CZ122899A3 - Method and compounds for inhibiting and / or synthesizing beta-amyloid peptide - Google Patents

Abstract

Disclosed are compounds which inhibit beta -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed pharmaceutical compositions comprising a compound which inhibits beta -amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.

Description

Method and compounds for inhibiting the release and/or synthesis of β-amyloid peptide

References to related patent applications

This application is related to the following U.S. provisional applications:

1. U.S. Provisional Application No. 60/_ made pursuant to 37 C.F.R. §1.53(b)(2)(ii) of U.S. Patent Application No. 08/755,442, filed November 22, 1996;

2. U.S. Provisional Application No. 60/_ made pursuant to 37 C.F.R. §1.53(b)(2)(ii) of U.S. Patent Application No. 08/808,528, filed February 28, 1997;

3. U.S. Provisional Application No. 60/__ created under the provisions of 37 C.F.R. §l,53(b)(2)(ii) of U.S. Patent Application No. 08/807,528, filed February 28, 1997; and

4. U.S. Provisional Application No. 60/_ made pursuant to 37 C.F.R. §l,53(b)(2)(ii) of U.S. Patent Application No. 08/807,427, filed February 28, 1997.

Each of these applications is incorporated herein by reference in its entirety.

Technical field

The present invention relates to methods of inhibiting the cellular release of β-amyloid peptide and/or its synthesis and, consequently, is useful in the treatment of Alzheimer's disease. The present invention also relates to pharmaceutical compositions containing such compounds as well as to a method of inhibiting the release of β• · • ·

amyloid peptides.

State of the art

Reference

The following publications, patents and patent applications are cited numerically in this application:

¹ Glenner et al., "Alzheimer's Disease: Initial Report of the Purification and Characterization of a Novel Cerebrovascular 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, US Patent No. 4,666,829 issued

May 19, 1987.

³ Selkoe, The Molecular Pathology of Alzheimer's Disease", Neuron, 6:487-498 (1991).

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).

⁵ Chartier-Harlan et al., "Early-Onset Alzheimer's Disease Caused by Mutations at Codon 717 of the β-amyloid Precursor Protein Gene, Nature, 153:544-846 (1989).

⁶ Murrell et al., “A Mutation in the Amyloid Precursor Protein Associated with Hereditary Alzheimer's Disease, φ φ φφ • φ · φ • · ·· φ·φφ • · · · • · · · · · * » φ » ♦ • · · · »φ φ · ·· φφ » φ « φφφ • φ »· · φ

Science, 254:97-99 (1991).

⁷ Mullan et al., "A Pathogenic Mutation for Probable Alzheimer's Disease in the APP Gene at n-Terminus of βAmyloid, Nature Genet., 1:345-347 (1992).

⁸ S. Schenk et al., “Methods and Composition for the Detection of Soluble β-Amyloid Peptide ¹ ,” International Patent Application No. WO 94/10569, published May 11, 1994 .

⁹ Selicoe, Amyloid Protein and Alzheimer's Disease, Scientific American, pp. 2-8, November, 1991.

Losse et al., Tetrahedron, 27:1423-1434 (1971) ¹¹ Citron et al. , 'Mutation of the β-Amyloid Precursor Protein in Familial Alzheimer's Disease Increases β-Protein Production, Nature, 360:672-674 (1992).

¹² Hansen et al., "Reexamination and Further Development of a Precise and Rapid Dye Method for Measuring Cell Growth/Cell Kill, J. Immun. Meth., 119:203-210 (1989).

P. Seubert, Nature (1992) 359:325-327

Johnson-Wood et al., PNAS USA (1997) 94:1550-1555

Tetrahedron Letters, 34(48), 7685 (1993)

All of the above publications, patents, and patent applications are incorporated herein by reference in their entirety.

Alzheimer's disease (AD) is a degenerative brain disorder characterized by clinically progressive loss of memory, cognition, thinking, judgment, and emotional stability, leading to profound mental impairment and ultimately death. Alzheimer's disease is a very common cause of progressive mental decline (dementia) in the elderly and is considered the fourth leading cause of death in the United States. Alzheimer's disease has been observed in various racial and ethnic groups worldwide and represents one of the most serious current and future public health problems. It is estimated that the disease currently affects two to three million people in the United States alone. Alzheimer's disease is currently incurable. There is currently no known treatment that effectively prevents Alzheimer's disease or reduces its symptoms.

The brains of people with Alzheimer's disease exhibit characteristic lesions called senile (or amyloid) plaques, amyloid angiopathy (amyloid deposited in blood vessels), and neurofibrillary tangles. In patients with Alzheimer's disease, large numbers of these lesions, especially amyloid plaques and neurofibrillary tangles, are generally found in a number of areas of the human brain that are important for memory and cognitive functions. Smaller numbers of these lesions with a more restricted anatomical distribution are also found in the brains of most elderly people who do not have clinical Alzheimer's disease. Amyloid plaques and amyloid angiopathy also characterize the brains of people with Trisomy 21 (Down syndrome) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). Currently, a definitive diagnosis of Alzheimer's disease usually requires observation of the above lesions in brain tissue from patients who have died from the disease or, less commonly, in small biopsy samples of brain tissue taken during an invasive neurosurgical procedure.

The basic chemical component of amyloid plaques and vascular amyloid deposits (amyloid angiopathy), characteristic of Alzheimer's disease and the other disorders mentioned above, is a protein with a molecular weight of approximately 4.2 kilodaltons (kD) consisting of about 39-43 amino acids, which is referred to as β-amyloid peptide (βΑΡ) or sometimes

Aβ, AβΡ or β/Α4. The β-amyloid peptide was first purified and its partial amino acid sequence was determined by Glenner et al. ¹ The isolation method and sequence data for the first 28 amino acids are described in US Patent No. 4,666,829 ² .

Molecular biological and protein chemical analyses have shown that the β-amyloid peptide is a small fragment of a much larger precursor protein (APP), which is normally produced by cells in many tissues of various animals, including humans. Knowledge of the structure of the APP gene code has shown that the β-amyloid peptide arises as a peptide segment that is cleaved from APP by a protease enzyme or enzymes. The precise biochemical mechanism by which the β-amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in brain tissue and in

4 4 4 • 4 · · ► 4 4 4 4 •4 444 444 the walls of cerebral and meningeal blood vessels, is currently unknown.

A growing body of evidence suggests that cerebral deposition of β-amyloid peptide plays a central role in the pathogenesis of Alzheimer's disease and may precede cognitive symptoms by years or decades, see for example Selkoe ³ . The most important piece of evidence is the discovery that a missense DNA mutation at amino acid 717 of the 770-amino acid isoform of APP can be found in affected but not unaffected members of a number of families with a genetically determined (familial) form of Alzheimer's disease (Goate et al. ⁴ ; Chartier-Harlan et al. ⁵ ; and Murrell et al. ⁶ ) and is referred to as the Swedish variant. A double mutation, consisting of a lysine-methionine to asparagine leucine ⁵⁹⁶ mutation (referring to isoform 695) and found in a Swedish family, was described in 1992 (Mullan et al. ⁷ ). Genetic linkage analyses have shown that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of Alzheimer's disease in affected members of such families. In addition, mutations at amino acid 693 in the 770-amino acid isoform of APP have been identified as a cause of the disease, involving the deposition of the β-amyloid peptide, HCHWA-D, and an alanine to glycine change at amino acid 692 appears to cause a phenotype that resembles Alzheimer's disease in some patients but HCHWA-D in others. The discovery of these and other APP mutations in genetically determined cases of Alzheimer's disease provides evidence that alteration of APP and subsequent deposition of a β-amyloid peptide fragment can cause Alzheimer's disease. ^I

Despite the progress that has been made in understanding the mechanism underlying Alzheimer's disease and other diseases associated with β-amyloid peptide, there remains a need to develop methods and compositions for treating the disease or diseases. Ideally, the methods of treatment would be based on agents that are capable of inhibiting the release of β-amyloid peptide and/or its synthesis in vivo.

Subject matter of the invention

The present invention relates to the discovery of a class of compounds which inhibit the release of β-amyloid peptide and/or its synthesis and are therefore useful in the prevention of Alzheimer's disease in patients susceptible to Alzheimer's disease and/or in the treatment of patients suffering from Alzheimer's disease with the aim of inhibiting further deterioration of their condition. The class of compounds having the above properties is defined by the general formula I:

'1 wherein R' is alkenyl, alkynyl, selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic system;

R ² is selected from the group consisting of hydrogen, alkyl, ♦ ·

substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic system;

each R ³ is independently selected from the group consisting of hydrogen and methyl, and R ³ together with R ⁴ may be joined to form a cyclic structure containing from 3 to 8 atoms, which is optionally fused with an aryl or heteroaryl group;

each R ⁴ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic system, substituted alkyl, substituted alkenyl and substituted alkynyl;

each R ⁵ is selected from the group consisting of hydrogen and methyl or together with R ⁴ forms a cycloalkyl group containing from 3 to 6 carbon atoms;

X is selected from the group consisting of -C(O)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 does not include α-haloalkyl, adiazoalkyl, α-OC(0)alkyl, or α-OC(0)aryl, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic system, (i) -NR'R”, where R' and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, • ·· ·· ·»· ·· *· · ······· ·· ·· ·· ·· ·· substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic system, where one of R' or R is hydroxy or alkoxy and where R' and R are joined together to form a cyclic group having from 2 to 8 carbon atoms, optionally containing 1 to 2 further heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups, (j) -NHSO ₂ -R ⁸ , where R ⁸ is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic system, (k) -NR ⁹ NR ¹⁰ R ¹⁰ , where R ⁹ represents a hydrogen atom or alkyl and each R ¹⁰ is independently selected from the group consisting of hydrogen atom, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic system, and (l) -ONR ⁹ [C (0) 0] _Z R ¹⁰ , where z is zero or one and R ⁹ and R ¹⁰ have the meaning defined above;

X can also be -CR ⁶ R ⁶ Y', where each R ⁶ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic system groups and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -OC(O)R ⁷ , -SSR ⁷ , -SSC(O)R ⁷ , where R ⁷ is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic system groups,

X' represents a hydrogen atom, hydroxy, or fluorine;

X represents a hydrogen, hydroxy, or fluorine atom or X' and X • to ···· ·· ·· ··· ₉ · ··· ·

Z is selected from the group consisting of a covalent bond that binds R ¹ to -CX'X-, an oxygen atom, and a sulfur atom; n is an integer that is equal to 1 or 2; and pharmaceutically acceptable salts thereof with the proviso that:

A. if R ¹ represents phenyl or 3-nitrophenyl, R ² represents methyl, R ³ represents hydrogen, R ⁴ represents -CH(OH)CH 3 , R ⁵ represents hydrogen, X' and X represent hydrogen, Z represents a bond and n is equal to 1, then X does not represent -C(O)OH;

B. if R ¹ represents phenyl, R ² represents methyl, R ³ represents hydrogen, R ⁴ represents -CH(OH)CH3 derived from D-threonine, R ⁵ represents hydrogen, X' and X represent hydrogen, Z represents a bond and n is equal to 1, then X does not represent -C(O)OH or -C(O)OCH3;

C. if R ¹ represents phenyl, R ² represents methyl, R ⁴ represents benzyl, R ⁵ represents hydrogen, X is methoxycarbonyl, X ¹ and X 2 represent hydrogen, Z represents a bond and n is equal to 1, then R ³ does not represent methyl;

D. if R ¹ represents iso-propyl, R ² represents CH 2 C(O)NH 2 , R ³ represents hydrogen, R ⁴ represents isobutyl, R ⁵ represents hydrogen, X' and X represent hydrogen, Z represents a bond and n is equal to 1, then X does not represent -C(O)OCH 3 ;

E. if R ¹ represents phenyl, R ² represents methyl, R ⁵ represents a hydrogen atom, X is -C(O)OCH ₃ , X' and X represent a hydrogen atom, Z represents a bond and n is equal to 1, then R ³ , the nitrogen atom, bonded to R ³ and R ⁴ do not form 1,2,3,4-tetrahydroisoquinolin-2-yl or pyrrolidin-2-yl;

·· ···· • · • 999

- 11 99 99

9 9 9

9 9 9

9 99 99 9

9 9 » 99 99

F. if R ¹ represents phenyl, R ² represents methyl, R ³ represents hydrogen, R ⁵ represents hydrogen, X is C(O)OCH ₃ , X' and X represent hydrogen, Z represents a bond and n is equal to 1, then R ⁴ does not represent 4-amino-n-butyl;

G. if R ¹ represents 3-nitrophenyl, R ² represents methyl, R ³ represents hydrogen, R ⁴ represents CH(OH)CH 3 , R ⁵ represents hydrogen, X' and X represent hydrogen, Z represents a bond and n is equal to 1, then X does not represent -C(O)NH ₂ or -CH ₂ OH;

H. if R ¹ represents phenyl, R ² represents methyl, R ³ represents hydrogen, R ⁵ represents hydrogen, X is CH 2 OCH 3 , X' and X represent hydrogen, Z represents a bond and n is 1, then R ⁴ does not represent benzyl or ethyl;

I. if R ¹ represents 3,5-difluorophenyl, R ² represents methyl, R ³ represents methyl, R ⁴ represents methyl, R ⁵ represents hydrogen, X' and X represent hydrogen, Z represents a bond and n is equal to 1, then X does not represent -CHOH0;

J. when R ¹ represents 3,5-difluorophenyl, R ² represents methyl, R ³ represents hydrogen, R ⁴ represents phenyl c

derived from D-phenylglycine, R represents a hydrogen atom, X' and X represent a hydrogen atom, Z represents a bond and n is equal to 1, then X does not represent -CHOH<I> or -CH ₂ OH;

K. if R ¹ represents N-(2-pyrrolidinonyl), R ² represents methyl, R ³ represents hydrogen, R ⁴ represents benzyl, R ⁵ represents hydrogen, X' and X represent hydrogen, Z represents a bond and n is equal to 1, then X does not represent -C(O)OCH ₃ ;

L. if R ¹ represents 3,5-difluorophenyl, R ² represents methyl derived from D-alanine, R ³ represents a hydrogen atom, • Φ φφφφ

··· φφφ φφ φφ • · · φ φ · • φ φ φ φ · • · φφ ··

R ⁴ represents phenyl derived from D-phenylglycine, R ⁵ represents a hydrogen atom, X' and X represent a hydrogen atom, Z represents a bond and n is equal to 1, then X does not represent -C(O)NH-benzyl;

M. if R ¹ represents 3,5-difluorophenyl, R ² represents methyl, R ³ represents hydrogen, R ⁴ represents hydrogen, R ⁵ represents hydrogen, X' and X represent hydrogen, Z represents a bond and n is equal to 1, then X does not represent -CH ₂ OH;

N. if R ¹ represents 3,5-difluorophenyl, R ² represents methyl, R ³ represents hydrogen, R ⁴ represents 4-phenylphenyl, R ⁵ represents hydrogen, X' and X” represent hydrogen, Z represents a bond and n is equal to 1, then X does not represent -C(O)NHC(CH3)3; and

O. if R ¹ represents 3,5-difluorophenyl, R ² represents methyl, R ³ represents a hydrogen atom, R ⁴ represents phenyl derived from D-phenylglycine, R ⁵ represents a hydrogen atom, X' and X represent a hydrogen atom, Z represents a bond and n is equal to 1, then X does not represent -C(0)NHCH(CH ₃ ) Φ.

Preferably, the compounds of the present invention are derived from L-amino acids and are accordingly represented by the general formula IA:

•· ftft·· • · • ···

- 13 • · · · • · · · · • · ·· ·

One object of the present invention is a method of inhibiting the release and/or synthesis of β-amyloid peptide in a cell, which comprises administering to the cell a dose of a compound or mixture of compounds of general formula I as set forth above in an amount effective to inhibit the cellular release and/or synthesis of β-amyloid peptide.

Since the in vivo formation of β-amyloid peptide is associated with the pathogenesis of Alzheimer's disease, the compounds of formula I can also be used together with pharmaceutical compositions for prophylaxis and/or therapy in the prevention and/or treatment of Alzheimer's disease. Accordingly, another object of the present invention is a method of prophylaxis for preventing the onset of Alzheimer's disease in a patient at risk of developing Alzheimer's disease, which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or mixture of compounds of formula I as defined above.

Another object of the present invention is a method of treating a patient suffering from Alzheimer's disease with the aim of inhibiting further deterioration of the patient's condition, which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or mixture of compounds of general formula I as defined above.

Compounds suitable for use in the present invention include, by way of example only, the following compounds:

·· ·· • · · · • · · ·

- 14 ·· «··· «· » · ft * · » * · · • · ··· • · · • Μ · ·· ··· methyl ester Ν-[Ν-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2aminohexanoate methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-histidine

N-benzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]— (S) — 2 — aminohexanamide

N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-(S)-2-aminohexanamide

N-(2-Methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-(S)-2-aminohexanamide

N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-L-phenylalanine amide

N-(4-pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalanine amide

N-(3-pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalanine amide

N-(4-pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-(S)-2-aminohexanamide tert-butyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-aminohexanoate ··»·

0 • ·00

00

0 · · • · · ·

000 000 0 0 ♦ 0 ·· Ν-[Ν-(pent-4-enoyl)-L-alaninyl]-L-phenylalanine methyl ester Ν-[Ν-(dec-4-enoyl)-L-alaninyl]-L-phenylalanine methyl ester Ν-[Ν-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4[3-(N,N-dimethylamino)propoxy]phenylalanine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4[(tert-butyloxycarbonyl)methoxy]phenylalanine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Ltyrosine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4(2-morpholinoethoxy)phenylalanine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2amino-6-(N,N-dimethylamino)hexanoate methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]- (S)-2amino-3-(3-pyridyl)propionate methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Lproline methyl ester

- 16 ·· • · ···· 1-[Ν-(3,5-difluorophenylacetyl)-Lalaninyl]piperidine-2-carboxylate methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2amino-3-(4-pyridyl)propionate methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-3-morpholinopropionate

N-(2-Methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-4-(2-morpholinoethoxy)phenylalanineamide

N-(2-Methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-2-amino-3-methoxypropionamide methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine

N-(2-methoxyethyl)-Ν' -[N-(3,5-difluorophenylacetyl)-Lalaninyl]-2-amino-3-(4-pyridyl)propionamide

N-(2-Methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-2-amino-3-(2-pyridyl)propionamide methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2amino-3-(thiazol-4-yl)propionate methyl ester 2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]1,2,3,4-tetrahydroisoquinoline-3-carboxylate «· *· # 1 · · • r · ·

I o * 1 t

- 17 • ·· ···· ·» · * · · <

19· *>·» • · 9 1 9 · ·

9 · 1 1 ·«····· »» ♦··

N-(3-Methoxybenzyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalaninamide methyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2amino-3-(1-naphthyl)propionate methyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2amino-3-(2-thienyl)propionate benzyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine

N-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalanine 3-bromopropyl ester

N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-phenylalanine tert-butyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-leucine 3-iodopropyl ester

N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2pyridyl)acetamide

Ν' -[N-(3, 5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3pyridyl)acetamide • · · · · · • 9

- 18 • · • · · · · to • ··· · · · · • ·· ··· ··· • to N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N(tert-butoxycarbonyl)-L-lysine methyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]—(S)—2— amino-4-phenylbutanoate ethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine

2-phenyl

N-[N-(3,5-difluorophenylacetyl)-Lalaninyl]glycine 3-phenylpropyl ester

Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4pyridyl)acetamide N-[N-(phenylacetyl)-L-alaninyl]-L-threonine methyl ester

N'-[N-(phenylacetyl)-L-alaninyl]-L-leucinamide

Ν' -[N-(phenylacetyl)-L-alaninyl]-L-alaninamide

Ν' -[N-(phenylacetyl)-L-alaninyl]-L-phenylalanine amide

N'-[N-(phenylacetyl)-L-alaninyl]-L-valinamide ethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(3-pyridyl)acetate

N-methyl-N'-[N-(phenylacetyl)-L-alaninyl]-L-leucinamide

N,N-dimethyl-N'-[N-(phenylacetyl)-L-alaninyl]-L- 19 • · ··· ··· phenylalanine amide

N,N-dimethyl-N'-[N-(phenylacetyl)-L-alaninyl]-L-leucinamide

N,N-dimethyl-N'-[N-(phenylacetyl)-L-alaninyl]-L-valinamide

N-methyl-N'-[N-(phenylacetyl)-L-alaninyl]-L-phenylalanine amide

N-Methyl-N'-[N-(Phenylacetyl)-L-Alaninyl]-L-Valinamide

N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2aminohexanamide

N,N-dimethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S) 2-aminohexanamide

N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2aminohexanamide methyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(3-methoxyphenyl)acetate methyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(4-methoxyphenyl)acetate ethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(2-pyridyl)acetate ethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(4-pyridyl)acetate • to ·« » toto 4 • · · · · to

- 20 methyl ester Ν-[N-(cyclohexylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

N-2-(N,N-dimethylamino)ethyl-N-methyl-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-alaninamide methyl ester Ν-[N-(cyclopropylacetyl)-L-alaninyl]-Lphenylalanine benzyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine ethyl ester Ν-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine methyl ester Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-Lphenylalanine ethyl ester Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-alanine ethyl ester Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]glycine

N-hydroxy-N'-[N-(3-nitrophenylacetyl)-L-alaninyl]-D,Lthreoninamide • flflfl • · flflfl fl··· • · ···· · flfl · • flfl fl flfl ····· • flflfl flfl ····· flfl flflfl ·· · · iso-butyl ester Ν-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine methyl ester Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-2-amino-3(3-hydroxyphenyl)propionate ethyl ester Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-tyrosine iso-butyl ester Ν-[N-(isovaleryl)-L-isoleucinyl]-L-alanine iso-butyl ester Ν-[Ν-[N-(isovaleryl)-L-valinyl]-L-phenylglycinyl]-L-alanine iso-butyl ester Ν-[N-(isovaleryl)-L-phenylalanine]-L-alanine ethyl ester

Ν'-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]-L-Alaninamide

N-methoxy-N-methyl-N'-[N-(isovaleryl)-L-phenylglycinyl]-Lalaninamide

N-iso-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Lalaninamide

N,N-di-n-propyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-alanine amide

- 22 • « · · • 9 9 9 9

9 9999

9 9 · « • · · « • · · 9 9 9 9 99

N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valinamide

N-(4-nitrophenyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-alanine amide

N'-[N-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-phenylalanine amide N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine amide

N-iso-butyl-N'—[N-(isovaleryl)-L-phenylglycinyl]-L-alanine amide

N-(2-methoxyethyl)-Ν' -[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalanine amide

N-(4-nitrobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

N-(4-nitrophenyl)-N'-[N-[N-(isovaleryl)-L-phenylglycinyl]-Lalaninyl]-L-alanine amide

N-(4-nitrophenyl)-Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninylΙΕ-phenylalanine amide

N-benzyl-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

- 23 » · · · » • 4» ·

Ν-(3,5-Difluorobenzyl)-Ν' -[Ν-(3,5-Difluorophenylacetyl)-Lalaninyl]-L-Alaninamide

Ν-(3-nitrobenzyl)-Ν' -[Ν-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

N-benzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-lalaninamide

N-(4-nitrobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalaninamide methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophan

N-(4-methoxybenzyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alaninamide ethyl ester Ν-[N-(phenylacetyl)-L-phenylglycinyl]-L-alanine methyl ester Ν-[Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine]-L-phenylglycine ethyl ester Ν-[N-(cyclohexylacetyl)-L-phenylglycinyl]-Lalanine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine methyl ester

- 24 ft ·· ftft ftftftft ftft ftft • · · * ftftft ftftft· • · ftft··· ftftftft • · ftft · ftft ······ ftft ftftft ftft ······· ftft ftftft ftft ftft

N-(2-Phenylethyl)-N'-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]L-Alaninamide

Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophanamide methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2amino-3-cyclohexylpropionate

N-(2-Methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-(S)-2-amino-3-(4-nitrophenyl)propionamide ethyl ester Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-serine

N-[(R)-α-methylbenzyl]-Ν' -[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

N-[(S)-α-methylbenzyl]-Ν' -[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

N-(4-fluorobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

N -(4-pyridylmethyl)-Ν' -[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

N-(4-trifluoromethylbenzyl)-Ν' -[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alaninamide ethyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-phenylpropionate • ·

- 25 tert-butyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-phenylalanine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-methylpropionate ethyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-cyclohexylacetate

N-(2-Methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylglycinamide ethyl ester Ν-[N-(isovaleryl)-2-amino-2-cyclohexylacetyl]-Lalanine

N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-L-phenylglycinamide

N-(2-pyridylmethyl)-Ν' -[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylglycinamide methyl ester Ν-[N-(3-pyridylacetyl)-L-alaninyl]-Lphenylalanine methyl ester

- 26 • ·· ·»···· ·· 99

9 9 9 9 9 9 9 9 9

9 9 9 999 9 9 9 9

9 9 9 9 99 999999

9 9 9 9 9 9

9999999 99 999 99 99 Ν-[Ν-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(4-fluorophenyl)acetate ethyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(2-fluorophenyl)acetate ethyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-Lalanine ethyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-3-phthalimidopropionate neopentyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide tert-butyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-phenylglycine

N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

4-[Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valinyl]morpholine ethyl ester Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine methyl ester Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-Lthreonine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-299 9999 • ·

- 27 99 99

9 9 9

9 9 9

999 9*9

999 9999 99 999 ♦· 99 aminopentanoate

4-[Ν-[Ν-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-amino-3-tert.-butoxybutyryl]morpholine

4-[Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-Lisoleucinyl]morpholine methyl ester Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-Lisoleucine

Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine ethyl ester Ν-[Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threoninyl]-L-valine methyl ester Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2aminopentanoate methyl ester Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-leucine methyl ester Ν-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]-Lleucine

N-2-Methoxyethyl-N'-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]L-Alaninamide

N-2-(N,N-Dimethylamino)ethyl-N'-[N-(3,5-Difluorophenylacetyl)L-Alaninyl]-L-Alaninamide

N-Cyclohexyl-N'-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]-L94

4

- 28 φ ·« φ» φφφφ φ φ φφφ φ φ φφφφ φφφφ φ φ φφφ φφφφ φφ φφφ φφφ

ΦΦΦ

Φ

Φ Φ alaninamide

N-Neopentyl-N'-[Ν-(3,5-Difluorophenylacetyl)-L-Alaninyl]-Lalaninamide

N-tetrahydrofurfuryl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

N-2-pyridylmethyl-N ¹ -[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

3-[Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Lalaninyl]thiazolidine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2aminobutanoate methyl ester Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2aminobutanoate

N-(R)-sec-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-alanine amide

1-[Ν-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]-Lalaninyl]pyrrolidine

N-(S)-sec-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-alaninamide methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Lva1inu

- 29 • · » 99 999· 9 9 9 9 • 9 9 9 9 9 9 9 9 9 ·

9 9 9 999 9 9 9 9

9 9 9 9 99 999999

9 9 9 9 9 9

999 9999 99 999 99 99

N-2-fluoroethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Lalaninamide

N-[(S)-6-methyl-3-oxohept-2-yl]-Ν'-(3,5-difluorophenylacetyl)L-alanine amide

N-4-nitrobenzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-aminobutyramide

N-4-nitrobenzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-aminopentanamide methyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(3-fluorophenyl)acetate

N' - [N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2thienyl)acetamide methyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(5-chlorobenzothiophen-2-yl)acetate ethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(benzothiophen-2-yl)acetate methyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(benzothiophen-3-yl)acetate methyl ester

- 30 • ·· 4· ···* ·· ·· • · 9 · ··· 9 9 9·

9 9 9 999 9 9 9 9 · * · · ·♦ 999·99

9 9 ·9 9 9

999 9999 ·9 999 99 99 Ν-[Ν-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(benzothiophen-5-yl)acetate methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2amino-2-(2-thienyl)acetate tert-butyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-amino-2-(2-thienyl)acetate

Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2thienyl)acetic acid methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2amino-2-(6-methoxy-2-naphthyl)acetate methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(3-trifluoromethylphenyl)acetate methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetate methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(thieno[2,3-b]thiophen-2-yl)acetate methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(2-methylthiazol-4-yl)acetate methyl ester (3 S,4 S)-Ν-[N-(3,5-difluorophenylacetyl)-L- 31 • ·· « · • · • · »·· to··· • to «tototo • toto·· • to · ·· to ·· ··♦ • to «to • ·· · • ·· · ··· · ·· • « alaninyl]-4-amino-3-hydroxy-5-phenylpentanoate methyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2aminohex-4-enoate tert-butyl ester N-[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylglycine

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-amino-2-(4-phenylphenyl)acetamide tert-butyl ester N-[N-(3,5-difluorophenylacetyl)-(S)-2aminobutanoyl]-L-phenylglycine tert-butyl ester N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine methyl ester N-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-Lphenylglycine methyl ester N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-Lphenylglycine methyl ester N-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]L-phenylglycine methyl ester N-[N-(3,5-difluorophenylacetyl)-L-leucinyl]-Lphenylglycine methyl ester of N-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]L-phenylglycine

00

0 0 0

0 0 0

000 000

0

- 32 • 0 • ·· • · · 0 • 0 • 0 0 0

0 0 000

0000 0 0 0 000 0 0 • 0 0

000 methyl ester N-phenylglycine methyl ester NL-phenylglycine methyl ester N-[N methyl ester N-[N methyl ester N-[N methyl ester N-[N methyl ester N-[N methyl ester N-[N butoxycarbonyl)methyl ester N-[N methyl ester N-[N methyl ester N-[N aminobutanoate methyl ester N-[N aminopentanoate [-(3,5-difluorophenylacetyl)glycinyl]-L ^[ -(3,5-difluorophenylacetyl)-L-phenylglycinyl]-(phenylacetyl)-L-alaninyl]-L-alanine

-(phenylacetyl)-L-alaninyl]-L-leucine

-(phenylacetyl)-L-alaninyl]-L-isoleucine

-(phenylacetyl)-L-alaninyl]-L-proline

-(phenylacetyl)-L-alaninyl]-L-phenylalanine

-(phenylacetyl)-L-alaninyl]-N-(tert.L-lysine

-(phenylacetyl)-L-alaninyl]-glycine

-(phenylacetyl)-L-alaninyl]-L-valine

-(phenylacetyl)-L-alaninyl]-(S)-2-(phenylacetyl)-L-alaninyl]-(S)-2N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ·· • 0 * 0 • · 0 ·

000 000 • 0

- 33 • 0 0 0 0 • · • 0 00 methyl ester Ν-[Ν-(phenylacetyl)-L-alaninyl]-L-N-methylalanine iso-butyl ester Ν-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine iso-butyl ester Ν-[N-(isovaleryl)-L-isoleucinyl]-L-alanine

N-cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide ethyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4hydroxyproline methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-lysine

Ν-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]-L-Glutamide 1-[N-(3,5-Difluorophenylacetyl)-Lalaninyl]piperidine-2-carboxylate methyl ester

N-[(S)-3-hydroxy-6-methylhept-2-yl]-Ν' -(3,5difluorophenylacetyl)-L-alanine amide

N-[(S)-2-hydroxy-l-phenyleth-l-yl]-N ¹ -(3,5difluorophenylacetyl)-L-alaninamide tert-butyl ester Ν-[N-(3,5-difluorophenyl-a-fluoroacetyl)-Lalaninyl]-L-phenylglycine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-2-(S)- 34 • · • ···· ► ···< • · • flflfl • fl fl· » · · ·

I · · · ··· ··· • · • fl · · aminocyclohexylacetyl]-L-phenylglycine

N-[(IR,2S)-1-hydroxy-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide

N-[(IR, 2S)-1-hydroxy-1,2-diphenyleth-2-yl]-N'-(3,5difluorophenylacetyl)-L-alanine amide

N-[(1S,2R)-1-hydroxy-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide

N-2-methoxyethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycinamide

N-[(S)-α-hydroxy-cc-phenyl-iso-propyl]-N'-(3,5difluorophenylacetyl)-L-alanine amide

N-[(S)-2-hydroxy-1,2-diphenylethyl]-N'-(3,5difluorophenylacetyl)-L-alanine amide

N-[(S)-1-hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-lalaninamide

N-[α-hydroxy-o-(4-hydroxyphenyl)-iso-propyl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide

N-2-pyridylmethyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalanine amide

N-[α-hydroxy-α'-pyrid-2-yl-iso-propyl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide

- 35 • · · this · this · · ·· · · ·· this this· ··· ·· this • · · 9 • · · · ·· · ··· • · ·· ··

N-[α-hydroxy-α'-pyrid-4-yl-iso-propyl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide

N-[(S)-1-hydroxy-4-methylpent-2-yl]-N'-(3,5difluorophenylacetyl)-L-alanine amide

N-[α-methoxy-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-Lalaninamide

Ν-[1-hydroxy-3-methyl-but-2-yl]-N'-(3,5-difluorophenylacetyl)L-alaninamide methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(6-aminopyrid-2-yl)acetate

N-[1-hydroxy-prop-2-yl]-Ν'-(3,5-difluorophenylacetyl)-Lalaninamide

N-[(S)-2-methoxy-1-phenyleth-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide

N-[(S)-1-methoxy-2-phenyl-prop-2-yl]-Ν'-(3,5-difluorophenylacetyl)-L-alanine amide

N-[(S)-1-acetoxyhex-2-yl]-Ν'-(3,5-difluorophenylacetyl)-Lalaninamide

N-[(S)-1-(tert-butylcarbonyloxy)-hex-2-yl]-Ν'-(3,5-difluorophenylacetyl)-L-alanine amide

• ·

N-[2-hydroxy-1-(thien-2-yl)ethyl]—Ν'—(3,5-difluorophenylacetyl)-L-alanine amide

N-[(S)-2-hydroxy-2-methyl-1-phenylprop-1-yl]-N'-(3,5difluorophenylacetyl)-L-alanine amide tert-butyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-(thien-2yl)glycinyl]-L-phenylalanine

Ν-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinol

Ν-[N-(cyclopropaneacetyl)-L-phenylglycinyl]-L-phenylglycinol

Ν-[N-(cyclopentaneacetyl)-L-phenylglycinyl]-L-phenylglycinol

Ν-[N-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]-Donated lglycinamide

Ν- [N-(3,5-difluorophenylacetyl)-D,L-val inyl] - Donated lglyc i amide

Ν-[N-(2-thienylacetyl)-L-alaninyl]-L-phenylglycinamide

Ν-[N-(n-caprotyl)-L-alaninyl]-L-phenylglycinamide methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-norleucinyl]-Lphenylglycine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-Lphenylglycine

- 37 • ··

9 9 • · • · • · * · · · « ♦ · ·· ♦··»

9 9 999 • 9 9

9 · ·· ··· »· ··

9 9 « • · 9 9

999 999 • · «· ·4 methyl ester Ν-[Ν-(3,5-difluorophenylacetyl)-L-tert.-leucinyl]L-phenylglycine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-isoleucinyl]-Lphenylglycine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2(cyclopropyl)acetyl]-L-phenylglycine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2(thien-3-yl)acetyl]-L-phenylglycine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-(4fluorophenyl)glycinyl]-L-phenylglycine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-D-(4fluorophenyl)glycinyl]-L-phenylglycine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-(4methoxyphenyl)glycinyl]-L-phenylglycine tert-butyl ester Ν-[N-(3,5-difluorophenylacetyl)-Lphenylglycinyl]-L-phenylglycine • flfl • fl · i • · • · * • · • flfl flflflfl • fl flflflfl • · fl fl flflflfl • · · • · · ·> flflfl • fl ·* • · · · • flfl · • flflfl flflfl • · flfl flfl tert-butyl ester N-[N-(cyclopropylacetyl)-L-phenylglycinyl]L-phenylglycine tert-butyl ester N-[N-(cyclopentylacetyl)-L-phenylglycinyl]L-phenylglycine

N-[N-(tert-Butylacetyl)-L-Alaninyl]-L-Phenylglycinamide

N-tert-butyl-Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L(5-bromothien-2-yl)glycinamide

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D(5-bromothien-2-yl)glycinamide

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L(4-bromothien-2-yl)glycinamide

N-tert-butyl-Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L(thien-2-yl)glycinamide

N-tert-butyl-Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D(thien-2-yl)glycinamide

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L(thien-3-yl)glycinamide

N-tert-butyl-Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D(thien-2-yl)glycinamide

N-tert.-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Dphenylglycinamide • φ

- 39 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]D,L-(5-chlorothien-2-yl)glycinamide

N-cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-4 (phenyl)phenylglycinamide

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L3-(phenoxy)phenylglycinamide

N-(S)-(-)-α-methylbenzyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L3-(phenyl)phenylglycinamide

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-(ethyl)phenylglycinamide

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L2-(phenyl)phenylglycinamide

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L2-(benzyl)phenylglycinamide

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]D,L-4-bromophenylglycinamide

N-tert-butyl-N'-[Ν-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-(cyclohexyl)phenylglycinamide

N-tert-butyl-Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-(4-ethylphenyl)phenylglycinamide

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]D,L-4-(tert-butyl)phenylglycinamide

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]D,L-3-(4-chlorophenoxy)phenylglycinamide

N-cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4(phenyl)phenylglycinamide tert-butyl ester Ν-[N-(3,5-difluorophenyl-α-hydroxyacetyl)-Lalaninyl]-L-phenylglycine

N-tert-butyl-N'-[N-(3,5-difluorophenyl-α,α-difluoroacetyl)-Lalaninyl]-L-phenylglycinamide tert-butyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]D-phenylglycine

N-[(S)-1-oxo-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)L-alaninamide tert-butyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]D,L-(pyrid-3-yl)glycine [Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]morpholine methyl ester N-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]-D,L(2-Methoxy)phenylglycine

N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine N-tert.-butoxycarbonyl(hydroxylamine) ester

N-neopentyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D, L-phenylglycinamide

N-tetrahydrofurfuryl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

N-methoxy-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,Lphenylglycinamide [N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,Lphenylglycinyl]azetidine

N-iso-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Donated lglycinamide

N-cyclopropanemethyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

N-methoxy-N-methyl-N ¹ -[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

N-2-methylprop-2-enyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

Ν-(pyrid-3-yl)methyl-N'-[Ν-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

N-(pyrid-4-yl)methyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

N-furfuryl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,Lphenylglycinamide

N-cyclopentyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]D,L-phenylglycinamide

N-1-Benzylpiperidin-4-yl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

N,N-dimethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

N-2,2,6,6-tetramethylpiperidin-4-yl-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

N-2-methylcyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

N-4-methylcyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

N-1-ethoxycarbonylpiperidin-4-yl-N'—[N—(3,5—difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide • φ φ φ » Φ Φ 1 » Φ Φ 1

- 43 N-methyl-N'-[Ν-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

N-tert-butoxy-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]D,L-phenylglycinamide

N-tert-butyl(hydroxylamine) ester N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine hydrazide Ν-[N-(phenylacetyl)-L-alaninyl]-L-phenylglycine tert-butyl ester

N-4-(phenyl)butyl-Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-phenylglycinamide

N-3-(4-iodophenoxy)propyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylglycinamide hydrochloride N-6-(amino)hexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

N-1-(phthalimido)pent-2-yl-N'-(3,5-difluorophenylacetyl)-Lalaninamide methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-(3,5- 44 ·· difluorophenyl)glycinyl]-L-(3,5-difluorophenyl)glycine

Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-norleucine tert-butyl ester Ν-[N-(cyclopentaneacetyl)-L-alaninyl]-Lphenylglycine iso-propyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-fluorophenylglycine

N-(isopropyl) N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Lphenylglycinamide tert-butyl ester Ν-[N-(cyclopentylacetyl)-L-alaninyl]-Lphenylalanine tert-butyl ester Ν-[N-(cyclopropylacetyl)-L-alaninyl]-Lphenylalanine iso-butyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Lphenylglycine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Dphenylglycine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(3a-phenyl)proline methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Lazetidine

··· · • 4 44

4 4 4

4 · 4 • 4 • 444 • 4 444 · ·· Ν-[Ν-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-3-(5-chlorobenzothiophen-2-yl)acetate tert-butyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-amino-3-(thiazol-4-yl)propionate tert-butyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-phenylglycinamide

Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2yl)glycinamide

Ν-[N-(3,4-dichlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide

Ν-[N-(3-Chlorophenylacetyl)-L-Alaninyl]-D-Phenylglycinamide

Ν-[N-(3-bromophenylacetyl)-L-alaninyl]-D-phenylglycinamide

Ν-[N-(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide

Ν-[N-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide

Ν-[N-(3-Methylphenylacetyl)-L-Alaninyl]-D-Phenylglycinamide

Ν-[N-(4-Methylphenylacetyl)-L-Alaninyl]-D-Phenylglycinamide

Ν-[N-(3-trifluoromethylphenylacetyl)-L-alaninyl]-Dphenylglycinamide

Ν-[N-(3-Methoxyphenylacetyl)-L-Alaninyl]-D-Phenylglycinamide

-46• ·· 999999 99

9999 999 9999

9 99999 9999

9 9 · 9 99 999999

9 9 9 9 9 9

999 9999 99 ·'· 99 99

Ν-[N-(2-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide

Ν-[Ν-(1-Naphthylacetyl)-L-Alaninyl]-D-Phenylglycinamide

Ν-[N-(2-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide

Ν-[N-(phenylacetyl)-L-alaninyl]-D-phenylglycinamide

Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine

Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide

Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2furanyl)acetamide

N ¹ -[N-(3,5-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide

N'-[N-(3,4-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide

N'-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]-L-Phenylalanine-N-Methylsulfonamide

N-methyl-N-phenyl-N'-[N-(3,5-difluorophenylacetyl)-Laianinyi]-glycinamide

N-methyl-N-phenyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

N[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinamide

- 47 • ft ···· · · ·· • · ftftftft ···· · ftft · ft ftft ftftft ftftft • ftft ftft • ft ··· «· ftft ft · • ••ftft

N-methyl-N-benzyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-glycinamide

N-4-fluorobenzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-phenylglycinamide neopentyl ester Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L(4-fluoro)phenylglycine methyl ester N-[N-(2,3,4,5,6-pentafluorophenylacetyl)-Lalaninyl]-L-(pyrid-3-yl)glycine tert-butyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-(pyrid-3-yl)glycine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-(0-benzyl)serinyl]-L-phenylglycine methyl ester Ν-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-L-phenylglycine Ν-[N-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine methyl ester

N-4-methylphenyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-phenylglycinamide

N-tetrahydrofurfuryl-N'-[N-(3,5-difluorophenylacetyl)-L• · ·

- 48 ·♦ ·· • 9 9 9

9 9 9

9 99 999 ···· alaninyl]-L-phenylglycinamide

Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycinamide

Ν' -[N-(3,5-difluorophenylacetyl)-L-methionyl]-L-phenylglycinamide

N-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamide

Ν' -[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinamide

N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinamide

N-[(R)-α-methylbenzyl]-Ν' -[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylglycinamide

N-[l-phenyl-2-oxo-3-methylbutan-1-yl]—Ν'—(3,5-difluorophenylacetyl)-L-alanine amide

N-[l-phenyl-2-oxo-propan-l-yl]-N'-(3,5-difluorophenylacetyl)-Lalaninamide

N-[l-phenyl-2-oxo-pentan-l-yl]-Ν'-(3,5-difluorophenylacetyl)-Lalaninamide

N-[l-phenyl-2-oxo-2-phenyl-ethan-1-yl]-Ν'-(3,5-difluorophenylacetyl)-L-alanine amide

- 49 • 0 00 0000 00 00 ·· 000 0000

0 0000 0 00 0 00 0 00 000000

0 0 0 0 0 0000 00 00 00 00

Ν-[1-phenyl-2-oxo-butan-1-yl]-N'-(3,5-difluorophenyl-acetyl)-Lalaninamide

N-[l-phenyl-2-oxo-4-methylpentan-l-yl]-Ν' -(3,5-difluorophenylacetyl)-L-alaninamide methyl ester Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-ahydroxyphenylalanine

N-[4-((2-hydroxy-4-azido)-phenyl)-NHC(0)-)butyl] Ν' -[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

N-[(S)-1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N'-(3,5-difluorophenyl-acetyl)-L-alaninamide tert-butyl ester Ν'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-4-fluorophenylglycine tert-butyl ester N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-4-phenylphenylglycine [N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(2,3benzo[b]proline) methyl ester

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-n-butylphenylglycinamide

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]D,L-4-(phenylacetenyl)phenylglycinamide

Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L• ·· ·· ···· this this • · · this this this this this this this • this this··· · this · · cη · · · · · · · ··· ··· ~ Ú ~ this··· *· ··· ···· ·· ··· ·· ·· phenylglycinethioamide

N- [ 1,3-diphenyl-2-oxo-propan-l-yl]—Ν’ — (3,5—difluorophenylacetyl)-L-alanine amide

N-[1-phenyl-2-oxo-2-cyclopentylethan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide

N-[l-phenyl-2-oxo-hexan-l-yl]-Ν'-(3,5-difluorophenylacetyl)-Lalaninamide

N-[1-phenyl-2-oxo-3-methylpentan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide

N-n-hexyl-6-biotinamidyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinethioamide

Ν' -[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionine methyl ester of N'-[N-(2-tert.-BOC-amino)propionyl)-L-alaninyl]L-phenylglycine

N-tert-butyl N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L2-fluorophenylglycinamide methyl ester Ν'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L2-phenylglycin

N-[(S)-1-phenyl-2-oxo-3-phenylpropan-1-yl]-N'-(3,5difluorophenylacetyl)-L-alanine amide

- 51 BB BBBB ·· ·· « B BBBB

BBBB Β BB B • BB BBB BBB

B B B B B

N'-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L2-phenylglycine tert-butyl ester N'-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycine

Ν' -[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycine tert-butyl ester Ν'-[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycine

N-[2-hydroxy-1-(S)-phenyleth-1-yl]-N'-[(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alanine amide

N-[2-hydroxyeth-1-yl]-Ν' -[(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylglycinamide tert-butyl ester N'-[N-(3,5-difluorophenyl1-2-oxo-acetyl)-Lalaninyl]-L-2-phenylglycine methyl ester [N-(2,5-dichlorophenoxyacetyl)-L-alaninyl]-L-phenylglycinamide methyl ester [N-(3,5-difluorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl ester [N-(3,4-dichlorothiophenoxyacetyl)-L-alaninyl]-L-phenylglycine tert-butyl ester [N-(3-aminopropionyl)-L-alaninyl]-L• 9 99

- 52 • 9 9 9 · phenylglycine and tert-butyl ester [N-(3-tert-butoxycarbonylamino)propionyl)L-alaninyl]-L-phenylglycine.

The pharmaceutical compositions described above comprise a pharmaceutically inert carrier and a compound of general formula I as set forth above.

In the general formula I mentioned above, X preferably represents a hydrogen atom and X' preferably represents a hydrogen atom or a fluorine atom.

In general formula I above, Z preferably represents a covalent bond that binds R ¹ to -CX'X-.

In the general formula I above, R ¹ preferably represents an unsubstituted aryl group, including, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.

Preferred R ¹ substituted monosubstituted phenyls disubstituted phenyls trisubstituted phenyls Substituted phenyl with substituents.

aryl groups include, for example (preferably 3 or 5 substituents); (preferably 3.5 substituents) and (preferably 3,4,5 substituents). The group preferably does not carry more than 3

Examples of substituted phenyls include, for example, the groups 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-thiomethoxyphenyl, 3-methylphenyl,

- 53 • ·· ·· ··· ·· ·· • 9 9 9 9 9 9 9 9 9 9

9 9 t ttt 9 9 9 9 ’ 9 9 9 9 99 999999

9 9 9 9 9 9

999 9999 99 999 99 99

3-trifluoromethylphenyl, 2-hydroxyphenyl, 2-methylphenyl, 2fluorophenyl, 2-chlorophenyl, 3,4-difluorophenyl, 2,3,4,5,6pentafluorophenyl, 3,4-dibromophenyl, 3,4-dichlorophenyl, 3,4methylenedioxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl,

2,4-dichlorophenyl and 2,5-difluorophenyl.

Preferred R ¹ alkaryl groups include, by way of example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, and the like.

Preferred R ¹ alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups include, by way of example, iso-propyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2CH= _CH2 , CH2CH= _CH ( _CH2 )4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex- ₁ -enyl, -CH2 _- cyclopropyl, -CH2cyclobutyl, -CH2 _- cyclohexyl, -CH2 _- cyclopentyl, _{-CH2CH2cyclopropyl} , _{-CH2CH2 - cyclobutyl} , _{-CH2CH2 -} cyclohexyl, _{-CH2CH2cyclopentyl} , aminomethyl and _N -tert-butoxycarbonylaminomethyl groups and the like.

Preferred R ¹ heteroaryl and substituted heteroaryl groups include, by way of example, 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, thionaphten-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,

2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthene-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl and the like.

»000 • · «000 • 0 00 » 0 0 «

0 0 0

000 000

0

00

- 54 • 00

0 0 · » • 0 0 • 0 0 0

0 0

0004000 00

R ² is preferably selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic system. Particularly preferred substituents of R ² include, by way of example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl,

4-fluorophenyl, 3,5-difluorophenyl, 4-methoxyphenyl, benzyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, thien-2yl, thien-3-yl, -CH ₂ CH ₂ SCH ₃ , -CH ₂ OCH ₂ 0, -CH (CH ₃ ) ΟΟΗ ₂ Φ, CH(OH)CH ₃ and -CH ₂ OH and the like. As indicated below, R ² (as well as R ⁴ ) is preferably a side chain of an L-amino acid.

R ³ preferably represents a hydrogen atom, methyl or together with R ⁴ and the nitrogen atom to which R ³ is attached, forms pyrrolidin-2-yl, 2,3-dihydroindol-2-yl, piperidin-2-yl, 4-hydroxy-pyrrolidin-2-yl and 1,2,3,4-tetrahydroisoquinolin-3-yl and the like.

Preferred substituents R ⁴ include, for example, hydrogen, methyl, ethyl, iso-propyl, n-propyl, n-butyl, sec.butyl, iso-butyl, cyclopentyl, cyclohexyl, allyl, iso-but-2enyl, 3-methylpentyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclohexyl, CH ₂ -indol-3-yl, phenyl, p-(phenyl)phenyl, m-(phenyl)phenyl, ofluorophenyl, m-fluorophenyl, p-fluorophenyl, p-bromophenyl, mmethoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, mhydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, mtrifluoromethylphenyl, p-(CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ O-benzyl, p(CH ₃ ) ₃ COC(0)CH ₂ O-benzyl, p-phenylphenyl, 3,5-difluorophenyl, p(HOOCCH ₂ O)-benzyl, 2-aminopyrid-6-yl, 4-(N-morpholinoCH ₂ CH ₂ O)-benzyl, -CH ₂ CH ₂ C (0) NH ₂ , -CH ₂ -imidazol-4-yl, -CH ₂ -(3tetrahydrofuranyl), -CH ₂ ~thien-2-yl, -CH ₂ -thiazol-4-yl, CH ₂ (1-methyl)cyclopropyl, -CH ₂ -thien-3-yl, thien-3-yl, thien·· *»··

Λ9

9 9 9 • · <* 9

999 999 • · «· ·»

- 55 • ·· • ® 9 · • « A * • · ··♦ MM • « *

9 · · A · · • · 9

999

2-yl, -CH ₂ -C(O)O-tert.-butyl, -CH ₂ -C (CH ₃ ) ₃ , ~CH ₂ CH (CH ₂ CH ₃ ) ₂ , 2methylcyclopentyl, -cyclohex-2-enyl, -CH [CH (CH ₃ ) ₂ ] COOCH ₃ , (CH ₂ ) ₂ SCH ₃ , -CH ₂ CH ₂ N (CH ₃ ) 2, -CH ₂ C(CH ₃ ) = CH ₂ , -ch ₂ ch = CHCH ₃ (cis and trans), -CH ₂ OH, -CH(OH)CH ₃ , -CH (O-tert.-butyl) CH ₃ , CH ₂ OCH ₃ , - (CH ₂ ) 4NH-B0C, -(CH ₂ ) ₄ NH ₂ , -(CH ₂ ) ₄ N(CH ₃ ) ₂ , -ch ₂ pyridyl, pyridyl, -CH ₂ -naphthyl, -CH ₂ -(N-morpholino), ρ-(Nmorpholino-CH ₂ CH ₂ 0)-benzyl, benzo [b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7tetrahydrobenzo[b]thiophen-2-yl, tetrazol-5-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen5-yl, 6-methoxynaphth-2-yl, -CH ₂ -N-phthalimidyl, 2methylthiazol-4-yl, and thieno[2,3-b]thiophen-2-yl, 5-bromothien-2-yl, 5-bromothien-2-yl. 3-phenoxyphenyl, 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 and the like.

R ⁵ preferably represents a hydrogen atom. However, in another embodiment of the present invention, R ⁴ and R ⁵ are joined to form a cycloalkyl group, including, for example, cyclopropyl, cyclobutyl and the like.

One preferred substituent X is -C(O)Y. Y is preferably a hydroxy, alkoxy or substituted alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, tert-butoxy, neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, -ONHC(0)OC( _CH3 ) ₃ , -ONHC( _CH3 ) ₃ and the like. Other preferred Y groups are -NR'R, where R' and R are as defined above. Such preferred Y groups

- 56 • · · · · include, by way of example, the groups amino (-NH ₂ ), NH(iso-butyl), -NH(sec-butyl), N-methylamino, N,Ndimethylamino, N-benzylamino, N-morpholino, azetidino, Nthiomorpholino, N-piperidinyl, N-hexamethyleneimino, Nheptamethyleneimino, N-pyrrolidinyl, -NH-methallyl, -NHCH ₂ (furan-2-yl), -NHCH ₂ -cyclopropyl, -NH(tert-butyl), -NH(p-methylphenyl), -NHOCH3, -NHCH ₂ (p-fluorophenyl), -NHCH ₂ CH ₂ OCH ₃ , NH-cyclopentyl, -NH-cyclohexyl, -NHCH ₂ CH ₂ N(CH ₃ ) ₂ , NHCH ₂ C (CH ₃ ) 3, -NHCH ₂ - (pyrid-2-yl) , -NHCH ₂ -(pyrid-3-yl) , NHCH ₂ -(pyrid-4-yl) , N-thiazolindinyl, -N (CH2CH2CH3) ₂ , N [CH ₂ CH (CH ₃ ) ₂ ] ₂ , -NHOH, -NH (ρ-ΝΟ ₂ -Φ) , -NHCH ₂ (p-NO ₂ -Φ) , NHCH ₂ (m-NO ₂ -0) , -N(CH ₃ )OCH ₃ , -N (CH ₃ ) ΟΗ ₂ -Φ, -NHCH ₂ -(3,5difluorophenyl) , -NHCH ₂ CH ₂ F, -NHCH ₂ (ρ-ΟΗ ₃ Ο-Φ) , -NHCH ₂ (m-CH ₃ O-<P) , -NHCH ₂ (p-CF ₃ -tf>) , -N(CH ₃ )CH ₂ CH ₂ OCH ₃ , -NHCH ₂ CH ₂ <£, -NHCH(CH ₃ )0, NHCH ₂ -(pF-Φ) , -N (CH ₃ ) CH ₂ CH ₂ N (CH ₃ ) 2 , -NHCH ₂ -(tetrahydrofuran2-yl), -NHCH ₂ (p-trifluoromethylphenyl) , -NHCH ₂ C(CH ₃ ) = CH ₂ , NH-[(p-benzyl)pyrid-4-yl], -NH-[(2,6-dimethyl)pyrid-4-yl], NH-(2-methylcyclohexyl), -NH-(4-methylcyclohexyl), -NH-[Nethoxycarbonyl]-piperidin-4-yl, -NHOC(CH ₃ ) ₃ , -NHCH ₂ CH ₂ CH ₂ CH ₂ Φ, -C (0) NH (CH ₂ ) 3O-(p-CH ₃ ) Φ, -C (0) NH (CH ₂ ) ₆ NH ₂ , -NH(tetrahydrofuran-2-yl), -N(CH ₃ )</>, -NH (CH ₂ ) ₄ NHC (0) - (2-hydroxy4-azido)-phenyl and -NH (CH ₂ ) ₆ -(biotinamidyl) and the like.

Another preferred group Y is an alkyl group such as methyl, ethyl, iso-propyl, n-propyl, iso-butyl, n-butyl, sec-butyl, tert-butyl, -CH ₂ CH ₂ CH(CH ₃ ) 2, -CH ₂ -pyrid-2-yl, -CH ₂ -pyrid-3-yl, -CH ₂ -pyrid-4-yl, -CH ₂ -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.

• that ···· ·· ··

- 57 β ·· this this ······ • · · · · · ··· this ··· ·· this

Yet another preferred group Y is -NHSO ₂ -R, where R is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic system. An example of such a group is NH-SO ₂ CH ₃ .

Preferred groups Y' include a substituted alkyl group such as -CH ₂ OH, -CH (OH) CH ₂ CH ₂ CH (CH ₃ ) ₂ , -OH(OH)Φ, CH(OH)CH ₂ C(O)OCH ₃ , -C(OH) (CH ₃ ) 2 , -CH ₂ OCH ₃ , -CH ₂ OC(O)OCH ₃ , CH ₂ OC (O) C (CH ₃ ) ₃ and the like.

Preferred compounds for use in the method of the present invention include those listed in the following tables:

• ·

X z.o.o. z o u Invitation G. o o o ΰ G o o *w»» u -C(O)OCII, | Ϋ G z o «Η-* u 5 ž G G z *s» o O G o C G z o o G from and O ·» w* C from O ΉΖ at C£ from = = = - _{= =} and and T» G flr at Ci Θ- -with- ©· -©- G N G υ at •e- About. ·? G G C at *· «M With» at G G CC G G G — C G G G G G G.M. *3A s\ eating c -4 th 4 th -A tion A- A- tion -A. ci cc 3 dS About •3 •3 -□ *3 About ·“ u >» Ά *A •A «Α •A Ά at **í *A *n *-< *A

>> 3 ’C ε 3 5 I ** ο α ΊΑ Α .*2 >s C. 3 5 ο υ >> Γ2 ΣΣ >p C. 3 Ξ C φ α ο ο δ ΰ ϋ ο *·> C y υ ο «-> ο y ο ο ·*** ο y ΰ Ο χ~» C y α ο ο α ο ο δ α ο ο <—χ ο ο ο ο -Χ ο ο λ υ ο δ ο ο ο δ α α ο *«» ο y Β Κ μ Β I M· = = •M = = - = •M - _{= =} ·« •W κ Ϋ y -θ- 3 3 υ ΰ α α y -¾ 3 -¾ y ό ΰ ««< — N ο ά. Č α δ ?ί αχ 3 Ú. *>» ΰ δ ΊΑ k o λ» •τ? and. Ν C ζ ό r« ο 8 Ο ά. ό 2 ο JS §2. ŽS ά.α α ζ ο ΊΑ CM 2 bw >\ C. 3 ΊΑ Α á 1« X £ 3 οί • ν. ζ.ε 2 <9 Ο t y ά y ο ΰ ΰ y ΰ ΰ 3 ο ΰ α ο ο ο it -é ιί 5 Ά •Α -ό- ti. *3 «Α Ά •4 ‘*5 Ά Ά 4- νί *5 Ά Ά y ο η ΰ y ΰ 0 α ΰ ΰ •G· li. *·? «η *Α 4 *Α *Α 4 3 Ά *Α 4 ΰ. 3 Ά *Α 4 3 Ά *Α 4 *3 *Α *Α 4 ΰ. 3 Α *Α 4 U. 3 Α Ά 4 ιί 3 •Α Α

• ·

- 60 • ·· ·· 4 4 4 4 44

4 4 4 4 4 4 4 4

4 44444 4

4 44 4 44 444444

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Detailed description of the invention

As mentioned above, the present invention relates to methods of inhibiting the release of β-amyloid peptide and/or its synthesis, which are accordingly useful in the treatment of Alzheimer's disease. However, before the invention is described in further detail, the following terms will be defined.

Definition

The term "β-amyloid peptide" refers to a peptide of 39-43 amino acids having a molecular weight of approximately 4.2 kD, which peptide is essentially the homologous form of the protein described by Glenner et al. ¹ , including mutations and post-translational modifications of the normal β-amyloid peptide. In whatever form, the β-amyloid peptide is a fragment of approximately 39-43 amino acids of a large membrane glycoprotein, referred to as β-amyloid precursor protein (APP). Its 43 amino acid sequence is:

·· • · ···· • · · · · · · · • ···· · ···

Asp Ala Glu Phe Arg His Asp Shit Gly Tyr 11 Glu Val His His Gin Lys Leo Val Phe Phe 21 Ala Glu Asp Val Gly Shit Asn Lys Gly Ala 31 lle lle Gly Leo Meth Val Gly Gly Val Val 41 lle Ala Thr (SEQ ¹ ID NO: 1) or i sequence that is eats in • in principle homological

"Alkyl means a monovalent alkyl group containing preferably from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl and the like.

"Substituted alkyl means an alkyl group, preferably containing from 1 to 10 carbon atoms, which carries 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl,

4« • ·

- 87 99 9 99 9 9 9 9 9 9

9 9 9 9 9 9

9 9999 9 99 · • · « · · · ······ • 9 · · · · ······ · · 999 9 9 9 9 carboxyl, carboxylalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic system, nitro groups and mono- and dialkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and diheterocyclic amino and unsymmetrical di-substituted amines having various substituents selected from the group consisting of alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic system groups.

"Alkylene means a divalent alkylene group having preferably from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms. Examples include groups such as methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene isomers (e.g. -CH ₂ CH _{2 -and} -CH (CH ₃ ) CH ₂ -) and the like.

"Alkaryl" means an -alkylene-aryl group, preferably having from 1 to 10 carbon atoms in the alkylene portion and from 6 to 10 carbon atoms in the aryl portion. Examples of such alkaryl groups are benzyl, phenethyl, and the like.

"Alkoxy" means an "alkyl-O-" group. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy and the like.

"Substituted alkoxy" means a "substituted alkyl" group in which substituted alkyl has the meaning defined above.

"Alkylalkoxy" means the group "-alkylene-O-alkyl" in which alkylene and alkyl are as defined above. Such groups include, by way of example, methylenemethoxy (-CH 2 OCH 3 ), ethylenemethoxy (-CH _{2 CH 2} OCH ₃ ), n-propylene-iso-propoxy (CH 2 CH ₂ CH ₂ OCH ₍ CH ₃ ) ₂ ), methylene-tert-butoxy (-CH _{2 -OC} (CH _{3 ) 3} ) and _the like.

"Alkylthioalkoxy means the group,,-alkylene-S-alkyl, in which alkylene and alkyl are as defined above. Such groups include, by way of example, methylthiomethoxy (CH2SCH3), ethylthiomethoxy ( _-CH2CH2SCH3 ), n-propylisothiopropoxy _{(-CH2CH2CH2SCH ( CH3 ) 2 )} , methylthio _{-tert.-butoxy (CH2S(CH3)3 ) and the} like.

"Alkenyl" means an alkenyl group having preferably from 2 to 10 carbon atoms and more preferably from 2 to 6 carbon atoms and having at least 1 and preferably 1-2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (-CH=CH ₂ ), npropenyl (-CH ₂ CH=CH ₂ ), iso-propenyl (-C(CH ₃ )=CH ₂ ), but-2-enyl (-CH ₂ CH=CHCH ₃ ) and the like.

"Substituted alkenyl means an alkenyl group as defined above which bears 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 thioalkoxy, aryl, heteroaryl, heterocyclic system, nitro groups and mono- and dialkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and diheterocyclic-amino and unsymmetrical di-substituted amines having various substituents selected from the group, ·· • ·

Φ· ο··· • · · • · ··· • ···· • · ·♦ ··· including alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic groups.

"Alkynyl" means an alkynyl group having preferably from 2 to 10 carbon atoms and more preferably from 2 to 6 carbon atoms and having at least 1 and preferably 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (~CH=CH ₂ ), propargyl (-C 1 h C 5 H) and the like.

"Substituted alkynyl means an alkynyl group as defined above having 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 thioalkyloxy, aryl, heteroaryl, heterocyclic system, nitro groups 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 unsymmetrical di-substituted amines having various substituents selected from the group consisting of alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic system.

"Acyl means the groups alkyl-C(O)-, substituted alkylC(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic-C(O)-, where alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic system have the meanings given above.

"Acylamino means a group -C(O)NRR, in which each hydrogen, alkyl, heteroaryl and alkyl, heteroaryl and »· • ·

"Oxyacyl means the groups -OC(O)-alkyl, -OC(O)-aryl, -C(O)Oheteroaryl- and -C(O)O-heterocyclic, where each of the alkyl, aryl, heteroaryl and heterocyclic groups has the above meaning."

"Oxyacylamino means the groups -OC(O)NR-alkyl, -OC(O)NR-substituted alkyl, -OC(O)NR-aryl, -OC(O)NR-heteroaryl- and OC(O)NR-heterocyclic, substituted alkyl, heterocyclic system substituted alkyl, where R is cycloalkyl, and where each of the cycloalkyl, aryl, heterocyclic system has the above meaning.

hydrogen atom, alkyl, aryl, heteroaryl and alkyl, heteroaryl and "Aminocarboxy esters" means the groups -NRC(O)O-alkyl,

NRC(O)O-substituted alkyl, -NRC(O)O-aryl, -NRC(O)Oheteroaryl and -NRC(O)O-heterocyclic system, where R represents a hydrogen atom, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic system and where

• · · · · · · • · · a

and • · · each of the groups alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic system has the meaning given above.

"Aryl means an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl, and the like.

Unless otherwise limited by the definition of an aryl substituent, such aryl groups may be optionally substituted with from 1 to 5 and preferably from 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, halogen atom, nitro, heteroaryl, heterocyclic system, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and dialkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and diheterocyclic-amino and unsymmetrical di-substituted amines having various substituents selected from from the group consisting of alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic systems, and the like. Preferred substituents include alkyl, alkoxy, halogen, cyano, nitro, trihalomethyl and thioalkoxy groups.

"Aryloxy means an aryl-Ο- group in which the aryl group

- 92 • · · · or higher.

has the meaning defined above, including substituted aryl groups as defined

The term "carboxy terminal R ⁴ group" means the R ⁴ group in a compound of formula I which, when n is equal to two, is closest to the X group.

"Carboxyalkyl means the groups -C(O)O-alkyl and -C(O)O-substituted alkyl, where alkyl and substituted alkyl are as defined above."

"Cycloalkyl means cyclic alkyl groups having from 3 to 10 carbon atoms and having a single cyclic ring or multiple fused rings which may be optionally substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by 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 means cyclic alkenyl groups having from 4 to 8 carbon atoms and having a single cyclic ring and at least one site of internal unsaturation, which may be optionally substituted with from 1 to 3 alkyl groups. Examples of suitable cycloalkenyl groups include, for example, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl, and the like.

"Halo" or "halogen" means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and preferably either a chlorine atom or a bromine atom.

·· · · · · • fl ·· • ·

Unless otherwise limited in the definition of a heteroaryl substituent, such heteroaryl groups may 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, halogen, nitro, heteroaryl, heterocyclic system, 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-heterocyclic amino and unsymmetrical di-substituted amines having various substituents selected from alkyl, substituted heterocyclic system and including alkyl groups, trihalomethyl and thioalkoxy.

from the group consisting of alkyl, aryl, heteroaryl and the like. Preferred substituents are alkoxy, halo, cyano, nitro,

Such heteroaryl groups may have a single ring (e.g., pyridyl or furyl) or multiple fused rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, and furyl.

• ·

- 94 • · · ft · • ftft • · “Heteroaryloxy” means a heteroaryl-Ο- group, where the heteroaryl group is as defined above and includes optionally substituted heteroaryl groups as also defined above.

"Heterocycle" or "heterocyclic system" means a monovalent (i.e., single-point of attachment) saturated or unsaturated group consisting of a single ring or multiple fused rings containing 1 to 8 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms within the ring.

Unless otherwise limited in the definition of a heterocyclic substituent, such heterocyclic groups may be optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted substituted alkenyl, aminoacyl, aminocarboxy esters, alkaryl, carboxyl, carboxylalkyl, aminoacyl, cyano, alkyl, substituted substituted alkynyl, aryl, alkoxy, amino, aryloxy, halogen atom, nitro group, heteroaryl, heterocyclic system, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, monodi-alkylamino, monodi(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, unsymmetrical substituents, alkyl, substituted heterocyclic system mono- and di-heterocyclic amino and di-substituted amines having various selected from the group consisting of alkyl, aryl, heteroaryl and such heterocyclic and the like.

groups may have a single ring or multiple fused rings. Preferred heteroaryls include morpholino, piperidinyl, and • · · ·· · · · · · · · · · · · · · · · · · · · » · · · (9 · · · · ··«· • * 9 9 9 99 999999

9 9 9 9 9 9

999 9999 99 999 99 99 similarly.

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, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, 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.

"Heterocyclyloxy" means a heterocyclyl-O- group, where the heterocyclic group is as defined above, including optionally substituted heterocyclic groups as also defined above.

"Oxyacyl means the groups -OC(O)-alkyl, -OC(O)-aryl, -C(O)Cheteroaryl- and -C(O)C-heterocyclic system, where alkyl, aryl, heteroaryl and heterocyclic system have the meanings given above."

"Oxyacylamino means the groups -OC(O)NH-alkyl, -OC(O)NH-substituted alkyl, -OC(O)NH-aryl, -OC(O)NH-heteroaryl- and OC(O)NH-heterocyclic system, where alkyl, aryl, heteroaryl and heterocyclic system have the meanings given above.

“Thiol means a -SH group.

• ·

• · • ·· ···to··· • · ♦ ··· to ·« ··· “Thioalkoxy” means an -S-alkyl group.

“Substituted thioalkoxy” means an -S-substituted alkyl group.

“Thioaryloxy” means an aryl-S- group, where the aryl group is as defined above, including optionally substituted aryl groups which have also been defined above.

“Thioheteroaryloxy” means a heteroaryl-S- group, where the heteroaryl group is as defined above, including optionally substituted aryl groups which are also defined above.

"Pharmaceutically acceptable salt" means pharmaceutically acceptable salts of compounds of formula I which are derived from a variety of organic and inorganic ions well known to those skilled in the art, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and, where the molecule contains basic functionality, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

Preparation of compounds

Compounds of formula I are readily prepared by several divergent synthetic routes, the choice of a particular route being made depending on the difficulty of preparation, the commercial availability of starting materials, and the like.

- 97 • * · · · · 4 · · • 4 4·· • · · • · 4 4

4 4 4

444 444 ·

44

The first synthesis route involves the usual coupling of an acetic acid derivative with the primary amine of an esterified amino acid, as shown in reaction scheme (1) below:

2

d)

in which R ¹ represents , R ² , R ³ , X' and X are either an oxygen atom as defined above and X or a group -NH-.

Reaction (1) simply involves coupling the appropriate acid derivative i with the primary amine 2 of the amino acid ester under conditions that result in the formation of the N-acetyl derivative 3. This reaction is commonly performed in peptide synthesis, and these synthetic methods can also be used to prepare the N-acetyl esters 3 of the amino acids of the present invention. For example, well-known coupling agents can be used to facilitate the coupling.

- 98 • · « ·

Reaction (1) is preferably carried out at a temperature of from about 0°C to about 60°C until the reaction is complete, which typically occurs after a period of from about 1 to about 24 hours. After completion of the reaction, the N-acetyl ester of amino acid 3 is recovered by conventional methods, including precipitation, chromatography, filtration, and the like, or alternatively, it is hydrolyzed to the corresponding acid without using purification and/or isolation methods other than those commonly used (e.g., aqueous extraction, and the like). Alternatively, the synthesis described above in reaction (1) can be carried out on the amino acid (XR ³ = OH) followed by formation of the N-acetyl as described above.

In any case, if it is an amino acid, it is converted to an amino acid by performing a coupling step, HNR ³ CR ⁴ RSC(O)Y.

using known methods of peptide coupling using well-known coupling reagents formed N-acetyl ester corresponding with another acid before ester/amide coupling is achieved chemistry behind such as ·· ···· ·· 99 · ··· · # · ·

9 9 999 9 9 9 9

99 9 99 999 999

9 9 9 9 9

999 9 9 9 9 9 9 9 9 9 carbodiimides with or without the use of well-known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like, which can be used to facilitate the coupling. The reaction is usually carried out in an inert aprotic polar solvent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.

Such coupling provides compounds of formula I in which n is 1. The synthesis of compounds of formula I in which n is 2 is achieved by carrying out a second coupling reaction. Specifically, in the first coupling reaction HNR ³ CR ⁴ R ⁵ C (0) Y is chosen to be an amino acid ester. That is, Y represents -O-alkyl. After coupling, the ester is hydrolyzed using conventional conditions well known to those skilled in the art to give the corresponding carboxylic acid, which can then be used for coupling with a second amino acid ester/amide.

In reaction (1), each of the reagents (compound 1 and amino acid ester 2) is well known in the art and many of them are commercially available.

Alternatively, compounds of formula I can be prepared by first forming a dipeptide ester and then N-acylating the ester. That is, an ester or amide of the amino acid HNR ³ CR ⁴ R ⁵ C (0) Y is coupled to an N-blocked amino acid BlokNHCHR ² COOH under conventional coupling conditions to form the dipeptide BlokNHCHR ² C (0) N (R ³ ) CR ⁴ R ⁵ C (0) Y. The blocking group is then removed under conventional conditions to give the free amine which is then N-acylated as described above to form a compound of formula I.

···· ··

• « • · ♦ ·

-100After the coupling and N-acylation (in whatever order they are carried out) are completed, the resulting esters and amides can be derivatized using conventional chemical methods to produce derivatives of the synthesized compounds. For example, conventional reduction of the terminal ester group with lithium borohydride results in the formation of a terminal -CH ₂ OH group. Alternatively, the ester group can be converted to the primary amide [-C(O)NH ₂ ] by reaction with ammonium in methanol with a catalytic amount of sodium cyanide under heating.

Similarly, a reactive functionality that is blocked by either the R ² group and/or the R ³ group can be deprotected and then derivatized. For example, a BOC-protected amino group on R ³ (e.g., a lysine side chain) can be deprotected after synthesis and the amino group can be acylated or otherwise derivatized.

Additionally, the terminal ester may be subjected to transesterification techniques to form other esters. Numerous methods are known in the art for carrying out transesterification, each of which 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 isopropoxide is used to facilitate completion of the reaction. In one of these methods, the alcohol or thioalcohol is first treated with sodium hydride in a suitable solvent such as toluene to form the corresponding sodium alkoxide or thioalkoxide, which is then used to carry out the transesterification. The efficiency of this technique is particularly • ·· ·· ··«· ·· ·· • · · · *·« · * * * * · ♦ · ··« · · « · • ·

-101-······· ·· ·· ·· ·· ·· suitable for use with high boiling point alcohols or thioalcohols and/or expensive alcohols or thioalcohols.

When using another transesterification technique, the ester to be transesterified is placed with an alcohol or thioalcohol, transesterification.

sodium hydride and conditions to a large catalytic excess which ensures the amount

Then the reaction proceeds rapidly under normal conditions and the desired transesterified product is obtained.

Since this protocol requires the use of a large alcohol or thioalcohol, this procedure is particularly advantageous if the alcohol or thioalcohol is inexpensive.

Transesterification provides a simple means of obtaining a variety of ester substituents on compounds of formula I above. In all cases, the alcohols and thioalcohols used to carry out the transesterification are well known in the art and a significant number of them are commercially available.

Other methods for preparing esters of the present invention include, by way of example, first hydrolyzing the ester to the free acid, followed by O-alkylation with a halo-R ³ group in the presence of a base such as potassium carbonate.

Alternatively, esterification procedures for alcohols containing an ester group can be carried out using the method described by Losse et al. ¹¹ .

The compounds described herein may also be

9999

-1029 9 9

9 ·99

9 9

9 9

9«9

9· 99

9 9 9

9 9 9

999 999

9 «9 prepared using polymer supported forms of carbodiimide peptide coupling reagents. For example, a polymer supported form of EDC has been described (Tetrahedron Letters, 34(48), 7685 (1993)0 ¹⁰ . A new carbodiimide coupling reagent, PEPC and its corresponding polymer supported form, have also been discovered, which are very useful for the preparation of compounds of the present invention.

Polymers suitable for use as a carrier for polymer-supported coupling reagents are either commercially available or can be prepared by methods well known to those skilled in the polymer art. A suitable polymer must contain side chains that bear groups that react with the terminal amine of the carbodiimide. Such reactive groups include chlorine, bromine, iodine, and methanesulfonyl. The reactive group is preferably a chloromethyl group. In addition, the basic structure of the polymer must be inert to the carbodiimide and to the reaction conditions under which the final polymer-bound coupling reagents will be used.

Certain hydroxymethylated resins can be converted to chloromethylated resins, useful for preparing polymer-supported coupling reagents. Examples of these hydroxylated resins include 4-hydroxymethylphenylacetamidomethyl resin (Pam Resin) and 4-benzyloxybenzyl alcohol resin (Wang Resin), which are available from Advanced Chemtech, Louisville, Kentucky, USA (see Advanced Chemtech catalog 1993-1994, page 115). The hydroxymethyl groups of these resins can be converted to the desired chloromethyl groups ·· ·

• ·

9 99 by any of a number of methods well known to those skilled in the art.

Preferred resins are chloromethylated styrene/divinylbenzene resins due to their ready commercial availability. As the name suggests, these resins are already chloromethylated and do not require further chemical modification before use. These resins are known under the trade name Merrifield resins and are available from Aldrich Chemical Company, Milwaukee, Wisconsin, USA (see Aldrich catalog 1994-1995, page 899). Methods for preparing PEPC and its polymer supported forms are outlined in the following scheme.

LG

Functionalized resin where (p) = inert polymer and LG = Cl, Br, I or OCO CH, 2 3 ,N=c =N this ·· ·«··

-104• •this « • this this « • this* this «··

Such methods have been described in more detail in U.S. Patent Application Serial No. 60/019,790, filed June 14, 1996, which is incorporated herein by reference in its entirety. Briefly, PEPC is prepared by first reacting ethyl isocyanate with 1-(3-aminopropyl)pyrrolidine. The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC. The polymer supported form is prepared by reacting PEPC with a suitable resin under standard conditions to provide the desired reagent.

Coupling reactions of carboxylic acids using these reagents are carried out at temperatures from about ambient temperature to about 45 °C for a period of from about 3 to 120 hours. Typically, the product can be isolated by washing the reaction mixture with CHCl ₃ and concentrating the remaining organic component under reduced pressure. As discussed above, the isolation of products from reaction mixtures in which a polymer-bound reagent has been used is greatly simplified and requires only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.

Still other methods for preparing esters are given in the examples below.

Compounds in which X represents -CR ⁶ R ⁶ Y' are readily prepared by coupling, for example, an amino alcohol H2NCR ⁴ R ⁵ CR ⁶ R ⁶ OH to the carboxyl group in R ¹ ZCX'XC(O)NHCHR ² C (O) OH under standard coupling conditions well known in peptide coupling chemistry, which may employ well-known coupling reagents such as carbodiimides with or without the use of well-known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, and the like. If

-105• · · · • · · · • 0 0 · • · · · · ·

0 0 0 0 0 0

0·· 0000 00 00 00 00 If desired, well-known blocking groups on Y' can be used to protect this group during coupling. Such blocking groups are particularly desirable when Y' represents an amine group.

The reaction is usually carried out in an inert aprotic polar solvent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, etc. After completion of the reaction, all blocking groups on Y' are selectively removed to give the desired compound.

When Y' represents -OH or -SH, post-synthetic conversion of these groups to the corresponding ester (i.e. -OC(O)R ⁷ ), disulfide (i.e. -SSR ⁷ ) and -SSC(O)R ⁷ groups is carried out using well-known chemical procedures. For example, ester synthesis requires only reaction with a suitable acid, such as acetic acid (R ⁷ = methyl), a halogen acid (e.g. hydrochloric acid) or an acid anhydride, under suitable esterification conditions.

If one of the R ⁶ substituents is hydrogen, post-synthetic oxidation of the -CHR ⁶ OH group leads to ketone derivatives. Alternatively, such ketones can be prepared by coupling the HCl salt of the appropriate amino ketone with the terminal carboxyl group of an amino acid, as illustrated in Example 168 below.

In carrying out these synthetic methods, the starting materials may contain a chiral center (e.g., alanine) and if a racemic starting material is used, the resulting product is a mixture of R,S enantiomers. Alternatively, a chiral isomer may be used

-106·· *··· • · • ··· of the starting material and if the reaction protocol used does not racemize this starting material, a chiral product is obtained. Such reaction protocols may involve inversion of the chiral center during the synthesis.

Accordingly, unless otherwise indicated, the products of the present invention are mixtures of R,S enantiomers or diastereoisomers. Preferably, however, when a chiral product is desired, the chiral product corresponds to an L-amino acid derivative. Alternatively, chiral products can be obtained by purification techniques that separate the enantiomers from the R,S mixture to yield one or the other stereoisomer. Such techniques are well known in the art.

Pharmaceutical preparations

When used pharmaceutically, 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 compounds are effective as injectable and oral compositions. Such compositions can be prepared by methods well known in the pharmaceutical art and contain at least one active compound.

The present invention also relates to pharmaceutical compositions comprising as active ingredient one or more compounds of formula I as defined above together with a pharmaceutically acceptable carrier. In forming a composition according to the present invention, the active ingredient is usually mixed with

-107• ···· l ·· ft··· ft· ·· • » · · ftftft· • 9 · ··· 9 · · · » · · · · ftftft ··* ftft ft·· ·· ft· excipient, diluted with excipient or surrounded by such a carrier, which may be in the form of capsules, cachets, sachets or other containers. When the excipient serves as a diluent, it may be a solid, semi-solid or liquid material which serves as a vehicle, carrier or medium for the active ingredient. The composition may therefore be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, aerosols (in the form of a solid or in an ointment, 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.

solutions, syrups, liquid medium),

In the preparation of a formulation, it may be necessary to grind the active compound to achieve an appropriate particle size before combining it with the other ingredients. If the active compound is substantially insoluble, it is usually ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size is normally adjusted by grinding to a size that will achieve a substantially uniform dispersion in the formulation, for example to a size of about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulations may further contain: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives

-108 agents such as methyl and propyl hydroxybenzoate; sweeteners and flavoring agents. The compositions of the present invention may be formulated to provide immediate, sustained or delayed release of the active ingredient after administration to the patient, using procedures known in the art.

The compositions are preferably prepared as a unit dose, each dose containing from about 5 to about 100 mg, more usually from about 10 to about 30 mg, of the active ingredient. The term "unit dose" means a physically discrete unit suitable as a single dose for a human or other mammal, each unit containing a predetermined quantity of the active ingredient calculated to produce the desired therapeutic effect, together with a suitable pharmaceutical excipient. Preferably, the compound of formula I as defined above is used in such a way that it constitutes no more than 20 weight percent of the pharmaceutical composition, preferably no more than 15 weight percent, the balance being made up of a pharmaceutically inert carrier or carriers.

The active compound is effective over a wide range of doses and is generally administered in a pharmaceutically effective amount. It will be appreciated, however, that the amount of compound actually administered will be determined by the physician depending on relevant circumstances, including the condition to be treated, the route of administration chosen, the compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms and the like.

For the preparation of solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to • 0 0 · · 00 0 0 0 0 · ® _ Ί Γ)£·_ · ® · · · 9 9 9 9 · 0 · · · · 0 0 0 9 • · · 0 · 0· 000000 0 0 0 0 0 ·0

000 0000 00 ··· 99 00 formed a solid pre-processed composition containing a homogeneous mixture of the compounds of the present invention. When this pre-processed composition is referred to as homogeneous, it is meant that the active ingredient is dispersed uniformly throughout the composition, so that the composition can be easily divided into effective unit doses, such as tablets, pills and capsules, which contain the same amount of active ingredient. This solid pre-processed composition is then divided into unit doses of the type described above and which contain, for example, from about 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 formulated to provide a dosage form that provides the benefit of a sustained release. For example, the tablets or pills may comprise an inner dose of a component and an outer dose of a component, the outer dose forming a shell for the inner dose. These two components of the dosage form may be separated by an enteric layer which serves to prevent disintegration in the stomach and to allow the inner component to pass intact into the duodenum or to provide a delayed release thereof. A variety of materials may be used to form such an enteric layer or coating, such as materials comprising a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid forms in which the novel compositions of the present invention may be contained may be formulated for oral administration or by injection and include aqueous solutions of suitably flavored syrups, aqueous or oily • ·· • · · ·

9· ··· · .1101 · · · · ^{χ ν} · · · · · · » · · · • · · ··· ··« • · « · · * suspensions and flavored emulsions with edible oils such as cottonseed oil, sesame oil, peanut oil, as well as pharmaceutical vehicles.

coconut oil or elixirs and similar

Compositions for inhalation or inhaling include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof and powders. Liquid and solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, such compositions are administered by the oral or nasal respiratory route to produce a local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized using inert gases. Atomized solutions may be inhaled directly from a nebulizer device or the nebulizer device may be attached to a face mask or intermittent positive pressure breathing apparatus. Solutions, suspensions or powder compositions may be administered, preferably orally or nasally, from devices that deliver the preparation in a suitable manner.

The following formulation examples illustrate compositions of the present invention.

pharmaceutical

Example of preparation 1

Hard gelatin capsules were prepared containing the following ingredients.

this ·· ·· this this this · this this • ••to · · · to to to « • · · it · it it ···· - even that · ·· · *♦ ··· ··· — 1 1 i — · ·· · · it ······· ·· this this that* ·· Folder Quantity (mg/capsule) Active ingredient 30.0 Starch 305.0 Magnesium stearate 5.0 The above components were mixed and filled into hard gelatin capsules in quantity 340 mg. Preparation Example 2

Tablets were prepared using the ingredients listed below:

Amount

Ingredient (mg/tablet)

Active ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The ingredients were mixed and compressed into tablets, each weighing 240 mg.

Example of preparation 3

The dry powder inhalation preparation was prepared with the following ingredients:

Component

Weight %

-112*

Active ingredient 5

Lactose 95

The active ingredient is mixed with lactose and the inhalation device mixes with the dry powder.

is inserted into

Example of preparation 4

Tablets, each containing 30 mg of active ingredient, were prepared as follows:

Component

Quantity (mg/tablet)

Active ingredient 30.0 mg

Starch 45.0 mg

Microcrystalline cellulose 35.0 mg

Polyvinylpyrrolidone (as a 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

The active ingredient, starch and cellulose are sieved through a 20 U.S. mesh sieve and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powder, and • · · · » · · * » · · · · · · · · • ·

Example of preparation 5

Capsules, each containing 40 mg of the drug, were formulated as follows:

Amount

Folder (mg/capsule) Active ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg

The active ingredient, starch and magnesium stearate were mixed, sieved through a 20 U.S. mesh screen and filled into hard gelatin capsules in an amount of 150 mg.

Example of preparation 6

Suppositories, each containing 25 mg of active ingredient, were formulated as follows:

φ φ

Component

Quantity φφφφφ

-w-.

Active ingredient mg

Glycerides of saturated fatty acids up to 2,000 mg

The active ingredient was sieved through a 60 U.S. mesh screen and suspended in saturated fatty acid glycerides which had been previously melted using minimal heat. The mixture was then poured into a suppository mold of nominal capacity 2.0 g and allowed to cool.

Example of preparation 7

Suspensions containing 50 mg of drug in a dose of 5.0 ml were prepared as follows:

Ingredient Quantity

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

Flavoring and coloring q.v.

Purified water up to 5.0 ml

The active ingredient, sucrose and xanthan gum were mixed, sieved through a 10 U.S. mesh sieve and then mixed with a pre-formed solution of microcrystalline cellulose and sodium carboxymethylcellulose in water. Sodium benzoate, flavouring and colouring were dissolved in a small amount of water • ·· ·* ···· · · * · • · « « · t · · ♦ · * • · ····· · · · · · and added with mixing. Sufficient water was then added to make the desired volume.

