiyl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and irihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, and heteroaryl, and (0 a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy. aryl, alkaryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy, ihioaryloxy provided thai if dicre is an alkyl substituent on die substituted heteroaryl group then there is at least one other substituent which is not alkyl, each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkcnyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; each R5 is selected from hydiogen and rneinyl or rogeUier witii R,s forms a cycloalkyl gioup of from 3 to 6 < arbor atomr; X is -C(0)Y or -C(S)Y wheie Y is selected ficcb the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl with the proviso that dv substitution t u said substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl or a-0C(0)arvl groups, (c) alkoxy or diioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R" where R and R" arc independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl. substituceu alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and r" are joined to form a cyclic group having from 2 to S carbon atoms optionally containing I to 2 additional heteroatoms selected from oxygen, sulfur and mitogen and optionally substituted with one or more alkyl, alkoxy or carbcxyalkyl groups, (j) -NHS02-Rs where Rs is selected from alkvl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR5NR10R1d where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aiyl, heteroaryl, iicicrocy;'ic aril (1) -ONR°[C(0)0]JR.10 while z is zero or one, R1 and R10 die as defined above; 1 rec elved - 39p - '// V ' rAi ^ X can also be -CR6R6Y' where each R6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthalimido, -0C(0)R7, -SSR7, -SSC(0)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X' is hydrogen, hydroxy or fluoro; X" is hydrogen, hydroxy or fluoro. or X' and X" together form an oxo group, and n is an integer equal to 1 or 2, wherein R1 is selected fiom the grout, consisting ot alkyl, alk-myl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; R4 is selected from the gioup consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substiaited alkyl, substituted alkenyl and substituted alkynyl provided that at least one R1 is selected to be; (a) substituted alkyl provided that such substituted alkyl groups do not include aryl or heteroaryl substituted alkyl, or a side-chain of a naturally occurring ammo acid, (b) substituted alkenyl provided that seui substituted aikenyl groups do not include aryl or heteroaryl substituted alkenyl, (c) subsiituted alkynyl provided that such substituted alkynyl groups do not include aryl or heteroaryl substituted alkynyl, (d) heterocyclic, (c) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkory, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl. carboxylamido. cyano, halo, nitro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carbo.\yl, carboxylalkyl, carboxylamido, and heteroaryl, and 1 8 JUN 2001 RECEIVED 39q - 3 rf A R ( r> 5 (f) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, alkaryl, aryloxy, halo, nitro, heteioaryl, thioalkoxy, thioaryloxy provided iliac if there is an alkyl subsUtucnt on the substituted heteroaryl group then there is at least one other substituent which is not alkyl, each R5 is selected from hydrogen and methyl or together with R4 foinis a cycloalkyl gioup of from 3 to 6 carbon atoms; X is -C(0)Y or -C(S)Y where Y is selected from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include a-haloalkyl, a-dia7,oalkyi, a-0C(0)alkyl or a-0C(0)aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (c) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R" where R' and R" are mdependently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aiyl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy. and where R' and R" arc joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional hcLcroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groupc, (j) -NHSO,-R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR°NRl0R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocj'clic, and (1) -ONR9[C(0)OJ7R10 where z is zero or one, R9 and R!0 are as defined above; X can also bc-CR^Y' where each R6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthalimido. -0C(0)R7, -SSR7, -SSC(0)R7 wheie R7 's selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X' is hydrogen, hydroxy or fluoro; X" is hydrogen, hydroxy or fluorc, or X' and X" together form an oxo group, and n is an integer equal to 1 or 2; and - 39r - wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substiruted alkynyl, aryl, heteroaryl and heterocyclic; R2 is selected irom the group consisting of aikyl, suostitutec! alkyl, alkenyl, substituted alkenyl, alkynyl, sub.ititi.ted alkyryl, cycloalkyl. aryl, heteroaryl and heterocyclic. each R4 is independently selected from the groi p consisting of hydrogen, alkyl, alkenyl, alkynyl. aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alk>nyl; each R5 is selected from hydrogen ana methyl or together with R" forms a cycloalkyl group of from 3 to 6 carbon aLnms; X is selected from die group consisting of (a) -C(0)-alkyI. (b) -C(0)-substituted alkoxy or substituted thioalkoxy provided that the substituted alkoxy groups do not include benzyl and phenethyl, (c) -C(0)-aryl wherein the aryl group is substituted witii from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl- a'koxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomeihyl, (d) -C(0)-heteroaryl wherein the heteroaryl group is substituted wiUi 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, alkaryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy and diioaryloxy (e) -C(0)-NR'R" where R' and R" arc independently sclccted from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to S carbon atoms optionally containing i to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and opuorull} substituted with one or more alkyl or alkoxy groups, and X can also be -CRf'RcY' where each R6 is independendy selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is sclccted from the group consisting of amino, thiol, alkoxy, phthalimido, -0C(0)R\ -SSR7, -SSC(0)R7 INTELLECTUAL PROPERTY OFFICE OF N Z. 1 8 JUN 2001 received - 39s - where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl. aryl, heteroaryl and heterocyclic, provided thai R' and R" are not both independently selected from hydrogen, alkyl, phenyl, benzyl and phenethyl; X' is hydrogen, hydroxy or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, and n is an integer equal to 1 or 2; with the proviso thai: when R1 is ijo-propyl, R: is phenyl, R1 is methyl, R5 is hydrogen, X' and X" are hydrogen, n is 2, and the second R4 at the carboxy terminus is methyl, then X is not -C(0)NH-/>N02-<J>. Preferred compounds for use in the preparation of a medicament of this invention include those set forth in the tables below: INTELLECTUAL PROPERTY OFFICE OF N.Z. 0 3 AUG 2001 received WO 98/22494 PCT/US97/20804 - 40 - x z o u z o u u u o o u o o o u u o o cr z «»»s. o u o z G G z g cj u cd, G G z o u CJ z »♦ X CJ G z o o cj G G cj G G G u G -9- G u u u »> 3 •a >A -=j <A 'n "3 'o ■e. vL '■6 <o Printed from Mimosa WO 98/22494 PCT/US97/20804 - 41 - X s^> *2 >» Q. G z o u fO ."2 *i— >N C. U 5 o u •*T 3 *E >N C. G 2 C a <«* <•> a •w u o o s/ o 0 o c u u o o u u o o u O o c u C o o o G o o u u o o o U C o u u o c o u o o u S u o o u _ -©. G -©-a G o o 0 CJ u ■S; U -S; 0 a It cj S 2 - u •w' i. o a c . ?t u a c a 5 o k. >% Ci. ">> N c J8 6 G u o o 4 2 % — rO "c o II ff — i-~ 4.0 g z g cs ■i c, c _"3 c. U PC - 11 - 51 = § x-> G G w u o u U c i G G "S u u 0 0 G BS ■©. ■5 '•n u. ■3 <S •e- ■4 ci. "•3 >A 5 u 11^ o o u D 0 o •4- c. ■? fn ci <S -9- ■5 -f. *? •A rr{ -9- ■3 >A ■n -9- ■0 >n 'n -fr (L '•5 •A "i -©■ ■3 >A >n •4 c£ ? -•n Printed from Mimosa WO 98/22494 PCT/US97/20804 — 42 - r 7 u u O C) O o o n n — -7 -T -j1 —' u . **» •JT "©■ O u O CJ u u u o o C) u p f ) n m* X O O C — o -j* O o V o O O u o 0 1 o u CJ 0 u 1 y 2 u z o u y z u 2 o u o u C o o o u o u o o c O o o O £. o u o u o u 84 = r = = S = = s = = = s 5 B = s. := ° s ">N T .■£* — r f* •*r <N Tr 3 ei ."2 *w u o CL u O 2 -3 g-ff u c 12 >■> "H n "3 N « -©- 3- *£• c o -©• S -I" 2 O 0 -5* CL U T MT* a u u u o O (j o u 1 11 ^ II .§ >. Z <s 2 ■="? CJ ■3 C 55 "2 = = _ X ~ zz — = "=5 S j= rt 5 2 S = = = s ££ - ^7 = ^ C- - Ci 2 r* es U i u u u 0 0 c u 0 t 0 1 U V C c -cn, o -9- •4 •4 -4 -4 4 4 4 •4 4- 4 4- 4 4 t t- u. u. B. L. u. u. u. u. U. l r£ U. d -9- *7 ■5 ■5 -3 -5 ■5 •5 -5 ■5 •o •a •S ■o <A >A 'o "1 *-> 'n "1 "i 'n •n 'n •*> Printed from Mimosa WO 98/22494 PCT/US97/20804 -43 - X u o C u o o •w u u u u o o cj c o o o 5 o u 2 o cj □ O w u ( U o § u *€► u IN u o o u O o u o o o Z •»-s o cj U o o u £ o u z o o 2 o u t £ /■—N c o •n cj o o o o y £ o u 0 2 o u 1 v» at cs •f rJ cj -9-cj cj o o ">% (n >■. a ">v r~i *c >> c. o a o 0 y 2 Z 1 -e- 0 u = ■3 c a o o o 5, cj p u -& 0 a C x rn 3 *c c. x cj cj a ■©. ■m* G i e£ - * 9 0 0 cj o a V 0 1 V 5 CJ • u 0 u 1 u cj 0 U os 4 **? •A «S 4-7 vi, •"n 4 -3 •4 d ■5 -4 ti *5 «o *■> "f -5 *o -4 4 •3 4 ti •5 *■> 4 a. "? «o **1 -&■ u. ■a •A "-i 4 -9- •©- 4 -©■ 4 c£ ■5 A -s- t Printed from Mimosa WO 98/22494 PCT/US97/20804 — 44 — c, X 0 z o u G z o p G z c u. G z o u G z o u s z c u Z o u u o o u O o o o U <N u o o CJ O 0 o o u u c o u 0 o o o u o O U u c o U Z (J y u z /—V O u G o o V u u O O O • ">» a. 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"51 E 2 o u a w a e ■o >» "c5 k_i s <N 2 O w u 2 O u »*5* 2 O CJ e* BS <N 5 d -9- -©• G = o -©■ = c o o w o 3 rf -©-1 ■9- -e- -e- •9- -e- -fr £ o 3 c -9- cs G G G G 0 u &o u o G G G n G -©• G o G -e-U o o a • G o G q G G r*< G G U eo^ U 0 1 ■4 X -©- •3 *-T -4 ti *5 > "f ti ■5 •A H" -4 "5 •s-■J. •5 ■A •4 c£. '•3 •A «■» -4 4 "-5 -4 4 <A "4 4 *5 3 c CJ c. V •*T CN -4 *5 •A -4 ti •A •4 4 -5 •A -4 ci •5 *A -4 4 •3 ■A *■> *4 4 •5 *A -4 4 *A ■S -4 4 tj »A Printed from Mimosa WO 98/22494 PCT/US97/20804 -60- X z o o Z o o Z o w o £ G G z o "W u 0 G o u G O U G G G o u *©• O u G X u 0 u 1 G G G o u u o o u o . 5 N Z ra ~S"T S> 23 >. g O S £ S O e, "a Z >• O 04 0 w 1 G u o o u G a o o u G O O o »»»* G o z o u Vk x a - - 'a - B ~ K a = s - a a Bi ■e- ■e- -9- -9. -©-I -0- -0- -s- ■e-o o 3 c: Tj" -4 ■4 *>, C u Js->* a .a c Tf = = - = - s = - - - = a ii , >. ■r go jr fsj ll-H «5 ~ £> -* ' -S os ^ 2 ^ * S3 «•< PO , fiS rs - X G G -e- i G a G G G G V G 1 G G «>•* G G G G ^1 G X -4 ■5 A >n" -©• u. "•5 ^A *■> -6- ■3 ■A ■4 ti. '•5 •A 4 ■3 A 'n •4 ■3 >A ■4 uL *5 <A •4 u. *■5 *A •4 4 *"? •A *4 4 <A -4 • *3 <A <4 4 •A "■T ■4 4 '■3 <A 4 uL ■5 >A •n -4 4 ■3 •A *-T ■4 4 •3 «A •S" Printed from Mimosa WO 98/22494 PCT/US97/20804 - 61 - j x in X u C X 2 o cj X z 0 u -o. (Sl X u § u -C(0)-cyclopentyl 5 "3 JD C o u i X o X u X CJ u 5" ■*W u 1^1 T3 6 J o «. X* u X 2 0 u 1 x 8 o u 8 o u X u u X z § u i x 8 o u x O O w cj x cj 8 o u x 8 o1 u » x 8 G u 3? a o § o 04 - X x X x X x ■p* X X x X x X x X X 4-plienylacetylenylphenyl •f- -f- » -& ■0. wM u X o, X cj -©• •e-ti <N -e- t -©■ -o- 1 -6- cd X x X i X x x X = x X x ►f x ■*- T* os X u x (J x CJ X u »>■* X u x CJ x CJ X 0 "J. 5 rv X u 1 «•» o x cj Urn cj ">» m " c u •5 >» r*> § x CJ £ CJ X o Q£ ~¥ iL •3 *A *•» -e-a. V »A *■> -f '■3 -©-4 «A *-T -©■ li. "■5 •f tL *•5 •A *0- d. •6 «A **T •f 4 "*6 *A% u 2 U s ■f ci -5 «A •e- 4 ■a -6- ti '•3 •A ■4 4 '*5 *A O ? CJ *A o ? 4 ■3 <A ^n, 1 (S> -e- g •a >* Printed from Mimosa WO 98/22494 PCT/US97/20804 -62- 5- 01 >< T« MM K a »<■* NM 52 W4 Mm a k*4 Mm >" U O o u 0 1 IN c-> T- U — u <N MM U <N K U 1 M M M. MM -©■ » ■©• 1 M Mm ss HH mm M MM ci -9- u 1 u 1 -e- "©■ c4 MM U 1 u «*v ffi O I 1 r»» ffi C_> n X CJ ( *>» 1 c 3-B. B V S •u 12 •C £ <N ">> 'E Q. r-> MM M MM s MM M-t MM Mm a CC K MM M <N ess u 1 X u «n a u » r> «-r« U 1 <n SC u 1 m — u i ' IX u 1 r» tn u i r% X 0 1 rO S 0 1 m MM u 1 Bi 1 -e. t UH *5 1 •©■ 1 ii. t •5 i -s- 1 U. t V 1 -©-1 u* 1 •3 r *o <n » -©■ b I *3 t -©• i u. 1 •3 • *r> ( -0- i Up *3 i <*■? i -e-» u. i •3 i •S" 1 -e-■ a* l •3 i -©• •5 1 *o < -$• I u. 1 *3 i Printed from Mimosa WO 98/22494 PCT/US97/20804 - 63 - m Y" HU a B i—. HH U N»— MM HH »n M HM M 0 1 h-« i—i MM MM ei «T» U u U i (N «n Hr" u EC U M-i u t thien-2-yl -e- I T T -e- i a S S3 Mr* i—H ac K M M-t a a: n es K U 1 ffi U I r*i K U t EC u 1 as 0 1 -9- 1 -9- 1 1 -e- 1 1 -©• 1 -e- i ■©. 1 ■6- >> cu Bi tu i *5 i •5 *o u. 1 *A tu ■5 I to <n t, •5 i *o <n uL i •5 *n o u. c. CJ >> <J t c «u a. o 0 >> a 1 Printed from Mimosa WO 98/22494 PCT/US97/20804 -64- > DC >-■ r» M r> u fn O o IH £ a a 0 1 u O I O 0 1 o u o u o u 0 1 "S. > fl rt »T- b U **•> cS n u 1 -e- t -©• fN U u r-4 U CS u 1 h-» u rS U c* >T* MH U i u <N V rs U CI <N »-» SC U 1 m s u <n *T« U 1 m u t r»> 0 1 *** u 1 -e- f -e- » f ■e- f -e- 1 -©■ u* tu tu aL *5 *5 ■5 ■5 *■5 •5 •o <n <w Printed from Mimosa WO 98/22494 PCT/US97/20804 - 65 - X or /—S ft cj Nw' CM c? t rt a c) X o fN cj o o u 2 O u 2. 3. S z o u t U o 0 •w* a 1 -C(0)0CI ►n u 0 o cj 1 *U 0 <N u 1 0 X u 1 h rt a cj 1 -s- r-J MM cj t a o 1 -e- 1 -e- I ft h»U cj a u i •0- a HI ft -3- t <t N- r*i MM cj ft M r*> *0- i u 1 u 1 tJ? M U k—< u 1 0 W-* u 1 u 1 -©■ t N Pi i X u rt u -©■ » ■©• rn KM a «n 55 O » <t HP* u 1 -e- i a cj i CA I K o rvi x—v fi a: cj 1 X u *t ffi O t—< u (N f~*s n M HU cj •4 4 •3 i **1 1 -e- I u, >5 •A «*> 1 -e- i r<4 O 2 I i -©■ pL i •3 t **T t -e- 4 •3 » *n Printed from MimDsa WO 98/22494 PCT/US97/20804 - 66 - X zx OH r~i M ft n rn U u MM U O O O "W u X O K 2 O U 1 u a z 0 V u 1 ■V Om -9- 1 -©- 1 -©- r* r~> ffi ft *—1 Pi U l u 1 u 1 >< s ti. >< 0 1 u, 1 X'/X" = =0 -4 -4 -4 Ph U- Pi "5 *5 "5 *o Printed from Mimosa WO 98/22494 PCT/US97/20804 -67- DETAILED DESCRIPTION OF THE INVENTION As above, this invention generally relates to uses of compounds represented by formula I for inhibiting 3-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. However, prior to describing this invention in further 5 detail, the following terms will first be defined. Definitions The term "/3-amyloid peptide" refers to a 39-43 amino acid peptide having a molecular weight of about 4.2 kD, which peptide is substantially homologous to the form of the protein described by Glenner, et al.1 including 10 mutations and post-translational modifications of the normal /3-amyloid peptide. In whatever form, the /3-amyloid peptide is an approximate 39-43 amino acid fragment of a large membrane-spanning glycoprotein, referred to as the /S-amyloid precursor protein (APP). Its 43-amino acid sequence is: 1 15 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr il Glu Val His His Gin Lys Leu Val Phe Phe 21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala ® 20 21 lie lie Gly Leu Met Val Gly Gly Val Val 41 He Ala Thr (SEQ ID NO: 1) or a sequence which is substantially homologous thereto. 25 "Alkyl" refers to monovalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, /i-propyl, wo-propyl, n-butyl, iso-butyl, fl-hexyl, and the like. intellectual property office of n.z. 0 3 AUG 2001 received WO 98/22494 PCT/US97/20804 - 68 - "Substituted alkyl" refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, 5 cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxylalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono-and di-heterocyclic amino, and unsymmetric di-substxtuted amines having 10 different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic "Alkylene" refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the 15 propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-), and the like. "Alkaryl" refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like. 20 "Alkoxy" refers to the group "alkyl-O-". Preferred alkoxy groups include, by way of example, methoxy, ethoxy, /i-propoxy, wo-propoxy, /i-butoxy, tert-butoxy, sec-butoxy, /i-pentoxy, rc-hexoxy, 1,2-dimethylbutoxy, and the like. "Substituted alkoxy" refers to the group "substituted alkyl-O-" where 25 substituted alkyl is as defined above. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 69 -- "Alkylalkoxy" refers to the group "-alkylene-O-alkyl" where alkylene and alkyl are as defined above. Such groups include, by way of example, methylenemethoxy (-CH2OCH3), ethylenemethoxy (-CH2CH2OCH3), n-propylene-tro-propoxy (-CH2CH2CH2OCH(CH3)2), methylene-r-butoxy (-CH2-5 OC(CH3)3) and the like. "Alkylthioalkoxy" refers to the group "-alkylene-S-alkyl" wherein alkylene and alkyl are as defined above. Such groups include, by way of example, methylthiomethoxy (-CH2SCH3), ethylthiomethoxy (-CH2CH2SCH3), n-propyl-/j0-thiopropoxy (-CH2CH2CH2SCH(CH3)2), 10 methylthio-r-butoxy (-CH2SC(CH3)3) and the like. "Alkenyl" refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (-CH=CH2), w-propenyl (-CH2CH=CH2), wo-propenyl 15 (-C(CH3)=CH2), but-2-enyl (-CH2CH=CHCH3), and the like. "Substituted alkenyl" refers to an alkenyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, cycloalkyl, oxyacyl, 20 oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylammo, mono- and di-heteroarylamino, mono-and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and 25 heterocyclic. "Alkynyl" refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 Printed from Mimosa WO 98/22494 PCT/US97/20804 -70- and preferably from 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (-CH^CHj), propargyl (-CH2C = CH) and the like. "Substituted alkynyl" refers to an alkynyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkyoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono-and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic. "Acyl" refers to the groups alkyl-C(O)-, substituted alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(0)- and heterocyclic-C(O)- where alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein. "Acylamino" refers to the group -C(0)NRR where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein. "Aminoacyl" refers to the group -NRC(0)R where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 71 - "Oxyacyl" refers to the groups -0C(0)-alkyl, -0C(0)-aryI, -C(0)0-heteroaryl-, and -C(0)0-heterocyclic where alkyl, aryl, heteroaryl and heterocyclic are as defined herein. "Oxyacylamino" refers to the groups -0C(0)NR-alkyl, -0C(0)NR-5 substituted alkyl, -0C(0)NR-aryl, -0C(0)NR-heteroaryl-, and -0C(0)NR-heterocyclic where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein. "Aminocarboxy esters" refers to the groups -NRC(0)0-alkyl, 10 -NRC(0)0-substituted alkyl, -NRC(0)0-aryl, -NRC(0)0-heteroaryl, and -NRC(0)0-heterocyclic where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein. 15 "Aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like. Unless otherwise constrained by the definition for the aryl substituent, 20 such aryl groups can optionally be substituted with from 1 to 5 and preferably 1 to 3 substituents selected from the group consisting of hydroxy, biotinamidyl, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, acylamino, cyano, 25 halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and disubstituted alkyl)amino, mono- and di-arylamino, mono- and di- Pnnted from Mimosa WO 98/22494 PCT/US97/20804 - 72 - heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric disubstituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. 5 "Aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above. The term "carboxy terminal R4 group" refers to that R4 group in compounds of formula I which, when rt is two, is closest to the X group. 10 "Carboxyalkyl" refers to the groups -C(0)0-alkyl and -C(0)0- substituted alkyl where alkyl and substituted alkyl are as defined above. "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed nngs which can be optionally substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by 15 way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like. "Cycloalkenyl" refers to cyclic alkenyl groups of from 4 to 8 carbon 20 atoms having a single cyclic ring and at least one point of internal unsaturation which can be optionally substituted with from 1 to 3 alkyl groups. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like. "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and 25 preferably is either chloro or bromo. Printed from Mimosa WO 98/22494 PCT/US97/20804 -73 - "Heteroaryl" refers to a monovalent aromatic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Unless otherwise constrained by the definition for the heteroaryl 5 substituent, such heteroaryl groups can be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, 10 heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylammo, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and 15 heterocyclic, and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indohzinyl or benzothienyl). Preferred heteroaryls include pyndyl, pyrrolyl and furyl. 20 "Heteroaryloxy" refers to the group heteroaryl-O- wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above. "Heterocycle" or "heterocyclic" refers to a monovalent (i.e., one point of attachment) saturated or unsaturated group having a single ring or multiple 25 condensed nngs, from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 74 -- Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, 5 substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-10 heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, and the like. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heteroaryls include morpholino, piperidinyl, and the like. 15 Examples of heterocycles and heteroaryls include, but are not limited to, furan, thiophene, thiazole, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cmnohne, ptendine, carbazole, carboline, phenanthridine, acridine, 20 phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indohne, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like. 25 "Heterocyclyloxy" refers to the group heterocyclyl-O- wherein the heterocyclic group is as defined above including optionally substituted heterocyclic groups as also defined above. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 75 - "Oxyacyl" refers to the groups -0C(0)-alkyl, -0C(0)-aryl, -C(0)0-heteroaryl-, and -C(0)0-heterocyclic where alkyl, aryl, heteroaryl and heterocyclic are as defined herein. "Oxyacylamino" refers to the groups -0C(0)NH-alkyl, -0C(0)NH-5 substituted alkyl, -0C(0)NH-aryl, -0C(0)NH-heteroaryl-, and -0C(0)NH-heterocyclic where alkyl, aryl, heteroaryl and heterocyclic are as defined herein. "Thiol" refers to the group -SH. "Thioalkoxy" refers to the group -S-alkyl. 10 "Substituted thioalkoxy" refers to the group -S-substituted alkyl. "Thioaryloxy" refers to the group aryl-S- wherein the aryl group is as defined above including optionally substituted aryl groups also defined above. "Thioheteroaryloxy" refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups 15 as also defined above. "Pharmaceutically acceptable salt" refers to pharmaceutical^ acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, 20 tetraalkylammomum, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 76 — Compound Preparation The compounds of formula I are readily prepared via several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, commercial availability of starting materials, etc. 5 A first synthetic method involves conventional coupling of an acetic acid derivative with a primary amine of an estenfied amino acid as shown in reaction (1) below: wherein R1, R2, R3, X' and X" are as defined above, and X is either oxygen or -NH-. 25 Reaction (1) merely involves coupling of a suitable acid derivative 1 with the primary amine of amino acid ester 2 under conditions which provide for the N-acetyl derivative 3. This reaction is conventionally conducted for Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 77 - peptide synthesis and synthetic methods used therein can also be employed to prepare the N-acetyl amino acid esters 2 of this invention. For example, well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. 5 can be used to facilitate coupling. The reaction is conventionally conducted in an inert aprotic diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. Alternatively, the acid halide of compound 1 can be employed in reaction (1) and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid 10 generated during the reaction. Suitable bases include, by way of example, triethylamine, dnsopropylethylamine, N-methylmorpholine and the like. Reaction (1) is preferably conducted at from about 0°C to about 60°C until reaction completion which typically occurs within 1 to about 24 hours. Upon reaction completion, N-acetyl amino acid ester 3 is recovered by 15 conventional methods including precipitation, chromatography, filtration and the like or alternatively is hydrolyzed to the corresponding acid without purification and/or isolation other than conventional work-up (e.g., aqueous extraction, etc.). Alternatively, the synthesis described above in reaction (1) can be conducted on the amino acid (XR3 = OH) and subsequent to N-acetyl formation 20 as described above. In any event, if an N-acetyl amino acid ester is formed, it is converted to the corresponding acid prior to the coupling step with another amino acid ester/amide, HNR3CR4R5C(0)Y. Coupling is accomplished using well known peptide coupling chemistry with well known coupling reagents such as 25 carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotnazole, etc. which can be used to facilitate coupling. The reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitnle, tetrahydrofuran and the like. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 78- Such coupling yields compounds of formula I where n is 1. The synthesis of compounds of formula I where n is 2 is accomplished via a second coupling reacdon. Specifically, in the first coupling reaction, HNR3CR4R5C(0)Y is selected to be an amino acid ester. That is to say that Y 5 is -O-alkyl. After coupling, the ester is hydrolyzed via conventional conditions well known in the art to provide for the corresponding carboxylic acid which can now be used to couple a second amino acid ester/amide. In reaction (1), each of the reagents (compound 1 and amino acid ester 2) are well known in the art with a plurality of each being commercially 10 available. Alternatively, the compounds of formula I can be prepared by first forming the dipeptide ester and then N-acylating these esters. That is to say that the amino acid ester or amide HNR3CR4R5C(0)Y is coupled to the N-blocked amino acid BlockNHCHR2COOH via conventional coupling 15 conditions to provide for the dipeptide BlockNHCHR2C(0)N(R3)CR4R5C(0)Y. The blocking group is then removed via conventional conditions to provide for the free amine which is then N-acylated in the manner described above to provide for the compounds of formula I. After coupling and N-acylation (in whatever order) is complete, the 20 resulting esters and amides can be derivatized via conventional chemistry to provide for derivatives of the synthesized compounds. For example, conventional reduction of a terminal ester group with lithium borohydride leads to the terminal -CH2OH group. Alternatively, an ester group can be converted to a primary amide [-C(0)NH2] by reaction with ammonia in methanol with a 25 catalytic amount of sodium cyanide while heating. Similarly, reactive functionality which is blocked on either R2 and/or R3 groups can be deblocked and then derivatized. For example, the a BOC Printed from Mimosa WO 98/22494 PCIYUS97/20804 - 79 - protected amino group on R3 (e.g., lysine side chain) can be deblocked after synthesis and the amino group acylated or otherwised derivatized. Additionally, a terminal ester can be subjected to transesterification techniques to provide for other esters. Numerous techniques are known in the 5 art to effect transesterification and each technique merely replaces one ester group with a different ester group derived from the corresponding alcohol or thioalcohol and, in some cases, a catalyst such as titanium (IV) uopropoxide is used to facilitate reaction completion. In one technique, the alcohol or thioalcohol is first treated with sodium hydride in a suitable diluent such as 10 toluene to form the corresponding sodium alkoxide or thioalkoxide which is then employed to effect transesterification. The efficiency of this technique makes it particularly useful with high boiling and/or expensive alcohols or thioalcohols. In another transesterification technique, the ester to be transesterified is 15 placed in a large excess of the alcohol or thioalcohol which effects transesterification. A catalytic amount of sodium hydride is then added and the reaction proceeds quickly under conventional conditions to provide the desired transesterified product. Because this protocol requires the use of a large excess I of alcohol or thioalcohol, this procedure is particularly useful when the alcohol 20 or thioalcohol is inexpensive. Transesterification provides a facile means to provide for a multiplicity of different ester substituents on the compounds of formula I above. In all cases, the alcohols and thioalcohols employed to effect transesterification are well known in the art with a significant number being commercially available. 25 Other methods for preparing the esters include, by way of example, first hydrolyzing the ester to the free acid followed by O-alkylation with a halo-R3 group m the presence of a base such as potassium carbonate. intellectual prope office of n.z WO 98/22494 PCT/US97/20804 - 80 -- Alternatively, for esterification procedures for alcohols containing an ester group can be achieved by using the methods of Losse, et al.11 The compounds described herein can also be prepared by use of polymer supported forms of carbodiimide peptide coupling reagents. A polymer 5 supported form of EDC, for example, has been described (Tetrahedron Letters, 34(48), 7685 (1993))10. Additionally, a new carbodiimide coupling reagent, PEPC, and its corresponding polymer supported forms have been discovered and are very useful for the preparation of the compounds of the present invention. 10 Polymers suitable for use in making a polymer supported coupling reagent are either commercially available or may be prepared by methods well known to the artisan skilled in the polymer arts. A suitable polymer must possess pendant sidechains bearing moieties reactive with the terminal amine of the carbodiimide. Such reactive moieties include chloro, bromo, iodo and 15 methanesulfonyl. Preferably, the reactive moiety is a chloromethyl group. Additionally, the polymer's backbone must be inert to both the carbodiimide and reaction conditions under which the ultimate polymer bound coupling reagents will be used. Certain hydroxymethylated resins may be converted into 20 chloromethylated resins useful for the preparation of polymer supported coupling reagents. Examples of these hydroxylated resins include the 4-hydroxymethyl-phenylacetamidomethyl resin (Pam Resin) and 4-benzyloxybenzyl alcohol resin (Wang Resin) available from Advanced Chemtech of Louisville, Kentucky, USA (see Advanced Chemtech 1993-1994 25 catalog, page 115). The hydroxymethyl groups of these resins may be converted into the desired chloromethyl groups by any of a number of methods well known to the skilled artisan. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 81 -- Preferred resins are the chloromethylated styrene/divinylbenzene resins because of their ready commercial availability. As the name suggests, these resins are already chloromethylated and require no chemical modification prior to use. These resins are commercially known as Menifield's resins and are 5 available from Aldrich Chemical Company of Milwaukee, Wisconsin, USA (see Aldrich 1994-1995 catalog, page 899). Methods for the preparation of PEPC and its polymer supported forms are outlined in the following scheme. 0-^ Functionalized Resin where = an inert polymer and LG * CI, Br, I or OSQ2CHj a, 0—-' cr N=c =N Such methods are described more fully in U.S. Patent Application Serial No. 60/019,790 filed June 14, 1996 which application is incorporated herein by 10 reference in its entirety. Briefly, PEPC is prepared by first reacting ethyl isocyanate with l-(3-aminopropyl)pyrrolidine. The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC. The polymer supported form is prepared by reaction of PEPC with an appropriate resin under standard conditions to give the desired reagent. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 82 - The carboxyhc acid coupling reactions employing these reagents are performed at about ambient temperature to about 45°C, for from about 3 to 120 hours. Typically, the product may be isolated by washing the reaction with CHC13 and concentrating the remaining organics under reduced pressure. As 5 discussed supra, isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure. Still other methods for the preparation of esters are provided in the examples below. 10 Compounds where X is -CR6R6Y' are readily prepared by coupling, e.g., an amino alcohol H2NCR4R5CR6RfiOH, to the carboxyl group of R1ZCX'X"C(0)NHCHR2C(0)0H under standard coupling conditions well known in peptide coupling chemistry which can use well known coupling reagents such as carbodiimides with or without the use of well known additives 15 such as N-hydroxysuccinimide, 1-hydroxybenzotnazole, etc. If necessary, well known blocking groups on Y' can be employed to protect the group during coupling. Such blocking groups are particularly desirable when Y' is an amino group. The reaction is conventionally conducted in an inert aprotic polar diluent 20 such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. Upon reaction completion, any blocking groups on Y' are selectively removed to provide for the desired compound. When Y' is -OH or -SH, post-synthetic conversion of these groups to the corresponding esters (i.e., -0C(0)R7), disulfides (i.e., -SSR7) and 25 -SSC(0)R7 groups is accomplished using well known chemistry. For example, ester synthesis requires only reaction with a suitable acid such as acetic acid (R7 Printed from Mimosa WO 98/22494 PCT/US97/20804 - 83 - = methyl), acid halide (e.g., acid chloride) or acid anhydride under suitable esterification conditions. When one of R6 is hydrogen, post-synthetic oxidation of the -CHR6OH group leads to the ketone derivatives. Alternatively, such ketones 5 can be prepared by coupling the suitable aminoketone HC1 salt with the terminal carboxyl group of the amino acid as illustrated in Example 168 below. In these synthetic methods, the starting materials can contain a chiral center (e.g., alanine) and, when a racemic starting material is employed, the resulting product is a mixture of R,S enatiomers. Alternatively, a chiral isomer 10 of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained. Such reaction protocols can involve inversion of the chiral center during synthesis. Accordingly, unless otherwise indicated, the products of this invention are a mixture of R,S enatiomers or diasteriomers. Preferably, however, when a 15 chiral product is desired, the chiral product corresponds to the L-amino acid derivative Alternatively, chiral products can be obtained via purification techniques which separate enatiomers from a R,S mixture to provide for one or the other stereoisomer. Such techniques are well known in the art. 20 Pharmaceutical Formulations When employed as pharmaceuticals, the compounds of formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These 25 compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 84 10 15 NZ 513278 also describes and claims pharmaceutical compositions which contain as the active ingredient, one or more of the compounds of formula I above associated with pharmaceutically acceptable carriers. In making the compositions the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. 20 In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh. INTELLECTUAL PRC OFFICE OF N 0 3 AUG 2D receivi Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The 25 formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release WO 98/22494 PCT/US97/20804 -- 85 - of the active ingredient after administration to the patient by employing procedures known in the art. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to 5 about 30 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Preferably, the compound of formula I 10 above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutical^ inert carner(s). The active compound is effective over a wide dosage range and is generally administered in a pharmaceutical^ effective amount. It, will be 15 understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. 20 For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly 25 throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type Printed from Mimosa WO 98/22494 PCT/US97/20804 - 86 - described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged 5 action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can 10 be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include 15 aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutical^ acceptable, aqueous or organic solvents, or 20 mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutical^ acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutical^ acceptable solvents may be nebulized by use of inert gases. Nebulized solutions 25 may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 87 preferably orally or nasally, from devices which deliver the formulation in an appropriate manner. The following formulation examples illustrate the pharmaceutical compositions of the present invention. 5 Formulation Example 1 Hard gelatin capsules containing the following ingredients are prepared: Quantity Ingredient (mg/capsulel Active Ingredient 30.0 10 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities. Formulation Example 2 15 A tablet formula is prepared using the ingredients below: Quantity Ingredient (mg/tablef) Active Ingredient 25.0 Cellulose, microcrystalline 200.0 20 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are blended and compressed to form tablets, each weighing 240 mg. Formulation Example 3 25 A dry powder inhaler formulation is prepared containing the following components: Printed from Mimosa WO 98/22494 PCT/US97/20804 - 88 - Ingredient Weight % Active Ingredient 5 Lactose 95 The active ingredient is mixed with the lactose and the mixture is added 5 to a dry powder inhaling appliance. Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows: Quantity Ingredient Cme/tableO Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in sterile water) 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0 5 mg Talc 1.0 mg Total 120 mg 20 The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinyl-pyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50° to 60°C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium 25 stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. Formulation Example 5 Capsules, each containing 40 mg of medicament are made as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 - 89 - Quantity Ingredient Cms/capsule-) Active Ingredient 40.0 mg Starch 109.0 mg 5 Magnesium stearate 1.0 mg Total 150.0 mg The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities. 10 Formulation Example 6 Suppositories, each containing 25 mg of active ingredient are made as follows: Ingredient Amount Active Ingredient 25 mg 15 Saturated fatty acid glycerides to 2,000 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. 20 Formulation Example 7 Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 - 90 - Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purified water to 5.0 ml 10 The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalhne cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the 15 required volume. Formulation Example 8 Quantity Ingredient Cmg/capsule1) Active Ingredient 15.0 mg 20 Starch 407.0 mg Magnesium stearate 3 0 me Total 425.0 mg The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 560 25 mg quantities. Formulation Example 9 A subcutaneous formulation may be prepared as follows: Ingredient Quantity Active Ingredient 5.0 mg 30 corn oil 1 ml Printed from Mimosa WO 98/22494 PCT/US97/20804 -91 - Formulation Example 10 A topical formulation may be prepared as follows: intellectual property office of n.z. 0 3 AUG 2001 Ingredient Quantity received Active Ingredient Emulsifying Wax Liquid Paraffin White Soft Paraffin 1-10 g 30 g 20 g to 100 g The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid. Another preferred formulation useful to the present -invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent 5,011,472 which is herein incorporated by reference. Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion WO 98/22494 PCT/US97/20804 — 92 - of hydrophilic drugs into lipid-soluble drugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of 5 hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier. Other suitable formulations for use in the present invention can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985). 10 Utility The compounds and pharmaceutical compositions of the invention are useful in inhibiting 0-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease in mammals including humans. 15 As noted above, the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to enhance the in vivo serum half-life of the administered compound, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which 20 provide an extended serum half-life of the compounds. A variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al., U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporated herein by reference. The amount of compound administered to the patient will vary depending 25 upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions are administered to a Printed from Mimosa WO 98/22494 PCT7US97/20804 -- 93 - patient already suffering from AD in an amount sufficient to at least partially arrest further onset of the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective dose." Amounts effective for this use will depend on the judgment of the 5 attending clinician depending upon factors such as the degree or severity of AD in the patient, the age, weight and general condition of the patient, and the like. Preferably, for use as therapeutics, the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day. In prophylactic applications, compositions are administered to a patient at 10 risk of developing AD (determined for example by genetic screening or familial trait) in an amount sufficient to inhibit the onset of symptoms of the disease. An amount adequate to accomplish this is defined as "prophylactically effective dose." Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the age, weight and general 15 condition of the patient, and the like. Preferably, for use as prophylactics, the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day. As noted above, the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be 20 sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 and 25 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts. The following synthetic and biological examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of Printed from Mimosa WO 98/22494 PCT/US97/20804 ~ 94 „ this invention. Unless otherwise stated, all temperatures are in degrees Celsius. 10 15 20 25 30 35 40 EXAMPLES In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. BOC = tert-b utoxycarbonyl BOP = benzotnazol-1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate bd = broad doublet bs = broad singlet c — concentration (g/mL) CDI = 1,1 '-carbonyldiimidazole d = doublet dd = doublet of doublets DCM = dichloromethane DEAD = diethyl azodicarboxylate DMF = dimethylformamide DMSO = dimethylsulfoxide EDC - l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EEDQ = 2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline eq. = equivalents EtOAc = ethyl acetate EtOH = ethanol g = grams L = liter m = multiplet max = maximum MeOH = methanol meq = milliequivalent mg = milligram mL = milliliter mm — millimeter mmol — millimole N/A = not available N = normal ng = nanogram nm = nanometers OD = optical density <f> — phenyl PEPC = l-(3-(l-pyrrolidinyl)propyl)-3-ethylcarbodiimide psi — pounds per square inch q = quartet Printed from Mimosa WO 98/22494 PCT/US97/20804 - 95 - quint. = quintet rpm = rotations per minute s = singlet t = triplet TFA = trifluoroacetic acid THF = tetrahydrofuran tic = thin layer chromatography fiL = microliter UV = ultraviolet 10 In the examples below, all temperatures are in degrees Celcius (unless otherwise indicated) and each of the compounds set forth in these examples was prepared by one of the following general procedures, unless otherwise indicated. Additionally, the term "Aldrich" indicates that the compound or reagent 15 used in the following procedures is commercially available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, WI 53233 USA; the term "Fluka" indicates that the compound or reagent is commercially available from Fluka Chemical Corp., 980 South 2nd Street, Ronkonkoma NY 11779 USA; the term "Lancaster" indicates that the compound or reagent is 20 commercially available from Lancaster Synthesis, Inc., P.O. Box 100 Windham, NH 03087 USA; the term "Sigma" indicates that the compound or reagent is commercially available from Sigma, P.O. Box 14508, St. Louis MO 63178 USA; the term "Chemservice" indicates that the compound or reagent is commercially available from Chemservice Inc., Westchester, PA; the term 25 "Bachem" indicates that the compound or reagent is commercially available from Bachem Biosciences Inc., 3700 Horizon Drive, Renaissance at Gulph Mills, King of Prussia, PA 19406 USA; the term "Maybridge" indicates that the compound or reagent is commercially available from Maybridge Chemical Co. Trevillett, Tintagel, Cornwall PL34 OHW United Kingdom; and the term 30 "TCI" indicates that the compound or reagent is commercially available from TCI America, 9211 North Harborgate Street, Portland OR 97203; the term "Alfa" indicates that the compound or reagent is commercially available from Printed from Mimosa WO 98/22494 PCT/US97/20804 - 96 - Johnson Matthey Catalog Company, Inc. 30 Bond Street, Ward Hill, MA 01835-0747; the term "Novabiochem" indicates that the compound or reagent is commercially available from Calbiochem-Novabiochem Corp. 10933 North Torrey Pines Road, P.O. Box 12087, La Jolla CA 92039-2087; the term 5 "Oakwood" indicates that the compound or reagent is commercially available from Oakwood, Columbia, South Carolina; the term "Advanced Chemtech" indicates that the compound or reagent is commercially available from Advanced Chemtech, Louisville, KY; and the term "Pfaltz & Bauer" indicates that the compound or reagent is commercially available from Pfaltz & Bauer, 10 Waterbury, CT, USA. The following General Procedures A'-P' and Examples A1-A74 illustrate the synthesis of iV-(aryl/heteroarylacetyl)amino acid esters which can be hydrolyzed to provide for 2V-(aryl/heteroarylacetyl)amino acid starting materials of this invention. Other iV-(aryl/heteroarylacetyl)amino acid esters can be 15 prepared using these procedures from commerically available or known starting materials. GENERAL PROCEDURE A' Counting of R'CfX"irX"->CrO^Cl with H.NCH(R2>lCrOVXR3 To a stirred solution of (D,L)-alanine /jo-butyl ester hydrochloride (from 20 Example B below) (4.6 mmol) in 5 mL of pyridine was added 4.6 mmol of an acid chloride. Precipitation occurred immediately. The mixture was stirred for 3.5 h, diluted with 100 mL of diethyl ether, washed with 10% HC1 three times, brine once, 20% potassium carbonate once and brine once The solution was dried over magnesium sulfate, filtered, and evaporated at reduced pressure to 25 yield the product. Other amino acid esters may also be employed in this procedure. Printed from Mimosa WO 98/22494 PCT/US97/20804 -97 - GENERAL PROCEDURE B' Coupling of R'COC">rX^CrO^OH with H,NCHfR2)CrO)XR3 A solution of the acid (3.3 mmol) and CDI in 20 mL THF was stirred for 2 h. L-alanine wo-butyl ester hydrochloride (from Example B below) (3.6 5 mmol) was added, followed by 1.5 mL (10.8 mmol) of triethylamine. The reaction mixture was stirred overnight. The reaction mixture was diluted with 100 mL of diethyl ether, washed with 10% HC1 three times, brine once, 20% potassium carbonate once and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated at reduced pressure to yield the 10 product. Other amino acid esters may also be employed in this procedure. GENERAL PROCEDURE C' Esterification of R'CrX^OriaO^NHCHrR^CrOlOH With HOR3 To a stirred solution of phenylacetylvaline (1.6470 g, 7.0 mmol) in 20 mL THF was added CDI (1.05 g, 6.5 mmol) and the mixture was stirred for 1.5 h. 15 2-Methylbutanol (0.53 g, 6 mmol) was added the mixture, followed by addition of NaH (0.16 g, 6.5 mmol). Bubbling occurred immediately. The reaction mixture was stirred overnight. The reaction mixture was diluted with 100 mL of diethyl ether, washed with 10% HC1 three times, brine once, 20% potassium carbonate once and brine once. The solution was dned over magnesium 20 sulfate, filtered, and evaporated at reduced pressure to yield the product. Other N-acyl amino acids and alcohols may also be employed in this procedure. GENERAL PROCEDURE D' Ester Hydrolysis to the Free Acid Ester hydrolysis to the free acid was conducted by conventional methods. 25 Below are two examples of such conventional de-estenfication methods. To the ester in a 1:1 mixture of CH30H/H20 was added 2-5 equivalents of KjCO,. The mixture was heated to about 50°C for about 0.5 to 1.5 hours until tic showed complete reaction. The reaction was cooled to room temperature Printed from Mimosa WO 98/22494 PCT/US97/20804 - 98 - and the methanol was removed at reduced pressure. The pH of the remaining aqueous solution was adjusted to about 2, and ethyl acetate was added to extract the product. The organic phase was then washed with saturated aqueous NaCl and dried over MgSO„. The solution was stripped free of solvent at reduced 5 pressure to yield the product. The amino acid ester was dissolved in dioxane/water (4:1) to which was added LiOH (—2 eq.) that was dissolved in water such that the total solvent after addition was about 2:1 dioxane:water. The reaction mixture was stirred until reaction completion and the dioxane was removed under reduced pressure. 10 The residue was diluted with EtOAc, the layers were separated and the aqueous layer acidified to pH 2. The aqueous layer was back extracted with EtOAc, the combined organics were dried over Na2S04 and the solvent was removed under reduced pressure after filtration. The residue was purified by conventional methods (e.g., recrystallization). 15 The following exemplifies this later example. The methyl ester of 3-N02 phenylacetyl alanine 9.27 g (0.0348 mols) was dissolved in 60 mL dioxane and 15 mL of H20 and adding LiOH (3.06 g, 0.0731 mol) that has been dissolved in 15 mL of H20. After stirring for 4 hours, the dioxane was removed under reduced pressure and the residue diluted with EtOAc, the layers were separated 20 and the aqueous layer acidified to pH 2. The aqueous layer was back extracted with EtOAc (4 X 100 mL), the combined organics were dried over Na2S04 and the solvent was removed under reduced pressure after filtration. The residue was recrystallized from EtOAc/isooctane giving 7.5 g (85%) of 3-nitrophenylacetyl alanine. CnHnN205 requires C = 52.38, H = 4.80, and N 25 = 11.11. Analysis found C = 52.54, H = 4.85, and N = 11.08. [a]23 = - 29.9 @ 589 nm. Printed from Mimosa WO 98/22494 PCT/US97/20804 -99 - GENERAL PROCEDURE E' Low Temperature BOP Coupling of Acid and Alcohol A solution of methylene chloride containing the carboxylic acid (100M%) and N-methyl morpholine (150 M%) was cooled to -20°C under nitrogen. 5 BOP (105 M%) was added in one portion and the reaction mixture was maintained at -20°C for 15 minutes. The corresponding alcohol (120 M%) was added and the reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate (3x). The combined ethyl acetate portions were 10 backwashed with saturated aqueous citric acid (2x), saturated aqueous sodium bicarbonate (2x), brine (lx), dried over anhydrous magnesium sulfate or sodium sulfate and the solvent removed under reduced pressure to yield the crude product. GENERAL PROCEDURE F' 15 EDC Coupling of Acid and Amine The acid derivative was dissolved in methylene chloride. The amine (1 eq.), N-methylmorpholine (5 eq ), and hydroxybenzotnazole monohydrate (1.2 eq.) were added in sequence. The reaction was cooled to about 0°C and then 1.2 eq. of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 20 was added. The solution was allowed to stir overnight and come to room temperature under N, pressure. The reaction mix was worked up by washing the solution with saturated, aqueous Na;C03, 0.1M citric acid, and brine before drying with Na^O, and removal of solvents to yield crude product. Pure products were obtained by flash chromatography in an appropriate solvent. 25 GENERAL PROCEDURE G' EDC Coupling of Acid and Amine A round bottom flask was charged with carboxylic acid (1.0 eq.), hydroxybenzotnazole hydrate (1.1 eq.) and amine (1.0 eq.) in THF under nitrogen atmosphere. An appropnate amount (1.1 eq. for free amines and 2.2 eq. for Printed from Mimosa WO 98/22494 PCT/US97/20804 - 100 - hydrochloride amine salts) of base, such as Hunig's base was added to the well stirred mixture followed by EDC (1.1 eq.). After stirring from 4 to 17 hours at room temperature the solvent was removed at reduced pressure, the residue taken up in EtOAc (or similar solvent)/water. The organic layer was washed 5 with saturated aqueous sodium bicarbonate solution, IN HC1, brine and dried over anhydrous sodium sulfate. In some cases, the isolated product was analytically pure at this stage while, in other cases, purification via chromatography and/or recrystallization was required prior to biological evaluation. 10 GENERAL PROCEDURE H' Coupling of R'crx'vx^croin with H^NCHfR21C(O'tXR3 An excess of oxalyl chloride in dichloromethane was added to the acid derivative together with one drop of DMF. The resulting mixture was stirred for about 2 hours or until bubbling ceases. The solvent was then removed 15 under reduced pressure and rediluted with dry methylene chloride. To the resulting solution was added about 1.1 eq. of the appropriate amino acid ester and triethylamme (1.1 eq. in methylene chloride). The system was stirred at room temperature for 2 hours and then the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with IN HC1 20 followed by IN NaOH. The organic layer was dried over anhydrous soldium sulfate, filtered and the solvent removed under reduced pressure to provide for the desired product. GENERAL PROCEDURE I' P-EPC coupling 25 P-EPC coupling employs an amino acid ester and a substituted acetic acid compound. The acetic acid derivative is well known in the art and is typically commercially available. The amino acid ester is prepared by conventional methods from the known and typically commercially available N-BOC amino acid as described in GENERAL PROCEDURE J' below. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 101 - Specifically, the appropriate amino ester free base (0.0346 mmols) and substituted phenylacetic acid (0.069 mmols) were dissolved in 2.0 mL CHClj (EtOH free), treated with 150 mg of P-EPC (0.87 meq./g) and the reaction was mixed for 4 days at 23°C. The reaction was filtered through a plug of cotton, 5 rinsed with 2.0 mL of CHClj and the filtrate evaporated under a stream of nitrogen. The purity of each sample was determined by 'H NMR and ranged from 50% to >95%. Between 8.0 and 15.0 mg of final product was obtained from each reaction and was tested without additional purification. GENERAL PROCEDURE J' 10 Synthesis of Amino Acid Esters From the Corresponding N-BQC Amino Acid A. Esterification of the Acid. The N-BOC amino acid was dissolved in dioxane and treated with an excess of alcohol (~ 1.5 eq.) and catalytic DMAP (100 mg) at 0°C. Stirring was continued until reaction completion whereupon the product was recovered 15 by conventional methods. B. Removal of N-BOC Group. The N-BOC protected amino acid was dissolved in methylene chloride (0.05M) and treated with 10 eq. of TFA at room temperature under a nitrogen atmosphere. The reaction was monitored by tic until starting material was 20 consumed usually within 1-5 hours. An additional 10 eq. of TFA was added to the reaction if the starting material was still present after 5 hours. The reaction was carefully neutralized with Na2C03, separated, the organic layer washed with brine and dried over anhydrous Na2S04. The crude amine was then used without purification. 25 Specific exemplification of these procedures are as follows: 1. Racemic (+/-)-N-BOC-a-amino butyric acid (Aldrich) (9.29 g, 0.0457 mol) was dissolved in 100 mL of dioxane and treated with iso-butyl Printed from Mimosa WO 98/22494 PCT/US97/20804 - 102 - alcohol (6.26 mL, 0.0686 mol), EDC (8.72 g, 0.0457) and catalytic DMAP (100 mg) at 0°C. After stirring for 17 hours, the organics were evaporated at reduced pressure, the residue diluted with EtOAc washed with NaHCOj, brine and dried over Na2S04. Evaporation yields 8.42 g (71 %) of an oil. C^H^NO* 5 requires: C = 60.21, H = 9.72, and N = 5.40. Anal found: C = 59.91, H = 9.89, and N = 5.67. The above N-BOC amino acid ester (8.00 g, 0.032 mol) was deprotected as above giving 3.12 g (61%) of the free base as a colorless oil which solidifies upon standing. 10 2. L-N-BOC-alanine (Aldrich) (8.97 g, 0.047 mol) was dissolved in 100 mL of CH2C12, /jo-butyl alcohol (21.9 mL, 0.238 mol) and treated with DMAP (100 mg) and EDC (10.0 g, 0.52 mol) at OcC. The mixture was stirred for 17 hours, diluted with H20, washed with 1.0 N HC1, NaHC03, then brine and the organics were dned over Na2S04. Filtration and evaporation 15 yields 11.8 g (quantitative) of L-N-BOC alanine wo-butyl ester which is contaminated with a small amount of solvent. A sample was vacuum dned for analytical analysis. C12H23N04 requires: C = 58.79, H = 9.38, and N = 5.71. Anal found: C = 58.73, H = 9.55, and N = 5.96 The above N-BOC amino acid ester (11.8 g, 0.0481 mol) was deprotected 20 as above. The free base was converted to the corresponding HC1 salt using saturated HC1 (g)/EtOAc to give L-N-alanine wo-butyl ester hydrochloride. Obtained 4.2 g (48%) of a colorless solid. C7H15N02. HC1 requires: C = 46.28, H = 8.88, and N = 7.71. Anal found: C = 46.01, H = 8.85, and N = 7.68. Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 103 - GENERAL PROCEDURE K' Methyl ester formation from amino acids The amino acid (amino acid or amino acid hydrochloride) is suspended in methanol and chilled to 0°C. HC1 gas is bubbled through this solution for 5 5 minutes. The reaction is allowed to warm to room temperature then stirred for 4 hours. The solvents are then removed at reduced pressure to afford the desired amino acid methyl ester hydrochloride. This product is usually used without further purification. Example A' 10 Synthesis of free and polymer bound PEPC N-ethvl-N'-3-n-pyrrolidinyl)propvlurea To a solution of 27.7 g (0.39 mol) ethyl isocyanate in 250 mL chloroform was added 50 g (0.39 mol) 3-(l-pyrrolidinyl)propylamine dropwise with cooling. Once the addition was complete, the cooling bath was removed and 15 the reaction mixture stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure to give 74.5 g (96.4%) of the desired urea as a clear oil. l-(3-("l-pvrrolidinvl'>proDvlV3-ethvlcarbodiimide CP-EPO To a solution of 31.0 g (0.156 mol) N-ethyl-N'-3-(l-pyrrolidinyl)propyl-20 urea in 500 mL dichloromethane was added 62.6 g (0.62 mol) triethylamine and the solution was cooled to 0°C. To this solution were then added 59.17 g (0.31 mol) 4-toluenesulfonyl chloride in 400 mL dichloromethane dropwise at such a rate as to maintain the reaction at 0-5 °C. After the addition was complete, the reaction mixture was warmed to room temperature and then 25 heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was washed with saturated aqueous potassium carbonate (3 x 150 mL). The aqueous phases were combined and extracted with dichloromethane. All organic phases were combined and concentrated under reduced pressure. The resultant orange slurry was suspended in 250 mL diethyl ether and the solution Printed from Mimosa WO 98/22494 PCT/US97/20804 - 104 - decanted off from the solid. The slurry/decantation process was repeated 3 more times. The ether solutions were combined and concentrated under reduced pressure to give 18.9 g (67%) of the desired product as a crude orange oil. A portion of the oil was distilled under vacuum to give a colorless oil 5 distilling at 78-82°C (0.4 mm Hg). Preparation of a polymer supported form of l-(3-n-pvrrolidinv1')propvl>3-ethvlcarbodiimide fP-EPO A suspension of 8.75 g (48.3 mmol) l-(3-(l-pyrrolidin-yl)propyl)-3-ethylcarbodiimide and 24.17 g (24.17 mmol) Merrifield's resin (2% cross-10 linked, 200-400 mesh, chloromethylated styrene/divinylbenzene copolymer, 1 meq. Cl/g) in dimethylformamide was heated at 100°C for 2 days. The reaction was cooled and filtered and the resulting resin washed sequentially with IL DMF, IL THF and IL diethyl ether. The remaining resin was then dried under vacuum for 18 hours. 15 Example B' Preparation of alanine iso-butyl ester hydrochloride A mixture of 35.64 g (0.4 mol) of (D,L)-alanine (Aldrich) (or L-alanine (Aldrich)); 44 mL (0.6 mol) of thionyl chloride (Aldnch) and 200 mL of isobutanol was refluxed for 1.5 hours and the volatiles were removed 20 completely on a rotavapor of 90°C under reduced pressure to give (D,L)-alanine wo-butyl ester hydrochloride (or L-alanine wo-butyl ester hydrochloride), which was pure enough to be used for further transformations. Example C' Preparation of 3,5-dichlorophenylacetic acid 25 To a solution of 3.5 g of 3,5-dichlorobenzyl alcohol (Aldrich) in 75 mL of dichloromethane at 0°C was added 1.8 mL of methane sulfonylchloride followed by 3.5 mL of triethylamine added dropwise. After 2 hours the solution was diluted to 150 mL with dichloromethane, washed with 3N HC1, Printed from Mimosa WO 98/22494 PCT/US97/20804 - 105 - saturated aqueous NaHC03 dried with Na2S04 and the solvents removed to yield the desired 3,5-dichlorobenzyl methanesulfonate as a yellow oil that was used without purification. The crude sulfonate was dissolved in 50 mL of DMF at 0°C and then 3 g 5 of KCN was added. After 2 hours an additional 50 mL of DMF was added and the solution was stirred for 16 hours. The red solution was diluted with 1 L of H20 and acidified to pH 3 with 3N HC1. The aqueous solution was extracted with dichloromethane. The combined organics were washed with 3N HC1, dried with Na2S04 and the solvents removed at reduced pressure to yield crude 10 3,5-dichlorophenylacetonitrile which was used without purification. The nitnle was added to a mixture of 40 mL of concentrated sulfuric acid and 50 mL H20 and heated to reflux for 48 hours, cooled to room temperature and stirred for 48 hours. The reaction was diluted into 1 L of crushed ice, warmed to toom temperature and extracted with 2 x 200 mL of 15 dichloromethane and 2 x 200 mL of ethylacetate. Both sets of organics were combined and washed with saturated aqueous NaHC03. The NaHC03 fractions were combined and acidified to pH 1 with 3N HC1. The white solid was too fine to filter and was extracted out with 2 X 200 mL of dichloromethane. The combined organics were dried with Na2S04 and the solvents removed at reduced 20 presure to yield crude 3,5-dichlorophenylacetic acid as a white solid. The solid was slurried with hexane and filtered to get 1.75g of white solid. NMR (CDC13): (in ppm) 3.61 (s, 2H), 7.19 (s,lH), 7.30 (s, 1H) Example D' Synthesis of N-(3-chlorophenylacetyl)alanine 25 The title compound was prepared using L-alanine (Nova Biochem) and 3- chlorophenyl acetic acid (Aldrich) by following General Procedures F' or G', followed by hydrolysis using General Procedure D'. Printed from Mimosa WO 98/22494 -- 106 - PCT/US97/20804 Example Al Synthesis of N-(phenylacetyI)-D,L-alanine fro-butyl ester Following General Procedure A' above and using phenylacetyl chloride (Aldrich) and D,L-alanine ire-butyl ester hydrochloride (from Example B' 5 above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by extraction with EtjO followed by washes with aqueous K2C03 and aqueous HC1. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.23-7.36 (m, 5H), 6.18 (d, 1H), 4.58 (t, J = 7.3 10 Hz, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 1.90 (m, 1H), 1.34 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.8 Hz, 6H). 13C-nmr (CDC1,): S = 172.7, 170.3, 134.5, 129.2, 128.8, 127.2, 71.3, 48.1, 43.4, 27.5, 18.8, 18.3. C,5H21N03 (MW = 263.34; Mass Spectroscopy (MH+ = 264)) 15 Example A2 Synthesis of /V-(3-phenylpropionyl)-D,L-alanine iso-butyl ester Following General Procedure A' above and using 3-phenylpropionyl chloride (Aldnch) and D,L-alamne /jo-butyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid having a melting point of 20 from 51°-54°C. The reaction was monitored by tic on silica gel and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HC1. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.25 (m, 2H), 7.19 (m, 3H), 6.28 (d, J = 7.2 Hz, 25 1H), 4.58 (quint., J = 7.2 Hz, 1H), 3.89 (m, 2H), 2.95 (t, J = 7.7 Hz, 2H), 2.50 (m, 2H), 1.92 (m, 1H), 1.33 (d, J = 7.1 Hz, 3H), 0.91 (d, J = 6.7 Hz, 6H). 13C-nmr (CDClj): 5 = 173.0, 171.5, 140.6, 128.3, 128.1, 126.0, 71.2, 47.8, 37.9, 31.4, 27.5, 18.79, 18.77, 18.3. 30 C.sH^NOj (MW = 277.37, Mass Spectroscopy (MH+ 278)) Printed from Mimosa WO 98/22494 - 107 - PCT/US97/20804 Example A3 Synthesis of iV-(3-methylpentanoyl)-L-alaiiine i'so-butyl ester Following General Procedure B' and using 3-methylpentanoic acid (Aldrich) and L-alanine wo-butyl ester hydrochloride (from Example B' above), 5 the title compound was prepared as an oil. The reaction was monitored by tic on silica gel and purification was by extraction with EtjO followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: 'H-nmr (CDC1,): 5 = 6.08 (d, J = 5.9 Hz, 1H), 4.62 (quint., J = 7.3 Hz, 10 1H), 3.92 (m, 2H), 2.22 (m, 1H), 1.84-2.00 (m, 3H), 1.40 (d, J = 7.2 Hz, 3H), 1.35 (m, 1H), 1.20 (m, 1H), 0.85-0.96 (m, 12H). 13C-nmr (CDC13): 5 = 173.3, 172.1, 71.4, 47.9, 43.9, 32.3, 29.38, 29.35, 27.6, 19.10, 19.06, 18.93, 18.91, 18.72, 18.67, 11.3. C13H25N03 (MW = 243.35, Mass Spectroscopy (MH+ 244)) 15 Example A4 Synthesis of iV-[(4-chlorophenyl)acetyl]-L-alanine iso-butyl ester Following General Procedure B' and using 4-chlorophenylacetic acid (Aldrich) and L-alanine wo-butyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid having a melting point of 111°-20 113°C. The reaction was monitored by tic on silica gel and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.30 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.3 Hz, 25 2H), 6.18 (d, J = 5.5 Hz, 1H), 4.57 (quint., J = 7.2 Hz, 1H), 3.88 (m, 2H), 3.53 (s, 2H), 1.91 (m, 1H), 1.36 (d, J = 7.1 Hz, 3H), 0.90 (d, / = 6.8 Hz, 6H). 13C-nmr (CDC13): 5 = 172.8, 169.8, 133.1, 133.0, 130.6, 128.9, 71.4, 48.2, 42.6, 27.6, 18.85, 18.82, 18.4. 30 C15H20NO3Cl (MW = 297.78, Mass Spectroscopy (MH+ 298)) Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 108 --Example A5 Synthesis of iV-[(3,4-dichlorophenyI)acetyl]-L-alaiiinei?0-butyl ester Following General Procedure B' and using 3,4-dichlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B' above), 5 the tide compound was prepared as a solid having a melting point of 81°-83°C. The reaction was monitored by tic on silica gel and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: 10 'H-nmr (CDC1,): S = 0.90 (d, J = 6.8 Hz, 6H), 1.38 (d, J = 7.1 Hz, 3H), 1.91 (m, IH), 3.50 (s, 2H), 3.90 (m, 2H), 4.57 (quint., J = 7.1 Hz, IH), 6.31 (d, J = 4.9 Hz, 1H),7.12 (m, IH), 7.38 (m, 2H). 13C-nmr (CDC13): 5 = 18.4, 18.8, 18.9, 27.6, 42.2, 48.3, 71.5, 128.6, 130.6, 131.2, 131.3, 132.6, 134.7, 169.2, 172.8. 