Example of preparation 8

Quantity Folder (mg/capsule) Active ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg

The active ingredient, starch and magnesium stearate were mixed, sieved through a 20 U.S. mesh screen and filled into hard gelatin capsules in an amount of 560 mg.

Example of preparation 9

The subcutaneous preparation can be prepared as follows:

Folder Quantity Active ingredient 5.0 mg Corn oil 1ml

Example of preparation 10

The topical preparation can be prepared as follows:

« L

Component

Quantity • ·· ·· · «

Active ingredient

Emulsifying wax Liquid paraffin Soft white paraffin for

1-10g g 20g

100g

Soft white paraffin was heated until melted. Liquid paraffin and emulsifying wax were added and the mixture was stirred until dissolved. The active ingredient was added and stirring continued until a dispersion was formed. The mixture was then cooled until solidified.

Other preferred formulations utilizing the method of the present invention utilize transdermal delivery devices ("patches"). Such transdermal patches can be used to achieve 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, for example, U.S. Patent 5,023,252, issued June 11, 1991, which is incorporated herein by reference. Such patches can be designed to deliver the pharmaceutical agent in a continuous or burst manner or on an as-needed basis.

It is often desirable or necessary to deliver pharmaceutical compositions to the brain, either directly or indirectly. Direct techniques typically involve placing a drug delivery catheter into the recipient's ventricular system, which bypasses the blood-brain barrier.

barrier. One such implantable delivery system used for transporting biological factors to specific anatomical regions of the body is described in U.S. Patent No. 5,011,472, which is incorporated herein by reference.

Indirect techniques, which are generally preferred, typically involve preparing a composition to provide drug latency by converting a hydrophilic drug into a lipid-soluble drug. Latency is typically achieved by blocking hydroxyl, carbonyl, sulfate, and primary amine groups present in the compound to make the substance more lipid-soluble and thus more amenable to transport across the blood-brain barrier. Alternatively, delivery of a hydrophilic drug can be enhanced by intra-arterial infusion of hypertonic solutions that temporarily 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).

Applicability

The compounds and pharmaceutical compositions of the present invention are useful for inhibiting the release of β-amyloid peptide and/or its synthesis and can therefore be used for the treatment of Alzheimer's disease in mammals, including humans.

As previously mentioned, the compounds described above are suitable for use in a number of delivery systems.

0000 00 • · 0 0 0 0

0··· 0 ··

0 00 00001 drugs that have been mentioned above. In addition, in order to increase the serum half-life of the administered compound, the compounds can be encapsulated, inserted into lumenal liposomes, as a colloid or modified by other conventional methods to achieve an extension of the serum half-life. A number of methods that are useful for are described, for example, in documents

Szoka et al., U.S. Patents Nos. 4,235,871, 4,501,728 and

4,837,028, all of which are incorporated herein by reference.

prepared by the technique, compounds in serum. preparation of liposomes, which

The amount of compound administered to a patient will vary depending on the substance being administered, the purpose of administration, such as prophylaxis or therapy, the condition of the patient, the route of administration, and the like. In therapeutic administration, the compositions are administered to a patient already suffering from Alzheimer's disease in an amount sufficient to at least partially arrest further development of the symptoms of the disease and its complications. An amount suitable for achieving this purpose is referred to herein as a "therapeutically effective dose." The amount that is effective for such use will depend on the judgment of the attending physician and will be based on factors such as the degree or severity of Alzheimer's disease, the general condition of the patient, and the like. As therapeutic agents, the compounds of the present invention are administered in doses ranging from about 1 to about 500 mg/kg/day.

such as the patient's, Preferably, age, weight and when using

In the case of prophylactic administration, the compositions are administered to a patient at risk of developing Alzheimer's disease (determined, for example, by genetic screening or based on family history) in an amount sufficient to inhibit the onset of symptoms of the disease. An amount suitable for achieving this objective is

• A · · · A

• A · referred to herein as a "prophylactically effective dose. The amount that is effective for this use depends on the judgment of the attending physician and is based on factors such as the degree or severity of Alzheimer's disease in the patient, the age, weight and general condition of the patient, and the like. Preferably, when used as a prophylactic agent, the compounds of the present invention are administered in doses that range from about 1 to about 500 mg/kg/day.

As mentioned above, the compounds are administered to a patient in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. The resulting aqueous solutions can be packaged for use as received, can be lyophilized, and the lyophilized preparation can be combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation is typically between 3 and 11, more preferably from 5 to 9, and most preferably from 7 to 8. It is understood that the use of some of the excipients, carriers, or stabilizers listed will result in the formation of pharmaceutical salts.

Examples of embodiments of the invention

The following synthetic and biological examples are provided to illustrate the subject matter of the present invention and are not intended to limit the scope of the present invention in any way. Unless otherwise indicated, all temperatures are in degrees Celsius.

In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined here, it has ·

• 9

12»· ·· 9999 • 9 9 • · · · · • 9 · ··· ♦ ·· • 9 • 9 9 9 generally accepted meaning.

BOC = tert-butoxycarbonyl

BOP = benzotriazol-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 = dimethyl sulfoxide

EDC = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride

EEDQ = 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline equivalents = equivalent

EtOAc = ethyl acetate

EtOH = ethanol g = gram = liter m = multiplet max = maximum

MeOH = methanol meq - milliequivalent mg = milligram ml = milliliter mm = millimeter mmol = millimole

... ...

··

12.5 »«···

N/A = not available

N = normal ng = nanogram nm = nanometer

OD = optical density

Φ - phenyl

PEPC = 1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide psi = pounds per square inch q = quartet quint. = quintet rpm = revolutions per minute s = singlet t = triplet

TFA = trifluoroacetic acid

THF = tetrahydrofuran tle = thin layer chromatography μΐ = microliter

UV = ultraviolet

In the examples below, all temperatures are in degrees Celsius (unless otherwise noted) and each of the compounds described in these examples was prepared following one of the following General Procedures, unless otherwise noted.

In addition, the term "Aldrich" indicates that the compound or reagent 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

Street, Ronkonkoma NY 11779 USA; the term "Lancaster" indicates that the compound or reagent is 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 "Bachem" indicates that the compound or reagent is commercially available from Bachem Biosciences

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 "TCI" indicates that the compound or reagent is commercially available from TCI America, 9211 North Haborgate Street, Portland, Oregon 97203; the term "Alfa" indicates that the compound or reagent is commercially available from 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 "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, Waterbury, CT, USA.

• to • ·· ·· to··· ·· · · ··« • · · ···· • · · · · · • · I • · I >· · ··<

-123*-* ···· ···

The following General Procedures A'-P' and Examples A1-A74 illustrate the synthesis of N-(aryl/heteroarylacetyl)esters of amino acids that can be hydrolyzed to provide N-(aryl/heteroarylacetyl)amino acid starting materials of the present invention. Other N-(aryl/heteroarylacetyl)esters of amino acids can be prepared using these procedures and starting from commercially available or known starting materials.

General Procedure A'

Coupling R'C(X') (X”) C(0)Cl with H ₂ NCH (R ² ) C (0) XR ³

To a stirred solution of (D,L)alanine iso-butyl ester hydrochloride (prepared in Example B below) (4.6 mmol) in 5 mL of pyridine was added 4.6 mmol of the acid chloride. Precipitation occurred immediately. The mixture was stirred for 3.5 h, diluted with 100 mL of diethyl ether, washed with 10% HCl three times, brine once, 20% potassium carbonate once, and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give the product. Other amino acid esters can also be used in this procedure.

General Procedure B'

Coupling R'C(X') (X)C(O)OH with H ₂ NCH (R ² )C(O)XR ³

A solution of the acid (3.3 mmol) and CDI in 20 mL of THF was stirred for 2 hours. L-alanine iso-butyl ester hydrochloride (prepared in Example B below) (3.6 mmol) was ♦ · 00 » · · I

-124 »0 • 0 • 0 0 0 ·· 0000 » · · » 0 0 0 0 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% HCl three times, brine once, 20% potassium carbonate once, and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give the product. Other amino acid esters can also be used in this procedure.

General Procedure C'

Esterification of R' C (X ' ) (X ) C (O) NHCH (R ² ) C (O) OH with HOR ³

To a stirred solution of phenylacetylvaline (1.6470 g, 7.0 mmol) in 20 mL of THF was added CDI (1.05 g, 6.5 mmol) and the mixture was stirred for 1.5 h. 2-Methylbutanol (0.53 g, 6 mmol) was added to the mixture followed by the addition of NaH (0.16 g, 6.5 mmol). Effervescence immediately occurred. The reaction mixture was stirred overnight. The reaction mixture was diluted with 100 mL of diethyl ether, washed with 10% HCl three times, brine once, 20% potassium carbonate once, and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give the product. Other N-acylated amino acids and alcohols can also be used in this procedure.

General Procedure D'

Hydrolysis of ester to free acid

Hydrolysis of the ester to the free acid was carried out by conventional methods. Two examples of such conventional deesterification methods are given below.

To the ester in a 1:1 mixture of CH2OH/H2O was added 2-5 equivalents of ·· «« ·· ···· • · • · · · · · » · · • · »*· · · ·

-123 ⁴ ·* ····

K ₂ CO ₃ . The mixture was heated to about 50 °C for about 0.5 to

1.5 hours until thin layer chromatography indicated the reaction was complete. The reaction mixture was cooled to ambient temperature and the methanol was removed under reduced pressure. The pH of the remaining aqueous solution was adjusted to about 2 and ethyl acetate was added to the product extract. The organic phase was then washed with saturated aqueous NaCl and dried over MgSO ₄ . The solution was stripped of solvent under reduced pressure to give the product.

The amino acid ester was dissolved in dioxane/water (4:1) to which was added LiOH (approximately 2 equivalents), which was dissolved in water, so that the total solvent after addition was approximately 2:1 dioxane:water. The reaction mixture was stirred until the reaction was complete and the dioxane was removed under reduced pressure. The residue was diluted with EtOAc, the layers were separated and the aqueous layer was acidified to pH 2. The aqueous layer was back-extracted with EtOAc, the combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure after filtration. The residue was purified by conventional methods (e.g. recrystallization).

The following procedure illustrates this example. Phenylacetylalanine methyl ester 3NO ₂ 9.27 g (0.0348 mol) was dissolved in 60 mL dioxane and 15 mL H ₂ O was added to LiOH (3.06 g, 0.0731 mol), which had been dissolved in 15 mL H ₂ O. After stirring for 4 h, the dioxane was removed under reduced pressure and the residue was diluted with EtOAc, the layers were separated and the aqueous layer was acidified to pH 2. The aqueous layer was back-extracted with EtOAc (4 x 100 mL), the combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure from the

3• 99

9 9 to • Λ

12°£* ·*·· ·· ···** » 9 9

9 tttt

9 9 9

9 9 this ··· ·· 99 that · · ·

9 9 9 this· ··· 9 9 • this ·· after filtration. The residue was EtOAc/isooctane, which gave nitrophenylacetylalanine.

0ιιΗ ₁₂ Ν ₂ 0 ₅ corresponds to C = 52.38, H = 4.80 and Analysis found C = 52.54, H = 4.85 and [α] ₂ 3 = -29.9 @ 589 nm.

recrystallized 7.5 g (85%)

N = 11.11 N - 11.08.

General Procedure E'

BOP coupling of acid and alcohol at low temperature.

A methylene chloride solution containing carboxylic acid (100 mol %) and N-methylmorpholine (150 mol %) was cooled to -20 °C under nitrogen. BOP (105 mol %) was added in one portion and the reaction mixture was maintained at -20 °C for 15 min. The corresponding alcohol (120 mol %) was added and the reaction mixture was allowed to warm to ambient temperature and stirred for 12 h. The reaction mixture was then poured into water and extracted with ethyl acetate (3x). The combined ethyl acetate portions were backwashed with saturated aqueous citric acid (2x), saturated aqueous sodium bicarbonate (2x), brine (1x), dried over anhydrous magnesium sulfate or sodium sulfate and the solvent was removed under reduced pressure to give the crude product.

General Procedure F’

EDC coupling of acid and amine

The acid derivative was dissolved in methylene chloride. The amine (1 equivalent), N-methylmorpholine (5 equivalents) and hydroxybenzotriazole monohydrate (1.2 equivalents) were added · Φ Φ Φ Φ • Φ

-127-· · ·«·····

Φ Φ Φ · Φ · ·

Φ · ··· ··· sequence. The reaction mixture was cooled to about 0 °C and then 1.2 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. The solution was allowed to stir overnight and warmed to ambient temperature under nitrogen pressure. The reaction mixture was worked up by washing the solution with saturated aqueous _Na2CO3 , 0.1M citric acid and brine before drying _{over Na2SO4} and removing the solvents to give the crude product. The pure products were obtained by flash chromatography in the appropriate solvent.

General Procedure G’

EDO coupling of acid and amine

A round bottom flask was charged with the carboxylic acid (1.0 equivalents), hydroxybenzotriazole hydrate (1.1 equivalents) and amine (1.0 equivalents) in THF under nitrogen. An appropriate amount (1.1 equivalents for the free amine and 2.2 equivalents for the amine salt hydrochloride) of a base, such as Hunig's base, was added to the well stirred mixture followed by EDC (1.1 equivalents). After stirring for 4 to 17 hours at ambient temperature the solvent was removed under reduced pressure, the residue taken up in EtOAc (or similar solvent) and water. The organic layer was washed with saturated aqueous sodium bicarbonate, 1N HCl, brine and dried over anhydrous sodium sulfate. In some cases the isolated product was analytically pure at this stage, while in other cases purification by chromatography and/or recrystallization was required before biological evaluation.

General Procedure H'

Coupling R ^X C (X ' ) (X ) C (O) Cl with H ₂ NCH (R ² ) C (O) XR ³

-128• · · · · ···

Excess oxalyl chloride in dichloromethane was added to the acid derivative along with one drop of DMF. The resulting mixture was stirred for about 2 hours or until bubbling ceased. The solvent was then removed under reduced pressure and the mixture was diluted again with anhydrous methylene chloride. To the resulting solution was added about 1.1 equivalents of the appropriate amino acid ester and triethylamine (1.1 equivalents in methylene chloride). The system was stirred at ambient temperature for 2 hours and then the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with IN HCl followed by IN NaOH. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to give the product.

General Procedure I'

P-EPC copulation

The P-EPC coupling utilizes 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 known and typically commercially available N-BOC amino acids, as described in General Procedure J' below.

Specifically, the appropriate amino ester free base (0.0346 mmol) and substituted phenylacetic acid (0.069 mmol) were dissolved in 2.0 mL CHCl ₃ (without EtOH), treated with 150 mg PEPC (0.87 meq/g), and the reaction mixture was stirred for 4 days at 23 °C. The reaction mixture was filtered • · • · ** • · ·

-123- Z* ' ·· · « « · · »· ···« • · • ··» through a cotton pad, washed with 2.0 ml CHCl3 and the filtrate evaporated under a stream of nitrogen. The purity of each sample was determined by ¹ H NMR and ranged from 50% to >95%. Between 8.0 and 15.0 mg of final product were obtained from each reaction and were tested without further purification.

General Procedure I'

Synthesis of an amino acid ester from the corresponding N-BOC amino acid

A. Acid esterification.

The N-BOC amino acid was dissolved in dioxane and treated with excess alcohol (approximately 1.5 equivalents) and catalytic DMAP (100 mg) at 0° C. Stirring was continued until the reaction was complete, at which time the product was recovered by conventional methods.

B. Removal of the N-BOC group.

The N-BOC protected amino acid was dissolved in methylene chloride (0.05M) and treated with 10 equivalents of TFA at ambient temperature under a nitrogen atmosphere. The reaction was monitored by thin layer chromatography until the starting material was consumed over 1-5 hours. An additional 10 equivalents of TFA were added to the reaction mixture if starting material was still present after 5 hours. The reaction mixture was carefully neutralized with Na ₂ CO ₃ , separated, the organic layer washed with brine and dried over anhydrous Na ₂ SO ₄ . The crude amine was then used without purification.

A specific example of the procedure is as follows:

1. Racemic (+/-)-N-BOC-α-aminobutyric acid (Aldrich) • «4 • · · ·

-13Q• · · * · · · · · ·♦* > · · » · · · · (9.29 g, 0.0457 mol) was dissolved in 100 ml of dioxane and treated with iso-butyl alcohol (6.26 ml, 0.0686 mol), EDC (8.72 g, 0.045) and catalytic DMAP (100 mg) at 0 °C. After stirring for 17 h, the organics were evaporated under reduced pressure, the residue was diluted with EtOAc, washed with NaHCO3, brine and dried over _Na2SO4 . Evaporation gave 8.42 g (71%) of an oil.

C13H25NO4 requires: C = 60.21, H = 9.72, and N = 5.40.

Analysis found: C = 59.91, H = 9.89 and N = 5.67.

The above N-BOC ester of the amino acid (8.00 g, 0.032 mol) was deprotected as described above to give 3.12 g (61%) of the free base as a colorless oil which solidified on standing.

2. LN-BOC-alanine (Aldrich) (8.97 g, 0.047 mol) was dissolved in 100 mL CH ₂ Cl ₂ , iso-butyl alcohol (21.9 mL, 0.238 mol) and treated with DMAP (100 mg) and EDC (10.0 g, 0.52 mol) at 0 °C. The mixture was stirred for 17 h, diluted with H ₂ O, washed with 1.0 N HCl, NaHCO ₃ , then brine, and the organics were dried over Na ₂ SO ₄ . Filtration and evaporation gave 11.8 g (quantitative) of LN-BOC alanine iso-butyl ester, which was contaminated with a small amount of solvent. The sample was dried in vacuo for analytical purposes.

Ci ₂ H ₂₃ NO ₄ requires: C = 58.79, H = 9.38, and N = 5.71.

Analysis found: C = 58.73, H = 9.55 and N = 5.96.

The above N-BOC ester of the amino acid (11.8 g, 0.0481 mol) was deprotected as described above. The free base was converted to the corresponding HCl salt using saturated HCl (g)/EtOAc to give the iso-butyl ester hydrochloride L-N•φ φφφφ > φ φ » φφφφ

-131» alanine. 4.2 g (48%) of _a colorless solid were obtained. _C7H15NO2 . HCl requires: C=46.28, H=8.88 and N=7.71.

Analysis found: C = 46.01, H = 8.85 and N = 7.68.

General Procedure K'

Formation of methyl ester from amino acid

The amino acid (amino acid or amino acid hydrochloride) was suspended in methanol and cooled to 0 °C. HCl gas was bubbled through the solution for 5 minutes. The reaction mixture was allowed to warm to ambient temperature and then stirred for 4 hours. The solvents were then removed under reduced pressure to give the desired amino acid methyl ester hydrochloride. This product is usually used without further purification.

Example A'

Synthesis of free and polymer-bound PEPC

N-ethyl-N'-3-(1-pyrrolidinyl)propylurea

To a solution of 27.7 g (0.39 mol) of ethyl isocyanate in 250 ml of chloroform was added 50 g (0.39 mol) of 3-(1-pyrrolidinyl)propylamine dropwise with cooling. Once the addition was complete, the cooling bath was removed and the reaction mixture was stirred at ambient 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.

1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (P-EPC) To solution 31.0 g

(0.156 mole)

N-ethyl-N'-3-(1> · · · ► ♦ · * • · · · · · • ·

133• · · · · 4 cooled to 0 °C. g (0.31 mol) pyrrolidinyl)propylurea in 500 ml dichloromethane was added 62.6 g (0.62 mol) triethylamine and the solution was To this solution was then added 59.17 4-toluenesulfonyl chloride in 400 ml dichloromethane dropwise at such a rate as to maintain the reaction at 0-5 °C. After completion of the addition, the reaction mixture was warmed to ambient temperature and then heated to reflux for 4 hours. After cooling to ambient 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 resulting orange mixture was suspended in 250 mL of diethyl ether and the solution was decanted.

Suspending/settling was repeated

The ethereal 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 distilling at 78-82°C (0.4 mm Hg).

firmly 3 more fabrics, three times.

Preparation of polymer-supported form of 1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (P-EPC)

A suspension of 8.75 g (48.3 mmol) of 1-(3-(1-pyrrolidin-yl)propyl)-3-ethylcarbodiimide and 24.17 g (24.17 mmol) of Merrifield resin (2% crosslinking, 200-400 mesh, chloromethylated copolymer of styrene and divinylbenzene, 1 meq Cl/g) in dimethylformamide was heated at 100 °C for 2 days. The reaction mixture was cooled and filtered, and the resulting resin was washed successively with 1 L of DMF, 1 L of THF and diethyl ether. The remaining resin was then dried in ...

133·· ·· » · ♦ * • · · · • · · · · · vacuum for 18 hours.

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 (Aldrich) and 200 ml of isobutanol was heated to reflux for 1.5 hours and the volatiles were completely removed in a rotary evaporator at 90 °C under reduced pressure to give (D,L)-alanine iso-butyl ester hydrochloride (or L-alanine iso-butyl ester hydrochloride) which was sufficiently pure to be used for further transformations.

Example C'

Preparation of 3,5-dichlorophenylacetic acid

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 sulfonyl chloride, followed by 3.5 ml of triethylamine added dropwise. After 2 hours, the solution was diluted to 150 ml with dichloromethane, washed with 3N HCl, saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ and the solvents were removed to give the desired 3,5-dichlorobenzyl methanesulfonate as a yellow oil, which was used without purification.

The crude sulfonate was dissolved in 50 mL DMF at 0 °C and then 3 g KCN was added. After 2 h, another 50 mL DMF was added and the solution was stirred for 16 h. The red solution was diluted with 1 L H ₂ O and acidified to pH 3 « φφ • · · · -134!- .** ' • · · · φ · φ ·· ···

φφφ • φ φ φφφ φφ φφ φ φ φ φ φ φ φ · φφφ φφφ φ ♦ φ · · φ by adding 3N HCl. The aqueous solution was extracted with dichloromethane. The combined organic layers were washed with 3N HCl, dried over Na ₂ SO ₄ and the solvents were removed under reduced pressure to give crude 3,5-dichlorophenylacetonitrile, which was used without purification.

heated to the temperature of dichloromethane and 2

The nitrile was added to a mixture of 40 mL concentrated sulfuric acid and 50 mL H ₂ O and heated to reflux for 48 h, cooled to ambient temperature and stirred for 48 h. The reaction mixture was diluted with crushed ice, ambient and extracted with 2 x 200 mL x 200 mL ethyl acetate. Both sets of organics were combined and washed with saturated aqueous NaHCO3. The NaHCO3 fractions were combined and acidified to pH 1 by adding 3N HCl. The white solid was too fine to filter and was extracted with 2 x 200 mL dichloromethane. The combined organic layers were dried over Na ₂ SO ₄ and the solvents were removed under reduced pressure to give crude 3,5-dichlorophenylacetic acid as a white solid. The solid was suspended in hexane and filtered to give 1.75 g of a white solid.

NMR (CDCl ₃ ) : (in ppm) 3.61 (s, 2H), 7.19 (s, 1H), 7.30 (s, 1H)

Example D'

Synthesis of N-(3-chlorophenylacetyl)alanine

The title compound was prepared using L-alanine (Nova Biochem) and 3-chlorophenylacetic acid (Aldrich) following General Procedures F' or G', followed by hydrolysis following General Procedure D'.

0 0 · 0 · ·

0···

Example A1

Synthesis of N-(phenylacetyl)-D,L-alanine iso-butyl ester

Following general procedure A' above and starting from phenylacetyl chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (prepared in Example B' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica _gel and purification was performed by extraction with _Et2O followed by washing with aqueous _K2CO3 and aqueous HCl.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.23-7.36 (m, 5H), 6.18 (d, 1H), 4.58 (t,

J = 7.3 Hz, IH), 3.87 (m, 2H) , 3.57 (s, 2H) , 1.90 (m, IH) ,

1.34 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.8 Hz, 6H).

¹³ C-nmr (CDC1 ₃ ): δ = 172.7, 170.3, 134.5, 129, 2, 128.8,

127.2, 71.3, 48.1, 43.4, 27.5, 18.8, 18.3.

_{Ci5H2iNO3 :}

Molecular weight = 263.34;

Mass spectroscopy: (MH ⁺ = 264)

Example A2

Synthesis of N-(3-phenylpropionyl)-D,L-alanine iso-butyl ester

Following the general procedure A' above and starting from 3-phenylpropionyl chloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (prepared in Example B' above), the title compound was prepared as a solid having a melting point in the range of 51-54 °C. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by extraction with Et ₂ O followed by washing with aqueous K ₂ CO ₃ and aqueous HCl.

AND·

A • A

A • · » • o ·· A ·

-13S- .** • « · ···♦

A· AAAA • A • AAA

A* A

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.25 (m, 2H), 7.19 (m, 3H) , 6.28 ( d, J = 7.2 Hz, 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) , ú.91 (d, J = = 6.7 Hz, 6H) • ¹³ C-nmr (CDCl ₃ ) : δ = 173.ú, 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. C16H23NO3:

Molecular weight = 277.37;

Mass spectroscopy: (MH ⁺ 278)

Example A3

Synthesis of N-(3-methylpentanoyl)-L-alanine iso-butyl ester

Following general procedure B' and using 3-methylpentanoic acid (Aldrich) and L-alanine isobutyl ester hydrochloride (prepared in Example B' above), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel and purification was performed by extraction with Et ₂ O followed by washing with aqueous K ₂ CO ₃ and aqueous HCl.

The NMR data were as follows:

'H-nmr (CDCl ₃ ) : δ = 6.08 (d, J = 5.9 Hz, 1H), 4.62 (quint., J = 7.3 Hz, 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).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

_{C13H25NO3 : ​}

4 4 4

44 * ♦ • ·· ·

4

4 4 444

Tr444 4444

Molecular weight = 243.35;

Mass spectroscopy: (MH ⁺ 244)

Example A4

Synthesis of N-[(4-chlorophenyl)acetyl]-L-alanine iso-butyl ester

Following general procedure B' and using 4-chlorophenylacetic acid (Aldrich) and L-alanine isobutyl ester hydrochloride (prepared in Example B' above), the title compound was prepared as a solid, melting point 111-113 °C. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by extraction with Et ₂ O followed by washing with aqueous K ₂ CO ₃ and aqueous HCl.

The NMR data were as follows:

3-nmr (CDCl ₃ ): δ = 7.30 (d, J = 8.2 Hz, 2H), 7.21 (d, J =

8.3 Hz, 2H), 6.18 (d, J = 5.5 Hz, IH), 4.57 (quint., J = 7.2 Hz, IH), 3.88 (m, 2H), 3 ₅ 3 (s, 2H), 1.91 (m, IH), 1.36 (d, J = 7.1 Hz, 3H), 0.90 (d, J = 6.8 Hz, 6H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

_{C15H20NO3Cl : ​}

Molecular weight = 297.78;

Mass spectroscopy: (MH ⁺ 298)

Example A5

Synthesis of iso-butyl ester of N-[(3,4-dichlorophenylacetyl]-Lalanine

Following general procedure B' and using 3,4-dichlorophenylacetic acid (Aldrich) and iso-138 hydrochloride

BB BBBB «· • · · • BBBB •Β Β « Β ····♦«

B ♦ B B B

ΒΒΒΒΒΒ of L-alanine butyl ester (prepared in Example B' above), the title compound was prepared as a solid having a melting point in the range of 81-83 °C. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by extraction with Et ₂ O followed by washing with aqueous K 2 CO 3 and aqueous HCl.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 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, 1H), 7.38 (m, 2H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

Ci ₅ H ₁₉ NO ₃ C12 :

Molecular weight - 332.23;

Mass spectroscopy: (MH ⁺ 332)

Example A6

Synthesis of N-[(4-methylphenyl)acetyl]-D,Lalaninin iso-butyl ester

Following general procedure B' and using 4-methylphenylacetic acid (Aldrich) and D,L-alanine isobutyl ester hydrochloride (prepared in Example B' above), the title compound was prepared as a solid, melting point 102-104 °C. The reaction was monitored by thin layer chromatography on silica gel (R _f = 0.6 in 33% ethyl acetate/hexanes) and purification was accomplished by extraction with Et ₂ O followed by washing with aqueous K 2 CO 3 and aqueous HCl.

···

The NMR data were as follows:

3-nmr (CDCl ₃ ): δ = 0.90 (d, J = 6.7 Hz, 6H), 1.35 (d, J =

7.2 Hz, 3H), 1.91 (m, IH), 2.34 (s, 3H), 3.55 (s, 2H), 3.88 (m, 2H), 4.58 (m, IH), 6.05 (bd, IH), 7.16 (s, 4H).

¹³ C-nmr (CDCl 3 ): δ = 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.

_{C16H23NO3 ; ​}

Molecular weight = 277.37;

Mass spectroscopy: (MH ⁺ 278)

Example A7

Synthesis of N-[(3-pyridyl)acetyl]-D,L-alanine iso-butyl ester

Following general procedure F' 3-pyridylacetic acid hydrochloride D,L-alanine iso-butyl ester hydrochloride and using (Aldrich) and (prepared

Example B' above), the title compound was prepared as a solid having a melting point in the range of 62-64 °C. The reaction was monitored by thin layer chromatography on silica gel (R _f = 48 10% methanol/dichloromethane) and purification was carried out by silica gel chromatography.

The NMR data were as follows:

^x H-nmr (CDCI3) : δ = 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, 1H) ; 1.30 (d, J = 7.2, 3H) ; 0.81 (d, J =

6.7, 6H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

Ci ₄ H ₂₀ N ₂ O ₃ :

Molecular weight = 264;

4 9 • 9 9 999

9 #·

-140;Mass spectroscopy: (MH ⁺ 265)

Example A8

Synthesis of N-[(1-naphthyl)acetyl]-L-alanine iso-butyl ester

Following general procedure B' and using 1-naphthylacetic acid (Aldrich) and L-alanine isobutyl ester hydrochloride (prepared in Example B' above), the title compound was prepared as a solid, melting point 69-73 °C. The reaction was monitored by thin layer chromatography on silica gel and purification was performed by extraction with Et ₂ O followed by washing with aqueous K 2 CO 3 and aqueous HCl.

The NMR data were as follows:

^-nmr (CDCl ₃ ) : δ = 0.83 (m, 6H), 1.25 (d, J = 7.1 Hz, 3H), 1.81 (m, 1H), 3.79 (m, 2H), 4.04 (2s, 2H), 4.57 (quint., J=

7.3 Hz, 1H), 5.99 (d, J = 7.1 Hz; 1H), 7.44 (m, 2H), 7.53 (m, 2H), 7.85 (m, 2H), 7.98 (m, 1H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

_{C19H23NO3 ; ​}

Molecular weight - 313.40;

Mass spectroscopy: (MH ⁺ 314)

Example A9

Synthesis of N-[(2-naphthyl)acetyl]-L-alanine iso-butyl ester

Following general procedure B' and using 2-naphthylacetic acid (Aldrich) and L-alanine isobutyl ester hydrochloride (prepared in Example B' given below)

141·- .·’ ••9 9999

9999

9 9

9,999

9 ·

9 9

99· ·9

9 9 9

9 9 9 ·99 999

9 • 9 9· above), the title compound was prepared as a solid, melting at 128-129 °C. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by extraction with Et ₂ O followed by washing with aqueous K 2 CO 3 and aqueous HCl.

NMR data were as follows: ^! H-nmr (CDCI3) : 5=0.86 (m 1.78 (m, IH), 3.76 (s, 2H), 7.2 Hz, IH), 6.13 (d, J = (m, 2H) , 1.14 (s, IH), 7.83 ¹³ C-nmr (CDC1 ₃ ) : δ = 18.4, 71.4, 125.9, 126.3, 127.2 132.0, 132.5, 133.5, 170.3,

, 6H) , 1.35 (d, J = 7.1 Hz, 3H),

3.87 (m, 2H), 4.62 (quint., J =

7.1 Hz, 1H), 7.41 (m, 1H), 7.48 (m, 3H).

18.82, 18.85, 27.6, 43.7, 48.2, , 127.6, 127.7, 128.2, 128.7,

172.8.

C19H23NO3;

M = 313.40;

Mass spectroscopy: (MH ⁺ 314).

Example A10

Synthesis of N-(4-phenylbutanoyl)-L-alanine iso-butyl ester

Following general procedure B' and using 4-phenylbutanoic acid (Aldrich) and L-alanine isobutyl ester hydrochloride (prepared in Example B' above), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel and purification was performed by extraction with Et ₂ O followed by washing with aqueous K ₂ CO ₃ and aqueous HCl.

The NMR data were as follows:

'H-nrar (CDCl ₃ ) : δ = 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 (m, 2H), 4.59 (quint., J = 7.2 Hz,

1H), 6.31 (d, 1H), 7.16 (m, 3H), 7.24 (m, 2H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

C17H25NO3:

Molecular weight = 291.39;

Mass spectroscopy: (MH ⁺ 292).

Example All

Synthesis of N-(5-phenylpentanoyl)-L-alanine iso-butyl ester

Following general procedure B' and using 5-phenylpentanoic acid (Aldrich) and L-alanine isobutyl ester hydrochloride (prepared in Example B' above), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography on silica gel and purification was accomplished by extraction with Et2O followed by washing with aqueous K2CO3 and aqueous HCl.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 7.23 (m, 2H), 7.17 (m, 3H), 6.30 (d, IH) , 4.59 (quint., J = 7.3 Hz, IH), 3.91 (m, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.22 (t, J = 7.2 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) .

¹³ C-nmr (CDCl ₃ ): δ = 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.

C18H27NO3O;

Molecular weight = 305.391;

Mass spectroscopy: (MH+ 306).

Example A12

Synthesis of N-[(4-pyridyl)acetyl]-D,L-alanine iso-butyl ester * » * · ♦ • · ♦

-1439* ·

9999 ♦ ···

9« ···* ♦ · » « * ·« »««

Following general procedure F' and using 4-pyridylacetic acid hydrochloride (Aldrich) and (D,L)-alanine iso-butyl ester (the hydrochloride prepared in Example B' above), the title compound was prepared as a solid, melting point 64-66° C. The reaction was monitored by thin layer chromatography on silica gel (R _f = 0.43 10% methanol/dichloromethane) and purification was carried out by silica gel chromatography.

The NMR data were as follows:

¹ H-nmr (CDCl3) : δ = 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) . ¹³ C-nmr (CDCl3) : δ = 173.5, 169.3, 150 ,5, 144.4, 125.1, 72, and, 48.9, 4 3.0, 28.2, 19.5, 19 .5, 18.9.

C14H20N2O3:

Molecular weight = 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) and L-alanine iso-butyl ester hydrochloride (prepared in Example B' above), the title compound was prepared as a solid having a melting point in the range of 45-47 °C. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by extraction with Et ₂ O followed by washing with aqueous K ₂ CO ₃ and aqueous HCl.

·· ···♦ • · • 9 • 99· •144NMR data were as follows:

^H-nmr (CDCl3) : δ = 7.24-7.39 ( m, SH), 6.14 (dl IH) , 4.58 (lbs.) J = 7.3 Hzl IH) , 3.88 (ml 2HJ1 3.58 (sl 2H), 1.90 (ml IH) , 1.35 (dlJ = 7.2 Hzl 3H), 0.89 (dl J = 6.7 Hz, 6H) . ¹³ C-nmr (CDCl ₃ ) : δ = 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

C15H2, NO3:

Molecular weight = 263.34;

Mass spectroscopy: (MH ⁺ 2M) ).

Example A14

Synthesis of 2-[(3,4-dichlorophenyl)acetamido]butyric acid iso-butyl ester

Following general procedure 1' above and starting from 3,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 7.36 (m, 3H), 6.03 (bd, 1H), 4.54 (m, 1H), 3.87 (m, 2H), 3.49 (s, 2H), 1.93 (m, 2H), 1.72 (m, 1H), 0.88 (d, 6H), 0.80 (t, 3H).

Example A15

Synthesis of 2-[(3-methoxyphenyl)acetamido]butyric acid iso-butyl ester

Following the general procedure I above

• that • ··>·

-145• to this·· • this • · to·· • · · ··· Starting from 3-methoxyphenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

3-nmr (CDCl ₃ ): δ = 6.75 (m, 4H), 5.93 (bd, 1H), 4.51 (m,

1H), 3.83 (m, 2H), 3.75 (s, 2H), 3.52 (s, 2H), 1.82 (m; 2H), 1.60 (m, 1H), 0.84 (d, 6H), 0.74 (t, 3H).

C17H25NO4:

Molecular weight = 307.39;

Mass spectroscopy: (MH ⁺ 309).

Example A16

Synthesis of 2-[(4-nitrophenyl)acetamido]butyric acid iso-butyl ester

Following general procedure 1' above and starting from 4-nitrophenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 8.16 (d, 4.55 (m, 1H) , 3.86 (m, 2H) , (m, 1H), 0.85 (d, 6H) , 0.81

2H), 7.44 (d, 2H), 6.04 (Μ, 1H), 3.66 (s, 2H), 1.86 (m, 2H), 1.67 (t, 3H).

C16H22N2O5:

Molecular weight = 322.36;

·· • · • · ·· ···

-146-, • ···· • · · • » ··· • ft • ·

Mass spectroscopy: (MH ⁺ 323).

Example A17

Synthesis of 2-[(3,4-methylenedioxyphenyl)acetamido]butyric acid iso-butyl ester

Following general procedure 1' above and starting from 3,4-(methylenedioxy)phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.12 (m, 3H), 5.92 (Μ, 1H), 4.54 (m, 1H), 3.86 (m, 2H), 3.66 (s, 2H), 1.86 (m, 2H), 1.66 (m, 1H), 0.89 (d, 6H), 0.79 (t, 3H). .

Example A18

Synthesis of 2-[(thien-3-yl)acetamido]butyric acid iso-butyl ester

Following general procedure 1' above and starting from 3-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^-nmr (CDC1 ₃ ) : δ = 7.37 (m, 1H) , 7.16 (m, 1H) , 7.04 (m, • 4 «« 4444 • 4 • · · ·

-147IH), 6.05 (bd, IH) , 4.57 (m, IH) , 3.66 (s, 2H) , 1.93 (m,

2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H).

Example A19

Synthesis of 2-[(4-chlorophenyl)acetamido]butyric acid iso-butyl ester

Following general procedure I' above and starting from 4-chlorophenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

¹ H-nmr (CDCl 3 ): δ = 7.22 (m, 2H), 7.11 (m, 2H), 5.80 (m, 1H), 4.44 (m, 1H), 3.78 (m, 2H), 3.43 (s, 2H), 1.77 (m, 2H), 1.56 (m, 1H), 0.83 (d, 6H) 0.71 (t, 3H).

Example A20

Synthesis of 2-[(3-nitrophenyl)acetamido]butyric acid iso-butyl ester

Following general procedure I' above and starting from 3-nitrophenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

-148 ¹ H-nmr (CDCl ₃ ) : δ = 8.15 (m, 2H), 7.65 (m, 1H), 6.08 (m, 1H), 4.46 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 1.91 (m, 2H), 1.75 (m, 1H), 0.98 (d, 6H) 0.71 (t, 3H).

Example A21

Synthesis of 2-[(2-hydroxyphenyl)acetamido]butyric acid iso-butyl ester

Following general procedure I' above and starting from 2-hydroxyphenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ) : δ = 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, 1H), 0.89 (d, 6H) , 0.85

(t, 3H).

Example A22

Synthesis of 2-[(2-naphthyl)acetamido]butyric acid iso-butyl ester

Following general procedure I' above and starting from 2-naphthylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration, as

-149 is described in the general procedure.

NMR data were as follows: ^x H-nmr (CDCl ₃ ): δ = 7.83 (m, 7H),

3.84 (m, 2H), 3.75 (s, 2H), 1.89 (d, 6H), 0.81 (t, 3H).

_{C20H25NO3 : ​}

Molecular weight = 327.42;

Mass spectroscopy: (MH ⁺ 328).

Example A23

Synthesis of 2-[(2,4-dichlorophenyl)acetamido]butyric acid iso-butyl ester

Following general procedure I' above and starting from 2,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 7.49 (m, 1H), 7.22 (m, 2H) 5.98 (m, 1H), 4.52 (m, 1H), 3.86 (m, 2H), 3.61 (s, 2H), 1M (m, 2H) , 1.62 (m, 1H) 0.87 (d, 6H), 0.80 (t, 3H).

Example A24

Synthesis of 2-[(4-bromophenyl)acetamido]butyric acid iso-butyl ester

Following general procedure 1' above and starting from 4-bromophenylacetic acid (Aldrich) and iso5.95 (m, 1H), 4.58 (m, 1H), (m, 2H), 1.63 (m, 1H), 0.91

M • * » 9

150 butyl 2-aminobutyrate (prepared according to general procedure J' above) gave the title compound. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^-nrar (CDCl ₃ ): δ = 7.43 (d, 2H) , 7.19 (d, 2H) 5.85 (m, 1H) ,

4.51 (m, 1H), 3.81 (m, 2H), 3.47 (s, 2H), 1.84 (m, 2H), 1.61 (m, 1H) 0.84 (d, 6H), 0.76 (t, 3H).

_Ci6H22NC >3Br:

Molecular weight = 356.26;

Mass spectroscopy: (MH ⁺ 358).

Example A25

Synthesis of 2-[(3-chlorophenyl)acetamido] butyric acid iso-butyl ester

Following general procedure ¹¹ above and starting from 3-chlorophenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^x H-nmr (CDC1 ₃ ): δ = 7.25 (m, 3H) , 7.12 (m, 1H) 5.80 (m, 1H) ,

4.52 (m, 1H), 3.86 (m, 2H), 3.50 (s, 2H), 1.87 (m, 2H), 1.67 (m, 1H), 0.88 (d, 6H), 0.77 (t, 3H).

Ci ₆ H ₂₂ NO ₃ C1:

Molecular weight = 311.81;

Mass spectroscopy: (MH ⁺ 313).

•151 ·» ··

4« ···· » » β · • · · ··«.

• · · · · * • · · · · ·;.···· ·· ·«·* ·· *· » · · * ·, · · · ··♦ ··· • · ·· *C

Example A26

Synthesis of 2-[(3-fluorophenyl)acetamido]butyric acid iso-butyl ester

Following general procedure 1' above and starting from 3-fluorophenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.31 (m, 1H) , 7.01 (m, 3H) 5.95 (m, 1H) ,

4.54 (m, 1H), 3.84 (m, 2H), 3.54 (s, 2H), 1.88 (m, 2H), 1.65 (m, 1H) 0.87 (d, 6H), 0.81 (t, 3H).

C16H22NO3F:

Molecular weight = 295.35;

Mass spectroscopy: (MH ⁺ 296).

Example A27

Synthesis of 2-[(benzothiazol-4-yl)acetamido]butyric acid iso-butyl ester

Following general procedure 1' above and starting from 4-benzothiazol-4-ylacetic acid (Chemservice) and iso-butyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

-152NMR data were as follows:

^-nmr (CDCl ₃ ) : δ = 7.82 (m, 1H), 7.51-7.21 (m, 4H) 5.84 (m, 1H), 4.51 (m, 1H), 3.90 (s, 2H), 3.79 (m, 2H), 1.78 (m, 2H), 1.58 (m, 1H) 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 starting from 2-methylphenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^-nmr (CDCl ₃ ): δ = 7.18 (m, 4H), 5.79 (m, 1H), 4.54 (m, 1H), 3.85 (m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81 (m, 2H), 1.59 (m, 1H) 0.87 (d, 6H), 0.77 (t, 3H).

C17H25NO3:

Molecular weight = 291.39;

Mass spectroscopy: (M ⁺ 291).

Example A29

Synthesis of 2-[(2-fluorophenyl)acetamido]butyric acid iso-butyl ester

Following general procedure 1' above and starting from 2-fluorophenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared according to general procedure J' above), the compound was prepared from

· ·

The reaction was monitored by thin layer chromatography on silica gel and purification was performed by filtration as described in the general procedure.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.28 (m, 1H), 7.09 (m, 3H) 6.03 (m, 1H),

4.54 (m, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 1.89 (m, 2H), 1.64 (m, 1H) 0.88 (d, 6H), 0.80 (t, 3H).

Example A30

Synthesis of 2-[(4-fluorophenyl)acetamido]butyric acid iso-butyl ester

Following general procedure 1' above and starting from 4-fluorophenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.20 (m, 2H), 6.97 (m, 2H), 5.87 (m, 1H), 4.492 (m, 1H), 3.83 (m, 2H), 3.48 (s, 2H), 1.86 (m, 2H), 1.60 (m, 1H) 0.87 (d, 6H), 0.78 (t, 3H).

_{C16H22NO3F : ​}

Molecular weight = 295.35;

Mass spectroscopy: (MH ⁺ 296).

Example A31

Synthesis of 2-[(3-bromophenyl)acetamido]butyric acid iso-butyl ester

-154 Following general procedure 1' above and starting from 3-bromophenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

3-nmr (CDCl ₃ ): δ = 7.45 (m, 2H) , 7.23 (m, 2H) 5.95 (m, 1H) ,

4.55 (m, 1H) 3.84 (m, 2H) 3.55 (s, 2H), 1.89 (m, 2H), 1.68 (m, 1H) 0.91 (d, 6H), 0.81 (t, 3H).

_{C16H22NO3Br : ​}

Molecular weight = 356.26;

Mass spectroscopy: (M ⁺ 357).

Example A32

Synthesis of 2-[(3-trifluoromethylphenyl)acetamido]butyric acid iso-butyl ester

Following general procedure 1' above and starting from 3-trifluoromethylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.52 (m, 1H) , 7.47 (m, 2H) 6.01 (m, 1H) ,

4.56 (m, 1H), 3.86 (m, 2H), 3.61 (s, 2H), 1.84 (m, 2H), 1.62 (m, 1H) 0.87 (d, 6H), 0.80 (t, 3H).

_{C17H22NO3F3 : ​ ​}

-155Molecular weight = 345.36;

Mass spectroscopy: (MH ⁺ 345).

Example A33

Synthesis of 2-[(2-thienyl)acetamido]butyric acid iso-butyl ester

Following general procedure I' above and starting from 2-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^-nmr (CDCl ₃ ): δ = 6.89 (m, 3H), 6.07 (Μ, 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).

Ci ₄ H ₂ iNO ₃ S:

Molecular weight = 283.39;

Mass spectroscopy: (MH ⁺ 284).

Example A34

Synthesis of iso-butyl ester of 2-(phenylacetamido)butyric acid

Following general procedure H' above and starting from phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared according to general procedure I' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by chromatography on

-156-

silica gel using a 9:1 mixture of toluene:EtOAc as the elution solvent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.17-7.28 (m, 5H), 6.23 (d, 1H), 4.51 (m, 1H), 3.86 (m, 2H), 3.54 (s, 2H), 1.87 (m, 2H), 1.62 (m,

1H), 0.87 (d, 6H), 0.78 (t, 3H).

C16H23NO3:

Molecular weight = 277.36;

Mass spectroscopy: (MH+ 277).

Example A35

Synthesis of N-(phenylacetyl)valine 2-methylbutyl 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 mmol) of phenylacetyl chloride (Aldrich). A colorless oil precipitated. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h, washed with 50 mL of 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 compound. The NMR data were as follows:

^-nmr (DMSO-d ₆ ): δ = 12.63 (s, 1H), 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, 3H) 3) ¹³ C-nmr (DMSO-dg): δ = 173.2, 170.4, 136.6, 129.0, 128.2,

126, 3, 57, 1, 41.9, 30.0, 19, 2, 18.0

_{C13H17NO3 : ​}

• ·

-157Molecular weight = 235.29; Mass spectroscopy: (MH ⁺ = 236)

Step B. Synthesis of N-(phenylacetyl)valine 2-methylbutyl ester Following general procedure C' and using n(phenylacetyl)valine prepared in Step A above and 2methylbutan-1-ol (Aldrich), the title compound was prepared as a diastereomeric mixture. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

NMR data was following: ¹ H-nmr (CDCl ₃ ) : δ = 7.25-7.40 (m, 5H) , 5.95 (d, IH), 4.56 (m, IH), 3.84-4.00 (m, 2H), 3.61 (with, 2H) , 2, 10 (m, IH) , 1.68 (m, IH) , 1.38 (m, IH) , 1.15 (m 1 Η) , 0.82- -0.94 (m, 9H), 0.76 (d,

3H).

¹³ C-nmr (CDCl ₃ ): δ = 171.M, 171.81, 170.7, 134.6, 129, 31, 129.27, 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.

C18H27NO3:

Molecular weight = 305.42;

Mass spectroscopy: (MH 306).

Example A36

Synthesis of N-(phenylacetyl)-L-methionine iso-butyl ester

L-methionine (0.1299, 0.869 mmol) (Aldrich) was taken up in dioxane (5.0 mL) and treated with saturated sodium bicarbonate solution (5.0 mL) followed by phenylacetyl chloride (Aldrich) (0.114 mL, 0.822 mmol). After stirring for 17 hours at ambient temperature, the mixture was diluted with ethyl acetate, the layers separated, and the aqueous layer acidified to pH 2 by addition of 5N HCl. The crude product was extracted into ethyl acetate, dried over sodium sulfate, dried in vacuo, and used without further purification. N-Phenylacetyl-L-methionine (0.1285 g, 0.447 mmol) was dissolved in 3.0 mL of dioxane and iso-butyl alcohol (0.2 mL) and treated with EDC (0.094 g, 0.492 mmol) and catalytic DMAP (0.0159). After stirring for 17 h at 23 °C, the mixture was evaporated under 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 CHCl ₃ /MeOH as eluent gave the pure product.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 7.4-7.23 (m, 5H), 6.14 (bd, 1H), 4.70 (m, 1H), 3.89 (d, 2H), 3.62 (s, 2H), 2.43 (m, 2H), 2.12 (m, 1H), 1.93 (m, 2H) , 0.94 (d, 6H).

Ci ₇ H ₂₅ NO ₃ S:

Molecular weight = 323.17;

Mass spectroscopy: (M ⁺ 323)

Example A37

Synthesis of N-(phenylacetyl)-L-leucine iso-butyl ester

L-Leucine (Aldrich) (0.1149, 0.869 mmol) was taken up in dioxane (5.0 mL) and treated with saturated sodium bicarbonate solution (5.0 mL) followed by phenylacetyl chloride (Aldrich) (0.114 mL, 0.822 mmol). After stirring for 17 h at ambient temperature, the mixture was diluted with ethyl acetate, the layers were separated, and the aqueous layer was acidified to pH 2 by addition of 5N HCl. The crude product was extracted into ethyl acetate, dried over sodium sulfate, dried ·· ♦· » ♦ * <

·· ·« • · ·

-159 in vacuum and used without further purification.

N-Phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was dissolved in 2.0 mL CHCl ₃ (plain EtOH) and iso-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 cotton pad, and the filtrate was evaporated under reduced pressure to an oil that was sufficiently pure for testing.

The NMR data were as follows:

3-nmr (CDCl ₃ ): δ = 7.22 (m, 5H), 5.57 (d, 1H), 4.35 (m, 1H), 3.35 (m, 3H), 1.35 (m, 4H), 0.68 (m, 9H).

C18H27NO3:

Molecular weight = 305.40;

Mass spectroscopy: (M ⁺ 305).

Example A38

Synthesis of N-[(3-chlorophenyl)acetyl]alanine 3-methylbut-2-enyl ester

Following general procedure C' above and starting from N-(3-chlorophenyl)acetylalanine (prepared in Example D' above) and 3-methylbut-2-en-1-ol (Aldrich), the title compound can be prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was performed by liquid chromatography using 30% EtOAc/hexane as the eluent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 7.39-7.16 (m, 4H), 6.06 (bd, 1H), 5.385.29 (m, 1H), 4.63 (d, J = 9Hz, 2H), 3.56 (s, 2H), 1.79 (s, 3H), 1.7 (s, 3H), 1.39 (d, J = 9 Hz, 3H).

• · ftft ··

-160• ft • : :, • * · ?

·· ···· • · • ··· • ···· ·· ftftft

Example A39

Synthesis of N-[(3-chlorophenyl)acetyl]alanine cyclopropylmethyl ester

Following general procedure C' above and using N-(3-chlorophenyl)acetylalanine (prepared in Example D' above) and cyclopropylmethanol (Aldrich), the title compound can be prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by liquid chromatography.

using more mixtures 3:7 EtOAc:hexane like washout solvents. NMR data was following: ¹ H-nmr (CDCl ₃ ) : δ = 7.2-7.1 (m, 4H), 6.09 (bs, IH), 4.6 (dq, J = 9 Hz, IH) , 3.96 (dd, J = 9Hz, 2H), 3, 59 (with, 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 the general procedure C' above and using N-(3-chlorophenyl)acetylalanine (prepared in Example D' above) and 2-thiophenemethanol (Aldrich), the title compound can be prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was performed by liquid chromatography using 3:7 EtOAc:hexane as the eluent.

• · • · · · • · · ·

-161φ· ···

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.37-6.97 (m, 7H), 5.97 (q, J = 14 Hz, 2H), 4.6 (dq, J = 9 Hz, 1H), 3.76 (s, 2H), 1.38 (d, J = 9Hz, 3H).

Example A41

Synthesis of N-[(3-chlorophenyl)acetyl]-alanine (1-methylcyclopropyl)methyl ester

Following general procedure C' above and using N-(3-chlorophenyl)acetylalanine (prepared in Example D' above) and (1-methylcyclopropyl)methanol (Aldrich), the title compound can be prepared. The reaction was monitored by thin layer chromatography on

silica gel and cleaning was done with liquid chromatography using mixtures 3:7 EtOAc:hexane as elution solvent. NMR data were as follows: ¹ H-nmr (CDCl 3 ): δ = 8.6 (bd, J = 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).

Example A42

Synthesis of N-[(3chlorophenyl)acetyl]alanine 3-thienylmethyl ester

Following general procedure C' above and using N-(3-chlorophenylacetylalanine (prepared in Example D' above) and 3-thiophenemethanol (Aldrich), the title compound can be prepared. The reaction was monitored by thin layer chromatography on silica gel and

999 • ·

-162·· β··· • · • ··· purification was performed by liquid chromatography using 3:7 EtOAc:hexane as eluent.

The NMR data were as follows:

^-nmr (CDCl ₃ ) : δ = 8.03 (M, J = 9 Hz, IH), 7.56-7.5 (m, IH), 7.47 (bs, IH), 7.4-7.17 (m, 4H), 7.06 (d, J = 9 Hz, IH), 5.1 (s, 2H), 4.3 (dq, IH), 1.3 (d, J = 9 Hz, 3H).

Example A43

Synthesis of N-[(3-chlorophenyl)acetyl]alanine 2-methylcyclopentyl ester

Following general procedure C' above and using N-(3-chlorophenylacetylalanine (prepared in Example D' above) and 2-methylcyclopentanol (Aldrich), the title compound can be prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by liquid chromatography using 3:7 EtOAc:hexane as eluent.

The NMR data were as follows:

^X H- nmr (CDCl ₃ ): δ = 7, 39-7.16 (m, , 4H), 6.3 (bd, IH) , 4.79-4.7 (m, IH), 4.6-4.25 (m, J = 9 Hz, IH), 3.577 (with, 2H) , 2.09-1.8 (m, 2H), 1.74-1.6 (m, 2H), 1.39 (dd, J = 9 Hertz, 3H) , 1.2 (dt, J = ; 9 Hz, IH), 0.979 (dd, J = 9 Hz, 2H).

_{C17H22NO3C1 : ​}

Molecular weight = 323.82; Mass spectroscopy: (MH ⁺ 323).

···

-163• ···· » ···· • · • ···

Example A44

Synthesis of 2-methylprop-2-enyl ester of N-[(3-chlorophenyl)acetyl]alanine to be prepared. The reaction on a thin layer was carried out using a liquid 3:7 EtOAc:hexane as

Following general procedure C' above and using N-(3-chlorophenylacetylalanine (prepared in Example D' above) and 2-methylprop-2-en-1-ol (Aldrich), the title compound can be monitored by silica gel chromatography and purified by chromatography using eluent mixtures.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ) : δ = 7.39-7.16 (m, 4H), 6.03 (bs, 1H), (s, 2H), 4.7-4.29 (m, 3H), 2.59 (s, 2H), 1.73 (s, 3H), (d, J = 9 Hz, 3H)

4.77

1.43

_{C1H18NO3C1 ;}

Molecular weight = 295.76; Mass spectroscopy: (MH ⁺ 295).

Example A45

Synthesis of N-[(3-chlorophenyl)acetyl]alanine cyclohex-2-enyl ester

Following general procedure C' above and using N-(3-chlorophenylacetylalanine (prepared in Example D' above) and cyclohex-2-en-1-ol (Aldrich), the title compound can be prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by liquid chromatography using 3:7 EtOAc:hexane as eluent.

-164solvents.

The NMR data were as follows:

'H-nmr (CDCl3) : δ - 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, 1H) , 1.69-1.49 (m, 4H), 1.3 (dd, J = 9 Hz, 3H)

C17H20NO3Cl:

Molecular weight = 321.8;

Mass spectroscopy: (MH ⁺ 321.2)).

Example A46

Synthesis of N-[(2-phenylbenzoxazol-5-yl)acetyl]alanine iso-butyl ester

Following general procedure 1' above and using 5-(2-phenylbenzoxazol)-yl-acetic acid (CAS # 62143-69-5) and alanine iso-butyl ester (prepared according to general procedure I' above), the title compound was prepared.

The NMR data were as follows:

^-nmr (CDCl ₃ ): δ = 8.24 (m, 3H), 7.68 (m, 1H), 7.51 (m, 5H), 6.04 (m, 1H), 4.58 (m, 1H), 3.85 (m, 2H), 3.68 (s, 2H), 1.9 (m, 1H), 1.35 (d, 3H), 0.87 (d, 6H).

C22H24N2O4 :

Molecular weight = 380;

Mass spectroscopy: (MH ⁺ 381).

Example A47

Synthesis of N-[(3-methylthiophenyl)acetyl]alanine iso-butyl ester

Following the general procedure I ' above and ·<. ··»» • · • ·· ·

165·· 999 ·♦ • · · * • · · · ,· · · 119 Using 3-methylthiophenylacetic acid (CAS # 1869873-2) and alanine iso-butyl ester (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel by filtration as described in the general NMR data were as follows:

3-nmr (CDCl ₃ ): δ = 7.14 (m, 2H), 3.88 (m, 2H), 3.54 (s, 2H), 2.46 (d, 3H) 0.85 (d, 6H).

_{C16H23NO3S ; ​}

M = 309;

Mass spectroscopy: (MH ⁺ 310).

and cleaning was performed according to the procedure.

7.01 (m, IH), 4.56 (m, IH), (s, 3H), 1.89 (m, IH), 1.35

Example A48

Synthesis of N-4-[(2-furyl)acetyl]alanine iso-butyl ester

Following general procedure I' above and using 2-furylacetic acid (CAS # 2745-26-8) and alanine isobutyl ester (prepared according to general procedure 1' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

1H-nmr (CDCl ₃ ) : δ = 7.36 (m, 1H), 6.34 (m, 1H), 6.21 (m, 1H), 4.56 (m, 1H), 3.91 (m, 2H), 3.61 (s, 2H), 1.92 (m, 1H), 1.38 (d, 3H), 0.89 (d, 6H).

C13H19NO4:

Molecular weight = 253;

Mass spectroscopy: (MH ⁺ 254).

• · * • · · · · ·

-166Example A49

Synthesis of N-[(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 according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.51 (m, 1H), 7.44 (m, 1H), 7.25 (m, 2H), 6.67 (s, 1H), 4.60 (m, 1H), 3.87 (m, 2H), 3.77 (s, 2H), 1.88 (m, 1H), 1.38 (d, 3H), 0.87 (d, 6H).

C ₁₇ H ₂ iNO ₄ :

Molecular weight - 303;

Mass spectroscopy: (MH+ 3%)).

Example A50

Synthesis of N-[(benzothiophen-3-yl)acetyl]alanine iso-butyl ester

Following general procedure I' above and using thianaphthene-3-ylacetic acid (Lancaster) and alanine iso-butyl ester (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.89 (m, 1H), 7.76 (m, 1H), 7.38 (m, 3H),

-1676.07 (m, 1H), 4.57 (m, 1H), 3.92 (m, 2H), 3.82 (s, 4H), 1.84 (m, 1H), 1.32 (d, 3H) 0.85 (d, 6H).

C17H21NO3S:

Molecular weight = 319;

Mass spectroscopy: (MH ⁺ 320).

Example A51

Synthesis of N-[(2-chloro-5-thienyl)acetyl]alanine iso-butyl ester

Following general procedure I' above and using 5-chloro-2-thienyl)acetic acid (CAS # 1366919-7) and alanine iso-butyl ester (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 6.77 (m, IH) , 6, 68 (d, IH) , 6, 31 (bm, IH), 4.59 (m, IH), 1.39 (d, 1H) , 3.91 3H) 0.89 (d, (m, 6H) 211) , 3.38 (with, 2H) , 1, 90 (m,

_{C13H18NO3SC1 : ​}

Molecular weight = 303; Mass spectroscopy: (MH ⁺ 303).

Example A52

Synthesis of N-[(3-methylisoxazol-5-yl)acetyl]alanine iso-butyl ester

Following general procedure 1' above and using (3-methyl-isoxazol-5-yl)acetic acid (CAS # 19668-85-0) and alanine iso-butyl ester (prepared by procedure

-168• · · 9 9 · · • · 9 9 · 9 9 · · • · * · 999 ···

9 9 9 9 • · ··· 99 99 according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.07 (s, 2H), 4.56 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 2.29 (s, 3H), 1.94 (m, 1H), 1.89 (d, 3H), 0.91 (d, 6H).

C13H20N2O4 ;

Molecular weight = 268;

Mass spectroscopy: (MH ⁺ 2 69).

Example A53

Synthesis of N-[(2-phenylthiothienyl)acetyl]alanine iso-butyl ester

Following general procedure I' above and using (2-phenyl-thiothienyl)acetic acid and alanine isobutyl ester (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ) : δ = 7.21-7.11 (m, 6H), 6.92 (d, 1H), 4.56 (m, 1H), 3.87 (m, 2H), 3.72 (s, 2H), 1.94 (m, 1H), 1.38 (d, 3H) 0.89 (d, 6H).

C19H23NO3S2:

Molecular weight = 377;

Mass spectroscopy: (MH ⁺ 378).

• ·

-169• ·· · · ···· · · • · · « o·· · • · ····# · · · · • · ·· · ·· ······ • · · · · · · ······· ·· ··· 9 9 9 9

Example A54

Synthesis of N-[(6-methoxybenzothiophen-2yl)acetyl]alanine iso-butyl ester

Following general procedure 1' above and using (6-methoxythiaphten-2-yl)acetic acid and alanine iso-butyl ester (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ) : δ = 7.59 (d, 1H), 7.33 (d, 1H), 7.16 (s, 1H), 7.03 (dd, 1H), 4.56 (m, 1H), 3.87(s, 3H), 3.84 (m, 2H), 3.76 (s, 2H), 1.85 (m, 1H), 1.30 (d, 3H) 0.86 (d, 6H).

_{C18H23NO4S : ​}

Molecular weight = 349;

Mass spectroscopy: (MH ⁺ 350).

Example A55

Synthesis of N-[(3-phenyl-1,2,4-thiadiazol-5-yl)acetyl]alanine iso-butyl ester

Following general procedure 1' above and using (3-phenyl-1,2,4-thiadiazol-5-yl)acetic acid (CAS # 90771-06-5) and alanine iso-butyl ester (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

• 9

-170• · 99 9 9 · · 9 9

9 A · · 9 9 9 9

9 9 99 9 9 9 9 9 • · 0 · · ♦ ······ « · · · ·· ····· 99 999 99 99 ^-nmr (CDC1 ₃ ) : δ = 7.47 (m, 5H) , 4.66 (m, IH) , 4.16 (s, 2H) , 3.91 (m, 2H), 1.93 (m, 1H), 1.48 (d, 3H) 0.93 (d, 6H). Ci ₇ H ₂ iN ₃ O ₃ S:

Molecular weight = 347;

Mass spectroscopy: (MH ⁺ 348).

Example A56

Synthesis of N-[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 according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

Example A57

Synthesis of N-[(3-methylphenyl)acetyl]alanine iso-butyl ester

Following general procedure I' above and using 3-methylphenylacetic acid (Aldrich) and alanine isobutyl ester (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 7.21 (m, 1H), 7.07 (m, 3H), 4.54 (m, 1H), 3.83 (m, 2H), 3.52 (s, 2H), 2.35 (s, 3H), 1.87 (m, 1H), 1.32 (d, 3H), 0.88 (d, 6H).

Ci ₆ H ₂₃ NO ₃ :

Molecular weight = 277;

Mass spectroscopy: (MH ⁺ 278).

Example A58

Synthesis of N-[(2,5-difluorophenyl)acetyl]alanine iso-butyl ester

Following the general procedure using alanine 2,5-difluorophenylacetic iso-butyl ester (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

3-nmr (CDCl ₃ ): δ = 7.08-6.94 (m, 3H), 4.57 (m, 1H), 3.91 (m, 2H), 3.56 (s, 2H), 1.92 (m, 1H), 1.41 (d, 3H) 0.91 (d, 6H). Ci ₅ H ₁₉ NO ₃ F ₂ :

I' above and acid (Aldrich) and

Molecular weight = 299; Mass spectroscopy: (MH ⁺ 300).

Example A59

Synthesis of N-[(3,5-difluorophenyl)acetyl]alanine iso-butyl ester

Following general procedure 1' above and using 3,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration, as

-172 is described in the general procedure.

The NMR data were as follows:

^-nmr (CDCl ₃ ) : δ = 6.81 (m, 2H), 6.74 (m, 1H), 6.06 (m, 1H), 4.57 (m, 1H), 3.92 (m, 2H), 3.51 (s, 2H), 1.94 (m, 1H), 1.36 (d, 3H), 0.87 (d, 6H).

_{C15H19NO3F2 ; ​ ​}

Molecular weight = 299;

Mass spectroscopy: (MH ⁺ 300).

Example A60

Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester

Following general procedure I' above and using 3-thiopheneacetic acid (Aldrich) and alanine isobutyl ester (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

3-nmr (CDCl ₃ ): δ = 7.33 (m, 1H) , 7.14 (m, 1H) , 7.01 (m, 1H) ,

6.5 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H).

Optical rotation: [α] ₂ 3 -52 (c 1 MeOH) @ 589 nm.

_{C13H19NO3S : ​}

Molecular weight = 269;

Mass spectroscopy: (MH ⁺ 269).

Example A61

Synthesis of N-[(4-methylphenyl)acetyl]-L-alanine iso-butyl ester

-173• · · · · · · · · 4

44 · · * ······

4 4 4 · ·

44 4 4 · · · · · · ·

Following general procedure 1' above and using 4-methylphenylacetic acid (Aldrich) and L-alanine isobutyl ester (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by filtration as described in the general procedure.

The NMR data were as follows:

^-nmr (CDCl ₃ ): δ = 7.11 (s, 4H), 5.93 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.54 (s, 2H), 2.33 (s, 3H), 1.89 (m, 1H), 1.32 (d, 3H), 0.89 (d, 6H).

_{C16H23NO3 : ​}

Molecular weight = 277.35;

Mass spectroscopy: (MH ⁺ 278).

Example A62

Synthesis of N-(phenylacetyl)-L-alanine S-1(methoxycarbonyl) iso-butyl ester

Following general procedure K' and using (S)-( + )-2-hydroxy-2-methylbutyric acid (Aldrich) instead 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) following general procedure E' to give carbobenzyloxy-L-alanine S-1-(methoxycarbonyl) iso-butyl ester.

Carbobenzyloxy-L-alanine S-1(methoxycarbonyl) iso-butyl ester (1.0 g) was then dissolved in 20 ml

-174methanol and 6N HCl (0.5 mL) and 10% palladium on carbon (0.1 g) were added. The reaction mixture was hydrogenated at 40 psi hydrogen in a Parr apparatus for 5 hours at ambient temperature and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give L-alanine S-1-(methoxycarbonyl) iso-butyl ester hydrochloride (98% yield).

L-alanine S-1-(methoxycarbonyl) iso-butyl ester hydrochloride was then coupled with phenylacetic acid following general procedure G' to give the title compound.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 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).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

Example A63

Synthesis of N-[(3-nitrophenynacetyl]-L-alanine iso-butyl ester

Following general procedure H' above and starting from 3-nitrophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (prepared in Example B' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by recrystallization from butyl chloride.

The NMR data were as follows:

H1-nmr (CDCl ₃ ): δ = 8.17 (m, 2H), 7.68 (d, 1H), 7.52 (t, 1H),

-175«· ·Α·Α Α· AA

A A · A · · A • V ··· A A A · •A A AA AAA AAA

AAA A A ·· AAA AA AA

6.18 (m, 1H), 4.48 (m, 1H), 3.94 (m, 2H), 3.67 (s, 2H), 1.93 (m, 1H), 1.42 (d, 3H), 0.91 (d, 3H).

Optical rotation: [α] ₂ 3 49 (c 5, MeOH).

Example A64

Synthesis of N-[(3,5-difluorophenyl)acetyl]alanine ethyl ester

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 thin layer chromatography on silica gel (R _f = 0.8 in EtOAc) and purification was carried out by silica gel chromatography using EtOAc as eluent followed by recrystallization from 1-chlorobutane.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.30 (d, 3H); 3.52 (s, 2H) .

C13H15NO3E2:

Molecular weight = 271.26;

Mass spectroscopy: (MH ⁺ 271).

Example A65

Synthesis of N-[(3-nitrophenyl)acetyl]methionine ethyl ester

Following general procedure G’ above and starting from 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by recrystallization from butyl chloride.

The NMR data were as follows:

-17 6• 4444

H-nmr (CDCl3)

7.48 (t, IH), (s, 2H), 2.47 δ = 8.18 (s, IH), 8.15 (d, IH) 7.66 (d, IH), 6.30 (m, IH), 4.67 (m, IH) , 4.21 (t, 2H), 3.67 (t, 2H), 2.12 (m, 2H), 2.08 (s, 3H), 1.27 (t,

3H).

Optical rotation: [α] ₂ 3 ”30 (c 5, MeOH).

Example A66

Synthesis of N-[(3-chlorophenyl)acetyl]alanine iso-butyl ester

Following general procedure G' above and starting from 3-chlorophenylacetic acid (Aldrich) and alanine isobutyl ester (prepared according to general procedure J' above), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel.

The NMR data were as follows:

^-nmr (CDCl ₃ ): δ = 7.29 (m, 3H), 7.18 (m, 1H), 6.0 (m, 111), 4.56 (m, 1H), 3.89 (m, 2H), 3.53 (s, 2H), 1.91 (m, 1H), 1.39 (d, 3H), 0.91 (d, 3H).

Optical rotation: [α] ₂ 3 -45 (c 5, MeOH).

_{C15H20NO3Cl : ​}

Molecular weight = 297.78;

Mass spectroscopy: (MH ⁺ 297).

Example A67

Synthesis of N-[(3chlorophenyl)acetyl]alanine 2-(N,N-dimethylamino)ethyl ester

Following general procedure C' above and using N-(3-chlorophenylacetyl)alanine (prepared in

φφ φφ φ φ φ · φ φ φ · «φφ φφφ φ φ » φφφφ φ φ • φφφ

-177φφφφφ

Example D' above) and 2-(N,N-dimethylamino)ethanol (Aldrich), the title compound can be prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by liquid chromatography using a mixture of 0.1:2:0.79 NH ₄ OH:EtOH:CHCl ₃ as the eluent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : 7.37 (s, 1H), 7.33-7.2 (m, 3H), 4.675-4.6 (m, 1H), 4.5-4.37 (m, 1H), 4.25-4.13 (m, 1H), 3.6 (d, J = 7 Hz, 2H), 2.86 (bs, 2H), 2.3 (s, 6H), 1.23 (d, J = 9 Hz, 3H). C ₁₅ H ₂ iN ₂ O ₃ C1:

Molecular weight = 313.799;

Mass spectroscopy: (M ⁺ 313).

Example A68

Synthesis of 2-[(3,5-dichlorophenyl)acetamido]hexanoic acid methyl ester

Following general procedure F' above and using 3,5-dichlorophenylacetic acid (prepared in Example C' above) and L-norleucine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid, melting at 77-78° C. The reaction was monitored by thin layer chromatography on silica gel (R _f = 0.70 in 40% EtOAc/hexanes) and purification was carried out by flash chromatography on silica gel using 40% EtOAc/hexanes as the eluent.

The NMR data were as follows:

1H-nmr (CDCl ₃ ): δ = 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) .

-178• ·· ·· ···· ftft ftft • ft · ft ··· ···· ft ftftft ftftft · · · · • ftftftft ftft ftftft ··· • · ftftft ftft • ftft ftftftft ftft ftftft ft* ·· ¹³ C-nmr (CDC1 ₃ ) : δ = 173.54, 169.67, 138.43, 135, 72, 128.33,

128.07, 78.04, 77.621 77.19, 53.04, 52.90, 43.14, 32.571

27.87, 22.81, 14.41.

Example A69

Synthesis of N-[(3,5-dichlorophenyl)acetyl]-Lalanine iso-butyl ester

Following general procedure F' above and using 3,5-dichlorophenylacetic acid (prepared in Example C' above) and Lalanine iso-butyl ester hydrochloride (prepared in Example B' above), the title compound was prepared as a solid having a melting point in the range of 115-116 °C. The reaction was monitored by thin layer chromatography on silica gel (R _f = 0.40 in 39% methanol/dichloromethane) and purification was carried out by flash chromatography on silica gel using 3% methanol/dichloromethane as the eluent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 7.27 (d, J = 2 Hz, 1H), 7.19 (s, 2H), 6.22 (d, J = 6 Hertz, IH), 4.59 (quint., J = 7 Hz, IH), 3.9 (q, J = 4 Hz, 2H), 3, 5 (s, 2H), 1.9 (m, IH), 1.4 (d, J = 7 Hz, 3H), 0.91 (d, J = 7 Hz, 6H). ¹³ C-nmr (CDCl ₃ ) : δ = = 173.45, 169.37, 138.31, 135.75, 128,391 128.11, 78.04, 77, 61, 77,19, 72, 19, 54.03, 48.97, 43.12,

28.24, 19.52, 19.49, 19.09. C ₁₅ H ₁₉ NO ₃ C 1 ₂ ;

Molecular weight = 331.9; Mass spectroscopy: (MH ⁺ 332).

····

-1790 • 0 0 000 0 0 0 · 0 00 0 00 ······

0 0 0 · · 0 0000 00 000 «· ··

Example A70

Synthesis of N-(cyclohexylacetyl)-L-alanine iso-butyl ester

Following general procedure B' above and using cyclohexylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (prepared in Example B' above), the title compound was prepared as a solid, melting point 92°C-93°C. The reaction was monitored by thin layer chromatography on silica gel (R _f = 0.39 in 1:3 EtOAc:hexane) and purification was accomplished by extraction with Et ₂ O followed by washing with aqueous K 2 CO 3 and aqueous HCl.

The NMR data were as follows:

^X H- nmr (CDCl3) : δ = 0.93 (d, J = 6.7 Hertz, 6H) , 0.85-1.01 (m, 2H) , 1, 05-1.35 (m, 3H) , 1.40 (d, J = 7.1 Hertz, 3H), 1.60-1.85 (m, 6H) , 1.95 (m, IH) , 2.06 (d, J = 7.0 Hertz, 2H), 3.92 (m, 2H) , 4, 61 (m, IH), 6, 08 (M, 1 H) . ¹³ C- -nmr (CDCl3) : δ = 18 ,7, 18.9 , 26 ,0, 26, 1 , 27, 6, 33.0,

35.3, 44.6, 47.9, 71.4, 171.8, 173.3.

C15H27NO3;

Molecular weight = 269.39;

Mass spectroscopy: (MH ⁺ 270).

Example A71

Synthesis of N-(cyclopentylacetyl)-L-alanine iso-butyl ester

Following general procedure B' above and using cyclopentylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (prepared in Example B' above), the title compound was prepared as a solid having a melting point in the range of ... to ... 1

-180 ·* this this this · • ··· • · ··· ·*· • ··

-64° C. The reaction was monitored by thin layer chromatography on silica gel (Rf = 0.37 in 1:3 EtOAc:hexane) and purification was performed by extraction with Et2O followed by washing _with aqueous _K2CO3 and aqueous HCl.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 0.87 (d, J = 6.8 Hz, 6H), 1.01-1.17 (m,

2H), 1.34 (d, J = 7.2 Hz, 3Η), 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, J = 7.1 Hz, IH) .

¹³ C~nmr (CDCl ₃ ) : δ = 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.

Elemental analysis

Calculated (%): C, 65.85; H, 9.87; N, 5.49;

Found (%): C, 66.01; H, 10.08; N, 5.49.

_{C14H25NO3 ;}

Molecular weight = 255.36;

Mass spectroscopy: (MH ⁺ 256).

Example A72

Synthesis of N-[(cyclohex-1-enyl)acetyl]-L-alanine iso-butyl ester

Following general procedure B' above and using cyclohex-1-enylacetic acid (Alpha) and L-alanine iso-butyl ester hydrochloride (prepared in Example B' above), the title compound was prepared as a solid having a melting point in the range of 49°C-51°C. The reaction was monitored by thin layer chromatography on silica gel (R _f = 0.40 in 1:3 EtOAc:hexane) and purification was carried out by extraction with Et ₂ O followed by washing with

-181• ·· ··*·· ·· · · · · · · • 9 9 9 999

9 9 9 9 9

9 9 9 9

9999999 99 999 aqueous K ₂ CO ₃ and aqueous HCl. The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 0.91 (d, J = 4, 5Hz, 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, 2H) , 2.89 (s, 2H), 3.92 (m, 2H) , 4.59 (m, 1H), 5.65 (with, IH) , 6.33 (d, J = 6.6 Hz, IH)

¹³ C-nmr (CDC1 ₃ ): δ = 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

Calculated (%): C, 67.38; H, 9.42; N, 5.24;

Found (%): C, 67.34; H, 9.54; N, 5.16.

CisH ₂ 5NO ₃ :

Molecular weight = 267.37;

Mass spectroscopy: (MH ⁺ 268).

Example A73

Synthesis of N-[(3-chlorophenyl)acetyl]alanine 3-methylbut-2-enylthioester

Following the general procedure C' above and using N-[(3-chlorophenyl)acetyl]alanine and 3-methyl-2-butenethioester (TCI), the title compound can be prepared. The reaction was monitored by thin layer chromatography on silica gel and purification was carried out by liquid chromatography using 3:7 EtOAc:hexane as eluent.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 5.2-5.075 (m, IH), 4.37 (dq, J = 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 ₁₆ H ₂₀ NO ₂ ClS:

BB BBBB

BB

-182Molecular weight = 325.86;

Mass spectroscopy: (M ⁺ 325).

Example A74

Synthesis of N-[(2-phenyl-2-fluoroacetyl]alanine ethyl ester

Following general procedure F' above and using α-fluorophenylacetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography on silica gel (R _f = 0.75 in 1:1 EtOAc:hexane) and purification was performed by silica gel chromatography using 1:2 ethyl acetate/hexanes as the eluent.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 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).

_{Ci3H16NO3F : ​}

Molecular weight = 253.27;

Mass spectroscopy: (MH ⁺ 253).

Example A75

Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycine methyl ester

Following the general procedure F above and using

3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Bachem), the title compound was prepared.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.4-7.3 (m, 5H), 6.9-6.7 (m, 3H), 6.55 (d

94 • 9 9 9

9 9 9

999 999

9

99

-183• ··

9 4

9

9 • · • « · « · 9 ·

4499 • 4 · • · · · ·

9 9 9

9 9

999

IH, 7.1 Hz), 5.56 (d IH, 7 Hz) ,

3.72 (s, 3H),

3.57 (s, 2H) ¹³ C-nmr (CDCl ₃ ): δ = 197.6, 177.6, 171.8, 169.3,

129.6, 129.3, 127.8, 113.0, 112.9, 112.7, 111.4,

103.5, 65.1, 57.2, 53.5, 45.1, 43.3, 43.3

136.7,

103.8,

C17H15NO3F2:

Molecular weight = 319.31; Mass spectroscopy: (MH +320).

Example A76

Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycine iso-butyl ester

3,5-Difluorophenylacetic acid (Aldrich) was EDC coupled with L-phenylglycine methyl ester hydrochloride (Bachem) according to general procedure F above.

The resulting compound was placed in a large excess of the desired alcohol. A catalytic amount of anhydrous NaH was added and the reaction was monitored by thin layer chromatography until the presence of starting material was no longer detected. The reaction was quenched with a few milliliters of 1N HCl and after stirring for a few minutes, saturated aqueous NaHCO ₃ was added. The volume of the reaction mixture was reduced in a rotary evaporator until the excess alcohol was removed and then the remaining residue was taken up in ethyl acetate and more water was added. The organic phase was washed with saturated aqueous NaCl and dried over MgSO ₄ . The solution was freed from solvent in a rotary evaporator and the crude residue was then further purified by chromatography.

The NMR data were as follows:

^-nmr (CDCl ₃ ) : δ =

7.35-7.3 (m 5H) , 6.8-6.7 (m 3H) 6.60 (d

-184·· ·· • e t 4 · · * • · · ·»· e · · * • φ « « ·· ·*··*· . · · · · · » «•Φ ···· ·· «·· *· ··

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) ¹³ C-nmr (CDC1 ₃ ) : δ = 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.

C^iNO^:

Molecular weight = 361.39;

Mass spectroscopy: (MH ⁺ 362).

Example A77

Synthesis of N-(cyclopentylacetyl)-L-phenylglycine methyl ester

Following general procedure D' above and using cyclopentylacetic acid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem), the title compound was prepared.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ) : δ = 7.35 (s, 5H), 6.44 (bd, 1H), 5.6 (d, 1H), 3.72 (s, 3H), 2.24 (bs, 3H), 1.9-1.4 (m, 6H), 1.2-1.05 (m, 2H) ¹³ C-nmr (CDCl ₃ ): δ = 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

Example A78

Synthesis of N-(cyclopentylacetyl)-L-alanine methyl ester

Following general procedure I' above and using cyclopentylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared.

The NMR data were as follows:

-18599 ·® • · · · • 9 9 ·

999 999 ·

9 9 · ¹ H-nmr (CDCl3): δ = 6.38 (d, 1H), 4.50 (m, 1H), 3.65 (s, 3H), 2.13 (bs, 3H), 1.80-1.00 (m (includes d at 1.30, 3H), 11H) ¹³ C-nmr (CDCl3): δ = 173.7, 172.5, 52.1, 47.6, 42.3, 36.8,

32.15, 32.14, 18.0

C11H19NO3:

Molecular weight = 213.28;

Mass spectroscopy: (MH ⁺ 214).

Example A79

Synthesis of N-(cyclopropylacetyl)-L-phenylglycine methyl ester

Following general procedure D' above and using cyclopropylacetic acid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem), the title compound was prepared.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.35 (m, 5H) 6.97 (bd, J = 7.2 Hz, 1H),

5.59 (d, J = 7.8 Hz, 1H), 3.71 (s, 3H), 2.17 (m, 2H), 1.050.95 (m, 1H), 0.62 (m, 2H), 0.02 (m, 2H) ¹³ C-nmr (CDC1 ₃ ): δ = 171.9, 174.6, 136.6, 129.0, 128.5,

127.2, 56, 1, 52.7, 41.0, 6, 9, 4.37, 4.33

Example A80

Synthesis of N-(cyclopropylacetyl)-L-alanine methyl ester

Following general procedure D' above and using cyclopropylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared.

The NMR data were as follows:

4· ····

-186• *

^x H-nmr (CDCl3): δ = 6.60 (d, 1H), 4.55 (m, 1H) , 3, 69 (with, 3H) , 2.10 (m, 2H), 1.34 (d, 3H) , 0.95 (m, 1H), 0.58 (m, 2H) 0.15 (m, 2H) ¹³ C-nmr (CDCl ₃ ) : δ = 173.7, 172.3, 52.3, 47.7, 41, 0, 18.2,

6.7, 4.27, 4.22

Example A81

Synthesis of N-[(3-nitrophenyl)acetyl]-Lmethionine iso-butyl ester

Following general procedure H' above and using nitrophenylacetic acid (Aldrich) and L-methionine (Aldrich), the title compound was prepared as a brown oil. The reaction was monitored by thin layer chromatography on silica gel.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 8.16 (m,2H) 7.67 (d, 1H) 7.32 (t, 1H) , 6.31 (M, 1H), 4.69 (m, 1H) , 3.90 (d, 2H), 3.68 (with, 2H) , 2.47 (t, 2H), 2.15 (m, 1H), 2.02 (s, 3H), 1.90 (m, 2H) , 0.91 (d,

6H).

C17H24N2O5S:

Molecular weight = 368.4;

Mass spectroscopy: (MH ⁺ 368).

The following General Procedures A-B and Examples B1-B2 illustrate the synthesis of N-(aryl/heteroarylacetyl)amino acid starting materials from L-alanine, useful in the present invention. Other N-(aryl/heteroarylacetyl)amino acids can be prepared using these procedures from commercially available or known starting materials.

-187• · · · · · • · · · · ·

General Procedure A

Preparation of acetyl chloride

3,5-Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and the solution was cooled to 0 °C. DMF (0.5 mL, catalytic) was added followed by the dropwise addition of oxalyl chloride (18 mL, 0.20 mol) over a 5 minute period. The reaction mixture was stirred for 3 hours and then concentrated in a rotary evaporator under reduced pressure to a residue which was placed under high vacuum for 1 hour to give 3,5-difluorophenylacetyl chloride as a thick yellow oil. Other acetyl chlorides can be prepared in a similar manner.

General Procedure B

Schotten-Bauman procedure

3,5-Difluorophenylacetyl chloride (from General Procedure A) was added dropwise to a solution of L-alanine (Aldrich) (16.7 g, 0.187 mol) at 0 °C in 2 N sodium hydroxide (215 mL, 0.43 mol). The reaction mixture was stirred for 1 h at 0 °C and then overnight at ambient temperature. The reaction mixture 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 MgSO ₄ and rotary evaporated under reduced pressure to a residue. Recrystallization of the residue from ethyl acetate/hexanes gave the desired product (34.5 g, 82% yield). Other acetyl chlorides can be used in this procedure to obtain intermediates useful in the present invention.

-188Example B 1

Synthesis of N-(phenylacetyl)-L-alanine

Following general procedure B above, the title compound was prepared from phenylacetyl chloride (Aldrich) and Lalanine (Aldrich) as a solid having a melting point in the range of 102-104 °C.

The NMR data were as follows:

3-nmr (CDCl ₃ ): δ = 9.14 (br s, 1H), 7.21-7.40 (m, 5H), 6.20 (d, J = 7.0 Hz, 1H), 4.55 (m, 1H), 3.61 (s, 2H), 1.37 (d, J = 7.1 3H).

¹³ C-nmr (CDCl ₃ ): δ = 176.0, 171.8, 134.0, 129.4, 127.5, 48.3, 43.2, 17.9.

Example B2

Synthesis of N-(3,5-difluorophenylacetyl)-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).

The NMR data were as follows:

^-nntr (CD ₃ OD) : δ = 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) .

¹³ C-nmr (CD ₃ OD) : δ = 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, 17.5.

Following General Procedures A'''-C''' and Examples C1-C8

-189• · · · • · · · · · · · · · · · · illustrate the synthesis of dipeptide ester starting materials useful in the present invention. Other dipeptide esters can be prepared using these procedures and starting from commercially available or known starting materials.

General Procedure A'''

EDO coupling procedure

A round bottom flask containing a magnetic stirrer under nitrogen at 0°C or ambient temperature was charged with THF, carboxylic acid (1.0 equivalent), amine or amine hydrochloride (1.1 equivalent), 1-hydroxybenzotriazole hydrate (1.15-1.2 equivalents), N,N-diisopropylethylamine (2.2-2.9 equivalents), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDO) hydrochloride (1.15-1.2 equivalents). The cooling bath was removed and the mixture was allowed to warm to ambient temperature with stirring for 10-20 hours. The mixture was diluted with EtOAc and washed with 0.5 N aqueous HCl (2x), dilute aqueous NaHCO ₃ (1x), brine (1x), and dried over either Na ₂ SO ₄ or MgSO ₄ . The drying agent was removed by filtration and the filtrate was 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 recrystallization.

General Procedure B'''

Removal of the n-tert.-Boc protecting group

N-tert-Boc-amine was dissolved in a suitable anhydrous solvent (such as 1,4-dioxane or ethyl acetate) and the solution

-190 was cooled in an ice bath. HCl gas was passed 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 give the amine hydrochloride. The amine hydrochloride was used without purification or triturated using, for example, diethyl ether and the resulting solid was collected by filtration.

General Procedure C'''

EEDQ mating procedure

A round bottom flask containing a magnetic stirrer under a nitrogen atmosphere at ambient temperature was charged with THF, carboxylic acid (1 equivalent), amine hydrochloride (1.1 equivalents) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (1.1 equivalents). The reaction mixture was allowed to stir for 15 minutes and then 4-methylmorpholine (1.1 equivalents) was added and stirring was continued at ambient temperature for 15-20 hours. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between ethyl acetate and water. The organic phase was separated and washed with saturated aqueous NH ₄ Cl (2x), saturated aqueous NaHCO ₃ (2x), followed by brine (1x). The organic phase was then dried over Na ₂ SO ₄ and the drying agent was removed by filtration and the filtrate was 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 recrystallization.

Example C 1

Synthesis of N-(L-methionine)-L methyl ester hydrochloride

-191-

phenylglycine

Following general procedure A''' and using N-(tert-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 following general procedure B''' to afford the title compound as a crude solid or foam.

Example C2

Synthesis of N-(2-aminobutanoyl)-L-phenylglycine methyl ester hydrochloride

Following general procedure A''' and using N-(tert-butoxycarbonyl)-2-aminobutyric acid (Sigma) and L-phenylglycine methyl ester hydrochloride (Bachem), the protected dipeptide was prepared as a crude solid or foam. The resulting crude dipeptide was deprotected following general procedure B''' to afford the title compound as a crude solid or foam.

Example C3

Synthesis of N-(L-leucine)-Lphenylglycine methyl ester hydrochloride

Following general procedure A''' and using N-(tert-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 crude dipeptide was deprotected following general procedure

-1929 · 9 9

999 9999 99

Β''' and thus obtained the title compound as a crude solid or foam.

Example C4

Synthesis of N-(L-phenylalanine)-L-phenylglycine methyl ester hydrochloride

Following general procedure A''' and using N-(tert-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 following general procedure B''' to afford the title compound as a crude solid or foam.

Example C5

Synthesis of N-(glycine)-L-phenylglycine methyl ester hydrochloride

Following general procedure A''' and using N-(tert-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 dipeptide was deprotected following general procedure B''' to afford the title compound as a crude solid or foam.

Example C6

Synthesis of N-(L-phenylglycine)-L-phenylglycine methyl ester hydrochloride

Following the general procedure C''' and using N-(tert.-193• ···· ·· ··♦· • ·

494

49

4 9 9

4 4 4 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 following general procedure B''' to afford the title compound as a crude solid or foam.

Example C7

Synthesis of N-(L-valine)-Lphenylglycine methyl ester hydrochloride

Following general procedure A''' and using N-(tert-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 following general procedure B''' to afford the title compound as a crude solid or foam.

Example C8

Synthesis of N-[(S)-2aminocyclohexylacetyl)-L-phenylglycine methyl ester hydrochloride

Following general procedure A''' and using N-(tert-butoxycarbonyl)-(S)-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 following general procedure B''' to afford the title compound as a crude solid or foam.

-194• · · • · ···· • · • ···

The following Examples D1-D4 illustrate the synthesis of various intermediates useful as starting materials of the present invention. Similar intermediates can be prepared using these procedures and commercially available or known starting materials.

Example D 1

Synthesis of 3,5-difluorophenyl-α-fluoroacetic acid

Methyl-3,5-difluoromandelane was prepared according to the general procedure G below using commercially available 3,5-difluoromandelic acid. The resulting α-hydroxy methyl ester was fluorinated according to the general procedure described by WJ Middleton et al., Org. Synt. Col. Vol. VI, 835. Specifically, a solution of diethylaminosulfur trioxide (1.1 equivalents) in CH2Cl2 was cooled to 0°C and treated with methyl-3,5-difluoromandelane (1.0 equivalents) in _CH2Cl2 . After 10 minutes, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction was monitored by thin layer chromatography (Rf = 0.65, ₁ :1 ethyl acetate/hexanes). The mixture was then poured onto ice and the layers were separated. The organic phase was washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was purified by LC ₂₀₀₀ chromatography (180 mL/min) using 10% EtOAc/hexanes as the eluent. The resulting methyl 3,5-difluorophenyl-α-fluoroacetate was hydrolyzed by dissolving the ester in 70% aqueous dioxane and treating with lithium hydroxide (2.0 equivalents). No residue remained after 2 hours by thin layer chromatography.

-195•4 4444 • · · • 4 444

4 4

4 ·

444

44 • 4 · ·

4 4 4 starting material. Dioxane was removed by rotary evaporation. The aqueous mixture was first washed with ethyl acetate and then acidified by addition of 0.01 N HCl. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude solid was recrystallized from ethyl acetate/hexanes to give 3,5-difluorophenyl-α-fluoroacetic acid as a white solid, melting at 90-110 °C.

_{C8H5F3O2 : ​ ​}

Molecular weight = 190.1;

Mass spectroscopy: 190.1.

Example D2

Synthesis of (S)-2-hydroxy-2-methyl-1-phenylprop-1-ylamine (S)-2-Hydroxy-2-methyl-1-phenylprop-1-ylamine was prepared by adding 5.0 equivalents of methylmagnesium 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, the residue was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as eluent.

Example D3

Synthesis of methyl-(S)-2-amino-2-(6-methoxy-2-naphthyl)acetate (S)-2-(tert-butoxycarbonylamino)-2-(6-methoxy-2-naphthyl)acetic acid was prepared from 2-(6-methoxy-2-naphthyl)acetic acid by the general method described by D.A. Evans et al., J. Amer. Chem. Soc.,

-196 (1990), 112, 4011-4030. Briefly, (S)-3-(6-methoxy-2-naphthylacetyl)-4-benzyl~2-ozazolidinone was converted to (S)3-[(S)-6-methoxy-2-naphthyl-α-azidoacetyl)-4-benzyl-2-ozazolidinone by a standard enolate azidation procedure 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 gave (S)-2-azido-2-(6-methoxy-2-naphthyl)acetic acid. Reduction of this intermediate as its sodium salt in 1:1 1,4-dioxane/water (0.05 M) under 1 atm of hydrogen and 10% Pd/C at 25 °C gave (S)-2-azido-2-(6methoxy-2-naphthyl)acetic acid, which was then converted, without isolation, to its N-Boc derivative by treatment with 1.4 equivalents of di-tert-butyl dicarbonate and 0.47 equivalents of sodium carbonate. The product was isolated by acidification to pH 2 with 1 N NaHSO ₄ and extraction with three portions of ethyl acetate. The product was recrystallized from ethyl acetate/hexanes to give a white solid, mp = 176 °C (shrinkage); 197-199 °C (decomposition).

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ) : δ = 12.78 (s, IH), 7.84-7.77 (m, 3H), 7.62 (d, J = 8 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-(tert-butoxycarbonylamino)-2-(6-methoxy-2-naphthyl)acetic acid was then converted to the methyl ester following general procedure G below. The methyl ester was then dissolved in CH ₂ Cl ₂ and the solution was cooled to 0 °C. Trifluoroacetic acid (50 molar equivalents) was added and the reaction mixture was allowed to stand.

-197·· ··♦· ·· ·· » t · · · · » · «·· · · · » · ·· ·· ·« warmed to ambient temperature and stirring was continued for 2 hours. The reaction mixture was then concentrated and the residue was extracted into CH2Cl2 and washed with sodium bicarbonate solution. The organic layer was dried over _Na2SO4 , filtered and concentrated to give methyl-(S)-2-amino-2-(6methoxy-2-naphthyl)acetate.

Example D4

Synthesis of methyl 2-amino-2-(thieno[2,3-5]thiophen-2-yl)acetate thieno[2,3-b]thiophen-2a methyl methylsulfinyl then EtOAc brine and concentrated

To 3.75 molar equivalents of sodium hydride (plain oil) was added DMF and the resulting mixture was cooled to 0 °C. A solution of methyl carboxylate (1 molar equivalent) and methyl sulfide (1.1 molar equivalents) in DMF was then added dropwise and the reaction mixture was stirred at 0 °C for 30 minutes and then allowed to warm to ambient temperature and stirring was continued for 3 hours. The reaction was quenched with methanol and the product was extracted into The organic extracts were washed with water followed by drying over Na ₂ SO ₄ , filtered and a gummy brown oil was obtained.

The residue was suspended in diethyl ether and the resulting solid was collected. The solid was then dissolved in hot ethyl acetate and decolorizing carbon was added. The mixture was then filtered and the solvent removed to give a solid which was used without further purification.

Acetic anhydride (10 molar equivalents) and acetic acid (1.8 molar equivalents) were mixed together and heated

19899 9 · ·

9 9

9 9 9

9 ·

999 9999 • 9 9999 • ·

9 9 9

99 * · ·

9 9 9

999 999 at 70 °C for 15 minutes and then cooled to 65 °C. The solid sulfone obtained above was added portionwise and the reaction was allowed to stir at 70 °C for 30 minutes and then cooled and concentrated. The resulting solid was taken up in ethyl acetate and washed with sodium bicarbonate solution, followed by 1 N Na ₂ S ₂ O 3 solution. The solution was then dried over MgSO ₄ , filtered and concentrated to give methyl 2-keto-2-(thieno[2,3b]thiophen-2-yl)thioacetate as a solid which was used without further purification.

To the 2-keto compound (0.0165 mol) (4.0 g) was added 270 ml of methanol and 16.5 ml of 1 N NaOH. The reaction mixture was allowed to stir for 6 h at ambient temperature and then methoxyamine (1.38 g, 0.0165 mol) was added and stirring was continued for 18 h. The reaction mixture was then concentrated and the residue was dissolved in ethyl acetate and washed with water. The aqueous layer was then acidified with HCl and the oily product was extracted into ethyl acetate and washed with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated to give 4.0 g of 2-(hydroxyimino)-2(thieno[2,3-b]thiophen-2-yl)acetic acid as a yellow solid.

The methyl ester was then prepared according to general procedure G below and the oxime was reduced to the amino group according to general procedure R below to give methyl 2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetate.

-199• 44

4 * • 4

4 ·

4 4 4 Λ4 4

4«4* »0

4,444

4« 4

4 4

4· 4 44 «4 44

4 ♦ «

4 4 « • t« 4 44 4 4

4· >·

Example D5

Synthesis of N-methyl-N'-BOC-leucinamide

A solution of 0.9968 g (4 mmol) of N-BOC-leucine (Bachem) and 1.2323 g (7.6 mmol) of CDI in 40 mL of THF was stirred for 1 h, and then 0.5402 g (Aldrich) of methylamine and methylmorpholine were added. The mixture was evaporated under reduced pressure (8

0.8092 mmol) of Nd hydrochloride was stirred for 16 hours, and the residue was washed thoroughly with water, 1N NaOH, water, followed by diethyl ether to give 0.886 g (3.09 mmol, 70%) of the title compound.

after

Example D6

Synthesis of N-BOC-norleucinamide

To a stirred mixture of 3.47 g (15 mmol) BOC-norleucine (Bachem), 3.44 g (22.5 mmol) 1-hydroxybenzotriazole monohydrate and 50 mL dichloromethane at 0 °C was added 3.45 g (1.2 mmol) EDC. The resulting mixture was stirred at 0 °C for 1 h and then ammonium gas was bubbled through the mixture for 10 min. The cooling bath was allowed to warm to ambient temperature and the mixture was stirred for 18 h. The mixture was evaporated to dryness under reduced pressure, triturated with 20% Na ₂ CO ₃ . The resulting solid was collected by filtration and washed with water to give 2.69 g (11.7 mmol, 78%) of the title compound.

Example D7

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine

-200-

·· ·· • · · ·

I · ♦ · ► · · · •ftft ···

The title compound was prepared by dissolving 1.98 g (0.006 mol) of Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-alanine ethyl ester (prepared in Example 85 below) in 60 mL of dioxane and 15 mL of H ₂ O and adding LiOH (0.25 g, 0.006 mol) which had been dissolved in 15 mL of H ₂ O. After stirring for 3 h, the dioxane was removed under reduced pressure and the residue was diluted with EtOAc, the layers were separated and the aqueous layer was acidified to pH 2. The aqueous layer was back-extracted with EtOAc (4 x 100 mL) and the combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure after filtration. The residue was recrystallized from EtOAc/iso-octane to give 1.7 g (90%).

Ci ₄ Hi ₆ F ₂ N ₂ O ₄ corresponds to C, 53.50 H, 5.13 N, 8.91.

Analysis found C, 53.30 H, 5.26 N, 8.98.

Example D8

Synthesis of 2,4,5-trichlorophenyl ester of m-nitrophenylacetyl-L-alanine m-nitrophenylacetyl-L-alanine (1 equivalents) and 2,4,5-trichlorophenol (1.3 equivalents) were stirred in dichloromethane. A 1.0 M solution of 1,3-dicyclohexylcarbodiimide in dichloromethane (1.2 equivalents) 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 eluent to afford the title compound as a pink solid.

_{C17H13C13N2O5 : ​ ​ ​}

Calculated 47.30% C, 3.04% H, 6.49% N.

-201• · ···

Found 47.57% C, 3.18% H, 6.47% N.

Example D9

Synthesis of D,L-α-methylphenylglycine ethyl ester dry nitrogen, bis(trimethylsilyl)amide

The title compound was prepared using the procedure described by 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 to reflux under a dry nitrogen atmosphere for 4 hours. After cooling, the mixture was concentrated under reduced pressure to give a yellow oily solid. The mixture was suspended in diethyl ether and filtered through Celite. The filtrate was concentrated to an orange oil which was purified by vacuum distillation to give a yellow oil which solidified. The yellow solid was stirred in anhydrous THF at -20

Drop by drop lithium (1.05

C under atmosphere was added equivalents, 1.0M solution in THF). The resulting mixture was allowed to warm to -10 C and stirring was continued for 1 hour at this temperature. Methyl iodide (1.05 equivalents) was added and the mixture was allowed to warm to ambient temperature with stirring. After 14 hours the mixture was concentrated. The residue was partitioned between 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 give a yellow oil. The yellow oil was stirred in absolute ethanol. Anhydrous zinc chloride (4 equivalents) was added and the mixture was heated to reflux. After 14 hours the mixture was concentrated

-202- j .: :···.

• · · · · ······ ·· ··· under reduced pressure to give 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

Synthesis of D,L-phthalimidoalanine ethyl ester hydrochloride

N-(diphenylmethylene)glycine ethyl ester (1 equivalent) (Aldrich) was stirred in anhydrous THF at -78 °C under a dry nitrogen atmosphere. Lithium bis(trimethylsilyl)amide (1.02 equivalents, 1.0 M solution in THF) was added dropwise. The resulting mixture was stirred for 1 hour at -78 °C. A THF solution of N-(bromomethyl)phthalimide (1.1 equivalents) (Aldrich) was added and the mixture was allowed to warm to ambient temperature and then stirring was continued for 1 hour. Hydrochloric acid (600 mL, 2N) was added and the mixture was stirred for 20 minutes. THF was removed on a rotary evaporator. The resulting aqueous mixture was washed with diethyl ether and then concentrated (to 100 mL) to give a thick suspension. The white solid was collected, washed with cold water and dried in a vacuum oven to give the title compound, which was used without further purification.

Example According to

Synthesis of N-(3-nitrophenylacetyl)-L-alanine

The title compound was prepared by dissolving 9.27 g (0.0348 mol) of n-(3-nitrophenylacetyl)-L-alanine methyl ester

-203• φφ φφφφ ·· ·♦ φ φφφ φφφφ • φ φφφφ φ φφ φ • φφ φ φφ φφφφφ φφφφ φφφ φφφ φφφ φφφ φφφ φφφ ·· ·· ν 60 mL dioxane with 15 mL H ₂ O and the addition of LiOH (3.06 g, 0.0731 mol), which was dissolved in 15 mL H ₂ O. After stirring for 4 h, the dioxane was removed under reduced pressure and the residue was diluted with EtOAc, the layers were separated and the aqueous layer was acidified to pH 2. The aqueous layer was back-extracted with EtOAc (4 x 100 mL), the combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure after filtration. The residue was recrystallized from EtOAc/iso-octane to give 7.5 g (85%).

ΟιιΗ ₁₂ Ν ₂ 0 ₅ corresponds to C, 52.38 H, 4.80 N, 11.11.

Analysis found C, 52.54 H, 4.85 N, 11.08.

[oC]23 = -29.9 @ 589 nm.

Example D12

Synthesis of methyl 2-amino-2-(3-fluorophenyl)acetate hydrochloride

Potassium cyanide (6.3, 0.1 mol) and ammonium bicarbonate (15.7 g, 0.2 mol) were dissolved in 50 mL of water (in a well-ventilated fume hood). 3-Fluorobenzaldehyde (5.0 g, 0.04 mol) was dissolved in 50 mL of EtOH and added to the reaction mixture. After stirring at reflux under nitrogen for 17 h, the reaction mixture was cooled to 23 °C, the pH was adjusted to 2.0 by adding 5 N HCl, and the mixture was cooled to 5 °C. The resulting hydantoin was collected, washed with cold water, and dried in vacuo to give 3.5 g of an off-white solid. The hydantoin was hydrolyzed at reflux using 1 N NaOH to give 2-amino-2-(3-fluorophenyl)acetic acid, which was esterified according to Procedure H in methanol to give the title compound.

-204• · · · · ·

Example D13

Synthesis of Ν-[N-(S)-2-aminobutanoyl]-L-phenylglycine tert-butyl ester

A mixture of Ν-[N-(benzyloxycarbonyl)-(S)-2-aminobutanoyl]-L-phenylglycine tert-butyl ester (4.13 g) (which was prepared from N-(benzyloxycarbonyl)-(S)-2-aminobutanoic acid (Novabiochem) and L-phenylglycine tert-butyl ester hydrochloride (Novabiochem) following general procedure D) and 20% Pd(OH) ₂ /C (0.360 g) in EtOH (200 mL) was shaken in a Parr apparatus under a hydrogen atmosphere (40 psi) for 4 h. The solids were removed by filtration through a pad of Celite, rinsing with EtOH. The filtrate was concentrated to an off-white oil, which was used without further purification. ¹ H-NMR in CDCl 3 showed that approximately 10% transesterification to ethyl occurred during the reaction. The ethyl ester was collected by flash chromatography for further reactions with this compound.

Example: D14

Synthesis of N-[N-L-valinyl]-L-phenylglycine tert-butyl ester

A mixture of Ν-[N-(benzyloxycarbonyl)-L-valinyl]L-phenylglycine tert-butyl ester (4.63 g) (which was prepared from N(benzyloxycarbonyl)-L-valine (Aldrich) and L-phenylglycine tert-butyl ester hydrochloride (Novabiochem), following general procedure D) and 20% Pd(OH) ₂ /C (0.360 g) in EtOH (200 mL) was shaken in a Parr apparatus under a hydrogen atmosphere (40 psi) for 4 h. The solids were removed by filtration through a pad of Celite, rinsing with EtOH. The filtrate was concentrated to an off-white solid.

-205• 9 9 9 9 · • 9 9999 9

9·· · · « · · · · ·

9··· ·· · · · * · ·· substance which was used without further purification. ¹ H-NMR in CDCl ₃ showed that approximately 10% transesterification to ethyl occurred during the reaction. The ethyl ester was collected by flash chromatography for further reactions with this compound.

Example D15

Synthesis of (S)-Phenylglycinol Methyl Ether (S)-(+)-2-Phenylglycinol (1 equivalent) (Aldrich) was stirred in anhydrous THF under a dry nitrogen atmosphere. Sodium hydride (1 equivalent) was added and the resulting mixture was stirred for 1 hour at ambient temperature. THF solution of iodomethane (1 equivalent) was added and the mixture was stirred for 1 hour. The mixture was concentrated to give a residue which was taken up in water and extracted with chloroform. The organic extracts were concentrated under reduced pressure to give the title compound as an oil which was purified by silica gel chromatography to give the crude product which was used without further purification.

Example D16

Synthesis of (S)-2-hydroxy-2-methyl-1-phenylprop-1-ylamine

To a stirred and cooled (0 °C) suspension of 5.6 g (27.8 mmol) of L-phenylglycine methyl ester hydrochloride (Aldrich) in 200 mL of anhydrous THF was added methylmagnesium bromide (46.3 mL, 138.9 mmol, 3.0 M in diethyl ether). During the addition, the internal temperature rose to 24 °C. Stirring was continued for 1 h, then the reaction was carefully quenched by the addition of saturated sodium bicarbonate solution. The reaction mixture was partitioned between ethyl acetate and aqueous

-206·· φ· • · · · · · · · · · · · · · · · · «· ·· sodium bicarbonate and the aqueous layer was back-extracted with 3 volumes of ethyl acetate. The combined organic layers 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 give 1.96 g of the title compound.

Example D17

Synthesis of 5-chloro-2-thiophenecarboxaldehyde

A solution of 2-chlorothiophene (Aldrich; 1 molar equivalent) in THF was cooled to -78 °C and treated with n-butyllithium (1.6M in hexanes; 1.1 molar equivalents) added dropwise. The resulting yellow solution was stirred at -78 °C for 40 min. Dimethylformamide (1.1 molar equivalents) was added dropwise and the reaction mixture was stirred for an additional 30 min. The mixture was diluted with methylene chloride and washed with 10% acetic acid, 1 M potassium carbonate and brine. The organic phase was dried over _Na2SO4 , filtered and concentrated. The residue was purified by HPLC eluting with 15% ethyl acetate/hexanes to give the title compound.

Example D18

Synthesis of (S)-(-)-α-methylbenzylisocyanide

Prepared according to the general procedure described by Wolber, E. K. A.; Ruchardt, C. Chem. Ber. 1991, 124, 1667.

A suspension of 1,1'-carbonyldiimidazole (1.6 molar equivalents; Aldrich) in acetonitrile at 0 °C was

-207« · ♦···· ···· • · · · · · · · · · ···· • · · · · ♦ · ··

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 (S)-(-)-α-methylbenzylformamide (S)-(-)-α-methylbenzylamine (1 molar equivalent) was treated with ethyl formate (80 molar equivalents; 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 concentrated by rotary evaporation. The resulting solid was used without purification.

Example D20

Synthesis of 3-(phenyl)benzaldehyde

A solution of 3-bromobiphenyl (Aldrich; 1 molar equivalent) in anhydrous THF was cooled to -78 °C and treated with tert-butyllithium (Aldrich; 1.7 M in hexanes, 2 molar equivalent)

-208• _· ···· • _·

Example D21

Synthesis of 4-(cyclohexyl)benzaldehyde

18-Crown-6 (Aldrich; 4 molar equivalents) and pyridinium chlorochromate (Aldrich; 4 molar equivalents) were added together to chloroform and stirred for 20 minutes. 4-Cyclohexylbenzyl alcohol (prepared in Example D22 below; 1 molar equivalent) was added and stirring continued for 3 hours. Ether was added and the mixture was filtered through a pad of silica, eluting with ether. The solvent was removed by rotary evaporation. The residue was dissolved in ether and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated.

Example D22

Synthesis of 4-(cyclohexyl)benzyl alcohol

To a solution of 4-cyclohexylbenzoic acid (Aldrich; 1 molar equivalent) in toluene was added diisobutylaluminum hydride (Aldrich; 1 M in toluene; 4 molar equivalents) over a 2 hour period. After addition was complete, the reaction mixture was

4··· • 4 · · · · 4 94 4

44 · 99 444444

4 4 4 4 ·· ·· ·· ·· heated to 60 °C for 1 hour. The reaction mixture was cooled to 5 °C and quenched with saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were filtered to remove salts and concentrated.

Example D23

Synthesis of 3,5-difluorophenyl-α,α-difluoroacetic acid

A solution of ethyl 3,5-difluorophenyl-α,α-difluoroacetate (prepared in Example D24 below; 1 molar equivalent) in 50% aqueous ethanol was treated with lithium hydroxide (1.5 molar equivalent). The solution was stirred for 3 hours at ambient temperature and then concentrated by rotary evaporation. The residue was taken up in water; a small amount of 1 N NaOH was added to make the mixture basic. The aqueous mixture was extracted with ether. The aqueous layer was acidified to pH 3 by adding 1 N HCl. The acid was extracted twice with methylene chloride. The combined methylene chloride extracts were dried over Na ₂ SO ₄ , filtered and concentrated.

Example D24

Synthesis of ethyl-3,5-difluorophenyl-α,α-difluoroacetate

Ethyl-3,5-difluorophenyl-α-ketoacetate (Rieke Metals, Inc. #14014; 1 molar equivalent) was treated with (diethylamino)sulfur trifluoride (DAST) (2.5 molar equivalents). The reaction mixture was stirred at ambient temperature for 72 hours and then heated to 50 °C for 6

-2109999 999 9999

9 9 9999 9 99 9

9999 99999999

9 9 9 9 9 9

999 9999 99 949 99 99 hours. The mixture was poured onto ice and extracted with methylene chloride. The organic layer was washed with saturated sodium bicarbonate, dried over _Na2SO4 , filtered and concentrated. The residue was purified by HPLC, eluting with 2% ethyl acetate/hexanes.

Example D25

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,Lphenylglycine

The methyl ester of N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine (prepared in Example 111 below) was hydrolyzed following Procedure AF. The acid was recrystallized from isooctane/EtOAc to give a mixture of diastereomers at the phenylglycine center.

Elemental analysis:

Ci ₉ Hi ₈ F ₂ N ₄ O ₄ corresponds to 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

N-(3-Bromopropyl)phthalimide (1 equivalent, Aldrich) and 4-iodophenol (1 equivalent, Aldrich) and potassium carbonate (2 equivalents) were stirred in acetonitrile. The mixture was heated to reflux. After 64 hours, the reaction mixture was concentrated to a thick mixture which was suspended in water. A white solid was obtained which was washed with water and dried in vacuo.

-211• AA ·· AAAA AA AA • AAA AAA AAAA

A A AAAAA AAAA

A A AA A AA AAA AAA

A A AAA A A

AAAAAAA A* AAA AA AA

The white solid was stirred in ethanol. Anhydrous hydrazine (2 equivalents) was added and the mixture was heated to reflux for 18 hours. The reaction mixture was concentrated to give a solid which was treated with 1N NaOH and extracted with CHCl3. The organic portion was dried, concentrated and then diluted with ether. The mixture was treated with anhydrous HCl. The title compound was obtained as a white solid and dried in vacuo.

Example D27

Synthesis of 2-amino-1-phthalimidopentane hydrochloride

2-Amino-1-pentanol was stirred in a mixture of chloroform and saturated aqueous sodium bicarbonate. Di-tert-butyl dicarbonate (1.05 equivalents) was added in one portion and the mixture was stirred until the starting material was consumed. The organic portion was separated, dried (sodium sulfate) and concentrated. The crude material was purified by silica gel chromatography, eluting with 1:1 ethyl acetate/hexanes.

The product was dissolved in THF. Methanesulfonyl chloride (1.1) was added and the mixture was

Triethylamine (1.1 equivalents) cooled in an ice bath, equivalents) was added dropwise and the mixture was stirred until the starting material was consumed. The mixture was concentrated under reduced pressure and then partitioned between ethyl acetate and water. The organic portion was separated, dried (sodium sulfate) and concentrated to give a white solid which was chromatographed on silica gel, eluting with 30% ethyl acetate in hexanes and finally crystallized from 1-chlorobutane/hexanes.

212 ·· • · ·· ···« • · · • > ···

1 « · · • · · ·· ·»* • « ♦ · • · fl · • e · · · · • · * * ··

The crystalline product was stirred in anhydrous DMF and potassium phthalimide (1.1 equivalents) was added. The mixture was stirred for 18 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic portion was dried and concentrated to give a white solid. The solid was taken up in chloroform and filtered through a pad of silica. The eluent containing the product was concentrated to give the crude product as a white solid.

The white solid was taken up in anhydrous dioxane and the resulting solution was saturated with HCl gas. After stirring for 30 minutes, the mixture was concentrated to give a white solid which was triturated in ether. The title compound was collected, washed with ether and dried in a vacuum oven.

Example D28

Synthesis of D,L-3,5-difluorophenylglycine

KOH (11.76 grams), LiCl (2.95 grams), saturated aqueous ammonium (20 mL), and benzyltriethylammonium chloride (0.805 grams) were stirred and cooled in CH2Cl2 (17 mL). Ammonium gas was bubbled through the mixture with cooling (0 °C) until saturation. To the resulting mixture was added 3,5-difluorobenzaldehyde (5.0 grams) (Lancaster) and chloroform (4.46 mL), dissolved in _CH2Cl2 ( _17.5 mL) while saturating with ammonium gas. The resulting mixture was stirred cold for 4 hours and at 22.5 °C for 96 hours. Water (60 mL) and _CH2Cl2 (20 mL) were added; the layers were separated and the aqueous layer was extracted _three more times _{with CH2Cl2} . The aqueous layer was

-213BBB ♦ Β · · • ΒΒΒΒ Β ΒΒ Β

BB BB BBBBBBBB

B B B

ΒΒΒΒΒΒΒΒΒΒΒΒΒ was reduced in vacuo by 50%. The pH was adjusted to 6.5 with cold concentrated HCl, while crystals of D,L-3,5-difluorophenylglycine (3.4343 grams) formed.

Example D29

Synthesis of L-3,5-difluorophenylglycine methyl ester, tartrate salt

3.43 grams of D,L-3,5-difluorophenylglycine (prepared in Example D28 above) was suspended in 50 mL of methanol and 2.5 mL of concentrated H ₂ SO ₄ . The reaction mixture was gently heated to reflux for 18 hours. The mixture was cooled in an ice bath and the pH of the solution was adjusted to 7.0 with saturated aqueous ammonium. The volatile organic solvents were removed in vacuo and the aqueous portion was extracted three times with CH ₂ Cl ₂ ; the combined organic layers were dried, filtered and reduced in vacuo to give 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 while the title compound crystallized. The product was filtered and dried to give 3.4805 grams of the (-)-tartrate salt.

Example D30

Synthesis of N-(3,5-difluorophenylacetyl)-L-3,5-difluorophenylglycine

L-3,5-difluorophenylglycine (0.4291 g) (which was prepared from the (-)-tartrate salt of L-3,5-difluorophenylglycine (prepared in Example D29 above) by neutralization) and 3,5-difluoroacetic acid (0.367 grams) were dissolved in THF.

··· · • 9 99

9 9 9

9 9 9 • · · · · · · • 9

99

-214EEDQ coupling using General Procedure AN gave 0.7441 grams of the title compound as the methyl ester. The ester was dissolved in 1,4-dioxane (10 mL), cooled, and LiOH.H ₂ O (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 1N HCl were added and the aqueous layer was extracted twice. The combined organic layers were dried (MgSO ₄ ) and reduced in vacuo to give the title compound (700.8 mg).

Each of the compounds listed in the following examples was prepared according to one of the following General Procedures, unless otherwise noted.

General Procedure A

EDC copulation procedure I

To a 1:1 mixture of the corresponding carboxylic acid and amino ester/amide in CH ₂ Cl ₂ or DMF at 0 °C was added 1.5 equivalents of triethylamine, followed by 2.0 equivalents of hydroxybenzotriazole monohydrate, then 1.25 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The reaction mixture was stirred overnight at ambient temperature and then transferred to a separatory funnel. The mixture was washed with water, saturated aqueous NaHCO ₃ , 1 N aqueous hydrochloric acid and saturated aqueous sodium chloride and then dried over MgSO ₄ . The solution was removed from the solvent on a rotary evaporator to give the crude product.

General Procedure B

EDC copulation procedure II

-215φ φφ ·· φφφφ φφ ♦· • ΦΦΦ φφφ φφφφ φ φ φφφφφ φφφφ • φ φφ φ φ <* φφφφφφ φ φ φφφ φ φ φφφφφφ φφφφφφ ·· ··

The carboxylic acid was dissolved in methylene chloride in a round bottom flask. The amino acid (1 equivalent), N-methylmorpholine (5 equivalents) and hydroxybenzotriazole monohydrate (1.2 equivalents) were added sequentially. A cooling bath was used to cool the flask until the solution temperature reached 0 °C. At this point, 1.2 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. The solution was then allowed to stir overnight and the temperature was allowed to rise to ambient temperature under N ₂ . The reaction mixture was then washed with saturated aqueous Na ₂ CO ₃ , 0.1 M citric acid and brine before drying over Na ₂ SO ₄ and removal of the solvent to give the crude product. Pure products were typically obtained by flash chromatography in a suitable solvent.

General Procedure C

EDC copulation procedure III

A round bottom flask was charged with the appropriate carboxylic acid (1.0 equivalents), hydroxybenzotriazole hydrate (1.1 equivalents) and the appropriate amine (1.0 equivalents) in THF under a nitrogen atmosphere. An appropriate amount (1.1 equivalents for the free amine and 2.2 equivalents of the amine hydrochloride salt) of a suitable base, such as Hunig's base, was added to the stirred mixture, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) hydrochloride (1.1 equivalents). After stirring for about 4 hours to 17 hours at ambient temperature, the solvent was removed under reduced pressure and the residue was taken up in EtOAc (or similar solvent) and H ₂ O. The extracts were washed with saturated NaHCO ₃ , 1 N aqueous

-2164 4 · · · · · 4 4· • 44 · 4 4 4 • 4444 4 44 4 • 4 44 444 444

4 4 4 4

444 4 4 «4 hydrochloric acid, brine and dried over Na ₂ SO ₄ . In some cases the isolated product required further purification using standard procedures such as chromatography and/or recrystallization.

General Procedure D

EDC copulation procedure IV

A round bottom flask containing a magnetic stirrer under nitrogen atmosphere at 0 °C was charged with THF, amine or amine hydrochloride (1.0 equivalents), hydroxybenzotriazole carboxylic acid diisopropylethylamine (1.1 equivalents), 1-hydrate (1.15-1.2 equivalents), N,N (2.3 equivalents), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) hydrochloride (1.15-1.2 equivalents).

The cooling bath was removed and the mixture was allowed to warm to ambient temperature with stirring for 10-20 hours. The mixture was diluted with EtOAc and washed with 0.5 N aqueous HCl (2x), dilute aqueous NaHCO ₃ (1x), brine (1x) and dried over either Na ₂ SO ₄ or MgSO ₄ . The drying agent was removed by filtration and the filtrate was 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

Round-bottom flask containing a magnetic stirrer under β φ

-217 under nitrogen at 0 °C or ambient temperature was charged with THF, carboxylic acid (1.0 equivalents), amine or amine hydrochloride (1.0-1.1 equivalents), 1-hydroxybenzotriazole hydrate (1.1-1.2 equivalents), N,N-diisopropylethylamine (2.2-2.9 equivalents), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) hydrochloride (1.1-1.2 equivalents). The cooling bath was removed and the mixture was allowed to warm to ambient temperature with stirring for 10-20 hours. The mixture was diluted with EtOAc and washed with 0.5 N aqueous HCl (2x), dilute aqueous NaHCO ₃ (1x), brine (1x) and dried over either Na 2 SO ₄ or MgSO ₄ . The drying agent was removed by filtration and the filtrate was 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 VI

A round bottom flask containing a magnetic stirrer under nitrogen at 0 °C was charged with THF, carboxylic acid (1.0 equivalents), amine or amine hydrochloride (1.0-1.1 equivalents), N,N-diisopropylethylamine (2.2-2.3 equivalents), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) hydrochloride (1.1-1.2 equivalents). The cooling bath was removed and the mixture was allowed to warm to ambient temperature with stirring for 10-20 hours. The mixture was diluted with EtOAc and washed with 0.2 N aqueous HCl (2x), dilute aqueous NaHCO ₃ (1x), brine (1x) and dried over either Na ₂ SO ₄ or MgSO ₄ . The drying agent was removed by filtration and the filtrate was concentrated in vacuo.

-218• · · · · · · · ♦ · · • ·

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 G

Preparation of methyl ester

To 1-methyl-3-nitro-1-nitrosoguanidine (1.2 equivalents) in diethyl ether, cooled to 0 °C, was added 40% KOH until bubbling ceased. This mixture was then decanted into a plastic tube containing KOH tablets 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 thin layer chromatography). The reaction was then quenched with acetic acid and extracted into EtOAc. Removal of the solvent gave the desired methyl ester.

General Procedure Η

Preparation of carboxylic acid ester

Anhydrous HCl gas was bubbled into the appropriate amino acid or carboxylic acid in the appropriate alcohol until the solution was saturated. The reaction mixture was stirred overnight at 25 °C and the solvent was then removed under reduced pressure. The residue was then dissolved in EtOAc and this solution was washed with sodium bicarbonate solution. The organic layer was then dried over sodium sulfate, filtered and the solvent was removed to give the desired ester.

-219• 999 9 · 9 9··*

9 99999 9 999

9 9 · · · · ······ • 9 9 9 9 · ·

999 99·· ·· ··· ·· ··

General Procedure I

Preparation of tert-butyl ester I

To a solution of the N-CBZ-protected amino acid in CH ₂ Cl ₂ was added

1.5 equivalents of N,N'-diisopropyl-O-tert-butylisourea (prepared by standard literature methods such as those found in Synthesis (1979), p. 561) and the reaction mixture was heated to reflux for 17 hours. An additional 1.5 equivalents of isourea was then added and heating to reflux continued for an additional 7 hours. The reaction mixture was then cooled to ambient temperature and filtered through a pad 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 aqueous NaHCO ₃ , water, saturated aqueous NaCl and dried over MgSO ₄ . The solution was concentrated under reduced pressure to give the product.

General Procedure J

Preparation of tert-butyl ester II

The reaction was carried out in a sealed tube using the appropriate carboxylic acid, a catalytic amount of H ₂ SO ₄ (0.03 equivalents) and an excess of condensed iso-butylene in dioxane or CH ₂ Cl ₂ at -20 °C. The reaction time varied from about 48 hours to about 120 hours. When the reaction was complete, the solvent was removed under reduced pressure and the residue was dissolved in diethyl ether. This solution was washed with sodium bicarbonate solution and the organic layer was dried over sodium sulfate, filtered and the solvent was removed. The resulting product was purified using • * » ·

-220standard procedures such as HPLC or titration using, for example, diethyl ether/hexanes mixtures.

General Procedure K

Preparation of amide I

To a solution of 3 equivalents of the desired amine in 1,2-dichloroethane was added 5.2 equivalents of triethylalumina. After stirring for 30 minutes at ambient temperature, a solution of the desired ester dissolved in 1,2-dichloroethane was added. The reaction mixture was heated to reflux until thin layer chromatography indicated complete conversion, typically 3 hours. The reaction mixture was then cooled to 0 °C and quenched with 10% aqueous hydrochloric acid (note: the acid should be added slowly as foaming occurs during 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 aqueous NaCl, dried over MgSO ₄ and concentrated under reduced pressure to give the crude product.

Alternatively, if the product is soluble in acid, then after completion of the reaction the volume of the reaction mixture is reduced to about one third of the original volume under reduced pressure. To the resulting solution was added 20% aqueous potassium sodium tartrate (Rochelle salt) and ethyl acetate. The pH of the solution was then adjusted to -13 and the aluminum salts were dissolved in the aqueous solution. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic solutions were washed with saturated aqueous NaCl, dried over MgSO ₄ and

-221 were concentrated under reduced pressure to give the crude product.

General Procedure L

Preparation of amide II

The carboxamide was prepared from the corresponding ester using the method described by Hogberg, T. et al., J. Organic Chem., 1987, 52, 2033-2036.

General Procedure M

Preparation of amide III

To the appropriate carboxylic acid (1.0 equivalent) in THF was added N-methylmorpholine (1.1 equivalents) and the solution was cooled to -20°C to 0°C. Isobutyl chloroformate (1.1 to 2.1 equivalents) was then added and the reaction mixture was stirred at -20°C to 0°C for 30 minutes. A mixture of the appropriate amino acid, water and 1.5 equivalents of potassium carbonate was then added and the resulting mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was then poured into water and washed with EtOAc. The pH of the aqueous layer was then adjusted to 2.0 by adding 5N HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The 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.

φφφφ

-222• · ··*· Φ· Φ· • · φ · · · φ • φ · · φ · · φ · «φ φ φφ φφφ φφφ φ φ · φ φ • · ··· «φ φ·

General Procedure N

Hydrolysis of carboxylic acid esters

To the ester in a 1:1 mixture of CH3OH/H2O was added 2-5 equivalents _{of K2CO3} . The mixture was heated at 50 °C for 0.5-1.5 hours until thin layer chromatography indicated the reaction was complete. The reaction mixture was cooled to ambient temperature and the methanol was removed on a rotary evaporator. The pH of the resulting 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 MgSO4. The solution was stripped of solvent on a rotary evaporator to give the product.

General Procedure About

Removal of the N-carbobenzyloxy (CBZ) protecting group

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 under 20 psi H ₂ in a Parr apparatus for 30 minutes. The reaction mixture was then filtered through a pad of Celite 545 and the solvent was removed on a rotary evaporator to give the product.

General Procedure P

Removal of the n-tert.-Boc protecting group

N-tert-Boc-amine was dissolved in a suitable anhydrous solvent (such as 1,4-dioxane or ethyl acetate) and the solution was cooled in an ice bath. HCl gas was passed into the solution until the mixture was saturated with HCl. The mixture was then

-223• · · ·· ··♦ · *· · · ··· ·

General Procedure Q

Halide exchange reaction (Finkelstein reaction)

The corresponding alkyl bromide or alkyl chloride was dissolved in 20 mL of methyl ethyl ketone and 1 equivalent of NaI was added. The reaction mixture 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 rotary evaporated under reduced pressure to give the crude product. The pure products were typically obtained by flash chromatography in a suitable solvent.

General Procedure R

Reduction of oxime I

To the oximester in alcohol, corresponding to the ester, was added formic acid (500 equivalents) and water (500 equivalents). The reaction mixture was cooled to 5 °C and zinc powder (3.8 equivalents) was added portionwise over 20 minutes. The reaction mixture was then allowed to warm to ambient temperature and stirring was continued for 3 hours. The reaction mixture was then filtered through HYFLO and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc and this solution was washed with saturated sodium bicarbonate solution. The organic layer was then

999 9

9 9 9

9 9 9

999 999

9

224

9 9 999

9

999 9999

9 • 9 99 dried over sodium sulfate, filtered and the solvent was removed to give the product.

General Procedure S

Reduction of esters to alcohols

To a solution of the starting ester in anhydrous THF at 0 °C was added 1.0 equivalents of LiBH ₄ in THF. The reaction mixture was stirred at ambient temperature 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, dried over magnesium sulfate and concentrated under reduced pressure to give the alcohol product.

General Procedure T

CDI copulation procedure

A solution of the appropriate acid (3.3 mmol) and 1,1'-carbodiimidazole (CDI) in 20 mL of THF was stirred for 2 h. 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 once, and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give the product.

General Procedure U

EDC copulation procedure VII

-225• ·· ·» ···· 0· ·· ·«♦· · · · · · · · · • · · ♦ ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 99

A mixture of a suitable carboxylic acid (1 hydroxybenzotriazole (1.6 equivalents), an equivalent (3 equivalents), a suitable amine (1 equivalents) and

N-Methylmorpholine dichloromethane (or DMF for cooled in an ice-water bath, was stirred until a clear solution was obtained. EDC (1.3 equivalents) was added to the reaction mixture and the cooling bath was allowed to warm to ambient temperature over 1-2 hours. The reaction mixture was then stirred overnight. The reaction mixture was then evaporated under reduced pressure to dryness in vacuo and 20% aqueous potassium carbonate was added to the residue. The mixture was shaken vigorously and left to stand for several hours or overnight, if necessary, until the oily product solidified. The solidified product was insoluble substrates), then filtered off, washed thoroughly

20 ^% potassium carbonate, water, 10% HCl and water to obtain the product.

When using racemization.

no adverse effects were observed with this procedure

General Procedure for the O-Acylation of Alcohols

To a solution of an alcohol (e.g., N-[(S)-1-hydroxyhex-2-yl]-N'- (3,5-difluorophenylacetyl)-L-alaninamide prepared in Example 228 below) in pyridine was added 4 equivalents of acetic anhydride and the reaction mixture was stirred at ambient temperature for 2.5 hours. The reaction was quenched on ice and then ethyl acetate was added and the phases were separated. The organic phase was washed with 10% HCl, water, saturated aqueous NaCl and dried over MgSO ₄ . The solution was freed from solvent on a rotary evaporator to give the product.

-226• · ·

General Procedure W

O-esterification of alcohols

To a suspension of 0.95 equivalents of NaH in THF was added an alcohol (for example

N-[(S)-1-hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide, prepared in 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) were added. The reaction mixture was stirred at ambient temperature overnight, then quenched with water and ethyl acetate. The organic phase was washed with water, saturated aqueous NaCl and dried over MgSO ₄ . The solution was freed from solvent on a rotary evaporator to give the crude product.

General Procedure X

BOP copulation procedure

A solution of the carboxylic acid (1.0 equivalents) and N-methylmorpholine (1.5 equivalents) in dichloromethane was cooled to -20°C under nitrogen. BOP (1.05 equivalents) was added in one portion and the reaction mixture was maintained at -20°C for 15 minutes. The appropriate alcohol (1.2 equivalents) was added and the reaction mixture was allowed to warm to ambient 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), brine (1x) and then rotary evaporated under reduced pressure to give the crude product.

-22799 9999

99 999 9999

9 9 9 999 9 9 9 9

9999 99999 999

9 9 9 9 9 9

999 9999 99 999 99 99

General Procedure Y

Removal of BOC using TFA

The Boc-protected compound was added to a 1:1 mixture of dichloromethane and trifluoroacetic acid (TFA) and the reaction mixture was stirred until thin layer chromatography indicated complete conversion, typically 2 hours. The solution was then stripped to dryness. The residue was suspended in dichloromethane and stripped to dryness again to remove excess TFA. The residue was placed under high vacuum for several hours to provide the desired TFA salt.

General Procedure Z

Preparation of amide IV

The trichlorophenyl ester (1 equivalent) was stirred in DMF or THF and the oxime or amine (1.2 equivalents) was added. The mixture was stirred at ambient temperature for 1-4 hours. In cases where the hydrochloride salt of the formed amine was used, a suitable base such as diisopropylethylamine (1.2 equivalents) was also added. The resulting mixture was concentrated under reduced pressure to give an oil or residue which was used without further purification or purified by standard procedures such as silica gel chromatography and/or recrystallization.

General Procedure AA Reduction with sodium borohydride

The ketone was dissolved in MeOH and treated with 1.0 equivalent of

AA AA

A A A A

A A A A

A AAA AAA

A A

-228aa AAAA

AA • · · • AAAA • · ·

A A • A AAA sodium borohydride. The reaction mixture was stirred until thin layer chromatography indicated that the starting material was consumed, typically 1 hour. The reaction mixture was then concentrated under reduced pressure and chromatographed to give the alcohol product.

General Procedure AB

Preparation of amino acid derivatives using chiral amines (s;

+)-α-methylbenzylamine was added dropwise to the solution

of 4-(phenyl)benzaldehyde followed by the addition of (1 molar equivalent) of 1.0 molar equivalent of zinc chloride in THF. The reaction mixture was allowed to stir at ambient temperature for 5 hours. The greyish mixture was then cooled to -30 °C and treated with tert-butyl isocyanate (1.05 molar equivalents). After 20 minutes, N-(3,5-difluorophenylacetyl)-L-alanine was added and stirring continued at -30 °C for 120 hours. The reaction mixture was then poured into a separatory funnel and diluted with CH ₂ Cl ₂ , washing with sodium bicarbonate. The organic layer was then washed with 0.5 N HCl, followed by brine. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated to give N-tert-butylΝ'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Ν' -(S)-αmethylbenzyl-2-amino-2-(4-phenylphenyl)acetamide as a mixture of isomers. At this point, the isomers were usually separated by HPLC chromatography, using, for example, a 30 to 35% EtOAc/hexanes gradient. The α-methylbenzyl protecting group was then removed from the S,S-isomer by adding 10 molar equivalents of triethylsilane and 20 molar equivalents of »0

0 0 • 0 0 0 • 000 000

0

00

-229• 0 0000 • 0 · • 0 0 · · • 0

0 • 0 0 0 0 trifluoroacetic acid to the S,S-isomer. The reaction mixture was then heated to 37 °C for 3 hours and then poured into ethyl acetate and washed with sodium bicarbonate. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by recrystallization from ethyl acetate or ethyl acetate/hexanes. Various other aldehydes and carboxylic acids can be used in this procedure to provide a variety of compounds useful in the present invention.

General AC Procedure

Reduction of oxime II

To a solution of the oximester in the alcohol corresponding to the ester was added a catalytic amount of acetic acid and 0.1 molar equivalent of 10% Pd/C. The reaction (Parr) vessel was filled with 40 psi of hydrogen and the mixture was shaken for 3 hours. The reaction mixture was then filtered through HyFlo and concentrated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated to give the desired amine.

General AD Procedure

Mitsunobu reaction

To a solution of Ν-[N-(3,5-difluorophenylacetyl)-Lalaniny]-L-tyrosine methyl ester in 20 mL of THF were added 1.3 equivalents of each of triphenylphosphine and diethylazodicarboxylate (DEAD) and 1.0 equivalent of alcohol. The mixture was stirred at ambient temperature overnight and the solvent was then removed.

-230« ·· «« ··** ·· »· ·· · » e t · · · · · • « · · ··« · · · · • · « * · * « ··· ··· • · · · » · · ··« ··«· ·· *·· ·* >·

The residue was purified by standard chromatography and/or recrystallization.

procedures such as

General AE Procedure

O-alkylation of tyrosine derivatives

To a solution of Ν-[N-(3,5-difluorophenylacetyl)-Lalaniny]-L-tyrosine methyl ester in 20 mL of acetone were added 1.3 equivalents of alkyl bromide and 3.0 equivalents of finely powdered potassium carbonate and a catalytic amount of sodium iodide. The reaction mixture was stirred at ambient temperature overnight and then partitioned between DCM and water. The organic layer was dried over anhydrous sodium sulfate, stripped of solvents, and purified using standard procedures such as chromatography and/or recrystallization.

General AF Procedure

Hydrolysis of carboxylic acid esters

A solution of the carboxylic acid ester (1.0 equivalents) and lithium hydroxide (1.1 equivalents) in a 1:2 water/dioxane mixture was stirred at 23°C for 1 hour. The reaction mixture was then acidified to pH 3 by addition of 1 N HCl and extracted with ethyl acetate. Concentration of the ethyl acetate extracts afforded the product. In some cases, the product was further purified using standard procedures such as chromatography and/or recrystallization.

General Procedure AG

Formation of methyl ester from amino acid

-231 The amino acid (amino acid or amino acid hydrochloride) was suspended in methanol and cooled to 0 °C. HCl gas was bubbled through the solution for 5 minutes. The reaction mixture was allowed to warm to ambient temperature and then stirred for 4 hours. The solvents were then removed to give the desired amino acid methyl ester hydrochloride. This product is usually used without further purification.

General AH Procedure

EEDQ mating procedure

A round bottom flask containing a magnetic stirrer under a nitrogen atmosphere at ambient temperature was charged with THF, carboxylic acid (1 equivalent), amine hydrochloride (1.1 equivalents) and EEDQ (1.1 equivalents) and the reaction mixture was allowed to stir for 15 minutes. 4-Methylmorpholine (1.1 equivalents) was added to the reaction mixture and stirring was continued at ambient 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 was separated and washed with saturated NH ₄ Cl (2 x), saturated aqueous NaHCO ₃ (2 x), followed by brine (1 x). The organic phase was dried over Na 2 SO ₄ . The drying agent was removed by filtration and the filtrate was 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 recrystallization.

General AI Procedure

N-tert.-BOC protection of amino acid

-232A round bottom flask containing a magnetic stirrer under a nitrogen atmosphere at ambient temperature was charged with dioxane, water, 1.0 N aqueous sodium hydroxide and amino acid (1 equivalent). Stirring was started and the flask was cooled in an ice bath. Di-tert-butyl dicarbonate (1.1 equivalents) was added to the reaction mixture, followed by removal of the ice bath and slow warming to ambient temperature over 1 hour. The reaction mixture was partially concentrated on a rotary evaporator followed by addition of ethyl acetate. The flask was re-cooled in an ice bath and the mixture was acidified to pH 2-3 by addition of potassium hydrogen sulfate. The reaction mixture was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over _Na2SO4 . The drying agent was removed by filtration and the filtrate was concentrated in vacuo. The solid was used without further purification.

General Procedure AJ

Removal of the N-carbobenzyloxy (CBZ) protecting group o

A round bottom flask containing a magnetic stirrer under a nitrogen atmosphere at ambient temperature was charged with methanol, tetrahydrofuran, 20% Pd(OH) ₂ /C (1 weight equivalent) CBZ-protected dipeptide. Stirring was started and the flask was flushed with hydrogen (3x). The reaction mixture was allowed to stir at ambient temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting solid was used as obtained or purified by silica gel chromatography.

-233General Procedure AK

Addition of N-carbobenzyloxy (CBZ) protecting group

A round bottom flask containing a magnetic stirrer under a nitrogen atmosphere at ambient temperature was charged with water, sodium carbonate (2.2 equivalents), and amino acid (1.0 equivalents). The suspension was stirred at ambient temperature for 1 hour. Benzyl chloroformate was added and stirring was continued overnight. The reaction mixture was extracted with CH2Cl2 (3x) and the combined organic extracts were acidified to pH 2-3. The resulting solid was isolated by vacuum filtration.

General Procedure AL

Preparation of amino acid derivatives using chiral amines E

A solution of the arylaldehyde (1 molar equivalent) in THF was treated with S-(-)-α-methylbenzylamine (1 molar equivalent), followed by MgSO ₄ . The reaction mixture was _stirred for 1 hour and then treated with tert-butyl isocyanide (1.5-2.0 molar equivalents) and N-(3,5-difluorophenylacetyl)-Lalamine (1.5-2.0 molar equivalents). The reaction mixture was allowed to stir for 60 hours. The reaction mixture was diluted with methylene chloride and washed with 0.01 N HCl and saturated aqueous NaHCO ₃ . Each aqueous wash was back-extracted with methylene chloride. The combined organic layers were washed with brine, dried over _Na2SO4 , filtered and concentrated to give N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N'-Ra-methylbenzyl-2-amino2-DL-(aryl)acetamide. At this point, the isomers

-234separated, if possible, by HPLC chromatography using, for example, a 20 to 25% ethyl acetate/hexanes gradient. The α-methylbenzyl protecting group was then removed from the peptide by adding 10 molar equivalents of triethylsilane and 20 molar equivalents of trifluoroacetic acid to the compound. The reaction mixture was heated to 37 °C for 3 hours and then poured into ethyl acetate and washed with sodium bicarbonate. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by trituration with ether or ether/hexanes. Various other aldehydes, isocyanides and carboxylic acids can be used in this procedure to provide a variety of compounds useful in the present invention.

General AM Procedure

Preparation of amino acid derivatives using chiral amines III

A solution of aromatic aldehyde (3 molar equivalents) and S-()-α-methylbenzylamine (1 molar equivalent) in methanol was treated with titanium isopropoxide (1.5 molar equivalents). After stirring the mixture at ambient temperature for 6 hours, tert-butyl isocyanide (1.1 molar equivalents) was added followed by N-(3,5-difluorophenylacetyl)-Lalamine (1.2 molar equivalents) 40 minutes later. The reaction mixture was stirred for 72 hours. The methanol was removed by rotary evaporation. The residue was dissolved in methylene chloride and washed with 0.01 N HCl. The emulsion was filtered through celite eluting with methylene chloride. The layers were separated; the organic phase was washed with saturated NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ ,

-23520 to 25% group was filtered and concentrated to give N-tert-butylN'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N'-R-αmethylbenzyl-2-amino-2-DL-(aryl)acetamide. At this point, the isomers were separated, if possible, by HPLC chromatography using, for example, an ethyl acetate/hexanes gradient. The α-methylbenzyl protection was then removed from the peptide by adding 10 molar equivalents of triethylsilane and 20 molar equivalents of trifluoroacetic acid to the compound. The reaction mixture was heated to 37 °C for 3 hours and then poured into ethyl acetate and washed with sodium bicarbonate. The organic layer was dried over _Na2SO4 , filtered and concentrated. The residue was purified by trituration with ether or ether/hexanes. Various other aldehydes, isocyanides and carboxylic acids can be used in this procedure to provide a variety of compounds useful in the present invention.

General Procedure AN

EEDQ copulation procedure II

To a 1:1 mixture of the corresponding carboxylic acid and amino ester/amide in THF at 3 °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 reduced pressure or under a stream of nitrogen and the residue was dissolved in EtOAc. The organic solution was washed once with saturated NaHCO ₃ solution, once with N HCl and dried over MgSO ₄ . The organic solution was reduced in vacuo to give the product.

General AO Procedure

-236Preparation of primary amides

A sealable pressure tube containing a magnetic stirrer under a nitrogen atmosphere at ambient temperature was charged with methyl ester (1 equivalent), sodium cyanide (0.1 equivalent) and 7M ammonium in methanol. The tube was sealed and heated to 45 °C with stirring for 18 hours. The reaction mixture was allowed to cool to ambient temperature and the resulting precipitate was isolated by vacuum filtration. The solid was either washed with methanol or recrystallized from ethyl acetate/methanol.

Example 1

Synthesis of methyl N-(N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-aminohexanoate

Following general procedure A (without washing with IN HCl) and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in 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 thin layer chromatography (Rf = 0.71 in 10% CH3OH/CH2Cl2, 0.22 _r in 50% EtOAc/hexanes) and the product was purified by silica gel column chromatography using CH2Cl2 as the eluent.

The NMR data were as follows:

3-nmr (CDCl ₃ ): δ = 6.90 (d, J = 7.69 Hz, 1H), 6.80 (m, 3H), 6.70 (m, IH), 4.62 (quintet, J = 7.2 Hz, IH), 4.48 (m, 1H), 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).

¹³ C-nmr (CDCl 3 ): δ = 173.23, 172.69, 169.97, 165 × 30, 165.12,

-237162.00, 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.

C18H24F2N2O4:

Molecular weight - 370.40;

Mass spectroscopy: (MH ⁺ ) 371.

Example 2

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalanininyl]-L-histidine methyl ester

Following general procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2) and L-histidine methyl ester dihydrochloride (Sigma), the title compound was prepared as a solid (mp = 195-197 °C). The reaction was monitored by thin layer chromatography (Rf = 0.29 in 10% CH3OH/CH2C2).

The NMR data were as follows:

^-nmr (CD 3 OD) : δ = 7.M (s, 1H) / 7.00-6.81 (m, 4H), 4.70 (t, 1H), 4.39 (q, 1H), 3.72 (s, 3H), 3.60 (s, 2H), 3.22-3.00 (m, 2H), 1.38 (d, 3H).

¹³ C-nmr (CD ₃ OD) : δ = 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.

C18H20F2N4O4:

Molecular weight = .394.38;

Mass spectroscopy: (MH ⁺ ) 395.

Example 3 <

Synthesis of N-benzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-238(S)-2-aminohexanamide

Following General Procedure K and using methyl N-[N(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (prepared in Example 1 above) and benzylamine (Aldrich), the title compound was prepared as a solid (m.p. greater than or equal to 200°C). The reaction was monitored by thin layer chromatography (R _f = 0.29 in 5% CH3OH/CH2Cl2) and the product was purified by preparative planar chromatography.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.05 (m, 5H), 6.65 (m, 3H), 4.10 (m, 4H),

3.35 (d, 2H), 1.35 (m, 9H), 0.65 (m, 3H).

¹³ C-nmr (CDC1 ₃ ): δ = 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, 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.

C24H29E2N3O3:

Molecular weight 445.51;

Mass spectroscopy: (MH ⁺ ) 446.

Example 4

Synthesis of N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide'

Following General Procedure K and using methyl N-[N(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (prepared in Example 1 above) and N,N-dimethylethylenediamine (Aldrich), the title compound was prepared as a solid (mp = 182-187 °C).

-239The reaction was monitored by thin layer chromatography (R _f = 0.51 in 15% CH ₃ OH/CH ₂ Cl ₂ ) and the product was purified by preparative plane chromatography, using a mixture of 15% CH 3 OH/CH 2 Cl 2 as the eluent.

The NMR data were as follows:

^-nmr (CDCl 3 ): δ = 7.21 (d, 1H), 6.80 (m, 5H), 4.M (m, 1H), 4.48 (q, 1H), 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).

¹³ C-nmr (CDC1 ₃ ): δ = 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, 45.7, 43.3, 38.1, 33.2,

28.2, 23.0, 19.2, 14.4.

C21H32F2N4O3:

Molecular weight = 426.51;

Mass spectroscopy: (MH ⁺ ) 427.

Example 5

Synthesis of N-(2-methoxyethyl)-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-(S)-2-aminohexanamide

Following General Procedure K and using methyl N-[N(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (prepared in Example 1 above) and 2-methoxyethylamine (Aldrich), the title compound was prepared as a solid (m.p. greater than or equal to 200°C). The reaction was monitored by thin layer chromatography (Rf = 0.42 in 10% CH3OH/CH2Cl2) and the product was purified by flash chromatography using 12% CH3OH/CH2Cl2 as eluent.

The NMR data were as follows:

^x H-nmr (CDCl 3 ): δ = 7.85 (bd, J = 8.79 Hz, 0.5H), 7.64 (bd, J

-240= 7.81 Hz, 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) . ¹³ C-nmr (CDCl3) : δ 2 = 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, 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.

C20H29F2N3O4:

Molecular weight = 413.47;

Mass spectroscopy: (MH ⁺ ) 414.

Example 6

Synthesis of N-2 - (N', N-dimethylamino) ethyl-N' - [N- (3, 5difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

Following general procedure K and using Ν-[N-3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (prepared in Example 94 below) and N,N-dimethylethylenediamine (Aldrich), the title compound was prepared as a solid (mp = 174-182 °C).

The reaction was monitored by thin layer chromatography (R _f = 0.31 in 10% CH 3 OH/CH 2 Cl 2 ) and the product was purified by preparative plane chromatography, using 10% CH 3 OH/CH 2 Cl 2 as eluent.

The NMR data were as follows:

^-nmr (CD ₃ OD) : δ = 7.22 (m, 5h), 6.85 (m, 3H), 4.51 (m, 1H), 4.18 (m, 1H), 3.57 (m, 2H), 3.50-2.45 (m, 6H), 2.39 (s, 6H), 1.26 (d, 2.4H), 1.10 (d, 0.6H).

-241-

¹³ C-nmr (CD ₃ OD) : δ = 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, 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 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;

Molecular weight = 460.53;

Mass spectroscopy: (MH ⁺ ) 461.

Example 7

Synthesis of N-(4-pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-L-phenylalaninamide

Following General Procedure K and using N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (prepared in Example 94 below) and 4-(aminomethyl)pyridine (Aldrich), the title compound was prepared as a solid (m.p. greater than or equal to 200 °C). The reaction was monitored by thin layer chromatography (Rf = 0.46 in 10% CH3OH/ _CH2Cl2 ) and the product was purified by recrystallization from ethyl acetate.

The NMR data were as follows:

^x H-nmr (CD ₃ OD) : δ = 8.37 (d, 2H), 7.25 (m, 5H), 7.11 (d, 2H), 6.85 (m, 3H), 4.56 (t, 1H), 4.29 (m, 3H), 3.M (s, 2H), 3.08 (m, 2H), 1.30 (d, 3H).

¹³ C-nmr (CD ₃ OD): δ = 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,

-24238.93, 21.41, 18.16, 15.02.

C26H26R2N4O3:

Molecular weight = 480.52;

Mass spectroscopy: (MH ⁺ ) 481.

Example 8

Synthesis of N-(3-pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-L-phenylalaninamide

Following General Procedure K and using Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (prepared in Example 94 below) and 4-(aminomethyl)pyridine (Aldrich), the title compound was prepared as a solid (mp = 199-210 °C).

The reaction was monitored by thin layer chromatography (R _f = 0.46 in 10% CH3OH/CH2Cl2, minor isomer R _f = 0.50) and the product was purified by preparative planar chromatography, using 10% CH3OH/CH2Cl2 as eluent. NMR data were as follows:

^x H-nmr (CD ₃ OD) : δ = 8.42 (m, 2H), 7.61 (m, 1H), 7.29 1 (m, 610, 6.90 (m, 3H), 4.61 (m, 1H), 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). ¹³ C-nmr (CD ₃ OD): δ = 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, 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.

C26H26F2N4O3;

-243Molecular weight = 480.52;

Mass spectroscopy: (MH ⁺ ) 481.

Example 9

Synthesis of N-(4-pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-(S)-2-aminohexanamide

Following general procedure K and using methyl N-[N(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (prepared in Example 1 above) and 4-(aminomethyl)pyridine (Aldrich), the title compound was prepared as a solid (mp = 181-205 °C). The reaction was monitored by thin layer chromatography (R _f = 0.51 in 10% CH3OH/CH2Cl2) and the product was purified by preparative plane chromatography using ₁₀ % _CH3OH / _CH2Cl2 as eluent.

The NMR data were as follows:

^•H-nmr (CD3OD) : δ = 8.48 (m, 0.8H), 8.42 ^c (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). ¹³ C-nmr (CD3OD) : δ = 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, 141.41, 124.35, 124.20, 113.95, 113.85, 113.72, 113.62, 103.86, 103 _ï 57, 103.52, 103.18, 55.72, 55.N, 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.

_{C23H28F2N4O3 ; ​ ​ ​}

Molecular weight = 446.50; Mass spectroscopy: (MH ⁺ ) 447.

-244Example 10

Synthesis of tert-butyl N-[N-(3,5-difluorophenylacetyl)-Lalaninyl] - (S)-2-aminohexanoate

Step A. Formation of tert-butyl ester

To a solution of Z-norleucine-OH in CH2Cl2 was added 1.5 equivalents of N,N'-diisopropyl-O-tert-butylisourea (prepared according to the method of Synthesis (1979) p. 561) and the reaction mixture was heated to reflux for 17 hours. Another 1.5 equivalents of isourea was then added and heating to reflux continued for an additional 7 hours. The reaction mixture was then cooled to ambient temperature and filtered through a pad of Celite 545, then stripped to dryness to give a clear oil. The residue was dissolved in hexanes and filtered to remove solids and the filtrate was washed with saturated aqueous NaHCO3, water, saturated aqueous NaCl and dried over _MgSO4 . The solution was concentrated under reduced pressure to give the product.

Step B. Removing CBZ

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 H ₂ in a Parr apparatus for 30 minutes. The reaction mixture was then filtered through a pad of Celite 545 and the solvent was removed on a rotary evaporator to give the product, norleucine tert-butyl ester hydrochloride.

Step C.

Following general procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2

-245 above) and norleucine tert-butyl ester hydrochloride, the title compound was prepared as a semi-solid. The reaction was monitored by thin layer chromatography (R _f = 0.41 in 50% EtOAc/hexanes) and the product was purified by flash chromatography using 50% EtOAc/hexanes as the eluent, followed by preparative planar chromatography using 50% EtOAc/hexanes as the eluent.

The NMR data were as follows:

1H-nmr (CDCl ₃ ): δ = 7.63 (d, J = 7.7 Hz, 1H), 7.34 (d, J =

7.7 Hz, IH), 6.8 (m, 2H), 6.7 (m, IH), 4.8 (m, IH), 4.36 (g, J = 5.6 Hz, IH) , 3.52 (s, 2H) , 1.8-1.1 (m, 15H) , 0.8 (m,

3H).

¹³ C-nmr (CDC1 ₃ ): δ = 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, 53.6, 49.3, 43.0, 32.2,

28.4, 27.8, 22.7, 19.4, 14.7, 14.2.

_C2iH3oF2N2O4 :

Molecular weight = 412.48;

Mass spectroscopy: (MH ^4- ) 413.

Example 11

Synthesis of Ν-[N-(pent-4-enoyl)-L-alaninyl]-L-phenylalanine methyl ester

Following general procedure A and using N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Sigma) and _L -phenylalanine methyl ester (Sigma) following general procedure A, followed by removal of the BOC group following general procedure Y) and pent-4enoic acid (Aldrich), the compound was prepared from

-246 title compound as a solid (mp = 125.5-126.5 °C). The reaction was monitored by thin layer chromatography (R _f = 0.32 in 50% EtOAc/hexanes; 0.51 in 10% CH3OH/CH2Cl2) and the product was purified by flash chromatography using 10% CH3OH/CH2Cl2 as the eluent.

The NMR data were as follows:

¹ H-nmr (CDCl3) : δ = 7.27 (bd, J = 7.82 Hz, IH), 7.25-7.05 (m, 5H) , 6.72 (bd, J = 7.57 Hertz, IH), 5.75 (m, IH), 4.96 (m, 2H), 4, 59 (quintet, , J = 7.2 Hertz, IH), 3.65 (s, 3H), 3.05 (m, 4H), 2, 40-2.18 (m, 4H), 1.28 (d, J = 7.02 Hz, 3H) .

¹³ C-nmr (CDC1 ₃ ): δ = 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.

_{C18H24N2O4 : ​ ​}

Molecular weight = 332.40;

Mass Spectroscopy: (MNa ⁺ ) 355.0.

Example 12

Synthesis of Ν-[N-(dec-4-enoyl)-L-alaninyl]-L-phenylalanine methyl ester

Following general procedure A and using N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester (Sigma) according to general procedure A, followed by removal of the BOC group according to general procedure Y) and dec-4-enoic acid (which was prepared from ethyl dec-4-enoate (ICM) according to general procedure N), the title compound was prepared as a solid (mp = 115.5-117.5 °C). The reaction was monitored by thin layer chromatography (R _f = 0.52 in 50% EtOAc/hexanes; 0.60 in 10% • · · »

that «

-247• it· • ·

CH3OH/CH2Cl2) and the product was purified by flash chromatography, using a 10% CH3OH/CH2Cl2 mixture as eluent. The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.54 (bd, J = 7.69 Hz, IH) , 7.22-7.04 (m, 5H) , 6, 91 (bd, J = 7.69 Hz, IH), 5.37 (m, 2H ), 4.73 (q, J = 6.9 Hz, IH), 4.63 (quintet, 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). ¹³ C-nmr (CDC1 ₃ ): δ = 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, 29, 68, 29, 09, 23.06, 19.23, 14.61. C23H34N2O/]:

Molecular weight = 402.54;

Mass spectroscopy: (MNa ⁺ ) 425.0.

Example 13

Synthesis of N-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-4-[3-(N,N-dimethylamino)propoxy]phenylalanine methyl ester

Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2) and L-4-[3-(Ν,Ν-dimethylamino)propoxy]phenylalanine methyl ester (which was prepared from N-BOC-L-tyrosine methyl ester (Bachem) and 3-dimethylamino-1-propanol (Aldrich) using the Mitsunobu procedure essentially as described in General Procedure AD, followed by removal of the BOC group according to General Procedure Y), the title compound was prepared as a solid (mp = 153-155 °C).

The reaction was monitored by thin layer chromatography (R _f - 0.36 in 10% MeOH/DCM/1% TEA) and the product was purified by acid/base washing.

-248♦ ·

• · 4

4 4

44 to 4 4 · > 4 9 4

444 444

The NMR data were as follows:

¹ H-nmr (CDC1 ₃ ) : δ = 6, 973-6.947 (d, 2H); 6.794-6.766 (d, 2H); 6,743-6 .714 (d, 2H) ; 6,735-6,676 (t, 1H); 4.761-4.735 (q, 1H); 4, 511-4,463 (q, 1H); 3.967-3.924 (t, 2H); 3.703 (s, 3H); 3, 473 (with, 2H) ; 3.019-2.977 (t, 2H); 2,443-2,394 (t, 2H); 2, 233 (with, 6H) ; 1.944-1.897 (t, 2H); 1.319-1.296 (d, 3H) . ¹³ C-nmr (CDCl3) : δ = 172,292; 172,256; 169,808; 158,747; 130,731 ; 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.

_{C26H33F2N3O5 ; ​ ​}

Molecular weight = 505; Mass spectroscopy: (MH ⁺ ) 506.

Example 14

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-4-[(tert-butyloxycarbonyl)methoxy]phenylalanine methyl ester

Following the general procedure of AE and using tert-butyl bromoacetate (Aldrich) and N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester (prepared in Example 15 below), the title compound was prepared as a solid (mp = 116-119 °C). The reaction was monitored by thin layer chromatography (R _f = 0.54 in 50% EtOAc/hexanes) and the product was purified by silica gel column chromatography.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.648-7.615 (d, 1H); 7.513-7.407 (d, 1H); 6,943-6,914 (d, 2H); 6,756-6,669 (d+t, 4H); 6.621-6.562 (t, 1H); 4.662-4.590 (q+quintet, 2H); 4.382 (s, 2H); 3.571 (s, » · · · • · · • · · ·Μ ·· ··· ·

-2493H); 3.406 (s, 2Η) ; 3.006-2.648 (m, 2H); 1.417 (s, 9H);

1.243-1.221 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 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; 112,803; 103,250; 828,270;

66,039; 54,361; 52,730; 49,172; 42,832; 37,288; 28,509;

19,018.

C17H32F2N2O7:

Molecular weight = 534;

Mass spectroscopy: (MH ⁺ ) 535.

Example 15

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaniny]-L-tyrosine methyl ester

Following general procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in 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 thin layer chromatography (Rf = 0.27 in 50% EtOAc/hexanes) and the product was purified by silica gel column chromatography.

The NMR data were as follows:

1-nmr (CDCl ₃ ): δ = 8.036 (b, 1H); 7.369-7.344 (d, 1H);

7.205-7.151 (d, 1H); 6,869-6,841 (d, 2H); 6, 763-6, 738 (d,

2H); 6.657-6.615 (m, 3H); 4.741-4.697 (q, 1H); 4.566-4.491 (q, 1H); 3.671 (s, 3H); 3.415 (s, 2H); 3.061-2.771 (dm, 2H); 1.271-1.250 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 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.

C21H22F2N2O5 :

Molecular weight = 420;

Mass spectroscopy: (MH ⁺ ) 421.

Example 16

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-4-(carboxymethoxy)phenylalanine methyl ester

Following general procedure N and using Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[(tert-butyloxycarbonyl)methoxy]-phenylalanine methyl ester (prepared in

Example 14 above), the title compound was prepared. The reaction was monitored by thin layer chromatography (Rf = 0.49 in 10% MeOH/DCM + 1% AcOH) and the product was purified by silica gel column chromatography.

The NMR data were as follows:

1-nmr (CDCl ₃ ): δ = 7.817 (s, 1H); 7,648-7622 (d, IH) ; 7.5447.520 (d, 1H); 6,956-6,914 (d, 2H); 6.762-6.703 (d+d, 4H);

6.650-6.590 (t, 1H); 4.678-4.636 (q, 1H); 4.567-4.503 (quintet + s, 3H); 3.622 (s, 3H); 3.431 (s, 2H); 2.987-2.811 (m, 2H); 1.241-1.219 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 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.

C23H24F2N2O7:

Molecular weight = 478;

Mass spectroscopy: (MH ⁺ ) 479.

• ·

-251A

AA A· AAAA

A A AAA

A A AAAA A A

AAAA AAAA

A AAA A A

A AAAA AA AAA AA AA

AAA

Example 17

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-4-(2-morpholinoethoxy)phenylalanine methyl ester

Following the general procedure AD and using Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester (prepared in 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 thin layer chromatography (R _f = 0.6 in 10% MeOH/DCM + 1% TEA) and the product was purified by silica gel column chromatography, followed by trituration in diethyl ether.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 6.974-6.945 (d, 2H); 6, 795-6,726 (d+t,

2H); 6.697-6.682 (t, 1H); 4.755-4.689 (q, 1H); 4.535-4.468 (quintet, 1H); 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).

¹³ C-nmr (CDCl ₃ ): δ = 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.

C ₁₇ H ₃₃ F ₂ N ₃ O ₆ :

Molecular weight = 533;

Mass spectroscopy: (MH ⁺ ) 534.

Example 18

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl] (S)-2-amino-6-(N,N-dimethylamino)hexanoate

-252Β • · • ··· ··♦ ·

Following general procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and _Νε , N _E -dimethyl-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp = 123-126 °C). The reaction was monitored by thin layer chromatography (R _f = 0.22 in 10% MeOH/DCM + 1% TEA) and the product was purified by silica gel column chromatography.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.019-6.993 (d, 1H); 6, 828-6, 501 (dd,

2H); 6, 753-6, 723 (m, 1H); 6, 617-6, 592 (d, 1H); 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); 1.486-1.344 (m+d, 7H).

¹³ C-nmr (CDCl ₃ ): δ = 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.

C2oH29E2N ₃ 0 ₄ :

Molecular weight = 413;

Mass spectroscopy: (MH ⁺ ) 414.

Example 19

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-amino-3-(2-pyridyl)propionate

Following general procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2) and methyl-(S)-2-amino-3-(2-pyridyl)propionate hydrochloride (Syntetech), the title compound was prepared as a solid (mp = 121-124 °C). The reaction was monitored by thin layer chromatography (R _f = 0.39 in 10

-253 ft · ft • ft ftftft · • ♦ • ftftft • ftft • · ftftft • ftft · • ftft · • ftft ftftft • · ftft ftft %MeOH/DCM) and the product was purified by silica gel column chromatography.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 8.474-8.458 (d, 1H); 7.767-7.631 (m, 1H); 7.625-7.574 (t, 1H); 7.178-7.102 (t+d, 2H); 6,818-6,811 (d,

2H); 6, 734-6, 667 (t, 1H); 6, 593-6,542 (m, 1H); 4.933-4.873 (m, 1H); 4.5664.496 (m, 1H) ; 3.646 (s, 3H); 3.499 (s, 2H); 3.375-3.196 (m, 2H); 1.393-1.370 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 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. C20H21F2N3O4:

Molecular weight = 405;

Mass spectroscopy: (MH ⁺ ) 406.

Example 20

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl] (S)-2-amino-3-(3-pyridyl)propionate

Following general procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2) and hydrochloride (Syntetech), methyl (S)-2-amino-3-(3-pyridyl)propionate solids, the title compound was prepared as (mp = 101-103 °C). The reaction was monitored by thin layer chromatography (R _f = 0.48 in 10% MeOH/DCM) and the product was purified by silica gel column chromatography.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.492-8.396 (m, 7.505-7.452 (m, 1H); 7.248-7.170

IH); 8.359-8.322 (m, 1H); (m, IH) ; 6.976-6.908 (m, (m, 1H); 4.866-4.798

3H); 3.513 (s, 2H);

• v « v v « • ··· 9 9 9 9 • 99 999 999

9 9 9 » 999 99 99

IH) ; 6.855-6.668 (m, 3H); 6, 352-6,288 (m, 1H); 4.784-4.429 (m, 1H); 3,750 (with

3.220-2.964 (m, 2H); 1.310-1.287 (d, 3H) ¹³ C-nmr (CDCl ₃ ): δ = 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.

C20H21F2N3O4:

Molecular weight = 405;

Mass spectroscopy: (MH ⁺ ) 406.

Example 21

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalanininyl]-L-proline methyl ester

Following general procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-proline methyl ester hydrochloride (Bachem), the title compound was prepared as a viscous solid. The reaction was monitored by thin layer chromatography (R _f = 0.57 in 10% MeOH/DCM) and the product was purified by acid/base washing.

The NMR data were as follows:

'H-nmr (CDCl ₃ ) : δ = 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 (with, 2H) ,; 2,217-1,902 (m,

5H); 1.332-1.309 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 172.753; 172,152; 169,843; 165, 185;

161,894; 112,953; 112,850; 112,727; 112,624; 103,331,

102.996, 102.662; 59.352; 52.735; 47.495; 47.267; 43.069;

φ φ φ φφφ φ φ φ φ φ φφ φφ φ

• · φφ · ·

255 φ φ φ φ φ φφ φφφ

29,472; 25,403; 18,243.

C17H20F2N2O4:

Molecular weight = 354;

Mass spectroscopy: (MH ⁺ ) 355.

Example 22

Synthesis of methyl 1-[N-(3,5-difluorophenylacetyl)-Lalaninyl]piperidine-2-carboxylate

Following general procedure B and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and methyl pipecolinate hydrochloride (Aldrich), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography (Rf = 0.30 in 50% EtOAc/hexanes) and the product was purified by silica gel chromatography.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 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, IH) , 3.59 (s, 3H) , 3.47 (s, 2H) ,

3.1 (m, 1H), 2.16 (d, J = 11.5 Hz, 1H), 1.4 (m, 4H), 1.22 (dd, J = 1.3, 4.4, 1.2 Hz, 3H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

C18H24N2O4:

Molecular weight = 332;

Mass spectroscopy: (MH ⁺ ) 333.

Example 23

Synthesis of methyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]9· «9 9999

9

-2569 9999 9 99 9

9 99 999999

9 9 9 9

999 99 99 (S)-2-amino-3-(4-pyridyl)propionate

Step A. Preparation of 3-(3-pyridyl)alanine methyl ester dihydrochloride

Sodium metal (1.40 g, 61 mmol) was dissolved in EtOH (100 mL) and diethyl acetamidomalonate (6.62 g, 30.5 mmol) and 3-picolyl chloride hydrochloride (5.009, 30.5 mmol) were added. The mixture was heated to reflux for 6 h and then cooled and filtered to remove NaCl (washed with EtOH). The solvent was removed in vacuo and the mixture was taken up in saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (3 x 100 mL). The solvent was removed and the residue was purified by silica gel flash chromatography (95:5 _CH2Cl2 / _MeOH ) to give diethyl 2-(3-pyridylmethyl)-2-acenidomalonate (2.84 g, 30%).

Diethyl 2-(3-pyridylmethyl)-2-acetamidomalonate was dissolved in 6N HCl (30 mL) and heated to reflux for 19 hours, then cooled to ambient temperature and the HCl solution was removed by evaporation under vacuum. The intermediate, the dihydrochloride salt of the amino acid, was taken up in MeOH (30 mL) saturated with HCl gas and stirred for 3.5 hours. The MeOH/HCl was removed by evaporation under vacuum to give 3-(3-pyridyl)alanine methyl ester dihydrochloride (2.235 g, 100%).

Step B. Preparation of methyl N-[N-(3,5-difluorophenylacetyl)-L-alanine]-(S)-2-amino-3-(4-pyridyl)propionate Following general procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl-(S)-2-amino-3-(4-

Φ

257 φφ ·· φφφφ φ φ φ φ φφφφ φ

• e ΦΦΦ pyridyl)propionate (prepared as above using 4-picolyl chloride hydrochloride) , the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.49 in 10% MeOH/DCM) and the product was purified by silica gel column chromatography.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 8.423-8.335 (dd, 2H); 7.832-7.754 (q,

IH); 7.342-7.246 (dd, 1H); 7.032-6.972 (dd, 2H); 6.764-6.667 (t, 2H); 6, 659-6, 599 (m, IH); 4.837-4.768 (m, 1H); 4.5904.515 (m, 1H), 3.675 (s, 3H); 3.426 (s, 2H); 3.112-2.804 (m, 2H); 1.256-1.106 (dd, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 173.037; 171,739; 170,258; 170,225;

165.201; 165.012; 161.904; 101.721; 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.

_{C20H21F2N3O4 : ​ ​ ​}

Molecular weight = 405;

Mass spectroscopy: (MH ⁺ ) 406.

Example 24

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-3-methoxypropionate

Following general procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl 2-amino-3-methoxypropionate hydrochloride (Bachem), the title compound was prepared as a solid (mp = 165-168 °C).

The reaction was monitored by thin layer chromatography (R _f

-258« • ···· ·· flflfl^ flfl flfl > · A fl · · fl ft « flflfl · flfl · » · flfl flflfl ···

I · · · · fl· flflfl flfl ·· = 0.45 in 10% MeOH/DCM) and the product was purified by acid/base washing.

The NMR data were as follows:

1-nmr (CDCl ₃ ): δ = 6.971-6.944 (d, 1H); 6.813-6.801 (m, 2H);

6.741-6.678 (quintet + (m, 1H); 6.585-6.526 (m, 1H) ; 4.692-4.561 q, 2H); 3.836-3.802 (m, 1H); 3.738 (s, 3H);

3.592-3.516 (m+ds, 3H); 3.312 (s, 3H); 1.408-1.355 (dd, 3H). ¹³ C-nmr (CDCl ₃ ): δ = 172.705; 172,680; 170,908; 113,019;

112,978; 112,687; 112.M6; 103,347; 72,434; 72,405; 59,885;

59,837; 53,263; 53,240; 49,413; 49,329; 19,389; 18.9196. C16H20F2N2O5:

Molecular weight = 358;

Mass spectroscopy: (MH ⁺ ) 359.

Example 25

Synthesis of methyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-3-morpholinopropionate

Step A. Methyl-(2-N-CBZ-amino)-3-morpholino-propionate

To a solution of N-CBZ-dehydro-alanine methyl ester (Sigma) in acetonitrile were added 2.0 equivalents of morpholine and 0.25 equivalents of anhydrous ferric chloride. The mixture was stirred for 16 hours and monitored by thin layer chromatography. The solvent was removed and the residue was 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 rotary evaporated to dryness to give methyl-(2-N-CBZamino)-3-morpholino-propionate as a clear brown oil. See Perez et al., Tetrahedron 51(3) 8355-62 (1995)

-2 59• · · · · ·· · ·· · i • · 9 9 9 9 9 · · · ·' • 9 9*· 9 · ··· ··· • 9 · · · · «i • 9» 9999 99 999 » · ··

Step B. Methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2 ^L amino-3-morpholinopropionate

Following General Procedure A and using N-(3,5r difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl 2-amino-3-morpholinopropionate hydrochloride (prepared in General Procedure 0 above from methyl-(2-N-CBZ-amino)-3-morpholinopropionate), the title compound was prepared as a viscous solid. The reaction was monitored by thin layer chromatography (R _f = 0.44 in 10% MeOH/DCM) and the product was purified by acid/base washing.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.408-7.384 (d, 1H); 7.247-7.173 (m, 1H); 6.774-6.614 (m+t, 3H); 4.605-4.468 (m, 1H); 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, 4H); 1.344-1.307 (t;

3H).

¹³ C-nmr (CDCl ₃ ): δ = 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.

C1gH26F2N ₃ O5 :

Molecular weight = 413;

Mass spectroscopy: (MH ⁺ ) 414.

Example 26

Synthesis of N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-4-(2-morpholinoethoxy)phenylalaninamide

Following the general procedure K and using 2·· to·* · • · ····

-260• · * toto methoxyethylamine (Aldrich) and N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)phenylalanine methyl ester (prepared in Example 17 above), the title compound was prepared as a solid (mp = 165-168 °C). The reaction was monitored by thin layer chromatography (Rf = 0.67 in 10% MeOH/DCM + 1% TEA) and the product was purified by acid/base washing.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 8.258-8.232 (d, 1H); 8,014-7,989 (d, 1H); 7.532-7.370 (t, 1H); 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.M2 (t, 4H) ; 3,594-3, 453 (dd, 2H) ; 3, 404- 3.267 (t, 2H); 3.179 (with, 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).

¹³ C-nmr (CDCl ₃ ): δ = 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.