15 C15H19N03C12 (MW = 332.23, Mass Spectroscopy (MH+ 332)) Example A6 Synthesis of 2V-[(4-methylphenyl)acetyl]-D,L-alanine wo-butyl ester Following General Procedure B' and using 4-methylphenylacetic acid (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example B' 20 above), the title compound was prepared as a solid having a melting point of 102°-104°C. The reaction was monitored by tic on silica gel (Rf =0.6 in 33% ethyl acetate/hexanes) and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: 25 'H-nmr (CDC13): 5 = 0.90 (d, J = 6.7 Hz, 6H), 1.35 (d, J = 7.2 Hz, 3H), 1.91 (m, 1H), 2.34 (s, 3H), 3.55 (s, 2H), 3.88 (m, 2H), 4.58 (m, 1H), 6.05 (bd, IH), 7.16 (s, 4H). l3C-nmr (CDC13): 5 = 18.5, 18.85, 18.87, 21.0, 27.6, 43.1, 48.1, 71.3, 129.2, 129.6, 131.3, 136.9, 170.6, 172.8. 30 C16H23N03 (MW = 277.37, Mass Spectroscopy (MH+ 278)) Printed from Mimosa WO 98/22494 PCT/U S97/20804 - 109 -Example A7 Synthesis of iV-[(3-pyridyl)acetyl]-D,L-alanine iso-butyl ester Following General Procedure F' and using 3-pyridylacetic acid hydrochloride (Aldrich) and D,L-alanine ijo-butyl ester hydrochloride (from 5 Example B' above), the title compound was prepared as a solid having a melting point of 62°-64°C. The reaction was monitored by tic on silica gel (Rf = 0.48 10% methanol/dichloromethane) and purification was by silica gel chromatography. NMR data was as follows: 10 'H-nmr (CDC13): 5 = 8.40 (d, J = 2.8, 2H); 7.6 (m, IH): 7.16 (m, 2H); 4.5 (quint., J = 7.2, 7.2, IH); 3.8 (m, 2H); 3.48 (s, 2H); 1.8 (m, IH); 1.30 (d, J = 7.2, 3H); 0.81 (d, J = 6.7, 6H). 13C-nmr (CDClj): 5 = 173.4, 170.1, 150.6, 148.8, 137.4, 131.4, 124.1, 71.9, 48.9, 40.6, 28.1, 19.5, 19.4, 18.6. 15 C14H20NjO3 (MW = 264, Mass Spectroscopy (MH+ 265)) Example A8 Synthesis of W-[(l-naphthyl)acetyl]-I^alanine wo-butyl ester Following General Procedure B' and using 1-naphthylacetic acid (Aldrich) and L-alanme wo-butyl ester hydrochloride (from Example B' above), the title 20 compound was prepared as a solid having a melting point of 69°-73°C. The reaction was monitored by tic on silica gel and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: 'H-nmr (CDC1,): 5 = 0.83 (m, 6H), 1.25 (d, J = 7.1 Hz, 3H), 1.81 (m, 25 IH), 3.79 (m, 2H), 4.04 (2s, 2H), 4.57 (quint., J = 7.3 Hz, IH), 5.99 (d, J = 7.1 Hz, IH), 7.44 (m, 2H), 7.53 (m, 2H), 7.85 (m, 2H), 7.98 (m, IH). 13C-nmr (CDC13): 6 = 18.2, 18.81, 18.83, 27.5, 41.5, 48.2, 71.3, 123.7, 125.6, 126.1, 126.6, 128.2, 128.5, 128.7, 130.7, 132.0, 133.9, 170.3, 172.5. C19H23NOj (MW = 313.40, Mass Spectroscopy (MH+ 314)) Printed from Mimosa WO 98/22494 PCT/US97/20804 - 110 -Example A9 Synthesis of tf-[(2-naphthy])acetyl]-L-aIanine tso-butyl ester Following General Procedure B' and using 2-naphthylacetic acid (Aldrich) and L-alanine wo-butyl ester hydrochloride (from Example B' above), the title 5 compound was prepared as a solid having a melting point of 128°-129°C. The reaction was monitored by tic on silica gel and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: 'H-nmr (CDC1,): 5 = 0.86 (m, 6H), 1.35 (d, J = 7.1 Hz, 3H), 1.78 (m, 10 IH), 3.76 (s, 2H), 3.87 (m, 2H), 4.62 (quint., J = 7.2 Hz, IH), 6.13 (d, J = 7.1 Hz, IH), 7.41 (m, IH), 7.48 (m, 2H), 7.74 (s, IH), 7.83 (m, 3H). 13C-nmr (CDC13): 6 = 18.4, 18.82, 18.85, 27.6, 43.7, 48.2, 71.4, 125.9, 126.3, 127.2, 127.6, 127.7, 128.2, 128.7, 132.0, 132.5, 133.5, 170.3, 172.8. Ci9H23N03 (MW = 313.40, Mass Spectroscopy (MH+ 314)). 15 Example A10 Synthesis of Ar-(4-phenylbutanoyl)-L-alanine iso-butyl ester Following General Procedure B' and using 4-phenylbutanoic acid (Aldrich) and L-alanine /so-butyl ester hydrochloride (from Example B' above), the title compound was prepared as an oil. The reaction was monitored by tic on silica 20 gel and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: lH-nmr (CDC1,): 5 = 0.92 (d, J = 6.7 Hz, 6H), 1.38 (d, J = 7.1 Hz, 3H), 1.96 (m, 3H), 2.21 (t, J = 7.1 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 3.90 25 (m, 2H), 4.59 (quint., J = 7.2 Hz, IH), 6.31 (d, IH), 7.16 (m, 3H), 7.24 (m, 2H). 13C-nmr (CDC13): 5 = 18.3, 18.75, 18.78, 26.8, 27.5, 34.9, 35.3, 47.8, 71.2, 125.7, 128.2, 128.3, 141.3, 172.1, 173.0. Cl7H2JN03 (MW = 291.39, Mass Spectroscopy (MH+ 292)). Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 111 -Example All Synthesis of JV-(5-phenylpentanoyI)-L-alanine iyo-butyl ester Following General Procedure B' and using 5-phenylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B' above), S the title compound was prepared as an oil. The reaction was monitored by tic on silica gel and purification was by extraction with EtjO followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: 'H-nmr (CDC1,): 8 = 7.23 (m, 2H), 7.17 (m, 3H), 6.30 (d, IH), 4.59 10 (quint., J = 7.3 Hz, IH), 3.91 (m, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.22 (t, J = 12 Hz, 2H), 1.93 (m, IH), 1.66 (m, 4H), 1.38 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 6.7 Hz, 6H). 13C-nmr (CDClj): 5 = 173.1, 172.3, 142.0, 128.2, 128.1, 125.6, 71.2, 47.8, 36.1, 35.5, 30.8, 27.5, 25.0, 18.80, 18.77, 18.4. 15 C18H27N03 (MW = 305.39, Mass Spectroscopy (MH+ 306)). Example A12 Synthesis of N-[(4-pyridyl)acetyl]-D,L-alanine iso-butyl ester Following General Procedure F' and using 4-pyridylacetic acid hydrochloride (Aldrich) and (D,L)-alanine wo-butyl ester hydrochloride (from 20 Example B' above), the title compound was prepared as a solid having a melting point of 64°-66°C. The reaction was monitored by tic on silica gel (Rf = 0.43 10% methanol/dichloromethane) and purification was by silica gel chromatography. NMR data was as follows: 25 'H-nmr (CDC1,): 5 = 8.51 (dd, J = 1.6, 2.8, 1.6, 2H); 7.23 (dd, J = 4.3, 1.6, 4.4, 2H); 6.71 (d, J = 6.8, IH); 4.56 (quint., J = 7.3, 7.2, IH); 3.88 (m, 2H); 3.53 (s, 2H); 1.89 (m, IH); 1.36 (d, J = 7.2, 3H); 0.88 (d, J = 6.7, 6H). 13C-nmr (CDC13): 5 = 173.5, 169.3, 150.5, 144.4, 125.1, 72.1, 48.9, 30 43.0, 28.2, 19.5, 19.5, 18.9. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 112 - C14H20N2O3 (MW = 264, Mass Spectroscopy (MH+ 265)) Example A13 Synthesis of N-(phenylacetyl)-L-alanine iso-butyl ester Following General Procedure B' and using phenylacetyl chloride (Aldrich) 5 and L-alanine ijo-butyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid having a melting point of 45°-47°C. The reaction was monitored by tic on silica gel and purification was by extraction with EtzO followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: 10 'H-nmr (CDC1,): 5 = 7.24-7.39 (m, 5H), 6.14 (d, IH), 4.58 (t, J = 7.3 Hz, IH), 3.88 (m, 2H), 3.58 (s, 2H), 1.90 (m, IH), 1.35 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.7 Hz, 6H). 13C-nmr (CDC13): 5 = 172.8, 170.4, 134.5, 129.3, 128.9, 127.2, 71.3, 48.1, 43.5, 27.5, 18.9, 18.8, 18.4. 15 C15H21N03 (MW = 263.34, Mass Spectroscopy (MH+ 264)). Example A14 Synthesis of 2-[(3,4-dichlorophenyI)acetamido]butyric acid /so-butyl ester Following General Procedure I' above and using 3,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General 20 Procedure J' above) the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.36 (m, 3H), 6.03 (bd, IH), 4.54 (m, IH), 3.87 25 (m, 2H), 3 49 (s, 2H), 1.93 (m, 2H), 1.72 (m, IH), 0.88 (d, 6H), 0.80 (t, 3H). Printed from Mimosa WO 98/22494 PCT/US97/20804 — 113 — Example A15 Synthesis of 2-[(3-methoxyphenyl)acetamido]butyric acid iyo-butyl ester Following General Procedure V above and using 3-methoxyphenylacetic acid (Aldrich) and wo-butyl 2-aminobutyrate (prepared frollowing General 5 Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1,): 5 = 6.75 (m, 4H), 5.93 (bd, IH), 4.51 (m, IH), 3.83 10 (m, 2H), 3.75 (s, 2H), 3.52 (s, 2H), 1.82 (m, 2H), 1.60 (m, IH), 0.84 (d, 6H), 0.74 (t, 3H). C,7H25N04 (MW = 307.39, Mass Spectroscopy (MH+ 309)). Example A16 Synthesis of 2-[(4-nitrophenyI)acetamido]butyric acid iso-butyl ester 15 Following General Procedure I' above and using 4-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. 20 NMR data was as follows: 'H-nmr (CDC13): 5 = 8.16 (d, 2H), 7.44 (d, 2H), 6.04 (bd, IH), 4.55 (m, IH), 3.86 (m, 2H), 3.66 (s, 2H), 1.86 (m, 2H), 1.67 (m, IH), 0.85 (d, 6H), 0.81 (t, 3H). C16H22N203 (MW = 322.36, Mass Spectroscopy (MH+ 323)). 25 Example A17 Synthesis of 2-[(3,4-methylenedioxyphenyl)acetamido]butyricacid iso-butyl ester Following General Procedure I' above and using 3,4-(methyIenedioxy)-phenyl acetic acid (Aldrich) and wo-butyl 2-aminobutyrate (prepared following 30 General Procedure J' above), the title compound was prepared. The reaction Printed from Mimosa WO 98/22494 PCT/US97/20804 - 114 - was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1,): 5 = 6.72 (m, 3H), 5.92 (bd, IH), 4.54 (m, IH), 3.86 5 (m, 2H), 3.66 (s, 2H), 1.86 (m, 2H), 1.66 (m, IH), 0.89 (d, 6H), 0.79 (t, 3H). Example A18 Synthesis of 2-[(thien-3-yl)acetamido]butyric acid fro-butyl ester Following General Procedure I' above and using 3-thiopheneacetic acid 10 (Aldrich) and w-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 15 'H-nmr (CDC13): 5 = 7.37 (m, IH), 7.16 (m, IH), 7.04 (m, IH), 6.05 (bd, IH), 4.57 (m, IH), 3.66 (s, 2H), 1.93 (m, 2H), 1 67 (m, IH), 0.91 (d, 6H), 0.86 (t, 3H). Example A19 Synthesis of 2-[(4-chlorophenyl)acetamido]butyric acid iso-butyl ester 20 Following General Procedure I' above and using 4-chlorophenylacetic acid (Aldrich) and /so-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. 25 NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.22 (m, 2H), 7.11 (m, 2H), 5.80 (m, IH), 4.44 (m, IH), 3.78 (m, 2H), 3.43 (s, 2H), 1.77 (m, 2H), 1.56 (m, IH), 0.83 (d, 6H) 0.71 (t, 3H). Printed from Mimosa WO 98/22494 PCT/U S97/20804 - 115 - Example A20 Synthesis of 2-[(3-nitrophenyl)acetamido]butyric acid uo-butyl ester Following General Procedure I' above and using 3-nitrophenylacetic acid (Aldrich) and wo-butyl 2-aminobutyrate (prepared following General Procedure 5 J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1,): 5 = 8.15 (m, 2H), 7.65 (m, IH), 6.08 (m, IH), 4.46 (m, 10 IH), 3.92 (m, 2H), 3.68 (s, 2H), 1.91 (m, 2H), 1.75 (m, IH), 0.98 (d, 6H) 0.71 (t, 3H). Example A21 Synthesis of 2-[(2-hydroxyphenyl)acetamido]butyric acid uo-butyl ester Following General Procedure I' above and using 2-hydroxyphenylacetic 15 acid (Aldrich) and wo-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 20 'H-nmr (CDC1,): 5 = 7.14 (m, IH), 7.01 (m, IH), 6.93 (m, IH), 6.79 (m, IH), 6.46 (m, IH), 4.51 (m, IH), 3.87 (m, 2H), 3.57 (s, 2H), 2.01 (m, 2H), 1.75 (m, ih), 0.89 (d, 6H), 0.85 (t, 3H). Example A22 Synthesis of 2-[(2-naphthyl)acetamido]butyric acid iso-butyl ester 25 Following General Procedure I' above and using 2-naphthylacetic acid (Aldnch) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 116 — NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.83 (m, 7H), 5.95 (m, IH), 4.58 (m, IH), 3.84 (m, 2H), 3.75 (s, 2H), 1.89 (m, 2H), 1.63 (m, IH), 0.91 (d, 6H), 0.81 (t, 3H). CzoHzjNOs (MW = 327.42, Mass Spectroscopy (MH+ 328)). 5 Example A23 Synthesis of 2-[(2,4-dichlorophenyI)acetamido]butyric acid wo-butyl ester Following General Procedure I' above and using 2,4-dichlorophenylacetic acid (Aldrich) and /jo-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was 10 monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.49 (m, IH), 7.22 (m, 2H) 5.98 (m, IH), 4.52 (m, IH), 3.86 (m, 2H), 3.61 (s, 2H), 1.84 (m, 2H), 1.62 (m, IH) 0.87 (d, 6H), 15 0.80 (t, 3H). Example A24 Synthesis of 2-[(4-bromophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure I' above and using 4-bromophenylacetic acid (Aldrich) and z'so-butyl 2-aminobutyrate (prepared following General Procedure 20 J' above), the title compound was prepared. The reaction was monitored by dc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1,): 6 = 7.43 (d, 2H), 7.19 (d, 2H) 5.85 (m, IH), 4.51 (m, 25 IH), 3.81 (m, 2H), 3.47 (s, 2H), 1.84 (m, 2H), 1.61 (m, IH) 0.84 (d, 6H), 0.76 (t, 3H). C16H22N03Br (MW = 356.26, Mass Spectroscopy (MH+ 358)). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 117 — Example A25 Synthesis of 2-[(3-chlorophenyl)acetamido])butyric acid uo-butyl ester Following General Procedure I' above and using 3-chlorophenylacetic acid (Aldrich) and wo-butyl 2-aminobutyrate (prepared following General Procedure 5 J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1,): S = 7.25 (m, 3H), 7.12 (m, IH) 5.80 (m, IH), 4.52 (m, 10 IH), 3.86 (m, 2H), 3.50 (s, 2H), 1.87 (m, 2H), 1.67 (m, IH) 0.88 (d, 6H), 0.77 (t, 3H). C]6H22N03C1 (MW = 311.81 Mass Spectroscopy (MH+ 313)). Example A26 Synthesis of 2-[(3-fIuorophenyl)acetamido]butyric acid iso-butyl ester 15 Following General Procedure I' above and using 3-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reacaon was monitored by tic on silica gel and purification was by filtration as descnbed in the general procedure. 20 NMR data was as follows: 'H-nmr (CDC1,): 6 = 7.31 (m, IH), 7.01 (m, 3H) 5.95 (m, IH), 4.54 (m, IH), 3.84 (m, 2H), 3.54 (s, 2H), 1.88 (m, 2H), 1.65 (m, IH) 0.87 (d, 6H), 0.81 (t, 3H). C,6H22N03F (MW = 295.35 Mass Spectroscopy (MH+ 296)). 25 Example A27 Synthesis of 2-[(benzothiazoI-4-yl)acetamido]butyric acid iso-butyl ester Following General Procedure I' above and using 4-benzothiazol-4-yl acetic acid (Chemservice) and iro-butyl 2-aminobutyrate (prepared following General Procedure I' above), the title compound was prepared. The reaction was Printed from Mimosa WO 98/22494 PCT/US97/20804 - 118 — monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.82 (m, IH), 7.51-7.21 (m, 4H) 5.84 (m, IH), 4.51 5 (m, IH), 3.90 (s, 2H), 3.79 (m, 2H), 1.78 (m, 2H), 1.58 (m, IH) 0.80 (d, 6H), 0.66 (t, 3H). Example A28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric acid iso-butyl ester Following General Procedure I' above and using 2-methylphenylacetic acid 10 (Aldrich) and zso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as descnbed in the general procedure. NMR data was as follows: 15 'H-nmr (CDC1,): 6 = 7.18 (m, 4H), 5.79 (m, IH), 4.54 (m, IH), 3.85 (m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81 (m, 2H), 1.59 (m, IH) 0.87 (d, 6H), 0.77 (t, 3H). C17H2jN03 (MW = 291.39 Mass Spectroscopy (M+ 291)). Example A29 20 Synthesis of 2-[(2-fluorophenyI)acetamido]butyric acid iso-butyl ester Following General Procedure I' above and using 2-fluorophenylacetic acid (Aldrich) and z'so-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general 25 procedure. NMR data was as follows: 'H-nmr (CDC15): 8 = 7.28 (m, IH), 7.09 (m, 3H) 6.03 (m, IH), 4.54 (m, IH), 3.87 (m, 2H), 3.57 (s, 2H), 1.89 (m, 2H), 1.64 (m, IH) 0.88 (d, 6H), 0.80 (t, 3H). Printed from Mimosa WO 98/22494 PCT/US97/20804 — 119 - Example A30 Synthesis of 2-[(4-fluorophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure I' above and using 4-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.20 (m, 2H), 6.97 (m, 2H) 5.87 (m, IH), 4.492 (m, IH), 3.83 (m, 2H), 3.48 (s, 2H), 1.86 (m, 2H), 1.60 (m, IH) 0.87 (d, 6H), 0.78 (t, 3H). Ci6H22N03F (MW = 295.35 Mass Spectroscopy (MH+ 296)). Example A31 Synthesis of 2-[(3-bromophenyl)acetamido)butyric acid iso-butyl ester Following General Procedure I' above and using 3-bromophenylacetic acid (Aldrich) and zso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1,): 8 = 7.45 (m, 2H), 7.23 (m, 2H) 5.95 (m, IH), 4.55 (m, IH) 3.84 (m, 2H) 3.55 (s, 2H), 1.89 (m, 2H), 1.68 (m, IH) 0.91 (d, 6H), 0.81 (t, 3H). C16H22N03Br (MW = 356.26 Mass Spectroscopy (M+ 357)). Example A32 Synthesis of 2-[(3-trifluoromethylphenyl)acetamido]butyric acid iso-butyl ester Following General Procedure I' above and using 3-trifluoromethyl-phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction Printed from Mimosa WO 98/22494 PCT/US97/20804 « 120 - was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.52 (m, IH), 7.47 (m, 2H) 6.01 (m, IH), 4.56 (m, 5 IH), 3.86 (m, 2H), 3.61 (s, 2H), 1.84 (m, 2H), 1.62 (m, IH) 0.87 (d, 6H), 0.80 (t, 3H). C17H22NO3F3 (MW = 345.36 Mass Spectroscopy (MH+ 345)). Example A33 Synthesis of 2-[(2-thienyl)acetamido]butyric acid iso-butyl ester 10 Following General Procedure I' above and using 2-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. 15 NMR data was as follows: 'H-nmr (CDC1,): 5 = 6.89 (m, 3H), 6.07 (bd, IH), 4.50 (m, IH), 3.82 (m, 2H), 3.71 (s, 2H), 1.85 (m, 2H), 1.62 (m, IH), 0.81 (d, 6H), 0.75 (t, 3H). C14H21N03S (MW = 283.39, Mass Spectroscopy (MH+ 284)). 20 Example A34 Synthesis of 2-(phenylacetamido)butyric acid iso-butyl ester Following General Procedure H' above and using phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic 25 on silica gel and purification was by chromatography on silica gel using 9:1 toluene: EtOAc as the eluant. NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 - 121 - lH-nmr (CDC13): 5 = 7.17-7.28 (m, 5H), 6.23 (bd, IH), 4.51 (m, IH), 3.86 (m, 2H), 3.54 (s, 2H), 1.87 (m, 2H), 1.62 (m, IH), 0.87 (d, 6H), 0.78 (t, 3H). C16H23N03 (MW = 277.36, Mass Spectroscopy (MH+ 277)). 5 Example A35 Synthesis of ^-(phenylacetyl)valine 2-methyIbutyl ester Step A. Preparation of N-(phenylacetyl) valine To a stirred solution of 5.15 g (44 mmol) of valine (Bachem) in 50 mL (100 mmol) of 2N NaOH cooled to 0°C was added dropwise 5.3 mL (40 10 mmol) of phenylacetyl chloride (Aldrich). A colorless oil precipitated. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, washed with 50 mL diethyl ether, acidified to pH 2-3 with aqueous HCl. The white precipitate formed was filtered off, washed thoroughly with water, followed by diethyl ether to give 7.1 g (30 mmol, 69% yield) of the title 15 compound. NMR data was as follows: 'H-nmr (DMSO-rf6): 8 = 12.63 (s, IH), 8.25 (d, J = 8.6 Hz, IH), 7.27 (m, 5H), 4.15 (m, IH), 3.56 (d, J = 13.8 Hz, IH), 3.47 (d, J = 13.8 Hz, IH), 2.05 (m, IH), 0.87 (d, J = 6.8, Hz, 3H), 0.84 (d, J = 6.8 Hz, 3) 20 13C-nmr (DMSO-</6): 8 = 173.2, 170 4, 136.6, 129.0, 128.2, 126.3, 57.1, 41.9, 30.0, 19.2, 18.0 Cl3H,7N03 (MW=235.29; Mass Spectroscopy (MH+ = 236)) Step B. Synthesis of N-(phenylacetyl)valine 2-methylbutyl ester Following General Procedure C' and using the N-(phenylacetyl) valine 25 prepared in Step A above and 2-methylbutan-l-ol (Aldrich), the title compound was prepared as a diastereomeric mixture. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 - 122 - 'H-nmr (CDC1J: 8 = 7.25-7.40 (m, 5H), 5.95 (d, IH), 4.56 (m, IH), 3.84-4.00 (m, 2H), 3.61 (s, 2H), 2.10 (m, IH), 1.68 (m, IH), 1.38 (m, IH), 1.15 (m IH), 0.82-0.94 (m, 9H), 0.76 (d, 3H). 13C-nmr (CDC13): 5 = 171.84, 171.81, 170.7, 134.6, 129.31, 129.27, 5 128.9, 127.3, 69.8, 57.0, 43.7, 33.9, 31.3, 25.9, 25.8,, 18.9, 17.4, 16.34, 16.27, 11.12, 11.07. CigHyjNC^ (MW = 305.42, Mass Spectroscopy (MH 306)). Example A36 Synthesis of ^-(phenylacetyO-L-methionine iso-butyl ester 10 L-Methionine (0.129g, 0.869 mmols) (Aldrich) was taken-up in dioxane (5.0 mL) and treated with a saturated solution of sodium bicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldnch) (0.114 mL, 0.822 mmols). After stirring for 17 hours at room temperature the mixture was diluted with ethyl acetate, the layers separated and the aqueous layer acidified to pH 2 with 5N 15 HCl. The crude product was extracted into ethyl acetate, dried over sodium sulfate, vacuum dried and used without further purification. N-phenylacetyl-L-methionine (0.1285 g, 0.447 mmol) was dissolved in 3.0 mL dioxane and rso-butyl alcohol (0.2 mL) and treated with EDC (0.094 g, 0.492 mmol), and catalytic DMAP (0.015g). After stimng for 17 hours at 20 23°C, the mixture was evaporated at reduced pressure to an oil, the residue was diluted in EtOAc and washed with 0.1 N HCl and saturated sodium bicarbonate. Chromatography on silica gel using 98:2 CHCl3/MeOH as eluant provided the pure product. NMR data was as follows: 25 'h-nmr (CDC13): 5 = 7.4-7.23 (m, 5H), 6.14 (bd, IH), 4.70 (m, IH), 3.89 (d, 2H), 3.62 (s, 2H), 2.43 (m, 2H), 2.12 (m, IH), 1.93 (m, 2H), 0.94 (d, 6H). C17H25N03S (MW = 323.17, Mass Spectroscopy (M+ 323) Printed from Mimosa WO 98/22494 PCT/US97/20804 - 123 -Example A37 Synthesis of AKphenylacetyI)-L-leucine iso-butyl ester L-Leucine (Aldrich) (0.114g, 0.869 mmols) was taken-up in dioxane (5.0 mL) and treated with a saturated solution of sodium bicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich) (0.114 mL, 0.822 mmols). After stirring for 17 hours at room temperature the mixture was diluted with ethyl acetate, the layers separated and the aqueous layer acidified to pH 2 with 5N HCl. The crude product was extracted into ethyl acetate, dried over sodium sulfate, vacuum dried and used without further purification. N-Phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was dissolved in 2.0 mL CHC13 (EtOH free) and /io-butyl alcohol (0.055 mL) and treated with P-EPC (100 mg, 0.87 milliequivalents). The mixture was rotated for 4 days, filtered through a plug of cotton and the filtrate evaporated at reduced pressure to an oil which was sufficiently pure for testing. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.22 (m, 5H), 5.57 (d, IH), 4.35 (m, IH), 3.35 (m, 3H), 1.35 (m, 4H), 0.68 (m, 9H). C18H27N03 (MW = 305.40, Mass Spectroscopy (M+ 305)). Example A38 Synthesis of /V-[(3-chlorophenyl)acetyl]alanine 3-methylbut-2-enyl ester Following General Procedure C' above and using N-(3-chlorophenylacetyl alanine (from Example D' above) and 3-methylbut-2-en-l-ol (Aldrich), the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 30% EtOAc/hexane as the eluant. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.39-7.16 (m, 4H), 6.06 (bd, IH), 5.38-5.29 (m, IH), 4.63 (d, J = 9Hz, 2H), 3.56 (s, 2H), 1.79 (s, 3H), 1.7 (s, 3H), 1.39 (d, J = 9Hz, 3H). Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 124 -Example A39 Synthesis of jV-[(3-ch]orophenyI)acetyl]alanine cyclopropylmethyl ester Following General Procedure C' above, and using N-(3-chlorophenylacetyl alanine (from Example D' above) and cyclopropylmethanol (Aldrich), the title 5 compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant. NMR data was as follows: 'H-nmr (CDC1,): 6 = 7.2-7.1 (m, 4H), 6.09 (bs, IH), 4.6 (dq, J = 9 Hz, 10 IH), 3.96 (dd, J = 9Hz, 2H), 3.59 (s, 2H), 1.2 (d, J = 9Hz, 3H), 1.2-1.0 (m, IH), 0.603-0.503 (m, 2H), 0.300-0.203 (m, 2H). Example A40 Synthesis of N-[(3-chlorophenyl)acetyl]alanine 2-thienylmethyl ester Following General Procedure C' above, and using N-(3-chlorophenylacetyl 15 alanine (from Example D' above) and 2-thiophenemethanol (Aldrich) the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant. NMR data was as follows: 20 'H-nmr (CDC1,): 5 = 7.37-6.97 (m, 7H), 5.97 (q, J = 14 Hz, 2H), 4.6 (dq, J = 9 Hz, IH), 3.76 (s, 2H), 1.38 (d, J = 9Hz, 3H). Example A41 Synthesis of /V-[(3-chIorophenyl)acetyl]alanine (l-methylcyclopropyl)methyl ester 25 Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D' above) and (1-methylcyclopropyl) methanol (Aldrich) the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 125 - NMR data was as follows: 'H-nmr (CDC1S): 5 = 8.6 (bd, / = 9 Hz, IH), 3.86 (q, J = 14 Hz, 2H), 3.4 (s, 2H), 2.29 (q, J = 9 Hz, IH), 1.3 (d, J = 9Hz, 3H), 1.03 (s, 3H), 0.5-0.4 (m, 2H), 0.4-0.28 (m, 2H). 5 Example A42 Synthesis of 2V-[(3-chlorophenyl)acety]]alanine 3-thienylmethyl ester Following General Procedure C' above, and using N-(3-chlorophenylacetyl alanine (from Example D' above) and 3-thiophenemethanol (Aldrich) the title compound can be prepared. The reaction was monitored by tic on silica gel 10 and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant. NMR data was as follows: 'H-nmr (CDC1,): b = 8.03 (bd, J = 9 Hz, IH), 7.56-7.5 (m, IH), 7.47 (bs, IH), 7.4-7.17 (m, 4H), 7.06 (d, / = 9 Hz, IH), 5.1 (s, 2H), 4.3 (dq, 15 IH), 1.3 (d, J = 9 Hz, 3H). Example A43 Synthesis of /V-[(3-chlorophenyl)acetyl]alanine 2-methylcyclopentyl ester Following General Procedure C' above, and using N-(3-chlorophenylacetyl alanine (from Example D' above) and 2-methylcyclopentanol (Aldrich) the title 20 compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant. NMR data was as follows: 'H-nmr (CDC1,): b = 7.39-7.16 (m, 4H), 6.3 (bd, IH), 4.79-4.7 (m, IH), 25 4.6-4.25 (m, J = 9 Hz, IH), 3.577 (s, 2H), 2.09-1.8 (m, 2H), 1.74-1.6 (m, 2H), 1.39 (dd, J = 9 Hz, 3H), 1.2 (dt, J = 9 Hz, IH), 0.979 (dd, J = 9 Hz, 2H) CnH22NOjCl (MW = 323.82, Mass Spectroscopy (MH+ 323). Printed from Mimosa WO 98/22494 - 126 - PCT/US97/20804 Example A44 Synthesis of iV-[(3-chlorophenyl)acetyl]alanine 2-methyIprop-2-enyl ester Following General Procedure C' above, and using N-(3-chlorophenylacetyl alanine (from Example D' above) and 2-methylprop-2-en-l-ol (Aldrich) the title 5 compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant. NMR data was as follows: 'H-nmr (CDC1,): 6 = 7.39-7.16 (m, 4H), 6.03 (bs, IH), 4.77 (s, 2H), 4.7-10 4.29 (m, 3H), 2.59 (s, 2H), 1.73 (s, 3H), 1.43 (d, J = 9 Hz, 3H) C15H]8N03C1 (MW = 295.76, Mass Spectroscopy (MH+ 295)). Example A45 Synthesis of /V-[(3-chlorophenyl)acetyl]alanine cyclohex-2-enyl ester Following General Procedure C' above, and using N-(3-chlorophenylacetyl 15 alanine (from Example D' above) and cyclohex-2-en-l-ol (Aldrich) the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant. NMR data was as follows: 20 'H-nmr (CDC13): 6 = 8.6 (bd, J = 9 Hz, IH), 7.4-7.2 (m, 4H), 6.0-5.8 (m, IH), 5.7-5.5 (m, IH), 5.1 (bs, IH), 4.13-4.29 (m, IH), 3.5 (s, 2H), 2.1-1.9 (m, 2H), 1.8-1.69 (m, IH), 1.69-1.49 (m, 4H), 1.3 (dd, J = 9 Hz, 3H) C17H20NO3Cl (MW = 321.8, Mass Spectroscopy (MH+ 321.2)). Example A46 25 Synthesis of Ar-[(2-phenylbenzoxazoI-5-yl)acetyl]alanine iso-butyl ester Following General Procedure I' above, and using 5-(2-phenylbenzoxazol)-yl-acetic acid (CAS# 62143-69-5) and alanine zso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 127 - NMR data was as follows: 'H-nmr (CDC1,): 5 = 8.24 (m, 3H), 7.68 (m, IH), 7.51 (m, 5H), 6.04 (m, IH), 4.58 (m, IH), 3.85 (m, 2H), 3.68 (s, 2H), 1.9 (m, IH), 1.35 (d, 3H), 0.87 (d, 6H). 5 CnH24N204 (MW = 380, Mass Spectroscopy (MH+ 381)). Example 47 Synthesis of /V-[(3-methylthiophenyl)acetyl]aIanine iso-butyl ester Following General Procedure I' above, and using 3-methylthiophenylacetic acid (CAS# 18698-73-2) and alanine iso-butyl ester (prepared following General 10 Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.14 (m, 2H), 7.01 (m, IH), 4.56 (m, IH), 3.88 (m, 15 2H), 3.54 (s, 2H), 2.46 (s, 3H), 1.89 (m, IH), 1.35 (d, 3H) 0.85 (d, 6H). C15H23N03S (MW = 309, Mass Spectroscopy (MH+ 310)). Example A48 Synthesis of Ar-4-[(2-furyl)acetyl]alanine iso-butyl ester Following General Procedure I' above, and using 2-furylacetic acid (CAS# 20 2745-26-8) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 25 'H-nmr (CDC13): 6 = 7.36 (m, IH), 6.34 (m, IH), 6.21 (m, IH), 4.56 (m, IH), 3.91 (m, 2H), 3.61 (s, 2H), 1.92 (m, IH), 1.38 (d, 3H) 0.89 (d, 6H). CI3H19N04 (MW = 253, Mass Spectroscopy (MH+ 254)). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 128 --Example A49 Synthesis of A^-[(benzofuran-2-yl)acetyl]alanine iso-butyl ester Following General Procedure I' above, and using benzofuran-2-ylacetic acid (Maybridge) and alanine iso-butyl ester (prepared following General 5 Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: lH-nmr (CDC13): 5 = 7.51 (m, IH), 7.44 (m, 1H),7.25 (m, 2H), 6.67 (s, 10 IH), 4.60 (m, IH), 3.87 (m, 2H), 3.77 (s, 2H), 1.88 (m, IH), 1.38 (d, 3H), 0.87 (d, 6H). C17H2iN04 (MW = 303, Mass Spectroscopy (MH+ 304)). Example A50 Synthesis of iV-[(benzothiophen-3-yI)acetyl]alanine iso-butyl ester 15 Following General Procedure I' above, and using thianaphthen-3-ylacetic acid (Lancaster) and alanine zso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. 20 NMR data was as follows- 'H-nmr (CDC1,): 5 = 7.89 (m, IH), 7.76 (m, IH), 7.38 (m, 3H), 6.07 (m, IH), 4.57 (m, IH), 3.92 (m, 2H), 3.82 (s, 4H), 1.84 (m, IH), 1.32 (d, 3H) 0.85 (d, 6H). C17H21N03S (MW = 319, Mass Spectroscopy (MH+ 320)). 25 Example A51 Synthesis of N-[(2-chloro-5-thienyl)acetyl]alanine wo-butyl ester Following General Procedure I' above, and using 5-chloro-2-thienyl)acetic acid (CAS# 13669-19-7) and alanine jjo-butyl ester (prepared following General Printed from Mimosa WO 98/22494 PCT/US97/20804 - 129 - Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 5 'H-nmr (CDC1,): 5 = 6.77 (m, IH), 6.68 (d, IH), 6.31 (bm, IH), 4.59 (m, IH), 3.91 (m, 2H), 3.38 (s, 2H), 1.90 (m, IH), 1.39 (d, 3H) 0.89 (d, 6H). C13H18N03SC1 (MW = 303, Mass Spectroscopy (MH+ 303)). Example A52 Synthesis of iV-[(3-methylisoxazol-5-yl)acetyl]alanine iso-butyl ester 10 Following General Procedure I' above, and using (3-methyl-isoxazol-5- yl)acetic acid (CAS# 19668-85-0) and alanine jjo-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. 15 NMR data was as follows: 'H-nmr (CDC13): 5 = 6.07 (s, 2H), 4.56 (m, IH), 3.92 (m, 2H), 3.68 (s, 2H), 2.29 (s, 3H), 1.94 (m, IH), 1.89 (d, 3H) 0 91 (d, 6H). CI3H2oN204 (MW = 268, Mass Spectroscopy (MH+ 269)). Example A53 20 Synthesis of /V-[(2-phenylthiothienyl)acetyl]alanine iso-butyl ester Following General Procedure i' above, and using (2-phenyl-thiothienyl)acetic acid and alanine wo-butyl ester (prepared following General Procedure J' above), the title compound was prepared The reaction was monitored by tic on silica gel and purification was by filtration as described in 25 the general procedure. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.21-7.11 (m, 6H), 6.92 (d, IH), 4.56(m, IH), 3.87 (m, 2H), 3.72 (s, 2H), 1.94 (m, IH), 1.38 (d, 3H) 0.89 (d, 6H). C19H23N03S2 (MW = 377, Mass Spectroscopy (MH+ 378)). Printed from Mimosa WO 98/22494 PCT/US97/20804 — 130 - Example A54 Synthesis of N-[(6-methoxybenzothiophen-2-yl)acetyI]alanine iso-butyl ester Following General Procedure I' above, and using (6-methoxythianaphthen-2-yl)acetic acid and alanine iso-butyl ester (prepared following General 5 Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1,): 6 = 7.59 (d, IH), 7.33 (d, IH), 7.16 (s, IH), 7.03 (dd, 10 IH), 4.56 (m, IH), 3 87(s, 3H), 3.84 (m, 2H), 3.76 (s, 2H),1.85 (m, IH), 1.30 (d, 3H) 0.86 (d, 6H). C,8H23N04S (MW = 349, Mass Spectroscopy (MH+ 350)). Example A55 Synthesis of yV-[(3-phenyl-l,2,4-thiadiazol-5-yl)acetyl]alanine iso-butyl ester 15 Following General Procedure I' above, and using (3-phenyl-l,2,4- thiadiazol-5-yl)acetic acid (CAS# 90771-06-5) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. 20 NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.47 (m, 5H), 4.66 (m, IH), 4.16 (s, 2H), 3.91 (m, 2H), 1.93 (m, IH), 1.48 (d, 3H) 0.93 (d, 6H). C17H2IN303S (MW = 347, Mass Spectroscopy (MH+ 348)). Example A56 25 Synthesis of /V-[2-phenyloxazol-4-yl)acetyl]alanine iso-butyl ester Following General Procedure I' above, and using (2-phenyloxazol-4-yl)acetic acid (CAS# 22086-89-1) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The Printed from Mimosa WO 98/22494 PCT/US97/20804 — 131 - reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: Example A57 5 Synthesis of N-[(3-methylphenyI)acetyl]alanine iso-butyl ester Following General Procedure I' above, and using 3-methylphenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general 10 procedure. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.21 (m, IH), 7.07 (m, 3H), 4.54 (m, IH), 3.83 (m, 2H), 3.52 (s, 2H), 2.35 (s, 3H), 1.87 (m, IH), 1.32 (d, 3H), 0.88 (d, 6H). C16H23N03 (MW = 277, Mass Spectroscopy (MH+ 278)). 15 Example A58 Synthesis of /V-[(2,5-difluorophenyl)acetyl]alanine iso-butyl ester Following General Procedure I' above, and using 2,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was 20 monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC1}): 5 = 7.08-6.94 (m, 3H), 4.57 (m, IH), 3.91 (m, 2H), 3.56 (s, 2H), 1.92 (m, IH), 1.41 (d, 3H) 0.91 (d, 6H). 25 CI3H19N03F2 (MW = 299, Mass Spectroscopy (MH+ 300)). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 132 -- Example A59 Synthesis of N- [ (3,5-diflur opheny l)acetyl]alanine iso-butyl ester Following General Procedure I' above, and using 3,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General 5 Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC13): 5 = 6.81 (m, 2H), 6.74 (m, IH), 6.06 (m, IH), 4.57 (m, 10 IH), 3.92 (m, 2H), 3.51 (s, 2H), 1.94 (m, IH), 1.36 (d, 3H) 0.87 (d, 6H). C15H19N03F2 (MW = 299, Mass Spectroscopy (MH+ 300)). Example A60 Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester 15 Following General Procedure I' above, and using 3-thiopheneacetic acid (Aldrichy and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. 20 NMR data was as follows: 'H-nmr (CDC1S): 5 = 7.33 (m, 1H), 7.14 (m, IH), 7.01 (m, IH), 6.09 (m, IH), 4.58 (m, IH), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, IH), 1.37 (d, 3H) 0.92 (d, 6H). Optical Rotation: [a]23 -52 (c 1 MeOH) @ 589 nm. 25 C,3Hl9N03S (MW = 269, Mass Spectroscopy (MH+ 269)). Example A61 Synthesis of /V-[(4-methylphenyI)acetyl]-L-alanine iso-butyl ester Following General Procedure I' above, and using 4-methylphenylacetic acid (Aldrich) and L-alanine iso-butyl ester (prepared following General Procedure 30 J' above), the title compound was prepared. The reaction was monitored by tic Printed from Mimosa WO 98/22494 PCT/US97/20804 - 133 - on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.11 (s, 4H), 5.93 (m, IH), 4.58 (m, IH), 3.88 (m, 5 2H), 3.54 (s, 2H), 2.33 (s, 3H), 1.89 (m, IH), 1.32 (d, 3H), 0.89 (d, 6H). C.sHzjNC^ (MW = 277.35, Mass Spectroscopy (MH+ 278)). Example A62 Synthesis of /V-(phenylacetyI)-L-alanine S-l-(methoxycarbonyl) iso-butyl ester 10 Following General Procedure K' and using (S)-(+)-2-hydroxy-2- methylbutyric acid (Aldrich) in place of the amino acid, methyl (S)-(+)-2-hydroxy-2-methylbutyrate was prepared. Methyl (S)-(+)-2-hydroxy-2-methylbutyrate was then coupled with carbobenzyloxy-L-alanine (Aldrich) using General Procedure E' to provide 15 carbobenzyloxy-L-alanine S-l-(methoxycarbonyl) wo-butyl ester. Carbobenzyloxy-L-alanine S-l-(methoxycarbonyl) iso-butyl ester (1.0 g) was then dissolved in 20 mL of methanol and 6N HCl (0.5 mL) and 10% palladium on carbon (0.1 g) were added. This reaction mixture was hydrogenated at 40 psi of hydrogen on a Parr apparatus for 5 hours at room 20 temperature and then filtered through a pad of Celite. The filtrate was concentrated at reduced pressure to provide L-alanine S-l-(methoxycarbonyl) /so-butyl ester hydrochloride (98% yield). L-Alanine S-l-(methoxycarbonyl) /so-butyl ester hydrochloride was then coupled to phenylacetic acid using General Procedure G' to provide the title 25 compound. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.35 - 7.20 (m, 5H), 6.22 (bd, IH), 4.83 (d, IH), 4.65 (p, IH), 3.68 (s, 3H), 3.55 (s, 2H), 2.21 (m, IH), 1.40 (d, 3H), 0.97 (d, 3H), 0.93 (d, 3H). 30 13C-nmr (CDC13): 6 = 173.25, 171.18, 170.22, 135.11, 129.94, 129.50, 127.88, 52.67, 48 49, 43.98, 30.53, 19.21, 18.75, 17.58. Printed from Mimosa WO 98/22494 PCMJS97/20804 - 134 - Example A63 Synthesis of N-[(3-nitropheny I)acetyI]-L-aIanine iso-butyl ester Following General Procedure H' above and using 3-nitrophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B' above), 5 the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by recrystallization from butyl chloride. NMR data was as follows: "H-nmr (CDC1,): 5 = 8.17 (m, 2H), 7.68 (d, IH), 7.52 (t, IH), 6.18 (m, IH), 4.48 (m, IH), 3.94 (m, 2H), 3.67 (s, 2H), 1.93 (m, IH), 1.42 (d, 3H), 10 0.91 (d, 3H). Optical Rotation: [a}23 -49 (c 5, MeOH). Example A64 Synthesis of A^-[(3,5-difluorophenyl)acetyl]alanine ethyl ester 15 Following General Procedure G' and using 3,5-difluorophenylacetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93°-95°C. The reaction was monitored by tic on silica gel (Rf = 0.8 in EtOAC) and purification was by chromatography on silica gel using EtOAc as the eluant followed by recrystallization from 1-20 chlorobutane. NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 1.30 (d, 3H); 3.52 (s, 2H). C13H15N03F2 (MW = 271.26, Mass Spectroscopy (MH+ 271)). Example A65 25 Synthesis of ^-[O-nitrophenyOacetyllmethionine ethyl ester Following General Procedure G' above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich>, the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by recrystallization from butyl chloride. 30 NMR data was as follows- Printed from Mimosa WO 98/22494 PCT/US97/20804 - 135 - 'H-nmr (CDC1,): 5 = 8.18 (s, IH), 8.15 (d, IH) 7.66 (d, IH), 7.48 (t, IH), 6.30 (m, IH), 4.67 (m, IH), 4.21 (t, 2H), 3.67 (s, 2H), 2.47 (t, 2H), 2.12 (m, 2 H), 2.08 (s, 3H), 1.27 (t, 3H). Optical Rotation: [a^ -30 (c 5, MeOH). 5 Example A66 Synthesis of iV-[(3-chlorophenyl)acetyl]aIanine iso-butyl ester Following General Procedure G' above and using 3-chlorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic 10 on silica gel. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.29 (m, 3H), 7.18 (m, IH), 6.0 (m, IH), 4.56 (m, IH), 3.89 (m, 2H), 3.53 (s, 2H), 1.91 (m, IH), 1.39 (d, 3 H), 0.91 (d, 3H). Optical Rotation: [a]^ -45 (c 5, MeOH). 15 C15H20NO3Cl (MW = 297.78, Mass Spectroscopy (MH+ 297)). Example A67 Synthesis of ^-[(S-chlorophenyOacetyllalanine 2-(N,/V-dimethylamino)ethyl ester Following General Procedure C' above, and using N-(3-chlorophenyl-20 acetyl)alanine (from Example D' above) and 2-(N,N-dimethyl amino) ethanol (Aldrich), the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 0.1:2:0.79 NH4OH:EtOH:CHCl3 as the eluant. NMR data was as follows: 25 'H-nmr (CDC1,): 7.37 (s, IH), 7.33-7.2 (m, 3H), 4.675-4.6 (m, IH), 4.5- 4.37 (m, ih), 4.25-4.13 (m, IH), 3.6 (d, J = 7 Hz, 2H), 2.86 (bs, 2H), 2.3 (s, 6H), 1.23 (d, J = 9 Hz, 3H). C15H21N203CI (MW = 313.799, Mass Spectroscopy (M+ 313)). Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 136 -Example A68 Synthesis of 2-[(3,5-dichlorophenyI)acetamido]hexanoic acid methyl ester Following General Procedure F' above, an using 3,5-dichlorophenylacetic acid (from Example C' above) and L-norleucine methyl ester hydrochloride 5 (Bachem), the title compound was prepared as a solid having a melting point of 77°-78°C. The reaction was monitored by tic on silica gel (Rf = 0.70 in 40% EtOAC/hexanes) and purification was by flash chromatography on silica gel using 40% EtOAc/hexanes as the eluant. NMR data was as follows: 10 'H-nmr (CDC1,): 5 = 7.20 (s), 7.18 (s), 6.6 (m), 4.55 (m), 3.7 (s), 3.5 (s), 3.4 (s), 2.0 (s), 1.8 (m), 1.6 (m), 1.2 (m), 0.8 (t). 13C-nmr (CDC13): 5 = 173.54, 169.67, 138.43, 135.72, 128.33, 128.07, 78.04, 77.62, 77.19, 53.04, 52.90, 43.14, 32.57, 27.87, 22.81, 14.41. Example A69 15 Synthesis of A/-[(3,5-diclorophenyl)acetyl]-L-alanine iso-butyl ester Following General Procedure F' above, and using 3,5-dichlorophenylacetic acid (from Example C' above) and L-alanine /jo-butyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid having a melting point of 1150-116°C. The reaction was monitored by tic on silica gel 20 (Rf = 0.40 in 3% methanol/dichloromethane) and purification was by flash chromatography on silica gel using 3% methanol/dichloromethane as the eluant. NMR data was as follows- 'H-nmr (CDC1,): 5 = 7.27 (d, J = 2 Hz, IH), 7.19 (s, 2H), 6.22 (d, J = 6 Hz, IH), 4.59 (quint., J = 7 Hz, IH), 3.9 (q, J = 4 Hz, 2H), 3.5 (s, 2H), 25 1.9 (m, IH), 1.4 (d, J = 7 Hz, 3H), 0.91 (d, / = 7 Hz, 6H). 13C-nmr (CDClj): 5 = 173.45, 169.37, 138.31, 135.75, 128.39, 128.11, 78.04, 77.61, 77.19, 72.19, 54.03, 48.97, 43.12, 28.24, 19.52, 19.49, 19.09. Ci3H19N03Cl2 (MW = 331.9, Mass Spectroscopy (MH+ 332)). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 137 -Example A70 Synthesis of iV-(cyclohexylacetyI)-L-alanine iso-butyl ester Following General Procedure B' above, and using cyclohexylacetic acid (Aldrich) and L-alanine uo-butyl ester hydrochloride (from Example B' above), 5 the title compound was prepared as a solid having a melting point of 92 °C-93°C. The reaction was monitored by dc on silica gel (Rf = 0.39 in 1:3 EtOAc:hexane) and purification was by extraction with EtjO followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: 10 'H-nmr (CDC1,): 5 = 0.93 (d, J = 6.7 Hz, 6H), 0.85-1.01 (m, 2H), 1.05- 1.35 (m, 3H), 1.40 (d, J = 7.1 Hz, 3H), 1.60-1.85 (m, 6H), 1.95 (m, IH), 2.06 (d, J = 7.0 Hz, 2H), 3.92 (m, 2H), 4.61 (m, IH), 6.08 (bd, IH). l3C-nmr (CDC13): 5 = 18.7, 18.9, 26.0, 26.1, 27.6, 33.0, 35.3, 44.6, 47.9, 71.4, 171.8, 173.3. 15 C15H27N03 (MW = 269.39, Mass Spectroscopy (MH+ 270)). Example A71 Synthesis of /V-(cyclopentylacetyl)-L-alanine iso-butyl ester Following General Procedure B' above, and using cyclopentylacetic acid (Aldrich) and L-alanine wo-butyl ester hydrochloride (from Example B' above), 20 the title compound was prepared as a solid having a melting point of 62°C-64°C. The reaction was monitored by tic on silica gel (Rf = 0.37 in 1:3 EtOAc:hexane) and purification was by extraction with E^O followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: 25 'H-nmr (CDC1,): 5 = 0.87 (d, J = 6.8 Hz, 6H), 1.01-1.17 (m, 2H), 1.34 (d, J = 7.2 Hz, 3H), 1.40-1.62 (m, 4H), 1.70-1.83 (m, 2H), 1.89 (m, IH), 2.15 (m, 3H), 3.86 (m, 2H), 4.55 (m, IH), 6.30 (d, 7 = 7.1 Hz, IH). 13C-nmr (CDC13): 5 = 18.4, 18.78, 18.80, 24.8 (very high), 27.5, 32.27, 32.32, 36.9, 42.5, 47.7, 71.2, 172.2, 173.2. Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 138 - Elemental Analysis-Calc (%): C, 65.85; H, 9.87; N, 5.49; Found (%): C, 66.01; H, 10.08; N, 5.49. C14H2sN03 (MW = 255.36, Mass Spectroscopy (MH+ 256)). Example A72 5 Synthesis of iV-[(cycIohex-l-enyl)acetyl]-L-alanine iso-butyl ester Following General Procedure B' above, and using cyclohex-l-enyl acetic acid (Alfa) and L-alanine iso-butyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid having a melting point of 49°C-51°C. The reaction was monitored by tic on silica gel (Rf = 0.40 in 1:3 10 EtOAc :hexane) and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: 'H-nmr (CDC13): 5 = 0.91 (d, J = 4.5 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 1.40 (d, J = 7.2 Hz, 3H), 1.52-1.70 (m, 4H), 1.97 (m, 3H), 2.06 (bs, 15 2H), 2.89 (s, 2H), 3.92 (m, 2H), 4.59 (m, IH), 5.65 (s, IH), 6.33 (d, J = 6.6 Hz, IH). l3C-nmr (CDC13): 5 = 18.7, 18.91, 18.93, 21.9, 22.7, 25.3, 27.6, 28.3, 46.1, 47.9, 71.4, 127.1, 132.5, 170.6, 173.1. Elemental Analysis-Calc (%): C, 67.38; H, 9.42; N, 5.24; Found (%): C, 20 67.34; H, 9.54; N, 5.16. C.jHyNOa (MW = 267.37, Mass Spectroscopy (MH+ 268)). Example A73 Synthesis of JV-[(3-chlorophenyI)acetyl]alanine 3-methylbut-2-enyl thioester Following General Procedure C' above, and using N-[(3-25 chlorophenyl)acetyl] alanine and 3-methyl-2-butene thioester (TCI), the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:Hexane as the eluant. NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 - 139 - 'H-nmr (DMSO-d6>: 5 = 5.2-5.075 (m, IH), 4.37 (dq, / = 9 Hz, IH), 3.56 (s), 3.43 (d, J = 12 Hz, 2H), 1.266 (d, J = 12 Hz, 6H) 1.3 (d, J = 9 Hz, 3H). C^HjoNOjCIS (MW = 325.86, Mass Spectroscopy (M+ 325)). 5 Example A74 Synthesis of iV-[(2-phenyl)-2-fIuoroacetyl]alanine ethyl ester Following General Procedure F' above, and using a-fluorophenyl acetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared. The reaction was monitored by tic on silica gel (Rf = 0.75 in 1:1 10 EtOAc:hexane) and purification was by chromatography on silica gel using 1:2 ethyl acetate/hexanes as the eluent. NMR data was as follows: 'H-nmr (DMSO-d6): 5 = 1.14 (q, 3H), 1.34 (d, 3H), 4.07 (m, 2H), 4.33 (m, IH), 5.84 (d, IH), 6.01 (d, IH), 7.40-7.55 (m, 5H), 8.87 (m, IH). 15 C^H^NOjF (MW = 253.27, Mass Spectroscopy (MH+ 253)). Example A75 Synthesis of A^-(3,5-difluorophenylacetyl)-L-phenylglycine methyl ester Following General Procedure F above, and using 3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Bachem), the 20 title compound was prepared. NMR data was as follows. 'H-nmr (CDC13): 5 =7.4-7.3 (m, 5H), 6.9-6.7 (m, 3H), 6.55 (d IH, 7.1 Hz), 5.56 (d IH 7 Hz), 3.72 (s 3H), 3.57 (s 2H) '3C-nmr (CDCt3): 5 = 197.6, 177.6, 171.8, 169.3, 136.7, 129.6, 129.3, 25 127.8, 113.0, 112.9, 112.7, 111.4, 103.8, 103.5, 65.1, 57.2, 53.5, 45.1, 43.3, 43.3 C17H,jN03F2 (MW = 319.31, Mass Spectroscopy (MH +320)). Example 76 Printed from Mimosa WO 98/22494 PCT/US97/20804 — 140 - Synthesis of Ar-(3,5-difluorophenylacetyI)-L-phenylglycine iso-butyl ester The 3,5-difluorophenylacetic acid (Aldrich) was EDC coupled to L-phenylglycine methyl ester hydrochloride (Bachem) via General Procedure F above. 5 The resulting compound was placed in a large excess of the desired alcohol. A catalytic amount of dry NaH was added, and the reaction was followed by tic until the presence of starting material was no longer detected. The reaction was quenched with a few milliliters of IN HCl, and after a few minutes of stirring saturated aqueous NaHCOj was added. The volume of the 10 reaction mixture was reduced on a rotary evaporator until the excess alcohol was removed and then the remaining residue was taken up in ethyl acetate and additional water was added. The organic phase was washed with saturated aqueous NaCl and dried over MgS04. The solution was stripped free of solvent on a rotary evaporator, and the crude product residue was then further purified 15 by chromatography. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.35-7.3 (m 5H), 6 8-6.7 (m 3H) 6.60 (d IH, 7 Hz), 5.55 (d IH 7.1 Hz), 3.9 (m 2H), 3 60 (s 2H), 1.85 (m IH 7 Hz), 0.8 (q 6H 7 Hz) 20 13C-nmr (CDClj): 5 = 171.3, 169.3, 165.4, 138.5, 137.0, 129.5, 129.2, 127.6, 113.1, 113.0, 112.8, 112.7, 103.8, 103.5, 103.2, 75.5, 57.2, 43.4, 43.3, 28.2, 19.3 C20H21NO3F2 (MW = 361.39, Mass Spectroscopy (MH +362)). Example A77 25 Synthesis of <V-(cyclopentylacetyl)-I^phenyIglycine methyl ester Following General Procedure D' above, and using cyclopentylacetic acid (Aldnch) with L-phenylglycine methyl ester hydrochloride (Bachem) the title compound was prepared. NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 - 141 - 'H-nmr (CDC13): 5 = 7.35 (s, 5H), 6.44 (bd, IH), 5.6 (d, IH), 3.72 (s, 3H), 2.24 (bs, 3H), 1.9-1.4 (m, 6H), 1.2-1.05 (m, 2H) 13C-nmr (CDC13): 5 = 172.3, 171.7, 136.7, 129.0, 128.6, 127.3, 56.2, 52.7, 42.5, 36.9, 32.40, 32.38, 24.8 5 Example A78 Synthesis of JV-(cyclopentylacetyl)-L-aIanine methyl ester Following General Procedure D' above, and using cyclopentylacetic acid (Aldrich) with L-alamne methyl ester hydrochloride (Sigma) the title compound 10 was prepared. NMR data was as follows: "H-nmr (CDC13): 5 = 6.38 (d, IH), 4.50 (m, IH), 3.65 (s, 3H), 2.13 (bs, 3H), 1.80-1.00 (m (includes d at 1 30, 3H), 11H) nC-nmr (CDC13): 5 = 173.7, 172.5, 52.1, 47.6, 42.3, 36.8, 32.15, 32.14, 15 18.0 CnHi9N03 (MW = 213.28, Mass Spectroscopy (MH+ 214)). Example A79 Synthesis of iY-(cycIopropylacetyI)-L-phenylglycine methyl ester Following General Procedure D' above, and using cyclopropylacetic acid 20 (Aldnch) with L-phenylglycine methyl ester hydrochloride (Bachem), the title compound was prepared. NMR data was as follows: 'H-nmr (CDC13): 8 = 7.35 (m, 5H) 6.97 (bd, J = 7.2 Hz, IH) 5.59 (d, J = 7.8 Hz, IH), 3.71 (s, 3H), 2.17 (m, 2H), 1.05-0.95 (m, IH), 0.62 (m, 25 2H), 0.02 (m, 2H) 13C-nmr (CDC13): 8 = 171.9, 174.6, 136.6, 129.0, 128.5, 127.2, 56.1, 52.7, 41.0, 6.9, 4.37, 4.33 Prxnted from Mimosa WO 98/22494 PCT/US97/20804 - 142 --Example A 80 Synthesis of W-(cyclopropylacetyI)-Lralanine methyl ester Following General Procedure D' above, and using cyclopropylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma), the title compound 5 was prepared. NMR data was as follows: 'H-nmr (CDC13): 5 = 6.60 (d, IH), 4.55 (m, IH), 3.69 (s, 3H), 2.10 (m, 2H), 1.34 (d, 3H), 0.95 (m, IH), 0.58 (m, 2H) 0.15 (m, 2H) ,3C-nmr (CDC13): 5 = 173.7, 172.3, 52.3, 47.7, 41.0, 18.2, 6.7, 4.27, 10 4.22 Example A81 Synthesis of N-[(3-nitrophenyl)acetyI]-L-methionine iso-butyl ester Following General Procedure H' above, and using nitrophenylacetic acid (Aldrich) and L-methionine (Aldrich), the title compound was prepared as a tan 15 oil. The reaction was monitored by tic on silica gel. NMR data was as follows: 'H-nmr (CDC13): 5 = 8.16 (m,2H) 7.67 (d,lH) 7.32 (t, IH), 6.31 (bd, IH), 4.69 (m, IH), 3.90 (d, 2H), 3.68 (s, 2H), 2.47 (t, 2H), 2.15 (m, IH), 2.02 (s, 3H), 1.90 (m, 2H), 0.91 (d, 6H). 20 CI7Hj4N205S (MW = 368.4, Mass Spectroscopy (MH+ 368)). The following General Procedures A"-B" and Examples B1-B2 illustrate the synthesis of ^-(aryl/heteroarylacetytyamino acid starting materials useful in this invention. Other N-(aryl/heteroarylacetyl)amino acids can be prepared using these procedures from commerically available or known starting 25 materials. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 143 - GENERAL PROCEDURE A" Acid Chloride Preparation 3,5-Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and this solution was cooled to 0°C. DMF (0.5 mL, catalytic) 5 was added followed by the dropwise addition of oxalyl chloride (18 mL, 0.20 mol) over a 5 minute period. The reaction was stirred for 3 h and then rotoevaporated at reduced pressure to a residue which was placed on a high vacuum pump for 1 h to afford 3,5-difluorophenylacetyl chloride as a thin yellow oil. Other acid chlorides can be prepared in a similar manner. 10 GENERAL PROCEDURE B" Schotten-Bauman Procedure 3,5-Difluorophenylacetyl chloride (from General Procedure A") was added dropwise to a 0°C solution of L-alanme (Aldrich) (16.7 g, 0.187 mol) in 2 N sodium hydroxide (215 mL, 0.43 mol). The reaction was stirred for 1 h at 0°C 15 and then overnight at room temperature. The reaction was diluted with water (100 mL), then extracted with ethyl acetate (3 x 150 mL). The organic layer was then washed with brine (200 mL), dried over MgS04, and rotoevaporated at reduced pressure to a residue. Recrystallization of the residue from ethyl acetate/hexanes afforded the desired product (34.5 g, 82% yield). Other acid 20 chlorides may be used in this procedure to provide for intermediates useful in this invention. Example B1 Synthesis of /V-(PhenylacetyI)-L-alanine Following General Procedure B" above, title compound was prepared from 25 phenylacetyl chloride (Aldrich) and L-alanine (Aldrich) as a solid having a melting point of 102-104°C. NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 - 144 - 'H-nmr (CDC13): 8 = 9.14 (br s, IH), 7.21-7.40 (m, 5H), 6.20 (d, J = 7.0 Hz, IH), 4.55 (m, IH), 3.61 (s, 2H), 1.37 (d, J = 7.1 Hz, 3H). 13C-nmr (CDC13): 5 = 176.0, 171.8, 134.0, 129.4, 127.5, 48.3, 43.2, 17.9. 5 Example B2 Synthesis of jV-(3,5-Dlfluorophenylacetyl)-L-alanine Following General Procedure B" above, the title compound was prepared from 3,5-difluorophenylacetyl chloride (from General Procedure A" above) and L-alanine (Aldrich). 10 NMR data was as follows: 'H-nmr (CD3OD): 5 = 8.32 (br s, 0.3H), 6.71 (m, 2H), 6.60 (m, IH), 4.74 (br s, 1.7H), 4.16 (m, IH), 3.36 (s, 2H), 1.19 (d, J = 7.3 Hz, 3H). 13C-nmr (CD3OD): 5 = 175.9, 172.4, 164.4 (dd, J = 13.0, 245.3 Hz), 141.1, 113.1 (dd, J = 7.8, 17.1 Hz), 102.9 (t, J = 25.7 Hz), 49.5, 42.7, 15 17.5. The following General Procedures A'"-C'" and Examples C1-C8 illustrate the synthesis of dipeptide ester starting materials useful m this invention. Other dipeptide esters can be prepared using these procedures from commerically available or known starting materials. 20 GENERAL PROCEDURE A'" EDC Coupling Procedure A round bottom flask containing a magnetic stir bar under an atmosphere of nitrogen at 0°C or room temperature was charged with THF, carboxylic acid (1.0 eq), an amine or amine hydrochloride (1.1 eq.), 1-hydroxybenzotriazole 25 hydrate (1.15-1.2 eq.), N,N-diisopropylethylamine (2.2-2.9 eq.), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.15-1.2 eq.). The cooling bath was removed and the mixture allowed to warm to room temperature with stirring for 10-20 hours. The mixture was diluted with EtOAc Printed from Mimosa WO 98/22494 PCT/US97/20804 - 145 - and washed with 0.5 N aqueous HCl (2x), dilute aqueous NaHC03 (lx), brine (lx) and dried over either Na2S04 or MgS04. The drying agent was removed by filtration and the filtrate concentrated in vacuo. The residue was either used without further purification or purified using standard procedures, such as flash 5 chromatography on silica gel and/or recrystallization. GENERAL PROCEDURE B'" Removal of the N-tert-Boc Protecting Group The AT-re/f-Boc-amine was dissolved in a suitable dry solvent (such as 1,4-dioxane or ethyl acetate) and the solution was cooled in an ice bath. Gaseous 10 HCl was introduced into the solution until the mixture was saturated with HCl. The mixture was then stirred until the reaction was complete. The resulting mixture was concentrated under reduced pressure to yield the amine hydrochloride. The amine hydrochloride was used without purification or was triturated using, for example, diethyl ether and the resulting solid was collected 15 by filtration. GENERAL PROCEDURE C'" EEDO Coupling Procedure A round bottom flask containing a magnetic stir bar under as atmosphere of nitrogen at room temperature was charged with THF, a carboxylic acid (1 eq.), 20 an amine hydrochloride (1.1 eq.), and 2-ethoxy-l-ethoxycarbonyl-l,2- dihydroquinoline (EEDQ) (1.1 eq). The reaction mixture was allowed to stir for 15 minutes and then 4-methylmorpholine (1.1 eq) was added and stirring was continued at room temperature for 15-20 hours. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between ethyl 25 acetate and water. The organic phase was separated and washed with saturated aqueous NH4C1 (2x), saturated aqueous NaHCOj (2x), followed by brine (lx). The organic phase was then dried over Na2S04 and the drying agent was removed by filtration and the filtrate concentrated in vacuo. The residue was Printed from Miraosa WO 98/22494 PCT/US97/20804 — 146 - either used without further purification or purified using standard procedures, such as flash chromatography on silica gel and/or recrystallization. Example CI Synthesis of 5 iV-(L-Methionine)-L-phenylglycine Methl Ester Hydrochloride Following General Procedure Aw and using N-(terr-butoxycarbonyl)-L-methionine (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem), the Boc-protected dipeptide was prepared as a crude solid or foam. The resulting crude dipeptide was deprotected using General Procedure B'" to afford 10 the title compound as a crude solid or foam. Example C2 Synthesis of Ar-(2-Aminobutanoyl)-L-phenylglycine Methl Ester Hydrochloride Following General Procedure A'" and using N-(rerr-butoxycarbonyl)-2-15 aminobutyric acid (Sigma) and L-phenylglycme methyl ester hydrochloride (Bachem), the Boc-protected dipeptide was prepared as a crude solid or foam. The resulting crude dipeptide was deprotected using General Procedure B'" to afford the title compound as a crude solid or foam. Example C3 20 Synthesis of N-(L-Leucine)-I^phenylglycine Methl Ester Hydrochloride Following General Procedure A'" and using jV-(/m-butoxycarbonyl)-L-leucine (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem), the Boc-protected dipeptide was prepared as a crude solid or foam. The resulting 25 crude dipeptide was deprotected using General Procedure B'" to afford the title compound as a crude solid or foam. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 147 - Example C4 Synthesis of N- (L-PhenyIaIanine)-L-phenyIglycine Methl Ester Hydrochloride Following General Procedure A'" and using jV-(rm-butoxycarbonyl)-L-5 phenylalanine (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem), the Boc-protected dipeptide was prepared as a crude solid or foam. The resulting crude dipeptide was deprotected using General Procedure B'" to afford the title compound as a crude solid or foam. Example C5 10 Synthesis of A^(Glycine)-L-phenylglycine Methl Ester Hydrochloride Following General Procedure A'" and using iV-(/e/T-butoxycarbonyl)glycine (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem), the Boc-protected dipeptide was prepared as a crude solid or foam. The resulting crude 15 dipeptide was deprotected using General Procedure B"' to afford the title compound as a crude solid or foam. Example C6 Synthesis of 7V-(L-Phenylglycine)-L-phenylgIycine Methl Ester Hydrochloride 20 Following General Procedure C'" and using JV-(rerr-butoxycarbonyl)-L- phenylalanine (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem), the Boc-protected dipeptide was prepared as a crude solid or foam. The resulting crude dipeptide was deprotected using General Procedure B'" to afford the title compound as a crude solid or foam. 25 Example C7 Synthesis of Af-(L-VaIine)-L-phenylglycine Methl Ester Hydrochloride Printed from Mimosa WO 98/22494 PCT/US97/20804 — 148 - Following General Procedure A'" and using Af-(/m-butoxycarbonyl)-L-valine (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem), the Boc-protected dipeptide was prepared as a crude solid or foam. The resulting crude dipeptide was deprotected using General Procedure B'" to afford the title 5 compound as a crude solid or foam. Example C8 Synthesis of iV-[(S)-2-Aminocyclohexylacetyl)-L-phenyIglycine Methl Ester Hydrochloride Following General Procedure A'" and using /V-(/m-butoxycarbonyl)-(S)-10 aminocyclohexylacetic acid (e.g., Boc-L-cyclohexylglycine) and L- phenylglycine methyl ester hydrochloride (Bachem), the Boc-protected dipeptide was prepared as a crude solid or foam. The resulting crude dipeptide was deprotected using General Procedure B'" to afford the title compound as a crude solid or foam. 15 The following Examples D1-D4 illustrate the synthesis of various intermediates useful as starting materials for this invention. Similar intermediates can be prepared using these procedures and commerically available or known starting materials. Example D1 20 Synthesis of 3,5-Difluorophenyl-a-fluoroacetic Acid Methyl 3,5-difluoromandelate was prepared following General Procedure G below and using commmerically available 3,5-difluoromandelic acid. The resultant a-hydroxy methyl ester was fluorinated according to the general 25 procedure described in W. J. Middleton, et al., Org. Synth. Col. Vol. VI, 835. Specifically, a solution of diethylaminosulfur trifluoride (1.1 eq) in CH2C12 was cooled to 0°C and treated with methyl 3,5-difluoromandelate (1.0 eq) as a solution in CH2C12. After 10 min. the cooling bath was removed and the Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 149 - reaction was stirred at ambient temperature for 30 min. The reaction was monitored by tic (Rf = 0.65, 1:1 ethyl acetate/hexanes). The mixture was then poured onto ice and the layers separated. The organic phase was washed with saturated aqueous NaHC03 and brine. The organic layer was dried over 5 Na2S04, filtered, and concentrated in vacuo. The product was purified by LC2000 chromatograpy (180 mL/min) using 10% EtoAc/hexanes as the eluent. The resulting methyl 3,5-difluorophenyl-a-fluoroacetate was hydrolyzed by dissolving the ester in 70% aqueous dioxane and treating with lithium hydroxide (2.0 eq.). No starting material remained by tic after 2 h. The dioxane was 10 removed via rotary evaporation. The aqueous mixture was first washed with ethyl acetate and then acidified with 0.01 N HCl. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2S04, filtered, and concentrated. The crude solid was recrystallized from ethyl acetate/hexanes affording 3,5-difluorophenyl-a-fluoroacetic acid as a 15 white solid having a melting point of 90-110°C. CgHjFjC^ (MW = 190.1); mass spectroscopy: 190.1. Example D2 Synthesis of (S)-2-Hydroxy-2-methyl-l-phenylprop-l-y]amine 20 (S)-2-Hydroxy-2-methyl-l-phenylprop-l-ylamine was prepared by adding 5.0 equivalents of methyl magnesium bromide to a solution of L-phenylglycine methyl ester hydrochloride in THF at 0 C. The reaction mixture was stirred for 1 hour and then quenched with sodium bicarbonate. After standard work-up conditions, the residue was purified by silica gel chromatography using 10 % 25 MeOH/CHClj as the eluent. Example D3 Synthesis of Methyl (S)-2-Amino-2-(6-methoxy-2-naphthyI)acetate Printed from Mimosa WO 98/22494 PCT/US97/20804 - 150 - (S)-2-(/e/?-Butoxycarbonylamino)-2-(6-methoxy-2-naphthyl)aceticacid was prepared from 2-(6-methoxy-2-naphthyl)acetic acid according to the general method described by D.A. Evans, et al., J. Amer. Chem. Soc., (1990), 112, 4011-4030. Briefly, (S)-3-(6-methoxy-2-naphthylacetyl)-4-benzyl-2-5 ozazolidinone was converted to (S)-3-[(S)-6-methoxy-2-naphthyl-a-azidoacetyl)-4-benzyl-2-ozazolidinone via standard enolate azidation procedures using potassium 1,1,1,3,3,3-hexamethyldisilazane and trimethylsilyl azide at -78°C. Treatment of the azide derivative with 3 equivalents of lithium hydroxide in THF then provided (S)-2-azido-2-(6-methoxy-2-naphthyl)acetic acid. Reduction 10 of this intermediate, as its sodium salt, in 1:1 1,4-dioxane/water (0.05 M) with 1 atm of hydrogen, 10% Pd/C at 25°C afforded (S)-2-azido-2-(6-methoxy-2-naphthyl)acetic acid, which was then converted, without isolation, to its N-Boc derivative on treatment with 1.4 equivalents of di-fe/T-butyl dicarbonate and 0.47 equivalents of sodium carbonate. The product was isolated by the 15 acidification to pH 2 with 1 N NaHS04 and extraction with three portions of ethyl acetate. The product was recrystallized from ethyl acetate/hexanes to afford a white solid, m.p. = 176°C (shrink); 197-199°C (dec). NMR data was as follows: 'HMR (DMSO-rfJ: 8 = 12.78 (s, IH), 7.84-7.77 (m, 3H), 7.62 (d, J=8 20 Hz, IH), 7.49 (d, J = 8 Hz, IH), 7.31 (d, J=2 Hz, IH), 7.17 (dd, J=9, 2 Hz, IH), 5.22 (d, J=8 Hz, IH), 3.87 (s, 3H), 1.39 (s, 9H). (S)-2-(rm-Butoxycarbonylamino)-2-(6-methoxy-2-naphthyl)acetic acid was then converted into the methyl ester using General Procedure G below. The methyl ester was then dissolved in CH2C12 and this solution cooled to 0°C. 25 Trifluoroacetic acid (50 molar eq ) was added and the reaction was allowed to warm to room temperature and stirring was continued for 2 hrs. The reaction mixture was then concentrated and the residue extracted into CH2C12 and washed with sodium bicarbonate solution. The organic layer was dried over Na2S04, filtered and concentrated to yield methyl (S)-2-amino-2-(6-methoxy-2-30 naphthyl)acetate. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 151 - Example D4 Synthesis of Methyl 2-Amino-2-(thieno[2,3-£]thiophen-2-yl)acetate To a 3.75 mole equivalents of sodium hydride (oil free) was added DMF 5 and the resulting mixture was cooled to 0°C. A solution of methyl thieno[2,3-&]thiophen-2-carboxylate (1 mole eq.) and methyl methylsulfinyl methyl sulfide (1.1 mole eq.) in DMF was then added dropwise and the reaction mixture was stirred at 0°C for 30 min and then allowed to warm to room temperature and stirring was continued for 3 h. The reaction was then quenched with methanol 10 and the product extracted into EtOAc. The organic extracts were washed with water followed by brine, and then dried over Na2S04, filtered and concentrated to give a gummy brown oil. The residue was slurried in diethyl ether and the resulting solid collected. The solid was then dissolved in hot ethyl acetate and decolorizing carbon was added. The mixture was then filtered and solvent 15 removed to give a solid, which was used without further purification. Acetic anhydride (10 mole eq.) and acetic acid (1.8 mole eq.) were mixed together and heated to 70°C for 15 min. and then cooled to 65°C. The solid sulfone from above was added in portions and the reaction was allowed to stir at 70°C for 30 min. and then cooled and concentrated The resulting solid was 20 taken up in ethyl acetate and washed with sodium bicarbonate solution, followed by 1 N Na2S203 solution The solution was then dried over MgS04, filtered and concentrated to give methyl 2-keto-2-(thieno[2,3-£]thiophen-2-yl)thioacetate as a solid, which was used without further purification. To the 2-keto compound (0.0165 moles) (4.0g) was added 270 mL of 25 methanol and 16.5 mL of 1 N NaOH. The reaction was allowed to stir for 6 h at room temperature and then methoxyamine (1.38 g, 0.0165 moles) was added and stirnng was continued for 18 h. The reaction mixture was then concentrated and the residue dissolved in ethyl acetate and washed with water. The aqueous layer was then acidified with in HCl and the oily product was Printed from Mimosa WO 98/22494 PCT/US97/20804 — 152 - extracted into ethyl acetate and washed with brine. The organic layer was dned over MgS04, filtered and concentrated to give 4.0 g of 2-(hydroxyimino)-2-(thieno[2,3-£>]thiophen-2-yl)acetic acid as a yellow solid. The methyl ester was then prepared using General Procedure G below and 5 the oxime was reduced to an amino group using General Procedure R below to afford methyl 2-amino-2-(thieno[2,3-£]thiophen-2-yl)acetate. Example D5 Synthesis of iV-Methyl-W-BOC-Leucinamide 10 A solution of 0.9968 g (4 mmol) of jV-BOC-leucine (Bachem) and 1.2323 g (7.6 mmol) of CDI in 40 mL of THF was stirred for 1 hour, and then 0.5402 g (8 mmol) of methylamine hydrochloride (Aldnch) and 0.8092 g (8 mmol) of N-methylmorpholine were added. The mixture was stirred for 16 hours, evaporated at reduced pressure to dryness, and the residue was washed 15 thproughly with water, IN NaOH, water, followed by diethyl ether to yield 0.886 g (3.09 mmol, 70%) of the title compound. Example D6 Synthesis of N-BOC-Norleucine amide To a stirred mixture of 3.47 g (15 mmol) of BOC-norleucine (Bachem), 20 3.44 g (22.5 mmol) of 1-hydroxybenzotnazole monohydrate and 50 mL of dichloromethane at 0°C was added 3.45 g (1.2 mmol) of EDC. The resulting mixture was stirred at 0°C for 1 hour and then ammonia gas was bubbled through the mixture for 10 min. The cooling bath was allowed to warm to room temperature and the mixture stirred for 18 hours. The mixture was 25 evaporated at reduced pressure to dryness, triturated with 20% Na2C03. The resulting solid was collected by filtration and washed with water to yield 2.69 g (11.7 mmol, 78%) of the title compound. Printed from Mimosa WO 98/22494 PCT/U S97/20804 - 153 - Example D7 Synthesis of iV-[iV-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alanine The tide compound was prepared by dissolving 1.98 g (0.006 mols) of N-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester (from Example 85 below) in 60 mL dioxane and 15 mL of H20 and adding LiOH (0.25 g, 0.006 mol) that has been dissolved in 15 mL of HzO. After stirring for 3 hours, the dioxane was removed under reduced pressure and the residue diluted with EtOAc, the layers were separated and the aqueous layer acidified to pH 2. The aqueous layer was back extracted with EtOAc (4 X 100 ml), and the combined organics were dried over Na2S04 and the solvent was removed under reduced pressure after filtration. The residue was recrystalhzed from EtOAc/isooctane giving 1.7 g (90 %). C14H15F2N204 requires C, 53.50 H, 5.13 N, 8.91. Anal found C, 53.30 H, 5.26 N, 8.98. Example D8 Synthesis of m-Nitrophenylacetyl-L-alanine 2,4,5-Trichlorophenyl Ester /?i-Nitrophenylacetyl-L-alanine (1 eq.) and 2,4,5-tricholophenol (1.3 eq.) were stirred in dicholomethane. A 1.0 M solution of 1,3-dicyclohexylcarbodnmide in dichloromethane (1.2 eq.) was added and the mixture was stirred at ambient temperature for 16 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography using 1:2 ethyl acetate/hexanes as the eluant to provide the title compound as a pink solid. For C17H13Cl3N205: Calc. 47.30% C, 3.04% H, 6.49% N. Found 47.57% C, 3.18% H, 6.47% N. Example D9 Synthesis of D,L-a-Methylphenylglycine Ethyl Ester Printed from Mimosa WO 98/22494 PCT/US97/20804 - 154 - The title was prepared using the procedures described in J J. Fitt and H. W. Gschwend, J. Org. Chem., 42, No. 15, 2639 (1977). More specifically, D,L-phenylglycine (Aldrich) was stirred in dimethylformamide dimethylacetal and the mixture was heated at reflux under an atmosphere of dry nitrogen for 4 5 hours. After cooling, the mixture was concentrated under reduced pressure to provide a yellow oily solid. The mixture was slurried in diethyl ether and filtered through Cehte. The filtrate was concentrated to an orange oil which was purified by vacuum distillation to provide a yellow oil which solidified. The yellow solid was stirred in dry THF at -20 C under dry nitrogen. Lithium 10 bis(trimethylsilyl)amide (1.05 eq, 1.0M solution in THF) was added dropwise. The resulting mixture was allowed to warm to -10 C and stirring was continued for 1 hour at that temperature. Methyl iodide (1.05 eq) was added and the mixture was allowed to warm ambient temperature with stirring. After 14 hours, the mixture was concentrated. The residue was partitioned between 15 aqueous potassium carbonate and chloroform. The organic portion was dried (sodium sulfate) and concentrated under reduced pressure. The product was purified by silica gel chromatography to yield a yellow oil. The yellow oil was stirred in absolute ethanol. Dry zinc chloride (4 eq.) was added and the mixture was heated at reflux. After 14 hours, the mixture was concentrated 20 under reduced pressure to provide a yellow oil. The oil was partitioned between aqueous potassium carbonate and chloroform The organic portion was dried (sodium sulfate) and concentrated under reduced pressure. The title compound was purified by silica gel chromatography. Example D10 25 Synthesis of D,L-PhthalimidoaIanine Ethyl Ester Hydrochloride N-(Diphenylmethylene)glycine ethyl ester (1 eq.) (Aldrich) was stirred in dry THF at -78°C under an atmosphere of dry nitrogen. Lithium bis(trimethylsiyl)amide (1.02 eq, 1.0 M solution in THF) was added dropwise. 