_{C29H38F2N4O6 : ​ ​}

Molecular weight = 576;

Mass spectroscopy: (MH ⁺ ) 577.

Example 27

Synthesis of N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-2-amino-3-methoxypropionamide

Following general procedure K and using 2-methoxyethylamine (Aldrich) and methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionate (prepared in Example 24 above), was prepared.

-261• · • > · · • · · · · · » · · · · · · · · « · · * · · · »· · • ·

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.728-6.706 (d, 2H); 6, 648-6,586 (t, 1H); 4,244-4213 (m, IH) ; 4.092-4.068 (m, 1H); 3.553-3.503 (m, 2H); 3.393-3.347 (m, 2H); 3.2153.073 (m+s, 7H); 3.053 (s, 3H); 1.183-1.138 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 176.31; 173.28; 172.59; 141.65; 114.02; 113.79; 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.

C18H25F2N3O5:

Molecular weight = 401;

Mass spectroscopy: (MH ⁺ ) 402.

Example 28

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]glycine methyl ester

Following general procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and glycine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp = 158-160 °C). The reaction was monitored by thin layer chromatography (R _f = 0.61 in 10% MeOH/DCM) and the product was purified by silica gel chromatography.

The NMR data were as follows:

δ-nmr (CDCl ₃ ): δ - 6.882-6.866 (m, 1H); 6.827-6.794 (m, 2H); 6.748-6.689 (t, 1H); 6, 520-6, 494 (d, 1H); 4,611-4,563

-262 • ·· ······ β · · · · · · · • · ····· · • * · · 9 9 4 · · · · 4 4 (quintet, IH) ; 4.00-3.99 (d, 2H); 3.746 (s, 3H); 3.528 (with

2H); 1.389-1.366 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 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.

_{C14H16F2N2O4 : ​ ​ ​}

Molecular weight = 314;

Mass spectroscopy: (MH ⁺ ) 315.

Example 29

Synthesis of N-(2-methoxyethyl)-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-2-amino-3-(4-pyridyl)propionamide

Following general procedure K and using 2-methoxyethylamine and methyl N-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-(S)-2-amino-3-(4-pyridyl)propionate (prepared in Example 23 above), the title compound was prepared as a solid (mp = 202-206 °C). The reaction was monitored by thin layer chromatography (R _f = 0.72 in 10% MeOH/DCM) and the product was purified by acid/base washing.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 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 (with, 2H) ; 3,190-3,084 (m, 4H) ; 3, 060 (s, 3H) ; 2,918-2,629 (m, 2H) ; 1.077-0.905 (d, 3H) . ¹³ C-nmr (CDCl ₃ ) : δ = 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.

_{C22H26p2N4O4 : ​}

• · ··· ·

-263···· ··· · · · · · • · ····· · · · · · • · * · 4 44 ······

4 4 4 4 4 4

Molecular weight = 448;

Mass spectroscopy: (MH ⁺ ) 449.

Example 30

Synthesis of N-(2-methoxyethyl)-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-2-amino-3-(2-pyridyl)propionamide

Following General Procedure K and using 2-methoxyethylamine and methyl N-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-(S)-2-amino-3-(2-pyridyl)propionate (prepared in Example 19 above), the title compound was prepared as a solid (mp = 183-187 °C). The reaction was monitored by thin layer chromatography (R _f = 0.39 in 10% MeOH/DCM) and the product was purified by recrystallization from MeOH/DCM.

The NMR data were as follows:

1 H-nmr (CDCl ₃ ): δ = 8.457-8.442 (d, 1H); 8.029-8.005 (d, 1H); 7.642-7.585 (t, 1H); 7.395-7.379 (m, 1H); 7.267-7.141 (d+t, 2H); 6.828-6.802 (m, 2H); 6, 754-6,679 (t, 1H); 6, 604-6, 581 (m, IH); 4.871-4.809 (q, 1H); 4.532-4.485 (quintet, IH) ;

3.537 (s, 2H); 3.342-3.118 (m, 6H); 3.248 (s, 3H); 1.3941.371 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 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.

C22H26F2N4O4 :

Molecular weight = 448;

Mass spectroscopy: (MH ⁺ ) 449.

-264• · · • · · · » * · « c.

• · · · · · * ·· · · • · · • 9 9

999 999 • ·

9 99 ♦ · • ·

Example 31

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-amino-3-(thiazol-4-yl)propionate

Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl (S)-2-amino-3-(thiazol-4-yl)propionate hydrochloride (General Procedure H with methanol and HCl applied to methyl (S)-2-amino-3-(thiazol-4-yl)propyl acid (Syntetech)), the title compound was prepared as a solid (mp = 136-139 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 10% MeOH/DCM) and the product was purified by recrystallization from DCM. The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 8.737-8.731 (d, 1H); 7.410-7.385 (d, 1H);

7.065-7.059 (d, 1H) ; 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 (quintet, IH) ; 3.678 (s, 3H); 3.515 (with, 2H) ; 3,402-3,232 (dg, 2H); 1.384-1.361 (d, 3H) .

¹³ C-nmr (CDCl ₃ ): δ = 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.

C18H19F2N3O4S:

Molecular weight = 411;

Mass spectroscopy: (MH ⁺ ) 412.

Example 32

Synthesis of methyl 2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]1,2,3,4-tetrahydroisoquinoline-3-carboxylate

Following general procedure A and using N-(3.5000 000 *

0 « *0 0*00

-265difluorophenylacetyl)-L-alanine (prepared in 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 thin layer chromatography (R _f = 0.64 in 10% MeOH/DCM).

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.500-7.475 (d, 1H); 7.161-7.057 (m, 4H); 6.815-6.795 (dm, 2H); 6, 656-6, 596 (t, 1H); 5.336-5.088 (m, 2H); 4.924-4.841 (m, 1H); 4.718-4.453 (m, 1H); 3.530 (s, 3H); 3.500 (s, 2H); 3.329-3.058 (m, 2H); 1.423-1.400, 1.3271.304 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 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.

C22H22F2N2O4:

Molecular weight = 416;

Mass spectroscopy: (MH ⁺ ) 417.

Example 33

Synthesis of N-(3-Methoxybenzyl)-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-L-phenylalaninamide

Following General Procedure B and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared by coupling N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) with L-phenylalanine methyl ester hydrochloride (Sigma) following General Procedure E, followed by hydrolysis following General Procedure C) and

-26644 «4

4 4 4 4 4 4 4444

4 44444 * 44 · » 4 44 4 44 444444

4 4 4 4 4 4

444 4444 44 444 44 44

3-methoxybenzylamine (TCI), the title compound was prepared as a solid (melting point = 117-130 °C).

The reaction was monitored by thin layer chromatography (R _f = 0.8 in 3% MeOH/methylene chloride) and the product was purified by recrystallization from MeOH.

The NMR data were as follows:

¹ H-nmr ( DMSO-dg) : δ = 8.4 (t, IH), 8.32 (d, IH), 8.1 (d, IH), 6.95-7.2 (m, 9H) , 6.7 (m, 3H) , dl, 5 (m, IH), 4.2 (m, 3H) , 3.7 (s, 3H), 3.5 3H), 1.2 (m, 4H). (s, 2H), 3.3 (d, 2H), 3, 0 (m, 2H), 2.5 (s, ¹³ C-nmr (DMSO-dg) : δ = 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.

C28H29N3O4F2:

Molecular weight = 509;

Mass spectroscopy: (MH ⁺ ) 509.

Example 34

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-amino-3-(1-naphthyl)propionate

Following general procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl (S)-2-amino-3-(1-naphthyl)propionate hydrochloride (Bachem), the title compound was prepared as a solid (mp = 103-130 °C).

The reaction was monitored by thin layer chromatography (R _f = 0.8 in 5% MeOH/methylene chloride) and the product was purified by flash column chromatography using 6%

A A A A ► A A A » A A A

AAA AAA

A A

A A « A • A

-267A A AAAA » · A

AAAA

MeOH/methylene chloride as elution solvent.

NMR data was following: ^x H-nmr (C :dci ₃ ) : δ = 8.10 (d, 1H) , 7.85 (d, 1H), 7.71 (d, 7.50 (m, 3H) , 7.35 (t, 1H), 7.20 (d, 1H), 6.70 (m, 4H) , (d, 1H), 4.90 (m, 1H) , 4.45 (m, 1H), 3.3-3.7 (m, 8H) (s, 1H), 1.3 (d, 3H).

¹³ C-nmr (CDCl 3 ): δ = 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. C24H24N2O4F2:

Molecular weight = 442;

Mass spectroscopy: (MH ⁺ ) 442.

Example 35

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alananyl](S)-2-amino-3-(2-naphthyl)propionate

Following general procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in 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 thin layer chromatography (Rf = 0.55 in 5% MeOH/methylene chloride) and the product was purified by preparative thin layer chromatography using 5%

MeOH/methylene chloride as elution solvent.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 1.3 (d, 3H), 3.2 (m, 2H), 3.3 (s, 2H),

3.7 (s, 3H) , 4.55 (m, 1H) , 4.9 (quartet, 1H) , 6.7 (m, 4H) , • * to to to to

-268• 9 9 9 ·999 • · « · this · · · this this this · ·' · t ···♦·· • this · · this this· «· ··« »· ··

7.05 (d, 1H), 7.20 (d, 1H), 7.45 (m, 2H), 7.55 (s, 1H), 7.80 (m, 3H).

¹³ C-nmr (CDC1 ₃ ): δ = 172.43, 172.26, 169, 86, 133, 93, 133, 76, 133.02, 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.

C24H24N2O4F2 ^:

Molecular weight = 442;

Mass spectroscopy: (MH ⁺ ) 442.

Example 36

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-amino-3-(2-thienyl)propionate

Following general procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in 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 thin layer chromatography (R _f = 0.9 in 100% EtOAc) and the product was purified by preparative thin layer chromatography using EtOAc as the eluent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 7.15 (d, 1H), 6.9 (t, 1H), 6.7-6.8 (m, 5H), 6.3 (d, 1H), 4.8 (m, 1H), 4.5 (m, 1H), 3.8 (s, 3H), 3.5 (s, 2H), 3.35 (d, 2H), 1.35 (d, 3H).

^{X 3} C-nmr (CDCl ₃ ): δ = 172.22, 171.56, 169.7 9, 137.47, 127.71,

125.55, 113.04, 112.71, 103.48, 78.03, 77.M, 77.18, 53.78,

53.25, 49.51, 43.41, 32.37, 18.97.

C19H20N2O4F2S:

Molecular weight = 410;

• · 0 0 0 0

-2690 -00 0· 0000 •000 0 « 0 ·

0 00000 0 0 · 0 · 0 0 · • · 0 0 0 ·

0000000 00 ·00 0*

Mass spectroscopy: (MH ⁺ ) 410.

Example 37

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalanine benzyl ester

Following general procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in 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 thin layer chromatography (R _f = 0.7 in 5%

MeOH/methylene chloride) and the product was purified by recrystallization from MeOH.

The NMR data were as follows:

^-nmr (MeOH): 6 = 7.3 (m, 10H) , 6.9 (m, 3H) , 5.2 (s, 2H) , 4.75 (t, J = 7 Hz, 1H) , 4.4 (quartet, J = 6 Hz, 1H) , 3.6 (s., 2H), 3.1 (m, J = 6 Hz, 2H) 1.35 (d, J = 7 Hz, 3H).

¹³ C-nmr (MeOH): δ = 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:

Molecular weight = 480;

Mass spectroscopy: (MH ⁺ ) 480.

Example 38

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalanine 3-bromopropyl ester

Following general procedure B and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared

-2709 * · · « · · * · · to· • · · to to·· to « «···· · · · · • · · to to to * to · · to · · • « · · * ·· ·« »··· to· * * 9 ·· «· by coupling N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-phenylalanine (Aldrich) according to 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 thin layer chromatography (R _f = 0.75 in 60% EtOAc/hexanes) and the product was purified by flash column chromatography using 60% EtOAc/hexanes as the eluent.

The NMR data were as follows:

^x H-nmr (CDC1 ₃ ) : δ = 7.3-6.6 (m, 10H) , 4.8 (m, IH) , 4.55 (m, IH), 4 ,2 (t, J = 6 Hz, 2H), 3, 51 (with, 2H) , 3.3 (m, 2H), 3.05 (m, J = 6 and 8 Hertz, 2H), 2.1 (m , 2H), 1.3-1.2 (m, J - 7 Hz,

3H).

¹³ C-nmr (CDCl3) : δ = 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.

023^25^0,] F2Br:

Molecular weight = 511.1; Mass spectroscopy: (MH ⁺ ) 512.

Example 39

Synthesis of N-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalanine 3-iodopropyl ester

Following general procedure B and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared

-271-

by coupling N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-phenylalanine (Aldrich) following general procedure B) and 3-iodo-1-propanol (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.45 in 5% MeOH/methylene chloride) and the product was purified by preparative thin layer chromatography using 5% MeOH/methylene chloride.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.4-7.0 (m, 5H), 6.9-6.6 (m, 4H), 6.3 (m, 1H), 4.8 (s, 1H), 1.35-1.25 (m, 3H).

¹³ C-nmr (CDC1 ₃ ): δ = 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, 38.50, 32.57, 18.97,

18.91.

Example 40

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-leucine tert-butyl ester

Following general procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-leucine tert-butyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp = 128 °C). The reaction was monitored by thin layer chromatography (R _f = 0.85 in 5% MeOH/methylene chloride) and the product was purified by flash column chromatography using 5% MeOH/methylene chloride as the eluent.

The NMR data were as follows:

·· · ·

-272• · · · • « * · • · · · • · · · · · • · • · · · ^x H-nmr (CDC1 ₃ ) : δ = 6.9-6.5 (m, 5H) , 4.6 (m, 1H) , 4.4 (m,

1H), 3.5 (s, 2H), 1.7-1.4 (m, 15H), 0.9 (t, 6H).

¹³ C-nmr (CDC1 ₃ ): δ = 172.41, 172.20, 169, 87, 165, 30, 162.00,

161.83, 139.01, 138.89, 112.92, 112.82, 112.69, 112.59,

103.62, 103.29, 102.95, 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:

Molecular weight = 412.48;

Mass spectroscopy: (MH ⁺ ) 413.

Example 41

Synthesis of Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino2-(3-pyridyl)acetamide

Following General Procedure L and using ethyl N-[N(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetate (prepared in Example 65 below), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.1 in 9:1 CHCl ₃ /MeOH) and the product was purified by recrystallization from EtOH.

The NMR data were as follows:

^x H-nmr (DMSO-dfi) : δ = 8.54 (m, 1H) , 8.43 (d, IH) , 7.77 (m, IH), 7.59 (bs, IH), 7.46 (m, IH) , 7.33 (m, IH) , 7.22 (m, 1H), 7.09 (m, 1H), 6.98 (m, 2H), 5, .41 (m, IH) , 4.46 (m, IH) , 4.46 (m, IH), 3.52 (s, 2H), 1.26 (m , 3H) .

C18H17N3O3F2:

Molecular weight = 376.3; Mass spectroscopy: (MH ⁺ ) 377.

-273·· ··

4 4 · 4 4 4 · · · · • · 4 4 4 4· 4 · · · • 4 4 4 9 4 4 4 4 4 · 4 4

4 4 4 4 · · ··· ···· 99 999 99 99 ·· ·· ····

Example 42

Synthesis of N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino2-(3-pyridyl)acetamide

Following General Procedure L and using ethyl N-[N(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetate (prepared in Example 53 below), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.1 in 9:1 CHCl ₃ /MeOH) and the product was purified by recrystallization from EtOH.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ) : δ = 8.64 (m, 1H) , 8.55 (d, 1H) , 8.52 (d, 1H), 8.41 (d, 1H), 7.79 (m, 1H) , 7.37 (m, 1H) , 7.32 (m, 1H) , 7.09 (m, 1H), 6.98 (m, 2H), 5.42 (m, 1H) , 4.42 (m, 1H) , 3.53 (s, 2H), 1.26 (m, 3H) .

Ci ₈ H ₁₇ N ₄ O ₃ E ₂ :

Molecular weight = 376.3; Mass spectroscopy: (MH ⁺ ) 377.

Example 43

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaniny]-N ₆ - (tert-butoxycarbonyl)-L-lysine methyl ester

Following general procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N- _ε- (tert-butoxycarbonyl)-L-lysine methyl ester (Bachem), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography (R _f = 0.40 in 50% EtOAc/hexanes) and the product was purified by flash chromatography, using 50% EtOAc/hexanes as eluent.

-274• ·· ·· ···· ·· ·· ·· · · « »· · · · · • 9 9 9 999 9 9 9 9 • ft · · · ·· 999999

9 9 9 9 9 9 elution solvent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 6.80 (d, 2H), 6.66 (t, 1H), 4.82 (bs, 1H), 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), 1.2-1.30 (m, 2H).

¹³ C-nmr (CDCl ₃ ): δ = 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.

C23H33F2N3O6:

Molecular weight = 485.53;

Mass spectroscopy: (MH ⁺ ) N/A.

Example 44

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-amino-4-phenylbutanoate

Following general procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl (S)-2-amino-4-phenylbutanoate (which was prepared from ( + )-α-amino-4-phenylbutyric acid (Bachem) following general procedure AG), the title compound was prepared as a solid (m.p. = 147°C).

149.5 °C). The reaction was monitored by thin layer chromatography (Rf = 0.32 in 50% EtOAc/hexanes) and the product was purified by flash chromatography using EtOAc/hexanes as the eluent.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ) : δ = 7.63 (bd, 2H), 7.04 (m, 5H), 6.56-6.82 (m, 3H), 4.80 (ρ, IH), 4.48 (q, IH), 3.65 (s, 3H), 3.49 (s,

-275• 99 99 9999 99

9 9 9 9 9 9 • 9 9 9 999 9 9 9 9 • 9 99 9 99 999999

9 9 9 9 9 9

9999999 99 999 99 99

2H), 2.50-2.65 (m, _2H ), 1.80-2.16 (m, 2H), 1.29 (d, 3H). ¹³ C-nmr (CDC1 ₃ ): δ = 173.48, 172.89, 170.43, 165.17, 161.71,

140.91, 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:

Molecular weight = 418.44;

Mass spectroscopy: (MH ⁺ ) 419.

Example 45

Synthesis of 2-phenylethyl ester of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]glycine

Following General Procedure X and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (which was prepared from benzyl ester of N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared in Example 73 below) following General Procedure O) and 2-phenylethanol (Aldrich), the title compound was prepared as a solid (mp = 154.0-155.2 °C). The reaction was monitored by thin layer chromatography (R _f = 0.15 in 15% EtOAc/hexanes) and the product was purified by flash chromatography using 15% EtOAc/hexanes as the eluent.

NMR data was following: ^-nmr (CDCl ₃ ) : δ = 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) ¹³ C-nmr (CDCl ₃ ): δ = 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. C21H22N2O4F2 ·· ♦···

-276·· 4 » · · » · · ·»· 4 • · 4

Molecular weight = 404.42;

Mass spectroscopy: (MH ⁺ ) 405.

Example 46

Synthesis of N-[N-(3,5-difluorophenylacetyl)-Lalaninyl]glycine 3-phenylpropyl ester

Following General Procedure X and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (which was prepared from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester (prepared in Example 73 below) following General Procedure O) and 3-phenyl-1-propanol (Aldrich), the title compound was prepared as a solid (mp = 137 °C). The reaction was monitored by thin layer chromatography (R _f = 0.15 in 50% EtOAc/hexanes) and the product was purified by flash chromatography using 50% EtOAc/hexanes as the eluent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 7.55-7.32 (m, 5H), 6.73 (d, 2H), 6.65 (m, 1H), 4.74 (ρ, 1H), 4.14 (t, 2H), 3.93 (m, 2H), 3.49 (s, 2H), 2.66 (t, 2H) , 1.94 (ρ, 2H) , 1.41 (d, 3H) .

¹³ C-nmr (CDC1 ₃ ) : δ = 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.

C22H2 ₄ N2O ₄ F2 :

Molecular weight - 418.44;

Mass spectroscopy: (MH ⁺ ) 419.

Example 47

Synthesis of Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino·· *···

-2779 ··

M · · • · • 9

9 • · 9 · 9 · ♦ • » · • · · · ·

9 ·

9· ··· ·· • 9 · · • · · · · · · · · ·

·· ··

2-(4-pyridyl)acetamide

Following the general procedure (3,5-difluorophenylacetyl)-L-alanyl pyridyl)acetate (prepared in Example 1) the title compound was monitored by chromatography on CHCl ₃ /MeOH 9: 1 and the product was chromatographed using 9: 1 solvent.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.53 (m, 2

2H), 7.12 (m, 1H), 7.02 (m, 2H), 3.55 and 3.52 (s, 2H), 1.21 (m, 3H

L and using ethyl-N-[Nyl]-2-amino-2-(4-clade 66) , solids were prepared. The reaction was thin layer (R _f = 0.1 in was purified on silica gel with 1 CHCl 3 /MeOH as eluent

(i), 8.88 (bs, 1H), 7.41 (m,

5.46 (m, 1H), 4.46 (m, 1H),

C18H18N4O3F2 ^;

Molecular weight = 376.3; Mass spectroscopy: (MH ⁺ ) 377.

Example 48

Synthesis of Ν-[N-(phenylacetyl)-L-alaninyl]-L-threonine methyl ester

Following general procedure U and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and L-threonine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid.

The NMR data were as follows:

*H-nmr (CDCl3) : δ = 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, 1H), 3 , 62 (s, 3H), 3.46 (s, 2H), 1.29 (d, J = 7.0 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H) .

-278*· ·· ···· ·· ·· « · « « · · · · · • · · ··· · ·· « • ·· · · · ·····* • · · · · · • ···· ·· ··· ·· ¹³ C-nmr (CDC1 ₃ ) : δ = 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. C16H22N2O5:

Molecular weight = 322.36;

Mass spectroscopy: (MH ⁺ ) 323.

Example 49

Synthesis of Ν' -[N-(phenylacetyl)-L-alaninyl]-L-leucinamide

Following general procedure T and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and L-leucinamide hydrochloride (Aldrich), the title compound was prepared as a solid (mp = 207-209 °C). The product was purified by extraction with EtOAc and washing with aqueous potassium carbonate and aqueous hydrochloric acid.

The NMR data were as follows:

^x H-nmr (CD ₃ OD): δ =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), 0.650.76 (m, 6H).

^{L 3} C-nmr (CD ₃ OD): δ = 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 Ν' -[N-(phenylacetyl)-L-alaninyl]-L-alanine amide

Following general procedure U and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and L-alanine amide hydrochloride (Bachem), the title compound was prepared as a solid (melting point greater than

-279• «0 ·« ···· ·· ♦ · >0 0 0 · « · · Μ · • « 0 · ··· · »· · « 0 0 0 0 0 000 000 • 0 0 0 0 0 0 • 00 0000 >* ··♦ *0 ·· or equal to 260 °C) . The product was purified by washing with aqueous sodium hydroxide and aqueous hydrochloric acid.

The NMR data were as follows:

^x H-nmr (DMSO-dg) : δ = 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).

¹³ C-nmr (DMSO-d ₆ ): δ = 174.11 171.8, 170.0, 136.3, 129.0,

128.1, 126.3, 48.3, 47.9, 42.0, 18.3, 18.1.

Example 51

Synthesis of Ν' -[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide

Following general procedure T and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and L-phenylalanine amide (Bachem), the title compound was prepared as a solid (mp = 224-225 °C).

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 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 (with, IH) 4.40 (m, IH), 4.21 (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 ) · ¹³ C-nmr (DMSO -d ₆ ) : δ = 172, 7, 172.0, 170.0, 137.8 , 136.3 129.2, 129.0, 128.2, 128.0, 126, 3, 126.2, 53J6 , 48, 5, 41.9

37.3, 18.0.

Example 52

Synthesis of N'-[N-(phenylacetyl)-L-alaninyl)-L-valinamide

280-

·· ···· • · • · · · · • · ··· »» · ·

Following general procedure T and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and L-valinamide hydrochloride (Bachem), the title compound was prepared as a solid (melting point greater than or equal to 261 °C).

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 8.31 (d, J = 7.5 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, J = 7.2 Hz, IH), 4.08 (dd, J = 6.4, 15.3 Hz, IH), 3.45 (s, 2H), 1.91 (m, IH), 1.19 (d, J = 7.0 Hz 3H), 0.79 (dl J = 6.7 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H).

¹³ C-nmr (DMSO-d ₆ ): δ - 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 ethyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(3-pyridyl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and ethyl-2-amino-2-(3-pyridyl)acetate (prepared as described by P. Kolár et al., J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein), the title compound was prepared as a solid (mp = 146-157 °C). The reaction was monitored by thin layer chromatography (Rf = 0.1 in CHCl3/MeOH 98:2) and the product was purified by silica gel chromatography using 959:5 _CHCl3 /MeOH as eluent, followed by recrystallization from chlorobutane.

The NMR data were as follows:

9

-281

449· 'H-nmr (CDC1 ₃ ) : δ = 8.60 (m, 1H), 8.56 and 8.52 (m, 1H), 7.91 (m, 1H), 7.63 (m, 1H), 7.22 (m, 1H), 6.90 (m, 1H), 6.74 (m, 1H)

2H), 5.55 (m, 1H), 4.69 (m, 1H), 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).

_{C20H21N3O4F2 : ​ ​ ​}

Molecular weight = 405.4;

Mass spectroscopy: (MH ⁺ ) 405.

Example 54

Synthesis of N-methyl-N'-[N-(phenylacetyl)-L-alaninyl]-L-leucinamide

Following general procedure U and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and N-methyl-L-leucinamide (which was prepared from Nmethyl-N'-BOC-L-leucinamide (prepared in Example D5 above) following general procedure Y), the title compound was prepared as a solid (mp = 233-235 °C). The product was purified by recrystallization from MeOH.

The NMR data were as follows:

1H-nmr (CDCl ₃ /CD ₃ OD): δ - 7.25-7.40 (m, 5H), 4.36 (quartet, J = 7.2 Hz, 1H), 4.27 (dd, J = 5.1, 14.6 Hz, 1H), 3.56 (s,

2M) , 2.72 (s, 3M), 1.40-1.61 (m, 2H) , 1.32 (d, J = 7.1 Hz, 3M) , 0.89 (d, J = 6.2 Hz, 3H), 0.86 (d, J = 6.2 Hz 3H) .

Example 55

Synthesis of Ν,N-dimethyl-N'-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide

Following general procedure U and using N-282• · · · · to to to to to to to to to ···· to · · · • · to to to to to to ··· • · «· · ♦· ····· • to · · · · ······ ····· ····· ····· (phenylacetyl)-L-alanine (prepared in Example B1 above) and N,N-dimethyl-L-phenylalanineamide (prepared by coupling N-BOC-L-phenylalanine (Bachem) with dimethylamine hydrochloride (Aldrich) following general procedure B, followed by removal of the BOC group following general procedure Y), the title compound was prepared as a solid (m.p. = 152-155 °C). The product was purified by extraction

EtOAc, washing with aqueous sodium carbonate and aqueous hydrochloric acid, and trituration with _Et2O .

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.49 (d, J = 8.2 Hz, 1H), 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, 1M) , 4.60 (quintet, J:27.3 Hz, IH) , 3.56 (s,

2H), 2.95 (m, 2H), 2.86 (s, 3H), 2.61 (s, 3H), 1.26 (d, J = 6.9 Hz, 3H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

Example 56

Synthesis of N,N-dimethyl-N'-[N-(phenylacetyl)-L-alaninyl]-Lleucinamide

Following general procedure U and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and N,N-dimethyl-L-leucinamide (prepared by coupling N-BOCL-leucine (Bachem) and dimethylamine hydrochloride (Aldrich) according to general procedure B, followed by removal of the BOC group according to general procedure Y), the title compound was prepared as a solid (mp = 130-132 °C). The product was purified by extraction with EtOAc,

-283* ·· *· ···* ·· ···· 9 9 4 4 4 4

4 4 4 449 4 9 4 · · ·· ♦ ·· ······ • · · · · · ·

9499494 44 ··· * · ·· by washing with aqueous sodium carbonate and aqueous hydrochloric acid and trituration with Et2O.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 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) , 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).

¹³ C-nmr (CDC1 ₃ ): δ = 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

Synthesis of N,N-Dimethyl-N'-[N-(phenylacetyl)-L-alaninyl]-Lvalinamide

Following general procedure U and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and N,N-dimethyl-L-valinamide (prepared by coupling N-BOCL-valine (Bachem) with dimethylamine hydrochloride (Aldrich) following general procedure B, followed by removal of the BOC group following general procedure Y), the title compound was prepared as a solid (mp = 147-149 °C). The product was purified by extraction with EtOAc, washing with aqueous sodium carbonate and aqueous hydrochloric acid, and trituration with Et2O.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 7.24-7.38 (m, 5H) , 6, 64 (d, IH), 6, 05 (d, IH), 4.74 (dd, J = 5.9, 8.9 Hertz, IH) , 4.50 (quintet, J = 7.1 Hz, IH), 3.59 (with, 2H), 3.08 (with, 3H) , 2.96 (s, 3H), 1.97 (m, IH), 1.28 (d, J = 7.0 Hz, 3H) , 0.91 (d, J = 6.5 Hertz, 3H) ,

-284• ·

• · * ·

0.84 (d, J=6.8 Hz, 3H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

C18H27N3O3:

Molecular weight = 333.43;

Mass spectroscopy: (MH ⁺ ) 334.

Example 58

Synthesis of N-methyl-N'-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide

Following general procedure U and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and N-methyl-L-phenylalanine amide (prepared by coupling NBOC-L-phenylalanine (Bachem) with dimethylamine hydrochloride (Aldrich) following general procedure B, followed by removal of the BOC group following 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.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 8.23 (d, J = 7.0 Hz, 1H), 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 ,1Hz, IH) , 3.44 (s, 2H), 2, 96 (dd, J = 5.5 , 13.7 Hz, IH) , 2.78 (dd, J = 9.2, 13.7 Hertz, IH) , 2.52 (d, J = 4.4 Hz, 3H) , 1.11 (d, J = 7.0 Hz, 3H) • ¹³ C-nmr (DMSO-d ₆ ) : δ = 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.

• ♦ · · • · · • ···· ·· ·· ····

-285• · · · · • ··· · · · · • · · · · · 4

Example 59

Synthesis of N-methyl-N'-[N-(phenylacetyl)-L-alaninyl]-Lvalinamide

Following general procedure U and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and N-methyl-L-valinamide (prepared by coupling N-BOC-L-valine (Bachem) with dimethylamine hydrochloride (Aldrich) following general procedure B, followed by removal of the BOC group following 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.

The NMR data were as follows:

^-nmr (DMSO-d ₆ ): δ = 8.30 (d, J = 7.6 Hz, 1H), 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, 1H), 1.18 (d, J = 7.0 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H), 0.75 (d, J = 6.7 Hz, 3H).

¹³ C-nmr (DMSO-d ₆ ): δ = 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 N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-aminohexanamide

Following general procedure V and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2

-286 above) and N-methyl-L-norleucinamide (prepared by coupling N-BOC-L-norleucine (Bachem) with dimethylamine hydrochloride (Aldrich) according to general procedure B, followed by removal of the BOC group according to general procedure Y) to give the title compound as a solid. The product was purified by washing with aqueous sodium carbonate and aqueous hydrochloric acid.

The NMR data were as follows:

2-nmr (DMSO-dg): δ = 8.37 (d, 7.1, 1H), 7.88 (d, 8.1, 1H),

7.78 (d, 4.4, 1H), 7.08 (t, 9.5, 1H), 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, 1H), 1.46 (m, 1H), 1.19 (m, 7H), 0.81 (t, 6.5, 3H).

¹³ C-nmr (DMSO-dg): δ = 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, 41.3, 31.8, 27.4, 25.5, 21.8,

17.9, 13.5.

C18H25N3O3F2 ^:

Molecular weight = 369.42;

Mass spectroscopy: (MH ⁺ ) 384.

Example 61

Synthesis of N,N-dimethyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-(S)-2-aminohexanamide

Following general procedure U and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N,N-dimethyl-L-norleucinamide (prepared by coupling N-BOC-L-norleucine (Bachem) with dimethylamine hydrochloride (Aldrich) following general procedure B, followed by removal of the BOC group following general procedure

-287• · · procedures Υ) , the title compound was prepared as a solid (mp = 138-140 °C). The product was purified by extraction with EtOAc and washing with aqueous sodium carbonate and aqueous hydrochloric acid.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.11 (d, 8.1, 1H), 6.81 (m, 2H), 6.71 (m,

IH), 6.60 (d, 7.6, IH), 4.89 (q, J = 5.0, IH), 4.57 (quintet, J = 7.1, IH), 3.53 (s, 2H), 3.08 (s, 3H), 2.97 (s,

3H), 1.70 (m, 1H), 1.55 (m, 1H), 1.20-1.38 (m, 7H), 0.85 (t,

6, 9, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 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.

C19H27N3O3F2:

Molecular weight = 383.44;

Mass spectroscopy: (MH ⁺ ) 384.

Example 62

Synthesis of N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide

Following general procedure U and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-norleucinamide (which was prepared from NBOC-L-norleucinamide (prepared in Example D6 above) following general procedure Y), the title compound was prepared as a solid (melting point greater than or equal to 215°C). The product was purified by precipitation from water.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 8.37 (d, 7.4, 1H) , 7.83 (d, 8.0, 1H) , • ·

A A A A

A A A A

-288·· ·· ··· • A A A A

A A A AAA

AAA A

A A A

AAAA AA AAA

A·

7.29 (s, 1H) , 6.95-7.14 (m, 4H) , 4.29 (quintet, J = 7.2,

1H) , 4.14 (quartet, J = 5.0, 1H) , 3.52 (s, 2H) , 1.61 (m,

1H), 1.46 (m, 1H), 1.21 (m, 7H), 0.82 (m, 3H).

¹³ C-nmr (DMSO-d ₆ ): δ = 173.6, 171.9, 168.9, 162.0 (dd) ,

140.7, 112.2 (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.

C17H23N3O3F2 '·

Molecular weight = 355.39;

Mass spectroscopy: (MH ⁺ ) 356.

Example 63

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(3-methoxyphenyl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl 2-amino-2-(3-methoxyphenyl)acetate hydrochloride (prepared by Bucherer's modification of the Strecker procedure as described in JP 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 thin layer chromatography (Rf = 0.4 in 9: 1 CHCl ₃ /MeOH) and the product was purified by silica gel chromatography using 97: 3 CHCl ₃ /MeOH as the eluent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.27 (m, 1H), 7.18 and 7.06 (m, 1H), 6.876.67 (m, 6H), 6.25 (m, 1H), 5.46 (m, 1H), 4.58 (m, 1H), 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).

·· • 9 9 9

-289- : .· • · • · · 9 999 ·· ···· ·· ··

9 · · · · · • · · · · · · · · · · • 9 99 999999

9 9 9 9

9 99 99 99

C21H22N2O5F2 :

Molecular weight = 420.42;

Mass spectroscopy: (MH ⁺ ) 421.

Example 64

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(4-methoxyphenyl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl 2-amino-2-(4-methoxyphenyl)acetate hydrochloride (prepared by Bucherer's modification of the Strecker procedure as described in JP 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 = 170-174 °C). The reaction was monitored by thin layer chromatography (R _f = 0.1 in 98:2 CHCl 3 /MeOH) and the product was purified by silica gel chromatography using 98:2 CHCl ₃ /MeOH as the eluent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 7.26 (m, 2H), 7.01-6.68 (m, 5H), 6.14 (m, 1H), 5.41 (m, 1H), 4.56 (m, 1H), 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).

C21H22N2O5F2:

Molecular weight = 420.42;

Mass spectroscopy: (MH ⁺ ) 421.

Example 65

Synthesis of ethyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(2-pyridyl)acetate • · *· ··· ·

-290···· ··· * · · · • ···· to ·· · • to ·· ······ to · · · · ·· ··· ·· ··

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and ethyl 2-amino-2-(2-pyridyl)acetate hydrochloride (prepared as described by P. Kolár et al., J. Heteroryclic 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 thin layer chromatography (R _f = 0.1 in 98:2 CHCl ₃ /MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl ₃ /MeOH as eluent, followed by recrystallization from chlorobutane.

The NMR data were as follows:

δ = 8.53 (m, 1H), 7.70 (m, 2H) , 7.48 (m, IH) , 6.86 (m, 2H), 6.74 (m, IH) , 6, 52 (m, IH) , 5.58 (m, IH) , 4.18 (m, 2H), 3, 54 and 3.50 (with, 2H) ,

(m, 1H) , 4,

1.48 and 1.39 (d, 3H), 1.21 (m, 3H(

C20H21N3O4F2 '·

Molecular weight = 405.4; Mass spectroscopy: (MH ⁺ ) 405

Example 66

Synthesis of ethyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(4-pyridyl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and ethyl 2-amino-2-(4-pyridyl)acetate hydrochloride (prepared as described by P. Kolár et al., J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein), the title compound was prepared in the form

-291• ···· ·· ·* » · · · » · · · ··· ftft· • · ·· ·· solid (mp = 175-181 °C). The reaction was monitored by thin layer chromatography (R _f = 0.1 in 98:2 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 _CHCl3 /MeOH as eluent, followed by recrystallization from chlorobutane.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 8.59 (m, 2H), 7.39 (m, 1H), 7.26 (m, 2H), 6.80 (m, 3H), 6.21 (m, 1H), 5.51 (m, 1H), 4.62 (m, 1H), 4.21 (m, 2H), 3.57 and 3.51 (s, 2H), 1.38 (m, 3H), 1.23 (m, 3H). C20H21/N3O4F2:

Molecular weight = 405.4;

Mass spectroscopy: (MH ⁺ ) 40

Example 67

Synthesis of Ν-[N-(cyclohexylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

Following general procedure U and using cyclohexylacetic acid (Aldrich) and N-(Lalaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) following general procedure U, followed by removal of the BOC group following general procedure Y), the title compound was prepared as a solid.

(melting point = 156-158 °C). The reaction was monitored thin layer chromatography layer (Rf = 0.25 in 1:1 EtOAc/hexanes). NMR data were as follows: ^x H-nmr (CDC1 ₃ ): δ = 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 Hertz, 2H), 3.10 (m, 2H), 3.71 (s, 3H), 4.49 (m, IH), 4.81 (m, IH) ,

·· ·· • · · • · · · ·· ··· • ·

-292• ·

6.10 (d, J = 7.3 Hz, 1H), 6.65 (d, J = 7.7 Hz, 1H), 7.11 (m, 2H), 7.26 (m, 3H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

C ₂ iH ₃ oN ₂ 0 ₄ :

Molecular weight at 374.48;

Mass spectroscopy: (MH ⁺ ) 375.

Example 68

Synthesis of Ν-[N-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

Following general procedure U and using cyclopentylacetic acid (Aldrich) and N-(Lalaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) following general procedure U, followed by removal of the BOC group following general procedure Y), the title compound was prepared as a solid (mp = 137-139 °C). The reaction was monitored by thin layer chromatography (R _f = 0.23 in 1:1

EtOAc/hexanes).

The NMR data were as follows:

¹ H-nmr (CDCl 3 ): δ = 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, 1H) , 4.83 (m, 1H) , 6.12 (d, J = 7.4 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 7.2 (m, 2H), 7.25 (m, 3H). ¹³ C-nmr (CDCl 3 ): δ = 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.

44 · · · • ·4 · •94 444 • 44 4 4 44 • 4 ····

-293• · · • 4 4 44 • · · • · · «4 44 4

C20H28N2O4:

Molecular weight = 360.46;

Mass spectroscopy: (MH ⁺ ) 361.

Example 69

Synthesis of N-[N-(cyclohex-1-enylacetyl)-Lalaninyl]-L-phenylalanine methyl ester

Following general procedure U and using cyclohex-1-enylacetic acid (Alpha) and N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) following general procedure U, followed by removal of the BOC group following general procedure Y), the title compound was prepared as a solid (mp = 139142 °C). The reaction was monitored by thin layer chromatography (Rf = 0.27 in 1:1 EtOAc/hexanes).

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 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, 1H), 4.81 (m, IH), 5.60 (s, IH), 6.26 (d, J = 7.3 Hz, IH) , 6.67 (d, J = 7.7 Hz, IH), 7. 11 (m, 2H), 7.26 (m, 3H). ¹³ C-nmr (CDC1 ₃ ): δ = 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.

C21H28N2O4:

Molecular weight = 372.47;

Mass spectroscopy: (MH ⁺ ) 373.

·· ·· r · · · « · » · φ *»· « ·· · • ·

-294• ·· ·« · · • φ • » « • · ···* ·· ···»* • Ο · φ · Λ · * • · · • · · ·· ·· ·

Example 70

Synthesis of methyl-N-[Ν-(3,5-difluorophenylacetyl)-L-alaninyl]-1-aminocyclopropane-1-carboxylate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl-1-aminocyclopropane-1-carboxylate hydrochloride (Sigma), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.3 in 95:5 CHCl ₃ /MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl ₃ /MeOH as the eluent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 6.96 (s, 1H), 6.82 (m, 2H), 6.69 (m, 1H), 6.48 (d, 1H), 4.50 (m, 1H), 3.67 (s, 3H), 3.54 (s, 2H), 1.58 (m, 2H), 1.40 (d, 2H), 1.12 (m, 2H).

Optical rotation: [α] ₂₃ = -18° (c 1, MeOH).

Example 71

Synthesis of N-2-(N,N-dimethylamino)ethyl-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in

Example D7 above) and N,N,N'-trimethylethylenediamine (Aldrich), the title compound was prepared as a solid.

The NMR data were as follows:

^x H-nmr (DMSO-dg): δ = 8.37 (m, 2H) , 8, 19 (d, IH) , 8.08 (d, 2H), 7.10 (m, 1H), 6.99 (m, 2H) , 4.67 (m, IH) , 4.30 (m, IH) , 3.52 (s, 2H), 3.01 and 2.86 (with, 3H) , 2.47 (t, IH) , 2.31 (t,

-295-

· ···· · · ·9 • 99 · · 9 9 • 9 9 9 9 9 · 9 9 · • · 9« 999999

9 9 9 9 • 9 999 99 99

1H), 2.15 (s, 6H), 1.19 (m, 6H).

Optical rotation: [α] ₂₃ = -85° (c 1, MeOH).

_{Ci9H28N4O3F2 :}

Molecular weight = 398^45;

Mass spectroscopy: (MH ¹ ) 398.

Example 72

Synthesis of Ν-[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

Following general procedure U and using cyclopropylacetic acid (Lancaster) and N-(Lalaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) following general procedure U, followed by removal of the BOC group following general procedure Y), the title compound was prepared as a solid (mp = 128-131 °C). The reaction was monitored by thin layer chromatography (R _f = 0.14 in 1:1 EtOAc/hexanes).

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 0.17 (m, 2H) , 0.59 (m, 2H) , 0.92 (m, 1H) ,

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, 1H), 4.82 (m, 1H), 6.47 (d, J = 7.1 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H), 7.12 (m, 2H), 7.28 (m, 3H).

¹³ C-nmr (CDC1 ₃ ): δ = 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. CigH ₂ 4N ₂ 0zi:

Molecular weight ~ 332.40;

Mass spectroscopy: (MH ⁺ ) 333.

• ·

-296Example 73

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]glycine benzyl ester

Following general procedure Ά and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and glycine benzyl ester (which was prepared from N-BOC-glycine (Bachem) and benzyl alcohol (Aldrich) following general procedure X, followed by removal of the BOC group following general procedure Y), the title compound was prepared as a solid (mp = 167.5 °C). The reaction was monitored by thin layer chromatography (Rf = 0.35 in 2% MeOH/CH ₂ Cl 2 ) and the product was purified by flash chromatography using 2% MeOH/CH ₂ Cl ₂ as the eluent.

The NMR data were as follows:

*H-nmr (CDCl ₃ ) : δ = 7.12 (m, 5H) , 6.71 (m, 3H) , 6.60 (m, 2H) , 4.95 (s, 2H) , 4.18 (q, 1H) , 3.76 (dd, 2H) , 3.35 (s, 2H) , 1.13 (d, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 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 ^:

Molecular weight = 390.39;

Mass spectroscopy: (MH ⁺ ) 391.

Example 74

Synthesis of Ν-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl ester • ·

-297• · • · · ·

Following general procedure C and using N(isovaleryl)-L-phenylglycine (which was prepared from isovaleric acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich) following general procedure C followed by hydrolysis following general procedure AF) and L-alanine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp = 198201 °C). The reaction was monitored by thin layer chromatography (Rf = 0.3 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 5% MeOH/CHCl ₃ as the eluent, followed by recrystallization from EtOAc.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ) (1:5 mixture of diastereomers): δ = 1.25 and 1.30 (two d, 3H), 5.57 (d, 1H), 5.60 (d, 1H).

C18H26N2O4:

Molecular weight = 334.42;

Mass spectroscopy: (MH ⁺ ) 335.

Example 75

Synthesis of N-[N-(3-nitrophenylacetyl)-L-alaninyl]L-phenylalanine methyl ester

Following general procedure Z and using N-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (prepared in 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 thin layer chromatography (R _f = 0.3 in 1: 1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 50-100% • · · » • ·

-298EtOAc/hexanes as eluent.

The NMR data were as follows:

‘H-nmr (DMSO-dg) : (1:3 mixture of diastereomers): δ = 1.00 and 1.18 (two d, 3H), 2.96 (m, 2H).

C21H23N3O6:

Molecular weight = 413.43;

Mass spectroscopy: (MH ⁺ ) 413.

Example 76

Synthesis of Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-Lalanine ethyl ester

Following general procedure Z and using N-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (prepared in Example D8 above) and L-alanine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp = 193-195 °C).

The reaction was monitored by thin layer chromatography (R _f = 0.4 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent. The NMR data were as follows:

1H-nmr (DMSO-d ₆ ): δ = 1.20 (m, 9H), 3.65 (s, 2H); 4.05 (m,

2H).

Optical rotation: [α] 20 = -27.3° @ 589nm, (c = 1.02, DMSO). C16H21N3O6:

Molecular weight = 351.36;

Mass spectroscopy: (MH ⁺ ) 352.

Example 77

Synthesis of Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]glycine ethyl ester

-299·· ·

Following general procedure C and using N-(3-nitrophenylacetyl)-L-alanine (which was prepared from 1-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) following general procedure C, followed by hydrolysis following general procedure AF) and glycine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp = 164-165 °C). The product was purified by silica gel chromatography using EtOAc as the eluent, followed by recrystallization from EtOAc.

The NMR data were as follows:

3-nmr (DMSO-d ₆ ): δ = 1.20 (m, 6H), 4.08 (q, 2H); 4.32 (m,

IH).

Optical rotation: [α] ₂ o = -25° @ 589 nm, (c = 1.00, DMSO). C15H19N3O6:

Molecular weight - 337.33;

Mass spectroscopy: (MH ⁺ ) 338.

Example 78

Synthesis of N-hydroxy-N'-[N-(3-nitrophenylacetyl)-L-alaninyl]D,L-threoninamide

Following general procedure Z and using N-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (prepared in 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 thin layer chromatography (R _f = 0.25 in 15% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 15% MeOH/CHCl ₃ as eluent * · · ·

solvent, followed by recrystallization from EtOAc.

The NMR data were as follows:

¹ H-nitrogen (DMSO-d 6 ): (1:1 mixture of diastereomers): δ = 1.22 (m, 3H);

0.98 (m, 3H).

C15H20N4O7:

Molecular weight = 368.35;

Mass spectroscopy: (MH ⁺ ) 368.

Example 79

Synthesis of Ν-[N-(isovaleryl)-L-phenylglycinyl]L-alanine iso-butyl ester

Following general procedure C and using N(isovaleryl)-L-phenylglycine (which was prepared from isovaleric acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich) following general procedure C, followed by hydrolysis following general procedure AE) and L-alanine iso-butyl ester hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and 2-methyl-1-propanol (Aldrich) following general procedure C (with catalytic DMAP), followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 181-186 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 1:1 EtOAc/hexanes as the eluent.

The NMR data were as follows:

3-nmr (DMSO-d ₆ ): δ = 1.31 (d, 3H); 5.59 (d, 1H) .

Optical rotation: [<x] ₂ o = +19.0° @ 589 nm, (c = 1.03, DMSO). C20H29N2O4:

• · • ·

-301• · · ···· · · · · • « ·

0·····* · ·

Molecular weight = 362.47;

Mass spectroscopy: (MH ⁺ ) 363.

Example 80

Synthesis of methyl N-[N-(3-nitrophenylacetyl)-L-alaninyl]-2amino-3-(3-hydroxyphenyl)propionate

Following general procedure C and using N-(3-nitrophenylacetyl)-L-alanine (which was prepared from 3-nitrophenylacetic acid (Aldrich) and ethyl L-alanine hydrochloride (Sigma) according to general procedure C, followed by hydrolysis according to general procedure AF) and methyl 2-amino-3-(3-hydroxyphenyl)propionate (which was prepared from 2-amino-3-(3-hydroxyphenyl)propionate (Biosynt AG, Switzerland) and methanol according to general procedure H), the title compound was prepared as a solid (mp = 155-159 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): (1:1 mixture of diastereomers): δ = 1.02 and 1.20 (two d, 3H); 3.62 (2 s, 3H).

C21H23N2O7:

Molecular weight = 429.43; Mass spectroscopy: (MH ⁺ ) 429.

Example 81

Synthesis of Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-tyrosine ethyl ester using N—(3— prepared from 3a hydrochloride • · ·44·

-302 Following general procedure C and nitrophenylacetyl)-L-alanine (which was nitrophenylacetic acid (Aldrich) ethyl ester of L-alanine (Sigma) following general procedure C, followed by hydrolysis following general procedure AF) and ethyl ester of L-tyrosine (Sigma), the title compound was prepared as a solid (mp = 117-119 °C). The reaction was monitored by thin layer chromatography (R _f = 0.5 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.07 (t, 3H); 1.20 (d, 3H); 9.23 (s,

IH).

Optical rotation: [α] ₂ o ⁼ -13.1° @ 589 nm, (c = 1.08, DMSO). C22H25N3O7:

Molecular weight = 443.46;

Mass spectroscopy: (MH ⁺ ) 443/44.

Example 82

Synthesis of Ν-[N-(isovaleryl)-L-isoleucinyl]-Lalanine iso-butyl ester

Following general procedure C and using N(isovaleryl)-L-isoleucine (which was prepared from isovaleric acid (Aldrich) and L-isoleucine methyl ester hydrochloride (Aldrich) following general procedure C, followed by hydrolysis following general procedure AF) and L-alanine iso-butyl ester hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and 2-methyl-1-propanol (Aldrich) following general procedure C (with catalytic DMAP),

-303• · » · · · · · ·· ·· followed by removal of the BOC-group according to general procedure P) , the title compound was prepared as a solid (mp = 142-146 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 1:1 EtOAc/hexanes as the eluent.

The NMR data were as follows:

¹ H-nmr (DMSO-dg): (1:4 mixture of diastereomers): δ = 1.26 (d, 3H), 7.70, 7.80 (doublets, 1H); 8.30, 8.40 (doublets, 1H).

C18H34N2O4:

Molecular weight = 342.48;

Mass spectroscopy: (MH ⁺ ) 343.

Example 83 Step A. Synthesis iso-butyl ester Ν-[Ν-[N-(target

butoxycarbonyl)-L-valinyl]-D,L-phenylglycinyl]-L-alanine Following general procedure A and using N-[N-BOC-Lvalinyl]-D,L-phenylglycine (prepared by coupling N-BOC-L-valine (Bachem) and L-phenylglycine methyl ester hydrochloride (Sigma) following general procedure C, followed by hydrolysis of the methyl ester following general procedure AF) and L-alanine iso-butyl ester hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and 2-methyl-l-propanol (Aldrich) following general procedure C (with catalytic DMAP), followed by removal of the BOC group following general procedure P), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.3 in 5% MeOH/CH ₂ Cl 2 ) and the product was purified by silica gel chromatography using 5% MeOH/CH ₂ Cl ₂ as eluent.

····

-304NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): (1:1 mixture of diastereomers) : δ = 1.25 (d,

3H); 5.58 (d, 1H).

C25H39N3O6:

Molecular weight = 477.61;

Mass spectroscopy: (MH ⁺ ) 478.

Step B. Synthesis of N-[N-(L-Valinyl)-L-Phenylglycinyl]-L-Alanine Iso-Butyl Ester Hydrochloride

Following general procedure P and using the product prepared in Example 83, Step A above, the title compound was prepared as a solid (mp = 225-232 °C). The product was purified by trituration in Et ₂ O.

The NMR data were as follows:

^x H-nmr (DMSO-dg): (1:2 mixture of diastereomers): δ = 1.26, 1.32 (doublets, 3H); 5.60, 5.65 (doublets, 1H).

_{C20H32N3O4Cl : ​ ​}

Molecular weight = 413.94;

Mass spectroscopy: (MH ⁺ ) 378 (free base).

Step C. Synthesis of Ν-[Ν-[N-(isovaleryl)-Valinyl]-L-phenylglycinyl]-L-alanine iso-butyl ester

Following general procedure C and using isovaleric acid (Aldrich) and the product prepared in Example 83, Step B above, the title compound was prepared as a solid (mp = 217-221 °C). The reaction was monitored by thin layer chromatography (R _f = 0.25 in 5% MeOH/CHCl 3 ) and the product was purified by silica gel chromatography using 5% MeOH/CHCl ₃ ) as the eluent.

The NMR data were as follows:

^x H-nmr (DMSO-dg): (1:3 mixture of diastereomers): δ =

5.52, 5.58 ····

-305(doubles, IH).

C25H39N3O5:

Molecular weight = 461.60;

Mass spectroscopy: (MH ⁺ ) 462.

Example 84

Synthesis of N-[N-(isovaleryl)-L-phenylalaninyl]L-alanine iso-butyl ester

Following general procedure C and using isovaleric acid (Aldrich) and N-(L-phenylalaninyl)-L-alanine iso-butyl ester hydrochloride (which was prepared from N-BOC-L-phenylalanine (Sigma) and L-alanine iso-butyl ester hydrochloride (prepared as described in Example 83A above) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 135-138 °C). The reaction was monitored by thin layer chromatography (R _f = 0.3 in 3% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 3% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 0.75 (d, 3H), 0.84 (d, 3H); 0.90 (d,

6H); 1.33 (d, 3H).

Optical rotation: [α] ₂ o = +4.71° @ 589 nm, (c = 1.02, DMSO). C2iH ₃ 2N2Ozi:

M = 376.50;

Mass spectroscopy: (MH ⁺ ) 376.

Example 85

Synthesis of ethyl ester N-[N-(3,5-difluorophenylacetyl)-L• · ·« ····

-306alaninyl]-L-alanine

Following general procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and L-alanine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp = 197-199 °C).

The reaction was monitored by thin layer chromatography (R _f = 0.6 in EtOAc) and the product was purified from by-products by silica gel chromatography using EtOAc as eluent, followed by recrystallization from EtOAc.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 1.22 (m, 9H); 3.52 (s, 2H) .

Optical rotation: [α] ₂ o = -76.1° @ 589 nm, (c = 1.01, DMSO). C16H20N2O4F2:

Molecular weight = 342.34;

Mass spectroscopy: (MH ⁺ ) 343.

Example 86

Synthesis of ethyl 1-[N-(3-nitrophenylacetyl) L-alaninyl]indoline(S)-2-carboxylate

Following general procedure C and using N-(3-nitrophenylacetyl)-L-alanine (which was prepared from 3-nitrophenylacetic acid (Aldrich) and ethyl L-alanine hydrochloride (Sigma) following general procedure C, followed by hydrolysis following general procedure AF) and ethyl (S)-indoline-2-carboxylate (which was prepared from (S)-indoline-2-carboxylic acid (Aldrich) and ethanol following general procedure Η), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.4 in 2: 1 ·· ··*·

-307EtOAc/hexanes) and the product was purified by silica gel chromatography using 2:1 EtOAc/hexanes as the eluent.

The NMR data were as follows:

¹ H-nmr (DMSO-d 6 ): (1:2 mixture of diastereomers): δ = 1.05, 1.17 (triplets, 3H); 1.29, 1.39 (doublets, 3H).

C22H23N3O6:

Molecular weight = 425.44;

Mass spectroscopy: (MH ⁺ ) 425.

Example 87

Synthesis of N'-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]-Lalaninamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in 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 thin layer chromatography (R _f = 0.35 in 10% MeOH/CHCl 3 ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as the eluent, followed by recrystallization from EtOH.

The NMR data were as follows:

3-nmr (DMSO-d ₆ ): δ = 1.21 (m, 6H); 7.95 (d, 1H); 8.37 (d,

IH).

Optical rotation: [α] ₂ o = -26.84° @ 589 nm, (c = 1.01, DMSO). C14H17N3O3F2:

Molecular weight = 313.31;

Mass spectroscopy: (MH ⁺ ) 314.

AA AA

A A A A • A · A

A »·« AAA • A

A · A A • A ··«·

-308AAAAA • A A

A AAAA

A A A • A A

AA AAA

Example 88

Synthesis of N-methoxy-N-methyl-N'-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine amide

Following general procedure C and using N-[N(isovaleryl)-L-phenylglycinyl]-L-alanine (which was prepared from ethyl ester of N-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine (prepared in Example 74 above) following general procedure AF) and N,O-dimethylhydroxylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.6 in EtOAc) and the product was purified by silica gel chromatography using EtOAc as the eluent. The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): (1:1 mixture of diastereomers): δ = 3.67, 3.73 (singlets, 3H), 5.62 (m, 1H).

C18H27N3O4:

Molecular weight = 349.43;

Mass spectroscopy: (MH ⁺ ) 350.

Example 89

Synthesis of N-iso-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

Following general procedure C and using N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (which was prepared from ethyl ester of N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in Example 85 above) following general procedure AF) and iso-butylamine (Aldrich)), the title compound was prepared as a solid (mp = 258-260 °C). The reaction was

• · • 4 • · · * 4 44 444444

4 * 4 4 4 4

444 4444 44 444 44 4« was monitored by thin layer chromatography (R _f = 0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as eluent.

The NMR data were as follows:

¹ H-nmr (DMSO-de): δ = 0.80 (d, 6H); 1.20 (m, 6H).

Optical rotation: [α] ₂ o ⁼ -30.4° @ 589 nm, (c = 1.01, DMSO) C ₁₈ H ₂₅ N ₃ O ₃ F ₂ :

Molecular weight = 369.41;

Mass spectroscopy: (MH ⁺ ) 369.

Example 90

Synthesis of N,N-di-n-propyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (which was prepared from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester (prepared in 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 thin layer chromatography (R _f = 0.5 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH/CHCl ₃ as eluent.

The NMR data were as follows:

¹ H-nmr (DMSO-d 6 ): (1:2 mixture of diastereomers): δ = 3.50 (s, 2H), 4.30 (m, 1H), 4.63 (m, 1H).

C ₂ oH ₂ 9N ₃ 0 ₃ F ₂ :

Molecular weight = 397.46;

Mass spectroscopy: (MH ⁺ ) 397.

» «► • · · · · • · · · · · · • · · · · * · • · · · · · · ·

-310-:• · ♦ » • ·

4· · ·

Example 91

Synthesis of N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valinamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-valinamide hydrochloride (Sigma), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.3 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

1 H-nmr (DMSO-d ₆ ): (1:4 mixture of diastereomers): δ = 1.22 (m, 3H);

1.97 (m, 1H).

C16H21N3O3F2 ^:

Molecular weight = 341.36;

Mass spectroscopy: (MH ⁺ ) 342.

Example 92

Synthesis of N-(4-nitrophenyl)-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alaninamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(4-nitrophenyl)-L-alaninamide hydrochloride (Fluka), the title compound was prepared as a solid (mp = 242-244 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 10% MeOH/CHCl ₃ ) and • »· • · φ ·

311··«· φφφφ • · φφφφ • · · • · φ · φ φ * · · φ φ φ φφ ···

The product was purified by silica gel chromatography using 10% MeOH/CHCl3 as eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

3-nmr (DMSO-d ₆ ): δ = 1.24 (d, 3H); 1.33 (d, 3H).

Optical rotation: [α] ₂ o = -5.18° @ 589 nm, (c = 1.00, DMSO). C20H20N4O5F2:

Molecular weight = 434.40;

Mass spectroscopy: (MH ⁺ ) 434.

Example 93

Synthesis of Ν'-[Ν-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]L-phenylalaninamide

Following general procedure C and using N(isovaleryl)-L-phenylglycine (which was prepared from isovaleric acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich) following general procedure C, followed by hydrolysis following general procedure AF) and N'-(L-alaninyl)-L-phenylalaninamide hydrochloride, (which was prepared from N-BOC-L-alanine (Sigma) and L-phenylalaninamide (Sigma) following general procedure Cl followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 272-276 °C). The reaction was monitored by thin layer chromatography (R _f = 0.25 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl 3 as the eluent.

The NMR data were as follows:

¹ H-nmr (DMSO-d6): (1:1 mixture of diastereomers): δ = 1.071 1.17 (doublets, 3H); 5.40, 5.52 (doublets, 1H).

-312 ^±

4 4 4

4 4 4

4 4 4

444 444

4

4· · 4

C25H32N4O4:

Molecular weight = 452.55;

Mass spectroscopy: (MH ⁺ ) 453.

Example 94

Synthesis of N-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalanine methyl ester

Following general procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester hydrochloride (Sigma) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 173-175 °C).

The reaction was monitored by thin layer chromatography (R _f = 0.6 in 10% MeOH/CHCl 3 ) and the product was purified by silica gel chromatography using 4% MeOH/CHCl ₃ as eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.17 (d, 3H); 3.48 (s, 2H).

Optical rotation: [α]2o = -32.47° @ 589 nm, (c = 1.01, MeOH). C21H22N2O4F2:

Molecular weight = 404.41;

Mass spectroscopy: (MH ⁺ ) 404.

Example 95

Synthesis of Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Lphenylalaninamide • · · · · to · · · • · · · · · « · · « • · · · · · ······ • · · · · · ···· ·· ··· ·· ··

Following general procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and N'-(Lalaninyl)-L-phenylalaninamide hydrochloride (which was prepared from N-BOC-Lalanine (Sigma) and L-phenylalaninamide (Sigma) following general procedure C followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 252-253 °C). The reaction was monitored by thin layer chromatography (Rf = 0.5 in 15% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 15% MeOH/CHCl ₃ as eluent, followed by recrystallization from EtOH.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.15 (d, 3H); 3.51 (s, 2H) .

Optical rotation: [α] ₂ o - -24.4° @ 589 nm, (c = 1.01, DMSO). C2oH2lN ₃ 0 ₃ F2 :

Molecular weight = 389.41;

Mass spectroscopy: (MH ⁺ ) 389.

Example 96

Synthesis of N-iso-butyl-N'-[N-(isovaleryl)-L-phenylglycinyl]-Lalaninamide

Following general procedure C and using N-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine (which was prepared from N-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl ester (prepared in Example 74 above) following general procedure AF) and iso-butylamine (Aldrich)), the title compound was prepared as a solid (mp = 227-232 °C). The reaction was monitored by chromatography • · ·« ··· · · · · · · · · I

-314• · · · · in * « · » · • » · # • · · · 99 ···

9 9 9

999 999

9

91 on a thin layer (Rf = 0.3 in 5% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 5%

MeOH/CHCl ₃ as elution solvent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-d6): (1:4 mixture of diastereomers): δ = 1.58 (m, 1H);

1.95 (m, 1H); 5.55 (d, 1H).

C20H31N3O3:

Molecular weight = 361.48;

Mass spectroscopy: (MH ⁺ ) 361.

Example 97

Synthesis of N-(2-Methoxyethyl)-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalaninamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (which was prepared from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (prepared in Example 94) following general procedure AF) and 2-methoxyethylamine (Aldrich), the title compound was prepared as a solid (mp = 206-208 °C). The reaction was monitored by thin layer chromatography (R _f = 0.3 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 1.14 (d, 3H); 4.22 (m, 1H); 4.45 (m,

IH).

Optical rotation: [α] ₂ o = -25° @ 589 nm, (c = 1.00, DMSO). C ₂₃ H ₂₇ N ₃ O ₄ F ₂ :

• 0 • * • Φ

0 0

000

315- —·

Molecular weight = 447.49;

Mass spectroscopy: (MH ⁺ ) 447.

Example 98

Synthesis of N-(4-nitrobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (which was prepared from ethyl ester of N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in Example 85 above) following general procedure AF) and 4-nitrobenzylamine (Aldrich), the title compound was prepared as a solid (mp = 257-259 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as the eluent, followed by recrystallization from EtOH/acetonitrile.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 3.53 (s, 2H); 4.39 (d, 2H).

Optical rotation: [α] ₂ o = -29.3° @ 589 nm, (c = 1.00, DMSO). C ₂ iH ₂₂ N,jO5F ₂ :

Molecular weight = 448.43;

Mass spectroscopy: (MH ⁺ ) 448.

Example 99

Synthesis of N-(4-nitrophenyl)-N'-[Ν-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-alaninamide

Following general procedure C and using N-[N(isovaleryl)-L-phenylglycinyl]-L-alanine (which was prepared “ 9 9 9 9 · ·

-31b ·· · · · · ·· · · • 99 99·«

999» · · 9 9 • 9 9 » ·99 ··· • · 9 9 9

9 9 · ·· ·· from Ν-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl ester (prepared in Example 74 above) following general procedure AF) and N-(4-nitrophenyl)-L-alanine hydrochloride (Fluka), the title compound was prepared as a solid (mp = 255-257 °C). The reaction was monitored by thin layer chromatography (R _f = 0.5 in 10% MeOH/CHCl3) and the product was purified

10% MeOH/CHCl ₃ recrystallized on silica gel as eluent from a mixture of 1 solvent chromatography using chlorobutane/acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): (1:2 mixture of diastereomers): δ = 5.45, 5.55 (doublets, 1H); 10.20, 10.54 (singlets, 1H).

C25H31N4O6:

Molecular weight = 497.56; Mass spectroscopy: (MH ⁺ ) 497.

Example 100

Synthesis of N-(4-nitrophenyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalaninamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(4-nitrophenyl)-L-phenylalaninamide hydrochloride (Lancaster), the title compound was prepared as a solid (mp = 253-254 °C). The reaction was monitored by thin layer chromatography (R _f = 0.5 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 8% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

• · · • · · · · · · • 9 • ··· ·· • · · > · · • · · · · · _317-** **·· ** (s, IH) . z = 1.00, DMSO) ^-nmr (DMSO-d ₆ ) : δ = 1.17 (d, 3H) ; 10.52 Optical rotation: [α]2o ⁼ +40.6° @ 589 nm, (

C26H24N4O5F2:

Molecular weight = 510.50;

Mass spectroscopy: (MH ⁺ ) 510.

Example 101

Synthesis of N-benzyl-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (which was prepared from ethyl ester of N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in Example 85 above) following general procedure AF) and N-benzyl-N-methylamine (Aldrich), the title compound was prepared as a solid (mp = 167-169 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 5% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH/CHCl 3 as the eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): (1:3 mixture of diastereomers): δ = 3.52 (singlets, 2H); 2.95 (s, 2H).

Optical rotation: [α]20 ⁼ -55.8° @ 589 nm, (c = 1.01, DMSO).

C22H25N3O3F2:

Molecular weight = 417.45;

Mass spectroscopy: (MH ⁺ ) 417.

• · · · • · • ftft ·· ftftftft ··· ftftft· • · · · · · · · · · · • * ftft ft ftft ······ • · « · · ftft

-318-..... “ ” *'

Example 102

Synthesis of N-(3,5-Difluorobenzyl)-N'-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]-L-Alaninamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(3,5-difluorobenzyl)-L-alanine amide hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and 3,5-difluorobenzylamine (Lancaster) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 267-269 °C).

The reaction was monitored by thin layer chromatography (R _f = 0.25 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl 3 as eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.21 (d, 3H), 1.24 (d, 3H).

Optical rotation: [α] ₂ o = +26.9° @ 589 nm, (c = 1.01, DMSO). C21H21N3O3F4:

Molecular weight = 439.41;

Mass spectroscopy: (MH ⁺ ) 439.

Example 103

Synthesis of N-(3-nitrobenzyl)-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(3-nitrobenzyl)-L-

3194 4 444 • · • ··· • · • ·

444 alaninamide (which was prepared from N-BOC-L-alanine (Sigma) and 3-nitrobenzylamine hydrochloride (Aldrich) following general procedure C, followed by removal of the BOC group following general procedure P) gave the title compound as a solid (m.p. -245-247°C). The reaction was monitored by thin layer chromatography (Rf = 0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as the eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 1.21 (d, 3H); 1.25 (d, 3H).

Optical rotation: [α] ₂ o = -32.8° @ 589 nm, (c = 1.00, DMSO). C ₂ iH ₂₂ N ₄ O ₅ F ₂ :

Molecular weight = 448.43;

Mass spectroscopy: (MH ⁺ ) 449.

Example 104

Synthesis of N-benzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-alaninamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-benzyl-L-alaninamide hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and benzylamine (Aldrich) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 260-262 °C). The reaction was monitored by thin layer chromatography (R _f = 0.3 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using • 9 • · ··

-320• 9

9999

9999 • 9 9 999

9 9 ·

9 9 9

999 999

9

9 9 9

10% MeOH/CHCl ₃ as eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.20 (d, 3H); 1.24 (d, 3H).

Optical rotation: [α] ₂ o = -29.3° @ 589 nm, (c = 1.03, DMSO).

C ₂ iH 23 N ₃ O ₃ F ₂ :

Molecular weight = 403.43;

Mass spectroscopy: (MH ⁺ ) 403.

Example 105

Synthesis of N-(4-nitrobenzyl)-N ¹ -[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalaninamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (which was prepared from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (prepared in Example 94) following 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 thin layer chromatography (R _f = 0.4 in 12% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 12% MeOH/CHCl ₃ as eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 1.15 (d, 3H); 7.35 (d, 2H); 8.12 (d,

2H).

Optical rotation: [a] ₂₀ = -27.6° @

_{C27H26N4O5F2 :}

Molecular weight = 524.52;

589 nm (c=1.01, DMSO).

-321

9999

99

99 • 99 9 • 9 9 9

999 999

9

9 9

Mass spectroscopy: (MH ⁺ ) 524.

Example 106

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalanininyl]-L-tryptophan methyl ester

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in 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 thin layer chromatography (R _f = 0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH/CHCl 3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.

The NMR data were as follows:

δ-nmr (DMSO-d ₆ ): δ = 1.20 (d, 3H); 3.55 (s, 3H) .

Optical rotation: [α] ₂₀ ⁼ -8.82° @ 589 nm (c = 1.02, DMSO). C23H2N3O4F2:

Molecular weight = 443.45;

Mass spectroscopy: (MH ⁺ ) 443.

Example 107

Synthesis of N-(4-Methoxybenzyl)-N'-[N-(3,5-Difluorophenylacetyl)L-Alaninyl]-L-Alaninamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(4-methoxybenzyl)-L-alanine hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and 4-methoxybenzylamine hydrochloride (Aldrich) according to

-322 to ·· to to ··· ·· ·· to ·· • toto·· • to · toto · toto ··· • to ·· • ·· · • ·· · to ·to· ··· • · •« ·· general procedure C, followed by removal of the BOC-group according to general procedure P), the title compound was prepared as a solid (mp = 234236 °C). The reaction was monitored by thin layer chromatography (Rf = 0.3 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/ _CHCl3 as eluent, followed by recrystallization from EtOH/acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 1.20 (d, 6H); 3.51 (s, 2H); 3.72 (s,

3H).

Optical rotation: [α] ₂ o ⁼ +27.9° @ 589 nm ( c = 1.00, DMSO). 022^25^3*04^2 ^:

Molecular weight = 433.46;

Mass spectroscopy: (MH ⁺ ) 433.

Example 108

Synthesis of N-[N-(phenylacetyl)-L-phenylglycinyl]-L-alanine ethyl ester

Following general procedure C and using phenylacetic acid (Aldrich) and ethyl ester N-(L-phenylglycinyl)-L-alanine hydrochloride (which was prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and ethyl ester L-alanine hydrochloride (Aldrich) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (m.p.

208-210 °C) monitored by thin layer chromatography

The product was purified by MeOH/CHCl chromatography using 5% MeOH/CHCl ₃

The reaction was (Rf 0.4 in 5% silica gel as eluent

·· • · 9 9

9 9 · • ··· 999

9

99

-323 ··♦· solvent, followed by recrystallization from a 1-chlorobutane/acetonitrile mixture.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 3.55 (s, 2H); 5.55 (d, 1H) .

Optical rotation: [ct] ₂ o - +44.8° @ 559 nm (c = 1.02, DMSO). C21H24N2O4:

Molecular weight = 368.43;

Mass spectroscopy: (MH ⁺ ) 369.

Example 109

Synthesis of Ν-[Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalaninyl]-L-phenylglycine methyl ester

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (which was prepared from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (prepared in Example 94) following 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 thin layer chromatography (R _f = 0.3 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as eluent, followed by trituration in 1-chlorobutane.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 1.13 (d, 3H); 3.62 (s, 3H).

Optical rotation: [α] ₂₀ = +42.1° @ 589 nm (c = 1.03, DMSO). C ₂ 9H29N ₃ O ₅ F2:

Molecular weight = 537.56;

Mass spectroscopy: (MH ⁺ ) 537.

Φ· φφφφ φφ

3245-.

• φφφ • · · • φ φ · · · • φ · · φφφ φφφ

Example 110

Synthesis of Ν-[N-(cyclohexylacetyl)-L-phenylglycinyl]L-alanine ethyl ester

Following general procedure C and using cyclohexylacetic acid (Aldrich) and ethyl ester N-(L-phenylglycinyl)-L-alanine hydrochloride (which was prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and ethyl ester L-alanine hydrochloride (Aldrich) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 196-198 °C). The reaction was monitored by thin layer chromatography (R _f = 0.3 in 5% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH/CHCl ₃ as the eluent, followed by trituration in 1-chlorobutane.

The NMR data were as follows:

3-nmr (DMSO-d ₆ ): δ = 2.08 (d, 2H); 5.56 (d, 1H) .

Optical rotation: [α] ₂ o = ¹ +26.3° @ 589 nm (c = 1.01, DMSO). C ₂ iH ₃₀ N ₂ O ₄ :

Molecular weight = 374.48;

Mass spectroscopy: (MH ⁺ ) 375.

Example 111

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaniny]-L-phenylglycine methyl ester

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2

-325 • ·· ·· ··· ·· ·· « · · ««· ···· • · _{····· ·} to · to • · ·· _·

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 1.26 (d, 3H); 3.64 (s, 3H).

Optical rotation: (DMSO) [α] ₂ o = +69.9° @ 589 nm (c = 1.01, DMSO).

C ₂ oH ₂ oN ₂ 0 ₄ F ₂ :

Molecular weight = 390.39;

Mass spectroscopy: (MH ⁺ ) 391.

Example 112

Synthesis of Ν-[Ν-[N-(3,5difluorophenylacetyl)-Lalaninyl]-L-alaninyl]-L-phenylglycine methyl ester

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(L-alaninyl)-L-phenylglycine methyl ester hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 243-245 °C). The reaction was monitored by thin layer chromatography (R _f = 0.5 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as the eluent, followed by .....

-32&♦· ···· · · · · · · · • · ··· ·

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.19 (d, 3H); 1.24 (d, 3H).

Optical rotation: [α] ₂ o = +38.2° @ 589 nm (c = 1.02, DMSO). C23H25N3O5F2:

Molecular weight = 461.46;

Mass spectroscopy: (MH ⁺ ) 461.

Example 113

Synthesis of N-(2-phenylethyl)-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(2-phenylethyl)-L-alanine amide hydrochloride (which was prepared

N-BOC-L-alanine (Sigma) was chromatographed using phenethylamine (Aldrich) according to general procedure C, followed by removal of the BOC group according to general procedure P) to give the title compound as a solid (mp = 241-243 °C). The reaction was monitored by thin layer chromatography (R _f = 0.3 in 8% MeOH/CHCl3) and the product was purified

8% MeOH/CHCl ₃ on silica gel as eluent, followed by recrystallization from acetonitrile. NMR data were as follows:

¹ H-nmr (DMSO-dg): δ = 1.14 (d, 3H); 1.21 (d, 3H).

Optical rotation: [α] ₂ o = -33.7° @ 589 nm (c = 1.00, DMSO). C22H25N3O3F2:

Molecular weight = 417.45;

Mass spectroscopy: (MH ⁺ ) 417.

•in · ·* ·

Example 114

Synthesis of Ν' -[Ν-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophanamide

Following general procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and N'-(Lalaninyl)-L-tryptophanamide hydrochloride (which was prepared from N-BOC-Lalanine (Sigma) and L-tryptophanamide hydrochloride (Sigma) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 199-202 °C). The reaction was monitored by thin layer chromatography (R _f = 0.3 in 15% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 15% MeOH/CHCl ₃ as the eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 1.17 (d, 3H); 4.26 (m, 1H); 4.44 (m,

IH).

Optical rotation: [α] ₂₀ - -31.0° @ 589 nm (c - 1.05, DMSO). C22H22N4O3F2 :

Molecular weight = 428.44;

Mass spectroscopy: (MH ⁺ ) 428.

Example 115

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-amino-3-cyclohexylpropionate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2

Φ φ

-328 φφ φφφφ φ _φ • ΦΦΦ φ

4% MeOH/CHCl ₃ recrystallization on silica gel as eluent from 1MeOH/CHCl ₃ ) solvent chromatography, followed by chlorobutane/hexanes.

The NMR data were as follows:

^x H-nmr (DMSO-dg): δ = 1.22 (d, 3H); 3.62 (s, 3H).

Optical rotation: [α] ₂ o = -21.2° @ 589 nm (c = 1.01, DMSO).

C ₂ iHg7N ₂ O ₄ F ₂ :

Molecular weight = 410.46; Mass spectroscopy: (MH ⁺ ) 411.

Example 116

Synthesis of N-(2-Methoxyethyl)-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-(S)-2-amino-3-(4-nitrophenyl)propionamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(2-methoxyethyl)-(S)-2amino-3-(4-nitrophenyl)propionamide hydrochloride (which was prepared from NBOC-L-4-nitrophenylalanine (Advanced Chemtech) and 2methoxyethylamine (Aldrich) following general procedure C followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 263-265 °C). The reaction was monitored by thin layer chromatography (R _f = 0.5 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as eluent.

-329Í·.·!·· ·· ···· '4 9 4 • 9 49 9 • · · * • * · ·· ··« ♦· · · · • « · · ··· 499 • · #· ·· solvent, followed by recrystallization from EtOH/acetonitrile. NMR data were as follows:

1H-nmr (DMSO-d ₆ ): δ = 1.15 (d, 3H); 4.23 (m, 1H); 4.54 (m,

IH).

Optical rotation: [α] ₂ o ⁼ -19/9° @ 589 nm (c = 1.00, DMSO). C23H26N4O6F2:

Molecular weight = 492.48;

Mass spectroscopy: (MH ⁺ ) 493.

Example 117

Synthesis of Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-serine ethyl ester

Following general procedure C and using N-(3-nitrophenylacetyl)-L-alanine (which was prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) following general procedure C, followed by hydrolysis following general procedure AF) and L-serine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp = 179-181 °C). The reaction was monitored by thin layer chromatography (R _f = 0.2 in 5% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

1H-nmr (DMSO-d ₆ ): δ1H); 5.04 (t, 1H).

Optical rotation: [a] ₂ o = -19.7°

1.20 (m, 6H); 4.30 (m, 1H) ; 4.41 (m, @ 589 nm (c = 1.01, DMSO).

C16H21N3O7:

Molecular weight =

367.36;

• ···

-330• 4 4 4

444 444 • 4

44

Mass spectroscopy: (MH ⁺ ) 368.

Example 118

Synthesis of N-[(R)-α-methylbenzyl]-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-alaninamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(R)-α-methylbenzyl-L-alanine amide hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and (R)-α-methylbenzylamine (Aldrich) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 240-242 °C).

The reaction was monitored by thin layer chromatography (R _f = 0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 9% MeOH/CHCl ₃ as eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.19 (t, 6H); 1.31 (d, 3H).

Optical rotation: [ct] ₂ o = +1.0° @ 589 nm (c = 1.00, DMSO). C ₂₂ H ₂ 5N ₃ O ₃ F ₂ :

Molecular weight = 417.45;

Mass spectroscopy: (MH ⁺ ) 417.

Example 119

Synthesis of N-[(S)-α-methylbenzyl]-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-alanine amide

Following general procedure C and using N-(3.5

-331difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(S)-α-methylbenzyl-L-alanine hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and (R)-α-methylbenzylamine (Aldrich) by general procedure C, followed by removal of the BOC group by general procedure P) gave the title compound as a solid (mp = 293-295 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 10% MeOH/CHCl 3 ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as the eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 1.20 (m, 6H); 1.30 (d, 3H).

Optical rotation: [α] ₂ o = -65.9° @ 589 nm (c = 1.05, DMSO). C22H25N ₃ O ₃ F2 :

Molecular weight = 417.45;

Mass spectroscopy: (MH ⁺ ) 417.

Example 120

Synthesis of N-(4-fluorobenzyl)-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(4-fluorobenzyl)-L-alanine amide hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and 4-fluorobenzylamine (Aldrich) following general procedure C followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 257-259 °C). The reaction was

-332 was monitored by thin layer chromatography (R _f - 0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 9% MeOH/CHCl ₃ as eluent followed by trituration in 1-chlorobutane.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 1.20 (m, 6H); 3.52 (s, 2H) .

Optical rotation: [α] ₂ o = -28.7° @ 589 nm (c = 1.00, DMSO). C ₂₁ H ₂₂ N ₃ O ₃ F ₃ :

Molecular weight - 421.42;

Mass spectroscopy: (MH ⁺ ) 421.

Example 121

Synthesis of N-(4-pyridylmethyl)-Ν' -[N-(3,5-difluorophenylacetyl)L-alaninyl]-L-alaninamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(4-pyridylmethyl)-L-alanine dihydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and 4-(aminomethyl)pyridine (Aldrich) following general procedure C followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 244-247 °C). The reaction was monitored by thin layer chromatography (R _f = 0.3 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as the eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

1H-nmr (DMSO-d ₆ ): δ = 1.21 (d, 3H); 1.26 (d, 3H).

Optical rotation: [α] ₂₀ = -30.3° @ 589 nm (c = 1.00, DMSO).

-333• 0 0 0 0

00» · ·0 ·

0 000 000

0 0

C20H22N4O3F2 :

Molecular weight = 404.42;

Mass spectroscopy: (MH ⁺ ) 405.

Example 122

Synthesis of N-(4-trifluoromethylbenzyl)-Ν'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-alaninamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(4-trifluoromethylbenzyl)-L-alanine hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and 4-(trifluoromethyl)benzylamine (Aldrich) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 244-247 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 8% MeOH/CHCl ₃ as the eluent, followed by trituration in 1-chlorobutane.

The NMR data were as follows:

3-nmr (DMSO-d ₆ ): δ = 3.52 (s, 2H); 4.35 (d, 2H).

Optical rotation: [α] ₂ o - -27.4° @ 589 nm (c = 1.05, DMSO). C ₂₂ H ₂₂ N ₃ O ₃ F5 :

Molecular weight = 471.43;

Mass spectroscopy: (MH ⁺ ) 471.

Example 123

Synthesis of ethyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-phenylpropionate • flfl ·

-334• » · · • · · ··· • · · · • fl flfl • flfl · « flfl · ···· flfl flflfl

Following general procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and ethyl N-(L-alaninyl)-2-amino-2-phenylpropionate hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and D,L-amethylphenylglycine ethyl ester (prepared in Example D9 above) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 128-130 °C). The reaction was monitored by thin layer chromatography (R _f = 0.2 in 3% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 3% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

1 H-nmr (DMSO-d6): (1:1 mixture of diastereomers): δ = 1.72, 1.77 (singlets, 3H); 3.52 (s, 2H).

C22H24N2O4F2:

Molecular weight = 418.44;

Mass spectroscopy: (MH ⁺ ) 418.

Example 124

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalanine tert-butyl ester prepared from butyl ester

Following general procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and N-(L-alaninyl)-L-phenylalanine tert-butyl ester hydrochloride (which was

N-BOC-L-alanine (Sigma) and tert. hydrochloride (Advanced Chemtech) followed by removal of BOCL-phenylalanine according to general procedure C, group according to general procedure P), was prepared

-335·« 9 1 9 99 · ♦ ♦ ·· • 9 9 9 9 9 9 9 9

9 9 999 9 9 9 · w 9 1 1 9 1 999 999 • · * · · · • C9 9 9 9 9 9 9 9 9 9 9 the title compound in gel form. The reaction was monitored by thin layer chromatography (Rf = 0.5 in 4% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/ _CHCl3 as the eluent.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ= 1.19 (d, 3H); 1.30 (s, 9H) .

C24H28N2O4F2:

Molecular weight = 446.50;

Mass spectroscopy: (MH ⁺ ) 446.

Example 125

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-methylpropionate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl 2-aminoisobutyrate (which was prepared from 2-aminoisobutyric acid (Aldrich) following general procedure H), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (Rf = 0.25 in CHCl3/MeOH 95:5). The NMR data were as follows:

^x H-nmr (DMSO-dg) : δ = 8.32 (m, 3H), 7.13 (m, IH) , 7.00 (m, 2H), 4, 31 (m, IH) , 3.53 (m, 5H) , 7.08 (m, 1H), 1.36 (s, 3H), 1.34 (with , 3H), 1.19 (d, 3H). Optical rotation: [a] ₂ 3 = -25° (c 1, MeOH).

C ₁₆ H2oN ₂ 04F2 :

Molecular weight - 342.34; Mass spectroscopy: (MH ⁺ ) 343.

Example 126 • that

-336« et ♦· ··»· ·· it*·· ··· · • · ····· · « · ·· · this ··♦··· it· ··· · · ••it ···· ·· ··· ·· ··

Synthesis of ethyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-cyclohexylacetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and ethyl-2-amino-2-cyclohexyl acetate hydrochloride (which was prepared from cyclohexylglycine (Advanced Chemtech) following general procedure Η), the title compound was prepared as a solid (mp = 146-150 °C). The reaction was monitored by thin layer chromatography (Rf = 0.3 in 3% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 3% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): (1:1 mixture of diastereomers): δ = 1.60 (m, 6H);

3.50 (s, 2H).

C21H28N2O4F2:

Molecular weight = 410.46;

Mass spectroscopy: (MH ⁺ ) 410.

Example 127

Synthesis of N-(2-methoxyethyl)-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylglycinamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(2-methoxyethyl)-L-phenylglycinamide hydrochloride (which was prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and 2-methoxyethylamine (Aldrich) following general procedure C, followed by removal of the BOC group following general procedure P), • 4· • « 9 9 • ·

-337• · ···· ·· ·· • · * 9 · ·

9 9 9 · · · · • 99 · · 9 9 · ·

9 · · ··· «· · * title compound as a solid (m.p. = 252254 °C). The reaction was monitored by thin layer chromatography (R _f = 0.3 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.22 (d, 3H); 5.43 (d, 1H).

Optical rotation: [α] ₂ o - +6.17° @ 589 nm (c = 1.04, DMSO). C22H25N3O4F2:

Molecular weight = 433.46;

Mass spectroscopy: (MH ⁺ ) 434.

Example 128

Synthesis of Ν-[N-(isovaleryl)-2-amino-2cyclohexylacetyl]-L-alanine ethyl ester

Following general procedure C and using N(isovaleryl)-2-amino-2-cyclohexylacetic acid (which was prepared from isovaleric acid (Aldrich) and D,La-cyclohexylglycine ethyl ester hydrochloride (which was prepared from cyclohexylglycine (Advanced Chemtech) and ethanol according to general procedure H) according to general procedure C, followed by removal of the BOC group according to general procedure P) and Lalanine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp = 220-224 °C). The reaction was monitored by thin layer chromatography (R _f = 0.2 in 5% MeOH/CHCl 3 ) and the product was purified by silica gel chromatography using 5% MeOH/CHCl ₃ as eluent, followed by recrystallization from a mixture of 1» ·

-338» · ·· · • ft • · ft ftftft • · ftft ftft chlorobutane/acetonitrile.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 0.85 (d, 6H); 4.04 (m, 2H). C ₁₈ H ₃ 2 N ₂ O ₄ :

Molecular weight = 340.46;

Mass spectroscopy: (MH ⁺ ) 341.

Example 129

Synthesis of N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-2-(N,N-dimethylamino)ethyl-L-phenylglycinamide dihydrochloride (which was prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and N,N-dimethylethylenediamine (Aldrich) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 234-236 °C). The reaction was monitored by thin layer chromatography (R _f = 0.3 in 15% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl 3 , followed by suspension in acetonitrile.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.22 (d, 3H); 5.41 (d, 1H).

Optical rotation: [α] ₂ o = +5.7° @ 589 nm (c = 1.01, DMSO). C23H28N4O3F2:

Molecular weight = 446.50;

Mass spectroscopy: (MH ⁺ ) 446.

♦ · 9999

-339• 9 99 » · 9 9 ··

9 9 9 • 9 9 9

999 999

Example 130

Synthesis of N-(2-pyridylmethyl)-Ν'-[Ν-(3,5-difluorophenylacetyl)L-alaninyl]-L-phenylglycinamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-(2-pyridylmethyl)-L-phenylglycinamide dihydrochloride (which was prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and 2-(aminomethyl)pyridine (Aldrich) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 272-275 °C). The reaction was monitored by thin layer chromatography (Rf = 0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as the eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.24 (d, 3H); 5.50 (d, 1H).

Optical rotation: [α] ₂ o = +12.4° @ 589 nm (c = 1.02, DMSO). C ₂ 5H ₂ 4N4O ₃ F ₂ '

Molecular weight = 466.49;

Mass spectroscopy: (MH ⁺ ) 467.

Example 131

Synthesis of Ν-[N-(3-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

Following general procedure C and using 3-pyridylacetic acid hydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride (which was ···· • ·

-340• 9 9 9 9 * 9 9 * • 9 9999 · · 9 9

9« 9 · 9 »·····

9 9 9 ·· • 999 99 999 9« 99 prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester hydrochloride (Sigma) according to general procedure C, followed by removal of the BOC group according to general procedure P), the title compound was prepared as a solid (m.p. = 150-152 °C).

The reaction was monitored by thin layer chromatography (R _f = 0.3 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.16 (d, 3H); 347 (s, 2H) .

Optical rotation: [α] ₂ o = -19.0° @ 589 nm (c = 1.03, DMSO). C20H23N3O4:

Molecular weight = 369.42;

Mass spectroscopy: (MH ⁺ ) 369.

Example 132

Synthesis of Ν-[N-(2-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (which was hydrochloride

Following general procedure C and using 2-pyridylacetic acid hydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester (Sigma) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 131-139 °C).

The reaction was monitored by thin layer chromatography (R _f = 0.4 in 8% MeOH/CHCl3) and the product was purified by silica gel chromatography using 8% MeOH/CHCl3 as eluent.

-341-

• ♦ ··· ·

9 4 4

4 · »

9 4 ·

49· ··· « ·

4 4 4 solvent, followed by recrystallization from a 1-chlorobutane/acetonitrile mixture.

The NMR data were as follows:

3-nmr (DMSO-d ₆ ): δ = 1.17 (d, 3H); 3.65 (s, 2H) .

Optical rotation: [α] ₂ o = -17.48° @ 589 nm (c = 1.09, DMSO). C20H23N3O4:

Molecular weight = 369.42;

Mass spectroscopy: (MH ⁺ ) 369.

Example 133

Synthesis of Ν-[N-(4-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (which was hydrochloride

Following general procedure C and using 4-pyridylacetic acid hydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester (Sigma) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 152-154 °C). The reaction was monitored by thin layer chromatography (R _f =0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 10% MeOH/CHCl ₃ as eluent, followed by recrystallization from 1chlorobutane/acetonitrile.

The NMR data were as follows:

3-nmr (DMSO-d ₆ ): δ = 1.17 (d, 3H); 3.47 (s, 2H) .

Optical rotation: [α] ₂ o = -17° @ 589 nm (c = 1.00, DMSO). C ₂ oH ₂ 3N ₃ 04:

• 000

-342· • 0

0· ·

0000 · 00 0 •0 0 ·· 0000·· ·· 0 ·

Molecular weight = 369.42;

Mass spectroscopy: (MH ⁺ ) 369.

Example 134

Synthesis of ethyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(4-fluorophenyl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and ethyl 2-amino-2-(4-fluorophenyl)acetate hydrochloride (which was prepared from 4-fluorophenylglycine (Fluka) and ethanol following general procedure H), the title compound was prepared as a solid (mp = 169-183 °C). The reaction was monitored by thin layer chromatography (R _f = 0.3 in 4% MeOH/CHCl ₃ ) and the product was purified by chromatography using 4% MeOH/CHCl 3 solvent, followed by recrystallization from chlorobutane/acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-d 6 ): (1:1 mixture of diastereomers): δ = 3.49, 3.53 (singlets, 2H); 5.40 (m, 1H).

C21H21N2O4F3:

Molecular weight = 422.4;

Mass spectroscopy: (MH ⁺ ) 422.

silica gel as eluent from mixture 1Example 135

Synthesis of ethyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(2-fluorophenyl)acetate

Following general procedure C and using N-(3.5to

-343to *· ·· toto toto· · · ♦ · • · ···« toto to • ·· · ·· ··»· • · · · «· to··· ·· · · · * · • •toto difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and ethyl-2-amino-2-(2fluorophenyl)acetate hydrochloride (which was prepared from 2fluorophenylglycine (Fluka) and ethanol according to general procedure Η) , the title compound was prepared as a solid (mp = 153-170 °C). The reaction was monitored by thin layer chromatography (R _f = 0.3 in 5% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH/CHCl ₃ as the eluent, followed by recrystallization from 1chlorobutane/acetonitrile.

The NMR data were as follows:

¹ H-nmr (DMSO-d6): (1:1 mixture of diastereomers): δ = 3.50, 3.54 (singlets, 2H), 5.66 (m, 1H).

C21H21N2O4F3:

Molecular weight = 422.40;

Mass spectroscopy: (MH ⁺ ) 422.

Example 136

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alanine ethyl ester (which was Chemtech) and

Following general procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and N-(L-phenylglycinyl)-L-alanine ethyl ester hydrochloride prepared from N-BOC-L-phenylglycine (Advanced L-alanine ethyl ester hydrochloride (Aldrich) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.3 in 3%

9 ···· ·· ··

-3449 999 9 9 9 ·

···

9 9

9 9

999 999

9

MeOH/CHCl ₃ ) and the product by solvent chromatography, followed by chlorobutane/acetonitrile.

NMR data were as follows: ^x H-nmr (DMSO-d ₆ ): δ - 3.50 (s, was purified

3% MeOH/CHCl 3 and recrystallization on silica gel as eluent from the mixture 12H), 5.53 (d, 1H).

C21H22N2O4F2:

Molecular weight = 404.42; Mass spectroscopy: (MH ⁺ ) 405.

Example 137

Synthesis of ethyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-3-phthalimidopropionate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and ethyl 2-amino-3-phthalimidopropionate hydrochloride (prepared in Example D10 above), the title compound was prepared as a solid (mp = 197-201 °C). The reaction was monitored by thin layer chromatography (Rf = 0.5 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): (1: 1 mixture of diastereomers) : δ = 7.88 (m,

4H), 8.29 (t, 1H), 8.48, 8.55 (doublets, 1H).

_{C24H23N3OSF2 :}

Molecular weight = 487.46;

Mass spectroscopy: (MH ⁺ ) 487.

Example 138

-3454 44 44 4444 44 44

44 444 4444

4 4 4 444 4 4 4 4 · 44 4 44 444444

4 4 4 4 4 4

444 4444 44 444 44 44

Synthesis of N-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylglycine neopentyl ester

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-phenylglycine neopentyl ester hydrochloride (prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and 2,2-dimethyl-1-propanol (Aldrich) following general procedure C (with catalytic DMAP), followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 133-136 °C). The reaction was monitored by thin layer chromatography (R _f = 0.7 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 4%

MeOH/CHCl ₃ as eluent, followed by recrystallization from 1-chlorobutane/hexanes.

The NMR data were as follows:

3-nmr (DMSO-d ₆ ): δ = 3.50 (s, 2H), 5.42 (d, 1H).

Optical rotation: [α] ₂ o = +45.9° @ 589 nm (c = 1.02, DMSO). C24H28N2O4F2

Molecular weight = 446.50;

Mass spectroscopy: (MH ⁺ ) 446.

Example 139

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylglycinamide

Following the general procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), S-(+)-α-methylbenzylamine (Aldrich), benzaldehyde (Aldrich), and tert-butylisocyanide (Aldrich),

346 • φ • ·

·· φφφφ φ · φ φφφφ φ φ φ φ φ φ

ΦΦΦ φ

The title compound was prepared as a solid (mp = 233-235 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 8%

MeOH/CHCl ₃ as elution solvent, followed by recrystallization from 1-chlorobutane/acetonitrile.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ) : (1:1 mixture of diastereomers): δ = 3.52 (s, 2H),

5.40 (m, 1H).

_{C23H27N3O3F2 : ​ ​ ​}

Molecular weight = 431.49;

Mass spectroscopy: (MH ⁺ ) 432.

Example 140

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylglycine tert-butyl ester

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-phenylglycine tert-butyl ester hydrochloride (Advanced Chemtech), the title compound was prepared as a solid (mp = 145-147 °C). The reaction was monitored by thin layer chromatography (R _f - 0.5 in 5% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 2.5% MeOH/CHCl ₃ as the eluent, followed by recrystallization from 1-chlorobutane/hexanes.

The NMR data were as follows:

δ-nmr (DMSO-d ₆ ): δ = 1.26 (d, 3H); 5.20 (d, 1H) .

Optical rotation: [α] ₂ o = +14.8° @ 589 nm (c = 1.01, MeOH). C23H26N2O4 F ₂ :

·· ····

-3474 ·· · · · · · · • · ····« · · · · • · ··· · 9 4 444 494

4 4 4 4 9 4

4444449 44 944 49 44

Molecular weight = 432.47;

Mass spectroscopy: (MH ⁺ ) 433.

Example 141

Synthesis of N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-phenylglycinamide hydrochloride (which was prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and ammonia following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 288-290 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 15% MeOH/CHCl 3 ) and the product was purified by silica gel chromatography using 15% MeOH/CHCl 3 as the eluent, followed by recrystallization from EtOH.

The NMR data were as follows:

1H-nmr (DMSO-d ₆ ): δ = 1.22 (d, 3H), 5.36 (d, 1H).

Optical rotation: [α] ₂₀ = +27.5° @ 589 nm (c = 1.03, DMSO).

Ci9Hi9N3O3F ₂ :

Molecular weight = 375.38;

Mass spectroscopy: (MH ⁺ ) 376.

Example 142

Synthesis of 4-[Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-Lvalinyl]morpholine

Following the general procedure C and using N-(3AAA AAAA ·· »·Α·

-348• · AAAAAAAAA • AAA AAA nitrophenylacetyl)-L-alanine (prepared in Example Dli above) and 4-(L-valinyl)morpholine (which was prepared from N-BOC-L-valine (Aldrich) and morpholine (Aldrich) by general procedure M followed by removal of the BOC group by general procedure P), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (Rf = 0.5 in 9: 1 CHCl ₃ /MeOH) and the product was purified by silica gel chromatography using 98: 2 CHCl ₃ /MeOH as the eluent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 8.12 (d, 2H), 8.08 (dd, 1H), 7.59 (d, 1H, J = 7 Hz), 7.42 (t, 1H), 7.32 (d, J = 8 Hz, 1H), 7.03 (d, J = 8 Hz, 1H), 4.78 (m, 1H) , 4.68 (m, 1H) , 3.61 (m, 10H) , 1.90 (m, 1H) , 1.96 (d, 3H) , 1.31 (d, 3H) , 0.88 (d, 3H) , 0.80 (d, 3H) .

Optical rotation: [α] ₂₃ = -5° (c 5, MeOH).

Example 143

Synthesis of Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ethyl ester

Following general procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared in Example Dli above) and L-valine ethyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.2 in 97:3 CHCl ₃ /MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl ₃ /MeOH as the eluent.

The NMR data were as follows:

-34900 • ·

00 00 »··· • · • ··· •

0 0 • 0

0« • 0 0 0 • 0 0 0 •00 000

0

0 00 ^x H-nmr (CDCl 3 ) : δ = 8.13 (m, 2Η) , 7.62 (d, J = 7 Hz, 1H) ,

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: [α] 23 = -24.3° @ 589 nm (c 1, DMSO).

C18H25N3O6:

Molecular weight = 379.42;

Mass spectroscopy: (MH ⁺ ) 380.

Example 144

Synthesis of Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]L-threonine methyl ester

Following general procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared in Example D1i above) and L-threonine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (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.

The NMR data were as follows:

3-nmr (CDCl ₃ ): δ = 8.08 (d, 1H), 7.45 (d, 1H), 7.34 (t, 1H), 7.20 (dd, 1H), 4.13 (m, 1H), 3.59 (s, 3H), 1.03 (d, 3H).

Optical rotation: [a] ₂₃ = -20.80 (c

C ₁₆ 6H ₂ oN 2 O ₇ :

Molecular weight = 367.3; Mass spectroscopy: (MH ⁺ ) 368.

7.96 (d, IH), 7.59 (d, IH), (d, IH), 4.43 (m, IH), 4.39 3H), 3.51 (s, 2H), 1.20 (d,

5, MeOH).

-350• this ·· this··· this ·· «··· ··· · ·· · • · · · ··· · ·· · • ·<·· ·· this· *·· • · this · · ·· ·«· ···· «· this this this ··

Example 145

Synthesis of 4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2amino-3-tert.-butoxybutyryl]morpholine

Following general procedure C and nitrophenylacetyl)-L-alanine (prepared using N-(3-threonine morpholine in Example D1 above) and (which was (Sigma) and general procedure M,

4-[(S)-2-amino-3-tert-butoxybutyryl] prepared from N-BOC-O-tert-butyl-L-morpholine (Aldrich) by the procedure of followed by removal of the BOC group by the procedure of general procedure P) , the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.1 in 95:5 was purified on silica gel

96:4 _CHCl3 /MeOH

CHCl ₃ /MeOH) and the product by solvent chromatography.

The NMR data were as follows:

as a washout

^x H-nmr (CDCl ₃ ) : δ = 8.12 (m, 2H), 7 , 66 (d, IH), 7.47 (t, IH), 6.88 (d, IH), 6.32 (d, IH), 4.78 (m, IH), 4.50 (m, IH) , 3.90-3.40 (m, HH), 1.40 (d , 3H), 1.18 (with, 9H), 1.0 (d, 3H) .

O ₂₃ H ₃₃ N ₃ O7:

Molecular weight = 478.5; Mass spectroscopy: (MH ⁺ ) 47

Example 146

Synthesis of 4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-Lisoleucinyl]morpholine

Following general procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared in Example D1)

-351• φ φφφφ · φφ φφφφ φ φφφ φφφ φφφ φφφ · φ φφφ φφφ φφφ φφφ · φ φφφ φφφ φφφ ·· above) and 4-(L-isoleucinyl)morpholine (which was prepared from N-BOC-L-isoleucine (Aldrich) and morpholine (Aldrich) by general procedure M, followed by removal of the BOC group by general procedure P) , the title compound was prepared as a solid (mp = 156-160 °C). The reaction was monitored by thin layer chromatography (Rf = 0.45 in 9: 1 CHCl ₃ /MeOH) and the product was purified by silica gel chromatography using 98: 2 CHCl ₃ /MeOH as eluent.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ) : δ = 8.16 (d, IH) , 8.09 (d, IH) , 7.63 (d, IH), 7.45 (t, IH) , 7.30 (d, IH), 6.89 (d, IH) , 4.78 (m, IH) , 4.62 (m, 1H), 3, 6 (m, 10H) , 1.65 (m, 1H) , 1.4 (m, IH) , 1.29

(d, 3H), 1.03 (d, 3H), 0.90-0.76 (m, 6H).

Optical rotation: [α] ₂₃ = -55° @ 589 nm (c 1, MeOH).

Example 147

Synthesis of N-[N-(3-Nitrophenylacetyl)-L-Alaninyl]L-Isoleucine Methyl Ester

Following general procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared in Example D1i above) and L-isoleucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (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.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 8.12 (m, 2H) , 7.66 (d, 1H) , 7.49 (t, 1H) , 6.50 (m, 2H), 4.52 (m, 2H), 3.72 (s, 3H), 3.61 (s, 2H), 1.87 · · ·

-352(m, 1H), 1.32 (m, 4H), 1.07 (m, 1H), 0.81(d, 6H).

Optical rotation: [α] ₂ 3 = -7.3° (c 5, MeOH).

_{Ci8H25N2O6 :}

Molecular weight = 379;

Mass spectroscopy: (MH ⁺ ) 379.

Example 148

Synthesis of Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine

Following the general procedure AF and using Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine methyl ester (prepared in Example 147 above), the title compound was prepared as a solid.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 8.41 (d, IH), 8.15 (with, IH) , 8.07 (d, IH), 7.91 (d, IH), 7.68 (d, IH), 7.53 (t, IH) , 4.36 (m, IH) , 4.12 (m, 1H), 3.62 (s, 2H), 1.71 (m, IH), 1.31 (m, IH) , 1, 18 (d, 3H), 1.07 (m, 1H), 0.79 (m, 6H) . Optical rotation: [a] ₂₃ = -42° (c 5, MeOH).

_{C17H23N2O6 : ​ ​}

Molecular weight = 365.3;

Mass spectroscopy: (MH ⁺ ) 366.

Example 149

Synthesis of Ν-[Ν-[N-(3-nitrophenylacetyl)-L-lalaninyl]-L-threoninyl]-L-valine ethyl ester

Following general procedure C and using N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine (which was prepared from Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine methyl ester (prepared in Example 144) given below • · · · · · · ·

-353 _• · ···· _·

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ) : δ = 8.12 (m, IH) , 7.60 (d, IH), 7.48 (t, IH) , 7.05 (d, 1H), 6, 98 (d, IH), 6.48 (d, IH), 4.M (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 : [«] = -85° (c 5, MeOH)

Example 150

Synthesis of methyl N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2aminopentanoate

Following general procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared in Example D1i above) and methyl (S)-2-aminopentanoate hydrochloride (which was prepared from (S)-2-aminopentanoic acid (Novabiochem) following general procedure H), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R ₂ = 0.4 in 9:1 CHCl ₃ /MeOH).

The NMR data were as follows:

^-nmr (DMSO-d ₆ ) : δ = 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, 1H), 4.22 (m, IH) , 3.64 (m, 5H) , 1.62 (m, 2H) , 1.26 (m, 2H), 1.22 (d, 3H), 0.86 (m, 3H).

-354Optical rotation: [α] ₂₃ = -29° (c 1, MeOH).

C17H23N3O6:

Molecular weight = 365;

Mass spectroscopy: (MH ⁺ ) 366.

Example 151

Synthesis of Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]L-leucine methyl ester

Following general procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared in Example D1i above) and L-leucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (Rf = 0.75 in 9:1 _CHCl3 /MeOH) and the product was purified

silica gel chromatography using 97 :3 CHCl ₃ /MeOH as a washout solvent. NMR data was following: ^x H-nmr (CDCl ₃ ) : δ = 8.12 (m, 2H) , 8.04 (m, IH), 7.58 (m, IH), 7.48-7.30 1 (m, 2H), 7.11 (d, 1H), 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: [α] ₂₃ = -32° (c 1, MeOH).

C18H25N3O6: Molecular weight = 37 9; Mass spectroscopy: : (MH ⁺ ) 380.

Example 152

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalanininyl]-L-leucine methyl ester

ΦΦ φφ φ φ φ · φφ φφφ φφφ

-355 Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-leucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.5 in 9:1 CHCl ₃ /MeOH).

The NMR data were as follows:

¹ H-nmr (CDCl 3 ): δ = 6.78 (m, 2H) , 6.69 (m, 1H), 4.52 (m, 2H), 3.73 (m, 1H), 3.52 (d, 2H), 1.63 (m, 2H), 1.36 (m, 3H), 0.88 (m, 3H) . Optical rotation: [oc] ₂₃ = -34° (c 1, MeOH).

C18H24N2O4F2:

Molecular weight = 370;

Mass spectroscopy: (MH ⁺ ) 370.

Example 153

Synthesis of N-2-Methoxyethyl-N'-[N-(3,5-Difluorophenylacetyl)-Lalaninyl]-L-Alaninamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in Example D7 above) and 2-methoxyethylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.35 in 9:1 CHCl ₃ /MeOH.

The NMR data were as follows:

^-nmr (DMSO-d ₆ ): δ = 8.32 (m, 1H) , 7.98 (d, 1H) , 7.82 (m,

1H), 7.07 (m, 1H), 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: [α] ₂₃ = -50° (c 1, MeOH).

-356-

• · ··· · • · ··

C17H23N3O4F2:

Molecular weight = 371;

Mass spectroscopy: (MH ⁺ ) 372.

Example 154

Synthesis of N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-alanine amide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in

Example D7 above) and N,N-dimethyl-ethylenediamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (Rf = 0.05 in 9:1 CHCl3/MeOH).

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 8.38 (m, 1H) , 8.02 (m, 1H), 7.66 (m, 1H), 7.09 (m, 1H), 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).

C18H26N4O3F2:

Molecular weight = 384;

Mass spectroscopy: (MH ⁺ ) 384.

Example 155

Synthesis of N-cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in

Example D7 above) and cyclohexylamine (Aldrich), the title compound was prepared as a solid (temperature • 9

9 9

9 9 9

9

9

-3579 9 9 9 ···· * · · ·

9 9999

9 9 9 9

9 9 9 mp = 239-244 °C). The reaction was monitored by thin layer chromatography (R _f = 0.25 in 9:1 CHCl 3 /MeOH).

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ) : δ = 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, 1H), 1.64 (m, 4H), 1.54 (m, 2H), 1.20 (m, 10H) . Optical rotation: [a] 23 = -58° (c 1, MeOH).

C20H27N3O3F2:

Molecular weight = 395;

Mass spectroscopy: (MH ⁺ ) 395.

Example 156

Synthesis of N-neopentyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in Example D7 above) and neopentylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.25 in 9:1 CHCl ₃ /MeOH).

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ) : δ = 8.37 (d, IH), 8.01 (m, IH), 7.67 (m, IH), 7.11 (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] I23 = -54° (c 1, MeOH).

C ₁₉ H ₂₇ N ₃ O ₃ F ₂ :

Molecular weight - 383; Mass spectroscopy: (MH ⁺ ) 383.

» ·· · · • · • ···

-358Example 157

Synthesis of N-tetrahydrofurfuryl-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-L-alanine amide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in Example D7 above) and tetrahydrofurfurylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.20 in 9:1 CHCl ₃ /MeOH).

The NMR data were as follows:

^-nmr (DMSO-d ₆ ): δ = 8.36 (d, 1H) , 8.01 (m, IH) , 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, 1H), 1.19 (m, 6H).

Optical rotation: [α] ₂₃ = -70° (c 1, MeOH).

C19H25N3O4F2:

Molecular weight = 397;

Mass spectroscopy: (MH ⁺ ) 398.

Example 158

Synthesis of N-2-pyridylmethyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in

Example D7 above) and 2-(aminomethyl)pyridine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.1 in 9:1 CHCl ₃ /MeOH).

The NMR data were as follows:

-359·· ·· ···· <· ·· • to · to to * ^··· • · · ··· _·

Molecular weight = 404; Mass spectroscopy: (MH ⁺ )

(m, IH), 8.41 (m, 2H), 8.14 (d, 2H), 7.09 (m, IH), 6.98 (m, 2H), 1.24 (m, 6H). (c 5, MeOH).

405.

Example 159

Synthesis of 3-[Ν-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]-Lalaninyl]thiazolidine

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in Example D7 above) and thiazolidine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.25 in 9:1 CHCl ₃ /MeOH.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ) : δ = 8.34 (m, 2H) , 8.22 (m, 1H) , 7.5 (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: [α] ₂ 3 = -67° (c 1, MeOH).

C17H21N3O3F2 ·

Molecular weight = 385;

Mass spectroscopy: (MH ⁺ ) 385.

Example 160

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-aminobutanoate

-360• ·· *··· ··· ···· • · · · · ♦·· · · · · · · • ·

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl-(S)-2-aminobutanoate hydrochloride (prepared from (S)-(+)-2-aminobutyric acid (Aldrich) following general procedure H), the title compound was prepared as a solid (mp = 103-106 °C).

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ) : δ = 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, 1H), 1.39 (d, 3H), 0.86 (t, 3H).

Optical rotation: [α] ₂₃ = -70° (c 1, MeOH).

C16H20N2O4F2:

Molecular weight = 342.35;

Mass spectroscopy: (MH ⁺ ) 342.

Example 161

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl](S)-2-aminopentanoate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl (S)-2-aminopentanoate hydrochloride (which was prepared from (S)-2-aminopentanoic acid (Novabiochem) following general procedure H), the title compound was prepared as a solid (mp = 154-155 °C).

The NMR data were as follows:

Vnmr (CDCl ₃ ) : δ = 6.80 (m, 2H), 6.69 (m, 1H), 6.45 (d, 1H), 6.28 (d, 1H), 4.52 (m, 2H), 3.71 (s, 3H), 3.51 (s, 2H), 1.77 « ·

-36199 999*

9 9

9 99 9 99 9 • · · · 9 · · · ·

9 9 9 9

9 99 9 9 9 9 (m, 1H) , 1.58 (m, 1H) , 1.35 (d, 3H) , 1.27 (m, 2H) , 0.87 (t, 3H) .

Optical rotation: [α]23 = -69° (c 1, MeOH).

Example 162

Synthesis of methyl N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2aminobutanoate

Following general procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared in Example Dli above) and methyl (S)-2-aminobutanoate hydrochloride (which was prepared from (S)-(+)-2-aminobutyric acid (Aldrich) following general procedure H), the title compound was prepared as a solid (mp = 154-157 °C).

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 8.13 (m, IH) , 8.04 (m, IH) , 7.57 (m, IH) , 7.38 (m, 1H), 4.72 (m, IH) , 4.39 (m, IH) , 3, 69 (with, 3H), 3.41 (s, 2H), 1.73 (m, IH) , 1.61 (m, IH) , 1.34 (d, 3H) , 0.79 (t,

3H).

Optical rotation: [α] ₂₃ = 2 -75° (c 1, MeOH).

Example 163

Synthesis of N-(R)-sec-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alaninamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in Example D7 above) and (R)-(-)-sec-butylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography.

-362• this ·<·« this · • · * this · ······>

·· tototo* • · to to·· ·· ·· • to · ·· 9 ·« to· • ·· « to ·· to ·«· to·· • · ·· ·· layer (Rf = 0.15 in 95:5 CHCl ₃ /MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl ₃ MeOH as eluent.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 8.39 (m, IH) , 7.95 (m, IH) , 7.49 (m, IH), 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).

Optical rotation: [α] ₂ 3 = -50° (c 1, MeOH).

_Ci8H25N3O3F2 ^: _​

Molecular weight = 369.41;

Mass spectroscopy: (MH ⁺ ) 370.

Example 164

Synthesis of 1-[N-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]-Lalaninyl]pyrrolidine

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in Example D7 above) and pyrrolidine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.15 in 95:5 CHCl ₃ /MeOH) and the product was purified by silica gel chromatography using CHCl ₃ /MeOH as the eluent.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ) : δ = 8 ,31 (m, IH), 8.08 (m, IH), 7.09 (m, 1H), 6.99 (m, 2H), 4.48 (m, IH) , 4.29 (m, 1H), 3.51 (s, 2H) , 3.44-3.22 (m, 4H), 1.80 (m, 4H) , 1.27 (m, 6H).

_{Ci8H23N3O3F2 :}

Molecular weight = 367.40;

ft · ·

I · · · « • · • ftftft

-363Mass spectroscopy: (MH ⁺ ) 367.

Example 165

Synthesis of N-(S)-sec-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in

Example D7 above) and (S)-(+)-sec-butylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.25 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using _CHCl3 /MeOH as eluent.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 8.38 (m, 1H) , 7.92 (m, IH) , 7.30 (m, 1H), 7.18 (m, 1H), 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) . Optical rotation: [α] ₂₃ = -52° (c 1, MeOH).

C19H25N3O3F2:

Molecular weight = 369.41;

Mass spectroscopy: (MH ⁺ ) 370.

Example 166

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-valine methyl ester

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2

-364• · · · · ··· • · · · · ··· · • c · · · · · · · · • ·

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 6.81 (m, 2H), 6.73 (m, 1H), 6.48 (d, 1H), 6.22 (d, 1H), 4.48 (m, 2H), 3.70 (s, 3H), 3.51 (s, 2H), 2.16 (m, 1H), 1.37 (m, 1H), 0.87 (t, 3H).

Optical rotation: [rot] ₂ 3 = -65° (c 1, MeOH).

C17H22N2O4F2:

Molecular weight - 356.37;

Mass spectroscopy: (MH ⁺ ) 3M.

Example 167

Synthesis of N-2-fluoroethyl-N ¹ -[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-alanine amide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared in

Example D7 above) and 2-fluoroethylamine hydrochloride (Aldrich), the title compound was prepared as a solid (mp = 230-235 °C).

The NMR data were as follows:

^-nmr (DMSO-d ₆ ) : δ = 8.38 (d, 1H), 8.04 (m, 2H), 7.07 (m, 1H), 6.99 (m, 2H), 4.39 (m, 2H), 4.24 (m, 1H), 3.53 (s, 2H), 3.35 (m, 2H), 1.20 (m, 6H).

Optical rotation: [α] ₂₃ -33° (c 1, MeOH).

C16H20N3O3F3:

Molecular weight = 359.37;

Mass spectroscopy: (MH ⁺ ) 359.

• 4

-365Example 168

Synthesis of N-[(S)-6-methyl-3-oxohept-2-yl]-Ν' -(3,5-difluorophenylacetyl)-L-alanine amide

Following general procedure M and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and (S)-6-methyl-3-oxohept-2-ylamine hydrochloride (prepared by treating N-BOC-L-alanine with 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 according to general procedure P), the title compound was prepared as a solid. The product was purified by silica gel chromatography using CHCl ₃ /MeOH as eluent.

The NMR data were as follows:

1H-nmr (CDCl ₃ ): δ = 6.M (m, 2H), 6.69 (m, 1H), 6.31 (m, 1H), 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: [α] ₂ 3 = -42° (c 1, MeOH).

C19H26N2O3F2:

Molecular weight = 368;

Mass spectroscopy: (MH ⁺ ) 368.

Example 169

Synthesis of N-4-nitrobenzi1-N ¹ -[N-(3,5-difluorophenylacetyl)-Lalaninyl]-(S)-2-aminobutyramide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutyric acid (which was prepared from methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate (prepared in Example 160)

AAA

AND

A A

-366 above) following general procedure AF) and 4-nitrobenzylamine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (Rf = 0.3 in 95:5 CHCl ₃ /MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl ₃ /MeOH as eluent.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ) : δ = 8.57 (t, 1H) , 8.40 (d, 1H) , 8.21 (d, 2H), 8.02 (d, 1H), 7.50 (d, 2H) , 7.08 (m, 1H) , 6, 98 (m, 2H) , 4.42 (d, 2H), 4.37 (m, 1H), 4.17 (m, 1H) , 3, 53 (with, 2H) , 1, 64

(m, 2H), 1.21 (m, 3H), 0.83 (t, 3H).

Optical rotation: [α]23 - -42° (c 1, MeOH).

C22H24N4O5F2:

Molecular weight = 462.45;

Mass spectroscopy: (MH ⁺ ) 462.

Example 170

Synthesis of N-4-nitrobenzyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-(S)-2-aminopentanamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoic acid (which was prepared from methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate (prepared in Example 161 above) following general procedure AF) and 4-nitrobenzylamine (Aldrich)), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.3 in 95:5 CHCl ₃ /MeOH) and the product was purified by recrystallization from acetonitrile.

The NMR data were as follows:

• ·

1H-nmr (DMSO-d ₆ ): δ = 8.57 (m, 1H), 8.41 (d, IH), 8.22 (d, 2H), 8.06 (d, 1H), 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: [α] ₂ 3 = +970 (c 1, MeOH).

_{C23H26N4O5F2 : ​ ​ ​}

Molecular weight = 476.4;

Mass spectroscopy: (MH ⁺ ) 476.

Example 171

Synthesis of methyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(3-fluorophenyl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl 2-amino-2-(3-fluorophenyl)acetate hydrochloride (prepared in Example D12 above), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (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.

The NMR data were as follows:

'H-nmr (CDCl ₃ ) : δ = 7.36 (m, IH) , 7.18 (m, IH) , 7.13 (m, IH) , 7.06 (m, 1H), 6.87 (m, 2H), 6.74 (m, IH) , 6.09 (m, IH), 5.49 (d, IH) , 4.59 (m, IH), 3.74 (with, 3H) , 3.57 (with, 2H) , 1.35 (d,

3H), 0.97 (d, 3H).

C ₂ oH ₁₉ N ₂ 0 ₄ F ₃ :

Molecular weight = 408.38; Mass spectroscopy: (MH ⁺ ) 408.

0 0

-368Example 172

Synthesis of Ν' -[Ν-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2amino-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 (prepared in Example 178 below), the title compound was prepared as a solid (mp = 190 °C decomposition). The product was purified by preparative LC 2000 chromatography using 8:2 EtOAc/hexanes as the eluent.

The NMR data were as follows:

^-nmr (CDCl ₃ /DMSO-d 6 ): δ = 8.9-6.14 (Ar+F NH 10 Η), 5.435.39 (m, IH), 4.16-4.10 (m, J = 7 Hz, IH), 3.19 (s, 2H),

1.15 (d, J=7.05 Hz, 3H).

C ₁₇ Hi ₇ F ₂ N ₃ O ₃ S:

Molecular weight = 381.4;

Mass spectroscopy: (MH ⁺ ) 381.

Example 173

Synthesis of methyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(5-chlorobenzothiophen-2-yl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl 2-amino-2-(5-chlorobenzothiophen-2yl)acetate (which was prepared from 5-chlorobenzothiophen-2-acetic acid [CAS No. 23799-65-7] following general procedure G, followed by amination following a procedure essentially the same as that described in Example D4 above), the title compound was prepared as a solid.

-369• · · · · · · · · · · · • 9 99999 9999

9 99 9 99 99···· • ·

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ) : δ = 7.7-7.63 (m, 2H), 7.33-7.17 (m, 2H) , 6.89-6.63 (m, 3H) , 6.16-6.03 (m, IH) , 5.85 (dd, IH) , 4.7- 4.53 (m, 1H), 3.83 (s, 1.5H), 3.8 (with, 1.5H), 3.59 (with, 1H) , 3.5 (s, IH), 1.4 (dt , 3H) .

C22H19CIF2N2O4S:

Molecular weight = 481;

Mass spectroscopy: (MH ⁺ ) 480.

Example 174

Synthesis of ethyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(benzothiophen-2-yl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and ethyl 2-amino-2-(benzothiophen-2-yl)acetate [CAS No. 98800-64-7], the title compound was prepared as a solid (mp = 189-190 °C). The product was purified by preparative LC 2000 chromatography using 2:8 EtOAc/hexanes as the eluent.

The NMR data were as follows:

^X H -nm r (C DC1 ₃ ) : δ = 7.8-7.75 (ra, 2H), 7.34-7.27 (ra, 2H) , 7, 25- 7.09 (m, 3H), 6.81-6.76 (ra, IH), 6.76-6.63 (m, IH), 6, 23 (dd, J = 7 Hz, IH), 5.84 (d, J = 7.07 Hz, IH), 4.61- 4, 59 (m, 1H), 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) .

C23H22N2O4SF2:

Molecular weight = 460.49;

• · ··

-370φφ φφ φ φ · · φ φ φ · • φφφ φφφ φ φ φφ φφ

Mass spectroscopy: (ΜΗ ⁺ ) 460.

Example 175

Synthesis of methyl-N-[Ν-(3,5-difluorophenylacetyl)-L-alaninyl]-1amino-2-(benzothiophen-2-yl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl 2-amino-2-benzothiophen-3-yl)acetate (which was prepared from 1-amino-2-benzothiophen-3-yl)acetic acid [CAS 95834-94-9] following general procedure H), the title compound was prepared as a solid (mp = 185-186 °C).

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 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, 1H), 5.95-5.85 (m, 1H), 4.55-4.5 (m, 1H), 3.75 (s, 1.5H), 3.65 (s, 1.5H), 3.55 (s, 1H), 3.35 (s, 1H), 1.4 (d, 1.5H), 1.3 (d, 1.5H). C22H20N2O4F2S:

Molecular weight = 446;

Mass spectroscopy: (MH ⁺ ) 446.

Example 176

Synthesis of methyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(2-thienyl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl-2-amino-2-(2-thienyl)acetate (which was prepared from L-α-2-thienylglycine (Sigma) following general procedure G), the title compound was prepared in • ·

9 9 99 9 • 9 9 999

-37199 99

9 9 9

9 9 9 • 9 999 999

9 9

9 9 9 as a solid (mp = 161-162 °C). The product was purified by preparative LC 2000 chromatography using 1:4 EtOAc/hexanes.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 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 (overlapping d, 3H).

_{C18H18N2O4F2S : ​ ​}

Molecular weight = 396;

Mass spectroscopy: (MH ⁺ ) 396.1.

Example 177

Synthesis of ethyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(benzothiophen-5-yl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and ethyl 2-amino-2-(benzothiophen-5-yl)acetate (prepared according to the procedure described by 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.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 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 (g, 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:

• · · • · · • · · · • ·

• ••fl • fl · • · · ··

372

Molecular weight = 460;

Mass spectroscopy: (MH ⁺ ) 460.

Example 178

Synthesis of methyl-N-[N-(3,5-difluorophenylacetyl)-L-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)acetic acid (prepared in 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 elution solvent.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 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).

Ci ₈ H ₁₈ N ₂ O ₄ SF ₂ :

Molecular weight = 396;

Mass spectroscopy: (MH ⁺ ) 396.1.

Example 179

Synthesis of tert-butyl Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-(S)-2-amino-2-(2-thienyl) acetate

Following General Procedure J and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetic acid (prepared in Example 180 below), the title compound was prepared as a solid (mp = 117-118 °C). The product was purified

0000 000 * • 0 00··· 000· • 0 0 0 0 0 0 000 ·00 • · ·· · ·by trituration in ether/hexanes. The NMR data were as follows:

¹ H-nmr (CDCl3) : δ = 7.24 (d, J = 6.5 Hz, 1H), 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) t 3.5 (s, 2H), 1.44 (s, 9H), 1.38 (d, J = 7.1

Hz, 3H).

C21H24N2O4SF2:

Molecular weight = 438.5;

Mass spectroscopy: (MH ⁺ ) 438.

Example 180

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2amino-2-(2-thienyl)acetic acid

Following general procedure M and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-α-2-thienylglycine (Sigma), the title compound was prepared as a solid. The product was purified by trituration in EtOAc/hexanes.

The NMR data were as follows:

^x H-nmr (DMSO-dg) : δ = 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) , 3.33 (s, 2H), 1.23 (d, J = 7 Hertz,

3H).

_{Ci7H16N2O4SF2 : ​}

Molecular weight = 382;

Mass spectroscopy: (MH ⁺ ) 382.

Example 181

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(1H-tetrazol-5-yl)acetate

·· • ·

-374•· this·· that · · * • · · · · · ·· · · · • · · ·· ···

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl-2-amino-2-(1H-tetrazol-5-yl)acetate (prepared from ethyl-1H-tetrazol-5-acetate [CAS 173367-99-2] using procedures essentially the same as described by S. Kukolja, J. Med. Chem., 1985, 28, 1886-1896), the title compound was prepared as a solid. The reaction product was purified by trituration in EtOAc/hexanes.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ) : δ = 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 (s, 3H), 1.27-1.11 (m, 6H). C16H18NSO4F2 ·'

Molecular weight = 396.3;

Mass spectroscopy: (MH ⁺ ) 396.3.

Example 182

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl] (S)-2-amino-2-(6-methoxy-2-naphthyl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl-(S)-2-amino-2-(6-methoxy-2-naphthyl)acetate (prepared in Example D3 above), the title compound was prepared as a solid (mp = 177-178 °C). The product was purified by trituration in hexanes/EtOAc.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 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 = • ·

-375Hz, 1H) , 4.243 (d, J = 3.5 Hz, 1H) , 3.86 (s, 3H) , 3.6 (s,

3H), 3.29 (s, 2H), 1.26 (d, J = 7.5 Hz, 3H).

C25H24N2O5F2:

Molecular weight = 470.48;

Mass spectroscopy: (MH ⁺ ) 470.

Example 183

Synthesis of methyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(3-trifluoromethylphenyl)acetate

Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl 2-amino-2-(3-trifluoromethylphenyl)acetate (which was 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 trituration in EtOAc/hexanes.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 7.57-7.37 (m, 4H), 6.8-6.6 (m, 3H), 6.05 (BA, 1H), 5.5 (A, J = 7.5Hz, 1H), 3.7 (s, 1.5H), 3.675 (s, 1.5H), 3.5 (s, 1H), 3.45 (s, 1H), 1.33 (d, J = 7.5 Hz,

1.5H), 1.275 (d, J = 7.5 Hz, 1.5H).

C21H19N2O4F5:

Molecular weight = 458.39;

Mass spectroscopy: (MH ⁺ ) 459.

Example 184

Synthesis of methyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetate

-376• ···· ·* ···· • · ·· ·· • · · · · • · · ·

Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) methyl-2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetate (prepared from N-Boc-2amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetic acid [CAS 95361-97-0] using General Procedure G above and removing Boc according to the procedure described in Example D3 above), the title compound was prepared as a solid. The product was purified by trituration in Et ₂ O/hexanes.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 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).

C ₂₂ H ₂ 4N ₂ O 2 sF ₂ S:

Molecular weight = 450;

Mass spectroscopy: (MH ⁺ ) 450.

Example 185

Synthesis of methyl N-[N-(3,5-difluorophenylacetye-L-alaninyl]-2amino-2-(thieno[2,3-b]thiophen-2-yl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl 2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetate (prepared in Example D4 above), the title compound was prepared as a solid. Product

• ·

-377• · ··· was purified by trituration in Et ₂ O/hexanes.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.35 (d, J = 7.5 Hz, 1H), 7.2-7.0 (m,

3H), 6.9-6.69 (m, 3H), 6.13-6.0 (m, IH), 5.8 (dd, IH), 4.634.5 (m, IH), 3.8 (s, 3H), 3.58 (s, IH), 3.469 (IH), 1.4 (dd,

3H).

C20H18N2O4F2S2:

Molecular weight = 452;

Mass spectroscopy: (MH ⁺ ) 452.

Example 186

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(2-methylthiazol-4-yl)acetate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl 2-amino-2-(2-methylthiazol-4-yl)acetate (which was prepared from N-Boc-2-amino-2-(2-methylthiazol-4-yl)acetic acid [CAS 105381-90-6] following general procedure H above), the title compound was prepared as a solid. The product was purified by trituration in Et ₂ O/hexanes.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.2-6.66 (pr + NH, 5H), 5.69-5.6 (m, IH), 4.8-4.69 (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).

Ci ₈ Hi ₉ N ₃ O4F ₂ S:

Molecular weight = 411;

Mass spectroscopy: (MH ⁺ ) 411.

• ·

Example 187

Synthesis of methyl-(3S,4S)-Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-4-amino-3-hydroxy-5-phenylpentanoate

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in 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 thin layer chromatography (R _f = 0.2 in 95:5 CHCl 3 /MeOH) and the product was purified by flash column chromatography using 95:5 CHCl 3 /MeOH as the eluent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 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 3, 51 (m, 3H) , 2.72 (m, 2H), 2.31

(m, 2H), 1.19 (m, 2H).

Optical rotation: [α] ₂ 3 = -66° (c 1, MeOH).

C23H26N2O5F2:

Molecular weight = 448;

Mass spectroscopy: (MH ⁺ ) 449.

Example 188

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-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 equivalents) of 4-hexenoic acid (commercially available from Lancaster, Catalog #252-427-6) and 13.9 mL (10.1 • · φ · · • · · · · _ 7 y Q _· · · ·

Λ 4 < · · · · φ · ··· g, 99.7 mmol, 1.33 equiv) of triethylamine in 150 mL of anhydrous THF, cooled to -78 °C under dry N ₂ , was added 10.71 mL (10.49 g, 87.0 mmol, 1.15 equiv) of pivaloyl chloride (Aldrich). The mixture was warmed to 0 °C for 60 min and then cooled again to -78 °C. A solution of 13.4 g (75.6 mmol, 1.00 equivalents) of (S)-(-)-(phenylmethyl)-2-oxazolidone (Aldrich) and 22 mg of triphenylmethane (indicator) in 150 mL of anhydrous THF, stirred at -30 °C to -45 °C under N ₂ , was treated dropwise with n-butyllithium (approx.

2.5

M in (Aldrich) until the orange color persisted (approximately 30 mL). The resulting solution was cooled to 78 °C and then the above stirred mixture containing the stirred anhydride was added by rapid cannulation. The residual lithiated oxazolidone was rinsed in two 10 mL portions of anhydrous THF and the resulting mixture was stirred at -78 °C for 1.5 h and then at 0 °C for 1 h. The mixture was partitioned between CH ₂ Cl ₂ and phosphate buffer pH 7. The CH 2 Cl 2 phase was washed with saturated aqueous NaHCO ₃ , followed by half-saturated aqueous NaCl, dried (MgSO ₄ ), and evaporated in vacuo. The residual cream-colored solid (22.4 g) was chromatographed (Vaters Prep 2000, 5.0 cm x 25 cm 10 μ Kromasil KR60-10SIL-5025 column) in two batches, eluting with 85:15 hexanes/EtOAc. The chromatographed product was recrystallized from hexane to afford 14.34 g (first batch, 69%) of the title compound as fine white needles.

³ H NMR (300 MHz, CDCl ₃ ) : δ 7.37-7.20 (m, 5H, -C ₆ H ₅ ), 5.605.43(m, 2H, CH=CHCH ₃ ), 4.71-4.63(m, IH, NCH(phenyl)CH ₂ O),

4.23-4.14(m, 2H, NCH (phenyl) (CH ₂₀ ) , 3.295(dd, J = 13.3, 3.3

Hz, 1H, CHHC ₆ H ₅ ), 3.11-2.90 (m, 2H, CH ₂ C = O), 2.758 (dd, J = hexanes) (required ·· ····

I « · » · · · ·

13.3, 9.6 Hz, IH, CHHC ₆ H ₅ ), 2.42-2.34 (m, 2H, CH = CHCH ₂ ) ,

1.67-1.65 (m, 2H, CH=CHCH ₃ ).

Step B. Synthesis of (4S)-3-[(S)-2-azidohex-4-enoyl]-4(phenylmethyl)-2-oxazolidinone

A solution of 5.47 g (20.0 mmol, 1.00 equiv) of the product from Step A above in 60 mL of anhydrous THF, stirred at -78 °C under dry N ₂ , was added by rapid cannulation to a stirred, cooled (-78 °C) solution of 43.6 mL (22.0 mmol, 1.10 equiv) of potassium hexamethyldisilazide (0.505 M in toluene) (Aldrich) and 60 mL of anhydrous THF. The residual imide solution was rinsed with two 5 mL portions of anhydrous 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 N ₂ , was added and cooled (-78 °C) a solution of 7.43 g (24.0 mmol, 1.2 equiv.) of trisyl azide (prepared as described in RE Harmon et al., J. Org. Chem., 1973, 38, 1116) in 60 mL of anhydrous THF by rapid cannulation. (Note: the reaction exothermed to -68 °C during the addition). After 1-2 minutes, 4.24 mL (4.459, 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 minutes and then allowed to warm to 25 °C with stirring overnight. The mixture was partitioned between CH ₂ Cl ₂ and pH 7 phosphate buffer. The aqueous phase was extracted with CH ₂ Cl ₂ (3x) and the organic extracts were combined, washed with dilute aqueous NaHCO ₃ , dried (MgSO ₄ ) and evaporated in vacuo. The residual oil (9.55 g) was chromatographed (Vaters Prep 2000, 5.0 cm x 25 cm 10 μ Kromasil KR60-10SIL-5025 column), eluting with a 3 L linear gradient of 30:70 to 80:20 CH ₂ Cl ₂ /hexanes. After rechromatography of the combined fractions (2x), a total of 5.27 g (84% yield) of the title compound (faster elution, major diastereomer) was isolated as a colorless, viscous oil.

^X H NMR (300 MHz; CDCl ₃ ) : δ 7.38-7.20 (m, 5H, -C ₆ H ₅ ), 5.73-5.62 (m, IH, CH = CHCH ₃ ), 5.52-5.41 (m, IH, CH = CHCH ₃ ), 5.011 (dd, J = 8.3, 5.5 Hz, IH, CH(N ₃ )C = 0), 4.71-4.63 (m, 1H,

NCH (phenyl) CH ₂ O) , 4.236 (d, J = 5.1 Hz, 2H, NCH(phenyl)CH ₂ O) , 3.338 (dd, J = 13.4, 3.3 Hz, IH, CHHC _h5 ) , 2.827 (dd, J = 13.4, 9.5 Hz, IH, CHHC ₆ H ₅ ) , 2.64-2.46 (m, 2Η, CH ₂ CH = CHCH ₃ ), 1.694 (dd, J = 6.4, 1.1 Hz, 3H, CH = CHCH ₃ ).

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 240 mL of THF and 80 mL of deionized water, stirred at 0 °C under N ₂ , was treated with 762 mg (31.8 mmol, 2.00 equiv) of LiOH (anhydrous powder). After stirring at 0 °C for 30 min, 100 mL of 0.5 N aqueous NaHCO ₃ was added and the THF was removed by rotary evaporation in vacuo. The residue was diluted to 400-500 mL with water and extracted with 5 portions of CH ₂ Cl ₂ . The aqueous phase was acidified to pH 1-2 by careful addition of 5 N HCl and then extracted with 4 portions of EtOAc. The EtOAc extracts were combined, dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 2.45 g (99%) of the title compound as a light amber oil.

^x H-nmr (300 MHz, CDC1 ₃ ) : δ 11.38 (br s, IH, CO ₂ H) , 5.73-5.62 (m, IH, CH ₃ CH - CH), 5.48-5.38 (m, IH, CH = CHCH ₂ ), 3.928 (dd, J = 7.8, 5.4 Hz, IH, CH(N ₃ )CO _2H ), 2.66-2.47(m, 2H, CH = CHCH ₂ ), 1.703 (dd, J = 6.41 1.1 Hz, 3H, CH ₃ ).

Step D. Methyl-N-[N-tert.-butoxycarbonyl-L-alaninyl]-(S)-2• · · ·

3»S 2 rt aminohex-4-enoate

A solution of 504.7 mg (3.25 mmol) of the product from Step C above in diethyl ether, cooled to 0 °C, was treated dropwise with ethereal diazomethane (prepared by the method described by LF Fieser et al., "Reagents for Organic Synthesis, Vol. 1, p. 191, Wiley & Sons (1961)) until a yellow color persisted. Excess diazomethane was removed by N ₂ drift and the ether was evaporated under a stream of N ₂ . The residual oil was dissolved in 10 mL of anhydrous methanol. The solution was cooled to 0 °C under an atmosphere of dry N ₂ and 1.24 g (6.54 mmol, 2.0 equivalents) of anhydrous SnCl ₂ was added. The mixture was stirred at a temperature not exceeding 25 °C for 4 hours and the solvent was evaporated in vacuo and thus a solid tin-amine complex was obtained.

A solution of 1.23 g (6.50 mmol, 2.00 equiv) of N-Boc-L-alanine (Sigma) 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 N ₂ , was treated dropwise with 0.861 mL (0.907 g, 6.50 mmol, 2.00 equiv) of isobutyl chloroformate (Aldrich). After stirring at -15 to -20 °C for 20 min, the resulting mixture containing the stirred anhydride was added by cannulation to the solid tin-amine complex (see above). The residual stirred anhydride was rinsed with 7 mL of THF and 1.1 g (13.1 mmol, 4.0 equiv) of powdered NaHCO ₃ and 5 mL of H ₂ O were added. The mixture was stirred at 0 °C for 5 h. Another 1.1 g (13.1 mmol, 4.0 equiv) of powdered NaHCO ₃ and 5 mL of H ₂ O were added and the mixture was stirred at 20 °C for 1.5 h. The mixture

A A AAA • · · • · A A A

A A A

A AAA

AA

3&3• ·

AND

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 NaHCO ₃ (the aqueous phase was back-extracted with 3 portions of EtOAc), followed by pH 4-5 phosphate buffer (the aqueous phase was back-extracted with 3 portions of EtOAc). The organic phase was dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residual straw-colored oil (1.21 g) was chromatographed (Vaters Prep 2000, 5.0 cm x 25 cm 10 μ Kromasil KR60-10SIL-5025 column), eluting with a 3 L linear gradient of 80:20 to 40:60 hexane/EtOAc to afford 0.9088 g (89%) of the title compound as a white solid. Thin layer chromatography R _f = 0.25 [silica, hexane/EtOAc 6:4)];

¹ H-nmr (300 MHz, CDCl ₃ ) δ 6.61 (d, J = 7.6 Hz, 1H, NH) , 5.605.48(m, 1H, CH = CHCH ₃ ) , 5.33-5.23 (m, 1H, CH = CHCH ₃ ) , 5.08 (d, J = 7.3 Hz, 1H, NH) , 4.591 (dt, J _d = 7.8 Hz, J _t = 5.7 Hz, 1H, HNCH(CH ₂ CH = CHCH ₃ ) ) , 4.19 (br m, 1H, HNCH(CH ₃ ), 3.74(s, 3H, OCH ₃ ) , 2.56-2.39 (sym m, 2H, CH ₂ CH = CHCH ₃ ), 1.658 (dd, J = 6.4, 1.2 Hz, 3H, CH ₂ CH = CHCH ₃ ), 1.454 (s, 9H, OC(CH ₃ ) ₃ ), 1.358 (d, J = 7.1 Hz, 3H, HNCH(CH ₃ )).

Step E. Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-(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 CH ₂ Cl ₂ was cooled to 0 °C under dry N ₂ and 5 mL of trifluoroacetic acid was added via syringe at a temperature not exceeding 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 a rotary evaporator. The addition of toluene and evaporation of the solvent were repeated. The residue was dissolved in 20 mL of CH ₂ Cl ₂ and the solution was cooled to • ·

temperature 0 °C under an atmosphere of dry N ₂ . To this mixture was added 1.35 mL (1.00 g, 7.74 mmol, 3.0 equiv.) of ethyldiisopropylamine (Aldrich), followed by the dropwise addition at a temperature not exceeding 6 °C of 0.728 mL (0.938 g, 5.16 mmol, 2.0 equiv.) of 3,5-difluorophenylacetyl chloride (which was prepared from 3,5-difluorophenylacetic acid (Aldrich) according to general procedure H'). The resulting solution was stirred at 0 °C for 2 h. Excess saturated aqueous NaHCO 3 was added and the biphasic mixture was stirred in an ice bath for 30 min. The mixture was diluted with CH2Cl2 and washed successively with aqueous _NaHCO3 / _Na2CO3 (pH 10), 1N aqueous _NaHSO4 and saturated aqueous NaCl. _{The CH2Cl2} solution was dried ( _Na2SO4 ) and evaporated in vacuo to give 1.17 g of a yellow solid. This was recrystallized from EtOAc to give 602 mg (63%) of the title compound as a white, free-flowing solid. The material was determined by 300 MHz ^X H NMR to be a 92:8 mixture of E and Z isomers.

The NMR data were as follows:

^x H-nmr (300 MHz, CDCl ₃ ) : δ = 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) , 4.58-4.45 (m, 2H) 3.745 (s, 3H) , 3.528 (s, 2H) , 2.457 (apparent t, J = 6.4 Hz, 2H), 1.650 (dd, J = 6.51 1.3Hz, 3H), 1.58 (dm, J = 6.5 Hz, 0.08H), 1.375 (d, J = 7.0 Hz, 3H).

IR (CHCI3) 3421, 1742, 1667, 1626, 1597, 1503 and 1120 cm* ¹ Elemental analysis for Ci8H ₂₂ F ₂ N2O ₄ :

C, 58.69; H, 6.02; N, 7.60.

Found: C, 58.83; H, 5.89; N, 7.67.

C18H22F2N2O5:

Molecular weight = 368;

Mass spectroscopy: (MH ⁺ ) 368.

• · · · · · • · · « • · <

·· ...

I · * > · ·

... I

Example 189

Synthesis of Ν-[N-(cyclopropylacetyl)-Lalaninyl]-L-phenylglycine tert-butyl ester

Following General Procedure U and using cyclopropylacetic acid (Lancaster) and N-(L-alaninyl)-L-phenylglycine tert-butyl ester (General Procedure CJ with Zalanin (Bach) and phenylglycine tert-butyl (Novabio) and then General Procedure 0), the title compound was prepared as a solid (mp = 105-107 °C).

The reaction was monitored by thin layer chromatography (R _f = 0.33 in 1:1 EtOAc/hexane, 0.13 in 5% MeOH/DCM).

The NMR data were as follows:

^-nmr (CDCl ₃ ): δ = 0.15 (m, 2H), 0.56 (m, 2H), 0.91 (m, 1H), 1.38 (m, 12H), 2.09 (d, J = 7.1 Hz, 2H), 4.62 (m, 1H), 5.39 (d, J = 7.2 Hz, 1H). 6.52 (d, J = 7.2 HZ, IH), 7.31 (m, 6H). ¹³ C-nmr (CDCl ₃ ): δ = 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:

Molecular weight = 360.46;

Mass spectroscopy: (MH ⁺ ) 361.

Example 190

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-(S)-2-amino-2-(4-phenylphenyl)acetamide

Following general procedure AB and using 3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and 4-biphenylcarboxaldehyde (Aldrich), the title compound was prepared as a solid (temperature ·· ···· • *·

9 · · • · · • · · · • 4 4 4

4 9 4

499 4 4 9

9 • 4 4 9 mp = 266-267 °C). The product was purified by recrystallization from EtOAc and/or EtOAc/hexanes.

The NMR data were as follows:

‘H- nmr (DMSO- _d6 ): δ = 8.42 (d, IH, J = 7 Hz) , 8.31 (d, IH, J = = 7 Hz), 7.91 (with, 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 (with, IH) , 1,2 (doublet at the top

singlet, 12H).

C29H31N3O3F2:

Molecular weight = 508;

Mass spectroscopy: (MH ⁺ ) 508.4.

Example 191

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-(S)2-aminobutanoyl]-L-phenylglycine tert-butyl ester

Following general procedure D and using 3,5-difluorophenylacetic acid (Aldrich) and N[(S)-2-aminobutanoyl]-L-phenylglycine tert-butyl ester (prepared in Example D13 above), the title compound was prepared as a solid (mp = 138.7-140.0 °C). The reaction was monitored by thin layer chromatography (R _f = 0.24 in 2/1 hexanes:EtOAc) and the product was purified by flash chromatography and HPLC.

The NMR data were as follows:

'H-nmr (DMSO-d ₆ , 250 MHz): δ = 8.66 (d, J = 6.75 Hertz, IH) , 8, 30 (d, J = s 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 = 7.881 5.50 Hertz, IH) , 3.53 (AB _q , J _AB = 14.05 1 Hz, AV _ab = = 7.75 Hz, 2H), 1.85- -1.48 (m, 2H), 1.34 (s, 9H), 0, 88 (t, J = 7.38 Hz, 3H).

• 9 9·9 9 • 9

-3.37th..

• 9 ··

I · · ♦

I 9 9 ·

9·· 99·

9 • 9 9 9

Optical rotation: [α] ₂₀ = 21.8° (c 1.0, MeOH). C24H28N2O4F2:

Molecular weight = 446.50;

Mass spectroscopy: (MH ⁺ , minus CO ₂ -tBu) 345.2.

Example 192

Synthesis of tert-butyl ester of Ν-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine

Following general procedure D and using 3,5-difluorophenylacetic acid (Aldrich) and N(L-valinyl)-L-phenylglycine tert-butyl ester (prepared in Example D14 above), the title compound was prepared as a solid (mp = 170.5-171.8 °C). The reaction was monitored by thin layer chromatography (R _f - 0.39 in 2: 1 hexanes/EtOAc) and the product was purified by flash chromatography and HPLC.

The NMR data were as follows:

¹ H-nmr (DMSO-d 3 , 2 50 MHz) : δ = 8.71 (d, J = 6.75 Hz, IH) , 8.22 (d, J = 9.26 Hz, 1H) , 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 _q , J _AB = 13.88 Hz, Δν _AB = 21.56 Hz, 2H), 2.10-1.95 (m, 1H), 1.34 (s, 9H), 0.88 (d, J = ^: 6.75 Hz, 3H) , 0.86 (d, J = 6, 50Hz, 3H) . Optical rotation: [a] ₂ o ⁼ 20 .8° (c 1.0, MeOH ) ·

C25H30N2O4F2:

Molecular weight = 460.53;

Mass spectroscopy: (MH ⁺ , minus CO2~tBu) 359.2.

Example 193

I · · ♦ · • · • · · ·

9

-3.38τ:..

··

9 9

9 9

999 999 • 9 ··

Synthesis of Ν-[Ν-(3,5-difluorophenylacetyl)-L-methioninyl-L-phenylglycine methyl ester

Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and N-(L-methioninyl)-L-phenylglycine methyl ester hydrochloride (which was prepared from N-BOC-L-methionine (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) following General Procedure E followed by removal of the BOC group following General Procedure P), the title compound was prepared as a solid (mp = 189.3 °C). The reaction was monitored by thin layer chromatography (R _f = 0.53 in 5:95 MeOH/CH ₂ Cl 2 ) and the product was purified by recrystallization from ethyl acetate/hexanes.

The NMR data were as follows:

¹ H-nmr (DMSO-dg): δ = 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 (m, J = 8.2 Hz, 1H), 3.62 (s, 3H), 3.51 (d, 2H), 2.46 (t, 2H), 2.04 (s, 3H), 1.89 (m, 2H).

¹³ C-nmr (DMSO-dg): δ = 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, 102.6M, 102.340, 93.065, 57.205, 53.063, 42.231, 33.075, 30.221, 15.465.

_{C22H24N2O4F2S : ​}

Molecular weight = 450.51; Mass spectroscopy: (MH ⁺ ) 450.

Example 194

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine methyl ester • ·· 99 9999

9 9 9 9 9 • 999 999

9 9 9 9 9

-US·?»*«· *·· ··· ·· ·· • « · • · · * · · » · · * · • · · *

Following general procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and N-(L-valinyl)-L-phenylglycine methyl ester hydrochloride prepared from N-BOC-L-valine (Sigma) and L-phenylglycine methyl ester (Aldrich) following general procedure E, followed by removal of the BOC group following general procedure P), the compound was prepared from (which was the title hydrochloride as a solid (m.p. = 226.5 °C). The reaction was monitored by thin layer chromatography (Rf = 0.49 in 5:95 MeOH/CH ₂ Cl 2 ) and the product was purified by flash chromatography using MeOH/CH ₂ Cl ₂ as eluent.

The NMR data were as follows:

^x H-nmr ( DMSO-d ₆ ) : δ = 8.84 (d, J = 6.2 Hz, IH), 8.23 (d, J 8.8 Hz, IH), 7.38 (m, , 5H), 7.07 (m, 1H), 6.98 (m, 2 H), 5.3 (d, J = 6.5 Hz, IH) f 4.34 (m, J = 8.9 Hz, IH), 3.55 (m, 5H) 2.01 (m, IH), 0.87 (m , 6H) . ¹³ C-nmr (DMSO- _d6 ): δ = 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, 57,914, 57,262, 52,935, 42,274, 31,728, 19,845, 18,815.

C22H24N2O4F2:

Molecular weight = 418.44; Mass spectroscopy: (MH ⁺ ) 418.1.

Example 195

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-2aminobutanoyl]-L-phenylglycine methyl ester

4444 • 444

-3 9ÍÍ7 «4 • 4

4444

444

44

4 4 4

4 4 4

444 444

4

4 4·

Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and N-(2-aminobutanoyl)-L-phenylglycine methyl ester hydrochloride (which was prepared from N-BOC-L-aminobutyric acid (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) following General Procedure E, followed by removal of the BOC group following General Procedure P), the title compound was prepared as a solid (mp = 215.3 °C). The reaction was monitored by thin layer chromatography (Rf = 0.46 in 5:95 MeOH/CH2Cl2) and the product was purified by recrystallization from ethyl acetate/hexanes.

The NMR data were as follows:

¹ H-nmr (DMSO-dg): δ = 8.83 (d, J = 6.8 Hz, 1H), 8.32 (d, =

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), l.M (m, 2H), 0.88 (t, 3H). ¹³ C-nmr (DMSO-dg) : δ = 171.684, 170.934, 168.984, 164,193, 163,980, 160,295 , 1M.083, 141,059, 140,902, 140,743, 135,857, 128,689 , 128,372, 127,892, 112,387, 112,257, 112,131, 111,999, 102.254, 101.M5, 101.438, 56.351 , 53, 441,

52,212, 41,436, 25,675, 10,067.

C21H22N2O4F2:

Molecular weight = 404.42;

Mass spectroscopy: (MH ⁺ ) 405.1.

Example 196

Synthesis of N-[N-(3,5-difluorophenylacetyl)-Lleucinyl]-L-phenylglycine methyl ester

Following general procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and hydrochloride to··· • · • ··· • · · • ·

• · ttt ···· to ·· ··· _{· « ·· • ·}

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ) : δ = 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, 1H), 3.60 (s, 3H), 3.49 (d, 2H), 1.55 (m, 3H), 0.89 (d, 3H), 0.82 (d, 3H).

¹³ C-nmr (DMSO-d ₆ ): δ = 172.225, 170.899, 168.858, 164.197,

163.984, 1M.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 : ​ ​ ​}

Molecular weight = 432.47;

Mass spectroscopy: (MH ⁺ ) 432.1.

Example 197

Synthesis of N-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-L-phenylglycine methyl ester

Following general procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and N-(L-phenylalaninyl)-L-phenylglycine methyl ester hydrochloride (which was • ·· ·· ···

Ο · · · · · “ J “ · · · ··· • · · · · * • · · · · ··· ···· 94 994

44

4 4

4 4

494 494

4

49 prepared from N-BOC-L-phenylalanine (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich) according to general procedure E, followed by removal of the BOC group according to general procedure P) gave the title compound as a solid (mp = 188.3 °C). The reaction was monitored by thin layer chromatography (R _f = 0.59 in 5:95 MeOH/CH ₂ Cl 2 ) and the product was purified by flash chromatography using MeOH/CH ₂ Cl ₂ as eluent.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 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 Hz, IH), 4.70 (m, J = 8, 5 Hz, IH), 3.63 (s, 3H), 3.40 (m, 2H), 3.08 (m, 1H), 2.76 (m, IH) . ¹³ C-nmr (DMSO- _d6 ): δ = 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, 102,189, 101,782, 101,373, 56,411, 53,461, 52,306, 41,513, : 37,796.

_{C26H24N2O4F2 : ​ ​}

Molecular weight = 466.49; Mass spectroscopy: (MH ⁺ ) 466.

Example 198

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)glycinyl]L-phenylglycine methyl ester

Following general procedure E and difluorophenylacetic acid (Aldrich) of N-(glycinyl)-L-phenylglycine methyl ester prepared from N-BOC-glycine (Aldrich) using 3,5a hydrochloride (which was _a hydrochloride ·· _··· • · · · · · · · · · · · · _··

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.82 (d, J = 7.2 Hz, 1H), 8.39 (t, IH) , 7.37 (m, 5H) , 7.05 (m, 3H) , 5.44 (d, 7.1 Hz, 1H) , 3.83 (d, 2H), 3.62 (s, 3H), 3.53 (s, 2H). ¹³ C-nmr (DMSO-d ₆ ): δ = 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, 56,200, 52, 321,

41,731, 41,464.

C19H18N2O4F2:

Molecular weight = 376.36;

Mass spectroscopy: (MH ⁺ ) 376.0.

Example 199

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine methyl ester

Following general procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and N-(L-phenylglycinyl)-L-phenylglycine methyl ester hydrochloride (which was prepared from N-BOC-L-phenylglycine (Novabiochem) and L-phenylglycine methyl ester hydrochloride (Aldrich) following general procedure AH, followed by removal of the BOC group following general procedure P), the following was prepared:

-3^4·· φφφφ • φ • φφφ φφ φφ • φ φ · • · · · ··· φφφ • · · φ φ φφ φφφ φφ ·· title compound as a solid (mp = 222.8 °C). The reaction was monitored by thin layer chromatography (Rf = 0.61 in 5:95 MeOH/CH ₂ Cl ₂ ) and the product was purified by recrystallization from ethyl acetate.

The NMR data were as follows:

^-nmr (DMSO-d ₆ ): δ = 9.22 (d, J = 6.8 Hz, 1H), 8.85 (d, J = 8.2 Hz, IH) , 7.37 (m, 10H), 7.08 (m, 1H), 6.97 (d, 2H), 5.69 (d, J = 8.2 Hz, IH) , 5.43 (d, J = 6.8 Hz, 1H), 3.61 (d, 2H), 3.55 (s, 3H). ¹³ C-nmr (DMSO-d ₆ ) : δ = 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, 112,082,

102.292, 101.884, 101.475, 56.431, 55.621, 52.203, 41.205. C ₂ 5 H ₂₂ N ₂ O 4 F ₂ :

Molecular weight = 452.46;

Mass spectroscopy: (MH ⁺ ) 452.2.

Example 200

Synthesis of Ν-[N-(phenylacetyl)-L-alaninyl]-L-alanine methyl ester

Following general procedure A and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and L-alanine methyl ester hydrochloride (Aldrich),

the compound from the title was prepared in solid form substances (temperature melting point = 140.5-142 °C). The reaction was monitored thin layer chromatography layer (Rf = 0.17 at 50% EtOAc/hexanes). NMR data were as follows: 3-nmr (CDCl ₃ ): δ = 1.3-1.4 (m, 6H) , 3.55 (s, 2H) , 3.75 (s,

-3*35• · ··

3H), 4.4-4.6 (m, 2Η), 6. 1-6.3 (brd, 1Η), 6.6-6.7 (brd, 1H) 7.2-7.4 (m, 5H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

Ci ₅ H ₂₀ N ₂ O ₄ :

Molecular weight = 292.34;

Mass spectroscopy: (MH ⁺ -) 293.

Example 201

Synthesis of Ν-[N-(phenylacetyl)-L-alaninyl]-Lleucine methyl ester

Following general procedure A and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and L-leucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp = 102.5-105 °C). The reaction was monitored by thin layer chromatography (R _f = 0.25 in 50%

EtOAc/hexanes).

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 0.8-0.95 (m, 6H), 1.3 (d, J = 7 Hz, 3H), 1.4-1.6 (m, 3H), 3.58 (s, 2H), 3.75 (s, 3H), 4.4-4.6 (m, 2H), 6.2 (brd, 1H), 6.7 (brd, 1H), 7.2-7.4 (m, 5H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

_{Ci8H26N2O4 :}

Molecular weight = 334.42;

Mass spectroscopy: (MH ⁺ ) 335.

Example 202

3^- :

• * • · • * · · · · · · ·· ··* • · · • · · · · · · • · · · · ♦ »· ·· ·· • · « · • ·

Synthesis of Ν-[N-(phenylacetyl)-L-alaninyl]-Lysoleucine methyl ester

Following general procedure A and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and L-isoleucine methyl ester hydrochloride (Sigma), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.24 at 50%

EtOAc/hexanes).

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 0.8-0.95 (m, 6H), 1.0-1.2 (m, 1H), 1.ΣΙ.4 (m including 1.3 (d, J = 7 Hz, 4H)), 1.8-1.9 (m, 1H), 3.58 (s, 2H), 3.75 (s, 3H), 4.4-4.6 (m, 2H), 6.2 (brd, 1H), 6.7 (brd, 1H), 7.2-7.4 (m, 5H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

C18H26N2O4:

Molecular weight = 334.42;

Mass spectroscopy: (MH ⁺ ) 335.

Example 203

Synthesis of Ν-[N-(phenylacetyl)-L-alaninyl]-L-proline methyl ester

Following general procedure A and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and L-proline methyl ester hydrochloride (Bachem), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography (R _f = 0.12 in 50% EtOAc/hexanes).

• flfl

3M-' :

• · • · • flfl »·»· • fl flflflfl • flfl • flflflfl fl e · fl • · · ·· ·α· ·« ·· • ·· · • ·· · • «·· ··· • · ·· ··

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 1.33 (d, J = 7 Hz, 3H) , 1.9-2.1 (m, 3H) ,

2.1- 2.25 (m, 1H), 3.5-3.8 (m including 3.58 (s) and 3.75 (s), total 7H), 4-4.4 (m, 1H), 4.7-4.8 (m, 1H), 6.5 (brd, 1H),

7.2-7.4 (m, 5H).

¹³ C-nmr (CDC1 ₃ ): δ = 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:

Molecular weight = 318.38;

Mass spectroscopy: (MH ⁺ ) 319.

Example 204

Synthesis of N-[N-(phenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

Following general procedure A and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and L-phenylalanine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp = 148-149.5 °C). The reaction was monitored by thin layer chromatography (R _f = 0.24 in 50%

EtOAc/hexanes) and the product was not purified.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 1.25 (d, J = 7 Hz, 3H), 3.02 (dd, J = 7, 14Hz, IH), 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).

¹³ C-nmr (CDC1 ₃ ): δ = 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,

0000 • 0

0

-398Φ 0 0 0 0 • 0 0 0 • 0 0

0 0» 0 00 000000 0 0 0 0 0 0 0000000 00 00 00 0·

171.4, 172.2, 172.3.

C21H24N2O4:

Molecular weight = 368.44;

Mass spectroscopy: (MH ⁺ ) 369.

Example 205

Synthesis of Ν-[N-(phenylacetyl)-L-alaninyl]-Ν _ε (tert.-butoxycarbonyl)-L-lysine methyl ester

Following general procedure A and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and N _ε -(tert-butoxycarbonyl)L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp = 119-121 °C). The reaction was monitored by thin layer chromatography (R _f t = 0.46 in 90:10:1 CH ₂ Cl 2 /MeOH/NH ₄ OH).

The NMR data were as follows:

¹ H-nmr (CDCl 3 ): δ = 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,

1H), 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). ¹³ C-nmr (CDC1 ₃ ): δ = 18.6, 22.9, 29, 0, 29.9, 32.0, 40.5, 44.0, 49.4, 52.7, 53.0, 79.8, 127.9, 129.5, 129.8, 135.1,

156.7, 171.6, 172.7, 173.0.

C23H35N3O6:

Molecular weight = 449.55;

Mass spectroscopy: (MH ⁺ ) = 450.

Example 206

Synthesis of Ν-[N-(phenylacetyl)-L-alaninyl]glycine methyl ester

• 0

0 0 000 0 0

0 0 0

Following general procedure A and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and glycine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid (mp = 152-153.5 °C). The reaction was monitored by thin layer chromatography (R _f = 0.10 in 50%

EtOAc/hexanes).

The NMR data were as follows:

^-nmr (CDCl ₃ ) : δ = 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 (br s, IH), 7.2-7.6 (m, 5H).

¹³ C-nmr (CDCl ₃ ): δ = 18.7, 41.6, 43, 9, 49.2, 52, 9, 127.9, 129.5, 129.9, 135.0, 170.6, 171.7, 173.2.

C14H18N2O4:

Molecular weight = 278.31;

Mass spectroscopy: (MH ⁺ ) 279.

Example 207

Synthesis of Ν-[N-(phenylacetyl)-L-alaninyl]-L-valine methyl ester

Following general procedure A and using N(phenylacetyl)-L-alanine (prepared in 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 thin layer chromatography (R _f = 0.33 in 50% EtOAc/hexanes) and the product was not purified.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 0.8-0.9 (overlapping d appearing as t, J = 6 Hz, 6H), 2.52.2 (m, 1H), 3.57 (s, 2H), 3.72 (s, • ·

-400• ··· ···· • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··

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).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

C17H24N2O4:

Molecular weight = 320.39;

Mass spectroscopy: (MH ⁺ ) 321.

Example 208

Synthesis of methyl N-[N-(phenylacetyl)-L-alaninyl]-2-(S)aminobutanoate

Following General Procedure A and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and methyl L-2-aminobutanoate hydrochloride (prepared from L-2-aminobutyric acid (Bachem) following General Procedure H (without extractions)), the title compound was prepared as a solid (mp = 120 °C). The reaction was monitored by thin layer chromatography (Rf = 0.2 in 50% EtOAc/hexanes).

The NMR data were as follows:

^-nmr (CDCl ₃ ) : δ = 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) , 4.44.6 (m, 2H), 6.2 (brd, 1H), 6.75 (brd, 1H), 7.2-7.4 (m, 5H). ¹³ C-nmr (CDCl ₃ ): δ = 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. Ci ₆ H ₂₂ N ₂ O ₄ :

Molecular weight = 306.36;

Mass spectroscopy: (MH ⁺ ) 307.

Example 209 • * • ·

-401• · φ • · · • · · φ · · φ φ • φ φ φ

Synthesis of methyl N-[Ν-(phenylacetyl)-L-alaninyl]-2-(S)aminopentanoate

Following General Procedure A and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and methyl 2-(S)-aminopentanoate hydrochloride (which was prepared from L-2-aminovaleric acid (Bachem) following General Procedure H (without extractions)), the title compound was prepared as a solid (mp = 135-137 °C). The reaction was monitored by thin layer chromatography (Rf = 0.30 in 50% EtOAc/hexanes).

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): δ = 0.87 (t, J = 6 Hz, 3H), 1.2-1.4 (m total sd, 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, 1H), 7.0 (brd, 1H), 7.2-7.4 (m, 5H).

¹³ C-nmr (CDC1 ₃ ): δ = 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. C17H24N2O4:

Molecular weight = 320.39;

Mass spectroscopy: (MH ⁺ ) 321.

Example 210

Synthesis of Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine

Following the general procedure of AF and using Ν-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ethyl ester (prepared in Example 143 above), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.05 in 9:1 CHCl ₃ /MeOH). The NMR data were as follows:

• ·

-402-

^x H-nmr (DMSO-d ₆ ) : δ = 8.41 (d, IH), 8.13 (with, IH), 8.09 (d, IH), 7.91 (d, IH), 7.68 (d, IH) , 7.56 (t, IH) , 4.4 (m, IH) , 4.10 (m, 1H), 3.63 (s, 2H), 2.01 (m, IH), 1.19 (m, 3H), 0.89 (d, 6H) . Optical rotation: [a] ₂₃ = -49° (c 1 , MeOH).

C16H21N3O6:

Molecular weight = 351.3;

Mass spectroscopy: (MH ⁺ ) 352.

Example 211

Synthesis of Ν-[N-(phenylacetyl)-L-alaninyl]-L-Nmethylalanine methyl ester

Following General Procedure A and using N(phenylacetyl)-L-alanine (prepared in Example B1 above) and LN-methylalanine methyl ester hydrochloride (prepared from LN-methylalanine hydrochloride (Bachem) following General Procedure H (without extractions)), the title compound was prepared as an oil. The reaction was monitored by thin layer chromatography (R _f = 0.13 in 50% EtOAc/hexanes) and the product was purified by column chromatography using 60% EtOAc/hexanes as the eluent.

The NMR data were as follows:

^x H-nmr (CDCl3): δ = 1.2-1.6 (m including 1.32 (d, J = 7 Hz,

6H), 2.97 (s (rotomers), 3H), 3.57 (s, 2H), 3.7-3.8 (s (rotomers), 3H), 4.4-5.2 (m, 2H), 6.6 (brd, 1H), 7.2-7.4 (m, 5H).

¹³ C-nmr (CDC1 ₃ ): δ = 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, •403129.45, 129.48, 129.9, 135.2, 170.60, 170.67, 172.19, 172.4, 173.25, 173.31.

C16H22N2O4:

Molecular weight = 306.36;

Mass spectroscopy: (MH ⁺ ) 307.

Example 212

Synthesis of Ν-[N-(isovaleryl)-L-phenylglycinyl]L-alanine iso-butyl ester

Following general procedure C and using N(isovaleryl)-L-phenylglycine (which was prepared from isovaleric acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Aldrich) following general procedure C, followed by hydrolysis following general procedure AF) and L-alanine iso-butyl ester hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and 2-methyl-1-propanol (Aldrich) following general procedure C (with catalytic DMAP), followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 181-186 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 1:1 EtOAc/hexanes as the eluent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 1.31 (d, 3H), 5.59 (d, 1H).

Optical rotation: [α] ₂ o = +19° @ 589 nm (c 1.03, DMSO).

C20H30N2O4:

Molecular weight = 362;

Mass spectroscopy: (MH ⁺ ) 363.

-404Example 213

Synthesis of Ν-[N-(isovaleryl)-L-isoleucinyl]-Lalanine iso-butyl ester

Following general procedure C and using N(isovaleryl)-L-isoleucine (which was prepared from isovaleric acid (Aldrich) and L-isoleucine methyl ester hydrochloride (Aldrich) following general procedure C, followed by hydrolysis following general procedure AF) and L-alanine iso-butyl ester hydrochloride (which was prepared from N-BOC-L-alanine (Sigma) and 2-methyl-1-propanol (Aldrich) following general procedure C (with catalytic DMAP), followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 142-146 °C). The reaction was monitored by thin layer chromatography (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 to give a 1:4 mixture of diastereomers.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ) : δ = 1.26 (d, 3H) , 7.70 (d, 1H) , 7.80 (d,

1H), 8.30 (d, 1H), 8.40 (d, 1H).

C18H34N2O4:

Molecular weight = 342.45;

Mass spectroscopy: (MH ⁺ ) 343.

Example 214

Synthesis of N-cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylglycinamide

-405·· ·· 9··· 9« 9· • · · · · · · 9 • 9 ·999 · 99 9 • · · · 9« ······

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-cyclohexyl-L-phenylglycinamide (which was prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and cyclohexylamine (Aldrich) following general procedure M followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (Rf = 0.5 in 9:1 _CHCl3 /MeOH) and the product was purified by trituration from ethanol.

The NMR data were as follows:

^-nmr (CDCl ₃ ): δ = 8.55 (m, 2H), 8.08 (d, 1H), 7.30 (m, 5H), 7.08 (m, 1H), 6.97 (d, 2H), 5.37 (m, 1H), 3.47 (s, 2H), 1.81.6 (m, 6H) , 1.23-0.98 (m, 7H).

Optical rotation: [α]23 = -32.7° (c 1, MeOH).

C25H29F2N3O3:

Molecular weight = 451;

Mass spectroscopy: (MH ⁺ ) 458.

Example 215

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalanininyl]-L-4-hydroxyproline ethyl ester

Following general procedure F and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-4-hydroxyproline ethyl ester hydrochloride (Pfaltz & Bauer), the title compound was prepared as a foam. The reaction was monitored by thin layer chromatography (Rf - 0.32 in 95:5 CH ₂ Cl ₂ /MeOH) and the product was purified by flash column chromatography.

The NMR data were as follows:

·· ··♦·

-406♦ w ·♦ • · · · ··· * · · * • · · · ··· · · · · • · * · · · · ······ • · · · · · · 'H-nmr (CDC1 ₃ , 250 MHz): δ = 7.31 (d, IH, J = 7.00 Hz), 6.836.64 (m, 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 (with, 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).

C18H23F2N2O5:

Molecular weight = 384.38;

Mass spectroscopy: (MH ⁺ ) 385.1.

Example 216

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalanininyl]-L-lysine methyl ester

Following general procedure Y and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N _ε -(tert-butoxycarbonyl)-L-lysine methyl ester (prepared in Example 43 above), the title compound was prepared as an oil. The title compound was isolated as the trifluoroacetic acid salt (containing about 5% excess trifluoroacetic acid).

The NMR data were as follows:

1H-nmr (CDCl ₃ + 2 drops of CD ₃ OD) : δ = 6.40-6.52 (m, 3H), 4.17 (t, 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).

¹³ C-nmr (CDC1 ₃ + 2 drops of CD ₃ OD): δ = 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.

-407-

• · · ···· ·· ·· • ♦ · · • · · · · · • · · · · · · · · · ·

C21H26F5N3O6:

Molecular weight = 511.4;

Mass spectroscopy: (MH ⁺ ) 512.

Example 217

Synthesis of N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Lglutamide

Following general procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in 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 thin layer chromatography (R _f = 0.77 in 10% MeOH/DCM) and the product was purified by silica gel chromatography.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 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). ¹³ C-nmr (CDCl ₃ ) : δ = 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. C16H20F2N4O4:

Molecular weight = 370;

Mass spectroscopy: (MH ⁺ ) 371.

Example 218

Synthesis of methyl 1-[N-(3,5-difluorophenylacetyl)-Lalaninyl]piperidine-2-carboxylate

Following general procedure A and using N-(3,5-408-

to · » · • to · • · ··· ··· • ·· • · «· • to to·· difluorophenylacetyl)-L-alanine (prepared in 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 thin layer chromatography (R _f = 0.71 in 10% MeOH/DCM) and the product was purified by acid/base washing.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 6, 95 (dd, J = 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 Hertz, 12.6, 5.4, IH) , 4.93 (q, J = 7.0, 6, 9, 7.0 Hz, IH), 3.75 (with, IH), 3.70 (s, 3H) , 3 , 50 (s, 2H), 3.2 (m, 1H), 2.27 (d, J = 3.5 Hz, IH) , 1.5 (m, 5H) , 1.31 (d, J = 5.2 Hz, 3H). ¹³ C-nmr (CDCl ₃ ) : δ = 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.

C18H22F2N2O4:

Molecular weight = 368;

Mass spectroscopy: (MH ⁺ ) 369.

Example 219

Synthesis of N-[(S)-3-hydroxy-6-methylhept-2-yl]-N'-(3,5difluorophenylacetyl)-L-alanine amide

Following the general procedure AA and using N—[(S)—6—methyl-3-oxohept-2-yl]-N'-(3,5-difluorophenylacetyl)-Lalaninamide (prepared in Example 168 above), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.75 in 9:1 CHCl 3 /MeOH) and the product was purified by silica gel chromatography using 99:1 CHCl ₃ /MeOH as eluent λ r\ r\ ··· · · ·

-40 9- · · · · ··· • · · · · ·

solvent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 6.81 (m, 1H), 6.72 (m, 2H), 6.39 (m, 2H), 4.45 (m, 1H), 3.97 (m, 1H), 3.60 (m, 1H), 3.52 (s, 2H), 1.54 (m, 5H), 1.4 (m, 5H), 1.09 (m, 3H), 0.9 (m, 6H).

Optical rotation: [α] 23 = -39° (c 1, MeOH).

C19H28F2N2O3:

Molecular weight = 448;

Mass spectroscopy: (MH ⁺ ) 449.

Example 220

Synthesis of N-[(S)-2-hydroxy-l-phenyleth-l-yl]-Ν'-(3,5-difluorophenylacetyl)-L-alanine amide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and (S)-2-hydroxy-1-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 thin layer chromatography (R _f = 0.5 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 5% MeOH/CHCl ₃ as the eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-dg): δ = 1.24 (d, 3H) , 4.38 (m, 1H) , 4.80 (m,

2H).