30 The resulting mixture was stirred 1 hour at -78°C. A THF solution of N-(bromomethyl)phthalimide (1.1 eq) (Aldrich) was added and the mixture was Printed from Mimosa WO 98/22494 PCT/US97/20804 - 155 - allowed to warm to ambient temperature and then stimng was continued for 1 hour. Hydrochloric acid (600mL, 2N) was added and the mixture was stirred for 20 minutes. The THF was removed on a rotoevaporator. The resulting aqueous mixture was washed with diethyl ether, and then concentrated (to 100 5 mL) to yield a thick slurry. A white solid was collected, washed with cold water and dried in a vacuum oven to yield the title compound which was used without further purification. Example D11 Synthesis of 10 A7-(3-Nitrophenylacetyl)-L-alanine The title compound was prepared by dissolving 9.27 g (0.0348 mols) of the 7V-(3-nitrophenylacetyI)-L-alanine methyl ester in 60 mL of dioxane and 15 mL of H20 and adding LiOH (3.06 g, 0.0731 mol) that has been dissolved in 15 mL of HzO. After stirring for 4 hours, the dioxane was removed under 15 reduced pressure and the residue diluted with EtOAc, the layers were separated and the aqueous layer acidified to pH 2. The aqueous layer was back extracted with EtOAc (4 X 100 ml), the combined organics were dried over Na2S04 and the solvent was removed under reduced pressure after filtration. The residue was recrystalhzed from EtOAc/isooctane giving 7.5 g (85 %). CUHI2N205 20 requires C, 52.38 H, 4.80 N, 11.11. Anal found C, 52.54 H, 4.85 N, 11.08. M23 = - 29.9 @ 589 nm. Example D12 Synthesis of Methyl 2-Amino-2-(3-fluorophenyl)acetate Hydrochloride 25 Potassium cyanide (6.3, 0.1 mol) and ammonium carbonate (15.7 g, 0.2 mol) were dissolved in 50 mL of water (in a well ventilated fume hood). 3-Fluorobenzaldehyde (5.0 g, 0.04mol) was dissolved in 50 mL of EtOH and added to the reaction. After stirring at reflux under nitrogen atmosphere for 17 hours, the reaction was cooled to 23°C, the pH adjusted to 2.0 by the addition 30 of 5 N HCl and cooled to 5°C. The resulting hydantoin was collected, rinsed Printed from Mimosa WO 98/22494 PCT/US97/20804 - 156 - with cold water and vacuum dried giving 3.59 of an off-white solid. The hydantoin was hydrolyzed at reflux using 1 N NaOH giving 2-amino-2-(3-fluorophenyl)acetic acid which was esterified via Procedure H in methanol to give the title compound. 5 Example D13 Synthesis of iV-[A/-(S)-2-Aminobutanoyl]-L-phenylglycine tert-Butyl ester A mixture of N-[7V-(benzyloxycarbonyl)-(S)-2-aminobutanoyl]-L-phenylglycine /erf-butyl ester (4.13 g) (prepared from N-(benzyloxycarbonyl)-10 (S)-2-aminobutanoic acid (Novabiochem) and L-phenylglycine /err-butyl ester hydrochlonde (Novabiochem) using General Procedure D) and 20% Pd(OH)i/C (0.360 g) in EtOH (200 mL) was shaken in a Parr Apparatus under a hydrogen atmosphere (40 psi) for 4 hours. The solids were removed by filtration through a plug of Cehte, while rinsing with EtOH. The filtrate was concentrated to an 15 off-white oil, which was used without further purification. "H-NMR in CDC13 revealed that — 10% trans-esterification to the ethyl occurred during this reaction. The ethyl ester was removed by flash chromatography after subsequent reaction of this compound. Example D14 20 Synthesis of N-[iV-L-ValinyI]-L-phenylglycine /erf-Butyl ester A mixture of ZV-[W-(benzyloxycarbonyl)-L-valinyl]-L-phenylglycine tert-butyl ester (4.63 g) (prepared from AHbenzyloxycarbonyl)-L-valine (Aldrich) and L-phenylglycine rerr-butyl ester hydrochloride (Novabiochem) using 25 General Procedure D) and 20% Pd(OHyC (0.360 g) in EtOH (200 mL) was shaken in a Parr Apparatus under a hydrogen atmosphere (40 psi) for 4 hours. The solids were removed by filtration through a plug of Celite, while rinsing with EtOH. The filtrate was concentrated to an off-white solid, which was used without further purification. 'H-NMR in CDC13 revealed that ~ 1 % 30 trans-estenfication to the ethyl occurred during this reaction. The ethyl ester Printed from Mimosa WO 98/22494 PCT/US97/20804 — 157 - was removed by flash chromatography after subsequent reaction of this compound. Example D15 Synthesis of 5 (S)-Phenylglycinol Metbyl Ether (S)-(+)-2-phenylglycinol (1 eq.) (Aldrich) was stirred in dry THF under an atmosphere of dry nitrogen. Sodium hydride (1 eq.) was added and the resulting mixture was stirred for 1 hour at ambient temperature. A THF solution of iodomethane (1 eq.) was added and the mixture was stirred for 1 10 hour. The mixture was concentrated to provide a residue which was taken up in water and extracted with chloroform. The organic extracts were concentrated under reduced pressure to yield the title compound as an oil which was purified by silica gel chromatography to yield a crude product which was used without further purification. 15 Example D16 Synthesis of (S)-2-Hydroxy-2-metbyl-l-phenylprop-l-yIamine To a stirred, cooled (0°C) suspension of 5.6 g (27.8 mmol) of L-phenylglycine methyl ester hydrochloride (Aldrich) in 200 mL of dry THF was 20 added methylmagnesium bromide (46.3 mL, 138.9 mmol, 3.0 M in diethyl ether). During the addition, the internal temperature increased to 24°C. Stirnng was continued for 1 hour, after which the reaction was carefully quenched by addition of saturated sodium bicarbonate solution. The reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate 25 solution, back extracting the aqueous layer with 3 volumes of ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by flash chromatography on silica gel, eluting with 10% methanol in chloroform (neutralized with ammonium hydroxide) to afford 1.96 g to the title compound. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 158 - Example D17 Synthesis of 5-ChIoro-2-thiophenecarboxaldehyde A solution of 2-chlorothiophene (Aldrich; 1 molar eq.) in THF was cooled 5 to -78°C and treated with n-butyllithium (1.6M in hexanes; 1.1 molar eq.) in a dropwise manner. The resultant yellow solution was stirred at -78°C for 40 minutes. Dimethylformamide (1.1 molar eq.) was added dropwise and the reaction stirred and additional 30 minutes. The mixture was diluted with methylene chloride and washed with 10% acetic acid, 1 M potassium carbonate, 10 and brine. The organic phase was dried over Na2S04, filtered, and concentrated. The residue was purified by HPLC eluting with 15% ethyl acetate/hexanes to afford the title compound. Example D18 Synthesis of 15 (S)-(-)-a-MethylbenzyIisocyanide Prepared according to the general procedure of Wolber, E. K. A.; Ruchardt, C. Chem. Ber. 1991, 124, 1667. To a suspension of 1,1'-carbonyldiimidazole (1.6 molar eq.; Aldrich) in acetonitrile at 0°C was treated with methanesulfonic acid (3.2 molar eq.; Aldrich) in a dropwise fashion. A 20 very thick suspension results. S-(-)-a-Methylbenzyl formamide (1 molar eq.; from Example D19 below) was added as a solution in acetonitrile via cannulation. The mixture was stirred overnight at ambient temperature. The suspension was filtered, washing with acetonitrile. The filtrate was concentrated and purified via flash chromatography eluting with 30% ethyl 25 acetate/hexanes. The oil was further purified via bulb-to-bulb distillation (80°C, 0.04 mm Hg) giving a pale yellow oil in 51% yield. Calcd for C9H9N: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.56; H, 6.82; N, 10.71. Example D19 Synthesis of 30 (S)-(-)-a;-MethylbenzyI formamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 159 - (S)-(-)-o!-Methylbenzylamine (1 molar eq.) was treated with ethyl formate (80 molar eq.; Aldrich). A precipitate formed immediately. The suspension was heated to reflux (55 °C) for 3 hours. The precipitate went into solution upon heating. The solution was cooled to ambient temperature and 5 concentrated via rotary evaporation. The resultant solid was used without purification. Example D20 Synthesis of 3-(Phenyl)benzaldehyde 10 A solution of 3-bromobiphenyl (Aldnch; 1 molar eq.) in dry THF was cooled to -78°C and treated with fm-butyllithium (Aldrich; 1.7 M in hexanes, 2 molar eq.) in a dropwise manner. The reaction was allowed to stir at -78°C for 40 minutes. Dimethylformamide (Aldrich; 2.5 molar eq.) was added and stirring continued an additional 20 minutes. The mixture was partitioned in a 15 separatory funnel between methylene chloride and water. The organic layer was dried over Na2S04, filtered, and concentrated. The residue was purified via HPLC eluting with 5% ethyl acetate/hexanes. The desired aldehyde was obtained in 71% yield. Example D21 20 Synthesis of 4- (Cyclohexyl) benzaldehyde 18-Crown-6 (Aldrich; 4 molar eq.) and pyridinium chlorochromate (Aldrich; 4 molar eq.) were added together in chloroform and stirred for 20 minutes. 4-Cyclohexylbenzylalcohol (from Example D22 below; 1 molar eq.) 25 was added and stirring continued for 3 hours. Ether was added and the mixture filtered through a plug of silica eluting with ether. The solvent was removed via rotary evaporation. The residue was dissolved in ether and washed with water. The organic layer was dried over Na2S04, filtered, and concentrated. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 160- Example D22 Synthesis of 4-(Cyclohexyl)benzyl Alcohol To a solution of 4-cyclohexylbenzoic acid (Aldrich; 1 molar eq.) in toluene 5 was added di/so-butylaluminum hydride (Aldrich; 1 M in toluene; 4 molar eq.) over a 2 hour period. After addition was complete, the reaction was heated to 60° C for 1 hour. The reaction was cooled to 5°C and quenched with saturated aqueous ammonium chloride. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organics were filtered to remove 10 salts and concentrated. Example D23 Synthesis of 3,5-Difluorophenyl-or,a-difluoroacetic Acid A solution of ethyl 3,5-difluorophenyl-a,a-difluoroacetate (from Example 15 D24 below; 1 molar eq.) in 50% aqueous ethanol was treated with lithium hydroxide (1.5 molar eq.). The solution was stirred for 3 hours at ambient temperature then concentrated via rotary evaporation. The residue was taken up in water; a small amount of 1 N NaOH was added to make basic. The aqueous mixture was extracted with ether. The aqueous layer was acidified to 20 pH 3 with 1 N HCl. The acid was extracted thrice with methylene chloride. The combined methylene chloride extracts were dried over Na2S04, filtered, and concentrated. Example D24 Synthesis of 25 Ethyl 3,5-Difluorophenyl-a,a-difIuoroacetate Ethyl 3,5-difluorophenyl-a-ketoacetate (Rieke Metals, Inc. #14014; 1 molar eq.) was treated with (diethylamino)sulfur trifluonde (DAST) (2.5 molar eq.). The reaction was stirred at ambient for 72 hours then heated to 50°C for 6 hours. The mixture was poured over ice and extracted with methylene 30 chloride. The organic layer was washed with saturated sodium bicarbonate, Printed from Mimosa WO 98/22494 PCT/US97/20804 — 161 - dried over Na2S04, filtered, and concentrated. The residue was purified via HPLC eluting with 2% ethyl acetate/hexanes. Example D25 Synthesis of S N- [N- (3,5-difluoropheny lacetyl) -L-alaniny 1]-D, L-phenylglycine ./V-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine methyl ester (from Example 111 below) was hydrolyzed according to Procedure AF. The acid was recrystalhzed from isooctane/EtOAc providing a mixture of diastereomers at the phenylglycine center. Elemental analysis; C19H18F2N404 10 requires C, 60.63 H, 4.82 N, 7.44. Found; C, 60.65 H, 5.02 N, 7.37. Mass spectroscopy (MH+ 377). Example D26 Synthesis of 3-(4-Iodophenyl)propylamine 15 iV-(3-bromopropyl)phthalimide (1 eq., Aldrich) and 4-iodophenol (1 eq., Aldrich) and potassium carbonate (2 eq.) was stirred in acetonitrile. The mixture was heated at reflux. After 64 hour, the reaction mixture was concentrated to a thick mixture which was slurried in water. A white solid was collected, washed with water and vacuum dned. 20 The white solid was stirred in ethanol. Anhydrous hydrazine (2 eq.) was added and mixture was heated at reflux for 18 hours. The reaction mixture was concentrated to yield a solid which was treated with IN NaOH and extracted with CHC13. The organic portion was dried, concentrated then diluted with ether. The mixture was treated with dry HCl. The title compound was 25 collected as a white solid and vacuum dried. Example D27 Synthesis of 2-Amino-l-phthalimidopentane Hydrochloride Printed from Mimosa WO 98/22494 PCT/US97/20804 - 162 - 2-Amino-l-pentanol was stirred in a mixture of chloroform and saturated aqueous sodium bicarbonate. Di-rerr-butyl dicarbonate (1.05 eq.) was added in one portion and the mixture was stirred until starting material was consumed. The organic portion was separated, dried (sodium sulfate) and concentrated. 5 The crude material was purified by silica gel chromatrography using 1:1 ethyl acetate/hexanes. The product was dissolved in THF. Triethylamine (1.1 eq.) was added and the mixture was cooled in an ice bath. Methanesulfonyl chloride (1.1 eq.) was added dropwise and the mixture was stirred until starting material was 10 consumed. The mixture was concentrated under reduced pressure then was partitioned between ethyl acetate and water. The organic portion was separated, dried (sodium sulfate) and concentrated to yield a white solid which was chromatographed on silica gel using 30% ethyl acetate in hexanes and finally crystallized from 1-chlorobutane/hexanes. 15 The crystalline product was stirred in dry DMF and potassium phtalimide (1.1 eq.) was added. The mixture was stirred for 18 hours then was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic portion was dried and concentrated to yield a white solid. The solid was taken up in chloroform and filtered through 20 a plug of silica. Eluent containing product was concentrated to yield the crude product as a white solid. The white solid was taken up in dry dioxane and resulting solution was saturated with gaseous HCl. After stirring for 30 minutes, the mixture was concentrated to yield a white solid which was triturated in ether. The title 25 compound was collected, washed with ether and dried in a vacuum oven. Example D28 Synthesis of D ,L-3,5-Diflu oropheny Iglycine Printed from Mimosa WO 98/22494 PCT/US97/20804 — 163 -- KOH (11.76 grams), LiCl (2.95 grams), saturated aqueous ammonia (20 mL), and benzyltriethylammonium chloride (0.805 grams) were stirred and chilled in CH2C12 (17 mL). Gaseous ammonia was bubbled into this mixture with chilling (0°C) to saturation. To the resulting mixture was added 3,5-difluorobenzaldehyde (5.0 grams) (Lancaster) and chloroform (4.46 mL), dissolved in CH2C12 (17.5 mL) with concurrent saturation with ammonia gas. The resulting mixture was stirred cold for 4 hours and at 22.5 °C for 96 hours. Water (60 mL) and CH2C12 (20 mL) were added; the layers separated, and the aqueous layer was extracted 3 times more with CH2C12. The aqueous layer was reduced in vacuo by 50%. The pH was adjusted to 6.5 with cold conc. HCl whereupon white crystals of D,L-3,5 difluorophenylglycme formed (3.4343 grams). Example D29 Synthesis of L-3,5-Difluorophenylglycine Methyl Ester Tartate Salt 3.43 Grams of D,L-3,5 difluorophenylglycine (from Example D28 above) was slurried in 50 mL methanol and 2.5 mL conc. H2S04. The reaction mixture was heated under gentle reflux for 18 hours. The mixture was chilled in and ice bath and the pH of the solution was adjusted to 7.0 with saturated aqueous ammonia. The volatile organic solvents were removed in vacuo and the aqueous portion was extracted three times with CH2C12; the combined organic layers dried, filtered, and reduced in vacuo to provide 2.680 grams of crude ester. This ester, benzaldehyde (1.4085 grams), and (-) tartaric acid (1.9921 grams), were dissolved in 20.5 mL of hot ethanol and stirred slowly for 72 hours as the title compound crystallized. The product was filtered and dned to provide 3.4805 grams of the (-) tartarate salt. Example D30 Synthesis of N-(3,5-Difluorophenylacetyl)-L-3,5-difliJorophenylgIycine Printed from Mimosa WO 98/22494 PCT/US97/20804 - 164 - L-3,5-Difluorophenylglycine (0.4291 g) (prepared from L-3,5-difluorophenylglycine (-)-tartarate salt (from Example D29 above) by neutralization) and 3,5-difluoroacetic acid 0.367 gram were dissolved in THF. EEDQ coupling using General Procedure AN afforded 0.7441 grams of the title 5 compound as the methyl ester. The ester was dissolved in 1,4-dioxane (10 mL), chilled and LiOH.H20 (89.0 mg) in water (10 mL) was added slowly and the mixture was stirred for 2 hours at 22.5°C. EtOAc (30 mL) and IN HCl were added and the aqueous layer extracted two times. The combined organic layers were dried (MgS04) and reduced in vacuo to provide the title compound 10 (700.8 mg). Each of the compounds set forth in the following examples was prepared by one of the following general procedures, unless otherwise indicated. GENERAL PROCEDURE A EDC Coupling Procedure T 15 To a 1:1 mixture of the corresponding carboxylic acid and amino ester/amide in CH2C12 or DMF at 0°C was added 1.5 equivalents tnethylamine, followed by 2.0 equivalents hydroxybenzotnazole monohydrate, then 1.25 equivalents of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The reaction mixture was stirred overnight at room temperature and 20 then transferred to a separatory funnel. The mixture was washed with water, saturated aqueous NaHC03, 1 N aqueous hydrochloric acid, and saturated aqueous sodium chlonde, and then dried over MgS04. The solution was stnpped free of solvent on a rotary evaporator to yield the crude product. GENERAL PROCEDURE B 25 EDC Coupling Procedure II The carboxylic acid was dissolved in methylene chloride in a round-bottomed flask. The amino acid (1 eq.), iV-methylmorpholine (5 eq.) and hydroxybenzotnazole monohydrate (1.2 eq.) were added in sequence. A Printed from Mimosa WO 98/22494 PCT/US97/20804 — 165 -- cooling bath was applied to the round-bottomed flask until the solution reached 0°. At that time, 1.2 eq. of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added. The solution was then allowed to stir overnight and come to room temperature under N2 pressure. The reaction mixture was then 5 washed with saturated aqueous Na2C03, 0.1 M citric acid, and brine before drying with Na2S04 and removing the solvents to yield the crude product. Pure products were typically obtained by flash chromatography in an appropriate solvent. GENERAL PROCEDURE C 10 EDC Coupling Procedure III A round-bottomed flask was charged with the appropriate carboxylic acid (1.0 eq), hydroxybenzotriazole hydrate (1.1 eq) and the appropriate amine (1.0 eq) in THF under a nitrogen atmosphere. An appropriate amount (1.1 eq. for the free amine and 2.2 eq. for amine hydrochloride salt) of a suitable base, 15 such as Hunig's base was added to the stirred mixture, followed by l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.1 eq). After stirring for about 4 h to 17 h at room temperature, the solvent was removed at reduced pressure and the residue taken up in EtOAc (or a similar solvent)/H20. The extracts were washed with saturated NaHC03, 1 N aqueous 20 hydrochloric acid, brine and dried over Na2S04. In some cases, the isolated product required further purification using standard procedures, such as chromatography and/or recrystallisation. GENERAL PROCEDURE D EDC Coupling Procedure IV 25 A round bottom flask containing a magnetic stir bar under an atmosphere of nitrogen at 0°C was charged with THF, an amine or amine hydrochloride (1.0 eq.), carboxylic acid (1.1 eq.), 1-hydroxybenzotriazole hydrate (1.15-1.2 eq), N,N-diisopropylethylamine (2.3 eq.), followed by l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlonde (EDC) (1.15-1.2 eq.). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 166 - The cooling bath was removed and the mixture allowed to warm to room temperature with stirring for 10-20 hours. The mixture was diluted with EtOAc and washed with 0.5 N aqueous. HCl (2x), dilute aqueous NaHC03 (lx), brine (lx) and dried over either Na2S04 or MgS04. The drying agent was removed 5 by filtration and the filtrate concentrated in vacuo. The residue was either used without further purification or purified by standard procedures, such as flash chromatography on silica gel and/or recrystallization. GENERAL PROCEDURE E EDC Coupling Procedure V 10 A round bottom flask containing a magnetic stir bar under an atmosphere of nitrogen at 0°C or room temperature was charged with THF, carboxylic acid (1.0 eq), an amine or amine hydrochloride (1.0-1.1 eq.), 1-hydroxybenzotriazole hydrate (1.1-1.2 eq.), N,N-diisopropylethylamine (2.2-2.9 eq.), followed by l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 15 (EDC) (1.1-1.2 eq.). The cooling bath was removed and the mixture allowed to warm to room temperature with stirring for 10-20 hours. The mixture was diluted with EtOAc and washed with 0.5 N aqueous HCl (2x), dilute aqueous NaHC03 (lx), brine (lx) and dried over either Na2S04 or MgS04. The drying agent was removed by filtration and the filtrate concentrated in vacuo. The 20 residue was either used without further purification or purified using standard procedures, such as flash chromatography on silica gel and/or recrystallization. GENERAL PROCEDURE F EDC Coupling Procedure VI A round bottom flask containing a magnetic stir bar under an atmosphere 25 of nitrogen at 0°C was charged with THF, carboxylic acid (1.0 eq.), an amine or amine hydrochloride (1.1 eq.), N,N-diisopropylethylamine (2.2-2.3 eq.), followed by l-(3-dimethylaminopropyI)-3-ethylcarbodiimide hydrochloride (EDC) (1.1-1.2 eq.). The cooling bath was removed and the mixture allowed to warm to room temperature with stirring for 10-20 hours. The mixture was Printed from Mimosa WO 98/22494 PCT/US97/20804 - 167 -- diluted with EtOAc and washed with 0.2 N aqueous HCl (2x), dilute aqueous NaHC03 (lx), brine (lx) and dried over either Na2S04 or MgS04. The drying agent was removed by filtration and the filtrate concentrated in vacuo. The residue was either used without further purification or purified using standard 5 procedures, such as flash chromatography on silica gel and/or recrystallization. GENERAL PROCEDURE G Methvl Ester Preparation To l-methyl-3-nitro-l-nitrosoguanidine (1.2 eq.) in diethyl ether cooled to 0°C was added 40% KOH until bubbling ceased This mixture was then 10 decanted into a plastic tube containing KOH pellets as a drying agent. The solution was then added to the appropriate carboxylic acid and the mixture was stirred until the reaction was complete (as determined, for example, by tic). The reaction was then quenched with acetic acid and extracted into EtOAc. Removal of the solvent afforded the desired methyl ester. 15 GENERAL PROCEDURE H Carboxylic Acid Ester Preparation To the appropriate amino acid or carboxylic acid in the appropriate alcohol was bubbled anhydrous HCL gas until the solution was saturated. The reaction was stirred overnight at 25 °C and the solvent was then removed under reduced 20 pressure. The residue was then dissolved in EtOAc and this solution was washed with sodium bicarbonate solution. The organic layer were then dried over sodium sulfate, filtered and solvent removed to afford the desired ester. GENERAL PROCEDURE I tert-Butvl Ester Preparation I 25 To a solution of an JV-CBZ-protected amino acid in CH2C12 was added 1.5 equivalents of N,N'-diisopropyl-0-t-butylisourea (prepared by standard literature methods such as those found in Synthesis (1979), p. 561), and the reaction was heated to reflux for 17 h. An additional 1.5 equivalents of isourea Printed from Mimosa WO 98/22494 PCT/US97/20804 - 168 - were then added, and reflux was continued for another 7 h. The reaction was then cooled to room temperature and filtered through a bed of Celite 545, then stripped to dryness to leave a clear oil. The residue was dissolved in hexanes and filtered to remove solids, and the filtrate was washed with saturated 5 aqueous NaHC03, water, saturated aqueous NaCl, and dried over MgSO„. The solution was concentrated under reduced pressure to leave the product. GENERAL PROCEDURE J ferr-Butvl Ester Preparation II The reaction was conducted in a sealed tube using the appropriate 10 carboxylic acid, a catalytic amount of H2S04 (0.03 eq.) and an excess of condensed jso-butylene in dioxane or CH2C12 at -20°C. The reaction times varied from about 48 hours to about 120 hours. When the reaction was complete, the solvent was removed under reduced pressure and the residue dissolved in diethyl ether. This solution was washed with sodium bicarbonate 15 solution and the organic layer dried over sodium sulfate, filtered and solvent removed. The resulting product was purified using standard procedures, such as HPLC or titration using, for example, diethyl ether/hexanes. GENERAL PROCEDURE K Amide Preparation I 20 To a solution of 3 equivalents of the desired amine in 1,2-dichloroethane was added 5.2 equivalents triethylaluminum subsurface. After stirring for 30 minutes at room temperature, a solution of the desired ester dissolved in 1,2-dichloroethane was added. The reaction was refluxed until tic showed complete conversion, typically 3h. The reaction was then cooled to 0°C and quenched 25 with 10% aqueous hydrochloric acid (Note: the acid should be added slowly as some foaming occurs during its addition). The mixture was transferred to a separatory funnel and the layers were separated. The aqueous phase was washed with ethyl acetate, and the organic phases were washed with saturated Printed from Mimosa WO 98/22494 PCT/US97/20804 - 169 - aqueous NaCl, dried over MgS04, and concentrated under reduced pressure to leave the crude product. Alternatively, if the product is acid soluble, after the reaction is quenched, the reaction volume was reduced to about one-third of its initial volume under 5 reduced pressure. To the resulting solution was added 20% aqueous potassium sodium tartrate (Rochelle's salt) and ethyl acetate. The pH of the solution was then adjusted to -13, and the aluminum salts dissolved in the aqueous solution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic solution was washed with saturated 10 aqueous NaCl, dried over MgS04, and concentrated under reduced pressure to leave the crude product. GENERAL PROCEDURE L Amide Preparation IT The carboxamide was prepared from its corresponding ester using the 15 procedure described in Hogberg, T., et.al., J. Organic Chem., 1987, 52, 2033-2036. GENERAL PROCEDURE M Amide Preparation III To the appropriate carboxylic acid (1.0 eq.) in THF was added N-20 methylmorpholine (1.1 eq.) and the solution was cooled to -20°C to 0°C. iso-butyl chloroformate (1.1 to 2.1 eq.) was then added and the reaction mixture was stirred at -20°C to 0°C for 30 min. A mixture of the appropriate amino acid, water and 1.5 eq. of potassium carbonate was then added, and the resulting mixture was allowed to warm to room temperature and stir for 2 hrs. 25 The reaction mixture was then poured into water and washed with EtOAc. The pH of the water layer was then adjusted to 2.0 with 5 N HCl and the water layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The Printed from Mimosa WO 98/22494 PCT/US97/20804 - 170 - resulting crude amide was used without further purification or purified using standard procedures such as chromatography or titration using, for example, diethyl ether/hexanes or EtOAc/hexanes. GENERAL PROCEDURE N 5 Hydrolysis of Carboxvhc Acid Esters To the ester in a 1:1 mixture of CH3OH/H20 was added 2-5 equivalents of K2C03. The mixture was heated to 50°C for 0.5-1.5 h until tic showed complete reaction. The reaction was cooled to room temperature and the methanol was removed on a rotary evaporator. The pH of the remaining 10 aqueous solution was adjusted to about 2, and ethyl acetate was added to extract the product. The organic phase was then washed with saturated aqueous NaCl and dried over MgS04. The solution was stripped free of solvent on a rotary evaporator to yield the product. GENERAL PROCEDURE O 15 Removal of iV-Carbobenzvloxv (CBZ) Protecting Groups The N- CBZ-protected compound was dissolved in ethanol in a hydrogenation flask and a catalytic amount of 10% Pd/C was added. The mixture was hydrogenated at 20 psi H2 on a Parr shaker for 30 min. The reaction was then filtered through a pad of Celite 545 and stripped free of 20 solvent on a rotary evaporator to yield the product. GENERAL PROCEDURE P Removal of the N-tert-hoc Protecting Group The AT-re/r-Boc-amine was dissolved in a suitable dry solvent (such as 1,4-dioxane or ethyl acetate) and the solution was cooled in an ice bath. Gaseous 25 HCl was introduced into the solution until the mixture was saturated with HCl. The mixture was then stirred until the reaction was complete. The resulting mixture was concentrated under reduced pressure to yield the amine hydrochloride. The amine hydrochloride was used without purification or was Printed from Mimosa WO 98/22494 PCT/US97/20804 — 171 - triturated using, for example, diethyl ether and the resulting solid was collected by filtration. GENERAL PROCEDURE Q Halide Exchange (Tinkelstein) Reaction 5 The corresponding alkyl bromide or alkyl chloride was dissolved in 20 mL of methyl ethyl ketone and 1 eq. of Nal was added. The reaction was heated to 60°C and stirred overnight. The cooled reaction mixture was extracted with dichloromethane (2 x 30 mL) and the combined extracts were roto-evaporated at reduced pressure to give the crude product. Pure products were typically 10 obtained by flash chromatography in an appropriate solvent. GENERAL PROCEDURE R Oxime Reduction I To the oxime ester in the alcohol corresponding to the ester was added formic acid (500 eq.) and water (500 eq.). The reaction mixture cooled to 5°C 15 and zinc dust (3.8 eq.) was added in portions over 20 min. The reaction was then allowed to warm to room temperature and stirring was continued for 3 hours. The reaction was then filtered over HYFLO and the solvent removed under reduced pressure. The residue was dissolved in EtOAc and this solution washed with saturated sodium bicarbonate solution. The organic layer was then 20 dried over sodium sulfate, filtered and solvent removed to afford the product. GENERAL PROCEDURE S Reduction of Esters to Alcohols To a 0°C solution of the starting ester in anhydrous THF was added 1.0 equivalents of LiBH4 in THF. The reaction was stirred at room temperature 25 overnight and then quenched with water. The THF was removed on a rotary evaporator and ethyl acetate was added. The phases were separated and the organic phase was washed with saturated aqueous sodium chloride solution, Printed from Mimosa WO 98/22494 PCT/US97/20804 - 172 — dried over magnesium sulfate, and concentrated under reduced pressure to afford the alcohol product. GENERAL PROCEDURE T CDI Coupling Procedure 5 A solution of the appropriate acid (3.3 mmol) and 1,1 '-carbodiimidazole (CDI) in 20 mL THF was stirred for 2 h. The amino acid ester hydrochloride (3.6 mmol) was added, followed by 1.5 mL (10.8 mmol) of triethylamine. The reaction mixture was stirred overnight and then dissolved in 100 mL of diethyl ether, washed with 10% HCl three times, brine once, 20% potassium carbonate 10 once and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated at reduced pressure to yield the product. GENERAL PROCEDURE U EDC Coupling Procedure VII A mixture of the appropriate carboxylic acid (1 eq.), 1-15 hydroxybenzotnazole (1.6 eq.), the appropriate amine (1 eq.), N- methylmorpholine (3 eq.) and dichloromethane (or DMF for insoluble substrates), cooled in an ice-water bath, was stirred until a clear solution was obtained. EDC (1.3 eq.) was added to the reaction mixture and the cooling bath was allowed to warm to ambient temperature over 1-2 h. The reaction 20 was then stirred overnight. The reaction mixture was then evaporated at reduced pressure to dryness under vacuum and 20% aqueous potassium carbonate was added to the residue. The mixture was shaken vigorously and allowed to stand for hours or overnight, if necessary, until the oily product to solidify. The solidified product was then filtered off, washed thoroughly with 25 20% potassium carbonate, water, 10% HCl, and water to give the product. No racemization was observed using this procedure. GENERAL PROCEDURE V O-Acvlation of Alcohols Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 173 - To a solution of the alcohol (e.g., N-[(S)-1 -hydroxyhex-2-yl]-W-(3,5-difluorophenylacetyl)-L-alaninamide from Example 228 below) in pyridine was added 4 equivalents of acetic anhydride and the reaction was stirred at room temperature for 2.5 h. The reaction was quenched onto ice and then ethyl 5 acetate was added and the phases were separated. The organic phase was washed with 10% HCl, water, saturated aqueous NaCl, and dried over MgS04. The solution was stripped free of solvent on a rotary evaporator to yield the product. GENERAL PROCEDURE W 10 O-Esterification of Alcohols To a suspension of 0.95 equivalents of NaH in THF was added an alcohol (e.g., N-[(S)-l-hydroxyhex-2-yl]-W-(3,5-difluorophenylacetyl)-L-alaninamide from Example 228 below) dissolved in THF. This solution was cooled to 0°C, then 1.1 equivalents of an acyl chloride (e.g. trimethylacetyl chloride) was 15 added. The reaction was stirred at room temperature overnight, then was quenched with water and ethyl acetate. The organic phase was washed with water, saturated aqueous NaCl, and dried over MgS04. The solution was stripped free of solvent on a rotary evaporator to yield the crude product. GENERAL PROCEDURE X 20 BOP Coupling Procedure A solution of the carboxylic acid (1.0 eq.) and N-methyl morpholine (1.5 eq.) in dichloromethane was cooled to -20°C under nitrogen. BOP (1.05 eq.) was added in one portion and the reaction mixture was maintained at -20°C for 15 minutes. The appropriate alcohol (1.2 eq.) was added and the reaction 25 mixture was allowed to warm to room temperature and stirring was continued for 12 hours The reaction mixture was then poured into water and extracted with ethyl acetate (3x) and the combined organic layers were washed with saturated aqueous citric acid (2x), saturated aqueous sodium bicarbonate (2x), Printed from Mimosa WO 98/22494 PCT/US97/20804 - 174 - brine (lx), and then rotoevaporated at reduced pressure to provide the crude product. GENERAL PROCEDURE Y BOC Removal Using TFA 5 The Boc-protected compound was added to a 1:1 mixture of dichloromethane and trifluoroacetic acid (TFA) and the reaction mixture was stirred until tic indicated complete conversion, typically 2 hours. The solution was then stripped to dryness. The residue was suspended in dichloromethane and again stripped to dryness to remove excess TFA. The residue was placed 10 under high vacuum for several hours to afford the desired TFA salt. GENERAL PROCEDURE Z Amide Preparation IV The trichlorophenyl ester (1 eq.) was stirred in DMF or THF and the oxime or amine (1.2 eq.) was added. The mixture was stirred at ambient 15 temperature for 1-4 hours. In cases where the hydrochloride salt form of an amine was used, a suitable base such as diisopropylethylamine (1.2 eq.) was also added. The resulting mixture was concentrated under reduced pressure to yield an oil or residue which was used without further purification or was purified by standard procedures, such as silica gel chromatography and/or 20 recrystallization. GENERAL PROCEDURE AA Sodium Borohvdride Reduction The ketone was dissolved in MeOH and treated with 1.0 equivalent of sodium borohydride. The reaction was stirred until tic showed the starting 25 material was consumed, typically 1 hour. The reaction mixture was then evaporated at reduced pressure and chromatographed to afford the alcohol product. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 175 - GENERAL PROCEDURE AB Preparation Amino Acid Derivatives Using Chiral Amines (S)-(+)-a-Methylbenzyl amine was added dropwise to a solution of 4-(phenyl)benzaldehyde (1 molar eq.) in THF followed by the addition of 1.0 5 molar eqivalent of zinc chloride. The reaction mixture was allowed to stir at room temperature for 5 h. The cloudy mixture was then cooled to -30°C and treated with rm-butylisocyanide (1.05 molar eq.). After 20 minutes, N-(3,5-difluorophenylacetyl)-L-alanine was added and stirring was continued at -30°C for 120 h. The reaction mixture was then poured into a seperatory funnel and 10 diluted with CH2C12, washed with sodium bicarbonate. The organic layer was then washed with 0.5 N HCl, followed by brine. The organic layer was then dried over Na2S04, filtered and concentrated to give N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-/V'-(S)-a-methylbenzyl-2-amino-2-(4-phenylphenyl)acetamide, as a mixture of isomers. At this stage, the isomers 15 were typically separated by HPLC chromatography using, for example, a gradient of 30 to 35 % EtOAc/hexanes. The a-methylbenzyl protecting group was then removed from the S,S isomer by added 10 molar equivalents of triethylsilane and 20 molar equivalents of trifluoroacetic acid to the S,S isomer. The reaction was then heated to 37°C for 3 h and then poured into ethyl acetate 20 and washed with sodium bicarbonate. The organic layer was dried over Na2S04, filtered and concentrated The residue was purified by recrystallisation from ethyl acetate or ethyl acetate/hexanes. Various other aldehydes and carboxylic acids can be used in this procedure to provide for a variety of compounds useful in this invention. 25 GENERAL PROCEDURE AC Oxime Reduction II To a solution of the oxime ester in the alcohol corresponding to the ester was added a catalytic amount of acetic acid and 0.1 mole equivalent of 10% Pd/C. The reaction vessel (Parr shaker) was charged with hydrogen to 40 PSI 30 and this mixture was shaken for 3 h. The reaction mixture was then filtered Printed from Mimosa WO 98/22494 - 176 - PCT/US97/20804 over HyFlo and concentrated. The residue was dissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate. The organic layer was then dried over Na^O,, filtered and concentrated to give the desired amine. GENERAL PROCEDURE AD 5 Mitsunobu Reaction To a solution of iV-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester in 20 mL of THF was added 1.3 equivalents each of triphenylphosphine and diethyl azodicarboxylate (DEAD), and 1.0 equivalents of an alcohol. The mixture was stirred a room temperature overnight and the 10 solvent was then removed. The residue was purified by standard procedures, such as chromatography and/or recrystallization. GENERAL PROCEDURE AE O-Alkvlation of Tyrosine Derivatives To a solution of 2V-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine 15 methyl ester in 20 mL of acetone was added 1.3 equivalents of an alkyl bromide and 3.0 equivalents of potassium carbonate as a fine powder and a catalytic amount of sodium iodide. The reaction mixture was stirred at room temperature overnight and then partitioned between DCM and water. The organic layer was dned over anhydrous sodium sulfate, stripped of solvents and 20 purified using standard procedures, such as chromatography and/or recrystallization. GENERAL PROCEDURE AF Hvdrolvsis of Carboxylic Acid Esters A solution of the carboxylic acid ester (1.0 eq.) and lithium hydroxide (1.1 25 eq.) in 1:2 water/dioxane was stirred at 23°C for 1 hour. The reaction mixture was then acidified to pH 3 with 1 N HCl and extracted with ethyl acetate. Concentration of the ethyl acetate extracts provided the product. In some cases, Printed from Mimosa WO 98/22494 - 177 - PCT/US97/20804 the product was further purified using standard procedures, such as chromatography and/or recrystallization. GENERAL PROCEDURE AG Methyl Ester Formation from Amino Acids 5 The amino acid (amino acid or amino acid hydrochloride) is suspended in methanol and chilled to 0°C. HCl gas is bubbled through this solution for 5 minutes. The reaction is allowed to warm to room temperature then stirred for 4 hours. The solvents are then removed to afford the desired amino acid methyl ester hydrochloride. This product is usually used without further 10 purification. GENERAL PROCEDURE AH EEDO Coupling Procedure A round bottom flask containing a magnetic stir bar under as atmosphere of nitrogen at room temperature was charged with THF, the carboxylic acid (1 15 eq.), the amine hydrochloride (1.1 eq.) and EEDQ (1.1 eq.) and the reaction mixture was allowed to stir for 15 minutes. 4-Methylmorpholine (1.1 eq.) was added to the reaction and stirring was continued at room temperature for 15-20 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was partitioned between ethyl acetate and water. The organic phase 20 was separated and washed with saturated aq. NH»C1 (2x), saturated aq. NaHC03 (2x), followed by brine (lx). Organic phase dried over Na2S04. The drying agent was removed by filtration and the filtrate concentrated in vacuo. The residue was either used without further purification or purified using standard procedures, such as flash chromatography on silica gel and/or 25 recrystallization. GENERAL PROCEDURE Al N-tert-BOC Protection of Amino Acids Printed from Mimosa WO 98/22494 PCT/US97/20804 - 178 - A round bottom flask containing a magnetic stir bar under an atmosphere of nitrogen at room temperature was charged with dioxane, water, 1.0 N aq. sodium hydroxide, and the amino acid (1 eq). Stirring was initiated and the flask was cooled in an ice bath. Di-t-butyldicarbonate (1.1 eq) was added to 5 the reaction mixture, followed by removal of the ice bath and slow warming to room temperature over 1 hour. The reaction was partially concentrated on the rotary evaporator followed by the addition of ethyl acetate. The flask was re-cooled in an ice bath and the mixture was acidified to a pH of 2-3 through the addition of potassium bisulfate. The reaction was transferred into a seperatory 10 funnel and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over Na2S04. The drying agent was removed by filtration and the filtrate concentrated in vacuo. The solid was used without further purification. GENERAL PROCEDURE AJ 15 Removal of N-Carbobenzvloxv CCBZ1 Protecting Groups A round bottom flask containing a magnetic stir bar under an atmosphere of nitrogen at room temperature was charged with methanol, tetrahydrofuran, 20% Pd(OH)2/C (1 mass eq ), and the CBZ-protected dipeptide. Stirring was initiated and the flask was purged (3x) with hydrogen. The reaction mixture 20 was allowed to stir at room temperature overnight under an atmosphere of hydrogen. The reaction was filtered and the filtrate was concentrated in vacuo. The resulting solid was used as is or purified via silica gel chromotography. GENERAL PROCEDURE AK Addition of /V-Carbobenzvloxv (CBZ) Protecting Groups 25 A round bottom flask containing a magnetic stir bar under an atmosphere of nitrogen at room temperature was charged with water, sodium carbonate (2.2 eq.), and amino acid (1.0 eq.). The slurry was stirred at room temperature for 1 hour. Benzylchloroformate was added to the reaction and stirring was continued overnight. The reaction mixture was extracted with CH2C12 (3x) and Printed from Mimosa WO 98/22494 - 179 - PCT/US97/20804 the combined organic extracts were acidified to a pH of 2-3. The resulting solid was isolated via vacuum filtration. GENERAL PROCEDURE AL Preparation of Amino Acid Derivatives Using Chiral Amines II 5 A solution of aryl aldehyde (1 molar eq.) in THF was treated with S-(-)-cr- methylbenzylamine (1 molar eq.), followed by MgS04. The reaction mixture was stirred for 1 hour then treated with /err-butylisocyanide (1.5-2.0 molar eq.) and N-(3,5-difluorophenylacetyl)-L-alanine (1.5-2.0 molar eq.). The reaction was allowed to stir for 60 hours. The reaction was diluted with methylene 10 chlonde and washed with 0.01 N HCl and saturated aqueous NaHC03. Each aqueous wash was back-extracted with methylene chlonde. The combined organics were washed with bnne, dried over Na2S04, filtered and concentrated to give N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alanmyl]-iV'-R-ar-methylbenzyl-2-amino-2-DL-(aryl)acetamide. At this stage, the isomers were 15 separated if possible by HPLC chromatography using, for example, a gradient of 20 to 25 % ethyl acetate/hexanes. The a-methylbenzyl protecting group was then removed from the peptide by adding 10 molar equivalents of tnethylsilane and 20 molar equivalents of trifluoroacetic acid to the compound. The reaction was heated to 37°C for 3 hours and then poured into ethyl acetate and washed 20 with sodium bicarbonate. The organic layer was dned over Na2S04, filtered, and concentrated. The residue was purified by trituration with ether or ether/hexanes. Various other aldehydes, isocyanides, and carboxylic acid can be used in this procedure to provide for a vanety of compounds useful in this invention. 25 GENERAL PROCEDURE AM Preparation of Amino Acid Denvatives Using Chiral Amines III A solution of an aromatic aldehyde (3 molar eq.) and S-(-)-a-methylbenzylamine (1 molar eq.) in methanol was treated with titanium(IV) isopropoxide (1.5 molar eq.). After stirring the mixture at ambient temperature Printed from Mimosa WO 98/22494 PCT/US97/20804 - 180 - for 6 hours, rm-butylisocyanide (1.1 molar eq.) was added followed by N-(3,5-difluoropheny Iacetyl) -L-alanine (1.2 molar eq.) 40 minutes later. The reaction mixture was stirred for 72 hours. The methanol was removed via rotary evaporation. The residue was dissolved in methylene chloride and washed with 5 0.01 N HCl. The emulsion was filtered through celite washing with methylene chloride. The layers were separated; the organic phase was washed with saturated NaHC03 and brine. The organic layer was dned over Na2S04, filtered, and concentrated to give N-tert butyl-W-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-JV'-R-a-methylbenzyl-2-amino-2-DL-(aryl)acetamide. At this stage 10 the isomers were separated if possible by HPLC chromatography using, for example, a gradient of 20 to 25% ethyl acetate/hexanes. The a-methylbenzyl protecting group was then removed from the peptide by adding 10 molar equivalents of tnethylsilane and 20 molar equivalents of trifluoroacetic acid to the compound. The reaction was heated to 37°C for 3 hours and then poured 15 into ethyl acetate and washed with sodium bicarbonate. The organic layer was dried over Na2S04, filtered, and concentrated. The residue was purified by trituration with ether or ether/hexanes. Vanous other aldehydes, isocyanides, and carboxylic acid can be used in this procedure to provide for a variety of compounds useful in this invention. 20 GENERAL PROCEDURE AN EEDO Coupling Procedure II To a 1:1 mixture of the corresponding carboxylic acid and amino ester/amide in THF at 0°C was added 1.1 equivalents of EEDQ. The reaction mixture was stirred for 18 hours at 22.5°C. The solvent was removed under 25 reduced pressure or under a stream of nitrogen and the residue dissolved in EtOAc. The organic solution was washed 1 time with saturated NaHC03 solution, 1 time with N HCl, and dried over MgS04. The organic solution was reduced in vacuo to yield the product. Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 181 - GENERAL PROCEDURE AO Preparation of Primary Amides A sealable pressure tube containing a magnetic stir bar under an atmosphere of nitrogen at room temperature was charged with a methyl ester (1 5 eq.), sodium cyanide (0.1 eq.) and a 7M solution of ammonia in methanol. The tube was sealed and heated to 45 °C with stirring for 18 hours. The reaction was allowed to cool to room temperature and the resulting precipitate was isolated by vacuum filtration. The solid was either washed with methanol or recrystallyzed from ethyl acetate/methanol. 10 Example 1 Synthesis of Methyl /V-[>V-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate Following General Procedure A (without the IN HCl wash) and using N- 15 (3,5-difluorophenylacetyl)-L-alanine (from Example B2) and norleucine methyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp = 142-143°C). The reaction was monitored by tic (Rf = 0.71 in 10% CH30H/CH2C12, 0.22 in 50% EtOAc/hexanes) and the product was purified by silica plug chromatography using CH2C12 as the eluent. 20 NMR data was as follows: "H-nmr (CDC13)- 5 = 6.90 (d, J=7.69 Hz, IH), 6.80 (m, 3H), 6.70 (m, IH), 4.62 (quint, J=7.2 Hz, IH), 4.48 (m, IH), 3.72 (s, 3H), 3.51 (s, 2H), 1.78 (m, IH), 1.60 (m, IH), 1.36 (d, J=7.02 Hz, 3H), 1.25 (m, 4H), 0.85 (m, 3H). 25 I3C-nmr (CDC13): 5 = 173.23, 172.69, 169.97, 165.30, 165.12, 162.00, 139.01, 138.88, 138.76, 112.93, 112.83, 112.70, 112.60, 103.63, 103.30, 102.97, 52.94, 49.38, 43.28, 32 32, 27.95, 22.75, 19.23, 14.35. C18H24F2N204 (MW = 370.40); mass spectroscopy (MH+) 371. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 182 - Example 2 Synthesis of N-[/V-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-histidineMethyl Ester Following General Procedure A and using N-Q ,5-difluorophenylacetyl)-L-5 alanine (from Example B2) and L-histidine methyl ester dihydrochloride (Sigma), the tide compound was prepared as a solid (mp = 195-197°C). The reaction" was monitored by tic (Rf = 0.29 in 10% CH3OH/CH2CI2). NMR data was as follows: 'H-nmr (CD3OD): 5 = 7.60 (s, IH), 7.00-6.81 (m, 4H), 4.70 (t, IH), 4.39 10 (q, IH), 3.72 (s, 3H), 3.60 (s, 2H), 3.22-3.00 (m, 2H), 1.38 (d, 3H). I3C-nmr (CD3OD): 8 = 175.46, 172.56, 172.94, 166.64, 166.47, 163.38, 163.20, 141.73, 141.60, 141.47, 136.85, 113.92, 113.82, 113.70, 113.59, 103.89, 103.55, 103.21, 54.55, 53.31, 51.00, 43.21, 43.19, 30.36, 18.44. Ci8H2oF2N404 (MW = 394.38); mass spectroscopy (MH+) 395. 15 Example 3 Synthesis of Af-BenzyI-Af'-[N-(3,5-difluorophenyIacetyI)-L-aIaninyl]-(S)-2-aminohexanamide Following General Procedure K and using methyl N-[N-(3,5-20 difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (from Example 1 above) and benzylamine (Aldrich), the title compound was prepared as a solid (mp = >200°C). The reaction was monitored by tic (Rf = 0.29 in 5% CH3OH/CH2Cl2) and the product was purified by preparative plate chromatography. 25 NMR data was as follows: 'H-nmr (CDC13): S = 7.05 (m,5H), 6.65 (m, 3H), 4.10 (m, 4H), 3.35 (d, 2H), 1.35 (m, 9H), 0.65 (m, 3H). 13C-nmr (CDC13): 5 = 175.48, 174.75, 173.16, 166.64, 166.46, 163.37, 141.55, 141.42, 140.38, 130.04, 129.95, 129.05, 128.95, 128.73, 113.94, Printed from Mimosa WO 98/22494 PCT/US97/20804 — 183 - 113.83, 113.71, 113.60, 103.90, 103.88, 103.56, 103.22, 55.43, 51.26, 44.53, 43.21, 33.38, 29.56, 23.91, 18.28, 14.78. C2,H29F2N303 (MW = 445.51); mass spectroscopy (MH+) 446. Example 4 5 Synthesis of A'-2-(A',iV-Diniethylaniino)ethyl-./V'-[/V-(3,5-difluorophenyIacetyI)-L-alaainyl]-(S)-2-aminohexanamide Following General Procedure K and using methyl A^-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (from Example 1 above) 10 and iV,N-dimethylethylenediamine (Aldrich), the title compound was prepared as a solid (mp = 182-187°C). The reaction was monitored by tic (Rf = 0.51 in 15 % CH30H/CH2C12) and the product was purified by preparative plate chromatography using 15% CH30H/CH2C12 as the eluent. NMR data was as follows: 15 'H-nmr (CDC13): 5 = 7.21 (d, IH), 6.80 (m, 5H), 4.64 (m, IH), 4.48 (q, IH), 3.57 (s, 2H), 3.30 (q, 2H), 2.41 (t, 2H), 2.22 (s, 6H), 1.70 (m, 2H), 1.32 (m, 7H), 0 87 (m, 3H). l3C-nmr (CDC13): S = 172.2, 172.0, 170.0, 165.4, 165.3, 163.9, 162.1, 162.0, 139.1, 138.8, 113.1, 112.8, 103.6, 103.3, 103.0, 58.1, 54.0, 49.7, 20 45.7, 43.3, 38.1, 33.2, 28.2, 23.0, 19.2, 14.4. C21H32F2N403 (MW = 426.51); mass spectroscopy (MH+) 427. Example 5 Synthesis of yV-(2-Methoxyethyl)-/V'-[Af-(3,5-difluorophenylacetyl)-25 L-alaninyl]-(S)-2-aminohexanamide Following Genera] Procedure K and using methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (from Example 1 above) and 2-methoxyethylamine (Aldnch), the title compound was prepared as a solid (mp = >200°C). The reaction was monitored by tic (Rf = 0.42 in 10% Printed from Mimosa WO 98/22494 PCT/US97/20804 — 184 - CH3OH/CH2Cl2) and the product was purified by flash chromatography using 12% CH3OH/CH2Cl2 as the eluent. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.85 (bd, J=8.79 Hz, 0.5H), 7.64 (bd, J=7.81 Hz, 5 0.5H), 7.35 (m, IH), 7.16 (bd, J=7.27 Hz, 0.5H), 7.06 (bs, 0.5H), 6.83 (m, 2H), 6.68 (m, IH), 4.70 (m, 2H), 3.56 (d, J=9.89 Hz, 2H), 3.40 (m, 7H), 1.57 (m, 10H), 0.84 (m, 3H). "C-nmr (CDC13): 6 = 172.62, 172.58, 172.14, 172.04, 170.02, 169.91, 165.33, 165.15, 162 08, 112.99, 112.92, 112.82, 112.77, 112.66, 112.59, 10 103.54, 103.34, 103.31, 103.29, 71.46, 71.44, 59.27, 59.24, 53.76, 49.64, 49.43, 43.29, 39.79, 33.26, 33.22, 28.10, 28.03, 22.97, 22.91, 19.71, 19 61, 19.56, 19.51, 14.46, 14.43 C20H39F2N3O4 (MW = 413.47); mass spectroscopy (MH+) 414. Example 6 15 Synthesis of AL2-(/V,Ar-DimethyIamino)ethyl-/V'-[/V-(3,5-difluorophenylacetyI)-L-alaninyl]-L-phenylalaninamide Following General Procedure K and using N-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (from Example 94 below) and N,N-20 dimethylethylenediamine (Aldnch), the title compound was prepared as a solid (mp = 174-182°C). The reaction was monitored by tic (Rf = 0.31 in 10% CH3OH/CH2Cl2) and the product was punfied by preparative plate chromatography using 10% CH30H/CH2C12 as the eluent. NMR data was as follows: 25 'H-nmr (CD3OD): 5 = 7.22 (m, 5h), 6.85 (m, 3H), 4.51 (m, IH), 4.18 (m, IH), 3.57 (m, 2H), 3.50-2.45 (m, 6H), 2.39 (s, 6H), 1.26 (d, 2.4H), 1.10 (d, 0.6H). "C-nmr (CD3OD): 5 = 176.03, 175.50, 174.20, 173.99, 173.50, 173.22, 166.63, 166 46, 163.36, 163.19, 141.65, 141.52, 141.39, 139.38, 139.00, 30 130.90, 130.74, 130.05, 130.01, 128.37, 128.30, 114 03, 113.93, 113.80, 113.70, 103.96, 103.62, 103.57, 103.28, 59.18, 59.14, 56.78, 56.51, 51.93, Printed from Mimosa WO 98/22494 PCT/US97/20804 — 185 - 51.74, 45.53, 45.47, 43.21, 43.18, 42.92, 38.84, 38.65, 37.94, 37.85, 18.09, 17.73. C24H30F2N4O3 (MW = 460.53); mass spectroscopy (MH+) 461. Example 7 Synthesis of yV-(4-Pyridyl)methyl-/V'-[jV-(3,5-difluorophenyIacetyl)-L-alaninyl]-L-phenylalaninamide Following General Procedure K and using A^-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (from Example 94 below) and 4-(aminomethyl)pyridine (Aldrich), the title compound was prepared as a solid (mp = >200°C). The reaction was monitored by tic (Rf = 0.46 in 10% CH30H/CH2C12) and the product was punfied by recrystallization from ethyl acetate. NMR data was as follows: 'H-nmr (CD3OD): 8 = 8.37 (d, 2H), 7.25 (m, 5H), 7.11 (d, 2H), 6.85 (m, 3H), 4.56 (t, IH), 4.29 (m, 3H), 3.64 (s, 2H), 3.08 (m, 2H), 1.30 (d, 3H). I3C-nmr (CD3OD): 8 = 175.46, 174.04, 173.26, 166.60, 166.43, 163.34, 163.16, 150.97, 150.44, 141.59, 141.45, 138.84, 130.95, 130.13, 128.44, 124.28, 113.98, 113.87, 113.75, 113.64, 103.91, 103.57, 103.23, 62.08, 57.01, 43.33, 43.12, 38.93, 21.41, 18.16, 15.02. C26H26F2N403 (MW = 480.52); mass spectroscopy (MH+) 481. Example 8 Synthesis of ^V-(3-Pyridyl)methyl-A''-[A?-(3,5-difluorophenyIacetyl)-L-alaninyl]-L-phenylalaninamide Following General Procedure K and using 7V-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanme methyl ester (from Example 94 below) and 4-(aminomethyl)pyndme (Aldnch), the title compound was prepared as a solid (mp = 199-210°C). The reaction was monitored by tic (Rf = 0.46 in 10% Printed from Mimosa WO 98/22494 PCT/US97/20804 - 186 - CH30H/CH2C12, minor isomer Rf = 0.50) and the product was purified by preparative plate chromatography using 10% CH3OH/CH2Cl2 as the eluent. NMR data was as follows: 'H-nmr (CD3OD): 5 = 8.42 (m, 2H), 7.61 (m, IH), 7.29 (m, 6H), 6.90 5 (m, 3H), 4.61 (m, IH), 4.33 (m, 3H), 3.58 (s, 1.5H), 3.54 (s, 0.5H), 3.10 (m, 2H), 1.33 (d, 2.25H), 1.15 (d, 0.75H). l3C-nmr (CDjOD): 5 = 176.00, 175.34, 174.03, 173.81, 173.23, 166.61, 166.44, 163.35, 163.17, 149.93, 149.20, 141.48, 139.20, 138.72, 138.10, 138.03, 136.88, 136.79, 130.89, 130.70, 130.06, 130.02, 128.40, 128.33, 10 125.71, 113.97, 113.87, 113.74, 113 64, 103.92, 103.58, 103.53, 103.23, 56.88, 56.66, 55.74, 53.21, 43.22, 43.15, 42.89, 42.06, 41.98, 39.04, 38.88, 38.77, 18.18, 17.79. C^HjjFjNiOj (MW = 480.52); mass spectroscopy (MH+) 481. Example 9 15 Synthesis of JV-(4-Pyridyl)methyl-iV"-[iV-(3,5-difluorophenylacetyl)-L-aIaninyl]-(S)-2-aminohexanamide Following General Procedure K and using methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (from Example 1 above) 20 and 4-(aminomethyl)pyridine (Aldrich), the title compound was prepared as a solid (mp = 181-205°C). The reaction was monitored by tic (Rf = 0.51 in 10% CH3OH/CH2Cl2) and the product was purified by preparative plate chromatography using 10% CH3OH/CH2Cl2 as the eluent. NMR data was as follows: 25 'H-nmr (CD3OD): 8 = 8.48 (m, 0.8H), 8.42 (m, 1 2H), 7.37 (d, J=6.10, 0.8H), 7.28 (d, J=6.11, 1.2H), 6.85 (m, 3H), 4.39 (m, 4H), 3.61 (s, 0.8H), 3.53 (d, J=2.99, 1.2H), 2.05-1.25 (m, 9H), 0.90 (m, 3H). 13C-nmr (CD3OD): 5 = 176.61, 175.71, 175.33, 175.29, 173.32, 173.24, 166.49, 166.32, 163.22, 163.05, 151.30, 151.24, 150.55, 150.41, 141.54, 30 141.41, 124.35, 124.20, 113.95, 113.85, 113.72, 113.62, 103.86, 103.57, Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 187 - 103.52, 103.18, 55.72, 55.64, 51.98, 43.38, 43.19, 42.82, 33.07, 32.57, 29.87, 29.67, 23.90, 23.82, 18.24, 17.86, 14.80. C23H2gF2N403 (MW = 446.50); mass spectroscopy (MH+) 447. Example 10 5 Synthesis of /e/f-butyl Af-[2V-(3,5-Dinuorophenylacetyl)-L-aIaninyl]-(S)-2-aminohexanoate Step A - /-Butyl Ester Formation To a solution of Z-norleucine-OH in CH2C12 was added 1.5 equivalents of 10 N,N'-dusopropyl-0-t-b\ity\houTea (prepared by the method of Synthesis (1979) p.561 for review) and the reaction was heated to reflux for 17 hours. An additional 1.5 equivalents of isourea was then added, and reflux was continued for another 7 hours. The reaction was then cooled to room temperature and filtered through a bed of Cehte 545, then stripped to dryness to leave a clear 15 oil. The residue was dissolved in hexanes and filtered to remove solids, and the filtrate was washed with saturated aqueous NaHCOj, water, saturated aqueous NaCl, and dried over MgS04 The solution was concentrated under reduced pressure to leave the product. Step B - CBZ Removal 20 The CBZ-protected amino ester was dissolved in ethanol in a hydrogenation flask and a catalytic amount of 10% Pd/C was added. The mixture was hydrogenated at 20 psi H2 on a Parr shaker for 30 min. The reaction was then filtered through a pad of Cehte 545 and stripped free of solvent on a rotary evaporator to yield the product, norleucine /erf-butyl ester hydrochloride. 25 Step C Following General Procedure D and using jV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and the norleucine rm-butyl ester hydrochloride, the title compound was prepared as a semi-solid. The reaction was monitored by tic (Rf = 0.41 in 50% EtOAc/hexanes) and the product was Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 188 - purified by flash chromatography using 50% EtOAc/hexanes as the eluent, followed by preparative plate chromatography using 50% EtOAc/hexanes as the eluent. NMR data was as follows: 5 'H-nmr (CDC13): 5 = 7.63 (d, J=7.7 Hz, IH), 7.34 (d, J=7.7 Hz, IH), 6.8 (m, 2H), 6.7 (m, IH), 4.8 (m, IH), 4.36 (q, J=5.6 Hz, IH), 3.52 (s, 2H), 1.8-1.1 (m, 15H), 0.8 (m, 3H). 13C-nmr (CDC13): 5 = 173.0, 171.8, 170.2, 165.1, 165.0, 161.9, 161.7, 139.6, 139.4, 139.3, 112.8, 112.7, 112.6, 112.5, 103.2, 102.9, 102.6, 82.3, 10 53.6, 49.3, 43.0, 32.2, 28.4, 27.8, 22.7, 19.4, 14.7, 14.2. C21H3uF2N204 (MW = 412.48); mass spectroscopy (MH+) 413. Example 11 Synthesis of N-[/V-(Pent-4-enoyI)-L-aIaninyl]-L-phenylalanine Methyl Ester 15 Following General Procedure A and using /V-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling /V-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester (Sigma) using General Procedure A, followed by removal of the BOC-group using General Procedure Y) and pent-4-enoic acid (Aldrich), the title compound was prepared as a solid (mp = 125.5-126.5°C). 20 The reaction was monitored by tic (Rf = 0.32 in 50% EtOAc/hexanes; 0.51 in 10% CH30H/CH2C12) and the product was purified by flash chromatography using 10% CH30H/CH2C12 as the eluent. NMR data was as follows: 'H-nmr (CDC13): <5 = 7.27 (bd, J=7.82 Hz, IH), 7.25-7.05 (m, 5H), 6.72 25 (bd, J=7.57 Hz, IH), 5.75 (m, IH), 4.96 (m, 2H), 4.59 (quint, J=7.2 Hz, IH), 3.65 (s, 3H), 3.05 (m, 4H), 2.40-2.18 (m, 4H), 1.28 (d, J=7.02 Hz, 3H). 13C-nmr (CDC13): 5 = 173.06, 172.77, 172.36, 137.47, 136.53, 129.76, 129.07, 116.09, 54.10, 52.87, 49.06, 38.31, 25.93, 30.03, 19.17. 30 C18H24N204 (MW = 332.40); mass spectroscopy (MNa+) 355.0. Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 189 - Example 12 Synthesis of 2V-[/V-(Dec-4-enoyl)-L-alaninyl]-L-phenylalanine Methyl Ester Following General Procedure A and using //-(L-alaninyl)-L-phenylalanine 5 methyl ester (prepared by coupling jV-BOC-L-alanine (Sigma) and L- phenylalanine methyl ester (Sigma) using General Procedure A, followed by removal of the BOC-group using General Procedure Y) and dec-4-enoic acid (prepare from ethyl dec-4-enoate (ICM) using General Procedure N), the title compound was prepared as a solid (mp = 115.5-117.5°C). The reaction was 10 monitored by tic (Rf = 0.52 in 50% EtOAc/hexanes; 0.60 in 10% CH3OH/CH2CI2) and the product was purified by flash chromatography using 10% CH3OH/CH2Cl2 as the eluent. NMR data was as follows: lH-nmr (CDC13): 5 = 7.54 (bd, J=7.69 Hz, IH), 7.22-7.04 (m, 5H), 6.91 15 (bd, 1=1.69 Hz, IH), 5.37 (m, 2H), 4.73 (q, J=6.9 Hz, IH), 4.63 (quint, J=7.2 Hz, IH), 3.61 (s, 3H), 3.02 (m, 2H), 2.40-2.10 (m, 4H), 1.89 (m, 2H), 1.35-1.13 (m, 9H), 0.82 (m, 3H). 13C-nmr (CDC13): 8 = 173.26, 173.05, 172.38, 136.65, 132.30, 129.74, 128.99, 128.68, 127.48, 54.19, 52.74, 48.97, 38.28, 36.70, 33.04, 31.93, 20 29.68, 29.09, 23 06, 19.23, 14.61. C23H34N204 (MW = 402.54); mass spectroscopy (MNa+) 425.0. Example 13 Synthesis of iV-[iV-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4-25 [XiVj/V-dunethylaminoipropoxylphenylalanine Methyl Ester Following General Procedure A and using iV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and L-4-[3-(/V,/V-dimethylamino)propoxy]-phenylalanine methyl ester (prepared from iV-BOC-L-tyrosine methyl ester (Bachem) and 3-dimethylamino-l-propanol (Aldrich) using a Mitsunobu 30 procedure essentially as descnbed in General Procedure AD, followed by removal of the BOC-group using General Procedure Y), the title compound was Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 190 - prepared as a solid (mp = 153-155°C). The reaction was monitored by tic (Rf = 0.36 in 10% MeOH/DCM/l%TEA) and the product was purified by acid/base washes. NMR data was as follows: 5 'H-nmr (CDC13): 5 = 6.973-6.947 (d, 2H); 6.794-6.766 (d, 2H); 6.743- 6.714 (d, 2H); 6.735-6.676 (t, IH); 4.761-4.735 (q, IH); 4.511-4.463 (q, IH); 3.967-3.924 (t, 2H); 3.703 (s, 3H); 3.473 (s, 2H); 3.019-2.977 (t, 2H); 2.443-2.394 (t, 2H); 2.233 (s, 6H); 1.944-1.897 (t, 2H); 1.319-1.296 (d, 3H). 13C-nmr (CDCl,): 5 = 172.292; 172.256; 169.808; 158.747; 130.731; 10 127.887; 115.149; 112.900; 112.672; 66.690; 56.945; 54.039; 52.971; 49.400; 46.105 ; 43.302; 37.421; 28.129; 19.029. C25H33F2N30, (MW = 505); mass spectroscopy (MH+) 506. Example 14 Synthesis of 15 iV-[iV-(3,5-Difluorophenylacetyl)-I^alaninyl]- L-4-[(fert-butyloxycarbonyl)methoxy]phenylalanine Methyl Ester Following General Procedure AE and using /err-butyl bromoacetate (Aldnch) and A^t/V-^S-difluorophenylacetyty-L-alamnylj-L-tyrosine methyl ester (from Example 15 below), the title compound was prepared as a solid (mp 20 = 116-119°C). The reaction was monitored by tic (Rf = 0.54 in 50% EtOAc/hexanes) and the product was punfied by silica gel column chromatography. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.648-7.615 (d, IH); 7.513-7.407 (d, IH); 6.943-25 6.914 (d, 2H); 6.756-6.669 (d+t, 4H); 6.621-6.562 (t, IH); 4.662-4.590 (q+quintex, 2H); 4.382 (s, 2H); 3.571 (s, 3H); 3.406 (s, 2H); 3.006-2.648 (m, 2H); 1.417 (s, 9H); 1.243-1.221 (d, 3H). 13C-nmr (CDC13): 5 = 173.14; 173.001; 172.294; 170.273; 168.614; 168.546; 165.107; 161.816; 157.428; 139.493; 130.749; 129.385; 115.077; 30 112.803; 103.250; 828.270; 66.039; 54.361; 52.730; 49.172; 42.832; 37.288; 28.509; 19.018. Prxnted from Mxmosa WO 98/22494 PCT/US97/20804 - 191 -- C27H32F2N2O7 (MW = 534); mass spectroscopy (MH+) 535. Example 15 Synthesis of N- [iV- (3,5-Difluor opheny lacety 1)-L-alaninyl]-5 L-tyrosine Methyl Ester Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-tyrosine methyl ester (Bachem), the title compound was prepared as a solid (mp = 85-88 °C). The reaction was monitored by tic (Rf = 0.27 in 50% EtOAc/hexanes) and the product was 10 purified by silica gel column chromatography. NMR data was as follows: 'H-nmr (CDC13): 5 = 8.036 (b, IH); 7.369-7.344 (d, IH); 7.205-7.151 (d, IH); 6.869-6.841 (d, 2H); 6.763-6.738 (d, 2H); 6.657-6.615 (m, 3H); 4.741-4.697 (q, IH); 4.566-4.491 (q, IH); 3.671 (s, 3H); 3.415 (s, 2H); 3.061-2.771 15 (dm, 2H); 1.271-1.250 (d, 3H). 13C-nmr (CDC13): 5 = 173.049; 172.666; 172.444; 170.768; 165.211; 161.917; 156 098, 130.862; 127.542; 116 093, 112.990; 112.659; 103.236; 61.112; 54.306; 49.441; 42.947; 18.923. Cj.HzjFjNjOj (MW = 420); mass spectroscopy (MH+) 421. 20 Example 16 Synthesis of A/-[W-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4-(carboxymethoxy)phenylalanine Methyl Ester Following General Procedure N and using A/-[iV-(3,5-difluorophenylacetyl)-25 L-alaninyl]-L-4-[(rm-butyloxycarbonyl)methoxy]phenylalanine methyl ester (from Example 14 above), the tide compound was prepared. The reaction was monitored by tic (Rf = 0.49 in 10% MeOH/DCM + 1% AcOH) and the product was purified by silica gel column chromatography. NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/U S97/20804 - 192 -- 'H-nmr (CDC13): 5 = 7.817 (s, IH); 7.648-7622 (d, IH); 7.544-7.520 (d, IH); 6.956-6.914 (d, 2H); 6.762-6.703 (d+d, 4H); 6.650-6.590 (t, IH); 4.678-4.636 (q, IH); 4.567-4.503 (quinex + s, 3H); 3.622 (s, 3H); 3.431 (s, 2H); 2.987-2.811 (m, 2H); 1.241-1.219 (d, 3H). 5 13C-nmr (CDC13): 6 = 173.618; 173.534; 172.215; 171.209; 171.108; 165.148; 164.973; 161.855; 161.683; 157.309; 139.052; 130.887; 129.376; 115.104; 112.895; 112.667; 103.083; 65.324; 54.155; 52.933; 50.538; 49.384; 42.683; 37.168; 18.678. C23H24F2N207 (MW = 478); mass spectroscopy (MH+) 479. 10 Example 17 Synthesis of /V-[7V-(3,5-Difluoropheny]acetyI)-L-alaninyI]-L-4-(2-morpholinoethoxy)phenylalanine Methyl Ester Following General Procedure AD and using N-[N-(3,5-15 difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester (from Example 15 above) and 4-(2-hydroxyethyl)morpholine (Aldrich), the title compound was prepared as a solid (mp = 138-141 °C). The reaction was monitored by tic (Rf = 0.56 in 10%MeOH/DCM 4- 1%TEA) and the product was purified by silica gel column chromatography, followed by tntuation using diethyl ether. 20 NMR data was as follows: 'H-nmr (CDC13): 5 = 6.974-6.945 (d, 2H); 6.795-6.726 (d+t, 2H); 6.697-6.682 (t, IH); 4.755-4.689 (q, IH); 4.535-4.468 (quintex, IH); 4.050-4.012 (t, 2H); 3.723-3.606 (t+s, 7H); 3.463 (s, 2H); 3.039-2.892 (m, 2H); 2.779-2.741 (t, 2H); 2.562-2.531 (t, 4H); 1.297-1.274 (d, 3H). 25 13C-nmr (CDC13): 5 = 1721.477; 172.428; 172.303; 169.925; 158.397; 130.778; 128.504; 115.179; 112.988; 112.769; 112.659; 67.457; 66.249; 58.187; 54.631; 54.119; 52.956; 49.358; 43.202; 37.496; 19.028. C27H33F2N306 (MW = 533); mass spectroscopy (MH+) 534. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 193 - Example 18 Synthesis of Methyl iV-[iV-(3,5-Difluorophenylacetyl)-L-a]aiiinyl]- (S)-2-amino-6-(A^,Ar-dimethylamino)hexanoate 5 Following General Procedure A and using N-^S-difluorophenylacetyl)-!.- alanine (from Example B2 above) and Ne,Ne-dimethy 1-L-lysine methyl ester hydrochlonde (Bachem), the title compound was prepared as a solid (mp = 123-126°C). The reaction was monitored by tic (Rf = 0.22 in 10% MeOH/DCM + 1 % TEA) and the product was purified by silica gel column 10 chromatography. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.019-6.993 (d, IH); 6.828-6.801 (dd, 2H); 6.753-6.723 (m, IH); 6.617-6.592 (d, IH); 4.557-4.447 (q+q, 2H); 3.730 (s, 3H); 3.522 (s, 2H); 2.593-2.572 (m, 2H); 2.196 (s, 6H); 1.837-1.642 (m, 2H); 15 1.486-1.344 (m+d, 7H). ,3C-nmr (CDClj): 8 = 173.070; 172.544, 169.809; 112.986; 112.655; 103.384: 59 393; 52.991; 49.368; 45.947; 43.427; 43.403; 43.375; 31.870; 27.376; 23.378; 19.155. C20H29F2N3O4 (MW = 413); mass spectroscopy (MH+) 414. 20 Example 19 Synthesis of Methyl /V-[/V-(3,5-Difluorophenylacetyl)-L-alaninyI]-(S)-2-amino-3-(2-pyridyl)propionate Following General Procedure A and using Af-(3,5-difluorophenylacetyl)-L-25 alanine (from Example B2) and methyl (S)-2-amino-3-(2-pyridyl)propionate hydrochloride (Synthetech), the title compound was prepared as a solid (mp = 121-124°C). The reaction was monitored by tic (Rf = 0.39 in 10%MeOH/DCM) and the product was purified by silica gel column chromatography. 30 NMR data was as follows: Printed from Mimosa WO 98/22494 « 194 - PCT/US97/20804 "H-nmr (CDC13): 5 = 8.474-8.458 (d, IH); 7.767-7.631 (m, IH); 7.625-7.574 (t, IH); 7.178-7.102 (t+d, 2H); 6.818-6.811 (d, 2H); 6.734-6.667 (t, IH); 6.593-6.542 (m, IH); 4.933-4.873 (m, IH); 4.566-4.496 (m, IH); 3.646 (s, 3H); 3.499 (s, 2H); 3.375-3.196 (m, 2H); 1.393-1.370 (d, 3H). 5 13C-nmr (CDC13): 5 = 172.453; 172.020; 169.527; 157.454; 149.608; 137.449; 124.366; 124.328; 122.694; 113.032; 112.992; 112.661; 103.333; 53.032; 52.997; 52.349; 52.252; 49.427; 49.405; 43.464, 43.437, 38.486; 19.548; 19.232. C20H2lF2N3O4 (MW = 405); mass spectroscopy (MH+) 406. 10 Example 20 Synthesis of Methyl /V-[/V-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(3-pyridyl)propionate Following General Procedure A and using JV-(3,5-difluorophenylacetyl)-L-15 alanine (from Example B2) and methyl (S)-2-amino-3-(3-pyridyl)propionate hydrochloride (Synthetech), the title compound was prepared as a solid (mp = 101-103°C) The reaction was monitored by tic (Rf = 0 48 in 10% MeOH/DCM) and the product was purified by silica gel column chromatography. 20 NMR data was as follows: "H-nmr (CDC13): 5 = 8.492-8 396 (m, IH); 8.359-8.322 (m, IH); 7.505-7.452 (m, IH); 7.248-7.170 (m, IH); 6.976-6.908 (m, IH); 6.855-6.668 (m, 3H); 6.352-6.288 (m, IH); 4.866-4.798 (m, IH); 4.784-4.429 (m, IH); 3.750 (s, 3H); 3.513 (s, 2H); 3.220-2.964 (m, 2H); 1.310-1.287 (d, 3H). 25 "3C-nmr (CDC13): 5 = 172.867; 171.831; 170.307; 161.942; 150.892; 150.753; 148.907; 148.750; 137.523, 137.388; 132.460; 124.106; 124.034; 112.981; 112.754; 103.228; 53.623; 53 461; 53.146; 49.368; 49.259; 43.137; 43.115; 43.086; 35.485; 18.664. C2oH21F2N304 (MW = 405); mass spectroscopy (MH+) 406. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 195 -- Example 21 Synthesis of /V-|W-(3,5-DifluorophenylacetyI)-L-alaniiiyI]-L-proline Methyl Ester 5 Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L- alanine (from Example B2 above) and L-proline methyl ester hydrochloride (Bachem), the title compound was prepared as a viscous solid. The reaction was monitored by tic (Rf = 0.57 in 10% MeOH/DCM) and the product was purified by acid/base washes. 10 NMR data was as follows* 'H-nmr (CDC13): 5 = 7.524-7.498 (d, IH); 6.813-6.793 (d, 2H); 6.681-6.613 (m, IH); 4.788-4.717 (m, IH); 4.484-4.442 (m, IH); 3.705-3.590 (m+s, 4H); 3.465 (s, 2H); 2.217-1.902 (m, 5H); 1.332-1.309 (d, 3H). 13C-nmr (CDClj): 5 = 172.753; 172.152; 169.843; 165.185; 161.894; 15 112.953; 112.850; 112.727; 112.624; 103.331, 102.996, 102.662; 59.352; 52.735; 47.495; 47.267; 43.069; 29.472; 25.403; 18.243. C,7H20F2N2O4 (MW = 354); mass spectroscopy (MH+) 355. Example 22 Synthesis of 20 Methyl l-[/V-(3,5-DifluorophenyIacetyI)- L-alaninyl]piperidine-2-carbo\ylate Following General Procedure B and using /V-(phenylacetyl)-L-alanine (from Example B1 above) and methyl pipecolinate hydrochloride (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tic (Rf = 25 0.30 in 50% EtOAc/hexanes) and the product was purified by silica gel chromatography. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.2 (m, 5H), 6.95 (dd, J=7.2, 15.2, 7.2 Hz, IH), 5.21 (dd, J=5.0, 11.0, 5.0 Hz, IH), 4.89 (q, J=7.1, 7.1 Hz, IH), 3.7 (m, 30 IH), 3.59 (s, 3H), 3.47 (s, 2H), 3.1 (m, IH), 2.16 (d, J=11.5 Hz, IH), 1.4 (m, 4H), 1.22 (dd, J=1.3, 4.4, 1.2 Hz, 3H). Printed from Mimosa WO 98/22494 PCT/US97/20804 — 196 - ,3C-nmr (CDC13): 6 = 172.6, 171.8, 170.7, 135.5, 129.8, 129.3, 127.6, 52.9, 52.8, 46.0, 43.9, 27.1, 26.8, 25.6, 21.4, 19.9, 18.5. C18HmN204 (MW = 332); mass spectroscopy (MH+) 333. Example 23 5 Synthesis of Methyl Af-[iV-(3,5-DifluorophenylacetyI)-L-alaninyl]-(S)-2-amino-3-(4-pyridyl)propionate Step A - Preparation of 3-(3-pyridyI)alanine methyl ester dihydrochloride Sodium metal (1.40 g, 61 mmol) was dissolved in EtOH (lOOmL) and 10 diethyl acetamidomalonate (6.62 g, 30.5 mmol) and 3-picolylchloride hydrochloride (5.00g, 30.5 mmol) were added. The mixture was heated to reflux for 6 hours, and then cooled and filtered to remove NaCl (washed with EtOH). The solvent was removed in vacuo and the mixture was taken up into saturated aqueous NaHCOj (100 mL) and extracted with EtOAc (3 x 100 m L). 15 The solvent was removed and the residue purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to give diethyl 2-(3-pyridylmethyl)-2-acetamidomalonate (2.84 g, 30%). Diethyl 2-(3-pyridylmethyl)-2-acetamidomalonate was dissolved in 6N HCl (30 mL) and heated to reflux for 19 hours whereupon it was cooled to room Printed from Mimosa WO 98/22494 PCT/US97/20804 - 197 - temperature and the HCl solution was removed by evaporation in vacuo. The intermediate amino acid dihydrochloride salt was taken up into MeOH (30 mL) saturated with HCl gas and stirred for 3.5 hours. The MeOH/HCl was removed by evaporation in vacuo to give 3-(3-pyridyl)aIanine methyl ester 5 dihydrochloride (2.235 g, 100%). Step B - Preparation of Methyl N-[iV-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-pyridyl)propionate Following General Procedure A and using iV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(4-10 pyndyl)propionate hydrochlonde (prepared by the method set forth above using 4-picolylchloride hydrochloride), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.49 in 10% MeOH/DCM) and the product was purified by silica gel column chromatography. NMR data was as follows: 15 'H-nmr (CDC13): 8 = 8.423-8.335 (dd, 2H); 7.832-7.754 (q, IH); 7.342- 7.246 (dd, IH); 7.032-6.972 (dd, 2H); 6.764-6.667 (t, 2H); 6.659-6.599 (m, IH); 4.837-4.768 (m, IH); 4.590-4.515 (m, IH); 3.675 (s, 3H); 3.426 (s, 2H); 3.112-2.804 (m, 2H); 1.256-1.106 (dd, 3H). 13C-nmr (CDC13): 5 = 173.037, 171.739; 170.258; 170.225; 165.201; 20 165.012; 161.904; 161.721; 150.183; 150.063; 146.115, 146.012; 139.100; 125.180; 125.122; 112.951; 112.915; 112.846; 103.492; 103.153; 53.088, 49.318; 42.977, 37.593; 37.547; 19.297; 18.882. C20H2,F2N3O4 (MW - 405); mass spectroscopy (MH+) 406. Example 24 25 Synthesis of Methyl Ar-[/V-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionate Following General Procedure A and using /V-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-3-methoxypropionate 30 hydrochloride (Bachem), the title compound was prepared as a solid (mp = Printed from Mimosa WO 98/22494 - 198 - PCT/US97/20804 165-168°C). The reaction was monitored by tic (Rf = 0.48 in 10% MeOH/DCM) and the product was purified by acid/base washes. NMR data was as follows: 'H-nmr (CDC13): 5 = 6.971-6.944 (d, IH); 6.813-6.801 (m, 2H); 6.741-5 6.678 (m, IH); 6.585-6.526 (m, IH); 4.692-4.561 (quintex + q, 2H); 3.836-3.802 (m, IH); 3.738 (s, 3H); 3.592-3.516 (m+ds, 3H); 3.312 (s, 3H); 1.408-1.355 (dd, 3H). ,3C-nmr (CDC13): 5 = 172.705; 172.680; 170.908; 113.019; 112.978; 112.687; 112.646; 103.347; 72.434; 72.405; 59.885; 59.837; 53.263; 53.240; 10 49.413; 49.329; 19.389; 18.9196. C16H20F2N,O5 (MW = 358); mass spectroscopy (MH+) 359. Example 25 Synthesis of Methyl iV-[/V-(3,5-Difluorophenylacetyl)-15 L-aIaninyl]-2-amino-3-morpholinopropionate Step A methyl f2-N-CBZ-aminoV3-morpholino-pronionate To a solution of N-CBZ-dehydro-alanine methyl ester (Sigma) in acetonitrile was added 2.0 equivalent of morpholine and 0.25 equivalents of anhydrous ferric chloride. The mixture was stirred for 16 hours and monitored 20 by TLC. The solvent was stripped off and the residue extracted with ethyl acetate and washed with IN HCl. The aqueous layer was basified with IN potassium carbonate to pH = 9 and extracted with ethyl acetate again, dried over sodium sulfate and rotovapped to dryness to give methyl (2-N-CBZ-amino)-3-morpholino-propionate as a clear tan oil. See Perez et al., 25 Tetrahedron 51(3) 8355-62 (1995) Step B Methyl /V-r/V-(3.5-Dif1uorophenvlacetvr>-L-alaninv1"l-2-amino-3-morpholinopropionate Following General Procedure A and using yV-(3,5-difluorophenylacetyl)- Printed from Mimosa WO 98/22494 PCT/US97/20804 _ 199 - L-alanine (from Example B2 above) and methyl 2-amino-3-morpholinopropionate hydrochloride (prepared by General Procedure O above from methyl (2-N-CBZ-amino)-3-morpholino-propionate), the title compound was prepared as a viscous solid. The reaction was monitored by tic (Rf = 0.44 5 in 10% MeOH/DCM) and the product was purified by acid/base washes. NMR data was as follows: 'H-nmr (CDClj): S = 7.408-7.384 (d, IH); 7.247-7.173 (m, IH); 6.774-6.614 (m+t, 3H); 4.605-4.468 (m, IH); 3.667 (s, 3H); 3.642 (s, 2H); 3.576-3.561 (t, 4H); 3.479-3.461 (s+s, 2H); 2.639-2.618 (d, 2H); 2.395-2.366 (m, 10 4H); 1.344-1.307 (t, 3H). 13C-nmr (CDC13): 5 = 173.120; 172.245; 172.192; 170.275; 170.159; 165.189; 165.020; 161.897; 161.727; 139.167; 112.937; 112.863; 112.759; 112.610; 112.533; 103.103; 102.774; 67.379; 67.301; 59.346; 59.110; 54.030; 52.936; 51.116; 49.283; 43.053; 18.980; 18.921. 15 C19H26F2N305 (MW = 413); mass spectroscopy (MH+) 414. Example 26 Synthesis of N-(2-Methoxyethyl)-,iV'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)phenylalaninamide 20 Following General Procedure K and using 2-methoxyethylamine (Aldrich) and N-[,/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)-phenylalanine methyl ester (from Example 17 above), the title compound was prepared as a solid (mp = 165-168°C). The reaction was monitored by tic (Rf = 0.67 in 10% MeOH/DCM+1% TEA) and the product was purified by 25 acid/base washes. NMR data was as follows: 'H-nmr (CDC13): 6 = 8.258-8.232 (d, IH); 8.014-7.989 (d, IH); 7.532-7.370 (t, IH); 7.035-7.008 (d, 2H); 6 842-6.630 (m, 5H); 4.980-4.905 (m, IH); 4.794-4.772 (m, IH); 4.026-3.992 (t, 2H); 3.713-3.642 (t, 4H); 3.594-30 3.453 (dd, 2H); 3.404-3.267 (t, 2H); 3.179 (s, 3H); 2.930-2.914 (t, 2H); 2.763-2.731 (t, 2H); 2.538-2.502 (m, 4H); 1.335-1.314 (d, 3H). Printed from Mimosa WO 98/22494 PCT/US97/20804 -200 - ,3C-nmr (CDClj): 5 = 172.956; 172.918; 171.756; 170.142; 161.677; 158.131; 130.973; 129.270; 114.968; 114.875; 112.908; 112.696; 112.571; 71.423; 71.367; 67.440; 66.164; 59.072; 58.232; 58.188; 54.636; 42.827; 42.800; 39.757; 39.642; 20.449; 20.135. 5 C29H38F2N406 (MW = 576); mass spectroscopy (MH+) 577. Example 27 Synthesis of 2V-(2-Methoxyethyl)-/V'-[/V-(3,5-difluorophenylacetyl)-L-aIaninyl]-2-amino-3-methoxypropionamide 10 Following General Procedure K and using 2-methoxyethylamine (Aldrich) and methyl /V-[^-(3f5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionate (from Example 24 above), the title compound was prepared as a solid (mp = 181-184°C). The reaction was monitored by tic (Rf = 0.43 in 10% MeOH/DCM) and the product was purified by acid/base washes. 15 NMR data was as follows: lH-nmr (CDC13): 5 = 6.728-6.706 (d, 2H); 6.648-6.586 (t, IH); 4.244-4213 (m, IH); 4.092-4.068 (m, IH); 3.553-3.503 (m, 2H); 3.393-3.347 (m, 2H); 3.210-3.073 (m+s, 7H); 3.053 (s, 3H); 1.183-1.138 (d, 3H). 13C-nmr (CDC13): 6 = 176.31; 173.28; 172.59; 141.65; 114.02; 113.79; 20 113.69; 109.467; 103.528; 80.369; 73.210; 72.265, 72.011; 59.839; 59.801; 59.374; 55.584; 51.773; 51.731; 51 445; 42.915; 40.846, 17.751. C|8H25F2N303 (MW = 401); mass spectroscopy (MH+) 402. Example 28 Synthesis of 25 A'-[A'-(3,5-Difluorophenylacetyl)- L-alaninyl]glycine Methyl Ester Following General Procedure A and using /V-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and glycine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp = 158-160°C). The Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 201 - reaction was monitored by tic (Rf = 0.61 in 10%MeC>H/DCM) and the product was purified fay silica gel chromatography. NMR data was as follows: 'H-nmr (CDC13): 5 = 6.882-6.866 (m, IH); 6.827-6.794 (m, 2H); 6.748-6.689 (t, IH); 6.520-6.494 (d, IH); 4.611-4.563 (quintex, IH); 4.00-3.99 (d, 2H); 3.746 (s, 3H); 3.528 (s, 2H); 1.389-1.366 (d, 3H). ,3C-nmr (CDClj): 5 = 172.926; 172.524; 170.524; 113.056; 112.951; 112.723; 103.769; 103.437; 103.214; 103.105; 85.309; 53.009; 49.333; 43.292; 41.692; 18.810. C,4H16F2N204 (MW = 314); mass spectroscopy (MH+) 315. Example 29 Synthesis of A?-(2-Methoxyethyl)-/V'-[N-(3,5-dcfluorophenylacetyl)-I^alaninyl]-2-amin o-3- (4-py r idyl) propionamide Following General Procedure K and using 2-methoxyethylamine and methyl Af-[7V-(3,5-difluorophenylacetyl)-L-alamnyl]-(S)-2-amino-3-(4-pyridyl)propionate (from Example 23 above), the title compound was prepared as a solid (mp = 202-206°C). The reaction was monitored by tic (Rf = 0.72 in 10%MeOH/DCM) and the product was purified by acid/base washes. NMR data was as follows: 'H-nmr (CDC13): 5 = 8.214-8.198 (d, 2H); 7.117-7.100 (d, 2H); 6.707-6.687 (m, 2H); 6.638-6.576 (t, IH); 4.498-4.448 (m, IH); 3.985-3.939 (q, IH); 3.386 (s, 2H); 3.190-3.084 (m, 4H); 3.060 (s, 3H); 2.918-2.629 (m, 2H); 1.077-0.905 (d, 3H). 13C-nmr (CDC13): B = 175.831; 173.229; 150.440; 150.249; 126.887; 113.995; 113.662; 103.662; 103.529; 72.081; 59.370; 55.201; 51.674; 42.949; 40.889; 38.350; 17.933. C22H26F2N404 (MW = 448); mass spectroscopy (MH+) 449. Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 202 -- Example 30 Synthesis of Ar-(2-Methoxyethyl)-iV'-[/V-(3,5-difluorophenyIacetyI)-L-aIaninyl]-2-amino-3-(2-pyridyl)propionamide 5 Following General Procedure K and using 2-methoxyethylamine and methyl N-|W-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propionate (from Example 19 above), the title compound was prepared as a solid (mp = 183-187°C). The reaction was monitored by tic (Rf = 0.39 m 10% MeOH/DCM) and the product was purified by recrystallization from 10 MeOH/DCM. NMR data was as follows: 'H-nmr (CDC13): 5 = 8.457-8.442 (d, IH); 8.029-8.005 (d, IH); 7.642-7.585 (t, IH); 7.395-7.379 (m, IH); 7.267-7.141 (d+t, 2H); 6.828-6.802 (m, 2H); 6.754-6.679 (t, IH); 6.604-6.581 (m, IH); 4.871-4.809 (q, IH); 4.532-15 4.485 (quintex, IH); 3.537 (s, 2H); 3.342-3.118 (m, 6H); 3.248 (s, 3H); 1.394-1.371 (d, 3H) ,3C-nmr (CDC13): 5 = 172.360; 171.140; 158.43; 149.113; 137.59; 124.98; 122.54; 113.02; 112.69; 103.40; 71.376; 59.203; 53.143; 49.984; 43.355; 43.328; 39.685; 39.626; 19.295. 20 C2iHMF2N404 (MW = 448); mass spectroscopy (MH+) 449. Example 31 Synthesis of Methyl /V-[/V-(3,5-Difluorophenylacety 1)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)propionate 25 Following General Procedure A and using N-(3,5-difluorophenylacetyl)- L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(thiazol-4-yl)propionate hydrochloride (General Procedure H with methanol and HCl on methyl (S)-2-amino-3-(thiazol-4-yl)propylacid (Synthetech)), the title compound was prepared as a solid (mp = 136-139°C). The reaction was monitored by tic 30 (Rf = 0.4 in 10% MeOH/DCM) and the product was purified by recrystallization from DCM. Printed from Mimosa WO 98/22494 - 203 - PCT/U S97/20804 NMR data was as follows: 'H-nmr (CDC13): 5 = 8.737-8.731 (d, IH); 7.410-7.385 (d, IH); 7.065-7.059 (d, IH); 6.828-6.802 (m, 2H); 6.747-6.687 (m, IH); 6.542-6.518 (d, IH); 4.904-4.844 (q, IH); 4.553-4.505 (quintex, IH); 3.678 (s, 3H); 3.515 (s, 2H); 3.402-3.232 (dq, 2H); 1.384-1.361 (d, 3H). l3C-nmr (CDClj): 5 = 172.497; 171.726; 169.619; 153.831; 152.613; 116.431; 113.019; 112.688; 112.014; 103.396; 53.113; 52.625; 49.476; 43.460; 43.435; 32.850; 19.422. C18H19F2N304S (MW = 411); mass spectroscopy (MH+) 412. Example 32 Synthesis of Methyl 2-[Ar-(3,5-DifluorophenyIacetyl)-L-alaninyl]-l,2,3,4-tetrahydroisoquinoline-3-carboxylate Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Aldrich), the title compound was prepared as a solid (mp = 37-40°C). The reaction was monitored by tic (Rf = 0.64 in 10% MeOH/DCM). NMR data was as follows: 'H-nmr (CDC13): 5 = 7.500-7.475 (d, IH); 7.161-7.057 (m, 4H); 6.315-6.795 (dm, 2H); 6.656-6.596 (t, IH); 5.336-5.088 (m, 2H); 4.924-4.841 (m, IH); 4.718-4.453 (m, IH); 3.530 (s, 3H); 3.500 (s, 2H); 3.329-3.058 (m, 2H); 1.423-1.400, 1.327-1.304 (d, 3H). 13C-nmr (CDC13): 5 = 173.428; 173.329; 171.690; 171.559; 169.558; 165.020; 161.899; 161.728; 139.368; 132.549; 128.912; 127.723; 126.648; 112.929; 103.360; 60.915; 53.318; 53.001; 46.377; 43.121; 31.027; 21.537; 19.545; 18.771; 14.716. C22H22F2N204 (MW = 416); mass spectroscopy (MH+) 417. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 204 - Example 33 Synthesis of iV-(3-Methoxybenzyl)-/V'-[/V-(3,5-difluorophenylacetyI)-L-alaninyl]-L-phenylalaninamide Following General Procedure B and using W-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared by coupling N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) with L-phenylalanine methyl ester hydrochloride (Sigma) using General Procedure E, followed by hydrolysis using General Procedure C) and 3-methoxybenzylamine (TCI), the title compound was prepared as a solid (mp = 117-130°C). The reaction was monitored by tic (Rf = 0.8 in 3% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH. NMR data was as follows: 'H-nmr (DMSO-<4): 8 = 8.4 (t, IH), 8.32 (d, IH), 8.1 (d, IH), 6.95-7.2 (m, 9H), 6.7 (ra, 3H), 4.5 (m, IH), 4.2 (m, 3H), 3.7 (s, 3H), 3.5 (s, 2H), 3.3 (d, 2H), 3.0 (m, 2H), 2.5 (s, 3H), 1.2 (m, 4H). 13C-nmr (DMSO-rf6): 5 = 172.40, 171.08, 169.28, 159.62, 141.09, 138.06, 129.62, 129.51, 128.41, 126.63, 119.56, 112.97, 112.79, 112.59, 112.46, 55.31, 48.77, 40.69, 40.42, 40.28, 40.14, 40.03, 39.86, 39.70, 39.58, 39.46, 39.44, 39.31, 39.20, 39.03, 18.45. C28H29N304F2 (MW = 509); mass spectroscopy (MH+) 509. Example 34 Synthesis of Methyl iV-[iV-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(l-naphthyl)propionate Following General Procedure B and using iV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(l-naphthyl)propionate hydrochloride (Bachem), the title compound was prepared as a solid (mp = 103-130°C). The reaction was monitored by tic (Rf = 0.8 in 5% MeOH/methylene chloride) and the product was purified by flash column chromatography using 6% MeOH/methylene chloride as the eluent. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 205 - NMR data was as follows: 'H-nmr (CDCI3): 5 = 8.10 (d, IH), 7.85 (d, IH), 7.71 (d, IH), 7.50 (m, 3H), 7.35 (t, IH), 7.20 (d, IH), 6.70 (m, 4H), 6.30 (d, IH), 4.90 (m, IH), 4.45 (m, IH), 3.3-3.7 (m, 8H), 1.7 (bs, IH), 1.3 (d 3H). 5 13C-nmr (CDC13): 8 = 172.43, 172.29, 169.77, 134.41, 132.61, 132.58, 129.51, 128.63, 128.33, 128.28, 128.06, 126.97, 126.80, 126.42, 126.29, 125.94, 125.86, 124.06, 123.90, 112.96, 112.63, 103.44, 78.03, 77.61, 77.19, 61.01, 54.02, 53.83, 52.99, 51.40, 49.33, 43.29, 35.64, 18.82, 14.77. C24H24N204F2 (MW = 442); mass spectroscopy (MH+) 442. 10 Example 35 Synthesis of Methyl N- [/V- (3,5-Difluorophenylacetyl)-L-aIaninyl]-(S)-2-amino-3-(2-naphthyl)propionate Following General Procedure B and using AT-(3,5-difluorophenylacetyl)-L-15 alanine (from Example B2 above) and methyl (S)-2-amino-3-(2- naphthyl)propionate hydrochloride (Bachem), the title compound was prepared as a solid (mp = 166°C). The reaction was monitored by tic (Rf = 0.55 in 5% MeOH/methylene chloride) and the product was punfied by preparative tic using 5% MeOH/methylene chloride as the eluent. 20 NMR data was as follows: 'H-nmr (CDC13): 5 = 1.3 (d, 3H), 3.2 (m, 2H), 3.3 (s, 2H), 3.7 (s, 3H), 4.55 (m, IH), 4.9 (quart, IH), 6.7 (m, 4H), 7.05 (d, IH), 7.20 (d, IH), 7.45 (m, 2H), 7.55 (s, IH), 7.80 (m, 3H). 13C-nmr (CDC13): 5 = 172.43, 172.26, 169.86, 133.93, 133.76, 133.02, 25 128.86, 128.64, 128.23, 128.20, 127.69, 126.85, 126.45, 112.95, 112.62, 103.37, 78.05, 77.62, 77.20, 53.93, 53.05, 49.37, 43.12, 38.46, 18.81. C24H24N204F2 (MW = 442); mass spectroscopy (MH+) 442. Printed from Mimosa WO 98/22494 - 206 - PCT/U S97/20804 Example 36 Synthesis of Methyl W-[Af-(3,5-DifluorophenyIacetyl)-L-alaninyI]-(S)-2-amino-3-(2-thienyl)propionate Following General Procedure B and using JV-(3,5-difl uoropheny lacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(2-thienyl)-propionate (Bachem), the title compound was prepared as a solid (mp = 145-147°C). The reaction was monitored by tic (Rf = 0.9 in 100% EtOAc) and the product was purified by preparative tic using EtOAc as the eluent. NMR data was as follows: lH-nmr (CDC13): 5 = 7.15 (d, IH), 6.9 (t, IH), 6.7-6.8 (m, 5H), 6.3 (d, IH), 4.8 (m, IH), 4.5 (m, IH), 3.8 (s, 3H), 3.5 (s, 2H), 3.35 (d, 2H), 1.35 (d, 3H). "C-nmr (CDC13): 8 = 172.22, 171.56, 169.79, 137.47, 127.71, 125.55, 113.04, 112.71, 103.48, 78.03, 77.60, 77.18, 53.78, 53.25, 49.51, 43.41, 32.37, 18.97. C,9H2oN204F2S (MW = 410); mass spectroscopy (MH+) 410. Example 37 Synthesis of /V-i7V-(3,5-Dinuorophenylacetyl)-I^aIaninyI]-L-phenylalanine Benzyl Ester Following General Procedure B and using N-(3,5-d i fl uoropheny lacetyl)-L-alanine (from Example B2 above) and L-phenylalanine benzyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp == 170-171 °C). The reaction was monitored by tic (Rf = 0.7 in 5% MeOH/methylene chloride) and the product was punfied by recrystallization from MeOH. NMR data was as follows: 'H-nmr (MeOH): 6 = 7.3 (m, 10H), 6.9 (m, 3H), 5.2 (s, 2H), 4.75 (t, J=7 Hz, IH), 4.4 (quart, J=6 Hz, IH), 3.6 (s, 2H), 3.1 (m, J= 6 Hz, 2H), 1.35 (d, J=7 Hz, 3H). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 207 - 13C-nmr (MeOH): 5 = 175.29, 173.09, 172.78, 141.54, 138.35, 137.53, 130.88, 130.08, 130.05, 129.92, 128.42, 113.93, 113.83, 113.60, 103.90, 103.55, 103.21, 68.59, 55.87. C27H26N2O4F2 (MW = 480); mass spectroscopy (MH+) 480. 5 Example 38 Synthesis of N-[iV-(3,5-Difluorophenylacetyl)-Lralaninyl]-L-phenylalanine 3-Bromopropyl Ester Following General Procedure B and using A/-[/V-(3,5-difluorophenylac:etyl)-10 L-alaninyl]-L-phenylalanine (prepared by coupling /V-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine (Aldrich) using General Procedure B) and 3-bromo-l-propanol (Aldrich), the title compound was prepared as a solid (mp = 138-142°C). The reaction was monitored by tic (Rf = 0.75 in 60% EtOAc/hexanes) and the product was purified by flash 15 column chromatography using 60% EtOAc/hexanes as the eluent. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.3-6.6 (m, 10H), 4.8 (m, IH), 4.55 (m, IH), 4.2 (t, J=6 Hz, 2H), 3.51 (s, 2H), 3.3 (m, 2H), 3.05 (m, J=6 and 8 Hz, 2H), 2.1 (m, 2H), 1.3-1.2 (m, J=7 Hz, 3H). 20 ,3C-nmr (CDC13): 5 = 172.49, 171.78, 171.71, 170.01, 169.96, 165.31, 162.02, 161.84, 138.91, 138.78, 138.66, 136.26, 136.19, 129.76, 129.72, 129.22, 129.18, 127.80, 113.04, 113.02, 112.93, 112.91, 112.82, 112.79, 112.71, 112.69, 103.72, 103.69, 103.36, 103.05, 103.03, 63.75 , 63.70, 54.11, 53.91, 49.38, 49.32, 43.26, 38.56, 38.51, 31.92, 29.76, 29.71, 19.14, 19.06. 25 C23H25N204F2Br (MW = 511.1); mass spectroscopy (MH+) 512. Example 39 Synthesis of /V-[/V-(3,5-Difluorophenylacetyl)-L-alaninyI] L-phenylalanine 3-Iodopropyl Ester Printed from Mimosa WO 98/22494 PCT/US97/20804 - 208 - Following General Procedure B and using /V-[/V-(3,5-difluorophenylacetyI)-L-alaninyl]-L-phenylalanine (prepared by coupling iV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylalanine (Aldrich) using General Procedure B) and 3-iodo-l-propanol (Aldrich) , the title compound was 5 prepared as a solid. The reaction was monitored by tic (Rf = 0.45 in 5% MeOH/methylene chloride) and the product was purified by preparative tic using 5% MeOH/methylene chloride. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.4-7.0 (m, 5H), 6.9-6.6 (m, 4H), 6.3 (m, IH), 4.8 10 (m, IH), 4.5 (m, IH), 4.2 (t, 2H), 3.5 (s, 2H), 3.1 (m, 4H), 2.1 (m, 2H), 1.7 (s, IH), 1.35-1.25 (m, 3H). 13C-nmr (CDClj): 5 = 172.24, 171.72, 169.95, 136.12, 136.09, 129.77, 129.75, 129.28, 129.24, 127.87, 113.06, 113.02, 112.73, 112.70, 103.80, 103.49, 103.47, 65.73, 65.70, 54.00, 53.84, 49.42, 49.33, 43.38, 38.54, 15 38.50,32.57,18.97,18.91. Example 40 Synthesis of N- [AM 3,5-Diflu orophen ylacetyl)-L-alaninyI]-L-Ieucine tert-Butyl Ester 20 Following General Procedure B and using iV-(3,5-difluorophenylacetyI)-L- alanine (from Example B2 above) and L-leucine /m-butyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp = 128°C). The reaction was monitored by tic (Rf = 0.85 in 5% MeOH/methylene chloride) and the product was purified by flash column chromatography using 5 % 25 MeOH/methylene chloride as the eluent. NMR data was as follows: 'H-nmr (CDClj): 5 = 6.9-6.5 (m, 5H), 4.6 (m, IH), 4.4 (m, IH), 3.5 (s, 2H), 1.7-1.4 (m, 15H), 0.9 (t, 6H). ,3C-nmr (CDClj): 5 = 172.41, 172.20, 169.87, 165.30, 162.00, 161.83, 30 139.01, 138.89, 112.92, 112.82, 112.69, 112.59, 103.62, 103.29, 102.95, Printed from Mimosa WO 98/22494 PCT/US97/20804 — 209 - 82.50, 78.03, 77.61, 77.18, 52.12, 49.39, 43.34, 41.86, 28.52, 25.42, 23.26, 22.46, 19.18. C27H30N2O4F2 (MW = 412.48); mass spectroscopy (MH+) 413. Example 41 5 Synthesis of Af'-[iV-(3,5-Difluorophenylacety])-L-alamnyI]-2-amino-2-(2-pyridyl) acetamide Following General Procedure L and using ethyl N-[N-(3,5~ difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetate (from Example 10 65 below), the title compound was prepared as a solid. The reaction was; monitored by tic (Rf = 0.1 in 9:1 CHCl3/MeOH) and the product was purified by recrystallizaion from EtOH. NMR data was as follows: 'H-nmr (DMSO-</6): 5 = 8.54 (m, IH), 8.43 (d, IH), 7.77 (m, IH), 7.59 15 (bs, IH), 7.46 (m, IH), 7.33 (m, IH), 7.22 (m, IH), 7.09 (m, IH), 6.98 (m, 2H), 5.41 (m, IH), 4.46 (m, IH), 4.46 (m, IH), 3.52 (s, 2H), 1.26 (m, 3H). C18HI7N303F2 (MW = 376.3); mass spectroscopy (MH+) 377. Example 42 Synthesis of 20 N'- [/V- (3,5-DifIu oropheny lacetyl)-L-alaninyI]- 2-amino-2- (3-pyridyl) acetamide Following General Procedure L and using ethyl iV-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetate (from Example 53 below), the title compound was prepared as a solid. The reaction was 25 monitored by tic (Rf = 0.1 in 9:1 CHCl3/MeOH) and the product was purified by recrystallization from EtOH. NMR data was as follows: 'H-nmr (DMSO-</«): 8 = 8.64 (m, IH), 8.55 (d, IH), 8.52 (d, IH), 8.41 (d, IH), 7.79 (m, IH), 7.37 (m, IH), 7.32 (m, IH), 7.09 (m, IH), 6.98 (m, 30 2H), 5.42 (m, IH), 4.42 (m, IH), 3.53 (s, 2H), 1.26 (m, 3H). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 210 -- Cl8Hl7N403F2 (MW = 376.3); mass spectroscopy (MH+) 377. Example 43 Synthesis of /V-[A/-(3,5-Difluorophenylacetyl)-L-aIaninyI]-5 /V,-(/ert-butoxycarbonyl)-L-Iysine Methyl Ester Following General Procedure A and using AT-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and JVe-(rm-butoxycarbonyl)-L-lysine methyl ester (Bachem), the tide compound was prepared as an oil. The reaction was monitored by tic (Rf = 0.40 in 50% EtOAc/hexanes) and the product was 10 purified by flash chromotography using 50% EtOAc/hexanes as the eluent. NMR data was as follows: 'H-nmr (CDC13): 5 = 6.80 (d, 2H), 6.66 (t, IH), 4.82 (bs, IH), 3.73 (s, 3H), 3.52 (s, 2H), 3.04 (bs, 2H), 1.60-1.15 (m, 2H), 1.38 (s, 9H), 1.32 (d, 2H), 1.20-1.30 (m, 2H). 15 "C-nmr (CDC13): 5 = 173.00, 172.80, 165.28, 165.11, 161.98, 161.78, 156.79, 138.95, 129.06, 128.72, 103.59, 103.26, 102.92, 79.81, 52.99, 52.76, 49 44, 43.25, 31.92, 29.98, 28.99, 22.95, 18.94. C23H33F2N306 (MW = 485.53); mass spectroscopy (MH+) N/A. Example 44 20 Synthesis of Methyl /V-[/V-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-4-phenylbutanoate Following General Procedure A and using iV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-4-phenylbutanoate 25 (prepared from (+)-a-amino-4-phenylbutyric acid (Bachem) using General Procedure AG), the title compound was prepared as a solid (mp = 147-149.5°C). The reaction was monitored by tic (Rf = 0.32 in 50% EtOAc/hexanes) and the product was purified by flash chromotography using EtOAc/hexanes as the eluent. 30 NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 - 211 -- 'H-nmr (CDC13): 5 = 7.63 (bd, 2H), 7.04 (m, 5H), 6.56-6.82 (m, 3H), 4.80 (p, IH), 4.48 (q, IH), 3.65 (s, 3H), 3.49 (s, 2H), 2.50-2.65 (m, 2H), 1.80-2.16 (m, 2H), 1.29 (d, 3H). 13C-nmr (CDClj): 5 = 173.48, 172.89, 170.43, 165.17, 161.71, 140.91, 5 139.34, 129.07, 129.01, 128.89, 126.81, 126.76, 112.90, 112.67, 103.37, 103.03, 102.69, 52.86, 52.71, 49.36, 42.99, 33.79, 32.21, 19.34. C22H24F2N2O4 (MW = 418.44); mass spectroscopy (MH+) 419. Example 45 Synthesis of 10 N-[N- (3,5-Difluoropheny lacetyl)- L-alaninyl] glycine 2-Phenylethyl Ester Following General Procedure X and using /V-[AT-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared from 7V-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester (from Example 73 below) using General Procedure 15 O) and 2-phenylethanol (Aldrich), the title compound was prepared as a solid (mp = 154.0-155.2°C). The reaction was monitored by tic (Rf = 0.15 in 15% EtOAc/hexanes) and the product was purified by flash chromotography using 15% EtOAc/hexanes as the eluent. NMR data was as follows: 20 'H-nmr (CDC13): 8 = 7.35-7.20 (m, 5H), 6.76 (bs, IH), 6.72-6.67 (m, 3H), 6.54 (bd, IH), 4.58 (p, IH), 4.34 (t, 2H), 3.96 (d, 2H), 3.52 (s, 2H), 2.93 (t, 2H), 1.26 (d, 3H). 13C-nmr (CDC13): 5 = 172.9, 170.1, 169.9, 137.8, 129.4, 129.1, 127.3, 112.94, 103.4, 103.0, 65.5, 49.3, 43.2, 41.8, 35.4, 18.8. 25 C21H22N204F2 (MW = 404.42); mass spectroscopy (MH+) 405. Example 46 Synthesis of Air-[Af-(3,5-Difluorophenylacetyl)-L-aIaninyl]glycine 3-Phenylpropyl Ester Printed from Mimosa WO 98/22494 PCT/US97/20804 - 212 - Following General Procedure X and using iV-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared from iV-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester (from Example 73 below) using General Procedure O) and and 3-phenyl-l-propanol (Aldrich), the title compound was prepared as 5 a solid (mp = 137°C). The reaction was monitored by tic (Rf = 0.15 in 50% EtOAc/hexanes) and the product was purified by flash chromotography using 50% EtOAc/hexanes as the eluent. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.55-7.32 (m, 5H), 6.73 (d, 2H), 6.65 (m, IH), 10 4.74 (p, IH), 4.14 (t, 2H), 3.93 (m, 2H), 3.49 (s, 2H), 2.66 (t, 2H), 1.94 (p, 2H), 1.41 (d, 3H). 13C-nmr (CDClj): 5 = 173.8, 170.5, 170.1, 165.2, 165.0, 161.9, 161.7, 141.5, 139.2, 129.1, 128.9, 126.7, 112.9, 112.8, 103.4, 103.1, 102.8, 65.4, 49.3, 42.9, 41.8, 32.6, 30.6, 19.3. 15 C22H24N204F2 (MW = 418.44); mass spectroscopy (MH+) 419. Example 47 Synthesis of W-[/V-(3,5-Difluorophenylacetyl)-L-alaninyI]-2-amino-2-(4-pyridyl)acetamide 20 Following General Procedure L and using ethyl N-[N-(3,5- difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetate(from Example 66), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.1 in CHCl3/MeOH 9:1) and the product was purified by silica gel chromatography using 9:1 CHCl3/MeOH as the eluent. 25 NMR data was as follows: 'H-nmr (DMSO-6f6): 5 = 8.53 (m, 2H), 8.88 (bs, IH), 7.41 (m, 2H), 7.12 (m, IH), 7.02 (m, 2H), 5.46 (m, IH), 4.46 (m, IH), 3.55 and 3.52 (s, 2H), 1.21 (m, 3H). C18Hi8N403F2 (MW = 376.3); mass spectroscopy (MH+) 377. Printed from Mimosa WO 98/22494 PCT/US97/20804 213 - Example 48 Synthesis of iV-[/V-(PhenylacetyI)-L-alaninyl]-L-threonine Methyl Ester Following General Procedure U and using iV-(phenylacetyl)-L-alanine (from 5 Example B1 above) and L-threonine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.45 (d, J=8.9 Hz, IH), 7.11-7.27 (m, 6H), 4.55 (quintet, J=7.2 Hz, IH), 4.43 (dd, J=2.6,8.8 Hz, IH), 4.20 (m, IH), 3.62 (s, 10 3H), 3.46 (s, 2H), 1.29 (d, J=7.0 Hz, 3H), 1.04 (d, J=6 4 Hz, 3H). 13C-nmr (CDClj): 5 = 172.8, 171.1, 170.9, 134.5, 128.9, 128.4, 126.8, 67.5, 57.7, 52.1, 48.7, 42.8, 19.6, 18.3. C16H22N205 (MW = 322.36); mass spectroscopy (MH+) 323. Example 49 15 Synthesis of /V'-[/V-(Phenylacetyl)-L-alaninyl]-L-Ieucinamide Following General Procedure T and using /V-(phenylacetyl)-L-alanine (from Example B1 above) and L-leucinamide hydrochloride (Aldrich), the title compound was prepared as a solid (mp = 207-209°C). The product was 20 purified by extraction with EtOAc and washing with aqueous potassium carbonate and aqueous hydrochloric acid. NMR data was as follows: 'H-nmr (CD3OD): 5 = 7.00-7.12 (m, 5H), 4.10-4.20 (m, 2H), 3.34 (s, 2H), 1.30-1.50 (m, 2H), 1.12-1.23 (m, 4H), 0.65-0.76 (m, 6H). 25 ,3C-nmr (CD3OD): 5 = 177.5, 174.9, 174.1, 136.8, 130.1, 129.6, 127.9, 52.8, 50.7, 43.4, 41.9, 25.8, 23.5, 21.8, 17.7. Example 50 Synthesis of N -[A/-(PhenyIacetyl)-L-aIaninyl]-L-alaninamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 214 - Following General Procedure U and using iV-(phenylacetyl)-L-alanine (from Example B1 above) and L-alaninamide hydrochloride (Bachem), the title compound was prepared as a solid (mp = >260°C). The product was purified by washing with aqueous sodium hydroxide and aqueous hydrochloric acid. 5 NMR data was as follows: 'H-nmr (DMSO-Js): 3 = 8.27 (d, J=7.1 Hz, IH), 7.88 (d, J=7.6 Hz, IH), 7.26 (m, 6H), 6.99 (s, IH), 4.25 (quintet, J=7.1 Hz, IH), 4.16 (quintet, J=7.1 Hz, IH), 3.46 (s, 2H), 1.19 (t, J=6.3 Hz, 6H). 13C-nmr (DMSO-t/6): 8 = 174.1, 171.8, 170.0, 136.3, 129.0, 128.1, 10 126.3, 48.3, 47.9, 42.0, 18.3, 18.1. Example 51 Synthesis of W-|W-(Phenylacetyl)-L-alaninyI]-L-phenylaIaninainide Following General Procedure T and using ^-(phenylacetyl)-L-alanine (from 15 Example B1 above) and L-phenylalaninamide (Bachem), the title compound was prepared as a solid (mp = 224-225 °C). NMR data was as follows: 'H-nmr (DMSO-tf6): 8 = 8.24 (d, J=7.2 Hz, IH), 7.89 (d, J=8.2 Hz, IH), 7.36 (s, IH), 7.13-7.34 (m, 10H), 7.11 (s, IH), 4.40 (m, IH), 4.21 20 (quintet, J=7.1 Hz, IH), 3.44 (d, 2H), 3.01 (dd, J=4.9, 13.7 Hz, IH), 2.82 (dd, J=9.0, 13.7 Hz, IH), 1.13 (d, J=6.9 Hz, 3H) '3C-nmr (DMSO-rf5): 8 = 172.7, 172.0, 170.0, 137.8, 136.3, 129.2, 129.0, 128.2, 128.0, 126.3, 126.2, 53.6, 48.5, 41.9, 37.3, 18.0. Example 52 25 Synthesis of ^'-[^-(PhenylacetyO-L-alaninyD-L-valinamide Following General Procedure T and using JV-(phenylacetyl)-L-alanine (from Example B1 above) and L-valinamide hydrochloride (Bachem), the title compound was prepared as a solid (mp = >261 °C). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 215 - NMR data was as follows: 'H-nmr (DMSO-d6): 5 = 8.31 (d, 1=1.5 Hz, IH), 7.62 (d, J=9.0 Hz, IH), 7.38 (s, IH), 7.15-7.30 (m, 5H), 7.05 (s, IH), 4.34 (quintet, 1=1.2 Hz, IH), 4.08 (dd, J=6.4, 15.3 Hz, IH), 3.45 (s, 2H), 1.91 (m, IH), 1.19 (d, 5 J=7.0 Hz, 3H), 0.79 (d, J=6.7 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H). 13C-nmr (DMSO-d6): 5 = 172.8, 172.1, 170.0, 136.3, 129.0, 128.2, 126.3, 57.2, 48.2, 42.0, 30.5, 19.2, 17.9, 17.8. Example 53 Synthesis of 10 Ethyl iV-[/V-(3,5-Difluorophenylacetyl)- L-alaninyl]-2-amino-2-(3-pyridyl)acetate Following General Procedure C and using jV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(3-pyridyl)acetate (prepared as described in P. Kolar et al., J. Heterocyclic Chem., 28, 1715 15 (1991) and references cited therein), the title compound was prepared as a solid (mp = 146-157°C). The reaction was monitored by tic (Rf = 0.1 in CHCl3/MeOH 98:2) and the product was punfied by silica gel chromatography using 959:5 CHCl3/MeOH as the eluent, followed by recrystallization from chlorobutane. 20 NMR data was as follows: 'H-nmr (CDC13): 5 = 8.60 (m, IH), 8.56 and 8.52 (m, IH), 7.91 (m, IH), 7.63 (m, IH), 7.22 (m, IH), 6.90 (m, IH), 6.74 (m, 2H), 5.55 (m, IH), 4.69 (m, IH), 4.17 (m, 2H), 3.50 and 3.41 (s, 2H), 1.33 and 1.29 (d, 3H), 1.21 (m, 3H), 1.18 (m, 3H). 25 C20H21N3O4F2 (MW = 405.4); mass spectroscopy (MH+) 405. Example 54 Synthesis of /V-Methyl-yV'-[/V-(phenylacetyl)-L-alaninyl]-L-leucinamide Following General Procedure U and using N-(phenyIacetyl)-L-alanine (from 30 Example B1 above) and iV-methyl-L-leucinamide (prepared from N-methyl-W- Printed from Mimosa WO 98/22494 PCT/US97/20804 ~ 216 — BOC-L-leucinamide (from Example D5 above) using General Procedure Y), the title compound was prepared as a solid (mp = 233-235 °C). The product was purified by recrystallization from MeOH. NMR data was as follows: 5 'H-nmr (CDC]3/CD3OD): 5 = 7.25-7.40 (m, 5H), 4.36 (quartet, J=7.2 Hz, IH), 4.27 (dd, J=5.1, 14.6 Hz, IH), 3.56 (s, 2H), 2.72 (s, 3H), 1.40-1.61 (m, 2H), 1.32 (d, J=7.1 Hz, 3H), 0.89 (d, J=6.2 Hz, 3H), 0.86 (d, J=6.2 Hz, 3H). Example 55 10 Synthesis of /V,/V-Dimethyl-iV'-[iV-(phenyIacetyl)-L-alaninyl]-L-phenylalaninamide Following General Procedure U arid using N-(phenylacetyl)-L-alanine (from Example B1 above) and iV,N-dimethyl-L-phenylalaninamide (prepared by 15 coupling N-BOC-L-phenylalanine (Bachem) with dimethylamine hydrochloride (Aldrich) using General Procedure B, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp = 152-155 °C). The product was purified by extraction with EtOAc, washing with aqueous sodium carbonate and aqueous hydrochloric acid, and trituration with 20 EtiO. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.49 (d, J=8.2 Hz, IH), 7.20-7.26 (m, 8H), 7.14 (m, 2H), 6.45 (d, J=7.5 Hz, IH), 5.08 (quartet, J=8.0 Hz, IH), 4.60 (quintet, J=7.3 Hz, IH), 3.56 (s, 2H), 2.95 (m, 2H), 2.86 (s, 3H), 2.61 (s, 25 3H), 1.26 (d, J=6.9 Hz, 3H). ,3C-nmr (CDC13): 5 = 171.6, 170.8, 170.4, 136.0, 134.7, 129.3, 129.2, 128.9, 128.8, 128.3, 127.1, 50.2, 48.7, 43.4, 39.5, 36.8, 35.6, 18.8. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 217 -- Example 56 Synthesis of A/,iV-Dimethyl-W-[AMphenylacetyl)-L-alaninyl]-L-leucinamide 5 Following General Procedure U and using //-(phenylacetyl)-L-alanine (from Example B1 above) and A^iV-dimethyl-L-leucinamide (prepared by coupling N-BOC-L-leucine (Bachem) with dimethylamine hydrochloride (Aldrich) using General Procedure B, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp = 130-132°C). 10 The product was purified by extraction by EtOAc, washing with aqueous sodium carbonate and aqueous hydrochloric acid, and tnturation with EtzO. NMR data was as follows: lH-nmr (CDC13): 5 = 7.23-7.36 (m, 5H), 7.04 (d, J=8.7 Hz, IH), 6.30 (d, J=7.6 Hz, IH), 4.92 (m, IH), 4.56 (quintet, J=7.2 Hz, IH), 3.56 (s, 2H), 15 3.07 (s, 3H), 2.94 (s, 3H), 1.33-1.64 (m, 3H), 1.27 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 0.88 (d, J=6.5 Hz, 3H). 13C-nmr (CDC13): 5 = 172.0, 171.7, 170.4, 134.6, 129.2, 128.8, 127.2, 48.7, 47.3, 43.5, 42.1, 36.9, 35.8, 24.6, 23.3, 21.8, 18.6. Example 57 20 Synthesis of Ar,Ar-Dimethyl-A^'-[A?-(phenylacetyl)-L-alaninyI]-L-valinamide Following General Procedure U and using /V-(phenylacetyl)-L-alanine (from Example B1 above) and /V,/V-dimethyl-L-valinamide (prepared by coupling N-BOC-L-valine (Bachem) with dimethylamine hydrochloride (Aldrich) using 25 General Procedure B, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp = 147-149°C). The product was purified by extraction by EtOAc, washing with aqueous sodium carbonate and aqueous hydrochloric acid, and trituration with EtjO. NMR data was as follows: 30 'H-nmr (CDC13): 8 = 7.24-7.38 (m, 5H), 6.64 (d, IH), 6.05 (d, IH), 4.74 (dd, J=5.9, 8.9 Hz, IH), 4.50 (quintet, J=7.1 Hz, IH), 3.59 (s, 2H), 3.08 (s, Printed from Mimosa WO 98/22494 PCT/US97/20804 - 218 -- 3H), 2.96 (s, 3H), 1.97 (m, IH), 1.28 (d, 1=1.0 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H), 0.84 (d, J=6.8 Hz, 3H). 13C-nmr (CDC13): 5 = 172.3, 171.4, 170.4, 134.6, 129.0, 128.5, 126.8, 53.5, 48.5, 43.2, 37.3, 35.6, 31.2, 19.2, 18.6, 17.5. 5 QgH^NjOj (MW = 333.43); mass spectroscopy (MH+) 334. Example 58 Synthesis of iV-Methyl-iV'-[7V-(phenylacetyl)-Lralaninyl]-L-phenylaIaninamide Following General Procedure U and using N-(phenylacetyl)-L-alanine (from 10 Example B1 above) and N-methyl-L-phenylalaninamide (prepared by coupling N-BOC-L-phenylalanine (Bachem) with methylamine hydrochloride (Aldrich) using General Procedure B, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid. The product was purified by washing with aqueous sodium carbonate and aqueous 15 hydrochloric acid. NMR data was as follows: 'H-nmr (DMSO-</6): 5 = 8.23 (d, J=7.0 Hz, IH), 7.95 (d, J=8.2 Hz, IH), 7.79 (d, J=4.4 Hz, IH), 7.10-7.32 (m, 10H), 4.37 (quintet, J=5.4 Hz, IH), 4.19 (quintet, J=7.1 Hz, IH), 3.44 (s, 2H), 2.96 (dd, J=5.5, 13.7 Hz, 20 IH), 2.78 (dd, J=9.2, 13.7 Hz, IH), 2.52 (d, J=4.4 Hz, 3H), 1.11 (d, J=7.0 Hz, 3H). I3C-nmr (DMSO-rf6): 6 = 172.0, 171.0, 170.1, 137.8, 136.3, 129.11, 129.07, 128.2, 128.1, 126.31, 126.26, 53.9, 48.5, 41.9, 37.5, 25.5, 18.0. Example 59 25 Synthesis of Ar-Methyl-A''-[A'-(phenylacetyl)-L-alaninyl]-L-valinamide Following General Procedure U and using 2V-(phenylacetyl)-L-aIanine (from Example B1 above) and N-methyl-L-valinamide (prepared by coupling N-BOC-L-valine (Bachem) with methylamine hydrochloride (Aldrich) using General Printed from Mimosa WO 98/22494 - 219 - PCT/US97/20804 Procedure B, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid. The product was purified by washing with aqueous sodium carbonate and aqueous hydrochloric acid. NMR data was as follows: 5 'H-nmr (DMSO-^: 5 = 8.30 (d, J=7.6 Hz, IH), 7.88 (d, J=4.7 Hz, IH), 7.69 (d, J=9.1 Hz, IH), 7.17-7.32 (m, 5H), 4.34 (quintet, J=7.2 Hz, IH), 4.04 (dd, J=7.0, 8.9 Hz, IH), 3.45 (s, 2H), 2.56 (d, J=4.6 Hz, 3H), 1.87 (m, IH), 1.18 (d, J=7.0 Hz, 3H), 0.76 (d, J=6.6 Hz, 3H), 0.75 (d, 1=6.1 Hz, 3H). 10 ,3C-nmr (DMSO-d5): 5 = 172.0, 171.1, 170.0, 136.3, 129.0, 128.1, 126.3, 57.6, 48.2 , 42.0, 30.6, 25.4, 19.2, 18.1, 17.9. Example 60 Synthesis of 2V-MethyI-W-[/V-(3,5-difluorophenylacetyl)-15 L-alaninyl]-(S)-2-aminohexanamide Following General Procedure U and using AH3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and N-methyl-L-norleucinamide (prepared by coupling Af-BOC-L-norleucine (Bachem) with methylamine hydrochloride (Aldrich) using General Procedure B, followed by removal of the BOC-group 20 using General Procedure Y), the title compound was prepared as a solid. The product was purified by washing with aqueous sodium carbonate and aqueous hydrochloric acid. NMR data was as follows: 'H-nmr (DMSO-</6): 5 = 8.37 (d, 7.1, IH), 7.88 (d, 8.1, IH), 7.78 (d, 25 4.4, IH), 7.08 (t, 9.5, IH), 6.98 (d, 6.90, 2H), 4.27 (quintet, 7.0, IH), 4.13 (quartet, 5.5, IH), 3.51 (s, 2H), 2.54 (d, 4.4, 3H), 1.58 (m, IH), 1.46 (m, IH), 1.19 (m, 7H), 0.81 (t, 6.5, 3H). 13C-nmr (DMSO-</6): 5 = 172.0, 171.9, 169.0, 162.2(dd, J=13.6, 244.0 Hz), 140.7, 112.2(dd, J=8.3, 17.0 Hz), 101.9(t, J=25.5 Hz), 52.4, 48.4, 30 41.3, 31.8, 27.4, 25.5, 21.8, 17.9, 13.8. Ci8H25N303F2 (MW = 369.42); mass spectroscopy (MH+) 384. Prxnted from Mimosa WO 98/22494 PCT/US97/20804 — 220 - Example 61 Synthesis of iV,iV-DimethyI-iV'-[iV-(3,5-clifluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide 5 Following General Procedure U and usmg W-(3,5-difluorophenylacetyl)-L- alanine (from Example B2 above) and N.N-dimethyl-L-norleucinamide (prepared by coupling iV-BOC-L-norleucine (Bachem) with dimethylamine hydrochloride (Aldrich) using General Procedure B, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a 10 solid (mp = 138-140°C). The product was purified by extraction with EtOAc and washing with aqueous sodium carbonate and aqueous hydrochloric acid. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.11 (d, 8.1, IH), 6.81 (m, 2H), 6.71 (m, IH), 6.60 (d, 7.6, IH), 4.80 (q, J=5.0, IH), 4.57 (quint, J=7.1, IH), 3.53 (s, 2H), 3.08 15 (s, 3H), 2.97 (s, 3H), 1.70 (m, IH), 1.55 (m, IH), 1.20-1.38 (m, 7H), 0.85 (t, 6.9, 3H). 13C-nmr (CDC13): 8 = 171.6, 171.5, 168.9, 163.0 (dd, J=12.9, 247.3 Hz), 138.4, 112.2 (dd, J=7.8, 17.0 Hz), 102.7 (t, J=25.0 Hz), 49.1, 48.9, 42.9, 37.1, 35.8, 32.6, 27.1, 22.4, 19.1, 13.8. 20 C19H27N303F2 (MW = 383.44); mass spectroscopy (MH+) 384. Example 62 Synthesis of W-[/V-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide 25 Following General Procedure U and using N-(3,5-difluorophenylacetyl)-L- alanine (from Example B2 above) and L-norleucinamide (prepared from N-BOC-L-norleucinamide (from Example D6 above) using General Procedure Y), the title compound was prepared as a solid (mp = >215°C). The product was purified by precipitation from water. 30 NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/U S97/20804 — 221 - 'H-nmr (DMSO-d6): 6 = 8.37 (d, 7.4, IH), 7.83 (d, 8.0, IH), 7.29 (s, IH), 6.95-7.14 (m, 4H), 4.29 (quintet, J=7.2, IH), 4.14 (quartet, J=5.0, IH), 3.52 (s, 2H), 1.61 (m, IH), 1.46 (m, IH), 1.21 (m, 7H), 0.82 (m, 3H). 13C-nmr (DMSO-JJ: 5 = 173.6, 171.9, 168.9, 162.0 (dd), 140.7, 112.2 5 (dd, J=7.5, 16.6 Hz), 101.9 (t), 52.2, 48.3, 41.3, 31.8, 27.4, 21.8, 18.0, 13.8. C17H23N303F2 (MW = 355.39); mass spectroscopy (MH+) 356. Example 63 Synthesis of 10 Methyl N-[N-(3,5-Difluorophenylacetyl)- L-alaninyl]-2-amino-2-(3-methoxyphenyl)acetate Following General Procedure C and using Af-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(3-methoxyphenyl)acetate hydrochlonde (prepared by the Bucherer Modification of 15 the Strecker procedure as described in J. P. Greenstein et al., "The Chemistry of Amino Acids", Vol. 1, p. 698, Wiley, New York (1961)), the title compound was prepared as a solid (mp = 163-170°C). The reaction was monitored by tic (Rf = 0.45 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent. 20 NMR data was as follows: 'H-nmr (CDC13): 5 = 7.27 (m, IH), 7.18 and 7.06 (m, IH), 6.87-6.67 (m, 6H), 6.25 (m, IH), 5.46 (m, IH), 4.58 (m, IH), 3.82 (s, 3H), 3.71 and 3.69 (s, 3H), 3.53 and 3.48 (s, 3H), 1.39 and 1.30 (d, 3H). C2]H22NAF2 (MW = 420.42); mass spectroscopy (MH+) 421. 25 Example 64 Synthesis of Methyl N-[iV-(3,5-Dinuorophenylacetyl)-L-aIaninyl]-2-amino-2-(4-methoxyphenyl)acetate Printed from Mimosa WO 98/22494 PCT/US97/20804 - 222 - Following General Procedure C and using JV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(4-methoxyphenyl)acetate hydrochloride (prepared by the Bucherer Modification of the Strecker procedure as described in J. P. Greenstein et al., "The Chemistry 5 of Amino Acids", Vol. 1, p. 698, Wiley, New York (1961)), the title compound was prepared as a solid (mp = 170-174°C). The reaction was monitored by tic (Rf = 0.1 in 98:2 CHCl3/MeOH) and the product was purified by silica gel chromatography using 98:2 CHCl3/MeOH as the eluent. NMR data was as follows: 10 'H-nmr (CDC13): 5 = 7.26 (m, 2H), 7.01-6.68 (m, 5H), 6.14 (m, IH), 5.41 (m, IH), 4.56 (m, IH), 3.80 (s, 3H), 3.74 and 3.71 (s, 3H), 3.54 and 3.47 (s, 3H), 1.39 and 1.29 (d, 3H). C21H22N205F2 (MW = 420.42); mass spectroscopy (MH+) 421. Example 65 15 Synthesis of Ethyl N-[Af-(3,5-Difluorophenylacetyl)-L-alaninyI]-2-amino-2-(2-pyridyl)acetate Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(2-pyndyl)acetate 20 hydrochloride (prepared as descnbed in P. Kolar et al., J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein), the title compound was prepared as a solid (mp = 123-125°C). The reaction was monitored by tic (Rf = 0.1 in 98:2 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent, followed by recrystallization from 25 chlorobutane. NMR data was as follows: 'H-nmr (CDC13): 5 = 8.53 (m, IH), 7.70 (m, 2H), 7.48 (m, IH), 7.27 (m, IH), 6.86 (m, 2H), 6.74 (m, IH), 6.52 (m, IH), 5.58 (m, IH), 4.67 (m, IH), 4.18 (m, 2H), 3.54 and 3.50 (s, 2H), 1.48 and 1.39 (d, 3H), 1.21 (m, 30 3H). C2oH21N304F2 (MW = 405.4); mass spectroscopy (MH+) 405. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 223 - Example 66 Synthesis of Ethyl N-[N-(3,5-Difluoropheny lacety I)-L-alaninyl]-2-amino-2-(4-pyridyl)acetate 5 Following General Procedure C and using 7V-(3,5-difluorophenylacetyl)-L- alanine (from Example B2 above) and ethyl 2-amino-2-(4-pyridyl)acetate hydrochloride (prepared as described in P. Kolar et al., J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein), the title compound was prepared as a solid (mp = 175-181 °C). The reaction was monitored by tic (Rf = 0.1 in 10 98:2 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent, followed by recrystallization from chlorobutane. NMR data was as follows: 'H-nmr (CDC13): 8 = 8.59 (m, 2H), 7.39 (m, IH), 7.26 (m, 2H), 6.80 15 (m, 3H), 6.21 (m, IH), 5.51 (m, IH), 4.62 (m, IH), 4.21 (m, 2H), 3.57 and 3.51 (s, 2H), 1.38 (m, 3H), 1.23 (m, 3H). C20H21N3O4F2 (MW = 405.4); mass spectroscopy (MH+) 405. Example 67 Synthesis of 20 iV-[/V-(Cyc!ohexylacetyl)-I^alaninyl]- L-phenylalanine Methyl Ester Following General Procedure U and using cyclohexylacetic acid (Aldrich) and JV-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) 25 using General Procedure U, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp = 156-158°C). The reaction was monitored by tic (Rf = 0.25 in 1:1 EtOAc/hexanes). NMR data was as follows: 30 'H-nmr (CDC13): 5 = 0.95 (m, 2H), 1.10-1.38 (m, 3H), 1.33 (d, J=7.0 Hz, 3H), 1.60-1.86 (m, 6H), 2.02 (d, J=7.5 Hz, 2H), 3.10 (m, 2H), 3.71 (s, Printed from Mimosa WO 98/22494 PCT/US97/20804 — 224 - 3H), 4.49 (m, IH), 4.81 (m, IH), 6.10 (d, J=7.3 Hz, IH), 6.65 (d, J=7.7 Hz, IH), 7.11 (m, 2H), 7.26 (m, 3H). 13C-nmr (CDC13): 6 = 18.4, 26.0, 26.1, 33.0, 33.1, 35.3, 37.8, 44.5, 48.5, 52.4, 53.3, 127.1, 128.6, 129.2, 135.6, 171.6, 172.0, 172.2. 5 C21H30N2O4 (MW = 374.48); mass spectroscopy (MH+) 375. Example 68 Synthesis of iV-[iV-(Cyclopentylacetyl)-L-alaninyl]-L-phenylalanine Methyl Ester 10 Following General Procedure U and using cyclopentylacetic acid (Aldrich) and JV-(L-aIaninyl)-L-phenyIalamne methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) using General Procedure U, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp = 137-15 139°C). The reaction was monitored by tic (Rf = 0.23 in 1:1 EtOAc/hexanes). NMR data was as follows: 'H-nmr (CDC13): 6 = 1.13 (m, 2H), 1.33 (d, J=7.0 Hz, 3H), 1.58 (m, 4H), 1.80 (m, 2H), 2.17 (m, 3H), 3.10 (m, 2H), 3.71 (s, 3H), 4.50 (m, IH), 20 4.83 (m, IH), 6.12 (d, J=7.4 Hz, IH), 6.69 (d, J=7.7 Hz, IH), 7.2 (m, 2H), 7.25 (m, 3H). ,3C-nmr (CDC13): 5 = 18.3, 24.9, 32.4, 32.5, 37.0, 37.7, 42.7, 48.4, 52.3, 53.3, 127.1, 128.5, 129.2, 135.7, 171.6, 172.0, 172.6. C20H2gNA (MW = 360.46); mass spectroscopy (MH+) 361. 25 Example 69 Synthesis of #-[N-(Cyclohex-l-enylacetyI)-L-alaninyl]-L-phenylalanine Methyl Ester Following General Procedure U and using cyclohex-l-enylacetic acid (Alfa) 30 and JV-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC- Printed from Mimosa WO 98/22494 PCT/US97/20804 — 225 - L-alanine (Bachem) with L-phenylalamne methyl ester hydrochloride (Bachem) using General Procedure U, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp = 139-142°C). The reaction was monitored by tic (Rf = 0.27 in 1:1 5 EtOAc/hexanes). NMR data was as follows: 'H-nmr (CDC13): 5 = 1.31 (d, J=7.0 Hz, 3H), 1.58 (m, 4H), 1.89 (m, 2H), 2.04 (br s, 2H), 2.83 (s, 2H), 3.00-3.20 (m, 2H), 3.71 (s, 3H), 4.47 (m, IH), 4.81 (m, IH), 5.60 (s, IH), 6.26 (d, J=7.3 Hz, IH), 6.67 (d, J=7.7 Hz, 10 IH), 7.11 (m, 2H), 7.26 (m, 3H). 13C-nmr (CDClj): 8 = 18.1, 21.9, 22.7, 25.3, 28.3, 37.7, 46.0, 48.4, 52.3, 53.3, 127.1, 127.2, 128.5, 129.1, 132.2, 135.7, 171.0, 171.6, 171.8. CjiH^NjOj (MW = 372.47); mass spectroscopy (MH+) 373. Example 70 15 Synthesis of Methyl /V-[iV-(3,5-DifIuorophenylacetyl)-L-alaninyl]-l-aminocyclopropane-l-carboxylate Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alamne (from Example B2 above) and methyl 1-aminocyclopropane-1-20 carboxylate hydrochloride (Sigma), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.3 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent. NMR data was as follows: 25 'H-nmr (CDC13): 8 = 6.96 (bs, IH), 6.82 (m, 2H), 6.69 (m, IH), 6.48 (d, IH), 4.50 (m, IH), 3.67 (s, 3H), 3.54 (s, 2H), 1.58 (m, 2H), 1.40 (d, 2H), 1.12 (m, 2H). Optical Rotation: [a]23 = -18° (c 1, MeOH). Printed from Mimosa WO 98/22494 PCT/US97/20804 — 226 - Example 71 Synthesis of A^2-(Af,N4)imethylamino)ethyl-iV-methyl-2V-[N-(3,5-difIuorophenylacetyl)-L-alaninyI]-L-alaninamide 5 Following General Procedure C and using A4AH3,5-difluorophenylacetyl)- L-alaninyl]-L-alanine (from Example D7 above) and iV.N.iV'-trimethylethylene-diamine (Aldrich), the title compound was prepared as a solid. NMR data was as follows: 'H-nmr (DMSO-d6): 8 = 8.37 (m, 2H), 8.19 (d, IH), 8.08 (d, 2H), 7.10 10 (m, IH), 6.99 (m, 2H), 4.67 (m, IH), 4.30 (m, IH), 3.52 (s, 2H), 3.01 and 2.86 (s, 3H), 2.47 (t, IH), 2.31 (t, IH), 2.15 (s, 6H), 1.19 (m, 6H). Optical Rotation: [o:]23 = -85° (c 1, MeOH). C19H2gN403F2 (MW = 398.45); mass spectroscopy (MH+) 398. Example 72 15 Synthesis of /V-[/V-(Cyclopropylacetyl)-L-alaninyI]-L-phenylalanine Methyl Ester Following General Procedure U and using cyclopropylacetic acid (Lancaster) and jV-(L-alamnyl)-L-phenylalanine methyl ester (prepared by 20 coupling 7V-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) using General Procedure U, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp = 128-131°C). The reaction was monitored by tic (Rf = 0.14 in 1:1 EtOAc/hexanes). 25 NMR data was as follows: lH-nmr (CDC13): 8 = 0.17 (m, 2H), 0.59 (m, 2H), 0.92 (m, IH), 1.35 (d, J=7.0 Hz, 3H), 2.11 (m, 2H), 3.05 (dd, J=6.7, 13.9 Hz, IH), 3.16 (dd, J=5.5, 13.9 Hz, IH), 3.73 (s, 3H), 4.52 (m, IH), 4.82 (m, IH), 6.47 (d, J=7.1 Hz, IH), 6.70 (d, J=7.5 Hz, IH), 7.12 (m, 2H), 7.28 (m, 3H). 30 l3C-nmr (CDC13): 8 = 4.6, 6.9, 18.2, 37.7, 41.2, 48.4, 52.4, 53.2, 127.1, 128.5, 129.2, 135.7, 171.7, 171.9, 172.3. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 227 - ClgH24N204 (MW = 332.40); mass spectroscopy (MH+) 333. Example 73 Synthesis of /V-[2V-(3,5-DifluorophenyIacetyI)-S L-alaninyl] glycine Benzyl Ester Following General Procedure A and using iV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and glycine benzyl ester (prepared from N-BOC-glycine (Bachem) and benzyl alcohol (Aldnch) using General Procedure X, followed by removal of the BOC-group using General Procedure Y), the 10 title compound was prepared as a solid (mp = 167.5°C). The reaction was monitored by tic (Rf = 0.35 in 2% MeOH/CH2Cl2) and the product was purified by flash chromotography using 2% MeOH/CH2Cl2 as the eluent. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.12 (m, 5H), 6.71 (m, 3H), 6.60 (m, 2H), 4.95 (s, 15 2H), 4.18 (q, IH), 3.76 (dd, 2H), 3.35 (s, 2H), 1.13 (d, 3H). nC-nmr (CDC13): 8 = 176.0, 172.9, 171.5, 166.46, 163.30, 141.54, 137.70, 130.11, 129.88, 113.98, 113.87, 113.75, 113.64, 103.89, 103.55, 103.21, 68.44, 50.93, 43.25, 42.61, 18.65. C20H20N2O4F2 (MW = 390.39); mass spectroscopy (MH+) 391. 20 Example 74 Synthesis of /V-f/V-dsovaleryO-L-phenylglycinyll-L-alanine Ethyl Ester Following General Procedure C and using N-(isovaleryl)-L-phenylglycine (prepared from isovaleric acid (Aldrich) and L-phenylglycine methyl ester 25 hydrochloride (Aldrich) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-alanine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp = 198-201 °C). The reaction was monitored by tic (Rf = 0.3 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 5 % MeOH/CHCl3 as the eluent, 30 followed by rerystallization from EtOAc. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 228 -- NMR data was as follows: 'H-nmr (DMSO-JaXLS mixture of diastereomers): 5 = 1.25 and 1.30 (two d, 3H), 5.57 (d, IH), 5.60 (d, IH). C,8H26N204 (MW = 334.42); mass spectroscopy (MH+) 335. 5 Example 75 Synthesis of /V-[iV-(3-Nitrophenylacetyl)-L-alaninyl]-L-phenylalanine Methyl Ester Following General Procedure Z and using jV-(3-nitrophenylacetyl)-L-alanine 10 2,4,5-tnchlorophenyl ester (from Example D8 above) and L-phenylalanine methyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp = 154-158°C). The reaction was monitored by tic (Rf = 0.3 in 1:1 EtOAc/hexanes) and the product was punfied by silica gel chromatography using 50-100% EtOAc/hexanes as the eluent. 15 NMR data was as follows: 'H-nmr (DMSO-J6)(l:3 mixture of diastereomers): 5 = 1.00 and 1.18 (two d, 3H), 2.96 (m, 2H). C21H23N3O5 (MW = 413.43); mass spectroscopy (MH+) 413. Example 76 20 Synthesis of /V-[/V-(3-Nitrophenylacetyl)-L-alaninyl]-L-alanine Ethyl Ester Following General Procedure Z and using jV-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (from Example D8 above) and L-alanine ethyl ester 25 hydrochloride (Sigma), the title compound was prepared as a solid (mp = 193-195°C). The reaction was monitored by tic (Rf = 0.4 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent. NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 1.20 (m, 9H), 3.65 (s, 2H); 4.05 (m, 2H). 30 Optical Rotation: [a]20 = -27.3° @ 589nm, (c = 1.02, DMSO). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 229 - C16H21N306 (MW = 351.36); mass spectroscopy (MH+) 352. Example 77 Synthesis of iV-[iV-(3-NitrophenyIacetyI)-L-alaninyl]glycine Ethyl Ester 5 Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and glycine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp = 164-165°C). The product was 10 purified by silica gel chromatography using EtOAc as the eluent, followed by recrystallization from EtOAc. NMR data was as follows: 'H-nmr (DMSO-</6): 5 = 1.20 (m, 6H), 4.08 (q, 2H); 4.32 (m, IH). Optical Rotation: [a]20 = -25° @ 589 nm, (c = 1.00, DMSO). 15 C15H19N306 (MW = 337.33); mass spectroscopy (MH+) 338. Example 78 Synthesis of ZV-Hydroxy-iV'-|7V-(3-nitrophenylacetyl)-L-alaninyl]-D,L-threoninamide 20 Following General Procedure Z and using N-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (from Example D8 above) and D,L-threonine hydroxamate (Sigma), the title compound was prepared as a solid (mp = 180-183°C). The reaction was monitored by tic (Rf = 0.25 in 15% MeOH/CHCl3) and the product was purified by silica gel chromatography using 15 % 25 MeOH/CHCl3 as the eluent, followed by recrystallization from EtOAc. NMR data was as follows: 'H-nmr (DMSO-d6)(l:l mixture of diastereomers): 5 = 1.22 (m, 3H); 0.98 (m, 3H). C15H2oN407 (MW = 368.35); mass spectroscopy (MH+) 368. Printed from Mimosa WO 98/22494 FCT/US97/20804 - 230 - Example 79 Synthesis of iV-[2V-(IsovaleryI)-L-phenylglycinyl]-L-alanine iso-butyl Ester Following General Procedure C and using N-(isovaleryl)-L-phenylglycine 5 (prepared from isovaleric acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-alanine wo-butyl ester hydrochloride (prepared from A/'-BOC-L-alanine (Sigma) and 2-methyl-l-propanol (Aldrich) using General Procedure C (with catalystic DMAP), followed by removal of the 10 BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 181-186°C). The reaction was monitored by tic (Rf = 0.4 in 1:1 EtOAc/hexanes) and the product was punfied by silica gel chromatography using 1:1 EtOAc/hexanes as the eluent. NMR data was as follows: 15 'H-nmr (DMSO-rf6): 5 = 1.31 (d, 3H); 5.59 (d, IH). Optical Rotation: [a]^ = +19.0° @ 589 nm, (c = 1.03, DMSO). C20H29N2O,, (MW = 362.47); mass spectroscopy (MH+) 363. Example 80 Synthesis of 20 Methyl /V-[7V-(3-nitrophenylacetyl)- L-alaninyI]-2-amino-3-(3-hydroxyphenyl)propionate Following General Procedure C and using iV-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using 25 General Procedure AF) and methyl 2-amino-3-(3-hydroxyphenyl)propionate (prepared from 2-amino-3-(3-hydroxyphenyl)propionate (Biosynth AG, Switzerland) and methanol using General Procedure H), the title compound was prepared as a solid (mp = 155-159°C). The reaction was monitored by tic (Rf = 0.4 in EtOAc) and the product was purified by silica gel chromatography 30 using EtOAc as the eluent. NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 -231 - 'H-nmr (DMSO-J6)(l:l mixture of diastereomers): 5 = 1.02 and 1.20 (two d, 3H); 3.62 (2 s, 3H). CaiHaNjGj (MW = 429.43); mass spectroscopy (MH+) 429. Example 81 S Synthesis of /V-[/V-(3-Nitrophenylacetyl)-L-alaninyl]-L-tyrosineEthyl Ester Following General Procedure C and using iV-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using 10 General Procedure AF) and L-tyrosine ethyl ester (Sigma), the title compound was prepared as a solid (mp = 117-119°C). The reaction was monitored by tic (Rf = 0.5 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent. NMR data was as follows: 15 'H-nmr (DMSO-d6): 5 = 1.07 (t, 3H); 1.20 (d, 3H); 9.23 (s, IH). Optical Rotation: [a]20 = -13.1° @ 589 nm, (c = 1.08, DMSO). C22H25N307 (MW = 443.46); mass spectroscopy (MH+) 443/444. Example 82 Synthesis of 20 jV-[JV-(Isovaleryl)-L-isoIeucinyl]-L-alanine iso-butyl Ester Following General Procedure C and using /V-(isovaleryl)-L-isoleucine (prepared from isovaleric acid (Aldrich) and L-isoleucine methyl ester hydrochloride (Aldrich) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-alanine iso-butyl ester hydrochloride 25 (prepared from /V-BOC-L-alanine (Sigma) and 2-methyl-l-propanol (Aldrich) using General Procedure C (with catalystic DMAP), followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 142-146°C). The reaction was monitored by tic (Rf = 0.4 in 1:1 Prxnted from Mxmosa WO 98/22494 PCT/US97/20804 - 232 - EtOAc/hexanes) and the product was purified by silica gel chromatography using 1:1 EtOAc/hexanes as the eluent. NMR data was as follows: "H-nmr (DMSO-d6)(l:4 mixture of diastereomers): 5 = 1.26 (d, 3H), 7.70, 5 7.80 (doublets, IH); 8.30, 8.40 (doublets, IH). C.gH^NA (MW = 342.48); mass spectroscopy (MH+) 343. Example 83 Step A —Synthesis of /V-[Ar-[AL(tert-Butoxycarbonyl)-L-valinyl]-D,L-phenylglycinylj-I^alanine iso-butyl Ester 10 Following General Procedure A and using /V-{W-BOC-L-valinyl]-D,L- phenylglycine (prepared by coupling N-BOC-L-valine (Bachem) and L-phenylglycine methyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis of the methyl ester using General Procedure AF) and L-alanine iso-butyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) 15 and 2-methyl-l-propanol (Aldrich) using General Procedure C (with catalytic DMAP), followed by removal of the BOC-group using General Procedure P), the title compound was prepared. The reaction was monitored by tic (Rf = 0.3 in 5% MeOH/CH2Cl2) and the product was punfied by silica gel chromatography using 5% MeOH/CH2Cl2 as the eluent. 20 NMR data was as follows: "H-nmr (DMSO-d6)(l:l mixture of diastereomers): 5 = 1.25 (d, 3H); 5.58 (d, IH). C^^^Oj (MW = 477.61); mass spectroscopy (MH+) 478. Step B —Synthesis of /V-[/V-(L-Valinyl)-L-phenylgIycinyl]-L-alanineiso-25 butyl Ester Hydrochloride Following General Procedure P and using the product from Example 83 -Step A above, the title compound was prepared as a solid (mp = 225-232°C). The product was purified by trituration in Et20. NMR data was as follows: Printed from Mxmosa WO 98/22494 PCT/US97/20804 - 233 - 'H-nmr (DMSO-J6)(l:2 mixture of diastereomers): 6 = 1.26, 1.32 (doublets, 3H); 5.60, 5.65 (doulets, IH). C20H32N3O4CI (MW = 413.94); mass spectroscopy (MH+) 378 (free base). Step C —Synthesis of /V-[N-[iV-(IsovaleryI)-L-valinyI]-L-phenylglycinyl]-5 L-alanine iso-butyl Ester Following General Procedure C and using isovaleric acid (Aldrich) and the product from Example 83 - Step B above, the title compound was prepared as a solid (mp = 217-221 °C). The reaction was monitored by tic (Rf = 0.25 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography 10 using 5 % MeOH/CHCl3) as the eluent. NMR data was as follows: 'H-nmr (DMSO-fif6)(l:3 mixture of diastereomers): 5 = 5.52, 5.58 (doublets, IH). C2sH39N30j (MW = 461.60); mass spectroscopy (MH+) 462. 15 Example 84 Synthesis of ^-[^-(IsovaleryO-L-phenylalaninyll-L-alanine iso-butyl Ester Following General Procedure C and using isovaleric acid (Aldrich) and N-(L-phenylalaninyl)-L-alanine tro-butyl ester hydrochloride (prepared from N-20 BOC-L-phenylalanine (Sigma) and L-alanine wo-butyl ester hydrochloride (prepared as described in Example 83A above) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 135-138°C). The reaction was monitored by tic (Rf = 0.3 in 3% MeOH/CHCl3) and the product was purified 25 by silica gel chromatography using 3% MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-<4): 5 = 0.75 (d, 3H), 0.84 (d, 3H); 0.90 (d, 6H); 1.33 (d, 3H). Optical Rotation: [a]20 = +4.71° @ 589 nm, (c = 1.02, DMSO). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 234 - C21H32N204 (MW = 376.50); mass spectroscopy (MH+) 376. Example 85 Synthesis of 2V-[/V-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-aIaniiie Ethyl Ester 5 Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and L-alanine ethyl ester hydrochlonde (Sigma), the title compound was prepared as a solid (mp = 197-199°C). The reaction was monitored by tic (Rf = 0.6 in EtOAc) and the product was purified from bi-products by silica gel chromatography using EtOAc as the eluent, followed by recrystallization 10 from EtOAc. NMR data was as follows: 'H-nmr (DMSO-<f6): 8 = 1.22 (m, 9H); 3.52 (s, 2H). Optical Rotation: [a]20 = -76.1° @ 589 nm, (c = 1.01, DMSO). C16H20N2O4F2 (MW = 342.34); mass spectroscopy (MH+) 343. 15 Example 86 Synthesis of Ethyl l-[/V-(3-Nitrophenylacetyl)-L-aIaninyl]indoline-(S)-2-carboxylate Following General Procedure C and using A^-(3-nitrophenylacetyl)-L-alanine 20 (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and ethyl (S)-indoline-2-carboxylate (prepared from (S)-indoline-2-carboxyhc acid (Aldnch) and ethanol using General Procedure H), the title compound was prepared as a solid. The reaction was monitored by tic 25 (Rf = 0.4 in 2:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 2:1 EtOAc/hexanes as the eluent. NMR data was as follows: 'H-nmr (DMSO-*/6)(l:2 mixture of diastereomers): 5 = 1.05, 1.17 (triplets, 3H); 1.29, 1.39 (doublets, 3H). 30 Cza^aNjOj (MW = 425.44); mass spectroscopy (MH+) 425. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 235 -- Example 87 Synthesis of N '-{7V-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-aIaninamide Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-5 alanine (from Example B2 above) and L-alaninamide hydrochloride (Sigma), the title compound was prepared as a solid (mp = 285-288°C). The reaction was monitored by tic (Rf = 0.35 in 10% MeOH/CHClj) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from EtOH. 10 NMR data was as follows: 'H-nmr (DMSO-rf6): 8 = 1.21 (m, 6H); 7.95 (d, IH); 8.37 (d, IH). Optical Rotation: [a]20 = -26.84° @ 589 nm, (c = 1.01, DMSO). C14H17N303F2 (MW = 313.31); mass spectroscopy (MH+) 314. Example 88 15 Synthesis of Ar-Methoxy-A'-methyl-Ar'-[yV-(isovaleryl)-L-phenylgIyciny]]-L-alaninamide Following General Procedure C and using N-[Af-(isovaleryl)-L-phenylglycinyl]-L-alanine (prepared from N-[W-(isovaleryl)-L-phenylglycinyl]-L-20 alanine ethyl ester (from Example 74 above) using General Procedure AF) and N,O-dimethylhydroxylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.6 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent. NMR data was as follows: 25 'H-nmr (DMSO-J6)(l: 1 mixture of diastereomers): 5 = 3.67, 3.73 (singlets, 3H), 5.62 (m, IH). ClgH27N304 (MW = 349.43); mass spectroscopy (MH+) 350. Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 236 - Example 89 Synthesis of ZV-iso-bu tyl-N[N- (3,5-diflu oropheny Iacety 1) -L-alaninyl]-L-aIaninamide 5 Following General Procedure C and using N'-[N-(3,5-difluorophenylacetyl)- L-alaninyl]-L-alanine (prepared from iV-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester (from Example 85 above) using General Procedure AF) and uo-butylamine (Aldrich), the title compound was prepared as a solid (mp = 258-260°C). The reaction was monitored by tic (Rf = 0.4 in 10 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-J6): 5 = 0.80 (d, 6H); 1.20 (m, 6H). Optical Rotation: [a]20 = -30.4° @ 589 nm, (c = 1.01, DMSO). 15 C18H2jN303F2 (MW = 369.41); mass spectroscopy (MH+) 369. Example 90 Synthesis of A',Ar-Di-/i-propyl-AM-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide 20 Following General Procedure C and using N-[W-(3,5-difluorophenylacetyl)- L-alaninyl]-L-alanine (prepared from /V-(7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester (from Example 85 above) and di-n-propylamine (Aldrich), the title compound was prepared as a solid (mp = 137-146°C). The reaction was monitored by tic (Rf = 0.5 in 10% MeOH/CHCl3) and the 25 product was purified by silica gel chromatography using 5 % MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-J6)(l:2 mixture of diastereomers): 8 = 3.50 (s, 2H), 4.30 (m, IH), 4.63 (m, IH). 30 C20H29N3O3F2 (MW = 397.46); mass spectroscopy (MH+) 397. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 237 - Example 91 Synthesis of ^'-[iV-GjS-Difluomphenylacetyi^-T^-alaninylj-T^valinamidg Following General Procedure C and using iV-(3,5-difluorophenylacetyl)-L-5 alanine (from Example B2 above) and L-valinamide hydrochloride (Sigma), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.3 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent. NMR data was as follows: 10 'H-nmr (DMSO-</6)(l:4 mixture of diastereomers): 5 = 1.22 (m, 3H); 1.97 (m, IH). C16H21N303F2 (MW = 341.36) mass spectroscopy (MH+) 342. Example 92 Synthesis of 15 2V-(4-Nitrophenyl)-W-[7V-(3,5-difluorophenylacetyl)- L-alaninyl]-L-alaninamide Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and jV-(4-nitrophenyl) L-alaninamide hydrochloride (Fluka), the title compound was prepared as a solid (mp = 242-20 244°C). The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile. NMR data was as follows: 'H-nmr (DMSO-</6): 5 = 1.24 (d, 3H); 1.33 (d, 3H). 25 Optical Rotation: [a]20 = -5.18° @ 589 nm, (c = 1.00, DMSO). C2oH2oN405F2 (MW = 434.40); mass spectroscopy (MH+) 434. Example 93 Synthesis of W-[/V-[Af-(Isovaleryl)-L-phenyIglycinyl]-30 L-alaniny]]-L-phenyIalaninamide Printed from Mimosa WO 98/22494 PCT/US97/20804 — 238 - Following General Procedure C and using 7V-(isovaleryl)-L-phenylglycine (prepared from isovaleric acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure C, followed by hydrolysis using General Procedure AF) and JV'-(L-alaninyl)-L-phenylalaninamide 5 hydrochloride (prepared from iV-BOC-L-alanine (Sigma) and L- phenylalaninamide (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 272-276°C). The reaction was monitored by tic (Rf = 0.25 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography 10 using 10% MeOH/CHClj as the eluent. NMR data was as follows: 'H-nmr (DMSO-c/6)(l: 1 mixture of diastereomers): 5 = 1.07, 1.17 (doublets, 3H); 5.40, 5.52 (doublets, IH). C25H32N4O4 (MW = 452.55); mass spectroscopy (MH+) 453. 15 Example 94 Synthesis of iV-[Af-(3,5-Difluorophenylacetyl)-L-alaninyI]-L-phenylalanine Methyl Ester Following General Procedure C and using 3,5-difluorophenylacetic acid 20 (Oakwood) and N-(L-alaninyl)-L-phenylalamne methyl ester hydrochloride (prepared from jV-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 173-175°C). The reaction was monitored by tic (Rf = 0.6 in 25 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile. NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 1.17 (d, 3H); 3.48 (s, 2H). 30 Optical Rotation: [a]20 = -32.47° @ 589 nm, (c = 1.01, MeOH). C21H22N204F2 (MW = 404.41); mass spectroscopy (MH+) 404. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 239 - Example 95 Synthesis of iV'-[^-(3,5-DifluorophenylacetyI)-L-alaninyl]-L-phenylalaniiiamide Following General Procedure C and using 3,5-difIuorophenylacetic acid (Oakwood) and W-(L-alaninyl)-L-phenylalaninamide hydrochloride prepared from N-BOC-L-alanine (Sigma) and L-phenylalaninamide (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 252-253°C). The reaction was monitored by tic (Rf = 0.5 in 15% MeOH/CHCl3) and the product was purified by silica gel chromatography using 15% MeOH/CHCl3 as the eluent, followed by recrystallization from EtOH. NMR data was as follows: 'H-nmr (DMSO-<4): 6 = 1.15 (d, 3H); 3.51 (s, 2H). Optical Rotation: [a]20 = -24.4° @ 589 nm, (c = 1.01, DMSO). Q,oH2iN303F2 (MW = 389.41); mass spectroscopy (MH+) 389. Example 96 Synthesis of N-iso-butyl-/V'-[/V-(isovaleryl)-L-phenylglycinyl]-L-alaninamide Following General Procedure C and using //-(TV-(isovaleryl)-L-phenylglycinyl]-L-alanine (prepared from N-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl ester (from Example 74 above) using General Procedure AF) and iso-butylamine (Aldrich), the title compound was prepared as a solid (mp = 227-232°C). The reaction was monitored by tic (Rf = 0.3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile. NMR data was as follows: 'H-nmr (DMSO-c?6)(l:4 mixture of diastereomers): 6 = 1.58 (m, IH); 1.95 (m, IH); 5.55 (d, IH). C20H31N3O3 (MW = 361.48); mass spectroscopy (MH+) 361. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 240 - Example 97 Synthesis of Af-(2-Methoxyethyl)-2V'-[iV-(3,5-difluorophenylacetyI)-L-alaninyll-L-phenylalaninamide Following General Procedure C and using /V-[7V-(3,5-difluorophenyIacetyl)-L-alaninyl]-L-phenylalanine (prepared from N-[./V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (from Example 94) using General Procedure AF) and 2-methoxyethylamine (Aldrich), the title compound was prepared as a solid (mp = 206-208<>C). The reaction was monitored by tic (Rf = 0.3 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitnle. NMR data was as follows: 'H-nmr (DMSO-t/6): 5 = 1.14 (d, 3H); 4.22 (m, IH), 4.45 (m, IH). Optical Rotation: [a]20 = -25° @ 589 nm, (c = 1.00, DMSO). C23H27N304F2 (MW = 447.49); mass spectroscopy (MH+) 447. Example 98 Synthesis of /V-(4-Nitrobenzyl)-iV'-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Following General Procedure C and using N-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared from N-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester (from Example 85 above) using General Procedure AF) and 4-nitrobenzylamine (Aldrich), the title compound was prepared as a solid (mp = 257-259 °C). The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from EtOH/acetonitrile. NMR data was as follows: 'H-nmr (DMSO-rfs): 5 = 3.53 (s, 2H); 4.39 (d, 2H). Optical Rotation: [a]20 = -29.3° @ 589 nm, (c = 1.00, DMSO). Printed from Mimosa WO 98/22494 PCT/US97/20804 -241 - C21H22N405F2 (MW = 448.43); mass spectroscopy (MH+) 448. Example 99 Synthesis of N- (4-Nitropheny))-/V '-[AqAT-OsovaleryD-5 L-phenyIglycinyI]-L-alaninyl]-L-alaninamide Following General Procedure C and using N-[N-(iso valery 1)-L-phenylglycinyl]-L-alanine (prepared from N-|W-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl ester (from Example 74 above) using General Procedure AF) and N-(4-nitrophenyl)-L-alaninamide hydrochloride (Fluka), the title compound 10 was prepared as a solid (mp = 255-257 °C). The reaction was monitored by tic (Rf = 0.5 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile. NMR data was as follows: 15 'H-nmr (DMSO-rf6)(l:2 mixture of diastereomers): 5 = 5.45, 5.55 (doublets, IH); 10.20, 10.54 (singlets, IH). C2jH3,N406 (MW = 497.56); mass spectroscopy (MH+) 497. Example 100 Synthesis of 20 /V-(4-Nitrophenyl)-/V '-[/V-(3,5-difluorophenyJacetyl)- L-alaninyl]-L-phenylalaninamide Following General Procedure C and using iV-(3,5-difluorophenyIacetyl)-L-alanine (from Example B2 above) and N-(4-nitrophenyl)-L-phenylalaninamide hydrochloride (Lancaster), the title compound was prepared as a solid (mp = 25 253-254°C). The reaction was monitored by tic (Rf = 0.5 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 8% MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-d6): 6 = 1.17 (d, 3H); 10.52 (s, IH). 30 Optical Rotation: [a]20 = +40.6° @ 589 nm, (c = 1.00, DMSO). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 242 - C26H24N405F2 (MW = 510.50); mass spectroscopy (MH+) 510. Example 101 Synthesis of Ar-BenzyI-yV-niethyl-/V'-[7V-(3,5-difluorophenylacetyl)-5 L-alaninyl]-L-alaninamide Following General Procedure C and using iV-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared from N-[N-(3,5-difluorophenylacety 1)-L-alamnyl]-L-alanine ethyl ester (from Example 85 above) using General Procedure AF) and 7V-benzyl-/V-methylamine (Aldrich), the title compound was 10 prepared as a solid (mp = 167-169°C). The reaction was monitored by tic (Rf = 0.4 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5 % MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile. NMR data was as follows: 15 'H-nmr (DMSO-</6)(l:3 mixture of diastereomers): 5 = 3.52 (singlets, 2H); 2.95 (s, 2H). Optical Rotation: [a]M = -55.8° @ 589 nm, (c = 1.01, DMSO). C22H25N303F2 (MW = 417.45); mass spectroscopy (MH+) 417. Example 102 20 Synthesis of iV-(3,5-DifluorobenzyI)-/V'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alamne (from Example B2 above) and AT-(3,5-difluorobenzyl)-L-alaninamide 25 hydrochloride (prepared from /V-BOC-L-alanine (Sigma) and 3,5- difluorobenzylamine (Lancaster) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 267-269 °C). The reaction was monitored by tic (Rf = 0.25 in 10% MeOH/CHC13) and the product was purified by silica gel Printed from Mimosa WO 98/22494 - 243 - PCT/US97/20804 chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile. NMR data was as follows: 'H-nmr (DMSO-d6): 8 = 1.21 (d, 3H), 1.24 (d, 3H). 5 Optical Rotation: [a]20 = +26.9° @ 589 nm, (c = 1.01, DMSO). C21H21N303F4 (MW = 439.41); mass spectroscopy (MH+) 439. Example 103 Synthesis of AM3-Nitrobenzyl)-W-[W-(3,5-difluorophenylacetyl)-10 L-alaninyll-I^alaninamide Following General Procedure C and using N-(3,5-difluorophenylacety^-L-alanine (from Example B2 above) and 2V-(3-nitrobenzyl)-L-alaninamide hydrochloride (prepared from JV-BOC-L-alanine (Sigma) and 3-nitrobenzylamine hydrochloride (Aldnch) using General Procedure C, followed by removal of the 15 BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 245-247°C). The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile. 20 NMR data was as follows: 'H-nmr (DMSO-d6): 8 = 1.21 (d, 3H); 1.25 (d, 3H). Optical Rotation: [a]20 = -32.8° @ 589 nm, (c = 1.00, DMSO). C21H22N405F2 (MW = 448.43); mass spectroscopy (MH+) 449. Example 104 25 Synthesis of N-Benzyl-ZV[/V-(3,5-diflu oropheny lacetyl)-L-alaninyl]-L-alaninamide Following General Procedure C and using A/-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and AT-benzyl-L-alaninamide hydrochloride 30 (prepared from /V-BOC-L-alanine (Sigma) and benzylamine (Aldrich) using Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 244 - General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 260-262°C). The reaction was monitored by tic (Rf = 0.3 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCI3 as the eluent, followed by recrystallization from acetonitrile. NMR data was as follows: 'H-nmr (DMSO<): 5 = 1.20 (d, 3H); 1.24 (d, 3H). Optical Rotation: [ck]20 = -29.3° @ 589 nm, (c = 1.03, DMSO). Cj.HaNAFj (MW = 403.43); mass spectroscopy (MH+) 403. Example 105 Synthesis of /V-(4-Nitrobenzyl)-/V'-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide Following General Procedure C and using 7V-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared from iV-|W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (from Example 94) using General Procedure AF) and 4-nitrobenzylamine hydrochloride (Aldrich), the title compound was prepared as a solid (mp = 248-250°C) The reaction was monitored by tic (Rf = 0.4 in 12% MeOH/CHCl3) and the product was purified by silica gel chromatography using 12% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile. NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 1.15 (d, 3H); 7.35 (d, 2H); 8.12 (d, 2H). Optical Rotation: [a]M = -21.6° @ 589 nm (c = 1.01, DMSO). CnHttNAFj (MW = 524.52); mass spectroscopy (MH+) 524. Example 106 Synthesis of /V-[;V-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-tryptophan Methyl Ester Printed from Mimosa WO 98/22494 PCT/US97/20804 - 245 - Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-tryptophan methyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp = 191-193°C). The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the 5 product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile. NMR data was as follows: 'H-nmr (DMSO-J6): 5 = 1.20 (d, 3H); 3.55 (s, 3H). Optical Rotation: [a]20 = -8.82° @ 589 nm (c = 1.02, DMSO). 10 C23H23N304F2 (MW = 443.45); mass spectroscopy (MH+) 443. Example 107 Synthesis of 2V-(4-Methoxybenzyl)-/V'-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide 15 Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L- alanine (from Example B2 above) and iV-(4-methoxybenzyl)-L-alaninamide hydrochloride (prepared from iV-BOC-L-alanine (Sigma) and 4-methoxybenzylamine hydrochloride (Aldrich) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title 20 compound was prepared as a solid (mp = 234-236 °C). The reaction was monitored by tic (Rf = 0.3 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from EtOH/acetonitrile. NMR data was as follows: 25 'H-nmr (DMSO-d6): 5 = 1.20 (d, 6H); 3.51 (s, 2H); 3.72 (s, 3H). Optical Rotation: [a]20 = +27.9° @ 589 nm (c = 1.00, DMSO). C22H2JN304F2 (MW = 433.46); mass spectroscopy (MH+) 433. Example 108 Synthesis of 30 /V-[iV-(PhenylacetyI)-L-phenylglycinyl]-L-alanine Ethyl Ester Printed from Mimosa WO 98/22494 PCT/US97/20804 - 246 -- Following General Procedure C and using phenylacetic acid (Aldrich) and N-(L-phenylglycinyl)-L-alanine ethyl ester hydrochloride (prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and L-alanine ethyl ester hydrochloride (Aldrich) using General Procedure C, followed by removal of the 5 BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 208-210°C). The reaction was monitored by tic (Rf = 0.4 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetomtrile. 10 NMR data was as follows: 'H-nmr (DMSO-</6): 5 = 3.55 (s, 2H); 5.55 (d, IH). Optical Rotation: [ajjo = +44.8° @ 589 nm (c = 1.02, DMSO). C21H24N204 (MW = 368.43); mass spectroscopy (MH+) 369. Example 109 15 Synthesis of iV-[iV-[iV-(3,5-Difluorophenylacetyl)-L-alaniriyl]-L-phenylalaninyl]-I^phenylglycine Methyl Ester Following General Procedure C and using N-[N-(3 ,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared from N-[W-(3,5-difluorophenylacetyl)-L-20 alaninyl]-L-phenylalanine methyl ester (from Example 94) using General Procedure AF) and L-phenylglycine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp = 203-207°C). The reaction was monitored by tic (Rf = 0.3 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, 25 followed by trituration using 1-chlorobutane. NMR data was as follows: 'H-nmr (DMSO-rf6): 6 = 1.13 (d, 3H); 3.62 (s, 3H). Optical Rotation: [a]20 = +42.1° @ 589 nm (c = 1.03, DMSO). C29H29N3OjF2 (MW = 537.56); mass spectroscopy (MH+) 537. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 247 - Example 110 Synthesis of 2V-[iV-(CycIohexyiacetyI)-L-phenylglycinyI]-L-alanine Ethyl Ester 5 Following General Procedure C and using cyclohexylacetic acid (Aldrich) and AT-(L-phenylglycinyl)-L-alanine ethyl ester hydrochloride (prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and L-alanine ethyl ester hydrochloride (Aldrich) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a 10 solid (mp = 196-198°C). The reaction was monitored by tic (Rf = 0.3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by trituration using 1-chlorobutane. NMR data was as follows: 'H-nmr (DMSO-d6): 5 = 2.08 (d, 2H); 5.56 (d, IH). 15 Optical Rotation: [a]20 = +26.3° @ 589 nm (c = 1.01, DMSO). C2iH30N2O4 (MW = 374.48); mass spectroscopy (MH+) 375. Example 111 Synthesis of /V-[iV-(3,5-DifIuorophenylacetyl)-L-alaninyI]-20 L-phenylglycine Methyl Ester Following General Procedure C and using JV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylglycine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp = 198-200°C). The reaction was monitored by tic (Rf = 0.4 in 4% 25 MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile. NMR data was as follows: 'H-nmr (DMSO-tf6): 6 = 1.26 (d, 3H); 3.64 (s, 3H). 30 Optical Rotation: (DMSO) [a]20 = +69.9° @ 589 nm (c = 1.01, DMSO). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 248 - C20H20N2O4F2 (MW = 390.39); mass spectroscopy (MH+) 391. Example 112 Synthesis of N-[iV-[iV-(3,5-DifluorophenylacetyI)-L-alamnyl]-5 L-alaninyi]-L-phenylglycine Methyl Ester Following General Procedure C and using 2V-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and N-(L-alaninyl)-L-phenylglycine methyl ester hydrochloride (prepared from iV-BOC-L-alamne (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure C, 10 followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 243-245 °C). The reaction was monitored by tic (Rf = 0.5 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile. 15 NMR data was as follows: 'H-nmr (DMSO-rf6): 8 = 1.19 (d, 3H); 1.24 (d, 3H). Optical Rotation: [a]20 = +38.2° @ 589 nm (c = 1.02, DMSO). C^H^NjO^ (MW = 461 46); mass spectroscopy (MH+) 461. Example 113 20 Synthesis of jV-(2-PhenyIethyl)-A"-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Following General Procedure C and using iV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and N-(2-phenylethyl)-L-alaninamide 25 hydrochloride (prepared from JV-BOC-L-alanine (Sigma) and phenethylamine (Aldrich) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 241-243°C). The reaction was monitored by tic (Rf = 0.3 in 8% MeOH/CHCl3) and the product was purified by silica gel chromatography using 30 8% MeOH/CHClj as the eluent, followed by recrystallization from acetonitrile. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 249 - NMR data was as follows: 'H-nmr (DMSO-rf*): 5 = 1.14 (d, 3H); 1.21 (d, 3H). Optical Rotation: ta]M = -33.7° @ 589 nm (c = 1.00, DMSO). C22H25N3O3F2 (MW = 417.45); mass spectroscopy (MH+) 417. 5 Example 114 Synthesis of JV'-[/V-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-tryptophanamide Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and N '-(L-alaninyl)-L-tryptophanamide hydrochloride (prepared 10 from /V-BOC-L-alanine (Sigma) and L-tryptophanamide hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 199-202°C). The reaction was monitored by tic (Rf = 0.3 in 15% MeOH/CHCl3) and the product was purified by silica gel chromatography using 15% 15 MeOH/CHClj as the eluent, followed by recrystallization from acetonitrile. NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 1.17 (d, 3H); 4.26 (m, IH); 4.44 (m, IH). Optical Rotation: [a]20 = -31.0° @ 589 nm (c = 1.05, DMSO). C22H22N403F2 (MW = 428.44); mass spectroscopy (MH+) 428. 20 Example 115 Synthesis of Methyl /V-[iV-(3,5-DifluorophenylacetyI)-L-alaninyl]-(S)-2-amino-3-cyclohexylpropionate Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-25 alanine (from Example B2 above) and methyl (S)-2-amino-3- cyclohexylpropionate (Novabiochem), the title compound was prepared as a solid (mp = 116-119°C). The reaction was monitored by tic (Rf = 0.4 in 4% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-30 chlorobutane/hexanes. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 250 - NMR data was as follows: xH-nmr (DMSO-rf*): 6 = 1.22 (d, 3H); 3.62 (s, 3H). Optical Rotation: [a]20 = -21.2° @ 589 nm (c = 1.01, DMSO). C^NA^ (MW = 410.46); mass spectroscopy (MH+) 411. 5 Example 116 Synthesis of Ar-(2-MethoxyethyI)-A''-[Ar-(3,5-difluorophenyIacetyl)-L-alaninyl]-(S)-2-amino-3-(4-nitrophenyl)propionamide Following General Procedure C and using iV-(3,5-difluorophenylacetyl)-L-10 alanine (from Example B2 above) and iV-(2-methoxyethyl)-(S)-2-amino-3-(4-nitrophenyl)propionamide hydrochloride (prepared from N-BOC-L-4-nitrophenylalanine (Advanced Chemtech) and 2-methoxyethylamine (Aldrich) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 263-15 265°C). The reaction was monitored by tic (Rf = 0.5 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHClj as the eluent, followed by recrystallization from EtOH/acetonitnle. NMR data was as follows: 20 'H-nmr (DMSO-d6): 5 = 1.15 (d, 3H); 4.23 (m, IH); 4.54 (m, IH). Optical Rotation: [a]20 = -19.9° @ 589 nm (c = 1.00, DMSO). C23H26N406F2 (MW = 492.48); mass spectroscopy (MH+) 493. Example 117 Synthesis of 25 A4W-(3-NitrophenylacetyI)-L-aianinyI]-L-serine Ethyl Ester Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-serine ethyl ester hydrochloride (Sigma), the title 30 compound was prepared as a solid (mp = 179-181 °C). The reaction was Printed from Mimosa WO 98/22494 PCT/US97/20804 — 251 - monitored by tic (Rf = 0.2 in 5 % MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-dd: 5 = 1.20 (m, 6H); 4.30 (m, IH); 4.41 (m, IH); 5.04 5 (t, IH). Optical Rotation: [or]^ = -19.7° @ 589 nm (c = 1.01, DMSO). CI6H2iN307 (MW = 367.36); mass spectroscopy (MH+) 368. Example 118 Synthesis of 10 A'-[(R)-G!-MethylbenzyI]-/V'-[Ar-(3,5-difluorophenylacetyl)- L-alaninyl]-L-alaninamide Following General Procedure C and using Ar-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and Ar-(R)-a-methylbenzyl-L-alaninamide hydrochloride (prepared from A'-BOC-L-alanine (Sigma) and (R)-a-15 methylbenzylamine (Aldrich) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 240-242°C). The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 9% MeOH/CHCl3 as the eluent, followed by recrystallization from 20 acetonitrile. NMR data was as follows: 'H-nmr (DMSO-d6): 6 = 1.19 (t, 6H); 1.31 (d, 3H). Optical Rotation: [a]20 = +1.0° @ 589 nm (c = 1.00, DMSO). C,2H25N303F2 (MW = 417.45); mass spectroscopy (MH+) 417. 25 Example 119 Synthesis of A'-[(S)-Q!-MethyIbenzyl]-A''-[/V-(3,5-difluorophenyIacetyl)-L-alaninyl]-L-alaninamide Following General Procedure C and using Ar-(3,5-difluorophenylacetyl)-L-30 alanine (from Example B2 above) and Ar-(S)-a-methylbenzyl-L-alaninamide Printed from Mimosa WO 98/22494 PCT/US97/20804 — 252 - hydrochloride (prepared from N-BOC-L-alanine (Sigma) and (R)-a-methylbenzylamine (Aldrich) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 293-295°C). The reaction was monitored by tic (Rf = 0.4 in 5 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile. NMR data was as follows: 'H-nmr (DMSO-J6): 5 = 1.20 (m, 6H); 1.30 (d, 3H). 10 Optical Rotation: [a]20 = -65.9° @ 589 nm (c = 1.05, DMSO). C22H2JN303F2 (MW = 417.45); mass spectroscopy (MH+) 417. Example 120 Synthesis of Ar-(4-Fluorobenzyl)-Af'-[A'-(3,5-difluorophenyIacetyl)-15 l^alaninyl]-L-alaninamide Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and /V-(4-fluorobenzyl)-L-alaninamide hydrochlonde (prepared from N-BOC-L-alanine (Sigma) and 4-fluorobenzylamine (Aldrich) using General Procedure C, followed by removal 20 of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 257-259°C). The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 9% MeOH/CHCl3 as the eluent, followed by trituration using 1-chlorobutane. 25 NMR data was as follows: 'H-nmr (DMSO-d6): d = 1.20 (m, 6H); 3.52 (s, 2H). Optical Rotation: [a]20 = -28.7° @ 589 nm (c = 1.00, DMSO). C21H22N303F3 (MW = 421.42); mass spectroscopy (MH+) 421. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 253 -- Example 121 Synthesis of iV-(4-Pyridylmethyl)-iV'-[yV-(3,5-difluorophenylacetyl)-L-alaninyI]-L-alaninamide 5 Following General Procedure C and using JV-(3,5-difluorophenylacetyl)-L- alanine (from Example B2 above) and N-(4-pyridylmelhyl)-L-alaninamide dihydrochloride (prepared from JV-BOC-L-alanine (Sigma) and 4-(aminomethyl)pyridine (Aldrich) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was 10 prepared as a solid (mp = 244-247°C). The reaction was monitored by tic (Rf = 0.3 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile. NMR data was as follows: 15 'H-nmr (DMSO<): 5 = 1.21 (d, 3H); 1.26 (d, 3H). Optical Rotation: [a]20 = -30.3° @ 589 nm (c = 1.00, DMSO). C20H22N4O3F2 (MW = 404.42); mass spectroscopy (MH+) 405. Example 122 Synthesis of 20 /V-(4-Trifluoromethylbenzyl)-/V'-[A'-(3,5-difluorophenylacetyI)- L-alaninyl]-L-alaninamide Following General Procedure C and using /V-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and N-(4-trifluoromethylbenzyl)-L-alaninamide hydrochloride (prepared from N-BOC-L-alanine (Sigma) and 4-25 (trifluoromethyl)benzylamine (Aldnch) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 244-247 °C). The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 8% MeOH/CHCl3 as the eluent, followed by triturated 30 using 1-chlorobutane. NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 — 254 - 'H-nmr (DMSO-rf5): 5 = 3.52 (s, 2H); 4.35 (d, 2H). Optical Rotation: [a]M = -27.4° @ 589 nm (c = 1.05, DMSO). C22H22N3O3F5 (MW = 471.43); mass spectroscopy (MH+) 471. Example 123 5 Synthesis of Ethyl /V-[iV-(3,5-DifluorophenylacetyI)-L-alaninyl]-2-amino-2-phenylpropionate Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and ethyl 7V-(L-alaninyl)-2-amino-2-phenylpropionate hydrochloride 10 (prepared from iV-BOC-L-alanine (Sigma) and D,L-a-methylphenylglycine ethyl ester (from Example D9 above) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 128-130°C). The reaction was monitored by tic (Rf = 0.2 in 3 % MeOH/CHCl3) and the product was purified by silica gel 15 chromatography using 3% MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-rf6)(l:l mixture of diastereomers): 5 = 1.72, 1.77 (singlets, 3H); 3.52 (s, 2H). C22H24N2O4F2 (MW = 418.44); mass spectroscopy (MH+) 418. 20 Example 124 Synthesis of /V-[iV-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylalanine /erf-Butyl Ester Following General Procedure C and using 3,5-difluorophenylacetic acid 25 (Oakwood) and iV-(L-alamnyl)-L-phenylalanine zerr-butyl ester hydrochloride (prepared from N-BOC-L-alamne (Sigma) and L-phenylalanine tert-butyl ester hydrochloride (Advanced Chemtech) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a gel. The reaction was monitored by tic (Rf = 0.5 in 4% Printed from Mimosa WO 98/22494 PCT/US97/20804 - 255 - MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-dj: 5 = 1.19 (d, 3H); 1.30 (s, 9H). 5 C24H28N2O4F2 (MW = 446.50); mass spectroscopy (MH+) 446. Example 125 Synthesis of Methyl iY-[/V-(3,5-difluorophenylacetyI)-L-alaninyl]-2-amino-2-melhylpropionate 10 Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L- alanine (from Example B2 above) and methyl 2-aminoisobutyrate (prepared from 2-aminoisobutyric acid (Aldrich) using General Procedure H), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.25 in CHClj/MeOH 95:5). 15 NMR data was as follows: 'H-nmr (DMSO-J6): 5 = 8.32 (m, 3H), 7.13 (m, IH), 7.00 (m, 2H), 4.31 (m, IH), 3.53 (m, 5H), 7.08 (m, IH), 1.36 (s, 3H), 1.34 (s, 3H), 1.19 (d, 3H). Optical Rotation: [a]23 = -25° (c 1, MeOH). 20 C16H2oN204F2 (MW = 342.34); mass spectroscopy (MH+) 343. Example 126 Synthesis of Ethyl A'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-cyclohexylacetate 25 Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L- alanine (from Example B2 above) and ethyl 2-amino-2-cyclohexylacetate hydrochloride (prepared from cyclohexylglycine (Advanced Chemtech) using Genera] Procedure H), the title compound was prepared as a solid (mp = 146-150°C). The reaction was monitored by tic (Rf = 0.3 in 3% MeOH/CHCl3) Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 256 - and the product was purified by silica gel chromatography using 3% MeOH/CHClj as the eluent. NMR data was as follows: 'H-nmr (DMSO-</6)(l: 1 mixture of diastereomers): 5 = 1.60 (m, 6H); 3.50 5 (s, 2H). C2,H28N204F2 (MW = 410.46); mass spectroscopy (MH+) 410. Following General Procedure C and using A?-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and N-(2-methoxyethyl)-L-phenylglycinamide hydrochloride (prepared from vV-BOC-L-phenylglycine (Advanced Chemtech) and 2-methoxyethylamine (Aldrich) using General Procedure C, followed by 15 removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 252-254°C). The reaction was monitored by tic (Rf = 0.3 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile. 20 NMR data was as follows: Example 127 10 Synthesis of A?-(2-Methoxyethyl)-/V'-[A'-(3,5-difluorophenylacetyI)-I^aIaninyl]-L-phenylglycinamide 'H-nmr (DMSO-rf6): 5 = 1-22 (d, 3H); 5.43 (d, IH). Optical Rotation: [a]20 = +6.17° @ 589 nm (c = 1.04, DMSO). C22H25N304F2 (MW = 433.46); mass spectroscopy (MH+) 434. Example 128 25 Synthesis of A^iV-dsovaleryO^-amino-l-cyclohexylacetyl]-L-alanine Ethyl Ester Following General Procedure C and using iV-(isovaleryl)-2-amino-2-cyclohexylacetic acid (prepared from isovaleric acid (Aldrich) and D,L-a- Pnnted from Mimosa WO 98/22494 PCT/US97/20804 — 257 ~ cyclohexylglycine ethyl ester hydrochlonde (prepared from cyclohexylglycine (Advanced Chemtech) and ethanol using General Procedure H) using General Procedure C, followed by removal of the BOC-group using General Procedure P) and L-alanine ethyl ester hydrochloride (Sigma), the title compound was 5 prepared as a solid (mp = 220-224°C). The reaction was monitored by tic (Rf = 0.2 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile. NMR data was as follows: 10 'H-nmr (DMSO-rf6): 8 = 0.85 (d, 6H); 4.04 (m, 2H). C18H32N204 (MW = 340.46); mass spectroscopy (MH+) 341. Example 129 Synthesis of N-2-(2V,iV-Dimethy!amino)ethyl-Ar'-[iV-(3,5-difluorophenylacetyl)-15 I^alaninyl]-I^phenylglycinamide Following General Procedure C and using vV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and N-2-(N,N-dimethylamino)ethyl-L-phenylglycinamide dihydrochloride (prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and N./V-dimetbylethylenediamine (Aldnch) using 20 General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 234-236°C). The reaction was monitored by tic (Rf = 0.3 in 15% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3, followed by slurrying in acetonitrile. 25 NMR data was as follows: 'H-nmr (DMSO-</6): 8 = 1.22 (d, 3H); 5.41 (d, IH). Optical Rotation: [a]20 = +5.7° @ 589 nm (c = 1.01, DMSO). C23H2gN403F2 (MW = 446.50); mass spectroscopy (MH+) 446. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 258 - Example 130 Synthesis of A/-(2-PyridylmethyI)-/V'-[/V-(3,5-difluorophenylacetyl)-L-aIaninyl]-L-phenylglycinamide 5 Following General Procedure C and using JV-(3,5-difluorophenylacetyl)-L- alanine (from Example B2 above) and iV-(2-pyridylmethyl)-L-phenylglycinamide dihydrochloride (prepared from /V-BOC-L-phenylglycine (Advanced Chemtech) and 2-(aminomethyl)pyridine (Aldrich) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was 10 prepared as a solid (mp = 272-275 °C). The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile. NMR data was as follows: 15 'H-nmr (DMSO-d6): 5 = 1.24 (d, 3H); 5.50 (d, IH). Optical Rotation: [a]20 = +12.4° @ 589 nm (c = 1.02, DMSO). C25H24N4O3F2 (MW = 466.49); mass spectroscopy (MH+) 467. Example 131 Synthesis of 20 N- [N- (3-Pyridylacety l)-L-alaninyl]- L-phenylalanine Methyl Ester Following General Procedure C and using 3-pyridylacetic acid hydrochloride (Aldrich) and A^-(L-alamnyl)-L-phenylalanine methyl ester hydrochloride (prepared from jV-BOC-L-alanine (Sigma) and L-phenylalamne 25 methyl ester hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 150-152°C). The reaction was monitored by dc (Rf = 0.3 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by 30 recrystallization from acetonitrile. NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 - 259 - 'H-nmr (DMSO-J6): 5 = 1.16 (d, 3H); 347 (s, 2H). Optical Rotation: [a]^ = -19.0° @ 589 nm (c = 1.03, DMSO). C20H23N3O4 (MW = 369.42); mass spectroscopy (MH+) 369. Example 132 5 Synthesis of A/-[iV-(2-Pyridylacetyl)-L-alaninyl]-L-pheiiylalanine Methyl Ester Following General Procedure C and using 2-pyridylacetic acid hydrochloride (Aldnch) and iV-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride (prepared from /V-BOC-L-alanine (Sigma) and L-phenylalanine 10 methyl ester hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 137-139°C). The reaction was monitored by tic (Rf = 0.4 in 8 % MeOH/CHCl3) and the product was purified by silica gel chromatography using 8% MeOH/CHCl3 as the eluent, followed by 15 recrystallization from 1-chlorobutane/acetonitnle. NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 1.17 (d, 3H); 3.65 (s, 2H). Optical Rotation: [a]20 = -17.48° @ 589 nm (c = 1.09, DMSO). C20H23N3O4 (MW = 369.42); mass spectroscopy (MH+) 369. 20 Example 133 Synthesis of /V-[7V-(4-PyridylacetyI)-L-alariinyI]-L-phenylalanine Methyl Ester Following General Procedure C and using 4-pyridylacetic acid hydrochlonde (Aldrich) and /V-(L-alaninyl)-L-phenylalanine methyl ester 25 hydrochloride (prepared from /V-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 152-154°C). The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel Printed from Mimosa WO 98/22494 PCT/US97/20804 - 260 - chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile. NMR data was as follows: 'H-nmr (DMSO-^): 5 = 1.17 (d, 3H); 3.47 (s, 2H). Optical Rotation: [a]M = -17° @ 589 nm (c = 1.00, DMSO). C20H23N3O4 (MW = 369.42); mass spectroscopy (MH+) 369. Example 134 Synthesis of Ethyl jV-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-fIuorophenyl)acetate Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(4-fluorophenyl)acetate hydrochloride (prepared from 4-fluorophenylglycine (Fluka) and ethanol using General Procedure H), the title compound was prepared as a solid (mp = 169-183°C). The reaction was monitored by tic (Rf = 0.3 in 4% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHClj as the eluent, followed by recrystallization from 1-chlorobutane/acetonitnle. NMR data was as follows: 'H-nmr (DMSO-</6)(l:l mixture of diastereomers): 5 = 3.49, 3.53 (singlets, 2H); 5.40 (m, IH). C21H2IN204F3 (MW = 422.4); mass spectroscopy (MH+) 422. Example 135 Synthesis of Ethyl A'-[A'-(3,5-Difluorophenylacetyl)-L-aIaninyl]-2-amino-2-(2-fluorophenyl)acetate Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(2-fluorophenyl)acetate hydrochlonde (prepared from 2-fluorophenylglycine (Fluka) and ethanol using General Procedure H), the title compound was prepared as a solid (mp = 153- Printed from Mimosa WO 98/22494 PCT/US97/20804 - 261 - 170°C). The reaction was monitored by tic (Rf = 0.3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile. 5 NMR data was as follows: 'H-nmr (DMSO-d6)(l:l mixture of diastereomers): 5 = 3.50, 3.54 (singlets, 2H), 5.66 (m, IH). C2jH21N204F, (MW = 422.40); mass spectroscopy (MH+) 422. Example 136 10 Synthesis of N- [A/- (3,5-Difluoropheny lacety I) -I^phenylgly ciny I]-L-alanine Ethyl Ester Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and N-(L-phenylglycinyl)-L-alanine ethyl ester hydrochloride 15 (prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and L-alanine ethyl ester hydrochloride (Aldrich) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.3 in 3% MeOH/CHCl3) and the product was purified by silica gel chromatography using 20 3% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile. NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 3.50 (s, 2H), 5.53 (d, IH) C21H22NAF2 (MW = 404.42); mass spectroscopy (MH+) 405. 25 Example 137 Synthesis of Ethyl Ar-[Ar-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-3-phthalimidopropionate Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-30 alanine (from Example B2 above) and ethyl 2-amino-3-phthalimidopropionate Printed from Mimosa WO 98/22494 PCT/US97/20804 ~ 262 - hydrochloride (from Example D10 above), the title compound was prepared as a solid (mp = 197-201 °C). The reaction was monitored by tic (Rf = 0.5 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5 % MeOH/CHCl3 as the eluent. 5 NMR data was as follows: 'H-nmr (DMSO-d6)(l:l mixture of diastereomers): 5 = 7.88 (m, 4H), 8.29 (t, IH), 8.48, 8.55 (doublets, IH). C24H23N308F2 (MW = 487.46); mass spectroscopy (MH+) 487. Example 138 10 Synthesis of iV-[/V-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine Neopentyl Ester Following General Procedure C and using /V-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylglycine neopentyl ester 15 hydrochloride (prepared from iV-BOC-L-phenylglycine (Advanced Chemtech) and 2,2-dimethyl-l-propanol (Aldrich) using General Procedure C (with catalytic DMAP), followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 133-136°C). The reaction was monitored by tic (Rf = 0.7 in 10% MeOH/CHCl3) and the 20 product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/hexanes. NMR data was as follows: 'H-nmr (DMSO-^): 8 = 3.50 (s, 2H), 5.42 (d, IH). Optical Rotation: [a]20 = +45.9° @ 589 nm (c = 1.02, DMSO). 25 C24H28N204F2 (MW = 446.50); mass spectroscopy (MH+) 446. Example 139 Synthesis of /V-fe/t-Butyl-iV'-[A'-(3,5-difluorophenyIacetyl)-L-alaninyl]-L-phenylglycinamide Printed from Mimosa WO 98/22494 PCT/US97/20804 — 263 - Following General Procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), S-(+)-a-methylbenzylamine (Aldrich), benzaldehyde (Aldrich) and rerr-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 233-235°C). The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHClj) and the product was purified by silica gel chromatography using 8% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile. NMR data was as follows: 'H-nmr (DMSO-</6)(l:l mixture of diastereomers): 5 = 3.52 (s, 2H), 5.40 (m, IH). CaH^NjOjFj (MW = 431.49); mass spectroscopy (MH+) 432. Example 140 Synthesis of Af-[N-(3,5-DifluorophenylacetyI)-L-alaninyl]-L-phenylglycine tert-Butyl Ester Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylglycine rm-butyl ester hydrochloride (Advanced Chemtech), the title compound was prepared as a solid (mp = 145-147°C). The reaction was monitored by tic (Rf = 0.5 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 2.5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/hexanes. NMR data was as follows: 'H-nmr (DMSO-<4): 6 = 1.26 (d, 3H); 5.20 (d, IH). Optical Rotation: [a]20 = +14.8° @ 589 nm (c =1.01, MeOH). C23H26N204F2 (MW = 432.47); mass spectroscopy (MH+) 433. Example 141 Synthesis of W-[iV-(3,5-DifluorophenylacetyI)-L-alaninyl]-I^phenylglycinamide Printed from Mimosa WO 98/22494 PCT/US97/20804 -264 - Following General Procedure C and using N-(2,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-phenylglycinamide hydrochloride (prepared from iV-BOC-L-phenylglycine (Advanced Chemtech) and ammonia using General Procedure C, followed by removal of the BOC-group using 5 General Procedure P), the title compound was prepared as a solid (mp = 288-290°C). The reaction was monitored by tic (Rf = 0.4 in 15% MeOH/CHCl3) and the product was purified by silica gel chromatography using 15 % MeOH/CHCl3 as the eluent, followed by recrystallization from EtOH. NMR data was as follows: 10 'H-nmr (DMSO-^: 8 = 1.22 (d, 3H), 5.36 (d, IH). Optical Rotation: [a]20 = +27.5° @ 589 nm (c = 1.03, DMSO). C19H19N303F2 (MW = 375.38); mass spectroscopy (MH+) 376. Example 142 Synthesis of 15 4-[/V-|W-(3-NitrophenyIacetyl)-L-alaninyl]-I^valinyl]morpholine Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example Dll above) and 4-(L-valinyl)morpholine (prepared from N-BOC-L-valine (Aldrich) and morpholine (Aldrich) using General Procedure M, followed by removal of the BOC-group using General Procedure P), the title 20 compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.5 in 9:1 CHCyMeOH) and the product was purified by silica gel chromatography using 98:2 CHCl3/MeOH as the eluent. NMR data was as follows: 'H-nmr (CDC13): 8 = 8.12 (d, 2H), 8.08 (dd, IH), 7.59 (d, IH, J=7 Hz), 25 7.42 (t, IH), 7.32 (d, J = 8 Hz, IH), 7.03(d, J=8 Hz, IH), 4.78 (m, IH), 4.68 (m, IH), 3.61 (m, 10H), 1.90 (m, IH), 1.96 (d, 3H), 1.31 (d, 3H), 0.88 (d, 3H), 0.80 (d, 3H). Optical Rotation: [a]23 = -5° (c 5, MeOH). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 265 -- Example 143 Synthesis of iV-[iV-(3-Nitrophenylacetyl)-L-alaiiinyl]-L-valine Ethyl Ester Following General Procedure C and using iV-(3-nitrophenylacetyl)-L-alanine 5 (from Example Dll above) and L-valine ethyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.2 in 97:3 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent. NMR data was as follows: 10 'H-nmr (CDC13): 5 = 8.13 (m, 2H), 7.62 (d, J=7 Hz, IH), 7.47 (t, IH), 6.52 (m, 2H), 4.57 (m, IH), 4.46 (m, IH), 4.19 (m, 2H), 3.65 (s, 2H), 2.13 (m, IH), 1.38 (d, 3H), 1.22 (t, 3H), 0.82 (d, 3H). Optical Rotation: [c*]23 = -24.3° @ 589 nm (c 1, DMSO). C18H25N306 (MW = 379.42); mass spectroscopy (MH+) 380. 15 Example 144 Synthesis of Af-[/V-(3-NitrophenylacetyI)-L-alaninyl]-L-threonine Methyl Ester Following General Procedure C and using A/-(3-nitrophenylacetyl)-L-alanine (from Example Dll above) and L-threonine methyl ester hydrochloride 20 (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.1 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent. NMR data was as follows: 'H-nmr (CDC13): 5 = 8.08 (d, IH), 7.96 (d, IH), 7.59 (d, IH), 7.45 (d, 25 IH), 7.34 (t, IH), 7.20 (d, IH), 4.43 (m, IH), 4.39 (dd, IH), 4.13 (m, IH), 3.59 (s, 3H), 3.51 (s, 2H), 1.20 (d, 3H), 1.03 (d, 3H). Optical Rotation: [a]^ = -20.8° (c 5, MeOH). C,6H20N2O7 (MW = 367.3); mass spectroscopy (MH+) 368. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 266 - Example 145 Synthesis of 4-[iV-[iV-(3-Nitrophenylacetyl)-L-alanmyl]-(S)-2-amino-3-fert-butoxybutyryI]morpholine 5 Following General Procedure C and using Ar-(3-nitrophenylacetyl)-L-alanine (from Example Dll above) and 4-[(S)-2-amino-3-ferf-butoxybutyryl]-morpholine (prepared from N-BOC-O-terr-butyl-L-threonine (Sigma) and morpholine (Aldrich) using General Procedure M, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a 10 solid. The reaction was monitored by tic (Rf = 0.1 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 96:4 CHCl3/MeOH as the eluent. NMR data was as follows: 'H-nmr (CDC13): 8 = 8.12 (m, 2H), 7.66 (d, IH), 7.47 (t, IH), 6.88 (d, 15 IH), 6.32 (d, IH), 4.78 (m, IH), 4.50 (m, IH), 3.90-3.40 (m, 11H), 1.40 (d, 3H), 1.18 (s, 9H), 1.0 (d, 3H). C23H33N3O7 (MW = 478.5); mass spectroscopy (MH+) 479. Example 146 Synthesis of 20 4-[/V-[7V-(3-NitrophenylacetyI)-I^alaninyl]-L-isoleucinyl]morpholine Following General Procedure C and using iV-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and 4-(L-isoleucmyl)morpholine (prepared from N-BOC-L-isoleucme (Aldrich) and morpholine (Aldrich) using General Procedure M, followed by removal of the BOC-group using General Procedure P), the 25 title compound was prepared as a solid (mp = 156-160°C). The reaction was monitored by tic (Rf = 0.45 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 98:2 CHCl3/MeOH as the eluent. NMR data was as follows: 'H-nmr (CDC13): 5 = 8.16 (d, IH), 8.09 (d, IH), 7.63 (d, IH), 7.45 (t, 30 IH), 7.30 (d, IH), 6.89 (d, IH), 4.78 (m, IH), 4.62 (m, IH), 3.6 (m, 10H), 1.65 (m, IH), 1.4 (m, IH), 1.29 (d, 3H), 1.03 (d, 3H), 0.90-0.76 (m, 6H). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 267 - Optical Rotation: [a]23 = -55° @ 589 nm (c 1, MeOH). Example 147 Synthesis of /V-[2V-(3-NitrophenylacetyI)-Lralaninyl]-L-isoIeucine Methyl Ester Following General Procedure C and using iV-(3-nitrophenylacetyl)-L-alanine (from Example Dll above) and L-isoleucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.15 in 97:3 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent. NMR data was as follows: 'H-nmr (CDC13): 8 = 8.12 (m, 2H), 7.66 (d, IH), 7.49 (t, IH), 6.50 (m, 2H), 4.52 (m, 2H), 3.72 (s, 3H), 3.61 (s, 2H), 1.87 (m, IH), 1.32 (m, 4H), 1.07 (m, IH), 0.81(d, 6H). Optical Rotation: [a]23 = -7.3° (c 5, MeOH). C.gHyNjOs (MW = 379); mass spectroscopy (MH+) 379. Example 148 Synthesis of N-[iV-(3-NitrophenylacetyI)-L-alaninyl]-L-isoleucine Following General Procedure AF and using Af-[/V-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine methyl ester (from Example 147 above), the title compound was prepared as a solid. NMR data was as follows: 'H-nmr (DMSO-</6): 8 = 8.41 (d, IH), 8.15 (s, IH), 8.07 (d, IH), 7.91 (d, IH), 7.68 (d, IH), 7.53 (t, IH), 4.36 (m, IH), 4.12 (m, IH), 3.62 (s, 2H), 1.71 (m, IH), 1.31 (m, IH), 1.18 (d, 3H), 1.07 (m, IH), 0.79 (m, 6H). Optical Rotation: [a]23 = -42° (c 5, MeOH). C17H23N206 (MW = 365.3); mass spectroscopy (MH+) 366. Prxnted from Mimosa WO 98/22494 PCT/US97/20804 — 268 - Example 149 Synthesis of Af-[iV-[Af-(3-NitrophenylacetyI)-L-aIaninylJ-L-threoninyl]-1^ valine Ethyl Ester Following General Procedure C and using N-[JV-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine (prepared from N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine methyl ester (from Example 144 above) using General Procedure AF) and L-valine ethyl ester hydrochloride (Aldnch), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.1 in 96:4 CHCl3/MeOH) and the product was purified by silica gel chromatography using 96:4 CHCl3/MeOH as the eluent. NMR data was as follows: 'H-nmr (CDC13): 8 = 8.12 (m, IH), 7.60 (d, IH), 7.48 (t, IH), 7.05 (d, IH), 6.98 (d, IH), 6.48 (d, IH), 4.60 (m, IH), 4.47 (m, 3H), 4.22 (m, 2H) 3.65 (s, 2H), 2.19 (m, IH), 1.38 (d, 3H), 1.28 (t, 3H), 1.09 (d, 3H), 0.87 (m, 6H). Optical Rotation: [a]23 = -85° (c 5, MeOH). Example 150 Synthesis of Methyl Ar-fA'-(3-nitrophenylacetyl)-L-aIaninyI]-(S)-2-aminopentanoate Following General Procedure C and using JV-(3-nitrophenylacetyl)-L-alanine (from Example Dll above) and methyl (S)-2-aminopentanoate hydrochlonde (prepared from (S)-2-aminopentanoic acid (Novabiochem) using General Procedure H), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.4 in 9:1 CHCl3/MeOH). NMR data was as follows: lH-nmr (DMSO-d6): 8 = 8.39 (m, IH), 8.28 (m, IH), 8.19 (m, IH), 8.11 (m, IH), 7.73 (d, IH), 7.61 (d, IH), 4.36 (m, IH), 4.22 (m, IH), 3.64 (m, 5H), 1.62 (m, 2H), 1.26 (m, 2H), 1.22 (d, 3H), 0.86 (m, 3H). Optical Rotation: [a]23 = -29° (c 1, MeOH). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 269 - CnH^NjOa (MW = 365); mass spectroscopy (MH+) 366. Example 151 Synthesis of /V-[AM3-Nitrophenylacetyl)-L-alaninyl]-L-leucine Methyl Ester Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example Dll above) and L-leucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.75 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent. NMR data was as follows: 'H-nmr (CDC13): 5 = 8.12 (m, 2H), 8.04 (m, IH), 7.58 (m, IH), 7.48-7.30 (m, 2H), 7.11 (d, IH), 4.63 (m, IH), 4.48 (m, IH), 3.68 (s, 2H), 3.64 (s, 3H), 1.63 (m, IH), 1.31 (m, 2H), 0.85 (d, 3H), 0.82 (m, 3H). Optical Rotation: [a]^ = -32° (c 1, MeOH). Ci8H2JN306 (MW = 379); mass spectroscopy (MH+) 380. Example 152 Synthesis of N-t/V-PjS-DifluorophenylacetyO-L-alaninyl]-L-leucine Methyl Ester Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-leucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.5 in 9:1 CHCl3/MeOH). NMR data was as follows: 'H-nmr (CDC13): 5 = 6.78 (m, 2H), 6.69 (m, IH), 4.52 (m, 2H), 3.73 (m, IH), 3.52 (d, 2H), 1.63 (m, 2H), 1.36 (m, 3H), 0.88 (m, 3H). Optical Rotation: [a]^ = -34° (c 1, MeOH). Ci8H24N204F2 (MW = 370); mass spectroscopy (MH+) 370. Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 270 - Example 153 Synthesis of W-2-Methoxyethyl-iV'-[W-(3,5-difluoroplienylacetyI)-L-alaniny]]-L-aIaninamide 5 Following General Procedure C and using N-[N-(3 .S-difluorophenylacetyO- L-alaniny 1] -L-alanine (from Example D7 above) and 2-methoxyethylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.35 in 9:1 CHCl3/MeOH). NMR data was as follows: 10 'H-nmr (DMSO-rfe): 5 = 8.32 (m, IH), 7.98 (d, IH), 7.82 (m, IH), 7.07 (m, IH), 6.97 (m, 2H), 4.25 (m, 2H), 3.52 (s, 2H), 3.32 (m, 3H), 3.20 (m, 4H), 1.19 (m, 6H). Optical Rotation: [a]23 = -50° (c 1, MeOH). Cl7H23N304F2 (MW = 371); mass spectroscopy (MH+) 372. 15 Example 154 Synthesis of /V-2-(/V,/V-Dimethylamino)ethyl-A''-I7V-(3,5-difiuorophenyIacetyl)-L-alaninylJ-L-alaninamide Following General Procedure C and using N-[7V-(3,5-difluorophenylacetyl)-20 L-alaninyl]-L-alanine (from Example D7 above) and iV,N-dimethyl- ethylenediamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.05 in 9:1 CHCl3/MeOH). NMR data was as follows: 'H-nmr (DMSO-^): 5 = 8.38 (m, IH), 8.02 (m, IH), 7.66 (m, IH), 7.09 25 (m, IH), 6.97 (m, 2H), 4.22 (m, 2H), 3.53 (s, 2H), 3.08 (m, 2H), 2.22 (m, 2H), 2.11 (m, 6H), 1.21 (d, 6H). Optical Rotation: [a]23 = -55° (c 1, MeOH). C18H26N403F2 (MW = 384); mass spectroscopy (MH+) 384. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 271 - Example 155 Synthesis of Ar-CyclohexyWV'-[yV-(3,5-difluorophenylacetyI)-L-alaninyl]-L-alaninamide 5 Following General Procedure C and using Af-[N-(3,5-difluorophenylacetyl)- L-alaninyl]-L-alanine (from Example D7 above) and cyclohexylamine (Aldrich), the tide compound was prepared as a solid (mp = 239-244°C). The reaction was monitored by tic (Rf = 0.25 in 9:1 CHCl3/MeOH). NMR data was as follows: 10 'H-nmr (DMSO-</6): 8 = 8.39 (m, IH), 7.94 (m, IH), 7.56 (m, IH), 7.08 (m, IH), 6.97 (m, 2H), 4.20 (m, 2H), 3.32 (s, 2H), 3.27 (m, IH), 1.64 (m, 4H), 1.54 (m, 2H), 1.20 (m, 10H). Optical Rotation: [a]23 = -58° (c 1, MeOH). C20H27N303F2 (MW = 395); mass spectroscopy (MH+) 395. 15 Example 156 Synthesis of Ar-NeopentyI-A?'-[Ar-(3,5-difluorophenylacetyl)-L-alaninylJ-L-alaninamide Following General Procedure C and using AT-[7V-(3,5-difluorophenylacetyl)-20 L-alaninyl]-L-alanine (from Example D7 above) and neopentylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.25 in 9:1 CHCl3/MeOH). NMR data was as follows: 'H-nmr (DMSO-<4): 8 = 8.37 (d, IH), 8.01 (m, IH), 7.67 (m, IH), 7.11 25 (m, IH), 6.98 (m, 2H), 4.28 (m, 2H), 3.51 (s, 2H), 2.88 (m, 2H), 1.23 (d, 3H), 0.80 (m, 9H). Optical Rotation: [a]23 = -54° (c 1, MeOH). CI9H27N303F2 (MW = 383); mass spectroscopy (MH+) 383. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 272 - Example 157 Synthesis of iV-Tetrahyclrofurfuryl-Af'-[N-(3,5-difluorophenylacetyl)-L-aIaniny]]-L-alaninamide Following General Procedure C and using iV-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7 above) and tetrahydrofurfurylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.20 in 9:1 CHCl3/MeOH). NMR data was as follows: 'H-nmr (DMSO-</6): 5 = 8.36 (d, IH), 8.01 (m, 1H), 7.81 (m, IH), 7.11 (m, IH), 6.99 (m, 2H), 4.25 (m, 2H), 3.77 (m, 2H), 3.58 (m, IH), 3.51 (s, 2H), 3.21 (m, IH), 1.78 (m, 4H), 1.46 (m, IH), 1.19 (m, 6H). Optical Rotation: [a]23 = -70° (c 1, MeOH). CjjHjs^OjFj (MW = 397); mass spectroscopy (MH+) 398. Example 158 Synthesis of iV-2-Pyridylmethy I-N '-[A/- (3,5-difluoropheny lacetyl)-L-alaninyl]-L-alaninamide Following General Procedure C and using N-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7 above) and 2-(aminomethyl)pyridine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.1 in 9:1 CHCl3/MeOH). NMR data was as follows: 'H-nmr (DMSO-<4): 5 = 8.49 (m, IH), 8.41 (m, 2H), 8.14 (d, 1H), 7.74 (m, IH), 7.28 (m, 2H), 7.09 (m, IH), 6.98 (m, 2H), 4.33 (m, 4H), 3.52 (s, 2H), 1.24 (m, 6H). Optical Rotation: [a]^ = -68° (c 5, MeOH). C2oH22N403F2 (MW = 404); mass spectroscopy (MH+) 405. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 273 - Example 159 Synthesis of 3-[AT-[iV-(3,5-Difluorophenylacetyl)-LraIaninyl]-L-alaninyI]thiazoIidine Following General Procedure C and using N-|7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7 above) and thiazolidine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.25 in 9:1 CHCVMeOH). NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 8.34 (m, 2H), 8.22 (m, 1H), 7.09 (m, 1H), 6.98 (m, 2H), 4.68-4.23 (m, 4H), 3.81-3.6 (m, 2H), 3.52 (s, 2H), 3.01 (m, 2H), 1.19 (m, 6H). Optical Rotation: [a]23 = -67° (c 1, MeOH). CnH2iN303F2 (MW = 385); mass spectroscopy (MH+) 385. Example 160 Synthesis of Methyl Ar-[Ar-(3,5-difluorophenylacetyI)-L-alaninyl]-(S)-2-aminobutanoate Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alamne (from Example B2 above) and methyl (S)-2-aminobutanoate hydrochloride (prepared from (S)-(+)-2-aminobutyric acid (Aldrich) using General Procedure H), the title compound was prepared as a solid (mp = 103-106°C). NMR data was as follows: 'H-nmr (CDClj): 5 = 6.83 (m, 2H), 6.72 (m, IH), 6.49 (d, IH), 4.55 (m, IH), 4.48 (m, IH), 3.72 (s, 3H), 3.49 (s, 2H), 1.85 (m, IH), 1.69 (m, IH), 1.39 (d, 3H), 0.86 (t, 3H). Optical Rotation. fa]23 = -70° (c 1, MeOH). C,6H20N2O4F2 (MW = 342.35); mass spectroscopy (MH+) 342. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 274 - Example 161 Synthesis of Methyl iV-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate Following General Procedure C and using N-(3,5-difluorophenylacetylJ-L-alanine (from Example B2 above) and methyl (S)-2-aminopentanoate hydrochloride (prepared from (S)-2-aminopentanoic acid (Novabiochem) using General Procedure H), the title compound was prepared as a solid (mp = 154-155 °C). NMR data was as follows: 'H-nmr (CDC13): 8 = 6.80 (m, 2H), 6.69 (m, IH), 6.45 (d, IH), 6.28 (d, IH), 4.52 (m, 2H), 3.71 (s, 3H), 3.51 (s, 2H), 1.77 (m, IH), 1.58 (m, IH), 1.35 (d, 3H), 1.27 (m, 2H), 0.87 (t, 3H). Optical Rotation: [a]23 = -69° (c 1, MeOH). Example 162 Synthesis of Methyl A/-0V-(3-nitrophenylacetyI)-L-alaninyI]-(S)-2-aminobutanoate Following General Procedure C and using /V-(3-nitrophenylacetyl)-L-alanine (from Example Dll above) and methyl (S)-2-aminobutanoate hydrochloride (prepared from (S)-(+)-2-aminobutync acid (Aldrich) using General Procedure H), the title compound was prepared as a solid (mp = 154-157°C). NMR data was as follows: 'H-nmr (CDC13): 8 = 8.13 (m, IH), 8.04 (m, IH), 7.57 (m, IH), 7.38 (m, IH), 4.72 (m, IH), 4.39 (m, IH), 3.69 (s, 3H), 3.41 (s, 2H), 1.73 (m, IH), 1.61 (m, IH), 1.34 (d, 3H), 0.79 (t, 3H) Optical Rotation: [a]23 = -75° (c 1, MeOH). Example 163 Synthesis of Af-(R)-jec-Butyl-Ar'-[yV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 275 - Following General Procedure C and using /V-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7 above) and (R)-(-)-j«>butylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.15 in 95:5 CHCl3/MeOH) and the product was 5 purified by silica gel chromatography using 95:5 CHC13 MeOH as the eluent. NMR data was as follows: 'H-nmr (DMSO-^: 5 = 8.39 (m, IH), 7.95 (m, IH), 7.49 (m, ffl), 7.09 (m, IH), 7.01 (m, 2H), 4.20 (m, 4H), 3.61 (m, IH), 3.52 (s, 2H), 1.34 (m, 2H), 1.21 (m, 6H), 0.97 (d, 3H), 0.79 (m, 3H). 10 Optical Rotation: [ofla = -50° (c 1, MeOH). C^KyNjO^ (MW = 369.41); mass spectroscopy (MH+) 370. Example 164 Synthesis of l-[/V-[/V-(3,5-Difluorophenylacetyl)-I^alaninyl]-15 L-alaninyl]pyrrolidine Following General Procedure C and using /V-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7 above) and pyrrolidine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.15 in 95:5 CHCl3/MeOH) and the product was purified by silica gel 20 chromatography using CHCl3/MeOH as the eluent. NMR data was as follows: 'H-nmr (DMSO-<4): 5 = 8.31 (m, IH), 8.08 (m, IH), 7.09 (m, IH), 6.99 (m, 2H), 4.48 (m, IH), 4 29 (m, IH), 3.51 (s, 2H), 3.44-3.22 (m, 4H), 1.80 (m, 4H), 1.27 (m, 6H). 25 CjgH^NjO^ (MW = 367.40); mass spectroscopy (MH+) 367. Example 165 Synthesis of /V-(S)-sec-Butyl-W-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 276 -- Following General Procedure C and using iV-|W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7 above) and (S)-(+)-j£c-butylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.25 in 9:1 CHCl3/MeOH) and the product was purified 5 by silica gel chromatography using CHCl,/MeOH as the eluent. NMR data was as follows: 'H-nmr (DMSO-J6): 8 = 8.38 (m, IH), 7.92 (m, IH), 7.30 (m, IH), 7.18 (m, IH), 6.99 (m, 2H), 4.20 (m, 4H), 3.62 (m, IH), 3.52 (s, 2H), 1.34 (m, 2H), 1.20 (m, 6H), 1.01 (m, 3H), 0.81 (t, 3H). 10 Optical Rotation: [a]23 = -52° (c 1, MeOH). C19H25N303F2 (MW = 369.41); mass spectroscopy (MH+) 370. Example 166 Synthesis of Ar-[A'-(3,5-Dinuorophenylacetyl)-I^alaninyJ]-15 L-valine Methyl Ester Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-valine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. NMR data was as follows: 20 lH-nmr (CDC13): 5 = 6.81 (m, 2H), 6.73 (m, IH), 6 48 (d, IH), 6.22 (d, IH), 4.48 (m, 2H), 3.70 (s, 3H), 3.51 (s, 2H), 2.16 (m, IH), 1.37 (m, IH), 0.87 (t, 3H). Optical Rotation: [a]23 = -65° (c 1, MeOH). C17H22N204F2 (MW = 356.37); mass spectroscopy (MH+) 360. 25 Example 167 Synthesis of /V-2-Fluoroethyl-/V'-[/V-(3,5-difluorophenylacetyD-L-alaninyl]-L-alaninamide Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-30 L-alaninyl]-L-alanine (from Example D7 above) and 2-fluoroethylamine Printed from Mimosa WO 98/22494 PCT/US97/20804 - 277 - hydrochloride (Aldrich), the title compound was prepared as a solid (mp = 230-235°C). NMR data was as follows: 'H-nmr (DMSO-<4): 6 = 8.38 (d, IH), 8.04 (m, 2H), 7.07 (m, IH), 6.99 (m, 2H), 4.39 (m, 2H), 4.24 (m, IH), 3.53 (s, 2H), 3.35 (m, 2H), 1.20 (m, 6H). Optical Rotation: [a]23 = -33° (c 1, MeOH). C16H20N3O3F3 (MW = 359.37); mass spectroscopy (MH+) 359. Example 168 Synthesis of N-[(S)-6-Methyl-3-oxohept-2-yl]-Ar'-(3,5-difluorophenylacetyI)-L-alaninamide Following General Procedure M and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and (S)-6-methyl-3-oxohept-2-ylamine hydrochloride (prepared by treating N-BOC-L-alanine N-methoxy-N-methyl amide (Weinreb et al., Tetrahedron Lett., 22, 3815 (1981)) with isopropyl magnesium bromide (Aldrich), followed by removal of the BOC group using General Procedure P), the title compound was prepared as a solid. The product was purified by silica gel chromatography using CHCl3/MeOH as the eluent. NMR data was as follows: 'H-nmr (CDC13): 8 = 6.84 (m, 2H), 6.69 (m, IH), 6.31 (m, IH), 4.50 (m, 2H), 3.51 (s, 2H), 2.48 (m, 2H), 1.47 (m, 2H), 1.32 (m, 7H), 0.90 (d, 6H). Optical Rotation: [a]23 = -42° (c 1, MeOH). C,9H2«N20jF2 (MW = 368); mass spectroscopy (MH+) 368. Example 169 Synthesis of AT-4-Nitrobenzyl- N '-[N- (3,5-difluorophenylacety 1) -L-alaninyl]-(S)-2-aminobutyramide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 278 - Following General Procedure C and using iV-[JV-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutyric acid (prepared from methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate (from Example 160 above) using General Procedure AF) and 4-nitrobenzylamine (Aldrich), the title 5 compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.3 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCyMeOH as the eluent. NMR data was as follows: 'H-nmr (DMSO-</5): 5 = 8.57 (t, IH), 8.40 (d, IH), 8.21 (d, 2H), 8.02 10 (d, IH), 7.50 (d, 2H), 7.08 (m, IH), 6.98 (m, 2H), 4.42 (d, 2H), 4.37 (m, IH), 4.17 (m, IH), 3.53 (s, 2H), 1.64 (m, 2H), 1.21 (m, 3H), 0.83 (t, 3H). Optical Rotation: [a]23 = -42° (c 1, MeOH). C22H24N405F2 (MW = 462.45); mass spectroscopy (MH+) 462. Example 170 15 Synthesis of N-4-Nitrobenzyl-iV'-[iY-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanamide Following General Procedure C and using 7V-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoic acid (prepared from methyl N-[N-(3,5-20 difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate (from Example 161 above) using General Procedure AF) and 4-nitrobenzylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.3 in 95:5 CHCl3/MeOH) and the product was purified by recrystallization from acetonitrile. 25 NMR data was as follows: lH-nmr (DMSO-<4): 5 = 8.57 (m, IH), 8.41 (d, IH), 8.22 (d, 2H), 8.06 (d, IH), 7.51 (d, 2H), 7.12 (m, IH), 7.00 (m, 2H), 4.43 (d, 2H), 4.30 (m, 2H), 3.56 (s, 2H), 1.65 (m, 2H), 1.29 (m, 5H), 0.91 (t, 3H). Optical Rotation: [a]23 = +97° (c 1, MeOH). 30 C23H26N4OjF2 (MW = 476.4); mass spectroscopy (MH+) 476. Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 279 - Example 171 Synthesis of Methyl A/-[7V-(3,5-Difluorophenylacetyl)-L-aIaninyI]-2-amino-2-(3-fluorophenyl)acetate Following General Procedure C and using JV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(3-fluorophenyl)acetate hydrochloride (from Example D12 above), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.2 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.36 (m, IH), 7.18 (m, IH), 7.13 (m, IH), 7.06 (m, IH), 6.87 (m, 2H), 6.74 (m, IH), 6.09 (m, IH), 5.49 (d, IH), 4.59 (m, IH), 3.74 (s, 3H), 3.57 (s, 2H), 1.35 (d, 3H), 0.97 (d, 3H). C20H19N2O4F3 (MW = 408.38); mass spectroscopy (MH+) 408. Example 172 Synthesis of W-[iV-(3,5-DifIuorophenylacetyl)-L-alaninyI]-(S)-2-amino-2-(2-thienyl)acetamide Following General Procedure L and using methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetate(from Example 178 below), the title compound was prepared as a solid (mp = decomposition at 190°C). The product was purified by preparative LC 2000 chromatography using 8:2 EtOAc/hexanes as the eluent. NMR data was as follows: 'H-nmr (CDCl3/DMSO-</6): 5 = 8.9-6.14 (Ar + NH's 10 H), 5.43-5.39 (m, IH), 4.16-4.10 (m, J=7 Hz, IH), 3.19 (s, 2H), 1.15 (d, J=7.05 Hz, 3H). C17H17F2N303S (MW = 381.4); mass spectroscopy (MH+) 381. Example 173 Synthesis of Methyl /V-[/V-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiophen-2-yl)acetate Printed from Mimosa WO 98/22494 PCT/US97/20804 - 280 - Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(5-chlorobenzothiophen-2-yl)acetate (prepared from 5-chlorobenzothiophene-2-acetic acid [CAS No. 23799-65-7] using General Procedure G, followed by 5 amination using a procedure essentially the same as that described in Example D4 above), the title compound was prepared as a solid (mp = 189-190°C). The product was purified by titration using Et20/hexanes. NMR data was as follows: 'H-nmr (CDC13): 8 = 7.7-7.63 (m, 2H), 7.33-7.17 (m, 2H), 6.89-6.63 (m, 10 3H), 6.16-6.03 (m, IH), 5.85 (dd, IH), 4.7-4.53 (m, IH), 3.83 (s, 1.5H), 3.8 (s, 1.5H), 3.59 (s, IH), 3.5 (s. IH), 1.4 (dt, 3H). C22H19C1F2N204S (MW = 481); mass spectroscopy (MH+) 480. Example 174 Synthesis of 15 Ethyl iV-[Af-(3,5-Difluorophenylacetyl)- L-alaninyl]-2-amino-2-(benzothiophen-2-yl)acetate Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(benzothiophen-2-yl)acetate [CAS No. 98800-64-7], the tide compound was prepared as a solid 20 (mp = 189-190°C). The product was purified by preparative LC 2000 chromatography using 2:8 EtOAc/hexanes as the eluent. NMR data was as follows: 'H-nmr (CDC13): 8 = 7.8-7.75 (m, 2H), 7.34-7.27 (m, 2H), 7.25-7.09 (m, 3H), 6.81-6.76 (m, IH), 6.76-6.63 (m, IH), 6.23 (dd, J=7 Hz, IH), 5.84(d, 25 J=7.07 Hz, IH), 4.61-4.59 (m, IH), 4.33-4.2 (m, 2H), 3.54 (s, IH), 3.50 (s, IH), 1.70 (d, J=11.9 Hz, 1.5H), 1.38 (d, J = 11.9 Hz, 1.5 H), 1.36-1.23 (dt, 3H). C23H22N204SF2 (MW = 460.49); mass spectroscopy (MH+) 460. Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 281 - Example 175 Synthesis of Methyl N-[N-(3,S-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-3-y])acetate Following General Procedure C and using A/-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(benzothiophen-3-yl)acetate (prepared from 2-amino-2-(benzothiophen-3-yl)acetic acid [CAS 95834-94-9] using General Procedure H), the title compound was prepared as a solid (mp = 185-186°C). NMR data was as follows: 'H-nmr (CDC13): 5 = 7.86 (m, 2H), 7.4-7.3 (m, 3H), 7.4-7.2 (m, 2H), 6.9-6.6 (m, 3H), 6.3-6.13 (m, IH), 5.95-5.85 (m, IH), 4.55-4.5 (m, IH), 3.75 (s, 1.5H), 3.65 (s, 1.5H), 3.55 (s, IH), 3.35 (s, IH), 1.4 (d, 1.5H), 1.3 (d, 1.5H). C22H20N2O4F2S (MW = 446); mass spectroscopy (MH+) 446. Example 176 Synthesis of Methyl /V-[/V-(3,5-DifIuorophenylacetyl)-L-alaninyl]-2-amino-2-(2-thienyl)acetate Following General Procedure C and using /V-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(2-thienyl)acetate (prepared from L-c*-2-thienylglycine (Sigma) using General Procedure G), the title compound was prepared as a solid (mp = 161-162°C). The product was purified by preparative LC 2000 chromatography using 1:4 EtOAc/hexanes. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.3-6.65 (Ar, 7H), 6.25 (bt, IH), 5.8 (dd, IH), 4.68-4.5 (m, IH), 3.85 (s, IH), 3.75 (s, IH), 3.52 (s, IH), 3.5 (s, IH), 1.35 (overlaying d, 3H). C|8H,8N204F2S (MW = 396); mass spectroscopy (MH+) 396.1. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 282 - Example 177 Synthesis of Ethyl 2V-[/V-(3,5-DifluorophenyIacetyl)-L-alaninyl]-2-amino-2-(benzothiopben-5-yl)acetate Following General Procedure C and using //-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(benzothiophen-5-yl)acetate (prepared as described in S. Kukolja et al., J. Med. Chem., 1985, 28, 1896-1903), the title compound was prepared as a solid (mp = 126.5-127.5 °C). The product was purified by preparative LC 2000 chromatography using 1:1 hexanes/EtOAc as the eluent. NMR data was as follows: 'H-nmr (CDC13): 5 = 8.1 (s, IH), 8.05 (s, IH), 7.6-7.5 (m, 2H), 7.4-7.25 (m, 3H), 7.15 (bd, J=12 Hz, 5H), 7.05 (bd, J=12 Hz, 5H), 6.89-6.675 (m, 2H), 6.225 (bd, J=12 Hz, 5H), 6.075 (bd, J = 12 Hz, 5H), 4.55 (q, J=7.5 Hz, IH), 4.2 (dq, 2H), 3.575 (s, IH), 3.242 (s, IH), 1.4 (d, J=7.05 Hz, 1.5H), 1.15 (d, J=7.05 Hz, 1.5H). C23H22N2O4F2S (MW = 460); mass spectroscopy (MH+) 460.1. Example 178 Synthesis of Methyl A,-[Ar-(3,5-Dinuorophenylacetyl)-I^alaninyl]-(S)-2-amino-2-(2-thienyl)acetate Following General Procedure G and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)aceticacid (from Example 180 below), the title compound was prepared as a solid (mp = 180-181 °C). The product was purified by preparative LC 2000 chromatography using 6:4 EtOAc/hexanes as the eluent. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.3-6.6 (Ar + NH, 7H), 6.37 (bd, J=7 Hz, IH), 5.77 (d, J=7 Hz, IH), 4.6-4.56 (m, J=7 Hz, IH), 3.7 (s, 3H), 3.4 (s, 2H), 1.38 (d, J=7 Hz, 3H). C18HlgN204SF2 (MW = 396); mass spectroscopy (MH+) 396.1. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 283 - Example 179 Synthesis of /erf-Butyl Af-[2V-(3,5-DifluorophenylacetyI)-L-alaninyl]-(S)-2-amino-2-(2-thienyI)acetate 5 Following General Procedure J and using /V-[//-(3,5-difluorophenylacetyl)- L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetic acid (from Example 180 below), the title compound was prepared as a solid (mp = 117-118°C). The product was purified by tituraration using ether/hexanes. NMR data was as follows: 10 'H-nmr (CDC13): 5 = 7.24 (d, J=6.5 Hz, IH), 7.05-6.63 (m, 6H), 6.19 (bd, J=7.2 Hz, IH), 5.66 (d, J=7.5 Hz, IH), 4.6-4.5 (m, IH), 3.5 (s, 2H), 1.44 (s, 9H), 1.38 (d, J=7.1 Hz, 3H). C2|H24N204SF2 (MW = 438.5); mass spectroscopy (MH+) 438. Example 180 15 Synthesis of /V-[/V-(3,5-DifluorophenylacetyI)-L-alaninyl]-(S)-2-amino-2- (2-thienyI)acetic Acid Following General Procedure M and using /V-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-a-2-thienylglycine (Sigma), the title 20 compound was prepared as a solid. The product was punfied by tituration using EtOAc/hexanes. NMR data was as follows: 'H-nmr (DMSO-</5): 8 = 8.73 (d, J=7 Hz, IH), 8.38 (d, J=7 Hz, IH), 7.56-7.4 (m, IH), 7.2-6.9 (m, 4H), 5.54 (d, J=8 Hz, IH), 4.5-4.3 (m, IH), 25 3.33 (s, 2H), 1.23 (d, J=7 Hz, 3H). C17H,6N204SF2 (MW = 382); mass spectroscopy (MH+) 382. Example 181 Synthesis of Methy! /V-[/V-(3,5-DifluorophenylacetyI)-L-alaninyl]-30 2-amino-2-(l//-tetrazol-5-yl)acetate Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 284 - Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(l#-tetrazol-5-yl)acetate (prepared from ethyl lH-tetrazole-5-acetate [CAS 173367-99-2] using procedures essentially the same as those described in S. Kukolja, J. Med. 5 Chem., 1985, 28, 1886-1896), the title compound was prepared as a solid. The reaction was product was purified by tituration using EtOAc/hexanes. NMR data was as follows: 'H-nmr (DMSO-ds): 5 = 9.13 (d, J=7.6 Hz, IH), 8.39 (t, J=7 Hz, IH), 7.1-6.95 (m, 3H), 5.9 (dd, IH), 4.4-4.3 (m, IH), 4.14 (q, J=7 Hz, 2H), 3.5 10 (s, 3H), 1.27-1.11 (m, 6H). C16H18N604F2 (MW = 396.3); mass spectroscopy (MH+) 396.3. Example 182 Synthesis of Methyl N- [N- (3,5-Difluorophenylacety l)-L-a!aninyl]-15 (S)-2-amino-2-(6-methoxy-2-naphthyl)acetate Following General Procedure C and using jV-(3,5-difluorophenylacetyl)-L-alamne (from Example B2 above) and methyl (S)-2-amino-2-(6-methoxy-2-naphthyl)acetate (from Example D3 above), the title compound was prepared as a solid (mp = 177-178°C). The product was purified by tituration using 20 hexanes/EtOAc. NMR data was as follows: 'H-nmr (DMSO-</6): 5 = 8.84 (d, J=9 Hz, IH), 8.4 (d, J=9 Hz, IH), 7.90-7.76 (m, 2H), 7.247-6.90 (m, 5H), 5.5 (J=7 Hz, IH), 4.243 (d, J=3.5 Hz, IH), 3.86 (s, 3H), 3.6 (s, 3H), 3.29 (s, 2H), 1.26 (d, J=7.5 Hz. 3H). 