Optical rotation: [α] ₂ o = +3.56° @ 589 nm (c 1.10, DMSO). C19H20F2N2O3:

Molecular weight = 362.38;

-410• Φ< ·« ···· «to ·· ·· · · · · * · · · · • · ····· ·»·· • « · · · · · ··· ··· • · 9 9 9 · · ·« · ···· 99 999 99 99

Mass spectroscopy: (MH ⁺ ) 363.

Example 221

Synthesis of Ν-[N-(3,5-difluorophenyl-afluoroacetyl)-L-alanine]-L-phenylglycine tert-butyl ester

Following general procedure M and using 3,5-difluorophenyl-α-fluoroacetic acid (prepared in Example D1 above) and N-(Lalaninyl)-L-phenylglycine tert-butyl ester (prepared using N-BOC-Lalanine (Sigma) and L-phenylglycine tert-butyl ester hydrochloride (Bachem) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared as a clear oil. The reaction was monitored by thin layer chromatography (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.

The NMR data were as follows:

^x H-nmr (CDCl3) :(1:1 mixture of diastereomers) : δ = 1.37 (s, 9H) ,

1.39 (s, 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 (pentet, J = 7.0 Hz,

2H), 5.36 (d, J = 7.1 Hz, IH) , 5.42 (d, J = 7.2 Hz, IH) ,

5.60 (d, J = 4.7 Hz, IH), 5.73 (d, 3 = 4.7 Hz, IH), 6.80 (m,

2H), 6.97 (m, 4H), 7.20-7.33 (m, 12H).

C23H25E3N2O4:

Molecular weight = 450.2;

Mass spectroscopy: (MH ⁺ ) 451.

Example 222 • I» · · » · • fl • ···

Synthesis of N-[(S)-α-hydroxy-α'-phenylisopropyl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide (for example, the compound

-411• flfl • fl · · • » • · ♦ • · • ί fl » * t · • fl ··· • fl flfl • flfl · • · · · fl flflfl flflfl • fl flfl flfl

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and (S)-α-hydroxy-α'-phenylisopropylamine L-phenylalaninol) (Aldrich), the title compound was prepared as a solid. The reaction was monitored by thin layer chromatography (R _f = 0.5 in 9:1 CHCl ₃ /MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl ₃ /MeOH as the eluent.

The NMR data were as follows:

¹ H-nmr (CDCl) : δ = 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, 1H), 3.61 (m, 2H), 3.45 (with , 2H), 2.84 (m, 2H), 1, 32 (d, 3H). Optical rotation: [a] 23 = “60° (c 1, MeOH).

C ₂ oH ₂₂ F ₂ N ₂ 0 ₃ :

Molecular weight = 37 6; Mass spectroscopy: (MH ⁺ ) 377.

Example 223

Synthesis of N-[(1S,2R)-1-hydroxy-1-phenylprop-2-yl]-N'-(3,5difluorophenylacetyl)-L-alanine amide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and (1S,2R)-1-hydroxy-1-phenylprop-2-ylamine hydrochloride (e.g. (1S,2R)-norephedrine hydrochloride) (Aldrich), the title compound was prepared as a solid.

-412·· ·· · · · · · · · · · · · • ··· · · · · · · · · · · _· · · _φ • * · · · · ······ _• ·

as a washout solvent. NMR data was following: ¹ H-nmr (CDCl ₃ ) : δ = 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 : [a] ₂₃ = -44° (c 1, , MeOH).

C20H22F2N2O3 ·

Molecular weight = 376;

Mass spectroscopy: (MH ⁺ ) 377.

Example 224

Synthesis of N-2-methoxyethyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]glycinamide

Following General Procedure K and using Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine methyl ester (prepared in Example 28 above) and 2-methoxyethylamine (Aldrich), the title compound was prepared as a solid (mp = 148-151 °C). The reaction was monitored by thin layer chromatography (R _f = 0.53 in 10% MeOH/DCM + 1% TEA) and the product was purified by silica gel chromatography.

The NMR data were as follows:

3-nmr (CDCl ₃ ): 0 = 8.2 (m, 1H), 7.1 (m, 1H), 6.6 (m, 8H),

4.7 (m, 1H), 4.0 (m, 1H), 3.6 (m, 2H), 3.39 (s, 2H), 3.2 (m,

4H), 3.1 (s, 3H), 1.17 (d, J = 7.2 Hz, 3H).

¹³ C-nmr (CDCl ₃ ): δ = 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,

-41372.2, 72.1, 59.4, 51.9, 44.0, 43.0, 40.7, 17.9. C16H21F2N3O4:

Molecular weight = 357;

Mass spectroscopy: (MH ⁺ ) 358.

Example 225

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-2-(S) aminocyclohexylacetyl]-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 (which was prepared from N-BOC-L-cyclohexylglycine (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) following general procedure E, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 234.4 °C). The reaction was monitored by thin layer chromatography (Rf = 0.65 in 5:95 MeOH/DCM) and the product was purified by recrystallization from ethyl acetate.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ) : δ = 8.85 (d, J = 6.5 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.37 (s, 5H), 7.07 (m, 1H), 6.97 (d, 2H), 5.36 (d, J = 6.4 Hz, 1H), 4.35 (t, J = 7.7 Hz, 1H), 3.53 (m, 5H), 1.65 (m, 6H), 1.06 (m, 5H).

δ = 171.065, 170.865, 168.953, 164.179,

160,070, 141,210, 141,058, 135,766,

128,004, 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.

C25H28N2O4F2:

C-nmr (DMSO-de) : 163.967, 160.282,

128,657, 128,374,

9

-41499 9 9 9 9 9 9 9 9 9

9 9 9 999 9 9 9 9 • 9 «· 9 99 999999

9 9 9 9 9 9

999 9999 »· ··· ·· ··

Molecular weight = 458.51;

Mass spectroscopy: (MH ⁺ ) 458.1.

Example 226

Synthesis of N-[(IR,2S)-1-hydroxy-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and (1R,2S)-1-hydroxy-1-phenylprop2-ylamine hydrochloride (e.g. (1R,2S)-norephedrine hydrochloride) (Aldrich), the title compound was prepared as a foam. The reaction was monitored by thin layer chromatography (R _f = 0.5 in 9:1 CHCl ₃ /MeOH).

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.35 (m, 5H), 7.75 (m, 3H), 6.57 (d, 1H), 4.47 (d, 1H), 4.26 (m, 1H), 3.48 (s, 2H), 1.32 (d, 3H), 1.01 (d, 3H).

Optical rotation: [α] ₂₃ = -64° (c 1, MeOH).

C ₂ oH ₂₂ F ₂ N ₂ 0 ₃ :

Molecular weight = 376;

Mass spectroscopy: (MH ⁺ ) 377.

Example 227

Synthesis of N - [(IR,2S)-1-hydroxy-1,2-diphenyleth-2-yl]—Ν’—(3,5—difluorophenylacetyl)-L-alanininamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and (1R,2S)-2-amino-1,2-diphenylethanol (Aldrich), the title compound was prepared as a solid.

-4150 0 · · 0 0 0 0 0 0 • 0 · 0 0

0 0000 0 00 0

00 0 00 000 000

0 0 0 0 0 0

000 0000 00 00 00 00 0 Ό substance (melting point = 217-219 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 7% MeOH/CHCl 3 as the eluent, followed by recrystallization from acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 0.76 (d, 3H), 5.43 (d, 1H).

Optical rotation: [α] ₂ o ⁼ -6.9° @ 589 nm (c 1.10, DMSO). C25H24F2N2O3:

Molecular weight = 438.48;

Mass spectroscopy: (MH ⁺ ) 439.

Example 228

Synthesis of N-[(S)-1-hydroxyhex-2-yl]-Ν'-(3,5-difluorophenylacetyl)-L-alanine amide

Following general procedure S and using methyl N-[N(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (prepared in Example 1 above), the title compound was prepared as a solid (mp = 157-158.5 °C). The reaction was monitored by thin layer chromatography (R _f = 0.62 in 10% CH3OH/CH2Cl2).

The NMR data were as follows:

¹ H-nmr (CD ₃ OD): δ = 5.9 (m, 2H), 5.8 (m, 1H), 4.37 (q, 1H),

3.8 (m, 1H), 3.58 (s, 2H), 3.5 (m, 2H), 1.4 (m, 9H), 0.9 (m,

3H).

¹³ C-nmr (CD ₃ OD): δ = 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.

-416-

• β ·

99

9 9 9

9 9 9

999 999

C17H24F2N2O3:

Molecular weight = 342.39;

Mass spectroscopy: (MH ⁺ ) 343.

Example 229

Synthesis of N-[α-hydroxy-α-(4-hydroxyphenyl)isopropyl]-N'-(3,5difluorophenylacetyl)-L-alanine amide

Following general procedure S and using Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester (prepared in Example 15 above), the title compound was prepared as a solid (mp = 179183 °C). The reaction was monitored by thin layer chromatography (Rf = 0.42 in 10% MeOH/DCM) and the product was purified by recrystallization from MeOH/diethyl ether.

The NMR data were as follows:

¹ H-nmr (CDCl3) : δ = 6 .82 (d, J = 8.3 Hertz, 2H), 6.7 (m, 2H), 6.62 (t , J = 9 .11 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, 7 = 7.1, 36.0, 7.1 Hertz, 3H) . ¹³ C-nmr (CDCI3) : δ = 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.

C20H22E2N2O4:

Molecular weight = 392;

Mass spectroscopy: (MH ⁺ ) = 393.

Example 230

Synthesis of N-2-pyridylmethyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylalaninamide « ·

-417► ·· · · φ φ φφφφ

Following general procedure K and using Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester (prepared in Example 94 above) and 2-(aminomethyl)pyridine (Aldrich), the title compound was prepared.

The NMR data were as follows:

¹ H-nmr (CD ₃ OD) : δ = 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 (with, 2H), 4, ,2-4,35 (m, IH) , 3.6 (s, 2H), 3, 6 (with, 2H), 3, 0-3.25 (m, 2H) , 1.30 ( d, 3H). ¹³ C-nmr (CD3OD) : δ = 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, 113.9, 113, 7, 113.6, 103.9, 103.2, 56.9, 51 ,4, 45, 8, 43.1, 39.0, 18.2.

C26H26F2N4O3:

Molecular weight = 480.52; Mass spectroscopy: (MH ⁺ ) = 481.

Example 231

Synthesis of N-[α-hydroxy-cc'-pyrid-2-ylisopropyl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide

Following general procedure S and using methyl N-[N(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propionate (prepared in Example 19 above), the title compound was prepared as a solid (mp = 225-229 °C). The reaction was monitored by thin layer chromatography (R _f = 0.66 in 10% MeOH/DCM) and the product was purified by recrystallization from a mixture of

MeOH/diethyl ether.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 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, 1H), 3.4 (m, IH), 3.33 (with, 2H) ,

3.3 (m, 2H), 1.06 (d, J = 7.0 Hz, 3H).

¹³ C-nmr (CDC1 ₃ ): δ = 172.754, 160.222, 150.134, 139, 137,

126.198, 123.6801 113.936, 113.M2, 103.578, 64.854, 53.689,

51,191, 43,304, 40,394, 18,769.

C19H21F2N3O3:

Molecular weight = 377;

Mass spectroscopy: (MH ⁺ ) 378.

Example 232

Synthesis of N-[α-hydroxy-α'-pyrid-4-ylisopropyl]-Ν' -(3,5-difluorophenylacetyl)-L-alanine amide

Following general procedure S and using methyl N-[N(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-pyridyl)propionate (prepared in Example 23 above), the title compound was prepared as a solid (mp = 189-193 °C). The reaction was monitored by thin layer chromatography (R _f = 0.47 in 10% MeOH/DCM) and the product was purified by silica gel chromatography.

The NMR data were as follows:

^x H-nmr (CDCl3) : δ = 8.18 (d, J = 5.6 Hertz, 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 ) · ¹³ C-nmr (CDCl3) : δ = 175.8 , 150.4, 150 ,2, 126.8, 113.9, 113.6, 103.6, 103.5, 72.0, 59.3, 5 5.2, 51.6, 42, 9, 40 ₈ ,

-419 ·· ·· » · · « · · ι

38.3, 17.9.

C19H21F2N3O3 '·

Molecular weight = 377;

Mass spectroscopy: (MH ⁺ ) 378.

Example 233

Synthesis of N-[(S)-1-hydroxy-4-methylpent-2-yl]-Ν'-(3,5-difluorophenylacetyl)-L-alanine amide

Isomer A:

Following general procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and (S)-1-hydroxy-4-methylpent-2-ylamine (leucinol) (Bachem), the title compound was prepared as a solid (mp = 141-151 °C). The reaction was monitored by thin layer chromatography (Rf = 0.5 in 5% MeOH/methylene chloride) and the product was purified by recrystallization from EtOAc/hexanes.

The NMR data were as follows:

^x H-nmr (CD ₃ OD) : δ = 8.15 (s IH) , 7.5 (t, J = 8 Hz, IH), 6.806.55 (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, 1H), 1.1 (m, 5H), 0.7 (m, 6H).

¹³ C-nmr (CD 3 OD) : δ = 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.

C17H24N2O3F2:

Molecular weight = 342.19;

Mass spectroscopy: (MH ⁺ ) 343.

• And ····

-420·· ··· ··· • A

Isomer B:

Following general procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and (S)-1-hydroxy-4-methylpent-2-ylamine (leucinol) (Aldrich), the title compound was prepared as a solid (mp = 151-153 °C). The reaction was monitored by thin layer chromatography (R _f = 0.8 in 10% MeOH/DCM) and the product was purified by recrystallization, followed by flash column chromatography, followed by preparative thin layer chromatography using 10% MeOH/DCM as the eluent.

The NMR data were as follows:

^x H-nmr (CD ₃ OD) : δ = 8.15 (s 1H) , 7.5 (t, J = 8 Hz, 1H) , 6.806.55 (m, 3H), 4.15 (m, J = 3.5 Hz, 1H) , 3.7 (m, 1H) , 3.35 (s, 2H), 3.22 (t, J = 3 Hz, 2H) , 1.4 (m, 1H) , 1.1(m, 5H) , 0.7 (m, 6H).

¹³ C-nmr (CD ₃ OD): δ = 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.

_{Ci7H24N2O3F2 : ​ ​}

Molecular weight = 342.19;

Mass spectroscopy: (MH+) 342.

Example 234

Synthesis of N-[l-methoxyprop-2-yl]-Ν'-(3,5-difluorophenylacetyl)L-alanine amide

Following general procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and 2-amino-1-methoxypropane (Aldrich),

-42199 9999

9 9 99 9 »

» · » 9

9 9 99

9

9 prepared the title compound as a solid (mp = 152 °C). The reaction was monitored by thin layer chromatography (R _f = 0.45 in 5% MeOH/DCM) and the product was purified by recrystallization from methanol/water.

The NMR data were as follows:

^x H-nmr (CDCl3) : δ = 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) . ¹³ C-nmr (CDCl3) : δ = 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, 19, 4, 19, 38, 18.9, 18.0. C17H20N2O3F2:

Molecular weight = 314.14;

Mass spectroscopy: (MH ⁺ ) 315.

Example 235

Synthesis of Ν-[1-hydroxy-3-methylbut-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide

Following general procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and valinol (Bachem), the title compound was prepared as a solid (mp = 176-179 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 5% MeOH/DCM) and the product was purified by recrystallization from EtOAc/hexanes.

The NMR data were as follows:

¹ H-nmr (CD ₃ OD) : δ = 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).

• fl fl ·

-422• fl flflflfl • · fl • fl flfl • flfl · • flfl fl • flfl flflfl fl · ¹³ C-nmr (acetone-dg) : δ = 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.

C16H22N2O3F2 ·

Molecular weight = 329.19;

Mass spectroscopy: (MH ⁺ ) 329.

Example 236

Synthesis of methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino-2-(6-aminopyrid-2-yl)acetate

Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl 2-amino-2-(6-aminopyrid-2-yl)acetate (which was 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.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.65-6.5 (m, 6H), 6.4 (d, J = 8.19 Hertz, IH) , 5.49-5.33 (m, IH) , 4.8-4.5 (m, 2H) , 3.7 (with, 3H) , 3, 6 (s, 1H), 3.5 (s, 1H), 2.06 (bs, 2H) , 1.44 (d, J = 7.06 Hertz,

1.5 Η), 1.35 (d, 7.06 Hz, 1.5H). C19H20N4O4F2:

Molecular weight = 406.39; Mass spectroscopy: (MH ⁺ ) 406.3.

Example 237 • ····

-423• ft ftftftft • · • ftftft • ft ftft ft ftft · ft ftft ft ··· ftftft ftftft

Synthesis of N-[l-hydroxyprop-2-yl]-Ν'-(3,5-difluorophenylacetyl)L-alanine amide

Following general procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and alanol (Bachem), the title compound was prepared as a solid (mp = 158-163 °C). The reaction was monitored by thin layer chromatography (R _f = 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.

The NMR data were as follows:

^x H-nmr (CD3OD) : δ = 8.2 (m, IH), 7.6 (m, IH) , 4.1 (m, J = 7 Hz, IH) , 3.7 (m, J = 5 Hz, IH), 3.35 (with, 2H) , 3.25 (m, 2H), 1.15 (d , J = 7 Hz, 3H), 0.9 (d, J = 7 Hertz, 3H) . ¹³ C-nmr (CD3OD) : δ = 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, 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.

C14H18N2O3F2:

Molecular weight = 300;

Mass spectroscopy: (MH ⁺ ) 301.

Example 238

Synthesis of N-[(S)-2-methoxy-l-phenyleth-l-yl]—Ν'—(3,5- difluorophenylacetyl)-L-alanininamide

Following general procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and N-[(S)-2-methoxy-1-phenyleth-1-yl]-L-alanine amide (which was prepared from N-BOC-L«·

-424·· ···· • · • ··· ·« ·· • · * · • · · * • 4 4 99 · • ·

44 alanine (Sigma) and methyl ether (S)-phenylglycinol (prepared in Example D15 above) following general procedure C, followed by removal of the BOC group following general procedure P) gave the title compound as a solid (mp = 180-182 °C). The reaction was monitored by thin layer chromatography (R _f = 0.4 in 10% MeOH/CHCl 3 ) and the product was purified by silica gel chromatography using 5% MeOH/CHCl ₃ as eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.

The NMR data were as follows:

1H-nmr (DMSO-d ₆ ): δ = 1.22 (d, 3H), 3.23 (s, 3H).

Optical rotation: [rot] 20 = +12.3° @ 589 nm (c 1.04, DMSO). C20H22F2N2O3:

Molecular weight = 376.41;

Mass spectroscopy: (MH ⁺ ) 377.

Example 239

Synthesis of N-[(S)-1-methoxy-2-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide

Following general procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-phenylalaninol methyl ester hydrochloride (Fluka), the title compound was prepared as a solid. The product was purified by recrystallization from MeOH/EtOAc.

The NMR data were as follows:

1H-nmr (CDCl ₃ ): δ = 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, 1H), 4.35-4.5 (m, 1H) , 6.3-6.5 (m, 2H) , 6.6-6.9

-4259 9 9 9 9

9 9 9

9999 99 99

9 9 (m, 3H), 7.1-7.35 (m, 5H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

Example 240

Synthesis of N-[(S)-1-acetoxyhex-2-yl]—Ν'—(3,5-difluorophenylacetyl)-L-alanine amide

Following General Procedure V and using N-[(S)-1-hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide (prepared in Example 228 above), the title compound was prepared as a solid (mp = 144-145 °C). The reaction was monitored by thin layer chromatography (R _f = 0.42 in 10% CH ₃ OH/CH ₂ Cl ₂ ).

The NMR data were as follows:

^-nmr (CD ₃ OD): δ = 6.7 (m, 2H), 6.6 (m, 1H), 4.09 (q, 1H),

3.9-3.7 (m, 3H), 3.35 (s, 2H), 1.79 (s, 3H), 1.4-1.0 (m,

9H), 0.6 (m, 3H).

¹³ C-nmr (CD ₃ OD): δ - 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.

C19H26F2N2O4:

Molecular weight = 384.43;

Mass spectroscopy: (MH ⁺ ) 385.

Example 241

Synthesis of N-[(S)-1-(tert-butylcarbonyloxy)-hex-2-yl]-N'-(3,5difluorophenylacetyl)-L-alaninamide • · · φ ·· ΦΦΦΦ • φ • *··

-426φ φ φ φ φ φ φ φ φ ΦΦΦ ΦΦΦ φ φ φ *·· ΦΦ φφ

Following general procedure W and using N-[(S)-1-hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide (prepared in 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 thin layer chromatography (Rf = 0.43 in 10% CH3OH/CH2Cl2) and the product was purified by preparative thin layer chromatography using 10% CH3OH/CH2Cl2 as the eluent.

The NMR data were as follows:

¹ H-nmr (CD 3 OD) : δ = 7.67 (bd, 1H) , 6.7 (m, 2H) , 6.6 (m, 1H) ,

4.14 (q, 1H), 3.9-3.6 (m, 3H), 3.35 (s, 2H), 1.4-1.0 (m,

9H), 0.98 (s, 9H), 0.6 (m, 3H).

¹³ C-nmr (CD ₃ OD): δ = 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.

C22H32F2N2O4:

Molecular weight = 426.51;

Mass spectroscopy: (MH ⁺ ) 427.5.

Example 242

Synthesis of N-[2-hydroxy-1-(thien-2-yl)ethyl]-N'-{3,5-difluorophenyacetyl)-L-alanine amide

Following general procedure S and using methyl N-[N(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetate (prepared in Example 178 above), the title compound was prepared as a solid (mp = 201-202 °C). The product was purified by trituration with 1:1 hexanes/EtOAc.

·· ····

-427• ·« ···· ··· · · · · • 9 9 9 9 9 9 9 9 9 9 9

9 99 9 99 999999

9 9 9 9 9 9

999 9999 99 999 99 99

The NMR data were as follows: ¹ H-nmr (DMSO-d ₆ ): δ = 8.4-8.25 7.3-6.91 (m, 4H), 5.1-4.85 (m, (m, 2H), 3.51 (s,

IH), 3.50 (s, (m,

IH) , IH) ,

2H), 7.4-7.35 (m, 2H),

4.4-4.3 (m, 1H), 3.7-3.5

1.23-1.19 (overlapping doublets, 3H).

C21H23F2N2O3:

Molecular weight = 368.4; Mass spectroscopy: (MH ⁺ ) 368.

Example 243

Synthesis of N-[(S)-2-hydroxy-2-methyl-1-phenylprop-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and (S)-2-hydroxy-2-methyl-1-phenylprop-1-ylamine (prepared in Example D16 above), the title compound was prepared as a solid. The product was purified by recrystallization from methanol/ethyl acetate.

The NMR data were as follows:

'H-nmr (DMSO-d ₆ ) : δ = 8.32 (d, 1H), 8.11 (d, 1H), 7.20-7.33 (m, 5H), 7.08 (m, 1H), 6.96 (m, 2H), 4.68 (d, 1H), 4.53 (s, 1H), 4.95 (m, 1H), 3.50 (d, 2H), 1.25 (d, 3H), 1.08 (s, 3H), 0.98 (s, 3H).

Optical rotation: [α] 23 = -11° (c 1, MeOH).

C21H24F2N2O3:

Molecular weight - 390.42;

Mass spectroscopy: (MH ⁺ ) 391.

Example 244

Synthesis of tert-butyl ester N-[N-(3,5-difluorophenylacetyl)-L··

4280 0

(thien-2-yl)glycinyl]-L-phenylalanine

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-fluorenylmethoxycarbonyl)-L-(2-thienyl)glycine (prepared as described below) and L-phenylglycine tert-butyl ester hydrochloride following general procedure AH, followed by deprotection using dicyclohexylamine in 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 eluent.

C26H26N2O4F2:

Molecular weight = 500.56;

Mass spectroscopy: (MH ⁺ ) 500.

Preparation of N-(9-fluorenylmethoxycarbonyl)-L-(2thienyl)glycine:

A round bottom flask containing a magnetic stirrer under a nitrogen atmosphere at ambient temperature was charged with water, dioxane, sodium carbonate (2.5 equivalents) and L-α-(2thienyl)glycine (1.0 equivalents) (Sigma). Stirring was started and the suspension was cooled in an ice bath. 9-Flurenylmethyl chloroformate was added portionwise to the reaction mixture and stirring was continued in an ice bath for 4 hours followed by 8 hours at ambient temperature. The reaction mixture was poured into water and extracted with diethyl ether. The aqueous layer was cooled in an ice bath and acidified with vigorous stirring to pH 2. The resulting solid was isolated by vacuum filtration, washed with water (3x) and dried.

-429-* this ·· ··«· »· ·« ·· ··· to · to · • ·· ··« · ·· · this·· ···· ··· • · · · · · »··« ·· ··· ·· ·· under reduced pressure.

Example 245

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinol

Following general procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycinol (which was prepared from N-BOC-L-phenylglycine (Novabiochem) and L-phenylglycinol (Novabiochem) following general procedure AH, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (m.p. =

231.4 °C). The product was purified by crystallization from ethyl acetate. C24H22N2O3F2:

Molecular weight = 424.45;

Mass spectroscopy: (MH ⁺ ) 424.9.

Example 246

Synthesis of Ν-[N-(cyclopropaneacetyl)-L-phenylglycinyl]-Lphenylglycinol

Following general procedure E and using cyclopropaneacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycinol (which was prepared from N-BOC-L-phenylglycine (Novabiochem) and L-phenylglycinol (Novabiochem) following general procedure AH, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (m.p. =

202.5 °C). The product was purified by crystallization from ethyl acetate. C21H24N2O3:

• ·

-430-

Molecular weight = 352.43;

Mass spectroscopy: (MH ⁺ ) 353.2.

Example 247

Synthesis of Ν-[N-(cyclopentaneacetyl)-L-phenylglycinyl]-Lphenylglycinol

Following general procedure E and using cyclopentaneacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycinol (which was prepared from N-BOC-L-phenylglycine (Novabiochem) and L-phenylglycinol (Novabiochem) following general procedure AH, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 201.4 °C). The product was purified by flash chromatography using MeOH/CH ₂ CH ₂ as eluent. C ₂₃ H ₂ 8N ₂ O ₃ :

Molecular weight = 380.49;

Mass spectroscopy: (MH ⁺ ) 381.4.

Example 248

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]D,L-phenylglycinamide

Following the general procedure of AO and using Ν-[N-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycine methyl ester (prepared in Example 99 above), the title compound was prepared as a solid (mp = 285.5-288.5 °C).

_{C24H2iN3O3F2 : ​}

Molecular weight = 437.45;

• · ·· • ·

-431-* • · ·* · · ·

Mass spectroscopy: (MH ⁺ ) 437.1.

Example 249

Synthesis of N-[N-(3,5-difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamide

Following the general procedure of AO and using N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine methyl ester (prepared in 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.

C21H23N3O3F2:

Molecular weight = 403.43;

Mass spectroscopy: (MH ⁺ ) 404.

Example 250

Synthesis of N-[N-(2-thienylacetyl)-L-alaninyl·]-Lphenylglycinamide

The title compound was prepared following the General Procedures described above.

Example 251

Synthesis of N-[N-(n-caproyl)-L-alaninyl]-L-phenylglycinamide

The title compound was prepared following the General Procedures described above.

Example 252

Synthesis of methyl ester N-[N-(3,5-difluorophenylacetyl)-L-432• 0 ·· ···· norleucinyl]-L-phenylglycine

Following general procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycine methyl ester hydrochloride (which was prepared from N-BOC-L-norleucine (Lancaster) and L-phenylglycine methyl ester hydrochloride (Aldrich) following general procedure E, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 188-189.5 °C).

The product was purified by flash chromatography using ethyl acetate/hexanes as eluent.

C23H26N2O4F2:

Molecular weight = 432.47;

Mass spectroscopy: (MH ⁺ ) 432.

Example 253

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-L-phenylglycine methyl ester (which was hydrochloride

Following general procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-norvaline-1-L-phenylglycine methyl ester hydrochloride prepared from N-BOC-L-norvaline (Lancaster) L-phenylglycine methyl ester (Aldrich) following general procedure E, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (m.p. = 204-205 °C).

The product was purified by flash chromatography using ethyl acetate/hexanes as the eluent.

C22H24N2O4 _F2 :

-433-* ·· ···#

Molecular weight =418 44;

Mass spectroscopy: (MH ⁺ ) 418.3.

Example 254

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-L-tert.leucinyl]-L-phenylglycine methyl ester

Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-tert-leucinyl-L-phenylglycine methyl ester hydrochloride (which was prepared from N-BOC-L-tert-leucine (Bachem) and L-phenylglycine methyl ester hydrochloride (Aldrich) following General Procedure E, followed by removal of the BOC group following General Procedure P), the title compound was prepared as a solid (m.p. = 176.4 °C).

The product was purified by flash chromatography using ethyl acetate/hexanes as the eluent.

C23H26N2O4F2:

Molecular weight = 432.47;

Mass spectroscopy: (MH ⁺ ) 432.0.

Example 255

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lysoleucinyl]-L-phenylglycine methyl ester prepared from

Following general procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-isoleucinyl-L-phenylglycine methyl ester hydrochloride

N-BOC-L-isoleucine (Aldrich) and (which was L-phenylglycine methyl ester hydrochloride (Aldrich) by the general procedure • * • to · · · ·

-434• · · procedure E, followed by removal of the BOC-group according to general procedure P), the title compound was prepared as a solid (melting point = 228.8 °C).

The product was purified by flash chromatography using ethyl acetate/hexanes as the eluent.

C23H26N2O4F2:

Molecular weight = 432.46;

Mass spectroscopy: (MH ⁺ ) 433.4.

Example 256

Synthesis of N-[N-(3,5-difluorophenylacetyl)-L-cyclohexylalaninyl]-L-phenylglycine methyl ester

Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-cyclohexylalaninyl-L-phenylglycine methyl ester hydrochloride (which was prepared from N-BOC-L-cyclohexylalanine (Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) following General Procedure E, followed by removal of the BOC group following 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.

C26H30N2O4F2:

Molecular weight = 472.53;

Mass spectroscopy: (MH ⁺ ) 473.2.

Example 257

Synthesis of N-[N-(3,5-difluorophenylacetyl)-(S)-2amino-2-(cyclopropyl)acetyl]-L-phenylglycine methyl ester

-435 Following general procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and methyl ester (S)-2-amino-2-(cyclopropyl)acetyl-L-phenylglycine hydrochloride (which was prepared from N-BOC-(S)-2-amino-2-cyclopropylacetic acid (which was prepared from cyclopropylacetic acid (Lancaster) and (4S)-4-benzyl-2-oxaxolidinone (Aldrich) following the procedure described by Evans et al., J. Am. Chem. Soc., 1990, 112, 40114030 and references cited therein) and methyl ester L-phenylglycine hydrochloride (Aldrich) following general procedure E, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (mp = 225-226.5 °C). The product was purified by flash chromatography using a mixture of MeOH/CHCl ₃ as eluent.

C22H22N2O4F2:

Molecular weight - 416.42;

Mass spectroscopy: (MH ⁺ ) 417.3.

Example 258

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-(S)-2amino-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 hydrochloride (which was prepared from N-BOC-L-thien-3-ylglycine (prepared from L-α-2-thienylglycine (Sigma) following General Procedure M) and L-phenylglycine methyl ester hydrochloride (Aldrich) following General Procedure E,

-436• · ·· fl··· • · • flflfl • · · fl • · followed by removal of the BOC group according to general procedure P) , the title compound was prepared as a solid (melting point = 229.3 °C). The product was purified by crystallization from ethyl acetate/hexanes.

C23H20N2O4SF2:

Molecular weight = 458.49;

Mass spectroscopy: (MH ⁺ ) 458.

Example 259

Synthesis of N-[N-(3,5-difluorophenylacetyl)-(S)-2amino-2-(thien-2-yl)acetyl]-L-phenylglycine methyl ester

Following general procedure AH and using 3,5-difluorophenylacetic acid (Aldrich) and methyl ester L-(S)-2-amino-2-(thien-2-yl)acetyl-L-phenylglycine hydrochloride (which was prepared from N-BOC-L-thien-2-ylglycine (which was prepared from L-α-(thien-2-yl)glycine (Sigma) following general procedure AI) and methyl ester L-phenylglycine hydrochloride (Aldrich) following general procedure E, followed by removal of the BOC group following general procedure P), the title compound was prepared as a solid (m.p. = 230.8 °C).

The product was purified by flash chromatography using MeOH/CH ₂ CH ₂ as eluent.

C23H20N2O4F2S:

Molecular weight - 458.49;

Mass spectroscopy: (MH ⁺ ) 458.

Example 260

Synthesis of methyl ester N-[N-(3,5-difluorophenylacetyl)-L-(4fluorophenyl)glycinyl]-L-phenylglycine φ φφ φφ φφφφ *· ·♦ .-ι-»·· Φ · ·· 9 9 · * — 4 3 / W · · 9 999 9 9 9 · ^Ί _{φΦΦΦΦΦΦΦ}

Φ Φ ΦΦΦ 9 9 ••ΦΦΦΦ ΦΦ ·ΦΦ ·· · ·

Following general procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-(4-fluorophenyl)glycinyl-L-phenylglycine methyl ester hydrochloride (which was prepared from N-Cbz-(4-fluorophenyl)glycine (which was prepared from (4-fluorophenyl)glycine (prepared as described below) by general procedure AK) and L-phenylglycine methyl ester hydrochloride (Aldrich) by general procedure E, followed by silica gel chromatography using 5% ethyl acetate/toluene as eluent and removal of the Cbz group by general procedure M), the title compound was prepared as a solid (mp = 213.1 °C). The product was purified by flash chromatography using ethyl acetate/CHCl ₃ as eluent.

C25H21N2O4E2:

Molecular weight = 470.44;

Mass spectroscopy: (MH ⁺ ) 470.1.

Preparation of (4-fluorophenyl)glycine:

(S)-(-)-4-Benzyl-2-oxazolidinone (15.0 g, 93 mmol) (Aldrich) was dissolved in THE (100 mL). The solution was cooled to -70 °C and the reaction flask was flushed with nitrogen twice. n-Butyllithium (44.6 mL, 2.0 M, 89 mmol) was added to form a solid precipitate which disintegrated upon stirring to form a suspension. 4-Fluorophenylacetyl chloride (16.1 g, 93 mmol) (Aldrich) was added to form a light green solution and stirring was continued for 45 min. The reaction mixture was then stirred at ambient temperature for 1 h. The reaction mixture was then treated with saturated sodium hydrogen sulfate (100 mL) and ethyl acetate (100 mL).

9 9

9 9

999 999 •9 9··· • 99

-438Γ ’ ;

9

9 • 9 9 9 9 9 9 9

9

999 9

9

9 ·

999 99 99

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 give an oil. The oil was crystallized to give 24.4 g of 1-(4-fluorophenylacetyl)-(S)-(-)-4-benzyl-2-oxazolidinone.

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 1-(4fluorophenylacetyl)-(S)-(-)-4-benzyl-2-oxazolidinone (15.0 g, 46 mmol) in THF (100 mL) was added. The resulting mixture was allowed to stir at -70 °C for 1 h and warmed to about -20 °C. The mixture was cooled again to -70 °C and a cold solution (-65 °C) of trasylazide (21.6 g, 70.0 mmol) was added. The mixture was allowed to stir for about 15 minutes 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 which was removed by filtration. The filtrate was concentrated to half and then washed with water, saturated sodium bicarbonate solution and brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give 37.7 g of crude 1-[2-(4-fluorophenyl)-2-azidoacetyl]-(S)-(-)-4-benzyl-2-oxazolidinone.

Crude 1-[2-(4-fluorophenyl)-2-azidoacetyl]-(S)-(-)-4-benzyl2-oxazolidinone (10.0 g, 28.0 mmol) was dissolved in 100 mL THF and 100 mL methanol and trifluoroacetic acid (4.31 mL, 75.3 mmol) were added. Palladium on carbon (10%, 2.0 g) was added and the mixture was hydrogenated in a Paar apparatus at 50 psi overnight at ambient temperature.

-439• · • ··· • 9 ···· ♦ 9 9 • 9 9 9

9 9 9 9 « « • · 9 ·♦ · 9 9 9 9

The reaction mixture was then filtered through a pad of Celite and the solid cake was washed with 100 mL of methanol. The filtrate was concentrated to give the trifluoroacetate salt of 1-[2-(4-fluorophenyl)-2-aminoacetyl]-(S)-(-)-4-benzyl-2-oxazolidinone as a yellowish oil.

To a mixture of THF and deionized water (50 mL/50 mL) was added 1-[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 homogeneous solution was stirred for 2 h at ambient temperature, at which time thin layer chromatography showed complete disappearance of the starting material. The mixture was extracted with dichloromethane (3 x 100 mL) and 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 h and then filtered. The solid was washed with water followed by pentane to give 4-fluorophenylglycine hydrochloride.

Example 261

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-D-(4fluorophenyl)glycinyl]-L-phenylglycine methyl ester

Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and D-(4-fluorophenyl)glycinyl-L-phenylglycine methyl ester hydrochloride (which was prepared from N-Cbz-(4-fluorophenyl)glycine (which was prepared from (4-fluorophenyl)glycine (prepared as in Example 260) following General Procedure AK) and L-phenylglycine methyl ester hydrochloride (Aldrich) following General Procedure E, followed by silica gel chromatography

-440ft ftft ftft ftftftft ·· ·· • ••ft ftftft ftftftft ft ftftft ftftft · ftft ft • · ftft ft ftft ftftft··· • · ftftft ftft • ftft ftftftft ftftft ·· ·· using 5% ethyl acetate/toluene as eluent and removing the Cbz group following general procedure Μ) , the title compound was prepared as a solid (m.p. = 188.0 °C). The product was purified by flash chromatography using ethyl acetate/CHCl ₃ as eluent.

C25H21N2O4F3:

Molecular weight = 470.44;

Mass spectroscopy: (MH ⁺ ) 470.1.

Example 262

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-L-(4methoxyphenyl)glycinyl]-L-phenylglycine methyl ester

Following general procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and methyl ester L-(4-methoxyphenyl)glycinyl-L-phenylglycine hydrochloride (which was prepared from N-Cbz-L-(4-methoxyphenyl)glycine (prepared from (4-methoxyphenyl)glycine (prepared by Bucherer's modification of the Strecker procedure as described in Greenstein et al., "The Chemistry of Amino Acids, Vol. 1, p. 698, Wiley, New York (1961)) following general procedure AK) and methyl ester L-phenylglycine hydrochloride (Aldrich) following general procedure E, followed by removal of the Cbz group following general procedure AJ), the title compound was prepared as a solid (m.p. = 224.6 °C). The product was purified by flash chromatography using MeOH/CHCl ₃ as eluent. washing solvent.

C26H24N2O5F2:

Molecular weight = 482.48;

• ·· ·♦ ··«· ·· ·· • · · · · · · * · · * • · · 9 999 9 9 9 9

9 99 9 99 999999

9 9 9 9 9 9

999 9999 99 999 99 99

Mass spectroscopy: (MH ⁺ ) 482.1.

Example 263

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-butyl ester

Following general procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycine tert-butyl ester (which was prepared from N-Cbz-L-phenylglycine (Novabiochem) and L-phenylglycine tert-butyl ester hydrochloride (Novabiochem) following general procedure AH, followed by removal of the Cbz group following general procedure AJ), the title compound was prepared as a solid (m.p. -185.0 °C). The product was purified by flash chromatography using ethyl acetate/CH ₂ CH ₂ as eluent.

_{C28H28N2C4F2 : ​ ​}

Molecular weight - 494.54;

Mass spectroscopy: (MH ⁺ , minus CO ₂ -t-Bu) 393.

Example 264

Synthesis of Ν-[N-(cyclopropylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-butyl ester

Following general procedure E and using cyclopropylacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycine tert-butyl ester hydrochloride (which was prepared from N-Cbz-L-phenylglycine (Novabiochem) and L-phenylglycine tert-butyl ester hydrochloride (Novabiochem) following general procedure AH, followed by removal of the Cbz group following general procedure AJ),

-442Φ· ···· «φ 44

Φ Φ ΦΦΦΦ

Φ ΦΦΦΦ 4 44 4

4 44 444444

4 4 4 4

4 4 44 4 4 4 4 prepared the title compound as a solid (melting point = 187.5 °C). The product was purified by crystallization from ethyl acetate.

C25H30N2O4:

Molecular weight = 422.53;

Mass spectroscopy: (MH ⁺ ) 423.4.

Example 265

Synthesis of Ν-[N-(cyclopentylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-butyl ester

Following general procedure E and using cyclopropylacetic acid (Aldrich) and L-phenylglycinyl-L-phenylglycine tert-butyl ester hydrochloride (which was prepared from N-Cbz-L-phenylglycine (Novabiochem) and L-phenylglycine tert-butyl ester hydrochloride (Novabiochem) following general procedure AH, followed by removal of the Cbz group following general procedure M), the title compound was prepared as a solid (mp = 190.8 °C). The product was purified by crystallization from ethyl acetate.

C27H34N2O4:

Molecular weight = 450.58;

Mass spectroscopy: (MH ⁺ ) 451.

Example 266

Synthesis of Ν-[N-(t-butylacetyl)-L-alaninyl]-L-phenylglycinamide

The title compound was prepared following the General Procedures described above.

-443• ·· this this·· this this ··· · · · «··· • · ····· ···· • · ·· · ·· ······ ·· ··· ·· this ···· ·· ··· ·· ··

Example 267

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-(5-bromothien-2-yl)glycinamide

Following general procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 5-bromo-2-thiophenecarboxaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine (Aldrich), and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 227-228 °C). The product was purified by recrystallization from ethyl acetate/hexanes.

_{C2iH24N3O3BrS :}

Molecular weight = 515;

Mass spectroscopy: (MH ⁺ ) 515, 415.

Example 268

Synthesis of N-tert-butyl-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D-(5-bromothien-2-yl)glycinamide

Following general procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 5-bromo-2-thiophenecarboxaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine (Aldrich), and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 216-217 °C). The product was purified by recrystallization from ethyl acetate/hexanes.

_{C2iH24N3O3BrS : ​}

Molecular weight = 515;

Mass spectroscopy: (MH ⁺ ) 515, 415.

Example 269

-444·· »··· • · • · · ·

Synthesis of N-tert-butyl-N'-[Ν-(3,5-difluorophenylacetyl)-Lalaninyl]-L-(4-bromothien-2-yl)glycinamide

Following general procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 4-bromo-2-thiophenecarboxaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine (Aldrich), and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp - 246-247 °C). The product was purified by recrystallization from ethyl acetate/hexanes.

_{C2iH24N3O3BrS :}

Molecular weight = 515;

Mass spectroscopy: (MH ⁺ ) 515, 415.

Example 270

Synthesis of N-tert-butyl-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-(thien-2-yl)glycinamide

Following general procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 2-thiophenecarboxaldehyde (Aldrich), (S)-(+)-amethylbenzylamine (Aldrich), and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 241-242 °C). The product was purified by recrystallization from ethyl acetate/hexanes.

_{C2iH25N3O3F2S : ​}

Molecular weight = 438;

Mass spectroscopy: (MH ⁺ ) 438.338.

Example 271

Synthesis of N-tert.-butyl-N'-[N-(3,5-difluorophenylacetyl)-L·· ) · · » · · • · · • ·

-445 ·· ···· • · • · · · alaninyl]-D-(thien-2-yl)glycinamide

Following general procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 2-thiophenecarboxaldehyde (Aldrich), (S)-(+)-amethylbenzylamine (Aldrich), and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 235-236 °C). The product was purified by recrystallization from ethyl acetate/hexanes.

C21H25N3O3F2S:

Molecular weight = 438;

Mass spectroscopy: (MH ⁺ ) 438.338.

Example 272

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-(thien-3-yl)glycinamide

Following general procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 3-thiophenecarboxaldehyde (Aldrich), (S)-(+)-amethylbenzylamine (Aldrich), and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 240-241 °C). The product was purified by recrystallization from ethyl acetate/hexanes.

C ₂ iH ₂₅ N ₃ O ₃ F ₂ S:

Molecular weight = 438;

Mass spectroscopy: (MH ⁺ ) 438.338.

Example 273

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D-(thien-3-yl)glycinamide

-4 4 6··· *· ··· ·· »· • ·

Following the general procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 3-thiophenecarboxaldehyde (Aldrich), (S)-(+)-amethylbenzylamine (Aldrich), and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 245-246 °C). The product was purified by recrystallization from ethyl acetate/hexanes.

C21H25N3O3F2S:

Molecular weight = 438;

Mass spectroscopy: (MH ⁺ ) 438.338.

Example 274

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D-phenylglycinamide

Following general procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), benzaldehyde (Aldrich), (S)-(+)-amethylbenzylamine (Aldrich), and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 239-240 °C). The reaction was monitored by thin layer chromatography (R _f = 0.25 in 50% ethyl acetate/hexanes).

C23H27N3O3F2:

Molecular weight 2 = 431.53;

Mass spectroscopy: (MH ⁺ ) 432.

Example 275

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylglycinamide

-447fl « 9 fl fl •

• Oflfl • fl flflflfl • fl • ··· flfl • flfl • fl * · fl • · · flflfl flflfl • 9 • fl flfl

Following general procedure AL and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), benzaldehyde (Aldrich), (S)-(+)-a-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 240-241 °C).

C23H27N3O3F2:

Molecular weight = 431.53;

Mass spectroscopy: (MH ⁺ ) 432.

Example 276

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-(5-chlorothien-2-yl)glycinamide

Following general procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 5-chloro-2-thiophenecarboxaldehyde (from Example D17 above), (S)-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 195-198 °C).

The reaction was monitored by thin layer chromatography (R _f = 0.15 in 50% ethyl acetate/hexanes).

_{C2iH24N3O3F2Cl : ​ ​ ​}

Molecular weight = 472;

Mass spectroscopy: (MH ⁺ ) 472.

Example 277

Synthesis of N-cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-4-(phenyl)phenylglycinamide • · • · · · • · • · · · • · · <5 ·

-44Í8 Following general procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 4-biphenylcarboxaldehyde (Aldrich), (S)-(+)-amethylbenzylamine (Aldrich), and cyclohexylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 300 °C (decomposition)). The reaction was monitored by thin layer chromatography (R _f = 0.23 in 50% ethyl acetate/hexanes).

C31H33N3O3F2:

Molecular weight = 533.62;

Mass spectroscopy: (MH ⁺ , minus cyclohexylamide) 408.2.

Example 278

Synthesis of N-tert-butyl-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-3-(phenoxy)phenylglycinamide

Following the general procedure of AM and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 3-phenoxybenzaldehyde (Aldrich), (S)-(+)-amethylbenzylamine (Aldrich), and tert-butylisocyanide (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.29 in 50% ethyl acetate/hexanes).

C29H31N3O4F2:

Molecular weight = 523.63;

Mass spectroscopy: (MH ⁺ ) 524.24.

Example 279

Synthesis of N-(S)-(-)-α-Methylbenzyl-N'-[N-(3, 5difluorophenylacetyl)-L-Alaninyl]-D,L-Phenylglycinamide ··· ·· ·«

Following general procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), benzaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine (Aldrich), and (S)-(-)-α-methylbenzylisocyanide (prepared in Example D18 above), the title compound was prepared.

C27H27N3O3F2:

Molecular weight = 479.53;

Mass spectroscopy: (MH ⁺ ) 480.21.

Following the above procedures, N-(R)(+)-α-methylbenzyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide was prepared by simply substituting the appropriate isomer.

C27H27N3O3F2:

Molecular weight = 479.53;

Mass spectroscopy: (MH ⁺ ) 480.1.

Example 280

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-3-(phenyl)phenylglycinamide

Following the general procedure of AM and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 3-phenylbenzaldehyde (prepared in Example D20 above), (S)-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.25 in 50% ethyl acetate/hexanes).

C29H31N3O3F2:

• · • ·· · · ··· • · · · · · ·

Λ cn· · · · · ···

-4bU·- · » · · • · · · ······· ·· ···

Molecular weight = 507.63;

Mass spectroscopy: (MH ⁺ ) 508.2.

Example 281

Synthesis of N-tert-butyl-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-4-(ethyl)phenylglycinamide

Following the general procedure of AM and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 4-ethylbenzaldehyde (Aldrich), (S)- (+)-a-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.20 in 50% ethyl acetate/hexanes).

C25H31N3O3F2:

Molecular weight = 459.59;

Mass spectroscopy: (MH ⁺ ) 460.2.

Example 282

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-2-(phenyl)phenylglycinamide

Following the general procedure of AM and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 2-phenylbenzaldehyde (Aldrich), (S)-(+)-amethylbenzylamine (Aldrich), and tert-butylisocyanide (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.15 in 50% ethyl acetate/hexanes).

C29H31N3O3F2:

Molecular weight = 507.63;

-4 511 ·· ·· ···· ·· ·· • · · · · · · · · • · · · · · · · · · • * · · · * ······ • · · · · · ···· ·Ο ··· ·· ··

Mass spectroscopy: (MH ⁺ , minus tert-butylamide) 409.

Example 283

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-2-(benzyl)phenylglycinamide

Following the general procedure of AM and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 2-(benzyl)benzaldehyde (Aldrich), (S)-(+)-amethylbenzylamine (Aldrich), and tert-butylisocyanide (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (Rf = 0.19 in 50% ethyl acetate/hexanes).

_{C3oH33N303F2 : ​ ​}

Molecular weight = 521.66;

Mass spectroscopy: (MH ⁺ ) 522.26.

Example 284

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-4-bromophenylglycinamide

Following the general procedure of AM and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 4-bromobenzaldehyde (Aldrich), (S)-(+)-amethylbenzylamine (Aldrich), and tert-butylisocyanide (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.06 in 50% ethyl acetate/hexanes).

C2 ₃ H26N ₃ O ₃ F ₂ :

Molecular weight = 510.42;

Mass spectroscopy: (MH ⁺ ) 512.1.

• · · · · · • · · · • · · ·

······· · · • · · ·

Example 285

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-4-(cyclohexyl)phenylglycinamide

Following general procedure AL and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 4-(cyclohexyl)benzaldehyde (prepared in Example D21 above), (S)-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 232-235 °C).

C29H37N3O3F2:

Molecular weight = 513.69;

Mass spectroscopy: (MH ⁺ ) 514.29.

Example 286

Synthesis of N-tert-butyl-Ν'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-4-(4-ethylphenyl)phenylglycinamide

Following general procedure AL and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 4,4'-ethylbiphenylcarboxaldehyde (Aldrich), (S)-( + )-α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 231-233 °C).

C31H35N3O3F2:

Molecular weight = 513.69;

Mass spectroscopy: (MH ⁺ ) 514.29.

Example 287

A A

A AAA

A A

A A A

-4 53JSynthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-4-(tert-butyl)phenylglycinamide

Following general procedure AL and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 4-(tert-butyl)benzaldehyde (Aldrich), (S)(+)-α-methylbenzylamine (Aldrich), and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 280 °C (decomposition)). The reaction was monitored by thin layer chromatography (R _f = 0.13 in 50% ethyl acetate/hexanes).

C27H35N3O3F2:

Molecular weight = 487.65;

Mass spectroscopy: (MH ⁺ ) 488.27.

Example 288

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-3-(4-chlorophenoxy)phenylglycinamide

Following general procedure AL and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 3-(4-chlorophenoxy)benzaldehyde (Aldrich), (S)-( + )-α-methylbenzylamine (Aldrich) and tert-butylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 192-195 °C).

C29H30N3O4F2Cl:

Molecular weight = 558.07;

Mass spectroscopy: (MH ⁺ ) 558.20.

Example 289

Synthesis of N-cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L• · · · · fl

-4545• · flflflfl • flflfl · flfl fl • flfl flflfl flflfl • · · · • flfl · · · · alaninyl]-D-4-(phenyl)phenylglycinamide

Following general procedure AB and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above), 4-biphenylcarboxaldehyde (Aldrich), (S)-(+)-amethylbenzylamine (Aldrich) and cyclohexylisocyanide (Aldrich), the title compound was prepared as a solid (mp = 290-291 °C).

C31H33N3O3F2 ·

Molecular weight = 533.62;

Mass spectroscopy: (MH ⁺ ) 534.3.

Example 290

Synthesis of N-[N-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]-L-phenylglycine tert-butyl ester

Following general procedure C and using 3,5-difluoromandelic acid (Fluorchem) and N(L-alaninyl)-L-phenylglycine tert-butyl ester (prepared using N-BOC-L-alanine (Sigma) and L-phenylglycine tert-butyl ester hydrochloride (Bachem) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared.

C23H26N2O5F2:

Molecular weight = 479.53.

Elemental analysis:

Calculated (%) C, 61.60; H, 5.84; N, 6.25.

Found (%) C, 61.32; H, 6.02; N, 6.17.

Example 291

Synthesis of N-tert-butyl-N'-[N-(3,5-difluorophenyl-α,α-

9

9 9 9 • 9 · · ·

9 9 9

999 9 · ·

999 9999 difluoroacetyl)-L-alaninyl]-L-phenylglycinamide

Following general procedure C and using 3,5-difluorophenyl-α,α-difluoroacetic acid (prepared in Example D23 above) and N-(Lalaninyl)-L-phenylglycine tert-butyl ester (prepared using N-BOC-Lalanine (Sigma) and L-phenylglycine tert-butyl ester hydrochloride (Bachem) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.39 in 30% ethyl acetate/hexanes) and the product was purified by HPLC using 17% ethyl acetate/hexanes as the eluent.

C23H24N2O4F4 :

Molecular weight = 468.49;

Mass spectroscopy: (MH ⁺ ) 469.17.

Example 292

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D-phenylglycine tert-butyl ester

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and D-phenylglycine tert-butyl ester (which was prepared from D-phenylglycine (Sigma) following general procedure J), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.1 in 10% MeOH/CHCl ₃ ).

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 8.64 (d, IH) , 8.38 (d, IH) , 7.34 (m, ·· ····

-456 • ·· J· · · • · · · ftft 4 • · ··· · · ft 4 • ft · ·· ftftft ··<

··· · I ·· ··· ·· · ·

5H), 7.09 (m, 1H), 6.99 (m, 2H), 5.27 (d, 1H), 4.45 (m, 1H), 3.32 (s, 2H) 1.28 (s, 9H), 1.18 (d, 3H).

Optical rotation: [α]20 ~ -103.58 (c = 1, MeOH).

C23H26N2O4F2:

Molecular weight = 432.47;

Mass spectroscopy: (MH ⁺ ) 433.

Example 293

Synthesis of N-[(S)-l-oxo-l-phenylprop-2-yl]-Ν'-(3,5difluorophenylacetyl)-L-alanine amide

Oxidation of N-[(1R, 2S)-1-hydroxy-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide (prepared in Example 226 above) using Jones reagent in acetone gave the title compound. The reaction was monitored by thin layer chromatography (Rf = 0.7 in 9:1 _CHCl3 /MeOH) and the product was purified by flash chromatography using 97:3 chloroform/methanol as eluent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 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, 2H), 1.41 (d, 3H), 1.38 (d, 3H) . Optical rotation : [ot] 20 ⁼ -106 @ 589 nm (c = 1, MeOH).

C20H20F2N2O3:

Molecular weight = 374.39;

Mass spectroscopy: (MH ⁺ ) 374.

Example 294

Synthesis of tert-butyl ester of Ν-[N-(3,5-difluorophenylacetyl)-L-]D,L-(pyrid-3-yl)glycine ·· ··♦·

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and tert-butyl 2-amino-2-(3-pyridyl)acetate (prepared by the method described in Kolár et al., J. Heterocyclic Chem., 28, 171 (1991) and references therein), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.2 in 5% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 5% MeOH/CHCl 3 as the eluent.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ) : δ = 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, 1H), 6.47 and 6.36 (d, IH) , 5.42 (d, IH), 4.59 (m,1H), 3.52 and 3.47 (two s, 2H), 1.38 a 1.36 (with , 9H), 1.34 and 1.28 (two days, 3H).

C22H25N3O4F2:

Molecular weight = 433.46; Mass spectroscopy: (MH ⁺ ) 434.

Example 295

Synthesis of [N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,Lphenylglycinyl]morpholine

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and morpholine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 5% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

^x H-nmr (DMSO-dg): δ = 8.60 and 8.49 (two d, IH) , 8.49 (m, IH) , • · • φ φ

-458-;

φφφφ ♦ · φ Φφφφ • · φφφ φ φ φ · ·φ φφφφφφφφ • · φ · φ φ · φφφ φφφφ ·Φ « _Μ ·Φ ♦ ♦

7.25 (m, 5Η), 7.18 (m, 2H), 6.95 (m, IH), 5.82 (m, IH), 4.38 (m, IH), 3.52 (m, 10H), 1.21 and 1.12 (two d, 3H).

C23H25N3O4F2:

Molecular weight = 445.47;

Mass spectroscopy: (MH ⁺ ) 446.

Example 296

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-(2-methoxy)phenylglycine methyl ester

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and methyl-2-amino-2-(2-methoxy)acetate (which was prepared from 2-methoxybenzaldehyde (Aldrich) using the Bucherer modification of the Strecker procedure 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 thin layer chromatography (Rf = 0.3 in 10% MeOH/CHCl3) and the product was purified by flash chromatography using 10% MeOH/CHCl3 as the eluent.

The NMR data were as follows:

^-nmr (CDCl ₃ ) : δ = 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).

C21H22N2O5F2:

Molecular weight = 420.42;

Mass spectroscopy: (MH ⁺ ) 420.

Example 297

-4595ΦΦ φφφφ » · · φφ φφφ φφ < I Φ Φ » φ φ φφφ « φ

φφ «

Synthesis of N-tert.-butoxycarbonyl(hydroxyl amine)ester Ν-[N(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and N-BOC hydroxylamine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.35 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 2% MeOH/CHCl ₃ as the eluent. The NMR data were as follows:

^x H-nmr (CDCl ₃ ) : δ = 7.79 (m, 1H), 7.41-7.28 (m, 5H), 6.786.59 (m, 3H), 5.52 (m, 1H), 4.69 (m, 1H), 3.38 (two s, 1H), 1.38 (d, 3H), 1.30 (s, 9H) .

_{C24H27N3O4F2 ​}

Molecular weight = 491.49;

Mass spectroscopy: (MH ⁺ ) 492.

Example 298

Synthesis of N-neopentyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

Following General Procedure M and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and neopentylamine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 10% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

^x H-nmr (DMSO-dg): δ =

8.44 (m, IH), 7.41 (m, 2H), 7.31 (m, , 4.47 (m, IH),

0.71 (s, 9H).

·· · ·

-460-:

• · ··· ···« ·« ···· • · * • · · · · • · · • · · · · · · · · · * ·

3H) ,

3.52

7.12 (two

_{C24H29N3O3F2 : ​ ​}

(m, 1H) , 6.99 (m, 2H), 5.50 (m, 1H) s, 2H), 2.84 (m, 2H), 1.22 (m, 3H) ,

Molecular weight = 460; Mass spectroscopy: (MH ⁺ ) 460.

Example 299

Synthesis of N-tetrahydrorurfuryl-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-D,L-phenylglycinamide

Following general procedure M and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and tetrahydrofurfurylamine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.4 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 10% MeOH/CHCl ₃ as the eluent. The NMR data were as follows:

^-nmr (DMSO-d ₆ ) : δ = 8.41 (m, 2H), 7.32 (m, 5H), 7.08 (m, H), 6.99 (m, 2H) , 5.48 (m, IH), 4.42 (m, IH) , 3.85-3.54 (m, 3H) , 3.48 (two seconds, 2H) , 3.14 (m, 2H), 1.76 (m, 4H), 1.21 (m,

3H).

C24H27N3O4F2:

Molecular weight = 459.49;

Mass spectroscopy: (MH ⁺ ) 460.

Example 300

Synthesis of N-methoxy-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

Following the general procedure M and using N-[N-(3.59 9

·· 9999

9 9 9 9 9

9 9 9 9 *9 9

999

999 999 difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and methoxyamine hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.35 in 10% MeOH/CHCl 3 ) and the product was purified by flash chromatography, using 10% MeOH/CHCl ₃ as the eluent. The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ) : δ = 8.63 (m, IH), 8.35 (m, IH), 7.34 (m, SH), 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).

C ₂ oH ₂₁ N ₃ 0 ₄ F ₂ 1

Molecular weight = 405;

Mass spectroscopy: (MH ⁺ ) 405.

Example 301

Synthesis of [Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,Lphenylglycinyl]azetidine

Following general procedure M and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and azetidine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (Rf = 0.6 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 10% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

^x H-nmr (DMSO-dg): δ = 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, 1H), 3.88 (m, 3H); 3.5 (two s, 2H), 2.36 (m, 2H), 1.18 (two d, 3H).

C22H2 ₃ N ₃ O ₃ F ₂ :

-4 62*5 • 0 »000 ·· 00 • 0 0 0

0 0 ·

000 ··· • 0

0« 00

Molecular weight = 415.44;

Mass spectroscopy: (MH ⁺ ) 416.

Example 302

Synthesis of N-iso-butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

Following general procedure M and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and iso-butylamine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.65 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 10% MeOH/CHCl 3 as the eluent.

The NMR data were as follows:

^-nmr (DMSO-d ₆ ): δ = 8.41 (m, 1H) , 8.22 (m, 1H) , 7.38 (m,

2H) , 7.09 (m, IH), 6, 98 (m, 2H), 5.52 (two days, IH), 4.41 (m, IH) , 3.34 (two s, 2H) , 2.85 (s, 2H), 1 ₆ 1 (m, IH), 1.20 (m, 3H) , 0.92 (m, 6H) .

C23H27N3O3F2:

Molecular weight = 431.48; Mass spectroscopy: (MH ⁺ ) 432.

Example 303

Synthesis of N-cyclopropanemethyl-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-D,L-phenylglycinamide

Following general procedure M and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and (aminomethyl)cyclopropane (Aldrich), the title compound was prepared. The reaction was • ·· • to to · *

-463-5 .·. :

• · to • «••••to •v to··· « to to to · · ·« «to • ·· to

And this to this ·>· ··· ·> · · ·*· to· to« was monitored by thin layer chromatography (R _f = 0.25 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography, using a mixture of 10% MeOH/CHCl ₃ as the eluent. C23H25N3O3F2 ·

Molecular weight = 429.47;

Mass spectroscopy: (MH ⁺ ) 374.

Example 304

Synthesis of N-methoxy-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and N-methoxy-N-methylamine hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.3 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 2% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

^x H-nmr (DMSO-dg): δ = 8.65 and 8.53 (two days, IH), 8.37 (m, IH) , 7.31 (m, SH), 7.12 (m, IH), 6.98 (m, 2H) , 5.91 and 5.82 (two d, 1H), 4.49 (m, 1H), 3.60-3.42 (m, 5H), 3.08 (two seconds, 3H) ,

1.21 and 1.16 (two d, 3H).

C21H23N3O4F2:

Molecular weight = 419;

Mass spectroscopy: (MH ⁺ ) 420.

Example 305

Synthesis of N-2-methylprop-2-enyl-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

-464 Following general procedure M and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and 1-amino-2-methylprop-2-ene (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (Rf = 0.45 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 3% MeOH/CHCl ₃ as eluent. The NMR data were as follows:

¹ H-nm tr (DMSO- _d6 ): δ = 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, 1H) , 3.6 (m, 2H), 3.49 (s, 2H), 1.56 (with, 3H), 1.21

(d, 3H).

_{C23H25N3O3F2 : ​ ​}

Molecular weight = 429.47;

Mass spectroscopy: (MH ⁺ ) 430.

Example 306

Synthesis of N-(pyrid-3-yl)methyl-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-D,L-phenylglycinamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and 3-(aminomethyl)pyridine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.1 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 3% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

1H-nmr (DMSO-d ₆ ): δ = 8.82 (m, 1H) , 8.55 (m, 1H) , 8.42 (m,

3H), 7.52 (m, 1H), 7.35 (m, 5H), 7.10 (m, 1H), 6.99 (m, 2H), • · • ·

-465• · · · · ·· ·· ·· ·· ·· ··

5.43 (d, 2H), 4.44 (m, 1H), 4.30 (bd, 2H), 3.52 (s, 2H),

1.26 (d, 3H).

C23H24N4O3F2:

Molecular weight = 466.49;

Mass spectroscopy: (MH ⁺ ) 467.

Example 307

Synthesis of N-(pyrid-4-yl)methyl-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-D,L-phenylglycinamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and 4-(aminomethyl)pyridine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.1 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography, using 3% MeOH/CHCl ₃ as the eluent. The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ) : δ = 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, 1H) , 4.31 (d, 2H), 3.51 (s, 2H) , 1.25 (d, 3H) . _{C23H24N4O3F2 : ​} Molecular weight = 466.49;

Mass spectroscopy: (MH ⁺ ) 467.

Example 308

Synthesis of N-furfuryl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared • ·

-466• · · « • · · · · 4 • 4 • · · · in Example D25 above) and furfurylamine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (Rf = 0.5 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using a mixture

3% MeOH/CHCl3 as eluent NMR data were as follows: solvent. ¹ H-nmr (DMSO-d ₆ ): δ = 8.66 (m, IH) , 8.45 (d, IH) , 8.39 (m, IH), 7.57 (s, IH), 7.33 (m, SH), 7.09 (m, IH) , 6, 99 (m, 2H), 6.36 (m, IH), 6.12 (s, IH), 5.41 (d, 1H), 4.22 (m, IH), 3.52 (s, 2H) 1.24 (d, 3H). C24H23N3O4F2: Molecular weight - 455; Mass spectroscopy: (MH ⁺ ) 456.

Example 309

Synthesis of N-cyclopentyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and cyclopentylamine (Aldrich), the title compound was prepared. The product was purified by recrystallization from ethanol.

The NMR data were as follows:

^-nmr (DMSO-d ₆ ) : δ = 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).

C24H27N3O3F2 ^;

Molecular weight = 443.49.;

Mass spectroscopy: (MH ⁺ ) 444.

-467• ·

Example 310

Synthesis of N-1-benzylpiperidin-4-yl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and 4-amino-1-benzylpiperdine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.2 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 3% MeOH/CHCl 3 as the eluent. The NMR data were as follows:

^-nmr (DMSO-d ₆ ): δ = 8.39 (m, 2H) , 8.21 (m, 1H) , 7.30 (m,

5H), 7.11 (m, 1H), 6.98 (m, 2H), 5.39 (d, 1H), 4.21 (m, 1H),

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).

_{C3iH34N4O3F2 : ​}

Molecular weight = 548.64;

Mass spectroscopy: (MH ⁺ ) 548.

Example 311

Synthesis of N,N-dimethyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and dimethylamine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.65 in 10% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using a mixture of ·· • · • ·

• · · · · · · • · ··· ··· • · · · • · · · · ·

5% MeOH/CHCl ₃ as elution solvent.

The NMR data were as follows:

'H-nmr (DMSO-d ₆ ) : δ = 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). C21H23N3O3F2:

Molecular weight = 403.43;

Mass spectroscopy: (MH ⁺ ) 404.

Example 312

Synthesis of N-2,2,6,6-tetramethylpiperidin-4-yl-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-D-L-phenylglycinamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and 4-amino-2,2,6,6-tetramethylpiperidine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.2 in 2% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 2% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

‘H-nmr (DMSO-dg) : δ = 8.46 (d, IH) , 8.33 (d, IH), 8.12 (bm, 1H), 7.33 (m, 5H), 7.13 (m, H) , 6.99 (m, 2H) ; 5.37 (d, IH) , 4.41 (m, 1H), 3.98 (m, IH) , 3.52 (s, 2H) , 1.67 (bm, IH) , 1.44

(bm, 1H), 1.22 (d, 3H), 1.01 (bm, 14H). C28H36N4O3F2:

Molecular weight = 514.62;

Mass spectroscopy: (MH ⁺ ) 514.

Example 313

A A

A A

A· ····

-469A A · 4 > A A

A · • · · «4

A· ··

Synthesis of N-2-methylcyclohexyl-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-D,L-phenylglycinamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and 2-methylcyclohexylamine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.4 in 2% MeOH/CHCl ₃ ).

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.41 (m, 2H), 8.0 (m, 1H), 7.33 (m, 5H), 7.11 (m, 1H), 6.99 (m, 2H), 5.35 (m, 1H), 4.41 (m, 1H), 3.52 (s, 2H), 3.18 (m, 1H), 1.78-0.82 (m, 11H), 0.81 (m, 3H).

C26H31N3O3F2 ^:

Molecular weight = 472.5;

Mass spectroscopy: (MH ⁺ ) 472.

Example 314

Synthesis of N-4-methylcyclohexyl-N'-[N-(3,5-difluorophenylacetyl)L-alaninyl]-D,L-phenylglycinamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and 4-methylcyclohexylamine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.2 in 2% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 2% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.38 (m, 2H) , 8.08 (m, 1H) , 7.33 (m, • this this·· • this • this this

-470• · « •

it ·· • · ··· 4

5H) , 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).

C24H31N3O3F2:

Molecular weight = 472.5;

Mass spectroscopy: (MH ⁺ ) 472.

Example 315

Synthesis of N-1-ethoxycarbonylpiperidin-4-yl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and 4-amino-ethoxycarbonylpiperidine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (Rf = 0.2 in 2% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 2% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 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, 1H), 1.54 (m, 1H), 1.2 (m, 6H).

C27H32N4O5F2:

Molecular weight = 530.57;

Mass spectroscopy: (MH ⁺ ) 531.

Example 316

Synthesis of N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninylΙΕ-phenylglycinamide

• ·

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-methyl-(S)-2-amino-2-phenylacetamide [CAS 129213-83-8], the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.2 in 5% MeOH/CHCl ₃ ) and the product was purified by flash chromatography using 5% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.43 (m, 2H) , 8.21 (m, 1H) , 7.36 (m,

5H), 7.09 (m, 1H), 6.95 (m, 2H), 5.36 (m, 1H), 4.40 (m, 1H),

3.41 (s, 2H), 2.56 (d, 3H), 1.22 (d, 3H).

Optical rotation: [α] ₂ o = “67 (c = 1, MeOH).

C ₂ oH 2 iN ₃ 0 ₃ F ₂ . 0.75 H ₂ O:

Molecular weight = 403.43;

Mass spectroscopy: (MH ⁺ ) 404.

Example 317

Synthesis of N-tert-butoxy-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinamide

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and O-(tert-butoxy)hydroxylamine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.65 in 10% MeOH/CHCl ₃ ).

The NMR data were as follows:

^-nmr (DMSO-d ₆ ): δ = 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

-472

99 99 9999 99 99

9999 999 9999 • · 9 9··· · · · 9 • · 99 9 99 999999

9 9 9 9 9 9 •99 9999 99 999 99 99 (m, IH), 3.51 (two s, 3H), 1.22 (m, 3H), 1.09 (s, 9H). C23H27N3O4F2:

Molecular weight = 447.48;

Mass spectroscopy: (MH ⁺ ) 448.

Example 318

Synthesis of N-tert-butyl (hydroxylamine) N-[N-(3,5difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine ester

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and N-(tert-butoxy)hydroxylamine (Aldrich), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.65 in 10% MeOH/CHCl ₃ ).

C ₂₃ H ₂₇ N ₃ O 4 F ₂ . 0.25 H ₂ O:

Molecular weight = 447.48;

Mass spectroscopy: (MH ⁺ ) 448.

Example 319

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-phenylglycine hydrazide

N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine methyl ester (2.0 g, 5.1 mmol) (prepared in Example 111 above) was stirred in ethanol (40 mL) and anhydrous hydrazine (0.3 mL, 10 mmol) (Aldrich) was added. The solution was heated to reflux for 12 hours and then allowed to cool to ambient temperature with stirring. The title compound was obtained as a white solid by filtration, washing with ethanol and drying in a vacuum oven (52%

-473- * ·9 1« » · · » I *·· • · »· • · » · • · · · ·· · ·· ·

5.41 (m, 1H).

yield).

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 1.20 (t, 3H),

C19H20N3O4F2:

Molecular weight = 390.39;

Mass spectroscopy: (MH ⁺ ) 390.

Example 320

Synthesis of N-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-L-phenylglycine acetohydrazonate

N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine hydrazide (0.5 g, 1.3 mmol) (prepared in Example 319 above) was heated to reflux in triethyl orthoacetate (40 mL). After 14 h, the reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (84% yield). The reaction was monitored by thin layer chromatography (Rf = 0.65 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/ _CHCl3 as the eluent.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 4.03 (q, 2H), 5.54 (m, 1H).

C23H26N4O4F2:

Molecular weight = 460.49;

Mass spectroscopy: (MH ⁺ ) 460.

Example 321

Synthesis of N-[N-(phenylacetyl)-L-alaninyl]-L-phenylglycine tert-butyl ester • · ·· · · • · . —9Λ · · · · · • 4 7 4·— · · · ··· • · » · · « » · · <

··· ··« • <

• 9 9 9

Following general procedure C and using phenylacetic acid (Aldrich) and L-alaninyl-L-phenylglycine tert-butyl ester (prepared using N-BOC-L-alanine (Sigma) and L-phenylglycine tert-butyl ester hydrochloride (Bachem) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared. The reaction was monitored by thin layer chromatography (Rf = 0.25 in 3% MeOH/CHCl ₃ ) and the product was purified by crystallization from chlorobutane/hexanes. NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 4.43 (m, 1H), 5.20 (d, 1H).

C23H28N2O4:

Molecular weight = 396.49;

Mass spectroscopy: (MH ⁺ ) 397.

Example 322

Synthesis of N-4-(phenyl)butyl-N'-[N-(3,5-difluorophenylacetyl)-Lalananyl]-L-phenylglycinamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-4-(phenyl)butyl-L-phenylglycinamide (which was prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and 4-phenylbutylamine (Aldrich) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.45 in 5% MeOH/CHCl3) and the product was purified by trituration in water followed by trituration in acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 4.42 (m, 1H), 5.37 (d, 1H).

·· ·· « · · · • · · · · • · · · · · · · ·♦

C29H31N3O3F2 :

Molecular weight = 507.5;

Mass spectroscopy: (MH ⁺ ) 507.

Example 323

Synthesis of N-3-(4-iodophenyl)propyl-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and N-3-(4-iodophenyl)propyl-L-phenylglycinamide (which was prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and 3-(4-iodophenyl)propylamine (prepared in Example D26 above) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared. The product was purified by trituration in water followed by trituration in ethanol.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 4.41 (q, 2H), 5.35 (m, 1H).

C28H28N3O4F2I:

Molecular weight = 635.45;

Mass spectroscopy: (MH ⁺ ) 635.

Example 324

Synthesis of N-6-(amino)hexyl-N'-[N-(3,5difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide hydrochloride

Following general procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (prepared in Example D25 above) and N-BOC-1,6-hexanediamine

-476»-

(Fluka), followed by removal of the BOC group according to general procedure P) to prepare the title compound. The product was isolated as a white solid.

The NMR data were as follows:

^x H-nmr (DMSO-dg): δ = 4.41 (m, 1H), 5.40 (t, 1H).

C25H32N4O3F2:

Molecular weight = 474.56;

Mass spectroscopy: (MH ⁺ ) 475.

Example 325

Synthesis of N-1-(phthalimido)pent-2-yl-N'-(3,5-difluorophenylacetyl)-L-alaninamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and 2-amino-1-phthalimidopentane hydrochloride (prepared in Example D27 above), the title compound was prepared. The reaction was monitored by thin layer chromatography (R _f = 0.3 in 5% MeOH/CHCl ₃ ) and the product was purified by silica gel chromatography using 5%

MeOH/CHCl ₃ as elution solvent, followed by recrystallization from chlorobutane/acetonitrile.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 4.1 (m, 2H), 7.83 (bs, 4H).

C24H25N3O4F2:

Molecular weight = 457.48;

Mass spectroscopy: (MH ⁺ ) 457.

Example 326

Synthesis of N-[N-(3,5-difluorophenylacetyl)-L-(3,5difluorophenyl)glycinyl]-L-(3,5-difluorophenyl)glycine methyl ester

··· φφ ♦· • φ Β » φφ · · » · • φ φφφ φφφ φ · ·

Following the general procedure of AN and using N-(3,5-difluorophenylacetyl)-L-(3,5-difluorophenyl)glycine (prepared in Example D30 above) and L-3,5-difluorophenylglycine methyl ester (prepared in Example D29 above), the title compound was prepared. The product was purified by crystallization.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 9.40 (m, 1H), 9.0 (m, 1H), 6.80-7.70 (m, 9H), 5.45 (d, 1H), 5.25 (m, 1H), 3.55-365 (m, 5H).

Example 327

Synthesis of Ν-[N-(3,5-Difluorophenylacetyl)-L-Alaninyl]-Lnorleucine

Following the general procedure of AF and using THF/H2O (1:1) for Ν-[N-(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 thin layer chromatography (R _f = 0.29 in 10%

MeOH/ _CH2Cl2 ) _.

The NMR data were as follows:

^x H-nmr (CD ₃ OD): δ = 8.46 (bd, J = 6.71, IH), 8.25 (bd, J =

7.69, 1H), 7.00-6.79 (m, 3H), 4.50-4.35 (m, 2H), 3.61 (d,

2H), 1.94-1.79 (m, 1H), 1.78-1.60 (m, (includes d at 1.40, J = 7.14, 3H), 0.92 (m, 3H).

¹³ C-nmr (CD ₃ OD): δ = 176.0, 175.5,

163.4, 163.2, 141.7, 141.6, 141.5,

113.6, 103.9, 103.6, 103.2, 54.1, 50.9, 43.3, 32.9, 29.4,

23.8, 18.6, 14.8.

172, 9, 166, 6, 166, 5, 113.9, 113.8, 113.7,

C17H22N2O4 Formula:

• · · · ·

9 9

9 9 · 9 9 9

-478ř • 9 ·

9 9 *

9 9 9

999 999 ·

9 9 9

Molecular weight - 356.37;

Mass spectroscopy: (MH ⁺ ) 357.

Example 328

Synthesis of Ν-[N-(cyclopentaneacetyl)-Lalaninyl]-L-phenylglycine tert-butyl ester

Following general procedure D and using cyclopentylacetic acid (Aldrich) and Lalaninyl-L-phenylglycine tert-butyl ester (which was prepared from N-CBZ-Lalani (Sigma) and L-phenylglycine tert-butyl ester hydrochloride (Bachem) following general procedure C, followed by removal of the CBZ group following general procedure Y), the title compound was prepared as a solid (mp = 133-138 °C). The reaction was monitored by thin layer chromatography (R _f = 0.48 in 50% EtOAc/hexanes) and the product was purified by flash chromatography using 25-50% EtOAc/hexanes as the eluent.

The NMR data were as follows:

^x H-nmr (CDCl ₃ ): δ = 7.86 (bd, J = 7.2 Hz, 1H), 7.30-7.15 (m,

5H), 6.81 (bd, J = 7.82 Hz, IH), 5.34 (d, J = 7.20 Hz, IH),

4.72 (quintet, J=7.2 Hz, 1H), 2.04 (m, 3H), 1.75-1.28 (m (includes s at 1.34, 9H), 18H), 1.1-0.9 (m, 2H).

¹³ C-nmr (CDC1 ₃ ): δ = 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.

_{C22H32N2O4 : ​}

Molecular weight - 388.51;

Mass spectroscopy: (MH ⁺ ) 389.5.

ftft ·

9- 9 9 9 · · 99·· « 9 9 · · · · 9··· · · · ♦ »9 9 · « »99999 ft· ···

Example 329

Synthesis of Ν-[N-(2,5-dichlorophenylmercaptoacetyl)L-alaninyl]-L-phenylglycine methyl ester

2,5-Dichlorophenylmercaptoacetic acid (TCI America, Portland, OR) (237 mg) was converted to the acetyl chloride following General Procedure A and used for the acylation of methyl-L-alaninyl-L-phenylglycinate as described in General Procedure B. The title compound (210 mg) was isolated as crystals from ethyl ether.

The NMR data were as follows:

¹ H-nmr (DMSO-d ₆ ): δ = 8.85 (d, 1H), 8.20 (d, 1H), 6.70-7.45 (m, 5H), 5.45 (d, 1H), 4.45-4.65 (m, 3H), 3.65 (s, 3H), 1.30 (d, 3H).

C ₂ oH2oC1 ₂ N ₂ 0 ₄ S :

Molecular weight = 455.363;

Mass spectroscopy: (MH ⁺ ) 454.1.

Analysis: Calcd for C20H20Cl2N2O4S: C, 52.75 H, 4.42 N, 6.15;

Found: C, 53.58; H, 5.01; N, 6.34.

Example 330

Synthesis of Ν-[N-(3,4-dichlorophenylmercaptoacetyl)-Lalanininyl]-L-phenylglycine methyl ester

3,4-Dichlorophenylmercaptoacetic acid (J. Med. Chem., 15(9), 940-944 (1972)) (237 mg) was converted to the acetyl chloride by the general procedure A and used for the acylation of methyl-L-alaninyl-L-phenylglycinate as described in General Procedure B. The title compound (182 mg) was isolated as crystals from ethyl ether.

The NMR data were as follows:

^-nmr (DMSO-d ₆ ) : δ = 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).

C20H20Cl2N2O4S:

Molecular weight = 455.363;

Mass spectroscopy: (MH ⁺ ) 454.1

Elemental analysis for C20H20Cl2N2O4S: C, 52.75 H, 4.42 N, 6.15;

Found: C, 53.05 H, 4.67 N, 6.26.

Example 331

Synthesis of Ν-[N-(3,5-difluorophenoxyacetyl)-Lalaniny]-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 acetyl chloride according to General Procedure A and used for the acylation of methyl-L-alaninyl-L-phenylglycinate as described in General Procedure B. The title compound (210 mg) was isolated as crystals from ethyl ether.

The NMR data were as follows:

^x H-nmr (DMSO-d ₆ ): δ = 8.85 (d, 1H), 8.20 (d, 1H), 6.70-7.45 (m, 8H), 5.45 (d, 1H), 4.45-4.65 (m, 3H), 3.65 (s, 3H), 1.30 (d, 3H).

C20H20E2N2O5:

Molecular weight - 406.39;

Mass spectroscopy: (MH ⁺ ) 406.3.

Elemental analysis for C20H20E2N2O5:

C, 59.11 H, 4.96 N, ·· ····

-48156.89;

Found: C, 53.34 Η, 4.80 Ν, 6.94.

Example 332

Synthesis of methyl N-[N-(3,5-difluorophenoxyacetyl)-L-alaninyl]-L2.3-dihydroisoindole-1-carboxylate

Following the general procedure of AN, L-2,3-dihydro-1H-isoindole-1-carboxylic acid methyl ester hydrochloride (Gazz. Chim. Ital., 106 (1-2) pp. 65-75 (1976)) (417 mg) was coupled with N-(3,5-difluorophenylacetyl-L-alanine (prepared in Example B2) to give the title compound (150 mg).

The NMR data were as follows:

^-nmr (DMSO-d ₆ ): δ = 8.55 (d, 1H), 6.85-7.45 (m, 7H), 5.50(m, 1H), 4.95(s, 1H), 4.55-4.90 (m, 2+H), 3.65 (m, 3H), 1.30 (m, 3H).

C21H20F2N2O4:

Molecular weight - 402.40;

Mass spectroscopy: (MH ⁺ ) 402.3.

Example 333

Synthesis of Ν-[N-(3,5-difluorophenylacetye-L-alaninyl]-1-amino1,3-diphenylpropan-2-one

To a solution of 200 mg of N-methoxy-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide (prepared in Example 304 above) in THF was added 1.91 mL of a 2M solution of benzylmagnesium bromide in THF (Aldrich) at 0 °C. The reaction mixture was stirred at ambient temperature for 72 hours and then quenched by the addition of

-482-* ’ • · water. The reaction mixture was partitioned between ethyl acetate and water and the organic phase was washed with 1N HCl solution. After removal of the solvent under reduced pressure, the crude ketone was purified by chromatography on silica gel, eluting with ethyl acetate, to give 62 mg of the title compound as a 1:1 mixture of phenyl diastereomers.

The NMR data were as follows:

¹ H-nmr (CDCl3): (approximately 1:1 mixture of diastereomers) δ = 7.27.5 (m, 2H), 1.28-1.45 (doublets in the ratio 1:1, 3H).

Example 334

Synthesis of Ν-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycine thiocarboxamide

Step A. Preparation of tert-butoxycarbonylphenylglycine thiocarboxamide:

To a suspension of 500 mg (2.00 mmol) of tert-butoxycarbonyl-L-phenylglycine carboxamide (prepared as in Example 141) in 50 mL of anhydrous toluene was added 808 mg (2.00 mmol) of Lawesson's reagent (Aldrich). The reaction mixture was heated to 95 °C for 5 min. Cooling to ambient temperature and dilution with 1:1 ethyl acetate/hexanes resulted in precipitation of insoluble material. Removal of the soluble phase, followed by further washing of the solid and combination of the soluble phase and removal of the solvent provided the crude thiocarboxamide as a semi-solid. Purification by chromatography on silica gel, eluting with ethyl acetate, gave 364 mg of thiocarboxamide.

Step B. Preparation of phenylglycinethiocarboxamide hydrobromide: Solution 364 mg tert-butoxycarbonyl phenylglycine

-483 • fl ···· • flfl fl flfl·· • · · flfl · ·· ··· • fl flfl • ♦ · · fl · · · • flfl flflfl thiocarboxamide in 4 mL of 30% HBr in acetic acid was stirred for 1 h. The volatile materials were removed under reduced pressure and crude phenylglycinethiocarboxamide hydrobromide was obtained as a pale solid. The material was used without further purification.

To a stirred solution of 486 mg of (3,5-difluorophenylacetyl)-Lalanine (from Example B2) in 30 mL of dichloromethane was added 383 mg of EDCI, 270 mg of HOBT hydrate, followed by 350 μΐ of diisopropylethylamine. To this suspension was added phenylglycinethiocarboxamide hydrobromide in dichloromethane. The reaction mixture was stirred at ambient temperature for 72 hours. The reaction mixture was partitioned between water and dichloromethane and the organic phase was washed with 1N HCl solution, followed by saturated aqueous sodium bicarbonate solution. Removal of the solvent gave the crude product which was purified by chromatography on silica gel, eluting with ethyl acetate, to give 271 mg of the title compound (approximately 3:2 mixture of phenylglycine diastereomers) as a pale solid.

The NMR data were as follows:

¹ H-nmr (CDCl ₃ ): (approx. 3:2 mixture of diastereomers): δ = 7.37.7 (m, 8H), 6.7-6.8 (m, 4H).

Example 335

Synthesis of Ν-[N-(3,5-difluorophenyl-2oxoacetyl)-L-alaninyl]-L-phenylglycine tert-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 ··

-48ит ·· ···· ·· ·· • · · · · · · • ···· · 9 9 · • · 99 999 999

9 9 9 9 ·99 99 99 (prepared as described in J. Org. Chem., 45(14), 28883 (1980)), the title compound was prepared as a solid. The product was purified by suspending in EtOAc/hexanes.

Elemental analysis:

Calculated (%) C, 61.88, H, 5.42, N, 6.27;

Found: C, 62.15, H, 5.51, N, 6.18.

Example 336

Synthesis of N-(2-hydroxy-l-phenyleth-l-yl)-Ν'-[N-(3,5difluorophenylacetyl)-L-phenylglycinyl]-L-alaninamide

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-phenylglycinyl-L-alanine (which was prepared from N-(3,5-difluorophenylacetyl)-L-phenylglycinyl-L-alanine ethyl ester) and (S)-phenylglycinol (Aldrich), the title compound was prepared (mp = 269-272 °C). The reaction was monitored by thin layer chromatography (R _f = 0.3 in 10% MeOH/CHCl ₃ ) and the product was purified by chromatography using 10% MeOH/CHCl ₃ as the eluent.

The NMR data were as follows:

1 H-nmr (DMSO-d ₆ ): δ = 1.25 (d, 3H), 8.01 (d, 1H), 8.52 (d,

1H), 8.82 (d, 1H).

Optical rotation: [α]2o = -62.7 @ 589 nm (c = 1.02, DMSO). C27H27N ₃ O ₃ F2:

Molecular weight = 495.53;

Mass spectroscopy: (MH ⁺ ) 496.

Example 337

Synthesis of N-(2-hydroxyeth-1-yl)-N'-[N-(3,5-difluorophenylacetyl)-L-alanyl]-L-phenylglycinamide

-4 85·-:

Following general procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) and L-phenylglycine (2-hydroxyethyl)amide hydrochloride (which was prepared from N-BOC-L-phenylglycine (Bachem) and 2-aminoethanol (Aldrich) following general procedure C, followed by removal of the BOC group following general procedure P), the title compound was prepared. The product was purified by chromatography using 10% MeOH/CHCl3 as the eluent, followed by crystallization from EtOH.

The NMR data were as follows:

1H-nmr (DMSO-d ₆ ): δ = 1.22 (d, 3H), 5.42 (d, 1H).

Optical rotation: [α] ₂ o = +8.77 @ 589 nm (c = 1.03, DMSO). C21H23N3O4E2:

Molecular weight = 419.43;

Mass spectroscopy: (MH ⁺ ) 420.

Example 338

Synthesis of N-(4-(4-azido-2-hydroxybenzamido)but-1-yl)-N'-[N(3,5-difluorophenylacetyl)-L-alanyl]-L-phenylglycinamide

Following general procedure A and using N-(3,5-difluorophenylacetyl)-L-alanyl-L-phenylglycine (prepared as described above) and 4-(4-azidosalicylamido)butylamine (Pierce Chemical), the title compound was prepared as a light-sensitive solid. The reaction was carried out in low light and the reaction vessel was protected from light. The reaction was monitored by thin layer chromatography (R _f = 0.2 in 2.5% MeOH/dichloromethane).

The NMR data were as follows:

0

• 0

0 0 • · • 000 • 0 0 0 0 0 0 0

000 ¹ H-nmr (CD ₃ OH/CDC1 ₃ ) : δ = 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).

Example 339

Synthesis of N-(methanesulfonyl)-Ν' -[N-(3,5-difluorophenylacetyl)-Lalanyl]-L-phenylalanamide

N-Cbz-L-Phenylalanine (Sigma) was coupled with N-hydroxysuccinimide (Aldrich) using DCC in dichloromethane. The resulting intermediate was reacted with methanesulfonamide in DMF with diisopropylethylamine to give N-methanesulfonyl-N'-Cbz-L-phenylalanamide amide. The Cbz group was removed following general procedure O and the resulting intermediate was coupled with N-(3,5-difluorophenylacetyl)-L-alanine (prepared in Example B2 above) following general procedure B to give the title compound (mp = 203-205 °C).

Examples 340-407

Using the above procedures, the following additional compounds were prepared:

Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine, methyl ester (Example 340)

Ν-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(3-aphenyl)proline, methyl ester (Example 341)

-487-* ·· ···» ·< · · ·

N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-azetidine, methyl ester (Example 342) methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3(5-chlorobenzothiophen-2-yl)acetate (Example 343) tert-butyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2 amino-3-(thiazol-4-yl)propionate (Example 344) tert-butyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L phenylglycinamide (Example 345)

N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2yl)glycinamide (Example 346)

Ν-[N-(3,5-dichlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Example 347)

Ν-[N-(3-Chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Example 348)

N-[N-(3-Bromophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Example 349)

N-[N-(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Example 350)

Ν-[N-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Example 351)

Ν-[N-(3-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide ·· •· flfl«* flfl flfl

-488• fl ··· flflflfl • · · flflfl · flfl fl fl · · · flfl flflfl flflfl • flflfl flfl • flflfl flflfl flflfl flflfl (Example 352)

N-[N-(4-Methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide (Example 353)

N-[N-(3-trifluoromethylphenylacetyl)-L-alaninyl]-D-phenylglycinamide (Example 354)

N-[N-(3-Methoxyphenylacetyl)-L-alaninyl]-D-phenylglycinamide (Example 355)

N-[N-(2-Chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Example 356)

N-[N-(1-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide (Example

357)

N-[N-(2-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide (Example

358)

N-[N-(phenylacetyl)-L-alaninyl]-D-phenylglycinamide (Example

359)

N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine (Example 360)

Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino~2-(2-furanyl)acetamide (Example 361)

Ν' -[N-(3,4-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide (Example 362) • · • · ··· ···

-489• · • ·♦·

N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine-N-methylsulfonamide (Example 363)

N-Methyl-N-phenyl-N'-[n-(3,5-difluorophenylacetyl)-Lalaninyl]-glycinamide (Example 364)

N-Methyl-N-phenyl-N'-[N-(3,5-difluorophenylacetyl)-L-alanine]-L-alanineamide (Example 365)

N'-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinamide (Example 366)

N-methyl-N-benzyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-glycinamide (Example 367)

N-4-fluorobenzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl] L-phenylglycinamide (Example 368)

Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4fluoro)phenylglycine, neopentyl ester (Example 369)

Ν-[N-(2,3,4,5,6-pentafluorophenylacetyl)-L-alaninyl]-L-(pyrid 3-yl)glycine, methyl ester (Example 370)

N-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)serinyl]-L-phenylglycine, methyl ester (Example 371)

N-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)threoninyl]-L-phenylglycine, methyl ester (Example 372)

• ·

-490Ν-[Ν-(3,5-difluorophenylacetyl)-L-threoninyl]-L-phenylglycine, methyl ester (Example 373)

Ν-[N-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine, methyl ester (Example 374)

N-4-Methylphenyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl] L-phenylglycinamide (Example 375)

N-tetrahydrofurfuryl-N'-[N-(3,5-difluorophenylacetyl)-Lalaniny]-L-phenylglycinamide (Example 376)

Ν'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycinamide (Example 377)

N'-[N-(3,5-difluorophenylacetyl)-L-methionyl]-L-phenylglycinamide (Example 378)

N-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamide (Example 379)

N'-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinamide (Example 380)

Ν-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinamide (Example 381)

N-[(R)-α-methylbenzyl]-N'-[N-(3,5-difluorophenylacetyl)-Lalaniny]-L-phenylglycinamide (Example 382)

N-[1-phenyl-2-oxo-3-methylbutan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide (Example 383)

N-[1-Phenyl-2-oxo-propan-1-yl]-Ν'-(3,5-difluorophenylacetyl)-Lalaninamide (Example 384)

N-[1-Phenyl-2-oxo-pentan-1-yl]-Ν'-(3,5-difluorophenylacetyl)-Lalaninamide (Example 385)

N-[1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-Ν'-(3,5-difluorophenylacetyl)-L-alanine amide (Example 386)

N-[1-Phenyl-2-oxo-butan-1-yl]-N'-(3,5-difluorophenyl-acetyl)-Lalaninamide (Example 387)

N-[1-phenyl-2-oxo-4-methylpentan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide (Example 388)

Ν'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-αhydroxyphenylalanine, methyl ester (Example 389)

N-[4-((2-hydroxy-4-azido)-phenyl)-NHC(0)-)butyl] N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide (Example 390)

N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4fluorophenylglycine, tert-butyl ester (Example 391)

Ν' -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4phenylphenylglycine, tert-butyl ester (Example 392) [N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(2,3 • · • ·

-492benzo[b]proline), methyl ester (Example 393)

N-tert-butyl-N ¹ -[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-n-butylphenylglycinamide (Example 394)

N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]D,L-4-(phenylacetenyl)phenylglycinamide (Example 395)

N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinethioamide (Example 396)

N-[1,3-Diphenyl-2-oxo-propan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide (Example 397)

N-[1-Phenyl-2-oxo-2-cyclopentylethan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alanine amide (Example 398)

N-[1-Phenyl-2-oxo-hexan-1-yl]-N'-(3,5-difluorophenylacetyl)-Lalaninamide (Example 399)

N-[1-phenyl-2-oxo-3-methylpentan-1-yl]-Ν'-(3,5-difluorophenylacetyl)-L-alanine amide (Example 400)

N-n-hexyl-6-biotinamidyl-N'-[N-(3,5-difluorophenylacetyl)-Lalaninyl]-D,L-phenylglycinethioamide (Example 401)

Ν'-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionine (Example 402)

N'-[N-(2-t-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycine, methyl ester (Example 403) • ·

-493N-tert-butyl Ν'-[Ν-(3,5-difluorophenylacetyl)-L-alaninyl]-L2-fluorophenylglycinamide (Example 404)

N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-2-phenylglycine, methyl ester (Example 405)

Ν'-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L2-phenylglycine (Example 406)

N'-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L2-phenylglycine, tert-butyl ester (Example 407)

Example 408

Using the above procedures, the following additional compounds of general formula I were or could be prepared:

R ¹ represents 3,5-difluorophenyl; X' and X represent a hydrogen atom; R ² represents methyl; R ³ represents a hydrogen atom; R ⁴ represents p-fluorophenyl; R ⁵ represents a hydrogen atom; Z represents a bond, X is -C(O)OCH ₂ C(CH ₃ ) ₃ ; and n is equal to 1;

R ¹ represents 3,5-difluorophenyl; X' and X represent a hydrogen atom; R ² represents methyl; R ³ represents a hydrogen atom; R ⁴ represents p-(phenyl)phenyl; R ⁵ represents a hydrogen atom; X is -C(O)NHC(CH ₃ ) ₃ ; Z represents a bond; and n is equal to 1;

R ¹ represents cyclopentyl; X' and X represent a hydrogen atom; R ² represents methyl; R ³ represents a hydrogen atom; R ⁴ represents phenyl; R ⁵ represents a hydrogen atom; X is C(O)OC(CH ₃ ) ₃ ; Z represents a bond; and n is 1;

• ·

-494R ¹ represents cyclopropyl; X' and X” represent a hydrogen atom; R ² represents methyl; R ³ represents a hydrogen atom; R ⁴ represents phenyl; R ⁵ represents a hydrogen atom; X is C(0)OC(CH ₃ ) ₃ ; Z represents a bond; and n is equal to 1; and

R ¹ represents 3,5-difluorophenyl; X' and X represent a hydrogen atom; R ² represents methyl; R ³ represents a hydrogen atom; R ⁴ represents phenyl; R ⁵ represents a hydrogen atom; X is C(O)OCH ₂ C (CH ₃ ) 3; Z represents a bond; and n is equal to 1.

Example 409

Cellular screening for detection or inhibition of βamyloid formation

A number of compounds of formula I above were tested for their ability to inhibit β-amyloid formation in cells containing the Swedish mutation. This screening assay used cells (K293 = human kidney cell line) that had been stably transfected with the amyloid precursor protein 751 (APP751) gene containing the double mutation Lys65iMet65 ₂ to Asn ₆ 5iLeu ₆ 5 ₂ (in APP751 numbering) as described in International Patent Application Publication No. 94/105698 and in Citron et al. ¹² . This mutation is commonly referred to as the Swedish mutation and the cells, designated "293,751 SWE", were plated in Corning 96-well plates at 1.5-2.5 x ¹⁰⁴ cells per well in Dulbecco's minimal essential medium supplemented with 10% fetal bovine serum. The number of cells is important to achieve ELISA results for β-amyloid in the linear range of the assay (approximately 0.2 to 2.5 ng per ml).

-495After overnight incubation at 37°C in an incubator equilibrated with 10% carbon dioxide, the media was removed and replaced with 200 μΐ of the compound of general formula I (drug) containing media per well for a two-hour pretreatment and the cells were incubated as above.

Drug stock solutions were prepared

100) of dimethyl sulfoxide, so that at the final concentration of the drug used in the processing, the concentration of dimethyl sulfoxide does not exceed 0.5% and is in fact usually equal to 0.1%.

At the end of the pretreatment period, the media was again removed and replaced with fresh drug-containing media as described above and the cells were incubated for an additional two hours. Following this treatment, the plates were centrifuged in a Beckman GPR at 1200 rpm for five minutes at ambient temperature to pellet cell debris from the treated media. From each well, 100 μΐ of treated media or an appropriate dilution thereof was transferred to an ELISA plate coated with the antibody 266 ¹⁴ against amino acids 13-28 of the β-amyloid peptide, which is described in International Patent Application Publication No. 94/105698, and stored at 4°C overnight. An ELISA assay using labeled antibodies 6C6 ¹⁴ against amino acids 1-16 of the β-amyloid peptide was performed the following day to determine the amount of β-amyloid peptide formed.

The cytotoxic effects of the compounds were measured by a modification of the method described by Hansen et al., ¹³ . To the cells remaining in the tissue culture plate, 25 μΐ of stock • ·

-496solution (5 mg/ml) of 3,(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) to a final concentration of 1 mg/ml. Cells were incubated at 37°C for one hour and cell activity was stopped by adding an equal volume of MTT lysis buffer (20% w/v sodium dodecyl sulfate in 50% dimethylformamide, pH 4.7). Complete extraction was achieved by shaking overnight at ambient temperature. The difference between OD5 ₆ 2nm and OD _650nm was measured in a Molecular Device UV _max microplate reader as an indicator of cell viability.

The results of the ELISA analysis of β-amyloid peptides were adjusted to a standard curve and expressed as ng/ml of β-amyloid peptides. To normalize for cytotoxicity, these results were divided by the MTT results and expressed as a percentage of the result against the control sample without drug. All results represent the mean value and standard deviation of at least six replicate experiments.

The test compounds were analyzed for activity in inhibiting the formation of β-amyloid peptides in cells using this assay. The results of this assay show that each of the compounds of the present invention tested reduced the formation of β-amyloid peptides by at least 30% compared to the control sample.

Example 410

In vivo inhibition of β-amyloid release and/or synthesis

This example illustrates how the compounds of the present invention

-497• φφ ·· φφφφ ·· ·· · · φφφ · · · ♦ • · φ···· φφφφ • φ φφ φφ φφφφφφ φ φ φφφφ φ φ φ φφφ φ •ΦΦ φφφφ φφφφ φφφ ·· ·· of the invention can be tested for in vivo inhibition of β-amyloid release and/or synthesis. 3- to 4-month-old PDAPP mice were used for these experiments [Games et al., (1995) Nature 373:523-527]. Depending on which compound was tested, the compound was usually prepared at a concentration of 5 or 10 mg/ml. Due to the low solubility of the compounds, they could be administered with various vehicles, such as corn oil (Safeway, South San Francisco, CA); 10% EtOH in corn oil (Safeway); 2-hydroxypropyl-cyclodextrin (Research Biochemicals International, Natick MA); and carboxymethyl cellulose (Sigma Chemical Co., St. Louis MO). Specifically for Example 141, the vehicle was carboxymethyl cellulose (Sigma).

Mice were dosed subcutaneously using a 26-gauge needle and after 3 hours the animals were sacrificed under _CO2 anesthesia and blood was collected by cardiac puncture using a 1 cc 25G 5/8 tuberculin syringe/needle coated with 0.5 M EDTA solution, pH 8.0. The blood was placed in a Becton-Dickinson vacuum tube containing EDTA and centrifuged for 15 minutes at 1500 g at 5°C. The mouse brains were then removed and the cortex and hippocampus were dissected and placed on ice.

1. Brain test

To prepare hippocampal and cortical tissue for enzyme-linked immunosorbent assay (ELISA), each brain region was homogenized in 10 volumes of ice-cold guanidine buffer (5.0 M guanidine-HCl, 50 mM Tris-HCl, pH 8.0) using a Kontes motorized grinder (Fisher, Pittsburgh PA). The homogenates were gently homogenized on a rotating platform for three to four hours at ambient temperature and stored at ...

-498 at -20 °C by quantitative determination of β-amyloid.

Brain homogenates were diluted 1:10 with ice-cold casein buffer [0.25% casein, phosphate-buffered saline (PBS), 0.05% sodium azide, 20 μg/ml aprotinin, 5 mM EDTA, pH 8.0, 10 pg/ml leupeptin], reducing the final guanidine concentration to 0.5 M before centrifugation at 16,000 g for 20 min at 4°C. β-amyloid standards (amino acids 1-40 or 1-42) were prepared so that the final composition was equal to 0.5 M guanidine in the presence of 0.1% bovine serum albumin (BSA).

The total β-amyloid sandwich ELISA, measuring both β-amyloid (amino acids 1-40) and β-amyloid (amino acids 1-42), consisted of two monoclonal antibodies (mAbs) against β-amyloid. The capture antibody, 266 ¹⁴ , is specific for amino acids 13-28 of β-amyloid. The 3D6 ¹⁵ antibody, which is specific for amino acids 1-5 of β-amyloid, was biotinylated and served as the second (reporter) antibody in the assay. The 3D6 biotinylation procedure used the manufacturer's protocol (Pierce, Rockford IL) for NHS-biotin labeling of immunoglobulin except that 100 mM sodium bicarbonate, pH 8.5 buffer was used. The 3D6 antibody does not recognize secreted amyloid precursor protein (APP) or full-length APP, but only detects β-amyloid amino-terminal aspartic acid species. The assay had a lower limit of sensitivity of approximately 50 pg/mL (11 pM) and showed no cross-reactivity to endogenous mouse β-amyloid peptide at concentrations up to 1 ng/mL.

-499• fl fl··· flfl flfl • fl · · · · • flflfl · flfl fl • flfl flflfl flflfl • · · · • fl flflfl flfl flfl

The sandwich ELISA assay configuration for βamyloid (amino acids 1-42) uses monoclonal antibody 21F12 ¹⁵ (which recognizes amino acids 33-42 of βamyloid) as the first (capture) antibody. Biotinylated 3D6 is also the indicator antibody in this assay, which has a lower limit of sensitivity of approximately 125 pg/mL (28 pM).

266 and 21F12 capture monoclonal antibodies were coated at 10 μg/mL on 96-well immunoassay plates (Costar, Cambridge MA) overnight at ambient temperature. Plates were then aspirated and blocked with 0.25% human serum albumin in PBS buffer for at least 1 hour at ambient temperature, then stored desiccated at 4°C until use. Plates were rehydrated with wash buffer (Tris-buffered saline, 0.05% Tween 20) prior to use. Samples and standards were added to the plates and incubated overnight at 4°C. Plates were washed 3 times with wash buffer between each assay step. Biotinylated 3D6, diluted to 0.5 μg/ml in casein incubation buffer (0.25% casein, PBS, 0.05% Tween 20, pH 7.4) was incubated in the wells for 1 hour at ambient temperature. Avidin-HRP (Vector, Burlingame CA) diluted 1:4000 in casein incubation buffer was added to the wells for 1 hour at ambient temperature. The colorimetric substrate, Slow TMB-ELISA (Pierce, Cambridge MA), was added and allowed to react for 15 minutes, after which the enzymatic reaction was stopped by adding 2 N H2SO4. The reaction product was quantified using a Molecular Devices V _raax (Molecular Devices, Menlo Park CA) by measuring the difference in absorbance

-500- • «· ·· ···« *· 9 · · · · · * ·· * · · r ··· * * • · · · · ♦ e ··* 9 · · · · · ítt «999 »* ··· • · • · 9 9* 9 • » at 450 nm and 650 nm. 2. Blood test EDTA plasma was diluted 1:1 in sampling diluent (0.2 g/l phosphate sodium . h ₂ o (monobasic) , 2.16 g/i sodium phosphate _.7H2O (dibasic) , 0.5 g/l thimerosal,

8.5 g/L sodium chloride, 0.5 ml TritonX-405, 6.0 g/L globulin-free bovine serum albumin and water). Samples and standards in sample diluent were tested using the total βamyloid assay (266 capture antibody/3D6 indicator antibody) described above for the brain assay except that sample diluent was used instead of casein diluent.

Various modifications and changes to the compositions and methods may be made by those skilled in the art in comparison with the above description. All such modifications fall within the scope of the appended claims.

Claims (38)