25 C25H24N2O5F2 (MW = 470.48), mass spectroscopy (MH+) 470. Example 183 Synthesis of Methyl /V-[A''-(3,5-DifIuorophenylacetyl)-L-alaninyl]-2-amino-2-(3-trifluoromethylphenyl)acetate Printed from Mimosa WO 98/22494 PCT/US97/20804 - 285 - Following General Procedure C and using A/-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(3-trifluoromethylphenyl)acetate (prepared from 2-(hydroxyimino)-2-(3-trifluoromethylphenyl)acetic acid [CAS 179811-81-5] using General Procedures G and R above), the title compound was prepared as a solid (mp = 133-134°C). The product was purified by tituration from EtOAc/hexanes. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.57-7.37 (m, 4H), 6.8-6.6 (m, 3H), 6.05 (BA, IH), 5.5 (A, J=7.5Hz, IH), 3.7 (s, 1.5H), 3.675 (s, 1.5H), 3.5 (s, IH), 3.45 (s, IH), 1.33 (d, J=7.5 Hz, 1.5H), 1.275 (d, J=7.5 Hz, 1.5H). C21H,9N204Fj (MW = 458.39); mass spectroscopy (MH+) 459. Example 184 Synthesis of Methyl /V-IN-0,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4,S,6,7-tetrahydrobenzothiophen-2-yl)acetate Following General Procedure C and using /V-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetate (prepared from N-Boc-2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetic acid [CAS 95361-97-0] using General Procedures G above and the Boc removal procedure descnbed in Example D3 above), the title compound was prepared as a solid. The product was purified by tituration using Et20/hexanes. NMR data was as follows: 'H-nmr (CDC13): 8 = 7.05 (d, J=5 Hz, IH), 7.02 (d, J=5 Hz, IH), 6.82-6.66 (m, 3H), 6.31 (bd, J=8 Hz, IH), 5.66 (dd, J=7.2 Hz, IH), 4.63-4.55 (m, IH), 3.76 (s, 1.5H), 3.75 (s, 1.5H), 3.52 (s, IH), 3.50 (s, IH), 2.67-2.65 (m, 2H), 2 54-2.52 (m, 2H), 1.77-1.7 (m, 4H), 1.36 (dd, J=7 Hz, 3H). C22H24N2O4F2S (MW = 450); mass spectroscopy (MH+) 450. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 286 -- Example 185 Synthesis of Methyl Af-[7V-(3,5-DifluorophenylacetyI)-L-alaninyl]-2-amino-2-(thieno[2,3-i]thiophen-2-yl)acetate 5 Following General Procedure C and using /V-(3,5-difluorophenylacetyl)-L- alanine (from Example B2 above) and methyl 2-amino-2-(thieno[2,3-£]thiophen-2-yl)acetate (from Example D4 above), the title compound was prepared as a solid. The product was purified by titruation from EtjO/hexanes. NMR data was as follows: 10 'H-nmr (CDC13): 5 = 7.35 (d, J=7.5 Hz, IH), 7.2-7.0 (m, 3H), 6.9-6.69 (m, 3H), 6.13-6.0 (m, IH), 5.8 (dd, IH), 4.63-4.5 (m, IH), 3.8 (s, 3H), 3.58 (s, IH), 3.469 (IH), 1.4 (dd, 3H). C20H18N2O4F2S2 (MW = 452); mass spectroscopy (MH+) 452. Example 186 15 Synthesis of Methyl /V-[/V-(3,5-DifluorophenyIacetyl)-L-alaninyl]-2-amino-2-(2-methylthiazol-4-yl)acetate Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(2-methyIthiazol-4-20 yl)acetate (prepared from /V-Boc-2-amino-2-(2-methylthiazol-4-yl)acetic acid [CAS 105381-90-6] using General Procedure H above), the title compound was prepared as a solid. The product was purified by tituration using Et20/hexanes. NMR data was as follows: 'H-nmr (CDC13): 5 = 7.2-6.66 (pr + NH, 5H), 5.69-5.6 (m, IH), 4.8-25 4.69 (m, IH), 3.76 (s, 3H), 3.56 (s, IH), 3.5 (s, IH), 2.69 (s, 3H), 1.4 (d, J = 14 Hz, 1.5H), 1.35 (s, J = 14 Hz, 1.5H). C18H19N304F2S (MW = 411); mass spectroscopy (MH+) 411. Example 187 Synthesis of 30 Methyl (3S,4S)-/V-[/V-(3,5-DifluorophenylacetyI)- L-alaninyl]-4-amino-3-hydroxy-5-phenyIpentanoate Printed from Mimosa WO 98/22494 PCT/US97/20804 - 287 - Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (3S>4S)-4-amino-3-hydroxy-5-phenylpentanoate (Novabiochem), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.2 in 95:5 CHCl3/MeOH) and the 5 product was purified by flash column chromatography using 95:5 CHCl3/MeOH as the eluent. NMR data was as follows: 'H-nmr (CDC13): 5 = 8.29 (d, IH), 7.65 (d, IH), 7.40-7.20 (m, 5H), 7.10 (m, IH), 6.99 (m,2H), 5.27 (d, IH), 4.47 (bs, 2H), 4.09 (m, 2H), 3.57 and 10 3.51 (m, 3H), 2.72 (m, 2H), 2.31 (m, 2H), 1.19 (m, 2H). Optical Rotation: [a]23 = -66° (c 1, MeOH). C23H26N205F2 (MW = 448); mass spectroscopy (MH+) 449. Example 188 Synthesis of 15 Methyl /V-[/V-(3,5-DifluorophenyIacetyI)-L-alaninyl]- (S)-2-aminohex-4-enoate Step A — Synthesis of (S)-3-(Hex-4-enoyl)-4-(phenylmethyl)-2-oxazolidinone To a mechanically stirred solution of 9.50 g (83.2 mmol, 1.10 equiv.) of 4-20 hexenoic acid (commericially available from Lancaster, Catalog #252-427-6) and 13.9 mL (10.1 g, 99.7 mmol, 1.33 equiv.) of tnethylamine in 150 mL of dry THF, cooled to -78°C under dry N2, was added 10.71 mL (10.49 g, 87.0 mmol, 1.15 equiv.) of pivaloyl chloride (Aldnch) The mixture was warmed to 0°C for 60 min, and then recooled to -78°C. A solution of 13.4 g (75.6 mmol, 25 1.00 equiv) of (S)-(-)-(phenylmethyl)-2-oxazolidone (Aldrich) and 22 mg of triphenylmethane (indicator) in 150 mL of dry THF, stirred at -30°C to -45°C under N2, was treated dropwise with n-butyllithium (—2.5 M in hexanes) (Aldrich) until an orange color persisted (~30 mL required). The resulting solution was cooled to -78°C and then added, via rapid cannulation, to the 30 above stirred mixture containing the mixed anhydride. The residual lithiated oxazolidone was rinsed in with two 10-mL portions of dry THF and the Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 288 - resulting mixture was stirred at -78°C for 1.5 h, and then at 0°C for 1 h. The mixture was partitioned between CH2C12 and pH 7 phosphate buffer. The CH2C12 phase was washed with saturated aqueous NaHCOj followed by half-saturated aqueous NaCl, dned (MgSOJ, and evaporated in vacuo. The residual 5 cream-colored solid (22.4 g) was chromatographed (Waters Prep 2000, 5.0 cm x 25 cm 10 ft Kromasil KR60-10SIL-5025 column) in two batches eluting with 85:15 hexanes/EtOAc. The chromatographed product was recrystallized from hexane to yield 14.34 g (first crop, 69%) of the title compound as fine white needles. 'H NMR (300 MHz, CDC13) 5 7.37-7.20 (m, 5H, -C6H5), 5.60-10 5.43(m, 2H, Cfi=CHCH3), 4.71-4.63(m, IH, NCH(Ph) CH20), 4.23-4.14(m, 2H, NCH(Ph)CH20), 3.295(dd, J = 13.3, 3.3 Hz, IH, CHHQHj), 3.11-2.90 (m, 2H, CHjC=0), 2.758 (dd, J=13.3, 9.6 Hz, IH, CHHC^j), 2.42-2.34 (m, 2H, CH=CHCH2), 1.67-1.65 (m, 2H, CH=CHCH3). 15 Step B — Synthesis of (4S)-3-[(S)-2-Azidohex-4-enoyl]-4- (phenylmethyl)-2-oxazolidinone A solution of 5.47g (20.0 mmol, 1.00 equiv) of the product from Step A above in 60 mL of dry THF, stirred at -78°C under dry N2, was added via rapid cannulation to a stirred, cooled (-78°C) solution of 43.6 mL (22.0 mmol, 20 1.10 equiv) of potassium hexamethyldisilazide (0.505 M in toluene) (Aldrich) and 60 mL of dry THF. The residual imide solution was rinsed in with two 5-mL portions of dry THF. The resulting solution was stirred at -78 °C for 30 min. To the above solution of the K-enolate, stirred at -78°C under dry N2, was added a cooled (-78°C) solution of 7.43 g (24.0 mmol, 1.2 equiv) of trisyl 25 azide (prepared as described in R. E. Harmon et al., J. Org. Chem., 1973, 38, 11-16) in 60 mL of dry THF via rapid cannulation. (Note the reaction exothermed to -68°C during the addition). After 1-2 min, 4.24 mL (4.45g, 74.1 mmol, 3.7 equiv) of glacial acetic acid was added in one portion. The resulting mixture was stirred at -78°C for 15 min, and was then allowed to 30 warm to 25 °C on stirring overnight. The mixture was partitioned between CH2C12 and pH 7 phosphate buffer. The aqueous phase was extracted with CH2C12 (3X) and the organic extracts were combined, washed with dilute Printed from Mimosa WO 98/22494 PCT/US97/20804 — 289 -- aqueous NaHC03, dned (MgS04), and evaporated in vacuo. The residual oil (9.55 g) was chromatographed (Waters Prep 2000, 5.0cm x 25 cm 10 n Kromasil KR60-10SIL-5025 column) eluting with a 3 L linear gradient from 30:70 to 80:20 CH2Cl2/hexanes. After rechromatographing the mixed fractions 5 (2X), a total of 5.27 g (84% yield) of the title compound (faster eluting, major diastereomer) was isolated as a colorless, viscous oil. *H NMR (300 MHz; CDC13) 8 7.38-7.20 (m, 5H, -C6H5), 5.73-5.62 (m, IH, CH=CHCH3), 5.52-5.41 (m, IH, CH=CHCH3), 5.011 (dd, J=8.3, 5.5 Hz, IH, CH(N3) C=0), 4.71-4.63 (m, IH, NCH(Ph)CH20), 4.236 (d, J=5.1 Hz, 2H, NCH(Ph)CH20), 10 3.338 (dd, J= 13.4, 3.3 Hz, IH, CHHC6H5), 2.827 (dd, J= 13.4, 9.5 Hz, IH, CHHC6H3), 2.64-2.46 (m, 2H, CH2CH=CHCH3), 1.694 (dd, J=6.4, 1.1 Hz, 3H, CH=CHCE3). Step C — Synthesis of (S)-2-Azidohex-4-enoic Acid A solution of 5.00 g (15.91 mmol) of the product from Step B above in 15 240 mL of THF and 80 mL of deionized water, stirred at 0°C under N2, was treated with 762 mg (31.8 mmol, 2.00 equiv) of LiOH (anhydrous powder). After stirnng at 0°C for 30 mm, 100 mL of 0.5 N aqueous NaHC03 was added and the THF was removed by rotary evaporation in vacuo. The residue was diluted to 400-500 mL with H20 and extracted with 5 portions of CH2C12. The 20 aqueous phase was acidified to pH 1-2 by the cautious addition of 5 N HCl, and then was extracted with 4 portions of EtOAc. The EtOAc extracts were combined, dried (Na2S04), and evaporated in vacuo to yield 2.45 g (99%) of the title compound as a light amber oil. :H NMR (300 MHz, CDC13) 8 11.38 (br s, IH, C02H), 5.73-5.62 (m, IH, CH3CH=CH), 5.48-5.38 (m, 25 1H,CH=CHCH2), 3.928 (dd, J= 7.8, 5.4 Hz, IH, CH(N3)C02H), 2.66-2.47(m, 2H, CH=CHCH2), 1.703 (dd, J=6.4, 1.1 Hz, 3H, CH3. Step D — Methyl A'-[A'-te/t-Butoxycarbonyl-L-alaninyl]-(S)-2-aminohex-4-enoate A solution of 504.7 mg (3.25 mmol) of the product from Step C above in 30 diethyl ether, cooled to 0°C, was treated dropwise with ethereal diazomethane Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 290 - (prepared as described in L. F. Fieser et al., "Reagents for Organic Synthesis", Vol. 1, p. 191, Wiley & Sons (1967)) until a yellow color persisted. The excess diazomethane was removed by entraining with N2, and the ether was evaporated under a stream of N2. The residual oil was dissolved in 10 mL of 5 anhydrous methanol. The solution was cooled to 0°C under dry N2 and 1.24 g (6.54 mmol, 2.0 equiv) of anhydrous SnCl2 was added. The mixture was stirred at <25°C for 4 h, and the solvent was evaporated in vacuo to afford a solid tin-amine complex. A solution of 1.23 g (6.50 mmol, 2.00 equiv.) of N-Boc-L-alanine (Sigma) 10 and 0.715 mL (0.658 g, 6.50 mmol, 2.0 equiv.) of 4-methylmorpholine (redistilled, 99.5%) (Aldrich) in 15 mL of anhydrous THF, cooled to -15 to -20°C under dry N2, was treated dropwise with 0.861 mL (0.907 g, 6.50 mmol, 2.00 equiv.) of wo-butyl chloroformate (Aldrich). After stirring at -15 to -20°C for 20 min, the resulting mixture containing the mixed anhydride was 15 added via cannulation to the solid tin-amine complex (vide supra). The residual mixed anhydride was rinsed in with 7 mL of THF and 1.1 g (13.1 mmol, 4.0 equiv.) of NaHC03 powder and 5 mL of H20 was added. The mixture was stirred at 0°C for 5 h. An additional 1.1 g (13.1 mmol, 4 0 equiv ) of NaHCOj powder and 5 mL of H20 was added and the mixture was stirred at 20 20°C for 1.5 h. The mixture was filtered to remove the gelatinous precipitate, and the filter cake was washed with several portions of EtOAc. The filtrate was washed with saturated aqueous NaHCOj (the aqueous phase was back-extracted with 3 portion of EtOAc), followed by pH 4-5 phosphate buffer (the aqueous phase was back-extracted with 3 portions of EtOAc) The organic 25 phase was dried (Na2S04) and evaporated in vacuo. The residual straw colored oil (1.21 g) was chromatographed (Waters Prep 2000, 5 0 cm x 25 cm 10 ^ Kromasil KR60-10SIL-5025 column) eluting with a 3-L linear gradient from 80:20 to 40:60 hexane/EtOAc to yield 0.9088 g (89%) of the tide compound as a white solid. Tic Rf 0.25 [silica, hexane/EtOAc 6:4)]; 'H NMR (300 MHz, 30 CDClj) 5 6.61 (d, J= 7.6 Hz, IH, NH), 5.60-5.48(m, IH, CH=CHCH3), Printed from Mimosa WO 98/22494 PCT/US97/20804 - 291 - 5.33-5.23 (m, IH, CH=CHCH3), 5.08 (d, J=7.3 Hz, IH, NH), 4.591 (dt, Jd = 7.8 Hz, Jt = 5.7 Hz, IH, HNCH(CH2CH=CHCH3)), 4.19 (br m, IH, HNCH(CH3), 3.74(s, 3H, OCH3), 2.56-2.39 (sym m, 2H, CH2CH=CHCH3), 1,658 (dd, J= 6.4, 1.2 Hz, 3H, CH2CH=CHCH3), 1-454 (s, 9H, OC(CH3)3), 5 1.358 (d, J=7.1 Hz, 3H, HNCH(CH3)). Step E ~ Synthesis of Methyl A/-[/V-(3,5-D[fluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-4-enoate A solution of 0.811 g (2.58 mmol) of the product from Step D above in 5 mL of CH2C12 was cooled to 0°C under dry N3 and 5 mL of trifluoroacetic acid 10 was introduced by syringe at <4°C. The solution was stirred at 0°C for 40 min. Toluene (15 mL) was added and the mixture was evaporated in vacuo on the rotary evaporator. The addition of toluene and solvent evaporation was repeated. The residue was dissolved in 20 mL of CH2C12 and the solution was cooled to 0°C under dry N2. To this was added 1.35 mL (1.00 g, 7.74 mmol, 15 3.0 equiv) of ethyldiisopropylamine (Aldrich), followed by the dropwise addition at S 6°C of 0.728 mL (0.938 g, 5.16 mmol, 2.0 equiv) of 3,5-difluorophenylacetyl chloride (prepared from 3,5-difluorophenylacetic acid (Aldrich) using General Procedure H'). The resulting solution was stirred at 0°C for 2 h. Excess saturated aqueous NaHC03 was added and the two phase 20 mixture was stirred in an ice bath for 30 mm. The mixture was diluted with CH2C12 and washed successively with aqueous NaHC03/Na2C03 (pH 10), 1 N aqueous NaHS04, and saturated aqueous NaCl. The CH2C12 solution was dried (Na2S04) and evaporated in vacuo to afford 1.17 g of a yellow solid. This was recrystallized from EtOAc to yield 602 mg (63%) of the title compound as a 25 fluffy white solid. This material was found by 300 mHz 'H NMR analysis to consist of a 92:8 mixture of E and Z isomers, respectively. NMR data was as follows: 'H-nmr (300 MHz, CDC13): 5 = 6.85-6.69 (m, 3H), 6.335 (br d, J=7.8 Hz, IH), 6.289 (br d, J=7.0 Hz, IH), 5.58-5.47 (m, IH), 5.28-5.18 (m, IH), 30 4.58-4.45 (m, 2H) 3.745 (s, 3H), 3.528 (s, 2H), 2.457 (apparent t, J=6.4 Hz, Printed from Mimosa WO 98/22494 PCT/US97/20804 - 292 - 2H), 1.650 (dd, J=6.5, 1.3Hz, 3H), 1.58 (dm, J=6.5 Hz, 0.08H), 1.375 (d, J=7.0 Hz, 3H). IR (CHC13) 3421, 1742, 1667, 1626, 1597, 1503, and 1120 cm1 Anal. Calcd for C,gHnF2N204: C, 58.69; H, 6.02; N, 7.60. Found: C, 5 58.83, H, 5.89; N, 7.67. C,8H22F2NA (MW = 368); mass spectroscopy (MH+) 368. Example 189 Synthesis of Ar-[Ar-(CyclopropylacetyI)-L-alaninyl]-10 L-phenylglycine fe/f-Butyl Ester Following General Procedure U and using cyclopropylacetic acid (Lancaster) and N-(L-aIaninyl)-L-phenylglycine rm-butyl ester (General Procedure U of Z-alanine (Bachem) to phenylglycine-r-butyl (Novabio) and then General Procedure O), the title compound was prepared as a solid (mp = 15 105-107°C). The reaction was monitored by tic (Rf = 0.33 in 1:1 EtOAc/hexane, 0.13 m 5% MeOH/DCM). NMR data was as follows: 'H-nmr (CDCI3): 5 = 0.15 (m, 2H), 0.56 (m, 2H), 0.91 (m, IH), 1.38 (m, 12H), 2.09 (d, J = 7.1 Hz, 2H), 4.62 (m, IH), 5.39 (d, J = 7.2 Hz, IH), 20 6.52 (d, J = 7.2 Hz, IH), 7.31 (m, 6H). ,3C-nmr (CDC13): 5 = 4.53, 4.55, 6.9, 18.4, 27.8, 41.2, 48.4, 57.1, 82.6, 127.0, 128.2, 128.7, 136.8, 169.4, 171.4, 172.3. C20H28N2O4 (MW = 360.46); mass spectroscopy (MH+) 361. Example 190 25 Synthesis of /V-terf-Butyl-iV'-[jV-(3,5-DifluorophenyIacetyI)-L-alaniny]]-(S)-2-amino-2-(4-phenyIphenyl)acetamide Following General Procedure AB and using 3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and 4-biphenylcarboxaldehyde (Aldrich) , the Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 293 - title compound was prepared as a solid (mp = 266-267°C). The product was purified by recrystallization from EtOAc and/or EtOAc/hexanes. NMR data was as follows: 'H-nmr (DMSO-rf6): 8 = 8.42 (d, IH, J=7 Hz) , 8.31 (d, IH, J=7 Hz), 5 7.91 (s, IH), 7.6-7.56 (m, 4H) , 7.42-7.59 (m, 5H), 7.2-7.69 (m, 3H), 5.42 (d, IH, J=8 Hz), 4.42 (pentet, IH, J=8 Hz), 3.5 (s, IH) , 1.2 (doublet on top of a singlet, 12H). C29H3IN303F2 (MW = 508); mass spectroscopy (MH+) 508.4. Example 191 10 Synthesis of Ar-[Ar-(3,5-Difluorophenylacetyl)-(S)-2-aminobutanoyl]-L-phenylglycine tert-Butyl Ester Following General Procedure D and using 3,5-difluorophenylacetic acid (Aldrich) and iV-[(S)-2-aminobutanoyl]-L-phenyIglycine rm-butyl ester (from 15 Example D13 above), the title compound was prepared as a solid (mp = 138.7-140.0°C). The reaction was monitored by tic (Rf = 0.24 in 2/1 hexanes:EtOAc) and the product was purified by flash chromromatography and HPLC. NMR data was as follows: 20 JH-nmr (DMSO-^,, 250 MHz): <5 = 8 66 (d, J=6.75 Hz, IH), 8.30 (d, J=8.26 Hz, IH), 7.37 (bs, 5H), 7.11-6.96 (m, 3H), 5.23 (d, J=7.00 Hz, IH), 4.36 (td, J=7.88, 5.50 Hz, IH), 3.53 (AB„, JAB= 14.05 Hz, avab=7.75 Hz, 2H), 1.85-1 48 (m, 2H), 1.34 (s, 9H), 0.88 (t, J=7.38 Hz, 3H). Optical Rotation: [o]20 = 21.8° (c 1.0, MeOH). 25 C24H2gN204F2 (MW = 446.50); mass spectroscopy (MH+, minus C02-fBu) 345.2. Example 192 Synthesis of A'-[A'-(3,5-DifIuorophenylacetyl)-L-vaHnyI]-30 L-phenylglycine tert-Butyl Ester Printed from Mimosa WO 98/22494 PCT/US97/20804 - 294 - Following General Procedure D and using 3,5-difluorophenylacetic acid (Aldrich) and JV-(L-valinyl)-L-phenylglycine /erf-butyl ester (from Example D14 above), the title compound was prepared as a solid (mp = 170.5-171.8°C). The reaction was monitored by tic (Rf = 0.39 in 2:1 hexanes/EtOAc) and the 5 product was purified by flash chromromatography and HPLC. NMR data was as follows: 'H-nmr (DMSO-tf6, 250 MHz): 5 = 8.71 (d, J=6.75 Hz, IH), 8.22 (d, J=9.26 Hz, IH), 7.37 (bs, 5H), 7.11-6.96 (m, 3H), 5.23 (d, J=6.50 Hz, IH), 4.36 (dd, J=8.88, 6.38 Hz, IH), 3.55 (AB„ JAB= 13.88 Hz, avab= 21.56 Hz, 10 2H), 2.10-1.95 (m, IH), 1.34 (s, 9H), 0.88 (d, J=6.75 Hz, 3H), 0.86 (d, J=6.50 Hz, 3H). Optical Rotation: [a]20 = 20.8° (c 1.0, MeOH). C25H3aN204F2 (MW = 460.53); mass spectroscopy (MH+, minus C02-/Bu) 359.2. 15 Example 193 Synthesis of iV-[/V-(3,5-DifluorophenyIacetyl)-L-methioninyl]-L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid 20 (Aldrich) and 7V-(L-methioninyl)-L-phenylglycine methyl ester hydrochloride (prepared from /V-BOC-L-methionine (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 189.3°C). The reaction was monitored by tic (Rf = 0.53 in 5:95 25 MeOH/CH2Cl2) and the product was punfied by recrystallization from ethyl acetate/hexanes. NMR data was as follows: 'H-nmr (DMSO-^): 8 = 8.85 (d, J=6.7 Hz, IH), 8.41 (d, J=8.1 Hz, IH), 7.38 (m, 5H), 7.09 (m, IH), 6.98 (m, 2H), 5.38 (d, J=6.6 Hz, IH), 4.47 30 (m, J=8.2 Hz, IH), 3.62 (s, 3H), 3.51 (d, 2H), 2.46 (t, 2H), 2.04 (s, 3H), 1.89 (m, 2H). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 295 - ,3C-nmr (DMSO-^): 5 = 172.036, 171.729, 169.883, 164.658, 164.479, 161.406, 161.227, 141.689, 141.557, 141.427, 136.524, 129.512, 129.213, 128.717, 126.274, 113.187, 113.085, 112.961, 112.862, 103.023, 102.684, 102.340, 93.065, 57.205, 53.063, 42.231, 33.075, 30.221, 15.465. 5 C22H24N204F2S (MW = 450.51); mass spectroscopy (MH+) 450. Example 194 Synthesis of iV-[N-(3,5-DifluorophenyIacetyl)-L-vaIinyl]- L-phenylglycine Methyl Ester 10 Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and AKL-valinyl)-L-phenylglycine methyl ester hydrochloride (prepared from N-BOC-L-valine (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a 15 solid (mp = 226.5°C). The reaction was monitored by tic (Rf = 0.49 in 5:95 MeOH/CH2Cl2) and the product was purified by flash chromotography using MeOH/CH2Cl2 as the eluent. NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 8.84 (d, J=6 2 Hz, IH), 8.23 (d, J=8.8 Hz, 20 IH), 7.38 (m, 5H), 7.07 (m, IH), 6.98 (m, 2H), 5.37 (d, J=6.5 Hz, IH), 4.34 (m, J=8.9 Hz, IH), 3.55 (m, 5H), 2.01 (m, IH), 0.87 (m, 6H). ,3C-nmr (DMSO-*/6): 5 = 171.988, 171.690, 169.861, 164.633, 164.456, 161.382, 161.204, 141.987, 141.859, 141.727, 136.553, 129.470, 129.192, 128.791, 113.128, 113.026, 112.902, 112.803, 102.961, 102.619, 102.281, 25 57.914, 57.262, 52.935, 42.274, 31.728, 19.845, 18.815. C22H24N204F2 (MW = 418.44); mass spectroscopy (MH+) 418.1. Example 195 Synthesis of A'-[/V-(3,5-DifluorophenyIacetyI)-2-aniinobutanoyI]-30 L-phenylglycine Methyl Ester Printed from Mimosa WO 98/22494 PCI7US97/20804 - 296 - Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and N-(2-aminobutanoyl)-L-phenylglycine methyl ester hydrochloride (prepared from Af-BOC-L-aminobutyric acid (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by 5 removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 215.3 9C). The reaction was monitored by tic (Rf = 0.46 in 5:95 MeOH/CH2Cl2) and the product was purified by recrystallization from ethyl acetate/hexanes. NMR data was as follows: 10 'H-nmr (DMSO<): 8 = 8.83 (d, J=6.8 Hz, 1H), 8.32 (d, J=8.1 Hz, IH), 7.38 (m, 5H), 7.08 (m, IH), 6.98 (m, 2H), 5.38 (d, J=6.8 Hz, IH), 4.35 (m, J=7.9 Hz, IH), 3.61 (s, 3H), 3.52 (d, 2H), 1.64 (m, 2H), 0.88 (t, 3H). 13C-nmr (DMSO-rf6): 5 = 171.684, 170.934, 168.984, 164.193, 163.980, 160.295, 160.083, 141.059, 140.902, 140.743, 135.857, 128.689, 128.372, 15 127.892, 112.387, 112.257, 112.131, 111.999, 102.254, 101.845, 101.438, 56.351, 53.441, 52.212, 41.436, 25.675, 10.067. C21H22N204F2 (MW = 404.42); mass spectroscopy (MH+) 405.1. Example 196 Synthesis of 20 /V-[A^-(3,5-DifluorophenyIacetyl)-L-leucinyl]- L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and //-(L-leucinyl)-L-phenylglycine methyl ester hydrochloride (prepared from /V-BOC-L-leucine (Aldrich) and L-phenylglycine methyl ester 25 hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 178.4°C). The reaction was monitored by tic (Rf — 0.51 in 5:95 MeOH/CHjCy and the product was purified by flash chromotograph using MeOH/CH2Cl2 as the eluent. 30 NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 „ 297 -- lH-nmr (DMSO-^): 5 = 8.85 (d, J=6.8 Hz, IH), 8.33 (d, J=8.3 Hz, IH), 7.37 (m, 5H), 7.08 (m, IH), 6.95 (m, 2H), 5.37 (d, J=6.8 Hz, IH), 4.46 (m, J=8.3 Hz, IH), 3.60 (s, 3H), 3.49 (d, 2H), 1.55 (m, 3H), 0.89 (d, 3H), 0.82 (d, 3H). 5 l3C-nmr (DMSO-d6): 8 = 172.225, 170.899, 168.888, 164.197, 163.984, 160.298, 160.086, 141.029, 140.887, 140.723, 135.875, 128.657, 128.348, 127.944, 112.340, 112.207, 112.084, 111.951, 102.251, 101.842, 101.435, 56.343, 52.214, 50.697, 41.510, 40.982, 24.449, 23.056, 21.575. C23H26N2O4F2 (MW = 432.47); mass spectroscopy (MH+) 432.1. 10 Example 197 Synthesis of N-[iV-(3,5-DifIuorophenylacetyl)-L-phenylalaninyl]-L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid 15 (Aldrich) and N-(L-phenylalaninyl)-L-phenylglycine methyl ester hydrochloride (prepared from jV-BOC-L-phenylalanine (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 188.3°C). The reaction was monitored by tic (Rf = 0.59 in 20 5:95 MeOH/CH2Cl2) and the product was purified by flash chromotography using MeOH/CH2Cl2 as the eluent. NMR data was as follows: !H-nmr (DMSO-J6): 8 = 8.99 (d, J=6.9 Hz, IH), 8.44 (d, J=8.6 Hz, IH), 7.4 (m, 5H), 7.21 (m, 5H), 7.03 (m, IH), 6.77 (m, 2H), 5.42 (d, J=6.9 25 Hz, IH), 4.70 (m, J=8.5 Hz, IH), 3.63 (s, 3H), 3.40 (m, 2H), 3.08 (m, IH), 2.76 (m, IH). 13C-nmr (DMSO-</6): 8 = 171.428, 170.896, 168.853, 164.127, 163.915, 160.222, 160.010, 140.756, 140.601, 140.438, 137.662, 135.918, 130.638, 129.247, 128.737, 128.415, 127.908, 126.281, 112.147, 112.025, 111.892, 30 102.189, 101 782, 101.373, 56.411, 53.461, 52.306, 41.513, 37.796. C26H24N204F2 (MW = 466.49); mass spectroscopy (MH+) 466. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 298 - Example 198 Synthesis of N-[iV-(3,5-Dlfluorophenylacetyl)glycinyI]-L-phenylglycine Methyl Ester 5 Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and AT-(glycinyl)-L-phenylglycine methyl ester hydrochloride (prepared from N-BOC-glycine (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a 10 solid (mp = 142.3°C). The reaction was monitored by tic (Rf = 0.33 in 5:95 MeOH/CH2Cl2) and the product was purified by recrystallization from diethyl ether/hexanes. NMR data was as follows: 'H-nmr (DMSO-4,): 5 = 8.82 (d, J=7.2 Hz, IH), 8.39 (t, IH), 7.37 (m, 15 5H), 7.05 (m, 3H), 5.44 (d, 7.1 Hz, IH), 3.83 (d, 2H), 3.62 (s, 3H), 3.53 (s, 2H). l3C-nmr (DMSO-^: 5 = 170.956, 169.427, 168.788, 164.226, 164.013, 160.329, 160.115, 140.817, 140.663, 140.499, 136.222, 128.728, 128.338, 127.687, 112.494, 112.360, 112.238, 112.104, 102.310, 101.900, 101.492, 20 56.200, 52.321, 41.731, 41.464. C19H18N204F2 (MW = 376.36); mass spectroscopy (MH+) 376.0. Example 199 Synthesis of A,-[yV-(3,5-Difluorophenylacetyl)-L-phenylglyrinyl]-25 L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and iV-(L-phenylglycinyl)-L-phenylglycine methyl ester hydrochloride (prepared from /V-BOC-L-phenylglycine (Novabiochem) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure AH, followed by 30 removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 222.8°C). The reaction was monitored by tic (Rf = Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 299 - 0.61 in 5:95 MeOH/CH2Cl2) and the product was purified by recrystallization from ethyl acetate. NMR data was as follows: 'H-nmr (DMSO-</6): 8 = 9.22 (d, J=6.8 Hz, IH), 8.85 (d, J=8.2 Hz, 5 IH), 7.37 (m, 10H), 7.08 (m, IH), 6.97 (d, 2H), 5.69 (d, J=8.2 Hz, IH), 5.43 (d, J=6.8 Hz, IH), 3.61 (d, 2H), 3.55 (s, 3H). uC-nmr (DMSO-t/6): 5 = 170.606, 169.727, 168.777, 164.194, 163.982, 160.296, 160.082, 140.920, 140.757, 140.603, 138.391, 135.900, 128.732, 128.425, 128.233, 127.871, 127.556, 127.222, 112.467, 112.340, 112.209, 10 112.082, 102.292, 101.884, 101.475, 56.431, 55.621, 52.203, 41.205. C2jH22N204F2 (MW = 452.46); mass spectroscopy (MH+) 452.2. Example 200 Synthesis of A,-[/V-(Phenylacety])-L-alaninyl]-L-alanine Methyl Ester 15 Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-alanine methyl ester hydrochlonde (Aldrich), the title compound was prepared as a solid (mp = 140.5-142°C). The reaction was monitored by tic (Rf = 0.17 in 50% EtOAc/hexanes). NMR data was as follows: 20 'H-nmr (CDClj): 8 = 1.3-1.4 (m, 6H), 3.55 (s, 2H), 3.75 (s, 3H), 4.4-4.6 (m, 2H), 6.1-6.3 (brd, IH), 6.6-6.7 (brd, IH), 7.2-7.4 (m, 5H). 13C-nmr (CDClj): 8 = 18.4, 19.0, 44.1, 48.6, 49.3, 53.0, 127.9, 129.5, 129.8, 135.1, 171.5, 172.4, 173.6. CisH20N2O4 (MW = 292.34); mass spectroscopy (MH+) 293. 25 Example 201 Synthesis of N-[N-(Phenylacetyl)-L-alaninyI]-L-leucine Methyl Ester Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-leucine methyl ester hydrochloride (Aldrich), the title Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 300 - compound was prepared as a solid (mp = 102.5-105°C). The reaction was monitored by tic (Rf = 0.25 in 50% EtOAc/hexanes). NMR data was as follows: 'H-nmr (CDC13): 8 = 0.8-0.95 (m, 6H), 1.3 (d, J=7 Hz, 3H), 1.4-1.6 (m, 5 3H), 3.58 (s, 2H), 3.75 (s, 3H), 4.4-4.6 (m, 2H), 6.2 (brd, IH), 6.7 (brd, IH), 7.2-7.4 (m, 5H). l3C-nmr (CDC13): 5 = 18.7, 22.3, 23.4, 25.3, 41.5, 44.1, 49.2, 51.4, 52.8, 127.9, 129.5, 129.8, 135.0, 171.5, 172.6, 173.7. C,8H26N204 (MW = 334.42); mass spectroscopy (MH+) 335. 10 Example 202 Synthesis of iV-[/V-(Phenylacetyl)-L-alaninyl]-L-isoleucine Methyl Ester Following General Procedure A and using /V-(phenylacetyl)-L-alanine (from Example B1 above) and L-isoleucine methyl ester hydrochloride (Sigma), the 15 title compound was prepared. The reaction was monitored by tic (Rf = 0.24 in 50% EtOAc/hexanes). NMR data was as follows: 'H-nmr (CDC13): 8 = 0.8-0.95 (m, 6H), 1.0-1.2 (m, IH), 1.2-1.4 (m including 1.3 (d, J=7 Hz, 4H)), 1.8-1.9 (m, IH), 3.58 (s, 2H), 3.75 (s, 3H), 20 4.4-4.6 (m, 2H), 6.2 (brd, IH), 6.7 (brd, IH), 7.2-7.4 (m, 5H). 13C-nmr (CDC13): 8 = 12.1, 16.0, 18.5, 25.6, 38.1, 44.1, 49.3, 52.7, 57.2, 127.9, 129.6, 129.8, 135.0, 171.5, 172.5, 172.6. C,8H26N204 (MW = 334.42); mass spectroscopy (MH+) 335. Example 203 25 Synthesis of N-[/V-(PhenylacetyI)-L-alaninyl]-L-proline Methyl Ester Following General Procedure A and using /V-(phenylacetyl)-L-alanine (from Example B1 above) and L-proline methyl ester hydrochloride (Bachem), the Printed from Mimosa WO 98/22494 PCT/US97/20804 — 301 - title compound was prepared as an oil. The reaction was monitored by tic (Rf = 0.12 in 50% EtOAc/hexanes). NMR data was as follows: 'H-nmr (CDClj): 8 = 1.33 (d, J=7 Hz, 3H), 1.9-2.1 (m, 3H), 2.1-2.25 5 (m, IH), 3.5-3.8 (m including 3.58 (s) and 3.75 (s), total 7H), 4-4.4 (m, IH), 4.7-4.8 (m, IH), 6.5 (brd, IH), 7.2-7.4 (m, 5H). 13C-nmr (CDC13): 5 = 18.5, 25.5, 29.5, 44.1, 47.3, 47.4, 52.8, 59.3, 127.8, 129.42, 129.48, 129.9, 135.2, 170.9, 171.8, 172.8. C17H22N2O4 (MW = 318.38); mass spectroscopy (MH+) 319. 10 Example 204 Synthesis of N-[/V-(PhenyIacetyl)-L-aIaninyI]-L-phenylalanine Methyl Ester Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-phenylalanine methyl ester hydrochloride (Aldrich), 15 the title compound was prepared as a solid (mp = 148-149.5°C). The reaction was monitored by tic (Rf = 0.24 in 50% EtOAc/hexanes) and the product was not purified. NMR data was as follows: 'H-nmr (CDC13): 8 = 1.25 (d, J=7 Hz, 3H), 3.02 (dd, J=7, MHz, IH), 20 3.12 (dd, J=5, 14 Hz, IH), 3.53 (s, 2H), 3.72 (s, 3H), 4.4-4.5 (m, IH), 4.75-4.85 (m, IH), 5.9 (brd, IH), 6.5 (brd, IH), 7.0-7.5 (m, 10H). 13C-nmr (CDC13): 5 = 18.6, 38.3, 44.0, 49.2, 52.9, 53.9, 127.7, 128.0, 129.1, 129.6, 129.8, 129.9, 135.0, 136.3, 171.4, 172.2, 172.3. C21H24N2O4 (MW = 368.44); mass spectroscopy (MH+) 369. 25 Example 205 Synthesis of /V-[/V-(Phenylacetyl)-L-alaninyI]-iV.-^crt-butoxycarbonyO-L-lysine Methyl Ester Following General Procedure A and using 7V-(phenylacetyl)-L-alanine (from 30 Example B1 above) and 7V(-(rm-butoxycarbonyl)-L-lysine methyl ester Printed from Mimosa WO 98/22494 PCT/US97/20804 - 302 - hydrochloride (Bachem), the tide compound was prepared as a solid (mp = 119-121°C). The reaction was monitored by tic (Rf = 0.46 in 90:10:1 CH2Cl2\Me0H\NH40H). NMR data was as follows: 5 'H-nmr (CDC13): 5 = 1.2-1.9 (m, 18H)(includes 1.3 (d, J=7 Hz) and 1.4 (s)), 3.0-3.15 (m, 2H), 3.12 (dd, J=5, 14 Hz, IH), 3.57 (s, 2H), 3.72 (s, 3H), 4.4-4.5 (m, 2H), 4.75-4.85 (m, IH), 6.2 (brd, IH), 6.75 (brd, IH), 7.2-7.4 (m, 5H). 13C-nmr (CDC13): 5 = 18.6, 22.9, 29.0, 29.9, 32.0, 40.5, 44.0, 49.4, 10 52.7, 53.0, 79.8, 127.9, 129.5, 129.8, 135.1, 156.7, 171.6, 172.7, 173.0. C23H33N3Os (MW = 449.55); mass spectroscopy (MH+)= 450. Example 206 Synthesis of N-t/V-fPhenylacetyO-L-alaninylJglycine Methyl Ester 15 Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and glycine methyl ester hydrochloride (Aldnch), the title compound was prepared as a solid (mp = 152-153.5°C). The reaction was monitored by tic (Rf = 0.10 in 50% EtOAc/hexanes). NMR data was as follows: 20 'H-nmr (CDC13): 8 = 1.33 (d, J=7 Hz, 3H), 3.59 (s, 2H), 3.75 (s, 3H), 3.97 (d, J=6.5 Hz, 2H), 4.5-4.6 (m, IH), 6.1 (brd, IH), 6.8 (brs, IH), 7.2-7.6 (m, 5H). "C-nmr (CDC13): 8 = 18.7, 41.6, 43.9, 49.2, 52.9, 127.9, 129.5, 129.9, 135.0, 170.6, 171.7, 173.2. 25 C14H18N2O4 (MW = 278.31); mass spectroscopy (MHV) 279. Example 207 Synthesis of /V-[JV-(Phenylacetyl)-L-alaninyl]-L-valine Methyl Ester Printed from Mimosa WO 98/22494 PCT/US97/20804 - 303 - Following General Procedure A and using /V-(phenylacetyl)-L-alanine (fromo Example B1 above) and L-valine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp = 112-115°C). The reaction was monitored by tic (Rf = 0.33 in 50% EtOAc/hexanes) and the product was 5 not purified. NMR data was as follows: 'H-nmr (CDC13): 5 = 0.8-0.9 (overlapping d appearing as t, J=6 Hz, 6H), 2.0-2.2 (m, IH), 3.57 (s, 2H), 3.72 (s, 3H), 4.4-4.5 (m, IH), 4.5-4.65 (m, IH), 6.2 (brd, IH), 6.75 (brd, IH), 7.2-7.4 (m, 5H). 10 13C-nmr (CDC13): 5 = 18.3, 18.5, 19.5, 31.5, 44.1, 49.3, 52.7, 57.9, 127.9, 129.5, 129.8, 135.0, 171.5, 172.7, 172.7. C17H24N204 (MW = 320.39); mass spectroscopy (MH+) 321. Example 208 Synthesis of 15 Methyl /V-[/V-(Phenylacetyl)-L-alaninyl]-2-(S)-aminobutanoate Following General Procedure A and using /V-(phenylacetyl)-L-alanine (from Example B1 above) and methyl L-2-aminobutanoate hydrochloride (prepared from L-2-aminobutanoic acid (Bachem) using General Procedure H (without extractions)), the title compound was prepared as a solid (mp = 120°C). The 20 reaction was monitored by tic (Rf = 0.2 in 50% EtOAc/hexanes). NMR data was as follows: 'H-nmr (CDC13): 6 = 0.85 (t, J=6 Hz, 3H), 1.32 (d, J=7 Hz, 3H), 1.6-1.9 (m, 2H), 3.57 (s, 2H), 3.72 (s, 3H), 4.4-4.6 (m, 2H), 6.2 (brd, IH), 6.75 (brd, IH), 7.2-7.4 (m, 5H). 25 I3C-nmr (CDC13): 8 = 10.2, 18.9, 25.8, 44.0, 49.3, 52.8, 54.0, 127.9, 129.5, 129.8, 135.1, 171.5, 172.7, 173.0. C16H22N204 (MW = 306.36); mass spectroscopy (MH+) 307. Example 209 Synthesis of 30 Methyl Ar-[iV-(Phenylacetyl)-L-alaninyl]-2-(S)-aminopentanoate Printed from Mimosa WO 98/22494 PCT/US97/20804 - 304 - Following General Procedure A and using /V-(phenylacetyl)-L-alanine (from Example B1 above) and methyl 2-(S)-aminopentanoate hydrochloride (prepared from L-2-aminovaleric acid (Bachem) using General Procedure H (without extractions)), the title compound was prepared as a solid (mp = 135-137°C). 5 The reaction was monitored by tic (Rf = 0.30 in 50% EtOAc/hexanes). NMR data was as follows: !H-nmr (CDC13): 5 = 0.87 (t, J=6 Hz, 3H), 1.2-1.4 (m with d, J=7 Hz, 5H), 1.5-1.8 (m, 2H), 3.57 (s, 2H), 3.72 (s, 3H), 4.4-4.5 (m, 2H), 6.4 (brd, IH), 7.0 (brd, IH), 7.2-7.4 (m, 5H). 10 13C-nmr (CDC13): 8 = 14.2, 19.0, 19.2, 34.5, 44.0, 49.2, 52.7, 52.8, 127.8, 129.4, 129.8, 135.2, 171.5, 172.8, 173.3. C17H24N204 (MW = 320.39); mass spectroscopy (MH+) 321. Example 210 Synthesis of 15 A'-[/V-(3-NitrophenylacetyI)-L-alaninyI]-L-valine Following General Procedure AF and using iV-|W-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ethyl ester (from Example 143 above), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.05 in 9:1 CHClj/MeOH). 20 NMR data was as follows: ■H-nmr (DMSO-d6): 8 = 8.41 (d, IH), 8.13 (s, IH), 8.09 (d, IH), 7.91 (d, IH), 7.68 (d, IH), 7.56 (t, IH), 4.4 (m, IH), 4.10 (m, IH), 3.63 (s, 2H), 2.01 (m, IH), 1.19 (m, 3H), 0.89 (d, 6H). Optical Rotation: [a]23 = -49° (c 1, MeOH). 25 C16H2,N306 (MW = 351.3); mass spectroscopy (MH+) 352. Example 211 Synthesis of Ar-[iV-(PhenyIacetyl)-L-aIaninyl]-L-/V-methyIalanine Methyl Ester Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 305 - Following General Procedure A and using /V-(phenylacetyl)-L-alanine (from Example B1 above) and L-iV-methylalanine methyl ester hydrochloride (prepared from L-N-methylalanine hydrochloride (Bachem) using General Procedure H (without extractions)), the title compound was prepared as an oil. 5 The reaction was monitored by tic (Rf = 0.13 in 50% EtOAc/hexanes) and the product was purified by column chromatography using 60% EtOAc/hexanes as the eluent. NMR data was as follows: 'H-nmr (CDC13): 5 = 1.2-1.6 (m including 1.32 (d, J=7 Hz, 6H), 2.97 (s 10 (rotomers), 3H), 3.57 (s, 2H), 3 7-3.8 (s (rotomers), 3H), 4.4-5.2 (m, 2H), 6.6 (brd, IH), 7.2-7.4 (m, 5H). I3C-nmr (CDC13): 5 = 14.7, 15.0, 18.8, 19.1, 31.6, 32.3, 44.3, 46.2, 46.3, 52.7, 52.88, 52.93, 53.6, 127.81, 127.85, 129.45, 129.48, 129.9, 135.2, 170.60, 170.67, 172.19, 172.4, 173.25. 173.31. 15 C16H22N204 (MW = 306.36); mass spectroscopy (MH+) 307. Example 212 Synthesis of /V-[/V-(Isovaleryl)-L-phenylglycinyI]-L-alanine Isobutyl Ester Following General Procedure C and using /V-(isovaleryl)-L-phenylglycine 20 (prepared from isovaleric acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldnch) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-alanine isobutyl ester hydrochloride (prepared from /V-BOC-L-alanine (Sigma) and 2-methyl-l-propanol (Aldrich) using General Procedure C (with catalystic DMAP), followed by removal of the 25 BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 181-186°C). The reaction was monitored by tic (Rf = 0.4 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 1:1 EtOAc/hexanes as the eluent. NMR data was as follows: 30 'H-nmr (CDC13): 5 = 1.31 (d, 3H), 5.59 (d, IH). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 306 - Optical Rotation: [a]20 = +19° @ 589 nm (c 1.03, DMSO). C20H30NA (MW = 362); mass spectroscopy (MH+) 363. Example 213 Synthesis of 5 iV-[/V-(Isovaleryl)-L-isoleucinyI]-L-alaiime Isobutyl Ester Following General Procedure C and using Af-(isovaleryl)-L-isoleucine (prepared from isovaleric acid (Aldrich) and L-isoleucine methyl ester hydrochloride (Aldrich) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-alanine isobutyl ester hydrochloride 10 (prepared from /V-BOC-L-alanme (Sigma) and 2-methyl-l-propanol (Aldnch) using General Procedure C (with catalystic DMAP), followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 142-146°C). The reaction was monitored by tic (Rf = 0.4 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography 15 using 1:1 EtOAc/hexanes as the eluent to provide a 1.4 mixture of diastereomers. NMR data was as follows: 'H-nmr (DMSO-d6): 6 = 1.26 (d, 3H), 7.70 (d, IH), 7.80 (d, IH), 8.30 (d, IH), 8.40 (d, IH). 20 Cjg^NA (MW = 342.48); mass spectroscopy (MH+) 343. Example 214 Synthesis of /V-Cyclohexyl-jV'-[AM3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide 25 Following General Procedure C and using 7V-(3,5-difluorophenylacetyl)-L- alanine (from Example B2 above) and /V-cyclohexyl-L-phenylglycinamide (prepared from jV-BOC-L-phenylglycine (Advanced Chemtech) and cyclohexylamine (Aldrich) using General Procedure M, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 307 - a solid. The reaction was monitored by tic (Rf = 0.5 in 9:1 CHCl3/MeOH) and the product was purified by trituration from ethanol. NMR data was as follows: 'H-nmr (CDC13): 5 = 8.55 (m, 2H), 8.08 (d, IH), 7.30 (m, 5H), 7.08 (m, 5 IH), 6.97 (d, 2H), 5.37 (m, IH), 3.47 (s, 2H), 1.8-1.6 (m, 6H), 1.23-0.98 (m, 7H). Optical Rotation: [c*]^ = -32.7° (c 1, MeOH). C25H29F2N303 (MW = 457); mass spectroscopy (MH+) 458. Example 215 10 Synthesis of jV-[/V-(3,5-Difluorophenylacetyl)-L-aIaninyl]-L-4-hydroxyproIine Ethyl Ester Following General Procedure F and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-4-hydroxyproline ethyl ester 15 hydrochlonde (Pfaltz & Bauer), the title compound was prepared as a foam. The reaction was monitored by tic (Rf = 0.32 in 95:5 CH2Cl2/MeOH) and the product was purified by flash column chromatography. NMR data was as follows: 'H-nmr (CDC13, 250 Mz): 5 = 7.31 (d, IH, J= 7.00 Hz), 6.83-6.64 (m, 20 3H), 4.67 (p, IH, J=7.09 Hz), 4.58 (t, IH, J= 8.26 Hz), 4.47 (bs, IH), 4.25-4.06 (m, 2H), 3.81 (bd, IH, J=11.01 Hz), 3.62 (dd, IH, J = 10.76, 3.75 Hz), 3.46 (s, 2H), 2.30 (dd, IH, J= 13.51, 8.26 Hz), 1.96 (ddd, IH, J= 13.44, 8.82, 4.56 Hz), 1.33 (d, 3H, J= 6.75 Hz), 1.24 (t, 3H, J= 7.13 Hz). C,8H23F2N205 (MW = 384.38); mass spectroscopy (MH+) 385.1. 25 Example 216 Synthesis of iV-|7V-(3,5-Difluorophenylacetyl)-L-alaninyl]-I^lysineMethyl Ester Following General Procedure Y and using N-[jV-(3,5-difluorophenylacetyl)-L-alaninyl]-;Ve-(/e/T-butoxycarbonyl)-L-lysine methyl ester (from Example 43 30 above), the title compound was prepared as an oil. The title compound was Printed from Mimosa WO 98/22494 PCT/US97/20804 - 308 - isolated as the trifluoroacetic acid salt (containing about 5% excess trifluoroacetic acid). NMR data was as follows: 'H-nmr (CDC13 + 2 drops of CD3OD): 5 = 6.40-6.52 (m, 3H), 4.17 (t, 5 IH), 4.40 (q, IH), 3.42 (s, 3H), 3.23 (s, 3H), 2.53 (bs, 2H), 1.60 (m, IH), 1.32 (m, 3H), 1.02-1.13 (m, 2H), 1.10 (d, 2H). 13C-nmr (CDC13 + 2 drops of CD3OD): 5 = 174.1, 166.4, 166.2, 163.1, 163.0, 141.3, 113.8, 113.7, 113.5, 103.5, 55.2, 56.3, 43.0, 40.9, 32.2, 28.1, 24.0, 18.2. 10 C21H2sF5N306 (MW = 511.4); mass spectroscopy (MH+) 512. Example 217 Synthesis of /V'-[iV-(3,5-Difluorophenylacetyl)-L-aIaninyI]-L-g!utamide Following General Procedure B and using N-(3,5-difluorophenylacetyl)- 15 L-alanine (from Example B2 above) and L-glutamide hydrochloride (Bachem), the title compound was prepared as a solid (mp = 260-263°C). The reaction was monitored by tic (Rf = 0.77 in 10% MeOH/DCM) and the product was purified by silica gel chromatography. NMR data was as follows: 20 'H-nmr (CDC13): 8 = 8 40 (d, J=7.1 Hz, IH), 8.02 (d, J=6.9, IH), 7.2 (m, 2H), 7.0 (m, 4H), 6.76 (s, IH), 4.2 (m, IH), 3.56 (s, 2H), 2.1 (m, 2H), 1.9 (m, 2H), 1.21 (d, J=7.0 Hz, 3H). 13C-nmr (CDC13): 8 = 173.5, 172.4, 169.5, 112.5, 110.4, 102.3, 52.5, 49.0, 41.6, 35.7, 31.8, 28.1, 18.4. 25 C16H20F2N4O4 (MW = 370); mass spectroscopy (MH+) 371. Example 218 Synthesis of Methyl l-[/V-(3,5-Difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxylate 30 Following General Procedure A and using jV-(3,5-difluorophenylacetyl)- Printed from Mimosa WO 98/22494 PCT/US97/20804 - 309 - L-alanme (from Example B2 above) and methyl pipecolinate hydrochloride (Aldrich), the title compound was prepared as a solid (mp = 114-118°C). The reaction was monitored by tic (Rf = 0.71 in 10% MeOH/DCM) and the product was purified by acid/base washes. 5 NMR data was as follows: 'H-nmr (CDC13): 5 = 6.95 (dd, 3=7.1, 7.1, 7.1 Hz; IH), 6.81 (d, J=6.1 Hz, 2H), 6.7 (m, IH), 5.28 (dd, J=5.0 Hz, 12.6, 5.4, IH), 4.93 (q, J=7.0, 6.9, 7.0 Hz, IH), 3.75 (s, IH), 3.70 (s, 3H), 3.50 (s, 2H), 3.2 (m, IH), 2.27 (d, J=3.5 Hz, IH), 1.5 (m, 5H), 1.31 (d, J=5.2 Hz, 3H). 10 13C-nmr (CDClj): 5 = 172.8; 172.6; 171.7; 171.6; 169.2; 169.1; 112.9; 112.8; 112.7; 112.6; 103.2; 102.8; 53.0; 52 9; 52.9; 52.7; 46.2; 46.1; 43.9; 43.9; 27.1; 26.8; 25.6; 21.4; 19.9; 18.5. ClgH22F2N204 (MW = 368); mass spectroscopy (MH+) 369. Example 219 15 Synthesis of iV-[(S)-3-Hydroxy-6-methylhept-2-yl]-A<"-(3,5-difluorophenyIacetyl)-L-alaninamide Following General Procedure AA and using Ar-[(S)-6-methyl-3-oxohept-2-yl]-W-(3,5-difluorophenylacetyl)-L-alamnamide (from Example 168 above), the 20 title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.75 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 99:1 CHCl3/MeOH as the eluent. NMR data was as follows: 'H-nmr (CDClj): 8 = 6.81 (m, IH), 6.72 (m, 2H), 6.39 (m, 2H), 4.45 25 (m, IH), 3.97 (m, IH), 3.60 (m, IH), 3.52 (s, 2H), 1.54 (m, IH), 1.4 (m, 5H), 1.09 (m, 3H), 0.9 (m, 6H). Optical Rotation: [a]^ = -39° (c 1, MeOH). C,9H28F2N203 (MW = 448); mass spectroscopy (MH+) 449. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 310 - Example 220 Synthesis of AT-[(S)-2-Hydroxy-l-phenyleth-l-yI]-jV'-(3,5-Difluorophenylacetyl)-L-alaninamide 5 Following General Procedure C and using N-@ ,5-difluorophenylacetyl)- L-alanine (from Example B2 above) and (S)-2-hydroxy-l-phenyleth-1-ylamine (e.g., (S)-phenylglycinol) (Aldrich), the title compound was prepared as a solid (mp = 204-206°C). The reaction was monitored by tic (Rf = 0.5 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10 5% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile. NMR data was as follows: 'H-nmr (DMSO-d6): 6 = 1.24 (d, 3H), 4.38 (m, IH), 4.80 (m, 2H). Optical Rotation: [a]20 = +3.56° @ 589 nm (c 1.10, DMSO). C19H20F2N2O3 (MW = 362.38); mass spectroscopy (MH+) 363. 15 Example 221 Synthesis of /V-|W-(3,5-Difluorophenyl-ar-nuoroacetyl)-L-alaniny]-L-phenylglycine tert-Butyl Ester 20 Following General Procedure M and using 3,5-difluorophenyl-a- fluoroacetic acid (from Example D1 above) and Ar-(L-alaniny)-L-phenylglycine rm-butyl ester (prepared using N-BOC-L-alanine (Sigma) and L-phenylglycine rm-butyl ester hydrochloride (Bachem) using General Procedure C, followed by removal of the BOC group using General Procedure P), the title compound 25 was prepared as a clear oil. The reaction was monitored by tic (Rf = 0.44 and 0.51 in 1:1 EtOAc/hexanes) and the product was purified by LC 2000 chromatography using 20% EtOAc/hexanes as the eluent. NMR data was as follows: 'H-nmr (CDC13)(1:1 mixture of diasteromers). 5 = 1.37 (s, 9H), 1.39 (s, 30 9H), 1.42 (d, J = 7.0 Hz, 3H), 1.48 (d, J = 7.0 Hz, 3H), 3.80 (d, J = 7.0 Hz, IH), 4.62 (pent, J = 7.0 Hz, 2H), 5 36 (d, J = 7.1 Hz, IH), 5.42 (d, J = Printed from Mimosa WO 98/22494 PCT/US97/20804 -311 - 7.2 Hz, IH), 5.60 (d, J = 4.7 Hz, IH), 5.73 (d, J = 4.7 Hz, IH), 6.80 (m, 2H), 6.97 (m, 4H), 7.20-7.33 (m, 12H). C23H2jF3N204 (MW = 450.2); mass spectroscopy (MH+) 451. Example 222 5 Synthesis of AT-[(S)-a-Hydroxy-a'-phenyIisopropyl]-iV'-(3,5-difluorophenylacetyI)-L-alaninamide Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanme (from Example B2 above) and (S)-a-hydroxy-a'-10 phenylisopropylamine (e.g., L-phenylalaninol) (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.5 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent. NMR data was as follows: 15 'H-nmr (CDC13): 8 = 7.33-7.17 (m, 5H), 6.72 (m, 3H), 6.62 (d, IH), 6.32 (d, IH), 4.43 (m, IH), 4.10 (m, IH), 3.61 (m, 2H), 3.45 (s, 2H), 2.84 (m, 2H), 1.32 (d, 3H). Optical Rotation: [or^ = -60° (c 1, MeOH). C20H22F2N2O3 (MW = 376); mass spectroscopy (MH+) 377. 20 Example 223 Synthesis of A,-[(lS,2R)-l-Hydroxy-l-phenylprop-2-yl]-/V'-(3,5-difluorophenylacetyl)-L-alaninamide Following General Procedure C and using 7V-(3,5-difluorophenylacetyl)-25 L-alanine (from Example B2 above) and (lS,2R)-l-hydroxy-l-phenylprop-2-ylamine hydrochloride (e.g., (lS,2R)-norephedrine hydrochloride) (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tic (Rf = 0.5 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 98:2 CHCVMeOH as the eluent. 30 NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 — 312 -- 'H-nmr (CDClj): 5 = 7.31 (m, 5H), 6.84-6.64 (m, 4H), 4.86 (m, IH), 4.51 (m, IH), 4.23 (m, IH), 3.52 (s, 2H), 1.38 (d, 3H), 0.97 (d, 3H). Optical Rotation: [al^ = -44° (c 1, MeOH). C20H22F2N2OJ (MW = 376); mass spectroscopy (MH+) 377. 5 Example 224 Synthesis of iV-2-Methoxyethyl-iV'-[iV-(3,5-difluoropheiiylacetyl)-L-alaiiinyl]glycinamide Following General Procedure K and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine methyl ester (from Example 28 above) and 2-10 methoxyethylamine (Aldnch), the title compound was prepared as a solid (mp = 148-151°C). The reaction was monitored by tic (Rf = 0.53 in 10% MeOH/DCM + 1 % TEA) and the product was purified by silica gel chromatography. NMR data was as follows: 15 'H-nmr (CDClj): 5 = 8.2 (m, IH), 7.1 (m, IH), 6.6 (m, 8H0, 4.7 (m, IH), 4.0 (m, IH), 3.6 (m, 2H), 3.39 (s, 2H), 3.2 (m, 4H), 3.1 (s, 3H), 1.17 (d, J=7.2 Hz, 3H). 13C-nmr (CDClj): 5 = 176.3, 173.4, 172.2, 166.5, 163.4, 150.4, 141.6, 114.1, 114.0, 113.9, 113.8, 103 9, 103.5, 72.2, 72.1, 59.4, 51.9, 44.0, 43.0, 20 40.7, 17.9. C16H2iF2Nj04 (MW = 357); mass spectroscopy (MH+) 358. Example 225 Synthesis of Ar-[N-(3,5-DifIuorophenylacetyl)-2-(S)-aminocyclohexylacetyI]-25 L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and N-[2-(S)-aminocyclohexylacetyl]-L-phenylglycine methyl ester hydrochloride (prepared from N-BOC-L-cyclohexylglycine (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, 30 followed by removal of the BOC-group using General Procedure P), the title Printed from Mimosa WO 98/22494 PCT/US97/20804 -313 - compound was prepared as a solid (mp = 234.4°C). The reaction was monitored by tic (Rf = 0.65 in 5:95 MeOH/DCM) and the product was purified by recrystallization from ethyl acetate. NMR data was as follows: 5 'H-nmr (DMSO-rf3): 5 = 8.85 (d, J=6.5 Hz, IH), 8.21 (d, J=8.9 Hz, IH), 7.37 (s, 5H), 7.07 (m, IH), 6.97 (d, 2H), 5.36 (d, J=6.4 Hz, IH), 4.35 (t, J=7.7 Hz, IH), 3.53 (m, 5H), 1.65 (m, 6H), 1.06 (m, 5H). 13C-nmr (DMSO-rf3): 5 = 171.065, 170.865, 168.953, 164.179, 163.967, 160.282, 160.070, 141.210, 141.058, 135.766, 128.657, 128.374, 128.004, 10 112.371, 112.238, 112.115, 111.981, 102.217, 101.808, 101.399, 56.568, 56.471, 41.467, 40.354, 28.884, 28.025, 25.926, 25.669. C25H28N204F2 (MW = 458.51); mass spectroscopy (MH+) 458.1. Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alamne (from Example B2 above) and (lR,2S)-l-hydroxy-l-phenylprop-2-20 ylamine hydrochlonde (e.g., (lR,2S)-norephednne hydrochlonde) (Aldrich), the title compound was prepared as a foam. The reaction was monitored by tic (Rf = 0.5 in 9:1 CHCl3/MeOH). NMR data was as follows: 'H-nmr (CDC13): 5 = 7.35 (m, 5H), 7.75 (m, 3H), 6.57 (d, IH), 4.47 (d, 25 IH), 4.26 (m, IH), 3.48 (s, 2H), 1.32 (d, 3H), 1.01 (d, 3H). Optical Rotation: [a]23 = -64° (c 1, MeOH). C20H22F2N2O3 (MW = 376); mass spectroscopy (MH+) 377. Example 226 15 Synthesis of N-[(lR,2S)-l-Hydroxy-l-phenylprop-2-yl]-N '-(3,5-difluorophenylacetyD-L-aIaninamide Example 227 30 Synthesis of Ar-[(lR,2S)-l-hydroxy-l,2-diphenyleth-2-yl]-N'- (3,5-difluorophenyIacety l)-L-alaninamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 314 - Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and (lR,2S)-2-amino-l,2-diphenylethanol (Aldrich), the title compound was prepared as a solid (mp = 217-219°C). The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the 5 product was purified by silica gel chromatography using 1% MeOH/CHCl3 as the eluent, followed by recrystallization from acetonitrile. NMR data was as follows: lH-nmr (DMSO-4,): 8 = 0.76 (d, 3H), 5.43 (d, IH). Optical Rotation: [a]20 = -6.9° @ 589 nm (c 1.10, DMSO). 10 C^H^FjNA (MW = 438.48); mass spectroscopy (MH+) 439. Example 228 Synthesis of Ar-[(S)-l-Hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-l^alaninamide Following General Procedure S and using methyl N-[N-(3,5-15 difluorophenylacetyl)-L-alamnyl]-(S)-2-aminohexanoate (from Example 1 above), the title compound was prepared as a solid (mp = 157-158.5°C). The reaction was monitored by tic (Rf = 0.62 in 10% CH3OH/CH2Cl2). NMR data was as follows: 'H-nmr (CD3OD): 8 = 5.9 (m, 2H), 5.8 (m, IH), 4.37 (q, IH), 3.8 (m, 20 IH), 3.58 (s, 2H), 3.5 (m, 2H), 1.4 (m, 9H), 0.9 (m, 3H) l3C-nmr (CD3OD): 8 = 175.4, 172.9, 166.7, 166.5, 163.5, 163.2, 141.8, 141.7, 113.9, 113.8, 113.7, 113.6, 103.9, 103.6, 103.2, 65.6, 53.2, 51.2, 43.3, 32.3, 29.7, 24.1, 18.7, 14.9. C,7H24F2N203 (MW = 342.39); mass spectroscopy (MH+) 343. 25 Example 229 Synthesis of ZV-[a-Hydroxy-a'-(4-hydroxyphenyl)isopropyl]-/V'-(3,5-difluorophenylacetyl)-L-alaninainide Following General Procedure S and using N-[N-(3,5-30 difluorophenylacetyl)-L-alaninyl]-L-tyrosme methyl ester (from Example 15 Printed from Mimosa WO 98/22494 PCT/US97/20804 - 315 - above), the title compound was prepared as a solid (mp = 179-183°C). The reaction was monitored by tic (Rf = 0.42 in 10% MeOH/DCM) and the product was purified by recrystallization from MeOH/diethyl ether. NMR data was as follows: 5 'H-nmr (CDC13): 5 = 6.82 (d, J=8.3 Hz, 2H), 6.7 (m, 2H), 6.62 (t, J=9.1, 9.1 Hz, IH), 6.47 (d, J=8.5 Hz, 2H), 4.1 (m, IH), 3.7 (m, IH), 3.34 (s, 2H), 3.2 (m, 2H), 2.5 (m, 2H), 1.08-0.94 (dd, J=7.1, 36.0, 7.1 Hz, 3H). 13C-nmr (CDC13): 6 = 175.0, 172.8, 157.4, 131.8, 131.8, 130.7, 116.6, 116.5, 113.9, 113.5, 64.1, 54.9, 51.1, 43.3, 37.4, 18.6. 10 C20H22F2N2O4 (MW = 392); mass spectroscopy (MH+)= 393. Example 230 Synthesis of /V-2-Pyridylmethyl-W-[7V-(3,5-dinuorophenylacetyl)-L-alaninyl]-L-phenylalaninamide 15 Following General Procedure K and using N-[N-(3,5- difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (from Example 94 above) and 2-(aminomethyl)pyridine (Aldnch), the title compound was prepared. NMR data was as follows: 20 'H-nmr (CD3OD): 5 = 8.45 (d, IH), 7.75 (t, IH), 7.2-7.4 (m, 6H), 7.1 (d, IH), 6.8-7.0 (m, 3H) 4.63 (t, IH) 4.45 (s, 2H), 4.2-4.35 (m, IH), 3.6 (s, 2H), 3.6 (s, 2H), 3.0-3.25 (m, 2H), 1.30 (d, 3H) l3C-nmr (CD3OD): 5 = 175.4, 174.0, 173.3, 166.6, 163.3, 163.2, 159.5, 150.0, 141.4, 139.4, 138.9, 130.9, 130.1, 128.4, 124.2, 123.2, 114.0, 25 113.9, 113.7, 113.6, 103.9, 103.2, 56.9, 51.4, 45.8, 43.1, 39.0, 18.2 C26H26F2N403 (MW = 480.52); mass spectroscopy (MH+)= 481. Example 231 Synthesis of N-[a!-Hydroxy-ar'-pyrid-2-ylisopropyl]-30 W-(3,5-difluorophenylacetyl)-L-alaninamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 316 - Following General Procedure S and using methyl N-[N-(3,5-difluorophenylacelyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propionate(from Example 19 above), the title compound was prepared as a solid (mp = 225-229°C). The reaction was monitored by tic (Rf = 0.66 in 10% MeOH/DCM) 5 and the product was purified by recrystallization from MeOH/diethyl ether. NMR data was as follows: lH-nmr (CDC13): S = 8.21 (d, J=4.5 Hz, IH), 7.46 (t, J=6.3, 7.6 Hz, IH), 7.11 (d, J=7.6 Hz, IH), 7.01 (t, J=5.5, 7.1 Hz, IH), 6.70 (d, J=6.3 Hz, 2H), 6.62 (t, J=9.6, 9.0 Hz, IH), 4.1 (m, IH), 3.4 (m, IH), 3.33 (s, 10 2H), 3.3 (m, 2H), 1.06 (d, J=7.0 Hz, 3H). 13C-nmr (CDClj): 6 = 172.754, 160.222, 150.134, 139.137, 126.198, 123.680, 113.936, 113.602, 103.578, 64.854, 53.689, 51.191, 43.304, 40.394, 18.769. C,9H21F2NjOj (MW = 377); mass spectroscopy (MH+) 378. 15 Example 232 Synthesis of /V-[a-Hydroxy-a'-pyrid-4-ylisopropyI]-/V'-(3,5-difluorophenylacetyl)-L-alaninamide Following General Procedure S and using methyl N-[N-(3,5-20 difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-pyridyl)propionate(from Example 23 above), the title compound was prepared as a solid (mp = 189-193°C). The reaction was monitored by tic (Rf = 0.47 in 10% MeOH/DCM) and the product was purified by silica gel chromatography. NMR data was as follows: 25 'H-nmr (CDClj): 5 = 8.18 (d, J=5.6 Hz, 2H), 7.27 (d, J=5.6 Hz, 2H), 6.7 (m, 2H), 6.6 (m, IH), 4.0 (m, IH), 3.9 (m, IH), 3.32 (s, 2H), 3.10 (s, 2H), 2.9 (m, 2H), 1.07 (d, J=7.2, 3H). 13C-nmr (CDClj): 6 = 175.8, 150.4, 150.2, 126.8, 113.9, 113.6, 103.6, 103.5, 72.0, 59.3, 55.2, 51.6, 42.9, 40.8, 38.3, 17.9. 30 Qs^FjNjOj (MW = 377); mass spectroscopy (MH+) 378. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 317 - Example 233 Synthesis of Ar-[(S)-l-Hydroxy-4-methylpent-2-yl]-W-(3,5-difluorophenylacetyl)-L-alaninamide S Isomer A: Following General Procedure B and using /V-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and (S)-l-hydroxy-4-methylpent-2-ylamine (leucinol) (Bachem), the title compound was prepared as a solid (mp = 141-151°C). The reaction was monitored by tic (Rf = 0.5 in 5% MeOH/methylene 10 chloride) and the product was purified by recrystallization from EtOAc/hexanes. NMR data was as follows: 'H-nmr (CD3OD): 5 = 8.15 (s IH), 7.5 (t, J=8 Hz, IH), 6.80-6.55 (m, 3H), 4.15 (m, J=3.5 Hz, IH), 3.7 (m IH), 3.35 (s 2H), 3.22 (t, J=3 Hz, 2H), 1.4 (m, IH), 1.1 (m, 5H), 0.7 (m, 6H). 15 ,3C-nmr (CDjOD): 6 = 175.4, 175.3, 173.0, 113.9, 113.9, 113.6, 113.5, 103.9, 103.6, 103.2, 66.1, 51.6, 51.4, 51.3, 51.3, 43.4, 41.7, 41.6, 26.5, 26.3, 24.3, 22.8, 22.7, 19.0, 18.7, 18.6. C17H24N203F2 (MW = 342.19); mass spectroscopy (MH+) 343. Isomer B: 20 Following General Procedure B and using A^-(3,5-difluoropheny]acetyl)- L-alanine (from Example B2 above) and (S)-l-hydroxy-4-methylpent-2-ylamine (leucinol) (Aldrich), the title compound was prepared as a solid (mp = 151-153°C). The reaction was monitored by tic (Rf = 0.8 in 10% MeOH/DCM) and the product was purified by recrystallization, followed by flash column 25 chromatography, followed by a preparative tic using 10% MeOH/DCM as the eluent. NMR data was as follows: 'H-nmr (CD3OD): 5 = 8.15 (s IH), 7.5 (t, J=8 Hz, IH), 6.80-6.55 (m, 3H), 4.15 (m, J=3.5 Hz, IH), 3.7 (m, IH), 3.35 (s, 2H), 3.22 (t, J=3 Hz, 30 2H), 1.4 (m, IH), l.l(m, 5H), 0.7 (m, 6H). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 318 - ,3C-nmr (CDjOD): 5 = 175.2, 172.9, 166.6, 166.5, 141.7, 113.9, 113.9, 113.8, 113.6, 113.6, 103.9, 103.6, 103.2, 66.1, 51.2, 50.4, 50.1, 50.0, 49.8, 49.7, 49.6, 49.4, 49.38, 49.3, 49.0, 48.7, 43.4, 43.3, 41.7, 26.3, 24.3, 22.8, 18.7. 5 C,7H24NAF2 (MW = 342.19); mass spectroscopy (MH+) 342. Example 234 Synthesis of /V-[l-Methoxyprop-2-yl]-Ar'-(3,5-difluorophenylacetyl)-L-alaninamide Following General Procedure B and using N-(3,5-difluorophenylacetyl)-10 L-alanine (from Example B2 above) and 2-amino-l-methoxypropane (Aldrich), the title compound was prepared as a solid (mp = 152°C). The reaction was monitored by tic (Rf = 0.45 in 5% MeOH/DCM) and the product was purified by recrystallization from methanol/water. NMR data was as follows: 15 'H-nmr (CDC13): 5 = 6.9-6.7 (m, 3H), 6.6 (d, J=7 Hz, IH), 6.3 (m, IH), 4.5 (m, J=7 Hz, IH), 4.1 (m, IH), 3.5 (s, 2H), 3.3 (m, 5H), 1.4 (d, J=7 Hz, 3H), 1.15 (t, J = 8 Hz, 3H). 13C-nmr (CDClj): d = 172.0, 113.0, 112.9, 112.62, 112.60, 103.7, 103.4, 78.0, 77.6, 77.2, 75.8, 75.7, 59.6, 59.58, 49.6, 49.5, 45.6, 45.6, 43.4, 20 19.4, 19.38, 18.9, 18.0. C17H20N2O3F2 (MW = 314.14); mass spectroscopy (MH+) 315. Example 235 Synthesis of A'-[l-Hydroxy-3-methylbut-2-yl]-25 /V'-(3,5-difluorophenylacetyl)-L-alaninamide Following General Procedure B and using /V-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and valinol (Bachem), the title compound was prepared as a solid (mp = 176-179°C). The reaction was monitored by tic (Rf = 0.4 in 5% MeOH/DCM) and the product was purified by 30 recrystallization from EtOAc/hexanes. Printed from Mimosa WO 98/22494 PCMJS97/20804 - 319 - NMR data was as follows: 'H-nmr (CD3OD): 8 = 7.5 (d, J=9 Hz, IH), 6.8-6.5 (m, 3H), 4.15 (m, IH), 3.45 (m, 2H), 3.35 (m, 3H), 1.65 (m, J=7 Hz, IH), 1.20 (d, J=5 Hz, 3H), 0.7 (m, 6H). 5 13C-nmr (acetone-d6): 8 = 113.7, 113.4, 103.0, 63.3, 57.7, 57.69, 50.5, 50.4, 43.2, 31.1, 30.8, 30.6, 30.5, 30.3, 30.2, 30.1, 29.9, 29.9, 29.8, 29.7, 29.6, 20.5, 20.4, 19.5, 19.1, 19.0, 18.8. C1SH22N203F2 (MW = 329.19); mass spectroscopy (MH+) 329. Example 236 10 Synthesis of Methyl N-[Af-(3,5-Dinuorophenylacetyl)-L-alaninyI]-2-amino-2-(6-aminopyrid-2-yl)acetate Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(6-aminopyrid-2-15 yl)acetate (prepared from 2-(methoxyimino)-2-(6-aminopyrid-2-yl)acetic acid [CAS 71470-33-2] using General Procedures G and AC above), the title compound was prepared. The product was purified by LC 2000 preparative column chromatography using 1:1 EtOAc/hexanes as the eluent. NMR data was as follows: 20 'H-nmr (CDC13): 8 = 7.65-6.5 (m, 6H), 6.4 (d, J=8.19 Hz, IH), 5.49- 5.33 (m, IH), 4.8-4.5 (m, 2H), 3.7 (s, 3H), 3.6 (s, IH), 3.5 (s, IH), 2.06 (bs, 2H), 1.44 (d, J=7.06 Hz, 1.5 H), 1.35 (d, 7.06 Hz, 1.5H). C19H20N4O4F2 (MW = 406.39); mass spectroscopy (MH+) 406.3. Example 237 25 Synthesis of Ar-[l-Hydroxyprop-2-yl]-W-(3,5-difluorophenylacetyl)-L-aIaninamide Following General Procedure B and using 7V-(3,5-difluorophenylacetyl)-L-alamne (from Example B2 above) and alanol (Bachem), the title compound 30 was prepared as a solid (mp = 158-163°C). The reaction was monitored by tic Printed from Mimosa WO 98/22494 PCT/U S97/20804 - 320 - (Rf = 0.7 in 10% MeOH/DCM) and the product was purified by recrystallization from ethyl acetate, followed by flash column chromatography using 10% MeOH/DCM. NMR data was as follows: 5 'H-nmr (CD3OD): 5 = 8.2 (m, IH), 7.6 (m, IH), 4.1 (m, J=7 Hz, IH), 3.7 (m, J=5 Hz, IH), 3.35 (s, 2H), 3.25 (m, 2H), 1.15 (d, J=7 Hz, 3H), 0.9 (d, J=7 Hz, 3H). 13C-nmr (CDjOD): S = 175.1, 175.06, 172.9, 166 6, 166.5, 163.4, 163.2, 141.6, 113.9, 113.8, 113.7, 113.6, 103.9, 103.6, 103.2, 66.5, 51.4, 10 51.3, 51.3, 51.2, 50.4, 50.1, 49.8, 49.77, 49.6, 49.5, 49.3, 49.1, 49.0, 48.7, 43.3, 18.8, 17.5. C14H18N203F2 (MW = 300); mass spectroscopy (MH+) 301. Example 238 Synthesis of 15 iV-[(S)-2-methoxy-l-phenyleth-l-yl]- N(3,5-difluoropheny lacety I)-L-alaninamide Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and iV-[(S)-2-methoxy-l-phenyleth-l-yl]-L-alamnamide(prepared from N-BOC-L-alamne (Sigma) and (S)-phenylglycinol methyl ether (from 20 Example D15 above) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 180-182°C). The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the product was punfied by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-25 chlorobutane/acetonitrile. NMR data was as follows: 'H-nmr (DMSO-<f6): 6 = 1.22 (d, 3H), 3.23 (s, 3H). Optical Rotation: [or]20 = +12.3° @ 589 nm (c 1.04, DMSO). C20H22F2N2O3 (MW = 376.41); mass spectroscopy (MH+) 377. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 321 -- Example 239 Synthesis of iV-[(S)-l-Methoxy-2-phenyIprop-2-yI]-N'-(3,5-difluorophenylacetyl)-L-alaninamide 5 Following General Procedure B and using iV-(3,5-difluorophenylacetyl)- L-alanine (from Example B2 above) and L-phenylalaninol methyl ether hydrochloride (Fluka), the title compound was prepared as a fluffy solid. The product was purified by recrystallization from MeOH/EtOAc. NMR data was as follows: 10 'H-nmr (CDC13): 5 = 1.31 (d, J=7 Hz, 3H), 2.8 (d, J=7 Hz, 2H), 3.28 (d, J=3 Hz, 2H), 3.32 (s, 3H), 3.47 (s, 2H), 4.15-4.3 (m, IH), 4.35-4.5 (m, IH), 6.3-6.5 (m, 2H), 6.6-6.9 (m, 3H), 7.1-7.35 (m, 5H). l3C-nmr (CDC13): 5 = 19.1, 37.8, 43.4, 49.6, 51.0, 59.6, 72.7, 103.4, 112.6, 113.0, 127.1, 129.0, 129.9, 138.3, 169.8, 172.1. 15 Example 240 Synthesis of N- [(S)-1 -Acetoxyhex-2-yl]-iV'-(3,5-difluorophenyIacetyl)-L-alaninainide Following General Procedure V and using Af-[(S)-l-hydroxyhex-2-yl]-W-20 (3,5-difluorophenylacetyI)-L-alaninamide (from Example 228 above), the title compound was prepared as a solid (mp = 144-145 °C). The reaction was monitored by tic (Rf = 0.42 in 10% CH30H/CH2C12). NMR data was as follows: 'H-nmr (CD3OD): 5 = 6.7 (m, 2H), 6.6 (m, IH), 4.09 (q, IH), 3.9-3.7 25 (m, 3H), 3.35 (s, 2H), 1.79 (s, 3H), 1.4-1.0 (m, 9H), 0.6 (m, 3H). 13C-nmr (CD3OD): 5 = 175.5, 173.2, 172.8, 166.6, 166.5, 163.4, 163.2, 141.8, 141.7, 141.5, 113.9, 113.8, 113.7, 113.6, 103.9, 103.5, 103.2, 67.5, 51.2, 43.28, 43.26, 32.2, 29.6, 24.0, 21.3, 18.8, 14.8. C19H26F2N204 (MW = 384.43); mass spectroscopy (MH+) 385. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 322 - Example 241 Synthesis of iV-[(S)-l-(fe/f-Butylcarbonyloxy)-hex-2-yI]- Ar,-(3>5-difluoropheaylacetyl)-L-alaninamide 5 Following General Procedure W and using JV-[(S)-l-hydroxyhex-2-yl]- A/'-(3,5-difluorophenylacetyl)-L-alaninamide (from Example 228 above) and trimethylacetyl chloride (Aldrich), the title compound was prepared as a solid (mp = 104-107.5°C). The reaction was monitored by tic (Rf = 0.43 in 10% CH3OH/CH2Cl2) and the product was purified by preparative thin layer 10 chromatography using 10% CH30H/CH2C12 as the eluent. NMR data was as follows: 'H-nmr (CD3OD): 5 = 7.67 (bd, IH), 6.7 (m, 2H), 6.6 (m, IH), 4.14 (q, IH), 3.9-3.6 (m, 3H), 3.35 (s, 2H), 1.4-1.0 (m, 9H), 0.98 (s, 9H), 0.6 (m, 3H). 15 ,3C-nmr (CD3OD): 5 = 180.3, 175.3, 175.2, 172.8, 166.6, 166.5, 163.4, 163.2, 141.8, 141.7, 141.5, 133.9, 113.8, 113.7, 113.6, 103.9, 103.6, 103.2, 67.6, 51.1, 51.0, 43.3, 40.4, 32.4, 32.3, 29.5, 28.2, 24.0, 19.0, 14.9. C22H32F2N204 (MW = 426.51); mass spectroscopy (MH+) 427.5. Example 242 20 Synthesis of iV-[2-Hydroxy-l-(thien-2-yl)ethyl]-W-(3,5-difluorophenylacetyl)-L-alaninamide Following General Procedure S and using methyl N-[N-(3,5-25 difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetate(from Example 178 above), the title compound was prepared as a solid (mp = 201-202°C). The product was purified by trituration using 1:1 hexanes/EtOAc. NMR data was as follows: 'H-nmr (DMSO-d6): 6 = 8.4-8.25 (m, 2H), 7.4-7.35 (m, 2H), 7.3-6.91 30 (m, 4H), 5.1-4.85 (m, IH), 4.4-4.3 (m, IH), 3.7-3.5 (m, 2H), 3.51 (s, IH), 3.50 (s, IH), 1.23-1.19 (overlaying doublets, 3H). C2IH23F2N203 (MW = 368.4); mass spectroscopy (MH+) 368. Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 323 - Example 243 Synthesis of iV-[(S)-2-hydroxy-2-methyl-l-phenylprop-l-yI]-A^-(3,5-difluorophenyIacetyl)-L-alaninamide 5 Following General Procedure C and using //-(3,5-difluorophenylacetyl)- L-alanine (from Example B2 above) and (S)-2-hydroxy-2-methyl-l-phenylprop-1-ylamine (from Example D16 above), the title compound was prepared as a solid. The product was purified by recrystallization from methanol/ethyl acetate. 10 NMR data was as follows: 'H-nmr (DMSO-<i6): 5 = 8.32 (d, IH), 8.11 (d, IH), 7.20-7.33 (m, 5H), 7.08 (m, IH), 6.96 (m, 2H), 4.68 (d, IH), 4.53 (s, IH), 4.95 (m.lH), 3.50 (d, 2H), 1.25 (d, 3H), 1.08 (s, 3H), 0.98 (s, 3H). Optical Rotation: [a]23 = -11° (c 1, MeOH). 15 C21H24F2N203 (MW = 390.42); mass spectroscopy (MH+) 391. Example 244 Synthesis of Ar-[Ar-(3,5-DifluorophenylacetyI)-L-(thien-2-yl)glycinyl]-L-phenylalanine ferf-Butyl Ester 20 Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-(2-thienyl)glycinyl-L-phenylglycine tert-butyl ester (prepared using N-(9-florenylmethoxycarbonyl)-L-(2-thienyl)glycine (prepared as described below) and L-phenylglycine tert-butyl ester hydrochloride using General Procedure AH, followed by deprotection using dicyclohexylamine in 25 DMF and THF), the title compound was prepared as a solid (mp = 176-177 °C). The product was purified by flash chromatography using EtOAc/dichloromethane as the eluent. C26H26N204F2 (MW = 500.56); mass spectroscopy (MH+) 500. Preparation of N-(,9-Fluorenvlmethoxvcarbonvl')-L-('2-Thienvl')glvcine: 30 A round bottom flask containing a magnetic stir bar under an atmosphere of Printed from Mimosa WO 98/22494 PCT/US97/20804 - 324 -- nitrogen at room temperature was charged with water, dioxane, sodium carbonate (2.5 eq.) and L-a-(2-thienyl)glycine (1.0 eq.) (Sigma). Stirring was initiated and the slurry was cooled in an ice bath. 9-Flurenylmethyl chloroformate was added portionwise to the reaction and stirring was continued 5 in an ice bath for 4 hours followed by 8 hours at room temperature. The reaction mixture was poured onto water and extracted wilth diethyl ether. The aqueous layer was cooled in an ice bath and acidified with vigorous stirring to a pH of 2. The resulting solid was isolated via vacuum filtration, washed with water (3X) and dried under reduced pressure. 10 Example 245 Synthesis of iV-[7V-(3,5-DifluorophenyIacetyI)-L-phenyIglycinyl]-l^phenylglycinol Following General Procedure E and using 3,5-difluorophenylacetic acid 15 (Aldrich) and L-phenylglycinyl-L-phenylglycinol (prepared from N-BOC-L-phenylgycine (Novabiochem) and L-phenylglycinol (Novabiochem) using General Procedure AH, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 231.4°C). The product was punfied by crystallization from ethyl acetate. 20 C24H22N203F2 (MW = 424.45); mass spectroscopy (MH+) 424.9. Example 246 Synthesis of iV-[7V-(CycIopropaneacetyI)-L-phenylglycinyI]-L-phenylglycinol 25 Following General Procedure E and using cyclopropaneacetic acid (Aldnch) and L-phenylglycinyl-L-phenylglycinol (prepared from /V-BOC-L-phenylgycme (Novabiochem) and L-phenylglycinol (Novabiochem) using General Procedure AH, followed by removal of the BOC-group using General Printed from Mimosa WO 98/22494 PCT/US97/20804 - 325 -- Procedure P), the title compound was prepared as a solid (mp = 202.5°C). The product was purified by crystallization from ethyl acetate. C21H24N203 (MW = 352.43); mass spectroscopy (MH+) 353.2. Example 247 5 Synthesis of iV-[iV-(Cyclopentaneacetyl)-L-phenylglycinyl]-L-pbenylglycinol Following General Procedure E and using cyclopentaneacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycinol (prepared from jV-BOC-L-10 phenylgycine (Novabiochem) and L-phenylglycinol (Novabiochem) using General Procedure AH, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 201.4°C). The product was purified by flash chromatography using MeOH/CH2CH2 as the eluent. 15 C23H28N203 (MW = 380.49); mass spectroscopy (MH+) 381.4. difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycine methyl ester (from Example 99 above), the title compound was prepared as a solid (mp = 285.5-288.5°C). C24H21N303F2 (MW = 437.45); mass spectroscopy (MH+) 437.1. Example 248 Synthesis of A*-[N-(3,5-DifIuorophenylacetyI)-D,L-phenylgIycinyl]-D,L-phenyIgIycinamide 20 Following General Procedure AO and using #-[#-(3,5- 25 Example 249 Synthesis of N-[N-(3,5-Difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamide Prxnted from Mimosa WO 98/22494 PCT/US97/20804 - 326 - Following General Procedure AO and using N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine methyl ester (from Example 94 above), the title compound was prepared as a solid (mp = 260.3-264.3°C). The product was purified by recrystallization from ethyl acetate/methanol. 