PATENT CLAIMS JUDr. Otakar Švorčík attorney 120 00 Prague 2, Halkova 2 501? (/ ·· ·· A method for inhibiting the release of β-amyloid peptide and / or its synthesis in a cell, comprising administering to said cell an amount of a compound or mixture of compounds effective to inhibit cell release and / or synthesis of β-amyloid peptide, and said compounds being represented by the general formula (I): wherein R ¹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and a heterocyclic system; R ² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, and the heterocyclic system; each R ³ is independently selected from the group consisting of hydrogen and methyl, and R ³ together with R ⁴ may be joined to form a cyclic structure containing from 3 to 8 atoms, which is optionally fused with an aryl or heteroaryl group; each R ⁴ is independently selected from the group consisting of: Hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl, and substituted alkynyl groups; each R ⁵ is selected from the group consisting of hydrogen and methyl or together with R ⁴ forms a cycloalkyl group containing from 3 to 6 carbon atoms; X is selected from the group consisting of -C (O) Y and -C (S) Y, wherein Y is selected from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl, with substitution on said substituted alkyl does not include α-haloalkyl, adiazoalkyl, α-OC (O) alkyl, or α-OC (O) aryl, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl (g) heteroaryl, (h) a heterocyclic system, (i) -NR'R, wherein R 'and R are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl , cycloalkyl, aryl, heteroaryl, a heterocyclic system wherein one of R 'or R is hydroxy or alkoxy and wherein R' and R are joined together to form a cyclic group having from 2 to 8 carbon atoms, optionally containing 1 to 2 others heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups, -503 (j) -NHSO ₂ -R ⁸ wherein R ⁸ is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, and a heterocyclic system, (k) -NR ⁹ NR ¹⁰ R ¹⁰ wherein R ⁹ is hydrogen or alkyl and each R ¹⁰ is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -ONR ⁹ [C (O) O] _Z R ¹⁰ , wherein z is zero or one and R ⁹ and R ¹⁰ are as defined above; X may also be -CR ⁶ R ⁶ Y ', wherein each R ⁶ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and the heterocyclic system and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -OC (O) R ⁷ , -SSR ⁷ , -SSC (O) R ⁷ , wherein R ⁷ is selected from the group consisting of alkyl, substituted alkyl , cycloalkyl, aryl, heteroaryl and heterocyclic systems, X 'represents a hydrogen atom, hydroxy, or fluorine; X is hydrogen, hydroxy, or fluoro, or X 'and X together form an oxo group; Z is selected from the group consisting of a covalent bond that binds R ¹ to -CX'X-, an oxygen atom, and a sulfur atom; n is an integer equal to 1 or 2; and pharmaceutically acceptable salts thereof, provided 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 "• • · · · · * · -504 represents a hydrogen atom, Z represents a bond and n is 1, then X is not -C (O) OH; 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 and n is 1, then X is not -C (O) OH or -C (O) OCH 3; C. when R ¹ is phenyl, R ² is methyl, R ⁴ is benzyl, R ⁵ is hydrogen, X is methoxycarbonyl, X 'and X are hydrogen, Z is a bond and is 1, then R ^{3 is} not methyl; D. when ^R1 is iso-propyl, ^R2 is -CH2C (O) NH2, ^R3 is hydrogen, ^R4 is isobutyl, ^R5 is hydrogen, X 'and X are hydrogen, Z is a bond and n is equal to 1, then X is not -C (O) OCH 3; E. when R ¹ is phenyl, R ² is methyl, R ⁵ is hydrogen, X is -C (O) OCH ₃ , X 'and X are hydrogen, Z is a bond and n is 1, then R ³ , nitrogen atom attached to R ³ and R ⁴ do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. when R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁵ is hydrogen, X is C (O) OCH ₃ , X 'and X are hydrogen, Z is a bond and is 1, then R ^{4 is} not 4-amino-n-butyl; G. when R ¹ is 3-nitrophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is CH (OH) CH ₃ , R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and is equal to 1, then X -505 is not -C (O) NH ₂ or -CH ₂ OH; H. when R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁵ is hydrogen, X is CH 2 OCH 3, X 'and X are hydrogen, Z is a bond and n is 1, then R ^{4 is} not benzyl; or ethyl; I. when R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is methyl, R ⁴ is methyl, R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and is 1, then X is not -CHOHO; J. when ^R1 is 3,5-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 <Z> or -CH2OH; K. when ^R1 is N- (2-pyrrolidinonyl), ^R2 is methyl, ^R3 is hydrogen, ^R4 is benzyl, ^R5 is hydrogen, X 'and X are hydrogen, Z is a bond and n is equal to 1, then X is not -C (O) OCH ₃ ; L. when ^R1 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 represents hydrogen, Z is a bond and n is 1, then X is not -C (O) NH-benzyl; M. when R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is hydrogen, R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and is 1 then X is not -CH ₂ OH; -507 • 0 • 0 0 • 0 · · 0 0 0 · 0 0 0 0 0 0 0 0 0 0 · 0000 0 · · · 0 0 0 0 0 0 0000 0 00 · 0,000,000 ··· 0 0 · 00 000 0 · · · N. when R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is ^4- phenylphenyl, R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and is 1, then X is not -C (O) NHC (CH ₃ ) ₃ ; and O. when R ¹ represents 3,5-difluorophenyl, R ² represents methyl, R ³ represents hydrogen, R ⁴ represents phenyl derived from D-phenylglycine, R ⁵ represents hydrogen, X 'and X represent hydrogen, Z represents a bond and n is 1, then X is not -C (O) NHCH (CH ₃ ) Φ. 2. A method of preventing the onset of Alzheimer's disease in a patient at risk of developing Alzheimer's disease, comprising administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or mixture of compounds of Formula I: wherein R ¹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and a heterocyclic system; R ² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, ·· ·· · a · • • • · · -507 and the heterocyclic system; each R ³ is independently selected from the group consisting of hydrogen and methyl, and R ³ together with R ⁴ may be joined to form a cyclic structure containing from 3 to 8 atoms, which is optionally fused with an aryl or heteroaryl group; each R ⁴ 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 R ⁵ is selected from the group consisting of hydrogen and methyl or together with R ⁴ forms a cycloalkyl group containing from 3 to 6 carbon atoms; X is selected from the group consisting of -C (O) Y and -C (S) Y, wherein Y is selected from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl, with substitution on said substituted alkyl does not include α-haloalkyl, adiazoalkyl, α-OC (O) alkyl, or α-OC (O) aryl, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl (g) heteroaryl, (h) a heterocyclic system, (i) -NR'R, wherein R 'and R are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl , cycloalkyl, aryl, heteroaryl, heterocyclic A -508 system wherein one of R 'or R is hydroxy or alkoxy and wherein R' and R are joined together to form a cyclic group having from 2 to 8 carbon atoms, optionally containing 1 to 2 additional heteroatoms selected from the group consisting of: comprising an oxygen atom, a sulfur atom and a nitrogen atom and optionally substituted by one or more alkyl, alkoxy or carboxylalkyl groups; (j) -NHSO ₂ -R ⁸ wherein R ⁸ is selected from alkyl, substituted alkyl, alkenyl, substituted an alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic system, (k) -NR ⁹ NR ¹⁰ R ¹⁰ wherein R ⁹ is hydrogen or alkyl and each R ¹⁰ is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic system, and (1) -ONR ⁹ [C (O) O] _Z R ¹⁰ , wherein z is zero or one and R ⁹ and R ¹⁰ are as defined above; X may also be -CR ⁶ R ⁶ Y ', wherein each R ⁶ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and the heterocyclic system and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -OC (O) R ⁷ , -SSR ⁷ , -SSC (O) R ⁷ , wherein R ⁷ is selected from the group consisting of alkyl, substituted alkyl , cycloalkyl, aryl, heteroaryl and heterocyclic systems, X 'represents a hydrogen atom, hydroxy, or fluorine; X is hydrogen, hydroxy, or fluoro, or X 'and X together form an oxo group; Z is selected from the group consisting of a covalent bond which -509 • 9 9 • 99 9 99,999 • 9 9 9 9 9 9 9999998 99 999 99 99 9 9 999 999 binds R ¹ to -CX'X-, an oxygen atom and a sulfur atom; n is an integer equal to 1 or 2; and pharmaceutically acceptable salts thereof, provided that: A. when R ¹ is phenyl or 3-nitrophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is -CH (OH) CH ₃ , R ⁵ is hydrogen, X 'and X are hydrogen, Z is and n is 1, then X is not -C (O) OH; 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 and n is 1, then X is not -C (O) OH or -C (O) OCH 3; C. when R ¹ is phenyl, R ² is methyl, R ⁴ is benzyl, R ⁵ is hydrogen, X is methoxycarbonyl, X 'and X are hydrogen, Z is a bond and is 1, then R ^{3 is} not methyl; D. when ^R1 is iso-propyl, ^R2 is -CH2C (O) NH2, ^R3 is hydrogen, ^R4 is isobutyl, ^R5 is hydrogen, X 'and X are hydrogen, Z is a bond and n is equal to 1, then X is not -C (O) OCH 3; E. when R ¹ is phenyl, R ² is methyl, R ⁵ is hydrogen, X is -C (O) OCH ₃ , X 'and X are hydrogen, Z is a bond and n is 1, then R ³ , nitrogen atom attached to R ³ and R ⁴ do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. when R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁵ is hydrogen, X is * φ φ φ φ φ φ φ φ φφφ φφφφ -510 ·· «··· C (O) OCH ₃ , X 'and X represent a hydrogen atom, Z represents a bond and is 1, then R ^{4 is} not 4-amino-n-butyl; G. when ^R1 is 3-nitrophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is CH (OH) CH3, ^R5 is hydrogen, X 'and X are hydrogen, Z is a bond and n is equal to 1, then X is not -C (O) NH ₂ or -CH ₂ OH; H. when R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁵ is hydrogen, X is CH ₂ OCH 3, X 'and X are hydrogen, Z is a bond and n is 1, then R ^{4 is} not benzyl or ethyl; I. when R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is methyl, R ⁴ is methyl, R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and is 1, then X does not represent -ΟΗΟΗΦ; J. when ^R1 is 3,5-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 -ΟΗΟΗΦ or -CH ₂ OH; K. when ^R1 is N- (2-pyrrolidinonyl), ^R2 is methyl, ^R3 is hydrogen, ^R4 is benzyl, ^R5 is hydrogen, X 'and X are hydrogen, Z is a bond and n is equal to 1, then X is not -C (O) OCH ₃ ; L. when ^R1 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 "represent hydrogen atom, -511 ·· ·· · · · · · · · Z is a bond and n is 1, then X is not -C (O) NH-benzyl; M. when R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is hydrogen, R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and is 1 then X is not -CH 2 OH; N. when R ¹ represents 3,5-difluorophenyl, R ² represents methyl, R ³ represents hydrogen, R ⁴ represents ^4- phenylphenyl, R ⁵ represents hydrogen, X 'and X represent hydrogen, Z represents a bond and is 1, then X is not -C (O) NHC (CH ₃ ) ₃ ; and O. when ^R1 is 3,5-difluorophenyl, ^R2 is methyl, ^R3 is hydrogen, ^R4 is phenyl derived from D ·-phenylglycine, ^R5 is hydrogen, X 'and X are hydrogen, Z is and n is 1, then X is not -C (O) NHCH (CH ₃ ) Φ. 3. A method of treating a patient suffering from Alzheimer's disease to prevent further deterioration of the condition of said patient, comprising administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or mixture of compounds of Formula I: -512 ο R ⁴ R ⁵ · R ⁴ · · · 4 X ’X R’Z R2 R 3 wherein R ¹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and a heterocyclic system; R ² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, and the heterocyclic system; each R ³ is independently selected from the group consisting of hydrogen and methyl, and R ³ together with R ⁴ may be joined to form a cyclic structure containing from 3 to 8 atoms, which is optionally fused with an aryl or heteroaryl group; each R ⁴ 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 R ⁵ is selected from the group consisting of hydrogen and methyl or together with R ⁴ forms a cycloalkyl group containing from 3 to 6 carbon atoms; X is selected from the group consisting of -C (O) Y and -C (S) Y, wherein Y is selected from the group consisting of (a) alkyl or cycloalkyl, -513 • ΦΦ ΦΦ φ φφφ Φ ΦΦΦ Φ ΦΦΦ φφφ (B) substituted alkyl, with the substitution on said substituted alkyl not including α-haloalkyl, adiazoalkyl, α-OC (0) alkyl, or α-OC (0) aryl, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) a heterocyclic system, (i) -NR'R wherein R 'and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, a heterocyclic system wherein one of R 'or R is hydroxy or alkoxy and wherein R' and R are taken together 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 to (j) -NHSO 2 -R ⁸ , wherein R ⁸ is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, and a heterocyclic system, (k) -NR ⁹ NR ¹⁰ R ¹⁰ wherein R ⁹ is hydrogen or alkyl and each R ¹⁰ is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -ONR ⁹ [C (O) 0] _Z R ¹⁰ where z is zero or one and R ⁹ and R ¹⁰ have ·· to · · -514 it to this it to it this to it this to · this · to · this · to · this · to · this · to · this · to · this · to · this · to · this · · To the meaning defined above; X may also be -CR ⁶ R ⁶ Y ', wherein each R ⁶ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and the heterocyclic system and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -OC (O) R ⁷ , -SSR ⁷ , -SSC (O) R ⁷ , wherein R ⁷ is selected from the group consisting of alkyl, substituted alkyl , cycloalkyl, aryl, heteroaryl and heterocyclic systems, X 'represents a hydrogen atom, hydroxy, or fluorine; X is hydrogen, hydroxy, or fluoro, or X 'and X together form an oxo group; Z is selected from the group consisting of a covalent bond that binds R ¹ to -CX'X-, an oxygen atom, and a sulfur atom; n is an integer equal to 1 or 2; and pharmaceutically acceptable salts thereof, provided that: A. when R ¹ is phenyl or 3-nitrophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is -CH (OH) CH ₃ , R ⁵ is hydrogen, X 'and X are hydrogen, Z is and n is 1, then X is not -C (O) OH; 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 and n is 1, then X is not -C (O) OH or -C (O) OCH 3; C. when R ¹ is phenyl, R ² is methyl, R ⁴ is benzyl, R ⁵ is hydrogen, X is methoxycarbonyl, X 'and X are hydrogen, Z -515 ·· flflfl · ** 44 9 · fc · flflfl 4 9 4 4 9 fl fl * flflfl flflfl • flfl flfl • fl ··· ·· ·· represents a bond and is equal to 1, then R ^{3 is} not methyl; D. when ^R1 is iso-propyl, ^R2 is -CH2C (O) NH2, ^R3 is hydrogen, ^R4 is isobutyl, ^R5 is hydrogen, X 'and X are hydrogen, Z is a bond and n is equal to 1, then X is not -C (O) OCH 3; E. when R ¹ is phenyl, R ² is methyl, R ⁵ is hydrogen, X is -C (O) OCH ₃ , X 'and X are hydrogen, Z is a bond and n is 1, then R ³ , nitrogen atom attached to R ³ and R ⁴ do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. when R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁵ is hydrogen, X is C (O) OCH ₃ , X 'and X are hydrogen, Z is a bond and is 1, then R ^{4 is} not 4-amino-n-butyl; G. when ^R1 is 3-nitrophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is CH (OH) CH3, ^R5 is hydrogen, X 'and X are hydrogen, Z is a bond and n is equal to 1, then X is not -C (O) NH 2 or -CH ₂ OH; H. when R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁵ is hydrogen, X is CH ₂ OCH ₃ , X 'and X are hydrogen, Z is a bond and n is 1, then R ⁴ it is not benzyl or ethyl; I. when R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is methyl, R ⁴ is methyl, R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and n is 1, then X is not -CHOH <P; • 9 9 9 -516 · 9 9 9 · 9 9 9 9 9 999 9 99 9 9 99 99 99 999999 9 9 9 9 9 9 999 99 99 99 99 99 J. when ^R1 is 3,5-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 -CHOHO or -CH ₂ OH; K. when ^R1 is N- (2-pyrrolidinonyl), ^R2 is methyl, ^R3 is hydrogen, ^R4 is benzyl, ^R5 is hydrogen, X 'and X are hydrogen, Z is a bond and n is equal to 1, then X is not -C (O) OCH ₃ ; L. when R ¹ represents 3,5-difluorophenyl, R ² represents methyl derived from D-alanine, R ³ represents hydrogen, R ⁴ represents phenyl derived from D-phenylgiycin, R ⁵ represents hydrogen, X 'and X represent atom hydrogen, Z is a bond and n is 1, then X is not -C (O) NH-benzyl; M. when R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is hydrogen, R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and is 1 then X is not -CH ₂ OH; N 'when R ¹ represents 3,5-difluorophenyl, R ² represents methyl, R ³ represents hydrogen, R ⁴ represents ^4- phenylphenyl, R ⁵ represents hydrogen, X' and X represent hydrogen, Z represents a bond and is 1, then X is not -C (O) NHC (CH ₃ ) ₃ ; and 0 when R ¹ is 3,5-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 (O) NHCH (CH ₃ ) Φ. · ·-·------------------------- · · · · · · · · · · · * A process according to claim 1, 2 or 3 wherein R ¹ represents an unsubstituted aryl group and Z represents a covalent bond that binds R ¹ to -CX'X-. The process of claim 4 wherein the unsubstituted R ¹ aryl group is selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl. A process according to claim 1, 2 or 3 wherein R ¹ represents a substituted aryl group and Z represents a covalent bond that binds R ¹ to -CX'X-. The process of claim 6, wherein said substituted aryl group is a mono-substituted, disubstituted or tri-substituted phenyl group. The method of claim 7, wherein the substituted phenyl group is selected from the group consisting of 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2-hydroxyphenyl, 2-methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 3,4-dibromophenyl, 3,4-dichlorophenyl, 3,4-methylenedioxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2,4- dichlorophenyl and 2,5-difluorophenyl. A method according to claim 1, 2 or 3, characterized in that: R ¹ represents an alkaryl group and Z represents 99 99 9 - ^ 18 * μ. • 99 9 • 99 9 A covalent bond that binds R ¹ to -CX'X-. The process of claim 9, wherein the R ¹ alkaryl group is selected from benzyl, 2-phenylethyl and 3-phenyl-n-propyl. The process of claim 1, 2 or 3 wherein R ¹ is selected from the group consisting of alkyl, alkenyl, cycloalkyl and cycloalkenyl and Z is a covalent bond that binds R ¹ to -CX'X-. 12. Method represents according to claim alkyl. 11, confessing se by that R ¹ 13. Method represents according to claim cycloalkyl. 11, confessing se by that R ¹ 14. Method represents according to claim alkenyl. 11, characterized se by that R ¹ 15. Method according to claim 11, confessing se by that R ¹ represents cycloalkenyl. 16. The method of claim 11 wherein said R ¹ alkyl, cycloalkyl, alkenyl and cycloalkenyl groups are selected from the group consisting of isopropyl, n-propyl, n-butyl, iso-butyl, sec-butyl, tert. butyl, -CH ₂ CH = CH ₂ , -CH ₂ CH = CH (CH ₂ ) ₄ CH ₃ , cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH ₂ cyclopropyl, -CH ₂ -cyclobutyl, - CH ₂ -cyclohexyl, -CH ₂ cyclopentyl, -CH ₂ CH ₂ -cyclopropyl, -CH ₂ CH ₂ -cyclobutyl, -CH ₂ CH ₂ ···· · · cyclohexyl, -CH ₂ CH ₂ -cyclopentyl, aminomethyl and N -tert-butoxycarbonylaminomethyl. The method of claim 1, 2 or 3 wherein R ¹ is selected from the group consisting of heteroaryl and substituted heteroaryl and Z represents a covalent bond that binds R ¹ to -CX'X-. The method of claim 17 wherein R ¹ heteroaryl and substituted heteroayl are selected from pyrid-2-yl, pyrid-3yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyridine) 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, thionaphten-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2 (thiophenyl) thiophen-5-yl, 6-methoxythionaphten-2-yl, 3-phenyl-1,2,4- thiooxadiazol-5-yl and 2-phenyloxazol-4-yl. 19. The method of claim 1, 2 or 3, characterized in that R ² is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. 20. The method according to claim 9, characterized in that R ² is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl ·, iso-butyl, sec-butyl, phenyl, 4-fluorophenyl , 3,5-difluorophenyl, 4-methoxyphenyl, benzyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, thien-2-yl, thien-3-yl, -CH ₂ CH ₂ SCH ₃ , -CH ₂ OCH ₂ O, -CH (CH ₃ ) OCH ₂ <Z>, CH (OH) CH _3, and -CH ₂ OH. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 21. The method of claim 1, 2 or 3, characterized in that X 'and X are hydrogen and Z is a covalent bond, which links R ¹ to -CX'X-. The method of claim 21, wherein R ³ is selected from the group consisting of hydrogen, methyl, or together with R ⁴ and the nitrogen atom to which R ^{3 is} attached to form pyrrolidin-2-yl, 2,3 -dihydroindol-2-yl, piperidin-2-yl, 4-hydroxy-pyrrolidin-2-yl and 1,2,3,4-tetrahydroisoquinolin-3-yl. A process according to claim 1, 2 or 3 wherein R ⁴ is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, iso- butyl, cyclopentyl, cyclohexyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH ₂ -cyclopropyl, CH ₂ -cyclohexyl, -CH ₂ -indol-3-yl, phenyl, p- (phenyl) phenyl, m (phenyl) phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, p-bromophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, mtrifluoromethylphenyl, p- ( CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ O-benzyl, p (CH ₃ ) ₃ COC (O) CH ₂ O-benzyl, p-phenylphenyl, 3,5-difluorophenyl, p (HOOCCH ₂ O) -benzyl, 2 -aminopyrid-6-yl, 4- (N-morpholinoCH ₂ CH ₂ O) -benzyl, -CH ₂ CH ₂ C (O) NH ₂ , -CH ₂ -imidazol-4-yl, -CH ₂ - (3-tetrahydrofuranyl) , -CH ₂ -thien-2-yl, -CH ₂ -thiazol-4-yl, CH ₂ (1-methyl) cyclopropyl, -CH ₂ -thien-3-yl, thien-3-yl, thien-2-yl, -CH ₂ -C (O) O-tert. -butyl, -CH ₂ -C (CH ₃ ) ₃ , -CH ₂ CH (CH ₂ CH ₃ ) ₂ , 2-methylcyclopentyl, -cyclohex-2-enyl, -CH [CH (CH ₃ ) ₂ ] COOCH ₃ , (CH ₂ ) ₂ SCH ₃ , -CH ₂ CH ₂ N (CH ₃ ) 2, -CH ₂ C (CH ₃ ) = ch ₂ , -ch ₂ ch = ch ₃ (cis and trans), -CH ₂ OH, -CH (OH) CH ₃ , -CH (O-tert-butyl) CH ₃ , flflflflflflfl CH ₂ OCH _3, - (CH ₂₎ 4 NH-B0C, - (CH _{2) 4} NH _2, - (CH ₂₎ 4 N (CH 3) 2, -CH ₂ pyridinyl, pyridyl, -CH ₂ -naphthyl, -CH ₂ - (N-morpholino), ρ- (Nmorpholino-CH ₂ CH ₂ O) -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, -CH ₂ -N-phthalimidyl, 2-methylthiazol-4-yl, and thieno [2,3-b] thiophen-2-yl, 5-bromothien-2-yl, 4-bromothien -2-yl, 5-chlorothien-2-yl, 3-phenoxyphenyl, 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. The method of claim 1, 2 or 3, characterized in that Z is a covalent bond, which links to R ¹ and R -CX'X- ⁴ and R ⁵ are joined to form a cycloalkyl group selected from the group consisting of cyclopropyl and cyclobutyl. 25. The method of claim 1, 2 or 3, characterized in that Z is a covalent bond, which links R ¹ to -CX'X-, X is -C (O) Y and Y is selected from the group consisting of hydroxy , alkoxy or substituted alkoxy. 26. The method of claim 25 wherein Y is alkoxy or substituted alkoxy selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy. , neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, -ONHC (O) OC (CH ₃ ) 3, -ONHC (CH _{3) 13} and hydroxy. 00 0000 • 0 0.000 • 0 .0 * • 0 · · 0 · · · 00 000 000 0 0 0 0 · 0 0 27. The method of claim 1, 2 or 3, characterized in that Z is a covalent bond, which links R ¹ to -CX'X ~, X is -C (O) Y and Y is -NR'R. 28. The method according to claim 27, characterized in that Y is selected from the group consisting of amino _(-NH2), -NH (iso-butyl), -NH (sec-butyl), N-methylamino, N, N-dimethylamino , N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethylenimino, N-heptamethylenimino, N-pyrrolidinyl, -NH-methallyl, -NHCH ₂ (furan-2-yl), -NHCH ₂ -cyclopropyl, - NH (tert-butyl), -NH (pmethylphenyl), -NHOCH ₃ , -NHCH 2 (p-fluorophenyl), -NHCH ₂ CH ₂ OCH ₃ , NH-cyclopentyl, -NH-cyclohexyl, -NHCH ₂ CH ₂ N (CH ₃ ) ₂ , NHCH ₂ C (CH ₃ ) ₃ , -NHCH ₂ - (pyrid-2-yl), -NHCH ₂ - (pyrid-3-yl), NHCH ₂ - (pyrid-4-yl), N-thiazolindinyl, -N (CH ₂ CH ₂ CH ₃ ) ₂ , N [CH ₂ CH (CH ₃ ) ₂ ] ₂ , -NHOH, -ΝΗ (ρ-ΝΟ ₂ -Φ), -NHCH ₂ (Ρ-ΝΟ2-Φ), NHCH ₂ (m -NO ₂ - (2), -N (CH ₃ ) OCH ₃ , -N (CH ₃ ) CH ₂ - <Z>, -NHCH ₂ - (3,5-difluorophenyl), -NHCH ₂ CH ₂ F, -NHCH ₂ (p-CH ₃ O-?), -NHCH ₂ (m-CH ₃ O-O), -NHCH ₂ (p-CF ₃ -? Z), -N (CH ₃ ) CH ₂ CH ₂ OCH ₃ , -NHCH ₂ CH ₂ O, -NHCH (CH ₃ ) 0, NHCH ₂ - (pF-Φ), -N (CH ₃ ) CH ₂ CH ₂ N (CH ₃ ) ₂ , -NHCH ₂ - (tetrahydrofuran- ₂ -yl), -NHCH ₂ (p-trifluoromethylphenyl), -NHCH ₂ C (CH ₃ ) - CH ₂ , NH - [(p-benzyl) pyrid- 4-yl], -NH - [(2,6-dimethyl) pyrid-4-yl], NH- (2-methylcyclohexyl), -NH- (4-methylcyclohexyl), -NH- [N-methoxycarbonyl] -piperidine-4 -yl, -NHOC (CH ₃ ) ₃ , -NHCH ₂ CH ₂ CH ₂ CH ₂ -C, -C (O) NH (CH ₂ ) ₃ 0- (P-CH 3) Φ, -c (0) NH (CH ₂ ) ₆ NH ₂ , -NH (tetrahydrofuran-2-yl), -N (CH ₃ ) P P, -NH (CH ₂ ) ₄ NHC (O) - (2-hydroxy-4-azido) -phenyl, and -NH (CH ₂₎ 16- (biotinamidyl). The method of claim 1, 2 or 3 wherein X is -C (O) Y and Y is selected from the group consisting of: 0 00 0 «0000 * * 0 0 0 0 0 - yr j - 0 e 0000 9 9 9 9 9 9 0 0 0 0 0000000 00 000 0 0 0 0 0 0 0 0 0 0 000 000 0 0 -CH ₂ CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH ₂ OH, -CH (OH) CH ₂ CH ₂ CH (CH ₃ ) ₂ , ΟΗ (ΟΗ) Φ, -CH (OH ) CH ₂ C (O) OCH ₃ , -C (OH) (CH ₃ ) ₂ , -CH ₂ OCH ₃ , CH ₂ OC (O) OCH _3, and -CH ₂ OC (O) C (CH ₃ ) ₃ , methyl, ethyl, iso-propyl, n-propyl, iso-butyl, n-butyl, sec-butyl, tert-butyl, CH ₂ CH ₂ CH (CH ₃ ) 2, -CH ₂ -pyrid-2-yl, - CH ₂ -pyrid-3-yl, -CH ₂ -pyrid4-yl, -CH ₂ -fur-2-yl, benzyl, cyclopentyl, phenyl and -NH-SO ₂ CH ₃ . The method of claim 1, 2 or 3 wherein Z represents a covalent bond that binds R ¹ to -CX'X-. A method according to claim 1, 2 or 3, wherein the compound of formula I is selected from the group consisting of: Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohexanoate methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lhistidine methyl ester N-benzyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohexanamide N-2- (N, N-dimethylamino) ethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohexanamide N- (2-methoxyethyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] - (S) -2-aminohexanamide N-2- (N, N-dimethylamino) ethyl-N '- [N- (3,5-difluorophenylacetyl)} this to this this to this to ·· to · 99 L-alaninyl] -L-phenylalaninamide N- (4-pyridyl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide N- (3-pyridyl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide N- (4-pyridyl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] - (S) -2-aminohexanamide tert-butyl ester N- [N- (3,5-difluorophenylacetyl) - L-alaninyl] (S) -2-aminohexanoate N- [N- (pent-4-enoyl) -L-alaninyl] -L-phenylalanine methyl ester N- [N- (dec-4-enoyl) -L-alaninyl] methyl ester L-phenylalanine N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- [3- (N, N-dimethylamino) propoxy] phenylalanine methyl ester N- [N- (3,5) -difluorophenylacetyl) -L-alaninyl] -L-4 [(tert-butyloxycarbonyl) methoxy] phenylalanine N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Ltyrosine methyl ester N- [N- (3 5-difluorophenylacetyl) -L-alaninyl] -L-4 (carboxymethoxy) phenylalanine N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4'-methyl ester φ -326 · -: 2- [Ν- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2- (2-morpholinoethoxy) phenylalanine • (S) -2- (2-morpholinoethoxy) phenylalanine • (S) -2 · • · e · e · e · e · amino-6- (N, N-dimethylamino) hexanoate methyl Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2 amino-3- (2-pyridyl) propionate methyl ester Ν- [ N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-3- (3-pyridyl) propionate methyl ester of N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lproline 1- [N- (3,5-difluorophenylacetyl) -Lalaninyl] piperidine-2-carboxylate methyl Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2 amino-3- ( 4- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-methoxypropionate methyl ester of Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-4-pyridyl) propionate methyl ester 3-morpholinopropionate N- (2-methoxyethyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-4- (2-morpholinoethoxy) phenylalaninamide N- (2-methoxyethyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -2-amino-3-methoxypropionamide -52 6 ‘·· ·· ···· 9 9 9 9 9 9 99 999999 9 9 9 9 9 9 999 9999 99 999 99 99 Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine methyl ester N- (2-methoxyethyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -2-amino-3- (4-pyridyl) propionamide N- (2-Methoxyethyl) - N - [N- (3,5-difluorophenylacetyl) -Lalaninyl] -2-amino-3- (2-pyridyl) propionamide methyl ester 2- [N- (3,5-difluorophenylacetyl) -L-alaninyl] 1,2,3,4-tetrahydroisoquinoline methyl ester-L-alaninyl] - (S) -2-amino-3- (thiazol-4-yl) propionate 3-carboxylate N- (3-methoxybenzyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) 2- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-3- (2-naphthyl) propionate methyl ester Ν- [N- (3,5-difluorophenylacetyl) -2-amino-3- (1-naphthyl) propionate methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-3- (2-thienyl) propionate benzyl ester 3-Bromo-propyl lu - [N- (3,5-difluorophenylacetyl) -L • ·· Α · AAAA AA AAAAAAA AAAAAAAAA I / A AND AAAA AND AA A A A A A A AAAAA AAA A A A A A A A AAA AAAA AA AAA AA AA alaninyl] -L-phenylalanine Ν- [N- (3,5-Difluorophenylacetyl) -L-alaninyl] -L-phenylalanine 3-iodo-tert-butyl les- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-leucine tert-butyl ester Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-pyridyl) acetamide Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-pyridyl) acetamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -N ( tert-butoxycarbonyl) -L-lysine methyl Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-4-phenylbutanoate ethyl ester Ν- [N- (3,5-difluorophenylacetyl)] -L-alaninyl] glycine 2-phenyl 3- [N- (3,5-difluorophenylacetyl) -Lalaninyl] glycine 3-phenylpropyl ester Ν - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-pyridyl) acetamide methyl ester of Ν- [N- (phenylacetyl) -L-alaninyl] -L-threonine -328 ·· ···················· 9 9 · 9 9 9 9 “· 9 9 999 9 9 9 9 9 99 99 99 999 999 9 9 9 9 9 9 999 99 99 99 99 99 N '- [N- (phenylacetyl) -L-alaninyl] -L-leucinamide N '- [N- (phenylacetyl) -L-alaninyl] -L-alaninamide N - [N- (phenylacetyl) -L-alaninyl] -L-phenylalaninamide N '- [N- (phenylacetyl) -L-alaninyl] -L-valinamide N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-pyridyl) acetate ethyl ester N-methyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-leucinamide N, N-dimethyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-phenylalaninamide N, N-dimethyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-leucinamide N, N-dimethyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-valinamide N-methyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-phenylalaninamide N-methyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-valinamide N-methyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohexanamide N, N-dimethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) 2-aminohexanamide N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2- • φφφφφφohoh oh amin amin amin amin aminoh aminohohohoh aminoh N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-methoxyphenyl) acetate methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2 amino-2- (4-methoxyphenyl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-pyridyl) acetate ethyl ester N- [N- (3,5-difluorophenylacetyl) -L -alaninyl] -2-amino-2- (4-pyridyl) acetate N- [N- (cyclohexylacetyl) -L-alaninyl] -L-phenylalanine methyl ester N- [N- (cyclopentylacetyl) -L-alaninyl] -L-phenylalanine methyl ester N- [ N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -1-aminocyclopropane-1-carboxylate, N- (cyclohex-1-enylacetyl) -L-alaninyl] -L-phenylalanine methyl ester N-2- (N, N-dimethylamino) ethyl-N-methyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide methyl ester Ν- [N- (cyclopropylacetyl) -L-alaninyl] ] -Lphenylalanine -5 * 50 999 99 99 9999 99 _ 9 9 9 9 99 999 999 9 9 9 9 9 999 99 999 99 99 Ν- [Ν- (3,5-difluorophenylacetyl) -L-alaninyl] glycine benzyl ester Ν- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine methyl ester Ν- [N- (3 nit- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-alaninyl ethyl ester Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] glycine ethyl ester -nitrophenylacetyl) -L-alaninyl N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine methyl ester Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -D, L-threoninamide N-hydroxy-N '- Ν- [N- (3-Nitrophenylacetyl) -L-alaninyl] -L-tyrosine ethyl ester Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -2-amino-3- (3-hydroxyphenyl) propionate is- [N- (isovaleryl) -L-valinyl] -L-phenylglycinyl] -L-alanine iso-butyl ester Ν- [N- (isovaleryl) - (isovaleryl) -L-isoleucinyl] -L-alanine L-phenylalaninyl] -L-alanine Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalanine ethyl ester -55JL • • • • φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ ethy ethy ethy ethy indoline (S) -2-carboxylate Ν '- [Ν- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide N-methoxy-N-methyl-N '- [N- (isovaleryl) -L-phenylglycinyl] -Lalaninamide N-iso-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninamide N, N-di-n-propyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-valinamide N- (4-nitrophenyl) -N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-alaninamide Ν '- [[- [N- (isovaleryl) -L-phenylglycinyl] -L-alaninyl] -L-phenylalaninamide ter- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalaninamide N-iso-butyl-N '- [N- (isovaleryl) -L-phenylglycinyl] -L-alaninamide N- (2-methoxyethyl) -N ¹ - [N- (3,5-difluorophenylacetyl) -L99 ·· «··· -5 * 32 9 9 9 9 9 9 9 9 9 9 99,997 alaninyl] -L-phenylalaninamide N- (4-nitrobenzyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (4-nitrophenyl) -1 '- [Ν- [N- (isovaleryl) -L-phenylglycinyl] -Lalaninyl] -L-alaninamide N- (4-nitrophenyl) -N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-phenylalaninamide N-Benzyl-N-methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (3,5-difluorobenzyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (3-nitrobenzyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N-Benzyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninamide N- (4-nitrobenzyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Ltryptophan N- (4-methoxybenzyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide • ft ···· · · Ít- [N- (phenylacetyl) -L-phenylglycinyl] -L-alanine methyl ester ft - ít ft ft ít ft ft ft ft ft [[[[ - [Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalaninyl] -L-phenylglycine ethyl ester Ν- [N- (cyclohexylacetyl) -L-phenylglycinyl] -Lalanine methyl ester Ν- [N- (3 Ν- [Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninyl] -L-phenylglycine methyl ester, 5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine N- (2-phenylethyl) -N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-alaninamide Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tryptophanamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2 amino-3- cyclohexylpropionate N- (2-methoxyethyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] - (S) -2-amino-3- (4-nitrophenyl) propionamide ethyl ester Ν- [N- (3- nitrophenylacetyl) -L-alaninyl] -L-serine N - [(R) -α-methylbenzyl] - Ν - [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide -5 · fc4 ·· ·· ft · · « Ν - [(S) -α-methylbenzyl] - Ν - [Ν- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (4-fluorobenzyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (4-pyridylmethyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (4-Trifluoromethylbenzyl) -1 '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide ethyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino- 2- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester 2-phenylpropionate átu- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- methyl ester methyl propionate ethyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-cyclohexyl acetate N- (2-methoxyethyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide ethyl- [N- (isovaleryl) -2-amino-2-cyclohexylacetyl] -Lalanine N-2- (N, N-dimethylamino) ethyl-N '- [N- (3,5-difluorophenylacetyl) &quot; -5 * 45 _ · · · · 41 · · · · * * «* * * * * * * * * · · 9t 99 L-alaninyl] -L-phenylglycinamide N- (2-pyridylmethyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide N- [N- (3-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester N- [ N- (2-pyridylacetyl) -L-alaninyl] -L-phenylalanine N- [N- (4-pyridylacetyl) -L-alaninyl] -L-phenylalanine ethyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-fluorophenyl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-fluorophenyl) acetate N- [N- (3,5-fluorophenyl) acetate ethyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-phthalimidopropionate neopentyl N- [N- (3,5-difluorophenylacetyl) -L-difluorophenylacetyl] -L-phenylglycinyl] -L alanine ethyl ester -alaninyl] -L-phenylglycine N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide * flflflflflf 9 · · ··· · -5fg6 4 _ · fl flfl • · ··· ···· 50 ·· * 9 4 4 4 4 4 4 99 4,444 fl 4 9 · 44 Ν- [N- (3,5-Difluoro-phenylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide 4- [Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valinyl] morpholine Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valine methyl ester Ν- [N- Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminopentanoate (3-nitrophenylacetyl) -L-alaninyl] -L-threonine methyl ester 4- [Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] - (S) -2-amino-3-tert-butoxybutyryl] morpholine 4- [Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -Lisoleucinyl] morpholine methyl ester of Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -Lisoleucine Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isoleucine ethyl ester Ν- [Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-threoninyl] -L-valine methyl ester Ν- [N - (3-nitrophenylacetyl) -L-alaninyl] - (S) -2to -537 to this to this to this aminopentanoate methyl ester N- [+] N- (3-nitrophenylacetyl) -L-alaninyl] -L-leucine N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lleucine methyl ester N-2-methoxyethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide N-2- (Ν, Ν-dimethylamino) ethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide N-cyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninamide N-neopentyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninamide N-tetrahydrofurfuryl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N-2-pyridylmethyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide 3- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninyl] thiazolidine methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminobutanoate • * · · · · · · · · · 9 · · · · · · · · · · · · · · · · · -538 ^Α [- [Ν- (3-Nitrophenylacetyl) -L-alaninyl] - (S) -2-aminobutanoate methyl ester N- (R) -sec-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-alaninamide 1- [Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninyl] pyrrolidine N- (S) -sec-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-alaninamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lvaline N-2-Fluoroethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L alaninamide N - [(S) -6-methyl-3-oxohept-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N-4-nitrobenzyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] (S) -2-aminobutyramide N - [N- (3,5-difluorophenylacetyl) -L-alaninyl] - [N- (3,5-difluorophenylacetyl) -L-alaninyl] (S) -2-aminopentanamide methyl ester - N-4-nitrobenzyl-N '- 2 amino-2- (3-fluorophenyl) acetate Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-2- (2 -539 • · ···· β · ··· · - · ····· · 9999 999 999 99 99 thienyl) acetamide N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- ( 5-chlorobenzothiophen-2-yl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (benzothiophen-2-yl) acetate ethyl ester N- [N- (3,5) -difluorophenylacetyl) -L-alaninyl] -2-amino-2- (benzothiophen-3-yl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-thienyl) acetate methyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (benzothiophen-5-yl) acetate ethyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - ethyl ester - (S) -2-amino-2- (2-thienyl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] (S) -2-amino-2- (2-thienyl) tert -butyl ester )acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-2- (2-thienyl) acetic acid methyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl 2-amino-2- (1H-tetrazol-5-yl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2 amino-2- (6-methoxy-2) methyl ester (naphthyl) acetate -540 · · 40 40 40 40 40 40 40 - 9 · 9-methyl ester 9) 9 methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-amino-2- (3-trifluoromethylphenyl) acetate methyl ester - (4,5,6,7-tetrahydrobenzothiophen-2-yl) acetate methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (thieno [2,3-b] thiophene) methyl ester -2-yl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-methylthiazol-4-yl) acetate methyl ester (3S, 4S) -Ν- [N - [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohex-4 - (3,5-difluorophenylacetyl) -Lalaninyl] -4-amino-3-hydroxy-5-phenylpentanoate methyl ester Ν- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] (S) -2-amino-2- (4-phenylphenyl) acetamide tert-butyl ester Ν- [N- Ν- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L phenylglycine tert-butyl ester (3,5-difluorophenylacetyl) - (S) -2-aminobutanoyl] -L-phenylglycine -541 • with • with methyl ester in N- [N- ( 3,5- Difluorophenylacetyl) -L-methioninyl] -L-phenylglycine N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine methyl ester N- [3,5-difluorophenylacetyl) -2-aminobutanoyl L- [N- (3,5-difluorophenylacetyl) -L-phenylalaninyl] -L-phenylglycine methyl ester Ν- [N (3,5-difluorophenylacetyl) -L-leucinyl] -L-phenylglycine methyl ester - (3,5-difluorophenylacetyl) glycinyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] L-phenylglycine methyl ester methyl ester methyl ester methyl ester Ν- [N- (phenylacetyl) -L-alaninyl] -L-alanine Ν- [N- (phenylacetyl) -L-alaninyl] -L-leucine Ν- [N- (phenylacetyl) -L-alaninyl] -L-isoleucine Ν- [N- (phenylacetyl) -L-alaninyl] -L-proline methyl ester Ν- [N- (phenylacetyl) -L-alaninyl] -L-phenylalanine -542 ♦♦ »· · • φ Φ 9 99 · 999999 9 9 9 9 9 9 999 9 999 99 999 99 99 Ν- [N- (phenylacetyl) -L-alaninyl] -L- (tert-butoxycarbonyl) -L-lysine methyl ester Ν- [N- (phenylacetyl) -L-alaninyl] -glycine methyl ester [- [N- (phenylacetyl) -L-alaninyl] -L-alaninyl ter- [N- (phenylacetyl) -L-alaninyl] - (S) -2-aminobutanoate methyl ester ] - (S) -2-aminopentanoate Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valine methyl ester Ν- [N- (phenylacetyl) -L-alaninyl] -LN-methylalanine iso-butyl ester Ν- [N- (isovaleryl) -L Ν- [N- (isovaleryl) -L-isoleucinyl] -L-alanine iso-butyl ester -phenylglycinyl] -L-alanine N - [N- (3,5-difluorophenylacetyl) -L-4-hydroxyproline methyl ester] - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide ethyl ester N- (3,5-difluorophenylacetyl) -L-alaninyl] -Llysine Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-glutamide -543 «A A · A · A · A · A · A · A · A · A · A · A · AAA A A · A A A » AAAAAAA AA AAA AA AA 1- [N- (3,5-Difluorophenylacetyl) -Lalaninyl] piperidine-2-carboxylate methyl ester N - [(S) -3-hydroxy-6-methylhept-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -2-hydroxy-1-phenyleth-1-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide tert-butyl ester N- [N- (3,5-difluorophenyl-α-) Fluoroacetyl) -Lalaninyl] -L-phenylglycine N- [N- (3,5-difluorophenylacetyl) -2- (S) aminocyclohexylacetyl] -L-phenylglycine methyl ester N - [(1R, 2S) -1-hydroxy-1-phenylprop-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(1R, 2S) -1-hydroxy-1,2-diphenyleth-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(1S, 2R) -1-hydroxy-1-phenylprop-2-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N-2-methoxyethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl glycinamide N - [(S) -α-hydroxy-α-phenyl-isopropyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide -544 99 ·· · 9 · 9 9 9 9 « 999 · 99 10 ·· 99 99 »9 9 9» ·· · 999 999 9 9 9 Ν - [(S) -2-hydroxy-1,2-diphenylethyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -1-hydroxyhex-2-yl] -N '- (3,5-difluorophenylacetyl) -Lalaninamide N- [α-hydroxy-α- (4-hydroxyphenyl) -isopropyl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N-2-pyridylmethyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide N- [α-hydroxy-α'-pyrid-2-yl-isopropyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [α-hydroxy-1 H -pyrid-4-yl-isopropyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -1-hydroxy-4-methylpent-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [α-methoxy-prop-2-yl] -1 '- (3,5-difluorophenylacetyl) -Lalaninamide N- [1-hydroxy-3-methyl-but-2-yl] -1 '- (3,5-difluorophenylacetyl) L-alaninamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - 2 amino-2- (6-aminopyrid-2-yl) acetate ΦΦ φφφφ -54 5 - * • φ · · · · · φφφφφφφφφφφφφφφφφφφφφφφφφ φφφφφφφφφφφ N- [1-Hydroxy-prop-2-yl] -1 '- (3,5-difluorophenylacetyl) -Lalaninamide Ν - [(S) -2-methoxy-1-phenyleth-1-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide Ν - [(S) -1-methoxy-2-phenyl-prop-2-yl] -N'- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -1-acetoxyhex-2-yl] -1 '- (3,5-difluorophenylacetyl) -Lalaninamide N - [(S) -1- (tert-butylcarbonyloxy) -hex-2-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N- [2-hydroxy-1- (thien-2-yl) ethyl] -N'- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -2-hydroxy-2-methyl-1-phenylprop-1-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide tert-butyl ester Ν- [N- (3,5- difluorophenylacetyl) -L- (thien-2-yl) glycinyl] -L-phenylalanine Ν- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycinol Ν- [N- (cyclopropaneacetyl) -L-phenylglycinyl] -L-phenylglycinol Ν- [N- (cyclopentaneacetyl) -L-phenylglycinyl] -L-phenylglycinol • φ Φ φ φ φ • • φ • • φ φ φ φ «Φ Ν- [Ν- (3,5-difluorophenylacetyl) -D, L-phenylglycinyl] -D, L-phenylglycinamide Ν- [N- (3,5-difluorophenylacetyl) -D, L-valinyl] -D, L-phenylglycinamide Ν- [N- (2-thienylacetyl) -L-alaninyl] -L-phenylglycinamide Ν- [N- (n-caprotyl) -L-alaninyl] -L-phenylglycinamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-norleucinyl] -L-phenylglycine methyl ester Ν- [N- (3,5- difluorophenylacetyl) -L-norvalinyl] -L-phenylglycine Ν- [N- (3,5-difluorophenylacetyl) -L-tert-leucinyl] L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-isoleucinyl] methyl ester L- [N- (3,5-difluorophenylacetyl) -L-cyclohexylalaninyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) - (S) -2-amino-2 (cyclopropyl) acetyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) - (S) -2-amino-2 (thien-3-yl) acetyl] -L-phenylglycine methyl ester-L-phenylglycine -547 9 9 9999 9 9 9 9 9 9 9999998 99 99 9 9 9 · · 998 9 9 9 9 9 9 9 9 9 Methyl Ν- [N- (3,5-difluorophenylacetyl) - (S) -2-amino-2 (thien-2-yl) acetyl] -L-phenylglycine methyl ester -Difluorophenylacetyl) -L- (4-fluorophenyl) glycinyl] -L-phenylglycine Ν- [N- (3,5-difluorophenylacetyl) -D- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester if - [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester Ν - [N- (cyclopropylacetyl) -L-phenylglycinyl] L-phenylglycine Ν- [N- (cyclopentylacetyl) -L-phenylglycinyl] L-phenylglycine tert-butyl ester Ν- [N- (tert-butylacetyl) -L-alaninyl] -L-phenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (5-bromothien-2-yl) glycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D (5-bromothien-2-yl) glycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (4-bromothien-2-yl) glycinamide -548 - » 9 9 99 9 9 ftftft ftftftft ftftftft ft ft 999999 ftft 99,999 9,999 N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (thien-2-yl) glycinamide N-tert-butyl-Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D (thien-2-yl) glycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (thien-3-yl) glycinamide N-tert-butyl-Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D (thien-2-yl) glycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L- (5-chlorothien-2-yl) glycinamide N-cyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-4 (phenyl) phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L 3 - (phenoxy) phenylglycinamide N- (S) - (-) - α-Methylbenzyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide -549 · to to to to to to to to toto toto toto toto toto 49 49 49 49 49 N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L3- (phenyl) phenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L4- (ethyl) phenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L2- (phenyl) phenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L2- (benzyl) phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-4-bromophenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L4- (cyclohexyl) phenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L4- (4-ethylphenyl) phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-4- (tert-butyl) phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-3- (4-chlorophenoxy) phenylglycinamide N-cyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4 (phenyl) phenylglycinamide N- [N- (3,5-difluorophenyl-α-hydroxyacetyl) tert-butyl ester -L-550 - * · · ··· 9 · 999 9 9 9 9 9 9 999 999 alaninyl] -L-phenylglycine N-tert-butyl-N '- [N- (3,5-difluorophenyl-α, α-difluoroacetyl) -L-alaninyl] -L-phenylglycinamide tert-butyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D-phenylglycine N - [(S) -1-oxo-1-phenylprop-2-yl] -N '- (3,5-difluorophenylacetyl) L-alaninamide tert-butyl ester N- [N- (3,5-difluorophenylacetyl) - L-alaninyl] D, L- (pyrid-3-yl) glycine [Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] morpholine methyl ester Ν- [N- (3,5 -difluorophenylacetyl) -L-alaninyl] -D, L (2-methoxy) phenylglycine N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine N-tert-butoxycarbonyl (hydroxylamine) ester N-neopentyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide N-tetrahydrofurfuryl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-Methoxy-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Denenyl glycidamide -551 ·· • · 9 9999 ·· 99 · 9 99 • · 9 9 · · ··· · 9 9 9 99 999 9 9 N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] azetidine N-iso-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L phenylglycinamide N-cyclopropanomethyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-methoxy-N-methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-2-methylprop-2-enyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N- (pyrid-3-yl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N- (pyrid-4-yl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-furfuryl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide N-cyclopentyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-phenylglycinamide N-1-Benzylpiperidin-4-yl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide -552 ΦΦ · φ · • · φ · · · ΦΦΦ · · φ · · φ «φ φ φ φ φ φ φ φ φ φ φφφ Ν, N-dimethyl-N '- [Ν- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L phenylglycinamide N-2,2,6,6-tetramethylpiperidin-4-yl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide N-2-methylcyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-4-methylcyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-1-ethoxycarbonylpiperidin-4-yl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide N-methyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide N-tert-butoxy-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-phenylglycinamide N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine hydrazide N-tert-butyl (hydroxylamine) ester- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - N- (1-ethoxyethen-1-yl) - [-'- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester Ν- [N- (phenylacetyl) -L-alaninyl] -phenylglycine hydrazide ] -L-553 Too Too Too Too Too Phenylglycine N-4- (phenyl) butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-phenylglycinamide N-3- (4-iodophenoxy) propyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide hydrochloride N-6- (amino) hexyl-N' - [N- (3, 5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide N - [N- (3,5-Difluorophenylacetyl) -L- (3,5-difluorophenylacetyl) -L- (3,5-difluorophenylacetyl) -Lalaninamide methyl ester - N - (phthalimido) pent-2-yl-L- ( 3,5-difluorophenyl) glycine Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-norleucine tert-butyl ester Ν- [N- (cyclopentaneacetyl) -L-alaninyl] -L-phenylglycine iso-propyl ester Ν- [N- (3 (5-difluorophenylacetyl) -L-alaninyl] -L4-fluorophenylglycine N - [N- (Cyclopentylacetyl) -L-alaninyl] -L-phenylalanine N- (isopropyl) N - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide tert-butyl ester -554 flflfl flflfl flflfl flfl flfl tert-butyl ester Ν- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylalanine iso-butyl ester Ν- [N- ( 3,5-Difluorophenylacetyl) -L-alaninyl] -L-alaninyl-L-alaninyl-N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -phenylglycine methyl ester L- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lazetidine ter- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino ester-L- (3α-phenyl) proline methyl ester -3- (5-chlorobenzothiophen-2-yl) acetate tert-butyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] (S) -2-amino-3- (thiazol-4-yl) ) Ν- [N- (3,5-Difluoro-phenylacetyl) -L-alaninyl] -L-phenylglycinamide tert-butyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D- (thien-2-yl) glycinamide N - [N- (3,4-dichlorophenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (3-chlorophenylacetyl) -L-alaninyl] -D-phenylglycinamide Φ · φφφφ -55 5 ·· φφ φφφφ φ φ φ · · φ · - φ · · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ Ν- [Ν- (3-bromophenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (3-fluorophenylacetyl) -L-alaninyl] -D-phenylglycinamide N - [N- (4-fluorophenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (3-methylphenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (4-methylphenylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (3-Trifluoromethylphenylacetyl) -L-alaninyl] -phenylglycinamide Ν- [N- (3-methoxyphenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (2-chlorophenylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (1-naphthylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (2-naphthylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (phenylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycinamide Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-2- (2-furanyl) acetamide Ν '- [N- (3,5-difluorophenylacetyl) -D-alaninyl] -D-phenylglycinamide -556 ·· ··· · 99 9 9 9 · · · 9 9 9 99 9 9 9 9 9 9 9,999 9 9 9 9 Ν '- [Ν- (3,4-difluorophenylacetyl) -D-alaninyl] -D-phenylglycinamide N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine-N-methylsulfonamide N-methyl-N-phenyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -glycinamide N-methyl-N-phenyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide Ν '- [N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-phenylglycinamide N-methyl-N-benzyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -glycinamide N-4-fluorobenzyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-phenylglycinamide neopentyl ester Ν' - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (4 -fluoro) phenylglycine N- [N- (2,3,4,5,6-pentafluorophenylacetyl) -Lalaninyl] -L- (pyrid-3-yl) glycine methyl ester Ν- [N- (3,5-tert-butyl) ester -difluorophenylacetyl) -L-alaninyl] L- (pyrid-3-yl) glycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L- (0 ···) 0 · -557 0 0 0 0 0 0 · 00 0 0 0 0 0 0 0 Benzyl) serinyl] -L-phenylglycine N- [N- (3,5-difluorophenylacetyl) -L- (O-benzyl) threoninyl] -L-phenylglycine methyl ester N- [N- (3,5-difluorophenylacetyl) - L-threoninyl] -L-phenylglycine - [N- (3,5-difluorophenylacetyl) -L-serinyl] -L-phenylglycine methyl ester N-4-methylphenyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-phenylglycinamide N-tetrahydrofurfuryl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenylglycinamide Ν '- [N- (3,5-difluorophenylacetyl) -L-methionyl] -L-phenylglycinamide Ν- [N- (3,5-difluorophenylacetyl) -2-aminobutanoyl] -L-phenylglycinamide N '- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycinamide Ν- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycinamide -558 flfl fl flfl fl flfl flfl · ·· • flflfl »· fl flflflfl flflfl flflfl • · · • flfl flflflfl flfl flflfl flflfl • · flflfl flfl • flfl flflflfl flfl flflfl flfl flfl N - [(R) -? - Methylbenzyl] - N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide N- [1-phenyl-2-oxo-3-methylbutan-1-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [1-phenyl-2-oxo-propan-1-yl] -1 '- (3,5-difluorophenylacetyl) -L alaninamide N- [1-phenyl-2-oxo-pentan-1-yl] -1 '- (3,5-difluorophenylacetyl) -L alaninamide N- [1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N- [1-phenyl-2-oxo-butan-1-yl] -N '- (3,5-difluorophenyl-acetyl) -L alaninamide N- [1-phenyl-2-oxo-4-methylpentan-1-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide methyl ester -' - [N- (3,5-difluorophenylacetyl)] - L-alaninyl] -L-ahydroxyphenylalanine N- [4 - ((2-hydroxy-4-azido) -phenyl) -NHC (O) -) butyl] N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide N - [(S) -1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -N '- (3,5-difluorophenyl-acetyl) -L-alaninamide tert-butyl ester N' - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -559 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · · · · · · · · · · · · · · · · · · · · · · · · · L-4-Fluorophenylglycine N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-4-phenylphenylglycine tert-butyl ester [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L - (2,3-benzo [b] proline) N-tert-butyl-Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L 4-n-butylphenylglycinamide N-tert-butyl-Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-4- (phenylacetenyl) phenylglycinamide N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinthioamide N- [1,3-Diphenyl-2-oxo-propan-1-yl] -N- (3,5-difluorophenylacetyl) -L-alaninamide N- [1-phenyl-2-oxo-2-cyclopentylethan-1-yl] -N '- (3,5-di-fluorophenylacetyl) -L-alaninamide N- [1-Phenyl-2-oxo-hexan-1-yl] -1 '- (3,5-difluorophenylacetyl) -Lalaninamide N- [1-phenyl-2-oxo-3-methylpentan-1-yl] -N- (3,5-difluorophenylacetyl) -L-alaninamide N-n-hexyl-6-biotinamidyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinthioamide -560 · · · · · 9 · ·········· · · 99 · · ······ 9 · · · · 99 99 ··· ·· ··· ·· ·· Ν '- [Ν- (3,5-difluorophenylacetyl) -L-methioninyl] -L-methionine methyl ester Ν' - [N- (2-tert-BOC-amino) propionyl) -L-alaninyl] L-phenylglycine N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-tert-butyl N' - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L 2-fluorophenylglycinamide methyl ester , L2-phenylglycine N - [(S) -1-phenyl-2-oxo-3-phenylpropan-1-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide Ν '- [N- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L2-phenylglycine tert-butyl ester N' - [N- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L-2-phenylglycine N '- [N- (3,5-difluorophenylacetyl) -L-thien-3-ylglycinyl] -L-2-phenylglycine tert-butyl ester N' - [N- (3,5-difluorophenylacetyl) -L-thien-3-ylglycinyl] -L-2-phenylglycine N- [2-hydroxy-1- (S) -phenyleth-1-yl] -N '- [(3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-alaninamide N- [2-hydroxyeth-1-yl] -N '- [(3,5-difluorophenylacetyl) -L] -561 ·· · alaninyl] -L-phenylglycinamide tert-butyl ester N '- [N- (3,5-difluorophenyl-2-oxo-acetyl) -Lalaninyl] -L-2-phenylglycine methyl ester [N- (2 [N- (3,5-Difluorophenoxyacetyl) -L-alaninyl] -L-alaninyl] -L-alaninyl] -L-alaninyl] -L-alaninyl] -L-phenylglycine tert-butyl ester, 5-dichloro-phenoxyacetyl) -L-alaninyl] -L-alaninyl] -L-phenylglycine tert. [N- (3-Amino-propionyl) -L-alaninyl] -L-phenylglycine-butyl ester and [N- (3-tert-butoxycarbonylamino) -propionyl) -L-alaninyl] -L-phenylglycine tert-butyl ester. 32. A pharmaceutical composition comprising a pharmaceutically inert carrier and a pharmaceutically effective amount of a compound of Formula I: X * X "of ^{R 4} R ⁵ R ¹ 2 T R ³ AND -562 wherein R ¹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and a heterocyclic system; R ² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, and the heterocyclic system; each R 3 is independently selected from the group consisting of hydrogen and methyl, and R ³ together with R ⁴ may be joined to form a cyclic structure containing from 3 to 8 atoms, which is optionally fused with an aryl or heteroaryl group; each R ⁴ 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 R ⁵ is selected from the group consisting of hydrogen and methyl or together with R ⁴ forms a cycloalkyl group containing from 3 to 6 carbon atoms; X is selected from the group consisting of -C (O) Y and -C (S) Y, wherein Y is selected from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl, with substitution on said substituted alkyl does not include α-haloalkyl, adiazoalkyl, α-OC (O) alkyl, or α-OC (O) aryl, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, -563 9 9 9 9 1 • · · < (F) aryl, (g) heteroaryl, (h) a heterocyclic system, (i) -NR'R, where R 'and R are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, a heterocyclic system wherein one of R 'or R' is hydroxy or alkoxy and wherein R 'and R' are joined together 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, (j) -NHSO ₂ -R ⁸ , wherein R ⁸ is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and a heterocyclic system, (k) -NR ⁹ NR ¹⁰ R ¹⁰ , wherein R ⁹ is hydrogen or alkyl and each is R ¹⁰ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -ONR ⁹ [C (O) 0] _Z R ¹⁰ wherein z is zero or one and R ⁹ and R ¹⁰ are as defined above; X may also be -CR ⁶ R ⁶ Y ', wherein each R ⁶ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and the heterocyclic system and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -564 -OC (O) R ^7, -SSR ^7, -SSC (O) R ⁷ wherein R ⁷ is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X 'represents a hydrogen atom, hydroxy, or fluorine; X is hydrogen, hydroxy, or fluoro, or X 'and X together form an oxo group; Z is selected from the group consisting of a covalent bond that binds R ¹ to -CX'X-, an oxygen atom, and a sulfur atom; n is an integer equal to 1 or 2; and pharmaceutically acceptable salts thereof, provided that: A. when R ¹ is phenyl or 3-nitrophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is -CH (OH) CH 3, R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and n is 1, then X is not -C (O) OH; 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 and n is 1, then X is not -C (O) OH or -C (O) OCH 3; C. when R ¹ is phenyl, R ² is methyl, R ⁴ is benzyl, R ⁵ is hydrogen, X is methoxycarbonyl, X 'and X are hydrogen, Z is a bond and is 1, then R ^{3 is} not methyl; D. when ^R1 is iso-propyl, ^R2 is -CH2C (O) NH2, ^R3 is hydrogen, ^R4 is isobutyl, ^R5 is hydrogen, X 'and X are hydrogen, Z is a bond and n is equal to 1, then X is not -C (O) OCH 3; • «• · -565 E. when R ¹ is phenyl, R ² is methyl, R ⁵ is hydrogen, X is -C (O) OCH ₃ , X 'and X are hydrogen, Z is a bond and n is 1, then R ³ , nitrogen atom attached to R ³ and R ⁴ do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. when R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁵ is hydrogen, X is C (O) OCH ₃ , X 'and X are hydrogen, Z is a bond and is 1, then R ^{4 is} not 4-amino-n-butyl; G. when ^R1 is 3-nitrophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is CH (OH) CH3, ^R5 is hydrogen, X 'and X are hydrogen, Z is a bond and n is equal to 1, then X is not -C (O) NH 2 or -CH ₂ OH; H. when R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁵ is hydrogen, X is CH ₂ OCH ₃ , X 'and X are hydrogen, Z is a bond and n is 1, then R ⁴ it is not benzyl or ethyl; I. when R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is methyl, R ⁴ is methyl, R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and is 1, then X does not represent -ΟΗΟΗΦ; J. when ^R1 is 3,5-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 -ΟΗΟΗΦ or -CH ₂ OH; K. when R ¹ represents N- (2-pyrrolidinonyl), R ² represents methyl, R ³ represents hydrogen, R ⁴ ft · -566 ftftftftftft ftftftft represents benzyl, R ⁵ represents hydrogen, X 'and X is hydrogen, Z is a bond and n is 1, then X is not -C (O) OCH ₃ ; L. when ^R1 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 represents hydrogen, Z is a bond and n is 1, then X is not -C (O) NH-benzyl; M. when R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is hydrogen, R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and is 1 then X is not -CH 2 OH; N. when R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is ^4- phenylphenyl, R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and is 1, then X is not -C (O) NHC (CH ₃ ) ₃ ; and O. when R ¹ represents 3,5-difluorophenyl, R ² represents methyl, R ³ represents hydrogen, R ⁴ represents phenyl derived from D-phenylglycine, R ⁵ represents hydrogen, X 'and X represent hydrogen, Z represents a bond and n is 1, then X is not -C (O) NHCH (CH ₃ ) Φ. 33. The pharmaceutical composition according to claim 32, characterized in that R ¹ represents an unsubstituted aryl group and Z is a covalent bond, which links R ¹ to -CX'X-. The pharmaceutical composition of claim 33, wherein the unsubstituted R ¹ aryl group is selected from The group consisting of phenyl, 1-naphthyl and 2-naphthyl. 35. The pharmaceutical composition according to claim 32, characterized in that R ¹ is a substituted aryl group and Z is a covalent bond, which links R ¹ to -CX'X-. 36. The pharmaceutical composition of claim 35 wherein said substituted aryl group is a monosubstituted, di-substituted or tri-substituted phenyl group. 37. The pharmaceutical composition of claim 36 wherein the substituted phenyl group is selected from the group consisting of 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluorophenyl. , 3-chlorophenyl, 3-bromophenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2-hydroxyphenyl, 2-methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 3,4-dibromophenyl, 3,4-dichlorophenyl, 3,4-methylenedioxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2,4- dichlorophenyl and 2,5-difluorophenyl. 38. A pharmaceutical composition according to claim 32, characterized in that R ¹ is an alkaryl group and Z is a covalent bond, which links R ¹ to -CX'X-. The pharmaceutical composition of claim 38, wherein the R ¹ alkaryl group is selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-n-propyl. -568 · · 56 56 56 56 56 56 56 56 56 40. The pharmaceutical composition according to claim 32, characterized in that R ¹ is selected from the group consisting of alkyl, alkenyl, cycloalkyl and cycloalkenyl groups and Z is a covalent bond, which links R ¹ to -CX'X-. 41. The pharmaceutical composition of claim ¹ wherein R1 is alkyl. claim 40, characterized se 42. The pharmaceutical composition of claim ¹ wherein R1 is cycloalkyl. claim 40, characterized se 43. The pharmaceutical composition of claim ¹ wherein R1 is alkenyl. claim 40, characterized se 44. The pharmaceutical composition of claim ¹ wherein R1 is cycloalkenyl claim 40, characterized se 45. The pharmaceutical composition of claim 40 wherein R &lt; ¹ & gt ^; alkyl, cycloalkyl, alkenyl, and cycloalkenyl are selected from the group consisting of isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl and tert-butyl. -butyl, -CH ₂ CH = CH 2, CH ₂ CH = CH (CH ₂ ) 4 CH ₃ , cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH ₂ -cyclopropyl, -CH ₂ cyclobutyl, -CH ₂ -cyclohexyl, -CH ₂ -cyclopentyl, -CH ₂ CH ₂ cyclopropyl, -CH ₂ CH ₂ -cyclobutyl, -CH ₂ CH ₂ -cyclohexyl, -CH ₂ CH ₂ cyclopentyl, aminomethyl and N-tert-butoxycarbonylaminomethyl. -569 · • 56 56 56 56 56 56 56 56 56 56 56 56 56 56 56 56 56 · · · · · · ··· 46. The pharmaceutical composition according to claim 32, characterized in that R ¹ is selected from the group consisting of heteroaryl and substituted heteroaryl, and Z is a covalent bond, which links R ¹ to -CX'X-. 47. The pharmaceutical composition of claim 46, wherein R &lt; ¹ &gt; heteroaryl and substituted heteroayl are selected from pyrid2-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, thionaphten-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2- (thiophenyl) thiophen-5-yl, 6-methoxythionaphten-2-yl, 3-phenyl- 1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl. 48. A pharmaceutical composition according to claim 32, characterized in that R ² is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. 49. The pharmaceutical composition according to claim 48, characterized in that R ² is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, 4 -fluorophenyl, 3,5-difluorophenyl, 4-methoxyphenyl, benzyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, thien-2-yl, thien-3-yl, -CH ₂ CH ₂ SCH ₃ , -ΩΗ ₂ ΟΩΗ ₂ Φ, CH (CH ₃ ) OCH ₂ <Z>, -CH (OH) CH ₃ and -CH ₂ OH. A pharmaceutical composition according to claim 32, characterized in that it is: -570 · · φ φ 70 70 70 70 <<< Φ · φ φφ in that X 'and X represent a hydrogen atom and Z represents a covalent bond which binds R ¹ to -CX'X-. 51. The pharmaceutical composition according to claim 50, characterized in that R ³ is selected from the group consisting of hydrogen, methyl or together with ^R4 and the nitrogen atom to which ^R3 is attached forms pyrrolidin-2-yl, 2 3-dihydroindol-2-yl, piperidin-2-yl, 4-hydroxy-pyrrolidin-2-yl and 1,2,3,4-tetrahydroisoquinolin-3-yl. 52. The pharmaceutical composition according to claim 32, characterized in that R ⁴ is selected from the group consisting of hydrogen, methyl, ethyl, iso-propyl, n-propyl, n-butyl, sec-butyl, iso-butyl , cyclopentyl, cyclohexyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH ₂ cyclopropyl, -CH ₂ -cyclohexyl, -CH ₂ -indol-3-yl, phenyl, p (phenyl) phenyl, m- (phenyl) phenyl, o-fluorophenyl, m-fluorophenyl, pfluorophenyl, p-bromophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, pnitrobenzyl, m-trifluoromethylphenyl, p- (CH) ₃ ) ₂ NCH ₂ CH ₂ CH ₂ Obenzyl, p- (CH ₃ ) ₃ COC (O) CH ₂ O-benzyl, p-phenylphenyl, 3,5-difluorophenyl, p- (HOOCCH ₂ O) -benzyl, 2-aminopyrid- 6-yl, 4- (N-morpholino-CH ₂ CH ₂ O) -benzyl, -CH ₂ CH ₂ C (O) NH ₂ , -CH ₂ -imidazol-4-yl, -CH ₂ - (3-tetrahydrofuranyl), -CH ₂ -thien-2-yl, -CH ₂ -thiazol-4-yl, -CH ₂ (1-methyl) cyclopropyl, -CH ₂ -thien-3-yl, thien-3-yl, thien-2-yl, -CH ₂ -C (O) O-tert-butyl, -CH ₂ -C (CH ₃ ) ₃ , CH ₂ CH (CH ₂ CH ₃ ) 2, 2-methylcyclopentyl, -cyclohex-2-enyl, CH [CH (CH ₃ ) ₂ ] COOCH ₃ , - (CH ₂ ) ₂ SCH ₃ , -CH ₂ CH ₂ N (CH ₃ ) ₂ , -CH ₂ C (CH ₃ ) = CH ₂ , -CH ₂ CH = CHCH ₃ (cis and trans), -CH ₂ OH, -CH (OH) CH ₃ , -CH (tert -butyl) CH ₃ , -CH ₂ OCH ₃ , - (CH ₂ ) ₄ NH-Boc, - (CH ₂ ) ₄ NH ₂ , (CH ₂ ) ₄ N (CH ₃ ) 2, -CH ₂ -pyridyl, pyridyl, -CH ₂ -naphthyl, -CH ₂ - (N «ΦΦφ) Φ -571 ΦΦΦ φ φ (morpholino), β- (N-morpholino-CH ₂ CH ₂ O) -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, -CH ₂ -N-phthalimidyl, 2-methylthiazol-4-yl and thieno [2,3-b] thiophen-2-yl, 5-bromothien-2-yl, 4-bromothien -2-yl, 5-chlorothien-2-yl, 3-phenoxyphenyl, 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. 53. The pharmaceutical composition of claim 32, wherein Z is a covalent bond, which links to R ¹ and R CX'X- ⁴ and R ⁵ are joined to form a cycloalkyl group selected from the group consisting of cyclopropyl and cyclobutyl. 54. The pharmaceutical composition of claim 32, wherein Z is a covalent bond, which links R ¹ to CX'X-, X is -C (O) Y and Y is selected from the group consisting of hydroxy, alkoxy or substituted alkoxy. 55. The pharmaceutical composition of claim 54 wherein Y is alkoxy or substituted alkoxy selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy. , neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, -ONHC (O) OC (CH ₃ ) ₃ , -ONHC (CH _{3) 13} and hydroxy. 56. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition is a pharmaceutical composition By Z being a covalent bond that binds R ¹ to CX'X-, X is -C (O) Y, and Y is -NR'R. 57. The pharmaceutical composition of claim 56, wherein Y is selected from the group consisting of amino (-NH _2), -NH (iso-butyl), -NH (sec-butyl), N-methylamino, N , N-dimethylamino, N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethylenimino, N-heptamethylenimino, N-pyrrolidinyl, -NH-methallyl, -NHCH ₂ (furan-2-yl), -NHCH ₂ -cyclopropyl , -NH (tert-butyl), -NH (pmethylphenyl), -NHOCH ₃ , -NHCH ₂ (p-fluorophenyl), -NHCH ₂ CH ₂ OCH ₃ , NH-cyclopentyl, -NH-cyclohexyl, -NHCH ₂ CH ₂ N (CH ₃ ) ₂ , NHCH ₂ C (CH ₃ ) ₃ / -NHCH ₂ - (pyrid-2-yl), -NHCH ₂ - (pyrid-3-yl), NHCH ₂ - (pyrid-4-yl) ), N-thiazolindinyl, -N (CH ₂ CH ₂ CH ₃ ) ₂ , N [CH ₂ CH (CH ₃ ) ₂ ] 2, -NHOH, -ΝΗ (ρ-ΝΟ ₂ -Φ), -NHCH ₂ (ρ -ΝΟζ-Φ), NHCH ₂ (m-NO ₂ -Φ), -N (CH ₃ ) OCH ₃ , -N (CH ₃ ) ΟΗ ₂ -Φ, -NHCH ₂ - (3,5-difluorophenyl), -NHCH ₂ CH ₂ F, -NHCH ₂ (p-CH ₃ O-O), -NHCH ₂ (m-CH ₃ O- #), -NHCH ₂ (p-CF ₃ - <Z>), -N (CH ₃ ) CH ₂ CH ₂ OCH ₃ , -NHCH ₂ CH ₂ O, -NHCH (CH ₃ ) ₂ Z, NH CH ₂ - (pF-Φ), -N (CH ₃ ) CH ₂ CH ₂ N (CH ₃ ) ₂ , -NHCH ₂ - (tetrahydrofuran- ₂ -yl), -NHCH ₂ (p-trifluoromethylphenyl), -NHCH ₂ C (CH ₃ ) = CH ₂ , NH - [(p-benzyl) pyrid-4-yl], -NH - [(2,6-dimethyl) pyrid-4-yl], NH- (2-methylcyclohexyl), -NH- (4-methylcyclohexyl), -NH- [N-methoxycarbonyl] -piperidin-4-yl, -NHOC (CH ₃ ) ₃ , -NHCH ₂ CH ₂ CH ₂ CH _{2 -} , -C (O) NH (CH ₂ ) ₃ 0- (p-CH ₃ ) Φ, -C (O) NH (CH ₂ ) ₆ NH ₂ , -NH (tetrahydrofuran-2-yl), -N (CH ₃ ) <Z>, -NH (CH ₂ ) 4 NHC (O) - ( 2-hydroxy-4-azido) -phenyl and -NH _(CH2) 6 "(biotinamidyl). 58. The pharmaceutical composition according to claim 32, characterized in that X represents -C (O) Y and Y is selected from the group consisting of -CH2CH2CH2CH _{(CH3) 2,} -CH ₂ OH • · -573 • · · to · CH (OH) CH ₂ CH ₂ CH (CH ₃ ) 2, -CH (OH) 2 Z, -CH (OH) CH ₂ C (O) OCH ₃ , C (OH) (CH ₃ ) ₂ , -CH ₂ OCH ₃ , -CH ₂ OC (O) OCH _3, and -CH ₂ OC (O) C (CH ₃ ) ₃ , methyl, ethyl, isopropyl, n-propyl, iso-butyl, n-butyl, sec. -butyl, tert-butyl, -CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH ₂ -pyrid-2-yl, CH ₂ -pyrid-3-yl, -CH ₂ -pyrid-4-yl, - CH _{2-furyl-2-yl,} benzyl, cyclopentyl, phenyl, and -NH-SO ₂ -CH _third 59. The pharmaceutical composition of claim 32, wherein Z is a covalent bond, which links R ¹ to CX'X-. 60. The pharmaceutical composition of claim 32 wherein the compound of Formula I is selected from the group consisting of: N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohexanoate methyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lhistidine methyl ester N-benzyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohexanamide N-2- (N, N-dimethylamino) ethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohexanamide N- (2-methoxyethyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] - (S) -2-aminohexanamide N-2- (N, N-dimethylamino) ethyl-N '- [N- (3,5-difluorophenylacetyl) -574] • · ····· · 4 · · · · ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ L-alaninyl] -L-phenylalaninamide N- (4-pyridyl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide N- (3-pyridyl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide N- (4-pyridyl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] - (S) -2-aminohexanamide tert-butyl ester N- [N- (3,5-difluorophenylacetyl) - L-alaninyl] (S) -2-aminohexanoate Ν- [N- (pent-4-enoyl) -L-alaninyl] -L-phenylalanine methyl ester Ν- [N- (dec-4-enoyl) -L-alaninyl] methyl ester L- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- [3- (N, N-dimethylamino) propoxy] phenylalanine methyl ester - [N- (3,5-difluorophenylacetyl)] - L-phenylalanine methyl ester -Difluorophenylacetyl) -L-alaninyl] -L-4 [(tert-butyloxycarbonyl) methoxy] phenylalanine methyl Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Ltyrosine methyl ester Ν- [N- (3 [- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4 (5-difluorophenylacetyl) -L-alaninyl] -L-4 (carboxymethoxy) phenylalanine methyl ester -575 (2-Morpholinoethoxy) phenylalanine Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2 amino-6- (N, N-dimethylamino) hexanoate methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-3- (2-pyridyl) propionate methyl ester (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2- [3- (3-pyridyl) propionate] - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-proline methyl ester 1- [N- (3,5-difluorophenylacetyl) -Lalaninyl] piperidine- 2 - [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2 amino-3- (4-pyridyl) propionate methyl ester - [N- (3,5-difluorophenylacetyl) 2-carboxylate methyl ester [1- (3,5-Difluorophenylacetyl) -L-alaninyl] -2-amino-3-morpholinopropionate methyl ester -L-alaninyl] -2-amino-3-methoxypropionate N- (2-methoxyethyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-4- (2-morpholinoethoxy) phenylalaninamide N- (2-methoxyethyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -2-amino-3-methoxypropionamide -576 · · * · · · · · · · · · · · · · · · · · · · · 9- [Ν- (3,5-difluorophenylacetyl) -L-alaninyl] glycine methyl ester N- (2-methoxyethyl) -N '- [N- (3,5-difluorophenylacetyl) -alaninyl] -2-amino-3- (4-pyridyl) propionamide N- (2-methoxyethyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -2-amino-3- (2-pyridyl) propionamide methyl ester Ν- [N- (3,5-difluorophenylacetyl)] 2- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-3- (thiazol-4-yl) -propionate-L-alaninyl] -1,3,3-tetrahydroisoquinoline methyl ester 3-carboxylate N- (3-methoxybenzyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) 2- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-3- (2-naphthyl) propionate methyl ester Ν- [N- (3,5-difluorophenylacetyl) -2-amino-3- (1-naphthyl) propionate methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-3- (2-thienyl) propionate benzyl ester 3- [N- (3,5-Difluoro-phenylacetyl) -L-3-bromo-propyl ester -5Π · · · · · · · · < • · · < 4-alaninyl] -L-phenylalanine Ν- [N- (3,5-Difluorophenylacetyl) -L-alaninyl] -L-phenylalanine 3-iodo-tert-butyl les- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-leucine tert-butyl ester N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-pyridyl) acetamide Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-pyridyl) acetamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -N ( tert-butoxycarbonyl) -L-lysine methyl Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-4-phenylbutanoate ethyl ester Ν- [N- (3,5-difluorophenylacetyl)] -L-alaninyl] glycine 2-phenyl 3- [N- (3,5-difluorophenylacetyl) -Lalaninyl] glycine 3-phenylpropyl ester 9 '- [N- (Phenylacetyl) -L-alaninyl] -L-threonine N' - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-pyridyl) acetamide methyl ester 9 -578 -: 9 9 9 9 9 9 9 9 9 9 9 · 9 * 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 Ν '- [Ν- (phenylacetyl) -L-alaninyl] -L-leucinamide Ν '- [Ν- (phenylacetyl) -L-alaninyl] -L-alaninamide N - [N- (phenylacetyl) -L-alaninyl] -L-phenylalaninamide N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-pyridyl) acetate N '- [N- (phenylacetyl) -L-alaninyl] -L-valinamide ethyl ester N-methyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-leucinamide N, N-dimethyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-phenylalaninamide N, N-dimethyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-leucinamide N, N-dimethyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-valinamide N-methyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-phenylalaninamide N-methyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-valinamide N-methyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohexanamide N, N-dimethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) 2-aminohexanamide Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-579 ftft ftft ftftft # _ · · · · Aminohexanamide methyl ester Ν- [N- (- (-) - - - - - - - - - - - - - - 3,5- Difluorophenylacetyl) -L-alaninyl] -2 amino-2- (3-methoxyphenyl) acetate methyl ester of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2 amino-2- (4- methoxyphenyl) acetate Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-pyridyl) acetate ethyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] ethyl ester 2-amino-2- (4-pyridyl) acetate N- [N- (cyclohexylacetyl) -L-alaninyl] -L-phenylalanine methyl ester N- [N- (cyclopentylacetyl) -L-alaninyl] -L-phenylalanine methyl ester N- [N- ( cyclohex-1-enylacetyl) -L-alaninyl] -L-phenylalanine Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -1-aminocyclopropane-1-carboxylate methyl ester N-2- (N, N-dimethylamino) ethyl-N-methyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide methyl ester Ν- [N- (cyclopropylacetyl) -L-alaninyl] ] -Lphenylalanine -580 9 9 9 9 9 9 9900 9 99 9 9,999,999,999 9 99 9 99 9 9 Ν- [Ν- (3,5-difluorophenylacetyl) -L-alaninyl] glycine benzyl ester Ν- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine methyl ester Ν- [N- (3 nit- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-alaninyl ethyl ester Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] glycine ethyl ester -nitrophenylacetyl) -L-alaninyl N- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine methyl ester Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -D, L-threoninamide N-hydroxy-N '- Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-tyrosine iso-butyl ester Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -2-amino-3- (3-hydroxyphenyl) propionate is- [N- (isovaleryl) -L-valinyl] -L-phenylglycinyl] -L-alanine iso-butyl ester Ν- [N- (isovaleryl) - (isovaleryl) -L-isoleucinyl] -L-alanine L-phenylalaninyl] -L-alanine Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalanine ethyl ester -581 AAAA A 1- [N- (3-nitrophenylacetyl) -L-alaninyl] -indoline (S) -2-carboxylate ethyl ester Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide N-methoxy-N-methyl-N '- [N- (isovaleryl) -L-phenylglycinyl] -Lalaninamide N-iso-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninamide Ν, N-di-n-propyl-N - - [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-alaninamide Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-valinamide N- (4-nitrophenyl) -N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-alaninamide Ν '- [[- [N- (isovaleryl) -L-phenylglycinyl] -L-alaninyl] -L-phenylalaninamide ter- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalaninamide N-iso-butyl-N '- [N- (isovaleryl) -L-phenylglycinyl] -L-alaninamide N- (2-methoxyethyl) -N '- [N- (3,5-difluorophenylacetyl) -L] -582 • · · · · 4 4 4 · 4,444 44,949 4 4 4 9 444 44 44 alaninyl] -L-phenylalaninamide N- (4-nitrobenzyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (4-nitrophenyl) -1 '- [Ν- [N- (isovaleryl) -L-phenylglycinyl] -Lalaninyl] -L-alaninamide N- (4-nitrophenyl) -N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-phenylalaninamide N-Benzyl-N-methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (3,5-difluorobenzyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (3-nitrobenzyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N-Benzyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninamide N- (4-nitrobenzyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Ltryptophan N- (4-methoxybenzyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide AND -583 00 00 t ··· 00 0 000 0000 0 0 0000 0 00 0 0 00 0 00 «00000 • 0 0 0 0 · 000 00 000 0« * · [- [N- (phenylacetyl) -L-phenylglycinyl] -L-alanine ethyl ester Ν- [ Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalaninyl] -L-phenylglycine ethyl ester Ν- [N- (cyclohexylacetyl) -L-phenylglycinyl] -Lalanine methyl ester Ν- [N- (3,5 -Difluorophenylacetyl) -L-alaninyl] -L-phenylglycine Ν- [Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninyl] -L-phenylglycine methyl ester N- (2-phenylethyl) -N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-alaninamide Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tryptophanamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2 amino-3- cyclohexylpropionate N- (2-methoxyethyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] - (S) -2-amino-3- (4-nitrophenyl) propionamide ethyl ester Ν- [N- (3- nitrophenylacetyl) -L-alaninyl] -L-serine N - [(R) -α-methylbenzyl] -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide -584 to it to it to it to it to it to it N - [(S) -α-methylbenzyl] -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (4-fluorobenzyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (4-pyridylmethyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (4-trifluoromethylbenzyl) -N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide ethyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino- 2- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester 2-phenylpropionate átu- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- methyl ester methyl propionate ethyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-cyclohexyl acetate N- (2-methoxyethyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide ethyl- [N- (isovaleryl) -2-amino-2-cyclohexylacetyl] -Lalanine N-2- (N, N-dimethylamino) ethyl-N '- [N- (3,5-difluorophenylacetyl)] -585 · «· 58 • • • • · 58 58 58 58 58 58 58 58 58 58 58 58 58 58 • · · · · · · · · · «« « L-alaninyl] -L-phenylglycinamide N- (2-pyridylmethyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide N- [N- (3-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester N- [ N- (2-pyridylacetyl) -L-alaninyl] -L-phenylalanine N- [N- (4-pyridylacetyl) -L-alaninyl] -L-phenylalanine ethyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-fluorophenyl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-fluorophenyl) acetate N- [N- (3,5-fluorophenyl) acetate ethyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-phthalimidopropionate neopentyl N- [N- (3,5-difluorophenylacetyl) -L-difluorophenylacetyl] -L-phenylglycinyl] -L alanine ethyl ester -alaninyl] -L-phenylglycine N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide -586 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · φ φ φ φ φ Ν- [Ν- (3,5-Difluorophenylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester Ν '- [Ν- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide 4- [Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valinyl] morpholine Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valine methyl ester Ν- [N- Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminopentanoate (3-nitrophenylacetyl) -L-alaninyl] -L-threonine methyl ester 4- [Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] - (S) -2-amino-3-tert-butoxybutyryl] morpholine 4- [Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -Lisoleucinyl] morpholine methyl ester of Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -Lisoleucine Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isoleucine ethyl ester Ν- [Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-threoninyl] -L-valine methyl ester Ν- [N - (3-nitrophenylacetyl) -L-alaninyl] - (S) -2 99,999 aminopentanoate N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-leucine methyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lleucine methyl ester N-2-methoxyethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide N-2- (N, N-dimethylamino) ethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide N-cyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninamide N-neopentyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninamide N-tetrahydrofurfuryl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N-2-pyridylmethyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide 3- [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninyl] thiazolidine methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminobutanoate 9 9 9 -588 9 9 • 9 9999 9 9 9 999 9 9999 Ν- [Ν- (3-Nitrophenylacetyl) -L-alaninyl] - (S) -2-aminobutanoate methyl ester N- (R) -sec-butyl-N ¹ - [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-alaninamide 1- [Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninyl] pyrrolidine N- (S) -sec-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-alaninamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lvaline N-2-Fluoroethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L alaninamide N - [(S) -6-methyl-3-oxohept-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N-4-nitrobenzyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] (S) -2-aminobutyramide N - [N- (3,5-difluorophenylacetyl) -L-alaninyl] - [N- (3,5-difluorophenylacetyl) -L-alaninyl] (S) -2-aminopentanamide methyl ester - N-4-nitrobenzyl-N '- 2 amino-2- (3-fluorophenyl) acetate Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-2- (2 -589 ················ 99 99 thienyl) acetamide N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (5-chlorobenzothiophen-2-yl) acetate methyl ester N- [N- (3,5-difluorophenylacetyl) ester - L-alaninyl] -2-amino-2- (benzothiophen-2-yl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (benzothiophen-3-yl) acetate methyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-thienyl) acetate methyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino- 2- (benzothiophen-5-yl) acetate methyl ester of (- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2 amino-2- (2-thienyl) acetate tert-butyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] (S) -2-amino-2- (2-thienyl) acetate Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-2- (2-thienyl) acetic acid methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl ] - [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2 amino-2- (6-methoxy-2) -2-amino-2- (1H-tetrazol-5-yl) acetate methyl ester (naphthyl) acetate -590 • 99 • 9 9 · 9 9 9 9 98 · 9 · 9 9 9 9 9 9 999 9 9 9 9 9 9 99 999 99 99 9 9 9 9 9 9 9 9 9 99 N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-trifluoromethylphenyl) acetate methyl ester N- [N- (3,5-difluorophenylacetyl) -L-methyl ester -alaninyl] -2-amino-2- (4,5,6,7-tetrahydrobenzothiophen-2-yl) acetate methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (thieno [ 2,3-b] thiophen-2-yl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-methylthiazol-4-yl) acetate methyl ester (3S, 4S) N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -4-amino-3-hydroxy-5-phenylpentanoate methyl ester S) -2- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester -2-aminohex-4-enoate N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] (S) -2-amino-2- (4-phenylphenyl) acetamide tert-butyl ester Ν- [N- (3,5-Difluorophenylacetyl) - (S) -2-aminobutanoyl] -L-phenylglycine tert-butyl ester of Ν- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L phenylglycine • fl · -591 fl * fl fll fll fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl methyl ester N- [N - [3,5-difluorophenylacetyl] -L-methioninyl] -L phenylglycine N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine methyl ester N- [N- (3,5-difluorophenylacetyl) - 2-aminobutanoyl] L-phenylglycine N- [N- (3,5-difluorophenylacetyl) -L-leucinyl] -L-phenylglycine methyl ester N- [N- (3,5-difluorophenylacetyl) -L-phenylalaninyl] L-phenylglycine methyl ester N - [N- (3,5-difluorophenylacetyl) glycinyl] -L-phenylglycine N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] L-phenylglycine methyl ester N- [N- (phenylacetyl) -L-alaninyl] -L-alanine N- [N- (phenylacetyl) -L-alaninyl] -L-leucine methyl ester N- [N- (phenylacetyl) -L-alaninyl] -L-isoleucine N- [N- (phenylacetyl) methyl ester - L-alaninyl] -L-proline N- [N- (phenylacetyl) -L-alaninyl] -L-phenylalanine methyl ester 0 0 00 0000 0 0 0 0 0 0 0 0 ♦ · * · «0 0 »- [N- (phenylacetyl) -L-alaninyl] -N- (tert-butoxycarbonyl) -L-lysine methyl ester Ν- [N- (phenylacetyl) -L-alaninyl] -glycine methyl ester Ν- [N- (phenylacetyl) -L-alaninyl] -L-alaninyl] - [N- (phenylacetyl) -L-alaninyl] - (S) -2-aminobutanoate methyl ester - [N- (phenylacetyl) -L-alaninyl] - (S) -2-aminopentanoate Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valine methyl ester Ν- [N- (phenylacetyl) -L-alaninyl] -LN-methylalanine iso-butyl ester Ν- [N- (isovaleryl) -L Ν- [N- (isovaleryl) -L-isoleucinyl] -L-alanine iso-butyl ester -phenylglycinyl] -L-alanine N - [N- (3,5-difluorophenylacetyl) -L-4-hydroxyproline methyl ester] - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide ethyl ester N- (3,5-difluorophenylacetyl) -L-alaninyl] -Llysine Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-glutamide -593 1- [N- (3,5-difluorophenylacetyl) -Lalaninyl] piperidine-2-carboxylate methyl ester N - [(S) -3-hydroxy-6-methylhept-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -2-hydroxy-1-phenyleth-1-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide tert-butyl ester N- [N- (3,5-difluorophenyl-α-) - Fluoroacetyl) -Lalaninyl] -L-phenylglycine N- [N- (3,5-difluorophenylacetyl) -2- (S) -aminocyclohexylacetyl] -L-phenylglycine methyl ester N - [(1R, 2S) -1-hydroxy-1-phenylprop-2-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(1R, 2S) -1-hydroxy-1,2-diphenyleth-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(1S, 2R) -1-hydroxy-1-phenylprop-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N-2-Methoxyethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycinamide N - [(S) -α-Hydroxy-α-phenyl-iso-propyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide ···· -594 A · A AAA A A · Ν - [(S) -2-hydroxy-1,2-diphenylethyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -1-hydroxyhex-2-yl] -1 '- (3,5-difluorophenylacetyl) -Lalaninamide N- [α-hydroxy-α '- (4-hydroxyphenyl) -isopropyl] -N' - (3,5-difluorophenylacetyl) -L-alaninamide N-2-pyridylmethyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide N- [α-hydroxy-α'-pyrid-2-yl-isopropyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [α-hydroxy-α'-pyrid-4-yl-isopropyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -1-hydroxy-4-methylpent-2-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N- [α-methoxy-prop-2-yl] -N '- (3,5-difluorophenylacetyl) -Lalaninamide N - [N- (3,5-Difluoro-phenylacetyl) -L-alaninyl] -2-amino- [1-hydroxy-3-methyl-but-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide methyl ester Of 2- (6-aminopyrid-2-yl) acetate -595 »· 99 N- [1-Hydroxy-prop-2-yl] -1 '- (3,5-difluorophenylacetyl) -Lalaninamide Ν - [(S) -2-methoxy-1-phenyleth-1-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -1-methoxy-2-phenyl-prop-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -1-acetoxyhex-2-yl] -N '- (3,5-difluorophenylacetyl) -Lalaninamide N - [(S) -1- (tert-butylcarbonyloxy) -hex-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [2-hydroxy-1- (thien-2-yl) ethyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -2-hydroxy-2-methyl-1-phenylprop-1-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide tert-butyl ester ter- [N- (3,5- difluorophenylacetyl) -L- (thien-2-yl) glycinyl] -L-phenylalanine Ν- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycinol Ν- [N- (cyclopropaneacetyl) -L-phenylglycinyl] -L-phenylglycinol Ν- [N- (cyclopentaneacetyl) -L-phenylglycinyl] -L-phenylglycinol -596 -i · · · · · 9 9999999 4 Ν- [Ν- (3,5-difluorophenylacetyl) -D, L-phenylglycinyl] -D, L-phenylglycinamide Ν- [N- (3,5-difluorophenylacetyl) -D, L-valinyl] -D, L-phenylglycinamide Ν- [N- (2-thienylacetyl) -L-alaninyl] -L-phenylglycinamide Ν- [N- (n-caprotyl) -L-alaninyl] -L-phenylglycinamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-norleucinyl] -L-phenylglycine methyl ester Ν- [N- (3,5- difluorophenylacetyl) -L-norvalinyl] -L-phenylglycine Ν- [N- (3,5-difluorophenylacetyl) -L-tert-leucinyl] L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-isoleucinyl] methyl ester L- [N- (3,5-difluorophenylacetyl) -L-cyclohexylalaninyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) - (S) -2-amino-2 (cyclopropyl) acetyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) - (S) -2-amino-2 (thien-3-yl) acetyl] -L-phenylglycine methyl-L-phenylglycine -597 [- [Ν- (3,5-Difluorophenylacetyl) - (S) -2-amino-2 (thien-2-yl) acetyl] -L-phenylglycine methyl ester methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -D- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L- (4-methoxyphenyl) glycinyl] -L-phenylglycine tert-butyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycine tert- Ν- [N- (cyclopropylacetyl) -L-phenylglycinyl] L-phenylglycine butyl ester tert-butyl Ν- [N- (cyclopentylacetyl) -L-phenylglycinyl] L-phenylglycine tert -butyl ester Ν- [N- (tert-butylacetyl) -L-alaninyl] -L-phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (5-bromothien-2-yl) glycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D (5-bromothien-2-yl) glycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (4-bromothien-2-yl) glycinamide 4 · -598 4 4 4 · 4 4 4 « 4 4 · 4 · 4 · 4 44 N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (thien-2-yl) glycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D (thien-2-yl) glycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (thien-3-yl) glycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D (thien-2-yl) glycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L- (5-chlorothien-2-yl) glycinamide N-cyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-4 (phenyl) phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L 3 - (phenoxy) phenylglycinamide N- (S) - (-) - α-Methylbenzyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide -599 · fl fl fl * * * * * * * * * * * * * * * 99 99 99 99 99 99 9 9 9 9 9 9 999 9999 N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L 3- (phenyl) phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L 4- (ethyl) phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-2- (phenyl) phenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L2- (benzyl) phenylglycinamide N-tert-butyl-Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-4-bromophenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L4- (cyclohexyl) phenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L4- (4-ethylphenyl) phenylglycinamide N-tert-butyl-Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-4- (tert-butyl) phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-3- (4-chlorophenoxy) phenylglycinamide N-cyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4 (phenyl) phenylglycinamide N- [N- (3,5-difluorophenyl-α-hydroxyacetyl) tert-butyl ester -L-600 • 9999 alaninyl] -L-phenylglycine N - [N- (3,5-difluorophenylacetyl) - N - tert -butyl-Ν - [N- (3,5-difluorophenyl-α, α-difluoroacetyl) -L-alaninyl] -L-phenylglycinamide tert-butyl ester -L-alaninyl] D-phenylglycine N - [(S) -1-oxo-1-phenylprop-2-yl] -N '- (3,5-difluorophenylacetyl) L-alaninamide tert-butyl ester N- [N- (3,5-difluorophenylacetyl) - L-alaninyl] D, L- (pyrid-3-yl) glycine [Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] morpholine methyl ester Ν- [N- (3,5 -difluorophenylacetyl) -L-alaninyl] -D, L (2-methoxy) phenylglycine N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine N-tert-butoxycarbonyl (hydroxylamine) ester N-neopentyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L phenylglycinamide N-tetrahydrofurfuryl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-methoxy-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide 601 [999- [Ν- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] azetidine N-iso-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L phenylglycinamide N-cyclopropanomethyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-methoxy-N-methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-2-methylprop-2-enyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N- (pyrid-3-yl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N- (pyrid-4-yl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-furfuryl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide N-cyclopentyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-phenylglycinamide N-1-Benzylpiperidin-4-yl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide -602 • 0 00 ···· 0 · 0 0 0 0 0 0 0 0 0 00 000 N, N-dimethyl-N '- [Ν- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L phenylglycinamide N-2,2,6,6-tetramethylpiperidin-4-yl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide N-2-methylcyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-4-methylcyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide Ν-1-ethoxycarbonylpiperidin-4-yl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide N-methyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide N-tert-butoxy-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-phenylglycinamide N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine hydrazide N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] N-tert-butyl (hydroxylamine) ester - L-phenylglycine N- (1-ethoxyethen-1-yl) - [N '- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester N- [N- (phenylacetyl) -L-alaninyl] - L- -603 to phenylglycine N-4- (phenyl) butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-phenylglycinamide N-3- (4-iodophenoxy) propyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide hydrochloride N-6- (amino) hexyl-N' - [N- (3, 5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide N- [N- (3,5-difluorophenylacetyl) -L- (3,5-difluorophenylacetyl) -L- (3,5-difluorophenylacetyl) -La (3,5-difluorophenylacetyl) -L- (3,5-difluorophenylacetyl) -L- (3,5-difluorophenylacetyl) -L- ( 3,5-difluorophenyl) glycine N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-norleucine tert-butyl N- [N- (cyclopentaneacetyl) -L-alaninyl] -L-phenylglycine isopropyl N- [N- (3) (5-difluorophenylacetyl) -L-alaninyl] -L4-fluorophenylglycine N- (isopropyl) N ¹ - [N- (3,5-difluorophenylacetyl) Iralaninyl] -Lfenylglycinamid tert-butyl N- [N- (cyclopentylacetyl) -L-alaninyl] • it -Lfenylalaninu -604 it this it it it it it it it it it it it it it it it it it N- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylalanine iso-butyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine methyl ester N- [N] N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (3α-phenyl) proline methyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -phenylglycine 5-difluorophenylacetyl) -L-alaninyl] -Lazetidine N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3- (5-chlorobenzothiophen-2-yl) acetate tert-butyl ester N - [N- (3,5-difluorophenylacetyl) -L-alaninyl] (S) -2-amino-3- (thiazol-4-yl) propionate N- [N- (3,5-difluorophenylacetyl) tert-butyl ester - -L-alaninyl] L-phenylglycinamide N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D- (thien-2-yl) glycinamide N- [N- (3,4-dichlorophenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (3-chlorophenylacetyl) -L-alaninyl] -D-phenylglycinamide -605 «9 · ·· 9999 ··» · 99 99 999 9999 * 9 9 9 9999 9 9 99 9 99 999 9 9 9 9 9 9 999 99 99 99 99 99 Ν- [Ν- (3-bromophenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (3-fluorophenylacetyl) -L-alaninyl] -D-phenylglycinamide N - [N- (4-fluorophenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (3-methylphenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (4-methylphenylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (3-Trifluoromethylphenylacetyl) -L-alaninyl] -phenylglycinamide Ν- [N- (3-methoxyphenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (2-chlorophenylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (1-naphthylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (2-naphthylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (phenylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycinamide Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-2- (2-furanyl) acetamide N ¹ - [N- (3,5-difluorophenylacetyl) -D-alaninyl] -D-phenylglycinamide -606 ···· «♦ ·· · · · · ··· 9 9 99 99 9 9 9 9 9 * 999 999 9 9 9 · 99 Ν ^1- [Ν- (3,4-difluorophenylacetyl) -D-alaninyl] -D-phenylglycinamide N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine-N-methylsulfonamide N-methyl-N-phenyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -glycinamide N-methyl-N-phenyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N '- [N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-phenylglycinamide N-methyl-N-benzyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -glycinamide N-4-fluorobenzyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-phenylglycinamide neopentyl ester N' - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (4 -fluoro) phenylglycine N- [N- (2,3,4,5,6-pentafluorophenylacetyl) -Lalaninyl] -L- (pyrid-3-yl) glycine methyl ester Ν- [N- (3,5-tert-butyl) ester -difluorophenylacetyl) -L-alaninyl] L- (pyrid-3-yl) glycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L- (O to · ····) 607 · «···· · · to« · · « benzyl) -L-phenylglycine Ν- [N- (3,5-difluorophenylacetyl) -L- (O-benzyl) threoninyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-threoninyl methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-serinyl] -L-phenylglycine methyl ester N-4-methylphenyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-phenylglycinamide N-tetrahydrofurfuryl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenylglycinamide Ν '- [N- (3,5-difluorophenylacetyl) -L-methionyl] -L-phenylglycinamide Ν- [N- (3,5-difluorophenylacetyl) -2-aminobutanoyl] -L-phenylglycinamide N '- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycinamide Ν- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycinamide -608 • ·· ·· 9 · * · * 9 · · · ♦ 9 9 9 9 9 9 9 9 9 9 9 99 99 99 999 999 9 9 9 9 9 9 999 99 99 99 99 99 Ν - [(R) -α-Methylbenzyl] - Ν - [Ν- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide N- [1-phenyl-2-oxo-3-methylbutan-1-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [1-phenyl-2-oxo-propan-1-yl] -1 '- (3,5-difluorophenylacetyl) -L alaninamide N- [1-phenyl-2-oxo-pentan-1-yl] -1 '- (3,5-difluorophenylacetyl) -L alaninamide N- [1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [1-phenyl-2-oxo-butan-1-yl] -N '- (3,5-difluorophenyl-acetyl) -L alaninamide N- [1-phenyl-2-oxo-4-methylpentan-1-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide methyl ester Ν' - [N- (3,5-difluorophenylacetyl) -L -alaninyl] -L-ahydroxyphenylalanine N- [4 - ((2-hydroxy-4-azido) -phenyl) -NHC (O) -) butyl] N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide N - [(S) -1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -1 '- (3,5-difluorophenyl-acetyl) -L-alaninamide tert-butyl ester N' - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -609 • 9 9 9 · 9 9 9999 9 9 99999 9 9 99 99 99 999999 9 9 9 9 9 9 999 99 99 99 99 99 L-4-Fluorophenylglycine N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-4-phenylphenylglycine tert-butyl ester [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L - (2,3-benzo [b] proline) N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L 4-n-butylphenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-4- (phenylacetenyl) phenylglycinamide N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinthioamide N- [1,3-Diphenyl-2-oxo-propan-1-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N- [1-phenyl-2-oxo-2-cyclopentylethan-1-yl] -N - (3,5-difluorophenylacetyl) -L-alaninamide N- [1-phenyl-2-oxo-hexan-1-yl] -N '- (3,5-difluorophenylacetyl) -Lalaninamide N- [1-phenyl-2-oxo-3-methylpentan-1-yl] -N- (3,5-difluorophenylacetyl) -L-alaninamide N-n-hexyl-6-biotinamidyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinthioamide -610 • · ··· 0 · 0 · N '- [N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-methionine methyl ester N' - [N- (2-tert-BOC-amino) propionyl) -L-alaninyl] L-phenylglycine N '- [N- (3,5-Difluorophenylacetyl) -L-alaninyl] -D-tert-butyl N' - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L 2-fluorophenylglycinamide methyl ester , L2-phenylglycine N - [(S) -1-phenyl-2-oxo-3-phenylpropan-1-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N '- [N- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L2-phenylglycine tert-butyl ester N' - [N- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L-2-phenylglycine Ν '- [N- (3,5-difluorophenylacetyl) -L-thien-3-ylglycinyl] -L-2-phenylglycine tert-butyl ester Ν' - [N- (3,5-difluorophenylacetyl) -L-thien-3-ylglycinyl] -L-2-phenylglycine N- [2-hydroxy-1- (S) -phenyleth-1-yl] -1 '- [(3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-alaninamide N- [2-hydroxyeth-1-yl] -N '- [(3,5-difluorophenylacetyl) -L-611] alaninyl] -L-phenylglycinamide tert-butyl ester Ν' - [N - (3,5-Difluorophenyl-2-oxo-acetyl) -Lalaninyl] -L-2-phenylglycine [N- (2,5-dichlorophenoxyacetyl) -L-alaninyl] -L-phenylglycine methyl ester [N- (3,5- [N- (3,4-dichlorothiophenoxyacetyl) -L-alaninyl] -L-phenylglycine tert-butyl [N- (3-aminopropionyl) -L-alaninyl] -L-phenylglycine methyl ester and tert- [N- (3-tert-butoxycarbonylamino) propionyl) -L-alaninyl] -L-phenylglycine butyl ester. 61. Compound of Formula I: wherein R ¹ is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, and £ 10 O; * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · And a heteroaryl and heterocyclic system; R ² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, and the heterocyclic system; each R ³ is independently selected from the group consisting of hydrogen and methyl, and R ³ together with R ⁴ may be joined to form a cyclic structure containing from 3 to 8 atoms, which is optionally fused with an aryl or heteroaryl group; each R ⁴ 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 R ⁵ is selected from the group consisting of hydrogen and methyl or together with R ⁴ forms a cycloalkyl group containing from 3 to 6 carbon atoms; X is selected from the group consisting of -C (O) Y and -C (S) Y, wherein Y is selected from the group consisting of (a) alkyl or cycloalkyl, (b) substituted alkyl, with substitution on said substituted alkyl does not include α-haloalkyl, adiazoalkyl, α-OC (O) alkyl, or α-OC (O) aryl, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl , (g) heteroaryl, (h) heterocyclic system, to (I) -NR'R, wherein R 'and R are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic system wherein one of R 'or R is hydroxy or alkoxy and wherein R' and R are joined together 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; (j) -NHSO ₂ -R ⁸ wherein R ⁸ is selected from; from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and a heterocyclic system, (k) -NR ⁹ NR ¹⁰ R ¹⁰ wherein R ⁹ is hydrogen or alkyl and each R ¹⁰ is independently selected from the file, incl hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -ONR ⁹ [C (O) 0] _Z R ¹⁰ where z is zero or one and R 1 ⁹ and R ¹⁰ are as defined above; X may also be -CR ⁶ R ⁶ Y ', wherein each R ⁶ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and the heterocyclic system and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -OC (O) R ⁷ , -SSR ⁷ , -SSC (O) R ⁷ , wherein R ⁷ is selected from the group consisting of alkyl, substituted alkyl , cycloalkyl, aryl, heteroaryl and heterocyclic systems, -614 4 4 flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl flfl X 'represents a hydrogen atom, hydroxy, or fluorine; X is hydrogen, hydroxy, or fluoro, or X 'and X together form an oxo group; Z is selected from the group consisting of a covalent bond that binds R ¹ to -CX'X-, an oxygen atom, and a sulfur atom; n is an integer equal to 1 or 2; and pharmaceutically acceptable salts thereof, provided that: A. when R ¹ is phenyl or 3-nitrophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is -CH (OH) CH ₃ , R ⁵ is hydrogen, X 'and X are hydrogen, Z is and n is 1, then X is not -C (O) OH; 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 and n is 1, then X is not -C (O) OH or -C (O) OCH 3; C. when R ¹ is phenyl, R ² is methyl, R ⁴ is benzyl, R ⁵ is hydrogen, X is methoxycarbonyl, X 'and X are hydrogen, Z is a bond and is 1, then R ^{3 is} not methyl; D. when ^R1 is iso-propyl, ^R2 is -CH2C (O) NH2, ^R3 is hydrogen, ^R4 is isobutyl, ^R5 is hydrogen, X 'and X are hydrogen, Z is a bond and n is equal to 1, then X is not -C (O) OCH 3; E. when R ¹ is phenyl, R ² is methyl, R ⁵ is hydrogen, X is -C (O) OCH ₃ , X 'and X are hydrogen, Z is a bond and is equal to -615 • · 1, then ^R3, the nitrogen atom attached to R ³ and R ⁴ do not form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. when R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁵ is hydrogen, X is C (O) OCH 3, X 'and X "are hydrogen, Z is a bond and is 1, then R ^{4 is} not 4-amino-n-butyl; G. when ^R1 is 3-nitrophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is CH (OH) CH3, ^R5 is hydrogen, X 'and X "are hydrogen, Z is a bond and n is equal to 1, then X is not -C (O) NH 2 or -CH ₂ OH; H. when R ¹ is phenyl, R ² is methyl, R ³ is hydrogen, R ⁵ is hydrogen, X is CH ₂ OCH ₃ , X 'and X are hydrogen, Z is a bond and n is 1, then R ⁴ it is not benzyl or ethyl; I. when R ¹ represents 3,5-difluorophenyl, R ² represents methyl, R ³ represents methyl, R ⁴ represents methyl, R ⁵ represents hydrogen, X 'and X' represent hydrogen, Z represents a bond and is 1, then X is not -CHOHO; J. when ^R1 is 3,5-difluorophenyl, ^R2 is methyl, ^R3 is hydrogen, ^R4 is phenyl derived from D-phenylglycine, ^R5 is hydrogen, X 'and X "are hydrogen, Z is and n is 1, then X is not -CHOH or -CH ₂ OH; K. when ^R1 is N- (2-pyrrolidinonyl), ^R2 is methyl, ^R3 is hydrogen, ^R4 is benzyl, ^R5 is hydrogen, X 'and X "are hydrogen, Z is a bond and n is equal to 1, then X is not -C (O) OCH ₃ ; 4 4 -616 44 44 4 4 4 4 4 4 4 4 44 44 4 4 4 L. when ^R1 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 represents hydrogen, Z is a bond and n is 1, then X is not -C (O) NH-benzyl; M. when R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is hydrogen, R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and is 1 then X is not -CH ₂ OH; N. when R ¹ is 3,5-difluorophenyl, R ² is methyl, R ³ is hydrogen, R ⁴ is ^4- phenylphenyl, R ⁵ is hydrogen, X 'and X are hydrogen, Z is a bond and is 1, then X is not -C (O) NHC (CH ₃ ) ₃ ; and O. when R ¹ represents 3,5-difluorophenyl, R ² represents methyl, R ³ represents hydrogen, R ⁴ represents phenyl derived from D-phenylglycine, R ⁵ represents hydrogen, X 'and X represent hydrogen, Z represents a bond and n is 1, then X is not -C (O) NHCH (CH ₃ ) Φ. The compound of claim 61, wherein R ¹ represents an unsubstituted aryl group and Z represents a covalent bond that binds R ¹ to -CX'X-. The compound of claim 62, wherein the unsubstituted R ¹ aryl group is selected from phenyl, 1-naphthyl and 2-naphthyl. The compound of claim 61, wherein R ¹ is • H -617 φφφφ ΦΦΦ φ φ φ substituted aryl and Z represents a covalent bond that binds R ¹ to -CX'X-. The compound of claim 64, wherein said substituted aryl group is a mono-substituted, di-substituted or tri-substituted phenyl group. The compound of claim 65, wherein the substituted phenyl group is selected from the group consisting of 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3- bromophenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2-hydroxyphenyl, 2-methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 3,4-difluorophenyl, 2,3,4,5,6pentafluorophenyl, 3,4-dibromophenyl, 3,4-dichlorophenyl, 3,4-methylenedioxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2,4-dichlorophenyl and 2,5-difluorophenyl. A compound according to claim 61, wherein R ¹ represents an alkaryl group and Z represents a covalent bond that binds R ¹ to -CX'X-. The compound of claim 67, wherein the R ¹ alkaryl group is selected from benzyl, 2-phenylethyl, and 3-phenyl-n-propyl. The compound of claim 61, wherein R ¹ is selected from the group consisting of alkyl, alkenyl, cycloalkyl, and cycloalkenyl, and Z is a covalent bond that binds R ¹ to -CX'X-. • · -618 The compound of claim 69, wherein R ¹ is alkyl. The compound of claim 69, wherein R ¹ is cycloalkyl. The compound of claim 69, wherein R ¹ is alkenyl. The compound of claim 69, wherein R ¹ is cycloalkenyl. 74. A compound according to claim 69 wherein R &lt; ¹ & gt ^; alkyl, cycloalkyl, alkenyl and cycloalkenyl are selected from the group consisting of isopropyl, n-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, CH ₂ CH = CH ₂ , -CH ₂ CH = CH (CH ₂ ) 4 CH ₃ , cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclohexyl, -CH ₂ -cyclopentyl, -CH ₂ CH ₂ cyclopropyl, -CH ₂ CH ₂ -cyclobutyl, -CH ₂ CH ₂ -cyclohexyl, -CH ₂ CH ₂ cyclopentyl, aminomethyl and N-tert-butoxycarbonylaminomethyl. A compound according to claim 61, wherein R ¹ is selected from the group consisting of heteroaryl and substituted heteroaryl, and Z represents a covalent bond that binds R ¹ to CX'X-. A compound according to claim 75 wherein R ¹ heteroaryl and substituted heteroayl are selected from pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3) -yl), chloropyridyls (including 5-chloropyrid-3-yl), thien-2-yl, -619 9 9 9 9 9999 999 999 9 9 9 9999 9 100 9 9 9 99 · 99 999999 9 9 9 9 9 9 999 9999 99 999 99 99 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 (thiophenyl) thiophen-5-yl, 6-methoxythionaphten-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl. The compound of claim 61, wherein R ² is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and a heterocyclic system. A compound according to claim 77 wherein R ² is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, phenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4-methoxyphenyl, benzyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, thien-2-yl, thien-3-yl, -CH ₂ CH ₂ SCH ₃ , -CH ₂ OCH ₂ 0, -CH (CH ₃ ) OCH ₂ 0, - CH (OH) CH ₃ and -CH ₂ OH. 79. The compound of claim 61 wherein X 'and X are hydrogen and Z is a covalent bond, which links R ¹ to CX'X-. A compound according to claim 79 wherein R ³ is selected from the group consisting of hydrogen, methyl or together with R ⁴ and the nitrogen atom to which R ^{3 is} attached to form pyrrolidin-2-yl, 2,3-dihydroindol-2-yl, piperidin-2-yl, 4-hydroxy-pyrrolidin-2-yl and 1,2,3,4-tetrahydroisoquinolin-3-yl. 81. A compound according to claim 61 wherein R &lt; ⁴ &gt; is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, iso-butyl, cyclopentyl, cyclohexyl, allyl, iso-but-2-enyl, A A -620 3-methylpentyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclohexyl, -CH ₂ indol-3-yl, phenyl, p- (phenyl) phenyl, m- (phenyl) phenyl, of fluorophenyl, m-fluorophenyl, p-fluorophenyl , p-bromophenyl, mmethoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, mhydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, trifluoromethylphenyl, p- (CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ O-benzyl, p (CH ₃ ) ₃ COC (O CH ₂ O -benzyl, p-phenylphenyl, 3,5-difluorophenyl, p (HOOCCH 2 O) -benzyl, 2-aminopyrid-6-yl, 4- (N-morpholinoCH ₂ CH ₂ O) -benzyl, -CH ₂ CH ₂ C (O NH ₂ , -CH ₂ -imidazol-4-yl, -CH ₂ - (3-tetrahydrofuranyl), -CH ₂ -thien-2-yl, -CH ₂ -thiazol-4-yl, CH ₂ (1-methyl) cyclopropyl , -CH ₂ -thien-3-yl, thien-3-yl, thien-2-yl, -CH ₂ -C (O) O-tert-butyl, -CH ₂ -C (CH ₃ ) 3, -CH ₂ CH (CH ₂ CH ₃ ) 2, 2-methylcyclopentyl, -cyclohex-2-enyl, -CH [CH (CH ₃ ) ₂ ] COOCH ₃ , (CH ₂ ) ₂ SCH ₃ , -CH ₂ CH ₂ N (CH ₃ ) 2, - CH ₂ C (CH ₃ ) = CH ₂ , -CH ₂ CH = CHCH ₃ (cis and trans), -CH ₂ OH, -CH (OH) CH ₃ , -CH (O-tert-butyl) CH ₃ , CH2OCH3, - _(CH2) 4NH-B0C, - (CH ₂₎ 4 NH _2, - (CH ₂₎ 4 N (CH ₃₎ 2, -CH ₂ pyridyl, pyridyl, -CH ₂ -naphthyl, -CH ₂ - (N-morpholino), p- (Nmorpholino-CH ₂ CH ₂ O) -benzyl, benzo [b] thiophen-2-yl, benzo [b] thiophene- 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, -CH ₂ -N-phthalimidyl, 2-methylthiazol-4-yl and thieno [2,3-b] thiophene- 2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl, 5-chlorothien-2-yl, 3-phenoxyphenyl, 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. A compound according to claim 61, wherein Z represents a covalent bond that binds R ¹ to -CX'X- and R ⁴ and R ⁵ are joined to form a cycloalkyl group selected from the group consisting of: -621 000 00 0000 00 0000 000 0 0 0 000000 0000 0 0000 00 000 · 00 0 0 0 0 0 0 · 000 0000 00 000 «including« cyclopropyl and cyclobutyl. The compound of claim 61, wherein Z is a covalent bond that binds R ¹ to -CX'X-, X is -C (O) Y, and Y is selected from hydroxy, alkoxy or substituted alkoxy. 84. The compound of claim 83 wherein Y is alkoxy or substituted alkoxy, selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, tert-butoxy, neo-pentoxy, benzyloxy. 2-phenylethoxy, 3-phenyl-n-propoxy, 3-iodopropoxy, 4-bromo-n-butoxy, -ONHC (O) OC (CH ₃ ) ₃ , -ONHC (CH ₃ ) _3, and hydroxy. A compound according to claim 61, wherein Z is a covalent bond that binds R ¹ to -CX'X-, X is -C (O) Y, and Y is -NR'R. A compound according to claim 85, wherein Y is selected from the group consisting of amino (-NH ₂ ), -NH (iso-butyl), -NH (sec-butyl), N-methylamino, N, N-dimethylamino, N -benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethylenimino, N-heptamethylenimino, N-pyrrolidinyl, NH-methallyl, -NHCH ₂ - (furan-2-yl), -NHCH ₂ -cyclopropyl, NH (target) -butyl), -NH (p-methylphenyl), -NHOCH ₃ , -NHCH ₂ (pfluorophenyl), -NHCH ₂ CH ₂ OCH ₃ , -NH-cyclopentyl, -NH-cyclohexyl, -NHCH ₂ CH ₂ N (CH ₃ ) 2, -NHCH ₂ C (CH ₃ ) 3, -NHCH ₂ - (pyrid-2-yl), -NHCH ₂ (pyrid-3-yl), -NHCH ₂ - (pyrid-4-yl), N -thiazolindinyl, N (CH ₂ CH ₂ CH ₃ ) 2, -N [CH ₂ CH (CH ₃ ) ₂ ] ₂ , -NHOH, -NH (ρ-Ν ₂ -Φ), -NHCH ₂ (pΝ0 ₂ ~ Φ) ), -NHCH ₂ (m-NO ₂ - <2>), -N (CH ₃ ) OCH ₃ , -N (CH ₃ ) CH ₂ - <Z>, -NHCH ₂ -622 9 99 99 99 9 9 9 9 9 9 9 9 9 • 9 9 9 9 9 9 99 99 99 999999 9 9 9 9 9 9 999 9999 99 999 99 99 (3,5-difluorophenyl), -NHCH ₂ CH ₂ F, -NHCH ₂ (p-CH ₃ O- <Z>), -NHCH ₂ (mCH ₃ O-0), -NHCH ₂ (p-CF ₃ -O), -N (CH ₃ ) CH ₂ CH ₂ OCH ₃ , -NHCH ₂ CH ₂ O, NHCH (CH ₃ ) £, -NHCH ₂ - (pF-Φ), -N (CH ₃ ) CH ₂ CH ₂ N (CH ₃ ) ₂ , -NHCH ₂ (tetrahydrofuran-2-yl), -NHCH ₂ (p-trifluoromethylphenyl), NHCH ₂ C (CH ₃ ) = CH ₂ , -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 (CH ₃ ) ₃ , -NHCH ₂ CH ₂ CH ₂ CH ₂ -O, -C (O) NH (CH ₂ ) ₃ 0- (p-CH ₃ ) Φ, C (0) NH (CH ₂ ) ₆ NH ₂ , -NH- (tetrahydrofuran-2-yl), -N (CH ₃ ) 4 Z, NH (CH ₂ ) ₄ NHC (O) - (2-hydroxy-4) azido) -phenyl and -NH _{(CH2) 6} (biotinamidyl). A compound according to claim 61, wherein X is -C (O) Y and Y is selected from the group consisting of -CH ₂ CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH ₂ OH, -CH (OH) CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH (OH) 0, -CH (OH) CH ₂ C (O) OCH ₃ , C (OH) (CH ₃ ) ₂ , -CH ₂ OCH ₃ , -CH ₂ OC (O) OCH ₃ and -CH ₂ OC (O) C (CH ₃ ) ₃ , methyl, ethyl, isopropyl, n-propyl, iso-butyl, n-butyl, sec-butyl, tert-butyl , -CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH ₂ -pyrid-2-yl, CH ₂ -pyrid-3-yl, -CH ₂ -pyrid-4-yl, -CH ₂ -fur-2- yl, benzyl, cyclopentyl, phenyl and -NH-SO ₂ -CH ₃ . The compound of claim 61, wherein Z is a covalent bond that binds R ¹ to -CX'X-. A compound according to claim 61, wherein the compound of formula I is selected from the following compounds Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohexanoate methyl ester -623 · · toto toto toto toto toto toto toto to to to to to to to to to to to to to to to to to to [- [N- (3,5-Difluoro-phenylacetyl) -L-alaninyl] -Lhistidine methyl ester · ______________________________________ N-benzyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohexanamide N-2- (N, N-dimethylamino) ethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohexanamide N- (2-methoxyethyl) -N ¹ - [N- (3,5-difluorophenylacetyl) -Lalaninyl] - (S) -2-aminohexanamide N-2- (N, N-dimethylamino) ethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalaninamide N- (4-pyridyl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide N- (3-pyridyl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide N- (4-Pyridyl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] - (S) -2-aminohexanamide tert-butyl ester N- [N- (3,5-difluorophenylacetyl) - L-alaninyl] (S) -2-aminohexanoate Ν- [N- (pent-4-enoyl) -L-alaninyl] -L-phenylalanine methyl ester Ν- [N- (dec-4-enoyl) -L-alaninyl] methyl ester -L-phenylalanine -624 9 9 9 99 99 N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4- [3- (N, N-dimethylamino) propoxy] phenylalanine methyl ester N- [N- (3,5-difluorophenylacetyl) methyl ester -L-alaninyl] -L-4 [(tert-butyloxycarbonyl) methoxy] phenylalanine N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Ltyrosine methyl ester N- [N- (3,5- difluorophenylacetyl) -L-alaninyl] -L-4- (carboxymethoxy) phenylalanine N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4 (2-morpholinoethoxy) phenylalanine methyl ester N- [N- ( 3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2 amino-6- (N, N-dimethylamino) hexanoate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) ) N- [N- (3,5-Difluoro-phenylacetyl) -L-alaninyl] - (S) -2-amino-3- (3-pyridyl) -propionate methyl ester N- (2-pyridyl) propionate methyl ester 1- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninyl] -L-proline methyl ester 1- [N- (3,5-difluorophenylacetyl) -Lalaninyl] piperidine-2-carboxylate ··· 9999 • 9 -625 • · 999 · · 9 · 9 9 9 9 • 9 9 99 9 9 9 9 · · 99 9 9 9 9 99 N - [N- (3,5-Difluorophenylacetyl) - (S) -2-amino-3- (4-pyridyl) propionate methyl ester N - [N- (3,5-difluorophenylacetyl) - L-alaninyl] -2-amino-3-methoxypropionate methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-morpholinopropionate methyl ester N- (2-methoxyethyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-4- (2-morpholinoethoxy) phenylalaninamide N- (2-methoxyethyl) -N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-methoxypropionamide methyl ester glycine N- (2-methoxyethyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -2-amino-3- (4-pyridyl) propionamide N- (2-methoxyethyl) -1 '- [N- (3,5-difluorophenylacetyl) -alaninyl] -2-amino-3- (2-pyridyl) propionamide methyl ester 2- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-3- (thiazol-4-yl) -propionate-L-alaninyl] -1,3,3-tetrahydroisoquinoline methyl ester 3-carboxylate N- (3-methoxybenzyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide 9 · -626 ········ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2 amino-3- (1-) methyl ester naphthyl propionate methyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-3- (2-naphthyl) propionate methyl ester of N- [N- (3,5-difluorophenylacetyl)] - [N- (3,5-Difluorophenylacetyl) -L-alaninyl] -L-phenylalanine-L-alaninyl] - (S) -2-amino-3- (2-thienyl) propionate benzyl ester Ν- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalanine 3-bromo-propyl ester Ν- [N- (3,5-Difluorophenylacetyl) -L-alaninyl] -L-phenylalanine 3-iodo-tert-butyl les- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-leucine tert-butyl ester N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-pyridyl) acetamide Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-pyridyl) acetamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -N ( tert-butoxycarbonyl) -L-lysine -627 9 9 9 9 944 4 99 methyl 4 - [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-4-phenylbutanoate ethyl- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine 2-phenyl 3- [N- (3,5-difluorophenylacetyl) -Lalaninyl] glycine 3-phenylpropyl ester Ν - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-pyridyl) acetamide methyl ester of Ν- [N- (phenylacetyl) -L-alaninyl] -L-threonine N '- [N- (phenylacetyl) -L-alaninyl] -L-leucinamide N - [N- (phenylacetyl) -L-alaninyl] -L-alaninamide N '- [N- (phenylacetyl) -L-alaninyl] -L-phenylalaninamide N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-pyridyl) acetate N '- [N- (phenylacetyl) -L-alaninyl] -L-valinamide ethyl ester N-methyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-leucinamide N, N-dimethyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-phenylalaninamide N, N-dimethyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-leucinamide -628 this to it to it to it to it to * e · to · to · e · to · to · to · to · to · to · to · to · to · to · to · to · to · to · to · ·· ··· · «to · N, N-dimethyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-valinamide N-methyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-phenylalaninamide N-methyl-N '- [N- (phenylacetyl) -L-alaninyl] -L-valinamide N-methyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohexanamide N, N-dimethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) 2-aminohexanamide N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminohexanamide methyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3- methoxyphenyl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-methoxyphenyl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] ethyl ester -2-amino-2- (2-pyridyl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-pyridyl) acetate ethyl ester N- [N- (cyclohexylacetyl) - L-alaninyl] -L-phenylalanine -629 * β β β β β β β β β β β β 62 62 62 62 62 62 62 62 62 62 62 4 - [- (cyclopentylacetyl) -L-alaninyl] -L-phenylalanine methyl ester N- [N- (cyclohex-1-enylacetyl) -L -alaninyl] -L-phenylalanine Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -1-aminocyclopropane-1-carboxylate methyl ester N-2- (N, N-dimethylamino) ethyl-N-methyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide methyl ester Ν- [N- (cyclopropylacetyl) -L-alaninyl] - [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycine lan- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine ethyl ester Ν- [N- (3-nitrophenylacetyl) -L-phenylalanine benzyl ester 1-L-alaninyl] -L-phenylalanine Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-alanine ethyl ester Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] glycine N-hydroxy-N '- [N- (3-nitrophenylacetyl) -L-alaninyl] -D, L-threoninamide iso-butyl ester Ν- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine -630 · Ν methy methy [[N N N- [N - [3-Nitrophenylacetyl] -L-alaninyl] -2-amino-3- (3-hydroxyphenyl) propionate iso- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-tyrosine ethyl ester Ν- [N - (isovaleryl) -L-isoleucinyl] -L-alanine iso- [N- (isovaleryl) -L-valinyl] -L-phenylglycinyl] -L-alanine iso-butyl ester Ν- [N- (isovaleryl)] -L-phenylalaninyl] -L-alanine ethyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalanine 1- [N- (3-nitrophenylacetyl) -L-alaninyl] -indoline (S) ethyl ester -2-carboxylate Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide N-methoxy-N-methyl-N '- [N- (isovaleryl) -L-phenylglycinyl] -Lalaninamide N-iso-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninamide N, N-di-n-propyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-valinide 631 ί «0 ···· Ν- (4-nitrophenyl) -1 '- [Ν- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide Ν- [N- (3,5-Difluorophenylacetyl) -L-alaninyl] -L-phenylalanine '- [Ν- [Ν- (isovaleryl) -L-phenylglycinyl] -L-alaninyl] -L-phenylalaninamide methyl ester Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalaninamide N-iso-butyl-N '- [N- (isovaleryl) -L-phenylglycinyl] -L-alaninamide N- (2-methoxyethyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide N- (4-nitrobenzyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (4-nitrophenyl) -1 '- [Ν- [N - (isovaleryl) -L-phenylglycinyl] -Lalaninyl] -L-alaninamide N- (4-nitrophenyl) -N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-phenylalaninamide N-Benzyl-N-methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (3,5-difluorobenzyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide -632 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · N- (3-nitrobenzyl) -1 '- [Ν- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N-Benzyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninamide N- (4-Nitrobenzyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Ltryptophan N- (4-methoxybenzyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide ethyl ester Ν- [N- (phenylacetyl) -L-phenylglycinyl] -L-alanine methyl ester Ν- [ Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalaninyl] -L-phenylglycine ethyl ester Ν- [N- (cyclohexylacetyl) -L-phenylglycinyl] -Lalanine methyl ester Ν- [N- (3,5 -Difluorophenylacetyl) -L-alaninyl] -L-phenylglycine Ν- [Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninyl] -L-phenylglycine methyl ester N- (2-phenylethyl) -N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-alaninamide -633 Ν '- [Ν- (3,5-difluorophenylacetyl) -L-alaninyl] -L-tryptophanamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2 amino-3- cyclohexylpropionate N- (2-methoxyethyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] - (S) -2-amino-3- (4-nitrophenyl) propionamide ethyl ester Ν- [N- (3- nitrophenylacetyl) -L-alaninyl] -L-serine N - [(R) -α-methylbenzyl] -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N - [(S) -α-methylbenzyl] - N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (4-fluorobenzyl) -1 '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (4-pyridylmethyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N- (4-Trifluoromethylbenzyl) -1 '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide ethyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino- 2-phenylpropionate Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester ·· ··· · -634 9 N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-methylpropionate ethyl ester N - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2-cyclohexyl acetate N- [N- (isovaleryl) -2-amino-2-cyclohexylacetyl] -Lalanine N- (2-methoxyethyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide ethyl ester N-2- (N, N-dimethylamino) ethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide N- (2-pyridylmethyl) -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide N- [N- (3-pyridylacetyl) -L-alaninyl] -L-phenylalanine methyl ester N- [ N- (2-pyridylacetyl) -L-alaninyl] -L-phenylalanine N- [N- (4-pyridylacetyl) -L-alaninyl] -L-phenylalanine ethyl ester N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (4-fluorophenyl) acetate -635: N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-fluorophenyl) acetate N- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] ethyl ester -Lalanine N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-3-phthalimidopropionate neopentyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine ester N- [N- (3,5-Difluorophenylacetyl) -L-alaninyl] -L-alaninyl] -L-alaninyl] -L-alaninyl] -L-alaninyl] L- phenylglycine Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide 4- [N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valinyl] morpholine N- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valine ethyl ester N- [N- (3-Nitrophenylacetyl) -L-alaninyl] -L-threonine N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminopentanoate methyl ester 4- [N- [N- (3-nitrophenylacetyl) -L-alaninyl] - (S) -2-amino-3 636: ftft ftft ft ftft · ft ftftft · < And tert-butoxybutyryl] morpholine 4- [Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -Lisoleucinyl] morpholine methyl ester of Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -Lisoleucine Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-isoleucine ethyl ester Ν- [Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-threoninyl] -L-valine methyl ester Ν- [N - [N- (3-nitrophenylacetyl) -L-alaninyl] -L-leucine methyl ester - [N- (3,5-difluorophenylacetyl) - (3-nitrophenylacetyl) -L-alaninyl] - (S) -2-aminopentanoate -L-alaninyl] -Lleucine N-2-methoxyethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide N-2- (N, N-dimethylamino) ethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide N-cyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninamide N-neopentyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-637: - Φ φ φ φ φ φ a a a a lan φ φ φ φ φ φ φ φ φ φ a a a a a Ν-tetrahydrofurfuryl-Ν '- [Ν- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N-2-pyridylmethyl-N '- [Ν- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide 3- [Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninyl] thiazolidine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-aminobutanoate methyl ester Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] - (S) -2-aminobutanoate N- (R) -sec-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-alaninamide 1- [Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lalaninyl] pyrrolidine N- (S) -sec-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-alaninamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -Lvaline N-2-Fluoroethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L alaninamide -638J * toto toto toto to to to to t t t t t t t t t t t t t N - [(S) -6-methyl-3-oxohept-2-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N-4-nitrobenzyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] (S) -2-aminobutyramide N - [N- (3,5-difluorophenylacetyl) -L-alaninyl] - [N- (3,5-difluorophenylacetyl) -L-alaninyl] (S) -2-aminopentanamide methyl ester - N-4-nitrobenzyl-N '- 2 amino-2- (3-fluorophenyl) acetate N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-2- (2-thienyl) acetamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L- alaninyl] -2-amino-2- (5-chlorobenzothiophen-2-yl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (benzothiophen-2-yl) acetate methyl ester Ν - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (benzothiophen-3-yl) acetate methyl ester of N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino- 2- (2-thienyl) acetate ethyl N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (benzothiophen-5-yl) acetate * 99 99 · · φ r η π * · · · · · ♦ - ojy ···· ^·· · • · · · · · · · · • · ·· ··· ··· ···· 99 • · methylester Ν- [Ν- (3 5- [N- (3,5-Difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-2- (2-thienyl) acetate tert-butyl ester (S) -5-difluorophenylacetyl) -L-alaninyl] (S) -2-amino-2- (2-thienyl) acetate Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-2- (2-thienyl) acetic acid methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl ] - [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2 amino-2- (6-methoxy-2) -2-amino-2- (1H-tetrazol-5-yl) acetate methyl ester na- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (3-trifluoromethylphenyl) acetate methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -naphthyl) acetate ] - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (thieno [2, 2, 4, 6, 7-tetrahydro-benzothiophen-2-yl) -acetate] 3-b] thiophen-2-yl) acetate N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-2- (2-methylthiazol-4-yl) acetate methyl ester (3S, 4S) Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) - Ν - [N- (3,5-difluorophenylacetyl) -Lalaninyl] -4-amino-3-hydroxy-5-phenylpentanoate methyl ester -2 99 9 9 9 -640 • 9 9,999 • 9,999 9 . 9 9999 9 9 9 9 9 oh- [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester aminohex-4-enoate N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] (S) -2-amino-2- (4-phenylphenyl) acetamide tert-butyl ester Ν- [N- (3,5-Difluorophenylacetyl) - (S) -2-aminobutanoyl] -L-phenylglycine tert-butyl les- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -2-aminobutanoyl], 5-difluorophenylacetyl) -L-methioninyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-leucinyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-phenylalaninyl] L-phenylglycine methyl ester Ν- [N - (3,5-difluorophenylacetyl) glycinyl] -L-phenylglycine -641 • · • fl ·· · · A fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl (3,5-difluorophenylacetyl) -L-phenylglycinyl (L-phenylglycine) - [N- (phenylacetyl) -L-alaninyl] -L-alanine methyl ester- [N- (phenylacetyl) -L-alaninyl] -L- uc- [N- (phenylacetyl) -L-alaninyl] -L-isoleucine uc- [N- (phenylacetyl) -L-alaninyl] -L-proline methyl ester Ν- [N- (phenylacetyl) -L-alaninyl] methyl ester - [N- (phenylacetyl) -L-alaninyl] -L-alaninyl] -N- (tert-butoxycarbonyl) -L-lysine methyl ester Ν- [N- (phenylacetyl) -L-alaninyl] -glycine methyl ester - [N- (phenylacetyl) -L-alaninyl] -L-alaninyl] - [N- (phenylacetyl) -L-alaninyl] - (S) -2-aminobutanoate methyl ester - [N- (phenylacetyl) -L-alaninyl] - (S) -2-aminopentanoate Ν- [N- (3-nitrophenylacetyl) -L-alaninyl] -L-valine methyl ester Ν- [N- (phenylacetyl) -L-alaninyl] -LN-methylalanine » · • · -642 Ν- [N- (isovaleryl) -L-phenylglycinyl] -L-alanine iso-butyl ester Ν- [N- (isovaleryl) -L-isoleucinyl] -L-alanine iso-butyl ester N - [N- (3,5-difluorophenylacetyl) -L-4-hydroxyproline methyl ester] - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide ethyl ester N- (3,5-difluorophenylacetyl) -L-alaninyl] -Llysine 1- [N- (3,5-difluorophenylacetyl) -Lalaninyl] piperidine-2-carboxylate Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-glutamide methyl ester N - [(S) -3-hydroxy-6-methylhept-2-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -2-hydroxy-1-phenyleth-1-yl] -1- (3,5-difluorophenylacetyl) -L-alaninamide tert-butyl ester N- [N- (3,5-difluorophenyl-α-) - Fluoroacetyl) -Lalaninyl] -L-phenylglycine N- [N- (3,5-difluorophenylacetyl) -2- (S) -aminocyclohexylacetyl] -L-phenylglycine methyl ester N - [(1R, 2S) -1-hydroxy-1-phenylprop-2-yl] -Ν '- (3,5 ·· ·· · · · · -643 (Difluorophenylacetyl) -L-alaninamide N - [(1R, 2S) -1-hydroxy-1,2-diphenyleth-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(1S, 2R) -1-hydroxy-1-phenylprop-2-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N-2-Methoxyethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] glycinamide N- [(S) -α-hydroxy-α-phenyl-iso-propyl] —N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -2-hydroxy-1,2-diphenylethyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -1-hydroxyhex-2-yl] -1 '- (3,5-difluorophenylacetyl) -Lalaninamide N- [α-hydroxy-α '- (4-hydroxyphenyl) -isopropyl] -N' - (3,5-difluorophenylacetyl) -L-alaninamide N-2-pyridylmethyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylalaninamide N- [α-hydroxy-α'-pyrid-2-yl-isopropyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [α-hydroxy-α'-pyrid-4-yl-isopropyl] - N '- (3,5-difluorophenylacetyl) -L-alaninamide » -644 • to «to • to to ··· · to * to to · · <· N - [(S) -1-hydroxy-4-methylpent-2-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N- [c-methoxy-prop-2-yl] -N '- (3,5-difluorophenylacetyl) -Lalaninamide N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -2-amino-N- (1-hydroxy-3-methyl-but-2-yl) -N- (3,5-difluorophenylacetyl) L-alaninamide methyl ester Of 2- (6-aminopyrid-2-yl) acetate N- [1-Hydroxy-prop-2-yl] -1 '- (3,5-difluorophenylacetyl) -Lalaninamide N - [(S) -2-methoxy-1-phenyleth-1-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -1-methoxy-2-phenyl-prop-2-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(S) -1-acetoxyhex-2-yl] -1 '- (3,5-difluorophenylacetyl) -Lalaninamide N - [(S) -1- (tert-butylcarbonyloxy) -hex-2-yl] - N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [2-hydroxy-1- (thien-2-yl) ethyl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide -645 Ν - [(S) -2-hydroxy-2-methyl-1-phenylprop-1-yl] -1- (3,5-difluorophenylacetyl) -L-alaninamide tert-butyl ester Ν- [N- (3,5- difluorophenylacetyl) -L- (thien-2-yl) glycinyl] -L-phenylalanine Ν- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycinol Ν- [N- (cyclopropaneacetyl) -L-phenylglycinyl] -L-phenylglycinol Ν- [N- (cyclopentaneacetyl) -L-phenylglycinyl] -L-phenylglycinol Ν- [N- (3,5-difluorophenylacetyl) -D, L-phenylglycinyl] -D, L-phenylglycinamide Ν- [N- (3,5-difluorophenylacetyl) -D, L-valinyl] -D, L-phenylglycinamide Ν- [N- (2-thienylacetyl) -L-alaninyl] -L-phenylglycinamide Ν- [N- (n-caprotyl) -L-alaninyl] -L-phenylglycinamide methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-norleucinyl] -L-phenylglycine methyl ester Ν- [N- (3,5- difluorophenylacetyl) -L-norvalinyl] -L-phenylglycine Ν- [N- (3,5-difluorophenylacetyl) -L-tert-leucinyl] L-phenylglycine methyl ester -646 Ν- [Ν- (3,5-difluorophenylacetyl) -L-isoleucinyl] -L phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-cyclohexylalaninyl] -L-phenylglycine methyl ester Ν- [N- ( 3,5-difluorophenylacetyl) - (S) -2-amino-2 (cyclopropyl) acetyl] -L-phenylglycine [- [N- (3,5-difluorophenylacetyl) - (S) -2-amino-2 (thien) methyl ester -3-yl) acetyl] -L-phenylglycine Ν- [N- (3,5-difluorophenylacetyl) - (S) -2-amino-2 (thien-2-yl) acetyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -D- (4-fluorophenyl) glycinyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L- (4-methoxyphenyl) glycinyl] -L-phenylglycine tert-butyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycine tert-butyl ester Ν - [N- (cyclopropylacetyl) -L-phenylglycinyl] L-phenylglycine -647 Ν- [N- (cyclopentylacetyl) -L-phenylglycinyl] L-phenylglycine tert-butyl ester Ν- [N- (tert-butylacetyl) -L-alaninyl] -L-phenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (5-bromothien-2-yl) glycinamide N-tert-butyl-Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D (5-bromothien-2-yl) glycinamide N-tert-butyl-Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (4-bromothien-2-yl) glycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (thien-2-yl) glycinamide N-tert-butyl-Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D (thien-2-yl) glycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L (thien-3-yl) glycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D' (thien-2-yl) glycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide -648 • · · • · · N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L- (5-chlorothien-2-yl) glycinamide N-cyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-4 (phenyl) phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L 3 - (phenoxy) phenylglycinamide N- (S) - (-) - α-Methylbenzyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L3- (phenyl) phenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L4- (ethyl) phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L2- (phenyl) phenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L2- (benzyl) phenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-4-bromophenylglycinamide N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L4- (cyclohexyl) phenylglycinamide -649 to β · to · to * to 9 9 9,999 9,999,999 9 9 9 9 9 9,999 99,999 99,99 N-tert-Butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L4- (4-ethylphenyl) phenylglycinamide N-tert-butyl-Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-4- (tert-butyl) phenylglycinamide N-tert-butyl-Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-3- (4-chlorophenoxy) phenylglycinamide N-cyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4 (phenyl) phenylglycinamide N- [N- (3,5-difluorophenyl-α-hydroxyacetyl) tert-butyl ester -Lalaninyl] -L-phenylglycine N- [N- (3,5-difluorophenylacetyl) - N - tert -butyl- [N- (3,5-difluorophenyl-α, α-difluoroacetyl) -Lalaninyl] -L-phenylglycinamide tert-butyl ester L-alaninyl] D-phenylglycine N - [(S) -1-oxo-1-phenylprop-2-yl] -N '- (3,5-difluorophenylacetyl) L-alaninamide tert-butyl ester N- [N- (3,5-difluorophenylacetyl) - L-alaninyl] D, L- (pyrid-3-yl) glycine [N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] morpholine N- [N- (3,5-methyl) ester (difluorophenylacetyl) -L-alaninyl] -D, L- -650 (2-methoxy) phenylglycine N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine N-tert-butoxycarbonyl (hydroxylamine) ester N-neopentyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L phenylglycinamide N-tetrahydrofurfuryl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-methoxy-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide [Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinyl] azetidine N-iso-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L phenylglycinamide N-cyclopropanomethyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-methoxy-N-methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-2-methylprop-2-enyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N- (pyrid-3-yl) methyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide -651 9 9 9 9 9999 9 9 9 9 9 9900 9 99 9 9 ·· · 9 · 9 9 99 99 99 99 N - (pyrid-4-yl) methyl-N '- [N - (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-furfuryl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide N-cyclopentyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-phenylglycinamide N-1-Benzylpiperidin-4-yl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N, N-dimethyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L phenylglycinamide N-2,2,6,6-tetramethylpiperidin-4-yl-N ¹ - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide N-2-methylcyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide N-4-methylcyclohexyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinamide Ν-1-ethoxycarbonylpiperidin-4-yl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide N-methyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide -652 • · ► * 4 I · 4 · 4 · 4 · 4 · N-tert-butoxy-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-phenylglycinamide N- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycine hydrazide N-tert-butyl (hydroxylamine) ester- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - L-phenylglycine N- (1-ethoxyethen-1-yl) - [Ν '- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine tert-butyl ester Ν- [N- (phenylacetyl) -L-alaninyl] - Lphenylglycine N-4- (phenyl) butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-phenylglycinamide N-3- (4-Phenoxy) propyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide hydrochloride N-β- (amino) hexyl-N' - [N- (3 (5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinamide N - [N- (3,5-difluorophenylacetyl) -L- (3,5-difluorophenyl) glycinyl] -N- (3,5-difluorophenylacetyl) -Lalaninamide methyl ester N1- (phthalimido) pent-2-yl-L- ( 3,5-difluorophenyl) glycine Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-norleucine -653 «to to to * * * * * * tert-butyl Ν- [N- (cyclopentaneacetyl) -L-alaninyl] -L-phenylglycine isopropyl ester les- [N- (3,5-difluorophenylacetyl) -L-alaninyl] t-butyl ester -L 4-fluorophenylglycine N- [isopropyl] -N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide tert-butyl ester [- [N- (cyclopentylacetyl) -L-alaninyl] -L-phenylalanine tert-butyl ester Ν- N-- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L [N- (cyclopropylacetyl) -L-alaninyl] -L-phenylalanine -alaninyl] -Diphenylglycine Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (3α-phenyl) proline methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] methyl ester L- [N- (3,5-Difluorophenylacetyl) -L-alaninyl] -2-amino-3- (5-chlorobenzothiophen-2-yl) acetate methyl ester -654 ftft ftftftft ft ftftftft ft ftft ft · · · · · · ftft · · · ftft ftftft · ftft ft * ftft · · ftft ftftft · t-butyl ester Ν- [N- (3,5-difluorophenylacetyl) - L- alaninyl] (S) -2-amino-3- (thiazol-4-yl) propionate cin- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-phenylglycinamide tert-butyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D- (thien-2-yl) glycinamide N - [N- (3,4-dichlorophenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (3-chlorophenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (3-bromophenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (3-fluorophenylacetyl) -L-alaninyl] -D-phenylglycinamide N - [N- (4-fluorophenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (3-methylphenylacetyl) -L-alaninyl] -D-phenylglycinamide N- [N- (4-methylphenylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (3-Trifluoromethylphenylacetyl) -L-alaninyl] -phenylglycinamide Ν- [N- (3-methoxyphenylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (2-chlorophenylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (1-naphthylacetyl) -L-alaninyl] -D-phenylglycinamide -655 »· 9949 4 · 4 4 4 • · · · · 49 49 • 4 • 4 449 944 4 4 4 4 4 4 Ν- [Ν- (2-naphthylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (phenylacetyl) -L-alaninyl] -D-phenylglycinamide Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycine Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-phenylglycinamide Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] - (S) -2-amino-2- (2-furanyl) acetamide Ν '- [N- (3,5-difluorophenylacetyl) -D-alaninyl] -D-phenylglycinamide Ν '- [N- (3,4-difluorophenylacetyl) -D-alaninyl] -D-phenylglycinamide N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylalanine-N-methylsulfonamide N-methyl-N-phenyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -glycinamide N-methyl-N-phenyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-alaninamide N '- [N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-phenylglycinamide N-methyl-N-benzyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -glycinamide -656 • · • «·· ·· ·· 9 9 999 999 9 9 9 · ·· N-4-fluorobenzyl-N ¹ - [Ν- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide neopentyl Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L- (4 -fluoro) phenylglycine N- [N- (2,3,4,5,6-pentafluorophenylacetyl) -Lalaninyl] -L- (pyrid-3-yl) glycine methyl ester Ν- [N- (3,5-tert-butyl) ester if- [N- (3,5-difluorophenylacetyl) -L- (O-benzyl) serinyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L- (pyrid-3-yl) glycine methyl ester 3,5- Difluorophenylacetyl-L- (O-benzyl) threoninyl] -L-phenylglycine Ν- [N- (3,5-difluorophenylacetyl) -L-threoninyl] -L-phenylglycine methyl ester Ν- [N- (3,5-difluorophenylacetyl) -L-serinyl] -L-phenylglycine N-4-methylphenyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] · L-phenylglycinamide N '-tetrahydrofurfuryl-N' - [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide Ν '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-4-fluorophenyl-657 flflflflflfl fl flflfl glycinamide N '- [N- (3,5-difluorophenylacetyl) -L-methionyl] -L-phenylglycinamide N- [N- (3,5-difluorophenylacetyl) -2-aminobutanoyl] -L-phenylglycinamide N '- [N- (3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-phenylglycinamide N- [N- (3,5-difluorophenylacetyl) -L-valinyl] -L-phenylglycinamide N - [(R) -α-methylbenzyl] -N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide N- [1-phenyl-2-oxo-3-methylbutan-1-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [1-phenyl-2-oxo-propan-1-yl] -1 '- (3,5-difluorophenylacetyl) -L alaninamide N- [1-phenyl-2-oxo-pentan-1-yl] -1 '- (3,5-difluorophenylacetyl) -L alaninamide N- [1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [1-phenyl-2-oxo-butan-1-yl] -1 '- (3,5-difluorophenyl-acetyl) -L alaninamide -658 * 9,999 · 99 9 9 9 9 4 9 9 4 999 994 9 4 99 99 N '- [N- (3,5-difluorophenylacetyl) -L' - (3,5-difluorophenylacetyl) -L-alaninamide methyl ester N - [1-phenyl-2-oxo-4-methylpentan-1-yl] -L -alaninyl] -L-ahydroxyphenylalanine N- [4 - ((2-hydroxy-4-azido) -phenyl) -NHC (O) -) butyl] N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L-phenylglycinamide N - [(S) -1-phenyl-2-oxo-2-phenyl-ethan-1-yl] -N '- (3,5-difluorophenyl-acetyl) -L-alaninamide tert-butyl ester N' - [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-4-fluorophenylglycine tert-butyl ester N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] L-4-phenylphenylglycine methyl ester [N- (3 5-difluorophenylacetyl) -L-alaninyl] -L- (2,3-benzo [b] proline) N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L 4-n-butylphenylglycinamide N-tert-butyl-N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] D, L-4- (phenylacetenyl) phenylglycinamide N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D, L-phenylglycinthioamide N- [1,3-diphenyl-2-oxo-propan-1-yl] -1 '- (3,5 • -659 «· · 999 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 999 9999 99 999 99 99 difluorophenylacetyl) -L-alaninamide N- [1-phenyl-2-oxo-2-cyclopentylethan-1-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [1-phenyl-2-oxo-hexan-1-yl] -1 '- (3,5-difluorophenylacetyl) -alaninamide N- [1-phenyl-2-oxo-3-methylpentan-1-yl] -1 '- (3,5-difluorophenylacetyl) -L-alaninamide N-n-hexyl-6-biotinamidyl-N '- [N- (3,5-difluorophenylacetyl) -Lalaninyl] -D, L-phenylglycinthioamide N '- [N- (3,5-difluorophenylacetyl) -L-methioninyl] -L-methionine methyl ester N' - [N- (2-tert-BOC-amino) propionyl) -L-alaninyl] L-phenylglycine N '- [N- (3,5-difluorophenylacetyl) -L-alaninyl] -D-tert-butyl N' - [N- (3,5-difluorophenylacetyl) -L-alaninyl] -L 2-fluorophenylglycinamide methyl ester , L2-phenylglycine N - [(S) -1-phenyl-2-oxo-3-phenylpropan-1-yl] -N'- (3,5-difluorophenylacetyl) -L-alaninamide Ν '- [N- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L2-phenylglycine -660 φ φ φ φ φ φ φ φ · · · · φ φ φ φ φ · · · · · · · · · · · · φ φ · · · · φ φ φ φ Ν- (3,5-difluorophenylacetyl) -D, L-thien-3-ylglycinyl] -D, L-2-phenylglycine N '- [N- (3,5-difluorophenylacetyl) -L-thien-3-ylglycinyl] -L-2-phenylglycine tert-butyl ester N' - [N- (3,5-difluorophenylacetyl) -L-thien-3-ylglycinyl] -L-2-phenylglycine N- [2-hydroxy-1- (S) -phenyleth-1-yl] -1 '- [(3,5-difluorophenylacetyl) -L-phenylglycinyl] -L-alaninamide N- [2-hydroxyeth-1-yl] -N '- [(3,5-difluorophenylacetyl) -Lalaninyl] -L-phenylglycinamide tert-butyl ester N' - [N- (3,5-difluorophenyl-2-oxo) -acetyl) -Lalaninyl] -L-2-phenylglycine methyl ester [N- (2,5-dichlorophenoxyacetyl) -L-alaninyl] -Lphenylglycine methyl ester [N- (3,5-difluorophenoxyacetyl) -L-alaninyl] -Lphenylglycine methyl ester [ N- (3,4-dichlorothiophenoxyacetyl) -L-alaninyl] -L-phenylglycine tert-butyl [N- (3-aminopropionyl) -L-alaninyl] -L-phenylglycine and tert-butyl ester [N- (3-tert-butoxycarbonylamino) Propionyl) • · ···· -661 L-alaninyl] -phenylglycine.