5 C21H23N3O3F2 (MW = 403.43); mass spectroscopy (MH+) 404. Example 250 Synthesis of Af-[N-(2-ThienyIacety])-L-alaninyl]-L-phenyIglycinamide Following the General Procedures descnbed herein, the title compound 10 was prepared. Example 251 Synthesis of /V-[/V-(n-Caproyl)-L-alaninyl]-L-phenylglycinamide Following the General Procedures descnbed herein, the title compound 15 was prepared. Example 252 Synthesis of N- [/V-(3,5-Diflu oropheny Jacety l)-L-norleuciny 1]-L-phenylglycine Methyl Ester 20 Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycine methyl ester hydrochloride (prepared from N-BOC-L-norleucine (Lancaster) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared 25 as a solid (mp = 188-189.5°C). The product was purified by flash chromatography using ethyl acetate/hexanes as the eluant. C2:)H26N204F2 (MW = 432.47); mass spectroscopy (MH+) 432. Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 327 - Example 253 Synthesis of iV-[iV-(3,5-Difluorophenylacetyl)-L-norvaIinyI]-L-phenylglycine Methyl Ester 5 Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-norvalinyl-L-phenylglycine methyl ester hydrochloride (prepared from N-BOC-L-norvaline (Lancaster) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared 10 as a solid (mp = 204-205 CC). The product was purified by flash chromatography using ethyl acetate/hexanes as the eluent. C22H24N204F2 (MW = 418.44); mass spectroscopy (MH+) 418.3. Example 254 Synthesis of 15 Af-|W-(3,5-Dinuorophenylacetyl)-L-tert-leucinyI]- L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-rm-leucinyl-L-phenylglycine methyl ester hydrochloride (prepared from /V-BOC-L-rerf-leucine (Bachem) and L-phenylglycine methyl 20 ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 176.4°C). The product was purified by flash chromatography using ethyl acetate/hexanes as the eluent. C23H26N204F2 (MW = 432.47); mass spectroscopy (MH+) 432.0. 25 Example 255 Synthesis of Ar-[Ar-(3,5-Difluorophenylacetyl)-L-isoleucinyl]-L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid 30 (Aldrich) and L-isoleucinyl-L-phenylglycine methyl ester hydrochloride Printed from Mimosa WO 98/22494 PCT/US97/20804 - 328 - (prepared from N-BOC-L-isoleucine (Aldnch) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 228.8°C). The product was purified by flash chromatography 5 using ethyl acetate/hexanes as the eluent. C23H25N2O4F2 (MW = 432.46); mass spectroscopy (MH+) 433.4. Example 256 Synthesis of /V-[/V-(3,5-DifluorophenylacetyI)-L-cyclohexylalaninyl]-10 L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldnch) and L-cyclohexylalaninyl-L-phenylglycine methyl ester hydrochloride (prepared from jV-BOC-L-cyclohexylalanine (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by 15 removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 174.8°C). The product was purified by flash chromatography using ethyl acetate/hexanes as the eluent. CzsHjoNjO^ (MW = 472.53); mass spectroscopy (MH+) 473.2. Example 257 20 Synthesis of A,-|7V-(3,5-Difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyI]-L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-amino-2-(cyclopropyl)acetyl-L-phenylglycine methyl ester 25 hydrochloride (prepared from jV-BOC-(S)-2-amino-2-cyclopropylacetic acid (prepared from cyclopropylacetic acid (Lancaster) and (4S)-4-benzyl-2-oxaxolidinone (Aldrich) using the procedures descnbed in Evans et al., J. Am. Chem. Soc., 1990, 112, 4011-4030 and references cited therein) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, 30 followed by removal of the BOC-group using General Procedure P), the tide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 329 - compound was prepared as a solid (mp = 225-226.5 °C). The product was purified by flash chromatography using MeOH/CHCl3 as the eluent. C^H^l^O^ (MW = 416.42); mass spectroscopy (MH+) 417.3. Example 258 5 Synthesis of Ar-[/V-(3,S-Difluorophenylacetyl)-(S)-2-amino-2-(thien-3-yl)acetyl]-L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-(S)-2-amino-2-(thien-3-yl)acetyl-L-phenylglycine methyl ester 10 hydrochloride (prepared from N-BOC-L-thien-3-ylgIycine (prepared from L-a-2-thienylglycine (Sigma) using General Procedure AJ) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 229.3 °C). The product was punfied by 15 crystallization from ethyl acetate/hexanes. C23H20N2O4SF2 (MW = 458.49); mass spectroscopy (MH+) 458. Example 259 Synthesis of #-[A'-(3,5-Difluorophenylacetyl)-(S)-2-amino-2-(thien-2-yl)acetyl]-20 L-phenylglycine Methyl Ester Following General Procedure AH and using 3,5-difluorophenylacetic acid (Aldrich) and L-(S)-2-amino-2-(thien-2-yl)acetyl-L-phenylglycine methyl ester hydrochloride (prepared from iV-BOC-L-thien-2-ylglycine (prepared from L-a-(thien-2-yl)glycine (Sigma) using General Procedure Al) and L-25 phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp = 230.8°C). The product was purified by flash chromatographyl using MeOH/CH2CH2 as the eluant. C23H20N2O4F2S(MW = 458.49); mass spectroscopy (MH+) 458. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 330 - Example 260 Synthesis of Ar-[AM3,5-DifluorophenyIacetyI)-I^(4-fluorophenyl)glycinyl]-L-phenylglycine Methyl Ester 5 Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-(4-fluorophenyl)glycinyl-L-phenylglycine methyl ester hydrochloride (prepared from N-Cbz-(4-fluorophenyl)glycine (prepared from (4-fluorophenyl)glycine (prepared as described below) using General Procedure AK) and L-phenylglycine methyl ester hydrochlonde (Aldrich) using General 10 Procedure E, followed by silica gel chromatography using 5% ethyl acetate/toluene as the eluant and removal of the Cbz-group using General Procedure AJ), the title compound was prepared as a solid (mp = 213.1°C). The product was purified by flash chromatography using ethyl acetate/CHClj as the eluent. 15 C25H21N204F2 (MW = 470.44); mass spectroscopy (MH+) 470.1. Preparation of ("4-fluorophenvl'lglvcine: (S)-(-)-4-Benzyl-2-oxazolidinone (15.0 g, 93 mmol) (Aldnch) was dissolved in THF (100 mL). The solution was cooled to -70°C and reaction flask was purged twice with nitrogen. n-Butyl lithium (44.6 mL, 2.0M, 89 20 mmol) was added to form a solid precipitate which broke up on stirring wo afford a slurry. 4-Fluorophenylacetyl chlonde 16.1 g, 93 mmol) (Aldrich) was added to afford a light green solution and stirring was continued for 45 minutes. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was then treated with saturated sodium bisulfate 25 (100 mL) and ethyl acetate (100 mL). The organic phase was washed with water, followed by brine. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford an oil. The oil was crystallized to afford 24.4 g of l-(4-fluorophenylacetyl)-(S)-(-)-4-Benzyl-2-oxazolidinone. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 331 - Potassium hexamethyldisilazane (140 mL, 0.5M, 70.0 mmol) was added to THF (80 mL). The solution was cooled to -50°C under nitrogen and a cold solution (-60°C) of l-(4-fluorophenylacetyl)-(S)-(-)-4-benzyl-2-oxazolidinone (15.0 g, 46 mmol) in THF (100 mL). The resulting mixture was allowed to 5 stir at -70°C for 1 hour and to warm to about -20°C. The mixture was re-cooled to -70°C and a cold solution (-65°C) of trasyl azide (21.6 g, 70.0 mmol) was added. The mixture was allowed to stir for about 15 min. while warming to -45°C and then glacial acetic acid (18 mL) was added. The mixture was then stirred at about 30°C for 3 hours. A precipitate formed and 10 was removed by filtration. The filtrate was concentrated by 50 and then washed with water, saturated sodium bicarbonate solution and brine. The organic phase was dried over sodium sulfate, concentrated under reduced pressure to afford 37.7 g of crude l-[2-(4-fluorophenyl)-2-azidoacetyl]-(S)-(-)-4-benzyl-2-oxazolidinone. 15 Crude l-[2-(4-fluorophenyl)-2-azidoacetyI]-(S)-(-)-4-benzyl-2- oxazolidinone (10.0 g, 28.0 mmol) was dissolved in 100 mL of THF and 100 mL of methanol and trifluoroacetic acid (4.31 mL, 75.3 mmol) was added. Pallidium on carbon (10%, 2.0 g) was added and the mixture was hydrogenated on a Paar shaker at 50 psi overnight at room temperature. The reaction 20 mixture was then filtered through a plug of Celite and the solid cake was rinsed with 100 mL of methanol. The filterate was concentrated to afford l-[2-(4-fluorophenyl)-2-aminoacetyl]-(S)-(-)-4-benzyl-2-oxazolidinonetrifluoroacetate salt as a yellowish oil. To a mixture of THF and de-ionized water (50 mL/50 mL) was added 25 l-[2-(4-fluorophenyl)-2-aminoacetyl]-(S)-(-)-4-benzyl-2-oxazolidinone trifluoroacetate salt (4.14 g, 9.7 mmol) and lithium hydroxide monohydrate (1.22 g, 29 mmol). The homogenous solution was stirred for 2 hours at room temperature at which time Tic indicated complete disappearance of starting material. The mixture was extracted with dichloromethane (3 x 100 mL) and Printed from Mimosa WO 98/22494 PCT/US97/20804 - 332 - the aqueous phase was acidified to pH 2-3 while cooling in an ice-bath. A precipitate formed. The mixture was then cooled in an ice-bath for 1.5 hours and then filtered. The solid was washed with water followed by pentane to afford 4-fluorophenylglycine hydrochloride. 5 Example 261 Synthesis of A'-[N-(3,5-Difluorophenylacetyl)-D-(4-fluorophenyl)glycinyl]-L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid 10 (Aldrich) and D-(4-fluorophenyl)glycinyl-L-phenylglycine methyl ester hydrochloride (prepared from jV-Cbz-(4-fluorophenyl)glycine (prepared from (4-fluorophenyl)glycine (prepared as in Example 260) using General Procedure AK) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by silica gel chromatography using 5 % ethyl 15 acetate/toluene as the eluant and removal of the Cbz-group using General Procedure AJ), the title compound was prepared as a solid (mp = 188.0°C). The product was purified by flash chromatography using ethyl acetate/CHCl, as the eluent. C25H21N204F3 (MW = 470.44); mass spectroscopy (MH+) 470.1. 20 Example 262 Synthesis of jV-[AM3,5-DifluorophenylacetyI)-L-(4-methoxyphenyl)glycinyl]-L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid 25 (Aldrich) and L-(4-methoxyphenyl)glycinyl-L-phenylglycine methyl ester hydrochlonde (prepared from A7-Cbz-L-(4-methoxyphenyl)glycine (prepared from (4-methoxyphenyl)glycine (prepared by the Bucherer modification of the Strecker procedure as described in Greenstein et al., "The Chemistry of Amino Acids", Vol. 1, p. 698, Wiley, New York (1961)) using General Procedure 30 AK) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Printed from Mimosa WO 98/22494 PCT/US97/20804 - 333 - Procedure E, followed by removal of the Cbz-group using General Procedure AJ), the title compound was prepared as a solid (mp = 224.6°C). The product was purified by flash chromatography using MeOH/CHCl3 as the eluent. C26H24N2O5F2 (MW = 482.48); mass spectroscopy (MH+) 482.1. Example 263 Synthesis of 2V-[N-(3,5-Difluorophenylacetyl)-L-phenylgIyciuyl]-L-phenylglycine te/t-Butyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycine fm-butyl ester (prepared from iV-Cbz-L-phenylglycine (Novabiochem) and L-phenylglycine te/T-butyl ester hydrochloride (Novabiochem) using General Procedure AH, followed by removal of the Cbz-group using General Procedure AJ), the title compound was prepared as a solid (mp = 185.0°C). The product was purified by flash chromatography using ethyl acetate/CH2CH2 as the eluant. CjgH^NjC^Fj (MW = 494.54); mass spectroscopy (MH+, minus CO2-t-Bu) 393. Example 264 Synthesis of N-[/V-(Cyclopropylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-Butyl Ester Following General Procedure E and using cyclopropylacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycine terr-butyl ester hydrochloride (prepared from JV-Cbz-L-phenylglycine (Novabiochem) and L-phenylglycine rm-butyl ester hydrochloride (Novabiochem) using General Procedure AH, followed by removal of the Cbz-group using General Procedure AJ), the title compound was prepared as a solid (mp = 187.5°C). The product was purified by crystallization from ethyl acetate. C25H30N2O4 (MW = 422.53); mass spectroscopy (MH+) 423.4. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 334 - Example 265 Synthesis of iV-[/V-(CyclopentylacetyI)-L-phenylglycinyI]-L-pbenylglycine /erf-Butyl Ester 5 Following General Procedure E and using cyclopropylacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycine rm-butyl ester hydrochloride (prepared from iV-Cbz-L-phenylglycine (Novabiochem) and L-phenylglycine terf-butyl ester hydrochloride (Novabiochem) using General Procedure AH, followed by removal of the Cbz-group using General Procedure AJ), the title 10 compound was prepared as a solid (mp = 190.8°C). The product was purified by crystallization from ethyl acetate. C27H34N2O4 (MW = 450.58); mass spectroscopy (MH+) 451. Example 266 Synthesis of 15 N-[N- (f-Butylacetyl)-L-alaninyl]-L-phenyIglycinamide Following the General Procedures descnbed herein, the title compound was prepared. Example 267 Synthesis of 20 N-tert-Butyl-N '-[W-PjS-DifluorophenylacetyD-L-alaninyl]- L-(5-bromothien-2-yl)glycinamide Following General Procedure AB and using #-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), 5-bromo-2-thiophenecarboxaldehyde (Aldnch), (S)-(+)-a-methylbenzylamine (Aldrich) and 25 rm-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 227-228°C). The product was purified by recrystallization from ethyl acetate/hexanes. C2iH24N303BrS (MW = 515); mass spectroscopy (MH+) 515, 415. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 335 - Example 268 Synthesis of #-terf-ButyI-#'-[#-(3,5-DifluorophenyIacetyl)-L-alaninyI]- D-(5-bromothien-2-yl)glycinamide 5 Following General Procedure AB and using #-(3,5- difluorophenylacetyl)-L-alanine (from Example B2 above), 5-bromo-2-thiophenecarboxaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and /erf-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 216-217°C). The product was purified by recrystallization from ethyl 10 acetate/hexanes. C2iH24N303BrS (MW = 515); mass spectroscopy (MH+) 515, 415. Example 269 Synthesis of #-tert-Butyl-#'-[#-(3,5-Difluorophenylacetyl)-L-alaninyl]-15 L-(4-bromothien-2-yl)glycinamide Following General Procedure AB and using #-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), 4-bromo-2-thiophenecarboxaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and rm-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp 20 = 246-247°C). The product was purified by recrystallization from ethyl acetate/hexanes. C2iH24N303BrS (MW = 515); mass spectroscopy (MH+) 515, 415. Example 270 Synthesis of 25 #-/e/f-Butyl-#'-[#-(3,5-Difluorophenylacetyl)-L-aIaninyI]- L-(thien-2-yl)glycinamide Following General Procedure AB and using #-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), 2-thiophenecarboxaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and 30 terr-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp Printed from Mimosa WO 98/22494 PCT/US97/20804 « 336 - = 241-242°C). The product was purified by recrystallization from ethyl acetate/hexanes. C21H25N303F2S (MW = 438); mass spectroscopy (MH+) 438, 338. Example 271 5 Synthesis of #-te/f-Butyl-#'-[iV-(3,5-Difluorophenylacetyl)-L-aIaninyIJ-D-(thien-2-yl)glycinamlde Following General Procedure AB and using #-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), 2-10 thiophenecarboxaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and rm-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 235-236°C). The product was purified by recrystallization from ethyl acetate/hexanes. C2iH25N303F2S (MW = 438); mass spectroscopy (MH+) 438, 338. 15 Example 272 Synthesis of Ar-/ert-Butyl-#'-[#-(3,5-Difluorophenylacetyl)-I^alaninyl]-L-(thien-3-yl)glycinamide Following General Procedure AB and using #-(3,5-20 difluorophenylacetyl)-L-alanine (from Example B2 above), 3- thiophenecarboxaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and /m-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 240-241 °C). The product was purified by recrystallization from ethyl acetate/hexanes. 25 C21H2jN303F2S (MW = 438); mass spectroscopy (MH+) 438, 338. Example 273 Synthesis of #-/crt-ButyI-#'-[#-(3,5-Difluorophenylacetyl)-L-alaninyI]-D-(thien-3-yI)glycinamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 337 - Following General Procedure AB and using #-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), 3-thiophenecarboxaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and fm-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp 5 = 245-246°C). The product was purified by recrystallization from ethyl acetate/hexanes. C21H2jN3C>3F2S (MW = 438); mass spectroscopy (MH+) 438, 338. Example 274 Synthesis of 10 #-te/t-Butyl-#'-[#-(3,5-Difluorophenylacetyl)-L-aIaninyl]- D-phenylglycinamide Following General Procedure AB and using #-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), benzaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and ferr-butylisocyanide 15 (Aldrich), the title compound was prepared as a solid (mp = 239-240°C). The reaction was monitored by tic (Rf = 0.25 in 50% ethyl acetate/hexanes). C-jjHJ7N3O3F2 (MW = 431.53); mass spectroscopy (MH+) 432. Example 275 Synthesis of 20 #-fe/*-Butyl-# -[#-(3,5-Difluorophenylacetyl)-L-alaninyl]- L-phenylglycinamide Following General Procedure AL and using #-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), benzaldehyde (Aldnch), (S)-(+)-or-methylbenzylamine (Aldnch) and rm-butylisocyanide 25 (Aldrich), the title compound was prepared as a solid (mp = 240-241 °C). C23H27N303F2 (MW = 431.53); mass spectroscopy (MH+) 432. Example 276 Synthesis of #-tert-Butyl-#'-[#-(3,5-Difluorophenylacetyl)-L-alaninyl]-30 D,L- (5-ch lorothien-2-y 1) glycinamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 338 - Following General Procedure AB and using #-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), 5-chloro-2-thiophenecarboxaldehyde (from Example D17 above), (S)-(+)-a-methylbenzylamine (Aldrich) and fe/T-butylisocyanide (Aldrich), the title 5 compound was prepared as a solid (mp = 195-198°C). The reaction was monitored by tic (Rf = 0.15 in 50% ethyl acetate/hexanes). CjiH^NjOjFzCI (MW = 472); mass spectroscopy (MH+) 472. Example 277 Synthesis of 10 #-CycIohexyI-#'-[#-(3,5-DifluorophenylacetyI)-l^alaninyI]- L-4-(phenyI)phenylglycinamide Following General Procedure AB and using #-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), 4-biphenylcarboxaldehyde (Aldnch), (S)-(+)-a-methylbenzylamine (Aldrich) and 15 cyclohexylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 300°C (dec.)). The reaction was monitored by tic (Rf = 0.23 in 50% ethyl acetate/hexanes). C3,H33N303F2 (MW = 533.62); mass spectroscopy (MH+, minus cyclohexylamide) 408.2. 20 Example 278 Synthesis of #-ferf-Butyl-#'-[#-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-3-(phenoxy)phenylglycinamide Following General Procedure AM and using #-(3,5-25 difluorophenylacetyl)-L-alanine (from Example B2 above), 3- phenoxybenzaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and /m-butylisocyanide (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.29 in 50% ethyl acetate/hexanes). C29H3,N304F2 (MW = 523.63); mass spectroscopy (MH+) 524.24. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 339 - Example 279 Synthesis of iV-(S)-(-)-of-Methylbenzyl-#'-[/V-(3,5-DifluorophenyIacetyl) -L-alaninyl]-D, L-phenylglycinamide 5 Following General Procedure AB and using #-(3,5- difluorophenylacetyl)-L-alanine (from Example B2 above), benzaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and (S)-(-)-a-methylbenzylisocyanide (from Example D18 above), the title compound was prepared. 10 C27H27N303F2 (MW = 479.53); mass spectroscopy (MH+) 480.21. By following the procedures set forth above, N-(R)-(+)-a-Methylbenzyl-#'-[#-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide was prepared merely by substitution of the appropriate isomer. C^H^NjO^ (MW = 479.53); mass spectroscopy (MH+) 480.1. 15 Example 280 Synthesis of #-fe/t-ButyI-#'-[7V-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-3-(phenyl)phenylgIycinamide Following General Procedure AM and using #-(3,5-20 difluorophenylacetyl)-L-alanine (from Example B2 above), 3- phenylbenzaldehyde (from Example D20 above), (S)-(+)-a-methylbenzylamine (Aldrich) and /e/T-butylisocyanide (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.25 in 50% ethyl acetate/hexanes). C29H3iN303F2 (MW = 507.63); mass spectroscopy (MH+) 508.2. 25 Example 281 Synthesis of #-fert-Butyl-#'-(7V-(3,5-DifluorophenyIacetyl)-L-alaninyl]-L-4- (ethyl) phenylglycinamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 340 - Following General Procedure AM and using #-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), 4-ethylbenzaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and /e/r-butylisocyanide (Aldrich), the tide compound was prepared. The reaction was monitored by tic 5 (Rf = 0.20 in 50% ethyl acetate/hexanes). C2jH3,N303F2 (MW = 459.59); mass spectroscopy (MH+) 460.2. Example 282 Synthesis of #-tert-Butyl-#'-[#-(3,5-Difluorophenylacetyl)-L-alaninyl]-10 L-2-(phenyl) phenylglycinamide Following General Procedure AM and using #-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), 2-phenylbenzaldehyde (Aldrich), (S)-(+)-<*-me thylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich), the title compound was prepared. The reaction was 15 monitored by tic (Rf = 0.15 in 50% ethyl acetate/hexanes). C29H3lN303F2 (MW = 507.63); mass spectroscopy (MH+, minus tert-butylamide) 409. Example 283 Synthesis of 20 #-/e/t-Butyl-#'-[#-(3,5-DifluorophenyIacetyI)-L-alaninyI]- L-2-(benzyl)phenylglycinamide Following General Procedure AM and using #-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), 2-(benzyl)benzaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and 25 /m-butylisocyanide (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.19 in 50% ethyl acetate/hexanes). C30H33N3O3F2 (MW = 521.66); mass spectroscopy (MH+) 522.26. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 341 - Example 284 Synthesis of iV-tert-ButyI-W-[2V-(3,5-DifluorophenylacetyI)-L-alaiwiyl]-D,L-4-bromophenylglycinamide 5 Following General Procedure AM and using #-(3,5- difluorophenylacetyl)-L-alanine (from Example B2 above), 4-bromobenzaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.06 in 50% ethyl acetate/hexanes). 10 C^H^NjC^ (MW = 510.42); mass spectroscopy (MH+) 512.1. Example 285 Synthesis of #-te/f-Butyl-#'-[#-(3,5-Difluorophenylacetyl)-L-aIaninyI]-L-4-(cyclohexyI)phenylglycinamide 15 Following General Procedure AL and using #-(3,5- difluorophenylacetyl)-L-alanine (from Example B2 above), 4-(cyclohexyl)benzaldehyde (from Example D21 above), (S)-(+)-o:-methylbenzylamine (Aldrich) and rm-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 232-235 °C) 20 C29H37N303F2 (MW = 513.69); mass spectroscopy (MH+) 514.29 Example 286 Synthesis of #-/e/t-Butyl-#'-[#-(3,5-Difluorophenylacetyl)-L-alaninyI]-L-4-(4-ethylphenyl)phenylglycinamide 25 Following General Procedure AL and using #-(3,5- difluorophenylacetyl)-L-alanme (from Example B2 above), 4,4'-ethylbiphenylcarboxaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and /m-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 231-233°C). 30 C3.H35NAF2 (MW = 513.69); mass spectroscopy (MH+) 514.29. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 342 - Example 287 Synthesis of iV-te/f-Butyl-/V'-[iV-(3,5-Difluorophenylacetyl)-L-aIaninyI]-D ,L-4- (f erf-butyl) phenylglycinamide 5 Following General Procedure AL and using #-(3,5- difluorophenylacetyl)-L-alanine (from Example B2 above), 4-(tert-butyl)benzaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 280°C (dec.)). The reaction was monitored by tic (Rf = 0.13 in 50% ethyl 10 acetate/hexanes). C27H35N3O3F2 (MW = 487.65); mass spectroscopy (MH+) 488.27. Example 288 Synthesis of #-ferf-Butyl-#'-[#-(3,5-Difluorophenylacetyl)-L-alaninyl]-15 D,L-3-(4-chlorophenoxy)phenylglycinamide Following General Procedure AL and using #-(3,5-difluorophenylacetyl)-L-alamne (from Example B2 above), 3-(4-chlorophenoxy)benzaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and rerr-butylisocyanide (Aldrich), the title compound was prepared as a solid 20 (mp = 192-195°C). C29H30N3O4F2CI (MW = 558.07); mass spectroscopy (MH+) 558.20. Example 289 Synthesis of #-Cyclohexyl-#'-[#-(3,5-Difluorophenylacetyl)-L-alaninyl]-25 D-4-(phenyl)phenylgIycinamide Following General Procedure AB and using #-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above), 4-biphenylcarboxaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and cyclohexylisocyanide (Aldrich), the title compound was prepared as a solid (mp 30 = 290-291°C). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 343 - (MW = 533.62); mass spectroscopy (MH+) 534.3. Example 290 Synthesis of iV-[7V-(3,5-DifIuorophenyl-a-hydroxyacetyI)-L-aIaninyl]-5 L-phenylglycine tert-Butyl Ester Following General Procedure C and using 3,5-difluoromandelic acid (Fluorochem) and //-(L-alaninyl)-L-phenylglycine ferr-butyl ester (prepared using N-BOC-L-alanine (Sigma) and L-phenylglycine tert-butyl ester hydrochloride (Bachem) using General Procedure C, followed by removal of 10 the BOC group using General Procedure P), the title compound was prepared. C23H26N205F2 (MW = 479.53). Elemental analysis: Calc. (%) C, 61.60; H 5.84; N, 6.25. Found (%) C, 61.32; H, 6.02; N, 6.17. Example 291 Synthesis of 15 #-tert-Butyl-Ar'-[iV-(3,5-Difluorophenyl-a,a-difluoroacetyl)-L-alaninyl]- L-phenylglycinamide Following General Procedure C and using 3,5-difluorophenyl-a,a-difluoroacetic acid (from Example D23 above) and iV-(L-alaninyl)-L-phenylglycine rm-butyl ester (prepared using N-BOC-L-alanine (Sigma) and L-20 phenylglycine tert-butyl ester hydrochloride (Bachem) using General Procedure C, followed by removal of the BOC group using General Procedure P), the title compound was prepared. The reaction was monitored by tic (Rf = 0.39 in 30% ethyl acetate/hexanes) and the product was purified by HPLC using 17% ethyl acetate/hexanes as the eluent. 25 C2-,H24N204F4 (MW = 468.49); mass spectroscopy (MH+) 469.17. Example 292 Synthesis of /V-[/V-(3,5-Difluorophenylacetyl)-L-aIaninyl]-D-phenylglycine te/t-Butyl Ester Printed from Mimosa WO 98/22494 PCT/US97/20804 — 344 - Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and D-phenylglycine rm-butyl ester (prepared from D-phenylglycine (Sigma) using General Procedure J), the title compound was prepared. The reaction was monitored by tic (Rf = 0.1 in 10% 5 MeOH/CHCl3). NMR data was as follows: 'H-nmr (DMSO-d6): 6 = 8.64 (d, IH), 8. 38 (d, IH), 7.34 (m, 5H), 7.09 (m, IH), 6.99 (m, 2H), 5.27 (d, IH), 4.45 (m, IH), 3.32 (s, 2H) 1.28 (s, 9H), 1.18 (d, 3H). 10 Optical Rotation: [a]20 = -103.58 (c =1, MeOH). CaH^NAFj (MW = 432.47); mass spectroscopy (MH+) 433. Example 293 Synthesis of 7V-[(S)-l-Oxo-l-phenylprop-2-yl]-15 /V'-(3,5-difluorophenylacetyl)-L-alaninamide By oxidation of Af-[(lR,2S)-l-hydroxy-l-phenylprop-2-yl]-W-(3,5-difluorophenylacetyl)-L-alaninamide (from Example 226 above) using Jones reagent in acetone, the title compound was prepared. The reaction was 20 monitored by tic (Rf = 0.7 in 9:1 CHCI3/MeOH) and the product was purified by flash chromatography using 97 3 chloroform/methanol as the eluent. NMR data was as follows: lH-nmr (CDC13): 5 = 7.98 (m, 2H), 7.26 (m, IH), 7.50 (m, 2H), 6.84 (m, 2H), 6.72 (m, IH), 6.25 (d, IH), 5.49 (m, 3H), 4.54 (m, 3H), 3.54 (s, 25 2H), 1.41 (d, 3H), 1.38 (d, 3H). Optical Rotation: [a]20 = -106° @ 589 nm (c = 1, MeOH). C20H20F2N2O3 (MW = 374.39); mass spectroscopy (MH+) 374. Example 294 Synthesis of 30 N-I7V-(3,5-Difluorophenylacetyl)-L-]- D,L-(pyrid-3-yI)gIycine tert-Butyl Ester Printed from Mimosa WO 98/22494 PCT/US97/20804 - 345 -- Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and tert-butyl 2-amino-2-(3-pyridyl)acetate (prepared as described in Kolar et al., J. Heterocyclic Chem., 28, 171 (1991) and reference cited therein), the title compound was prepared. The reaction 5 was monitored by tic (Rf = 0.2 in 5% MeOH/CHCl3) and the product was purified by flash chromatography using 5 % MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (CDC13): 8 = 8.63 (m, IH), 8.54 (m, IH), 7.62 (m, IH), 7.45 (t, IH), 7.26 (m, IH), 6.82(m, 2H), 6.71 (m, IH), 6.47 and 6.36 (d, IH), 10 5.42 (d, IH), 4.59 (m,lH), 3.52 and 3.47 (two s, 2H), 1.38 and 1.36 (s, 9H), 1.34 and 1.28 (two d, 3H). C22H23N304F2 (MW = 433.46); mass spectroscopy (MH+) 434. Example 295 Synthesis of 15 [A'-[A'-(3,5-Difluorophenylacetyl)-I^alaninyl]- D,L-phenylglycinyl]morpholine Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and morpholine (Aldrich), the title compound was prepared. The reaction was 20 monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 5% MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-^): 8 = 8.60 and 8.49 (two d's, IH), 8.49 (m, IH), 7.25 (m, 5H), 7.18 (m, 2H), 6.95 (m, IH), 5.82 (m, IH), 4.38 (m, IH), 3.52 25 (m, 10H), 1.21 and 1.12 (two d's, 3H). CbH^NAF, (MW = 445.47); mass spectroscopy (MH+) 446. Example 296 Synthesis of Ar-[#-(3,S-Difluorophenylacetyl)-L-alaninyl]-30 D,L-(2-methoxy)phenylgIycine Methyl Ester Printed from Mimosa WO 98/22494 PCT/US97/20804 ~ 346 - Following General Procedure C and using jV-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(2-methoxy)acetate (prepared from 2-methoxybenzaldehyde (Aldrich) using the Bucherer modification of the Strecker procedure as described in J. P. Greenstein et al., "The Chemistry of Amino Acids", Wiley: New York, 1961, Vol. 1, p. 698), the title compound was prepared. The reaction was monitored by tic (Rf = 0.3 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 10% MeOH/CHClj as the eluent. NMR data was as follows: 'H-nmr (CDC13): 6 = 7.28 (m, 2H), 6.93 (d, IH), 6.88 (m, 2H), 6.69 (m, 2H), 6.34 (m, IH), 5.67 (m, IH), 4.52 (m, IH), 3.81 (two s, 3H), 3.68 (two s, 3H), 3.59 and 3.45 (two s, 3H) 1.41 and 1.28 (two d, 3H). C21H22N205F2 (MW = 420.42); mass spectroscopy (MH+) 420. Example 297 Synthesis of A/-|7V-(3,5-DifIuorophenylacetyl)-L-alaninyl]- D,L-phenylglycine ;V-fe/<-Butoxycarbonyl(hydroxyl amine) Ester Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and N-BOC hydroxyl amine (Aldnch), the title compound was prepared. The reaction was monitored by tic (Rf = 0.35 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 2% MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (CDC13): 8 = 7.79 (m, IH), 7.41-7.28 (m, 5H), 6.78-6.59 (m, 3H), 5.52 (m, IH), 4.69 (m, IH), 3.38 (two s, IH), 1.38 (d, 3H), 1.30 (s, 9H). C24H27N306F2 (MW = 491.49); mass spectroscopy (MH+) 492. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 347 - Example 298 Synthesis of iV-Neopentyl-iV-[iV-(3,5-DifliiorophenylacetyI)-L-alaninyI]-D, L-phenylglycinamide 5 Following General Procedure M and using N-[N-(3,5- difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and neopentylamine (Aldrich) , the title compound was prepared. The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 10% MeOH/CHCl3 as the eluent. 10 NMR data was as follows: 'H-nmr (DMSO-</6): 8 = 8.44 (m, IH), 7.41 (m, 2H), 7.31 (m, 3H), 7.12 (m, IH), 6.99 (m, 2H), 5.50 (m, IH), 4.47 (m, IH), 3.52 (two s, 2H), 2.84 (m, 2H), 1.22 (m, 3H), 0.71 (s, 9H). C24H29N303F2 (MW = 460); mass spectroscopy (MH+) 460. 15 Example 299 Synthesis of A?-Tetrahydrofurfuryl-/V'-[iV-(3,5-Difluorophenylacetyl)-L-alaninyl]-D, L-phenylglycinamide Following General Procedure M and using N-[N-(3,5- 20 difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and tetrahydrofurfurylamine (Aldrich) , the title compound was prepared. The reaction was monitored by tic (Rf = 0.4 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 10% MeOH/CHCl3 as the eluent. 25 NMR data was as follows: 'H-nmr (DMSO-</6): 8 = 8.41 (m, 2H), 7.32 (m, 5H), 7.08 (m, IH), 6.99 (m, 2H), 5.48 (m, IH), 4.42 (m, IH), 3.85-3.54 (m, 3H), 3.48 (two s, 2H), 3.14 (m, 2H), 1.76 (m, 4H), 1.21 (m, 3H). Q4H27N304F2 (MW = 459.49); mass spectroscopy (MH+) 460. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 348 - Example 300 Synthesis of Af-Methoxy-W-[iV-(3,5-DifluorophenylacetyI)-L-aIaniiiylJ-D,L-phenylglycinamide 5 Following General Procedure M and using N-[N-(3,5- difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and methoxyamine hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.35 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 10% MeOH/CHCl3 as the 10 eluent. NMR data was as follows* 'H-nmr (DMSO-d6): 5 = 8.63 (m, IH), 8.35 (m, IH), 7.34 (m, 5H), 7.12 (m, IH), 6.99 (m, 2H), 5.23 (d, IH), 4.42 (m, IH), 3.58 (s, 3H), 3.51 (two s, 2H), 1.22 (d, 3H). 15 C20H21NjO4F2 (MW = 405); mass spectroscopy (MH+) 405. Example 301 Synthesis of [/V-[7V-(3,5-Dinuorophenylacetyl)-L-aIaninyl]-D,L-phenylglycinyI]azetidine 20 Following General Procedure M and using N-[N-(3,5- difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and azetidine (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.6 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 10% MeOH/CHCl3 as the eluent. 25 NMR data was as follows: 'H-nmr (DMSO-^): 8 = 8.61 and 8.46 (two d, IH), 8.33 (m, IH), 7.34 (m, 5H), 7.19 (m, IH), 6.99 (m, 2H), 5.36 (two d, IH), 4.42 (m, IH), 4.31 (m, IH), 3.88 (m, 3H), 3.5 (two s, 2H), 2.36 (m, 2H), 1.18 (two d, 3H). CjjH^NjOjFj (MW = 415.44); mass spectroscopy (MH+) 416. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 349 - Example 302 Synthesis of jV-Isobutyl-jV'-[A/-(3,5-DifluorophenylacetyI)-L-alaninyI]-D,L-phenylg]ycinamide 5 Following General Procedure M and using N-[N-(3,5- difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and isobutylamine (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.65 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 10% MeOH/CHCl3 as the eluent. 10 NMR data was as follows: 'H-nmr (DMSO-</6): 5 = 8.41 (m, IH), 8.22 (m, IH), 7.38 (m, 2H), 7.09 (m, IH), 6.98 (m, 2H), 5.52 (two d, IH), 4.41 (m, IH), 3.34 (two s, 2H), 2.85 (s, 2H), 1.61 (m, IH), 1.20 (m, 3H), 0.92 (m, 6H). C23H27N3O3F2 (MW = 431.48); mass spectroscopy (MHL) 432. 15 Example 303 Synthesis of A/-CyclopropanemethyI-W-J7V-(3,5-DifIuorophenyIacetyl)-L-alaninyl]-D, L-phenylglycinamide 20 Following General Procedure M and using N-[N-(3,5- difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and (aminomethyl)cyclopropane (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.25 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 10% MeOH/CHCl3 as the 25 eluent. C23H25N303F2 (MW = 429.47); mass spectroscopy (MH+) 374. Example 304 Synthesis of A^Methoxy-A'-inethyl-Af-[#-(3,5-DifIuorophenyIacetyI)-L-aIaninyI]-30 D,L-phenylglycinamide Printed from Mimosa WO 98/22494 PCT/US97/20804 — 350 - Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and AT-methoxy-JV-methylamine hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.3 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 2% MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-rffi): 8 = 8.65 and 8.53 (two d, IH), 8.37 (m, IH), 7.31 (m, 5H), 7.12 (m, IH), 6.98 (m, 2H), 5.91 and 5.82 (two d, IH), 4.49 (m, IH), 3.60-3.42 (m, 5H), 3.08 (two s, 3H), 1.21 and 1.16 (two d, 3H). C2,H23N304F2 (MW = 419); mass spectroscopy (MH+) 420. Example 305 Synthesis of jV-2-Methylprop-2-enyl-/V'-[AL(3,5-Difluorophenylacetyl)-L-alaninyl]-D, L-phenylglycinamide Following General Procedure M and using N-[N-(3,5-difluorophenylacety])-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and l-amino-2-methylprop-2-ene (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.45 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 3 % MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-^): 5 = 8.43 (m, 2H), 7.40 (m, 2H), 7.29 (m, 3H), 7.11 (m, IH), 6.98 (m, 2H), 5.46 (d, IH), 4.68 (m, 2H), 4.42 (m, IH), 3.6 (m, 2H), 3.49 (s, 2H), 1.56 (s, 3H), 1.21 (d, 3H). C23H25N303F2 (MW = 429.47); mass spectroscopy (MH+) 430. Example 306 Synthesis of N-(Pyrid-3-yDmethyl-jV'-[JV-(3,5-DifluorophenylacetyI)-L-aIaninyI]-D, L-phenylglycinamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 351 - Following General Procedure C and using #-[#-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and 3-(aminomethyl)pyridine (Aldrich), the tide compound was prepared. The reaction was monitored by tic (Rf = 0.1 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 3% MeOH/CHClj as the eluent. NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 8.82 (m, IH), 8.55 (m, IH), 8.42 (m, 3H), 7.52 (m, IH), 7.35 (m, 5H), 7.10 (m, IH), 6.99 (m, 2H), 5.43 (d, 2H), 4.44 (m, IH), 4.30 (bd, 2H) 3.52 (s, 2H) 1.26 (d, 3H). C23H24N403F2 (MW = 466.49); mass spectroscopy (MH+) 467. Example 307 Synthesis of #-(Py rid-4-yl) methyl-#'-[#-(3,5-Dif]uorophenylacetyI)-I^alamnyl]-D,L-phenylglycinamide Following General Procedure C and using #-[#-(3,5-difluorophenylacetyI)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and 4-(aminomethyl)pyridine (Aldnch), the title compound was prepared. The reaction was monitored by tic (Rf = 0.1 in 10% MeOH/CHCl3) and the product was punfied by flash chromatography using 3 % MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-<4): 8 = 8.88 (m, IH), 8.54 (d, IH), 8.43 (m, 3H), 7.37 (m, 4H), 7.12 (m, 3H), 6.9(m, IH), 5.44 (d, IH), 4.45 (m, IH), 4.31 (d, 2H), 3.51 (s, 2H), 1.25 (d, 3H). C23H24N403F2 (MW = 466.49); mass spectroscopy (MH+) 467. Example 308 Synthesis of #-Furfuryl-#'-[#-(3,5-DifluorophenylacetyI)-L-alaninyI]-D,L-phenylglycinamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 352 - Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and furfurylamine (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.5 in 10% MeOH/CHCl3) and the product was 5 purified by flash chromatography using 3% MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-ds): 8 = 8.66 (m, IH), 8.45 (d, IH), 8.39 (m, IH), 7.57 (s, IH), 7.33 (m, 5H), 7.09 (m, IH), 6.99 (m, 2H), 6.36 (m, IH), 6.12 (s, IH), 5.41 (d, IH), 4.22 (m, IH), 3.52 (s, 2H) 1.24 (d, 3H). 10 C24H23N304F2 (MW = 455); mass spectroscopy (MH+) 456. Example 309 Synthesis of Ar-Cyclopentyl-#'-[Ar-(3,5-Difluofophenylacetyl)-L-alaninyl]-D, L-phenylglycinamide 15 Following General Procedure C and using N-[N-(3,5- difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and cyclopentylamine (Aldrich), the title compound was prepared. The product was purified by recrystallization from ethanol. NMR data was as follows: 20 'H-nmr (DMSO-rf6): 8 = 8.32 (m, 2H), 8.16 (m, IH), 7.33-7.20 (m, 5H), 7.04 (m, IH), 6.93 (m, 2H), 5.34 (d, IH), 4.37 (m, IH), 3.9 (m, IH), 3.49 (s, 2H), 1.80-1.29 (m, 8H), 1.19 (d, 3H). C24H27N3OjF2 (MW = 443.49); mass spectroscopy (MH+) 444. Example 310 25 Synthesis of ALl-Benzylpiperidin-4-yl-/V'-[A'-(3,5-Dinuorophenylacetyl)-L^aIaninyl]-D,L-ph eny lglvcinamide Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) 30 and 4-ammo-l-benzylpiperdine (Aldrich), the tide compound was prepared. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 353 -- The reaction was monitored by tic (Rf = 0.2 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 3% MeOH/CHCl3 as the eluent. NMR data was as follows: 5 'H-nmr (DMSO-</6): 5 = 8.39 (m, 2H), 8.21 (m, IH), 7.30 (m, 5H), 7.11 (m, IH), 6.98 (m, 2H), 5.39 (d, IH), 4.21 (m, IH), 3.54 (bm, 3H), 3.42 (bs, 2H), 2.70 (bm, 2H), 1.89 (bm, 2H), 1.71 (bm, 2H), 1.42 (3H), 1.22 (m, 3H). C3lH34N403F2 (MW = 548.64); mass spectroscopy (MH+) 548. 10 Example 311 Synthesis of iV,/V-DimethyI-A''-(7V-(3,5-DiniJorophenylacetyl)-L-alaninyl]-D, L-phenylglycinamide Following General Procedure C and using N-[N-(3,5-15 difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and dimethylamine (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.65 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 5% MeOH/CHCl3 as the eluent. NMR data was as follows: 20 'H-nmr (DMSO-rf6): 5 = 8.13 and 8.01 (two d, IH), 7.32 (m, 5H), 6.78 (m, 2H), 6.63 (m, IH), 5.88 (m, IH), 4.72 (m, IH), 3.45 (two s, 2H), 2.94 (two s, 6H), 1.32 and 1.17 (two d, 3H). C2IH23N303F2 (MW = 403.43); mass spectroscopy (MH+) 404. Example 312 25 Synthesis of Ar-2,2,6,6-TetramethyIpiperidin-4-yl-/V'-[W-(3,5-Difluorophenylacetyl)-L- alaninyl]-D,L-phenylgIycinamide Following General Procedure C and using jV-|W-(3,5-30 difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) Printed from Mimosa WO 98/22494 PCT/US97/20804 - 354 - and 4-amino-2,2,6,6,-tetramethylpiperdine (Aldrich), the title compound was prepared. The reaction was monitored by dc (Rf = 0.2 in 2% MeOH/CHCl3) and the product was purified by flash chromatography using 2% MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 8.46 (d, IH), 8.33 (d, IH), 8.12 (bm, IH), 7.33 (m, 5H), 7.13 (m, IH), 6.99 (m, 2H), 5.37 (d, IH), 4.41 (m, IH), 3.98 (m,lH), 3.52 (s, 2H), 1.67 (bm, IH), 1.44 (bm, IH), 1.22 (d, 3H), 1.01 (bm, 14H). C28H36N403F2 (MW = 514.62); mass spectroscopy (MH+) 514. Example 313 Synthesis of Ar-2-MethyIcyclohexyl-AT'-17V-(3,5-DifIuorophenylacetyl)-L-aIaninyl]-D,L-phenylglycinamide Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and 2-methylcyclohexylamine (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.4 in 2% MeOH/CHCl3). NMR data was as follows: 'H-nmr (DMSO-rf6): 8 = 8.41 (m, 2H), 8 0 (m, IH), 7.33 (m, 5H), 7.11 (m, IH), 6.99 (m, 2H), 5.35 (m, IH), 4.41 (m, IH), 3.52 ( s, 2H), 3.18 (m,lH), 1.78-0.82 (m 11H), 0.81 (m, 3H). C26H3,N303F2 (MW = 472.5); mass spectroscopy (MH+) 472. Example 314 Synthesis of Ar-4-Methylcyclohexyl-Af'-[#-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenyIgIycinamide Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and 4-methylcyclohexylamine (Aldrich), the title compound was prepared. The Printed from Mimosa WO 98/22494 PCT/US97/20804 — 355 - reaction was monitored by tic (Rf = 0.2 in 2% MeOH/CHCl3) and the product was purified by flash chromatography using 2% MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 8.38 (m, 2H), 8.08 (m, IH), 7.33 (m, 5H), 5 7.09 (m, IH), 7.01 (m, 2H), 5.54 and 5.36 (two d, IH), 4.43 (m, 2H), 3.76 (m, IH), 3.52 (s, 2H), 1.79-1.17 (m, 11H), 0.84 (d, 3H). C24H31N303F2 (MW = 472.5); mass spectroscopy (MH+) 472. Example 315 Synthesis of /V-l-EthoxycarbonyIpiperidin-4-yI-iV'-[/V-(3,5-DifluorophenyIacetyl)-L- alaninylj-D,L-phenylglycinamide Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and 4-amino-l-ethoxycarbonylpiperdine (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.2 in 2% MeOH/CHCl3) and the product was purified by flash chromatography using 2% MeOH/CHCl3 as the eluent. NMR data was as follows: 'H-nmr (DMSO-</6): 5 = 8 42 (m, 2H), 8.23 (m, IH), 7.33 (m, 5H), 7.09 (m, IH), 6.98 (m, 2H), 5.38 (m, IH), 4.41 (m, IH), 4.01 (q, 2H), 3.9-3.64 (m, 3H), 3.49 (s, 2H), 2.88 (bm, 2H), 1.75 (m,lH), 1.54 (m,lH), 1.2 (m, 6H). C^NAFj (MW = 530.57); mass spectroscopy (MH+) 531. 25 Example 316 Synthesis of A'-Methyl-#-[Ar-(3,5-Difluoropheiiylacetyl)-L-alaninyI]-L-phenylglycinamide Following General Procedure C and using Af-(3,5-difluorophenylacetyl)-30 L-alanine (from Example B2 above) and N-methyl-(S)-2-amino-2- Pnnted from Mimosa WO 98/22494 PCT/US97/20804 -- 356 - phenylacetamide [CAS 129213-83-8], the title compound was prepared. The reaction was monitored by tic (Rf = 0.2 in 5% MeOH/CHCl3) and the product was purified by flash chromatography using 5% MeOH/CHClj as the eluent. NMR data was as follows: 'H-nmr (DMSO-J«): 5 = 8.43 (m, 2H), 8.21 (m, IH), 7.36 (m, 5H), 7.09 (m, IH), 6.95 (m, 2H), 5.36 (m, IH), 4.40 (m, IH), 3.41 (s, 2H), 2.56 (d, 3H), 1.22 (d, 3H). Optical Rotation: [a]20 = -67 (c = 1, MeOH). C20H21N303F2*0.75 HjO (MW = 403.43); mass spectroscopy (MH+) 404. Example 317 Synthesis of N-/erf-Butoxy-/V'-[A'-(3,5-DifluorophenyIacetyI)-L-alaninyl]-D, L-phenylglycinamide Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) and 0-(/e/r-butoxy)hydroxylamine (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.65 in 10% MeOH/CHCl3). NMR data was as follows: 'H-nmr (DMSO-d6): 5 = 8.72 and 8.58 (two d, IH), 8.39 (m, IH), 7.37 (m, 5H), 7.10 (m, IH), 6.99 (m, 2H), 5.41 (m, IH), 4 46 (m, IH), 3.51 (two s, 3H), 1.22 (m, 3H), 1.09 (s, 9H). C23H27N304F2 (MW = 447.48); mass spectroscopy (MH+) 448. Example 318 Synthesis of Ar-[A7-(3,S-DifluorophenylacetyI)-L-alaninyl]-D,L-phenylglycine A'-/ert-Butyl(hydroxylamine) Ester Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (from Example D25 above) Printed from Mimosa WO 98/22494 PCT/US97/20804 - 357 - and 7V-(te/?-butoxy)hydroxylamine (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.65 in 10% MeOH/CHCl3). C23H27N304F2#0.25 H20 (MW — 447.48); mass spectroscopy (MH+) 448. 5 Example 319 Synthesis of iV-[AT-(3,5-DifluorophenyIacetyI)-L-aIaninyl]-L-phenylglycine Hydrazide jV-[7V-(3,5-difluorophenylacetyl)-L-a]aninyl]-L-phenylglycine methyl ester 10 (2.0 g, 5.1 mmol) (from Example 111 above) was stirred in ethanol (40 mL) and anhydrous hydrazine (0.3 mL, 10 mmol) (Aldrich) was added. The solution was heated at reflux for 12 hours and then allowed to cool to ambient temperature with stirring. A title compound was collected as a white solid by filtration, washing with ethanol and dnng in a vacuum oven (52% yield). 15 NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 1.20 (t, 3H), 5.41 (m, IH). C19H2oN304F2 (MW = 390.39); mass spectroscopy (MH+) 390. Example 320 Synthesis of 20 Af-[/V-(3,5-DifluorophenyIacetyl)-L-alaninyl]- L-phenylglycine Acetohydrazonate jV-IW-Q^-DifluorophenylacetylH—alaninyll-L-phenylglycine hydrazide (0.5 g, 1.3 mmol) (from Example 319 above) was heated at reflux in triethylorthoacetate (40 ml). After 14 hours, the reaction mixture was 25 concentrated under reduced pressure to afford the title compound as a white solid (84% yield). The reaction was monitored by tic (Rf = 0.65 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent. NMR data was as follows: 30 'H-nmr (DMSO-</6): 6 = 4.03 (q, 2H), 5.54 (m, IH). Printed from Mimosa WO 98/22494 PCT/US97/20804 - 358 - CaH^KAF, (MW = 460.49), mass spectroscopy (MH+) 460. Example 321 Synthesis of N-[N- (PhenylacetyI)-L-alaniny I]-5 L-phenylglycine /crt-Butyl Ester Following General Procedure C and using phenylacetic acid (Aldrich) and L-alaninyl-L-phenylglycine rm-butyl ester (prepared using N-BOC-L-alanine (Sigma) and L-phenylglycine rm-butyl ester hydrochloride (Bachem) using General Procedure C, followed by removal of the BOC group using 10 General Procedure P), the title compound was prepared. The reaction was monitored by tic (Rf = 0.25 in 3 % MeOH/CHCl3) and the product was purified by crystallization from chlorobutane/hexanes. NMR data was as follows: 'H-nmr (DMSO-J«): 5 = 4.43 (m, IH), 5.20 (d, IH). 15 C23H28N2O4 (MW = 396.49); mass spectroscopy (MH+) 397. Example 322 Synthesis of Ar-4-(phenyl)butyl-/V'-[A;-(3,5-DifluorophenyIacetyl)-L-alaninyI]-L-phenylglycinami de 20 Following General Procedure C and using jV-(3,5-difluorophenylacetyl)- L-alanine (from Example B2 above) and //-4-(phenyI)butyI-L~phenylglycinamide (prepared from iV-BOC-L-phenylglycine (Advanced Chemtech) and 4-phenylbutylamine (Aldrich) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared. 25 The reaction was monitored by tic (Rf = 0.45 in 5 % MeOH/CHCl3) and the product was purified by tnturation in water, followed by tnturation in acetonitnle. NMR data was as follows: 'H-nmr (DMSO-rf6): 5 = 4.42 (m, IH), 5.37 (d, IH). 30 C29H31N303F2 (MW = 507.5); mass spectroscopy (MH+) 507. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 359 - Example 323 Synthesis of Af-3-(4-Iodophenyl)propyl-iV'-[iV-(3,5-DifluorophenyIacetyl)-L-aIaninyl]- L-phenylglycinamide 5 Following General Procedure C and using A^(3,5-difluorophenylacetyl)- L-alanine (from Example B2 above) and 7V-3-(4-iodophenyl)propyl-L-phenylglycinamide (prepared from iV-BOC-L-phenylglycine (Advanced Chemtech) and 3-(4-iodophenyl)propylamine (from Example D26 above) using General Procedure C, followed by removal of the BOC-group using General 10 Procedure P), the title compound was prepared. The product was purified by trituration in water, followed by trituration in ethanol. NMR data was as follows: 'H-nmr (DMSO-rfs): 5 = 4.41 (q, 2H), 5.35 (m, IH). C28H28N304F2I (MW = 635.45); mass spectroscopy (MH+) 635. 15 Example 324 Synthesis of /V-6-(Amino)hexyl-/V'-[#-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide Hydrochloride Following General Procedure C and using N-[N-(3,5-20 difluorophenylacetyl)-L-alamnyl]-D,L-phenylglycine (from Example D25 above) and N-BOC-1,6-hexanediamine (Fluka), followed by removal of the BOC-group using General Procedure P, the title compound was prepared. The product was isolated as a white solid. NMR data was as follows: 25 'H-nmr (DMSO-rf,): 8 = 4.41 (m, IH), 5.40 (t, IH). C25H32N403F2 (MW = 474.56); mass spectroscopy (MH+) 475. Example 325 Synthesis of Ar-l-(PhthaIimido)pent-2-yl-#'-(3,5-difluorophenylacetyl)-L-alaninainide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 360 - Following General Procedure C and using iV-(3,5-difluorophenylacetyI)-L-alanine (from Example B2 above) and 2-amino-l-phthalimidopentane hydrochloride (from Example D27 above), the title compound was prepared. The reaction was monitored by tic (Rf = 0.3 in 5 % MeOH/CHCl3) and the product was purified by silica gel chromatography using 5 % MeOH/CHCl3 as the eluent, followed by recrystallization from chlorobutane/acetonitrile. NMR data was as follows: 'H-nmr (DMSO-^): & = 4.1 (m, 2H), 7.83 (bs, 4H). C24H25N304F2 (MW = 457.48); mass spectroscopy (MH+) 457. Example 326 Synthesis of jV-[AM3,5-Difluorophenylacetyl)-L-(3,5-difluorophenyl)glycinyl]-L-(3,5-difluorophenyl)glycine Methyl Ester Following General Procedure AN and using #-(3,5-difluorophenylacetyl)-L-(3,5-difluorophenyl)glycine (from Example D30 above) and L-3,5-difluorophenylglycine methyl ester (from Example D29 above), the title compound was prepared. The product was purified by crystallization. NMR data was as follows: 'H-nmr (DMSO-4): 8 = 9.40 (m, IH), 9.0 (m, IH), 6.80-7.70 (m, 9H), 5.45 (d, IH), 5.25 (m, IH), 3.55-365 (m, 5H). Example 327 Synthesis of #-[#-(3,5-DifluorophenylacetyI)-L-alaninyI]- L-norleucine Following General Procedure AF and using THF/H20 (1:1) on #-[#-(3,5-difluorophenylacetyl)-L-alaninyl]-L-norleucine methyl ester, the title compound was prepared as a solid (mp = 158.5-160.5°C). The reaction was monitored by tic (Rf = 0.29 in 10% MeOH/CH2Cl2). NMR data was as follows: Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 361 - 'H-nmr (CD3OD): 5 = 8.46 (bd, J = 6.71, IH), 8.25 (bd, J = 7.69, IH), 7.00-6.79 (m, 3H), 4.50-4.35 (m, 2H), 3.61 (d, 2H), 1.94-1.79 (m, IH), 1.78-1.60 (m, (includes d at 1.40, 3 = 7.14, 3H), 0.92 (m, 3H). "C-nmr (CD3OD): & = 176.0, 175.5, 172.9, 166.6, 166.5, 163.4, 5 163.2, 141.7, 141.6, 141.5, 113.9, 113.8, 113.7, 113.6, 103.9, 103.6, 103.2, 54.1, 50.9, 43.3, 32.9, 29.4, 23.8, 18.6, 14.8. C17H22N2O4F2 (MW = 356.37); mass spectroscopy (MH+) 357. Example 328 Synthesis of 10 /V-[/V-(CyclopentaneacetyI)-L-alaninyl]- I^phenylglycine ferf-Butyl Ester Following General Procedure D and using cyclopentylacetic acid (Aldnch) and L-alaninyl-L-phenylglycine rm-butyl ester (prepared from N-CBZ-L-alanine (Sigma) and L-phenylglycine tert-butyl ester hydrochloride 15 (Bachem) using General Procedure C, followed by removal of the CBZ-group using General Procedure Y), the title compound was prepared as a solid (mp = 133-138°C). The reaction was monitored by tic (Rf = 0.48 in 50% EtOAc/hexanes) and the product was purified by flash chromatography using 25-50% EtOAc/hexanes as the eluent. 20 NMR data was as follows: 'H-nmr (CDC13): 5 = 7/86 (bd, J = 7.2 Hz, IH), 7.30-7.15 (m, 5H), 6.81 (bd, J = 7.82 Hz, IH), 5.34 (d, J = 7.20 Hz, 1H0, 4.72 (quint, J = 7.2 Hz, IH), 2.04 (m, 3H), 1.75-1.28 (m (includes s at 1.34, 9H) 18H), 1.1-0.9 (m, 2H). 25 13C-nmr (CDC13): 6 = 173.3, 172.8, 170.0, 137.1, 129.2, 128.6, 127.7, 82.7, 57.7, 48.9, 43.0, 37.6, 32.9, 28.3, 25.4, 19.3. C22H32N204 (MW = 388.51); mass spectroscopy (MH+) 389.5. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 362 - Example 329 Synthesis of #-[Ar-(2,5-DichlorophenyImercaptoacetyI)-L-alaninyl]-L-phenylglycine Methyl Ester 5 2,5-Dichlorophenylmercaptoacetic acid (TCI America, Portland, OR) (237 mg) was converted to the acid chloride as described in the General Procedure A" and utilized to acylate methyl L-alaninyl-L-phenylglycinate as described in General Procedure B". The title compound (210 mg) was isolated as crystals from ethyl ether. 10 NMR data was as follows: 'H-nmr (DMSO-d6) 8 = 8.85 (d, IH), 8.20 (d, IH), 6.70-7.45 (m, 8H), 5.45 (d, IH), 4.45-4.65 (m, 3H), 3.65 (s, 3H), 1.30 (d, 3H). C20H20CI2N2O4S (MW = 455.363) mass spectroscopy (MH+) 454.1. Anal. Calcd. for CmHjoCIjNAS: C, 52.75 H. 4.42 N, 6.15; Found: 15 C, 53.58 H, 5.01, N, 6.34. Example 330 Synthesis of #-[7V-(3,4-DichlorophenyImercptoacetyl)-L-alaninyl]-L-phenyIglycine Methyl Ester 20 3,4-Dichlorophenylmercaptoacetic acid (J. Med. Chem., 15(9), 940-944 (1972)) (237 mg) was converted to the acid chloride as described in the General Procedure A" and utilized to acylate methyl L-alaninyl-l-phenylglycinate as described in General Procedure B". The title compound (182 mg) was isolated as cyrstals from ethyl ether. 25 NMR data was as follows: 'H-nmr (DMSO-d^ 8 = 8.8 (d, IH), 8.40 (d, IH), 7.25-7.65 (m, 8H), 5.40 (d, IH), 4.45 (m, IH), 3.80 (m, 2H), 3.65 (s, 3H), 1.25 (d, 3H). C^oCl^NAS (MW = 455.363); mass spectroscopy (MH+) 454.1 30 Anal. Calcd. for CmHmCIiNAS: C, 52.75 H, 4.42 N, 6.15; Found: C, 53.05 H, 4.67 N, 6.26. Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 363 - Example 331 Synthesis of 2V-[iV-(3,5-DifluorophenoxyacetyI)-L-alaninyI]-L-phenylglycine Methyl Ester 3,5-Difluorophenoxyacetic acid [prepared by refluxing an aqueous mixture of 3,5-difluorophenol (Aldrich), 2-chloroacetic acid, and NaOH] (188 mg) was converted to the acid chloride as described in the General Procedure A" and utilized to acylate methyl L-alaninyl-L-phenylglycmate as described in General Procedure B". The title compound (210 mg) was isolated as crystals from ethyl ether. NMR data was as follows: lH-nmr (DMSO-d6) 8 = 8.85 (d, IH), 8.20 (d, IH), 6.70-7.45 (m, 8H), 5.45 (d, IH), 4.45-4.65 (m, 3H), 3.65 (s, 3H), 1.30 (d, 3H). QqH^NA (MW = 406.39); mass spectroscopy (MH+) 406.3. Anal. Calcd. for C^^NA: C, 59.11 H, 4.96 N, 6.89; Found: C, 53.34 H, 4.80 N, 6.94. Example 332 Synthesis of Methyl A'-[A'-(3,5-Difluorophenoxyacetyl)-L-aIaninyl]-L-2,3-dihydroisoindole-l-carboxylate Following General Procedure AN, L-2,3-Dihydro-1 //-isoindole-1 -carboxylic acid methyl ester hydrochlonde (Gazz. Chim. Ital., 106 (1-2) p. 65-75 (1976)) (417 mg) was coupled to N-(3,5-difluorophenylacetyl-L-alanine (from Example B2) to provide the title compound (150 mg). NMR data was as follows: 'H-nmr (DMSO-d6) 5 = 8.55 (d, IH), 6.85-7.45 (m, 7H), 5.50(m, IH), 4.95(s, IH), 4.55-4.90(m, 2+H), 3.65 (m, 3H), 1.30 (m, 3H). C21H20F2N2O4 (MW = 402.40); mass spectroscopy (MH+) 402.3. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 364 - Example 333 Synthesis of N- [N- (3,5-Difluorophenylacety])-L-alaninyl]-l-amino-l,3-diphenylpropane-2-one 5 To a solution of 200 mg of N-methoxy-N-methyl-N'-[N-(3,5- difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide (from Example 304 above) in THF was added 1.91 mL of a 2M solution of benzyl magnesium bromide in THF (Aldrich) at 0°C. The reaction mixture was stirred at ambient temperature for 72 hours, and was subsequently quenched by addition of water. 10 The reaction mixture was partitioned between ethyl acetate and water and the organic phase was washed with IN HCl solution. Following removal of solvent under reduced pressure, the crude ketone was purified by chromatography on silica gel, eluting with ethyl acetate, to afford 62 mg of the title compound as a 1:1 mixture of phenyl diastereomers 15 NMR data was as follows: lH-Nmr (CDC13) (approx 1:1 mixture of diastereomers) 5 = 7.2-7.5 (m, 8H), 7.0-7.1 (m, 2H), 6.7-6.9 (m, 4H), 6.2 (m, IH), 5.5(t, IH), 3.5-3.6 (m, 2H), 1.28-1.45 (doublets in 1:1 ratio, 3H). phenylglycine carboxamide (prepared as in Example 141) in 50 mL of dry toluene was added 808 mg (2.00 mmol) Lawesson's reagent (Aldrich). The reaction mixture was heated to 95°C for 5 mm. Cooling to ambient temperature and dilution with 1:1 ethyl acetate/hexanes resulted in precipitation 30 of insoluble material. Removal of the soluble phase, followed by additional washing of the solids and combination of the soluble phase, and removal of solvent afforded crude thiocarboxamide as a semisolid. Purification by 20 Example 334 Synthesis of /V-[Af-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine Thiocarboxamide 25 Step A - Preparation of f-butoxvcarbonvl-phenvl glycine thiocarboxamide: To a suspension of 500 mg (2.00 mmol) f-butoxycarbonyl-L- Prmted from Mimosa WO 98/22494 PCT/US97/20804 — 365 - chromatography on silica gel, eluting with ethyl acetate afforded 364 mg of thiocarboxamide. Step B - Preparation of phenvlelvcine thiocarboxamide hydrobromide: A solution of 364 mg of r-butoxycarbonyl phenylglycine 5 thiocarboxamide in 4 mL 30% HBr in acetic acid was stirred for 1 hour. The volitile materials were removed under reduced pressure and the crude phenylglycine thiocarboxamide hydrobromide was obtained as a pale solid. The material was utilized without further purification. To a stirred solution of 486 mg of (3,5-difluorophenylacetyl)-L-alamne 10 (from B2) in 30 mL of dichoromethane was added 383 mg of EDCI, 270 mg of HOBT hydrate, followed by 350 pL of diisopropylethylamine. To this suspension was added phenylglycine thiocarboxamide hydrobromide in dichloromethane. The reaction mixture was stirred at ambient temperature for 72 hours. The reaction mixture was partioned between water and 15 dichloromethane and the organic phase was washed with IN HCl solution, followed by saturated aqueous sodium bicarbonate solution. Removal of solvent afforded the crude product, which was purified by chromatography on silica gel, eluting with ethyl acetate, to afford 271 mg of the title compound (approximately 3:2 mixture of phenylglycine diastereomers) as a pale solid. 20 NMR data was as follows: 'H-Nmr (CDC13) (approx 3:2 mixture of diastereomers): 5 = 7.3-7.7 (m, 8H), 6.7-6.8 (m, 4H). Example 335 Synthesis of 25 /V-[/V-(3,5-Difluorophenyl-2-oxoacetyI)- L-alaninyl]-L-phenylglycine /erf-Butyl Ester Following General Procedure C and using L-alaninyl-L-phenylglycine tert-butyl ester (prepared as described in Example 321) and 3,5-difluorophenylglyoxylate (prepared as descnbed in J. Org. Chem., 45(14), Printed from Mimosa WO 98/22494 PCT/US97/20804 - 366 - 28883 (1980)), the title compound was prepared as a solid. The product was purified by slurrying with EtOAc/hexanes. Elemental Anal.: Calc.(%) C, 61.88, H, 5.42, N, 6.27; Found: C, 62.15, H, 5.51, N, 6.18. 5 Example 336 Synthesis of N- (2-Hydroxy- 1-pheny leth-l-yl)-iV '-[N- (3,5-Difluorophenylacety 1)-L-phenyIglycinyl]-L-alaninamide Following General Procedure C and using /V- (3,5-difluorophenylacetyl)-10 L-phenylglycinyl-L-alanine (prepared from Ar-(3,5-difluorophenylacetyl)-L- phenylglycinyl-L-alanine ethyl ester) and (S)-phenylglycinol (Aldrich), the title compound was prepared (m.p. = 269-272°C). The reaction was monitored by tic (Rf = 0.3 in 10% MeOH/CHCl3) and the product was purified by chromatography using 10% MeOH/CHCl3 as the eluent. 15 NMR data was as follows: lH-nmr (DMSO-tf6): 5 = 1.25 (d, 3H), 8.01 (d, IH), 8.52 (d, IH), 8.82 (d, IH). Optical Rotation: [a]20 = -62.7 @ 589 nm (c = 1.02, DMSO). C27H27N303F2 (MW = 495.53); mass spectroscopy (MH+) 496. 20 Example 337 Synthesis of /V-(2-Hydroxyeth-l-yl)-/V'-[iY-(3,5-Difluorophenylacetyl)-L-alanyI]-L-phenylgIycinamide Following General Procedure C and using /V-(3,5-difluorophenylacetyl)-25 L-alanine (from Example B2 above) and L-phenylglycine (2-hydroxyethyl)amide hydrochloride (prepared from N-BOC-L-phenylglycine (Bachem) and 2-aminoethanol (Aldrich) using General Procedure C, followed by removal of the BOC group using General Procedure P), the title compound was prepared. The product was purified by chromatography using 10% MeOH/CHCl3 as the 30 eluent, followed by crystallization from EtOH. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 367 NMR data was as follows: 'H-nmr (DMSO-dfi): 5 = 1.22 (d, 3H), 5.42 (d, IH). Optical Rotation: [a]20 = +8.77 @ 589 nm (c = 1.03, DMSO). C21H23N3O4F2 (MW = 419.43); mass spectroscopy (MH+) 420. 5 Example 338 Synthesis of iV-(4-(4-Azido-2-hydroxybenzamido)but-l-yl)-AT'-[2V-(3,5-Difluorophenylacetyl)-L-alanyl]-L-phenyIglycinamide 10 Following General Procedure A and using N-(3,5-difluorophenylacetyl)- L-alanyl-L-phenylglycine (prepared as descnbed herein) and 4-(4-azidosalicylamido)butylamine (Pierce Chemical), the title compound was prepared as a ]:ght sensitive solid. The reaction was conducted under low light conditions and the reaction vessel was protected from light. The reaction was 15 monitered by tic (Rf = 0.2 in 2.5% MeOH/dichloromethane). NMR data was as follows: 'H-nmr (CD3OH/CDCl3): 5 = 7.72 (d, 2H), 7.30 (m, 5H), 6.84 (m, 2H), 6.73 (m, IH), 6.54 (m, 2H), 5.34 (s, IH), 4.39 (q, IH), 3.56 (s, 2H), 3.31 (bs, 2H), 3.21 (bs, 2H). 1.57 (bs, 4H), 1.35 (d, 2H). 20 Example 339 Synthesis of /V-(Methanesulfonyl)-/V'-[A'-(3,5-DifluorophenylacetyI)-L-alanyl]-L-phenylalanamide N-Cbz-L-Phenylalanine (Sigma) was coupled to N-hydroxysuccinimide 25 (Aldrich) using DCC in dicloromethane. The resulting intermediate was reacted with methanesulfonamide in DMF with diisopropylethylamine to provide N-methanesulfonyl-N'-Cbz-L-phenylalanamide amide. The Cbz group was removed using General Procedure O and the resulting intermediate was coupled to N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) 30 using General Procedure B to give the title compound, m.p. = 203-205°C. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 368 - Examples 340-407 By following the procedures set forth above, the following additional compounds were prepared: N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-phenylglycine methyl 5 ester (Ex 340) Af-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-(3-a-phenyl)proline methyl ester (Ex. 341) jV-[iV-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-azetidine methyl ester (Ex. 342) 10 methyl iV-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(5- chlorobenzothiophen-2-yl)acetate (Ex. 343) /-butyl iV-[JV-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)propionate (Ex. 344) f-butyl N-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide 15 (Ex. 345) N-[yV-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide (Ex. 346) N-fN-(3,4-dichlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide 20 (Ex. 347) N-[iV-(3-chlorophenylacetyl)-L-alaninyl]-D-phenylg]ycinamide (Ex. 348) N-(W-(3-bromophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex. 349) 25 N-[iV-(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex. 350) JV-jW-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex. 351) N-[N-(3-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide 30 (Ex. 352) N-[7V-(4-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex. 353) Printed from Mimosa 98/22494 PCT/US97/20804 — 369 - N-[AH3-trifluoromethylphenylacetyl)-L-alaninyl]-D-phenylglycinaniide (Ex. 354) N-|W-(3-methoxyphenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex. 355) Ar-[N-(2-chlorophenyIacetyl)-L-alaninyl]-D-phenylglycinamide (Ex. 356) iV-|W-(l-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex. 357) jV-[iV-(2-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex. 358) iV-[iV-(phenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex. 359) N-tN-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine (Ex. 360) W-|W-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-furanyl)acetamide (Ex. 361) W-|W-(3,4-difluorophenylacetyl)-D-alamnyl]-D-phenylglycinamide (Ex. 362) N'-[/V-(3,5-difluorophenylacetyl)-L-a]aninyI]-L-phenyIalanin-N-methylsulfonamide (Ex. 363) A?"-methyl-jV"-phenyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyI]-glycinamide (Ex. 364) /V"-methyl-7V"-phenyl-A''-[AL(3,5-difluorophenylacetyl)-L-a]aninyl]-L-alaninamide (Ex. 365) N'-[jV-(3,5-difluorophenyIacetyl)-L-methioninyl]-L-phenylglycinamide (Ex. 366) iV"-methyl-A?"-benzyl-A"-[N-(3>5-difluorophenylacetyl)-L-alaniny]]-glycmamide (Ex. 367) iV"-4-fluorobenzyl-yV'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide (Ex. 368) Printed from Mimosa 98/22494 PCT/US97/20804 -- 370 - A"-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-fluoro)phenylglycine neopentyl ester (Ex. 369) N-[N-(2,3,4,5,6-pentafluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycine methyl ester (Ex. 370) N- [N- (3,5-difluorophenylacetyl)-L-(0-benzyl)serinyl] -L-phenylglycine methyl ester (Ex. 371) JV-[N-(3,5-difluorophenylacetyl)-L-(0-benzyl)threoninyl]-L-phenylglycine methyl ester (Ex. 372) N-[A'-(3,5-difluorophenylacetyl)-L-threoninyl]-L-phenylglycine methyl ester (Ex. 373) Af-[W-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine methyl ester (Ex. 374) Ar"-4-methylphenyl-.iV'-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide (Ex. 375) iV"-tetrahydrofurfuryl-W-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide (Ex. 376) N'-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenyl-glycinamide (Ex. 377) N'-[N-(3,5-difluorophenylacetyl)-L-methionyl]-L-phenylglycinamide (Ex. 378) /V-[jV-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamide (Ex. 379) N'-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinamide (Ex. 380) iV-[7V-(3,5-difluorophenylacetyl)-L-valmyl]-L-phenylglycinamide (Ex. 381) JV-[(R)-a-methylbenzyl]-Af'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide (Ex. 382) A/-[l-phenyl-2-oxo-3-methylbutan-l-yl]-iV'-(3,5-difluorophenylacetyl)-L-alaninamide (Ex. 383) Printed from Mimosa WO 98/22494 PCT/US97/20804 -- 371 - N-[l-phenyl-2-oxo-propan-l-yl]-N'-(3,5-difluorophenylacetyl)-L-alanmamide (Ex. 384) N-[l-phenyl-2-oxo-pentan-l-yl]-N'-(3,5-difluorophenylacetyl)-L-aianinamide (Ex. 385) 5 Ar-[l-phenyl-2-oxo-2-phenyl-ethan-l-yl]-N'-(3,5-difluorophenyl-acetyl)-L- alaninamide (Ex. 386) AL[l-phenyl-2-oxo-butan-l-yl]-//'-(3,5-difluorophenyl-acetyl)-L-alaninamide (Ex. 387) N-[l -phenyl-2-oxo-4-methylpentan-1 -yl]-W-(3,5-difluorophenyl-acetyl)-10 L-alaninamide (Ex. 388) W-IW-P.S-difluorophenylacetylJ-L-alaninyll-L-of-hydroxyphenylalanine methyl ester (Ex. 389) W-[4-((2-hydroxy-4-azido)-phenyl)-NHC(0)-)butyl] #'-[#-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide (Ex. 390) 15 W-(W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycine r-butyl ester (Ex. 391) W-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-phenylphenylglycine /-butyl ester (Ex. 392) [TV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(2,3-benzo[b]prohne) methyl 20 ester (Ex. 393) N"-r-butyl-Ar'-[N-(3,5-difluorophenylacetyl)-L-alanmyl]-L-4-n-butylphenylglycinamide (Ex. 394) N"-t-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alamnyl]-D, L-4-(phenylacetenyl)phenylglycinamide (Ex. 395) 25 N'-[AH3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamide (Ex. 396) //-[l,3-diphenyl-2-oxo-propan-l-yl]-A'''-(3,5-difluorophenylacetyl)-L-alaninamide (Ex. 397) Ar-[l-phenyl-2-oxo-2-cyclopentylethan-l-yl]-//'-(3,5-30 difluorophenylacetyl)-L-alaninamide (Ex. 398) Printed from Mimosa WO 98/22494 PCT /US97/20804 — 372 - ,A/-[l-phenyl-2-oxo-hexan-l-yl]-,/V'-(3,5-difluorophenylacetyl)-L-alaninamide (Ex. 399) N-[l-phenyl-2-oxo-3-methylpentan-l-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide (Ex. 400) 5 N"-n-hexyl-6-biotinamidyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]- D,L-phenylglycinthioamide (Ex. 401) N'-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionine (Ex. 402) W-[W-(2-f-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycine methyl ester (Ex. 403) 10 W'-f-butyl iV'-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2- fluorophenylglycinamide (Ex. 404) iV'-|7V-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-2-phenylglycine methyl ester (Ex. 405) W-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-15 phenylglycine (Ex. 406) AT-[W-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycine f-butyl ester (Ex. 407) Example 408 Following the procedures set forth above, the following compounds of 20 formula I were or could be prepared: R1 is 3,5-difluorophenyl; X' and X" are hydrogen; R2 is methyl; R3 is hydrogen; R4 is ^-fluorophenyl; R5 is hydrogen; Z is a bond, X is -C(0)0CH2C(CH3)3; and n is 1; R1 is 3,5-difluorophenyl; X' and X" are hydrogen; R2 is methyl; R3 is 25 hydrogen; R4 is />-(phenyl)phenyl; Rs is hydrogen; X is -C(0)NHC(CH3)j; Z is a bond; and n is 1; Printed from Mimosa WO 98/22494 PCT/US97/20804 - 373 - R1 is cyclopentyl; X' and X" are hydrogen; R2 is methyl; R3 is hydrogen; R4 is phenyl; Rs is hydrogen; X is -C(0)0C(CH3)3; Z is a bond; and rt is 1; R1 is cyclopropyl; X' and X" are hydrogen; R2 is methyl; R3 is 5 hydrogen; R4 is phenyl; Rj is hydrogen; X is -C(0)0C(CH3)3; Z is a bond; and n is 1; and R1 is 3,5-difluorophenyl; X' and X" are hydrogen; R2 is methyl; R3 is hydrogen; R4 is phenyl; R5 is hydrogen; X is -C(0)0CH2C(CH3)3; Z is a bond; and n is 1. 10 Example 409 Cellular Screen for the Detection of Inhibitors of /3-Amyloid Production Numerous compounds of formula I above were assayed for their ability to inhibit /3-amyloid production in a cell line possessing the Swedish mutation. This screening assay employed cells (K293 = human kidney cell line) which 15 were stably transfected with the gene for amyloid precursor protein 751 (APP751) containing the double mutation Lys651Met652 to Asn65lLeu652 (APP751 numbering) m the manner described in International Patent Application Publication No 94/105698 and Citron et al.12. This mutation is commonly called the Swedish mutation and the cells, designated as "293 751 SWE", were 20 plated in Corning 96-well plates at 1.5-2.5 x 104 cells per well in Dulbecco's minimal essential media plus 10% fetal bovine serum. Cell number is important in order to achieve ^-amyloid ELISA results within the linear range of the assay (-0.2 to 2.5 ng per mL). Following overnight incubation at 37 °C in an incubator equilibrated with 25 10% carbon dioxide, media were removed and replaced with 200 nL of a compound of formula I (drug) containing media per well for a two hour pretreatment period and cells were incubated as above. Drug stocks were prepared in 100% dimethylsulfoxide such that at the final drug concentration Printed from Mimosa WO 98/22494 PCT/US97/20804 - 374 - used in the treatment, the concentration of dimethylsulfoxide did not exceed 0.5% and, in fact, usually equaled 0.1%. At the end of the pretreatment period, the media were again removed and replaced with fresh drug containing media as above and cells were 5 incubated for an additional two hours. After treatment, plates were centrifuged in a Beckman GPR at 1200 rpm for five minutes at room temperature to pellet cellular debris from the conditioned media. From each well, 100 fiL of conditioned media or appropriate dilutions thereof were transferred into an ELISA plate precoated with antibody 26614 against amino acids 13-28 of (3-10 amyloid peptide as described in International Patent Application Publication No. 94/105698 and stored at 4°C overnight. An ELISA assay employing labelled antibody 6C614 against amino acids 1-16 of /3-amyloid peptide was run the next day to measure the amount of /3-amyloid peptide produced. Cytotoxic effects of the compounds were measured by a modification of 15 the method of Hansen, et al.13. To the cells remaining in the tissue culture plate was added 25 ^L of a 3,(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) stock solution (5 mg/mL) to a final concentration of 1 mg/mL. Cells were incubated at 37 °C for one hour, and cellular activity was stopped by the addition of an equal volume of MTT lysis buffer (20% w/v sodium 20 dodecylsulfate in 50% dimethylformamide, pH 4.7). Complete extraction was achieved by overnight shaking at room temperature. The difference in the ODsttnm and the OD^ was measured in a Molecular Device's UV^ microplate reader as an indicator of the cellular viability. The results of the )3-amyloid peptide ELISA were fit to a standard curve 25 and expressed as ng/mL |8-amyloid peptide. In order to normalize for cytotoxicity, these results were divided by the MTT results and expressed as a percentage of the results from a drug free control. All results are the mean and standard deviation of at least six replicate assays. Printed from Mimosa WO 98/22494 PCT/US97/20804 — 375 - The test compounds were assayed for /3-amyloid peptide production inhibition activity in cells using this assay. The results of this assay demonstrate that, each of the compounds within this invention tested reduced /3-amyloid peptide production by at least 30% as compared to control. 5 Example 410 In Vivo Suppression of /3-Amyloid Release and/or Synthesis This example illustrates how the compounds of this invention could be tested for in vivo suppression of /3-amyloid release and/or synthesis. For these experiments, 3 to 4 month old PDAPP mice are used [Games et al., (1995) 10 Nature 373:523-527], Depending upon which compound is being tested, the compound is usually formulated at either 5 or 10 mg/ml. Because of the low solubility factors of the compounds, they may be formulated with various vehicles, such as corn oil (Safeway, South San Francisco, CA); 10% EtOH in corn oil (Safeway); 2-hydroxypropyl-/?-cyclodextrin (Research Biochemicals 15 International, Natick MA); and carboxy-methyl-cellulose (Sigma Chemical Co., St. Louis MO). Specifically, for example 141 the vehicle was carboxy-methyl-cellulose (Sigma). The mice are dosed subcutaneously with a 26 gauge needle and 3 hours later the animals are euthanized via C02 narcosis and blood is taken by cardiac 20 puncture using a 1 cc 25G 5/8" tuberculin syringe/needle coated with solution of 0.5 M EDTA, pH 8.0. The blood is placed in a Becton-Dickinson vacutainer tube containing EDTA and spun down for 15 minutes at 1500 xg at 5°C. The brains of the mice are then removed and the cortex and hippocampus are dissected out and placed on ice. 25 1. Brain Assay To prepare hippocampal and cortical tissue for enzyme-linked immunosorbent assays (ELISAs) each brain region is homogenized in 10 Printed from Mimosa WO 98/32494 PCT/US97/20804 - 376 - volumes of ice cold guanidme buffer (5.0 M guanidine-HCl, 50 mM Tris-HCl, pH 8.0) using a Kontes motorized pestle (Fisher, Pittsburgh PA). The homogenates are gently rocked on a rotating platform for three to four hours at room temperature and stored at -20°C prior to quantitation of /3-amyloid. 5 The brain homogenates are diluted 1:10 with ice-cold casein buffer [0.25% casein, phosphate buffered saline (PBS), 0.05% sodium azide, 20 /tg/ml aprotinin, 5 mM EDTA, pH 8.0, 10 /ig/ml leupeptin], thereby reducing the final concentration of guanidine to 0.5 M, before centrifugation at 16,000 xg for 20 minutes at 4°C. The /3-amyloid standards (1-40 or 1-42 amino acids) 10 were prepared such that the final composition equaled 0.5 M guanidine in the presence of 0.1% bovine serum albumin (BSA). The total /3-amyloid sandwich ELISA, quantitating both |8-amyloid (aa 1-40) and /3-amyloid (aa 1-42) consists of two monoclonal antibodies (mAb) to /S-amyloid. The capture antibody, 26614, is specific to amino acids 13 - 28 of /3-15 amyloid. The antibody 3D615, which is specific to amino acids 1 - 5 of /3- amyloid, is biotinylated and served as the reporter antibody in the assay. The 3D6 biotinylation procedure employs the manufacturer's (Pierce, Rockford IL) protocol for NHS-biotm labeling of immunoglobulins except that 100 mM sodium bicarbonate, pH 8.5 buffer is used. The 3D6 antibody does not 20 recognize secreted amyloid precursor protein (APP) or full-length APP but detects only /3-amyloid species with an amino terminal aspartic acid. The assay has a lower limit of sensitivity of —50 pg/ml (11 pM) and shows no cross-reactivity to the endogenous murine /3-amyloid peptide at concentrations up to 1 ng/ml. 25 The configuration of the sandwich ELISA quantitating the level of 0- amyloid (aa 1-42) employs the mAb 21F1215 (which recognizes amino acids 33-42 of /3-amyloid) as the capture antibody. Biotinylated 3D6 is also the reporter Printed from Mimosa WO 98/22494 PCT/US97/20804 - 377 - antibody in this assay which has a lower limit of sensitivity of — 125 pg/ml (28 PM). The 266 and 21F12 capture mAbs are coated at 10 fig/ml into 96 well immunoassay plates (Costar, Cambidge MA) overnight at room temperature. 5 The plates are then aspirated and blocked with 0.25% human serum albumin in PBS buffer for at least 1 hour at room temperature, then stored desiccated at 4°C until use. The plates are rehydrated with wash buffer (Tris-buffered saline, 0.05% Tween 20) prior to use. The samples and standards are added to the plates and incubated overnight at 4°C. The plates are washed > 3 times 10 with wash buffer between each step of the assay. The biotinylated 3D6, diluted to 0.5 ng/ml in casein incubation buffer (0.25% casein, PBS, 0.05% Tween 20, pH 7.4) is incubated in the well for 1 hour at room temperature. Avidin-HRP (Vector, Burlingame CA) diluted 1:4000 in casein incubation buffer is added to the wells for 1 hour at room temperature. The colorimetric substrate, Slow 15 TMB-ELISA (Pierce, Cambridge MA), is added and allowed to react for 15 minutes, after which the enzymatic reaction is stopped with addition of 2 N H2S04. Reaction product is quantified using a Molecular Devices Vmax (Molecular Devices, Menlo Park CA) measuring the difference in absorbance at 450 nm and 650 nm. 20 2. Blood Assay The EDTA plasma is diluted 1:1 in specimen diluent (0.2 gm/1 sodium phosphate*H20 (monobasic), 2.16 gm/1 sodium phosphate*7H20 (dibasic), 0.5gm/l thimerosal, 8.5 gm/1 sodium chloride, 0.5 ml TritonX-405, 6.0 g/1 globulin-free bovine serum albumin; and water). The samples and standards in 25 specimen diluent are assayed using the total /3-amyloid assay (266 capture/3D6 reporter) descnbed above for the brain assay except the specimen diluent was used instead of the casein diluents described. Printed from Mimosa WO 98/22494 PCT/US97/20804 - 378 - From the foregoing description, various modifications and changes in the composition and method will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein. Printed from Mimosa </div>

Claims

WO 98/22494 PCT/US97/20804 WHAT IS CLAIMED IS: 1. A use, in the preparation of a medicament for inhibiting (3-amyloid peptide release and/or its synthesis in a cell, of a compound or a mixture of compounds represented by formula I: 10 n X wherein R1 is selected from the group consisting of alkyl, alkenyl, 15 alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; 20 each R3 is independently selected from the group consisting of hydrogen and methyl and R3 together with R4 can be fused to form a cyclic structure of from 3 to 8 atoms which is optionally fused with an aryl or heteroaryl group; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, 25 substituted alkyl, substituted alkenyl and substituted alkynyl; each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms; X is selected from the group consisting of -C(0)Y and -C(S)Y where Y is selected from the group consisting of 30 (a) alkyl or cycloalkyl, (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl, or INTELLECTUAL PROPERTY OFFICE OF NZ. 1 8 JUN 2001 received WO 98/22494 PCT/US97/20804 25 -- 380 - L ^ ^ a-0C(0)aryl groups, ^ ^ 'if vj (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, 5 (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R" where R' and R" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted 10 alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, ^ where when either R' or R" are substituted alkyl, the substituted alkyl is an alkyl group of 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, acylamino, amino, 20 aminoacyl, aminocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxyalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, mono-alkylamino, mono-(substituted alkyl)ammo, di-(substituted alkyl)amino, mono-aryl amino, di-aryl, amino, mono-heteroarylamino, di-heteroarylamino, mono-heterocyclic amino, di-heterocyclic amino and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic. INTELLECTUAL PROPERTY OFFICE OF NZ. 1 8 JUN 2001 received - 380a - 4 « /; (j) -NHS02-R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NTR9NR1(>R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -0NR9[C(O)O]2R10 where z is zero or one, R9 and R10 are as defined above; X can also be -CR6R6Y' where each R6 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -0C(0)R7, -SSR7, -SSC(0)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X' is hydrogen, hydroxy, or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, INTELLECTUAL PROPERTY OT1CE OF N Z 1 8 JUN 2001 received WO 98/22494 PCT/US97/20804 - 381 - Z is selected from the group consisting of a bond covalently linking R1 to -CX'X"-, oxygen and sulfur; n is an integer equal to 1 or 2; and pharmaceutical^ acceptable salts thereof 5 with the provisos that: A. when R1 is phenyl or 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and rt is 1, then X is not -C(0)0H; B. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3 10 derived from D-threonine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0H or -C(0)0CH3; C. when R1 is phenyl, R2 is methyl, R4 is benzyl, R5 is hydrogen, X is methoxycarbonyl, X' and X" are hydrogen, Z is a bond, and n is 1, then R3 is not methyl; 15 D. when R1 is wo-propyl, R2 is -CH2C(0)NH2, R3 is hydrogen, R4 is iso-butyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH3; E. when R1 is phenyl, R2 is methyl, R5 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and /i is 1, then R3, the nitrogen atom 20 attached to R3, and R4 do not form l,2,3,4-tetrahydro«Jo-quinolin-2-yl or pyrrolidin-2-yl; F. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R5 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not 4-amino-«-butyl; 25 G. when R1 is 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NH2 or -CH2OH; H. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R5 is hydrogen, X is -CH2OCH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not 30 benzyl or ethyl; Printed from Mimosa WO 98/22494 PCT/US97/20804 - 382 - gy

I. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is methyl, R4 is methyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CHOH<£; J. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CHOH<£ or -CH2OH; K. when Rj is iV-(2-pyrroIidinonyl), R2 is methyl, R3 is hydrogen, R, is benzyl, Rs is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH3; L. when Rl is 3,5-difluorophenyl, R2 is methyl derived from D-alanine, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NH-benzyl; M. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is hydrogen, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CH2OH; N. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is 4-phenylphenyl, R3 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NHC(CH3)3; and O. when Rl is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NHCH(CH3)4> P. when Rl is ethyl, R2 is iso-butyl, R3 is hydrogen, X" and X" are hydrogen, Z is a bond and n is 1, then X is not -CH(C2H2F30) (C4H9) . intellectual property office OF hi 7 18 jun 2001 received 383
2. A use, m the preparation of a medicament for reventmg the onset of AD in a patient at risk for eveloping A.D, of a compound or a mixture of compounds of ormula I: wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R3 is independently selected from the group consisting of hydrogen and methyl and R3 together with R4 can be fused to form a cyclic structure of from 3 to 8 atoms which is optionally fused with an aryl or heteroaryl group; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms; X is selected from the group consisting of -C(0)Y and -C(S)Y where Y is selected from the group consisting of (a) alkyl or cycloalkyl, X' X" 0 R< ,RS I intellectual property OTICC OF N Z 1 8 JUN 2001 received WO 98/22494 PCT/US97/20804 - 383a - r// V;-V 'v (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl, or a-0C(0)aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i)-NR'R" where R' and R" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional intellectual property 0~~ ICE Oc N z. 1 8 JUN 2001 received WO 98/22494 PCT/US97/20804 55 * « 10 15 heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, where when either R1 or R" are substituted alkyl, the substituted alkyl is an alkyl group of 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, cyclalkyl, halogen, hydroxyl, carboxyl, carboxyalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, mono-alkylamino, di-alkylamino, mono-(substituted alkyl)amino, di-(substituted alkyl)amino, mono-aryl amino, di-aryl amino, mono-heteroarylamino, di-heteroarylamino, mono-heterocyclic amino, di-heterocyclic, amino and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, (j) -NHS02-R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -0NR9[C(0)0]zR10 where z is zero or one, R9 and R10 are as defined above; 25 X can also be -CR6R6Y' where each R6 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -0C(0)R7, -SSR7, -SSC(0)R7 where R7 is selected from the group 30 consisting of alkyl, substituted alkyl, cycloalkyl. aryl, heteroaryl and heterocyclic, INTELLECTUAL PROPERTY OTiCE OF NZ. 1 8 JUN 2001 received - 384a - I // iS 0 ' '^J o X' is hydrogen, hydroxy, or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, Z is selected from the group consisting of a bond covalently linking R1 to -CX'X"-, oxygen and sulfur; n is an integer equal to 1 or 2; and pharmaceutical^ acceptable salts thereof with the provisos that: A. when R1 is phenyl or 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0H; B. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3 derived from D-threonine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0H or -C(0)0CH3; intellectual property office of n z 1 8 JUN 2001 RECEIVED WO 98/22494 PCT/US97/20804 — 385 - C. when R1 is phenyl, R2 is methyl, R4 is benzyl, R5 is hydrogen, X is methoxycarbonyl, X' and X" are hydrogen, Z is a bond, and n is 1, then R3 is not methyl; D. when R1 is wo-propyl, R2 is -CH2C(0)NH2, R3 is hydrogen, R4 is 5 iso-butyl, RJ is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH3; E. when Rl is phenyl, R2 is methyl, R3 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R3, the nitrogen atom attached to R3, and R4 do not form l,2,3,4-tetrahydroiso-quinolin-2-yl or 10 pyrrolidin-2-yl; F. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R3 is hydrogen, X is -C(0)0CHj, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not 4-amino-n-butyl; G. when R1 is 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is 15 -CH(OH)CH3, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NH2 or -CH2OH; H. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R5 is hydrogen, X is -CHjOCHj, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not benzyl or ethyl; 20 I. when R1 is 3,5-difluorophenyl, R2 is methyl, R3 is methyl, R4 is methyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CHOH0; J. when R1 is 3,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycme, R5 is hydrogen, X' and X" are 25 hydrogen, Z is a bond, and n is 1, then X is not -CHOH<£ or -CH2OH; K. when R, is //-(2-pyrrolidinonyl), R2 is methyl, R3 is hydrogen, R, is benzyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0CH3; L. when R1 is 3,5-difluorophenyl, R2 is methyl derived from D-alanine, 30 R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NH-benzyl; Printed from Mimosa WO 98/22494 PCT/US97/20804 - 386 - (R ' ^ © - J ' ! 25 M. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is hydrogen, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CH2OH; N. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is 4-phenylphenyl, Rs is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NHC(CH3)3; and O. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NHCH(CH3)<£ P. when Rl is ethyl, R2 is iso-butyl, R3 is hydrogen, X' and X" are hydrogen, Z is a bond and n is 1, then X is not -CH(C2H2F30) (C4H9) .
3. A use, in the preparation of a medicament for treating a patient with AD m order to inhibit further deterioration in the condition of that patient of a compound or a mixture of compounds of formula I: wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; each R3 is independently selected from the group consisting of hydrogen and methyl and R3 together with R4 can be fused to form a cyclic structure of from 3 to 8 atoms which is optionally fused with an aryl or heteroaryl group; intellectual property 0_lr.- 1 8 JUN 2001 WO 98/22494 PCT/US97/20804 - 387 - 33 4^^ each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; each Rs is selected from hydrogen and methyl or together with R4 forms 5 a cycloalkyl group of from 3 to 6 carbon atoms; X is selected from the group consisting of -C(0)Y and -C(S)Y where Y is selected from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl with the proviso that the substitution on said 10 substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl, or a-0C(0)aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, 15 (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R" where R' and R" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted 20 alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, 25 where when either R' or R" are substituted alkyl, the substituted alkyl is an alkyl group of 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxyalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, 30 intellectual property office of nz. 1 8 JUN 2001 3 "T / CO':' j i 0 ^ v aryl , heteroaryl, , heterocyclic, nitro, mono-alkylamino, di-alkylamino, mono-(substituted alkyl)amino, di-(substituted alkyl)amino, mono-aryl anno, di-aryl amino, mono-heteroarylamoni, di-heteroarylamino, mono-heterocyclic amino, di-heterocyclic amino and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, (j) -NHS02-R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -0NR9[C(0)0]IR'° where z is zero or one, R9 and R10 are as defined above; intellectual property office of nz. 1 8 JUN 2001 received WO 98/22494 PCT/US97/20804 -- 388 - X can also be -CR6R6Y' where each R6 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted 5 thioalkoxy, -0C(0)R7, -SSR7, -SSC(0)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X' is hydrogen, hydroxy, or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo 10 group, Z is selected from the group consisting of a bond covalently linking R1 to -CX'X"-, oxygen and sulfur; n is an integer equal to 1 or 2; and pharmaceutical^ acceptable salts thereof 15 with the provisos that: A. when R1 is phenyl or 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3, Rs is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0H; B. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R4 is -CH(OH)CH3 20 derived from D-threonine, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)0H or -C(0)0CH3; C. when R1 is phenyl, R2 is methyl, R4 is benzyl, R5 is hydrogen, X is methoxycarbonyl, X' and X" are hydrogen, Z is a bond, and n is 1, then R3 is not methyl; 25 D. when R1 is wo-propyl, R2 is -CH2C(0)NH2, R3 is hydrogen, R4 is wo-butyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and rt is 1, then X is not -C(0)0CH3; E. when R1 is phenyl, R2 is methyl, R5 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R3, the nitrogen atom 30 attached to R3, and R4 do not form l,2,3,4-tetrahydrowo-quinolin-2-yl or pyrrolidin-2-yl; Printed from Mimosa WO 98/22494 PCT/US97/20804 - 389 - F. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R3 is hydrogen, X is -C(0)0CH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not 4-amino-/i-butyl; G. when R1 is 3-nitrophenyl, R2 is methyl, R3 is hydrogen, R4 is 5 -CH(OH)CH3, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NH2 or -CH2OH; H. when R1 is phenyl, R2 is methyl, R3 is hydrogen, R5 is hydrogen, X is -CH2OCH3, X' and X" are hydrogen, Z is a bond, and n is 1, then R4 is not benzyl or ethyl; 10 I. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is methyl, R4 is methyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CHOH0; J. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X' and X" are 15 hydrogen, Z is a bond, and n is 1, then X is not -CHOH<£ or -CH2OH; K. when R, is Ar-(2-pyrrolidinonyl), R2 is methyl, R3 is hydrogen, R4 is benzyl, Rs is hydrogen, X' and X" are hydrogen, Z is a bond, and rt is 1, then X is not -C(0)0CH3; L. when R1 is 3,5-difluorophenyl, R2 is methyl derived from D-alanine, 20 R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, Rs is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NH-benzyl; M. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is hydrogen, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -CH2OH; 25 N. when Rl is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is 4-phenylphenyl, R5 is hydrogen, X' and X" are hydrogen, Z is a bond, and n is 1, then X is not -C(0)NHC(CH3)3; and O. when R1 is 5,5-difluorophenyl, R2 is methyl, R3 is hydrogen, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, X' and X" are 30 hydrogen, Z is a bond, and n is 1, then X is not -C(0)NHCH(CH3)<£ P. when Rl is ethyl, R2 is iso-butyl, R3 is hydrogen, X' and X" are hydroifttff^LLfCT^^RJ^^ ind n 1S 1, then X is not -CH (C2H2F30) (C4IE9) . " 1 8 JUN 2001 received Cr WO 98/22494 PCT/US97/20804 ^ '33 46?.
4. A use according to claim 1, 2 or 3 wherein R1 is an unsubstituted aryl group ar.d Z is a bond covalently linking R1 to -CX'X"-.
5. A use according to claim 4 wherein the unsubstituted R1 aryl group is selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl. 5
6. A use according to claim 1, 2 or 3 wherein R1 is a substituted aryl group and Z is a bond covalently linking R1 to -CX'X"-.
7. A use according to claim 6 wherein said substituted aryl group is a mono-substituted, disubstituted or tri-substituted phenyl group. 10
8. . A use according to claim 7 wherein the substituted phenyl groups are selected from the group consisting of 4-fluorophenyl 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxy-phenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2-hydroxy-15 phenyl, 2-methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 3,4-dibromophenyl, 3,4-dichlorophenyl, 3,4-methylene-dioxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2,4-dichlorophenyl, and 2,5-difluorophenyl.
9. A use according to claim 1, 2 or 3 wherein R1 is an 20 alkaryl group and Z is a bond covalently linking R1 to -CX'X"-.
10. A use according to claim 9 wherein the R1 alkaryl group is selected from the group consisting of benzyl, 2-phenylethyl, and 3-phenyl-n- propyl. INTELLECTUAL PROPERTY OFFICE OF NZ. 1 8 JUN 2001 received 5 WO 98/22494 PCT/US97/20804 £ £. I. C* - 391 --
11. A use according to claim 1, 2 or 3 wherein R1 is selected from the group consisting of alkyl, alkenyl, cycloalkyl and cycloalkenyl groups and Z is a bond covalently linking R1 to -CX'X"-.
12. A use according to claim 11 wherein R1 is alkyl.
13. A use according to claim 11 wherein R1 is cycloalkyl.
14. A use according to claim 11 wherein R1 is alkenyl.
15. A use according to claim 11 wherein R1 is cycloalkenyl.
16. A use according to claim 11 wherein the R1 alkyl, cycloalkyl, alkenyl and cycloalkenyl groups are selected from the group 10 consisting of iso-propyl, /j-propyl, /i-butyl, iso-butyl, .sec-butyl, tert-butyl, -CH2CH=CH2, -CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl, aminomethyl, and N-tert-15 butoxycarbonylaminomethyl.
17. A use according to claim 1, 2 or 3 wherein R1 is selected from the group consisting of heteroaryl and substituted heteroaryl groups and Z is a bond covalently linking R1 to -CX'X"-. 18 . A use according to claim 17 wherein the R1 heteroaryl and 20 substituted heteroaryl groups are selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2- intellectual property office of nz. -
18. 1 8 JUN 2001 d r r. p i v f n WO 98/22494 PCT/US97/20804 -- 392 - (thiophenyl)thiophen-5-yI, 6-methoxythionaphthen-2-yI, 3-phenyI-1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl. O \J
19. A use according to claim 1, 2 or 3 wherein R2 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
20. A use according to claim 9 wherein R2 is selected from the group consisting of methyl, ethyl, /i-propyl, iso-propyl, n-butyl, /so-butyl, sec-butyl, phenyl, 4-fluorophenyl, 3,5-difluoro-phenyl, 4-methoxyphenyl, benzyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, thien-2-yl, thien-3-yl, -CH2CH2SCH3, -CH2OCH74>, -CH(CH3)OCH24>, -CH(OH)CH3 and -CH2OH.
21. A use according to claim 1, 2 or 3 wherein X' and X" are hydrogen and Z is a bond covalently linking R1 to -CX'X"-.
22. A use according to claim 21 wherein R3 is selected from the group consisting of hydrogen, methyl or together with R4 and the nitrogen to which R3 is attached forms pyrrolidin-2-yl, 2,3-dihydroindol-2-yl, piperidin-2-yl, 4-hydroxy-pyrrolidin-2-yl and l,2,3,4-tetrahydroisoquinolin-3-yl.
23. A use according to claim 1, 2 or 3 wherein R4 substituents are selected from the group consisting of hydrogen, methyl, ethyl, /so-propyl, n-propyl, n-butyl, sec-butyl, wo-butyl, cyclopentyl, cyclohexyl, allyl, zso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2-indol-3-yl, phenyl, />-(phenyl)phenyl, m-(phenyl)phenyl o-fluorophenyl, m-fluorophenyl, /7-fluorophenyl, /7-bromophenyl, m-methoxyphenyl, />-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, /7i-trifluoromethylphenyl, /?-(CH3)2NCH2CH2CH20-benzyl, p-(CH3)3C0C(0)CH20-benzyl, p-phenylphenyl, 3,5-difluorophenyl, intellectual property office of nz. 1 8 JUN 2001 received WO 98/22494 PCT/US97/20804 - 393 - 0 />-(H00CCH20)-benzyl, 2-aminopyrid-6-yl, 4-(N-morpholino-CH2CH20)-benzyl, -CH2CH2C(0)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofiiranyl), -CH2-thien-2-yl, -CH2-thiazol-4-yl, -CH2(l-methyl)cyclopropyl, -CH2-thien-3-yl, thien-3-yl, thien-2-yl, -CHrC(0)0-r-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, 2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -(CH^CHa, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(0-f-butyl)CH3, -CH2OCH3, -(CH^NH-Boc, -(CH2)4NH2, -(CH2)4N(CH3)2, -CH2-pyridyl, pyridyl, -CH2-naphthyl, -CH2-(N-morpholino), p-(N-morpholino-CH2CH20)-benzyl, benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, tetrazol-5-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2-N-phthalimidyl, 2-methylthiazol-4-yl, and thieno[2,3-Z?]thiophen-2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl, 5-chlorothien-2-yl, 3-phenoxyphenyI, 2-phenoxyphenyl, 4-ethylphenyl, 2-benzylphenyl, (4-ethylphenyl)phenyl, 4-tert-butylphenyl, 4-n-butylphenyl, o-(4-chlorophenoxy)phenyl, furan-2-yl, and 4-phenylacetylenylphenyl.
24. A use according to claim 1, 2 or 3 wherein Z is a covalent bond linking R1 to -CX'X"- and R4 and R5 are fused to form a cycloalkyl group selected from the group consisting of cyclopropyl and cyclobutyl.
25. A use according to claim 1, 2 or 3 wherein Z is a covalent bond linking Rl to -CX'X"-, X is -C(0)Y and Y is selected from the group consisting of hydroxy, alkoxy or substituted alkoxy.
26. A use according to claim 25 wherein Y is alkoxy or substituted alkoxy selected from the group consisting of methoxy, ethoxy, n-propoxy, wo-propoxy, n-butoxy, wo-butoxy, rm-butoxy, neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-pheny 1-rc-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, -0NHC(0)0C(CH3)3, -ONHC(CH3)3 and hydroxy. intellectual property office of n.z. 1 8 JUN 2001 D C r> P I 11 r- n WO 98/22494 PCT/US97/20804 F {Q\ - © & - 394 '■&] H t
27. A use according to claims 1, 2 or 3 wherein Z is a covalent bond linking R1 to -CX'X"-, X is -C(0)Y and Y is -NR'R".
28. A use according to claim 27 wherein Y is selected from the group consisting of amino (-NHJ, -NH(uo-butyl), -NH(5ec-butyl), N-5 methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino, N-heptamethylene-imino, N-pyrrolidinyl, -NH-methallyl, -NHCH2-(furan-2-yl), -NHCH2-cyclopropyl, -NH(rm-butyl), -NH(p-methylphenyl), -NHOCH3, -NHCH2(p-" fluorophenyl), -NHCH2CH2OCH3) -NH-cyclopentyl, -NH-cyclohexyl, 10 -NHCH2CH2N(CH3)2, -NHCH2C(CH3)3, -NHCH2-(pyrid-2-yl), -NHCH2-(pyrid-3-yl), -NHCH2-(pyrid-4-yl), N-thiazolindinyl, -N(CH2CH2CH3)2, -N[CH2CH(CH3)J2, -NHOH, -NHO-NOz-^), -NHCH2(p-N02-<£), -NHCH2(m-NO2-0), -N(CH3)OCH3, -N(CH3)CH2-<£, -NHCH2-(3,5-di-fluorophenyl), -NHCH2CH2F, -NHCH2(p-CH3O-0), -NHCH2(m-CH3O-0), -NHCH2(p-CF3-4>), 15 " -N(CH3)CH2CH2OCH3, -NHCH2CH2<£, -NHCH(CH3)<2>, -NHCH2-(/>-F-<£), -N(CH3)CH2CH2N(CH3)2, -NHCH2-(tetrahydrofuran-2-yl), -NHCH2(p-trifluoromethylphenyl), -NHCH2C(CH3)=CH2, -NH-[(p-benzyl)pyrid-4-yl], -NH-[(2,6-dimethyl)pyrid-4-yI], -NH-(2-methylcyclohexyl), -NH-(4-methylcyclohexyl), -NH-[N-ethoxycarbonyl]-pipendin-4-yl, -NHOC(CH3)3, 20 -NHCH2CH2CH2CH2-0, -C(O)NH(CH2)3O-(p-CH3)0, -C(0)NH(CH2)6NH2, -NH-(tetrahydrofuran-2-yl), -N(CH3)<£, -NH(CH2)4NHC(0)-(2-hydroxy-4-azido)-phenyl and -NH(CH2)6-(biotinamidyl).
29. A use according to claims 1, 2 or 3 wherein X is -C(0)Y and Y is selected from the group consisting of -CH2CH2CH2CH(CH3)2, 25 -CH2OH, -CH(OH)CH2CH2CH(CH3)2, -CH(OH)<£, -CH(0H)CH2C(0)0CH3, -C(OH)(CH3)2, -CH2OCH3, -CH20C(0)0CH3, and -CH20C(0)C(CH3)3, methyl, ethyl, /jopropyl, n-propyl, iso-butyl, /j-butyl, jec-butyl, rerr-butyl, -CH2CH2CH(CH3)2, -CH2-pyridy-2-yl, -CH2-pyridy-3-yl, -CH2-pyridy-4-yl, -CH2-fur-2-yl, benzyl, cyclopentyl, phenyl, and -NH-S02-CH3. intellectual property office of n.z. 1 a JUN 2001 WO 98/22494 PCT/US97/20804 ~ 395 7? ' /S ^ ^$3 '4?
30. A use according to claims 1, 2 or 3 wherein Z is a covalent bond linking Rl to -CX'X"-.
31. A use according to claims 1, 2 or 3 wherein the compound of formula I is selected from the group consisting of: 5 N-[N-(3 ,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate methyl ester #-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-histidine methyl ester Af-benzyl-jV'-[.V-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide 10 Ar-2-(N,Af-dimethylamino)ethyl-./V'-[Ar-(3,5-difluorophenylacetyl)-L- alamnyl]-(S)-2-aminohexanamide jV-(2-methoxyethyl)-A^'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide A^-2-(7V,N-dimethylamino)ethyl-A^'-[7V-(3,5-difluorophenylacetyl)-L-15 alaninyl]-L-phenylalaninamide AL(4-pyridyl)methyl-Ar'-[Air-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide AK3-pyridyl)methyl-iV'-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide 20 iV-(4-pyridyl)methyl-W-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2- aminohexanamide N-[jV-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoatererr-butyl ester AT-[iV-(pent-4-enoyl)-L-alaninyl]-L-phenylalanine methyl ester 25 Af-[/^(dec-4-enoyl)-L-alaninyl]-L-phenylalanine methyl ester N-[N-(3,5 -difluoropheny lacetyl)-L-alaninyl]-L-4-[3- (N,N-dimethylamino)propoxy]phenylalanine methyl ester N-[AK3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[(/m-butyloxycarbonyl)methoxy]phenylalanine methyl ester intellectual property office of n.z. 1 8 JUN 2001 received WO 98/22494 PCT/US97/20804 - 396 - A^-[A/-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester jV-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(carboxymethoxy)phenylalanine methyl ester A^-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)phenylalanine methyl ester AL[AK3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-6-(Ar,jV-dimethylamino)hexanoate methyl ester iV-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propionate methyl ester //-[AL(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(3-pyridyl)propionate methyl ester 2V-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-proline methyl ester l-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxylate methyl ester A'L[jV-(3,5-difluoropheriylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-pyridyl)propionate methyl ester A/-[AK3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionate methyl ester A^[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropionate methyl ester Ar-(2-methoxyethyl)-Ar'-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)phenylalaninamide //-(2-methoxyethyl)-iV'-[//-(3,5-difluorophenylacetyl)-L-alaninyl]-2-ammo-3-methoxypropionamide /V-fAKS.S-difluorophenylacetyty-L-alaninylJglycine methyl ester A''-(2-methoxyethyl)-A^'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(4-pyndyl)propionamide Af-(2-methoxyethyl)-iV'-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino -3-(2-pyridyl)propionamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 397 - A''-[A'1(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)propionate methyl ester 2-[A'1 (3,5 -difluorophenylacetyl)-L-alaniny 1] -1,2,3,4-tetrahydroisoquinoline-3-carboxylate methyl ester 5 N-(3-methoxybenzyl)-Ar'-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-L- phenylalaninamide AL[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(l-naphthyl)propionate methyl ester N-[A7-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-10 naphthyl)propionate methyl ester ALfyV-(3,5-difluorophenylacetyl)-L-aIaninyl]-(S)-2-amino-3-(2-thienyl)propionate methyl ester A^[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine benzyl ester jV-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine 3-bromo-15 propyl ester ^-[/^-(S^-difluorophenylacetyO-L-alaninylJ-L-phenylalanine 3-iodopropyl ester /Vr-[A'-(3,5-difluorophenylacety])-L-alaninyl]-L-leucine rm-butyl ester W-[Af-(3,5-difluorophenylacetyl)-L-alaninyI]-2-amino-2-(2-20 pyridyl)acetamide W-17V-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetamide //-[W-P^-difluorophenylacetyty-L-alaninylJ-Af-^m-butoxycarbonylVL-lysine methyl ester 25 methyl Ar-[Ar-(3,5-difluorophenylacetyl)-L-alamnyl]-(S)-2-amino-4- phenylbutanoate AT-fW-O^-difluorophenylacetyO-L-alaninyljglycine 2-phenylethyl ester Ar-[Af-(3,5-difluorophenyIacetyl)-L-alaninyl]glycine 3-phenylpropyl ester N'-[;V-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-30 pyridyl)acetamide Printed from Mimosa 98/22494 PCT/US97/20804 -- 398 - iV-[iV-(phenylacetyl)-L-alaninyl]-L-threonine methyl ester N[N- (pheny lacetyl)-L-alani nyl]-L-leucinamide iV'-[iV-(phenylacetyl)-L-alaninyl]-L-alaninamide W-[W-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide W-[Af-(phenylacetyl)-L-alaninyl)-L-valinamide JV-[iV-(3,5 -difluorophenylacetyl)-L-alaninyl] -2-amino-2-(3-pyridyl)acetate ethyl ester iV-methyl-Ar'-[A^-(phenylacetyl)-L-alaninyl]-L-leucinamide N,A/-dimethyl-.W-[A/-(phenylacetyI)-L-alaninyl]-L-phenylalaninamide //,iV-dimethyl-A^'-[A^-(phenylacetyl)-L-alaninyl]-L-leucinamide A^,Ar-dimethyl-Ar'-[A^-(phenylacetyl)-L-alaninyl]-L-valinamide A'-methyl-N'-[7V-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide ./V-methyl-.W-[./V-(phenylacetyl)-L-alamnyl]-L-valinamide A'-methyl-A''-[A^-(3,5-difluoropheny lacetyl)-L-alaninyl]-(S)-2-aminohexanamide A',Ar-dimethyl-A"-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-ammohexanamide W-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide AL[A^-(3,5-difluorophenylacetyl)-L-aJaninyl]-2-amino-2-(3-methoxyphenyl)acetate methyl ester N-|W-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-methoxyphenyl)acetate methyl ester A''-[A';-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetate ethyl ester //-[A?-(3,5-difluorophenylacetyl)-L-alaniny]]-2-amino-2-(4-pyridyl)acetate ethyl ester 2V-[iV-(cyclohexylacetyl)-L-alaninyl]-L-phenylalanine methyl ester Printed from Mimosa 98/22494 PCT/US97/20804 — 399 - A^[AT-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine methyl ester Af-[7V-(cyclohex-l-enylacetyl)-L-alaninyl]-L-phenylalanine methyl ester N-[A?-(3,5-difluorophenylacetyl)-L-alaninyl]-1 -aminocyclopropane-1-carboxylate methyl ester W-2-(iV,./V-dimethylamino)ethyl-N-methyl-,/V'-[A/-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Af-[AHcyclopropylacetyl)-L-alaninyl]-L-phenylalanine methyl ester iV-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester iV-[2V-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl ester JV-[JV-(3-nitrophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester N-[A/-(3-nitrophenylacetyl)-L-alaninyl]-L-alanine ethyl ester N-|VV-(3-nitrophenylacetyl)-L-alaninyl]glycine ethyl ester AT-hydroxy-iV'-[7V-(3-nitrophenylacetyl)-L-alaninyl]-D,L-threoninamide A^-[/V-(isovaleryl)-L-phenylglycinyl]-L-alanine uo-butyl ester 7V-[AK3-nitrophenylacetyl)-L-alaninyl]-2-amino-3-(3-hydroxyphenyl)propionate methyl ester //-[A^-(3-nitrophenylacetyl)-L-alamnyl]-L-tyrosine ethyl ester //-[A^-(isovaleryl)-L-isoleucinyl]-L-alanine wo-butyl ester A'-[AL[A'-(isova}eryl)-L-valinyl]-L-phenylglycinyl]-L-alanine wobutyl ester iV-[W-(isovaleryl)-L-phenylaIaninyl]-L-alanine wo-butyl ester A^-[Af-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester l-[AT-(3-nitrophenylacetyl)-L-alaninyl]-indoline-(S)-2-carboxylate ethyl ester jV'-[iV-(3,5-difluorophenylacetyl)-L-a]aninyl]-L-alaninamide N-methoxy-Af-methyl-A''-[W-(isovaleryl)-L-phenylglycinyl]-L-alaninanude Printed from Mimosa 98/22494 PCT/US97/20804 — 400 — iV-ij0-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide //,AT-di-n-propyl-A/ '-[N-( 3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide W-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valinamide iV-(4-nitrophenyl)-A^'-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Ar'-[A4AKisovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-phenylalaninamide N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester 2V'-[AH3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyla]aninamide A^/io-butyl-^'-tA^CisovaleryO-L-phenylglycinylJ-L-alaninamide iV-(2-methoxyethyl)-W-[//-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanmamide Ar-(4-nitrobenzyl)-W-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alamnamide N-(4-mtrophenyl)-A"-[7V-[A'-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-alaninamide Ar-(4-nitrophenyl)-A"-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide /V-benzyl-iV-methyl-./V'-[W-(3,5-difluorophenylacetyl)-L-alamnyl]-L-alaninamide N-(3,5-difluorobenzyl)-A"-[//-(3,5-difluorophenylacctyl)-L-alaninyl]-L-alaninamide A/1(3-nitrobenzyl)-iV'-[/V-(3,5-difluorophenylacetyl)-L-a]aninyl]-L-alaninamide 7V-benzyl-W-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Af-(4-nitrobenzyl)-A^'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide yv-[jV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophan methyl ester Printed from Mimosa WO 98/22494 PCT/US97/20804 - 401 - Ar-(4-methoxybenzyl)-A"-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L- alaninamide A^-[A'-(phenylacetyl)-L-phenylglycinyl]-L-alanine ethyl ester 7/-[iV-[A^(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninyl]-L-phenylglycine methyl ester iV-[AT-(cyclohexylacetyl)-L-phenylglycinyl]-L-alanine ethyl ester AT-[A/-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine methyl ester •/V-[//-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]-L-phenylglycine methyl ester A^-(2-phenylethyl)-A^'-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide A^'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophan amide /V-[Ar-(3,5-difluorophenylacetyl)-L-a]aninyl]-(S)-2-amino-3-cyclohexylpropionate methyl ester iV-(2-methoxyethyl)-A^'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-nitrophenyl)propionamide N-[/V-(3-nitrophenylacetyl)-L-alaninyl]-L-serine ethyl ester N-[(R)-a-methylbenzyl]-A'''-[Ar-(3,5-difluorophenylacety])-L-alaninyl]-L-alaninamide N-[(S)-a-methylbenzyl]-A'''-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide 7/-(4'fluorobenzyl)-A?'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Af-(4-pyridylmethyl)-./V'-[7V-(3,5-difluorophenylacetyI)-L-alaninyl]-L-alamnamide Af-(4-tnfluoromethylbenzyl)-iV'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Af-[./V-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-phenylpropicmate ethyl ester Printed from Mimosa 98/22494 PCT/US97/20804 -- 402 -- ./V-[Af-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyIalaninerm-butyl ester Ar-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-methylpropionate methyl ester N-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-2-anuno-2-cyclohexylacetate ethyl ester Af-(2-methoxyethyl)-iV'-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide A/-[/V-(isovaleryl)-2-amino-2-cycIohexylacetyl]-L-alanine ethyl ester iV-2-(iV,JV-dimethylamino)ethyl-.W-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide iV-(2-pyridylmethyl)-.W-[JV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide iV-[A^-(3-pyridylacetyl)-L-aIaninyl]-L-phenylalanine methyl ester Ar-[Ar-(2-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl ester Ar-[/V-(4-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl ester 7V-[N-(3,5-difluorophenylacetyl)-L-alaninyI]-2-amino-2-(4-fluorophenyl)acetate ethyl ester A^-[AL(3,5-difluorophenylacetyl)-L-alaninyI]-2-amino-2-(2-fluorophenyl)acetate ethyl ester A4AH3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alanine ethyl ester Af-[W-(3,5-difiuorophenylacetyl)-L-a]aninyl]-2-amino-3-phthalimidopropionate ethyl ester N-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine neopentyl ester A^-rerf-butyl-Af'-[//-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide N-[;V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine/erf-butyl ester Printed from Mimosa 98/22494 PCT/US97/20804 - 403 - AT'-[jV-(3,5-difiuorophenylacetyl)-L-alaninyl]-L-phenylglycinamide 4-[/V-[Ar-(3-nitrophenylacetyl)-L-a]aninyl]-L-valinyl]morpholine A^[//-(3-nitrophenylacetyl)-L-aIaninyl]-L-valine ethyl ester 2V-[iV-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine methyl ester iV-[A^(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methyl ester 4-[N-[iV-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-amino-3-/err-butoxybutyryl]morpholine 4-[iV-[iY-(3-nitrophenylacetyl)-L-alaninyl]-L-isoIeucinyl]morpholine AT-[AK3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine methyl ester Af-[iV-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine ^-[^-[^-(S-nitrophenylacetyO-L-alaninyll-L-threoninylJ-L-valine ethyl ester Ar-[//-(3-nitrophenylacetyl)-L-alaninylJ-(S)-2-aminopentanoate methyl ester Af-[Ar-(3-nitrophenyIacetyl)-L-alaninyl]-L-leucine methyl ester iV-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine methyl ester A/'-2-methoxyethyl-Ar'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide N-2-(iV,jV-dimethylamino)ethyl-.iV'-[N-(3,5-difluoTophenylacetyl)-L-alaninyl]-L-alaninamide A'1cyclohexyl-Ar'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide A'-neopentyl-A''-[Ar-(3)5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide A'-tetrahydrofurfuryl-/V'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide A7-2-pyridylmethyl-A^'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Printed from Mimosa 98/22494 PCT/US97/20804 — 404 -- 3-[2V-[AK3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]thiazolidine N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methyl ester Ar-[Ar-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methyl ester iV-(R)-jec-butyl-iV'-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide l-[Ar-[AK3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]pyrrolidine A^-(S)-jec-butyl-A/'-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alamnamide Ar-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valine methyl ester 7V-2-fluoroethyl-//'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide Ar-[(S)-6-methyl-3-oxohept-2-yl]-A^'-(3,5-difluorophenylacetyl)-L-alaninamide /V-4-nitrobenzyl-Ar'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutyramide Ar-4-nitrobenzyl-N'-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanamide N-[/V-(3,5-difluorophenylacetyl)-L-a]aninyl]-2-amino-2-(3-fluorophenyl)acetate methyl ester W-[Af-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetamide Af-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiophen-2-yl)acetate methyl ester Ar-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-2-yl)acetate ethyl ester //-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-3-yl)acetate methyl ester Af-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-thienyl)acetate methyl ester Prxnted from Mimosa 98/22494 - 405 - PCT/US97/20804 AT-[//-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-5-yl)acetate ethyl ester Ar-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetate methyl ester AL[/^-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetate /erf-butyl ester //-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetic acid N-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(lflr-tetrazol-5-yl)acetate methyl ester /V-[;V-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(6-methoxy-2-naphthyl)acetate methyl ester N-|W-(3,5-difluorophenylacetyl)-L-alaninyl]-2-arnino-2-(3-trifluoromethy]phenyl)acetate methyl ester /V-|W-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetate methyl ester A^[A^(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(thieno[2,3-Z>]thiophen-2-yl)acetate methyl ester /V-[jV-(3,5-difluorophenylacetyl)-L-alaninyI]-2-amino-2-(2-methylthiazol- 4-yl)acetate methyl ester (3S,4S)-Ar-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-4-amino-3-hydroxy- 5-phenylpentanoate methyl ester iV-|W-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-4-enoate _ methyl ester iV-[yV-(cyclopropylacetyl)-L-alaninyl]-L-pheny [glycine rert-butyl ester A'-rerr-butyl-Ar'-[A?-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(4-phenylphenyl)acetamide A^-[//-(3,5-difluorophenylacetyl)-(S)-2-aminobutanoyl]-L-phenylglycine rm-Butyl Ester /V-|W-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine ferr-butyl ester Printed from Mimosa 98/22494 PCT/US97/20804 — 406 - A^[AK3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycine methyl ester iV-[JV-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine methyl ester iV-[iV-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycine methyl ester N-[N-(3,5-difluorophenylacetyl)-L-leucinyl]-L-phenylglycine methyl ester ^-[^-(S.S-difluorophenylacetyO-L-phenylalaninyll-L-phenylglycine methyl ester N-[N-(3,5-difluorophenylacetyI)glycinyl]-L-phenyIglycine methyl ester jV-[7V-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine methyl ester N-[/V-(phenylacetyl)-L-alaninyl]-L-alanine methyl ester /V-[7V-(phenyIacetyl)-L-alaninyl]-L-leucine methyl ester ^-[^-(phenylacety^-L-alaninylJ-L-isoleucine methyl ester N-|7V-(phenylacetyl)-L-alaninyl]-L-prohne methyl ester iV-[iV-(phenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester A^-[A'-(phenylacetyl)-L-alamnyl]-A',<,-(rerr-butoxycarbonyl)-L-lysine methyl ester N-[7V-(phenylacetyl)-L-alaninyl]-glycine methyl ester jV-[/V-(phenylacetyl)-L-alamnyl]-L-valine methyl ester iV-[A?-(phenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methyl ester 7V-[A^-(phenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methyl ester iV-[/V-(3-mtrophenylacetyl)-L-alaninyl]-L-vahne JV-[A'-(phenylacetyl)-L-alaniny]]-L-/V-methylalanine methyl ester A^-[/V-(isovaleryl)-L-phenylglycinyl]-L-alanine wo-butyl ester Af-[N-(isovaleryl)-L-isoleucinyl]-L-alanine iso-butyl ester Printed from Mimosa 98/22494 PCT/U S97/20804 -- 407 - N-Cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-hydroxyproline ethyl ester JV-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-lysine methyl ester iV-tiV-O.S-difluorophenylacetyO-L-alaninylJ-L-glutamide l-fAf-^.S-difluorophenylacetyty-L-alaninyllpiperidine^-carboxylate methyl ester 7V-[(S)-3-hydroxy-6-methylhept-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide Ar-[(S)-2-hydroxy-1 -phenyleth-1 -yl]-N' -(3,5-difluorophenylacetyl)-L-alaninamide Ar-[Af-(3,5-difluorophenyl-a-fluoroacetyl)-L-alaniny]-L-phenylglycine ferr-butyl ester Af-[AK3,5-difluorophenylacetyl)-2-(S)-aminocyclohexylacetyl]-L-phenylglycine methyl ester /V-[(1R,2S)-1-hydroxy-l-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide N- [(1 R,2S)- l-hydroxy-1,2-diphenyleth-2-yl]-jV '-(3,5-di fl uorophenylacetyl)-L-alamnamide N- [(1S, 2R)-1 -hydroxy-1 -phenylprop-2-yl]-N'-(3,5-difluoropheny lacetyl)-L-alaninamide iV-2-methoxyethyl-A^'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamide Ar-[(S)-a-hydroxy-a-phenyl-i5o-propy]]-N'-(3,5-difluorophenylacetyl)-L-alaninamide iV-[(S)-2-hydroxy-l,2-diphenylethyl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide N- [(S)-1 -hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 408 - iV-[a-hydroxy-a'-(4-hydroxyphenyl)-/.ro-propyl]-N'-(3,5-difluorophenylacetyl)-L-alamnamide NL2-pyridylmethyl-//'-[A';-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide 5 iV-[a-hydroxy-a'-pyrid-2-yl-7Jopropyl]-N'-(3,5-difluorophenylacetyl)-L- alaninamide A^-[a-hydroxy-a'-pyrid-4-yl-«o-propyl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide A4(S)-l-hydroxy-4-methylpent-2-yl]-N'-(3,5-difluorophenylacetyl)-L-10 alaninamide A/-[a-methoxy-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide iV-[l-hydroxy-3-methyl-but-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide A?-[//-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(6-aminopyrid-2-15 yl)acetate methyl ester 2V-[l-hydroxy-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide A^-[(S)-2-methoxy-1-phenyleth-l-yl]-N'-(3,5-difluorophenylacetyl)-L- alaninamide iV-[(S)-l-methoxy-2-phenyl-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-20 alaninamide N-[(S)-l-acetoxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide jV-[(S)-l-(/m-butyIcarbonyloxy)-hex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide A'-[2-hydroxy-l-(thien-2-yl)ethyl]-N'-(3,5-difluorophenylacetyl)-L-25 alaninamide N-[(S)-2-hydroxy-2-methyl-1 -phenylprop- l-yl]-N' -(3,5-difluorophenylacetyl)-L-alaninamide /V-[Ar-(3,5-difluorophenylacetyl)-L-(thien-2-yl)glycinyl]-L-phenylalanine tert-butyl ester 30 //-[7V-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinol Printed from Mimosa PCT/US97/20804 — 409 - 7V-|W-(cyclopropaneacetyl)-L-phenylglycinyl]-L-phenylglycinol A^AKcyclopentaneacetylJ-L-phenylglycinylj-L-phenylglycinol N-[7V-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycinamide ^-[^-(3,5-difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamide N-[Af-(2-thienylacetyl)-L-alaninyl]-L-phenylglycinamide ^[//-(rt-caprotyO-L-alajiinyU-L-phenylglycinarnide A^-[iV-(3,5-difluorophenylacetyl)-L-norleucinyl]-L-phenylglycine methyl ester Ar-[W-(3,5-difluorophenylacetyl)-L-norvalinyl]-L-phenylglycine methyl ester JV-[AH3,5-difluorophenylacetyl)-L-re/?-leucinyl]-L-phenylglycine methyl ester iV-[jV-(3,5-difluorophenylacetyl)-L-isoleucinyl]-L-phenylglycine methyl ester yV-[/V-(3,5-difluorophenylacetyl)-L-cyclohexylaIaninyl]-L-phenylglycine methyl ester Ar-[iV-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-phenylglycme methyl ester jV-|W-(3,5-difluorophenyIacetyl)-(S)-2-amino-2-(thien-3-yl)acetyl]-L-phenylglycine methyl ester A'-[Ar-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-2-yl)acetyl]-L-phenylglycine methyl ester Ar-[Ar-(3,5-difluorophenylacetyl)-L-(4-fluorophenyl)glycinyl]-L-phenylglycine methyl ester AT-[Air-(3,5-difluorophenylacetyl)-D-(4-fluorophenyl)glycinyl]-L-phenylglycine methyl ester A?-[Ar-(3,5-difluorophenylacetyl)-L-(4-methoxyphenyl)glycinyl]-L-phenylglycine methyl ester Printed from Mimosa 98/22494 PCT/US97/20804 — 410 -- N-[AH3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinerm-butyl ester JV-[N-(cyclopropylacetyl)-L-phenylglycinyl]-L-phenylglycine/m-butyl ester //-[//-(cyclopentylacetyO-L-phenylglycinylj-L-phenylglycine ferf-butyl ester ^-[^/-(/erf-butylacetylJ-L-alaninylj-L-phenylglycinamide //-rerf-butyl-A^'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(5-bromothien-2-yl)glycinamide iV-rm-butyl-jV'-|W-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(5-bromothien-2-yl)glycinamide A7-/m-butyl-A^/-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-bromothien-2-yl)glycinamide iV-/err-butyl-iV'-[7V-(3,5-difluorophenylacetyl)-L-alaniny]]-L-(thien-2-yl)glycinamide A'-/erf-butyl-Ar'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide ./V-rm-butyl-Af'-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-3-yl)glycinamide /V-rerr-butyl-jV'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide iV-/err-butyl-^V'-[A''-(3,5-difluorophenylacetyl)-L-a]aninyl]-D-phenylglycinamide //-/m-butyl-A/'-[A?-(3,5-difluorophenylacetyl)-L-a]aninyl]-L-phenylglycinamide 2V-/,err-butyl-iV'-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-D)L-(5-chlorothien-2-yl)glycinamide ^/-Cyclohexyl-//'-[Ar-(3,5-difluorophenylacetyI)-L-alaninyl]-D-4-(phenyl)phenylglycinamide A/-/e/T-butyl-Ar'-[A^-(3,5-difluorophenylacetyl)-L-alaninyI]-L-3-(phenoxy)phenylglycinamide Prxnted from Mxmosa 98/22494 PCT/US97/20804 — 411 - iV-(S)-(-)-a-methylbenzyl-/Vr'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide //-rerr-butyl-Ar'-[A':-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenyl)phenylglycinamide N-retf-butyl-./V'-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(ethyl)phenylglycinamide A^-fe/t-butyl-/V'-tAr-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(phenyl)phenylglycinamide A^-/e/t-butyl-Ar'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(benzyl)phenylglycinamide /V-/err-butyl-iV'-|W-(3,5-difliJorophenylacetyl)-L-alaninyl]-D,L-4-bromophenylglycinamide Ar-/err-butyl-A^'-[A?-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(cyclohexyl)phenylglycinamide ■N-te/?-butyl-Ar'-(7V-(3,5-difluorophenylacetyl)-L-aIaninyl]-L-4-(4-ethylphenyl)phenylglycinamide A^re/r-butyl-/V'-[Af-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(ferf-butyl)phenylglycinamide N-re/r-butyl-./V'-{7V-(3,5-difluorophenylacetyl)-L-a]aninyl]-D,L-3-(4-chlorophenoxy)phenylglycinamide iV-cyclohexyl-iV'-[AH3,5-difluorophenylacetyI)-L-alaninyl]-L-4-(phenyl)phenylglycinamide A^[A^-(3,5-difluorophenyl-o;-hydroxyacetyl)-L-alaninyl]-L-phenylglycine tert-butyl ester iV-ferr-butyl-/V'-[/V-(3,5-difluorophenyl-ot,a-difluoroacetyl)-L-alaninyl]-L-phenylglycinamide Ar-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinererr-butyl ester Af-[(S)-l-oxo-l-phenylprop-2-yl]-2V'-(3,5-difluorophenylacetyl)-L-alaninamide Printed from Mimosa 98/22494 PCT/US97/20804 — 412 - iV-[AH3,5-difluorophenylacetyl)-L-alamnyl]-D,L-(pyrid-3-yl)glycine/err-butyl ester [N-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]morpholine N-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(2-methoxy)phenylglycine methyl ester N- [N-(3,5-difluorophenylacety l)-L-alaninyl]-D, L-phenylglycine N-tert-butoxycarbonyI(hydroxyl amine) ester N-neopentyl-iV'-[A',-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide /V-tetrahydrofurfuryl-./V'-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide jV-methoxy-A"-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide [/V-[jV-(3,5-difluorophenylacetyl)-L-alaninyl]-D ,L-phenylglycinyl]azetidine Ar-;.TO-butyl-A''-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide A/-cyclopropanemethyl-W-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide /V-methoxy-jV-methyl-W-[jV-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide /V-2-methylprop-2-enyl-/V'-[7V-(3,5-difluorophenylacetyl)-L-aIaninyl]-D,L-phenylglycinamide A/-(pyrid-3-yl)methyl-N'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide AL(pyrid-4-yl)methyl-A^'-[A/-(3,5-difluoropheny]acetyl)-L-a]aninyl]-D,L-phenylglycinamide /V-furfuryl-W-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide Printed from Mimosa WO 98/22494 PCT/US97/20804 - 413 - Af-cyclopentyl-/V'-[/V-(3,5-difluorophcnylacetyI)-L-alaninyl]-D,L-phenylglycinamide AM-benzylpiperidin-4-yl-N-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide 5 //,Ar-dimethyl-//'-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L- phenylglycinamide N-2,2,6,6-tetramethylpiperidin-4-yl-Ar'-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide A'L2-methylcyclohexyl-Ar'-[AL(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-10 phenylglycinamide A^4-methylcyclohexyl-yV'-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide N-l-ethoxycarbonylpiperidin-4-yl-/V'-[JV-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide 15 //-methyl-A^'-[A^-(3,5-difluorophcnylacetyl)-L-alaninyl]-L- phenylglycinamide N-ferf-butoxy-A^'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D, L-phenylglycine N-tert-20 butyl(hydroxylamme) ester /V-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine hydrazide Af-(l-ethoxyethen-l-yl)-[/V'-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine hydrazide iV-[A^-(phenylacetyl)-L-alaninyl]-L-phenylglycine /m-butyl ester 25 A'-4-(phenyl)butyl-Ar'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-L- phenylglycinamide Ar-3-(4-iodophenoxy)propyl-N'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide A^-6-(amino)hexyl-A/'-[A^-(3,5-difluorophenylacetyI)-L-alaninyl]-D,L-30 phenylglycinamide Hydrochloride Printed from Mimosa 98/22494 PCT/US97/20804 -414 - N-l-(phthalimido)pent-2-yl-iV'-(3,5-difluorophenylacetyl)-L-alaninamide iV-[iV-(3,5-difluorophenyIacetyl)-L-(3,5-difluorophenyl)glycinyl]-L-(3,5-difluoropheny 1)glycine methyl ester iV-[W-(3,5-difluorophenylacetyl)-L-alaninyl]-L-norleucine N- [N- (cyclopen taneacety 1) -L-alaninyl] -L-phenylgl ycine tert-butyl ester iV-[AH3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycine iso-propyl ester iV-(isopropyl) A/'-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide jV-[W-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine tert-butyl ester ^-[//-(cyclopropylacetyO-L-alaninylJ-L-phenylalanine rerr-butyl ester 7V-[7V-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine wo-butyl ester iV-[iV-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-phenyIglycine methyl ester iV-[AH3,5-Difluorophenylacetyl)-L-alaninyI]-L-(3-a-phenyl)proline methyl ester iV-[jV-(3,5-Difluorophenylacetyl)-L-a]aninyl]-L-azetidine methyl ester iV-[A^-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(5-chlorobenzothiophen-2-yl)acetate methyl ester A/L[A?-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)propionate rerr-butyl ester jV-[jV-(3,5-difluorophenylacetyl)-L-alamnyl]-L-pheny]glycinamide tert-butyl ester //-[AH3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide Af-[/V-(3,4-dichlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide iV-[/V-(3-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide /V-[W-(3-broinophenylacetyl)-L-alaninyl]-D-phenylglycinamide Printed from Mimosa 98/22494 PCT/US97/20804 - 415 - Af-[iV-(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide Ar-[iV-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide iV-[N-(3-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide 7V-[iV-(4-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide Af-[Ar-(3-trifluoromethylphenylacetyl)-L-alaninyl]-D-phenylglycinamide iV-[JV-(3-methoxyphenylacetyl)-L-alaninyl]-D-phenylglycinamide N-[7|7-(2-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide N-[N-( 1 -naphthy lacetyl)-L-alaninyl]-D-phenylglycinamide iV-[//-(2-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide //-[yV-(phenylacetyl)-L-alaninyl]-D-phenylglycinamide /V-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine /V-[AK3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide N'-[Af-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-furanyl)acetamide W-[/V-(3,5-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide jV'-[7V-(3,4-difLuorophenylacetyl)-D-alaninyl]-D-phenylglycinamide ^'-[^-(S^-difluorophenylacetyO-L-alanmylj-L-phenylalanin-N-methylsulfonamide A,"-methyl-N"-phenyl-A'''-[jV-(3,5-difluorophenylacetyl)-L-alaninyl]-glycmarrude A^"-methyl-A'"-phenyl-Af'-[Ar-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide A^'-[A^-(3,5-difluorophenylacetyl)-L-methioninyI]-L-phenylglycinamide jV"-methyl-A'"-benzyl-Ar'-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamide Printed from Mimosa 98/22494 PCT/US97/20804 — 416 - 2V"-4-fluorobenzyl-iV '-[iV-(3,5-di.fluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide W-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-fluoro)phenylglycine neopentyl ester N-[N-(2,3,4,5,6-pentafluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycine methyl ester iV-[iV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycine tert-butyl ester iV-[jV-(3,5-difluorophenylacetyl)-L-(0-benzyl)sennyl]-L-phenylglycine methyl ester iV-[AH3,5-difluorophenylacetyl)-L-(0-benzyl)threoninyl]-L-phenylglycine methyl ester iV-t//-(3,5-difluorophenylacetyl)-L-threoninyl]-L-phenylglycine methyl ester N-[N-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine methyl ester A,"-4-methylphenyl-/V'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide A,"-tetrahydrofurfuryl-A^'-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide W-|>V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenyl-glycinamide A^'-^V-CS^-difluorophenylacetyO-L-methionylJ-L-phenylglycinamide iV-[jV-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamide iV'-fN-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinamide //-[//-(S^-difluorophenylacetyO-L-valinylJ-L-phenylglycinamide A4(R)-a-methylbenzyl]-iV'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide /V-[l-phenyl-2-oxo-3-methylbutan-l-yl]-A^'-(3,5-difluorophenylacetyl)-L-alaninamide Printed from Mimosa 98/22494 PCT/US97/20804 - 417 - /V-[l-phenyl-2-oxo-propan-l-yl]-iV'-(3,5-difluorophenylacetyl)-L-alaninamide A/'-[l-phenyl-2-oxo-pentan-l-yl]-A^'-(3,5-difluorophenylacetyl)-L-alaninamide N-[ 1 -phenyl-2-oxo-2-phenyl-ethan-1 -ylJ-A^ '-(3,5-difluorophenyl-acetyl)-L-alaninamide A^-[ 1 -phenyl-2-oxo-butan-1 -yl]-/V '-(3,5-difluorophenyl-acetyl)-L-alaninamide N-[ 1 -phenyl-2-oxo-4-methylpentan- l-yI]-/V'-(3,5-difluorophenyl-acetyl)-L-alaninamide N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-a-hydroxyphenylalanine methyl ester A,"-[4-((2-hydroxy-4-azido)-phenyl)-NHC(0)-)butyl] ^'-[^-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide iV-[(S)-l-phenyl-2-oxo-2-phenyl-ethan-l-yl]-W-(3,5-difluorophenyl-acetyl)-L-alamnamide Ar'-[A?-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycine re/T-butyl ester W-[ZV-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-phenylphenylglycine tert-butyl ester [/V-(3,5-difluorophenylacetyl)-L-alaninyI]-L-(2,3-benzo[b]proline) methyl ester AT'-rm-butyI-/V'-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-/i-butylphenylglycinamide /V"-fm-butyl-/V'-[W-(3,5-difluorophenylacetyl)-L-aIaninyl]-D,L-4-(phenylacetenyl)phenylglycinamide N'- [N- (3,5 -difluoropheny lacetyl)-L-alan;nyl] -D ,L-phenylglycinthioamide iV-[l,3-diphenyl-2-oxo-propan-l-yl]-A^'-(3,5-difluorophenylacetyl)-L-alaninamide Af-[l-phenyl-2-oxo-2-cyclopentylethan-l-yl]-/V'-(3,5-difluorophenylacetyl)-L-alaninamide Printed from Mimosa 98/22494 - 418 - PCT/US97/20804 //-[l-phenyl-2-oxo-hexan-l-yl]-iV'-(3,5-difluorophenylacetyl)-L-alaninamide iV-[l-phenyl-2-oxo-3-methylpentan-l-yl]-JV'-(3,5-difluorophenylacetyl)-L-alaninamide A?"-«-hexyl-6-biotinamidyl-A''-[A'-(3,5-difluorophenylacetyl)-L-alaniiiyl]-D,L-phenylglycinthioamide /V'-[yV-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionine W-[7V-(2-rm-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycine methyl ester N"-tert-butyl N'-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-fluorophenylglycinamide W-[A'-(3,5-difluorophenylacetyl)-L-a]aninyl]-D,L-2-phenylglycine methyl ester AH(S)-1 -phenyl-2-oxo-3-phenylpropan-1 -yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide W-[/V-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycine /V"-(W-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycine rerr-butyl ester jV'-[jV-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycine N'-[/V-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycine rm-butyl ester A^-[2-hydroxy-l-(S)phenyleth-l-yl]-A''-t(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alaninamide TV-[2-hydroxyeth-l-yl]-N'-[(3,5-difl uoropheny lacetyl)-L-al aninyl]-L-phenylglycinamide A''-[A'-(3,5-difluorophenyl-2-oxo-acetyl)-L-alaninyl]-L-2-phenylglycine /erf-butyl ester [A/-(2,5-dichlorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl ester [yV-(3,5-difluorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl ester Printed from Mimosa -419 - [iV-(3,4-dichlorothiophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl esier [AH3-aminoproprionyl)-L-alaninyl]-L-phenylglycine rerr-butyl ester; and [iV-(3-ferr-butoxycarbonylamino)propionyl)-L-alamnyl]-L-phenylglycine rerr-butyl ester.
32. A use as defined in any one of claims 1 to 3 substantially as herein descnbed with reference to any example thereof. * INTELLECTUAL PROPERTY OFFICE OF N.Z. 0 3 AUG 2001 received END